Genitourinary Pathology (Including Adrenal Gland)

Rao, Priya; Perrino, Carmen M.; Zynger, Debra L.; Jorda, Merce; Tamboli, Pheroze; Sanchez, Diego Fernando; Cubilla, Antonio L.; Iczkowski, Kenneth; Zhang, Miao; Sircar, Kanishka

doi:10.1007/978-3-319-96681-6_16

Priya Rao⁴,
Carmen M. Perrino⁵,
Debra L. Zynger⁵,
Merce Jorda⁶,
Pheroze Tamboli⁴,
Diego Fernando Sanchez⁸,
Antonio L. Cubilla⁸,
Kenneth Iczkowski⁹,
Miao Zhang⁴ &
…
Kanishka Sircar⁷

4763 Accesses

Abstract

Our aims in constructing the Genitourinary Pathology chapter are to describe neoplasms of the adrenal gland, urothelial tract, kidney, penis, prostate, and testis in a manner that is both useful for the practicing surgical pathologist and that may be used as a reference for all students of urologic pathology. Whereas the text and figures describe the salient morphologic, immunohistochemical, and molecular attributes for each tumor type and encompass the latest classification schemes, the narrative integrates the clinical and pathological findings that are commonly encountered during surgical pathology sign-out of these cases. Accordingly, it is our hope that this chapter will serve as a guide for both general and subspecialized pathologists in contemporary practice.

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Genitourinary

Genitourinary Neoplasms

Genitourinary System

Keywords

Part I: Tumors of the Male Genital Tract

Prostate: Prostate Cancer Precursors

Prostatic Intraepithelial Neoplasia

Morphology

The bulk of evidence supports prostatic intraepithelial neoplasia (PIN) as the main precursor of invasive adenocarcinoma [1]. PIN consists of normal- to larger-sized prostatic acini with cytologic atypia , including nuclear enlargement and prominent nucleoli, without the architectural changes that characterize invasive cancer, namely, the absence of a basal cell layer, small to minute acinar size, and frequently angulated acinar contours. The tufted, papillary, and cribriform types of PIN all show nuclear stratification; the rare flat pattern of PIN is the only exception. The basal cell population may be decreased but basal cells are at least focally present.

Diagnosis

Both low-grade (Fig. 16.1) and high-grade (Figs. 16.2 and 16.3) PIN have been described, but only the diagnosis of high-grade PIN (HGPIN) is relevant to make because (1) high-grade PIN has predictive value for cancer on current or repeat biopsy while low-grade PIN lacks it; (2) interobserver reproducibility of the diagnosis of low-grade PIN is marginal; and (3) in radical prostatectomy specimens, 75% of high-grade PIN abuts carcinoma [2].

Differential Diagnosis

Often a source of consternation for pathologists and residents, multilayered epithelium carries a six-way differential diagnosis (Fig. 16.4). High-grade PIN (Fig. 16.4a) first needs to be ruled out by deciding whether any atypical cells are secretory. If they are not secretory, basal cell hyperplasia is the most likely alternative—easily overcalled as HGPIN. Nuclei are always less hyperchromatic than in HGPIN at low power. The nuclear chromatin of the basal cells is light blue, as opposed to the darker purple of secretory cells. Nuclear vacuolation is frequent, unlike in HGPIN. Most importantly, the basal cells are arrayed around the periphery of the acinus, in contact with the stroma, never in contact with the lumen.

Benign hyperplastic epithelium can be stratified. Cribriform or stratified epithelium is normal in the prostate’s central zone (located posterior and superior to the transition zone) and should not be overcalled as HGPIN or cancer. The central zone’s characteristic dense stroma and lack of nuclear atypia should help prevent this error. The central zone is sampled in prostatectomy specimens but less often in biopsy specimens. Finally, urothelium and seminal vesicle epithelium are both stratified.

Clinical Predictive Value

In 1995, the finding of isolated HGPIN (“isolated” means, no cancer elsewhere in the biopsy sampling) had a 35% predictive value for detection of cancer on repeat biopsy sampling [3]. One decade later, the same predictive value was variously reported as 21–48% [4]. The predictive value for cancer has fallen as the number of biopsy sites sampled at a time has increased. That is, after the 1990s, sampling of the prostate rose from just a few cores at a time to the current 6-site (sextant), 12-site, and 14- or more-site biopsy sampling. Concomitantly, the mean predictive value of HGPIN for cancer declined from 36% in the 1990s to 21% in follow-up studies of cases after year 2000 [4]. This change probably reflects a higher proportion of men who had concomitant cancer along with their HGPIN getting the cancer detected in the first round of biopsy sampling. Therefore, isolated HGPIN in the biopsies was less likely to be accompanied by cancer and more likely to belong to a gland that as a whole was free of invasive cancer. The most recent studies disclose a 26.7% predictive value for cancer after isolated HGPIN diagnosis. This is just modestly higher than 22.3% following an initial benign biopsy [5]. With either an initial benign or HGPIN biopsy, cancer that is subsequently detected tends to have favorable pathology [5]. The urgency to perform repeat biopsies after a diagnosis of isolated HGPIN [6] has been lessened, but it is usually being done. Also, some of what was formerly diagnosed as florid HGPIN is now termed intraductal carcinoma (See section on Intraductal carcinoma).

Atypical Adenomatous Hyperplasia

Occurring alongside benign nodular hyperplasia, and predominantly in the transition zone, atypical adenomatous hyperplasia (AAH) may be found at the periphery of the larger nodule. AAH consists of a circumscribed cluster of acini, small and architecturally crowded-like cancer, but without cytologic atypia (Fig. 16.5). AAH, also called adenosis, is rarely sampled on prostatic biopsy. The prevalence of allelic imbalance at five microsatellite polymorphic markers that are commonly altered in prostate cancer was 47% in AAH [7], suggesting that some AAH may be a cancer precursor [2, 8].

A rare AAH variant called sclerosing adenosis can mimic prostatic adenocarcinoma. Foci with poorly formed acinar contours (Fig. 16.6) can even mimic high-grade adenocarcinoma. However, acini are circumscribed like a hyperplastic nodule. They are invested with a hyaline sheath, not “naked,” and are set in a densely fibrotic stroma, features not found in adenocarcinoma. Also, the acinar structures lack significant atypia and retain occasional basal cells.

Post-inflammatory Atrophy

Since 1999, atrophy accompanied by chronic inflammation and showing an elevated proliferative index by Ki-67 staining has been designated post-inflammatory atrophy (PIA) and postulated as a cancer precursor [9]. However, a topographic study showed, at best, a weak correlation of inflammatory atrophy with cancer [2]. Moreover, recent data show that PIA actually correlated with decreased likelihood of prostate cancer on repeat biopsy. The finding of PIA in negative biopsies correlated with an 18% frequency of detecting prostate cancer in men with persistent suspicion of cancer, as opposed to 33% in men without PIA, p < 0.01 [10].

Acinar Prostatic Adenocarcinoma

Gross Appearance

On cut coronal sections of the prostate , cancer is firm, gray-yellow, possibly gritty, and poorly delimited (Fig. 16.7). It might be more easily palpated than seen. Often, however, no lesion is seen [11], corresponding to the presence of diffuse microscopic foci.

Minimal Diagnostic Criteria: Qualitative

Invasive prostatic cancer acini should properly be called pseudoacini , because they are not functional acini. There is loss of function, as shown by decreased immunohistochemical prostate-specific antigen (PSA) secretion per cell, in cancer compared with non-neoplastic acini. The main reason that cancer causes elevated serum PSA is that the PSA leaks from the pseudoacini into the stroma, rather than being secreted into the lumina. For convenience, we will henceforth use the term, cancer acini .

Three criteria for prostate cancer were defined in 1953 by Arthur Purdy Stout and colleagues: (1) an infiltrative (not clustered) pattern of (usually small) acini; (2) nuclear atypia including nuclear enlargement, peripheral placement (margination) of chromatin material in the nucleus, with macronucleoli visible in almost every cell; and (3) loss of the basal cell layer such that acini possess only a single-cell layer throughout [12]. Starting at scanning magnification, any acini either darker or paler than their neighbors should prompt closer examination [13]. Medium to high power is needed to assess cytologic features and the presence of basal cells. Mitotic figures are rare in prostatic carcinoma, even high-grade carcinoma, rendering them of lesser diagnostic importance than in most cancers.

Minimal Diagnostic Criteria: Quantitative

A minimal prostate cancer, defined as involving less than 5% of biopsy tissue in one or more specimen parts [14] (regardless of whether the specimen comprises 2, 6, 12, or more parts), prompts the pathologist’s need for reassurance. A minimum of three sufficiently atypical acini has been proposed for a definite diagnosis of minimal cancer [15]. Criteria studied in a set of 100 patients with definite minimal cancer on needle biopsy were compared with 56 in whom only a “suspicious” diagnosis could be rendered. Given that in both groups, basal cells appeared absent (or indistinguishable from flat stromal fibroblasts), the triad of nuclear enlargement, prominent nucleoli in the majority of cells (Fig. 16.8), and an infiltrative pattern proved to be the strongest discriminators [14]. An infiltrative pattern is characterized by variable size, shape, and spacing of acini. An example is shown of acini with the minimal qualitative and quantitative criteria to diagnose cancer on needle biopsy (Fig. 16.9). It is still worth noting that a minority of cancers may not present with appreciable nuclear enlargement or prominent nucleoli (Fig. 16.10), warranting the use of a “triple” immunostain (see below).

Ancillary Criteria for Cancer

Two other criteria are specific for and thus absolutely diagnostic of prostate cancer: collagenous micronodules and perineural invasion [16]. Collagenous micronodules are nodular aggregates of acellular to paucicellular eosinophilic fibrillary material immediately adjacent to acini (Fig. 16.11). Ultrastructurally, they are a mixture of collagen fragments and basement membrane material. They are present in 2–13% of prostate cancer and not found in PIN or benign acini [17].

Perineural invasion (PNI) should be diagnosed only when a cancer acinus is wrapping around the perineural space of a nerve twig. (Nerve twigs are numerous toward the edges of the peripheral zone.) In some instances, immunostaining for S-100 protein may be necessary to confirm that the wrapped-around structure is nerve. Importantly, acini with PNI must not count toward the Gleason grade, since the acini get distorted by their presence in the perineural space, making grade 3 cancer look like grade 4 (Fig. 16.12). Prostate cancer can also insinuate itself between nerve fibers (intraneural invasion) (Fig. 16.13) or show periganglionic invasion (Fig. 16.14). The prognostic importance of PNI in the biopsy is that it correlates with upstaging of cancer [18, 19] and surgical margin positivity [20] in subsequent radical prostatectomy specimens. PNI is particularly useful in intermediate-grade, Gleason 3 + 4 cancer, in predicting adverse pathologic findings in the prostatectomy specimen [21]. The literature, however, is not unanimous on the role of PNI [22]. Notably, benign acini can show perineural abutment while not wrapping around the nerve twig in the manner of cancer. The benign nature of the enwrapped acini can be shown with triple immunostain (Fig. 16.15).

This finding, along with extraprostatic extension, should be added to the line diagnosis if present in a sub-part of a prostatic biopsy set. If tumor is present in the prostate biopsy set but no sub-part has perineural invasion or extraprostatic extension, these facts should be documented with a separate “Comment” following the listing of diagnostic lines (e.g., parts A—F).

Several other “soft” criteria favoring cancer are presented (Table 16.1).

Table 16.1 Minor criteria for diagnosis of prostatic adenocarcinoma

Full size table

Diagnostic Immunostains

Types of Stains

The mainstay for cancer discrimination has been the 34βE12 clone that detects high-molecular-weight cytokeratins 1, 5, 10, and 14. Adding steam heat with an EDTA buffer to protease digestion for retrieval improves the percent of basal cells staining from 55% to 73% and the intensity from about 2+ to 3+ (on a 3+ scale) [24]. Other basal cell markers with about equal utility are cytokeratins 5/6 [25] and nuclear p63 and its isoform p40.

The need to rely on an absence of staining to diagnose cancer prompted the search for a positive-staining cancer marker in the early 2000s. P504S (alpha-methylacyl coA racemase (AMACR), for short: racemase) was validated as a HGPIN and prostate cancer marker, carrying a sensitivity and specificity for prostate cancer of 97% and 92%, respectively [26]. It is now commonly used as a component of a triple stain cocktail (commercially, PIN3 or PIN4) usually detected by a pink/red chromogen, in combination with two basal cell markers (nuclear p63 and cytoplasmic high-molecular-weight cytokeratin) detected by a brown chromogen. The combined use of this triple stain has facilitated diagnostic certainty in a high percent of cases, allowing a degree of certainty that did not exist before P504S. Most laboratories reserve the second and fourth (out of 5) unstained levels of a specimen for possible immunostains. These intervening levels maximize the potential to work up small suspicious foci.

An alternative to P504S is called membrane-associated guanylate kinase WW and PDZ domain-containing protein 2 (MAGI-2), which has gene rearrangements leading to its overexpression in HGPIN and prostate cancer. Using histologic score cutoffs, the accuracy of MAGI-2 for distinguishing malignant from benign acini was 95%, compared to 88% for AMACR [27]. MAGI-2 was more sensitive but less specific than AMACR in this capacity and was suggested as a useful diagnostic adjunct when AMACR is not discriminatory.

Finally, some laboratories use a quadruple stain cocktail incorporating c-myc nuclear oncoprotein along with the triple stain [28, 29]. Since c-myc shows nuclear positivity in cancer, it may reduce some of the instances of ambiguity arising with the triple stain.

ERG is a transcription factor and oncogene that is overexpressed when the ERG gene gets fused to the androgen-regulated transmembrane protease serine 2 (TMPRSS2) or NDRG1. The gene fusion is present in only 40–50% of prostate cancers. While this immunostain is quite specific for prostate cancer, its sensitivity is limited since it detects only 40% of prostate cancers [30]. However, its sensitivity rises with higher grade. An example of the diagnostic use of ERG is shown, with nuclear reactivity in a rib metastasis which was negative for prostatic acid phosphatase and weakly, equivocally positive for PSA (Fig. 16.16).

Deciding When to Stain

The decision to order immunostains must be deliberate and restricted to those cores or parts of the biopsy possessing potential to change therapy. The indiscriminate use of triple immunostains, or even automatic use on every core of every prostate biopsy, which is rumored to occur in some practices, is a waste of resources. Understandably, non-subspecialized pathologists resort to immunostains for extended-core prostate biopsies more often than do urologic pathologists, ordering on average 2.2 vs. 1.3 tests per case (p = 0.004) in a recent study [31].

Once cancer is established in one core (or block) of a needle biopsy set, the question arises whether the triple stain should be ordered on other cores (or blocks) suspicious for cancer. By consensus of the ISUP, the answer depends on the Gleason score and location [30]. If cancer with Gleason score of at least 7 is established on at least one part of the biopsy set, the workup of other parts suspicious for Gleason 3 + 3 = 6 cancer is not recommended. However, if the other part(s) are suspicious for at least Gleason 7 cancer, the workup of cores to rule out Gleason ≥7 cancer is recommended, since the extent of high-grade cancer could affect clinical treatment. If there is Gleason score 6 cancer in one part, workup of other parts of the biopsy set suspicious for Gleason score 6 cancer is usually justified since cancer extent and bilaterality influence treatment decisions—active surveillance versus surgery or radiation—unless the pathologist knows that this would not affect therapy.

Pitfalls of Stains

Some pitfalls exist with both the basal cell markers and the P504S. In 5–23% of cases, scattered absence of basal cell markers staining may be observed in obviously benign glands [32]. Benign proliferations that mimic cancer may show weak or rare to nonreactive staining. These include up to 23% of glandular atrophy, up to 50% of atypical adenomatous hyperplasia (AAH; adenosis), and 23% of post-atrophic hyperplasia . Nephrogenic adenoma , a reactive proliferation of tiny tubules similar to the distal nephron, can mimic carcinoma and show completely negative basal cell marker staining in 44–75% of instances [32].

P504S is not an infallible marker; technical optimization is tricky. First, some obvious cancers have a weak pink signal, a common problem in many laboratories—even despite a strong signal in the control cancer tissue. Immunoreactivity to P504S may even be absent in 5–25% of typical prostate carcinomas. P504S is negative in 30% of pseudoatrophic carcinoma , 32–38% of foamy gland carcinoma , and 23–30% of cases of the pseudohyperplastic carcinoma variant [33] (described below [34]).

Conversely, some benign conditions will stain positive for P504S. In the experience of many laboratories, benign acini can show minimal to moderate red reactivity for P504S using the triple stain. To avoid cancer overdiagnosis, the amount of red reactivity in a suspicious area must be compared to a benign internal control (Fig. 16.17). Thus, it is strong(er) reactivity that discriminates cancer (Figs. 16.18 and 16.19).

In our study, 13% of atypical adenomatous hyperplasia (AAH) was positive for P504S. However, this percentage was much higher in cases with coexistent cancer: Strong diffuse P504S positivity in over 50% of lesional cells was seen almost exclusively in AAH foci with coexisting cancer (P = 0.002) [8]. Nephrogenic adenoma is consistently P504S-positive [35]. Nephrogenic adenoma is positive for epithelial membrane antigen (EMA), while prostate cancer is negative for EMA, so EMA may be used to resolve this conflict [35]. Finally, we have recently reported that intense P504S reactivity can occur in benign acini with Paneth cell metaplasia [36] in which cells have increased cytoplasm with supranuclear granules.

Differential Diagnosis of Prostatic Carcinoma

A false-positive cancer diagnosis can result from at least a dozen benign mimics of cancer. Most of these consist of small acinar proliferations with some aspect of atypia, and all have been reviewed [37, 38].

Atrophy

Atrophy is by far the most common mimic of cancer. Atrophy may result in large cystic acini or small clustered acini; it is the latter type that most often mimics cancer. In atrophy, the presence of focal basal cells is usually confirmed by a triple immunostain. Post-atrophic hyperplasia is a type of small acinar atrophy in which the small atrophic acini are clustered around a dilated gland space with sometimes sclerotic stroma (Fig. 16.20).

Conversely, cancer can mimic atrophy [39, 40], illustrated by the pseudoatrophic and microcystic patterns of prostate cancer (Fig. 16.21). In this instance, the cancer acini are usually medium or large, with open lumens lined by an epithelium that is deceptively flat at low power. High-power is necessary to appreciate the nuclear atypia.

Seminal Vesicle

Seminal vesicle , or its intraprostatic portion, the ejaculatory duct, may be sampled on needle biopsy. Seminal vesicle atypia (Figs. 16.4 and 16.22) is another benign mimic of cancer, often with marked nuclear enlargement—more than usual for cancer—and prominent nucleoli. Clues to benignity include the presence of golden brown lipofuscin granules and the open, branching morphology of the gland spaces.

Atypical Adenomatous Hyperplasia

Atypical adenomatous hyperplasia (AAH) is a variant of benign prostatic hyperplasia in which the acini are particularly small and crowded such that they mimic cancer (Fig. 16.6). There is architectural atypia (infiltrative pattern with loss of most basal cells) without cytologic atypia—the opposite of high-grade PIN which has cytologic atypia without architectural atypia. Distinctive features include the merging of the small AAH acini with obvious benign acini and the circumscribed, non-infiltrative nature of the acini. Since the degree of circumscription can be appreciated only on prostatectomy or transurethral resection specimens and not needle biopsy specimens, it is not advisable to diagnose AAH on biopsy specimens. A consultation case in which AAH was mistaken for cancer is shown (Fig. 16.23).

Verumontanum Mucosal Gland Hyperplasia

The verumontanum is where the intraprostatic seminal vesicles join the urethra. Hyperplasia of the mucosal glands (VMGH) is always less than 1 mm in greatest dimension and is limited to the verumontanum, prostatic utricle, and ejaculatory ducts (Fig. 16.24). VMGH tends to coexist with atypical adenomatous hyperplasia [41]. Seen in 14% of prostatectomy specimens, it is less often sampled in needle biopsy cores. It is a small acinar proliferation lined by cuboidal, PSA-positive secretory cells with benign nuclei, and a basal layer is present which is positive for basal cell cytokeratin and negative for S-100 protein. Luminal concretions are a frequent feature.

Reactive Epithelium

Reactive change in response to inflammation. Mild to moderate epithelial nuclear atypia can occur in response to both acute inflammation and chronic inflammation. In some instances, this atypia may mimic cancer (Fig. 16.25). Particularly in the face of heavy inflammation, a triple immunostain may be warranted to resolve the diagnostic dilemma.

Nephrogenic Adenoma

Nephrogenic adenoma is a urothelium-derived reactive proliferation of minute tubular structures that can occur anywhere along the urothelial tract. In the prostate, it is most often found in the transition zone in proximity to the urethra, which is sampled by transurethral resection. The flat to cuboidal cells may have prominent nucleoli, raising a concern for prostate cancer. Dense colloid-like secretions may be seen in the tubules, favoring a benign diagnosis (Fig. 16.26). Immunohistochemically [35], nephrogenic adenoma may be positive for prostate-specific antigen, rendering this stain not useful in differential diagnosis. PAX8 and EMA are the most discriminatory stains, being positive in nephrogenic adenoma and negative in prostate cancer.

Basal Cell Adenoma

Occurring on the periphery of hyperplastic nodules, the small acini of basal cell adenoma can mimic cancer but are multilayered and form a circumscribed focus (Fig. 16.27).

Other Benign Mimics of Cancer

Table 16.2 is a more thorough list of the benign mimics of cancer; comprehensive reviews are available [37, 38].

Table 16.2 Benign mimics of prostatic adenocarcinoma

Full size table

Malignant mimics of prostatic carcinoma also must be considered.

Urothelial Carcinoma

Transurethral resection specimens, and, less frequently, the tips of prostatic needle core biopsies, sometimes sample periurethral (transition zone) tissue. Therefore, when nearly solid proliferations of malignant cells are encountered in either of these two specimens, consideration must be given to the differential diagnosis between large-duct (cribriform, solid, intraductal, or ductal) prostate cancer and urothelial carcinoma. Unnecessary cystoprostatectomy can result from misdiagnosing prostatic adenocarcinoma as urothelial carcinoma ; and the frequent overlap of their morphologies facilitates this error. Ductal or cribriform prostatic adenocarcinoma is favored when cells are columnar with focally prominent nucleoli and form gland spaces. When growth is solid with no lumen spaces (Fig. 16.28), morphology alone favors urothelial carcinoma, even though the overlying urothelium is normal in the resection specimen shown. Pathologists should keep a low threshold for use of immunostains for tumors that are clinically at the bladder neck or periurethral (both sampled on transurethral resection specimens). The most useful one for prostatic carcinoma is prostate-specific antigen (Fig. 16.29); prostatic acid phosphatase and P501S may be added as second- and third-line markers [30].

Urothelial carcinoma may also involve the prostate via spread through prostatic ducts, a phenomenon observed in 15–48% of cystoprostatectomy specimens [42,43,44,45,46], and again, confirmatory immunostains may be warranted. In transurethral resections, particularly from the bladder neck, diagnostic pitfalls abound. Urothelial carcinoma is favored when cells have indistinct cell borders, have relatively less-prominent nucleoli, and do not form gland lumens (Fig. 16.28).

Uroplakin II and uroplakin III are often markers of choice for urothelial carcinoma. Uroplakin II is the more sensitive of the two [47]. GATA-3, not available in all laboratories, is a sensitive but less-specific marker for urothelial carcinoma [30, 48]; it also marks breast carcinoma and several other malignancies. Other readily available markers that are positive in urothelial carcinoma and that discriminate it from prostatic carcinoma are p63, p40, thrombomodulin, cytokeratin 5/6, and high-molecular-weight cytokeratin clone 34βE12. Rarely, urothelial and prostatic carcinomas coexist (Figs. 16.30 and 16.31).

Rectal Adenocarcinoma

Infiltration of the prostate by rectal adenocarcinoma may resemble a large-duct prostatic primary cancer. In some of the reported cases, a primary colorectal tumor was not known before the prostatic biopsy specimen. The asymmetric thinning of gland walls, mucin, and “dirty” lumens with neutrophils and necrosis favor rectal origin. Positive staining for villin, CDX2, and cytokeratin 20 with negative reactivity for PSA and NKX3.1 can rule in rectal origin [49].

Atypical (Small) Acini Suspicious for Cancer: ASAP

Significance

Because of the broad differential diagnosis of prostatic atypia listed above, a diagnostic category is needed for about 2–5% of prostatic biopsy sets (and rarely, transurethral resection specimens) containing atypical acini that bear cytoarchitectural features falling short of the minimal diagnostic criteria for cancer. We [50] and others [51] first explored that category in 1997, designating it, atypical small acinar proliferation (ASAP), suspicious for but not diagnostic of cancer. However, the suspicious acini are not always “small.” ASAP has gained widespread use as a diagnostic term and as a research field. Let me stress that when an ASAP diagnosis is made, the diagnostic line should not be truncated at just “atypical small acinar proliferation” (as I often read on consultation case reports) without appending the phrase, “suspicious for but not diagnostic of cancer,” afterward to convey the full clinical impact of this finding.

Stated differently, ASAP represents our inability to render an incontrovertible diagnosis of cancer. Comparative analysis of ASAP versus cancer determined that the four main findings discriminating minimal cancer from ASAP were infiltrative growth, loss of basal cells, nuclear enlargement, and prominent nucleoli (Fig. 16.32).

The ASAP focus invariably has fewer than 2 dozen acini—less than the size of the head of a pin—and many have ≤5 acini. Rarely, ASAP may comprise not small- but medium-sized acini where the differential diagnosis is cystic atrophy versus atrophy-like cancer. Our initial studies determined that ASAP carried a predictive value of 42–45% for cancer on subsequent biopsy [50, 52, 53]. Our 2014 review of ASAP [54] disclosed that its predictive value for cancer on repeat biopsies has not changed since our studies of late-1990s specimens [52, 53] or our 2005 review [4] and remains about 40–50% in most of >37 studies [23, 54]. Notably, when cancer is diagnosed following an initial diagnosis of ASAP on a set of needle core biopsies, the clinicopathologic findings at radical prostatectomy are not significantly different from those of cancers that were diagnosed at initial biopsy [53]. The presence of ASAP concomitant with cancer does not worsen the rate of upgrading and upstaging in prostatectomy specimens of patients eligible for active surveillance [55].

Assignment of the ASAP Diagnosis

For pathologists, three questions need to be answered prior to diagnosing minimal cancer in a small lesion: (1) “Would you remain absolutely confident of this biopsy diagnosis if it were followed by a negative radical prostatectomy?”; (2) “Are you certain there would be diagnostic agreement if your work got audited by another pathologist?”; and (3) “Can the findings in this one core alone support an overall confident diagnosis of cancer for the case?” If these questions cannot be answered affirmatively, then the use of the more cautious diagnosis of ASAP is warranted. In this setting, “ASAP” is a durable, valid diagnostic category as long as it is employed judiciously and the maximum information has been extracted from the available tissue.

ASAP results from two main conditions. Small size of the focus of atypical acini is the culprit in 70% of cases [50]. “Too small” has generally been defined as three or fewer acini or acini situated on the edge or tip of a needle core [15]. A scant number of acini may be insufficient to call cancer (Fig. 16.33) even with fairly convincing support from an immunostain (Fig. 16.34). Particularly, disappearance of the atypical acini on some of the levels of prostate core(s) examined (in most laboratories, three slides per sample) justifies an ASAP diagnosis. The default diagnosis for such foci should be ASAP. It is not unusual for just a single acinus to be atypical; so even with a cancer-like immunostain result, it is best considered ASAP (Fig. 16.35). Van der Kwast et al. have noted that agreement between expert urologic pathologists and general surgical pathologists was particularly poor for foci comprising <6 atypical acini [56], so obtaining a second opinion for such cases, preferably from a trained expert, may be a better and more economical maneuver than ordering numerous immunostains—even if getting the second opinion results in a bill. The interobserver reproducibility for ASAP can be improved by didactic review and joint microscopic sessions [23].

Ambiguity of nuclear and cytologic features is the second condition supporting an ASAP diagnosis, often despite the number of suspicious acini being otherwise sufficient to diagnose cancer. ASAP often combines the above quantitative and qualitative reasons together, having six or fewer minute acini with morphology that overlaps with reactive or atrophic mimics of cancer that cannot be ruled out (Figs. 16.36 and 16.37).

ASAP Can Occur in Conjunction with HGPIN

In some instances, small atypical gland spaces are closely associated with a focus of high-grade PIN. It may be impossible to separate tangential cutting of medium-sized preexisting outpouchings of HGPIN from the smaller discrete acini of cancer (Figs. 16.38 and 16.39) [13]. In such cases, we prefer the term ASAP + HGPIN, referring to the coexistence of the two lesions—atypical small acinar proliferation suspicious for cancer—and HGPIN, in the same high-power microscopic field. This avoids the overdiagnosis of tangentially cut outpouchings of HGPIN as cancer.

On the diagnostic line, ASAP is placed first owing to its stronger predictive value for cancer detection. A common under-call is to diagnose only HGPIN, overlooking the more important ASAP. ASAP + HGPIN can be diagnosed after performing an immunostain (Figs. 16.16 and 16.17) or without the benefit of an immunostain if the atypical acini are lost on the levels used (Fig. 16.18). Notably, in biopsy material, ASAP was present in the same slide with adjacent HGPIN less than half as often (23%) as minimal cancer was present with HGPIN (57%) [14]. In a study using radical prostatectomy tissue, 75% of HGPIN abutted cancer [2]. ASAP + HGPIN, found in one core in up to 16% of all biopsies, has a predictive value ranging from 33% to 60% for cancer [4, 6, 57,58,59,60,61,62], similar to ASAP alone. As of 2005, the aggregate predictive value of this finding for cancer was 33%, not significantly different from that of ASAP alone [4].

Resolution of ASAP with Immunostains

Immunohistochemical findings should not be interpreted in isolation but in conjunction with hematoxylin-eosin stains. Pathologists are urged to place a dot at the focus of concern in the original slide and superimpose and dot the immunostained slide to ensure that the same foci are being studied. Avoid the common error of overcalling cancer based on immunostain results alone. If two independent, strong “votes” for cancer are not forthcoming—one from the hematoxylin-eosin stained slide (after examining all levels or possibly ordering more levels) and one from the immunostain—the default is ASAP.

In some instances, the triple immunostain can resolve an ASAP focus (Figs. 16.40 and 16.41). The addition of P504S can resolve 50% of cases that remain as ASAP on the basis of basal cell markers alone [26]. In other instances, the diagnostic dilemma is not resolved, as in a case (Fig. 16.42) where reactive benign acini, high-grade PIN, and cancer all remain under consideration after performance of the triple immunostain. ASAP is the best compromise here.

Some ASAPs are inadvertently disclosed when the triple immunostain performed to clarify the diagnosis in one focus of concern discloses a separate focus that “bumps” the diagnosis up to ASAP (Fig. 16.43). In this example, high-grade PIN is suggested on hematoxylin-eosin stain, but basal cells are not detected on triple immunostain (Figs. 16.44 and 16.45), making ASAP the best diagnosis. Even a cancer diagnosis can be supported as an abnormal-staining focus that was not appreciated on hematoxylin-eosin stain (Fig. 16.46). This happens when the suspicious acini emerge (or grow in number) on the level that got immunostained but escape sectioning on levels used for H&E.

Cancer Grading

An Origin of Grading System

Dr. Donald F. Gleason published his grading scheme for prostate cancer in 1966 [63] based on a study of 270 patients from the Minneapolis Veterans Administration Hospital. In 1974, Gleason and the Veterans Administrative Cooperative Urological Research Group expanded the study to 1032 men. These studies formed the foundation of the system endorsed by the International Society for Urologic Pathology, the World Health Organization [64], the Association of Directors of Anatomic and Surgical Pathology [65], and the College of American Pathologists: the Gleason system . This scheme assigns a primary grade of 1 through 5 to describe the most prevalent pattern, whether in a single biopsy core, a transurethral resection specimen, or a prostatectomy specimen. The secondary grade of 1 through 5 is the second most prevalent pattern, and the sum of these two grades forms the Gleason score.

Any atypical acinar focus large enough to call cancer is assigned a primary grade and a secondary grade. If only one pattern is present, the Gleason grade is doubled to form the Gleason score. A diagnosis of “prostatic adenocarcinoma, no grade assigned” is not an option (with the possible exceptions of cancer present following administration of radiotherapy, and a few rare cancer variants that are not graded, listed below in Table 16.4).

Contemporary Grading

Gleason grade 2 formerly comprised acini that are relatively uniform in size and spaced less than a gland’s width apart (Fig. 16.47). However, after the ISUP 2014 consensus conference (see below), the use of grade 2 was discontinued, and such acini are graded as Gleason 3, since the prognostic implications are identical to Gleason 3.

Gleason grade 3 cancer consists of single acinar spaces, usually ranging from small to minute but sometimes medium or large. If large, grade 3 acini may have papillary infoldings, consistent with the pseudohyperplastic variant described below [34], but must not have cribriform features of or merge in with cribriform areas. Although the acini may be crowded, at least a wisp of stroma intervenes between each (Fig. 16.48), precluding assignment of grade 4. Acini with elongated branching patterns are also accepted as grade 3 (Fig. 16.49), and by ISUP consensus [66], this does not constitute fusion. Pure Gleason grade 3 cancer essentially never metastasizes. A study of radical prostatectomy and lymphadenectomy specimens using the SEER database showed that Gleason 3 + 3 = 6 cancer metastasized to lymph nodes in <0.5% of cases [67] (based on grading done mostly by non-urologic pathologists). Only 7% of Gleason score 6 cancer has a molecular profile highly associated with metastatic behavior, with 13% showing an intermediate score and 80% a low score [68]. A name change for Gleason score 6 cancer, to indolent lesion of epithelial origin (IDLE), has been suggested by some, but we have editorialized against a name change [69], and the above molecular data support that.

Gleason grade 4 cancer comprises the fused, cribriform, and poorly formed patterns. Grade 4 most typically consists of small pseudoacinar spaces that are fused or coalesced into linear arrays, without intervening stroma (Fig. 16.50). Gleason grade 4 cancer may also comprise pseudoacinar spaces that are larger than a normal benign acinus. These may take on a cribriform or sieve-like arrangement (Fig. 16.51). Papillary patterns, provided they are complex, with cells bridging across the gland space or merging in with cribriform, are also Gleason 4 (Fig. 16.52). Larger acini with simple papilliform or undulated lumens remain Gleason 3. Poorly formed acini, a category that overlaps somewhat with fused category, consist of acini that barely form lumens (Fig. 16.53). The rarest Gleason 4 pattern is glomeruloid, resembling a renal glomerular tuft (Fig. 16.54).

The threshold for Gleason 3 versus 4 depends primarily on the presence of even a wisp of intervening stroma between all adjacent cancer acini. Poorly formed acini pose a special challenge for discriminating Gleason 3 from 4. An interobserver variability study concluded that larger foci with >10 poorly formed acini that were not immediately adjacent to well-formed acini were accepted by most urologic pathologists as Gleason 4 [70]. When those criteria are not met, grade 3 should be chosen and not grade 4 since the apparent poorly formed acini probably represent tangentially sectioned Gleason grade 3 cancer (Fig. 16.55).

Gleason grade 5 cancer is diagnosed when single cancer cells, or sheets of cells without acinar lumens, are perceptible in the stroma. A crucial comparison is that the single cells are almost always larger than lymphocytes (Fig. 16.56). Single file, solid nested, and solid cylinder arrangements also qualify as Gleason 5 because of the absence of glandular lumen space formation [50]. The presence of luminal comedonecrosis in a cancer gland space, alone, is sufficient to diagnose Gleason grade 5 (Fig. 16.57). However, pathologists often overlook the (focal) presence of individual cells or sheet-like growth of cancer cells, constituting patterns of grade 5 (Fig. 16.58). In two studies of second-opinion diagnoses, Gleason grade 5 cancer was missed in 49% [71]–58% [72] of cases by the outside hospital pathologist. On the other hand, interobserver variability among urologic pathologists in diagnosing Gleason 5 cancer was only fair, with comedocarcinoma having best agreement, followed by single cells/cords, and nests [73].

Grading Revisions

In the 50 years since the system’s inception, new aspects of cancer diagnosis and management have been introduced, most notably serum prostate-specific antigen screening (about 1990), transrectal ultrasonography, 18-gauge needle biopsy sampling, immunohistochemistry as a diagnostic adjunct, radical prostatectomy and radiation therapy as primary treatment modalities, and conservative management using cryotherapy or thermotherapy. The needs for reporting have thus changed and now include reporting cancer on multiple sub-specimens in needle biopsies, describing multiple nodules in prostatectomy specimens, tertiary patterns, and attention to variants of prostate cancer (Reviewed, 74).

The application of the Gleason system , therefore, is altered in contemporary surgical pathology practice. The use of the Gleason system has evolved enough that the International Society of Urologic Pathology (ISUP) saw fit to revise it twice, first in 2005 [75] and second in 2014 [66]; the latter rules on grading appear in the WHO blue book (44WHO). The emphasis of the 2005 consensus was the manner of grade assignment (Table 16.3), with attention to some less frequent variants of prostate cancer (Table 16.4).

Table 16.3 Manner of prostate cancer grade assignment (2005 consensus) [75]

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Table 16.4 Treatment of special prostate cancer patterns

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The 2014 consensus also set or refined criteria for use—or disuse—of all five Gleason grades (Table 16.5).

Table 16.5 Changes in criteria for each Gleason grade

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Gleason grades 1 and 2 are no longer viable entities [78], a matter addressed at both consensus conferences. Gleason grade 1 cancer was considered to represent a very tightly circumscribed nodule of uniform-shaped acini, but most of the grade 1 cancer in Gleason’s original collection is now recognized as atypical adenomatous hyperplasia (AAH). Gleason grade 2 cancer lacks interobserver reproducibility compared to grade 3 [79]. Its biologic potential is not any less than grade 3 since, when it is diagnosed on needle biopsy, grade 3 cancer is invariably present at prostatectomy [80]. An additional problem is human interpretation: rare atypical acini get misperceived as “incipient cancer.” Thus, as of 1998 when pathologists did assign grades 1 and 2, they were mostly “abusing” these grades to cover ASAP or marginally sampled grade 3 cancer [81].

Grade Migration

An increase in prostate cancer grades from 1998 to 2005, with acceleration in the rate of increase after 2005, has been documented by recent studies; presumably the 2005 revision of the Gleason system was the impetus. The revision has led to improved concordance between needle biopsy and prostatectomy specimens [82]. However, undergrading [81] has given way to overgrading, as the grades assigned by non-urologic pathologists are trending significantly higher than those assigned by urologic pathologists [83]. This disparity seems to result mainly from overcalling crowded but separate acini or less-well-formed acini as a secondary Gleason pattern 4 rather than 3. Overtreatment of indolent cancer may result.

The radiographic method used in prostate sampling may also introduce grade migration . The introduction of magnetic resonance imaging/ultrasound (MRI/US) fusion-guided prostate biopsy in the early to mid-2010s enables targeting of the most suspicious part of the prostate. MRI/US-targeted biopsy technique led to a significantly higher rate of detection of Gleason grade group 3 (4 + 3 = 7) and higher cancer compared to standard, 12-core sampling in patients who took part in concurrent sampling using both methods [84]. This was despite obtaining fewer cores using MRI/US. The superiority of MRI/US in detecting high-grade cancer is apparently propelling more upward migration of biopsy grades.

Prognostic Grade Grouping

The two main motives for developing a new grade grouping system came from the discontinuation of Gleason grades 1 and 2, plus the observation that not all Gleason score 7 tumor is the same, based on multiple studies. That is, Gleason 4 + 3 has a significantly worse outcome than 3 + 4 [85]. Moreover, breaking down the percentage of Gleason 4 component helps stratify outcome prediction [76, 86, 87] and has good interobserver reproducibility within ±10% intervals [88]. However, the “poorly formed” pattern of Gleason 4 cancer has lower interobserver reproducibility than other Gleason 4 patterns [89]. Like most urologic pathologists, I report the percent of Gleason 4 or Gleason 5 when admixed with Gleason 3 in any proportion, a practice encouraged in the WHO blue book [64].

At its 2014 meeting, the ISUP adopted a simplified patient-centric grading system comprising five prognostic grade groups [90] as proposed in 2013 based on data from Johns Hopkins [91] and subsequently validated by biochemical recurrence hazard ratios on cases from five large academic centers [92]. The grouping system now appears in the WHO blue book [64]. Grade groups 1 through 5 were designated as Gleason score (GS) 3 + 3 = 6, GS 3 + 4 = 7, GS 4 + 3 = 7, GS 8, and GS 9–10, respectively [93, 94]. The divisions of GS 3 + 4 = 7 from GS 4 + 3 = 7 and GS 8 from GS 9–10, which had often been bundled together for prognostic and research purposes, are supported by studies showing significantly different outcomes [95, 96].

Based on radical prostatectomy results, prognostic grade groups 2, 3, 4, and 5, with respect to Group 1 carried biochemical recurrence hazard ratios relative to Gleason score 6 of 1.9, 5.1, 8.0, and 11.7 [92].

An issue left unresolved by grade grouping is whether GS 8 that includes Gleason 5 cancer (causing a Gleason sum of either 3 + 5 = 8 or 5 + 3 = 8) differed in outcome from Gleason 4 + 4 = 8 cancer. In a recent study where urologic pathologists confirmed the Gleason scores from biopsy material [97], cancer-specific survival at 36-month follow-up was 97.8% in the 3 + 5 cases versus 92.6% in the 4 + 4 cases. This ran counter to expectations of a worse outcome attributable to the presence of Gleason 5 cancer. The difference was not significant (p = 0.089). The cribriform growth pattern (below, Sect. 8) was present in 63% of the 4 + 4 = 8 cases but only 26% of the 3 + 5 or 5 + 3 = 8 cases. The presence of cribriform cancer within the GS = 8 group turned out to be a finding sufficient to dichotomize cancer-free survival up to 36 months (p = 0.018) [97]. Presence of cribriform cancer, likewise, can stratify Gleason 3 + 4 = 7 cancer [98, 99].

Grading Impact on Treatment

The National Comprehensive Cancer Network uses this definition of favorable-risk prostate cancer : Gleason score 6, serum PSA <10 ng/mL, PSA density <0.15 ng/mL/cc, fewer than three biopsy cores with cancer, and ≤50% of any core with cancer (core being generally synonymous with subpart of a specimen) [100]. Patients whose cancer falls into the favorable-risk category are candidates for active surveillance, avoiding the side effects of surgery or radiation.

Sampling of Gross Specimens

Radical Prostatectomy

Most cancer arises from the C-shaped peripheral zone (posterior and lateral parts of the prostate); cancer can arise primarily in the transition zone (anteromedial part of the prostate) but is more often the result of tumor expansion from the peripheral zone. Unlike the clearly visible lesion of Fig. 16.7, however, the cut surface often discloses no grossly evident lesion. Thus prostate cancer is grossly identifiable in only 63% of cases; designating lesions grossly as prostate cancer carried a false-positive rate of 19% [11]. Harvesting prostate cancer tissue for research with frozen section confirmation may require two or three sampling attempts. The slices taken for tissue harvesting often end up 5 mm thick instead of the 3 mm optimal for processing. The remedy is to fix the slices several hours or overnight and then cut them thinner.

According to the 2009 International Society of Urological Pathology consensus, the prostate should be weighed after detaching the seminal vesicles. Measurements are taken of all three dimensions of the prostate, that is, apical to basal (vertical), left to right (sagittal), and anterior to posterior (transverse). The prostate is inked, usually blue on the left (both words have four letters) and black on the right (five letters). (More colors than two are used by some laboratories but are not needed because the presence of skeletal muscle in the stroma identifies anterior and because the gross description should list the quadrant from which sections originate.) Both the prostatic apex and base are then amputated and sagittally sectioned into strips to allow embedding perpendicular to the margin. The prostate may be fixed if time permits or cut fresh. Slices should be cut at about 3–4 mm and grossly visible abnormalities described. Complete or partial submission (e.g., slices 1, 3, 5, and 7) were both deemed acceptable as long as the method of sampling is specified. Slices may be sectioned into halves or quadrants or embedded as whole-mounts and processed on double-width slides [101]. Whole-mounting provides a superior view of the greatest dimension of tumor and margin status and lends itself to research applications. However, standard cassettes and slides fit in better with the work flow of most pathology departments and avoid the need for an adaptor apparatus on the microtome to hold a larger tissue block.

Vanishing Cancer

In about 0.7% [102]–2.1% [103] of radical prostatectomy specimens, cancer is not found. This conclusion is usually reached only after complete specimen submission (if the initial submission was partial). Moreover, “flipping” the blocks and having the opposite surfaces of the tissues sectioned, perhaps obtaining deeper sections, immunostaining of suspicious foci, and consulting a colleague with urologic pathology expertise are all useful maneuvers. DNA analysis for identification of the origin of the tissue might be considered. Notably, patients with a biopsy positive for cancer, but with no cancer in the radical prostatectomy specimen, have no difference in risk of tumor recurrence or progression compared with patients in whom tumor is found [102, 104,105,106]. It has been proposed that patients with definite cancer in the biopsies but none in the prostatectomy specimen be characterized as stage pT2(−), with the (−) sign added to convey this discrepancy [107].

Transurethral Resection

Humphrey et al. and the Association of Directors of Anatomic and Surgical Pathology recommend complete sampling for patients younger than age 60. For patients over age 60, random sampling of eight or ten blocks is adequate since the consequences of not detecting cancer are less [65, 108]. If high-grade PIN or cancer is detected in a partially submitted specimen, then complete submission is warranted, although it has been shown that complete submission after cancer is detected in the first six cassettes does not change grade or estimated tumor volume [109].

Staging, Tumor Volume, and Margin Status

Radical Prostatectomy

Staging

The current AJCC/WHO staging standards for prostate cancer [64, 110], based on earlier consensus meetings of the ISUP [111], are shown (Table 16.6).

Table 16.6 AJCC staging of prostate cancer [110]

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Stage pT2 cancer is clinically substaged as 2a, 2b, and 2c, but the corresponding pathologic (pT) stage has been compressed to pT2 [110]. This change was in response to evidence that the pT2 substages were not significant predictors of biochemical recurrence-free survival on multivariate analysis [112]. In a multivariate model, tumor percentage >25% did predict outcome; thus substaging tumor as <25% versus >25% was proposed [113] but is not part of current staging [110].

Stage pT3a carcinoma is discriminated from stage pT2 by the finding of extraprostatic extension (EPE) of cancer or microscopic invasion of bladder neck. Extraprostatic extension other than to bladder neck is defined as cancer cells in contact with the extraprostatic fat. A desmoplastic reaction surrounding cancer right at the extraprostatic tissue interface may complicate stage assignment. Staging is not based on the concept of a prostatic “capsule” for two reasons. First, the prostate does not have a true capsule but a pseudocapsule that is discontinuous at the apex, the anterior surface (where it interdigitates with skeletal muscle), and bladder base. An implication of these facts is that cancer acini within the skeletal muscle fibers of the anterior prostate should not be interpreted as extraprostatic extension.

Second, the notion of whether cancer is “into the capsule” or “through the capsule” has poor interobserver reproducibility, whereas cancer in contact with fat has excellent reproducibility. Some caution is advised, because on occasion, intraprostatic fat can be a normal finding (Fig. 16.59) [114]. In this instance, the fat cells are surrounded by abundant stroma, and the presence of cancer cells at the level of the fat does not raise the stage to pT3a (Fig. 16.60). Conversely, tumor nodules not in contact with fat but that bulge beyond the prostatic contour and are surrounded by desmoplastic stroma still qualify as stage pT3a.

Less commonly, bladder neck invasion occurs. Of note, microscopic bladder neck invasion was accepted as stage pT3a in recent consensus meetings [111]; this was previously graded as stage pT4.

The criterion for stage pT3b carcinoma is carcinoma invading the muscularis or epithelium of the seminal vesicle. The ISUP affirmed these criteria by consensus [115]. It is important for the pathologist to recognize the muscularis (Fig. 16.61). Seminal vesicle invasion occurs via (a) direct spread along ejaculatory duct complex, (b) spread outside the prostate and then into seminal vesicle, and (c) isolated deposits of cancer in seminal vesicle with no contiguous primary cancer in the prostate [116].

The M1a stage incorporates all lymph node metastases, regardless of size or number. Whenever a lymph node is positive for cancer, the size of the metastatic focus in millimeters should be reported. Also, one should report whether or not extranodal extension (ENE) of tumor into perinodal adipose tissue occurs. A meta-analysis on ENE highlights its relevance: ENE presence carries a higher risk of biochemical recurrence (relative risk, 1.15, 95% confidence interval 1.03–1.28, and hazard ratio 1.40, 95% confidence interval 1.12–1.74) [117].

Tumor Volume

The estimated percent of the prostate involved by carcinoma is an independent predictive factor for outcome [118], and a standard prostatectomy report should report it in intervals of 5%. The greatest dimension of the dominant nodule of cancer has long been recognized as an excellent proxy for tumor volume [119] and should also be listed in the pathology report.

Margin Status

A positive surgical margin is reported in 8.8–42% of prostatectomy cases and doubles or triples the likelihood of biochemical recurrence [120]. It is an independent predictor of biochemical recurrence, with prostate base positivity significantly associated with poor outcome [121]. Margin positivity should be reported on the prostatectomy report, at least, as focal (involving one high-power field on up to two separate sections) or non-focal [122, 123]. I follow the ISUP recommendation that measurements of its linear extent in millimeters and locations (e.g., left posterior) and numbers of the levels involved should be listed [112]. A positive margin has a significant predictive value for cancer on repeat biopsy, depending on its extent and distribution (reviewed, 120).

When tumor is close to but not contiguous with the inked margin, should this finding be reported? The usual practice of pathologists has been not to report close margins, although some evidence imparts predictive value for recurrence to tumor within 1 mm of the margin [124]. A recent study made a distinction between the posterior edge of the prostate and its anterior edge. The posterior edge is smooth and well-defined, adjacent to the tough Denonvilliers’ fascia which abuts the pseudocapsule and makes anterior rectal invasion rare. The anterior edge is rough owing to its interdigitating with skeletal muscle of the urogenital diaphragm. The distance of tumor from the posterior margin did not predict recurrence, while tumor that was <1 mm from the anterior margin did predict recurrence. It was recommended to report tumor that is <1 mm from the anterior margin [125].

Both margin positivity and tumor volume correlate with presence of anterior tumor [126]. Kryvenko et al. have shown that patients with significant prostate cancer more commonly had anterior-dominant cancer (58%) versus patients with insignificant cancer (21%) [127]; this probably reflects detection of anterior cancer at later phase of development because of its reduced accessibility to needle biopsy and palpation.

Putting all of the above together, my suggested line diagnosis is presented (Table 16.7). Some line items may be covered as part of a synoptic template.

Table 16.7 Suggested verbiage for line diagnosis of radical prostatectomy

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Biopsy

A staging issue pertaining to a set of needle biopsy specimens is the reporting of extraprostatic extension (Fig. 16.62). Many prostatic biopsy cores contain extraprostatic adipose tissue, and any tumor interdigitating with fat (if fat is sampled) should be reported in the pertinent core. This finding is easily overlooked by pathologists. The tips of biopsy cores are the most common places to find extraprostatic tumor, but not always (Fig. 16.63). It correlates with extraprostatic extension at radical prostatectomy and most importantly an increased incidence (approximately 14 times) of metastatic cancer [114]. In second-opinion practice, we commonly see extraprostatic extension overlooked by the outside diagnosis. Even though the presence of suspected extraprostatic extension is not a common finding in biopsy specimens, in a cohort of 65 consecutive cases, almost half of the specimens containing this lesion (5 out of 11) were not reported by the outside pathologists [73].

