Abstract
Purpose of Review
Urothelial carcinomas (UC) are characterized by variant morphologies. However, the diagnosis of these variants can be challenging, in part due to their evolving diagnostic criteria. This review discusses the diagnostic criteria, molecular features, and prognostic implications of the UC variants. Evolving subtypes of UC are also briefly discussed.
Recent Findings
The WHO 2016 classification of tumors of the urinary system has refined the morphologic criteria for the diagnosis of UC variants. Many of these follow a more aggressive clinical course, but conclusive data on their effect on survival are lacking. The molecular alterations characteristic of some of these variants may be amenable to targeted therapies.
Summary
Accurate identification of variant histology in UC has important implications for patient management. Despite identification of distinct molecular alterations in some of these variants, current molecular classifiers of invasive UC have not been significantly analyzed in these subtypes, opening up areas of future research.
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Introduction
Urothelial carcinoma (UC) accounts for about 90% of bladder cancers in industrialized countries with squamous cell carcinoma (1–7%) and adenocarcinomas (0.5–2%) forming a minor component of bladder cancers [1, 2]. UC is remarkable for showing marked diversity in its morphological appearance, which may in part be a reflection of its molecular heterogeneity, resulting in the recognition of various histologic variants. Variant histology is not uncommon and can be seen in as many as 33% of the cystectomy specimens [3]. Despite the high prevalence of variant histology its recognition remains challenging because of under-recognition, misclassification, lack of ancillary testing to confirm variant diagnosis, sampling limitations and the high interobserver variability in part due to evolving diagnostic criteria [4••, 5••, 6,7,8,9,10]. In some patients multiple variants may occur within a tumor, with many pathologists reporting the percentage of each variant within the lesion [11]. These variants are important to recognize because they may have important prognostic or therapeutic implications and misdiagnosis may result in inappropriate treatment [10]. The WHO 2016 classification of tumors of the urinary system and male genital organs addresses many of these issues by updating the diagnostic criteria and the molecular characteristics of the various subtypes (Table 1).
This review describes the diagnostic criteria of the histologic variants of UC with special emphasis on the morphologic features, molecular profiles and prognostic implications of the identification of the various subtypes. A brief description of the evolving UC subtypes not currently included in the WHO classification is included. Non-urothelial bladder cancer subtypes are not addressed in this review.
Urothelial Carcinoma with Divergent Differentiation
The most common UC variant is UC with divergent differentiation, which includes squamous, glandular, trophoblastic and small cell differentiation (Fig. 1a–d). These tumors are characterized by varying components of urothelial carcinoma (invasive and or in situ) with the aforementioned morphological subtypes [5••]. The general consensus among urologic pathologists is to report these cases with an estimated percentage of the divergent component.
Urothelial carcinoma (UC) with divergent differentiation. Squamous differentiation with squamous pearls (a); glandular spaces lined by cuboidal appearing cells in UC with glandular differentiation (b); syncytiotrophoblastic giant cells scattered along with UC component (c); small cell carcinoma component with urothelial carcinoma in situ (d)
Urothelial Carcinoma with Squamous Differentiation
Squamous differentiation is defined by the presence of intercellular bridges or keratinization (Fig. 1a) and is seen in up to 40% of urothelial carcinomas of the bladder [7, 8]. They are frequently associated with high-grade and high-stage tumors [12•] and may show less favorable response to intravesical BCG and intravesical chemotherapy [13•, 14]; however, the response to neoadjuvant chemotherapy may be comparable with that of conventional urothelial carcinoma [15•, 16,17,18,19]. The presence of squamous differentiation, however, has been associated with higher rates of recurrences and poor prognosis [13•, 18, 20].
One of the challenges in the identification of this variant, especially in transurethral resection (TUR) and biopsy specimens, is its distinction from pure squamous cell carcinoma of the bladder and from secondary involvement of the bladder by squamous cell carcinoma of other pelvic organs. Both squamous cell carcinomas and UC with squamous differentiation share many basal markers including cytokeratin 5/6 and p63. In the absence of specific immunohistochemical markers to make this distinction, and as suggested by previous studies, I rely on the clinical history and the absence of a conventional urothelial carcinoma component to make this distinction [7, 10]. Unlike squamous carcinoma of the cervix, human papilloma virus is generally not considered to be causative in the development of squamous cell carcinoma of the bladder or UC with squamous differentiation [21].
Urothelial Carcinoma with Glandular Differentiation
Glandular differentiation is not as frequent as squamous differentiation but has been documented in 6–18% of invasive bladder cancers [7, 22,23,24]. Glandular differentiation is characterized by true gland formation (Fig. 1b) resembling colonic adenocarcinoma, signet ring carcinoma or mucinous/colloid carcinoma (tumor cells floating in a pool of mucin). They may be associated with urothelial carcinoma in situ or rarely with in situ urothelial carcinoma with glandular differentiation [25]. Pseudo glandular spaces with intracellular mucin may be seen in conventional UC and should not be confused with either UC with glandular differentiation or bladder adenocarcinoma [26].
