Kidney Tumor

Abstract

The spectrum of renal neoplasms continues to expand with better understanding of histology, immunohistochemistry, and genetics, such that many renal cancer variants are now recognized. Diagnostic challenges for the pathologist include classifying renal masses based on biopsy material, as well as distinguishing subtle variants that may have implications for prognosis or diagnosis of hereditary cancer syndromes. This chapter addresses challenges in classifying renal tumor types and distinguishing entities with morphologic overlap. The common questions addressed include grading, staging, and immunohistochemical and molecular tools to resolve diagnostic problems. Most common renal tumor types include clear cell, papillary, chromophobe, and clear cell papillary (tubulopapillary) renal cell carcinomas; however, rarer variants are also discussed including hereditary cancer syndromes, sarcomatoid tumors, metanephric, and nephroblastic tumors.

Evaluating a Renal Epithelial Tumor in a Biopsy Specimen

In many institutions, renal mass biopsy is used conservatively, since most renal neoplasms will be treated with partial or radical nephrectomy. However, renal mass biopsy is often undertaken when the results may influence clinical management. Some goals of renal mass biopsy include distinguishing primary renal cell neoplasms from other tumors that would necessitate different treatment, particularly metastases, lymphoma, urothelial carcinoma, or rare variants (medullary, collecting duct, or sarcomatoid carcinomas). Secondly, subclassification and grading of primary renal epithelial neoplasms may lead to differences in management. For example, elderly patients with multiple comorbidities may be candidates for surveillance or ablation of nonaggressive tumor subtypes.

• Benign tumor types that can be recognized by biopsy include oncocytoma and angiomyolipoma, among other rarer entities (metanephric adenoma, mixed epithelial and stromal tumor).

• Lower-risk primary renal epithelial tumors include oncocytic neoplasms (possible or definite oncocytomas) and chromophobe renal cell carcinoma (RCC; particularly eosinophilic variant).

• Of note, some pathologists are unwilling to diagnose oncocytoma in a biopsy sample, instead giving a diagnosis of “oncocytic neoplasm” or “oncocytic tumor” with a comment that the features would be compatible with oncocytoma if representative of the entire tumor (since distinguishing eosinophilic chromophobe from oncocytoma remains challenging).

Table 1.1 shows clues to well-differentiated “clear cell tumors” in renal mass biopsy, and Table 1.2 shows high-grade carcinomas in renal mass biopsy (see also Fig. 1.1).

Table 1.1 Clues to well-differentiated “clear cell tumors” in renal mass biopsy

Table 1.2 High-grade carcinomas in renal mass biopsy

Fig. 1.1

(a) Clear cell renal cell carcinoma in renal mass biopsy is composed of fibrosis and bland epithelial cells. (b) Higher magnification demonstrates cells with clear cytoplasm. (c) Positive PAX8 immunohistochemistry supports a primary renal cell neoplasm and argues against an adrenal rest or non-renal lesion. (d) Diffuse membrane staining for carbonic anhydrase IX supports clear cell subtype. (e) A different case of high-grade clear cell renal cell carcinoma in renal mass biopsy shows clusters of cells with clear cytoplasm in fibrous stroma with marked nuclear atypia

References: [1,2,3,4,5,6,7,8,9].

Effectively Sampling a Renal Mass in a Resection Specimen

Sampling a renal mass and determining the pathologic stage are among the most critical steps to determine patient prognosis. RCCs often invade structures (renal sinus or veins) with subtle, finger-like outpouchings that are relatively easy to miss if the individual performing gross examination is not familiar with the usual growth patterns of tumors, especially clear cell RCC.

• The renal sinus is the central fat compartment that surrounds the hilar structures (renal pelvis, arteries, and veins).

• With increasing tumor size, the likelihood of clear cell RCC invading the renal sinus increases dramatically, to the point that >90% of tumors over 7 cm invade the renal sinus (Fig. 1.2a), making pT2 clear cell RCC rare.

• For tumors larger than 4–5 cm, the likelihood of renal sinus invasion increases to over 50%. Histologic assessment of the entire tumor-sinus interface should be strongly considered.

• Any deviation from a well-circumscribed, spherical tumor shape should be viewed with great suspicion for extension into a vein branch or tributary (Fig. 1.2b).

• Changes to the 2016 American Joint Commission on Cancer (AJCC) staging system include removal of the requirements that vein invasion be recognized grossly and that the vein wall contain muscle microscopically.

• Invasion of the renal pelvis has been added as a route to pT3a for RCC in the AJCC system.

• Invasion of the perinephric fat is less common than renal sinus or vein branch invasion in RCC, but qualifies for pT3a.

• In modern practice, surgeons usually attempt to spare the adrenal gland; however, pathologic assessment of adrenal involvement, when present, should aim to discern direct invasion (pT4) from metastatic involvement (pM1).

• Gerota fascia involvement (pT4) is quite rare but usually occurs in the context of RCC extending to the soft tissue surface of a radical nephrectomy, in conjunction with clinical/intraoperative impression of Gerota fascia involvement.

• RCC tumors can extend into the main renal vein and rarely follow the inferior vena cava (pT3b–pT3c) to the level of the heart.

• RCC tumor may be protruding from the vein margin; however, consensus among urologic pathologists is that this only constitutes a positive margin if the tumor is confirmed histologically to be adherent to or invading the vein wall at the margin (as the surgeon would not have necessarily transected tumor when freely mobile).

• Separately submitted vena cava “thrombus” should be examined histologically (at least 2–3 sections) to evaluate for adherent/invaded vein wall, which defines pT3c.

• In some cases (5–8%), RCC extending into the main renal vein subsequently spreads backwards into tributary veins, creating multiple nodules in the kidney (retrograde venous invasion). This can be misinterpreted as multiple tumors or a multinodular tumor by those unfamiliar with the phenomenon.

Fig. 1.2

(a) This clear cell renal cell carcinoma abuts the renal sinus (the fatty compartment containing the renal pelvis and vasculature) with an outpouching (arrow), concerning for renal sinus invasion. (b) This clear cell renal cell carcinoma has multiple outpouchings (arrows) that likely represent extension of the tumor into renal vein branches, which would qualify for pT3a

Table 1.3 shows recommended sampling of renal epithelial tumor specimens.

Table 1.3 Recommended sampling of renal epithelial tumor specimens

References: [10,11,12,13,14,15,16].

What Are the Typical Gross Features of Renal Tumors?

Gross examination is an important part of the pathology of renal tumors for two major reasons: (1) Staging of RCC, as discussed in question 1.2, and (2) differential diagnosis of renal neoplasms. In general, RCC tumors and other renal neoplasms are predominantly spherical, and deviation from this round shape should be viewed with caution for invasion of structures, as discussed previously. Tumors can bulge well beyond the contour of the normal kidney, markedly distorting its shape, which does not necessarily indicate invasion. Gross “necrosis” should be confirmed histologically to be coagulative tumor necrosis, as large zones of hemorrhage and fibrosis are relatively common and do not have the same prognostic implications as true necrosis. The significance of necrosis in papillary RCC is less clear, perhaps due to an increased tendency of the fragile papillary structures to undergo necrosis.

Table 1.4 shows gross features of renal neoplasms (see also Fig. 1.3).

Table 1.4 Gross features of renal neoplasms

Fig. 1.3

(a) This clear cell renal cell carcinoma is solid and cystic with a heterogeneous red-brown to golden-yellow cut surface. (b) This oncocytoma is a uniform tan-brown color with a central scar, which is classic but not specific for oncocytoma

References: [10, 14, 17,18,19,20,21,22,23,24].

What Are the Key Histologic Features for Common Renal Epithelial Tumors?

Most renal tumors can either be diagnosed based on histologic features alone, or a narrow differential diagnosis can be readily discerned based on the tumor histology.

Table 1.5 shows key histologic features of common renal epithelial tumors (see also Fig. 1.4).

Table 1.5 Key histologic features of common renal epithelial tumors

Fig. 1.4

(a) Clear cell renal cell carcinoma can have substantial areas with eosinophilic cells, shown in this case with abrupt transition from clear cells to eosinophilic cells. (b) Papillary renal cell carcinoma, type 1, is characteristically composed of papillary structures lined by basophilic cells (left) but can also have substantial clear cell changes, often caused by vacuolated cytoplasm (right). (c) Papillary renal cell carcinoma, type 2, exhibits elongated nuclei with pseudostratification and eosinophilic cytoplasm. (d) Classic chromophobe renal cell carcinoma exhibits prominent cell borders and low nuclear-cytoplasmic ratio with some cells appearing to have no nucleus (due to sectioning artifact). (e) Eosinophilic chromophobe renal cell carcinoma remains difficult to distinguish from oncocytoma. However, clues can include prominent trabecular architecture and perinuclear clearing. This case also contains cystic spaces with pigment. (f) Oncocytoma is characteristically composed of uniform eosinophilic cells with round, regular nuclei. Although large areas may appear solid, often discrete round nests are present in areas of edematous stroma. (g) Clear cell papillary renal cell carcinoma exhibits branched glandular structures with variable amounts of clear cytoplasm. Often, the nuclei appear to be aligned at the same height within the cytoplasm

References: [17, 21].

What Are the Key Features of Cystic Renal Tumors?

Most renal tumors have the potential to be at least partly cystic; however, tumors that are most commonly cystic include clear cell RCC, multilocular cystic renal neoplasm of low malignant potential (formerly multilocular cystic RCC), clear cell papillary RCC, and tubulocystic RCC. In general, a cystic component is thought to be favorable for clear cell RCC, even if the tumor does not meet the strict definition for a multilocular cystic tumor. Most tumors have a mixture of cystic and tubular architecture throughout the neoplasm; however, rarer variations that have been described include predominant central cystic necrosis or degeneration, leaving only a rim of viable neoplasm around a central cavity, and a single solid tumor growing in the wall of a cyst.

Table 1.6 shows key features of cystic renal tumors (see also Fig. 1.5).

Table 1.6 Key features of cystic renal tumors

Fig. 1.5

(a) Multilocular cystic renal neoplasm of low malignant potential is composed entirely of cysts lined by cells with clear cytoplasm. The septa can contain small clusters of tumor cells, but there should be no mass-forming solid component. (b) Clear cell papillary renal cell carcinoma can have an extensive cystic component, resembling multilocular cystic neoplasms; however, the presence of papillary structures or branched glands within the stroma favors clear cell papillary renal cell carcinoma. (c) Tubulocystic renal cell carcinoma is composed of eosinophilic, hobnail-shaped cells with prominent nucleoli lining cystic and tubular spaces. The nuclear grade is usually equivalent to ISUP/WHO grade 3

References: [4, 25,26,27,28,29,30,31].

What Are the Commonly Used Immunohistochemical Markers in Differentiating Renal Tumors?

Immunohistochemistry can be helpful in resolving differential diagnoses of renal tumors; however, it is important to take immunohistochemical (IHC) markers in the context of the histologic appearance and to know their limitations, as very few are highly specific in isolation. Predominant results are described in Table 1.7, with some notable exceptions or caveats as follows:

• Carbonic anhydrase IX is a robust marker of clear cell RCC, showing diffuse membranous staining in most cases (Fig. 1.6a). However, since carbonic anhydrase IX is part of the hypoxia pathway, many tumors and tissues can have some positivity in areas of ischemia or necrosis. In large tissue sections with abundant viable tumor cells, this typically does not account for more than focal positivity (Fig. 1.6b), but interpretation should be approached with caution for small biopsies with limited viable cells.