To document that this finding has been assessed in any needle biopsy set that is positive for cancer, I add a separate “Comment” section after all the line diagnoses (e.g., parts A–F), saying, “Tumor shows no perineural invasion or extraprostatic extension,” if this is true. If tumor does show either feature, it is mentioned in the diagnosis for the sub-part(s) of the specimen. Alternatively, some pathologists use mini-templates for each cancer diagnosis, to report the presence or absence of these two findings.

Tumor in biopsy specimens has been defined as clinically “significant” if Gleason score ≥ 3 + 4 or tumor length ≥3 mm [128] (measured by drawing in ink alongside the cancer) or both. Tumor unilaterality and unifocality in biopsy specimen sets is a fairly good predictor of unilaterality and unifocality of tumor in the prostatectomy specimen, particularly if 12 or more biopsy samples are taken [129].

Tumor volume in biopsy samples is a critical selection factor for men with Gleason 3 + 3 = 6 cancer to enter into active surveillance. Some variations exist in guidelines used by leading institutions [130], but the most commonly used criteria are PSA less than 10 ng/mL, unilaterality of cancer (clinical stage cT2a), and maximum of three positive cores, with less than 50% of each core involved by cancer. Some active surveillance protocols may accept men with Gleason 3 + 4 = 7 cancer, especially if the percentage of pattern 4 is low, but this remains controversial.

Cribriform/Large-Gland Types of Adenocarcinoma

The past 5 years have seen a revolution in our understanding of cribriform neoplasia of the prostate.

Invasive Large-Gland Carcinoma (Including Cribriform and Papillary)

The first indication that invasive cribriform carcinoma carried an elevated biologic potential came in 1999 when Egevad et al. noted that 40% of cribriform cancers were nondiploid, compared with only 12% of Gleason pattern 3 cancers [131]. This observation was not further pursued until a 2011 study. 76 men undergoing prostatectomy who had subsequent PSA failure were matched to 77 men without failure, and 9 distinct patterns of cancer were digitally annotated on scanned whole-mount slides. A cribriform pattern was present in 61% (46/76) of failures but 16% (12/77) of non-failures (p < 0.0001). Presence of cribriform cancer conferred about a sixfold greater odds ratio for PSA failure [132]. Cribriform carcinoma held a strong association with the individual cell pattern (grade 5) (Fig. 16.64). Also, the presence of small or loose “collapsible” cribriform structures (Fig. 16.65) had the same effect on prognosis as the more common large cribriform structures. Fourteen total studies, based on either biopsy and prostatectomy tissue, have emerged since 2011 [87, 98, 99, 132,133,134,135,136,137,138,139,140,141,142] supporting a special adverse effect of cribriform cancer among all Gleason 4 patterns. In particular, studies using death from prostate cancer showed that cribriform growth was highly predictive of metastasis and death from prostate cancer [139, 140]. Moreover, in needle biopsy sets, the presence of cribriform growth proved to be more strongly predictive of biochemical recurrence than whether the highest Gleason grade was 3 + 5 = 8 versus 4 + 4 = 8 [97]. Thus, many urologic pathologists now make a comment on the presence (not necessary to report the absence) of cribriform growth as a component of Gleason grade 4 cancer, adding that it is an adverse prognostic finding.

Intraductal Carcinoma

The term intraductal carcinoma (IDC) of the prostate was first used in 1972 [143], although that term as well as intraductal dysplasia were largely subsumed by high-grade prostatic intraepithelial neoplasia. IDC had not gained much attention as a separate entity until recent years [144]. Almost always occurring in association with invasive acinar cancer, IDC occurs as an isolated finding in only 2% of biopsy sets, where it poses both a diagnostic and therapeutic challenge. Molecular evidence points to retrograde colonization of duct spaces by the invasive cancer as the origin of IDC [145].

1.
Morphology

IDC is a lumen-spanning proliferation of neoplastic cells in preexisting ducts with a dense cribriform or partial solid growth pattern. Nuclear atypia exceeds that of high-grade PIN. The preexisting duct space is distended, usually, to at least twice the diameter of a normal duct and at least focal basal cells are preserved (Fig. 16.66). Branching of the distended duct spaces is diagnostically helpful (Fig. 16.67). Some pathologists employ a “borderline” category, called “atypical cribriform proliferation” for diagnostic findings in between HGPIN and IDC (Fig. 16.68) [146, 147].

We recently surveyed 39 urologic pathologists to assess the interobserver variability of an IDC diagnosis. We provided 38 images of high-grade PIN vs. IDC vs. invasive cancer. In 19 cases that were candidates for IDC, only 5 (26%) achieved at least a two-thirds consensus of IDC (e.g., Fig. 16.69), while 9 more (47%) of cases had a consensus for the broader category of either borderline or IDC [148]. Findings that differed across diagnostic categories were lumen-spanning neoplastic cells (P < 0.001), 2× benign duct diameters (P < 0.001), duct space contours (round, irregular, and branched) (P < 0.001), papillary growth (P = 0.048), dense cribriform or solid growth (both P = 0.023), and comedonecrosis (P = 0.015). Lack of IDC consensus was most often attributed to the image displaying loose (“collapsible”) cribriform growth, central nuclear maturation, or central comedonecrosis. Thus, subjectivity persists in the application of diagnostic criteria for IDC.

In summary, it is crucial to recognize IDC , since IDC and even atypical cribriform proliferation have both recently been proven to predict biochemical recurrence even after controlling for grade, stage, and margin status [135, 149].

Ductal Carcinoma

Originally termed “endometrioid carcinoma ” [150], this large-glandular growth occurs in 3% of prostate cancer and is most frequent in the transition zone. In all but 0.2–0.4% of cases, there is admixed acinar carcinoma. An exophytic mass usually protrudes into the urethra; thus, common symptoms are hematuria and bladder outlet obstruction. To the urologist performing urethroscopy, ductal carcinoma can mimic a urothelial carcinoma of the prostatic or membranous urethra. Because tumor cells secrete their PSA into the urethra and not the bloodstream, serum PSA may not be elevated; elevated PSA is most probably attributable to an admixed acinar component [150].

Histologically, columnar, stratified cells, often in a papillary to cribriform pattern, line a large gland space (Figs. 16.70 and 16.71). In an interobserver study, urologic pathologists reached a two-thirds consensus for or against the diagnosis of ductal carcinoma 76% of the time, with the differential diagnoses including intraductal carcinoma and high-grade PIN. Papillary architecture and stratification of nuclei were the two most essential diagnostic features in more than 80% of cases, with tall columnar epithelium and elongated nuclei contributory in more than 50% of cases [151]. If the definition of ductal carcinoma is broadened to any papillary/cribriform proliferation 5 mm in extent, regardless of the presence of columnar cells with stratified nuclei or periurethral location, the incidence may top 5% [152].

Ductal carcinoma , by ISUP consensus, should be graded as Gleason 4; any presence of comedonecrosis raises the grade to Gleason 5 (Table 16.4). By virtue of its constant, higher Gleason grade, ductal carcinoma on average carries a higher-stage, tumor volume, and more aggressive behavior than acinar adenocarcinoma. Ductal carcinoma metastasizes along routes similar to acinar adenocarcinoma [150].

Unusual Variants of Carcinoma

Pseudohyperplastic

Pseudohyperplastic cancer was noted in 11% of radical prostatectomy specimens and 2% of needle biopsy specimens [34]. This diagnostic pitfall is a mimic of benign nodular hyperplasia. Pseudohyperplastic cancer comprises large or dilated acinar spaces with papillary infoldings, undulated lumens, and branching. It should be graded as a large acinar type of Gleason grade 3 [66]. Constant findings are nuclear enlargement, prominent nucleoli, and (in radical prostatectomy specimens) a transition to usual small acinar carcinoma.

Adenoid Cystic/Basal Cell Carcinoma (ACBCC)

This histologic variant features an adenoid cystic-like pattern similar to salivary gland cancer. The growth can be predominantly adenoid cystic or have predominantly basaloid (Fig. 16.72) cancer cells.

Two studies reported 48 cases of this special type of prostate cancer, 34 with clinical outcome [76, 153]. Patients ranged in age from 42 to 89 years, and all but one presented with urinary obstruction and was diagnosed by transurethral resection, suggesting a predilection for the transition zone. Four patients had concurrent acinar adenocarcinoma. Some cases invaded skeletal muscle of the bladder neck. Immunohistochemically, the tumor cells of ACBCC were immunoreactive for p63 and cytokeratins 7 and 34βE12 but not cytokeratin 20. This basaloid phenotype overlaps with urothelial carcinoma. Interestingly, the tumors were positive for Her2Neu, predominantly in inner cell nests, unlike acinar carcinoma [154]. Extraprostatic extension was noted in a combined 10 of 12 patients who underwent prostatectomy. Eight metastases and 2 deaths were documented among the 34 patients who had follow-up in the 2 studies. Thus ACBCC is a potentially aggressive tumor requiring ablative therapy.

A case of aggressive ABCC has been reported, apparently distal to the prostate and involving the membranous urethra and penis as well as the prostate. The prostate also had high-grade acinar adenocarcinoma. The ACBCC was reactive for cytokeratin 7 and p63 [155]. However, the close proximity to the prostate as well as presence of concurrent prostatic acinar adenocarcinoma suggests contiguous spread from a prostatic primary.

Neuroendocrine

Scattered proportions of neuroendocrine cells have been reported in varying percentages—up to 50% [156]—of usual acinar prostatic adenocarcinoma. However, most studies failed to show any clinicopathologic significance of such changes [157]. The incidence of pure small-cell neuroendocrine carcinoma, resembling that in the lung, is <1%. It occurs in the pure form in half of cases, with the other half having antecedent or admixed acinar adenocarcinoma which is almost always high grade [158]. By consensus, pure small-cell carcinoma is not graded [75]. The prognosis is poor, with 60% of patients having metastatic cancer at presentation, and a median cancer-specific survival of 19 months [159], shorter if it arises following acinar prostatic carcinoma. Radiation therapy can be effective.

Immunohistochemically, small-cell carcinoma of the prostate does not express prostate-specific antigen or prostatic acid phosphatase [157]. About 90% of cases are positive with neuroendocrine markers such as chromogranin, synaptophysin, and CD56. More than half are positive for thyroid transcription factor 1.

Rarer forms of neuroendocrine differentiation include Paneth cell-like differentiation [36], well-differentiated neuroendocrine (carcinoid) tumor, and large-cell neuroendocrine carcinoma [160]. True carcinoid tumor should be diagnosed only when not admixed with acinar carcinoma and should be PSA-negative. Other tumors are carcinoid-like but retain PSA positivity. Well-differentiated neuroendocrine tumors may be locally advanced yet have a favorable prognosis [158, 159]. On the other hand, large-cell neuroendocrine carcinoma has frequent necrosis and mitotic activity, spreads rapidly, and has low survival.

Squamous

Seventy-six cases of squamous cell carcinoma of the prostate are reported, and about 50% of cases arise in prostate cancer patients following endocrine therapy or radiotherapy [161]. The origin is not clear; hypotheses include pure prostatic origin, including the basal cells of the prostatic acini, and squamous metaplasia of a prostatic urethral primary tumor [162]. Theories of histogenesis include metaplastic transformation of adenocarcinoma, a collision-type tumor with squamous component developing from metaplastic foci, derivation from pluripotent stem cells capable of multi-directional differentiation, and clonal evolution of treated adenocarcinoma secondary to the selective pressure of therapy.

The differential diagnosis includes squamous metaplasia , which may follow hormonal therapy. The prognosis is poor, with most patients having metastatic cancer at diagnosis, and short median survival after multimodal therapy.

Adenosquamous carcinoma is even more rare, with 27 cases documented, and the serum PSA is elevated [163]. Separate foci of squamous cell carcinoma and adenocarcinoma on needle biopsies without evidence of merging were reported [164]. The squamous component contained large cohesive cells characterized by keratinization and abundant eosinophilic glassy cytoplasm (Fig. 16.73). Compared to the adenocarcinoma component, nuclei were larger and more pleomorphic. In the latter case, neither squamous nor adenocarcinoma had been diagnosed previously, and there was no history of endocrine therapy or radiotherapy. Squamous carcinoma was confined to the left side with 20–90% involvement. The squamous cell carcinoma stained negative for S-100 protein, CDX-2, and uroplakin II. Additionally, Gleason 4 + 4 (score = 8) adenocarcinoma was seen focally in one core on the right. Cisplatin/5-FU and radiotherapy were given, with no evidence of metastasis 11 months after diagnosis.

Effects of Treatment on Carcinoma

It is common to see the effects of radiation or androgen deprivation in men followed by serial prostatic biopsies for active surveillance and in prostatectomy specimens. The histologic effects of these two treatments overlap somewhat, but differ in some respects, especially for cancer acini (Table 16.8).

Table 16.8 Comparison of treatment effects: Radiotherapy and androgen deprivation

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Radiotherapy

Both brachytherapy (seeds) and external beam therapy produce identical histologic changes. After 12 months radiotherapy, Crook et al. showed that 21% of patients still had cancer on needle biopsy but after 28 months fewer than 10% still did [165]. Thus, based on these studies, it was recommended that repeat biopsy sampling should take place at a minimum of 1 year after the initiation of radiotherapy . Cancer that is present following treatment may show DNA aneuploidy. Thirty-one percent of pretreatment diploid tumors were aneuploid following treatment [166].

Benign irradiated prostate shows marked nuclear enlargement and hyperchromasia exceeding that found in almost all cancer, with a smudged chromatin (Fig. 16.74). Biopsy samples in this situation are likely to require a triple immunostain to be certain basal cells are present.

Cancer displays a spectrum of histologic findings, including cytomegaly and nucleomegaly [167].

It was recommended in 1995 that cancer that persists following radiotherapy should not be graded owing to acinar distortion [168] and that recommendation holds today [74].

Androgen Deprivation

Androgen deprivation may be achieved by the synthetic antiandrogen cyproterone acetate, by finasteride (which inhibits the types 2 and 3 isoenzymes of 5-alpha-reductase, the enzyme that converts testosterone to dihydrotestosterone which stimulates growth of both benign and malignant prostate) or by dutasteride. Dutasteride inhibits isoenzyme types 1, 2, and 3. (Type 1 has increased expression in castration-resistant prostate cancer.) Placebo-controlled studies prior to radical prostatectomy showed atrophy of both benign and cancer epithelium in the dutasteride-treated group, as well as a lower tumor volume in the treated group [169]. Changes were less pronounced than those achieved with androgen ablation [170].

Following androgen deprivation, benign prostate shows changes similar to those after irradiation (Table 16.9). Acini become atrophic, with dilated lumens and flat epithelium (Fig. 16.75).

Table 16.9 Available molecular tests for prostate cancer

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The changes shown by prostate cancer after antiandrogens are distinct from those of post-radiation effect. Nuclei become pyknotic, not enlarged, while cytoplasm becomes clear; this distinctive appearance has been dubbed “nucleolus-poor clear cell carcinoma [171].” Cancer following antiandrogen treatment (Fig. 16.76) as illustrated here displays these changes although the cancer acini on the left still retain nucleoli. Also, the epithelial height of the cancer cells is decreased [169]. The triple immunostain is particularly helpful to confirm cancer in this setting. Notably, androgen deprivation therapy decreases the prevalence and extent of high-grade PIN [172], attesting to its preventive potential.

Mesenchymal Neoplasms

Lesions Particular to the Prostate

Purely stromal neoplasms that involve only the prostate are divided into stromal tumor of uncertain malignant potential (STUMP) , stromal sarcoma, and carcinosarcoma.

STUMP , which prior to 1998 [173] was termed atypical stromal hyperplasia, has been described occurring in four patterns [174, 175] that include (1) hypercellular stroma with scattered degenerative atypia featuring vacuolated nuclei and smudged chromatin (50% of cases), (2) hypercellular stroma with bland spindle stromal cells, (3) benign phyllodes-like (similar to breast, with hypocellular fibrous stroma surfaced by benign prostate epithelium), and (4) myxoid stroma with bland cells, lacking the nodularity seen in benign hyperplasia. The degenerative/smudged chromatin is actually pathognomonic of all four patterns (Fig. 16.77). STUMP occurs in a broad age range with median age of 58 years [173, 174], usually presenting with urinary obstruction, followed by hematuria, hematospermia, and rectal fullness. While many STUMPs are incidental findings and behave indolently, a minority recur after surgery or metastasize. Up to 46% [173] reportedly recur without definitive surgery.

Microscopically, STUMP should have rare to no mitotic activity and lack necrosis. The neoplastic cells insinuate between benign acini. STUMP should be cytokeratin-negative, ruling out sarcomatoid carcinoma. Other than that, immunostains are not particularly discriminatory for STUMP. CD34 and vimentin are most often positive, with variable staining for smooth muscle actin and desmin [174, 175]. The CD34 positivity helps rule out smooth muscle proliferations. STUMP arises from specialized, hormonally responsive prostatic stromal cells, and as such, progesterone receptor and androgen receptor are helpful immunostains and should be positive [176, 177].

Stromal sarcoma may assume a storiform, epithelioid, or fibrosarcomatoid pattern or a malignant phyllodes-like pattern. Stromal sarcoma affects a younger population, on average, than does prostatic adenocarcinoma or STUMP, with half of the patients under the age of 50. Sarcomas can be divided into low grade and high grade, based on the degree of pleomorphism and mitotic rate.

An admixed carcinoma component and sarcoma component can be seen, constituting carcinosarcoma. Carcinosarcoma represents 0.1% of prostate cancers. Serum PSA is usually not elevated. Prognosis is poor, and the observed biological behavior of these tumors is very aggressive irrespective of histologic variants [178]. Some authors speculate that the increasing use of external beam radiation therapy and brachytherapy in the treatment of prostatic adenocarcinomas may raise the incidence of carcinosarcoma [179]. Recently, carcinosarcoma was reported to arise 7 years status post-brachytherapy for prostate cancer (Fig. 16.78) [180]. We have also seen a case containing a benign stromal proliferation in the manner of phyllodes tumor, with a malignant epithelial component (Fig. 16.79).

Lesions Also Found at Other Sites

The most common sarcoma of the prostate is leiomyosarcoma , but fewer than 200 cases are reported. It presents with obstruction in adults or children. The tumors recur often and have a relatively poor prognosis [181]. A spindle-cell proliferation with mitotic activity and necrosis may be seen. Positive immunohistochemical markers are CD44, smooth muscle actin, and calponin, with variable desmin and, notably, negative CD34. Cytogenetics may disclose chromosomes 2, 3, 9, 11, and 19 clonal rearrangements.

In children and infants, embryonal rhabdomyosarcoma is the most common prostatic malignancy. It causes a firm, smooth enlargement of the prostate. Lymph node metastases are less common than in the head and neck counterpart of this tumor. Microscopically, cellularity also is greatest around blood vessels, with intervening myxoid and edematous areas. Tumor cells are primitive, round to spindled cells, with purely spindle-cell variants being described [182]. The finding of cross-striations in the cells is variable. Usually, the tumor extends outside the prostate. Only three cases have been reported in adults [183]. In both children and adults, prognosis is poor, and chemotherapy, radiation, and surgery may be used.

Other neoplasms described include synovial sarcoma , pseudotumor (inflammatory myofibroblastic tumor), solitary fibrous tumor , osteosarcoma , angiosarcoma , and gastrointestinal stromal tumor (GIST) . The GISTs may clinically present like a primary prostatic process on imaging studies but can be demonstrated to emanate from the rectum or perirectal space, and while they compress the prostate, they usually do not invade it [184]. CD117 and CD34 are the most useful markers for GIST. CD34 is also positive in synovial sarcoma, but the latter is distinguished by its stag-horn vasculature and “patternless pattern.”

Hematologic Neoplasms

In 1998 we reported 60 cases of non-Hodgkin’s lymphoma and 2 cases of Hodgkin’s lymphoma involving the prostate [185]. Mean patient age was 62 years (range, 5–89 years). Most patients had bladder outlet obstruction and prostatic enlargement, though without as much firmness as in carcinoma. Twenty-two patients (35%) presented with primary extranodal lymphoma of the prostate. That is, no patient had hepatosplenomegaly, inguinal lymphadenopathy, or an abnormal complete blood count at presentation. The histologic subtypes varied from diffuse large B-cell (12 patients) to small lymphocytic (4 patients); follicular center cell, diffuse, small cell (2 patients); follicular center cell, grade 1 (according to the revised European-American classification, small cleaved) (1 patient); grade 2 (mixed) (1 patient); and high-grade B-cell lymphoma, Burkitt-like (2 patients).

Thirty other patients (48%) with previously documented lymphoma at other sites developed prostatic involvement; these secondary prostatic lymphomas displayed a variety of subtypes, including small lymphocytic (8 patients, all with concomitant leukemia); follicular center cell lymphoma, diffuse, small cell (2 patients); follicular center, grade 1 (small cell) (1 patient); follicular center, grade 2 (1 patient); diffuse large B-cell (11 patients); peripheral T-cell lymphoma (2 patients); high-grade B-cell lymphoma, Burkitt-like (1 patient); Burkitt’s lymphoma (1 patient); Hodgkin’s lymphoma (nodular sclerosing in 1 patient and mixed cellularity in 1 patient); and unknown (1 patient). Ten cases were not classifiable as primary or secondary lymphomas. The lymphoma-specific survival was 64% at 1 year (95% confidence interval (CI), 51–80%), 50% at 2 years (95% CI, 36–68%), 33% at 5 years, 33% at 10 years, and 16% at 15 years.

In other series, a similar assortment of lymphoma types occurred but in varying proportions. Small lymphocytic leukemia (equivalent to CLL) and mantle cell lymphoma were notably more likely to involve the prostate secondarily than to present as primary to the prostate [186].

Leukemia rarely involves the prostate, with myeloid sarcoma (chloroma) being the most commonly reported tumor, either as the initial presentation of leukemia [187, 188] or as a site of relapse [189].

Molecular Biology of Prostate Cancer

Prognostic Tissue Markers

CpG Island Hypermethylation Profile: GSTP1 Methylation

GSTP1 is perhaps the best-studied epigenetic marker in prostatic adenocarcinoma [190]. The gene encodes glutathione S-transferase π 1 protein, which functions as a tumor suppressing detoxifying agent, preventing genomic damage by carcinogens. Methylation of GSTP1 was first reported as a specific biomarker for prostate cancer in 1994 [191]. Since that time, more than 30 independent studies have reported both high sensitivity and high specificity in detecting prostatic adenocarcinoma. The utility of gene hypermethylation analysis is generally reserved for cases in which there is a high clinical suspicion for prostate cancer, but initial prostate biopsy is negative. Rather than attempt a re-biopsy, the histologically non-cancerous tissue can be evaluated for the presence of hypermethylated genes associated with the presence of prostate cancer. These genetic alterations can be seen in histologically nonmalignant tissue adjacent to unsampled cancerous tissue, which is known as a “field effect.” A meta-analysis in 2012 showed that testing for GSTP1 methylation both retrospectively and for biopsy verification yielded a combined sensitivity and specificity of 82% and 95%, respectively [192].

In one pivotal study, the MATLOC study, hypermethylation of APC and RASSF1 was used in combination with GSTP1 [193]. Results were interpreted such that at least one gene in at least one tissue core produced a positive assay result, and the methylation ratio of all three genes was determined relative to an ACTB reference gene. The study demonstrated that methylation analysis on initially negative biopsies serves as a significant independent predictor of the presence of unsampled prostatic adenocarcinoma. Other variables, including subject age or race, or the presence of atypia or HGPIN, were not significantly correlated with the presence of unsampled malignancy. The overall negative predictive value of the combined methylation analysis was 90%, showing good agreement with the NPV documented in other studies.

HOXD3 Methylation

Homeobox D3 or HOXD3 is a gene whose silencing by methylation was shown to correlate with tumor grade [194]. By methylation-specific PCR, it was associated with biochemical recurrence in univariate analysis (P = 0.043) and showed evidence for interaction with pathological stage as a predictor variable in Cox regression analysis (p = 0.028) [194].

Serum and Urinary Markers

Serum PSA , a surrogate marker for prostate cancer, is a sensitive test for prostate cancer but lacks specificity: two-thirds of men undergoing prostate biopsy on the basis of elevated serum PSA will have benign histology. The US Preventive Services Task Force in 2012 recommended that no healthy men regardless of age undergo PSA testing because of perceived harm/benefit balance. This is mightily controversial; the many new tests that have since emerged may promise better specificity (Table 16.9).

The PCA3 test is a urine-based nucleic acid amplification assay, detecting PCA3, a noncoding mRNA which is selectively overexpressed in prostate cancer cells as a ratio to the expression of PSA mRNA which serves as a marker of prostate cells. A test score ≥35 is considered to warrant a repeat biopsy. PCA3 test has relatively lower sensitivity of 49% in the largest study (58% to 74% in other studies), but its great strength is its specificity, which is 78% in that study [195]. This test is mostly used to supplement serum PSA findings. Its use was approved in Europe in Nov. 2006, and it is now commercially available from many laboratories. In the USA the test became available commercially as uPM3 and has been available since May 2006. It was cleared by the FDA in 2011 and is marketed as Progensa PCA3 (Hologic Gen-Probe, Inc).

To perform the test, the urologist collects the first 20–30 ml of voided urine after careful digital rectal examination. 2 ml urine are transferred into a transport tube with lysis buffer, followed by overnight urine specimen shipment to testing center with frozen gel packs. The mean PCA3 score ranges from 30 to 50 and shows no correlation with prostate volume. PCA3 was shown by Whitman et al. [196] to predict both prostate cancer stage and volume. It was significantly higher in men with extraprostatic extension (49 vs. 19), showed a positive correlation with cancer volume (r = 0.38), and by multivariate analysis was an independent predictor of EPE and cancer volume. PCA3 + biopsy Gleason Score + PSA = gave a receiver operator characteristic of 0.90 (for EPE). Thus, PCA3 can be used after a negative set of biopsies to determine which men need immediate repeat biopsy and which are candidates for active surveillance.

The MLabs at University of Michigan have developed the Mi-Prostate Score test , a multiplex analysis that combines urinary PCA3 testing with TMPRSS2-ERG fusion (discussed below) and serum PSA for maximal specificity in predicting prostate cancer and whether the cancer is high grade [197, 198].

Another new, related test is the Prostate Health Index or PHI [199] from Beckman Coulter. The PHI is a new formula to aid in clinical decision-making that combines three kallikreins (total PSA, free PSA, and p2PSA). p2PSA stands for [-2]proPSA, a subtype of free PSA (the benign form of PSA). p2PSA is estimated to be 2.5 times more specific in detecting prostate cancer in patients than a PSA screening [200]. It was approved by the US Food and Drug Administration (FDA) in June 2012 and has been available since. PHI is p2PSA/free PSA × √totalPSA.

Rhodes et al. [201] note that, “ ...the annualized percent change increased with increasing age decade for [-2]proPSA and the rate of increase was significantly greater for men who developed enlarged prostates or prostate cancer [201]”.

The 4KScore measures four serum kallikreins, patient age, digital rectal exam, and prior biopsy status. Recent studies on 162 men screened for prostate cancer have shown that, assuming the conventional serum PSA cutoff of 4.0 ng/mL, biopsies could be avoided in 38.5% of patients by using the 4KScore, compared to use of PSA and rectal exam alone [202].

Sarcosine was markedly elevated in metastatic prostate cancer and moderately elevated in the urine from primary prostate cancer, and its biosynthetic enzyme was elevated in prostate cancer tissues [203]. Also, sarcosine induced invasion and intravasation of prostate cancer cells in an in vivo prostate cancer model. Metabolon and Bostwick Laboratories in 2013 introduced a noninvasive urine test called Prostarix [204] that involves metabolic assessment using a quantitative liquid chromatography-mass spectroscopy method to accurately measure the urinary concentrations of four amino acids. This test is considered an alternative method of deciding whether to perform a set of prostate biopsies in men with mildly elevated serum PSA and negative digital rectal examination—in other words, men at equivocal risk.

Prognostic Tissue Markers

ERG and PTEN

Some American laboratories test selected cases for the two most adverse prognostic markers in prostate pathology: ERG expression and PTEN loss. ERG is an androgen-responsive gene. Many studies have reproducibly shown that about 50% of prostate cancer acquires reactivity for ERG, reflecting TMPRSS2-ERG rearrangement. About 16% of high-grade prostatic intraepithelial neoplasia (HGPIN), the noninvasive precursor to invasive cancer [205], also is ERG-positive and benign prostate never is. Tomlins et al. [206] showed that the most common rearrangement is TMPRSS2: ERG (21q22.2) followed by TMPRSS2: ETV1 (7p21.2), while TMPRSS2 (21q22):ETV4 (17q21) is rare (2% of cases). Klezovich et al. [207] established a causal role of ERG overexpression in carcinogenesis. Overexpression of ERG in prostate cell lines increased cell invasion. Targeted expression in vivo in luminal prostate epithelial cells of transgenic mice resulted in development of focal precancerous prostatic intraepithelial neoplasia (PIN) [207]. Multifocal prostate cancer can show heterogeneity of ERG expression [208]. ERG expression alone has only a marginal [209] or no [210] effect on outcome as measured by biochemical recurrence-free survival.

PTEN (phosphatase and tensin homolog deleted on chromosome 10) is a key tumor suppressor gene in prostate cancer. On the average, loss of expression of PTEN occurs in one-third of prostate cancer [211].

In one study, PTEN deletions were present in 20.2% (458/2266) of prostate cancer (8.1% heterozygous and 12.1% homozygous [212]. PTEN deletions were linked to advanced stage, high Gleason grade, presence of lymph node metastasis, hormone-refractory disease, and presence of ERG gene fusion (all P < 0.0001). PTEN deletions were associated with biochemical recurrence in both univariate (P < 0.0001) and multivariate (P = 0.0158) analyses [213]. Given these findings, many private practice urologists, I have noted, are electing to have PTEN loss study performed reflexively for their newly diagnosed cancers with Gleason scores of 3 + 3 = 6 or 3 + 4 = 7 in order to stratify the otherwise heterogeneous outcomes of these grade groups.

Lotan et al. [214] have investigated PTEN protein loss by immunohistochemistry to compare its assessment with that of FISH. PTEN immunostaining (IHC) detected up to 86% of cases with PTEN genomic loss by comparison with single-nucleotide polymorphisms. IHC was 87% sensitive for hemizygous PTEN deletion and 86% sensitive for homozygous deletion. It was also found by IHC at times in the absence of apparent genomic loss. That is, in 37% of cases in which SNP did not demonstrate PTEN loss and 45% of cases in which FISH did not demonstrate PTEN loss, it was found by immunostaining. Others have reported similar findings in comparing IHC with FISH [215, 216]. Taken together, these data suggested that PTEN inactivation can occur by means other than genomic deletion, including insertions and epigenetic changes; and PTEN detection by IHC may hold some advantage over FISH. The main drawback, however, is that IHC cannot discriminate hemizygous and homozygous loss.

While ERG expression alone is not important alone, it becomes a significant prognostic factor only when combined with PTEN loss. Kaplan-Meier analysis shows that the status of these two markers can stratify men with prostate cancer into four significantly different groups [209]. ERG and PTEN, in combination [205], define three groups of patients by prognosis: a good prognosis, ERG-/PTEN no loss (29% of cases); intermediate prognosis, ERG+/PTEN no loss or ERG-/PTEN loss (43%); and poor prognosis, ERG+/PTEN loss (28%). PTEN loss is prognostically important regardless of ERG status. The ERG group was studied in 409 patients, and in this group PTEN loss predicted initiation of secondary treatments, shortened cancer-specific survival, and stratified Gleason score of seven patients into prognostic groups. The presence of androgen receptor expression in ERG-negative cancer accentuated an adverse prognosis [217].

Intraductal carcinoma (IDC) has a unique molecular biologic profile [144]. The rates of ERG fusion and PTEN loss in IDC are at least commensurate with those of invasive carcinoma and exceed the corresponding rates for HGPIN. Fine et al. [218] found no difference in ERG translocation/deletion or copy number increase in tumors from men with or without IDC. Immunoreactivity for ERG protein, reflecting a TMPRSS2-ERG gene fusion, has been reported in 35–75% [144] of IDC but rarely or never in “atypical cribriform lesions” that fall short of IDC criteria. In the case of a topographic study using proximity to invasive cancer to discriminate IDC [219], this provides a molecular justification for topography being discriminatory. Schneider and Osunkoya found that the presence or absence of ERG reactivity in IDC always matched that of the acinar carcinoma; but the 35% rate of expression of the invasive carcinoma associated with IDC was less than that separate from IDC, suggesting that when IDC is present, the accompanying invasive component tends to have a unique phenotype [220]. ERG immunostaining may be diagnostically useful in select cases. Cytoplasmic PTEN loss has been suggested as a marker to distinguish IDC from HGPIN, being observed in 84% of IDC and 100% of lesions intermediate between IDC and HGPIN, but never in HGPIN [222]. Nuclear reactivity for PTEN may be retained in IDC. IDC’s rate of PTEN loss exceeds the 35–45% rates reported for acinar carcinoma [221,222,223,224,225] but is similar to the significantly higher PTEN loss in Gleason grades 4–5 cancer [222], supporting IDC’s aggressiveness.

Oncotype Dx

Genomic Health, Inc. produces Oncotype Dx [226], a proprietary test of prostate cancer tissue for a series of genomic alterations pertaining to four pathways that drive prostate cancer. This furnishes a Genomic Prostate Score (GPS) that is said to predict outcome after surgery, regardless of what postoperative therapy is chosen. The original development studies looked at a subset of 185 prostate cancer patients who experienced biochemical recurrence after surgery.

Testicular Neoplasms

Gross Features and Handling of the Specimen

Biopsy or frozen section assessment of testicular tumors is rarely utilized as inguinal orchiectomy is the primary procedure for clinically suspicious testicular masses and one that serves both diagnostic and therapeutic purposes. Nevertheless, for small, asymptomatic, nonpalpable testicular masses, there is literature suggesting that frozen section may guide testis sparing tumor resection [227,228,229].

Orchiectomy specimens should be bivalved and fixed in formalin shortly after receipt from the operating room. Adequate tissue fixation is critical in histologic evaluation of the different germ-cell components (e.g., the distinction of seminoma from solid pattern embryonal carcinoma), pathologic staging (e.g., accurate determination of lymphovascular invasion) and for optimal exposure of antigenic epitopes for immunohistochemical studies. The spermatic cord resection margin should be submitted first prior to sectioning of the testicular parenchyma (Fig. 16.80). Sampling should include (a) non-neoplastic testis away from the tumor and (b) sections of the tumor, including its interface with the rete testis, testicular hilum, epididymis, and testicular capsule. The precise number of sections is variable; however, given the heterogeneity of germ-cell tumors and the clinical importance of identifying different components, we recommend submitting the entire tumor if possible. In cases where no obvious tumor is seen but where a scar is noted, we recommend submitting the scar in toto. For larger tumors (e.g., >10 cm in diameter) where it is not practical to submit the tumor entirely, we recommend sampling grossly different areas with at least one section per cm of tumor.

Surgical Pathology Report and Staging

The surgical pathology report should incorporate elements of pathologic staging as well as the tumor focality, type and proportion of each histologic component, surgical (spermatic cord) margin status, presence of germ-cell neoplasia in situ, and any associated lesions in the non-neoplastic testis such as testicular scar or intratubular calcifications. Pathologic staging of testicular germ-cell tumors takes into account the anatomic extent of disease as well as levels of serum tumor markers. The presence and degree of serum elevation of the tumor markers LDH, AFP, and βhCG constitutes the “S” category. Serum markers drawn post-orchiectomy are used for assignment of the pathologic S stage. The latest revision of TNM staging by the American Joint Committee on Cancer [230] is presented below. Notably, this staging system is applicable mainly to postpubertal germ-cell tumors. Other testicular tumors, including prepubertal germ-cell tumors, spermatocytic tumors, nonmalignant sex cord-stromal tumors, and paratesticular tumors, are not staged. Hematolymphoid tumors of the testis are staged in the manner of other lymphoproliferative neoplasms.

For tumors confined to the testis, the size of the primary tumor has been shown to influence the likelihood of relapse in pure seminomas [231,232,233]. Therefore, pT1 pure seminomas are substaged as below in the most recent iteration of the AJCC staging manual. In cases where the tumor is multifocal, the size of the largest discrete macroscopic tumor focus should be recorded for assigning pT stage. Rete testis invasion is not incorporated into staging since the literature regarding the clinical value of this parameter is not well established [232, 233]. Other notable changes and additions include categorizing invasion of hilar soft tissue and/or epididymis as pT2 disease, distinguishing invasion of spermatic cord stroma as continuous with the testis primary (pT3) or via discontinuous vascular invasion (pM1). Vascular invasion within the spermatic cord but without extension into cord stroma is pT2, as with lymphovascular invasion generally (Table 16.10 and Fig. 16.81).

Table 16.10 AJCC/TNM staging system for testicular tumors (8th Ed., 2016)

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The pathologic N category applies to regional lymph nodes. Tumors of the right testis travel mainly via the interaortocaval nodes, whereas left testicular tumors disseminate via the paraaortic nodes. In the absence of scrotal or inguinal surgery that may alter the lymphatic drainage, regional lymph nodes of the testis include interaortocaval, paraaortic, paracaval, preaortic, precaval, retroaortic, and retrocaval lymph nodes. The size criteria are based on the overall size of the positive lymph node involved by tumor as determined by pathologic examination and not the size of the metastatic focus within the lymph node (Table 16.11).

Table 16.11 Regional lymph bodes (N)

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Germ-Cell Neoplasia In Situ

Clinical Features

There are several lines of evidence that germ-cell neoplasia in situ (GCNIS) is the precursor lesion for invasive germ-cell tumors. Clinically , examination of testicular biopsies in men with infertility and contralateral germ-cell tumor revealed that patients with GCNIS frequently develop invasive germ-cell tumor, whereas no case of invasive germ-cell tumor was found in patients lacking GCNIS [234, 235]. From an epidemiological standpoint, GCNIS is overrepresented in patients at risk for germ-cell tumor, including men with undescended testis [236,237,238], gonadal dysgenesis [239, 240], prior germ-cell tumor [241, 242], and infertility [243, 244]. Germ-cell neoplasia in situ is associated with the vast majority of testicular germ-cell tumors and with extra-testicular tumors, particularly germ-cell tumors of putative retroperitoneal origin [245, 246]. Histologically and immunohistochemically, the neoplastic GCNIS cells most closely resemble seminoma. Isolated GCNIS is generally asymptomatic and arises in the background of a normal to slightly atrophic testis that shows ultrasound abnormalities [247, 248]. Detection of GCNIS by biopsy is reliable in cases where this procedure is performed [249].

Pathologic Features and Ancillary Studies

Germ-cell neoplasia in situ is an intratubular neoplastic proliferation that may involve variable proportions of seminiferous tubules (Fig. 16.82) [250]. The seminiferous tubules typically show a thickened basement membrane and reduced to absent spermatogenesis [251]. GCNIS may be seen anywhere within seminiferous tubules, though most commonly in a basal distribution, where the lesional cell possesses a clear, glycogen-rich cytoplasm and thickened, enlarged nuclei with prominent nucleoli. Pagetoid spread of GCNIS may occur with extension into the rete testis and epididymis. Specialized forms of GCNIS are less commonly seen, including intratubular seminoma [252] and intratubular embryonal carcinoma [253]. These lesions show the classic morphology and immunophenotype of seminoma and embryonal carcinoma cells, except that they expand preexisting seminiferous tubules. A plethora of immunohistochemical stains label GCNIS; however, only PLAP [254] and OCT 3/4 [254,255,257] are needed in clinical practice as they selectively label GCNIS and distinguish it from mature spermatogonia, its major morphologic mimicker. GCNIS itself typically does not show amplification of 12p, although it has been reported in a subset of GCNIS associated with invasive germ-cell tumor [258].

Invasive Germ-Cell Tumors

Invasive germ-cell tumors are now dichotomized into those derived from GCNIS and those that are unrelated to GCNIS as below [259] (Table 16.12). The most characteristic, recurrent cytogenetic aberration seen in invasive germ-cell tumors derived from GCNIS is the gain of chromosomal material on the short arm of chromosome 12, often as an extra copy or isochromosome 12p (i12p) (Fig. 16.83). Assays for i(12p) may be used to elucidate the germ-cell origin of tumors and thereby guide appropriate therapy.

Table 16.12 Germ-cell tumor classification according to WHO 2016

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Seminoma

Clinical Features

Seminoma is the most common type of germ-cell tumor , occurring frequently in a pure form without other admixed germ-cell histologies. Its incidence typically peaks around age 40 with a second peak in the sixth decade of life. Similar risk factors are associated with seminoma as with GCNIS and seminomas are overrepresented in immunosuppressed patients [260] and in those with undescended testis [261]. Most patients present with a unilateral, painless testicular mass that is hypoechogenic on ultrasound. Metastatic presentation is rare and is associated with symptomatology referable to common germ-cell tumor landing sites, particularly the retroperitoneum. Serum tumor markers are not useful in detecting seminoma: there is no elevation in AFP, and the elevations in hCG, PLAP, and LDH are neither specific nor clinically useful.

Seminomas , which are highly sensitive to both radiation therapy and chemotherapy, are largely managed according to various clinical and pathologic factors. Patients with clinical stage I disease relapse in approximately 15–20% of cases [233, 262, 263]. These relapses usually occur within 18 months of orchiectomy and overwhelmingly involve the retroperitoneal lymph nodes (~95%). Given the long-term complications of adjuvant therapy, and assuming a compliant patient, the standard of care has shifted in recent years toward surveillance protocols, with close follow-up and treatment of clinical relapses. Other options include adjuvant therapy in clinical stage I tumors to reduce the rate of relapse to <5%, using either low-dose radiation therapy to the retroperitoneum or a single dose of carboplatin-based chemotherapy [264, 265]. For clinically metastatic, non-bulky disease to the retroperitoneum, radiation therapy or chemotherapy are therapeutic options, while bulky metastases to the retroperitoneum or metastases beyond the retroperitoneum to visceral organs necessitate treatment with up-front chemotherapy [266].

Pathologic Features and Ancillary Studies

The large majority of seminomas are confined to the testis showing a circumscribed, lobulated tan-brown cut surface with occasional fibrotic and necrotic foci (Fig. 16.84). Microscopically, the neoplastic cells are arranged as nests of tumor separated by fibrous septa. The tumor cells show clear cytoplasm, non-overlapping thickened nuclei with prominent nucleoli and brisk mitoses. An accompanying lymphoplasmacytic infiltrate, conspicuous at low and high magnifications, is a diagnostically useful feature. Seminomas often show granulomatous inflammation, usually focal but which occasionally can be so extensive as to camouflage the underlying neoplastic element. Syncytiotrophoblastic cells are seen associated with seminoma in ~ 10% of cases by H&E [267, 268]. Such tumors show mild elevations of B-HCG, but they carry no prognostic significance [269]. It is, however, important that isolated syncytiotrophoblastic cells not be misdiagnosed as choriocarcinoma. Seminomas can occasionally show variant histology although it is rare that this is the exclusive morphology seen as these foci are generally admixed with more typical patterns. Notable variant histologies include tumor cells arranged in a tubular architecture [270, 271] mimicking a Sertoli cell tumor or seminoma cells infiltrating between seminiferous tubules resulting in so-called intertubular growth , which is frequently grossly inconspicuous [272]. Seminomas are not graded, and stratification based on mitotic index has not proven to be prognostic [273]. Marked cytologic atypia may be seen focally within seminoma and may represent early transformation to embryonal carcinoma; however, this is not a recognized or specific pathologic entity.

Seminomas show immunohistochemical labeling for a multitude of markers, including SALL4, OCT 3/4, PLAP, CD117, podoplanin, MAGEA4, NANOG, and SOX17 [64]. In routine clinical practice, labeling for the transcription factor OCT 3/4 and the receptor tyrosine kinase CD117 (KIT) is usually sufficient in order to establish a diagnosis of seminoma in conjunction with histologic interpretation and depending on the differential diagnosis that is entertained. Cytokeratins such as CAM 5.2, though generally negative in seminoma, can show scattered positivity—a feature that, by itself, is not indicative of a nonseminomatous component. Similar to other invasive germ-cell tumors, seminomas show amplification of 12p, often with i(12p). Otherwise, recurrent genomic changes in oncogenes or tumor suppressor genes are rare, with the notable exception of the c-KIT gene that shows activating mutations or amplification in a subset of patients [274, 275].

Pathologic features that are potentially consequential include tumor size and to a lesser extent, the presence of rete testis invasion [231,232,233], which have been correlated to relapse in stage I disease and which may provide pertinent information to the treating physician in managing the patient. Rete testis invasion should be distinguished from intratubular extension of GCNIS into the rete testis.

Nonseminoma

Clinical Features

Nonseminomas are clinically distinct from seminomas. They are chemosensitive and radioresistant and frequently show mixed histologic components, and their incidence peaks around age 30. Given their common genesis from GCNIS, similar risk factors are associated with them as with GCNIS. The majority of patients present with disease localized to the testis, although metastatic presentation is more common than with seminomas and varies according to histotype (e.g., metastatic presentation of ~ 10% in embryonal carcinoma and > 50% in pure choriocarcinoma). Serum tumor markers are important in the diagnosis and management of most nonseminomas. Indeed, seminoma histology with an elevated serum AFP signifies the presence of a nonseminomatous element, and hence, the tumor is considered as a mixed nonseminoma and treated accordingly [266].

The clinical protocols used to manage nonseminomas include surveillance, surgery, and chemotherapy, depending on patient- and disease-related factors. Patients with clinical stage I disease relapse in approximately 25–30% of cases, mostly within 12 months and primarily (50–80%) to the retroperitoneum [266]. Surveillance is an option in low-risk, compliant patients with stage I disease. Adjuvant therapy protocols include a single cycle of bleomycin-/etoposide-/cisplatin-based chemotherapy or a primary retroperitoneal lymph node dissection (RPLND) using a right- or left-sided template-type dissection. Pathologic factors that augment the rate of relapse in stage I nonseminoma, and therefore influence the decision of whether or not to undertake adjuvant therapy, include the presence of lymphovascular invasion and an increased proportion of embryonal carcinoma histology [276, 277]. Clinically metastatic nonseminoma to the retroperitoneum can be managed with bilateral RPLND or chemotherapy, whereas metastasis beyond the retroperitoneum to visceral organs is treated with chemotherapy.

Pathologic Features and Ancillary Studies

Embryonal Carcinoma

Embryonal carcinoma occurs mostly as part of a mixed germ-cell tumor, rarely as a pure form [278, 279]. As such it is frequently associated with elevated serum AFP and hCG, reflecting other histologic components. Grossly, embryonal carcinomas are poorly circumscribed, showing a soft, variegated cut surface with variable hemorrhage, necrosis, and fibrosis (Fig. 16.85). Microscopically, the tumor cells may show different architectural patterns, including solid, glandular, and papillary profiles. Neoplastic cells often show a syncytial arrangement with cohesive clusters of tumor cells displaying overlapping and high-grade pleomorphic nuclei [279]. Syncytiotrophoblasts are commonly encountered in the background, and embryonal carcinoma is often the histotype that shows lymphovascular invasion. Given the aggressive nature of embryonal carcinoma, estimation of its proportion as well as lymphovascular invasion [277, 280] may be useful in managing patients. The diagnosis is generally straightforward based on H&E stain. However, it can occasionally be mistaken for seminoma in poorly fixed specimens, and yolk sac tumor may also enter the differential diagnosis.

Numerous immunohistochemical markers are positive in embryonal carcinoma including SALL4, OCT 3/4, cytokeratins AE1/AE3 and CAM5.2, NANOG, and PLAP [64, 281]. CD30 and SOX-2 are the most specific markers, and using either of these in conjunction with SALL4, OCT 3/4 and cytokeratins generally suffice in confirming the diagnosis of embryonal carcinoma in the testis where it must be differentiated from other germ-cell histologies (e.g., seminoma, yolk sac tumor) or at a metastatic site, where it must be distinguished from somatic, non-germ-cell tumors (carcinoma, lymphoma) [281]. Assays for i(12p) may be useful in establishing the germ-cell origin of embryonal carcinoma in cases where the clinical or pathologic findings are equivocal [282].

Yolk Sac Tumor

Yolk sac tumor shows differentiation toward extraembryonic yolk sac, allantois, and mesenchymal elements. It occurs in the pediatric and postpubertal age groups as two distinct diseases. Prepubertal yolk sac tumor peaks between 1 and 2 years of age, is usually not admixed with other germ-cell histotypes [283, 284], shows no racial predisposition, is unassociated with GCNIS [285] or i(12p) [286], and rarely behaves aggressively. Notably, metastases may spread by both lymphatic and hematogenous routes and are successfully managed by chemotherapy [287].

Adult postpubertal yolk sac tumor generally occurs in the second to fourth decades of life and is virtually always associated with GCNIS and with other germ-cell tumor elements, occurring as a pure form in less than 1% of cases [288, 289]. It shows higher incidence in Caucasians, is associated with i(12p), and is treated as a nonseminomatous germ-cell tumor. Yolk sac tumor histology portends a relatively favorable prognosis when presenting within the testis [290]; given its chemotherapy resistance, however, it worsens prognosis at a metastatic site [291]. Yolk sac tumor exhibits myriad architectural patterns including reticular, microcystic, endodermal sinus (perivascular, festoon), polyvesicular vitelline, macrocystic, papillary, glandular-alveolar, solid, hepatoid, clear cell, parietal, and sarcomatoid profiles. The extracellular stroma frequently shows eosinophilic basement membrane-like material and hyaline globules, while the tumor cells are relatively bland, with far less pleomorphism compared to embryonal carcinoma. Schiller-Duval bodies are notable in that they are composed of a papillary core, containing a central small vessel and ringed by malignant cuboidal and columnar cells [66, 292]. Schiller-Duval bodies are only seen in a minority of yolk sac tumors and are not needed for diagnosis (Fig. 16.86).

Yolk sac tumors label for SALL4, cytokeratins AE1/AE3 and CAM5.2, glypican 3, AFP, alpha-1 anti-trypsin, CD117, and PLAP [47, 55, 64, 281]. SALL4 [293, 294] and glypican 3 [295, 296] are the most useful positive markers, whereas OCT 3/4 is the most useful negative marker in routine practice where yolk sac tumor must be differentiated from other germ-cell histologies (e.g., embryonal carcinoma, teratoma, seminoma) within the testis or at a metastatic site, where it must also be distinguished from somatic, non-germ-cell carcinoma. Assays for i(12p) may be useful in confirming germ-cell lineage in the latter instance. Serum alpha-fetoprotein levels are markedly elevated with yolk sac tumor histology [297] and are useful for monitoring disease.

Teratoma

Teratoma differentiates toward somatic structures, with structures recapitulating ectodermal, endodermal, and mesodermal lineages (Fig. 16.87). It is divided into prepubertal and postpubertal types based on a host of clinical, pathologic, and genetic parameters. Prepubertal teratoma generally presents in the pediatric age group where it may be associated with congenital anomalies (Down’s or Klinefelter’s syndrome ), without any racial predisposition, and unassociated with GCNIS [298], testicular scarring, calcifications, or i(12p) [64]. It generally shows mature histology without cytologic atypia or concomitant non-teratomatous elements and with a diploid DNA content [299]. Prepubertal teratomas may also be seen in a postpubertal age group [300, 301] as with epidermoid [302, 303] and dermoid cysts [304] and well-differentiated neuroendocrine tumors/carcinoids that are now subsumed under the category of prepubertal teratoma [259]. Regardless of age, prepubertal type teratomas follow an indolent clinical course [305].