Robust immunohistochemical markers to distinguish UC with glandular differentiation, from primary bladder adenocarcinomas and secondary involvement /metastatic colonic adenocarcinoma are lacking, making this distinction challenging [27, 28•]. Often in limited samples a definite diagnosis may not be possible and pathologists may give a general descriptive diagnosis and favor one of the differentials over the other. TERT mutations are seen in up to 70% of urothelial carcinoma with glandular differentiation and not in bladder adenocarcinomas [23]; however, this is seldom used in routine clinical practice.
UC with glandular differentiation tends to present at a higher stage but it is not a negative prognostic indicator in stage-matched patients [29].
Urothelial Carcinoma with Trophoblastic Differentiation
UC showing syncytiotrophoblastic giant cells are rare (Fig. 1c), although the use of immunohistochemical markers for the beta subunit of human chorionic gonadotropin (βhCG) can highlight trophoblastic differentiation in up to 35% of UC [30].
βhCG expression within urothelial carcinoma cells without morphological evidence of trophoblastic differentiation correlates with the grade and stage of tumor; however, it is not included in this subgroup. These variants need to be distinguished from pure choriocarcinoma of the bladder, which is extremely rare and requires the demonstration of isochromosome 12p, which is a hallmark of germ cell tumors [31]. Elevated serum βhCG has been reported in 20–76% of metastatic urothelial carcinomas, and response to chemotherapy in these patients can be correlated with the levels of this marker [32,33,34,35].
Other Forms of Divergent Differentiation
UC can show neuroendocrine differentiation in the form of small cell carcinoma (Fig. 1d), and any small cell carcinoma component when present should be reported. TERT promoter mutations have been reported in 55–95% of these tumors, similar to the concomitant UC component suggesting a common clonality [36••, 37]. TERT promoter mutation status may also help identify the site of origin of these tumors, as they are not present in small cell carcinomas of other sites including the prostate [36••, 38]. Coalterations in P53 and RB1, with resultant loss in function, are commonly seen in small cell carcinoma [37, 39••]. The small cell component is usually negative for both luminal and basal markers with few cases showing focal expression of CK5/6, a marker for the basal molecular subtype. This suggests evolution from a basal phenotype and better response to cisplatin-based chemotherapy [39••]. These tumors are treated similar to their counterpart in the lungs. Rarely urothelial carcinomas may show germ cell differentiation, including yolk sac tumor [5••].
Nested, Including Large Nested Urothelial Carcinoma
As per the 2016 WHO classification, large nested variant of UC and UC with small tubules and microcysts that were earlier considered as distinct entities are now included within the category of nested variant [5••, 40, 41••]. This variant is characterized by its deceptively benign cytology and its superficial resemblance to benign mimickers of UC including von Brunn nests, nephrogenic adenoma, and paraganglia [40, 41••, 42,43,44,45].
Nested variant is characterized by a disorderly proliferation of discrete to confluent nests of urothelial cells usually with minimal cytologic atypia (Fig. 2a). The absence of cytologic atypia can make the diagnosis of this variant extremely challenging in small biopsy specimens and transurethral resections. In many instances, the diagnosis may be delayed until the tumor declares itself with unequivocal evidence of invasion of the muscularis propria. Unlike the usual nested variant, which is composed of small- to intermediate-sized nests, the large nested variant is characterized by irregularly infiltrating large aggregates of bland tumor cells which may sometimes be difficult to differentiate from conventional UC with an inverted growth pattern [46].
Cytologically bland nests of invasive carcinoma characteristic of nested variant (a); micropapillary UC with small nests within lacunar spaces (b); tumor cells obscured by brisk inflammatory infiltrate in lymphoepithelioma-like UC (c); singly discohesive bland plasma cell-like cells of plasmacytoid UC (d)
Nested urothelial carcinomas may be admixed with a component of conventional UC or may occur in a pure form. They usually present as a high-stage disease, which may in part reflect the delay in diagnosis, associated with this tumor [47]. Pure large nested variant may have a better prognosis than cases with a mixed histology [41].
The immunohistochemical profile of this variant is similar to conventional UC. In particularly challenging cases the presence of TERT promoter mutation within the tumor cells can help distinguish it from its benign mimics [48]. Preliminary studies have shown that these tumors express immunohistochemical markers characterized by the luminal molecular subtype of urothelial carcinomas [49, 50••].
Microcystic Urothelial Carcinoma
Microcystic urothelial carcinoma, like nested urothelial carcinoma, is an example of urothelial carcinoma characterized by bland cytologic features. It is comprised of round-oval cysts up to 2 mm in diameter lined by urothelial, low columnar or flattened epithelium [51]. The cyst lining may be focally denuded and intraluminal secretions and calcifications may be present within some of the cysts. The cysts are infiltrating; however, a stromal response may be lacking. Focal high-grade conventional urothelial carcinoma may be present in up to 40% of the cases. Their immunohistochemical profile is similar to that of conventional UC [52].
These tumors should be differentiated from their benign mimics including cystitis cystica and cystitis glandularis [53]. TERT promoter mutation studies may help in difficult cases.