• Specificity of carbonic anhydrase IX is also lower in the context of unknown primary cancer, as many non-renal cancers can have positivity.

• Diffuse strong intensity for AMACR is characteristic of papillary RCC (Fig. 1.6c); however, many other tumors can have some degree of positivity. A very strong positive reaction (similar to normal proximal renal tubules) is supportive of papillary RCC but should be taken in the context of the other findings.

• In chromophobe RCC vs. oncocytoma, the classic expectation is that chromophobe will exhibit diffuse membranous cytokeratin 7 reactivity. However, this is most reliable only in tumors with classic (pale cell) features.

• In oncocytoma, a pattern of only scattered rare cells positive for cytokeratin 7 is expected (Fig. 1.6d).

• A cutoff for an amount of cytokeratin 7 positivity that warrants a diagnosis of eosinophilic chromophobe is not well agreed upon, but the amount of positivity can be much more limited than that of classic chromophobe.

• Positivity for cytokeratin 7 is most consistent in type 1 papillary RCC. In type 2 papillary RCC or tumors with eosinophilic features, reactivity for cytokeratin 7 is often focal or absent.

• TFE3 and TFEB protein immunohistochemistry may be helpful for raising suspicion for translocation-associated RCC (if strong); however, weak reactivity is less specific for gene rearrangement and often is better confirmed with molecular studies.

  References: [4, 21, 29, 32,33,34,35,36].

Table 1.7 Most widely used immunohistochemical markers for differential diagnosis of renal tumors

Fig. 1.6

(a) Clear cell renal cell carcinoma characteristically exhibits diffuse membrane positivity for carbonic anhydrase IX. (b) In contrast to clear cell cancer, other subtypes of renal cell carcinoma may exhibit focal nonspecific staining for carbonic anhydrase IX, which should not be interpreted as favoring clear cell subtype. (c) Diffuse strong staining for alpha-methylacyl-CoA racemase (AMACR) similar to that of the proximal renal tubules is supportive of papillary renal cell carcinoma in the appropriate context, although other renal cell neoplasms may exhibit some degree of positivity. (d) Oncocytoma characteristically exhibits a pattern of scattered cells positive for cytokeratin 7, usually not accounting for more than a few percent of tumor cells

What Are the Useful Molecular Tests in Diagnosis of Renal Epithelial Tumors?

Classification of renal cell neoplasms has evolved over the years based on integration of tumor histology with immunohistochemistry and genetics; however, fortunately in current practice, classification can still be achieved without using routine genetic assays, rather by relying on immunohistochemical and histologic surrogates of existing genetic knowledge. Still, several molecular techniques can be helpful in select instances, ranging from mutation analysis to copy number studies to fluorescence in situ hybridization (FISH).

Table 1.8 shows helpful molecular markers for renal tumor diagnosis (see also Fig. 1.7).

Table 1.8 Helpful molecular markers for renal tumor diagnosis

Fig. 1.7

Break-apart fluorescence in situ hybridization (FISH) for the TFEB gene in this case of TFEB rearranged renal cell carcinoma shows one normal signal result (white arrow). The other copy of the 6p21 region shows a split signal pattern (red and green signals and arrows)

References: [17, 21, 37,38,39,40,41,42,43,44,45,46,47,48,49].

Accurate Grading of Renal Cell Carcinoma in Small Tissue Biopsy and Nephrectomy Specimens

• The original Fuhrman grading system for renal cell carcinoma relied on several parameters to assign grade, including nuclear size, nuclear irregularity, and nucleolar prominence.

• Based on the difficulty of assessing multiple nuclear parameters at once, combined with data supporting nucleolar prominence as the key parameter, the 2013 ISUP Vancouver Consensus and 2016 WHO Classification recommend a modified grading system that relies primarily on the nucleolar prominence (Table 1.9, Fig. 1.8).

• The minimum number of cells showing a higher grade required to assign the higher grade overall is debatable; however, the most established method is to identify at least an entire high-power field composed of the higher grade.

• An alternate system incorporating tumor necrosis has also been proposed; however, in most practices, the nucleolar method endorsed by ISUP/WHO is now used, with presence or absence of necrosis also noted in synoptic reports.

• The nucleolar grading system is recommended for use in clear cell and papillary RCC. For other RCC subtypes, it can be used descriptively, but has not been validated as a prognostic factor.

• Chromophobe RCC has a favorable prognosis, yet often has inherent nuclear atypia. It is recommended that grading not be applied to chromophobe RCC, as it has not been shown to have definite prognostic value.

• An alternate grading system has been proposed for chromophobe RCC based predominantly on nuclear crowding (chromophobe tumor grade), although reporting this is currently not required (Table 1.10).

• Grading is approached in a similar way for core biopsy samples. Recent attention has been drawn to risk stratifying tumors in the biopsy setting based on histologic subtype of tumor and grade, such that grade 1–2 tumors of specific histologies may be more amenable to surveillance or less aggressive therapy.

  References: [1, 50,51,52,53,54,55].

Table 1.9 ISUP/WHO grading of RCC

Fig. 1.8

The main defining criterion for nuclear grade in the modified grading system is prominent nucleoli recognizable at 100x magnification (10x objective), which warrants grade 3. Prominent nucleoli recognizable only at higher magnification warrant grade 2, whereas inconspicuous nucleoli even at high magnification warrant grade 1

Table 1.10 Proposed “chromophobe tumor grade” as an alternate grading scheme for chromophobe RCC

What Are the Histologic Growth Patterns and Variants for Clear Cell RCC?

• Clear cell RCC can have a variety of patterns, especially when tumors are high-grade.

• A common pattern is that of eosinophilic cells (which likely often fell into the now defunct former category of “granular cell” RCC) (Fig. 1.9a).

• Clear cell RCC can often have cystic change (often accompanied by fibrosis and hemorrhage), with some areas mimicking multilocular cystic neoplasm of low malignant potential. Any solid component (defined as an expansile nodule that would be grossly visible, Fig. 1.9b) precludes a diagnosis of multilocular cystic neoplasm and favors clear cell RCC.

• Some clear cell RCCs have extensive degeneration and sclerosis, so that the vascular component predominates, mimicking hemangioma (Fig. 1.9c).

• Keys to recognizing an unusual RCC as clear cell RCC include: identification of classic golden-yellow/orange areas grossly (even if focal), identification of classic low-grade clear cell areas histologically (may require additional sampling), and diffuse membrane positivity for carbonic anhydrase IX.

• A list of select variants is discussed in Table 1.11.

  References: [8, 56,57,58,59,60,61,62].

Fig. 1.9

(a) Clear cell renal cell carcinoma can have a transition to granular eosinophilic cytoplasm (formerly known as granular cell renal cell carcinoma); however, identification of a classic low-grade clear cell component supports interpretation as clear cell renal cell carcinoma. (b) Some clear cell renal cell carcinomas are extensively cystic such that they mimic multilocular cystic low malignant potential tumors; however, a solid mass-forming component, as shown here, precludes a diagnosis of multilocular cystic neoplasm. Still, the behavior may be favorable, and a comment regarding extensive cystic change can be included. (c) In some cases, the epithelial component of a clear cell renal cell carcinoma is subtle or obliterated by scarring, which can mimic a hemangioma. Identification of classic clear cell areas or confirmation of epithelial tumors cells with immunohistochemistry can resolve this distinction

Table 1.11 Deceptive variants of clear cell RCC

What Are the Differential Diagnoses for Renal Epithelial Tumors with both Clear Cell and Papillary Features?

• Renal epithelial tumors with both clear cell and papillary features can include several different diagnostic entities, ranging from clear cell RCC to translocation RCC to the entity clear cell papillary (tubulopapillary) RCC.

• Key features helpful in distinguishing these entities are shown in Table 1.12 (see also Fig. 1.10).

Table 1.12 Differential diagnosis of renal epithelial tumors with clear cell and papillary features

Fig. 1.10

(a) Rarely clear cell renal cell carcinoma can exhibit papillary structures, often likely resulting from lack of cohesion in higher-grade tumors. (b) Clear cytoplasmic change can be observed in a subset of papillary renal cell carcinomas, often manifesting as numerous cytoplasmic vacuoles. (c) The entity clear cell papillary (tubulopapillary) renal cell carcinoma is composed of branched glandular structures with alignment of the nuclei at a similar height within the cytoplasm. (d) Translocation renal cell carcinomas often have mixed clear cell and eosinophilic patterns, as well as mixed nested and papillary patterns. The presence of psammoma bodies, as in this case, favors a translocation renal cell carcinoma over clear cell renal cell carcinoma. (e) Some clear cell renal cell carcinomas can have overlapping features of clear cell papillary (tubulopapillary) renal cell carcinoma. However, if the immunohistochemical phenotype is not perfect, a diagnosis of clear cell renal cell carcinoma should be used. (f) The same case as shown in 10E demonstrates areas more suggestive of typical clear cell renal cell carcinoma

References: [4, 9, 17, 47,48,49, 60,61,62,63].

Clear Cell RCC vs. Chromophobe RCC

Usually, distinction of clear cell RCC and chromophobe RCC is straightforward, based on their characteristic histologic features; however, some tumors may exhibit overlapping features that necessitate immunohistochemistry or other studies to resolve the differential diagnosis (Fig. 1.11). The behavior of chromophobe RCC is considered favorable, with few demonstrating progression or metastasis, compared to clear cell RCC, which can be less predictable, especially with larger tumor sizes.

Fig. 1.11

(a) This clear cell renal cell carcinoma demonstrates some nuclear wrinkling and prominent cell borders, raising consideration of chromophobe renal cell carcinoma. (b) The same case shows negative immunohistochemistry for KIT (CD117), arguing against chromophobe renal cell carcinoma. Other results included positive carbonic anhydrase IX and negative cytokeratin 7, further supporting this classification (not pictured)

Table 1.13 shows how to distinguish clear cell from chromophobe RCC.

Table 1.13 Distinguishing clear cell from chromophobe RCC

References: [17, 32, 57, 64].

RCC vs. Xanthogranulomatous Pyelonephritis

Xanthogranulomatous pyelonephritis is an unusual granulomatous process that may involve the kidney entirely or partially. This can variably mimic a renal neoplasm clinically, grossly, or microscopically (Fig. 1.12).

• Xanthogranulomatous pyelonephritis is associated with urinary tract infection, particularly with organisms like Escherichia coli or Proteus mirabilis, and obstruction.

• “Staghorn” calculus of the renal pelvis is also common.

• Extension of xanthogranulomatous pyelonephritis locally can mimic high-stage renal cancer, such as with involvement of the psoas muscle.

• Gross appearance of xanthogranulomatous pyelonephritis includes yellow nodules reminiscent of clear cell RCC, although often arrangement around the calyces is a clue to the infectious/inflammatory nature of this entity.

• Histologic differential diagnosis of xanthogranulomatous pyelonephritis could include sarcomatoid or poorly differentiated RCC, due to sheets of lipid-laden histiocytic cells (mimicking clear cell RCC cells), with lack of distinct glandular architecture.

• Cells of interest in xanthogranulomatous pyelonephritis are predominantly histiocytic and positive for histiocytic markers, such as CD68 or CD163.

• Cells of interest in RCC should have at least some evidence of epithelial differentiation, which with immunohistochemistry can include PAX8, keratin, or epithelial membrane antigen (EMA) positivity.

• Vimentin, although frequently positive in clear cell RCC, is also positive in xanthogranulomatous pyelonephritis and does not distinguish these entities.