Postpubertal teratomas present in adults and are similar to adult nonseminomas: they are associated with GCNIS, predominate in Caucasians, and show the i(12p) aberration. Postpubertal teratomas may present as a cystic mass lesion, showing mature and immature elements, and cytologic atypia and are frequently admixed with non-teratomatous germ-cell histologies [289]. Similar allelic losses have been demonstrated in teratomatous and non-teratomatous elements in a mixed germ-cell tumor [306], consistent with the relatedness of these histologies. Postpubertal teratomas have malignant potential with a capacity to metastasize irrespective of histologic maturity or immaturity [306,307,309].

Immunohistochemical labeling of teratomas generally reflects the lineage toward which the teratoma has differentiated. Hence, ectodermal and endodermal elements would label for epithelial markers, whereas mesodermal foci would label for mesenchymal markers. Markers of germ-cell lineage such as SALL-4 will also label teratomas, in contrast to most somatic, lymphoid, and mesenchymal tumors. However, one caveat is that SALL-4 labeling of more differentiated germ-cell tumors such as teratoma is weaker than other germ-cell tumor histotypes.

Trophoblastic Tumors

Testicular tumors that differentiate toward a trophoblastic lineage are divided into choriocarcinomas and non-choriocarcinomatous trophoblastic tumors , according to the recent WHO 2016 consensus. Choriocarcinomas typically present in the third and fourth decades and virtually always occur as part of a mixed germ-cell tumor and very rarely in isolation (Fig. 16.88) [310, 311]. It is an aggressive phenotype that may both metastasize and also regress within the testis. Notably, its metastatic route is typically hematogenous, rather than lymphatic as with other germ-cell tumor types, with metastases described in visceral organs such as the lung, liver, gastrointestinal tract, and brain [309,310,312]. Histologically, it shows a hemorrhagic focus on low power lined by a mixture of mononucleated cytotrophoblasts and multinucleated syncytiotrophoblasts that elaborate β-HCG. Serum levels of β-HCG are generally markedly elevated [310] and given the homology of β-HCG to LH and TSH may result in the clinical manifestations of gynecomastia and hyperthyroidism, respectively. Immunohistochemical labeling of neoplastic trophoblasts for β-HCG, human placental lactogen (HPL), and GATA-3 may be used as ancillary tests in the appropriate clinical and histological background.

Rarer non-choriocarcinomatous trophoblastic tumors include placental site trophoblastic tumor, epithelioid trophoblastic tumor, and cystic trophoblastic tumor. These mainly occur as metastatic deposits in patients who have been treated with germ-cell tumor chemotherapy regimens, though they can also arise in the treatment-naïve setting within the testis. These tumors are relatively chemoresistant; however, similar to teratoma post-chemotherapy, their malignant potential is limited, and surgical extirpation of these lesions is the favored approach. Cystic trophoblastic tumor , often associated with teratoma and without marked elevation in serum β-HCG, represents the most common histologic type among this family: it shows cystic spaces containing fibrinous material and lined by neoplastic trophoblastic cells with a vacuolated cytoplasm [313]. Given the rarity of placental site trophoblastic tumor and epithelioid trophoblastic tumor in the testis, the reader is referred to the gynecological pathology sections of the textbook for a detailed morphological and immunohistochemical characterization of analogous tumors of the female genital tract.

Metastatic Germ-Cell Tumors

Clinical Features

The pattern of metastatic spread is influenced by germ-cell tumor type and tumor laterality, with discrepant histology possible between the testis and metastatic site, especially post-chemotherapy. Moreover, a large metastatic tumor burden may be associated with a minute testis lesion, due to the propensity of germ-cell tumors to regress within the testis leaving few or no traces of their origin on clinical and radiological examination. This regression phenomenon may leave behind only a histologic scar in the testicular parenchyma, a feature historically referred to as a “burnt out” germ-cell tumor (Fig. 16.89). Not all testicular scars represent regressed germ-cell tumor, however, and features that are thought to be more specific for regression include the presence of GCNIS and associated stigmata, such as reduced spermatogenesis and the presence of bulky intratubular calcifications. Due to an enhanced appreciation of the regression phenomenon, retroperitoneal germ-cell tumor without an obvious primary source is now thought to uniformly represent metastases from regressed testicular primaries.

Surgical pathologists are asked to evaluate metastatic germ-cell tumors in the treatment-naïve and post-therapy settings. In the treatment-naïve patient with metastatic tumor, establishing a germ-cell origin is crucial, in view of the efficacy of therapies for advanced germ-cell tumors. The clinical background is first considered, but it may not be conclusive in patients without an obvious testicular mass or without elevations in serum tumor markers or with non-specific elevations thereof. Histology may also not be definitive in biopsy material, particularly given the overlapping features of germ-cell tumor with non-germ-cell tumor histologies.

Patients with metastatic germ-cell tumor treated with chemotherapeutic regimens may present with a radiologically detected mass in the retroperitoneum without elevated serum tumor markers or a so-called residual mass . The clinical management of residual masses differs according to whether the original tumor was a seminoma or nonseminoma. Residual masses arising from treated seminomas are observed unless they are larger (>3 cm) in which case they are evaluated by PET scan. Metabolically active masses by PET scan may be treated, usually by second-line chemotherapy. Residual masses derived from treated nonseminomas, however, are almost uniformly treated assuming that the mass is >1 cm in diameter. The therapeutic modality that is applied is the so-called post-chemotherapy RPLND, a relatively demanding surgical procedure wherein the urologist resects as much of the residual mass as feasible in the face of post-chemotherapy desmoplasia.

Pathologic Features and Ancillary Studies

The pathological features of surgically resected residual masses may be broadly divided into three categories (Fig. 16.90). The first category is an absence of viable tumor cells with inflammation, fibrosis, or coagulative necrosis of neoplastic cells after chemotherapy. These patients show a low risk of relapse (<10%) and no further treatment is indicated. The second diagnostic category consists of residual masses showing teratoma-type histology. Postpubertal teratomas are malignant from the outset and may show further cytologic atypia in the posttreatment setting. Nevertheless they generally show a relatively indolent clinical course, with a 10–15% risk of recurrence. Given their low recurrence risk and because they usually recur as teratomas, the indicated treatment is complete surgical resection. The third category comprises residual masses showing viable, non-teratomatous histology such as yolk sac tumor or embryonal carcinoma. These may pose a diagnostic challenge because of variant morphology post-chemotherapy (notably among yolk sac tumors) and due to the differential diagnosis of teratoma with atypia. Moreover, traditional immunohistochemical markers used to distinguish germ-cell tumor (e.g., CD30, OCT 3/4) are less sensitive in the post-chemotherapy setting [314, 315]. Notwithstanding the foregoing caveats, the diagnosis of non-teratomatous germ-cell tumor is vital, since it portends aggressive behavior and necessitates additional chemotherapy, including high-dose regimens with stem-cell rescue.

Fortunately, the accumulated experience with a group of newer tissue-based markers has facilitated the task of establishing germ-cell tumor origin and discriminating between different categories of germ-cell tumor. SALL4 is a zinc finger transcription factor important in embryonic development that shows broad immunoreactivity in germ-cell tumor. Though not specific for any germ-cell tumor subtype, it shows high sensitivity: for example, SALL4 has been reported to be more sensitive than AFP and glypican 3 in detecting yolk sac tumors. Hence, SALL4 is an appropriate marker to screen for germ-cell tumor lineage as it will label germ-cell tumor in contrast to immunonegativity for somatic carcinomas, lymphoid and mesenchymal tumors, as well as testicular non-germ-cell tumor [316]. It is not absolutely specific or sensitive, however, as a small subset of somatic carcinomas have shown SALL4 reactivity [316], and moreover, SALL-4 tends to show stronger staining in less-differentiated germ-cell tumors such as seminoma, embryonal carcinoma, and choriocarcinoma and weaker staining in the better-differentiated teratoma and spermatocytic tumor. OCT 3/4 is another transcription factor that has greater specificity than SALL4. OCT 3/4 acts downstream of SALL4 and regulates embryonic stem-cell function, and its expression is restricted to a subset of germ-cell tumors, namely, embryonal carcinoma, seminoma, and GCNIS. SOX2 is the most specific of the transcription factors regulating embryonic stem-cell function in that it is expressed by the embryonal carcinoma phenotype.

Occasionally, a tumor will manifest with both germ-cell and somatic (non-germ cell) tumor elements. When the somatic component exists in pure form and spans at least one low-power 5 mm microscopic field, it is considered to have overgrown the germ-cell element [317] and thus to represent so-called somatic transformation (Fig. 16.91). This phenomenon is generally, though not exclusively, seen in post-chemotherapy residual masses [318], where they augur a very poor prognosis. The germ-cell component is virtually always teratoma [319], though yolk sac tumor and spermatocytic tumor have also been reported [318, 320]. The somatic component is more likely to show sarcoma (e.g., rhabdomyosarcoma) [321, 322] or primitive neuroectodermal tumor (PNET) histology [323, 324] rather than carcinoma or hematolymphoid histology [319], and the cytogenetic aberrations often reflect the transformed element. The germ-cell origin of the somatically transformed element, however, may be established by the clinicopathologic background as well as identification of i(12p).

Late Relapse of Germ-Cell Tumors

Clinical Features

Most testicular germ-cell tumors relapse quickly, usually within 24 months. A minority (<5%) will relapse later, with nonseminoma showing a slightly higher incidence [325]. If relapse occurs 2 years after therapy with complete response and without a contralateral tumor, it is defined as a so-called late relapse of germ-cell tumor [326]. According to a large series at MSKCC, the median time to late relapse is 6.9 years (range 2.1–37.7 years) with the retroperitoneum as the most common anatomic site for relapse (~ 75%), followed by the lung and visceral organs [327]. Clinical outcome is generally poor and is strongly associated with a history of prior chemotherapy with a 93% 5-year cancer-specific survival in chemotherapy-naïve patients versus 49% 5-year cancer-specific survival in chemotherapy-treated patients [327]. Surgical excision is the preferred treatment approach [328], with various chemotherapeutic regimens also considered in nonsurgical cases [325].

Pathologic Features and Ancillary Studies

The accumulated pathologic data from North American and European cohorts has shown that teratoma and yolk sac tumor are the most prevalent histologies in late relapse of testicular germ-cell tumor [329]. Yolk sac tumors show myriad morphologic patterns including glandular, parietal, clear cell variants and may be mixed with other germ-cell tumor types (Fig. 16.92). Pure teratoma is associated with a significantly better prognosis compared to teratoma with somatic malignancy or non-teratomatous germ-cell tumor [329].

Spermatocytic Tumor

Clinical Features

The WHO 2016 has replaced the historical appellation and misnomer “spermatocytic seminoma” with “spermatocytic tumor. ” This is appropriate given that spermatocytic tumor is not particularly related to seminoma: it is commonly encountered in the sixth decade without elevated tumor markers or predilection for Caucasians, is seen only in the descended testis, and is unassociated with GCNIS or with other germ-cell tumor, and it lacks the i(12p) aberration. Furthermore, spermatocytic tumor virtually always follows an indolent clinical course, with only rare examples of aggressive behavior. If associated with sarcomatous transformation, however, metastatic spread and cancer-specific mortality is common.

Pathologic Features and Ancillary Studies

Spermatocytic tumor shows a lobular, tan cut surface. Tumor-associated cysts and necrotic foci may as well be seen. Microscopically, the architecture of spermatocytic tumor is solid to nodular with little intervening stroma and without a conspicuous inflammatory infiltrate. The neoplastic cell population characteristically shows three tumor cell types: small diameter cells with condensed chromatin; intermediate diameter cells with more abundant cytoplasm and more open, so-called “spireme” chromatin with prominent nucleoli; and giant cells with increased cytoplasmic volume and occasional multilobated nuclei. Spermatocytic tumor may rarely dedifferentiate to a sarcoma, usually rhabdomyosarcoma.

The immunohistochemical profile of spermatocytic tumor recapitulates the spermatogonia/spermatocyte stage (Fig. 16.93). Hence, tumor cells are immunoreactive for SALL4, CD117, and MAGE4 but immunonegative for stem-cell marker OCT 3/4 and the GCNIS-associated marker PLAP. The most characteristic recurrent genomic abnormality is amplification at 9p21.3, leading to copy number gain involving the DMRT1 gene and overexpression of the DMRT1 protein.

Testicular Sex Cord-Stromal Tumors

Leydig Cell Tumor

Clinical Features

Leydig cell tumors , comprising 1–3% of testicular tumors, are the most common sex cord-stromal tumor of all ages and the most common in prepubertal boys and young adults. Most tumors are diagnosed incidentally though patients may present with a palpable, painless mass. Prepubertal boys with androgen-producing tumors may present with precocious puberty. Whereas young adults with hormone-producing tumors are asymptomatic [330]. Surgical resection is the primary treatment of choice. The clinical outcome is excellent as only about 10% of cases are malignant [330]. For malignant cases, BEP-based chemotherapy is used as for germ-cell tumors.

Pathologic Features and Ancillary Studies

Leydig cell tumors are usually well-circumscribed masses with a yellow to tan cut surface, ranging from 1 to 10 cm (average 3 cm (Fig. 16.94a)). Extension to paratesticular soft tissue has been reported in 10% of cases and is not necessarily indicative of malignancy. Necrosis and hemorrhage, however, are uncommonly seen and could be signs of aggressive disease. Microscopically, the tumor is composed of polygonal cells with abundant eosinophilic cytoplasm (Fig. 16.94b, c). Leydig cell hyperplasia can be seen associated with the tumor. Nuclei are small to medium sized with central nucleoli. Reinke crystals and lipofuscin pigment can be seen in the cytoplasm of tumor cells. There are several histological variant growth patterns: solid, cordlike, spindled, pseudo glandular, adipose-like, and microcystic. Sarcomatoid transformation can be seen in malignant cases. The features suggestive of malignancy include large size (>5 cm), cytological atypia, increased mitoses, necrosis, lymphovascular invasion, and capsular invasion; however, metastasis is the only definitive criterion for malignancy [132]. Immunohistochemically, neoplastic cells are diffusely positive for inhibin, calretinin, and melan-A (Fig. 16.94d, e) and are negative for cytokeratins.

The differential diagnosis includes Leydig cell hyperplasia, which is much smaller in size (0.5 cm) and multifocal with intervening seminiferous tubules. Testicular tumor of the adrenogenital syndrome is usually multinodular and bilateral. Tumor cells show pigmentation, pleomorphism with prominent hyalinized stroma, and entrapped seminiferous tubules. Adrenal rests usually form microscopic foci consisting of small round cells with clear to eosinophilic bubbly cytoplasm; and metastatic carcinoma such as high-grade prostatic adenocarcinoma and melanoma metastatic to the testis can also mimic Leydig cell tumors. Metastatic tumors are usually bilateral with high-grade features cytologic and clinical history is crucial to make a definitive diagnosis [132].

Sertoli Cell Tumor

Clinical Features

Sertoli cell tumors constitute less than 1% of testicular tumors. They mostly affect adults with approximately 10% occurring in children [331]. Most patients present with a painless testicular mass. Infrequently, patients can present with gynecomastia. Some cases are associated with androgen insensitivity syndrome, Carney syndrome, and Peutz-Jeghers syndrome. The clinical outcome is excellent unless metastasis occurs [332] (Fig. 16.95e, f). Surgical resection is the primary treatment of choice.

Pathologic Features and Ancillary Studies

Tumors are generally small and well circumscribed, homogeneous, yellow to gray white in color with a lobulated cut surface. Necrosis is rarely seen [333]. Microscopically , tumors show solid, tubular, and cord-like growth, round to ovoid or spindle-shaped nuclei with eosinophilic or clear cytoplasm, and centrally located nucleoli (Fig. 16.95a, b). Mitotic count is low and cytological atypia is rarely seen. The stromal component can vary from scant to hyalinized, sclerotic to edematous [333]. Charcot-Bottcher filaments (perinuclear arrays of filaments) are considered pathognomonic of Sertoli cell differentiation. Large tumor size (>5 cm), increased mitoses, necrosis, infiltration of adjacent structures, and lymphovascular invasion are associated with aggressive behavior. Immunohistochemically, tumor cells are positive for cytokeratin, EMA, inhibin, (Fig. 16.95c, d) and vimentin; tumor cells can be focally positive for CD30 and OCT 3/4.

The main differential diagnosis is Leydig cell tumor, which usually shows solid growth with cells containing abundant eosinophilic cytoplasm and lack of a tubular growth pattern. Leydig cell tumors are negative for cytokeratin. Seminoma with tubular pattern [334] also enters the differential diagnosis. Classic seminoma is composed of large cells with clear cytoplasm, prominent nucleoli, and lymphocytic infiltrate. Seminoma cells are positive for CD117, PLAP and negative for inhibin and cytokeratin. Adenomatoid tumor can present as an incidental finding with small, well-circumscribe nodules. However, they are mostly located in the paratesticular tissue, and tumor cells are negative for inhibin. Sertoli cell nodules are small (<5 mm) and usually have thickened bands of basement membrane material separating Sertoli cells.

Large-Cell Calcifying Sertoli Cell Tumor

Clinical Features

A variant of Sertoli cell tumor with large polygonal Sertoli cells and prominent calcifications, it is an extremely rare entity with only around 60 cases reported [335]. The age ranges from 2 to 50 years (mean age: 21 years) and patients present with slowly enlarging, painless testicular masses. Other symptoms include acromegaly, hypercortisolism, gynecomastia, and precocious puberty in children; rarely, it is associated with cardiac myxoma and sudden death. Over 50% of cases presented bilaterally or multifocally. About 60% are sporadic, and one-third of the cases are associated with Carney or Peutz-Jeghers syndromes [336]. Radical orchiectomy is the treatment of choice. About 20% cases may have malignant behavior. Malignant cases are usually in older patients (mean 39 years) and are more often unilateral and solitary compared to benign tumors [337].

Pathologic Features and Ancillary Studies

Tumors are usually small in size (<4 cm, average 2 cm) well circumscribed, with a white-tan or yellow cut surface associated with calcifications or ossifications. Tumor shows nests, cords, trabeculae, or solid growth pattern with large polygonal or round tumor cells and abundant eosinophilic or granular cytoplasm. Occasionally, tumor cells are cuboidal or columnar in shape. Tumor cells have vesicular nuclei and prominent nucleoli. Mitotic figures are rarely seen in benign lesion. Tumor cells are separated by myxoid to hyalinized fibrous stroma with neutrophils. Large, laminated calcifications are a hallmark of this tumor [336, 338] (Fig. 16.96a, b). Small psammoma bodies and ossification can be seen. Some features are associated with malignancy: large size (>4 cm), marked nuclear atypia and increased mitosis (>3/10HPF), necrosis, lymphovascular invasion, and invasion into adjacent structures. Tumors with more than two features are diagnostic of malignancy [339]. Tumor cells are positive for inhibin, vimentin, EMA, Melan-A, NSE, S100, and desmin. Tumor cells are negative for cytokeratin, AFP, HCG, and Oct3/4.

Leydig cell tumor is in the differential diagnosis. Leydig cell tumors have a more solid growth pattern without fibrous stroma and the hallmark calcifications. Bilateral tumors are rarely seen in Leydig cell tumors. Sertoli cell tumors lack the large cells, calcification, and eosinophilic infiltration in the stroma. It is also rarely bilateral, which is seen in 50% of large-cell calcifying Sertoli cell tumor . A rare entity, tumor of adrenogenital syndrome also comes into differential, which shows more solid growth and no calcifications.

Sclerosing Sertoli Cell Tumor

Clinical Features

A rare variant of Sertoli cell tumor with prominent sclerosis . Patient’s age ranges from 18 to 80 years (mean 35 years) and presents with painless testicular nodule or mass [340]. Surgical resection is the primary treatment of choice. Most patients are cured after orchiectomy [340].

Pathologic Features and Ancillary Studies

Tumors are usually small (mean 1.5 cm), unilateral, well-circumscribed masses with solid white to yellow-tan cut surface [340]. Prominent dense sclerotic stroma (over 50% of the tumor) with cords, trabeculae, small nests, or focal tubules of Sertoli cells are seen. Tumor cells have small, round, oval to polygonal nuclei, pale eosinophilic cytoplasm and rare mitosis. The reported malignant case was large in size (3.8 cm) with lymphovascular invasion and lack of circumscription [340]. Tumor cells stain as Sertoli cells , positive for inhibin, cytokeratin, and vimentin. A recent study suggests that the tumor cells are positive for beta-catenin [341, 342].

Carcinoid tumor of the testis is uncommon and falls in the differential diagnosis. Carcinoid tumor shows insular and trabecular growth patterns without dense sclerotic stroma. Immunohistochemically, carcinoma tumor cells are positive for chromogranin and synaptophysin and are negative for inhibin.

Granulosa Cell Tumor

Clinical Features

Granulosa cell tumor is a sex cord-stromal tumor occurring in adult testis that resembles the ovarian counterpart; it is an extremely rare tumor with less than 50 cases reported in the literature [343]. The age ranges from 14 to 87 years (mean 40 years). Patients present with painless testicular mass, or with gynecomastia. Radical orchiectomy is the treatment of choice and most cases are cured after surgery. Metastases have been reported in up to 20% of cases, and long-term follow-up is warranted for all patients [344]. Overall, the role of chemotherapy and radiation therapy is less clear [345, 346].

Pathologic Features and Ancillary Studies

Tumor is well circumscribed, sometimes encapsulated . Tumor measures 0.5–6.0 cm (mean 2.8 cm). Cut surface is tan-yellow and homogeneous. Necrosis is uncommonly seen [347]. Like its ovarian counterpart, tumor shows diffuse growth with variable growth patterns including microfollicular, insular, spindled, trabecular, macrofollicular, gyriform, and solid. Cystic formation can be seen. Tumor cells are round or ovoid with scan cytoplasm and indistinct cellular borders. The nuclei is elongated or angulated with longitudinal nuclear grooves and peripherally located nucleoli. Most tumors contain limited amounts of fibrocollagenous stroma. Mitosis, necrosis, and nuclear polymorphism are rare in benign cases. The presence of Call-Exner bodies (eosinophilic material surrounded by palisading granulosa cells) is pathognomonic for this entity. Features associated with malignant behavior include large size (>4 cm), increase mitosis (>5/10HPF), necrosis, hemorrhage, infiltrative borders, and lymphovascular invasion [347]. Tumor cells are immunopositive for inhibin, vimentin, calretinin, Melan-A, and CD99. Tumor cells can be focally positive for cytokeratin [347]. Tumor cells are negative for EMA, Sall4, Oct3/4, and HCG.

Tumors with scant cytoplasm and relatively uniform nuclei, such as lymphoma, small-cell carcinoma, and carcinoid tumor, are in the differential diagnosis. Lymphomas are a systemic disease and frequently affect other organs or the contralateral testis. Lymphoma cells are discohesive and positive for lymphoma markers (CD45) and negative for cytokeratin. Small-cell carcinoma in the testis is exceedingly rare with tumor cells showing high mitotic count, apoptosis, cell molding, and salt pepper chromatin. Small-cell carcinomas are positive for synaptophysin and chromogranin and negative for inhibin. Carcinoid tumor typically shows nest, insular, or trabecular growth pattern with uniform cells that are positive for neuroendocrine markers (synaptophysin, chromogranin). Other sex cord-stromal tumors can also be in the differential diagnosis. Leydig cell tumors show solid growth with round to polygonal cells, abundant eosinophilic cytoplasm, round centrally located nuclei and prominent nucleoli; the cells may contain crystal of Reinke, which are not seen in adult granulosa cell tumor. Sertoli cell tumor shows tubular, nested growth with clear to lightly eosinophilic cytoplasm, large vesicular nuclei and centrally located nucleoli, and the lack of microfollicular pattern of adult granulosa tumor; tumor cells are positive for cytokeratin [347].

Juvenile Granulosa Cell Tumor

Clinical Features

Juvenile granulosa cell tumor is a rare benign testicular gonadal stromal tumor. Patients are typically younger than 4 years with over 60% of cases occurring before 6 months of age; however, rare cases of adolescent and adult patients have been reported. It is the most common cause of testicular enlargement in newborns younger than 6 month. Other presentations include testicular mass and rarely gynecomastia. About 20–30% cases are associated with undescended or dysgenetic gonads [348,349,350]. Surgical resection including radical orchiectomy and enucleation/wedge resection is the primary treatment of choice. The clinical outcome is excellent with no reported recurrences or metastases in the literature [351].

Pathologic Features and Ancillary Studies

Tumors are usually well circumscribed, cystic (about 2/3) to entirely solid with yellow-tan cut surface, ranging in size from 0.8 to 5 cm (mean 1.7 cm) [352]. Tumor shows lobular growth with cysts lined by multilayered cells, mimicking follicular differentiation. Tumor cells are small to medium in size with round to oval nuclei, inconspicuous nucleoli, and variable amount of lightly eosinophilic cytoplasm. Nuclear grooves are rarely seen. Call-Exner bodies can be seen. The stroma is fibrotic or loosely myxoid; hemorrhage and hemosiderin-laden macrophage can be seen. The cyst contents are amorphous proteinaceous and can be mucinous. In the non-cystic area, tumor cells show diffuse or cord-like growth pattern. Intratubular tumor growth has also been reported. Mitosis and apoptosis are seen in approximately 40–50% of cases [348, 352].

Tumor cells are immunopositive for inhibin, calretinin, WT-1, SF-1, vimentin, cytokeratin, and SOX-9. Tumor cells are negative for Sall-4 and glypican 3 [348, 353].

The main differential diagnosis is yolk sac tumor. Juvenile granulosa cell tumor patients are mostly less than 6 months old, whereas yolk sac tumor patients are older (peak age 16–17 months). Grossly, prepubertal yolk sac tumor lacks cystic appearance that is seen in over 50% of juvenile granulosa cell tumor. Microscopically, yolk sac tumor shows microcystic, macrocystic, or reticular growth pattern, lacking the follicle-like growth pattern in juvenile granulosa cell tumor. Schiller-Duval bodies in yolk sac tumor are not seen in juvenile granulosa cell tumor. In difficult cases, immunohistochemical studies are helpful. Juvenile granulosa cell tumors are positive for inhibin , calretinin, and SF-1 while negative for Sall4, glypican-3, and vice versa for yolk sac tumor. Rarely, AFP can be positive in juvenile granulosa cell tumor [352].

Fibrothecoma

Clinical Features

Fibrothecoma is an extremely rare sex cord-stromal tumor of the testis. Patients present with testicular mass or heaviness in the scrotum without hormonal alterations. The mean age at diagnosis is 44 years (16–69 years) [354]. Surgery includes radical orchiectomy, and partial orchiectomy/enucleation is the treatment of choice. Despite some worrisome histological features, fibrothecoma seems to be uniformly benign [354, 355].

Pathologic Features and Ancillary Studies

Tumors are usually well-circumscribed masses with yellow to white cut surface, ranging 0.5–7.6 cm (median 2 cm). Necrosis and hemorrhage are not seen [354, 355]. Tumor shows storiform pattern and/or short fascicles and hypercellular. Tumor cells have scant cytoplasm, plumped ovoid, or spindled pointed nuclei and inconspicuous nucleoli. Mitosis ranges from 0 to 10/ HPFs. Atypical mitoses are not seen. Collagen deposition either in bands or investing single cells ranges from non to extensive, small blood vessels are seen in the stroma [354, 355]. Tumor cells are immunopositive for inhibin and show variable positivity for calretinin, pancytokeratin, BCL-2, S100, desmin, and Melan-A [355].

Differential diagnoses include other more common sex cord-stromal tumors including Sertoli cell tumor. Sertoli cell tumor shows variable growth pattern, such as solid, tubular, and cord-like. The tubular structure observed in Sertoli cell tumors in not seen in fibrothecomas. Tumor cells in Sertoli cell tumors are ovoid and rarely spindled; in contrast, fibrothecomas often show a mixture of spindle and ovoid cells. Other differential diagnosis is granulosa cell tumor, a rare occurrence in the testis. Typical growth pattern for granulosa cell tumor is microfollicular, gyriform insular, and trabecular with round cells, eosinophilic cytoplasm, oval nuclei, and characteristic nuclear groove [354, 355].

Gonadoblastoma

Clinical Features

Gonadoblastoma is a tumor composed of mixture of seminoma-like large germ cells and small sex cord tumor cells resembling Sertoli or granulosa cell tumors. It is an exceeding rare tumor in the testis [356, 357]. Tumor usually arises in dysgenetic patients with an intersex syndrome with 80% phenotypically female and 20% male. XY gonadal dysgenesis or 45X, 46XY mosaic can be seen [358]. Patients are typically younger than 20 years with cryptorchidism, hypospadias or other ambiguous genitalia, and gynecomastia. Some cases are associated with Turner syndrome [359, 360]. Bilateral gonadectomy is the treatment of choice and often curative. Even when malignant components are present. Both seminoma and nonseminomatous germ-cell tumor can arise from gonadoblastoma [361].

Pathologic Features and Ancillary Studies

Grossly, the tumor displays rounded or irregularly shaped tumor nodules with gray to brown, soft or firm cut surface, up to 8 cm in size [356]. Tumor typically shows nested growth pattern with a mixture of two types of cells: seminoma-like large tumor cells with pale cytoplasm, central nuclei, and prominent nucleoli and sex cord-like small cells with eosinophilic, dark cytoplasm, and hyaline material, located at the peripheral of the nests. Call-Exner bodies and calcification can be seen. Adjacent seminiferous tumor shows germ-cell neoplasia in situ. Germ-cell tumor component may overgrow and obliterate the sex cord-like component [356]. The germ-cell tumor component is positive for Sall4, oct3/4, CD117, and PLAP. The sex cord-like component is positive for inhibin, calretinin, vimentin, and Melan-A. Recent studies have suggested the expression of SOX9 and FoxL2 in the sex cord component [362].

Classic seminoma is in the differential diagnosis. Clinically, patients are older (35–45 years) and are not associated with dysgenetic gonad. Microscopically, tumor lacks the sec cord-like component. Unclassified sex cord-stromal tumors are also in the differential and microscopically lack the germ-cell component. Sex cord-stromal tumor with annular tubules is an extremely rare tumor in testis. It lacks the germ-cell component and frequently associated with Peutz-Jeghers syndrome.

Stromal Tumor of Testis: Unclassified

Clinical Features

Stromal tumor of testis, unclassified, represents cases not showing a specific histologic differentiation. The incidence is rather low and variable, more common in children (30% in less than 1 year) with painless, unilateral testicular mass. About 15% of cases present with hormonal symptoms such as gynecomastia [138, 363]. Surgical resection is the treatment of choice and is often curative. Tumor is almost always benign in prepubertal children and has a 20% chance of being malignant in adult patients. In malignant cases, radical orchiectomy and retroperitoneal lymph nodes dissection are recommended [364].

Pathologic Features and Ancillary Studies

Tumors are usually well circumscribed, lobulated with white to yellow cut surface. Cystic changes may be seen; however, hemorrhage and necrosis are uncommon. This neoplasm is composed of undifferentiated and unclassifiable epithelioid and spindle-cell components. The epithelioid component shows tubular or solid growth patterns with round to ovoid cells, eosinophilic, amphophilic or vacuolated cytoplasm, prominent nucleoli, and occasional nuclear grooves. Call-Exner like bodies can be seen. Cells lining the tubules resemble Sertoli cells. The spindle-cell component is usually hypercellular, forming fascicles with nuclear grooves; stroma can be hyalinized [363]. Features of malignancy include cytological atypia, nuclear pleomorphism, increased mitotic activities, lymphovascular invasion, and necrosis [363]. Tumor cells stain like sex cord-stromal cells with immunopositivity for inhibin, vimentin, and S100. Tumor cells are negative for Sall4, PLAP, and Oct ¾ [365].

Differential diagnoses include other sex cord-stromal tumors such as adult granulosa tumor. Adult granulosa tumor is more homogeneous with well-formed Call-Exner bodies and prominent nuclear grooves. Another differential diagnosis is Sertoli cell tumor which demonstrates more prominent tubular growth pattern and lacking the spindle-cell component. Sarcoma is also in the differential. However sarcoma demonstrates higher degree of pleomorphism and mitotic activities and involves more paratesticular tissue than intraparenchymal. Immunohistochemically, sarcomas are negative for inhibin. Mix germ-cell tumor with immature teratoma component is in the differential diagnosis. Mix germ-cell tumor often shows other components and is positive for Sall4 and other germ-cell markers [366].

Ovarian Epithelial-Type Testicular Tumor

Clinical Features

Ovarian epithelial type testicular tumor is a group of rare tumors in the testis resembling surface epithelial tumors of the ovary [367]. Patients present with painless testicular mass or swelling with a wide age range (14–68 years). Surgical resection is the primary treatment of choice. Adenomas and borderline tumors have good prognosis; however, carcinomas can develop metastasis to a leading to poor prognosis.

Pathologic Features and Ancillary Studies

Tumors are usually cystic grossly with microscopic features that are identical to their ovarian counter parts, commonly are serous carcinoma, endometrioid carcinomas, mucinous cystadenomas, and borderline tumors. Rare cases of cystadenocarcinomas , clear cell carcinomas and Brenner tumors have also been reported [368,369,370,371,372]. Tumor cells stain similarly to their ovarian counterparts. The main differential diagnosis is papillary mesothelioma. Mesotheliomas are positive for calretinin, WT-1, D240, and CK5/6 and negative for Ber-Ep4 and B72.3. Metastatic adenocarcinoma is also in the differential diagnosis. Clinical history is crucial in these situations.

Tumors and Tumor-Like Lesions of the Penis and Scrotum: Penis

Anatomy

Embryology

The development of male external genitalia is driven by androgenic hormonal stimuli from the fetal testicles. The penis arises from the genital tubercle, which enlarges with the expansion of the anterior and cranial mesoderm of the urogenital sinus. This sinus is formed by two segments, a proximal endodermal region called urethral plate and a distal remaining of the cloacal membrane (ectoderm) designed as glans plate . The former originates the proximal penile urethra, and the latter remains as a solid glans plate. The urethral groove forms along the surface of the urogenital sinus. At each side of this groove arise two swellings of mesoderm covered by ectoderm called urogenital folds . All these tissues will form the phallus. Finally, on either side of the folds appears the labioscrotal swellings which fusion forms the scrotum. As a result, genital tubercle gives origin to glans, corpus spongiosum, and corpora cavernosa; urogenital plates and folds generate penile urethra and ventral structures; and labioscrotal folds origins scrotum tissues [373,374,375].

Penile Anatomy

The penis can be divided in two major areas: The distal penis that comprises the glans, coronal sulcus and foreskin, and the proximal penis that is composed by the shaft (Fig. 16.97). The majority of the epithelial tumors are located in the distal part.

The glans is a cone-shaped structure corresponding to the distal expansion of the corpus spongiosum . It is covered by squamous mucosa and contains the meatus, corona, and frenulum. The meatus urethralis forms the distal part of the urethra. The frenulum arises from the apex of the meatus and extends ventrally into the midline to the foreskin. The glans corona is the wider region of the glans and separates it from the coronal or balano-preputial sulcus located between the glans and the foreskin. Four histologic regions or layers can be seen at the cut surface: (a) the squamous epithelium of the mucosae composed by up to ten-cell layer; (b) the lamina propria, an underlying loose connective tissue of about 2 mm of thickness; (c) corpus spongiosum, the larger component of the glans; and (d) the corpora cavernosa that can reach the glans in a variable extension, surrounded by the tunica albuginea. The glans epithelium can be keratinized in circumcised men or not keratinized otherwise [373, 376].

The foreskin covers the glans and coronal sulcus. The free border of the foreskin is called the preputial ring and represents the continuity between its two anatomic surfaces. It presents an inner pale and smooth (mucosal) surface that covers directly the glans and an outer dark and wrinkled (cutaneous) surface that is in continuity with the skin of the shaft. The cut surface shows three anatomic layers: (a) The mucosal surface with underlying lamina propria, (b) loosely attached dartos muscle fibers, and (c) cutaneous surface composed by squamous epithelium and dermis [376].

Three types of foreskin can be seen:

(a)
Long-type, with the foreskin completely covering the glans.
(b)
Intermediate-type, partially covering the glans. The preputial ring is located between the meatus urethralis and the glans corona.
(c)
Short-type; the glans remains uncovered. The preputial ring is located at the level or below the glans corona.

Long foreskin can be more prone to the development of penile carcinoma [377, 378].

The penile shaft is the distal part of the penis. From outer to inner tissues, the following layers can be seen at the transversal cut: (a) the skin with appendages that continues the cutaneous surface of the prepuce, with an underlying loose connective tissue (the penile or Buck’s fascia) rich in nerves and vessels, and dartos muscle bundles; (b) the corpus spongiosum, located ventrally and surrounding the penile urethra; and (c) the corpora cavernosa, erectile tissues distributed in two dorsal columns encased in a dense connective tissue, the tunica albuginea [373, 377].

Specimen Handling/Grossing (Slightly Modified From the Cap Protocol) [379]

Circumcision (Fig. 16.98)

Measure the whole specimen . Identify abnormalities and describe gross features of the tumor. Ink the mucosal and skin margins with different colors. Most squamous cell carcinomas (SCCs) arise from the mucosal surface of the foreskin; therefore, the coronal sulcus (mucosal) margin is especially important. Superficially spreading tumors however may grow along the skin part of the foreskin. Lightly stretch and pin the specimen to a cardboard. Fix for several hours in 10% buffered formalin. Cut vertically the whole specimen labeling from 1 to 12, clockwise.

Penectomy

Describe the type of specimen (partial or total penectomy ), and identify and describe the tumor. Most SCCs of the penis arise from the epithelium of the distal portion of the organ (glans, coronal sulcus, and mucosal surface of the prepuce). The tumor may involve one or more of these anatomical compartments [376]. If present, classify the foreskin in short, medium, long, and/or phimotic [378]. Separate the foreskin from the penis and describe it as shown above. In the fresh state, include resection margins. They are the skin of the shaft with underlying dartos and penile fascia, corpora cavernosa with tunica albuginea, and the urethra and periurethral tissues (lamina propria, corpus spongiosum, albuginea, and penile fascia). Fix the rest of the specimen overnight. If the tumor is large and involves most of the glans, cut longitudinally and centrally using the meatus and the proximal urethra as reference points (Fig. 16.99). Do not probe the urethra . Separate the specimen in two halves, left and right. Then cut two to six serial sections of each half. If tumor is small and asymmetrically located in the dorsal or ventral area, the central portion of the tumor may be used as the axis of sectioning. If the tumor is large involving multiples sites (glans, sulcus, and foreskin), it is important not to remove the foreskin leaving the entire specimen intact for sectioning.

Glans Resurfacing Specimen (Fig. 16.100)

This is a rather complex specimen which is the result of a new surgical technique applied for small and superficial glans lesions [8, 380]. Surgeon cuts the glans from the meatal region toward the sulcus in four quadrants. Tissues are thin because the reason of this procedure is to preserve as much as possible corpus spongiosum [381]. Specimen is dissected after differential inking of true lateral/coronal and deep resection margins. There is no need to mark the lateral edges of the glans segments as these are not true margins. The entire specimen is sliced into 10/20 blocks [382].

Pathology Report for Penile Carcinoma

A complete pathology report of carcinoma of the penis should contain the following information: (1) tumor size; (2) tumor site (glans, coronal sulcus, foreskin or more than one site, shaft); (3) patterns of growth; (4) histological type and subtype; (5) histological grade, from 1 to 3; (6) anatomic levels; (7) depth of invasion (in mm); (8) vascular invasion; (9) perineural invasion; (10) margins of resection; (11) associated lesions; (12) and Prognostic Index and TNM are optional but provide valuable information and may be included in the report [377, 379].

Reporting inguinal nodes , site, total number, and size of dissected nodes, should be described. All nodes should be included for microscopic examination. The presence of metastatic disease should be reported with the number and site (e.g., inguinal vs. pelvic) of metastatic nodes, as well as the presence of extracapsular extension.

Epithelial Tumors of the Penis and Scrotum

Penile Intraepithelial Neoplasia (PeIN) (Table 16.13)

Penile intraepithelial neoplasia (PeIN) is the in situ precursor of penile squamous cell carcinomas. According to the WHO, this lesion is classified, based on its distinctive molecular pathways, in two main groups: non-HPV-related and HPV-related [383].

Table 16.13 PeIN and squamous cell carcinoma classification according to WHO 2016

Full size table

Non-HPV-related PeIN is represented by differentiated PeIN. It is mainly found in the foreskin of older patients, and it is frequently associated with lichen sclerosus [384]. Grossly, a whitish-tan, slightly raised plaque can be the only visible feature [385]. Histologically (Fig. 16.101) these are low-grade, keratinizing lesions characterized by architectural disorganization that sometimes affects just the lower third of the epithelium. Acanthosis with hyper and parakeratosis are common. Cellular atypia is most evident in basal and lower layers although a careful examination of the epithelium at high power evidences full-thickness compromise. Intraepithelial keratin pearls can be seen [377, 386, 387]. Atypical changes may be subtle, leading to under diagnoses, both clinically and histologically [385].

HPV-related PeIN are subdivided in basaloid PeIN, Warty PeIN, and Warty-basaloid PeIN [383, 384, 386]. Sometimes described as erythroplasia of Queyrat or Bowen’s disease, these lesions are more frequently located in the glans.

Gross differentiation among subtypes is difficult, but in basaloid PeIN the surface of the lesion is smooth, and in warty PeIN it is finely villous. But the lesions may be grossly heterogeneous varying from flat to slightly elevated, velvety, erythematous, dark brown or black macules, papules, or plaques. Microscopically, HPV-related lesions are of higher histological grade and show prominent changes [384]. Each subtype has distinctive features:

Basaloid PeIN (Fig. 16.102a, b) is composed of monotonous small blue (basaloid) cells compromising the full epithelium thickness. Nucleus/cytoplasm ratio is high, and numerous mitoses and apoptosis figures can be seen. Parakeratosis and isolated koilocytes can be found in the surface. p16 immunostain is strongly and diffusely positive “en bloc.”

Warty PeIN (Fig. 16.102c, d) shows squamous maturation, atypical koilocytosis, and parakeratosis, and a micropapillary pattern is characteristic. Mitoses are less evident than in basaloid PeIN. Immunostain with p16 is strongly positive in non-keratinizing cells.

Warty-basaloid PeIN (Fig. 16.102e, f) shows overlapping features of both previously described lesions with predominant basaloid cells in the lower half of the epithelium and warty features on the spiky surface. p16 is positive in the non-koilocytic cells, mainly in the lower half of the epithelium. Pleomorphic, spindle and clear cells, and cells with pagetoid features can be occasionally found in PeIN of unclassified subtypes.

Multicentric, homogeneous (same subtype), or heterogeneous (different subtypes) PeIN can be found associated or not with invasive carcinoma.

Invasive Squamous Cell Carcinoma (SCC) of the Penis

More than a half of penile invasive carcinomas have features of the usual or conventional squamous cell carcinomas (SCC) similar to other sites, especially vulva and head and neck [388,389,390,391]. However, a diversity of clinicopathological entities were reported, some quite unusual [383].

The bimodal hypothesis of penile neoplasia carcinogenesis , first postulated by Kurman in vulvar carcinomas [388] and extended to the penis by our studies [392,393,394,395], has accumulated a strong body of evidence. The new subclassification of penile squamous cell carcinoma proposed by the WHO is based on this premises separating penile carcinomas in HPV-related and non-HPV-related (Table 16.13) [383].

Non-HPV-Related SCC

Squamous Cell Carcinoma: Usual Type

These tumors are keratinizing neoplasms that vary from well- to poorly differentiated, where keratin pearls can easily be recognized in the first to more solid, cord-like, trabecular, or anaplastic tumors composed of poorly keratinizing large or small pleomorphic cells.

Clinical features

Usual SCC is the most prevalent subtype of penile carcinoma and comprises from 50% to 65% of cases. Usually, it affects glans of males in his 60s. It is frequently associated with long foreskin, phimosis, and lichen sclerosus.

Gross Features

This neoplasm varies from nodular or exophytic to flat ulcerated tumors. Tumor size is greater in countries with high incidence (average: 4.5 cm) than in those with low incidence (average: 2 cm) [396]. Cut surface appearance is white gray to brownish with or without necrosis. The interface between the tumor front and normal tissues is irregular, jagged. In superficially invasive carcinomas, tumors are subtle and difficult to be noted, with a white thickening of the epithelium as the only lesion in some cases [397]. Tumors limited to lamina propria are uncommon; the majority compromise dartos or corpus spongiosum and reach corpora cavernosa in up to one-third of the cases [377].

Microscopic Features

Keratinization must be present by definition and classification should be straightforward. Tumor grade varies from well-differentiated neoplasm with slight deviation from normal epithelia (grade 1) (Fig. 16.103a, b) to poorly differentiated (grade 3) (Fig. 16.103e, b) carcinomas where keratinization is hard to find and nuclear atypia, as well as presence of several mitotic figures, is the rule. Moderately differentiated (grade 2) (Fig. 16.103c, b) SCC is the most common finding, generally composed by ample sheets or nests of neoplastic cells with intra- and extracellular keratinization, sometimes forming keratin pearls infiltrating the underlying reactive stroma in an irregular fashion. Stromal reaction with inflammatory cells surrounding the infiltrative tumor border is common. p16 immunostain and high-risk HPV are usually negative. Finally, usual SCC is an exclusion diagnosis, and it is reached after ruling out all other known subtypes. Squamous hyperplasia, differentiated PeIN, and lichen sclerosus are frequently found adjacent to the tumor.

Differential Diagnosis

Among benign conditions, pseudoepitheliomatous hyperplasia needs special attention in the diagnosis of well-differentiated superficially infiltrating usual SCC . In the former, nests are orderly disposed with no atypia, peripheral palisading, or stromal reaction. Pseudohyperplastic SCC can be challenging to diagnose. Irregular tumor nests, absence of peripheral palisading, and presence of stromal reaction characterize this tumor which simulates hyperplasia. Furthermore, clinical aspects as older patients, foreskin location, and frequent multicentricity support the diagnosis of pseudohyperplastic SCC.

On the other end, poorly differentiated usual SCCs with solid and trabecular patterns need to be differentiated from urothelial, basaloid, and the most recently described medullary carcinoma. Urothelial carcinomas of the distal urethra normally are located on the ventral surface and usually but not always lack differentiation. Immunohistochemical stain may be needed in difficult cases. Urothelial carcinomas are positive for CK20, uroplakin, and GATA3 [377, 398]. Typical basaloid carcinomas, with its small-cell homogeneous features growing in tumor nests solid or centrally necrotic, are easy to distinguish from the usual SCC. However, there is an unrecognized spectrum of basaloid carcinomas with a more variable histology such as spindle, pleomorphic, or large cells [399]. As in basaloid carcinomas, there is a nesting pattern, the cells are basophilic or blue, and they stain strongly for p16 [377, 400]. In medullary carcinomas, keratinization is absent or minimal, the pattern is solid or syncytial, and there is a dense tumor-associated inflammatory cell, features not prominent in the usual SCC. In difficult cases, p16 and HPV positive in medullary carcinomas and negative in usual SCC can be useful [401].

Prognosis

Usual SCC has an intermediate prognosis with mortality rates of 20–40%. It recurs in about 30% of the cases in the surgical site or groin. Inguinal node metastasis varies from one-fourth to one-third of the cases [402,403,404].

Verrucous Squamous Cell Carcinoma

Originally described by Dr. Lauren Ackerman in the oral mucosae [405], this exophytic, extremely low-grade keratinizing variant of SCC is a rare tumor affecting older males. It is frequently associated with lichen sclerosus. It can be pure verrucous or more common mixed with usual SCC which is called hybrid verrucous SCC.

Gross Features

The neoplasm presents as an exophytic, white to gray, verruciform tumor involving foreskin or glans. The cut surface shows a broadly based tumor, sharply separated from the underlying stroma, commonly the corpus spongiosum, of which its reddish vascularized surface contrasts with the whiypical veratinizing tumor (Fig. 16.104a).

Microscopic Features

Three main variants can be recognized [5, 23, 377, 396] Classical verrucous carcinomas (Fig. 16.104b–e) show papillomatosis with marked hyperkeratosis. Papillae are acanthotic without a central fibrovascular core except in rare cases which shows slender ones. Intraepithelial keratin-filled cystic areas are not uncommon. The interface between tumor and stroma is characteristically sharply delineated. Verrucous carcinomas are by definition broadly based, “noninvasive,” although they may penetrate into underlying tissues with a bulbous tumor front. Cells are extremely well-differentiated and resemble normal squamous cells. Microinvasive verrucous carcinomas (Fig. 16.105a, b) are typical verrucous carcinomas with foci of detached tumor nests invading superficial lamina propria. The third variant is the hybrid verrucous carcinoma (Fig. 16.105d–d) where classical verrucous carcinoma is mixed with areas of higher-grade usual or sarcomatoid SCC. HPV and p16 (Fig. 16.104f) are negative [383].

Differential Diagnosis

They are verrucous squamous hyperplasia , giant condylomas, noninvasive warty carcinomas, and papillary NOS carcinoma. The size and the overall architecture of verrucous carcinoma are the only difference with hyperplasias because both harbor cells with minimal deviation from the normal squamous epithelium. That makes the distinction of these entities virtually impossible in small biopsies. Giant condyloma and warty carcinomas are HPV-related neoplasms, and both have koilocytes and condylomatous features in their papillae. Presence of low- or high-risk HPV genotypes would favor the diagnosis of condylomas or warty carcinomas, respectively. Papillary NOS SCC has an irregular front of invasion and cells are more atypical.

Prognosis

Classic (pure) and microinvasive neoplasms carry an excellent prognosis. Cancer-related death has not been reported in such cases [404]. There is no metastatic potential, and recurrences can be treated by simple excision because often recur with bland histology, but higher grades and sarcomatoid changes can be found [403, 406]. Hybrid verrucous carcinomas are associated with metastases in up to one-fourth of the cases [407].

Cuniculatum Squamous Cell Carcinoma

Carcinoma cuniculatum is an extremely well-differentiated squamous cell carcinoma histologically and cytologically similar to verrucous carcinoma but with a characteristic burrowing growth pattern simulating rabbit’s burrows [408].

Clinical Features

This tumor usually affects older males and multiple penile compartments, the most frequent being the glans.

Gross Features

The tumors are white to gray exo-endophytic, affecting the glans and extending to other penile anatomic compartments. Cuniculatum carcinomas are among the largest penile tumors. Gross description (Fig. 16.106a) is very important in these tumors; hence, diagnosis is made on examination of the cut surface, where deep invaginations form irregular, narrow, and elongated neoplastic sinus tracts connecting surface with corpora. Some fistulae can be noted [377, 396].

Microscopic features (Fig. 16.106b–e)

The most striking feature is the architecture, a labyrinthine borrowing pattern with keratin-filled sinuses and fistulae in otherwise broadly based verrucous carcinoma. Unlike other tumors, despite deep invasive behavior, the neoplastic cells are extremely well-differentiated. There is hyperkeratosis, acanthosis, and papillomatosis without koilocytes. Hybrid foci of usual squamous cell carcinoma (Fig. 16.109f) of higher grade can be found. Notwithstanding the deep borrowing infiltrative pattern, vascular and perineural infiltration are not found [408].

Differential Diagnosis

It is made with other verruciform tumors. Classic verrucous carcinomas share most of the features of cuniculatum carcinomas, but the main difference is the burrowing pattern not present in verrucous carcinomas. Warty carcinomas and giant condylomas harbor koilocytes and low- or high-risk HPV genotypes, respectively. Warty carcinomas may rarely show an endophytic growth which may simulate carcinoma cuniculatum [377, 383, 396].

Prognosis

Despite of the local destructive pattern of this tumor, no regional metastases or mortality were reported [383, 404, 408].

Papillary Squamous Cell Carcinoma, Not Otherwise Specified (NOS)

This is an unusual exophytic low-grade neoplasm diagnosed after exclusion of other more distinctive verruciform tumors [409].