Micropapillary Urothelial Carcinoma
This variant has been reported more commonly in men with a peak incidence in the 6th decade of life. It is associated with a poorer prognosis and usually presents at a higher stage with lymph node metastasis [54, 55]. The reported prevalence of this variant varies from 0.7 to 8% [56,57,58] and this may in part reflect the high interobserver variability and the cutoffs used in the diagnosis of this variant [58, 59]. The diagnosis of this tumor should be restricted to infiltrating tumors with slender filiform processes without fibrovascular cores and/or multiple small tumor nests within a single lacunar space (Fig. 2b). The tumor nests often show peripherally oriented nuclei with “reverse polarization” of the basal and luminal aspects of the cell, highlighted on electron microscopy and MUC1 staining [60]. Cytoplasmic vacuolization with indentation of the nuclei (ring forms) is also a characteristic of this tumor [59]. Lymphovascular invasion has also been commonly reported with this variant. Micropapillary carcinoma is frequently admixed with conventional UC and carcinoma in situ is present in more than 50% of the cases [61]. It is unclear if the prognosis of this variant depends on the proportion of the micropapillary component [61, 62]; however, most urologic pathologists report the percentage of this variant in the tumor. Although a surface micropapillary component may be identified in a non-invasive UC or rarely as a variant of urothelial carcinoma in situ, these should not be interpreted as micropapillary urothelial carcinoma. Micropapillary UC in addition to the usual urothelial markers also show immunoreactivity for MUC1 and CA-125 [28•]. They also usually express luminal markers including FOXA1 [37, 49] and have been reported to have a high prevalence of TERT promoter mutations [63••, 64]. HER2 amplifications have been documented in 15–42% of the cases [63, 65, 66].
Limited response to BCG therapy and adverse outcome despite chemotherapy has been reported in some studies, prompting early cystectomy in patients with T1 disease [67]. However, other studies have shown the utility of a bladder-sparing approach in select non-muscle-invasive patients [68, 69]. A recent prospective trial has also reported efficacy with aggressive neoadjuvant chemotherapy [70]. Neoadjuvant chemotherapy although decreased the frequency of non-organ confined disease it did not translate into a statistically significant overall survival benefit [71••]. HER2-amplified tumors have been associated with a worse cancer-specific survival, opening up the potential role of ERBB2-targeted therapy [65, 63].
Lymphoepithelioma-Like Urothelial Carcinoma
Lymphoepithelioma-like urothelial carcinoma is similar in morphology to the lymphoepitheliomas arising elsewhere in the body including the nasopharynx. However, unlike tumors of the nasopharynx this variant of UC is not associated with Epstein-Barr virus infection [72, 73]. It is more commonly seen in older men (mean age, 69 years) and usually presents as a stage 2 or 3 tumor [5••, 74].
It may occur either in the pure form or admixed with conventional urothelial carcinoma or other variants. The tumor is composed of sheets of undifferentiated cells with large pleomorphic nuclei and prominent nucleoli with indistinct cell borders forming a syncytium. The background comprises of an inflammatory infiltrate comprising predominantly of lymphocytes, which in some instances may be so dense so as to obscure the tumor cells (Fig. 2c). The tumor cells mark for urothelial markers including p63 and GATA-3.
Although it was suggested that pure/predominant forms of this carcinoma are associated with a relatively favorable outcome with good response to chemotherapy, a recent study of 30 cases has reported similar outcomes to conventional UC [75].
Plasmacytoid Urothelial Carcinoma
This is a rare but aggressive variant of UC characterized by cells resembling plasma cells that present at a high stage with extravesical disease and intraperitoneal spread in 27–33% of the cases [76, 77, 78•]. They also have higher incidence of lymph node metastasis and are more likely to have positive margins after radical cystectomy [78•]. They generally have a poor outcome with higher rates of recurrence and death but in a recent study of 98 patients, plasmacytoid urothelial carcinoma was not associated with worse overall mortality compared with conventional UC [79••].
This variant is characterized by singly infiltrating, discohesive cells in an edematous or myxoid stroma. The tumor cells have eccentric enlarged hyperchromatic nuclei with eosinophilic to clear cytoplasm, without significant cytologic atypia (Fig. 2d). Signet ring cells with or without intracytoplasmic mucin may be identified, but unlike a signet ring adenocarcinoma extracellular mucin is absent [80, 81, 5••]. A high-grade urothelial carcinoma component is seen in about 50% of the cases. Perrino et al. [82•] recently classified plasmacytoid UC into three morphological subtypes (classic, desmoplastic, and pleomorphic) and reported that the desmoplastic variant had the worst clinical behavior. However, many of their cases of the desmoplastic and pleomorphic variants appear to have a morphologic overlap with UC with rhabdoid morphology. Further studies are required to validate the significance of these findings.
Up to 84% of these tumors show truncating mutations in the CDH1 gene, which encodes for E-cadherin, whereas these mutations have not been reported in conventional UC ( [83••, 84]. These mutations lead to the loss of E-cadherin (a cell adhesion molecule), which may be responsible for the marked discohesion of tumor cells seen in this variant [85]. Recently Fox et al. showed the lack of immunohistochemical staining for RB (retinoblastoma) protein in 62% of their cases, suggesting abnormal function of the RB gene [78•]. Plasmacytoid urothelial carcinoma must be differentiated from tumors arising from the breast and gastrointestinal tract among others because of overlapping morphological features. This is possible by the judicious use of immunohistochemical markers [85, 86•].