• Other differential diagnostic considerations for xanthogranulomatous pyelonephritis include malakoplakia (in which Michaelis-Gutmann bodies can be found) or other nonspecific infectious/inflammatory processes.

  Ref: [65].

Fig. 1.12

The foamy histiocytes of xanthogranulomatous pyelonephritis can mimic a renal cell carcinoma microscopically

Papillary RCC vs. Papillary Adenoma

• Papillary RCC and papillary adenoma are analogous lesions, with distinction based predominantly on a few key parameters.

• In the prior WHO Classification (2004), the definition of papillary adenoma required size 5 mm or less to distinguish papillary adenoma from RCC.

• The current WHO Classification (2016) has increased the size threshold for papillary adenoma to 15 mm.

• Other requirements include lack of a fibrous pseudocapsule and low nucleolar grade (ISUP/WHO grades 1 and 2) (Fig. 1.13a, b).

• This change is based on data showing a lack of aggressive behavior from RCC tumors in general under 2.0 cm.

• Otherwise, the features of papillary adenoma are essentially identical to those of type 1 papillary RCC, including basophilic cuboidal cells, papillary or tubular architecture, and psammoma bodies or foamy macrophages.

• In view of this size threshold, it is now conceivable that papillary adenomas could be intentionally subjected to renal mass biopsy, in which case a diagnosis for a tumor up to 1.5 cm could be “papillary renal cell neoplasm” with a comment that distinction between adenoma and RCC is based on size, encapsulation, and grade, which cannot be entirely assessed in a biopsy.

  References: [66, 67].

Fig. 1.13

(a) Papillary adenomas generally resemble a grade 1–2 papillary renal cell carcinoma, but they are less than 15 mm (in the 2016 World Health Organization Classification) and lack a fibrous pseudocapsule. (b) This papillary lesion meets the size criteria for adenoma, but would in the current classification warrant designation as a small renal cell carcinoma due to fibrous pseudocapsule

Papillary Adenoma and RCC vs. Metanephric Adenoma and Wilms Tumor

• Differential diagnostic considerations for unusual patterns of papillary renal cell neoplasms include metanephric adenoma and Wilms tumor (nephroblastoma).

• In contrast to papillary neoplasms, metanephric adenomas typically have highly monotonous cells with very small, bland nuclei (Fig. 1.14).

• Conversely, Wilms tumor (nephroblastoma) exhibits prominent atypia and mitotic activity, especially in the blastemal component, and often will have more than one of the characteristic patterns of blastema, tubules, and stroma.

• Studies for chromosomes 7, 17, and Y can be used, as trisomy 7/17 and loss of Y appear largely specific to papillary RCC in this context and typically lacking in metanephric adenoma and Wilms tumor.

• Metanephric adenomas are often BRAF mutant and many label for mutant BRAF protein with immunohistochemistry.

Fig. 1.14

Metanephric adenomas may closely resemble papillary renal cell carcinomas in several ways; however, they are notable for their highly monotonous small, bland nuclei forming tight tubular structures or papillae (not pictured)

Table 1.14 shows features distinguishing papillary renal cell neoplasms from metanephric adenoma and nephroblastoma.

Table 1.14 Features distinguishing papillary renal cell neoplasms from metanephric adenoma and nephroblastoma

References: [68,69,70].

Type 1 Papillary RCC vs. Type 2 Papillary RCC

Type 1 and type 2 papillary RCC have been distinguished for many years, based on more aggressive behavior in the latter; however, some recent increased understanding of these two morphological types has challenged the thinking about some cases, particularly the subset of type 2 tumors that are now considered a distinct entity, fumarate hydratase (FH)-deficient RCC/HLRCC syndrome.

Table 1.15 shows a comparison of type 1 vs. type 2 papillary RCC and HLRCC syndrome/FH-deficient RCC (see also Fig. 1.15).

Table 1.15 Comparison of type 1 vs. type 2 papillary RCC and HLRCC syndrome/FH-deficient RCC

Fig. 1.15

(a) Type 1 papillary renal cell carcinomas are characteristically composed of cuboidal basophilic cells, often associated with foamy macrophages or psammoma bodies. (b) Type 2 papillary renal cell carcinomas contain eosinophilic cells with elongated pseudostratified nuclei. (c) A renal cell neoplasm with mixed histologic patterns (papillary, tubulocystic, collecting duct-like) and prominent nucleoli should raise concern for the possibility of hereditary leiomyomatosis and renal cell carcinoma syndrome/FH-deficient renal cell carcinoma

References: [6, 17, 71,72,73].

Papillary RCC vs. Mucinous Tubular and Spindle Cell Carcinoma

Mucinous tubular and spindle cell carcinoma is an unusual renal cell neoplasm composed of tubular structures resembling those of papillary RCC, mixed with areas of spindle-shaped cells (likely representing unusual compressed epithelial structures), and extracellular mucinous material. Papillary RCC and mucinous tubular and spindle cell carcinoma share several overlapping features, such that it has been speculated whether the latter is a variant of the same entity. Nonetheless, enough differences, including a distinct copy number profile, have been recognized such that mucinous tubular and spindle cell carcinoma is recognized as a distinct entity in the WHO Classification. Distinct features are summarized in Table 1.16 (see also Fig. 1.16).

Table 1.16 Comparison of papillary RCC and mucinous tubular and spindle cell carcinoma

Fig. 1.16

(a) Mucinous tubular and spindle cell carcinoma is composed of cuboidal glandular cells, similar to those of papillary renal cell carcinoma, with associated basophilic mucinous material. (b) Mucinous tubular and spindle cell carcinoma also contains areas of compact spindle-shaped cells, which despite their mesenchymal appearance are likely of epithelial origin (same case)

References: [74,75,76,77,78,79,80].

Papillary RCC vs. Papillary Urothelial Carcinoma

Papillary RCC and urothelial carcinoma are usually readily distinguished, due to their different clinical presentations (involvement of the renal pelvis with or without extension into the kidney vs. renal parenchymal spherical tumor with rare extension into renal pelvis) and different histologic features. However, rare cases can be challenging, such as for papillary RCCs that extend into the calyceal system (Fig. 1.17) or high-grade sarcomatoid tumors that overgrow the kidney. Features that may be helpful in such cases are summarized in Table 1.17.

Fig. 1.17

This papillary renal cell carcinoma extended into the renal pelvis and was originally diagnosed by a ureteroscopic biopsy, clinically mimicking urothelial carcinoma. Renal pelvis mucosa is evident at far right

Table 1.17 Features distinguishing papillary RCC from urothelial carcinoma

References: [8, 34, 81].

Chromophobe RCC vs. Oncocytoma

Despite being recognized as distinct tumors for decades, chromophobe RCC vs. oncocytoma continues to be a challenge for urologic pathologists, even today, owing to a lack of robust discriminatory markers. It remains incompletely understood whether these are two entirely unrelated entities that sometimes mimic each other, or if they exist as parts of a spectrum. Numerous histochemical and immunohistochemical markers have been explored over the years; however, only a few are widely used, with the most prevalent being cytokeratin 7. Helpful features are summarized in Table 1.18 (see also Fig. 1.18). Classic chromophobe RCC with pale cells rarely presents a diagnostic challenge with oncocytoma, and so this discussion focuses on eosinophilic chromophobe.

Table 1.18 Features distinguishing oncocytoma from chromophobe RCC with eosinophilic features

Fig. 1.18

(a) Oncocytoma can contain occasional atypical cells, generally considered to represent degenerative atypia. (b) The expected staining pattern of cytokeratin 7 in oncocytoma is labeling of scattered individual cells. (c) Eosinophilic chromophobe can mimic the cytology of oncocytoma, but extensive trabecular growth is a clue to the diagnosis. (d) Eosinophilic chromophobe may not necessarily exhibit diffuse cytokeratin 7, as expected of classic cases. However, patch-like contiguous areas of staining, as shown here, would be an argument against oncocytoma

References: [20, 21, 23, 32, 36, 57, 64, 82,83,84,85].

Collecting Duct Carcinoma vs. Mimics

With increased understanding of the pathology and genetics of renal cancer, collecting duct carcinoma has become essentially a diagnosis of exclusion, after several other entities are excluded. These tumors are highly aggressive renal malignancies, often necessitating aggressive therapy more akin to that of urothelial carcinoma than renal cell carcinoma. Features distinguishing this group of closely related entities are summarized in Table 1.19.

• All of the mimics of collecting duct carcinoma can have similar histologic features, including: infiltrating glands or cords/sheets/nests, papillary or tubular-papillary structures, or cribriform structures.

• Recently, disruption of INI-1 (SMARCB1 product) has been recognized in renal medullary carcinoma (Fig. 1.19a). Although medullary carcinoma occurs essentially by definition in the setting of sickle cell trait, an emerging subgroup of tumors with INI-1 loss in the absence of sickle trait has been described, under the proposed name “RCC unclassified with medullary phenotype.”

• Metastases to the kidney can mimic primary tumors, including solitary masses mimicking a primary tumor many years after original diagnosis.

• Most common metastases to the kidney include those of: lung (Fig. 1.19b), breast, gynecologic, colorectal, and head and neck primary origins.

  References: [6, 7, 72, 73, 86,87,88,89,90,91,92].

Table 1.19 Collecting duct carcinoma vs. mimics

Fig. 1.19

(a) Histologic features of renal medullary carcinoma (pictured), collecting duct carcinoma, fumarate hydratase-deficient carcinoma, and urothelial carcinoma can overlap significantly, such that the clinical scenario and special studies are routinely needed. This example is a medullary carcinoma in a 16-year-old boy with sickle trait. (b) Metastases to the kidney can mimic primary neoplasms. This is a metastatic adenocarcinoma of lung origin involving the kidney in a renal mass biopsy

Diagnostic Criteria for Sarcomatoid RCC and Clinical Significance

• The presence of sarcomatoid (sarcoma-like) histology is associated with a poor prognosis in cancers arising from various organs, and renal cell carcinoma with sarcomatoid differentiation represents the most aggressive, treatment-resistant group of renal tumors.

• RCC with sarcomatoid features is not currently recognized as a specific type of RCC mainly because sarcomatoid areas can be observed in all histologic subtypes of RCC. If no underlying RCC subtype is detected, then a tumor with pure sarcomatoid differentiation falls into the category of unclassified RCC and should be distinguished from sarcoma.

• The presence of sarcomatoid features is an independent predictor of poor survival and by many studies considered the most influential prognostic variable for patient outcome.

• Several studies have looked at the effect of the percentage of sarcomatoid differentiation on prognosis and demonstrated that greater amounts were associated with a worse outcome, however there is no agreed upon cut-point for risk stratification at this time. Therefore, any amount of sarcomatoid morphology and underlying RCC subtype should be reported.

• Recognition and reporting of sarcomatoid change in RCC is also required due to potential treatment implication (i.e., using more aggressive systemic therapy, targeted therapy after molecular profiling, including or excluding patients from experimental clinical trials).

• Sarcomatoid RCC is often considered and managed as a single clinical entity, regardless of the underlying parent RCC subtype with which it is associated. However, recent molecular studies have shown that sarcomatoid RCC is a heterogeneous disease requiring precise molecular classification to improve diagnosis, prognosis, and therapeutic management.

• Detailed characteristics of RCC with sarcomatoid features are listed in Table 1.20 (see also Fig. 1.20).

  References: [50, 93,94,95,96].