Clinical Features

It is a rare non-HPV-related carcinoma comprising about 5% of all SCCs and usually affects patients in their 60s. Tumors vary in size, but frequently they are large (up to 12 cm of diameter), arising in the glans and extent to other penile regions [396].

Gross Features

They are large, cauliflower-like, white-gray tumors which on cut surface show thin papillae lined by pearly white neoplastic tissue with an irregular serrated and poorly delineated interface between tumor and stroma [10, 36, 383, 409].

Microscopic features (Fig. 16.107)

Papillae are always present but morphologically variable. The base of the lesion is infiltrative and jagged formed by thin elongated epidermal ridges. There is acanthosis with hyperkeratosis. Cells are generally mature, low-grade, keratinizing variants, but moderately differentiated (grade 2) tumors are not unusual. Lack of koilocytes is the rule. HPV and p16 are negative [377, 383, 396].

Differential Diagnosis

Papillary hyperplasia, a rare entity, should be considered in the differential diagnosis. The absence of atypia in hyperplasia is the only key factor. Distinction in biopsies may be difficult. Papillary NOS can be confused with other verruciform tumors. The differentiation from Warty carcinomas and giant condylomas is through the presence of koilocytes and high- or low-risk HPV, respectively. Verrucous carcinomas have broad-based pushing borders, and fibrovascular cores are absent or inconspicuous [377, 409, 410].

Prognosis

Mortality is about 5%, regional metastases ranges from 0% to 25%, and recurrence is about one in ten patients. Papillary NOS SCC has an overall good prognosis [402,403,404].

Pseudoglandular (Acantholytic , Adenoid ) Squamous Cell Carcinoma

This is an unusual, high-grade SCC with acantholysis simulating glandular features. More than 30% of pseudo-glands are required for the diagnosis. Rather than a separate entity, it is considered a variant of the usual SCC [383, 411].

Clinical Features

It is an aggressive subtype associated with earlier groin metastases and local destructive behavior. It frequently affects the whole anterior compartment of the penis of males in their 50s [396, 411].

Gross Features

This tumor resembles usual SCC. Large ulcerated tumor involving multiple sites is the rule. White gray mass invading corpus spongiosum and corpora cavernosa is seen on cut surface [411].

Microscopic features (Fig. 16.108)

The histological aspect of this tumor is variegated, but the basic architecture is of a usual SCC. Only rarely basaloid carcinomas may present pseudoglandular features [412]. There is a microcystic honeycomb appearance at low-power view. Pseudo-glands lined by atypical high-grade keratinizing cells surrounding spaces partially filled with acantholytic cells, keratin, and cellular debris are the hallmark of this tumor. Vascular and perineural invasion are common [377, 383, 411].

Differential Diagnosis

The differential diagnosis includes adenosquamous SCC, urethral adenocarcinomas, and sarcomatoid SCC. In the first two, it is necessary to demonstrate true glandular differentiation. Mimicry to adenocarcinoma can be striking. Presence of luminal necrotic debris indicates probable pseudo-glands. Mucin stains or CEA immunohistochemistry helps in these cases. Sarcomatoid SCC sometimes simulates pseudovascular spaces that can be confused with pseudoglandular spaces; in this case, identification of foci of squamous differentiation is helpful [383, 396, 411]

Prognosis

Mortality is seen in one-third of the patients. Virtually all patients have inguinal metastases at the time of surgical resection [404, 411].

Pseudohyperplastic Squamous Cell Carcinoma

This is a multicentric, low-grade squamous cell carcinoma that mimics pseudoepitheliomatous hyperplasia [413].

Clinical Features

It mainly affects foreskin of older males (8th decade) but can compromise glans and coronal sulcus as well.

Gross Features

They are multicentric flat or slightly elevated whitish tumors sometimes resembling hyperplastic lesions (Fig. 16.109a).

Microscopic features (Fig. 16.109b–d)

Pseudoepitheliomatous pattern with superficially downward proliferation is the hallmark of this neoplasm. Usually, this tumor invades up to dartos or lamina propria in foreskin and glans, respectively. Cells are extremely well-differentiated with minimal or no atypia, but reactive stroma facing the infiltrative nests is seen. There is no vascular or perineural invasion. Squamous hyperplasia, differentiated PeIN, and lichen sclerosus are frequently associated with this SCC subtype [377, 413].

Differential Diagnosis

The main distinction is with pseudoepitheliomatous hyperplasia . This is difficult in biopsy materials . Pseudoepitheliomatous hyperplasia is limited to the subepithelial connective tissues, and atypia is minimal or absent. Low-grade usual SCC and verrucous carcinoma are well-differentiated tumors that can be confused with pseudohyperplastic SCC. Occasionally pseudohyperplastic carcinomas adopt verrucoid features, but the lesions are less compact and solid than verrucous carcinomas. Typical verrucous carcinoma may be found in association with pseudohyperplastic carcinomas [396, 413].

Prognosis

There are no reported cases of cancer death or regional metastases. Recurrence rate is about 10% and it can be related to multicentricity [404, 413].

Adenosquamous Squamous Cell Carcinoma

This unusual tumor, also known as mucoepidermoid carcinoma , is composed of a biphasic squamous and glandular cells population [414].

Clinical Features

This neoplasm is seen in glans of patients in their 50s.

Gross Features

Findings are similar to usual squamous cell carcinomas: large, firm, white-gray tumors that on cut surface arise from the glans and often compromise coronal sulcus and foreskin.

Microscopic features (Fig. 16.110)

Hallmark is the presence of squamous and glandular differentiation. The glands can be found mixed or separated from the squamous component. Glands are lined by cubic to columnar neoplastic epithelium or isolated mucinous cells among solid squamous malignant nests, the latter more frequently designated as mucoepidermoid carcinoma. Differentiated PeIN is usually present in adjacent mucosa [407, 414,415,416].

Differential Diagnosis

There are few cases reported of this subtype of SCC. Pure adenocarcinomas of the urethra or Littre glands should be discarded. There are not malignant squamous cells in these tumors. Metastatic adenocarcinomas are other potential confusing diagnosis. These tumors are often multricentric and have multiple intravascular metastases. Finally, pseudoglandular SCC just mimics glandular spaces and lacks true glandular differentiation [396, 403, 414].

Prognosis

Tumor is rare and there is no sufficient prognostic information. Groin metastasis occurs and mortal cases were reported [377, 403, 404].

Sarcomatoid Squamous Cell Carcinoma

This is the most aggressive penile carcinoma . They are spindle-cell tumors with at least focal features of squamous differentiation. Sometimes is called carcinosarcoma [417]. At least 30% of sarcomatoid features are required for the classification.

Clinical Features

This aggressive tumor represents 1–4% of all penile SCC . The average patient’s age is 59 years old at diagnosis. It can arise de novo, in the recurrence of a previous SCC of different subtype or following radiotherapy [396, 406].

Gross Features

Large exophytic fungating ulcerated and hemorrhagic tumor is characteristic at gross inspection. On the cut surface, they are gray to reddish exo-endophytic masses with typical vertical growth pattern. Due to rapid enlargement, macroscopic necrosis and hemorrhage is often found [417, 418].

Microscopic features (Fig. 16.111)

Histologic appearance is heterogeneous and simulates various sarcomas. Fascicular, storiform, or myxoid patterns are common. Spindle cells frequently predominate and resemble fibrosarcoma or leiomyosarcoma (Fig. 16.111d). Anaplastic, bizarre mono- or multinucleated giant cells resembling malignant fibrous histiocytoma are not uncommon. Myxoid, liposarcoma, or rhabdomyosarcoma-like patterns can be observed. Rarely, a chondro- or osteosarcomatous or highly vascular angiosarcoma-like areas are present (Fig. 16.112). Vascular and perineural invasion are common. Immunostaining is frequently required to confirm diagnosis. CK5/6, 34βE12, and p63 are usually positive in the sarcomatoid areas (Fig. 16.111e, f) [377, 417, 418].

Differential Diagnosis

True sarcomas are rare in the penis . Deep location in corpora cavernosa, lack of epithelial component or differentiation (cytokeratin and p63 negative), and absence of PeIN support the diagnosis of primary or metastatic sarcoma. Melanoma with spindle-cell features can be challenging. Recognition of in situ lesions or immunohistochemical markers of melanoma are necessary [396, 417].

Prognosis

Several studies suggest this subtype is the most aggressive penile SCC [402,403,404, 417]. Mortality ranges from 50% to 90%. Almost all patients have inguinal lymph node metastases at the time of diagnosis. Local, as well as, systemic recurrences are seen in about 70% of the cases [403, 406].

HPV-Related SCC

Basaloid

This is a high-grade , HPV-related tumor with a nesting pattern of growth and composed of uniform small basaloid cells [392, 419].

Clinical Features

This tumor accounts for 10–15% of penile SCC. It affects patients younger than usual SCC (50–55 years old). The glans is the most common site of origin but preputial cases can occur [377, 396].

Gross Features

Unicentric ulcerated mass located in the glans is the most common presentation. On cut surface, a white-tan, deeply invasive tumor with vertical growth is distinctive (Fig. 16.113a). Sometimes, minute yellow foci corresponding to comedo-like necrosis is seen macroscopically [377, 419].

Microscopic features (Fig. 16.113b–e)

Solid sheets or nests of uniform intermediate to small basaloid cells are the hallmark of this neoplasm. Clear retraction artifact is seen surrounding the tumoral nest. Stromal hyalinization can be rarely seen. Central abrupt keratinization with cellular debris resembling comedocarcinoma-like pattern is characteristic of the nests. Basaloid cells are poorly differentiated with high nucleus/cytoplasm ratio. Nucleoli are inconspicuous. Several mitoses and apoptotic cells are common findings. Parakeratinization and isolated koilocytes are uncommon. Spindle basaloid cells can be found mainly in the solid sheets component of the tumor. Vascular and perineural invasion are common. p16 immunohistochemistry (Fig. 16.113f) and high-risk HPV are positive [383, 400, 419].

Differential Diagnosis

High-grade usual SCC with nesting pattern can be confused with basaloid SCC. In the former, cell cytoplasm is ample and eosinophilic, keratinization is gradual and not abrupt, and usual SCC is p16 and HPV negative. Warty-basaloid carcinoma is an HPV-related SCC with papillary architecture composed by atypical koilocytes and basaloid cells (see below) in contrast with basaloid SCC which is almost completely formed by basaloid cells. Urothelial carcinoma of the distal urethra may look identical to basaloid SCC; in these cases, adjacent in situ urothelial neoplasia or immunohistochemical markers as uroplakin III, thrombomodulin, and GATA3 can be useful [398, 420, 421]. The distinction with neuroendocrine or Merkel cell carcinomas may be difficult in the occasional basaloid carcinoma predominantly composed of anaplastic small cells, and immunostains with neuroendocrine markers may be required [377].

Prognosis

Mortality ranges from 21% to 88%. Inguinal lymph node metastases rates are high (50–100%) [404]. Recurrence is about 39%, mainly associated with partial penectomies [403, 406]. The disparity between high metastatic ratio and variable mortality could be related to difference in primary treatment, stage of the pathology, or to the variable better outcome reported in HPV-related carcinomas of other sites [404].

Papillary Basaloid

It is an extremely rare penile carcinoma with papillary architecture, entirely lined by basaloid cells. It represents a variant of basaloid carcinoma [422].

Clinical Features

It generally affects older men. Glans is the most common site.

Gross Features

Unicentric papillary tumor with tan-gray spiky surface generally located in the glans is seen. On the cut surface, papillary exophytic component is evident with variable solid endophytic nest invading the distal penis.

Microscopic Features (Fig. 16.114)

Papillae with central fibrovascular cores lined by poorly differentiated basaloid cells are always present in the surface of the tumor. It resembles urothelial tumors. Keratinization, if exist, is abrupt. Parakeratinization and koilocytes can be seen in the tip of papillae. Cells are small with scanty basophilic cytoplasm and no evident cellular margins. Nuclei are central, round to ovoid with inconspicuous nucleoli. Mitotic figures and apoptotic cells are numerous. Deep invasive component is indistinguishable from basaloid SCC. Vascular and perineural invasion is variable and related to the presence of an invasive component. p16 immunostain and high-risk HPV genotypes are positive [396, 422].

Differential Diagnosis

Pure basaloid SCC, urothelial carcinomas, and papillary NOS SCC are considered in the differential diagnosis. Basaloid SCCs lack of papillae and frequently grow downward into the erectile corpora (vertical pattern of growth). Urothelial carcinomas have sharper cellular delimitation, frequently adjacent urothelial in situ neoplasia, and they are positive for uroplakin III, GATA3, and thrombomodulin immunostains [398]. Papillary NOS SCC papillae are lined by more differentiated eosinophilic cells. It is p16 and HPV negative [422].

Prognosis

There are two reported series of this entity. In the first one, prognosis was excellent with no mortality. In the second series, mortality reaches 80%. Tumors in the latter were larger of higher clinical stage and invaded deeper into the corpora cavernosa. Inguinal metastases range from 20% to 60%. There is no data about recurrences [404, 422].

Warty

It is an exophytic verruciform HPV-related squamous cell carcinoma [410]. It was initially described in the vulva by Kurman [388] but can occur in other anogenital sites.

Clinical Features

It comprises among 7–10% of penile SCC [404]. Warty carcinomas, as other HPV-related SCCs, are seen in younger patients than usual SCCs (10 years younger on average). It affects equally all penile compartments and is frequently unicentric arising on the glans with extension to coronal sulcus and foreskin [404, 410].

Gross Features

Cobblestone or cauliflower-like appearance is characteristic of this tumor. The grayish-white surface resembles common or giant condylomas. The cut surface shows papillary exophytic and endophytic architecture (Fig. 16.115a). On transverse cuts, papillae show a central dark core surrounded by white tumor tissue highlighting the cobblestone pattern [377, 410].

Microscopic Features (Fig. 16.115bd–d)

Long, thin papillae resembling condylomas are the hallmark of this tumor. There are hyper- and parakeratosis. The upper limits of the papillae are generally rounded. The limits of tumor and stroma are jagged and irregular but in rare cases can be blunt. Papillae have central fibrovascular cores covered by pleomorphic koilocytes. Their cells are ample with eosinophilic or clear cytoplasm and perinuclear halos. The nuclei are large, hyperchromatic, irregular, wrinkled, and frequently bi- or multinucleated. The majority of Warty carcinomas are grade 2. In low-grade variants, mature non-pleomorphic cells predominate making difficult the diagnosis. Vascular and perineural invasion are uncommon. p16 immunostain (Fig. 16.115d) and HPV are positive [377, 403, 410].

Differential Diagnosis

It should be distinguished from other verruciform tumors. Giant condylomas are benign or atypical tumors harboring low-risk HPV genotypes. Koilocytes are more prominent and there is no pleomorphism. Absence of koilocytes is the main different with the other verruciform non-HPV-related tumors. Distinction from verrucous carcinoma should be straightforward, but some cases show common features of both tumors; these cases should be classified as mixed verrucous-warty carcinomas. To distinguish papillary NOS from warty SCC is most difficult due to both share common architectural features; however, papillary NOS SCC lacks koilocytes, and it is p16 and HPV negative [377, 396, 410].

Prognosis

Warty carcinomas have an overall good-to-intermediate prognosis. Mortality rate is about 10%. Regional metastases are seen in up to 25%. Recurrences reach 10% [402,403,404].

Warty Basaloid

High-grade variant of penile SCC composed of mixed features of warty (condylomatous) and basaloid carcinomas [423].

Clinical Features

Represents 5–10% of penile SCC. Patients’ mean age is about 60 years old. It affects multiple penile compartments due its large size [396, 423].

Gross Features

Large exophytic or exo-endophytic white-gray tumor located in the distal penis is the common presentation. The cut surface shows a deeply invasive tan to white solid mass (Fig. 16.116a).

Microscopic Features

This neoplasm is biphasic with warty and basaloid features in the same tumor, intermixed or separated in different tumor areas. Three patterns can be seen: (1) warty appearance on the surface and basaloid features in the invasive nests (Fig. 16.116b–d), (2) features of warty and basaloid SCC present in the same tumor nest with basaloid cells at the periphery and gradual keratinization and atypical koilocytes in the center of the nest, and (3) papillary architecture with papillae lined by warty and basaloid cells (Fig. 16.117a–c). Vascular and perineural invasion is observed in 25 and 50% of the cases, respectively. p16 immunostain (Fig. 16.117d) and high-risk HPV genotypes are positive [383, 423].

Differential Diagnosis

Pure warty or basaloid SCCs need to be ruled out. Since focal features of both tumors can be seen on each other, the presence of at least 10% of basaloid cells in an otherwise warty SCC or the finding of at least 10% of clear koilocytic cells in a basaloid SCC excludes the diagnosis of pure warty or basaloid SCC, respectively [423].

Prognosis

Mortality ranges from 33% to 50%. Inguinal nodal metastasis is found in up to one-half of the cases and seems to be related to the proportion of basaloid cells in the tumor [404, 423].

Clear Cell

Originally reported as a carcinoma originating from the skin adnexal glands of the penis, [52, 424] this variant was recently presented as a subtype of squamous cell carcinoma arising from the mucosal epithelia of the glans [383, 425].

Clinical Features

Reported cases were seen in glans of uncircumcised males with ages ranging from 52 to 95 years old. The common clinical sign was a self-appreciated mass in the distal penis. The foreskin was focally affected in one case, and none had extension to the skin of the penile shaft [425].

Gross Features

These are large, white-gray granular, ulcerated tumors involving glans and coronal sulcus. Cut surface is white to tan with yellow small foci of necrosis. This neoplasm typically invades deeply into erectile tissues up to corpora cavernosa.

Microscopic Features (Fig. 16.118)

There are two patterns : solid and nesting. Solid tumors are composed of sheets or nests of clear cells with lobulated architecture surrounded by delicate strands of fibrovascular tissues. The second pattern consists of confluent nests of clear cells with prominent central comedo-like or geographical necrosis. At high power, there are poorly differentiated cells with prominent clear cytoplasm, central hyperchromatic nucleus, and frequent mitotic figures. There may be focal areas of tumor indistinguishable from warty/basaloid carcinomas, but when present they comprise less than 10% of the neoplasm. All cases show vascular and perineural invasion. HPV-related PeIN are found adjacent to tumors in the glans. p16 and in situ hybridization for HPV are positive in the neoplastic cells [396, 425].

Differential Diagnosis

Warty SCC, sweat glands tumors, and metastatic renal cell carcinomas could be confused with clear cell SCC. Warty carcinomas are composed of clear cells, as well, but the architecture is different: Condylomatous papillae are always present in warty SCCs and absent in clear cell SCC. Sweat gland tumors with clear cell features may compromise the distal penis. Nevertheless, they usually arise on the skin of the shaft and are consistently negative for p16 immunostain and high-risk HPV. Metastatic renal cell carcinomas are usually multicentric, involve preferentially corpora cavernosa, and are HPV negative [425, 426].

Prognosis

Two of the three reported cases were dead of disease in less than a year of initial diagnosis. One patient had pathologically proved inguinal lymph node metastasis; the other two had clinically positive nodes [425].

Lymphoepithelioma-Like

It is a rare poorly differentiated SCC with market inflammatory cells infiltrate among the neoplastic cells, resembling lymphoepithelioma-like carcinoma of the nasopharynx [383, 427].

Clinical Features

Two cases were reported. Patients were 58 and 75 years old, both uncircumcised.

Gross Features

They are glans-based firm well-circumscribed deeply invasive tumors [427].

Microscopic Features (Fig. 16.119)

Syncytial growth pattern of the neoplastic cells is one of the most remarkable features of this tumor. Nests and trabeculae of large eosinophilic undifferentiated cells without clear cellular margins give the syncytial appearance. Nuclei are large and irregular with prominent nucleoli. There is minimal or no keratinization. The other main feature is the dense lymphoplasmacytic and eosinophilic inflammatory infiltrate which obscures tumor cells. Stromal infiltration is irregular with some isolated cells detaching from the tumor occasionally simulating high-grade lymphomas. Vascular and perineural invasion is frequent. p16 immunostain and high-risk HPV are positive in neoplastic cells [383, 396, 427].

Differential Diagnosis

Like in their head and neck, counterpart malignant lymphomas should be rule out. Primary lymphomas of the penis are vanishingly rare. Appropriate immunostains for lymphomas and epithelial tumors make distinction easy. Medullary SCCs, a recently described HPV-related penile tumor, harbor stromal- or tumor-related inflammatory cells, but the histological pattern is that of a more cohesive solid and nesting tumor [383, 396].

Prognosis

In one series, both patients died from other causes. Lymph node metastasis was documented in one patient. There were no recurrences after 3 and 17 years of follow-up [427].

Medullary

It is the most recently described high-grade HPV-related penile SCC . It was the result of a careful reevaluation from a group of HPV-related tumors previously classified as usual SCC [401].

Clinical Features

A series of 12 patients was described. The prevalence was less than 1%. Patients’ average age at the diagnosis was 71 years old. Glans was the most common cancer location.

Gross Features

They were large irregular white-gray neoplasms arising in the glans with extension to coronal sulcus and foreskin, frequently replacing the distal penis.

Microscopic Features (Fig. 16.120)

Large sheets or solid nests of tumor infiltrating the stroma with a broad-front of invasion are characteristic. In some cases, less cohesive groups or lymphoepithelioma-like pattern surrounded by inflammatory cells are present. Individual cell or geographic necrosis can be seen. Cells are poorly differentiated with focal keratinization to anaplastic. Nuclei are large and irregular with prominent eosinophilic nucleoli. There are no basaloid cells or koilocytes. Mixed inflammatory infiltrate is always present. Microabscesses can be found. p16 immunostain and high-risk HPV are positive [401].

Differential Diagnosis

Poorly differentiated usual SCC and lymphoepithelioma-like SCC are the most important differential diagnosis. Squamous cell maturation, keratinization, and fibrous stromal reaction are more prominent in solid poorly differentiated usual SCC . p16 and high-risk HPV genotypes are negative. Lymphoepithelioma-like carcinoma is characterized by non-cohesive cells surrounded by lymphoplasmacytic infiltrate and irregular front of invasion [401].

Prognosis

There is no follow-up data available .

Others

Mixed

Mixed SCCs are tumors harboring two or more variants of penile squamous cell carcinomas in the same specimen [383]. This category comprises HPV- and non-HPV-related subtypes.

Clinical Features

Average age is 60 years, similar to usual SCC. It accounts from 10% to 35% of all penile SCCs. Glans located tumor with extension to other penile compartments is the most frequent presentation. Foreskin exclusive tumors are exceedingly rare [377, 383, 404].

Gross Features

The macroscopic appearance is variegated. Tumors tend to be whitish-gray exo-endophytic ulcerative masses replacing the distal penis. On cut surface, mixed patterns of growth are frequent [377, 383].

Microscopic Features

Virtually any variant of SCC can be seen in mixed tumors. The most common is Warty-basaloid SCC described as a separate entity. The other common combination is the also described hybrid verrucous carcinoma that mixed verrucous with usual SCC (Fig. 16.105c, d). Usual SCC can be found mixed with warty, basaloid, and papillary NOS carcinomas. Verruciform tumors are sometimes challenging to be typified in one entity. In these cases, the various components with their relative proportions should be mentioned.

Differential Diagnosis

As this category comprises of a mixture of various SCC variants, pure forms need to be ruled out. Except for Warty-basaloid SCC, a rule of thumb is if any subtype of SCC harbor a second variants in at least 20% of the tumor; this should be classified as mixed SCC, and the components should be mentioned [377].

Prognosis

It varies with the subtypes involves. For example, tumors with basaloid components have worst prognosis than pure low-grade subtypes. Presence of usual SCC in well-differentiated tumors (as verrucous or papillary NOS) impairs prognosis. As a group, mortality is up to 10%. Nodal metastases range from 10% to 40%, and recurrences are seen in about 20% [383, 404].

Others Rare Carcinomas

Despite of the large list of variants, it is evident by the variable morphology and behavior of the remaining usual SCCs (Fig. 16.121a, b) that there are some rare carcinomas waiting for description. Other exceedingly rare primary carcinomas, as desmoplastic , neuroendocrine , small, and Merkel cell carcinomas , were described (Fig. 16.121c, d). Basal cell carcinomas and skin adnexal tumors arising in the skin of the shaft also affect the penis [383].

Mesenchymal Tumors

Mesenchymal tumors are very unusual in the penis. Neural tumors, generally of neuroectodermal origin, are included in this classification by convention [383]. Soft tissue tumors accounts for 5% of all penile neoplasm. Vascular tumors are the most prevalent neoplasm closely followed by tumor of neural, smooth muscle, and fibrous origin [428]. Kaposi’s sarcoma is the most common malignant penile mesenchymal neoplasm, and hemangiomas are the most common benign tumors [428, 429]. In the largest study of penile soft tissue tumors by the Armed Forces Institute of Pathology (AFIP), benign tumors were seen most often in the glans and malignant tumors in the shaft [429]. A non-tender mass noted on patient self-examination is the most frequent clinical symptom. Unlike squamous carcinomas, both malignant and benign mesenchymal tumors can be seen at any age, including young children [377, 428, 429]. Among tumors diagnosed in children, giant cell fibroblastoma, rhabdomyosarcoma, epithelioid sarcoma, myointimomas, leiomyomas, and Ewing’s sarcoma are cited [383, 430, 431].

The limited available information about these tumors are mainly from isolated or small cases series. Pathologic features of these entities are quite similar to tumors of other locations [377]. We summarize here some of the most common mesenchymal neoplasms separated in benign and malignant tumors.

Benign Mesenchymal Tumors

Hemangiomas, leiomyomas , schwannomas, neurofibromas, lymphangiomas, glomus tumors, fibrous histiocytomas, myointimomas, and granular cell tumors have been reported in the penis [383, 429,430,431,432,432].

Macroscopically, vascular tumors tend to be solitary, red to bluish plaque or nodule. Neural, fibrous, or smooth muscle tumors are presented as firm well-circumscribed nodules to polypoid lesions [383].

About 30 epithelioid hemangiomas [433, 434] and less than 20 cases each one of granular cell tumors and myointimomas were described [430, 432, 435].

Epithelioid hemangioma is a rare vascular tumor that is characterized by capillary vessels lined by epithelioid endothelial cells and accompanied by an inflammatory cell infiltrate [436, 64]. The median reported age in a case series was 45 years [433]. Tender mass frequently located in the penile shaft is the most common presentation. This tumor can be mistaken for Peyronie’s disease or penile cancer. Microscopically (Fig. 16.122), they are non-encapsulated nodular proliferations of epithelioid endothelial cells associated with inflammatory infiltrate of lymphocytes and eosinophils. Endothelial cells are large, eosinophilic with large nuclei and prominent nucleoli. There are low mitotic index and absent nuclear atypia. Tumor can be considered typical or atypical (exuberant), the latter characterized by aggregates of epithelioid endothelial cells that did not form discrete vessels (immature capillary vessels). No metastases or death of disease were reported. Differential diagnoses include epithelioid hemangioendothelioma and epithelioid angiosarcoma [433]. Epithelioid hemangioendothelioma is a borderline malignant tumor characterized by proliferation of atypical epithelioid endothelial cells embedded in a hyaline connective tissue without eosinophil infiltrate. It is important to differentiate this benign tumor from the more histological and clinical aggressive malignant tumor, the epithelioid angiosarcoma. Prominent nuclear atypia, high mitotic index, and necrosis are usually distinctive [434].

The granular cell tumor of the penile dermis is very rare. Patient’s median age is 40 years at time of diagnosis [432]. Macroscopically, they are solitary, non-tender, firm masses on the penile shaft, prepuce, or glans corona. Microscopically (Fig. 16.123) the neoplasm is composed polygonal-shaped cells with prominent eosinophilic granular cytoplasm disposed in nests, cords, or trabeculae. Large vesicular nuclei without atypia are common. Mitoses range from 0 to 8 per 50 high-power field. Perineural and vessel wall invasion can be seen, but they are not indicative of malignant behavior [432]. S100, CD56, and CD68 immunostains are positive in the granular cells [437]. There are no reports of local recurrences or metastases [432].

Myointimoma of the penis is a rare benign myointimal proliferation involving exclusively the corpus spongiosum of the glans [430, 435]. Patients’ mean age is 29 years (range: 2–61 years old) [435]. Macroscopically, a glans-centered nodule of up to 2 cm of diameter is found. Microscopically (Fig. 16.124) there is an intravascular nodular to plexiform myofibroblastic (myointimal) proliferation that sometimes occluded the vascular spaces of the corpus spongiosum. Cells are mainly stellate-shaped or spindled, embedded in abundant fibromyxoid matrix. Immunohistochemistry is positive for SMA and negative for S100, CD34, and keratins in neoplastic cells. There are no recurrences or metastases [430, 435].

Malignant Mesenchymal Tumors

Penile primary sarcomas are a heterogeneous group including vascular (Kaposi’s sarcoma) and smooth muscle tumors (leiomyosarcoma) among the most frequent ones [428, 429]. Other less frequently cited tumors include fibrosarcoma, dermatofibrosarcoma protuberans, epithelioid sarcoma, malignant peripheral nerve sheath tumor, rhabdomyosarcomas, myxofibrosarcomas, Ewing’s sarcoma/PNET, synovial sarcoma, and osteogenic extraosseous sarcoma [383, 429, 440,441,442,441].

There are no differences between penile primary sarcomas and soft tissue tumors arising in other sites. We will describe the two most frequent mesenchymal neoplasms.

Kaposi’s sarcoma was referred as the most frequent penile malignant mesenchymal tumor [429]. This human herpes virus-8 (HHV-8)-driven tumor is common in HIV disease. A study based on data from the California Cancer Registry shows a fall in the prevalence of this tumor from 7.4% in the 1988–1995 cohort to 1.7% in the 1995–2004 cohort; nevertheless, from 1988 to 2004, the frequency of this cancer was 4.6% of all penile malignant neoplasms [442]. Macroscopically, this sarcoma presents commonly as multifocal; small bluish, black, or wine red; smooth-surfaced; or ulcerated papules or nodules, usually on the glans or coronal sulcus [5]. Microscopically (Fig. 16.125) hemorrhagic spindle cells with cytoplasmic eosinophilic globules proliferate in small vessels surrounding larger ecstatic ones. Early lesions can resemble hemangioma or lymphangioma but are typically associated with a lymphoplasmacytic reaction and may show protrusion of spindle cells into vascular lumina (so-called promontory sign). Nuclear HHV8-immunoreactivity is diagnostic. Endothelial markers CD34 and CD31 are also positive [383].

Primary leiomyosarcomas , as other penile sarcomas of the penis, are very rare. In a series of 14 patients with this tumor [443], mean age was 51 years (range 43–62 years). The masses are more frequent in penile shaft and range in size from 0.5 to 6 cm in greatest dimension. Leiomyosarcomas can be further divided in superficial or deep located; the latter arise from the supporting structures of the corpora cavernosa and spongiosum. Microscopically (Fig. 16.126) they are composed of variable amount of spindle cells with eosinophilic cytoplasm, significant nuclear atypia, mitotic activity, necrosis, and infiltrative growth pattern. Desmin immunostain is positive in neoplastic cells. Differential diagnoses are leiomyoma , Peyronie’s disease, epithelioid sarcoma, and rhabdomyosarcoma [377]. Local recurrences and metastases were reported. The best predictors of outcome are tumor depth and tumor size [443].

Non-neoplastic Mimics of Penile Neoplasias

A wide variety of dermatoses, congenital conditions, and infectious disorders affect the penis and can rarely be confused with penile neoplasms. Their features are essentially similar as those as seen elsewhere [444, 446], and the pathologic differential diagnosis with carcinoma is generally straightforward. Pathology knowledge is driven by frequency of the diseases, when lesions are very uncommon in one location or, in the other hand, if it is just seen in that location what makes it rare, diagnosis can be challenging. From the clinical viewpoint, it is important that problematic penile lesions be evaluated in concert with abnormalities in other areas of the body which may be key to establishing the diagnosis. We will look at some entities that can be confused with penile neoplasms.

Condyloma Acuminatum

It is a human papillomavirus (HPV)-related benign lesion affecting the anogenital area of sexually active young and middle-aged males. The commonest HPV genotypes are low-risk HPV 6 and 11, although other low- and high-risk HPV genotypes can also be involved [447, 448]. Common anatomical sites affected are the glans, the foreskin, the shaft, the meatus urethralis, or the distal urethra [444]. Macroscopically, it is frequently multicentric, variable in size from a millimetric papule to large typical cauliflower-like papillary appearance which sometimes lead to consider them malignant (Fig. 16.127a). Small flat lesions detected by peniscopy (treated with acetic acid) were described [444]. Microscopically (Fig. 16.127b–f) there are papillae with fibrovascular cores lined by epithelia with papillomatosis, acanthosis, parakeratosis, and hyperkeratosis. The hallmark of the lesion is the koilocyte, a superficial polygonal cell with ample cytoplasm, clear perinuclear halos, wrinkled nuclei, and frequent binucleation. Atypia is not present in common condylomas although dysplastic or atypical condylomas frequently associated with high-risk HPV were described [448, 449]. The differential diagnosis is straightforward based on histology. Although there are no considered premalignant lesions, malignant transformation was reported [451,452,452].

Giant Condyloma

Giant condyloma is a rare long-standing verruciform benign HPV-related tumor, which can sometimes be confused with warty or verrucous carcinomas, sometimes also designated as Buschke-Lowenstein tumor [410]. Most of the cases are associated with low-risk HPV [453, 454]. There are clinical differences. Affected males are older than those with typical condyloma acuminatum but younger than those with warty carcinomas. Malignant transformation to usual SCC may occur. Macroscopically, the lesion preferentially affects the foreskin and coronal sulcus, but they also occur in the glans. It is a usually unicentric whitish-gray, firm, cauliflower-like tumor larger than typical condyloma acuminatum (average size of 5–10 cm). The cut surface reveals solid cobblestone appearance with distinct sharply delineated boundary of tumor and underlying stroma. Microscopically (Fig. 16.128) this tumor is very similar to typical condyloma acuminatum, but the papillomatosis is more exuberant, and there is endophytic expansion into the subjacent tissue. There is a heterogeneous spectrum of pathological presentations, from that of typical condylomas to atypical condylomas, to malignant changes in situ within the condyloma, or to frank conversion to invasive squamous cell carcinomas [450, 453, 455].

The differential diagnoses include all other verruciform tumors: warty, verrucous, and papillary carcinomas. Warty carcinomas are characterized by condylomatous papillae that harbor cell atypia and jagged infiltrative tumor base, both features absent in giant condyloma. In verrucous SCC the fibrovascular cores are absent or minimal. In papillary SCC the tumor base is jagged and irregular. Koilocytes and HPV are consistently negative in these two aforementioned SCC variants [410].

Penile Cysts

Cysts arising in the penis are uncommon and can be found anywhere from the urethral meatus to the root of the penis involving glans, foreskin, or shaft. Epidermal inclusion cyst and median raphe cyst are the most frequent.

Epidermal Inclusion Cysts

Penile epidermal cysts are identical to similar lesions at other sites. Etiology is unknown, but some are most likely caused by injection of epidermoid tissue fragments (“epidermal inclusion cysts”) during hypospadia, phimosis, or penile girth enhancement surgical procedures. They are small (less than 1 cm) and typically occur on the coronal sulcus, near the frenulum, foreskin, or the shaft [457,458,458]. They affect patients of all ages from children to elderly. Small, pearly epidermal inclusion cysts in the foreskin of newborns called “Epstein preputial pearls” have been described [459]. Histologically, they are cavities lined by a stratified squamous epithelium with granular layer that surrounds the keratin content of the cyst [377]. There are no reports of recurrence or cancers developing from epidermal cysts.

Median Raphe (Urothelial) Cysts

These are also known as parameatal cysts when they are located on the border of the meatus. There were previously cited as “paraurethral cyst,” “genitoperineal cyst,” “mucoid cyst,” “urethroid cyst,” and “hidrocystoma/apocrine cystadenoma” [460, 461]. Their location gives rise to the hypothesis that these lesions are apparently caused by developmental defects in the embryogenesis of the genital and urinary tract resulting in an incomplete closure of the genital fold. Therefore, they are always located in the ventral aspect of the penis or on the median line of the perineum. Normally, they do not communicate with the urethra or cutaneous surface, but some cases can be connected with them [461]. Median raphe cysts are not uncommon, accounting for most of the cysts in one series of penile tumors and tumor-like lesions [462]. Clinically, they are mostly asymptomatic; however, some cases show dysuria, irregularity of the urinary stream, and difficulties or pain during sexual intercourse [464,465,465]. Median raphe cysts can contain a variety of epithelial linings: non-keratinizing squamous, pseudostratified and stratified columnar with or without mucous glands, urothelial type, ciliated, and apocrine-like [461]. Acute and chronic inflammation and reactive changes such as mucosal hyperkeratosis were observed in some cases. Differential diagnosis is with glomus tumor, epidermal cyst, dermoid cyst, pilonidal sinus, urethral diverticulum, and steatocystoma [466]. Presence of malignant transformation has been reported [467]. The variety of epithelial linings observed, the lack of definitive answers to their origin, and the potential difference in pathogenesis that they entail the term “median raphe cyst” seems vague, and it may be preferable to name these lesions by the histology they present [461].

Dermoid Cyst

They are dermal located tumors containing cutaneous adnexal structures such as sebaceous glands and hair follicles . They are typically found in the head and neck area, but a case of a penile dermoid has been reported [423]. Differential diagnosis should include with trichilemmal cysts, epidermoid cyst, and steatocystoma [377].

Lymphatic Cyst

Lymphatic cystic masses are exceptional in the penis [468, 469]. They are growing and multiloculated lump that presented as a firm and partially mobile lesion containing translucent fluid causing steady discomfort. Microscopically, endothelial-lined multiple cavities resembling a lymphatic vessel wall are seen [468, 469].

Verruciform Xanthoma

Verruciform genital-associated (Vegas) xanthomas are rare exophytic lesions that can involve the penis [470]. About 30 penile cases have been reported [471]. The mechanism of pathogenesis is unknown, multifactorial etiology involving inflammation, local immunosuppression, and/or metabolic dysfunction has been postulated [470]. Pathologically it is similar to the lesion of the oral cavity. Macroscopically, it may appear as verrucoid, polypoid, or even a flat lesion that can be grossly confused with penile verruciform tumors or condylomas. Microscopically (Fig. 16.129) they are characterized by papillary squamous hyperplasia with acanthosis, papillomatosis, hyperkeratosis, and parakeratosis. A distinctive feature is the presence of a prominent xanthomatous dermal infiltrate between elongated rete ridges, sometimes associated with neutrophils [377, 5]. The foamy cells are positive for CD68 [472], weakly positive for cytokeratin and factor XIII, and negative for S100 [473]. Differential diagnosis includes condyloma acuminatum, seborrheic keratosis, granular cell tumor, and verruciform penile tumors. Distinctive xanthomatous infiltrate should facilitate the diagnosis. Periodic acid Schiff-positive and CD68 positive, as well as S100 negative immunostains, can be helpful in difficult cases [471].

Peyronie’s Disease

Peyronie’s disease is a rare condition of unknown etiology characterized by one or multiple dense fibrotic plaques or nodules affecting dermis and Buck’s fascia and originating in the tunica albuginea of the penile shaft. Clinically, this lesion can produce an abnormal curvature of the penis with painful erection and sexual intercourse. Peyronie’s disease is considered a variant of superficial fibromatosis [474]. Tunica mechanical stress and microvascular trauma are pathogenetic contributory factors [475]. Prevalence of this disease is from 0.5% to 10% of males in general population, with a median of between 48 and 58 years [475, 476]. Typically, a firm area or plaque is detected on the dorsal surface of the erect penis. Examination in the flaccid state is usually unremarkable. Often, the process is diffuse, but a plaque-like lesion potentially causing concern for a neoplasm may be present [377]. Microscopically, it involves disorganization of collagen fibers and presence of myofibroblasts similar of other fibromatosis although it tends to be less cellular and more sclerotic than most superficial fibromatosis of other sites. A perivascular lymphoid infiltrate and rarely calcification or ossification were reported [477]. Severe deformation with local induration can be confused with penile neoplasm.

Papillomatosis of Glans Corona

It is a common condition present in 20–30% of normal males characterized by multiple small papules of the glans corona . There is an association with marked sexual activity [478]. The lesions are multiple, asymptomatic, pearly gray to white small papules arranged in one to three rows on the dorsal aspect of the glans corona [377]. They are often confused with HPV-related lesions, but diagnosis by dermoscopy is straightforward [479]. Microscopically, there are features of angiofibroma or fibroepithelial papilloma. Differential diagnosis is condyloma acuminatum and lacks of koilocytes is the clue.

Lipogranuloma

It is a chronic inflammatory granulomatous reaction secondary to the local subcutaneous injection of foreign substances into the penis, such as Vaseline, paraffin (hence the common denomination of penile paraffinoma), silicone, or wax [480]. The lesion can be solitary or involve adjacent structures, usually the scrotum. Grossly, there may be marked abnormalities of the penis with distortion of the organ, tumor mass, or ulceration that can lead to a confusion with a neoplasm [481]. An appropriate history may suggest the diagnosis before biopsy. Microscopic examination shows numerous, variably sized vacuoles, separated by a stroma with prominent inflammatory cell infiltrate and abundant foreign body-type multinucleated giant cells. Because of the marked sclerosis that is sometimes present, the designation sclerosing lipogranuloma is appropriate [480]. The differential diagnosis comprises adenomatoid tumor, sclerosing liposarcoma, or lymphangioma. The vacuoles are much more variable in size than those of the adenomatoid tumor and contain lipid. Absence of endothelial cells from the lining of the vacuoles and cysts differentiates lymphangioma from lipogranuloma. The foreign body giant cells of sclerosing lipogranuloma are not seen in the other entities, and, in contrast to sclerosing liposarcoma, lipoblasts are absent. Lipogranulomas involve the scrotum or penis, liposarcoma typically is in the paratesticular region, and adenomatoid tumor is near the head of the epididymis [377].

Lichen Sclerosus

Lichen sclerosus is a chronic inflammatory sclerotic disorder affecting the penis and vulva. The term “balanitis xerotica obliterans” was used for the end stage of the disease. This condition affects mainly the foreskin or glans and is identical to vulvar lichen sclerosus et atrophicus [378]. It may produce phimosis, with severe narrowing of the preputial orifice or the urethral meatus [482]. This lesion is associated with special subtypes of well-differentiated squamous cell carcinomas [378]. Macroscopically, gray-white, irregular, atrophic, or slightly raised areas located in the foreskin or glans are seen. In advanced stages, marked narrowing of the preputial ring and vanishing of the mucosal folds of the foreskin due to replacement of elastic fibers by fibrous tissue is the rule [377]. Microscopically (Fig. 16.130) a topographical evaluation of the tissue layers typically involved by penile lichen sclerosus is helpful because the lesion is usually restricted to lamina propria, rarely affecting preputial dartos [483]. Epithelium is either hyperplastic (more common) or atrophic. There is hyper- or parakeratosis, and ulceration with secondary inflammation can be seen. The basal layer at the interface shows vacuolar degeneration, and the epithelium may be found separated from lamina propria. Superficial lamina propria shows characteristic perivascular, globular, or linear hyalinization, while deeper lamina propria shows edema or sclerosis with hyper-vascularity in some cases. Sclerosis can reach dartos or superficial corpus spongiosum. A lymphocytic inflammatory infiltrate in the dermis is variable in topography or density.

The lesions tend to be broad and multifocal, may affect more than one epithelial compartment, and may even extend to the epithelium and lamina propria of the distal urethra [378].

The relationship of anogenital lichen sclerosus and squamous cell carcinoma is well documented [230, 484, 485]. A significant association of lichen sclerosus with special (non-HPV-related) variants of squamous cell carcinoma such as usual, pseudohyperplastic, verrucous, and papillary has been demonstrated. A distinct association of lichen sclerosus with differentiated penile intraepithelial neoplasia was found [385, 409, 413]. These findings suggest that lichen sclerosus may represent a precancerous condition for a subset of penile squamous cell carcinoma , especially the non-HPV-related variants [383].

Staging

Table 16.14 describes the last revision of TNM staging by the American Joint Committee on Cancer [230]:

Table 16.14 TNM staging system for penile carcinomas (TNM8, 2017)

Full size table

Scrotum

Non-neoplastic Lesions

Epidermal Inclusions Cysts

Epidermal inclusions cysts are common lesions, similar to those seen in other parts of body. They may present as single or multiple dermal nodules, containing keratinous debris. Cysts are lined by benign keratinizing squamous epithelium.

Idiopathic Scrotal Calcinosis

Idiopathic scrotal calcinosis is a rare benign condition that presents multiple painless nodules of the scrotal wall [486]. The condition typically presents in adolescence and early adulthood and is of unknown etiology. Metabolic panels are typically normal and do not show and abnormalities in calcium or phosphate levels. Some literature appears to suggest that these lesions may occur as a result of delayed secondary calcification of epidermal inclusion cysts. Nodules are slow growing and gradually increase over time, presenting as chalky white firm lesions within the scrotal skin. Histologically, lesions are characterized by large deposits of calcification within the dermis [487, 488]. Deposits are not associated with an epithelial lining, and long-standing lesions may be associated with a granulomatous reaction.

Neoplastic Lesions

Squamous Carcinoma

The incidence of squamous carcinoma is far less than that of penile squamous cell carcinoma (SCC). It was the first tumor that was linked directly to an occupation, after being linked to chimney sweepers by Pott in 1775 [488]. Since then, scrotal SCC has also been linked with exposure to HPV [489]. Other risk factors include exposure to psoralens and ultraviolet A radiation and immunosuppression etc. Squamous cell carcinoma represents the majority of primary scrotal neoplasms [490]. Tumors are generally locally invasive and frequently present as ulcerated masses. The prognosis is poor and inguinal lymph node metastasis is common. Histologically, the majority of cases present as well or moderately differentiated squamous cell carcinoma, although the basaloid and warty variants are commonly seen in HPV associated tumors [489]. Conventional staging systems that are applied to penile carcinoma are not applicable to scrotal tumors, and the current staging system used is the Lowe’s modification of the Ray and Whitmore system (Table 16.14) [490].

Basal Cell Carcinoma

The incidence of basal cell carcinoma (BCC) in non-sun-exposed areas remains quite low. The scrotum accounts for <1% of all BCCs as a primary site. Tumors present as painless, ulcerating nodules, and the histology is similar to that of BCC seen in the skin. The prognosis remains good, with no reported cases of metastasis in one large series [491, 492]

Paget Disease

Extramammary Paget disease can rarely occur in the penis and scrotum. Patients are commonly between 50 and 80 years of age and usually presents as a scaly, eczematous lesion [493]. Cases have been reported in association with underlying carcinomas of the penis, prostate, and urethra. Histologically, the epidermis shows involvement by neoplastic cells that show large nuclei, prominent nucleoli, and abundant pale to amphophilic cytoplasm. Cells may be seen in clusters or as isolated cells within the dermis, with frequent involvement of the cutaneous adnexal structures. Reactive changes, including hyperkeratosis and parakeratosis of the overlying epidermis, are commonly noted. The main differential diagnostic considerations include squamous carcinoma in situ, pagetoid Bowen’s disease, and melanoma. CK7 is a sensitive marker for Paget disease and is typically diffusely and strongly positive in the neoplastic cells (Fig. 16.131). Rare cases of CK7 expression have been described in pagetoid Bowen disease, which may be a cause of confusion and misdiagnosis. In addition, the neoplastic cells of Paget disease express CEA and are negative for melanocytic markers. A mucicarmine stain may help in the diagnosis as the cells of Paget disease express intracytoplasmic mucin, while the cells of Bowen disease and melanoma typically do not. GCDFP-15 is another immunohistochemical marker that has been reported to be positive in Paget disease and absent in Bowen disease and melanoma and is useful in the workup of these lesions when the diagnosis is in question (Table 16.15) [496,497,496].

Table 16.15 Lowe’s staging of scrotal squamous cell carcinoma

Full size table

Part II: Tumors of the Urinary Tract

Tumors of the Kidney

Gross Examination

Gross examination and proper handling of the kidney is the first and most critical step in the management of renal cell carcinoma. It is vital to be familiar with and correctly identify the various anatomic landmarks of the kidney, including the renal sinus, the renal pelvis, and the hilar and the ureteral margins. The types of resections for renal tumors include (a) radical nephrectomy, (b) partial nephrectomy, and (c) nephroureterectomy (for upper urothelial tract urothelial carcinoma). Although historically RCCs were treated with radical nephrectomies, partial nephrectomies are becoming increasingly common and now represent the most common type of surgical option for most small, organ-confined renal tumors. The protocol for gross examination is elucidated below.

Radical Nephrectomy

1.
Measure the specimen (three dimensions).
2.
Take renal vein and artery margins . Open renal vein to check for invasion by tumor. This is a critical step and should be done immediately after sampling the margin and before the kidney is bivalved in order to detect a small thrombus in the proximal renal vein (Fig. 16.132).
3.
Take the ureter margin. Open and examine the ureter. This step also provides information regarding side and orientation.
4.
Palpate for lymph nodes in hilar region.
5.
Completely bivalve kidney with perinephric adipose tissue intact. The renal capsule should NOT be peeled off as this provides valuable staging information.
6.
Measure three dimensions of the tumor and note location.
7.
Ink soft tissue margin closest to tumor. It is not necessary to ink the entire specimen.
8.
Section the entire kidney at 2.5 mm intervals from superior to inferior.
9.
Check for invasion into perinephric adipose tissue.
10.
Check renal sinus for invasion by tumor.
11.
Check for adenomas, other findings.
12.
Section the adrenal gland (if present) at 3.0 mm intervals.
13.
Sections should document the type of tumor, the extent of invasion, and any other incidental findings. Minimum sections include:
1. (a)
  Ureter, renal artery, and renal vein margins in one cassette.
2. (b)
  Tumor: one section per centimeter of maximum diameter (minimum 6 sections if tumor is ≤5 cm), including tumor/kidney junction, tumor/perinephric adipose tissue, tumor and closest inked soft tissue margin, tumor/renal sinus, tumor in renal vein, tumor foci with different appearance, and sarcomatoid appearing areas. Note: Avoid completely necrotic areas, gelatinous/hyaline areas, and areas of extensive hemorrhage.
3. (c)
  Other findings: adenomas, cysts, etc.
4. (d)
  Non-neoplastic kidney: two sections.
5. (e)
  Adrenal gland: one section if normal, one section/cm if tumor is present.
6. (f)
  Lymph nodes if palpable.
14.
Submit tissue for cytogenetics , research, tissue bank, etc. if indicated.

Partial Nephrectomy

1.
Speed is essential in processing these at time of frozen section.
2.
Measure the specimen.
3.
Ink the parenchymal resection margin.
4.
Make the first cut through the middle of the tumor.
5.
Section the entire specimen at 2.0 mm intervals, at right angles to the parenchymal resection margin (Fig. 16.133).
6.
Examine the tumor closely to determine the area closest to the parenchymal resection margin (including area marked by surgeon).
7.
If the tumor appears to be sufficiently away from the margin, a visual inspection will often suffice, thus eliminating the need for a histologic section. If the margin is grossly close, submit one section (rarely two) of the tumor and the closest parenchymal resection margin (perpendicular margins) for frozen section diagnosis. It is not advised to submit most of the tumor for frozen section if it is a small tumor. A small amount of the tumor with the margin (3–4 mm is usually enough).
8.
The renal parenchymal margin should always be taken perpendicularly. Enface margins should not be submitted, except when renal parenchymal margins are sent as separate specimens.
9.
Check for invasion into perinephric adipose tissue.
10.
Minimum sections required include the following:
1. (a)
  Minimum one section of tumor per cm including tumor/kidney junction and tumor/perinephric adipose tissue. Submit the entire tumor if less than 3.0 cm in maximum dimension (minimum of six sections if tumor is <5 cm).
2. (b)
  Report other gross findings: adenomas, cysts, etc.
3. (c)
  Perinephric adipose tissue: Slice thin to check for masses. Submit a single representative section unless otherwise indicated.