Giant Cell Urothelial Carcinoma
Giant cell urothelial carcinoma is a rare aggressive variant characterized by highly atypical giant cells usually admixed with conventional UC component [87•]. Rarely the tumor may be composed entirely of large pleomorphic tumor giant cells, and in such instances immunohistochemical stains may be necessary to identify its urothelial origin. Atypical mitotic figures and areas of necrosis are often present. They are usually highly invasive with involvement of the muscularis propria. The prognosis is uniformly poor [88].
Lipid-Rich Urothelial Carcinoma
This is another rare variant of urothelial carcinoma, with less than 40 cases reported in literature [5••]. The tumor cells resemble lipoblasts and have one or more vacuoles in the cytoplasm that indent the nucleus. The lipid-rich component usually comprises 10–50% of the tumor and is usually admixed with a component of conventional or other UC variants. These tumors usually present at a higher stage, with 60% of the patients dying of the disease within 58 months [89].
Clear Cell (Glycogen-Rich) Urothelial Carcinoma
The clear cytoplasm seen in this variant is because of the presence of intracytoplasmic glycogen, which stains with periodic-acid-Schiff (PAS) stain and disappears after diastase digestion [90].They resemble the cells seen in clear cell renal cell carcinoma, but can be differentiated from it because of its immunoreactivity with urothelial markers including GATA-3 and p63. This variant is also usually associated with in situ, papillary or conventional urothelial carcinoma [5••]. They are extremely rare with fewer than 25 cases reported in literature and therefore it is difficult to comment upon the effect of this variant morphology on prognosis.
Sarcomatoid Urothelial Carcinoma
Sarcomatoid urothelial carcinoma usually presents as advanced disease with poor clinical outcomes [91]. Radiation exposure and chemotherapy with cyclophosphamide have been documented as known risk factors for this variant [5••]. On histology the sarcomatoid component is composed of high-grade spindle or pleomorphic cells indistinguishable from those of a sarcoma. Heterologous components including osteosarcoma, chondrosarcoma, and rhabdomyosarcoma may be identified in some of the tumors and may portend a worse prognosis [92]. Conventional urothelial, squamous, glandular, or small cell carcinoma may be identified admixed with the sarcomatoid component. The epithelial component expresses vimentin in up to 100% of the cases while the sarcomatoid component shows at least focal immunoreactivity for high molecular weight cytokeratins, p63 and GATA-3 [93]. Markers of epithelial-mesenchymal transition have been documented in this tumor both immunohistochemically and at a molecular level with nearly half of the tumors showing a heavily infiltrated immune phenotype [93, 94••]. These findings have important implications for prognostication and development of therapies for this aggressive variant of bladder cancer. Neoadjuvant chemotherapy may be beneficial in muscle-invasive cancers to downstage the tumor at the time of cystectomy, but the overall prognosis remains poor [71••].
Poorly Differentiated Tumors (Including Those with Osteoclast-Like Giant Cells)
This entity has been introduced in the WHO 2016 classification and represents a wide range of tumors with mixed morphologies such as small cell carcinoma, giant cell carcinoma, and osteoclast-rich undifferentiated tumors. The latter tumors are characterized by osteoclast-like giant cells (CD68 positive) with undifferentiated UC cells (cytokeratin positive). Most of these cases are associated with in situ or invasive carcinoma, and the mononuclear cells mark for urothelial markers including GATA-3 [95••]. These are rare tumors and have been reported to be associated with a poor prognosis [95••].
Evolving Entities of Urothelial Carcinoma
There are certain morphological variants of urothelial carcinoma that have not yet been included in the 2016 WHO classification of bladder cancers, because of their rarity and consequent paucity of literature regarding their biology and behavior. A brief description of these tumors is included below.
Pseudoangiosarcomatous Variant of Urothelial Carcinoma
A total of 15 cases of this rare variant have been reported in literature and they have all been associated with poor prognosis [96, 97]. These tumors histologically resemble angiosarcomas with discohesive tumor cells forming pseudolumina (Fig. 3a). They are commonly accompanied with other UC types and show immunoreactivity for urothelial markers [96].
Vascular-like spaces lined by tumor cells in pseudoangiosarcomatous UC (a); rhabdoid UC with singly dispersed high-grade malignant cells in a myxoid stroma (b)
Urothelial Carcinoma with Myxoid Stroma
This variant shows extensive mucinous-myxoid stroma with cords of cells suspended within the stroma, morphologically resembling patterns seen in chordoma, yolk sac tumor, and myxoid chondrosarcoma. These tumors present with high-stage disease, have an urothelial immunophenotype, and usually are associated with some component of conventional UC [98].
Urothelial Carcinoma with Rhabdoid Features
UC with rhabdoid features are tumors comprised of undifferentiated tumor cells having eccentric nuclei, prominent nucleoli, and abundant inclusion like eosinophilic cytoplasm (Fig. 3b). These tumors are extremely rare and portend a poor prognosis [99]. Up to 70% of these tumors show loss of at least one SW1/SNF (chromatin remodeling complex) subunit. SMARCA2 is most frequently lost followed by ARID1A, SMARCB1/INI1, SMARCA4, and SMARCC1 [100•].