Table 1.20 Detailed diagnostic criteria of sarcomatoid RCC

Fig. 1.20

Gross image of clear cell renal cell carcinoma with extensive sarcomatoid dedifferentiation showing heterogeneous fleshy grayish cut surface and areas of geographic necrosis

How to Distinguish Sarcomatoid RCC from a Sarcoma?

Sarcomatoid dedifferentiation can be found in association with any of main subtypes of renal cell carcinoma (RCC). Sarcomatoid dedifferentiation is not very common (<5% of all RCC), but its prevalence is ten times higher than of primary kidney sarcoma.

• Although sarcomatoid RCCs resemble classic sarcomas, it is very important to distinguish them since the prognosis and treatment for both tumors are different.

• Grossly sarcomatoid RCC is centered in the kidney parenchyma, while a sarcoma is often developed from the renal capsule or soft tissue adjacent to the kidney.

• Sarcomatoid RCC can be derived from either low-grade (30%) or high-grade RCC (70%). Therefore, sarcomatoid RCC is typically composed of a low-grade or high-grade RCC component and a high-grade spindle cell sarcomatoid component (Fig. 1.21a–d).

• Sarcomatoid RCC is typically composed of multiple heterogeneous nodules in a large mass greater than 10 cm. Sufficient sampling from different tumor nodules is necessary to identify the lower-grade RCC component.

• Sarcomatoid RCC is usually positive for pan-cytokeratins and PAX8 (at least focally), whereas other markers of RCC subtypes may be negative.

• The comparison between sarcomatoid RCC and sarcoma is listed in Table 1.21.

  References: [93,94,95, 97, 98].

Fig. 1.21

(a) Clear cell renal cell carcinoma (left) with abrupt transition to area of sarcomatoid dedifferentiation (right). (b) Immunostaining with carbonic anhydrase IX shows strong expression in low-grade clear cell renal cell carcinoma area (left) and only focal scattered positivity within sarcomatoid area (right). (c) Microscopic image of sarcomatoid carcinoma arising in a background of chromophobe renal cell carcinoma (100×). (d) Higher magnification of sarcomatoid carcinoma surrounding area of low-grade classic chromophobe RCC with plant-like membranous accentuation, raisinoid nuclei, perinuclear halos, and cohesive solid growth pattern (200×)

Table 1.21 Sarcomatoid RCC vs. sarcoma

Sarcomatoid RCC vs. Sarcomatoid Urothelial Carcinoma

• Sarcomatoid carcinomas are highly aggressive tumors that demonstrate biphasic epithelial carcinomatous and mesenchymal sarcoma-like differentiation. The mesenchymal or sarcomatoid component of these tumors consists of either undifferentiated spindle cells or elements showing heterologous differentiation.

• Sarcomatoid carcinomas arise from almost any organ system with an epithelial component, including the kidney and urinary tract, and often have overlapping morphology. Distinction between sarcomatoid RCC and sarcomatoid urothelial carcinoma is very important due to different prognosis and patient management (see Table 1.22 and Fig. 1.22).

  References: [8, 50, 93, 99,100,101].

Table 1.22 Sarcomatoid RCC vs. sarcomatoid urothelial carcinoma (UC)

Fig. 1.22

(a) Small focus of low-grade urothelial carcinoma embedded into the sarcomatoid carcinoma. (b) High-grade urothelial carcinoma transitioning to sarcomatoid area

What Are the Histological Variants of Angiomyolipoma?

• Renal angiomyolipoma (AML) is a mesenchymal tumor composed of three main components in variable proportions: (1) angio—abnormal vasculature, (2) myo—smooth muscle cells, and (3) lipoma—mature adipocytes. Renal AML is believed to originate from pluripotent perivascular epithelioid cells (PEC) and also called PECOMA.

• The vast majority of renal AML are benign indolent tumors, although large tumors have tendency to massive retroperitoneal bleeding, and AML with epithelioid atypical features could show aggressive behavior. Multifocal and bilateral AMLs are often associated with tuberous sclerosis and genetic alterations in tuberous sclerosis genes TSC1 (hamartin, 9q34) and TSC2 (tuberin, 16p13.3). All renal AMLs are typically positive for smooth muscle markers actin and caldesmon, as well as melanocytic markers Melan-A (MART-1), HMB-45, MITF, tyrosinase, and cathepsin-K. Renal AMLs are negative for PAX8 and epithelial markers (EMA and cytokeratins) (Fig. 1.23a–f).

• Histological variants of renal AML in decreasing frequency are as follows: typical triphasic AML, predominantly leiomyomatous (fat-poor), lymphangiomyomatous AML, predominantly lipomatous (fat-rich), epithelioid AML, AML with epithelial cysts (AMLEC), oncocytoma-like AML, sclerosing AML, microscopic hamartomatous AML.

Fig. 1.23

(a) Perivascular epithelioid cells (PEC) surrounding abnormal vessel in PECOMA. (b) Strong reactivity with Melan-A in perivascular epithelioid cells. (c) Smooth muscle actin exhibiting bright labeling of abnormal vessel and spinning out perivascular epithelioid cells of PECOMA. (d) Classic morphology of triphasic angiomyolipoma (AML) with clusters of dysmorphic hyalinized vessels, spindled smooth muscle cells, and adipocytes. (e) Triphasic AML demonstrating scattered HMB45 positivity. (f) Triphasic AML exhibiting strong expression of Melan-A

Table 1.23 provides description of all histologic variants of AML and differential diagnoses for each of them.

Table 1.23 Variants of angiomyolipoma (AML)

References: [102,103,104,105,106].

Renal Angiomyolipoma vs. Medullary Fibroma

• Both renal angiomyolipoma (AML) and medullary fibroma (also known as renomedullary interstitial cell tumor) represent relatively common mesenchymal neoplasia with overlapping morphology in some cases.

• Monophasic, sclerosing, and microhamartomatous variants of AML are more likely to have similar to medullary fibroma presentation (Fig. 1.24a, b).

• The overwhelming majority of renal AML and medullary fibroma with overlapping morphology are incidental small tumors with benign biological behavior.

• Distinction of renal AML from medullary fibroma is most important in case of multifocal and bilateral tumors due to association with tuberous sclerosis complex.

• The comparison between renal AML and medullary fibroma is listed in Table 1.24.

Fig. 1.24

(a) Monophasic AML composed of spindled leiomyomatous cells with vascular clefts, abnormal thickened vessels with hyalinization and fibrosis at the periphery. These tumors frequently arise in the kidney capsule (hence the name “capsuloma”). (b) Renomedullary fibroma composed of spindled and stellate cells embedded into the myxoid or sclerotic stroma with abundant but normal vessels

Table 1.24 Renal angiomyolipoma (AML) vs. medullary fibroma

References: [103, 106,107,108,109].

Renal Angiomyolipoma vs. Mixed Epithelial and Stromal Tumor

• Mixed solid mesenchymal and cystic epithelial components could be seen in two unrelated renal tumors: angiomyolipoma with epithelial cysts (AMLEC) and mixed epithelial and stromal tumor (MEST). Despite striking radiologic, morphologic, and even some immunophenotypic overlap between these two neoplasms, their distinction could be made based on our understanding of etiology, pathogenesis, and molecular differences.

• AMLEC represents a very rare variant of fat-poor angiomyolipoma with characteristic combination of dysplastic vessels and plump epithelioid smooth muscle cells, plus cystically dilated epithelial tubules with cuboidal to hobnail lining and underlying compact “cambium-like” Mullerian-like stroma. Like any other angiomyolipoma, AMLEC shows prototypical co-expression of melanocytic and smooth muscle markers within the solid mesenchymal component (Fig. 1.25a, b).

• MEST is another rare biphasic tumor that typically occurs in perimenopausal women and consists of variably sized cysts and glands separated by more or less abundant stroma. Epithelial cells could be cuboidal, hobnailed, columnar, endometrioid, or intestinal type with eosinophilic, amphophilic, or vacuolated cytoplasm. Stroma ranges from scant hypocellular and fibrotic septa (adult cystic nephroma) to markedly cellular, condensed, edematous, and ovarian-like in classic MEST (Fig. 1.25c, d).

• Both AMLEC and MEST stromal component is positive for smooth muscle markers (actin, desmin, caldesmon), estrogen receptor (ER), progesterone receptor (PR), and CD10 highlighting condensed subepithelial Mullerian-like stroma underlying epithelial cysts.

• The detailed comparison focusing on differentiating features between AMLEC and MEST is listed in Table 1.25.

  References: [104, 110,111,112,113,114].

Fig. 1.25

(a) Angiomyolipoma with epithelial cysts (AMLEC) consists of solid areas with spindled smooth muscle cells and dysplastic vessels and cystically dilated epithelial cysts (40×). (b) Immunohistochemical expression of melanocytic marker HMB45 in AMLEC. (c) Mixed epithelial and stromal tumor (MEST) with variably sized cysts and solid component composed of tubules surrounded by spindle cells reminiscent of ovarian-type stroma (40×). (d) Mullerian-like stroma of MEST if highlighted by strong diffuse expression of estrogen receptor (ER)

Table 1.25 Renal AMLEC vs. MEST differentiating features

Epithelioid Angiomyolipoma vs. RCC

• Typically, angiomyolipoma (AML) is composed of three components: abnormal vessels, mature adipocytes, and spindle cells with muscle and melanocytic differentiation. Although it may have focal degenerative atypia within the spindle cell component, it is not a difficult diagnosis. However, epithelioid variant of AML may post diagnostic challenges due to marked pleomorphism, multinucleation, and prominent carcinoma-like appearance reminiscent of various types of high-grade renal cell carcinomas (Fig. 1.26a–d). Moreover, epithelioid AML may develop metastasis or recurrence and is, therefore, considered potentially malignant neoplasm in contrast to other variants of AML.

• According to the current WHO classification, only those AMLs consisting of at least 80% epithelioid components are considered as epithelioid AMLs. The main differential diagnosis is a high-grade RCC with prominent oncocytic change and/or rhabdoid dedifferentiation.

Fig. 1.26

(a) Epithelioid AML with “carcinoma-like” growth pattern imitating clear cell RCC. (b) Epithelioid AML mimicking clear cell RCC with pleomorphism and multinucleation. (c) Epithelioid AML with discohesive high-grade morphology and rhabdoid cells. (d) Epithelioid AML featuring perivascular growth pattern characteristic for PECOMAs

Table 1.26 shows epithelioid angiomyolipoma (eAML) vs. high-grade RCC.

Table 1.26 Epithelioid angiomyolipoma (eAML) vs. high-grade RCC

References: [17, 102, 115,116,117,118].

What Are Histologic Features Predicting a Malignant Angiomyolipoma?

• Epithelioid variant of angiomyolipoma (AML) constitutes ~5% of all resected AMLs and is characterized by predominantly carcinoma-like epithelioid architecture composing more than 80% of tumor volume.

• Etiology, pathogenesis, and epidemiology of epithelioid AML are similar to other AML variants; however, its morphology and biological behavior are drastically different.

• Five to sixty percent of patients with epithelioid AML develop distant metastases, have recurrence, or suffer death from disease, depending on the study. Although prognostic factors of malignant epithelioid AML are largely undetermined, several histological features have been linked to increased risk of aggressive behavior of this tumor and are summarized in Table 1.27.

• The majority of published series agree that presence of three of more of such adverse parameters as large tumor size (>7 cm), necrosis, atypical mitoses, severe atypia, perinephric fat, or renal vein invasion significantly increases the risk of malignant behavior (Fig. 1.27a–c).

  References: [115, 117, 119,120,121,122,123,124,125].