Benign Renal Tumors

Papillary Adenoma

The term renal papillary adenoma describes small papillary tumors within the kidney of low nuclear grade. Size criteria for what constitutes a papillary adenoma of the kidney have evolved over the years. Although metastasis has been reported in tumors as small as 9 mm [497], it was suggested that tumors that measure less than 1 cm with no nuclear atypia be classified as renal papillary adenomas [498]. A 1998 consensus conference proposed a cut off of 5 mm for the diagnosis of papillary adenoma [499]. The current recommendation by the international society of urologic pathologists (ISUP) suggests classifying tumors that measure 1.5 cm or less, with low-grade nuclei as papillary adenomas. In a retrospective review of over 500 nephrectomies, Wang et al. found the incidence of renal papillary adenomas to be 7% [500]. Histologically, papillary adenomas are unencapsulated lesions that are composed of closely packed renal tubules, without any significant nuclear atypia that are present within the renal cortex (Fig. 16.134). While these lesions, in general, do not pose a diagnostic dilemma, issues may arise, especially on frozen section, when there is a papillary lesion incompletely represented at the margin of a partial nephrectomy specimen. In such a scenario, it is our practice to compare the histology with that of the primary renal neoplasm. If it appears that the main tumor has been completely resected, it is best to communicate a diagnosis of “renal papillary neoplasm at the margin” to the surgeon and defer to imaging findings to assess the size of the secondary lesion.

Renal Oncocytoma

Renal oncocytoma (RO) comprises approximately 5–7% of all renal neoplasms and can occur in a wide range of age groups, with the mean age at presentation being the 7th decade. Tumors show a male predominance and most tumors are detected incidentally [501]. Early studies were unclear about the malignant potential of these neoplasms, but this was due to ambiguity about criteria that defined RO [502].

Macroscopic Appearance

Grossly the typical appearance of RO is that of a mahogany brown, well-circumscribed tumor, with or without a surrounding capsule (Fig. 16.135). Although areas of hemorrhage may be noted, necrosis is unusual. Gross involvement of the renal sinus or perinephric fat may sometimes occur. A characteristic feature is that a “central scar” that is thought to be the result of the slow pace of growth of the tumor. Tumors may be bilateral in approximately 10–13% of cases and multifocal in approximately 5–13% of cases [503, 504].

Histologic Appearance

Histologically most tumors show a nested appearance with intervening loose fibroconnective tissue or myxoid stroma separating the tumor nests. Tumors may also show a solid pattern that results from compression of tumor nests. Other patterns that may be noted include tubular, trabecular, or cystic. The typical neoplastic cells show prominent granular, eosinophilic cytoplasm that results from the accumulation of mitochondria (Fig. 16.136) [503,504,505,506,505]. Another cell type that may be seen is the “oncoblast” which is a cell with a more basophilic appearance due to the scant cytoplasm and the prominent hyperchromatic nuclei. In a seminal paper by Amin et al., the authors describe certain “atypical” features that are not commonly noted in benign neoplasms that are acceptable in RO and still allow the tumor to be classified as a benign tumor. These include invasion into the perinephric fat, hemorrhage, small vessel lymphovascular invasion, focal microscopic necrosis, and rare “typical” mitotic figures. However, the diagnosis of RO should not be made if the tumor displays extensive papillary features, prominent necrosis, frequent mitotic figures or atypical mitoses, or gross involvement of the renal vein. Areas of any other identifiable renal cell carcinoma subtype or sarcomatoid differentiation argue against a diagnosis of RO [506].

Immunohistochemical Findings

Immunohistochemistry can be helpful in the distinction of RO from other oncocytic tumors. Vimentin is typically negative in both RO and chromophobe RCC (ChRCC). CK7 can be useful in the distinction between the two entities, as it is typically only sporadically positive in a single-cell fashion in RO, in contrast to ChRCC which usually shows diffuse, strong expression of CK7. Other stains including CD117 and E-cadherin are positive in both RO and ChRCC and are not helpful in making the distinction.

Molecular Findings

Renal oncocytomas are characterized by various molecular patterns. The most frequent abnormality is the combined loss of chromosomes 1 and X/Y, with partial or complete loss of chromosome 1 being the most common alteration in both sporadic and inherited cases. Other molecular abnormalities that have commonly been reported include translocations involving chromosome 11. Other rare reported translocations include t(1;12)(p36;q13), loss of chromosome 14, and gain of chromosome 12 [506].

The prognosis of RO , when strictly defined, is excellent with no reported cases of metastases identified. Much of the older literature where cases of “metastatic oncocytoma” were reported are prior to the standardized nomenclature and the definition of histologic parameters that are acceptable for the diagnosis of RO. It has been postulated that metastatic oncocytic lesions likely result from inclusion of chromophobe renal cell carcinoma or oncocytoma coexisting with other histologic subtypes. Sampling of these tumors is critical as even a focal area of histology outside of the defined criteria should be the cause for exclusion of a diagnosis of RO.

Metanephric Adenoma and Metanephric Adenofibroma

Metanephric adenoma (MA) is a tumor that is thought to arise from the primitive proximal tubule of the kidney or nephrogenic rests. The tumor shows histologic similarities to Wilm’s tumor with certain authors postulating that Wilm’s tumor represents the malignant end of the spectrum of this family of neoplasms [507, 508]. Metanephric adenoma most commonly occurs in the 5th and 6th decades (age range of 5 to greater than 80 years) and shows a strong female preponderance. While about half of patients are diagnosed incidentally, a large number of patients present with polycythemia, which often resolves with the removal of the tumor [509]. These tumors typically follow a benign clinical course with no reported cases of metastases in the literature.

Macroscopic Appearance

MAs typically present as a unilateral, solitary, unencapsulated but well-circumscribed renal neoplasm with a solid gray-tan cut surface. Calcification, hemorrhage, and necrosis may also be identified (Fig. 16.137).

Histologic Appearance

The histologic appearance is that of a primitive epithelial neoplasm that bears a striking resemblance to type 1 papillary RCC. Tumor cells are typically arranged in nests and abortive papillae. A common histologic feature is the presence of “glomerulations” (Fig. 16.138). Calcifications or psammoma bodies are also a frequent histologic finding. Mitotic activity is infrequent, which helps in the distinction from epithelial predominant Wilms tumor.

Metanephric adenofibroma is a rare biphasic tumor that typically occurs in children and young adults. The epithelial component of this lesion is similar to that seen in MA. In addition there is a prominent low-grade spindle-cell component that is an integral part of the tumor. Like metanephric adenoma, patients often present with polycythemia that is related to the tumor. Hematuria is common as tumors are often centrally located and involve the pelvis.

Immunohistochemical Findings

By immunohistochemistry, these tumors show strong nuclear staining for WT-1 and CD57. CK7 is often positive in a patchy manner. EMA and p504S are typically not expressed in these neoplasms.

The main differential diagnoses are papillary renal cell carcinoma and epithelial predominant Wilm’s tumor. Lack of encapsulation, the presence of uniform structures resembling tubules, and the absence of diffuse staining with CK7 along with weak or absent staining for P504S help in the distinction from type 1 papillary renal cell carcinoma. The foamy macrophages that are commonly seen in PRCC are also not common in MA. The older age of the patients and absence of mitotic activity or a blastemal component and necrosis mitigate against a diagnosis of epithelial predominant Wilms tumor.

Renal Cell Carcinoma

The incidence of renal cell carcinoma (RCC) has been steadily rising over the years. Per the SEER data, there were approximately 62,000 new cases of kidney and renal pelvis cancer diagnosed in 2016 accounting for 15.6 new diagnoses per 100,000 people per year and making it the 9th most common cancer to be diagnosed. The mean age at diagnosis is 64 years, with the incidence peaking in the 6th and 7th decades of life (https://seer.cancer.gov/statfacts/html/kidrp.html). The identification of new histologic subtypes of RCC, coupled with increasing knowledge about the molecular genetics of these neoplasms, has led to a greatly expanded classification of renal tumors. The current classification of RCC as proposed by the consensus conference from the International Society of Urologic Pathologists (ISUP) in 2012 is elaborated in [510].

Clear Cell Renal Cell Carcinoma

It is estimated that there are approximately 63,000 newly diagnosed cases of RCC in the US each year [511]. Clear cell renal cell carcinoma (CCRCC) is the most common histologic subtype of RCC and accounts for approximately 75–85% of all RCCs.

Macroscopic Appearance

On gross examination, the typical appearance of a CCRCC is that of a “golden-yellow” tumor. Larger tumors often demonstrate hemorrhage and necrosis (Fig. 16.139). Occasionally tumors may show a more hemorrhagic appearance. It should be noted that when CCRCC is larger than 7 cm in size, it is almost always accompanied by invasion into the renal sinus, which should be sampled thoroughly to exclude a higher-stage tumor. When sarcomatoid dedifferentiation is present, these areas are often “fleshy” tan-white, often resembling a mesenchymal component (Fig. 16.140). Occasionally, CCRCC may present with an extensive cystic appearance that may superficially mimic a multilocular cystic renal neoplasm (Fig. 16.141). However, upon closer examination, there are almost always aggregates of golden-yellow tumor nodules present within the septae that are often visualized grossly. The presence of these aggregates of tumor cells mitigates against a diagnosis of multilocular cystic renal neoplasm, which, by definition, lacks expansile tumor nodules within the septae. The distinction is crucial as clear cell RCC with cystic change is prognostically similar to CCRCC, with the potential for metastasis due to a higher-tumor burden [512]. The wide range of gross morphologies noted in CCRCC makes it imperative to do a thorough gross evaluation and sample areas to identify different morphologies and grades within a single tumor.

Histologic Appearance

Histologically, the classic appearance of CCRCC is that of a tumor of nests of cells with clear cytoplasm surrounded by a delicate network of blood vessels. In addition, tumor may also show foci with more eosinophilic cytoplasm, resulting in the “granular” cell appearance of CCRCC that has been described in the older literature (Fig. 16.142).

Immunohistochemical Findings

By immunohistochemistry, most CCRCCs show diffuse staining with cytokeratin, EMA, CD10, PAX-8, PAX-2, and vimentin, with focal expression of P504S. Carbonic anhydrase IX shows a membranous staining pattern in virtually all CCRCCs and can be a useful adjunct, in conjunction with PAX8, in the workup of poorly differentiated renal neoplasms, especially at metastatic sites [513]. Although expression of CK7 is uncommon, some studies have reported CK7 expression in up to a third of CCRCCs, although the expression is usually only focal [514, 515]. In our experience, more diffuse and strong expression of CK7 can be observed in CCRCCs with more cystic areas with particularly strong CK7 expression around the cystic areas. This may represent a diagnostic pitfall, especially in small biopsies, and the presence of CK7 expression, solely, does not always exclude a diagnosis of CCRCC, especially in the presence of a cystic component.

Although the diagnosis of a typical low-grade CCRCC does not usually pose a diagnostic dilemma, high-grade tumors without and identifiable “clear cell” component may pose diagnostic difficulty. This is especially true when tumors are extensively granular or show sarcomatoid or rhabdoid dedifferentiation. Sarcomatoid transformation occurs in approximately 5% of CCRCCs and may mimic a sarcoma on light microscopy and immunohistochemistry. Before making a diagnosis of a primary renal sarcoma, a sarcomatoid carcinoma should always be excluded as it is a more commonly occurring scenario than the latter.

Molecular Findings

CCRCC shows consistent cytogenetic abnormalities affecting the short arm of chromosome 3. These changes may be seen in both the hereditary and sporadic forms of CCRCC. Cytogenetic abnormalities are detected in in 50–90% of CRCC with deletions of 3p25, associated with the von Hippel-Lindau gene (VHL), 3p21-22, and 3p13-14, associated with familial renal cell carcinoma. In over 90% of CRCC, an expanded area of deletion is encountered over 3p14.2 to 3p25 which encompasses both the VHL gene and the FHIT gene. Chromosome 3p deletions are observed in almost all CRCC including very small incidentally detected tumors, suggesting that they are the initial genetic event in the development of CRCC . Complex abnormalities of chromosomes 5, 17, 7, and 14 are reported to be late events in a sequence of malignant and sarcomatoid transformation [516, 517].

Specifically chromosome 9p loss is associated with a poor prognosis, and 14q loss is associated with higher-grade and pathologic stage.

Sarcomatoid Dedifferentiation in Renal Cell Carcinoma

Sarcomatoid transformation may occur and any histologic subtype of RCC and is no longer considered to be a diagnostic category by itself. Sarcomatoid dedifferentiation is reported in approximately 2–5% of all RCCs [518] and usually presents as locally advanced disease.

The term sarcomatoid dedifferentiation refers to the anaplastic transformation of the RCC into a high-grade biphasic tumor that has both carcinomatous and sarcomatous elements. The sarcomatoid component may be undifferentiated or resemble an unclassified spindle-cell sarcoma and rarely may show heterologous differentiation into bone, cartilage, or skeletal muscle (Fig. 16.142).

The main differential diagnosis for these tumors, especially when the sarcomatoid component predominates, is primary sarcomas of the kidney. However, primary renal sarcomas are rare, and due diligence which includes extensive sampling of the tumor must be performed to thoroughly exclude a malignant epithelial component before making a diagnosis of a primary renal sarcoma. The majority of these tumors present at high stage with poor prognosis. The amount of sarcomatoid dedifferentiation should be reported as a percentage of the entire tumor as this has historically shown some prognostic value. However, any amount of sarcomatoid dedifferentiation must be reported as even tumors with a minor sarcomatoid component (5–15%) has been reported to result in metastasis and cancer-specific death [519, 520].

By definition, all sarcomatoid RCCs must be assigned a Fuhrman nuclear grade of 4. Every attempt must be made to identify the “parent tumor” that has undergone sarcomatoid dedifferentiation. In a scenario, where a tumor is exclusively sarcomatoid, it is our policy to go back to the gross bench and extensively sample the tumor till an epithelial component is identified, as identification of the underlying parent tumor may play a crucial role in therapeutic decisions for the patient. If after extensive sampling, an epithelial component is still not identified, it is best to classify such tumors as “unclassified renal cell carcinoma, with extensive sarcomatoid dedifferentiation. ” It is also important to note that immunohistochemical stains may not necessarily be of help in establishing renal origin in a sarcomatoid tumor, as the sarcomatoid component may lack all typical markers of renal origin.

Multilocular Cystic Renal Cell Neoplasm of Low Malignant Potential/Multilocular Cystic Renal Cell Carcinoma

The 2004 WHO classification recognized multilocular cystic renal cell carcinoma (MCRCC) as a variant of clear cell renal cell carcinoma that has an excellent prognosis. Strictly defined, these tumors grossly are extensively cystic renal tumors that are often incidentally detected before patients are symptomatic (Fig. 16.143). Microscopically cysts are lined by clear cells with low-grade nuclei. The defining feature that separates these tumors from CCRCC with cystic change is the lack of expansile tumor nests within the septae that alter the septal configuration (Fig. 16.144). The low-tumor burden is presumably a contributing factor for the excellent prognosis reported for these tumors. The lack of metastasis and the overall excellent prognosis has prompted the International Society of Surgical Pathology (ISUP) to rename these tumors as “multilocular cystic renal cell neoplasm of low malignant potential” [510]. However, it is imperative to separate these tumors from both clear cell renal cell carcinoma with extensive cystic change and extensively necrotic renal cell carcinoma, both of which have a distinct potential to metastasize. The presence of expansile tumor nodules that alter the septal configuration and/or the presence of tumor necrosis should give the pathologist pause before making the diagnosis of MCRCC. On a molecular level, approximately 75% of MCRCCs show 3p deletions similar to those seen in CCRCC, thus underscoring the fact that this tumor likely represents a spectrum of CCRCC rather than a distinct entity [521]. It should be noted that the tumor shows an immunohistochemical staining pattern that is similar to that of CCRCC, except for the frequent expression of CK7 in MCRCC, due to the cystic nature of these neoplasms.

Papillary Renal Cell Carcinoma

Papillary renal cell carcinoma (PRCC) is the second most common subtype of RCC after CCRCC and accounts for approximately 10–15% of all renal cell carcinomas. The tumor is more common in males by a ratio of 2:1, and there is a wide range of age at diagnosis.

Macroscopic Appearance

Grossly, tumors tend to be friable, brown with extensive necrosis. Tumors often show a fibrous capsule at the periphery, even when the tumor size is large, and hence PRCC can be organ confined, even in the face of a larger tumor at presentation. Adequate fixation of the tumors prior to sectioning is often crucial to prevent artifactual carryover (Fig. 16.145).

Histologic Appearance

There are two major histologic subtypes of RCC. Type 1 PRCCs show more amphophilic to basophilic cells and show an extensive tubulopapillary appearance. Nuclei are usually low grade with inconspicuous nuclei. Glomerulations are commonly identified, as are the presence of foamy macrophages within the stroma. Type 2 PRCCs are usually more eosinophilic, and tumor cells show high-grade, pseudostratified nuclei with prominent nucleoli and abundant cytoplasm. Glomeruloid bodies and foamy macrophages are less common. A fibrous pseudocapsule is often a histologic feature in both subtypes (Fig. 16.145) [522].

Immunohistochemical Findings

Immunohistochemistry can be a useful adjunct in the characterization of PRCCs, especially on small biopsy specimens. AMACR (P504S) is diffusely positive in both subtypes. CK7 is usually diffusely positive in type 1 PRCCs but is only focally positive or negative in type 2 PRCCs. This is important to recognize while evaluation a biopsy specimen, where CK7 staining may be completely absent in an otherwise typical appearing type 2 PRCC.

Molecular Findings

Type 1 PRCCs are associated with a gain of chromosome 7 and/or 17. Multiple bilateral type 1 PRCCs can be associated with hereditary PRCC syndrome, which is associated with germ-line mutations in the MET gene and results in the development of countless bilateral type 1 PRCCs [523].

Clear Cell Papillary Renal Cell Carcinoma

Clear cell papillary renal cell carcinoma (CCPRCC) first received widespread recognition with Tickoo et al. who described 15 tumors with distinctive morphology in patients with end-stage renal disease [524]. Since then CCPRCC has been widely recognized in the non-end-stage renal disease setting and accounts for approximately 4% of renal tumors, making it the 4th most common renal tumor [525].

Macroscopic Appearance

Grossly, the majority of CCPRCCs are cystic and small in size. In a study of 36 tumors by Aydin et al., the authors found the mean tumor size to be 2.4 and described multifocal tumors in 17% of cases [526].

Histologic Appearance

Histologically, tumors are usually at least partially cystic and demonstrate a thick capsule around the tumor, either circumferentially or partially. Tumors show a tubulopapillary appearance with fibrotic intervening stroma. Nuclear features are distinct, with low-grade cytology and uniform nuclei that are arranged away from the basement membranes, imparting a “picket fence” appearance (Fig. 16.146).

Tumors with similar morphologic appearance and immunohistochemical profile were first reported by Michal et al. in 2000. The tumors in their study showed prominent smooth muscle stroma [529,530,529]. This variant, now termed renal angiomyoadenomatous tumor (RAT), shows a prominent smooth muscle component with the presence of abortive vascular structures and an epithelial component that is identical to that described in CCPRCC (Fig. 16.147) [527].

Immunohistochemical Findings

By immunohistochemistry , CCPRCC is diffusely and strongly positive for CK7, which helps in the distinction from CCRCC. Carbonic anhydrase IX is positive in greater than 90% of CCPRCCs and shows a “cup-like” pattern of staining. P504S and CD10 are usually negative or only focally positive in CCPRCC, which helps in its distinction from CCRCC and papillary RCC [530].

Distinction from other subtypes of RCC is important as CCRCC shows an excellent prognosis with no reported local recurrences or metastasis reported thus far. Genetically, these tumors do not show any distinct molecular aberrations. Importantly, tumors lack 3p deletions, even when they occur in the setting of Von Hippel-Lindau disease (VHL), thus underscoring that this tumor is indeed a unique entity [531].

It should be noted that tumors with CCPRCC-like morphology have been described in the setting of VHL disease. Tumors in this clinical setting are often concurrently seen with CCRCC and show a similar histologic appearance to that of CCPRCC including a tubulopapillary pattern of growth, flattened cysts, and apically arranged nuclei [532]. Unlike CCPRCC, this variant often shows only focal or absent expression of CK7 and CD10 expression in the majority of cases. Tumors in this setting also show 3p deletions classically associated with CCRCC in the setting of VHL disease. Awareness of this histologic variant of CCRCC is important for accurate classification and therapeutic options.

Molecular Findings

CCPRCC and RATs do not appear to demonstrate any consistent chromosomal abnormalities. These tumors lack the trisomy/polysomy for chromosomes 7 and 17 and do not demonstrate loss of chromosome Y, which are abnormalities typically associated with PRCC. A small number of CCPRCC cases have been reported to show mutations in the VHL gene, even in the setting of classic morphology and immunohistochemical findings [533].

Chromophobe Renal Cell Carcinoma and Hybrid Oncocytic/Chromophobe Tumors

Chromophobe renal cell carcinoma (ChRCC) is believed to arise from the intercalated cells in the collecting duct system [534]. While the majority occur as sporadic tumors, there are a subset of tumors that arise in the setting of Birt-Hogg-Dube syndrome that is associated with the development of cutaneous fibrofolliculomas, pneumothorax, and multiple oncocytic tumors [535].

Chromophobe RCC accounts for approximately 5% of renal neoplasms in most series and does not show a gender predilection [528]. Age at diagnosis ranges from the 3rd decade to the 9th, and tumors are often detected incidentally as tumors are slow growing and may not present with any symptoms [536].

Macroscopic Appearance

Grossly, sporadic ChRCCs most often solitary, well-circumscribed tumors, with a homogeneous, tan-brown cut surface. On occasion, focal areas of hemorrhage and/or necrosis may be noted. Tumor size can vary widely, and it is not uncommon to encounter very large tumors that are still confined to the kidney due to the slow-growing nature of the tumor (Fig. 16.148).

Histologic Appearance

Microscopically, there are two well-recognized histologic variants. The “classic” appearance is that of a tumor arranged in sheets with interspersed fibrous septae. The tumor cells display the typical “plant cell” appearance with clear cytoplasm, perinuclear halos, binucleation, and raisinoid nuclei (Fig. 16.149). The second widely recognized variant is the eosinophilic variant of ChRCC where the tumor cells show an extensively eosinophilic appearance and can often mimic oncocytoma. Careful attention should be paid to the nuclear features of this variant, as tumor cells display frequent perinuclear halos as well as binucleation and irregular nuclear membranes (Fig. 16.150).

Hybrid oncocytic tumors (HOCTs) refer to a subset of oncocytic neoplasms that show ambiguous histologic features that overlap between RO and ChRCC. These tumors have been described to occur in one of three clinical settings (1) sporadically (2) associated with renal oncocytosis and (3) associated with Birt-Hogg-Dube syndrome [537, 538]. The morphology of HOCTs that occur in the sporadic setting or in the setting of renal oncocytosis is similar. Tumors tend to be extensively eosinophilic with occasional binucleation and perinuclear clearing. HOCTs that occur in the setting of BHD have been described to have three distinct morphologic patterns: (a) admixed areas of RO and ChRCC, (b) scattered ChRCC-like areas in the background of a RO, and (c) a distinct pattern where the tumor cells display large intracytoplasmic vacuoles. It should be noted that when a suspicion of BHD syndrome arises, germ-line testing to detect a mutation of the folliculin gene remains the gold standard to make the diagnosis [538, 539].

Immunohistochemical Findings

Immunohistochemical stains may be of some help, especially in the distinction of ChRCC from oncocytoma and granular variant of clear cell RCC. ChRCC is invariably positive for CK7 (diffuse, membranous expression), parvalbumin, EMA, and CD117 and is negative for vimentin, CAIX, and P504s [540]. In contrast, oncocytoma is often negative (or only focally positive) for CK7, and this stain may be a useful adjunct in its distinction from ChRCC.

Molecular Findings

Recurrent genomic structural rearrangements involving the TERT promoter region and elevated TERT expression have been described in sporadic ChRCC [541]. Several genes including TP53, PTEN, FAAH2, PDHB, PDXDC1, and ZNF765 have been found to be mutated in ChRCC [542]. A comparative study of ChRCC in the sporadic setting and those that arise in association with BHD syndrome which looked at fluorescent and chromogenic in situ hybridization probes for the centromeric region of chromosome 17 long arm, demonstrating all BHD-associated ChRCCs and HOCTs to be disomic except for 1 ChRCC that showed monosomy. In contrast, 12 of 14 sporadic chromophobe RCCs were reported to be monosomic [543].

Collecting Duct Carcinoma

Collecting duct carcinoma (CDC) is a rare renal tumor that accounts for less than 1% of RCCs in most series. The tumor was first described in 1986 as a high-grade adenocarcinoma with a prominent tubulopapillary growth pattern and a desmoplastic stroma, arising from the collecting ducts of Bellini [544]. Literature review suggests a male preponderance and an aggressive clinical course.

Macroscopic Appearance

Grossly, tumors are often medullary based and large with a firm gray-white cut surface. Tumors are often locally invasive due to the innate aggressive nature of the neoplasm. The tumor often has infiltrative borders and extensive associated necrosis.

Histologic Appearance

Microscopically, tumors are high grade with an extensively glandular and tubulopapillary pattern of growth. Associated desmoplasia is a common finding and is often a diagnostic clue (Fig. 16.151). At the ISUP consensus conference in Vancouver 2012, it was suggested that a tumor can be called CDC if it meets all of the following diagnostic criteria: (1) at least some of the lesion involves the medullary region; (2) there is a predominant formation of tubules; (3) a desmoplastic stromal reaction should be present; (4) cytologic features are high grade; (5) growth pattern is infiltrative; and (6) there is an absence of other typical RCC subtypes or urothelial carcinoma [510].

Immunohistochemical Findings

Immunohistochemistry is of limited utility in the distinction from urothelial carcinoma, which is often the main differential diagnostic consideration. Both tumors can show expression of PAX-8 and p63. However, PAX-8 staining is often diffuse in CDC and patchy in urothelial carcinoma of the upper tract. Conversely p63 expression has been reported in 97% of upper tract urothelial carcinomas, while only 30% of CDCs express p63 [545]. The addition of GATA-3, to the panel of immunohistochemical stains, is useful as the majority of urothelial carcinomas stain with this marker, while all but rare CDCs are negative for the stain [546]. Although a PAX8+/p63−/GATA-3 immunohistochemical profile favors a diagnosis of CDC over urothelial carcinoma, a meticulous examination of the collecting duct system to exclude a precursor or coexisting urothelial lesions is crucial before arriving at the diagnosis of CDC [546]. Renal medullary carcinoma also enters into the differential diagnosis but is reserved for similar appearing tumors that arise in patients with sickle cell trait and is described in greater detail in the next section.

Renal Medullary Carcinoma

Renal medullary carcinoma (RMC) is a highly aggressive RCC that occurs in patients with sickle cell trait. This tumor occurs more frequently in males (2:1 M:F ratio) and in younger patients in the second or third decades of life. Tumors show a propensity for the right kidney, and the majority of patients diagnosed are of African-American heritage due to the high incidence of sickle cell trait in this population. Tumors are of advanced stage at diagnosis and patients frequently present with distant metastasis at the time of diagnosis [547].

Macroscopic Appearance

On gross examination, tumors are typically large and locally invasive and show a firm, fibrotic gray-white cut surface with infiltrative borders and extensive necrosis (Fig. 16.152).

Histologic Appearance

On microscopic examination, tumors can show a variety of histologic patterns including a reticular or microcystic pattern reminiscent of yolk sac tumor, which is a classic pattern for the neoplasm. Other histologic patterns include a tubulopapillary, glandular, or solid growth pattern. The presence of an associated inflammatory infiltrate is also frequently noted as is the presence of extracellular mucin (Fig. 16.153). Careful examination of the vessels within the tumor can often show thrombi composed of drepanocytes (sickle cells) that plug the small vessels, although this is not required for the diagnosis when the history of a hemoglobinopathy is available.

Immunohistochemical Findings

The classic immunohistochemical finding that is required for the diagnosis of RMC is the loss of nuclear staining with SMARCB1 (INI-1). Molecular profiling has demonstrated deletion of INI-1 that is encoded in chromosome 22, which translates to the loss of expression by immunohistochemistry [548]. Other than the loss of INI-1, immunohistochemistry does not play a role in the diagnosis of RMC. Tumors are positive for CK7, high-molecular-weight cytokeratin, EMA, and AE1/AE3. OCT3/4, a stem-cell marker that is typically expressed in germ-cell tumors, may also be expressed in approximately half of all RMCs [549]. Overall, the immunohistochemical profile is virtually indistinguishable from CDC, and the separation between the two entities relies solely on the presence of the history of sickle cell trait. It should be noted that although loss of INI-1 has been historically considered to be diagnostic of RMC, a small number of CDCs have also been reported to show loss of INI-1, which is important to bear in mind before relying solely on the immunohistochemical stain for INI-1 for diagnosis [510]. The prognosis of RMC is dismal with a median overall survival of less than 12 months.

MiT Family Translocation Renal Cell Carcinoma

Gene fusions involving the microphthalmia (MiT ) family of transcription factors, which include TFE3, TFEB, TFC, and MiTF, have been implicated in the development of RCC. Xp11 translocation carcinoma was first formally recognized as a variant in the 2004 WHO classification of renal tumors.

Xp11.2 translocation RCCs are a distinct subset of tumors that harbor translocations involving the TFE3 gene, which maps to the Xp11.2 locus. The result is the fusion of the TFE3 gene to any one of multiple partner genes, which may include the most ASPL, PRCC, SFPQ, CLTC, non-O, or a variety of unknown gene fusion partners. Xp11.2 translocation RCC was first recognized in children, and it constitutes approximately 40% of all RCCs diagnosed in this age group [550]. However, the tumor also occurs in adults, with reported incidences varying from 1.6% to 4.2% of all RCCs, making the absolute numbers in adults much higher than in children, due to the higher incidence of RCC in the adult population [551, 552].

t(6;11) renal cell carcinoma that harbor the t(6;11) (p21;q12) translocation has now been formally recognized by the 2012 Vancouver classification of renal neoplasia as a subtype of MiT family RCCSs. These tumors are far less common than the more common Xp11.2 RCCs with fewer than a hundred cases being reported in the literature. Like Xp11.2 RCCs, t(6;11) RCCs can also occur in any age group, although the mean reported age is 31 years. These tumors result from the fusion of the transcription factor EB (TFEB) gene, a transcription factor related to microphthalmia transcription factor (MiTF), with Alpha (MALAT1), thus resulting in overexpression of native TFEB [550].

Macroscopic Appearance

Grossly, Xp11.2 RCCs resemble often present as large tumors that are frequently locally invasive with areas of necrosis. These tumors have a propensity for lymph node metastasis, and it is not uncommon to find enlarged regional lymph nodes within the nephrectomy specimen that are involved by metastatic tumor (Fig. 16.154).

Histologic Appearance

The striking microscopic feature of Xp11.2 RCC’s is the presence of a neoplasm with papillary architecture, lined by predominantly clear cells with abundant voluminous cytoplasm. Often, there may be admixed solid or nested areas that mimic clear cell renal cell carcinoma. When these areas are sampled at biopsy, it may result in the misdiagnosis of clear cell RCC. Other clues to the diagnosis of Xp11.2 translocation RCC are the presence of psammoma bodies and the lack of the “chicken wire” vasculature that surrounds the tumor nests and is typical of clear cell RCC. Clues to the fusion gene partner involved may be apparent on microscopy. Tumors with the ASPSCR1–TFE3 gene fusion typically show larger tumor cells with voluminous cytoplasm, discrete cell borders, and prominent nucleoli and are associated with more extensive psammomatous calcification. In contrast, tumors harboring the PRCC–TFE3 gene fusion tend to be composed of tumor cells with a more nested growth pattern, less abundant cytoplasm, and less frequent psammoma bodies (Figs. 16.155 and 16.156) [550].

In contrast the typical microscopic appearance of t(6;11) renal cell carcinoma is that of a biphasic tumor that is composed of larger epithelioid cells with clear cytoplasm at the periphery and a second population of centrally located smaller cells clustered around pink hyaline or basement membrane material. Nuclear atypia is uncommon and cells show low-grade cytology. Entrapped single renal tubules at the periphery of the tumor are a common histologic finding (Fig. 16.157).

Immunohistochemical Findings

Xp11.2 RCCs characteristically show only focal staining or absent staining with epithelial markers such as EMA and cytokeratins, which help in the distinction from the more common RCC subtypes. Tumors also express PAX2 and PAX8 and occasionally may show focal expression of melanocytic markers [550]. The most specific immunohistochemical marker is the strong nuclear expression of TFE3 using an antibody directed to the C terminal potion of the TFE3 gene. However, the TFE3 immunohistochemical stain is technically challenging and highly dependent on proper fixation of the tumor. The TFE3 break-apart FISH assay is less susceptible to the vagaries of tumor fixation and is now widely considered to be the more reliable way to detect a translocation involving the TFE3 gene. It is our practice to confirm cases of Xp11.2 RCCs with FISH, even in the presence of convincing nuclear expression of TFE3.

For t(6;11) renal cell carcinoma, the diagnostic immunohistochemical stain is the nuclear expression of TFE B by immunohistochemistry. These tumors express PAX8, CD10, and low-molecular-weight cytokeratin Cam5.2. A unique finding is the consistent diffuse expression of Melan-A by these tumors which serves to distinguish this tumor type from other subtypes of RCC. Tumors also show patchy labeling for HMB45, but unlike malignant melanoma, they are negative for MiTF and S100 protein. Virtually all t(6;11) RCCs are also positive for cathepsin K, and the lack of expression of this marker in a translocation RCC would favor an Xp11.2 RCC as only half of the latter express this marker. A recent fluorescence in situ hybridization (FISH) break-apart probe for the TFEB gene has become available and is widely regarded to be more sensitive and specific than the immunohistochemical stain [553].

The differential diagnosis of the MiT family of RCCs includes the more common subtypes of RCC. Clear cell RCC enters the differential diagnosis of Xp11.2 RCC due to the abundant clear cytoplasm. However, presence of extensive papillary architecture, lack of the typical vascular pattern of CCRCC, and the presence of psammoma bodies should raise concern for a Xp11.2 RCC. The diffuse expression of CAIX in CCRCC is also usually lacking in MiT family RCCs and helps in the distinction from this tumor type. The presence of strong cytokeratin 7 expression in a tumor favors the diagnosis of papillary RCC. Clear cell papillary RCC may enter the differential diagnosis, but those tumors tend to be small, localized tumors with distinct nuclear features, wherein the nuclei are arranged away from the basement membrane. These tumors, like PRCC, also show diffuse expression of CK7, which helps in the separation from MiT family RCC.

The differential diagnostic considerations for t(6;11) RCC, in addition to clear cell RCC and Xp11.2 RCC, includes epithelioid angiomyolipoma. Both epithelioid angiomyolipoma and t(6;11) RCC show overlapping histology and immunohistochemical findings. These include epithelioid cells without significant atypia or mitosis activity. Both tumors show staining with cathepsin K, HMB45, and Melan A and may be negative for broad-spectrum cytokeratins. However, staining with PAX8 supports the diagnosis of t(6;11) RCC over that of epithelioid angiomyolipoma. However, TFEB FISH remains the single most definitive test to distinguish these two lesions [550].

The prognosis of Xp11.2 RCCs is variable. One large series reported the prognosis of this subtype to be similar to clear cell RCC, but prognosis is ultimately determined by stage of the tumor [554]. TFEB RCCs tend to follow a more indolent clinical course with some patients reported as developing late metastases, underscoring the need for long-term follow-up.

Mucinous Tubular and Spindle Cell Carcinoma

Mucinous tubular and spindle-cell carcinoma (MTSCC) is a relatively rare renal neoplasm that was first accepted a distinct subgroup of renal cell carcinoma in the 2004 World Health Organization (WHO) classification of tumors [555]. It usually occurs in adults, with a wide age range at the time of presentation (range 13–81 years; median 60 years). Tumors show a female predominance (male to female 1:4) [556]

Macroscopic Appearance

Grossly, tumors are generally well circumscribed with a solid tan cut surface. In contrast with clear cell renal cell carcinoma and papillary renal cell carcinoma, necrosis, cystic changes, and hemorrhage are uncommon features in MTSCC.

Histologic Appearance

Microscopically, classic histologic pattern of MTSCC consists of three components, which are (a) tubular component reminiscent of type 1 papillary RCC, (b) a low-grade spindle-cell component, and (c) extracellular blue mucin/myxoid matrix. The nuclei are relatively bland without any significant mitotic activity with small to intermediate nucleoli (Fig. 16.157). Attention should be paid to the spindle-cell component which shows histologic features that are identical to the adjacent tubular component. It is believed that the spindle cells result from compression of the tubules. It is crucial not to over diagnose sarcomatoid change based solely on the spindle cells, especially in needle biopsies where the other components may not be easily visible due to sampling bias. The indolent nuclear features and lack of mitotic activity should give pause to the pathologist before diagnosing sarcomatoid change. It is not necessary to identify all three components in order to make the diagnosis, and the presence of any two of the three abovementioned components is sufficient to establish a diagnosis of MTSCC . True sarcomatoid change, although rare, has been reported in MTSCC and can be identified by the presence of high-grade cytology and mitotic activity within the spindle-cell component [557].

The main differential diagnosis is with type 1 papillary renal cell carcinoma. While MTSCC may show a pseudopapillary appearance with foamy microphages, true papillary structures, such as those seen in PRCC, are rare. Additionally, psammomatous calcification, which is frequently seen in papillary renal cell carcinoma, is typically absent in MTSCC.

Immunohistochemical Findings

By immunohistochemistry, there is significant overlap with PRCC. MTSCC is positive for CK7, AE1/AE3, CK19, EMA, and AMACR [556]. Clinically, the majority of tumors are managed surgically and have an excellent prognosis, although rare cases of metastasis were reported (Fig. 16.158) [558].

Molecular Findings

Molecular analysis of MTSCC has shown loss of chromosomes 1, 4, 6, 8, 9, 13, 14, 15, 18, 21, and 22. However, gain of chromosome 7 and 17 and loss of Y chromosome that is characteristic of papillary renal cell carcinoma are usually not seen in MTSCC. Recently, next-generation sequencing data has reviewed the recurrent chromosomal loss and somatic mutations in hippo signaling pathways in MTSCC, suggesting a common mechanistic basis for this disease [559]

Tubulocystic Renal Cell Carcinoma

Tubulocystic renal cell carcinoma is a morphological variant of renal cell carcinoma that was first described in 1956 by Masson and designated as Bellinien epithelioma. It usually occurs in adults with age range of 30–80y (mean 57y) with male predominance (7:1 or greater). So far there are about 100 cases reports in the literature, making this a relatively rare tumor [560, 561].

Macroscopic Appearance

Grossly, tubulocystic renal cell carcinomas have a characteristic appearance. Tumors are well circumscribed but unencapsulated, with a unique sponge-like or “bubble-wrap” cut surface that results from the presence of macro- and microcysts. Hemorrhage and necrosis are uncommon.

Histologic Appearance

Microscopically, the tumor is composed of small- to medium-sized cysts and tubules that are lined by large eosinophilic cells with hobnail morphology and prominent Fuhrman nuclear grade 3 or 4 nucleoli. The intervening stroma is paucicellular. Mitotic figures can also be seen (Fig. 16.158).

Immunohistochemical Findings

By immunohistochemistry, tubulocystic carcinomas are positive for CK8, CK18, CK19, AMACR, and CD10. CK7 positivity is variable and can show weak staining. PAX2 and CAIX may be positive in about half the cases. Clinically, most tumors present as pT1 or pT2 tumors, thus making them amenable to surgical resection. Although the majority of cases behave in an indolent manner, cases with metastasis to the lymph nodes, bone, and liver have been reported [510].

Differential Diagnosis

Differential diagnostic considerations include collecting duct carcinoma and papillary renal cell carcinoma due to overlapping histologic features. The current recommendation is that the diagnosis of tubulocystic carcinoma be reserved only for those tumors that show classic gross morphology and microscopic features. Another differential diagnosis is cystic nephroma which is a biphasic tumor with both epithelial and mesenchymal components. The presence of a high nuclear grade that defines tubulocystic renal cell carcinoma helps in the distinction from cystic nephroma, which shows bland nuclear features in addition to an ovarian-type stoma that is lacking in the former. Special attention must be taken to not misdiagnose these tumors as multilocular cystic renal cell neoplasm, which is now widely considered to be an indolent neoplasm with no significant metastatic potential. The epithelium lining the cysts in multilocular cystic renal neoplasm is typically clear with a low nuclear grade, which helps separate it from tubulocystic RCC.

Molecular Findings

Molecular studies show that these tumors are similar to papillary renal cell carcinoma which has demonstrated gains of chromosome 17p and 17 q (trisomy 17). However, trisomy 7, which is also characteristic for papillary renal cell carcinoma, has not been identified in tubulocystic renal cell carcinoma, indicating differential genetic makeup in these two tumors.

Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome (HLRCC)

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an autosomal-dominant hereditary syndrome, which is caused by germ-line mutations in the FH gene. Patients have a propensity to develop cutaneous and uterine leiomyomas and kidney tumors. The association between leiomyomas and RCC was first recognized in 2001 where the authors described a familial cohort of patients with leiomyomas and RCCs, wherein the renal tumors had a distinct papillary morphology. The predisposition gene was shown to be inherited dominantly through the HLRCC gene, which was mapped to chromosome 1q [562]. Both the renal tumors and leiomyomas in the HLRCC syndrome demonstrate biallelic inactivation of fumarate hydratase, with germ-line mutations in one allele and loss of the second allele [510]. Due to the clinical significance of this diagnosis both for the patient and family members, the current recommendation is to recognize this entity as a distinct subtype of renal cell carcinoma.

Macroscopic Appearance

Grossly, tumors are usually unilateral and solitary and often present with locally advanced disease, displaying capsular and renal sinus invasion. Although tumors are largely solid, they may display a minor cystic component (Fig. 16.159) [563].

Histologic Appearance

Microscopically, the typical pattern is that of a papillary or tubulopapillary tumor. Cells lining the papillae are large and contain abundant eosinophilic cytoplasm. The hallmark of HLRCC tumors is the presence of a very large, prominent, eosinophilic nucleolus, surrounded by a perinuclear halo that resembles that which is seen is cytomegalovirus infection, thus warranting a Fuhrman nuclear grade 4 designation (Fig. 16.160) [563]. Another feature that is often seen, especially around the cystic areas of the tumor, is a prominent desmoplastic stroma. Prior to the formal recognition of HLRCC as a distinct tumor type, these were often classified as type 2 papillary RCCs or collecting duct carcinomas, due to the presence of this histologic feature [564].

Immunohistochemical Findings

By immunohistochemistry, tumors are generally negative for CK7, CK20, mucicarmine, Ulex Europaeus lectin, high-molecular-weight cytokeratin, and TFE3. Recently, immunohistochemical staining for FH and 2SC have been investigated as a potential surrogate marker for the diagnosis of HLRCC. An FH-/2SC+ immunohistochemical profile appears to be sensitive and specific for the diagnosis of HLRCC and has been shown to correlate well with the presence of the germ-line mutation [565]. Ultimately, if the suspicion for HLRCC is strong, patients should be referred for genetic counseling to establish a definitive diagnosis as tumors are aggressive and have important genetic implications.

Differential Diagnosis

The main differential diagnostic consideration is type 2 PRCC, and it may be impossible to distinguish between the two, especially on a needle core biopsy. HLRCC often shows the presence of a tubulocystic pattern, at least focally, which in combination with papillary architecture, desmoplastic stroma, and prominent nucleoli may be useful diagnostic clues to the diagnosis. Immunohistochemistry is not particularly helpful due to overlapping immunohistochemical profiles. When faced with a possible diagnosis of HLRCC in the absence of a history of a germ-line mutation, it is our practice to call these tumors “renal cell carcinoma with papillary features” and list the differential diagnosis in the comment line.

Acquired Cystic Disease-Associated Renal Cell Carcinoma

Acquired cystic disease-associated renal cell carcinoma (ACDK) was first recognized in 2006 as a unique tumor that arises specifically in the background of end-stage renal disease (ESRD) [524]. The tumor was formally inducted into the ISUP classification of renal tumors in 2013 as a distinct entity.

Macroscopic Appearance

On gross examination, the background kidneys have the appearance of typical ESRD including atrophy and diffuse cortical cysts. Tumors may be solitary or multifocal and may be bilateral in about 20% of cases. Size may be variable and the cut surface ranges from yellow-tan to white [566].

Histologic Appearance

Histologically, the classic pattern that has been described is that of a cribriform sieve/sieve-like lesion with papillary or tubulopapillary architecture, often arising within a cyst wall. Tumor cells are typically eosinophilic with a high nuclear grade. The pathognomonic feature is the presence of polarizable calcium oxalate crystals that are associated with the tumor and the surrounding renal parenchyma (Fig. 16.161).

Immunohistochemical Findings

Immunohistochemistry is typically not required for the diagnosis due to the classic clinical presentation and typical histology. However, tumor cells reportedly express PAX8, CD10, and AMACR and are usually negative or only focally positive for CK7.

Molecular Findings

Multiple chromosomal abnormalities have been reported including gains of chromosomes 1, 2, 3, 6, 7, 16, and Y; however, there have been no pathognomonic molecular abnormalities identified. Gains of chromosome 3 have been among the more consistently reported findings [510].

Although most reported cases have shown a good prognosis, this is likely due to early detection of these neoplasms. ACD-RCC is widely recognized as being a high-grade neoplasm with a distinct potential to metastasize, which makes accurate identification of this tumor crucial.

Other New and Emerging Renal Epithelial Neoplasms

Thyroid-Like Follicular Renal Cell Carcinoma

Thyroid-like follicular renal cell carcinoma (TLF-RCC) has been provisionally recognized by the ISUP as a distinct neoplasm that resembles well-differentiated follicular carcinoma of the thyroid. The reported age at presentation is wide, and there is a slight female preponderance.

Macroscopic Appearance

Macroscopically, tumors are homogeneous, tan brown, well circumscribed, and solid.

Histologic Appearance

Microscopically, these tumors show a striking follicular architecture with the tumor being composed exclusively of macro and microfollicles with eosinophilic colloid-like material in the lumen. The follicles are lined by uniform round to cuboidal cells with Fuhrman nuclear grade 2 or 3 (Fig. 16.162).

Immunohistochemical Findings

By immunohistochemistry, tumor cells are negative for thyroglobulin and TTF1 which helps to distinguish this tumor from metastatic follicular carcinoma of the thyroid. Beyond this, stains are rarely required due to the classic morphology; however, variable staining for CK7, PAX2, and PAX8 is reportedly variable [567].

Although the majority of cases have shown to behave in an indolent manner, there have been cases of lymph node and lung metastasis reported [568].

Succinate Dehydrogenase B Mutation-Associated RCC

Succinate dehydrogenase B mutation-associated RCC (SDHB RCC) is a subtype of RCC with unique morphologic features that are associated with germ-line mutations of the SDHB gene and the pheochromocytoma/paraganglioma syndrome. The histologic features of SDH-RCC were first described in a cohort of five tumors from four kindreds with proven germ-line SDHB mutations [569].

Macroscopic Appearance

On gross examination, most tumors are tan brown with a solid cut surface, although cystic change has been reported in a few tumors.

Histologic Appearance

Tumors may be solid or show micro- and macrocystic architecture, with cysts containing pale eosinophilic fluid. Tumors are usually well circumscribed but not encapsulated, with lobulated or pushing border, often entrapping benign tubules at the periphery. Tumor cells are typically cuboidal and with a solid, nested, or tubular growth pattern with variable cyst formation. The neoplastic cells are typically eosinophilic and range from round to cuboidal. Most are of low Fuhrman nuclear grade, although sarcomatoid change has been reported in some cases [570]. The most distinctive histological feature is the presence of intracytoplasmic vacuoles or flocculent inclusions which, when prominent, impart a bubbly appearance to the neoplastic cells (Fig. 16.135) [570].

Immunohistochemical Findings

By immunohistochemistry, the classic histologic finding is the loss of staining of SDHB within the cytoplasm of the tumor. The adjacent normal renal parenchyma can serve as a useful internal control to demonstrate retained staining. Additionally, tumors are at least focally positive for PAX8 and EMA. Variable staining for CK7 has been reported, with most cases showing only focal staining or absent staining with the marker. CD117 and cytokeratins are frequently completely absent in SDH-RCC, and this staining pattern should alert the pathologist to this diagnosis and help in the distinction from ChRCC and RO [570].

Differential Diagnosis

The main differential diagnostic consideration is renal oncocytoma. The presence of a “bubbly” cytoplasmic quality and a more solid appearance rather than the nested pattern seen in RO should prompt the addition of the SDHB stain to the immunohistochemical panel.

Although the majority of cases are indolent in behavior, there are cases of sarcomatoid transformation, and metastasis that have been reported [570]. Should SDH-RCC be suspected due to the typical morphology and absence of staining with SDHB on immunohistochemistry, communication with the treating physician is essential, to ensure that the patient undergoes germ-line testing to confirm mutational status, which remains the gold standard for the diagnosis.

ALK-Translocation RCC

ALK-translocation RCC is a rare variant of RCC, with gene fusions involving the ALK gene. Cases have been reported in younger patients with sickle cell trait as well as in patients without sickle cell trait. Unlike renal medullary carcinoma, these tumors do not demonstrate loss of INI-1 staining within the tumor. Tumors in younger patients have shown to harbor a t(2;10)(p23;q22) translocation resulting in a fusion of the gene for the cytoskeletal protein vinculin (VCL) with the anaplastic lymphoma kinase (ALK) gene. In the limited number of reported cases, tumors are composed of polygonal to spindle cells with vesicular nuclei, abundant eosinophilic cytoplasm, and intracytoplasmic lumina. Tumors without VCL as a partner have shown papillary, tubular, or cribriform morphology, but the case numbers are limited [571]. The prognosis of these tumors is less aggressive than that of RMC, and the presence of ALK rearrangement presents an opportunity for targeted therapy with ALK inhibitors. ALK expression can be seen by IHC in these tumors, which helps in the diagnosis. Distinction from RMC is crucial in patients with sickle cell trait due to therapeutic and prognostic implications.

Immunohistochemistry in the Diagnosis of Renal Neoplasms

Immunohistochemical stains are a useful adjunct in the diagnosis and work up of RCC. Although the majority of RCC can be diagnosed without the use of ancillary techniques, immunohistochemical stains are useful in cases where morphology is not typical or in the setting of limited samples such as needle core biopsies and fine needle aspiration biopsies.

Most RCCs stain for cytokeratin (CK) cocktail and epithelial membrane antigen (EMA) . The exception is MiTF family-associated RCC (translocation RCC) which typically underexpresses keratins and may be negative. CK7 is a specialized cytokeratin stain that is expressed in PRCC, ChRCC, tubulocystic RCC, CCPRCC, and MTSCC, while it is typically negative in CCRCC. As a note of caution, we have seen expression of CK7 in CCRCCs, especially when the tumor is cystic, and the expression of CK7 in an otherwise typical CCRCC is permissible in the setting of cystic change. High-molecular-weight CK34βE12 (HMWCK) and CK5/6 are positive in most CDCs.

PAX gene proteins (PAX-2 and PAX-8) are expressed in almost all renal tumors and may be useful for identifying RCC in metastatic sites. However, these proteins are not specific as they are also expressed in primary tumors from other sites (such as ovary and thyroid) [572].

Vimentin is an intermediate filament that is expressed in most mesenchymal tumors but in few carcinomas. All RCCs with the exception of ChRCC express this marker, and this is a useful marker to distinguish between CCRCC and ChRCC.