Molecular Classification of UC with Reference to UC variants
The molecular landscape of UC is very large and complex and recently there have been many attempts to classify invasive UC using molecular classifiers based on RNA expression profiles. Many of these molecular classifiers have overlapping profiles, and the most comprehensive of these classifications were proposed by the Lund University group and the TCGA [101, 102••]. The TCGA classification identifies 5 subtypes of muscle-invasive UC, including luminal, luminal-papillary, luminal infiltrated, basal-squamous, and neuronal. These subtypes are characterized by specific RNA expression signatures and have different prognostic and therapeutic implications. Although some of the UC variants are characterized by certain characteristic molecular alterations as mentioned previously in this review, there is limited information regarding the classification of UC variants using the abovementioned molecular classifiers. Using RNA expression or immunohistochemical profiles, micropapillary, nested, and plasmacytoid urothelial carcinomas were found to have luminal features, whereas urothelial carcinoma with squamous differentiation was found to have basal characteristics [37, 49, 50••]. However, the available data in these variants is limited and further comprehensive studies are needed to test the validity of these molecular classifiers in UC variants.
Conclusions
UC with variant histology is a heterogeneous group of tumors that are being increasingly identified because of their distinct morphological features and their reported association with variable clinical prognosis. Distinct molecular alterations have been described for some of these morphologic subtypes, which have implications for the use of targeted therapies. The use of molecular classifiers, currently used for invasive conventional UC, has yet to be fully explored in UC variants.
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• Giannico GA, Gowan AM, Epstein JI, Revetta F, Bishop JA. Role of SATB2 in distinguishing the site of origin in glandular lesions of the bladder/urinary tract. Hum Pathol. 2017;67:152–9. https://doi.org/10.1016/j.humpath.2017.07.002 This study highlights the challenges that arise in the diagnosis of glandular lesions of the bladder, because of the morphological and immunohistochemical overlap among these tumors. The authors investigated the role of SATB2, which is expressed in colorectal and appendiceal neoplasms. The study included 43 primary adenocarcinomas of the bladder/urinary tract, 20 urothelial carcinomas with glandular differentiation, 26 adenocarcinomas of the uterine cervix, and 22 colorectal adenocarcinomas involving the bladder. Positive SATB2 immunostaining was observed in 49% of primary bladder/urinary tract adenocarcinomas, in 77% colorectal adenocarcinomas, and in the glandular component of 22% of urothelial carcinomas with glandular differentiation. SATB2 was negative in 25 of 26 endocervical adenocarcinomas. SATB2 immunohistochemistry was not useful in supporting urothelial versus gastrointestinal or endocervical origin in the differential diagnosis of glandular lesions of the bladder/urinary tract.
Kim SP, Frank I, Cheville JC, Thompson RH, Weight CJ, Thapa P, et al. The impact of squamous and glandular differentiation on survival after radical cystec- tomy for urothelial carcinoma. J Urol. 2012;188:405–9. https://doi.org/10.1016/j.juro.2012.04.020.
Grammatico D, Grignon DJ, Eberwein P, Shepherd RR, Hearn SA, Walton JC. Transitional cell carcinoma of the renal pelvis with choriocarcinomatous differentiation: immunohistochemical and immunoelectron microscopic assessment of human chorionic gonadotropin production by transitional cell carcinoma of the urinary bladder. Cancer. 1993;71:835–1841.
Monn MF, Jaqua KR, Bihrle R, Cheng L. Primary choriocarcinoma of the bladder: a case report and review of literature. Clin Genitourin Cancer. 2017;15:188–91. https://doi.org/10.1016/j.clgc.2016.08.027.
Douglas J, Sharp A, Chau C, Head J, Drake T, Wheater M, et al. Serum total HCG beta level is an independent prognostic factor in transitional cell carcinoma of the urothelial tract. Br J Cancer. 2014;110:1759–66. https://doi.org/10.1038/bjc.2014.89.
Martin JE, Jenkins BJ, Zuk RJ, et al. Human chorionic gonadotrophin expression and histological findings as predictors of response to radiotherapy in carcinoma of the bladder. Virchows Arch A Pathol Anat Histopathol. 1989;414:273–7.
Monn MF, Kaimakliotis HZ, Pedrosa JA, et al. Contemporary bladder cancer: variant histology may be a significant driver of disease. Urol Oncol. 2015;33:18.e15–20. https://doi.org/10.1016/j.urolonc.2014.10.001.
Black PC, Brown GA, Dinney CP. The impact of variant histology on the outcome of bladder cancer treated with curative intent. Urol Oncol. 2009;27:3–7. https://doi.org/10.1016/j.urolonc.2007.07.010.
•• Priemer DS, Wang M, Zhang S, Lopez-Beltran A, Kouba E, Monitroni R, et al. Small-cell carcinomas of the urinary bladder and prostate: TERT promoter mutation status differentiates sites of malignancy and provides evidence of common clonality between small-cell carcinoma of the urinary bladder and urothelial carcinoma. Eur Urol Focus. 2018;4:880–8. https://doi.org/10.1016/j.euf.2017.03.007 In this study TERT promoter mutation status of small cell carcinoma (SCC) of the bladder was compared to TERT promoter mutation status in prostate SCC. Mutations were detected in 29/53 (55%) cases of urinary bladder and 0/26 (0%) cases of prostate SCC. Of 25 cases with concurrent urinary bladder SCC and non-small-cell components, all cases harbored identical TERT promoter mutation status in both phenotypes indicating a clonal evolution.