Table 1.27 Histologic features of primary epithelioid AML differentiating patients with and without tumor progression

Fig. 1.27

(a) Epithelioid AML with severe atypia in >70% cells arising in the background of monophasic leiomyomatous AML. (b) Liver metastasis of high-grade neoplasm with marked pleomorphism and atypia mimicking clear cell renal cell carcinoma. (c) Diffuse strong expression of Melan-A supports the diagnosis of metastatic epithelioid AML

Renal Angiomyolipoma vs. Sarcoma

• Renal angiomyolipoma (AML) is a mesenchymal tumor that classically exhibits triphasic morphology including abnormal vasculature (angio), smooth muscle cells (myo), and adipose tissue (lipoma). All three components are derived from pluripotent perivascular epithelioid cells (PEC) expressing melanocytic markers, thus renal AML is also known as PECOMA.

• Approximately 13% of renal AML have predominantly leiomyomatous (fat-poor) and 5% have predominantly lipomatous (fat-rich) morphology resembling well-differentiated leiomyosarcoma (Fig. 1.28) or liposarcoma, respectively. Their comparisons are presented in Tables 1.28a and 1.28b.

  References: [97, 103, 126,127,128].

Fig. 1.28

(a) Lipomatous AML comprised of large sheets of variably sized fat cells closely resembling atypical lipomatous tumor/well-differentiated liposarcoma. (b) Well-differentiated liposarcoma composed of rather mature-looking fat cells with minimal atypia. (c) Examination of the same case at higher power allows identification of fibrotic areas with enlarged hyperchromatic cells and lipoblasts. (d) Immunohistochemical staining shows strong nuclear reactivity with MDM2 further supported by MDM2 gene amplification by in situ hybridization in this case of well-differentiated liposarcoma

Table 1.28a Comparison of fat-poor AML and leiomyosarcoma

Table 1.28b Comparison of fat-rich AML and well-differentiated liposarcoma

Clinical Significance of Distinguishing Renal Cell Carcinoma from Urothelial Carcinoma of the Renal Pelvis

• Urothelial carcinoma of the renal pelvis (UCRP) develops from the renal pelvic urothelium. In general, UCRP is more aggressive than bladder urothelial carcinoma. In addition, there is a great risk of involving lower urinary tract because of tumor seeding. Therefore, UCRP will be treated more aggressively than either bladder urothelial carcinoma or RCC.

• Invasive and noninvasive UCRP are typically subject to more extensive surgical procedure, which includes radical nephrectomy, ureterectomy, and resection of portion of bladder (bladder cuff) (Fig. 1.29a). Since RCC is not a urothelial disease, it only requires a partial or radical nephrectomy without ureterectomy (Fig. 1.29b).

• If RCC is misdiagnosed as UCRP, the patient would undergo an unnecessary extensive resection including a ureter and portion of bladder. On the other hand, if UCRP is misdiagnosed as RCC, partial or radical nephrectomy alone is not sufficient for its treatment.

• Furthermore, the medical oncologists will use regimens such as gemcitabine or cisplatin-based neoadjuvant chemotherapy for UCRP patients, which are significantly different from treatment for RCC patients such as tyrosine kinase inhibitors (sorafenib, sunitinib), mTOR pathway inhibitors (i.e., everolimus), immune therapy with IL2, specific monoclonal antibodies (bevacizumab against VEGF), or PD1/PD-L1 inhibitors.

• Important clinical features allowing distinction of UCRP from RCC are listed in Table 1.29.

Fig. 1.29

(a) Gross photo of radical nephrectomy and ureterectomy performed for resection of urothelial carcinoma of the renal pelvis. (b) Gross photo of radical nephrectomy specimen performed for renal cell carcinoma, papillary type

Table 1.29 Clinically significant differences between UCRP and RCC

References: [17, 129,130,131,132,133].

How to Distinguish Urothelial Carcinoma of the Renal Pelvis (UCRP) from RCC by Histopathology and Immunohistochemistry?

• Both UCRP and RCC can have similar clinical presentation mimicking each other. Due to significant differences in surgical and oncologic treatments for these two cancers, it is very important to distinguish UCRP from RCC on pathology diagnosis.

• With limited material from needle core biopsy or fine needle aspirate, it can be difficult to differentiate UCRP from RCC. Moreover, intraoperative frozen section diagnosis to distinguish UCRP from RCC is not accurate and should be avoided if possible. In such a situation, immunohistochemistry can be particularly useful.

• UCRP will be positive for GATA3, S100P, Uroplakin II/III, high molecular weight cytokeratins (HMWCK), p63, and CK7/CK20. RCC will be positive for PAX8, CD10, RCC, vimentin, and other subtype specific markers (i.e., CAIX for clear cell RCC, AMACR and CK7 for papillary RCC, CD117 and CK7 for chromophobe RCC). However, it should be noted that approximately 18% of UCRP may be positive for PAX8, and a small percentage of RCC could express GATA3. Therefore, utilization of immunohistochemical panels is beneficial in difficult cases. The differential immunohistochemical profiles of these two morphologically overlapping tumors are summarized in Table 1.30 and Fig. 1.30.

Table 1.30 Distinction of UCRP from RCC by pathology and immunohistochemistry

Fig. 1.30

(a) This medulla-centered tumor was composed of variably sized tumor nests infiltrating between benign kidney tubules and filling collecting ducts thus closely resembling urothelial carcinoma. (b) Strong expression of cytokeratin 7 in this case favors the following differentiation diagnosis: urothelial carcinoma vs. collecting duct carcinoma vs. papillary renal cell carcinoma. (c) Negative GATA3 expression in this case in inconsistent with urothelial origin. (d) Diffuse and strong expression of AMACR/P504 antibody supports papillary RCC diagnosis

References: [17, 129, 130, 134,135,136].

Differential Diagnosis of Small Round Blue Cell Tumors

• “Small round blue cell tumor” (SRBCT) is a descriptive term referring to a large heterogeneous group of highly aggressive neoplasms, composed exclusively/predominantly of undifferentiated, small-sized cells with scant cytoplasm and round hyperchromatic nuclei. Due to their relative rarity in kidneys, similar morphology, and often overlapping immunohistochemical profiles, these tumors may be problematic to diagnose and classify. Moreover, the increasing use of small biopsies in daily practice makes correct diagnosis of these neoplasms even more challenging.

• The main differential diagnoses for SRBCT in pediatric population include Wilms tumor (nephroblastoma), neuroblastoma, clear cell sarcoma of the kidney (CCSK), and desmoplastic small round cell tumor (DSRCT), which are compared in Table 1.31a.

• The main differential diagnoses of SRBCT in adult patients include Ewing sarcoma/primitive neuroectodermal tumor (Ewing/PNET), small cell carcinoma (SmCC), lymphoma, and monophasic synovial sarcoma (SS), which are compared in Table 1.31b and Fig. 1.31a–c.

  References: [137,138,139,140,141,142,143,144,145,146,147].

Table 1.31a Differential diagnosis of pediatric SRBCT

Table 1.31b Differential diagnosis of adult SRBCT

Fig. 1.31

(a) Primitive neuroectodermal tumor (PNET) of the kidney. (b) Small cell carcinoma with cell molding, lack of nucleoli, and abundant apoptotic debris. (c) Diffuse large B-cell lymphoma infiltrating between tubules and glomeruli

Wilms Tumor vs. Neuroblastoma

• Wilms tumor (nephroblastoma) and neuroblastoma (peripheral neuroblastic tumor) are among the most common childhood malignancies. Both tumors affect the same age group of patients often with similar clinical presentation and morphological features of undifferentiated small blue cells phenotype making their differential diagnosis challenging, especially on small biopsies. This is particularly true in case of blastemal predominant Wilms tumor and undifferentiated neuroblastoma, which are considered high-risk malignancies and require more aggressive treatment (Fig. 1.32a, b).

• Table 1.32 highlights significant differences in epidemiology, presentation, pathology, molecular findings, and ancillary studies of these tumors.

  References: [148,149,150,151,152,153].

Fig. 1.32

(a) Wilms tumor (nephroblastoma) of predominantly blastemal morphology showing sheets of slightly spindled small blue cells. (b) Neuroblastoma with geographic necrosis and sheets of undifferentiated small blue cells

Table 1.32 Differential diagnosis of nephroblastoma (Wilms tumor) and neuroblastoma

Wilms Tumor vs. Clear Cell Sarcoma

• Both Wilms tumor and clear cell sarcoma of the kidney (CCSK) arise in pediatric patients with peak incidence at 2–3 years, similar presentation, and overlapping morphology.

• In the National Wilms Tumor Study Group (NWTSG), CCSK is listed as a renal tumor with “unfavorable histology.” Historically, CCSK was considered “Bone-metastasizing Wilms tumor,” although this term is outdated since CCSK and Wilms tumor are unrelated.

• CCSK classically has three components: (1) small round-to-oval streaming (cord) cells with bland cytology and cytoplasmic clearing, (2) branching chicken-wire vessels forming fibrovascular septa (hallmark feature), and (3) intercellular mucoid matrix. Depending on cellularity and matrix prominence, CCSK could mimic either predominantly blastemal (more cellular) or predominantly stromal (less cellular) monophasic Wilms tumor (Fig. 1.33a, b).

• Table 1.33 highlights distinctive features of these two tumors.

  References: [142, 147, 154,155,156].

Fig. 1.33

(a) Clear cell sarcoma of the kidney composed of spindled clear cells embedded into intercellular mucoid matrix with chicken-wire vascular network and few entrapped tubules. (b) Wilms tumor of predominantly blastemal type composed of sheets of spindled hyperchromatic cells with scant cytoplasm and coarse chromatin and few epithelial-like tubules

Table 1.33 Differential diagnosis of Wilms tumor and clear cell sarcoma

Wilms Tumor vs. Rhabdoid Tumor

• Renal malignancies are quite common in children and a leader among them is Wilms tumor (nephroblastoma), representing ~85% of all diagnoses. Fortunately, Wilms tumor also has the best prognosis with overall survival exceeding 90%. Despite advances in treatment achieved with Wilms tumor, other pediatric renal tumors still have overall survival less than 70%. The most aggressive of all pediatric tumors is rhabdoid tumor with overall survival of 15–30%.

• Rhabdoid tumor was initially classified as a possible rhabdomyosarcomatoid variant of Wilms and historically included in the treatment protocols of the National Wilms Tumor Study (NWTS) Group. Absence of muscular differentiation coined the term rhabdoid tumor of the kidney (RTK), which is now recognized as a distinct tumor type of uncertain origin.

• RTK and Wilms tumor could share similar radiologic and morphologic features, especially with blastemal and anaplastic variant. In contrast to Wilms, RTK is characterized by an early onset of local and distant metastases (stage IV), and resistance to chemotherapy.

• Classic RTK exhibit cytological triad of vesicular chromatin, prominent cherry-red nucleoli, and hyaline pink cytoplasmic inclusions. However, many rhabdoid tumors lack characteristic cytologic triad and have the appearance of undifferentiated polyphenotypic tumor (Fig. 1.34a, b).

• A key to the RTK diagnosis is negative immunostaining for SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily B, member 1 INI1.

• In Table 1.34, we outline the most important distinctive features of RTK vs. Wilms tumor, which should raise concern of this aggressive tumor and prompt diagnostic immunostaining.

  References: [142, 154, 157,158,159,160,161].