Alpha methylacyl CoA racemase ( AMACR ) is a mitochondrial enzyme that is involved in the oxidation of fatty acids and is strongly expressed in PRCC and MTSCC. While it may be expressed in other RCCs, the expression is typically focal and less strong than seen in PRCC and MTSCC [572]. CD10 is a cell-surface glycoprotein that is typically expressed in CCRCC and PRCC, with less frequent expression in other RCCs [572].

Renal cell carcinoma antigen is a glycoprotein that is present on the brush border of proximal renal tubular epithelial cells and is expressed in CCRCC and PRCC [572].

TFE-3/TFE B are nuclear proteins that are overexpressed, as a result of the specific translocation, and accumulate in the nuclei of tumor cells in translocation RCC. These are highly specific markers and not expressed in any of the other RCCs. Immunohistochemical profiles of the most common RCCs are as follows (Tables 16.16 and 16.17)

Table 16.16 International Society of Urological Pathology (ISUP ) Vancouver Classification of Kidney Tumors

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Table 16.17 Summary of immunohistochemical findings of common renal cell carcinomas

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Grading of Renal Cell Carcinoma

Renal cell carcinomas are graded according to Fuhrman nuclear grading system [573], which is divided into four grades based on the nuclear size, nuclear anaplasia, and nucleolar size (Fig. 16.163) (Table 16.18). A nuclear grade is assigned based on the highest grade within the entire tumor. Clinical utility of the Fuhrman nuclear grading system has only been proven in clear cell RCC [574] and not in the other types of RCC. The 2012 ISUP consensus meeting formalized the notion that nucleolar grading is emerging as a simpler alternative to Fuhrman grading and one that correlates better with prognosis. Both the Fuhrman and ISUP grading schema are appropriate for grading clear cell RCC and papillary RCC, but not for chromophobe RCC.

Table 16.18 Fuhrman nuclear grading for renal cell carcinoma

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Pathologic Staging of Renal Cell Carcinoma

The AJCC tumor, nodes, and metastasis (TNM) system is the most widely used system for staging RCC (Table 16.19). The older system known as Robson’s staging is no longer used. As with other organs, the TNM staging system is based on the size and extent of invasion by the tumor. The organ-confined tumors are low stage (pT1 and pT2), which are then further divided based on the size. The higher-stage tumors (pT3 and pT4) extend beyond the confines of the kidney. One of the important changes to the staging system occurred in the 2002 TNM staging system, which was the inclusion of renal sinus invasion into the pT3a category. The recognition of this invasion is dependent on pathologic sampling of the tumor in the renal hilar region. In the 2010 TNM system, the most significant changes are related to direct invasion of the ipsilateral adrenal gland by RCC (changed from pT3a to pT4), invasion of the renal vein (changed from pT3b to pT3a), invasion into the inferior vena cava (changed from pT3c to pT3b), and changes in the N stage (simplified to N0 and N1).

Table 16.19 TNM staging system for renal cell carcinoma

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Mixed Mesenchymal and Epithelial Tumors

Cystic Nephroma/Mixed Epithelial Stromal Tumor (MEST)

Cystic nephroma (CN) and mixed epithelial stromal tumor (MEST) are mixed epithelial-mesenchymal tumors that show overlapping morphologies and are widely regarded as within the same spectrum of neoplasms [575]. Both tumors show a female preponderance with a wide age at presentation (mean age at presentation being the 5th and 6th decades).

Macroscopic Appearance

Cystic nephroma presents as a solitary well-circumscribed tumor composed of variably sized cysts that are separated by thin septae lacking any solid areas. MEST also shows a similar gross appearance with variably sized cysts (Figs. 16.164 and 16.165). The stromal component is typically more prominent than which is seen in CN, which may lead to a more solid, firm gross appearance on occasion. Tumors have been reported to arise from within the renal parenchyma as well as from the central pelvicalyceal region of the kidney. Interestingly, although MEST is a benign tumor, cases of benign MEST with extension into the renal vein, mimicking a tumor thrombus, have been reported [576].

Histologic Appearance

Both CN and MEST show overlapping microscopic features. Both tumors are composed of variably sized cysts lined by benign appearing hobnail or cuboidal epithelium (Fig. 16.166). Cysts are separated by stroma that is composed of spindle cells that closely resemble ovarian stroma. The only distinguishing feature between the two entities is the thickness of the septa, which is 5 mm or less in CN and greater than 5 mm in MEST. Due to the similarities between the tumors, it has been proposed that the term “renal epithelial stromal tumor (REST)” be used as a unifying term that encompasses both lesions [575].

Immunohistochemical Findings

By immunohistochemistry, the stromal cells in both CN and MEST express ER, PR, CD10, inhibin, calretinin, actin, and desmin [577]. The epithelial component is typically positive for CK7 and PAX2 and PAX8. HMB-45 is negative, which helps in distinction from angiomyolipoma and angiomyolipoma with epithelial cysts (AMLEC).

Although the vast majority of reported cases of MEST have shown to have an indolent outcome, there are rare cases of malignant transformation of the stromal component identified. In these cases, the stromal component shows sarcomatous transformation, which supports the widely held belief that it is the stromal component of MEST that has malignant potential [578].

Mesenchymal Tumors of the Kidney

Angiomyolipoma

Angiomyolipoma (AML) is benign neoplasm composed of fat, smooth muscle and thick-walled blood vessels in varying proportions. They belong to the family of perivascular epithelioid cell tumors (PEComas) and occur predominantly in adults. Tumors show a female predilection and may occur sporadically or in association with tuberous sclerosis complex. The presence of multiple AMLs should raise suspicion for tuberous sclerosis and prompt referral to a genetic counselor for further screening [579].

Macroscopic Appearance

Macroscopically, the size range is large and can vary from microscopic lesions identified incidentally at nephrectomy to those that exceed 20 cm in greatest dimension. Most tumors show a homogeneous, golden-yellow, fatty cut surface similar to that of a lipoma; but the macroscopic appearance can vary depending on which component predominates. Tumors are typically unencapsulated but may have infiltrative borders. Rarely, an otherwise typical AML may show the presence of a renal vein or an inferior vena caval “thrombus,” which in of itself does not detract from the diagnosis in the setting of otherwise typical histology (Fig. 16.167) [580, 581].

Histologic Appearance

The histologic appearance varies depending on the proportions of fat, smooth muscle and vessels present within the tumor. The smooth muscle component is usually present as haphazardly arranged fibers present around thick-walled abnormal blood vessels (Fig. 16.167). When all three components are identified, the diagnosis rarely poses a dilemma. However when a single component predominates, the diagnosis may pose some challenges. Fat-poor AML in particular, especially on a core needle biopsy, may pose a dilemma when all that is seen in a biopsy is a low-grade smooth muscle spindle-cell component. Caution must be used to not call this a leiomyoma, as this diagnosis is exceedingly rare in the kidney and immunohistochemical stains may be helpful to distinguish between these entities. AML that is fat predominant may be mistaken for a lipoma or an atypical lipomatous tumor, and once again, immunohistochemistry along with clinical history and extensive sampling of the neoplasm will be helpful to arrive at the correct diagnosis.

Immunohistochemical Findings

By immunohistochemistry, tumors show absence of staining with epithelial markers and PAX 8. Actin and desmin highlight the smooth muscle component. The hallmark of AML is staining with HMB45, which is typically concentrated in the more cellular areas of the tumor around the blood vessels. Focal staining for HMB-45 is common, and often a careful search yields only a few cells that stain for this marker but is sufficient for the diagnosis. This staining pattern is typical of AML and helps separate this tumor from other tumors that may enter the differential diagnosis.

Angiomyolipoma with epithelial cysts (AMLEC) is a rare, recently described variant of AML. Unlike conventional angiomyolipoma, this variant is characterized grossly by both solid and cystic areas. The microscopic appearance of this tumor is characterized by three components. The first component is that of cystic or multicystic spaces lined by cuboidal to columnar epithelial cells with clear cytoplasm or flattened epithelial cells containing eosinophilic cytoplasm with nuclei protruding into the cyst lumen in a hobnail fashion. The second component is a “cambium-like layer” consisting of a subepithelial condensation of small stromal cells with indistinct cytoplasm and prominent capillaries, imparting a strong resemblance to the stroma of the endometrium, and histologically by the presence of single or multiple cysts lined by epithelial cells, a subepithelial “cambium-like” layer of small stromal cells with a prominent capillary vasculature, and a thick exterior wall composed of poorly formed fascicles of smooth muscle and thick-walled dysplastic blood vessels. These tumors demonstrate a slight female predominance and show a distinct immunohistochemical profile. Like conventional AML , tumors are reactive for melanocytic markers (HMB-45 and Melan-A), estrogen receptor, and progesterone receptor, which typically react most strongly in the subepithelial stroma. The lining of the cysts is positive for PAX2 and PAX8 and the smooth muscle stains for desmin and actin. These tumors have an indolent clinical course, with no reports of progression or metastasis in reported cases thus far [582, 583].

Epithelioid Angiomyolipoma

Epithelioid angiomyolipoma (EpAML) is a distinct variant of AML that is part of the PEComa family of tumors. These tumors occur predominantly in adults (mean age of 40 years) and do not show a gender predilection [584].

Macroscopic Appearance

On gross appearance, tumors are predominantly solid and may show areas of hemorrhage and necrosis.

Histologic Appearance

Microscopically, tumors may be composed of nests or sheets of cohesive cells that are typically large, polygonal with abundant eosinophilic cytoplasm or prominent nucleoli, imparting a ganglion-like appearance. Another variation is the presence of plump-spindled tumor cells arranged in sheets with clear to eosinophilic cytoplasm.

Although specific criteria to predict outcomes of EpAML have been historically difficult to establish, recent studies have proposed a mechanism for risk stratification for these neoplasms that has been recently recommended by the ISUP as the standard for reporting. In a single large study that elucidated these prognostic factors, these parameters include (1) associated tuberous sclerosis complex or concurrent AML, (2) necrosis, (3) tumor size >7 cm, (4) extrarenal extension and/or renal vein involvement, (5) and a carcinoma-like growth pattern. Tumors with <2 adverse prognostic parameters were considered to be low risk, with 15% having disease progression. Tumors with 2–3 adverse prognostic parameters were considered to be “intermediate risk,” with 64% having disease progression. Tumors with >4 adverse prognostic parameters were considered to be high risk, with all patients having disease progression. It is recommended that the aforementioned criteria be included in the diagnostic report and all EpAMLs be stratified based upon these published criteria.

Immunohistochemical Findings

By immunohistochemistry, tumor cells are uniformly negative for cytokeratins and typically express one or more melanocytic markers (HMB45, microphthalmia transcription factor, melan-A, tyrosinase) as well as smooth muscle actin or muscle-specific actin.

Differential Diagnosis

The main differential diagnosis includes high-grade renal cell carcinoma. The prominent epithelioid component combined with renal location is easy to mistake for RCC, especially a clear cell RCC. EpAML should always enter the diagnosis for a renal tumor that is composed of discohesive tumor cells. The use of immunohistochemistry as an ancillary technique is helpful in cases with unusual high-grade morphology. In the case of EpAML , the lack of staining with PAX8 and cytokeratins should prompt further investigation with melanocytic markers to arrive at the correct diagnosis.

Leiomyoma and Leiomyosarcoma (Including Renal Vein)

Leiomyomas of the kidney are rare and most arise from the renal capsule. Like their soft tissue counterpart, these tumors show a solid, whorled cut surface and are composed of spindle cells without any significant mitotic activity or atypia. Before making a diagnosis of leiomyoma, melanocytic markers should be performed to exclude the possibility of a smooth muscle predominant AML.

Leiomyosarcoma (LMS) is the most common primary sarcoma of the kidney. Most cases occur in adults in their 4th or 5th decades. Tumors may arise from the capsule or the renal vein. Tumors arising from the vein may present as a tumor that predominantly involve the renal sinus. The cut surface of LMS may closely resemble that of a leiomyoma with a whorled cut surface and areas of hemorrhage and necrosis. Histologically, the LMSs are identical to those seen in the soft tissue and are composed of spindle cells arranged in a bundles or fascicles with increased cellularity, mitotic activity, and necrosis (Figs. 16.168 and 16.169).

Grading for LMS is performed using the French Federation of Cancer Centers (FNCLCC) system on the basis of the extent of differentiation, the mitotic count, and the presence or absence of necrosis [585]. The majority of leiomyomas show a low mitotic count (<1/10hpf), with LMS showing a higher mitotic count (average 8/10hpf). Ki-67 analysis has been found to be helpful in distinguishing difficult cases, with a count of >5/10hpf favoring the diagnosis of LMS [585].

Immunohistochemistry may be useful in establishing lineage. Both leiomyoma and LMS are positive for SMA, desmin, caldesmon, and calponin. Estrogen receptor (ER) and progesterone receptor (PR) and WT1 show a differential staining pattern, and most leiomyomas show an ER/PR/WT1 + immunohistochemical profile, while LMSs are typically ER/PR/WT1-. Tumor recurrence is common in LMS, and approximately a third of patients die of disease, making identification of these neoplasms crucial.

Vascular Tumors of the Kidney

Renal hemangiomas are rare and typically consist of a well-demarcated but unencapsulated proliferation of capillary-sized blood vessels. Entrapped renal tubules at the periphery of the lesion may be seen. The typical well-defined lobular growth pattern as seen in soft tissue and cutaneous capillaries hemangiomas is lacking in renal parenchymal hemangiomas [586].

In contrast angiosarcoma often presents as large, necrotic masses, with an infiltrative and destructive growth pattern that frequently involves the perirenal adipose tissue (Fig. 16.136). Renal angiosarcomas are histologically similar to those seen in other organs. Tumors are typically cellular and composed of atypical endothelial cells with mitotic activity and necrosis. More epithelioid appearing angiosarcomas may have a more solid appearance, and some tumors may show more spindled morphology. By immunohistochemistry, tumors are typically negative for cytokeratins and positive for at least one endothelial marker, usually CD31, CD34, or ERG. Angiosarcoma is typically aggressive with a poor outcome, and most people eventually succumb to the disease.

Synovial Sarcoma

Primary synovial sarcoma is rare and primarily occurs in young to middle-aged adults. Tumors present as large solitary masses with varying degrees of cystic change and a tan rubbery cut surface with extensive areas of necrosis. The majority of tumors are monophasic and composed of spindle cells arranged in intersecting fascicles with a prominent hemangiopericytoma-like pattern (Fig. 16.170). Cells are frequently monomorphic, mitotically active, and hyperchromatic, with areas of necrosis [587].

By immunohistochemistry, tumors show diffuse nuclear staining for TLE1 and cytoplasmic reactivity for BCL2. Pancytokeratin may be only focally positive, especially in monophasic tumors. Definitive diagnosis requires confirmation of the presence of synovial sarcoma fusion genes SS18-SSX1 or SS18-SSX2 by RT-PCR or fluorescence in situ hybridization, which can be performed on formalin-fixed paraffin-embedded tissue.

Juxtaglomerular Cell Tumor

Juxtaglomerular cell tumor is a rare renal neoplasm that is associated with renin production. Patients are typically young and present with early-onset hypertension which often subsides upon resection. Most tumors are well circumscribed and at least partially invested by a fibrous capsule.

Macroscopic Appearance

Macroscopically, tumors are generally unilateral and well circumscribed and have a tan-yellow cut surface. The majority of reported tumors have been small is size and less than 3 cm. The tumor may also show the presence of cystic change.

Histologic Appearance

On microscopic examination, tumors may show a trabecular pattern of growth with polygonal tumor cells that have an indistinct border and eosinophilic cytoplasm. A focally microcystic growth pattern may be identified. Mitotic activity is usually absent, although nuclear atypia may be noted. Prominent vascularity is a frequent histologic finding, and vessels may be hyalinized of varying sizes, often mimicking the stag-horn pattern that has been described in hemangiopericytoma (Fig. 16.171). A prominent lymphocytic or mast cell infiltrate is also a common finding.

Immunohistochemical Findings

By immunohistochemistry, tumors are positive for renin, CD34, SMA, and CD117. Although rarely used for diagnosis, the hallmark is the presence of rhomboid renin containing granules within the cytoplasm of the neoplastic cells [590,591,590].

Differential Diagnosis

The main differential diagnostic consideration is glomus tumor due to the overlapping morphology. The clinical history of hypertension is helpful in the distinction, as glomus tumor is not associated with hypertension. An immunohistochemical stain for renin, if available, is also helpful as glomus tumor is negative for renin. The stag-horn pattern of vessels raises the concern for hemangiopericytoma, but the polygonal cells of JG cell tumor are lacking in the latter entity.

Renomedullary Interstitial Cell Tumor

Renomedullary interstitial cell tumor , previously known as medullary fibroma , is a common benign incidental histologic finding that has been reported to be present in approximately 40% of nephrectomy specimens in a single autopsy series. Lesions are incidentally detected and are seen as tiny well-circumscribed gray-white nodules that are identified within the renal medulla. Tumors range in size from microscopic tumors to 6 mm, with the mean reported size being 1.7 mm. Tumors are believed to arise from the interstitial cells of the renal medulla that play a role in the regulation of blood pressure. These lesions are composed of elongated spindled cells with bland nuclei. Ropy collagen between the cells and entrapped benign renal tubules are also common. Immunohistochemical stains are generally not needed for diagnosis due to the classic histologic appearance of these tumors [591].

Ewing Sarcoma/Primitive Neuroectodermal Tumors

Ewing sarcoma (ES) /primitive neuroectodermal tumor (PNET) is a rare tumor that is part of the Ewing family of tumors, which extend along a spectrum from Ewing sarcoma to the primitive neuroectodermal tumor (PNET). These tumors most often occur in the bone and soft tissue of young adults and children and occurrence in the kidney remains rare.

Macroscopic Appearance

Tumors are often large, unilateral, and locally advanced at presentation and are solid with extensive areas of hemorrhage and necrosis.

Histologic Appearance

Microscopically, tumors are typically arranged in solid sheets or a lobular growth pattern, with an infiltrative growth pattern. Rosettes and pseudorosettes are also common features. Mitotic activity and lymphovascular invasion are common. Nucleoli are inconspicuous, and tumors show the typical stippled nuclear chromatin of neuroendocrine tumors (Fig. 16.172).

Immunohistochemical Findings

Tumors express neuroendocrine markers including chromogranin and synaptophysin. Most tumors show diffuse membranous staining for CD99. The tumor is defined by the presence of the EWS-FLI-1 fusion transcript which is necessary for diagnosis. FISH studies employing a break-apart probes to detect a rearrangement of the EWSR1 locus are readily available and may be used to aid the diagnosis in otherwise typical cases. However, numerous other tumors may also show a rearrangement of the EWSR1 locus, and, hence, RT-PCR assay to detect the specific EWSR1-FLI-1 fusion transcript is the most specific test to confirm the diagnosis [592].

Differential Diagnosis

Tumors have significant morbidity and early and accurate diagnosis is critical. The differential diagnostic considerations include other “small blue round cell tumors” including blastema predominant Wilm’s tumor, small-cell carcinoma, synovial sarcoma, lymphoma, urothelial carcinoma, and poorly differentiated renal cell carcinoma. An appropriate panel on immunohistochemical markers including CD45, CD99, desmin, synaptophysin, chromogranin, and WT-1 should be performed for all cases with a small-blue-round-cell morphology [592].

Malignant Fibrous Histiocytoma

Primary renal malignant fibrous histiocytoma (MFH) is exceedingly rare with fewer than 100 cases reported [595,596,595]. Most MFHs are large, locally advanced tumors [598,599,600,601,600]. The most important differential diagnostic consideration is sarcomatoid renal cell carcinoma or urothelial carcinoma, and these should be excluded extensively sampling the tumor to identify an epithelial component before entertaining the diagnosis of MFH. Morphologically MFHs are composed of pleomorphic tumor cells that grow in short fascicles or a storiform or haphazard arrangement. Myxoid areas may also be present. The prognosis for patients with MFH is universally poor, even after surgical resection.

Neuroendocrine Tumors

Neuroendocrine and neuroectodermal tumors in the kidney span the gamut from carcinoid tumor to small-cell carcinoma. Tumors occur equally in men and women and show a wide range of age at diagnosis. Commonly seen tumors include renal carcinoid tumors, primary neuroendocrine carcinoma, and small-cell carcinoma. These cases are often misdiagnosed due to the rarity of this diagnosis, and it is not infrequent for these tumors to be confused with papillary renal cell carcinoma, urothelial carcinoma, or primitive neuroectodermal tumor.

Macroscopic Appearance

Most tumors present as solitary , unilateral masses that range in size from 3 cm to 11 cm [601]. Renal carcinoid tumors have a propensity to arise in horseshoe kidney and have also been reported to arise concurrently with mature teratomas of the kidney [602]. Carcinoid tumors may be associated with the secretion of neuropeptides or vasoactive substances that can result in systemic symptoms including flushing, dyspnea, and diarrhea [603].

Histologic Appearance

Tumors can be classified into carcinoid tumor (well-differentiated neuroendocrine carcinoma), atypical carcinoid (intermediate-grade neuroendocrine carcinoma), and neuroendocrine carcinoma (small-cell or large-cell neuroendocrine carcinoma), although the terminology that is used varies by institution. Renal carcinoids are low-grade neuroendocrine tumors that are composed of polygonal cells arranges in a nested or trabecular pattern. Nuclei are homogeneous, oval with salt and pepper cytoplasm (Fig. 16.173). Mitotic activity is typically low (<2 hpf) and necrosis is absent. Atypical carcinoid tumors (intermediate-grade neuroendocrine carcinomas) are associated with similar morphology as that of carcinoid tumors, except that these tumors tend to have a higher mitotic rate (>2–10 mitoses/hpf), necrosis, and calcification. Atypical carcinoid tumors tend to have a more aggressive clinical course than low-grade carcinoid tumors [603]. Large-cell and small-cell neuroendocrine carcinomas are high-grade malignant tumors that histologically resemble their counterparts in other sites. Small-cell carcinoma shows tumor cells with scant cytoplasm, finely granular chromatin inconspicuous nucleoli, and the typical nuclear molding. A high mitotic rate and tumor necrosis are common findings. In contrast, large-cell neuroendocrine carcinoma shows a larger cell size with more abundant cytoplasm, low nuclear to cytoplasmic ratio, and vesicular chromatin. Geographic areas of necrosis and frequent mitosis are common.

Immunohistochemical Findings

By immunohistochemistry , tumors express neuroendocrine markers including chromogranin, synaptophysin, and TTF-1. PAX8 may be expressed but is not specific to neuroendocrine tumors of the kidney, as it may be expressed in neuroendocrine tumors from other sites [604].

Differential Diagnosis

The main differential diagnostic considerations for low-grade neuroendocrine tumors include papillary renal cell carcinoma and metanephric adenoma. Lack of staining with neuroendocrine markers in these entities, coupled with expression of CK7 in papillary RCC and CD57 and WT-1 in metanephric adenoma, helps in this distinction. In the case of high-grade neuroendocrine carcinoma, the main differential diagnostic concern is that of an urothelial carcinoma with neuroendocrine differentiation. Careful examination for a conventional urothelial carcinoma component along with the absence of overlying carcinoma in situ in the adjacent urothelium can help sort this differential diagnosis out.

Tumors Occurring Predominantly in Children

Wilms’ Tumor

Wilms’ tumor (WT) is the most common pediatric renal tumor comprising more that 80% of all pediatric renal tumors. These tumors may rarely present in adults. Age at diagnosis ranges from 2 to 4 years, and they are rare in the first 6 months of life and after 6 years of age. There is an association of WT with both Beckwith-Wiedemann syndrome and Drash syndrome [605, 606]. Association with other congenital and genital abnormalities including cryptorchidism, hypospadias, aniridia, and hemihypertrophy has been well recognized in the literature.

Macroscopic Appearance

Macroscopically, tumors present as large masses with a solid, soft cut surface that appears gray white or pink in color. Hemorrhage, necrosis, and cystic change are common. The tumor is often circumscribed and compresses the adjacent renal parenchyma, giving the appearance of the pseudocapsule.

Histologic Appearance

Microscopically, the hallmark is an admixture of varying proportions of blastema, epithelial elements, and stroma. It is not unusual to have only two or occasionally only one of the three components within a tumor. The blastemal component is composed of hyperchromatic, closely packed small blue cells with dark nuclei, inconspicuous nucleoli, and frequent mitotic activity. The blastemal component may be arranged in a diffuse, nodular, or serpentine growth pattern. The epithelial component consists of primitive looking cells arranged in a tubular or cystic pattern. Glomeruloid areas may be noted, and occasionally the epithelial component may show divergent differentiation and show non-renal types of epithelium such as squamous, neural, or mucinous [607, 608]. The most common type of stromal component seen in Wilms tumor is a loose myxoid or fibroblastic stroma. However, other types of stroma including smooth muscle, neural, bone, fat, and cartilage have also been reported (Fig. 16.174) [607]. A variant of Wilms’ tumor which consists of varying proportions of differentiated epithelial components has been termed “teratoid Wilms tumor” [609].

Wilms’ tumors are divided into two categories: favorable and unfavorable histologies , based on the presence or absence of anaplasia. Anaplasia is defined by the NWTS as a combination of cells with large hyperchromatic cells and atypical mitoses. To meet the definition of anaplasia, tumor cells must be 3 times the size as the typical adjacent blastemal nuclei and show hyperdiploid, multipolar mitotic figures. When anaplasia is focal, the prognosis remains excellent [610, 611].

Immunohistochemical Findings

Wilms’ tumor expresses both cytokeratin and vimentin. Desmin may be positive in the blastemal component of up to 20% of tumors, although myogenin and myo-D1 are typically negative, which helps in the differential diagnosis with rhabdomyosarcoma [612]. Although nuclear staining for WT-1 is a sensitive marker for the diagnosis for Wilms tumor, it is not specific and may be expressed by other small blue round cell tumors, notably desmoplastic small blue round cell tumor. Some literature suggests that an antibody against the C-terminus of WT1 protein favors the diagnosis of DSRCT, while nuclear staining, by using antibodies against the N-terminus of WT1 protein, favors the diagnosis of Wilms’ tumor [613].

Rhabdoid Tumor

Rhabdoid tumor is a highly aggressive pediatric renal neoplasm that rarely occurs in adults. Tumors are typically detected in infancy are rare after 3 years of age. The prognosis is dismal and patients succumb to the disease within 12 months. Approximately 2/3rds of cases present with advanced disease and the lung and brain are the most common sites of metastasis. Younger age at diagnosis and advanced stage are associated with a worse outcome [614, 615].

Macroscopic Appearance

Grossly, tumors are large, typically medullary based and locally advanced. The cut surface is yellow-tan, friable with areas of necrosis and hemorrhage.

Histologic Appearance

Microscopically, the classic pattern is that of large polygonal cells arranged in a diffuse growth pattern. The tumor cells show characteristic features which include an eccentrically located nucleus with vesicular chromatin, a prominent nucleolus, and an eosinophilic cytoplasmic inclusion that displaces the nucleus (Fig. 16.175).

Immunohistochemical Findings

By immunohistochemistry , tumors may express a variety of epithelial and mesenchymal markers. Tumors are positive for vimentin and show scattered staining for epithelial markers including EMA and/or cytokeratin. The hallmark of this tumor is the loss of nuclear expression of SMARCB1(INI-1) which is demonstrated by immunohistochemistry or FISH.

Clear Cell Sarcoma

Clear cell sarcoma of the kidney (CCSK) is a rare renal tumor that accounts for <3% of all pediatric renal tumors. The peak incidence is between 2 and 3 years of age. The tumor is unilateral and unicentric, with a predominantly homogeneous solid and, occasionally, cystic cut surface. The typical histologic pattern demonstrates nests/cords of ovoid, epithelioid, or spindled cells with bland nuclei separated by fibrovascular septa. Other histologic patterns that have been reported include myxoid, sclerosing, cellular, epithelioid, palisading, spindle-cell, storiform, and anaplastic patterns [616, 617]. Approximately 5% of patients have metastatic disease at presentation, most commonly involving lymph nodes. Bone metastases and lung metastases are the most common sites of relapse. In about 20% of cases, late relapses, after 3 years of diagnosis, occur. Diagnosis is based on histologic appearance as there are no diagnostic immunohistochemical or molecular tests available. Immunohistochemistry is used as an adjunct to exclude other renal tumors. CCSK is only positive for vimentin and Bcl 2. Recently, a translocation t(10;17) and deletion 14q have also been described in CCSK, suggesting that they may play a role in its pathogenesis [618, 619].

Congenital Mesoblastic Nephroma

Congenital mesoblastic nephroma (CMN) is a low-grade spindle-cell neoplasm with a low malignant potential that is the most common congenital renal neoplasm and represents <5% of all pediatric renal tumors. Ninety percent present within the first year of life, and these tumors virtually never occur after the age of 3 years. These tumors may exhibit several subtypes including classical, cellular, and mixed.

The cellular variant, which represents 40–60% of MN, shows a t(12;15)(p13;q25) translocation with resultant ETV6-NTRK3 fusion, which is the identical gene fusion transcript that has been reported in congenital or infantile fibrosarcoma (IFS), which suggests cellular CMN represents intrarenal IFS, as both tumors share overlapping histology and genetics. Overall survival is >95%, but occasional stage III cellular MN, especially those presenting in older patients, may have a worse prognosis [620].

Grossly, the tumor is usually solid and occasionally cystic with a pale tan-white whorled fibrous cut surface. The cellular variant may have a softer cut surface and may show areas of hemorrhage.

The classic pattern of CMN is composed of bland spindle cells in a variably collagenous stroma and is histologically similar to infantile fibromatosis. A prominent interlacing fascicular pattern may be seen, and the tumor shows an infiltrative edge. The cellular subtype of CMN typically demonstrates solid cellular sheets of ovoid tumor cells with scant cytoplasm, mitoses, and focal necrosis. Mixed types showing areas of both the classical pattern and the cellular pattern may be seen. Risk factors for recurrence include cellular subtype and incomplete excision of the tumor. Most tumors relapse within a year of diagnosis and close follow-up is recommended [616]. Overall pediatric renal tumors are rare, but CMN is the commonest congenital renal neoplasm, with 90% presenting in the first year of life, and virtually never occurring after the age of 3 years. Therefore, caution should be exercised before diagnosing MN in a spindle-cell renal lesion in older patients, most of which will be metanephric stromal tumors. The cellular variant, which represents 40–60% of MN, shows a t(12;15)(p13;q25) translocation with a resultant ETV6-NTRK3 fusion 1, 2.

An identical gene fusion transcript has also been reported in congenital or infantile fibrosarcoma (IFS), which also affects the same age group and shows similar morphology, suggesting that cellular MN represents intrarenal IFS. This may be useful diagnostically using RT-PCR, although transcript expression levels are variable.

MN usually presents as an asymptomatic abdominal mass in an infant.

Tumors of the Urothelial Tract: Bladder, Urethra, Ureter, and Renal Pelvis (Anatomy)

Embryology

During the 4th to the 7th week of development , the cloaca divides into the urogenital sinus anteriorly and the anal canal posteriorly. The urorectal septum is a layer of mesoderm between the primitive anal canal and the urogenital sinus. The upper and larger portion of the urogenital sinus gives rise to the urinary bladder, the pelvic part of the urogenital sinus gives rise to the prostatic and membranous urethra, and the phallic part of the urogenital sinus give rise to the genital tubercle [621]. The bladder trigone is formed when the caudal portions of the mesonephric ducts become dilated and fused with the urogenital sinus in the midline dorsally. These ducts initially form the mucosa of the trigone, later replaced by the endodermal epithelium of the urogenital sinus. During embryogenesis, the allantois regresses completely forming the urachus extending from the umbilicus to the dome of the bladder; after birth, the urachus involutes becoming a fibrous cord. The epithelial lining of the urachus is similar to that of the urinary bladder and ureter but undergoes glandular metaplastic change. The epithelium of the urinary bladder is endodermally derived from the cranial portion of the urogenital sinus in continuity with the allantois. The lamina propria, the muscularis propria, and the adventitia develop from the splanchnic mesenchyme [622]. The epithelium of the urethra in both sexes originates in the endoderm and the surrounding connective tissue from the mesoderm. At the end of the first trimester, the epithelium of the prostatic urethra forms the prostate gland in males and urethral and paraurethral glands in females [621].

At the fifth week of development, the ureteric bud arises as a diverticulum from the mesonephric duct. The bud grows laterally and invades the center of the metanephrogenic blastema, the primordial renal tissue. The metanephrogenic blastema forms glomeruli, proximal tubules, and distal tubules. The ureteric bud divides and branches forming the renal pelvis, infundibula, calyces, and collecting tubules which will provide a conduit for urine drainage in the mature kidney [623].

Anatomy and Histology

In adults, the empty urinary bladder is located within the anteroinferior portion of the pelvis minor. When the bladder fills, it may reach the level of the umbilicus. At the level of the bladder neck, it is attached to the pubovesical ligaments in women, and to the puboprostatic ligaments in male [624, 625]. The adult empty bladder has a four-sided inverted pyramid. The posterior aspect of the bladder is separated from the rectum by the uterine cervix and the proximal portions of the vagina in females and by the seminal vesicles and the ampulla of the vasa deferentia in males. The inferolateral and anterior surfaces are in contact with the fascia of the levator ani muscles. The anterosuperior aspect of the bladder or apex (dome) is the point of insertion of the umbilical ligament and where urachal carcinoma can be seen. The trigone is located at the base of the bladder into posterior bladder neck and contains the ureteral orifices (Fig. 16.176a–c).

Histologically , the urinary bladder consists of four layers: urothelium, lamina propria, muscularis propria, and adventitia. The urothelium, previously called transitional epithelium, is two to seven cells thick depending on bladder distention; however, while evaluating urothelial thickness, the nature of the cut can strongly vary the appearance of the urothelial thickness (Fig. 16.177). The urothelial cells are classified in superficial or “umbrella cells” which are in contact with the urine, the intermediate cells, and the basal cells. The urothelium is virtually impenetrable to any components of the urine. The lamina propria lies between the mucosal basement membrane and the muscularis propria. It consists mainly of dense connective tissue, with many bundles of coarse collagenous fibers. It is rich in vessels, nerve, and elastic fibers and muscle layers constituting the muscularis mucosa [628,629,628]. The muscularis mucosae usually consist of an inner longitudinal and outer circular layer of smooth muscle cells, and it is not connected to the muscularis propria [622]. The muscularis propria is comprised of three layers of smooth muscle, inner and outer longitudinal layers, and the central circular layer. The adventitia is the outermost connective tissue covering the bladder.

The urethra is the tube that connects the urinary bladder to the external urethra orifice or meatus of the glands penis and transports the urine from the bladder to the urethral meatus. In male, it also transports the semen. The urethral epithelium is derived from the endodermal urogenital sinus. Male urethra is approximately 20 cm long, and it is divided in three segments: prostatic urethra, lined by urothelium; bulbomembranous urethra, lined by pseudostratified columnar epithelium; and penile urethra, lined pseudostratified columnar epithelium except at fossa navicularis which is lined by non-keratinizing squamous epithelium. The female urethra is lined by urothelium (proximal portion) and non-keratinizing squamous epithelium (mid and distal portion).

The ureter is the tubular structure that transports the urine from the kidney to the urinary bladder. It is lined by urothelium; however, lamina propria does not contain muscularis mucosa. The renal pelvicalyceal system , which is attached to the ureter, is also lined by urothelium and contains lamina propria and similar to the ureter muscularis mucosae are absent. Both ureter and renal pelvicalyceal system contain muscularis propria [623].

Specimen Handling/Grossing (Partially Adapted from CAP, 2017) [629]

Urinary Bladder

Biopsy/TURBT

Urinary bladder biopsies are processed as small biopsies. Transurethral resections of bladder tumors (TURBT ) sometimes result in specimens grossly recognizable as papillary tumor. Submit one section per centimeter of tumor diameter (up to 10 cassettes). If the tumor is noninvasive by the initial sampling, additional submission of tissue (including possibly submitting all tissue) is necessary to diagnose or rule out the presence of invasion. If tumor is invasive into lamina propria in the initial sampling, additional sections (including possibly submitting the entire specimen) may be necessary to diagnose or rule out the possibility of muscularis propria invasion [629].

Radical or Partial Cystectomy

The urinary bladder is usually resected because of proven invasive urothelial carcinoma by biopsy or TURBT. We need to be knowledgeable if neoadjuvant chemotherapy has been provided to the patient . Rarely, the urinary bladder will be removed because of prostatic carcinoma invasive into the urinary bladder or because of synchronous urinary bladder and prostatic primary tumors. It is not uncommon to have the majority of the tumor removed by biopsy or transurethral resection (TURBT) and have only minimal, or no, tumor present in the cystectomy specimen. It is also common to find an incidental (clinically occult) prostate carcinoma.

Specimen Processing (Partially Adapted from CAP, 2017) [629]

Record outer dimension of bladder and length and diameter of attached ureters.

Males

If the prostate is attached, record outer dimensions, seminal vesicles (dimensions), and vasa differentia (length and diameter).

Females

The anterior vaginal wall will be attached. Describe size (length, width, and depth), color (usually white), and any lesions.

Record the outer appearance of the specimen (i.e., is any gross tumor present at the resection margin). Usually the margin consists of unremarkable adipose tissue. Palpate (but do not remove) this tissue, looking for grossly involved lymph nodes. Usually lymph nodes will not be found. Ink the prostate (if present) and any suspicious areas of the external urinary bladder.
If the specimen is fresh and too friable to be grossed at that time, fix the entire specimen in formalin for few hours or overnight.
Before opening the urinary bladder, determine the location of the tumor by looking up prior biopsy specimens or radiology reports. Avoid cutting through the tumor when opening the urinary bladder.
If the location is unknown, or if it is in the usual location near the trigone, open the bladder anteriorly through the urethra, and extend the incision to the dome. A probe placed into the urethra is helpful to guide the knife.
Locate the site of the tumor. Avoid touching the mucosal surface because it is very delicate and is easily denuded. In some cases, the luminal tumor will be very small, or only a shallow ulceration from a prior biopsy will be present. Ink the deep margin at the site of the tumor. Make parallel sections through the tumor.
Record the tumor’s size, configuration (papillary, sessile, ulcerated, fungating, flat, or plaque-like), color, consistency (firm, soft), depth of penetration of wall (submucosa, into or through muscularis propria, into perivesical soft tissue), location (dome, anterior, posterior, lateral wall, trigone), and relationship to ureteral orifices (obstructing, extending into ureter).
Describe the remainder of the bladder mucosa (smooth and glistening, hemorrhagic, edematous). If there are any abnormal areas, describe location and appearance.
Submit representative sections of anterior wall, posterior wall, lateral wall, dome, and any abnormal areas.
The true ureteral margins are usually submitted separately and have often been examined by frozen section. Additional margins from the specimen do not need to be submitted.
The entire length of the ureter is examined for additional foci of tumor. Either take multiple cross sections or open longitudinally. Submit any suspicious lesions.
Males: The prostate can be processed similar to radical prostatectomies (see the section on prostatectomies for details). The prostate is sectioned through the posterior surface in serial sections perpendicular to the prostatic urethra. Describe color (white, yellow), consistency (firm, hard), and any areas of necrosis or hemorrhage and texture (nodular or effaced). The most common location of tumors is along the posterior wall. If no gross lesions are present, submit four sections from the posterior right lobe and four sections from the posterior left lobe. If lesion(s) are present, submit enough sections to document them as well as representative sections from the uninvolved prostate. If prostate is small, submit it in toto.

The urinary bladder base is not a margin and is not submitted. However, if gross tumor is present, take a section to document invasion into prostate.

The urethral margin (also the apex of the prostate) is best sampled with a perpendicular section through the urethra to try to assess urethral mucosa which may be retracted and not seen in an en face apical margin.

Section the seminal vesicles perpendicular to the long axis. Submit one section of each at the junction with the prostate.

Females

Submit one representative section of the vaginal mucosa and any gross lesions.

After all microscopic sections have been taken, the perivesical soft tissue is carefully sectioned to look for lymph nodes. These nodes are found in only a small percentage of cases and more often in females than in males.

Microscopic sections:

Tumor: At least one section for cm of tumor; sections should include junction with normal mucosa, deepest point of invasion, deep margin.
Urinary bladder mucosa: Up to six cassettes of representative sections of anterior, posterior, right and left lateral walls, if no gross tumor is present. If gross tumor is present, submit several sections of the mucosa remote from the carcinoma, especially if abnormal, including the anterior and lateral walls, dome and trigone.
Ureters: Submit one section of ureteral margin unless submitted separately or as intraoperative consultation. If a long segment of the ureter(s) is present, then additional sections from the mid-portion may be necessary. If lesions are present, submit sections.

Males:

Prostate: Four cassettes of posterior right lobe and four cassettes of posterior left lobe
Urethral margin: One perpendicular section
Seminal vesicles: Two cassettes documenting left seminal vesicle and right seminal vesicle

Females:

Anterior vaginal wall: One cassette documenting normal mucosa and any lesions present
Lymph nodes: All lymph nodes present in perivesical soft tissue

Urethrectomy

Measure entire specimen.
Identify and ink the margins.
Microscopic sections:
- In transurethral specimens , submit one section per centimeter of tumor diameter (up to ten cassettes).
- If the tumor is noninvasive, additional submission of tissue (including possibly submitting all tissue) is necessary to diagnose or rule out the presence of invasion.
- In urethrectomy specimens, submit one section per centimeter of tumor, including the macroscopically deepest penetration. Documentation of tumor in relation to surrounding anatomic structures (such as corpus spongiosum, corpus cavernosum, prostate, periurethral muscle, vagina, and bladder) is critical to proper staging.
- The distal and proximal urethral margins should be submitted (or distal urethra and bilateral ureteral margins if bladder is included), if not evaluated intraoperatively by frozen section. These margins are typically submitted en face in order to see the entire urothelial lining; however, if the tumor is grossly in close proximity to the margin, a perpendicular section showing relationship to ink may be more appropriate.
- The surrounding radial soft tissue margins should also be submitted, guided by the closest approximation of the tumor to ink by gross evaluation.

Nephroureterectomy

Measure entire specimen.
Identify and ink the margin of the ureter, or the urinary bladder cuff, which may be marked with a suture or ink.
Open urinary bladder cuff, ureter, and renal pelvis carefully under direct vision to avoid cutting through the tumor. Do not cut the margin en face.
Bivalve kidney with adipose tissue intact.
Pin out specimen and fix overnight.
Note tumor(s) location(s): renal pelvis, major or minor calyces, ureteropelvic junction, and upper, middle, or lower 1/3rd of ureter.
Size of tumor(s) in three dimensions.
Section the specimen at 2.5 mm intervals.
Check for maximal depth of invasion and tumor extension into pelvic/ureteral wall, renal sinus, renal parenchyma, or perinephric fat.
Find palpable hilar lymph nodes.
Check for adrenal gland.
Microscopic sections:
- One section/cm of tumor diameter (minimum six sections if tumor is ≤5 cm), including:
- Sections to demonstrate maximal depth of invasion.
- Include sections of all the grossly different areas of the tumor.
- Tumor/renal sinus interface.
- Tumor/normal kidney junction.
- Tumor/perinephric fat junction, if tumor is next to it.
- Sample adjacent soft tissue margin if tumor is close to it.
Urinary bladder cuff margin: Ink and submit perpendicular sections.
Ureter margin: Ink and submit en face. However, if the tumor is less than 1.5 cm from the margin, submit perpendicular sections.
Sections of uninvolved urothelium, especially granular red areas that may represent carcinoma in situ: from renal pelvis, upper, middle, and lower third of ureter (2–3 sections per cassette from each location).
Two blocks of normal kidney.
Sample hilar vessels only if tumor is close to them or involves them.
One section of adrenal gland.
Submit all hilar lymph nodes.

Urothelial Tumors

Urothelial neoplasms arise from any organ lined by urothelium, such as the urinary bladder, urethra, ureter, and renal pelvis. The organ most frequently affected is the urinary bladder. The neoplastic characteristics of urothelial neoplasms involving the urinary bladder also apply to the vast majority of the remaining urothelium lined organs, such as the urethra, ureter, and renal pelvis.

Epidemiology

Bladder cancer is the 9th most common cancer worldwide and the 4th most common in the USA. It is more frequent in males than in females (3–4X) with a median age of 65–70 years. Mortality is different between the sexes with 2–10 deaths per 100,000 males per year and 0.5–4 deaths per 100,000 females per year. The prevalence of bladder cancer is six times higher in developed countries than developing countries, with highest incidence in Western Europe, North America, and Australia [630]. Significant variations exist in incidence, morbidity, and mortality rates of bladder cancer in different ethnic groups. The incidence among White-Americans is twice the one observed in African-Americans; however, survival rates in African-Americans are worse [630]. Urothelial neoplasms are by far the most frequent tumors of the urinary bladder. The urothelial carcinoma represents more than 90% of the bladder malignancies. Approximately, 80% of the new diagnosis of bladder cancer is in the form of noninvasive or early invasive disease (pTis, pTa, pT1). Recurrence and progression of noninvasive tumors depends on the grade. The outcome of the invasive tumors depends on the stage.

Etiology

Bladder cancer has been associated with several inherited cancer syndromes: Lynch syndrome, an autosomal dominant inherited cancer disorder caused by germline mutations in DNA mismatch repair gene; hereditary retinoblastoma, related to radiation and cyclophosphamide therapy; and Costello syndrome, associated with childhood bladder cancer. In addition, environmental factors with carcinogenic effect in the bladder are several including smoking [631, 632], and occupational exposures such as aromatic amines (2-naphthylamine and 4-aminobiphenyl) among diesel exhaust-exposed individuals, painters, and workers of chemical plants [633]. Other etiology factors include arsenic, phenacetin, radiotherapy, congenital bladder exstrophy, and Schistosoma infection.

The 2016 WHO classification of tumors of the urothelial tract is currently in use (Table 16.20) [64].

Table 16.20 WHO classification of tumors of the urothelial tract [634]

Full size table

As in 2004, the 2016 WHO classification recommends the application of the grading classification of urothelial neoplasms first put forth by the International Society of Urological Pathology (ISUP) in 1997 [634]. This classification is widely accepted by the most influential agencies, and it is currently in use providing uniform terminology based on cytology and architectural features. WHO 2016 recommends its use since it provides uniform terminology and definitions based on the level of cytologic and architectural abnormalities (order and disorder) and the establishment of detailed criteria for various preneoplastic conditions and tumor grades, defines a group of lesions (high grade) with a high risk of progression that may be candidates for adjuvant therapy, eliminates the ambiguity of 1973 WHO system (grade 1–2, grade 2–3), and includes papillary neoplasm (i.e., PUNLMP) that is not associated with invasion at the time of diagnosis and has a negligible risk of progression, although the potential for recurrence requires clinical surveillance [635]. Grading of urothelial tumors has importance in noninvasive disease, specifically papillary neoplasms. Although a small percentage of invasive carcinomas are low grade, usually limited to the lamina propria, >95% of invasive tumors are high grade [64]. Tumors can be divided in noninvasive and invasive, they both can be papillary and flat, and papillary lesions can be exophytic or endophytic (Table 16.21). Endophytic (inverted) lesions may show areas with both exophytic and endophytic growth , but the later should be the predominant pattern to gain the denomination of endophytic (inverted) lesion [636].

Table 16.21 2016 WHO/ISUP classification of urothelial neoplasms

Full size table

Noninvasive Urothelial Lesions

Noninvasive urothelial lesions are the most frequent bladder neoplasms. They are classified into two categories: papillary and flat. Both types of lesions are varied, ranging from benign (reactive and atypical) and preneoplastic to neoplastic. Despite the efforts made for standardization of diagnosis in the current 2004–2016 WHO/International Society of Urological Pathology (ISUP) classification of urothelial neoplasms, grading of these lesions is still subjective.

Flat Lesions

Urothelial Carcinoma In Situ

Urothelial carcinoma in situ (CIS) is a flat urothelial lesion devoiced of papillary structures and containing high-grade malignant cells.

Clinical Features

Patients with CIS may be asymptomatic, or they may present with dysuria, urinary frequency, or urgency.

Gross Features

Cystoscopically it appears as an erythematous flat lesion, which may be focal, multifocal, or diffuse.

Microscopic Features

This is a flat high-grade lesion demonstrating loss of polarity with pleomorphic large cells with hyperchromatic and large nuclei (>5–6 of lymphocytes) and nucleoli. Mitosis is frequently present. Frequently, malignant cells are occupying the full thickness of the mucosa; however, isolated cells (pagetoid spread) can be seen, and they are sufficient for the diagnosis of CIS. CIS cells may be discohesive, and they may be found in the urine, showing as a completely urothelial denuded mucosa or only remaining the deepest layer(s) of the epithelium (Fig. 16.178).

Immunoprofile

Immunohistochemistry for CK20 and CD44 can be of help in the diagnosis of CIS; however, it will not distinguish CIS from urothelial dysplasia. Dysplastic cells are positive for CK20 demonstrating full-thickness reactivity (Fig. 16.178c); however, the only CK20-positive cells in normal urothelial mucosa are the umbrella cells. In contrast, CD44 is full-thickness positive in normal urothelial mucosa and tends to be completely negative in CIS (Fig. 16.178d).

Prognosis and Predictive Factors

Majority of cases respond to intravesical therapy with BCG; however, many of them will recur, and approximately one-quarter of them will progress to invasive urothelial carcinoma. Lack of response to intravesical therapy has been associated with disease progression [639,640,641,642,641].

Urothelial Dysplasia

Urothelial dysplasia , also called low-grade intraurothelial neoplasm , has cytological and architectural features that are considered preneoplastic; however, they fall short of the diagnosis of CIS [634].

Clinical Features

Frequently asymptomatic and frequently discovered associated with other urothelial malignancies.

Gross Features

It appears normal cystoscopically.

Microscopic Features

This flat lesion should be distinguished from normal urothelium and urothelium with atypia. Normal urothelial mucosa contains three to six layers of stratified urothelial cells without atypia. Urothelial atypia is frequently associated with inflammation, and it is characterized by nuclear enlargement with evenly distributed chromatin, smooth nuclear membrane, and prominent pinpoint nucleoli with preservation of the cellular perpendicular arrangement at 100×. When this arrangement is lost with slight cellular enlargement, absence of mitosis in upper layers of the urothelium, and absence of inflammation, the diagnosis of dysplasia can be issued.

Immunoprofile

CK20 can be immunoreactive in more than half of dysplastic cases, and therefore the presence of immunoreactivity for this marker is not helpful distinguishing dysplasia form CIS.

Prognosis and Predictive Factors

The prognosis is difficult to assess since it is for the vast majority of cases associated with other more aggressive urothelial processes.

Urothelial Proliferation of Uncertain Malignant

Urothelial proliferation of uncertain malignant potential is characterized by a marked thickening of the urothelium without or minimal cytological atypia. It can be flat (part of the differential diagnosis of flat urothelial lesions) and pseudopapillary (no true papillary formations). This termed substituted the previously called urothelial hyperplasia (flat and papillary).

Clinical Features

Frequently asymptomatic and frequently discovered associated with other urothelial malignancies or in follow-up consultations.

Gross Features

Cystoscopically normal; in cases where the lesion is papillary-like, it appears focal, elevated, raise, and bleb-like on cystoscopic examination.

Microscopic Features

It is characterized by thickened urothelium (>= 10 layers approximately) arranged into narrow undulating mucosal folds of various heights. There is no definitive formation of true papillae with fibrovascular cores, which are characteristic of papillary neoplasms. Cytologically, there is no atypia and, if present, should only be minimal.

Genetic profile: When associated with low-grade papillary tumors, the presence of nine deletions is seen in half of cases [642, 643]. FGFR3 amplification and mutations have been described [643].