Al-Ahmadie H, Iyer G. Updates on the genetics and molecular subtypes of urothelial carcinoma and select variants. Surg Pathol Clin. 2018;11(4):713–23. https://doi.org/10.1016/j.path.2018.07.011.
Zheng X, Zhuge J, Bezerra SM, Faraj SF, Munari E, Fallon JT 3rd, et al. High frequency of TERT promoter mutation in small cell carcinoma of the bladder, but not in small cell carcinoma of other origins. J Hematol Oncol. 2014;7:47. https://doi.org/10.1186/s13045-014-0047-7.
•• Wang G, Xiao L, Zhang M, Kamat AM, Siefker-Radtke A, Dinney CP, et al. Small cell carcinoma of the urinary bladder: a clinicopathologic and immunohistochemical analysis of 81 cases. Hum Pathol. 2018;79:57–65. https://doi.org/10.1016/j.humpath.2018.05.005 In this retrospective comprehensive analysis of clinicopathologic and immunohistochemical features of 81 cases of small cell carcinoma (SCC) including 25 pure SCC, 95% presented at advanced stage with muscularis propria invasion. Neuroendocrine markers were expressed in the majority of the cases, with loss of RB1 staining in 21/23 cases. Most SCC did not express luminal or basal markers but a few showed positivity for CK5/6 which may suggest evolution from a basal phenotype, and better response to cisplatinum based chemotherapy.
Lopez Beltran A, Cheng L, Montironi R, Bianca A, Leva M, Roupret M, et al. Clinicopathological characteristics and outcome of nested carcinoma of the urinary bladder. Virchows Arch. 2014;465:199–205. https://doi.org/10.1007/s00428-014-1601-y.
•• Comperat E, McKenney JK, Hartmann A, Hes O, Bertz S, Varinot J, et al. Large nested variant of urothelial carcinoma: a clinicopathological study of 36 cases. Histopathology 2017: 71: 703–710. Doi: 10.1111/his.13280. The largest study to date of large nested variant of UC, that describes the clinical, pathologic and immunohistochemical profile of these tumors. Tumors with pure large nested variant have similar immunohistochemical profile to conventional UC and nested variant of UC, but had a lower rate of advanced disease compared to cases with mixed histologies.
Drew PA, Furman J, Civantos F, Murphy WM. The nested variant of transitional cell carcinoma: an aggressive neoplasm with innocuous histology. Mod Pathol. 1996;9:989–94.
Young RH, Oliva E. Transitional cell carcinomas of the urinary bladder that may be underdiagnosed. A report of four invasive cases exemplifying the homology between neoplastic and non-neoplastic transitional cell lesions. Am J Surg Pathol. 1996;20:1448–54.
Murphy WM, Deanna DG. The nested variant of transitional cell carcinoma: a neoplasm resembling proliferation of Brunn’s nests. Mod Pathol. 1992;5:240–3.
Volmar KE, Chan TY, De Marzo AM, Epstein JI. Florid von Brunn nests mimicking urothelial carcinoma: a morphologic and immunohistochemical comparison to the nested variant of urothelial carcinoma. Am J Surg Pathol. 2003;27:1243–52.
Brimo F, Dauphin-Pierre S, Aprikian A, Kassouf W, Tanguay S, Ajise O, et al. Inverted urothelial carcinoma: a series of 12 cases with a wide morphologic spectrum overlapping with the large nested variant. Hum Pathol. 2015;46:1506–13. https://doi.org/10.1016/j.humpath.2015.06.010.
Mally AD, Tin AL, Lee JK, Satasivam P, Chae EK, Donat SM, et al. Clinical outcomes of patients with T1 nested variant of urothelial carcinoma compared to pure urothelial carcinoma of the bladder. Clin Genitourin Cancer. 2017. https://doi.org/10.1016/j.clgc.2017.07.002.
Zhong M, Tian W, Zhuge J, Zheng X, Huang T, Cai D, et al. Distinguishing nested variants of urothelial carcinoma from benign mimickers by TERT promoter mutation. Am J Surg Pathol. 2015;39:127–31. https://doi.org/10.1097/PAS.0000000000000305.
Warrick JI, Kaag M, Raman JD, Chan W, Tran T, Kunchala S, et al. FOXA1 and CK 14 as markers of luminal and basal subtypes in histologic variants of bladder cancer and their conventional urothelial carcinoma. Virchows Arch. 2017;471:337–45. https://doi.org/10.1007/s00428-017-2190-3.