Fig. 1.34

(a) Rhabdoid tumor of the kidney composed of nests of undifferentiated cells with irregular nuclei and vesicular chromatin. (b) Wilms tumor of blastemal type with anaplastic features composed of pleomorphic cells with coarse chromatin and scant cytoplasm

Table 1.34 Differential diagnosis of nephroblastoma (Wilms tumor) and rhabdoid tumor

Cystic Partially Differentiated Nephroblastoma vs. Pediatric Cystic Nephroma

• Unilateral multilocular cystic tumors in pediatric patients are represented by two different entities: cystic partially differentiated nephroblastoma and pediatric cystic nephroma. Both tumors affect young children, and have similar clinical presentation and undistinguishable radiologic and gross features causing significant diagnostic and therapeutic challenge. Definitive discrimination of these two entities should be based on detailed histologic assessment after rigorous tumor sampling.

• Cystic partially differentiated nephroblastoma (CPDN) is an indolent variant of Wilms tumor with pure multilocular architecture lacking discernible expansile nodules. Thin fibrovascular septa contain immature blastemal or differentiating epithelial elements that are not distorting septal contours or form expansile nodular areas (Fig. 1.35a, b). Due to low tumor burden, CPDN is characterized by indolent behavior with only two reported recurrences after incomplete resection or tumor spillage.

• Pediatric cystic nephroma (PCN) is a benign pediatric neoplasm composed of multilocular cysts with flattened, cuboidal, or hobnailed epithelium and fibrous septa with entrapped well-differentiated tubules lacking immature nephroblastic elements.

• PCN and CPDN have been regarded as part of the spectrum of Wilms tumor for a long time. However, recent molecular studies showed that DICER1 mutations are the major genetic event in the development of PCN, which could be rarely detected in conventional Wilms tumors (0.4% cases), but not in CPDN.

• DICER1 is mapped to chromosome 14q and function as a haplo-insufficient tumor suppressor gene. DICER1 gene loss of function and hotspot missense mutations were seen respectively in 70% and 90% of PCN cases. Approximately, 30% of PCN cases arise in a syndromic setting with germline-inactivating DICER1 mutations. These patients also develop more aggressive tumors including malignant pleuropulmonary blastoma (PPB), ovarian Sertoli–Leydig cell tumor, and urogenital embryonal rhabdomyosarcomas. Therefore, accurate diagnosis of PCN is crucial and should prompt further testing for DICER1 mutations.

• Detailed differential diagnosis between CPDN and PCN is summarized in Table 1.35.

  References: [162,163,164,165,166,167,168,169,170].

Fig. 1.35

Cystic partially differentiated nephroblastoma (CPDN) is characterized by multilocular architecture lacking expansile solid nodules (a) with fibrovascular septa containing immature nephroblastic elements (b)

Table 1.35 Differential diagnosis of cystic partially differentiated nephroblastoma vs. pediatric cystic nephroma

Rhabdoid Tumor vs. Rhabdomyosarcoma

• Malignant rhabdoid tumor of the kidney is a highly aggressive neoplasm that occasionally demonstrates phenotypic overlap with other soft tissue malignancies. This tumor was recognized as a distinct type in 1978 and characterized by large polygonal cells with eosinophilic cytoplasmic inclusions and eccentric nuclei suggestive of rhabdomyoblastic differentiation. However, ultrastructural examination revealed the filamentous nature of the cytoplasmic inclusions. Because of its striking microscopic resemblance to rhabdomyosarcoma but lack of acceptable rhabdomyoblastic features, this tumor was termed malignant rhabdoid tumor of the kidney (RTK) in 1981. Follow-up immunohistochemical studies also showed no expression of true myogenic markers in RTK.

• Pediatric rhabdomyosarcomas with exclusive/predominant solid growth pattern may be morphologically confused with RTK (Fig. 1.36). Both tumors are characterized by a frequent metastatic spread and poor prognosis, but their accurate distinction has important prognostic and treatment implications.

• The hallmark molecular feature of RTK is in biallelic inactivation of tumor suppressor gene hSNF5/INI1/SMARCB1 from SWI/SNF chromatin remodeling complex. Resulting loss of INI1 protein nuclear expression is a key immunohistochemical finding.

• The most important distinctive features of rhabdoid tumor vs. rhabdomyosarcoma are summarized in Table 1.36.

  References: [142, 158, 161, 171,172,173,174].

Fig. 1.36

(a) Malignant rhabdoid tumor (RTK) of the kidney with sheet-like architecture comprised of loosely cohesive ovoid-to-polygonal cells surrounded by a network of fibrovascular septa. (b) Embryonal rhabdomyosarcoma case with very similar to RTK morphology of highly cellular tumor with sheets of monotonous loosely cohesive cells. (c) The same tumor at higher magnification composed of spindle, ovoid, and polygonal eosinophilic cells representing rhabdomyoblasts at different stages of differentiation

Table 1.36 Differential diagnosis of rhabdoid tumor vs. rhabdomyosarcoma

Mesoblastic Nephroma vs. Wilms Tumor

• Congenital mesoblastic nephroma (CMN) is a mesenchymal renal tumor that was distinguished from Wilms tumor in 1967. CMN is the most frequent renal tumor in the neonates and infants comprising 3–10% of all childhood renal tumors (Fig. 1.37a, b). Three pathological variants of CMN are described: classic CMN (~25%), the more aggressive cellular CMN (~65%), and the mixed variant (~10%). Classic CMN has a good overall prognosis, but cellular CMN is associated with the potential for malignancy, and is capable of recurrence and metastasis. However, surgical resection with nephrectomy is considered an adequate therapy for all subtypes, provided that a complete resection is achieved.

• A differential diagnosis between CMN and Wilms tumor is critical to develop the most effective therapeutic approach. The examination of clinical symptoms, imaging characteristics, and histologic features shows that Wilms tumor has a lot of similarities with CMN, particularly the cellular variant. On the other hand, fewer than 2% patients with Wilms tumor (WT) present at under 3 months of age. Tumors with congenital syndromes or anomalies, and the presence of bilateral tumors are more suggestive of Wilms. These and other important characteristics allowing distinction of these two tumors are highlighted in Table 1.37.

  References: [153, 159, 175,176,177,178,179,180].

Fig. 1.37

(a) Classic variant of congenital mesoblastic nephroma with fascicles and bundles of spindle cells infiltrating between entrapped benign tubules. (b) Biphasic nephroblastoma (Wilms tumor) with blastemal and epithelial components

Table 1.37 Mesoblastic nephroma vs. Wilms tumor

Metanephric Adenoma vs. Congenital Mesoblastic Nephroma

• Metanephric kidney develops between fifth and ninth weeks of gestation and is derived from two main embryonic structures: nephrogenic blastema and embryonic bud. Nephrogenic blastema is composed of primitive tubules surrounded by cellular condensations developing into the glomeruli. The embryonic bud forms collecting system with cortical and medullary ducts, rudimentary calyces and pelvis embedded into supporting mesoblastic stroma. These two components of metanephric kidney are morphologically recapitulated in metanephric tumors including metanephric adenoma (MA), metanephric adenofibroma (MAF), and metanephric stromal tumor (MST), as well as in congenital mesoblastic nephroma (CMN; see Fig. 1.38a, b).

Fig. 1.38

(a) Metanephric adenofibroma composed of small blue cells arranged in tubules and papillary structures admixed with sheets of spindled cells within myxoid stroma. (b) Classic variant of congenital mesoblastic nephroma composed of tubules embedded into the cellular stroma with intersecting fascicles and bundles of spindle cells with minimal atypia

Table 1.38 shows metanephric adenoma vs. congenital mesoblastic nephroma.

Table 1.38 Metanephric adenoma vs. congenital mesoblastic nephroma

References: [68, 177,178,179, 181, 182].

What Are the Most Common Syndromes Associated with Renal Tumors?

Approximately, 4–5% of all renal tumors are associated with heritable autosomal dominant syndromes. In general, these renal tumors have an earlier age of onset, often multifocal and bilateral. Knowledge of molecular abnormalities, pathogenesis, specifics of renal pathology, and characteristic of extrarenal manifestations is important for early recognition of individuals and families at risk for early screening, active surveillance, and timely management (see Tables 1.39, 1.40, 1.41, 1.42, 1.43, and 1.44).

• Von Hippel-Lindau (VHL) Syndrome.

• Hereditary papillary renal cell carcinoma (PRCC).

• Birt-Hogg-Dube (BDH) syndrome.

• Hereditary leiomyomatosis renal cell carcinoma (HLRCC).

• Tuberous sclerosis complex (TSC).

• Hereditary paraganglioma-pheochromocytoma syndrome or

• Succinate Dehydrogenase (SDH) Complex deficiency syndrome.

  References: [183,184,185,186,187,188,189].

Table 1.39 Von Hippel-Lindau (VHL) Syndrome

Table 1.40 Hereditary papillary renal cell carcinoma (PRCC)

Table 1.41 Birt-Hogg-Dube (BDH) syndrome

Table 1.42 Hereditary leiomyomatosis renal cell carcinoma (HLRCC)

Table 1.43 Tuberous sclerosis complex (TSC)

Table 1.44 Hereditary paraganglioma-pheochromocytoma syndrome or succinate dehydrogenase (SDH) complex deficiency syndrome

Case Presentations

Case 1

Learning Objectives

• 1. To understand differential diagnostic considerations for renal mass biopsy.

• 2. To become familiar with the immunohistochemical profile of the tumor.

• 3. To generate a relevant differential diagnosis.

Case History

A 55-year-old man with history of pancreatic cancer is found to have multiple renal masses. Core biopsy is performed to evaluate for metastasis vs. primary renal neoplasm.

Gross

Core biopsy fragments of 1 mm diameter and 0.5–1.2 cm length are received.

Histologic Findings

• Sections demonstrate cells with clear cytoplasm forming glands and tubular structures with a somewhat branched configuration in edematous, loose stroma (Fig. 1.39a).

• At higher magnification, there is a suggestion that nuclei are aligned at a similar height within the cytoplasm (Fig. 1.39b).

Fig. 1.39

(a) Renal mass biopsy shows a neoplasm composed of glandular structures in loose stroma. (b) Higher magnification demonstrates some alignment of nuclei at a uniform height in the cytoplasm. (c) Immunohistochemistry shows diffuse strong positivity for cytokeratin 7. (d) Immunohistochemistry also shows substantial positivity for high molecular weight cytokeratin. (e) Immunohistochemistry is negative for alpha-methylacyl-CoA racemase (AMACR)

Differential Diagnosis

• Clear cell RCC.

• Clear cell papillary RCC.

• Papillary RCC with clear cell changes.

• Metastatic pancreatic cancer.

IHC and Other Ancillary Studies

• Carbonic anhydrase IX diffusely positive with cup-shaped pattern.

• Cytokeratin 7 is diffusely positive (Fig. 1.39c).

• High molecular weight cytokeratin is diffusely positive (Fig. 1.39d).

• AMACR is negative (Fig. 1.39e).

• GATA3 is patchy positive.

• CD10 is negative.

Final Diagnosis

Clear cell papillary (tubulopapillary) RCC .

Take-Home Messages

• 1. Clear cell papillary RCC is a nonaggressive subtype of RCC that accounts for 3–4% of adult renal neoplasms.

• 2. Despite similarity to clear cell RCC morphologically, the immunohistochemical profile is distinctive (cytokeratin 7 positive, carbonic anhydrase IX positive, high molecular weight cytokeratin often positive, GATA3 often positive, AMACR negative, CD10 negative).

• 3. Aggressive behavior from a prototypical case has not been described to date, suggesting this may be reclassified as a low malignant potential or benign neoplasm in the future.