Prognosis and Predictive Factors

It is considered a clonal process and may be an early manifestation of low-grade papillary urothelial neoplasm. The risk of developing urothelial neoplasm at 5 years is 40%. Therefore, clinical follow-up is suggested.

Papillary Lesions

Papillary neoplastic lesion of the urinary bladder is characterized by fibrovascular cores covered by neoplastic urothelium.

Clinical Features

They are localized anywhere of the urothelial surface, frequently in lateral and posterior walls. Painless intermittent hematuria is the most common symptomatology.

Gross Features

Exophytic lesions on cystoscopy. Inverted growth pattern exists (Table 16.20).

Microscopic Features

Fibrovascular cores covered by neoplastic urothelium. As in 2004, the 2016 WHO classification recommends the application of the grading classification of urothelial neoplasms first put forth by the International Society of Urological Pathology (ISUP) in 1997 [634]. According to this current classification, grading is based on different level of cytological and architectural disorder at low-to-medium magnification (100× and 200×). Cytological disorder refers to alterations in nuclear size, shape, and chromatin. and architectural disorder is defined as abnormalities in the orientation of the cells [634, 644]. Inverted (endophytic) forms of noninvasive papillary urothelial carcinoma exist, most frequently combined with exophytic forms. The differential diagnosis is between the other urothelial papillary neoplasms and with papillary-polypoid cystitis, prostatic-type polyp, and papillary nephrogenic adenoma. Papillary cystitis has a broader base without hierarchical branching; prostatic-type polyp has prostatic secretory cells, NKX 3.1 positive by immunohistochemistry; papillary nephrogenic adenoma has a single layer of cuboidal lining epithelium, PAX-8 positive by immunohistochemistry.

Noninvasive Papillary Urothelial Carcinoma

Papillary urothelial carcinoma is a cytological and architecturally disordered papillary neoplasm without invasion beyond the basement membrane (pTa). It is classified in two categories, low grade and high grade. Approximately, 75% of new urothelial carcinomas are of this type, and half of them are low grade. It is known that papillary urothelial neoplasm can demonstrate grade heterogeneity. When this occurs, as per 2004 WHO/ISUP classification, the highest grade should be the one assigned to the neoplasm. Immunohistochemistry and/or molecular assays are not helpful in that setting [636].

Low-grade Papillary Urothelial Carcinoma

It is characterized by delicate papillae that at low magnification have an orderly appearance. At low magnification (100×), we can appreciate some degree of disorder with loss of polarity, mild nuclear pleomorphism, and mitosis and, if present, are typical and scarce (Fig. 16.179a) [645]. Prognosis and predictive values: Recurrences are common (50–70%). Progression of disease is rare (5%)

High-Grade Papillary Urothelial Carcinoma

It is characterized by a thicker, and occasionally fused papillae, that at low and medium magnification (40×, 100×) demonstrates obvious cellular disorder, pleomorphism, and mitosis which may be atypical in nature (Fig. 16.179b) [645].

The distinction between high-grade and low-grade papillary urothelial carcinoma is purely histological, and immunohistochemistry cannot accurately distinguish these lesions.

Prognosis and Predictive Values

These tumors have a high rate of progression to invasive disease.

Papillary Urothelial Neoplasm of Low Malignant Potential

Papillary urothelial neoplasm of low malignant potential (PUNLMP) is a papillary urothelial neoplasm characterized with papillae that are thicker than normal urothelium and display no atypia.

Clinical Features

Gross or microscopic hematuria.

Gross Features

The vast majority of PUNLMPs are exophytic lesions on cystoscopy. Inverted forms exist but are rare.

Microscopic Features

PUNLMP shows papillary structures lined by urothelium that is thicker than normal urothelium. There are no architectural abnormalities and there is no cellular atypia. Mitoses are rare, and if present, they are limited to the basal layer (Fig. 16.179c).

Differential diagnoses are with urothelial papilloma, low-grade papillary urothelial carcinoma, papillary-polypoid cystitis, and nephrogenic adenoma. Urothelial papilloma is lined by normal thickness urothelium; low-grade papillary urothelial carcinoma is architecturally similar to PUNLMP; however it is disordered, with loss of cellular polarity and demonstrates cellular atypia. Papillary cystitis has a broader base without hierarchical branching and papillary nephrogenic adenoma typically shows a single layer of cuboidal lining epithelium, PAX-8 positive by immunohistochemistry.

Prognosis and Predictive Factors

Despite some low level of agreement in the histological distinction between PUNLMP and low-grade papillary urothelial carcinoma, the former has a more favorable prognosis demonstrating lower level of recurrences and never progresses in either stage or grade [648,649,650,651,652,651].

Urothelial Papilloma

Papillary urothelial neoplasm characterized with thin, slender papillae-lined urothelium of normal appearance and thickness without cellular atypia.

Clinical Features

Very uncommon lesion and more frequently seen in young adult patients. Gross or microscopic hematuria.

Gross Features

Exophytic lesions on cystoscopy. Solitary and small. More frequent in the posterior and lateral walls.

Microscopic Features

Slender papillae-lined normal appearance urothelium without cellular atypia and frequently prominent/multinucleated umbrella cells, which should not be considered atypical (Fig. 16.179d). CK20 immunostaining is confined to the umbrella cells as it is on normal urothelium. Alterations of p53 are not observed

Differential Diagnoses

Differential diagnostic considerations include PUNLMP, papillary-polypoid cystitis, prostatic-type polyp, and papillary nephrogenic adenoma. PUNLMP shows thicker urothelium; papillary cystitis has a broader base without hierarchical branching Prostatic-type polyp is composed of prostatic secretory cells, and is positive for NKX 3.1 by immunohistochemistry. Papillary nephrogenic adenoma has a single layer of cuboidal lining epithelium, and is positive for PAX8 by immunohistochemistry.

Prognosis and Predictive Factors

Recurrence is rare (0–8%).

Inverted Urothelial Papilloma

Inverted urothelial papilloma is a rare urothelial neoplasm (<1% of bladder urothelial neoplasms) with a complex, anastomosing inverted growth pattern and absent or minimal cytologic atypia.

Clinical Features

Gross or microscopic hematuria.

Gross Features

Tumors most commonly occur in the bladder neck and trigone and present as solitary and small lesions that appear as a raised, pedunculated lesions on cystoscopy.

Microscopic Features

Tumors show a trabecular growth pattern with an astomosing cords of similar width, arising from the urothelium with invagination into the lamina propria [636, 651]. An exophytic component if present should be minimal (Fig. 16.180).

Prognosis and Predictive Factors

Low recurrence rate (<2%) [652, 653].

Urothelial proliferation of uncertain malignant potential (see “Urothelial Proliferation of Uncertain Malignant in Potential” section) (H4).

Invasive Urothelial Carcinoma

It is defined as an urothelial carcinoma that invades beyond basement membrane.

Epidemiology

Infiltrating urothelial carcinoma is the most common malignant neoplasm of the urinary tract and represents the seventh most common cancer worldwide [654]. Bladder cancer is 3–4 times more frequent in men than in females with a median age at diagnosis of 65–70 years. Mortality is different between the sexes with 2–10 deaths per 100,000 males per year and 0.5–4 deaths per 100,000 females per year. The prevalence of bladder cancer is six times higher in developed countries than developing countries, with highest incidence in Western Europe, North America, and Australia [630]. Significant variations exist in incidence, morbidity, and mortality rates of bladder cancer in different ethnic groups. The incidence among White-Americans is twice the one observed in African-Americans; however, survival rates in African-Americans are worse [630].

Etiology

Bladder cancer has been associated with several inherited cancer syndromes: Lynch syndrome, an autosomic dominant disorder inherited cancer caused by germline mutations in DNA mismatch repair gene; hereditary retinoblastoma, related to radiation and cyclophosphamide therapy; and Costello syndrome, associated with childhood bladder cancer. In addition, environmental factors with carcinogenic effect in the bladder are several including smoking [631, 632] and occupational exposures such as aromatic amines (2-naphthylamine and 4-aminobiphenyl) among diesel exhaust-exposed individuals, painters, and workers of chemical plants [655]. Other etiology factors include arsenic, phenacetin, radiotherapy, congenital bladder exstrophy, and Schistosoma infection.

Clinical Features

The most frequent symptom of patients with invasive urothelial carcinoma is painless hematuria, followed by urgency, nocturia, and dysuria. Metastatic disease can be associated with weight loss, and it is frequently seen involving the liver, lung, and bones [655, 656]. Invasion into lamina propria is normally managed with intravesical therapy, whereas invasion into muscularis propria is normally managed by radical cystectomy; radiation therapy and neoadjuvant/adjuvant therapy can also be offered.

Gross Features

Invasive urothelial carcinoma can be unifocal or multifocal, and most of them are polypoid; however, nodular, solid, and ulcerated forms are present. If urothelial carcinoma in situ is also existent, area/s of erythematous discoloration is/are present.

Microscopic Features

Invasive bladder carcinoma is morphologically very varied. Some of the variants are now recognized as specific variants. The pattern of invasion has prognostic significance, with the more infiltrative cords and single-cell patterns having the worse outcome [657, 658]. Invasive urothelial carcinoma is a high-grade neoplasm displaying nuclear pleomorphism, hyperchromatic nuclei, irregular nuclear contours, and frequent and abnormal mitosis. The cytoplasm is usually pale to eosinophilic and moderate to abundant (Fig. 16.181a, b).

Immunoprofile

As per the ISUP consensus conference [659], there is no ideal marker or established panel to confirm urothelial differentiation. The ISUP recommends the use of GATA3, CK20, p63, HMWCK, and CK5/6 as first-line urothelial markers. S100P and uroplakin II are second line, and they consider CK7 and thrombomodulin of limited utility; however, CK7-negative tumor is less likely to be a urothelial carcinomas. Smoothelin immunostaining may distinguish muscularis mucosae from muscularis propria [660], but there may be overlap of staining between the two layers [660, 661]. For the later reason, it is not frequently used in that differential diagnosis. It is recommended that in cases of invasion into indeterminate muscle type, the diagnosis reads as “invasive urothelial carcinoma with invasion of muscle, indeterminate type,” which will prompt the urologist for a restaging biopsy procedure [662].

Invasive urothelial carcinoma has different histologic subtypes, morphologically different form the usual histologic patterns. Patients with urothelial carcinoma variants are treated similarly to conventional urothelial carcinoma except for small-cell carcinoma (different chemotherapy modality), lymphoepithelioma-like carcinoma (more sensitive to chemotherapy), micropapillary carcinoma (radical surgery for pT1 lesions), and urothelial carcinoma with squamous differentiation (less responsive to adjuvant therapy) [663]. Urothelial carcinoma with aberrant differentiation refers to a neoplasm with a typical papillary, in situ or invasive urothelial carcinoma with at least focal squamous differentiation, glandular differentiation, or trophoblastic differentiation. To designate a bladder tumor as squamous cell or adenocarcinoma, a pure or almost pure histology is required. Some authors suggest providing a percentage for each divergent morphologic component [673]. Different subtypes are discussed below.

Differential Diagnosis

Prostatic adenocarcinoma involving bladder, gynecologic carcinomas involving bladder, paraganglioma, inverted noninvasive urothelial neoplasms, nephrogenic adenoma, and pseudocarcinomatous hyperplasia.

Prognosis

It is stage dependent. pT2 or greater (muscularis propria and beyond) is associated with a bad prognosis in contrast to superficially invasive neoplasms (pT1) that may have an excellent prognosis. Therefore, clear reporting of the depth of invasion (lamina propria or muscularis propria) should be followed.

Genetic Profile

Studies have suggested that invasive urothelial tumors develop along at least two molecular pathways, via either high-grade papillary tumors or CIS [664]. Low-grade tumors recur however rarely they progress. Molecular alterations differ markedly between low- and high-grade tumors and between those that are invasive and those that are not. Recurrent mutations occur in genes such as TP53, FGFR3, PIK3CA, RB1, and HRAS, with TP53 and FGFR3 being the most common, together with promoter mutations of TERT [665, 666]. The Cancer Genome Atlas (TCGA) revealed that the mutational landscape of urothelial tumors are quite complex, with >300 mutations, >200 copy number alterations, and >20 rearrangements per tumor [667, 668]. Muscle-invasive bladder (MIBC) cancer has widely variable clinical outcomes and responses to conventional chemotherapy. Recently, three molecular subtypes of MIBC that resembled established molecular subtypes of breast cancer were described. Basal MIBCs shared biomarkers with basal breast cancers and were characterized by p63 activation, squamous differentiation, and more aggressive disease at presentation. Luminal MIBCs contained features of active PPARγ and estrogen receptor (ER) transcription and were enriched with activating FGFR3 mutations and potentially FGFR inhibitor sensitivity. p53-like MIBCs were consistently resistant to neoadjuvant MVAC chemotherapy, and all chemoresistant tumors adopted a p53-like phenotype after therapy, with important implications for prognostication, development of targeted agents, and disease management with conventional chemotherapy [669].

Nested Variant

This variant is more common in the bladder, and it is characterized by nests (small or large “large nested variant”) of infiltrating tumor cells with relatively bland cytological appearance [670, 671]. The pattern is a disorderly growth with confluent small/large nest beneath the urothelium. The nuclei are not atypical and are typically of low nuclear grade. The immunohistochemical profile is similar to that of usual urothelial carcinoma (Fig. 16.182a). Stage by stage has the same prognosis as usual urothelial carcinoma; however, this variant normally carries a poorer prognosis since it is discovered at a higher stage in comparison to usual forms. The differential diagnosis should include von Brunn nests (superficial location and more rounded urothelial nests), cystitis cystica/glandularis (more superficial), and nephrogenic adenoma (more tubular, single layer of cuboidal cells, hobnailing, PAX-8 positive).

Microcystic

This variant is characterized by round to oval microcysts (1–2 mm in size) lined by a bland or denuded-looking epithelium, intraluminal secretions, and calcifications. There is no desmoplastic reaction and invasion is frequently into muscularis propria. The immunohistochemical profile is similar to usual urothelial carcinoma. The differential diagnosis should include urothelial carcinoma with glandular differentiation (glandular component with columnar cells with or without intracytoplasmic mucin), cystitis cystica/glandularis (more superficial), and nephrogenic adenoma (more tubular, single layer of cuboidal cells, hobnailing, PAX-8 positive) and Mülleriosis (bland cytologic features, with endocervical, tubal, or endometrial-type glands).

Micropapillary

This variant displays small cellular nests and aggregates, surrounded by lacunae, resembling vascular invasion. Occasionally, as is characteristic of this histologic variant, we can identify multiple nests in the same lacuna. This finding is also the most reproducible diagnostic criterion. Othe histologic features associated with this variant include nuclei that are peripherally oriented and characteristic cytoplasmic vacuoles. It is high grade and may be associated with usual urothelial carcinoma (Fig. 16.182b). Since it is probable that any amount of this variant may influence patient’s outcome, it should always be reported, even if is focal [682, 54]. This variant is highly associated with CIS [672]. Micropapillary -like architecture may be seen in noninvasive papillary urothelial carcinoma. If this occurs without invasive component, the denomination of micropapillary urothelial carcinoma should not be used. Angiolymphatic invasion is common. Standard of care for patients with pT1 micropapillary urothelial carcinoma should be treated by early radical cystectomy [673]. This variant is immunoreactive for the established urothelial carcinoma markers [674]. HER2 is more frequently amplified in micropapillary carcinoma than in the conventional carcinoma. The differential diagnosis should include ovarian serous carcinoma (the later been frequently positive for ER and WT-1 by immunohistochemistry) and usual urothelial carcinoma with stromal retraction (absence of multiple nests in the same retraction space, immunohistochemistry is not helpful in this differential diagnosis).

Lymphoepithelioma-Like

Most patients present with stage T2-3 disease. Other than in the bladder, it can be found in urethra, ureter, and renal pelvis. Morphologically resembles lymphoepithelioma of the nasopharynx. Lymphoepithelial-like carcinoma may be pure, predominant, or focal admixed with conventional urothelial carcinoma (Fig. 16.182c). Pure forms may have a higher response to chemotherapy regimens. Histologically is composed of nests, sheets, and cords of undifferentiated cells with large pleomorphic nuclei and nucleoli and syncytial appearance. Surrounding the carcinoma there is a lymphoid infiltrate of T and B lymphocytes, plasma cells, histiocytes, neutrophils, and eosinophils. This variant is immunoreactive with p63 and GATA as well as with multiple types of cytokeratin [675]. The differential diagnosis should include lymphoma (negative for keratin-positive malignant cells) and small-cell carcinoma (cellular molding, cytokeratin expresssed in a dot-like pattern and expression of neuroendocrine markers).

Plasmacytoid

This is a rare variant of urothelial carcinoma characterized by malignant urothelial cells that resemble plasma cells or monocytes. At cystoscopy, a surface lesion is not always present. Characteristically this variant is composed of discohesive malignant cells in a loose stroma (Fig. 16.182d a). These plasmacytoid cells can be coupled with a variable number of single cells with cytoplasmic vacuoles, signet-ring cell like with or without intracellular mucin [676, 677]. Extracellular mucin is not seen. This can be a distinctive finding to differentiate this variant from mucinous adenocarcinoma with signet-ring cells, where extracellular mucin is observed. This variant is frequently associated with usual type high-grade urothelial carcinoma (50% of cases) and CIS. As usual type urothelial carcinoma, this variant is immunoreactive for different cytokeratin markers, including CK7, CK20, and HMWK, p63, GATA3, and uroplakins II and III (Fig. 16.182db ). They may express CD138 however do not express any additional lymphoid markers (Fig. 16.182dc ). E-cadherin is typically negative [674, 677, 678, 688]. Most patients with plasmacytoid variant of urothelial carcinoma present at an advanced stage (pT2, pT3) with poor outcome [679, 680]. The differential diagnosis should include mucinous adenocarcinoma with signet-ring cells (extracellular mucin), plasma cell neoplasm (expresses lymphoid markers other than CD138, such as CD38, CD79a, CD20, and kappa/lambda light chain), and secondary neoplasms involving the bladder [681, 682].

Sarcomatoid

This variant carries a poor prognosis, and is characterized by the presence of both epithelial and mesenchymal differentiation by morphology or immunohistochemistry (Fig. 16.182e). The epithelial component can be of any type including conventional urothelial, squamous, glandular, or small cell; the mesenchymal component is usually composed of high-grade spindle cells [683]. Heterologous elements such as osteosarcoma, chondrosarcoma, leiomyosarcoma, angiosarcoma, and rhabdomyosarcoma may also be present, and should be mentioned in the diagnosis since they may convey a worse prognosis. The sarcomatoid component at least focally expresses cytokeratins (especially high-molecular-weight keratin) and may also be immunoreactive for GATA3 and p63 [684, 685]. The differential diagnosis should include postoperative spindle-cell nodule, urothelial carcinoma with pseudosarcomatous stroma, inflammatory myofibroblastic tumor (cytokeratin expression limited to low-molecular-weight keratin, negative for p63, may be positive for ALK1), and primary sarcoma [686, 687].

Giant Cell

This is a rare variant with an aggressive behavior with poor prognosis, and it is considered to be a dedifferentiated form of urothelial carcinoma [688]. It is characterized by pleomorphic giant cells that may represent a small percentage of the urothelial carcinoma, or they may be diffuse (Fig. 16.182f). The giant cells should be distinguished from those seen in trophoblastic differentiation or osteoclast-like features. This variant is uniformly positive for CK 8/18 and AE1/AE3, while most tumors are positive for CK7, CK20, uroplakin III, and GATA3. β-human chorionic gonadotrophin (β-hCG) is negative [688].

Poorly Differentiated

This rare variant with poor prognosis, also called “large-cell undifferentiated carcinoma,” is a pleomorphic carcinoma without histologic features of urothelial carcinoma. This variant includes tumors with osteoclastic-like giant cells and other mixed morphologies. It is composed of mononuclear malignant undifferentiated cells (positive for epithelial markers) and multinucleated osteoclast-like giant cells (positive for macrophage markers) (Fig. 16.182g) [689].

Lipid-Rich

This variant usually presents at high stage , is associated with usual type urothelial carcinoma, and bears a poor prognosis. It is characterized by the presence of large lipoblast-like cells with true intracytoplasmic lipid [690]. This neoplasm, including the lipoblast-like cells, is immunoreactive for cytokeratins. The differential diagnosis should include primary liposarcoma (epithelioid variant of liposarcoma my express cytokeratin) and sarcomatoid urothelial carcinoma with liposarcoma (lipoblasts do not express cytokeratin) [690].

Clear Cell (Glycogen-Rich)

This variant is rare, frequently associated with usual forms of urothelial carcinoma, and the cells are characterized by clear cytoplasm due to glycogen accumulation (Fig. 16.182h) [691]. Histologically mimics clear cell renal cell carcinoma. The clear cells express usual urothelial markers by immunohistochemistry. The differential diagnosis should include metastatic clear cell renal cell carcinoma (PAX-8 positive, GATA3, and p63 negative) and clear cell Mullerian-type carcinoma (hobnail cells, GATA3, and p63 negative).

Squamous Cell Neoplasms

Pure Squamous Cell Carcinoma

Squamous cell carcinoma (SCC) is a carcinoma derived from the urothelium with pure squamous cell phenotype. Absence of SCC elsewhere is required to classify this neoplasm a primary malignancy.

Epidemiology

Worldwide, SCC represents less than 3% of all bladder tumors, with a higher incidence in females [692]. However, it is the most frequent form of urothelial tract neoplasm in some African countries and Egypt. It is associated with infection with Schistosoma haematobium, and the prevalence of this infection may account for differences on sex ratio, mean age at diagnosis, and stage [693].

Etiology

It is associated with smoking [693]; occupational and environmental factors; infection by Schistosoma haematobium and mansoni (creating granulomatous inflammatory reaction, squamous metaplasia, and SCC; there is growing evidence that points to angiogenesis playing a key role in schistosomiasis-associated bladder cancer) [697,698,696]; keratinizing squamous metaplasia and chronic irritation, as well as certain medications [697]; and HPV infection [698].

Clinical Features

The most frequent symptomatology is hematuria, dysuria, urinary obstruction, and urinary tract infection.

Gross Features

They are bulky nodular and/or sessile tumors. Most commonly affect the lateral walls of the bladder as well as dome and trigone [699].

Microscopic Features

The diagnosis of SCC is kept only for tumors with pure squamous elements with keratin pearls and intercellular bridges [699]. The majority are moderately to poorly differentiated. Basaloid forms exist associated with HPV [700]. In case of associated in situ and/or invasive urothelial carcinoma, the neoplasm should be classified as urothelial carcinoma with squamous differentiation. The presence of squamous metaplasia supports the diagnosis of SCC. In situ squamous cell carcinoma also can be identified in occasions. There is no a universally accepted criterion for grading invasive SCC of the bladder. It is normally graded by the amount of keratinization and the degree of nuclear pleomorphism (Fig. 16.183a, b) [701].

Immunoprofile

Immunohistochemistry has a limited role in SCC. Several markers such as CK14 and desmoglein3 have been reported as helpful ancillary tests for this diagnosis [702].

Differential Diagnosis

Invasive urothelial carcinoma with squamous differentiation (urothelial component is present) and metastatic SCC (morphologically and immunophenotypically indistinguishable, absence of squamous metaplasia in metastatic disease).

Prognosis

This tumor presents at advance stage [699] and its diagnosis carries a poor prognosis. Pathologic stage is the most important prognostic parameter for SCC [696, 703]. The staging protocol for urothelial carcinoma is also used for SCC. Schistosomiasis-associated SCC has a better prognosis than non-Schistosomiasis-associated tumors [704]. SCC of the bladder responds poorly to conventional urothelial carcinoma chemotherapy regimens.

Genetic Profile

Majority of the studies are based on schistosomiasis-associated tumors and show gains in chromosomes 5p, 6p, 7p, 8q, 11q, 17q, and 20 q and deletions in 3p, 4q, 5q, 8p, 13q, 17p, and 18 q [707,708,709,710,708]. Similar to urothelial carcinoma, SCC shows deletions in 9p, loss of the CDKN2 tumor suppressor gene, and mutations of the TP53 [706]. HPV has a limited role in the development of SCC of the bladder; however, it has been documented.

Verrucous Carcinoma

Verrucous carcinoma is an exophytic malignant neoplasm with filiform projections lined by thick folds of well-differentiated squamous epithelium with a pushing rather than infiltrative margin.

Etiology

This is a rare variant of SCC occurring almost always in patients with schistosomiasis [709]. Reports exist associating this type of carcinoma with condyloma accuminatum of the bladder [710].

Gross Features

Exophytic lesions.

Microscopic Features

Papillary proliferations with epithelial acanthosis and hyperkeratosis with minimal architectural and cytologic atypia, with pushing borders and no invasive foci [711].

Prognosis

This variant carries an excellent prognosis with rare reports documenting local invasion and metastasis [711].

Squamous Papilloma

Epidemiology

This is a rare benign neoplasm that most frequently occurs in elderly patients [712].

Clinical Features

Tumor may be asymptomatic or may present with hematuria [712]. These tumors are not associated with HPV infection [713].

Histopathology

These are exophytic lesions with papillary proliferations covered by benign keratinizing squamous epithelium (Fig. 16.184).

Glandular Neoplasms

Adenocarcinoma, NOS

Adenocarcinoma is a malignant neoplasm derived from the urothelium with a pure glandular phenotype.

Epidemiology

Primary adenocarcinoma is uncommon, representing 0.5–2% of the malignant tumors [714].

Etiology

Intestinal metaplasia is associated with adenocarcinoma. Chronic irritation and obstruction as well as pelvic lipomatosis are also related to the etiology of this neoplasm [715, 716].

Clinical Features

Hematuria is the most frequent symptom.

Gross Features

Although these tumors may occur anywhere in the urothelial tract; they are more frequently found in the urinary bladder.

Microscopic Features

A variety of histologies including an enteric phenotype that is similar to those in the gastrointestinal tract (Fig. 16.185a) [717].

Mucinous adenocarcinoma is a histologic variant that is characterized by nests of carcinoma cells floating in a background of extracellular mucin. Signet-ring cell morphology can also be identified where signet ring cells may be seen as a focal or predominant component of the invasive component (Fig. 16.185b, c). One or more histologic patterns may also simultaneously occur to form a mixed adenocarcinoma [717].

Immunoprofile

This neoplasm expresses CDX2 and CK20. This immunoprofile is similar to the one observed in gastrointestinal adenocarcinoma. Beta-catenin (nuclear) expression favors an adenocarcinoma of colonic origin [718].

Differential Diagnosis

The main differential diagnosis is with direct invasion by gastrointestinal adenocarcinoma (similar morphology and immunophenotype, beta-catenin is positive in a subset of gastrointestinal carcinomas) and by prostatic adenocarcinoma (positive for NK3.1, PSA, PAP, PSMA, P501s). In addition, urothelial carcinoma with glandular differentiation and cystitis glandularis should also be included in the differential diagnosis.

Prognosis

This variant carries a prognosis. It is best predicted by the TNM staging system [719].

Genetic Profile

KRAS mutations are identified.

Villous Adenoma

Rare benign neoplasm of the urinary tract and urachus similar to the same lesion in the colon.

Clinical Features

Hematuria is the most frequent symptom. In addition, irritative symptoms and rarely mucusuria.

Gross Features

Papillary neoplasm, macroscopically indistinguishable from the papillary urothelial neoplasm.

Microscopic Features

Villoglandular architecture. Similar to the colonic counterpart, it may exhibit low-grade dysplasia, high-grade dysplasia, and invasive carcinoma, enteric type. Therefore, all tissue should be submitted for evaluation to investigate the possibility of an associated invasive carcinoma [720].

Immunoprofile

The lesional cells are immunoreactive for CK7, CK20, and CDX-2, and they are negative for GATA3. This profile differentiates this neoplasm for an urothelial type neoplasm. Prostatic antigens (P501S and prostatic-specific membrane antigen) can be expressed [721].

Prognosis

Benign neoplasm that does not exhibit recurrence or progression behavior.

Urachal Carcinoma

Malignant neoplasm arising from the urachal remnants. Most urachal neoplasms are of glandular type, which is believed to arise in a background of intestinal metaplasia of the urachal epithelium [722].

Clinical Features

Hematuria is the most frequent symptom. In addition, mucusuria, pain, and irritative symptoms, umbilical discharge, and suprapubic mass.

Gross Features

Localized in the bladder dome and/or anterior wall.

Microscopic Features

There are various types of urachal carcinomas : adenocarcinomas (non-cystic and cystic), non-glandular neoplasms (urothelial, squamous, neuroendocrine, mixed-type), and mixed tumors [723].

Immunoprofile

The lesional cells of urachal adenocarcinoma are immunoreactive for CDX2, CK20, and high-molecular-weight keratin (HMWK) [724, 725]. CK7 is positive in half of cases. Nuclear beta-catenin is negative.

Prognosis

Similar or better prognosis than the non-urachal adenocarcinoma [726].

Tumor staging is an important independent prognostic factor. The Sheldon staging system is the most widely used system for urachal carcinomas [727]. The Sheldon system is as follows: stage I, carcinoma confined to the urachal mucosa; stage II, carcinoma invasion confined to the urachus; stage III, local carcinoma extension (IIIA, into the bladder; IIIB, into abdominal wall; IIIC, into the peritoneum; IIID, into other viscera); and stage IV, metastasis (IVA, to lymph nodes; IVB, distant sites).

Genetic Profile

Microsatellite instability and mutations of KRAS at codon 12 have been reported, and they are mutually exclusive [728]. KRAS mutations are associated with an overall better survival despite stage (2534 of WHO).

Tumors of Müllerian Type

These tumors are adenocarcinomas arising from preexisting Müllerian precursors within the urinary bladder, such as endometriosis and Mülleriosis (rare).

Clear Cell Carcinoma

Previously called mesonephric carcinoma , this neoplasm occurs more frequently in females, and it is composed of clear cells that form a polypoid/papillary mass and centered in lamina propria and muscularis mucosae [729]. It may represent a form of adenocarcinoma or it may arise from endometriosis [730]. Microscopically it has a characteristic morphology similar to the one seen in the female genital tract (tubulocystic, papillary, and diffuse patterns). Cells are flat, cuboidal, and columnar, and they may have abundant clear cytoplasm. Hobnail cells are common. The differential diagnosis is with nephrogenic adenoma. This neoplasm shows the following immunoprofile, positive for CAM5.2, CK7, epithelial membrane antigen, PAX-8, CA-125, and AMARC, and they are negative for prostatic-specific antigen, prostatic-specific acid phosphatase, p63, ER, PR, and GATA3 [730].

Endometrioid Carcinoma

This neoplasm occurs only in females, and it is composed of clear cells that form a polypoid/papillary mass centered in lamina propria and muscularis mucosae [734,735,733]. It arises from endometriosis [734,735,733] and rarely from mulleriosis. Endometrial adenocarcinoma of the urinary tract has a similar histomorphology and immunophenotype (ER and PR positive) to the one of the female genital tract [732].

Neuroendocrine Tumors

Small-Cell Neuroendocrine Carcinoma

Small-cell neuroendocrine carcinoma (SmCC) is a malignant neoplasm with neuroendocrine differentiation. SmCCs from the urothelial tract is histologically similar to its lung counterpart. It can occur in the upper urinary tract; however, the bladder is the organ more frequently affected.

Epidemiology

Rare neoplasm (<1% of bladder tumors).

Etiology

Tumors have a strong association with smoking and are considered to be of urothelial origin.

Clinical Features

Gross hematuria, dysuria, and obstructive symptoms. Metastases are common to lymph nodes and viscera. Paraneoplastic syndromes are rare.

Gross Features

Large, solid/nodular mass.

Microscopic Features

SmCC is invasive at presentation and often presents with a high tumor stage. This neoplasm is composed of sheets of small cells separated by scant stroma. The cells have round to oval nuclei without nucleoli. The cytoplasm is scarce and mitosis is frequent. SmCC can be associated with other carcinoma types; however, the small-cell component should predominate to classify a neoplasm as SmCC (Fig. 16.186a).

Immunoprofile

SmCC is positive for synaptophysin and chromogranin (focal); however, both can stains may be negative in very undifferentiated forms. Thyroid transcription factor-1 and CD56 can also be expressed in these tumors [746]. Pankeratin is positive in a dot-like fashion (Fig. 16.186b) [734, 735].

Differential Diagnosis

The main differential diagnosis is with poorly differentiated urothelial carcinoma (lacks neuroendocrine markers and pankeratin expression is non-dot-like fashion), malignant lymphoma (negative for keratin and positive for CD45 and other hematopoietic markers), metastatic SmCC (indistinguishable from primary SmCC), and rhabdomyosarcoma (myogenin positive).

Prognosis

Tumors have an aggressive clinical course and neoadjuvant chemotherapy with or without radiation therapy may improve patient outcomes.

Genetic Profile

Genomic instability with high number of genetic alterations. TP53 and TERT promoter mutations are seen [736].

Large-Cell Neuroendocrine Carcinoma

Rare and aggressive high-grade neoplasm with neuroendocrine histologic and immunophenotypic features.

Well-Differentiated Neuroendocrine Tumor

Rare, well-differentiated neuroendocrine neoplasm arising from the neuroendocrine cells located in the basal layer of the urothelium [737]. It may cause hematuria and irritative voiding symptoms. On cystoscopy, it appears as small polypoid masses, more frequently in trigone and bladder neck. The cytohistologic and immunophenotypic features are similar to those described at other sites.

Paraganglioma

Etiology

This neoplasm arises from the paraganglion cells located in the bladder wall and represents 0.05% of all bladder tumors.

Clinical Features

In the majority of cases, this lesion manifests with symptomatology associated with the catecholamine production including hypertension and headache. This tumor may be associated with hereditary syndromes, such as germ-line SDHB mutations (SDHB been the most common) and, less commonly, with von Hippel-Lindau disease and neurofibromatosis [738].

Gross Features

On cystoscopy, it appears as an exophytic lesion with intact mucosa, which can be rarely ulcerated.

Microscopic Features

Histologically, the cells are typically arranged in distinctive nests (Zellballen) with a delicate vascular network. Diffuse growth patterns also exist. The cells are large and polygonal and have amphophylic/acidophilic cytoplasm (Fig. 16.187a). Mitosis and/or necrosis are rare. There is no histologic criteria to predict malignant behavior.

Immunoprofile

This neoplasm expresses neuroendocrine markers (Synaptophysin, chromogranin, CD56 by immunohistochemistry), and sustentacular cells, when present, are positive for S100 protein. The lesional cells are negative for keratin; however, they are immunoreactive with GATA3 which can be a pitfall with urothelial carcinoma (Fig. 16.187b) [739]. In the cases associated with SDHB germ-line mutations, SDHB is absent (Fig. 16.187c).

Differential Diagnosis

The most important differential diagnosis is with urothelial carcinoma. Other differential diagnosis includes high-grade prostatic adenocarcinoma (immunoreactive for pankeratin, PSA, PAP, and NKX3.1), metastatic renal cell carcinoma (immunoreactive for pankeratin, vimentin and PAX-8), and malignant melanoma (immunoreactive for S100 (diffuse pattern), SOX10, and other melanocytic markers such as HMB-45, Melan-A, MITF, and catepsin-D).

Prognosis

The criteria of malignancy (5–15% of cases) are metastasis or extensive local disease [740]. Paragangliomas associated with SDHB mutations have been associated with a higher metastatic behavior [741].

Genetic Profile

Germline SDHA and SDHB mutations have been described.

Melanocytic Tumors

Malignant Melanoma

Malignant Neoplasm of Melanocytic Origin

Epidemiology

Metastatic melanoma is more frequent than primary melanoma in the urinary tract. When primary, urethra is the most frequent location. Primary malignant melanomas of the bladder, ureter, and renal pelvis are rare [742, 743].

Clinical Features

Hematuria is the most common symptom. To be considered as a primary malignant melanoma, a metastasis should be clinically excluded by ensuring that the patient does not have a primary melanoma elsewhere.

Gross Features

Dark pigmented polypoid solid mass.

Microscopic Features

Tumor are composed of large epithelioid or spindle cells with or without melanin pigment (Fig. 16.188a).

Immunoprofile

Immunoreactive for melanocytic markers such as S100 protein, HMB-45, SOX-10, Melan A, and microphthalmia transcription factor (MITF), among others (Fig. 16.188b). They are typically negative for epithelial markers.

Prognosis

Tumor are associated with a poor prognosis.

Other Melanocytic Lesions

Nevus is a benign proliferation of melanocytes, and it is extremely rare in the urinary tract [744]. Similarly, melanosis is a rare lesion in that location, characterized by the presence of melanin in macrophages and epithelial cells of the urothelium [745]. Both types of lesions are discovered as incidental findings. Both are considered to be benign.

Mesenchymal Tumors

Rhabdomyosarcoma

Malignant mesenchymal tumor showing skeletal muscle differentiation.

Epidemiology

It is the most common bladder tumor in children. The vast majority of them are of embryonal type (also called “sarcoma botryoides ”). Pure embryonal sarcoma in adults is rare, and more frequently we found it as a component of sarcomatoid urothelial carcinoma.

Clinical Features

Local genitourinary symptoms.

Gross Features

In children, the rhabdomyosarcoma of the botryoid type shows multiple polypoid proliferations in a grape-like appearance.

Microscopic Features

Embryonal rhabdomyosarcoma is typically composed of primitive spindled to round cells in a myxoid background. Rhabdomyoblast varies in quantity between different tumors. The botryoid subtype shows a condensation of tumor cells below the covering mucosa, called “cambium layer .” Alveolar-type rhabdomyosarcoma has back-to-back round cells with high N/C ratio. Other histologic types, spindle-cell and pleomorphic types, are also been described in the bladder.

Immunoprofile

They are immunoreactive for desmin and smooth muscle actin and demonstrate nuclear positivity for MYOD1 and myogenin.

Differential Diagnosis

The most important differential diagnosis is inflammatory myofibroblastic tumor (admixed with inflammatory cells, co-express smooth muscle actin, and cytokeratin and does not express MYOD1), small-cell carcinoma [746] (neuroendocrine markers, epithelial markers), lymphoma (hematopoietic markers), and sarcomatoid urothelial carcinoma (epithelial component).

Prognosis

These tumors show an excellent response to chemotherapy in children with an excellent prognosis, athough pronosis is poor in adults. Tumors with FOXO1 rearrangements are associated with a worse outcome.

Genetic Profile

In approximately 75% of cases, alveolar-type rhabdomyosarcoma may have chromosomal translocations resulting in the fusion of the DNA-binding domain of PAX3 on chromosome 2 or PAX7 on chromosome 1 to the transactivation domain of FOXO1 in chromosome 13.

Leiomyosarcoma

This sarcoma arises from urinary bladder smooth muscle.

Epidemiology

Leiomyosarcoma is the most common urinary bladder sarcoma in adults and accounts for 1% of all bladder malignancies. It has been associated with prior cyclophosphamide therapy.

Clinical Features

Hematuria is the most frequent symptom.

Microscopic Features

This is an infiltrative neoplasm characterized by interlacing fascicles of eosinophilic spindle cells with elongated nuclei and perinuclear vacuoles. These tumors are graded using cytologic atypia, mitotic activity (low grade: < 5 per 10 HPF and high grade: > 5 per 10 HPF), and necrosis. The majority of the bladder leiomyosarcomas are intermediate to high-grade neoplasms [747].

Immunoprofile

Immunoreactive for smooth muscle actin, desmin, and caldesmon, and they are negative for epithelial markers, ALK1, p63, HMWK, myogenin, and MYOD1.

Differential Diagnosis

Sarcomatoid urothelial carcinoma (positive for epithelial markers), inflammatory myofibroblastic tumor (ALK positive), and perivascular epithelioid cell neoplasm (PEComa) (HMB-45 and MART-1 positive lesions).

Prognosis

High-grade tumors demonstrate a poor prognosis.

Angiosarcoma

Rare and highly aggressive tumor of the bladder with endothelial differentiation. This neoplasm has been associated with history of pelvic radiation and vinyl chloride exposure [748]. The histopathological features are identical to those of angiosarcoma of other locations. These neoplasms are immunoreactive for endothelial markers including CD31, CD34, FLI1, and ERG. They may express cytokeratin markers (Fig. 16.189a, b).

Inflammatory Myofibroblastic Tumor

Neoplasm of fibroblastic and myofibroblastic origin. Urinary bladder is the most frequent visceral involvement [749].

Epidemiology

Affects all ages, from infants to elderly.

Clinical Features

Hematuria.

Microscopic Features

There are three different histomorphologies identified that may coexist: loose stellated cells in a myxoid background with inflammation, spindle cells growing in a fascicular pattern, and sparsely cellular collagenized areas (Fig. 16.190a, b) [750].

Immunoprofile

They express smooth muscle actin and desmin and may express cytokeratins. ALK1 is expressed in 60% of cases [750].

Differential Diagnosis

Rhabdomyosarcoma (MYOD1 and myogenin positive, LK negative), leiomyosarcoma (ALK negative), and sarcomatoid carcinoma (ALK negative).

Prognosis

They recur in approximately 25% of patients. They do not metastasize.

Genetic Profile

Approximately 60% of these neoplasms have chromosomal rearrangements activating ALK gene in the short arm of chromosome 2 (2p23).

Perivascular Epithelioid Cell Tumor (PEComa)

Neoplasm that expresses both melanocytic and smooth muscle differentiation. They occur in adults and patients present with hematuria . Histologically, they may be spindle or epithelioid. Blood vessels are prominent. Most of these tumors are benign. A PEComa that measures less than 5 cm, is low in nuclear grade and cellularity, and lacks infiltration, necrosis, and vascular invasion should be considered benign. A PEComa with two or more of the aggressive features should be considered malignant. These neoplasms express muscle actin, HMB45, Melan A, tyrosinase, and microphthalmia-associated transcription factor [751]. Cathepsin K and TFE3 expression have been also reported.

Solitary Fibrous Tumor

Fibroblastic mesenchymal tumor with malignant potential, with a specific NAB2-STST6 gene fusion and overexpressing STAT6. This tumor when localized in the bladder is identical to the ones occurring in other sites. These neoplasms demonstrate hemangiopericytomatous vascular pattern. They are immunoreactive for STAT6 and CD34, and most of them have a benign behavior.

Leiomyoma

Benign tumor of the smooth muscle. It is the most common benign mesenchymal tumor of the urinary bladder; however, it is uncommon incidentally detected. Most of these tumors are small and well circumscribed. Histologically are identical to the ones occurring in other sites.

Hemangioma

Benign vasoformative tumor. In the pediatric age group, they may be associated with angiomatosis; however, they are more frequent in adults. In adults they are an incidental finding, and cystoscopically they are raised reddish-blue submucosal tumors. Histologically they are identical to the ones occurring in other sites, and most of them are of cavernous type.

Granular Cell Tumor

This is a neoplasm of Schwann cell origin. They are rare in the bladder and most patients present with hematuria. Most of them are benign, and they are composed of cells with abundant eosinophilic granular cytoplasm; they are immunoreactive with S100.

Neurofibroma

Uncommon benign peripheral nerve sheath tumor. In kids, they are associated with neurofibromatosis 1 and 2. Patients present with hematuria. Histologically, they can be plexiform (associated with neurofibromatosis) or diffuse, and they are immunoreactive with S100.

Miscellaneous Tumors

Secondary Neoplasms of the Urinary Bladder

Secondary neoplasms are non-urinary tract tumors involving the urinary tract through direct spread or metastasis. They represent 2% of the bladder tumors. Direct extension to the bladder by neighboring malignancies such as colorectum, prostate, and uterine cervix is the most frequent mechanism of secondary metastasis. Hematogenous spread from the stomach, skin melanoma, kidney, breast, and lung are also possible (Fig. 16.191a, b) [752].

Epithelial Tumors of the Upper Urinary Tract

These are neoplasm involving the ureter and renal pelvis.

Etiology

Smoking is the major risk factor. Other predisposing factors are occupational exposure to chemicals and long-term phenacetin use.

Clinical Features

Hematuria and flank pain.

Gross features

These neoplasms may be multifocal and bilateral.

Microscopic features

The histomorphology is similar to the bladder urothelial neoplasms, and they are graded also using the WHO/ISUP system.

Prognosis

Pathologic stage and depth of invasion are the most important prognostic factors.

Genetic Profile

Some are associated with the Lynch syndrome.

Tumors Arising in Bladder Diverticulum

Neoplasms arising in the epithelial lining of a diverticulum (outpouching of the mucosa through the bladder wall).

Etiology

They arise in acquired diverticula.

Clinical features

Hematuria, urinary retention, and infection.

Microscopic features

Most of these neoplasms are noninvasive, low-grade, or high-grade urothelial carcinomas. Clear cell adenocarcinoma shows an especial propensity for diverticula and should be considered in the differential diagnosis of all glandular tumors arising in a dierticulum. Most of the invasive carcinomas are of the urothelial type; however, other subtypes may also be present. Of special note, staging of tumor that arise in a diverticulum differs from that of tumors arising in the bladder. The lack of a muscularis propria layer within a diveritcum, that causes the outpouching, also eliminates pT2 as a stage for primary diverticular tumors. As a consequence, invasive tumors that are arising primarily in the diverticulum are assigned a stage of pT1 (lamina propria invasion) or pT3 (invasion into the perivesical fat) [753].

Urothelial Tumors of the Urethra

Primary urothelial neoplasms of the urethra. They are rare tumors associated with chronic irritation and inflammation, recurrent urinary tract infection, urethral diverticula, and radiation therapy.

Gross and microscopic features

In women, 75% of cases are SCC and 25% are urothelial carcinoma or adenocarcinoma. When the neoplasm is arising in the proximal, 1/3 of the urethra are urothelial carcinomas. The neoplasms arising in distal 2/3 are generally SCCC. In men, carcinomas arising in proximal/prostatic urethra are urothelial carcinomas, and the ones in bulbomembranous and penile urethra are SCC.

Prognosis

They have a worse prognosis that the urinary bladder counterparts.

Carcinoma of Skene, Cowper, and Littre Glands

These are adenocarcinomas arising from the Skenes glands in females and from the Cowper and Littre glands in males. They are rare and present with hematuria. In males, the Cowper and Littre glands carcinomas are located in the bulbomembranous urethra and penile urethra, respectively. They are histologically similar to urethral adenocarcinoma. Littre gland adenocarcinoma is papillary or glandular with cuboidal or columnar cells. They may resemble prostatic adenocarcinoma, and they may express prostate-specific antigen (PSA).

Hematopoietic and Lymphoid Tumors

Lymphoma

Malignant lymphoma is a malignant lymphoid neoplasm that can be primary in the urothelial tract. It may present as a single mass or multinodular masses. The histological appearance of lymphoma of the urinary tract is similar to that observed at other sites. In the bladder, extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue origin (MALT lymphoma) is the most common type; however, other types of lymphoma have been also described in that setting. Primary MALT lymphoma has an excellent prognosis after surgical intervention.

Plasmacytoma

Malignant plasma cells that are histologically and immunophenotypically identical to plasma cell myeloma. This is a rare neoplasm of the urinary tract that may present with hematuria and multinodular masses. This neoplasm is morphologically and immunophenotypically identical to the plasmacytoma occurring in other sites.

Staging

This is the last revision of TNM staging by the American Joint Committee on Cancer.

TNM Staging System of the Urinary Bladder Carcinomas (TNM8, 2017)
Pathologic Staging of Carcinoma of the Urinary Bladder
Primary Tumor (pT)
TX	Primary tumor cannot be assessed.
T0	No evidence of primary tumor.
Ta	Noninvasive papillary carcinoma.
Tis	Carcinoma in situ: “flat tumor.”
T1	Tumor invades lamina propria (subepithelial connective tissue).
T2	Tumor invades muscularis propria (detrusor muscle).
	T2a: Tumor invades superficial muscularis propria (inner half).
	T2b: Tumor invades deep muscularis propria (outer half).
T3:	Tumor invades perivesical tissue.
	T3a: Microscopically
	T3b: Macroscopically (extravesicular mass)
T4:	Tumor invades any of the following: prostatic stroma, seminal vesicles, uterus, vagina, pelvic wall, and abdominal wall.
	T4a: Extravesical tumor invades directly into prostatic stroma (see note), uterus, or vagina.
	T4b: Extravesical tumor invades pelvic wall or abdominal wall.
Regional Lymph Nodes (pN)
NX	Lymph nodes cannot be assessed.
N0	No lymph node metastasis.
N1	Single regional lymph node metastasis in the true pelvis (hypogastric, obturator, external iliac, or presacral lymph node).
N2	Multiple regional lymph node metastasis in the true pelvis (hypogastric, obturator, external iliac, or presacral lymph node metastasis).
N3	Lymph node metastasis to the common iliac lymph nodes.
Distant Metastasis (pM
M1	Distant metastasis.
	Specify site (s) if known.

Note: As noted in the American Joint Committee) on Cancer (AJCC) 8th ed. (WHO 8th), involvement of the prostate gland may occur in several different patterns. Tumors (flat carcinoma in situ, papillary or invasive carcinoma) can first spread along the prostatic urethral mucosa and subsequently invade prostatic stroma (transurethral mucosal route) (Fig. 16.73a, b). Tumors may also invade through the bladder wall and the base of the prostate directly into the prostate gland (Fig. 16.73a, b, straight arrow) 0.26. Tumors can also invade into extravesical fat and then extend back into the prostate gland (Fig. 16.73b, curved arrow). The latter two routes are considered direct transmural invasion. The American Joint Committee on Cancer (AJCC) 7th edition staging manual defines direct extension of urinary bladder cancer into the prostate gland as T4 disease and excludes transurethral mucosal prostatic stroma invasion from the pT4a staging status. However, there is limited data on the best methodology to stage urothelial carcinoma that concurrently involves the urinary bladder and the prostatic urethra. In patients who have a large urinary bladder carcinoma that has invaded through the full thickness of the bladder wall and thereby secondarily involves the prostatic stroma, a T4 stage should be assigned per urinary bladder staging. In other circumstances in which involvement by urothelial carcinoma is seen in both sites, separate urinary bladder and prostatic urethral staging should be assigned.

TNM Staging System of the Urethra (TNM8, 2017)
Pathologic Staging of Carcinoma of the Urethra
Primary Tumor (pT)
Primary Tumor (pT) (Male and Female)
TX	Cannot be assessed.
T0	No evidence of primary tumor.
Ta	Noninvasive papillary carcinoma.
Tis	Carcinoma in situ.
T1	Tumor invades subepithelial connective tissue.
T2	Tumor invades any of the following: corpus spongiosum, prostate, and periurethral muscle.
T3	Tumor invades any of the following: corpus cavernosum, beyond prostatic capsule, anterior vagina, and bladder neck.
T4	Tumor invades other adjacent organs (invasion of the bladder).
Primary Tumor (pT) (urothelial carcinoma of the prostate).
TX	Cannot be assessed.
T0	No evidence of primary tumor.
Ta	Noninvasive papillary, polypoid, or verrucous carcinoma.
Tis pu	Carcinoma in situ, involvement of prostatic urethra.
Tis pd.	Carcinoma in situ, involvement of prostatic ducts.
T1	Tumor invades subepithelial connective tissue (only applied to tumors invading from the urethral lumen)#.
T2	Tumor invades any of the following: prostatic stroma, corpus spongiosum, and periurethral muscle.
T3	Tumor invades any of the following: corpus cavernosum, beyond prostatic capsule, and bladder neck (extraprostatic extension).
T4	Tumor invades other adjacent organs (invasion of the bladder).
# Tumors invading directly from prostatic ducts colonized by carcinoma in situ are designated as at least pT2, regardless of depth or extent of invasion (i.e., there is no pT1 category in that setting).
Regional Lymph Nodes (pN)
NX	Lymph nodes cannot be assessed.
N0	No lymph node metastasis.
N1	Metastasis in a single lymph node 2 cm or less in greatest dimension.
N2	Metastasis in a single lymph node more than 2 cm in greatest dimension or in multiple nodes.
Distant Metastasis (pM).
M1	Distant metastasis.
	Specify site(s) if known.