•• Weyerer V, Weisser R, Moksalev EA, Haller F, Stoehr R, Eckstein M, et al. Distinct genetic alterations and luminal molecular subtype in nested variant of urothelial carcinoma. Histopathology. 2019. https://doi.org/10.1111/his.13958 This study describes the molecular analysis of the largest cohort of nested variant of UC (60 cases) using SNaPshot analysis for TERT mutation anlaysis and target sequencing of 48 cancer related genes by Next Generation Sequencing (NGS) in 26 patients. Immunohistochemical analysis was performed in all cases to elucidate the molecular subtype of these tumors (luminal versus basal). 62.5% of cases showed TERT promoter mutations, with immunohistochemistry revealing a luminal molecular subtype. TP53, JAK3 and CTNNB1 were amongst the most frequently mutated genes by NGS.
Lopez-Beltran A, Montironi R, Cheng L. Microcystic urothelial carcinoma: morphology, immunohistochemistry and clinical behavior. Histopathology. 2014;64:872–9. https://doi.org/10.1111/his.12345.
Paner GP, Annaiah C, Gulmann C, Rao P, Ro JY, Hansel DE, et al. Immunohistochemical evaluation of novel and traditional markers associated with urothelial differentiation in a spectrum of variants of urothelial carcinoma of the urinary bladder. Hum Pathol. 2014;45:1473–82. https://doi.org/10.1016/j.humpath.2014.02.024.
Venyo AK. Microcystic variant of urothelial carcinoma. Ther Adv Urol. 2013;2013:654751. https://doi.org/10.1155/2013/654751.
Lopez-Beltran A, Montironi R, Blanca A, Cheng L. Invasive micropapillary urothelial carcinoma of the bladder. Hum Pathol. 2010;4:1159–64. https://doi.org/10.1016/j.humpath.2009.
Wang JK, Boorjian SA, Cheville JC, Kim SP, Tarrell RF, Thapa K, et al. Outcomes following radical cystectomy for micropapillary bladder cancer versus pure urothelial carcinoma: a matched cohort analysis. World J Urol. 2012;30:801–6. https://doi.org/10.1007/s00345-012-0976-0.
Amin MB, Ro JY, el-Sharkawy T, Lee KM, Troncoso P, Silva EG, et al. Micropapillary variant of transitional-cell carcinoma of the urinary bladder: histologic pattern resembling ovarian papillary serous carcinoma. Am J Surg Pathol. 1994;18:1224–32.
Kamat AM, Gee JR, Dinney CP, Grossman HB, Swanson DA, Millikan RE, et al. The case of early cystectomy in the treatment of non-muscle invasive micropapillary bladder carcinoma. J Urol. 2006;175:881–5. https://doi.org/10.1016/S0022-5347(05)00423-4.
Alkibay T, Sozen S, Gurocak S, Isik Gonul I, Poyraz A, Ure I. Micropapillary pattern in urothelial carcinoma: a clinicopathological analysis. Urol Int. 2009;83:300–5. https://doi.org/10.1159/000241672.
Sangoi AR, Beck AH, Amin MB, Cheng L, Epstein JI, Hansel DE, et al. Interobserver reproducibility in the diagnosis of invasive micropapillary carcinoma of the urinary tract among urologic pathologists. Am J Surg Pathol. 2010;34:1367–76. https://doi.org/10.1097/PAS.0b013e3181ec86b3.
Nassar H, Pansare V, Zhang H, Che M, Sakr W, Ali-Fehmi R, et al. Pathogenesis of invasive micropapillary carcinoma: role of MUC1 glycoprotein. Mod Pathol. 2004;17:1045–50. https://doi.org/10.1038/modpathol.3800166.
Comperat E, Roupret M, Yaxley J, Reynolds J, Varinot J, Ouzaid I, et al. Micropapillary urothelial carcinoma of the urinary bladder: a clinicopathological analysis of 72 cases. Pathology. 2010;42:650–4. https://doi.org/10.3109/00313025.2010.522173.
Samaratunga H, Khoo K. Micropapillary variant of urothelial carcinoma of the urinary bladder; a clinicopathological and immunohistochemical study. Histopathology. 2004;45:55–64. https://doi.org/10.1111/j.1365-2559.2004.01895.
•• Zinall U, Weyerer V, Comperat E, Camparo P, Gaisa TN, Knuechel-Clarke R, et al. Micropapillary urothelial carcinoma: evaluation of HER2 status and immunohistochemical characterization of the molecular subtype. Hum Pathol. 2018;80:55–64. https://doi.org/10.1016/j.humpath.2018.05.022 This study is the largest study to date of 94 cases of micropapillary urothelial carcinoma (MPUC, evaluated for HER2 status using immunohistochemistry, CISH and mutational analysis. HER2 overexpression and/amplification were seen in 30% of the cases while HER 2 mutations using Sanger sequencing for exons 4 and 8 were seen in a very small fraction of cases. Luminal markers were overexpressed in the majority of cases allowing for the subclassification of this variant into the luminal subtype. This finding has implications for targeted therapy in MPUC.
Nguyen D, Taheri D, Springer S, Cowan M, Guner G, Mendoza Rodriguez MA, et al. High prevalence of TERT promoter mutations in micropapillary urothelial carcinoma. Virchows Arch. 2016;469:427–34. https://doi.org/10.1007/s00428-016-2001.