• 4. Some cases may have multifocal or bilateral tumors, for unknown reasons.

• 5. This entity is associated with end-stage renal disease; however, most cases likely occur in non-end-stage kidneys.

  References: [4, 17, 29].

Case 2

Learning Objectives

• 1. To understand the differential diagnosis of renal cancers with clear cell and papillary features.

• 2. To apply relevant immunohistochemical profiles.

• 3. To understand the role of molecular testing in RCC.

Case History

A 40-year-old man presents for resection of a 5.5 cm renal mass.

Gross

Sectioning reveals a solid, yellow-tan renal mass that bulges from the normal contour of the kidney.

Histologic Findings

• Sections demonstrate a renal cancer composed of cells with clear cytoplasm, arranged in tubulopapillary structures with prominent nuclear alignment (Fig. 1.40a).

• Other areas demonstrate more papillary architecture with psammoma bodies (Fig. 1.40b).

Fig. 1.40

(a) Histology demonstrates a renal cell carcinoma with clear to eosinophilic cells and papillary architecture with nuclear alignment. (b) More prominent papillary architecture and psammoma bodies are evident in other areas

Differential Diagnosis

• Clear cell RCC.

• Papillary RCC.

• Translocation-associated RCC.

• Clear cell papillary RCC.

• Unclassified RCC.

IHC and Other Ancillary Studies

• Cytokeratin 7 negative.

• Carbonic anhydrase IX negative.

• PAX8 positive.

• Melan-A focal positive.

• Break-apart FISH for TFE3 shows a split signal pattern with small gaps between the signals.

Final Diagnosis

Translocation-associated RCC with NONO-TFE3 fusion .

Take-Home Messages

• 1. Translocation RCC is a relatively rare subtype of renal cancer.

• 2. Although children and young adults with RCC are more likely to have translocation tumors, there are likely more cases that occur in older adults in the conventional age range for renal cancer (>55).

• 3. Translocation tumors are consistently negative for carbonic anhydrase IX, positive for PAX8, and often have positivity for melanocytic markers or cathepsin-K.

• 4. Translocations NONO-TFE3 and RBM10-TFE3 can be difficult to detect with FISH, as both are caused by intrachromosomal fusions on the X chromosome, which may yield a small gap in the split signal, or a false-negative result.

• 5. NONO-TFE3 and SFPQ-TFE3 fusion tumors often have nuclear alignment resembling clear cell papillary RCC; however, psammoma bodies are not typical of the latter.

  References: [35, 47, 49, 190].

Case 3

Learning Objectives

• 1. To recognize morphologic clues for diagnosis of oncocytic renal tumors.

• 2. To be familiar with immunohistochemistry for diagnosis of oncocytic neoplasms.

• 3. Integrate genetic findings in the differential diagnosis of oncocytic tumors.

Case History

A 58-year-old woman presented for resection of a 5.5 cm renal mass.

Gross

Sectioning reveals a circumscribed, solid, tan-brown renal mass with a pushing border.

Histologic Findings

• Some areas exhibit nests of oncocytic cells, reminiscent of oncocytoma (Fig. 1.41a).

• Other areas contain large trabecular solid and microscystic structures (Fig. 1.41b).

• Higher magnification includes cribriform nests of cells with some nuclear irregularity and nuclear size variation (Fig. 1.41c).

Fig. 1.41

(a) Histology demonstrates an oncocytic neoplasm with relatively round, regular nuclei. (b) Other areas of the same neoplasm show trabecular architecture. (c) Cribriform architecture and some nuclear size variation are also present. (d) Immunohistochemistry shows patchy confluent staining for cytokeratin 7

Differential Diagnosis

• Oncocytoma.

• Chromophobe RCC.

• Succinate dehydrogenase-deficient RCC.

• Papillary RCC with oncocytic features.

• Unclassified RCC.

IHC and Other Ancillary Studies

• Cytokeratin 7 shows variable patchy staining with some confluent areas (Fig. 1.41d).

• Vimentin immunohistochemistry is negative.

• KIT (CD117) demonstrates positive membrane staining.

• FISH demonstrates losses of several chromosomes, including 1, 6, and 10.

Final Diagnosis

Eosinophilic variant chromophobe RCC .

Take-Home Messages

• 1. Distinguishing oncocytoma from chromophobe RCC remains challenging even today, despite numerous immunohistochemical and molecular markers that have been explored.

• 2. The most commonly used immunohistochemical method for distinguishing oncocytoma from chromophobe RCC is cytokeratin 7 staining, although a precise threshold of positivity that excludes oncocytoma is not well defined.

• 3. Oncocytoma generally should demonstrate only rare cells and small clusters of cells positive for cytokeratin 7.

• 4. Oncocytoma and chromophobe RCC are consistently negative for vimentin (except in central scar areas of oncocytoma) and usually positive for KIT.

• 5. Chromophobe RCC often exhibits losses of multiple chromosomes, particularly Y, 1, 2, 6, 10, 13, 17, and 21.

  References: [21, 36, 84, 85].

Case 4

Learning Objectives

• 1. To understand the differential diagnosis of renal cancers with clear cell and papillary features.

• 2. To apply relevant immunohistochemical profiles.

• 3. To be able to counsel clinical colleagues regarding the behavior of RCC variants.

Case History

A 59-year-old man presents for resection of a 5.7 cm renal mass with invasion of the renal sinus.

Gross

Sectioning reveals a circumscribed renal mass with finger-like extensions into the renal sinus. The cut surface is golden-yellow.

Histologic Findings

• The neoplasm is composed of cells with clear cytoplasm lining branched glandular structures (Fig. 1.42a).

• Some areas have small formations of branched papillae (Fig. 1.42b).

Fig. 1.42

(a) Histology demonstrates a neoplasm composed of clear cells arranged in glandular/papillary formations. (b) Other areas show small, branched papillary tufts protruding into small cystic spaces. (c) Immunohistochemical staining for cytokeratin 7 demonstrates partial but not diffuse positivity. (d) Carbonic anhydrase IX demonstrates diffuse positivity. (e) Substantial apical membrane positivity for CD10 is also present. (f) There is moderate to strong cytoplasmic staining for alpha-methylacyl-CoA racemase (AMACR)

Differential Diagnosis

• Clear cell RCC.

• Clear cell papillary RCC.

• Translocation RCC.

• Unclassified RCC.

IHC and Other Ancillary Studies

• Cytokeratin 7 demonstrates patchy (partial) positivity (Fig. 1.42c).

• Carbonic anhydrase IX exhibits diffuse membrane positivity (Fig. 1.42d).

• CD10 demonstrates substantial apical membrane positivity (Fig. 1.42e).

• AMACR demonstrates moderate to strong cytoplasmic positivity (Fig. 1.42f).

Final Diagnosis

Clear cell RCC (with areas mimicking clear cell papillary RCC).

Take-Home Messages

• 1. Some clear cell RCC tumors can demonstrate morphology overlapping with clear cell papillary RCC.

• 2. Although these tumors may have partial or substantial positivity for cytokeratin 7, they typically have an otherwise imperfect immunohistochemical profile for clear cell papillary subtype, such as with substantial positivity for AMACR and/or CD10.

• 3. High molecular weight cytokeratin, which is often positive in clear cell papillary tumors, is usually negative or focal in clear cell RCC, and GATA3 is typically negative.

• 4. Tumors with these overlapping features have been found to have chromosome 3p abnormalities, necrosis, high-stage parameters, and aggressive behavior, supporting exclusion from the diagnosis of clear cell papillary RCC.

  References: [29, 60, 61].

Case 5

Learning Objectives

• 1. To become familiar with the histologic features of the tumor.

• 2. To become familiar with the immunohistochemical profile of the tumor.

• 3. To generate a relevant differential diagnosis.

Case History

A 45-year-old woman presented with polycythemia and a 2.5 cm renal mass. Partial nephrectomy was performed.

Gross

Sectioning reveals a solid, white-tan mass with homogeneous cut surface.

Histologic Findings

• Histology demonstrates a well-circumscribed but unencapsulated neoplasm composed of crowded basophilic cells (Fig. 1.43a).

• Higher magnification demonstrates crowded nests of basophilic cells (Fig. 1.43b).

• Other areas contain edematous stroma with small, tight clusters of basophilic cells with bland nuclei (Fig. 1.43c).

Fig. 1.43

(a) Histology demonstrates a circumscribed neoplasm composed of crowded basophilic cells. (b) Higher magnification reveals small nests reminiscent of solid papillary renal cell carcinoma. (c) Other areas are composed of cells with small, bland nuclei in edematous stroma. (d) Diffuse nuclear positivity with WT1 antibody

Differential Diagnosis

• Papillary RCC.

• Metanephric adenoma.

• Wilms tumor (nephroblastoma).

IHC and Other Ancillary Studies

• WT1 demonstrates diffuse nuclear positivity (Fig. 1.43d).

• CD57 demonstrates diffuse positivity.

• AMACR, cytokeratin 7, and epithelial membrane antigen are negative.

Final Diagnosis

Metanephric adenoma .

Take-Home Messages

• 1. Metanephric adenoma is a rare benign renal neoplasm composed of compact clusters of basophilic cells with bland nuclei.

• 2. Papillary architecture and psammoma bodies can be present.

• 3. Morphologic features can overlap with papillary RCC and nephroblastoma; however, the immunohistochemical profile is helpful to distinguish these tumors.

• 4. Metanephric adenoma is typically positive for WT1 and CD57 and negative for AMACR and cytokeratin 7, whereas papillary RCC usually shows the opposite pattern.

• 5. The majority of metanephric adenomas harbor BRAF mutations and immunohistochemistry for the mutant BRAF protein often correlates with mutation.

  References: [68,69,70].

Case 6

Learning Objectives

• 1. To become familiar with the histologic features of the tumor.

• 2. To become familiar with the immunohistochemical profile of the tumor.

• 3. To generate the differential diagnosis.

Case History

A 51-year-old female presented with history of long-standing diabetes and hypertension, with status post renal transplant. She developed hematuria, ureteral stricture, and hydronephrosis in her native kidney. Due to severe stricture and nonfunctioning kidney, the patient elected to have a right nephrectomy.

Gross

A nephrectomy specimen weighing 144 g is bivalved showing dilated renal pelvis and calyces with tan-white smooth and glistening urothelial mucosa. Renal parenchyma is markedly atrophic, pale brown with blurred corticomedullary junction and areas of vague nodularity.

Histologic Findings

• Urothelial lining of renal calyces overlies highly atypical cellular areas of spindled pleomorphic cells with numerous mitoses and discohesive growth (Fig. 1.44a).

• Haphazardly arranged sarcomatoid cells embedded into myxoid stroma and undermine urothelium without any obvious in situ urothelial carcinoma (UC). No low-grade or high-grade renal cell carcinoma (RCC) or invasive UC are identified (Fig. 1.44b).

Fig. 1.44

(a) Histology shows high-grade pleomorphic cells undermining benign appearing surface urothelium of the renal pelvis. (b) Higher magnification reveals spindled malignant cells with multinucleation, hyperchromasia, and bizarre atypical nuclei. (c) Strong CK7 immunoreactivity in both infiltrating malignant tumor cells and urothelium. (d) GATA3 nuclear positivity is variable in sarcomatoid cells in contrast to strong expression in benign urothelium

Differential Diagnosis

• Sarcomatoid UC.

• Sarcomatoid RCC.

• Renal sarcoma.