TNM Staging System of the Ureter and Renal Pelvis (TNM8, 2017)
Pathologic Staging of Carcinoma of the Ureter and Renal Pelvis
Primary Tumor (pT)
TX	Cannot be assessed.
T0	No evidence of primary tumor.
Ta	Papillary noninvasive carcinoma.
Tis	Flat carcinoma in situ.
T1	Tumor invades subepithelial connective tissue (lamina propria).
T2	Tumor invades muscularis propria.
T3	Tumor invades beyond muscularis into periuretral fat or peripelvic fat or the renal parenchyma.
T4	Tumor invades adjacent organs or through the kidney into the perinephric fat.
Regional Lymph Nodes (pN)
NX	Lymph nodes cannot be assessed.
N0	No lymph node metastasis.
N1	Metastasis in a single regional lymph node, 2 cm or less in greatest dimension.
N2	Metastasis in a single regional lymph node, more than 2 cm but not more than 5 cm in greatest dimension, or multiple lymph nodes, none more than 5 cm in greatest dimension multiple nodes.
N3	Metastasis in a regional lymph node, more than 5 cm in greatest dimension.
Distant Metastasis (pM)
M1	Distant metastasis.
	Specify site (s) if known.

Part III: Tumors of the Adrenal Gland

Anatomy

Embryology

The adrenal cortex is derived from the mesoderm and becomes apparent in the 6th week of gestation. The adrenal gland greatly enlarges throughout the second trimester and is predominately composed of adrenal cortex. Within 1 month after birth, the centrally located provisional adrenal cortex undergoes involution and necrosis. The result of this process is a loss on approximately half of the weight of the adrenal gland.

The adrenal medulla is neuroectodermal in origin. The cells originated from the neural crest and then migrate from the primitive spinal ganglion to form the primitive sympathetic nervous system. Sympathogonia cells migrate into nerves and then penetrate the adrenal cortex most notably at the head of the adrenal gland. These cells aggregate into scattered clusters and cords and form the adrenal medulla.

Anatomy and Histology

The outer cortex and the inner medulla comprise the adrenal gland, which weigh roughly 4 grams each in the adult. The adult adrenal cortex is approximately 1 mm and is made of three layers of different cell types: the zona glomerulosa, zona fasciculata, and zona reticularis. Throughout life, the layers are less distinct, and there is an increase in lipofuscin pigment.

Adjacent to the adrenal capsule is the zona glomerulosa . This is the outermost layer of the adrenal cortex. In the adult, this layer is thin and may be discontinuous and difficult to visualize. The zona glomerulosa is composed of small nests of cells and compared to the adjacent zona fasciculata, the cells have less cytoplasm, appear more eosinophilic, and have darker staining nuclei (Fig. 16.192). Aldosterone is produced by the zona glomerulosa, and this layer is responsive to angiotensin, potassium, and adrenocorticotropic hormone.

The zona fasciculata is found between the zona glomerulosa and zona reticularis. This is the dominant layer, com posing more than half the width of the adrenal cortex. Architecturally, cells are arranged in columns and cords. The cytoplasm is abundant and finely vacuolated with a low nuclear to cytoplasmic ratio (Fig. 16.193). The cleared out, vacuolated cytoplasm is due to the lipid-rich content dissolving during histologic processing. Glucocorticoids are produced by the zona fasciculata, and this layer is responsive to adrenocorticotropic hormone levels.

The zona reticularis is the innermost layer of the adrenal cortex and abuts the adrenal medulla in the head and body of the adrenal gland. The zona reticularis is not apparent prior to 3 years of age. In the tail of the adrenal gland in which no adrenal medulla is present, the zona reticularis is back to back with another layer of adrenal cortical zona reticularis. Compared to the zona fasciculata, cells of the zona reticularis are smaller, have less cytoplasmic vacuolations, and are more eosinophilic (Fig. 16.194). Nearest to the adrenal medulla, more lipofuscin pigment is seen. Sex hormones are produced by the zona reticularis, and this layer is responsive to levels of circulating adrenocorticotropic hormone.

The medulla is the most central layer in the head and body of the adrenal gland and is usually no more than a few millimeters thick. The adrenal medulla is composed of pheochromocytes with occasional ganglion cells. Pheochromocytes are large, polygonal cells with very dense, granular cytoplasm. The cells appear deeply basophilic to eosinophilic (Fig. 16.195). S100-positive sustentacular cells circumscribe clusters of pheochromocytes. The supportive sustentacular cells are difficult to visualize without the use of immunohistochemistry. Catecholamines, epinephrine, and norepinephrine are produced by the adrenal medulla.

Specimen Handling/Grossing

Needle Core Biopsy

There are two main indications to perform a diagnostic adrenal core biopsy : (1) to work up a lesion with indeterminate imaging characteristics and (2) to evaluate a lesion for possible metastasis [754]. Adrenal core biopsies are usually performed with CT guidance but can also utilize ultrasonography and use 18–23 gauge needles. The utility of adrenal core biopsies is evolving as metastatic lesions may be biopsied with increased frequency to obtain tumoral tissue for molecular analysis instead of for the purpose of diagnostic staging.

Specimens should be entirely submitted with care not to break the fragile cores. Multiple H&E levels can be cut, particularly if there is difficulty obtaining a full-face section of the cores. Immunohistochemistry is frequently performed, and therefore it is ideal to either save 4–6 unstained sections at the time of initially effacing the block or to order and cut sections for immunohistochemistry and molecular testing at the same time. For example, in a case with a history of lung adenocarcinoma in which the adrenal needle core specimen demonstrates adenocarcinoma, it would be prudent to ascertain if pulmonary molecular studies are desired and if so to order confirmatory immunostains in conjunction with the molecular tests.

The most frequent finding encountered in adult adrenal biopsies is metastatic carcinoma followed by adrenal cortical tissue (Fig. 16.196). Between 50% and 75% of metastatic carcinoma in adrenal core biopsies is lung in origin followed by renal cell carcinoma, clear cell type [758,759,760,761,759, 766]. Pheochromocytoma is quite rare in adrenal needle biopsies as a suspected pheochromocytoma is a contraindication for biopsy. The accuracy of a diagnosis of the needle core biopsy as benign or malignant after elimination of nondiagnostic/normal adrenal tissue yields a reported sensitivity of 100% and a specificity of 100% [755]. Regarding a correct precise diagnosis, rather than benign versus malignant, and including cases that were nondiagnostic/normal adrenal biopsy has a reported sensitivity of 86%, specificity of 88%, negative predictive value of 58%, and positive predictive value of 97%. The specimens have a low negative predictive value due to frequent cases in which no lesional tissue is sampled [755]. As such, a repeat biopsy may be indicated if only adrenal cortical tissue is present.

Adrenalectomy

Following appropriate workup including imaging , serology, and possible needle core biopsy, surgical resection is indicated for the following three indications: (1) masses that are suspected to be endocrinologically functional, (2) tumors > 4 cm, and (3) lesions with radiological features concerning for malignancy [760]. (The current gold standard to remove an adrenal mass is laparoscopic adrenalectomy if a minimally invasive technique is technically feasible as open surgery has greater morbidity [760, 761]) The approach may be transperitoneal or retroperitoneal [760]. Alternatives to this gold standard include laparoscopic single-site surgery and robotic adrenalectomy.

Specimens should be weighed intact inclusive of periadrenal adipose unless this is abundant and the side should be documented. The exterior of the gland may be inked in order to better appreciate the surgical margins of the specimen. Black ink may be difficult to discern from hemorrhagic or dark lesions such as pheochromocytoma, and therefore other colors may be preferable. The gland should be serially sectioned, or “bread loafed,” perpendicular to the long axis (Fig. 16.197). Lesions should be described including size, location (periadrenal adipose, capsular/subcapsular, cortex, medulla), color, and consistency. Non-affected adrenal cortex and medulla should be described including thickness. Submission of one block of tumor per centimeter is sufficient. Additionally, submission of one block of non-affected adrenal tissue is recommended for comparison.

In the author’s experience, the most frequent finding encountered in adult adrenalectomies is adrenal cortical adenoma followed by pheochromocytoma and metastatic carcinoma (Fig. 16.198). Renal cell carcinoma and lung carcinoma are the most common metastases in these specimens.

Pathology Report

An adrenal needle core biopsy pathology report should state the diagnosis on the first diagnostic line. The presence or absence of adrenal cortical tissue may be noted in a second diagnostic line in order to confirm the location of the needle biopsy. If normal adrenal tissue is not identifiable, it may not be appropriate to diagnose the lesion as “metastatic.”

In an adrenalectomy report, the first line should state the diagnosis. The report should contain the size of the lesion and the status of surgical margins, if applicable.

Synoptic reporting is required by the College of American Pathologists for adrenal cortical carcinoma. Required elements per the College of American Pathologists cancer protocol for adrenal cortical carcinoma include (1) procedure, (2) laterality, (3) tumor size largest dimension, (4) weight, (5) histologic type, (6) histologic grade, (7) lymphovascular invasion, (8) extent of invasion, (9) margin status, (10) lymph nodes, and (11) pTNM [762]. The American Joint Committee on Cancer 8th edition Staging Manual contains the minimally changed pTNM staging for adrenal cortical carcinoma (described in the last section of this chapter).

At the time of writing, no synoptic report had been released by the College of American Pathologists for pheochromocytoma. The American Joint Committee on Cancer 8th edition Staging Manual newly defines pTNM staging for pheochromocytoma (described in the last section of this chapter). Tumor size and extent of invasion are utilized in pT classification for pheochromocytoma. Additionally, including the weight and other worrisome histologic features in the diagnostic portion of the report may be of value as this correlates with subsequent behavior.

Synoptic reporting is required by the College of American Pathologists for neuroblastoma. Required elements per the College of American Pathologists cancer protocol for neuroblastoma include (1) procedure, (2) tumor size largest dimension, (3) age, (4) histologic type, (5) degree of differentiation, (6) mitotic-karyorrhectic index, (7) treatment history, (8) International Neuroblastoma Pathology Classification (INPC), (9) extent of invasion, (10) lymph nodes, and (11) MYCN amplification status [763]. There is currently no pTNM staging system for neuroblastoma. Neuroblastic tumors are most commonly staged according to the International Neuroblastoma Staging System (INSS) or the more recent International Neuroblastoma Risk Group (INRG) system.

Adrenal Cortical Adenoma

Adrenal cortical adenoma is a common benign proliferation of cells originating from one or multiple layers of the adrenal cortex. Due to increasing utilization of imaging studies, the number of adrenal tumors diagnosed has increased in recent years. Adrenal tumors found when patients undergo abdominal imaging during evaluation for another cause are known as “incidentalomas ”. The majority of incidentalomas are adrenal cortical adenomas [764].

Clinical features

The incidence of adrenal tumors increases with increasing age. The true prevalence is unknown since many are nonfunctional; however, it is estimated that approximately 6% of people in their sixth decade have an adrenal cortical tumor, the great majority of which are adrenal cortical adenomas [765]. Adrenal cortical adenomas occur slightly more often in females. While the majority of adrenal cortical adenomas found incidentally on imaging or at autopsy are nonfunctional, they may secrete one or more of the three major classes of adrenal steroids: (1) glucocorticoids, (2) mineralocorticoids, and (3) sex steroids [764]. Cushing’s syndrome is due to excess glucocorticoid secretion and is characterized by a myriad of symptoms including central obesity, moon facies, plethora, striae, thin skin, easy bruising, hirsutism, telangiectasias, and hyperhidrosis. Hyperaldosteronism or Conn’s syndrome results from excess aldosterone, which is characterized by hypertension, hypernatremia, hypokalemia, hypocalcemia, proximal muscle weakness, headache, polyuria, and tachycardia with/without palpitations. Virilization or feminization results from excess sex steroids.

Gross features

Adenomas are typically solitary and unilateral, <6 cm in greatest dimension, and weigh <100 g. The lesion is usually well circumscribed with a smooth border (Fig. 16.199). Adrenal cortical adenoma is unencapsulated but may be surrounded by a fibrous pseudocapsule. Tumors are yellow-orange and may occasionally be brown or black on gross examination. Adrenal cortical adenoma may compress surrounding adrenal tissue, and in functional tumors the uninvolved cortex is atrophic.

Microscopic features

The architectural arrangement of the tumor is typically different than that of the surrounding adrenal cortex and forms nests, sheets, and cords. The cells of adrenal cortical adenoma mimic the cells comprising one or more of the three layers of the normal adrenal cortex. Adrenal cortical adenoma often resembles the zona fasciculata, which has characteristic abundant clear, flocculated cytoplasm due to high lipid content (Fig. 16.200). Adrenal cortical adenoma is made up of bland, indolent-appearing, uniform cells that are slightly larger than the normal adrenal cortex with more variation in nuclear size. By definition, adrenal cortical adenoma has a very low mitotic rate. It is difficult to impossible to characterize the endocrine activity of an adrenal cortical adenoma based on light microscopic features.

Uncommon histologic findings within an adrenal cortical adenoma include oncocytic cells, pseudoglandular growth, myxoid background, lipofuscin pigment, spironolactone bodies, myelolipomatous, lipomatous, osseous metaplasia, or degenerative changes (Figs. 16.201 , 16.202, 16.203, 16.204, 16.205, and 16.206). Adrenal cortical adenoma with oncocytic features may be referred to as adrenal oncocytomas, and these tumors can have cytologic and nuclear atypia without clinical consequence. They have abundant granular eosinophilic cytoplasm due to the presence of mitochondria [766]. Myxoid changes may rarely be seen in adrenal cortical adenomas, and this histologic feature is more common in adrenal cortical carcinoma. They are rare in both instances and slightly more common in carcinoma cases [767, 768]. Some tumors can have abundant, dark to golden brown, cytoplasmic lipofuscin granules thought to be a product of aging [769, 770]. In patients with hyperaldosteronism who are treated with aldosterone antagonists, spironolactone bodies may be seen. These inclusions are most often seen in the zona glomerulosa; are located in the cytoplasm, lightly eosinophilic, and scroll-like; and are surrounded by a clear halo. They contain phospholipids and aldosterone.

Features to evaluate for malignant potential have been described. The Weiss criteria and the more recently proposed Modified Weiss criteria are the most commonly used systems for this distinction [771, 782]. The Weiss system relies on histologic features, and the Modified Weiss System is slightly simpler and can be applied to oncocytic adrenal tumors [772, 773]. The most useful criteria for malignant potential are weight (>500 g), size (>6.5 cm), the presence of necrosis, mitotic activity (≥5 mitoses per 50 high-power fields or > 4% positive staining with Ki-67), and atypical mitotic figures [772, 773]. In tumors with some worrisome histologic features but insufficient to establish malignancy, a diagnosis of “adrenal cortical neoplasm with uncertain malignant potential” is warranted (Fig. 16.207).

Ancillary Studies

Adrenal cortical adenoma shows positive, cytoplasmic staining for α-inhibin, Melan-A (Mart-1), and calretinin (Figs. 16.208 and 16.209) [777,778,779,780,781,782,780]. Calretinin may also have some nuclear staining, and the use of polyclonal antibodies results in a more intense/diffuse stain than monoclonal antibodies. Positive, nuclear staining for SF-1 is present [781]. Adrenal cortical adenoma is negative for chromogranin A, S-100, HMB45, and EMA [774, 779, 782]. Carbonic anhydrase IX has minimal membranous staining [783]. Variable staining is seen with vimentin, cytokeratin, synaptophysin, and neurofilament [779, 780, 782]. In general, variants of adrenal cortical adenoma have an immunohistochemical profile similar to the conventional type [784].

The molecular pathogenesis of adrenal cortical adenomas is still not entirely clear, and diagnosis and differentiation from adrenal cortical carcinoma relies mainly on histopathologic features. There is currently no clinical utility to performing adjunct molecular testing in the workup of an adrenal cortical adenoma.

Differential Diagnosis

For indolent-appearing lesions , there is histologic overlap between adrenal cortical adenoma and adrenal cortical hyperplasia. Features that favor hyperplasia are multifocality, bilaterality, and nodules that are poorly circumscribed. Sometimes these two entities cannot be histological differentiated from each other on resection, and it is not possible to speculate between the two on biopsy.

Adrenal cortical adenoma resembles low-grade clear cell renal cell carcinoma . The cells of clear cell renal cell carcinoma are more cleared out and do not have the uniform vacuolated cytoplasm of adrenal cortical adenoma. Immunohistochemically, clear cell renal cell carcinoma is positive for AE1/3 and carbonic anhydrase IX (adrenal cortical adenoma is negative) and negative for Melan-A (Mart-1), calretinin, α-inhibin, and SF-1 (adrenal cortical adenoma is positive).

It is important to distinguish adrenal cortical adenoma from adrenal cortical carcinoma. Weiss criteria can be utilized as previously described. Ki-67 is the only immunohistochemical antibody consistently reported to aid in the differential diagnosis of adenoma versus carcinoma [784].

Prognosis

Adrenal cortical adenoma is a benign tumor with a good prognosis. If a lesion is thought to be an adrenal cortical adenoma and it is nonfunctioning, small (<4 cm), and < 10 Hounsfield units (HU) on non-contrast computed tomography (CT) scan, it can be managed conservatively with long-term follow-up [785, 786]. Conservative management entails reevaluation at 3–6 months, then annually for 1–2 years, and hormonal evaluation annually for up to 5 years. Any adrenal lesion with concerning characteristics or ≥ 4 cm should be resected due to risk of adrenal cortical carcinoma.

Adrenal Cortical Carcinoma

Adrenal cortical carcinoma is a rare, highly aggressive malignancy originating from the adrenal cortex.

Clinical Features

Adrenal cortical carcinoma occurs at a median age of 49–59 years with most studies reporting a slight female predominance (52–58% female) [790,791,792,793,794,795,796,794]. Approximately 10–40% of these tumors are functional [787, 788, 793, 794]. Most commonly the tumor causes hypercortisolism and hyperaldosteronism along with the associated signs and symptoms of Cushing syndrome as described in the prior section. Initial evaluation includes serum and urinary metanephrine and steroid levels and imaging via CT or MRI. It is not recommended to biopsy a suspected adrenal cortical carcinoma due to the poor sensitivity, possibility for complications due to the biopsy, and lack of impact in clinical management (Fig. 16.210).

Gross Features

Tumors have a mean size of 11–14 cm and over 2/3rds are at least 6.5 cm [787, 788, 795,796,794]. Mean weight is approximately 400–600 g, and over 80% are over 50 g [793, 794, 803, 804]. Malignant tumors are usually > 100 grams, and tumors that are >500 grams are frequently malignant. Tumors > 6.5 cm are also likely to be malignant. Lesions are unifocal, well circumscribed, and encapsulated with a yellow, heterogeneous, hemorrhagic, and necrotic cut surface (Fig. 16.211).

Microscopic Features

Tumors are composed of dense sheets, nests, and trabeculae with medium- to large-sized cells (Figs. 16.212 and 16.213). The cytoplasm is eosinophilic to clear, with or without vacuolization (Figs. 16.214 and 16.215). Cellular and nuclear pleomorphism may be minimal with monotonous cells or quite marked (Figs. 16.213 and 16.216). Necrosis is common as is capsular invasion and/or vascular invasion (Figs. 16.216 and 16.217). Cystic change and hemorrhage can be present. Rarely changes that may be seen include pseudoglandular formation, lipomatous or myelolipomatous metaplasia, fibrosis, calcification, or metaplastic bone formation.

Mitoses are usually abundant but in some tumors can be difficult to identify and are important diagnostic and prognostic features. Mitotic rate is used to assign a tumor grade. Low-grade tumors have ≤20 mitoses per 50 high-power fields, and high-grade tumors have >20 mitoses per 50 high-power fields.

There are three histologic variants : (1) oncocytic, (2) myxoid, and (3) sarcomatoid. Oncocytic adrenal cortical carcinoma is the most common variant (10–20%) and is composed of oncocytic cells (Figs. 16.218 and 16.219) [794]. There is no defined percentage of the tumor that must be oncocytic variant histology to warrant the variant classification. Some authors propose a distinction between pure, with >90% variant histology, and mixed with 10–50% variant histology [795]. The Weiss system does not apply to the oncocytic variant. Myxoid adrenal cortical carcinoma is the second most common variant (5–10%) and has a background of extracellular mucoid like material (Fig. 16.213) [794]. Sarcomatoid adrenal cortical carcinoma can have areas with classic cortical carcinoma and other areas that resemble sarcoma.

Ancillary Studies

α-inhibin, calretinin, Melan A, and SF-1 are highly expressed in the majority of adrenal cortical carcinoma (70–100%), similar to adrenal cortical adenoma [769, 777,778,779,780,781,782,780, 798,799,800,801,802,803,801]. Broad-spectrum cytokeratins, such as CAM5.2, are variably expressed, but the reactivity can be weak [801]. Tumors do not express chromogranin A, S-100 protein, or GATA3 [774, 801, 802]. Synaptophysin has variable expression [800, 801]. Membranous carbonic anhydrase IX (CAIX) is typically focal, and TTF-1 is negative [783, 795]. Alcian blue stains myxoid areas, but these areas are negative using mucicarmine and PAS [767, 803].

Differential Diagnosis

The main diagnostic consideration in tumors with worrisome histologic features but not overt malignancy is adrenal cortical adenoma or the uncertain designation “adrenal cortical tumor of uncertain malignant potential.” There are several histologic algorithms (Hough, Weiss, van Slooten, modified Weiss, etc.) to differentiate adrenal cortical carcinoma from adenoma as described in the previous section.

The most common pitfall for malignant appearing tumors is mistaking adrenal cortical carcinoma for pheochromocytoma [804]. Chromogranin, S-100, and GATA3 are expressed in pheochromocytoma but are negative/focal in adrenal cortical carcinoma, while Melan A, α-inhibin, and calretinin are negative in pheochromocytoma and variably positive in adrenal cortical carcinoma. Due to the variable expression of adrenal cortical carcinoma, use of a panel of markers is recommended.

Adrenal cortical carcinoma must be differentiated from metastatic carcinoma, including high-grade clear cell renal cell carcinoma, hepatocellular carcinoma, pulmonary carcinoma, and malignant melanoma [755]. High-grade clear cell renal cell carcinoma also features large, pleomorphic, eosinophilic cells but is negative for α-inhibin, calretinin, Melan A, and SF-1 and has diffuse membranous reactivity using carbonic anhydrase IX (CAIX). Hepatocellular carcinoma does not express Melan A, calretinin, or SF-1, but reactivity using α-inhibin has been described. The myxoid variant of adrenal cortical carcinoma can mimic adenocarcinoma, and also pseudoglandular architecture can further cause confusion between adrenal cortical carcinoma and metastatic adenocarcinoma. CK7 and CK20 along with lineage-specific markers such as TTF-1 for lung adenocarcinoma will be helpful to establish the correct diagnosis. There is expression overlap between malignant melanoma and adrenal cortical carcinoma in that both express Melan A but melanoma is negative for α-inhibin and calretinin.

Prognosis

The 5-year survival of adrenal cortical carcinoma is 20–40% [787, 788, 790, 791]. Due to the aggressive nature of the tumor, oncologic surveillance via cross-sectional imaging using CT or MRI for 10 years is indicated. Surveillance may also include biochemical studies if the tumor is functional. Adrenal cortical carcinoma is treated with adrenalectomy. Tumor resections with positive margins have a much worse 5-year survival (34% vs 65%). Functional tumors have more postoperative morbidity and increased subsequent mortality [789, 790, 792]. Higher Weiss score and ki-67 index are associated with worse overall survival [788, 792, 805]. Adjuvant mitotane, an adrenolytic drug, is reported to increase recurrence-free survival [806]. As such, use of adjuvant mitotane in tumors with a high risk for recurrence or those that were incompletely resected may be helpful.

Pheochromocytoma

Pheochromocytoma is a paraganglioma of the adrenal medulla. The tumor is composed of chromaffin cells which produce catecholamines. Pheochromocytoma is the second most common entity encountered in an adrenalectomy specimen and accounts for 7% of primary adrenal tumors [807, 808].

Clinical Features

One-third of pheochromocytomas are hereditary [809, 810]. Sporadic tumors present in the 4th and 5th decade, later than hereditary tumors which occur 1–2 decades earlier [773, 811]. Hereditary tumors are more commonly bilateral. Classic signs and symptoms of pheochromocytoma include the triad of episodic headaches, sweating, and tachycardia as well as paroxysmal hypertension, palpitations, and postural hypotension. Around 10% of patients have normal blood pressure [815,816,817,815]. Patients with suspected pheochromocytoma undergo laboratory testing for serum and urinary catecholamine breakdown products. These laboratory studies in combination with imaging yield a diagnosis of pheochromocytoma in the majority of cases. Of note, many other lesions can yield pheochromocytoma-like symptoms, including similar laboratory findings (“pseudopheochromocytomas”) [819,820,821,822,823,824,825,826,827,825].

Gross Features

Tumors have a mean diameter of 4–5 cm with metastatic tumors larger, approximately 9 cm [829,830,828]. Some tumors may be less than 1 cm. Maximum tumor dimension has been described to be an independent risk factor for recurrence and distant metastasis in some but not all studies [832,833,831]. The mean weight is 100 grams, approximately 90 grams for benign tumors and 250 grams for malignant tumors [832, 833]. Tumors are well circumscribed and unencapsulated and have a white solid to red-brown, hemorrhagic, soft cut surface (Fig. 16.220).

Microscopic Features

A nested (“zellballen”), solid , or trabecular appearance is characteristic of pheochromocytoma (Fig. 16.221). Cells are large and polygonal with fine granular, red-purple abundant cytoplasm. Nests of cells are circumscribed by supporting sustentacular cells. The cytoplasm can be dense and uniform or extensively vacuolated. Pigmented granules including hemosiderin, melanin, neuromelanin, and lipofuscin may be seen. Nuclei may be uniform or exhibit extensive variation in size. Within the round to oval nuclei, nucleoli are visible and prominent (Fig. 16.222). A tumor consisting of pheochromocytoma along with ganglioneuroma, ganglioneuroblastoma, neuroblastoma, or peripheral nerve sheath tumor is termed composite pheochromocytoma (Fig. 16.223). Scattered ganglion cells seen in a pheochromocytoma are insufficient to render the diagnosis of composite pheochromocytoma.

Using light microscopic features to determine which tumors will metastasize is difficult, with conflicting published results for various histologic findings. Pheochromocytomas may be evaluated using the following weighted features using the Pheochromocytoma of the Adrenal Gland Scaled Score (PASS) in which the following histologic features are weighted and a score of ≥4 is concerning for malignancy: periadrenal adipose invasion (+2), >3 mitosis per 10 high-power fields (+2), atypical mitoses (+2), necrosis (+2), cellular spindling (+2), marked nuclear pleomorphism (+2), cellular monotony (+2), large nests or diffuse growth (+2), high cellularity (+2), capsular invasion (+1), vascular invasion (+1), and hyperchromasia (+1) (Figs. 16.224, 16.225, 16.226, 16.227, and 16.228) [833]. Benign tumors reportedly average ≤ 1 mitosis per 30 high-power fields although some publications have found no relationship between mitotic rate and recurrence and/or metastasis [829, 834].

Ancillary Studies

The neuroendocrine proteins, synaptophysin and chromogranin A, are highly expressed in the cytoplasm of pheochromocytoma (Fig. 16.229). S-100 has strong expression in the nucleus and cytoplasm of the sustentacular cells and may be expressed in pheochromocytes throughout the tumor (Fig. 16.230) [835]. Additionally GATA3 has diffuse nuclear expression in most tumors [802]. Weak to no expression is found for α-inhibin, calretinin, and Melan A. In the rare event that a pheochromocytoma is suspected in a needle core biopsy specimen, use of several immunostains to confirm the diagnosis is recommended as there are life-threatening consequences for performing surgery on an unsuspected pheochromocytoma in which the patient does not receive the appropriate adrenergic blockade.

Transmission electron microscopy will reveal numerous dense secretory granules within the cytoplasm of 200–300 nm, which store catecholamines. Most tumors have both noradrenaline granules, with an eccentrically placed dense core surrounded by an empty halo, and adrenaline granules, with a centrally placed dense core that lacks a halo.

Approximately 30% of pheochromocytomas are hereditary and include the autosomal-dominant disorders von Hippel-Lindau syndrome, multiple endocrine neoplasia type 2 (MEN2), neurofibromatosis type 1 (NF1), and familial paraganglioma along with other recently described susceptibility genes [836, 837]. Patients and family members with a family history or symptoms of a syndrome, bilateral tumors, presentation of tumor <45 years of age, or a paraganglioma concurrent with the pheochromocytoma may undergo sequence analysis for the suspected germ-line mutation. SDHB immunohistochemistry can be performed to identify a loss of expression found in patients with familial paraganglioma due to SDHB mutations [838].

Differential Diagnosis

The diagnosis of pheochromocytoma is usually straightforward. However, tumors with marked spindling and pleomorphism raise the differential diagnosis of carcinoma, in particular adrenal cortical carcinoma. To rule out metastatic carcinoma, a broad-spectrum keratin such as AE1/3 in addition to CK7 and CK20 can be used. Most metastatic carcinomas will be positive using a broad-spectrum keratin. If adrenal cortical carcinoma is a consideration, workup including chromogranin and S-100 (positive in pheochromocytoma, negative in adrenal cortical tumors) and Melan A, α-inhibin, and calretinin (negative in pheochromocytoma, positive in adrenal cortical tumors) can be helpful. Synaptophysin is less useful as it can have patchy expression in adrenal cortical tumors. In a biopsy specimen, the main differential diagnosis will be exclusive sampling of adrenal medulla. A needle core biopsy specimen containing predominately pheochromocytes should raise concern for pheochromocytoma, and this differential should be noted in the report even if a definitive diagnosis is not possible.

Prognosis

Pheochromocytoma is treated with surgical resection via adrenalectomy, typically a total adrenalectomy unless the patient has bilateral tumors [839, 850]. It is important to note that few of these features have consistent predictive value across different published studies. Surveillance cannot rely solely on serum or urine metanephrines as 25% of tumor recurrences do not demonstrate an elevation [840].

After adrenalectomy, there is a 5-year survival 95%. Between 6% and 9% of tumors have local recurrence with a median time to recurrence of 35–38 months [832,833,831]. SDHB deficient tumors are more aggressive [829]. Composite pheochromocytomas are described to have similar prognosis as classic pheochromocytomas [840].

Ten to twenty percent of pheochromocytomas are metastatic. Metastatic pheochromocytomas have an approximately 65% 5-year survival and 35% 10-year survival [841]. Brain, liver, or lung metastases are reported to have a worse outcome versus patients with only bone metastases [842]. Metastatic tumor is treated with surgical resection if possible with or without a radiopharmaceutical similar to adrenaline such as 131-iodine-labeled meta-iodobenzylguanidine. Chemotherapeutic protocols such as cyclophosphamide, vincristine, and dacarbazine can be used for unresectable tumor.

Neuroblastic Tumors

Neural crest that gives rise to the sympathetic nervous system yields neuroblastic tumors. This group includes neuroblastoma, ganglioneuroblastoma intermixed, ganglioneuroblastoma nodular, and ganglioneuroma. The tumors differ with respect to neuroblastic differentiation and amount of Schwannian stroma.

Clinical Features

Neuroblastic tumors are the most common malignancy encountered in the first year of life. Almost all patients with neuroblastoma or ganglioneuroblastoma are diagnosed under the age of 5 years. There is a slight male predilection. African-American and Native American populations are noted to have worse survival [843]. The adrenal gland is the site for these tumors in 47% of cases, but they can occur anywhere that sympathetic tissue is present [844]. Ganglioneuroma occurs at an older age with a median presentation at 6–7 years and has a slight female predominance. The adrenal is the third most common location for ganglioneuroma, after the mediastinum and retroperitoneum [845].

Approximately 30% of tumors are incidentally discovered. The most common symptoms include abdominal pain, fever, and abdominal distention [846, 847]. Urine and serum catecholamine metabolites may be elevated. Infant screening programs for urinary metabolites did not impact survival and are no longer recommended [848]. Other paraneoplastic syndromes may rarely occur and include opsoclonus-myoclonus syndrome and vasoactive intestinal peptide-secreting tumors [849]. Around 1–2% of cases have a family history with an autosomal-dominant pattern of inheritance. Neuroblastic tumors have been associated with Hirschsprung disease, central hypoventilation syndrome, neurofibromatosis, von Recklinghausen disease, Beckwith-Wiedemann syndrome, and Di George syndrome.

Gross Features

Over half of adrenal neuroblastic tumors are less than 5 cm [846]. Tumors are typically well circumscribed and unencapsulated but may be infiltrative. Neuroblastoma has a softer cut surface than ganglioneuroblastoma or ganglioneuroma. Tumor color ranges from tan to white and often has areas of hemorrhage [845]. Ganglioneuroblastoma nodular has at least one grossly visible neuroblastic nodule (Fig. 16.231).

Microscopic Features

The International Neuroblastoma Pathology Classification (INPC) has classified the neuroblastic tumors as: (1) neuroblastoma (Schwannian stroma-poor); (2) ganglioneuroblastoma, intermixed (Schwannian stroma-rich); (3) ganglioneuroblastoma, nodular (composite, Schwannian stroma-rich/stroma-dominant and Schwannian stroma-poor); and (4) ganglioneuroma (Schwannian stroma-dominant).

Neuroblastoma is a highly cellular, primitive appearing tumor composed of neuroblasts with minimal Schwannian stroma. Neuroblastoma is divided into three subtypes: (1) undifferentiated, (2) poorly differentiated, and (3) differentiating. Undifferentiated neuroblastoma is a small round blue cell tumor that lacks neuropil, requires ancillary testing for diagnosis, and is uncommon (Fig. 16.232). Poorly differentiated neuroblastoma has neuropil; <5% of neuroblasts show differentiation and may be diagnosed without ancillary testing (Fig. 16.233). Homer-Wright rosettes can be present (Fig. 16.234). Differentiating neuroblastoma has >5% of neuroblasts that show differentiation toward mature neurons and usually has abundant neuropil. Neuroblastic differentiation is characterized by progressive vesicular nuclear changes, presence of nucleoli, enlarging amphophilic or eosinophilic cytoplasm with or without cytoplasmic processes, and synchronous maturation of the nucleus and cytoplasm.

Ganglioneuroblastoma , intermixed, is a tumor with >50% of the tissue being ganglioneuromatous that contains ganglion cells within Schwannian stroma (Fig. 16.235). The ganglioneuromatous areas are admixed with clusters of neuroblastic cells and neuropil. Most of the neuroblasts show differentiation.

Ganglioneuroblastoma, nodular, has a grossly visible neuroblastic nodule along with a ganglioneuroblastoma or ganglioneuroma component. The stroma-poor neuroblastic nodule is usually hemorrhagic and/or necrotic (Figs. 16.236 and 16.237). The transition between the neuroblastic nodule and other components is often well-demarcated.

Ganglioneuroma is characterized by a predominance of Schwannian stroma (Figs. 16.238 and 16.239). Ganglion cells are individually dispersed within the tumor, and no neuropil is present without associated Schwannian stroma (Figs. 16.240 and 16.241). There are two ganglioneuroma subtypes: (1) maturing and (2) mature. Maturing ganglioneuroma contains both mature ganglion cells and maturing ganglion cells. Mature ganglioneuroma only has mature ganglion cells.

Ancillary Studies

Neuroblasts express neuronal markers including neuron-specific enolase, CD56, protein gene product 9.5, synaptophysin, chromogranin, neurofilament protein, PHOX2B, NB84, and tyrosine hydroxylase as well as CD57/Leu7, ALK1, and cyclin D1 [613, 853,854,852]. Neuroblasts can express MYCN in MYCN-amplified tumors. Neuroblasts do not express epithelial markers (EMA, cytokeratin), myogenic markers (myogenin, MyoD1, desmin), CD99, vimentin, HMB45, WT1, CD45, glypican-3, or PAX2 [613, 854,855,856,854]. Schwannian cells are positive using S-100 [852]. Ganglion cells express WT1 (cytoplasmic), S-100, synaptophysin, neurofilament protein, glial fibrillary acidic protein, protein gene product 9.5, and type IV collagen [613, 852].

Electron microscopy can be helpful to diagnose undifferentiated or poorly differentiated neuroblastoma. Neurosecretory dense-core granules will be present. Primitive neurites will also be seen.

Molecular testing in neuroblastoma includes interrogation for MYCN amplification, 11q aberrations, and ploidy status [855, 856]. Amplification of MYCN localized to chromosome 2p24 is present in 20–25% of tumors, portends a worse prognosis, and is considered a main oncologic pathway for the development of neuroblastoma [855]. A large region of amplification inclusive of MYCN often yields small fragments of extrachromosomal DNA or double minutes. FISH is used to determine amplification and is reported as amplified (ratio ≥ 4), gain (ratio > threshold), or not amplified (ratio ≤ threshold). Both the ratio and type of amplification (double minutes versus homogeneously staining regions, i.e., linear integration) should be reported. Deletion of 11q23 is present in 40% of tumors and is associated with a worse prognosis. Diploid tumor status also yields a worse prognosis.

Differential Diagnosis

Small biopsies, tumors lacking differentiation, or suboptimal specimens may present a diagnostic dilemma. Other small round blue cell tumors should be considered if undifferentiated or poorly differentiated neuroblastoma is high on the differential diagnosis. Work-up should evaluate for entities such as Wilms tumor, lymphoma, leukemia, rhabdomyosarcoma, primitive neuroectodermal tumor/Ewing sarcoma, malignant rhabdoid tumor, and desmoplastic small round cell tumor. These entities usually lack expression of neuroendocrine markers, and therefore immunohistochemistry can be helpful to establish the diagnosis. Other helpful expression patterns include positivity for WT1 in Wilms tumor (negative in neuroblastoma), CD99 in primitive neuroectodermal tumor/Ewing sarcoma (negative in neuroblastoma), myogenic markers (desmin, myogenin, MyoD1) in rhabdomyosarcoma (negative in neuroblastoma), and hematopoietic markers in lymphoma or myeloid leukemia (negative in neuroblastoma). Of note, both neuroblastoma and Ewing sarcoma often express PGP9.5 and NB84.

Prognosis

Worse prognosis is associated with older age at diagnosis, undifferentiated/poorly differentiated tumors, MYCN amplification, deletion of chromosome 11q, diploidy, higher stage, elevated serum neuron-specific enolase, ferritin and lactic dehydrogenase, and a vanillylmandelic acid to homovanillic acid ratio < 1.0.

The International Neuroblastoma Pathology Classification (INPC) histology grouping combines the age of diagnosis and mitotic-karyorrhectic index with the histologic subtype to yield a favorable or unfavorable histology classification. Mitotic-karyorrhectic index (MKI) is low if <100/5000 cells (<2%), intermediate for 100–200/5000 cells (2–4%), or high if >200/5000 cells (>4%). Classification should be performed prior to systemic treatment.

The Children’s Oncology Group (COG) neuroblastoma risk grouping system uses the International Neuroblastoma Staging System (INSS) and International Neuroblastoma Risk Group (INRG) in addition to patient age, MYCN status, and ploidy to yield a prognostic risk group of low, intermediate, or high. Survival is excellent for the low- and intermediate-risk patients (90% 5-year survival), and low-risk patients may be managed with active surveillance. High-risk patients have a 50% 5-year survival and are treated with aggressive therapy.

Other Adrenal Neoplasms and Lesions

Myelolipoma

Myelolipoma is an uncommon lesion composed of mature adipose and hematopoietic elements (Fig. 16.242). It is hypothesized that a myelolipoma is not an actual neoplasm [857]. This tumor can appear in a wide variety of locations with the adrenal gland as the most common site. The diagnosis is usually made via imaging due to the visible adipose tissue with no further treatment indicated. Indeterminate lesions may result in a biopsy or resection. Histologic diagnosis is usually straightforward provided adequate tissue is sampled. Of note, myelolipomatous metaplasia can occur in other adrenal tumors including adrenal cortical adenoma, adrenal cortical carcinoma, and pheochromocytoma [858].

Secondary Tumors

The adrenal gland is a frequent location of metastases. Additionally, numerous tumors can secondarily involve the adrenal gland via direct extension. Carcinoma from other locations is the most common diagnosis in adrenal biopsies, with the lung and kidney accounting for the two most numerous sources [755, 859]. Approximately 70% of lung metastases in the adrenal gland are pulmonary adenocarcinoma, and 80% of the kidney tumors in the adrenal are clear cell renal cell carcinoma , either due to metastasis or direct extension (Figs. 16.243 and 16.244). Other types of carcinoma, malignant melanoma, sarcoma, and lymphoma rarely are found in the adrenal gland (Fig. 16.245).

Rare Primary Tumors

Numerous other tumors more common in other locations rarely develop or secondarily involve the adrenal gland. Benign lesions include adenomatoid tumor, hemangioma, and leiomyoma and malignant tumors or tumors with malignant potential include angiosarcoma, leiomyosarcoma, schwannoma, neurofibroma, and malignant peripheral nerve sheath tumor.

Cysts

The four types of adrenal cysts are (1) endothelial (vascular), (2) pseudocysts, (3) parasitic, and (4) epithelial [860]. Endothelial cysts and pseudocysts are the most common types [861]. Dilated ectatic vessels yield an endothelial cyst. Endothelial cysts that lose the epithelial lining are thought to give rise to pseudocysts [862]. Adrenal cysts can mimic tumors functionally and upon imaging, leading to resection. Adrenal tumors, including adrenal cortical adenoma, adrenal cortical carcinoma, pheochromocytoma, and neuroblastoma, can be mimic adrenal cysts [865,866,864].

Staging

The American Joint Committee on Cancer 8th edition Staging Manual provides an updated pTNM staging for adrenal cortical carcinoma and a newly defined pTNM staging for pheochromocytoma. There is currently no pTNM staging system for neuroblastoma. Neuroblastic tumors are most commonly staged according to the International Neuroblastoma Staging System (INSS) or the more recent International Neuroblastoma Risk Group (INRG) system.

Tumors of Collecting Duct and Rete Testis

Adenoma

Clinical Features

This is a rare tumor that mostly presents as polypoid nodules in the testis of adult patients.

Pathological Features and Ancillary Studies

Grossly, the nodules are polypoid with a tan yellow cystic cut surface and no necrosis. Microscopically, the nodules are composed of tubular structures with papillary projections into the lumen of the rete testis. Tumor cells are bland without appreciable mitotic activity.

Adenocarcinoma

Clinical Features

Adenocarcinoma of the rete testis is rare and usually presents in the fourth through eighth decades of life. Patients may present with a hilar mass, groin pain, hydrocele, or inguinal hernia. These tumors frequently recur and may extend to the epididymis, as well as spreading to the para-aortic or iliac lymph nodes and distantly to the bone. Cancer specific mortality is greater than 50%.

Pathological Features and Ancillary Studies

Grossly, these tumors present as non-encapsulated, firm, occasionally cystic hilar masses, ranging in size from 1 to 10 cm, with ill-defined borders. Microscopically, neoplastic cells show a solid nodular pattern of growth, protruding into the dilated channels of the rete testis with tumor necrosis occasionally seen [146]. It should be noted that rete testis adenocarcinoma is largely a diagnosis of exclusion and secondary involvement by a carcinoma via contiguous spread or metastasis needs to first be clinically and pathologically excluded. Rete testis adenocarcinomas label immunohistochemically for PAX8 and PAX2, which is useful in differentiating these tumors from other important differential diagnoses including mesothelioma, testicular germ-cell and sex cord-stromal tumors, which are all immunonegative for these markers [147].

Tumors of Paratesticular Structures

Adenomatoid Tumor

Clinical Features

Adenomatoid tumors are the most commonly encountered neoplasms of the paratestis, comprising approximately 30% of such tumors [148]. They affect a wide age range, generally between the third and fifth decades, and typically present as a solitary, unilateral, painless mass lesion of the scrotum [149]. In rare cases, torsion and infarction can result in a painful lesion. Adenomatoid tumors commonly involve the lower pole of the epididymis, though they can also affect the spermatic cord or tunica albuginea/vaginalis. Their location is typically extratesticular, though intratesticular extension may occasionally be seen [149]. Adenomatoid tumors are uniformly benign without any malignant potential reported.

Pathologic Features and Ancillary Studies

Adenomatoid tumors are circumscribed solid tumors, 1–5 cm in diameter, with a white tan cut surface [149]. Microscopically, the tumors show a tubulocystic and solid architecture. The neoplastic cells display a cuboidal to flat cytology with eosinophilic, vacuolated cytoplasm, and bland nuclear features without conspicuous nucleoli, mitoses, or necrosis. Infarcted tumors may, however, show reactive atypia with mitoses. The immunophenotype of adenomatoid tumors reflects their mesothelial origin with labeling for pancytokeratins, CK 5/6, calretinin, and WT1.

Mesothelioma

Clinical Features

Mesotheliomas arising from the tunica vaginalis usually present in the sixth and seventh decades as unilateral mass lesions or with hydrocele. Overall, they are much less frequent than mesotheliomas arising from the pleura or peritoneum [150], and asbestos exposure has been found in between one-third to two-thirds of such cases [151,152,153]. These tumors show an aggressive clinical course with a median survival of 23 months [154, 155].

Pathologic Features and Ancillary Studies

Mesotheliomas classically show a hydrocele, with thickened tunica and nodules extending into testicular and paratesticular structures [150]. The histological features are similar to those described for mesotheliomas at other sites, and the immunophenotype reflects its mesothelial derivation.

Papillary Cystadenoma

Clinical Features

Papillary cystadenoma is a tumor arising from efferent ducts at the head of the epididymis. It affects patients at a mean age of 35 years and may present incidentally or as a painless scrotal lump. Unilateral presentation is more common and is usually sporadic, whereas bilateral tumors generally occur in patients with von Hippel-Lindau syndrome [156]. These tumors are virtually always benign with isolated case reports describing malignant behavior [157, 158].

Pathologic Features and Ancillary Studies

Papillary cystadenoma forms a circumscribed cystic and solid nodule with a mean diameter of 2 cm. Microscopically, it shows a papillary architecture lined by clear cells reminiscent of the clear cell papillary renal cell carcinoma. Interestingly, it shows a similar immunoprofile as well with labeling for CAIX, CK7, and PAX8; tumor cells show negative staining for CD10 and P504S [159, 160]. Unlike clear cell papillary RCC, however, VHL mutations [161] have been described in papillary cystadenomas.

Hematopoietic tumors

Hematolymphoid tumors comprise the most common neoplasms affecting the testis in older men of greater than 50 years of age [162]. Large B-cell lymphomas are most common; however, various subtypes may involve the testis and paratestis. They generally present as a painless unilateral solid mass; however, they are more often bilateral and more prone to show extratesticular involvement than other categories of primary testicular tumors [163, 164]. Microscopically, interstitial growth of lymphoma is typical, although intratubular extension may as well occur. The reader is referred to the section on hematolymphoid malignancies for a detailed description of the different lymphoma subtypes.

Metastatic Tumors

Various tumors may metastasize to the testis usually via lymphatic and vascular routes, and with a reported incidence of up to 3.6% [165]. Though generally found in patients with a documented history of cancer, the majority of metastatic lesions are unilateral and solitary [166]. Features that are suspicious for a metastatic lesion include age greater than 50 years, tumor histology that is unusual for a testicular primary, interstitial growth, prominent lymphovascular invasion, and history of another primary neoplasm. The most common primary sites of origin with metastatic spread to the testis include, in descending order, prostate, gastrointestinal tract, kidney, lung, melanoma, and urinary tract (WHO Classification of Tumors of the Urinary System and Male Genital Organs 2016).

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Authors and Affiliations

Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
Priya Rao, Pheroze Tamboli & Miao Zhang
Department of Pathology, The Ohio State University Medical Center, Columbus, OH, USA
Carmen M. Perrino & Debra L. Zynger
Department of Pathology and Laboratory Medicine, University of Miami Miller School of Medicine, Miami, FL, USA
Merce Jorda
Departments of Pathology and Translational Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
Kanishka Sircar
Instituto de Patologia e Investigacion and Facultad de Ciencias Medicas, Universidad Nacional de Asuncion, Asunción, Paraguay
Diego Fernando Sanchez & Antonio L. Cubilla
Department of Pathology, Medical College of Wisconsin, Milwaukee, WI, USA
Kenneth Iczkowski

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Priya Rao
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Carmen M. Perrino
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Debra L. Zynger
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Merce Jorda
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Pheroze Tamboli
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Diego Fernando Sanchez
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Antonio L. Cubilla
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Kenneth Iczkowski
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Miao Zhang
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Kanishka Sircar
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Department of Pathology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA
Cesar A. Moran
Department of Pathology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA
Neda Kalhor
Department of Pathology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA
Annikka Weissferdt

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Rao, P. et al. (2020). Genitourinary Pathology (Including Adrenal Gland). In: Moran, C.A., Kalhor, N., Weissferdt, A. (eds) Oncological Surgical Pathology . Springer, Cham. https://doi.org/10.1007/978-3-319-96681-6_16

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DOI: https://doi.org/10.1007/978-3-319-96681-6_16
Published: 30 January 2020
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Genitourinary Pathology (Including Adrenal Gland)

Abstract

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Genitourinary

Genitourinary Neoplasms

Genitourinary System

Keywords

Part I: Tumors of the Male Genital Tract

Prostate: Prostate Cancer Precursors

Prostatic Intraepithelial Neoplasia

Morphology

Diagnosis

Differential Diagnosis

Clinical Predictive Value

Atypical Adenomatous Hyperplasia

Post-inflammatory Atrophy

Acinar Prostatic Adenocarcinoma

Gross Appearance

Minimal Diagnostic Criteria: Qualitative

Minimal Diagnostic Criteria: Quantitative

Ancillary Criteria for Cancer

Diagnostic Immunostains

Types of Stains

Deciding When to Stain

Pitfalls of Stains

Differential Diagnosis of Prostatic Carcinoma

Atrophy

Seminal Vesicle

Atypical Adenomatous Hyperplasia

Verumontanum Mucosal Gland Hyperplasia

Reactive Epithelium

Nephrogenic Adenoma

Basal Cell Adenoma

Other Benign Mimics of Cancer

Urothelial Carcinoma

Rectal Adenocarcinoma

Atypical (Small) Acini Suspicious for Cancer: ASAP

Significance

Assignment of the ASAP Diagnosis

ASAP Can Occur in Conjunction with HGPIN

Resolution of ASAP with Immunostains

Cancer Grading

An Origin of Grading System

Contemporary Grading

Grading Revisions

Grade Migration

Prognostic Grade Grouping

Grading Impact on Treatment

Sampling of Gross Specimens

Radical Prostatectomy

Vanishing Cancer

Transurethral Resection

Staging, Tumor Volume, and Margin Status

Radical Prostatectomy

Staging

Tumor Volume

Margin Status

Biopsy

Cribriform/Large-Gland Types of Adenocarcinoma

Invasive Large-Gland Carcinoma (Including Cribriform and Papillary)

Intraductal Carcinoma

Ductal Carcinoma

Unusual Variants of Carcinoma

Pseudohyperplastic

Adenoid Cystic/Basal Cell Carcinoma (ACBCC)

Neuroendocrine

Squamous

Effects of Treatment on Carcinoma

Radiotherapy

Androgen Deprivation

Mesenchymal Neoplasms

Lesions Particular to the Prostate

Lesions Also Found at Other Sites

Hematologic Neoplasms

Molecular Biology of Prostate Cancer

Prognostic Tissue Markers

CpG Island Hypermethylation Profile: GSTP1 Methylation

HOXD3 Methylation

Serum and Urinary Markers

Prognostic Tissue Markers