IHC and Other Ancillary Studies

• CK7 strongly positive (Fig. 1.44c).

• GATA3 variably positive: strong in benign overlying urothelium and variable in sarcomatoid cells (Fig. 1.44d).

• PAX8 negative.

Final Diagnosis

Pure sarcomatoid urothelial carcinoma of the renal pelvis .

Take-Home Messages

• 1. Carcinomas with pure sarcomatoid morphology of kidney are extremely rare aggressive tumors and pose significant morphologic challenge.

• 2. Distinction between sarcomatoid RCC and sarcomatoid UC is very important due to different prognosis and patient management. This patient received additional surgical treatment with removal of the entire right ureter with bladder cuff.

• 3. Immunohistochemistry with pan-cytokeratins, urothelial markers, markers of RCC, or markers of sarcoma histogenesis is important in making this diagnosis.

  References: [8, 93].

Case 7

Learning Objectives

• 1. To become familiar with the histologic and immunohistochemical features of the tumor.

• 2. To generate the differential diagnosis.

Case History

A 50-year-old male presented with back pain, weight loss, and hematuria.

Gross

Radical nephrectomy specimen with renal mass measuring 20.5 cm × 18 × 8 cm. On cut surface the tumor is partly cystic and partly solid with yellow-maroon variegated cut surface and friable necrotic hemorrhagic areas.

Histologic Findings

The neoplasm consists of sheets and nests of epithelioid cells with clear cytoplasm and well-defined cytoplasmic borders. Focal perinuclear clearing and nuclear wrinkling are seen. Other areas have a more prominent oncocytic appearance, in which the nuclei are round with prominent nucleoli and coarsely granular eosinophilic cytoplasm. There are also multiple entrapped benign renal tubules (Fig. 1.45a).

Fig. 1.45

(a) Histologically clear cell tumor composed of nests of epithelioid cells with sharp cell borders. (b) Immunohistochemistry demonstrates scattered HMB45 positivity. (c) Expression of another melanocytic marker Melan-A is more diffuse and uniform

Differential Diagnosis

• Clear cell renal cell carcinoma with eosinophilic features.

• Chromophobe renal cell carcinoma, eosinophilic variant.

• Oncocytoma.

• Epithelioid angiomyolipoma.

First Round of IHC Studies

• Positive immunostains: Vimentin, CAIX (focally), Cytokeratin 7 (focally).

• Negative immunostains: CD10, CKIT, TFE3.

Second Round of IHC Studies

• Positive immunostains: HMB45 (Fig. 1.45b), Melan-A (Fig. 1.45c).

• Negative immunostains: Smooth muscle actin (SMA).

Final Diagnosis

Epithelioid angiomyolipoma .

Take-Home Messages

• 1. Epithelioid angiomyolipomas (AMLs) show substantial morphologic overlap with oncocytoma and various subtypes of renal cell carcinoma posing diagnostic difficulties.

• 2. AMLs are always negative for PAX8, mostly negative for cytokeratins while positive for vimentin, SMA, and melanocytic markers.

• 3. Expression of melanocytic markers and SMA in epithelioid AML could be very focal or even negative; therefore, a panel of 3–4 markers may be necessary for definitive diagnosis.

  References: [116, 117].

Case 8

Learning Objectives

• 1. To become familiar with the histologic and immunohistochemical features of the tumor.

• 2. To generate the differential diagnosis.

Case History

The patient is a healthy 34-year-old female, former marathon-runner with two little children, who presented with acute flank pain and hematuria. Abdominal CT revealed a renal fatty mass with central density, consistent with hemorrhage.

Gross

Partial nephrectomy specimen with extrarenal 11.5 cm mass loosely attached to a portion of kidney parenchyma. On cut surface the mass has a central 7 cm hemorrhagic cavity surrounded by areas of brightly yellow discoloration.

Histologic Findings

At low power, this mass appears to be pure lipomatous neoplasm consisting of sheets of variably sized adipocytes with areas of hemorrhage (Fig. 1.46a). At higher power, the central portion of tumor shows extensive fat necrosis (Fig. 1.46b). At the periphery, tumor contains a few irregular thickened vessels and vascular channels surrounded by elongated plump smooth muscle cells (Fig. 1.46c). No obvious lipoblasts and pleomorphic atypical cells are identified. Renal parenchyma is unremarkable.

Fig. 1.46

(a) Large mass comprised of sheets of variably sized adipocytes. (b) Hemorrhage and fat necrosis were apparent at higher magnification. (c) Scant stroma represented by spindled plump eosinophilic cells surrounding dysmorphic vessels

Differential Diagnosis

• Lipoma.

• Well-differentiated liposarcoma.

• Fat-rich angiomyolipoma.

Ancillary IHC Studies

• Positive immunostains: HMB45 (rare cells), Melan-A (focally positive).

• Negative immunostains: MDM2, CDK4.

Final Diagnosis

Lipomatous angiomyolipoma (AML) .

Take-Home Messages

• 1. Angiomyolipomas can be fat-rich and predominantly extrarenal when arising from kidney capsule, thus mimicking retroperitoneal well-differentiated lipomatous tumors or even normal perinephric fat.

• 2. Presence of necrosis and hemorrhage raises concern for malignancy; however, vascular rupture and subsequent ischemic necrosis are well-known complications in larger AMLs.

• 3. Expression of melanocytic markers and presence of dysmorphic vessels are critical in making a diagnosis of fat-rich AML, whereas smooth muscle actin and MDM2 could be nonspecific (expressed in both AML and well-differentiated liposarcoma).

  References: [191, 192].

Case 9

Learning Objectives

• 1. To become familiar with the histologic and immunohistochemical features of the tumor.

• 2. To generate the differential diagnosis.

Case History

The patient is a 55-year-old female presented with a left upper quadrant pain after a mild body injury. Radiologic examination revealed a 2.1 cm solid mass with focal cystic change concerning for renal cell carcinoma, which was removed.

Gross

Partial nephrectomy specimen contains a 2.1 x 1.9 x 1.7 cm subcapsular mass with scattered cystic spaces and unremarkable adjacent renal parenchyma.

Histologic Findings

Low-grade mesenchymal neoplasm composed of fascicles and whorls of plump spindle cells surrounding small capillary channels and slit-like vascular spaces with nested, anastomosing pattern (Fig. 1.47a). Other histologic findings include a few cysts within a solid component lined by a single layer of flattened to cuboidal epithelium with hobnailing. These bland cells show eosinophilic cytoplasm, round nuclei, fine chromatin, and inconspicuous nucleoli (Fig. 1.47b).

Fig. 1.47

(a) Histology demonstrated a smooth muscle neoplasm with scattered cystic spaces. (b) Cyst lined by a single layer of eosinophilic cells with hobnailing. (c) Immunohistochemistry shows diffuse expression of smooth muscle actin. (d) HMB45 expression is obvious in the majority of tumor cells

Differential Diagnosis

• Leiomyoma with entrapped cystically dilated renal tubules.

• Angiomyolipoma with epithelial cysts (AMLEC).

• Mixed epithelial and stromal tumor (MEST).

Ancillary IHC Studies

• Positive immunostains: stromal component positive for SMA (Fig. 1.47c) and HMB45 (Fig. 1.47d), as well as CD10, ER/PR, and vimentin; cyst lining positive for PAX8 and pan-cytokeratin.

• Negative immunostains: Melan-A, CD34, S100.

Final Diagnosis

AML with epithelial cysts (AMLEC) .

Take-Home Messages

• 1. AMLEC is a rare variant of muscle-predominant AML mimicking MEST, but lacking ovarian-type stroma, stromal luteinization, and harboring abnormal vasculature.

• 2. Panel of melanocytic markers HMB45, Melan-A, and MITF is the most helpful ancillary study to diagnose AMLEC since other markers (SMA, caldesmon, CD10, ER/PR, vimentin) are shared by MEST.

• 3. AMLEC is a benign indolent tumor with excellent prognosis, whereas MEST could undergo malignant transformation.

  References: [110, 113].

Case 10

Learning Objectives

• 1. To become familiar with the histologic and immunohistochemical features of the tumor.

• 2. To generate the differential diagnosis.

Case History

The patient is a 55-year-old male who presented with hematuria and acute abdominal pain. He was found to have an extremely large mass in the left kidney, small lesions in the right kidney, and lymphadenopathy. The patient underwent left radical nephrectomy after embolization and regional lymph node dissection with a plan of subsequent potential second operation of right kidney exploration at a later date. His medical history is significant for pigmented cutaneous lesions, recent acute heart attack, aortic stenosis, and aortic valve replacement.

Gross

Radical nephrectomy specimen weighing 2813 gm is sectioned revealing a 14 × 13.5 × 10 cm tumor extending from the interpolar region into the pelvic fat. The tumor is 60% necrotic with large areas of hemorrhage. A second mass, measuring 5.0 × 4.0 × 2.5 cm, extends from the cortex of the superior pole anteriorly. This smaller mass is firm, tan, and somewhat fleshy. There is marked hydronephrosis. Additionally, a large aggregate of at least eight lymph node candidates was submitted.

Histologic Findings

The dominant tumor mass widely invasive into the hilar fat has variable morphology including intimately admixed epithelioid and mesenchymal areas with hemorrhagic background (Fig. 1.48a). The epithelioid component is composed of nests and sheets of round-to-cuboidal uniform cells with eosinophilic and vacuolated cytoplasm. These tumor nests are separated by abundant stroma with clusters of vessels with eccentrically thickened walls, adipocytes, and plump spindle cells (Fig. 1.48b). In some areas, tumor cells are forming large sheets of clear cells with prominent plant-like membranes, irregular wrinkled nuclei, and prominent perinuclear halos (Fig. 1.48c). Regional lymph nodes contain several areas of extensive spindle cell proliferations (Fig. 1.48d) splitting and invading into the sinusoidal spaces (Fig. 1.48e).

Fig. 1.48

(a) Renal hilum contains hemorrhagic tumor. (b) Clusters of clear to eosinophilic tumor cells infiltrate hilar fat and stroma. (c) Large confluent solid sheets are composed of cells with sharp borders and hyperchromatic raisinoid nuclei surrounded by clear halos. (d) Lymph node histology demonstrates pink area of spindle cell proliferation arising from capsule and extending into the extranodal adipose tissue. (e) Spindle cells with plump eosinophilic cytoplasm expand sinusoidal spaces of the lymph node

Differential Diagnosis

• Multifocal chromophobe renal cell carcinoma (RCC), suspicious for Birt-Hogg-Dube syndrome.

• Chromophobe RCC with sarcomatoid dedifferentiation and lymph node metastases.

• Multiple angiomyolipomas (AML) and RCC, suggestive of tuberous sclerosis syndrome.

• Clear cell RCC with abundant smooth muscle stroma.

Ancillary Studies

• Positive immunostains: PAX8 and CK7 in epithelioid areas (spindle cell areas negative).

• Negative immunostains: CAIX, AMACR, CD10.

Final Diagnosis

Chromophobe-like RCC and multiple angiomyolipomas (AMLs) involving kidney and lymph nodes, suggestive of tuberous sclerosis (later confirmed clinically).

Take-Home Messages

• 1. Multiple bilateral tumors including AML and RCC with AML-like stroma (Fig. 1.48a–c) are hallmark features of tuberous sclerosis complex.

• 2. Rare metastasis of RCC to regional lymph nodes has been reported, but death from RCC in patients with tuberous sclerosis is extremely uncommon.

• 3. Presence of AML in the lymph node is not considered a metastasis.

  References: [188, 193].