Schneider SA, Sukov WR, Frank I, Boorjian SA, Costello BA, Tarrell RF, et al. Outcome of patients with micro- papillary urothelial carcinoma following radical cystectomy: ERBB2 (HER2) amplification identifies patients with poor outcome. Mod Pathol. 2014;27:758–64. https://doi.org/10.1038/modpathol.2013.201.
Figueroa JD, Ye Y, Siddiq A, Garcia-Closas M, Chatterjee N, Prokunina-Olsson L, et al. Genome-wide association study identifies multiple loci associated with bladder cancer risk. Hum Mol Genet. 2014;23:1387–98. https://doi.org/10.1093/hmg/ddt519.
Willis DL, Flaig TW, Hansel DE, Milowsky MI, Grubb RL, Al-Ahmadie HA, et al. Micropapillary bladder cancer: current treatment patterns and review of the literature. Urol Oncol. 2014;32:826–32. https://doi.org/10.1016/j.urolonc.2014.01.020.
Willis DL, Fernandez MI, Dickstein RJ, Parikh S, Shah JB, Pisters LL, et al. Clinical outcomes of cT1 micropapillary bladder cancer. J Urol. 2015;193:1129–34. https://doi.org/10.1016/j.juro.2014.09.092.
Spaliviero M, Dalbagni G, Bochner BH, Poon BY, Huang H, Al-Ahmadie HA, et al. Clinical outcome of patients with T1 micropapillary urothelial carcinoma of the bladder. J Urol. 2014;192:702–7. https://doi.org/10.1016/j.juro.2014.02.2565.
Siefker-Radtke AO, Dinney CP, Shen Y, Williams DL, Kamat AM, Grossman HB, et al. A phase 2 clinical trial of sequential neoadjuvant chemotherapy with ifosfamide, doxo- rubicin, and gemcitabine followed by cisplatin, gemcitabine, and ifosfamide in locally advanced urothelial cancer: final results. Cancer. 2013;119:540–7. https://doi.org/10.1002/cncr.27751.
•• Vetterlein MW, Wankowicz SAM, Seisen T, Lander R, Loppenberg B, Chun FK. Neoadjuvant chemotherapy prior to radical cystectomy for muscle-invasive bladder cancer with variant histology. Cancer. 2017;15(123):4346–55. https://doi.org/10.1002/cncr.30907 2018 cases with histological variants were retrieved from the National Cancer Database. Logistic regression models estimated the odds of non-organ-confined disease at the time of RC for each histological variant, stratified by the receipt of neoadjuvant chemotherapy (NAC). Cox regression models were used to examine the effect of NAC on overall mortality in each variant subgroup. This study found that variant histology including neuroendocrine tumors, micropapillary UC and sarcomatoid urothelial carcinomas were less likely to have non organ-confined disease after neoadjuvant chemotherapy, but only patients with neuroendocrine tumors had an overall survival benefit because of the NAC.
Gulley ML, Amin MB, Nicholls JM, Banks PM, Ayala AG, Srigley JR, et al. Epstein-Barr virus is detected in undifferentiated nasopharyngeal carcinoma but not in lymphoepithelioma-like carcinoma of the urinary bladder. Hum Pathol. 1995;26:1207–14.
Lopez-Beltran A, Luque RJ, Vicioso L, Anglada F, Requena MJ, Quintero A, et al. Lymphoepithelioma- like carcinoma of the urinary bladder: a clinicopathologic study of 13 cases. Virchows Arch. 2001;438:552–7.
Williamson SR, Zhang S, Lopez-Beltran A, Shah RB, Montironi R, Tan P-H, et al. Lymphoepithelioma-like carcinoma of the urinary bladder: clinicopathologic, immunohistochemical and molecular features. Am J Surg Pathol. 2011;35:474–83. https://doi.org/10.1097/PAS.0b013e31820f709e.
Tamas EF, Nielsen ME, Schoenberg MP, Epstein JI. Lymphoepithelioma-like carcinoma of the urinary tract: a clinicopathological study of 30 pure and mixed cases. Mod Pathol. 2007;20:828–34. https://doi.org/10.1038/modpathol.3800823.
Ricardo-Gonzalez RR, Nguyen M, Gokden N, Sangoi AR, Presti JC Jr, McKenney JK, et al. Plasmacytoid carcinoma of the bladder: a urothelial carci- noma variant with a predilection for intraperitoneal spread. J Urol. 2012;187:852–5. https://doi.org/10.1016/j.juro.2011.10.145.
Kaimakliotis HZ, Monn MF, Cary KC, Pedrosa JA, Rice K, Materson TA, et al. Plasmacytoid variant urothelial bladder cancer: is it time to update the treatment paradigm? Urol Oncol. 2014;32:833–8. https://doi.org/10.1016/j.urolonc.2014.03.008.
• Fox MD, Xiao L, Zhang M, Kamat AM, Siefker-Radtke A, Zhang L, et al. Plasmacytoid urothelial carcinoma of the urinary bladder. A clinicopathologic and immunohistochemical analysis of 49 cases. Am J Clin Pathol. 2017;147:500–6. https://doi.org/10.1093/ajcp/aqx029 This study is a comprehensive clinicopathologic and immunohistochemical analysis of a large cohort of plasmacytoid urothelial carcinoma (PUC). All cases showed diffuse infiltration of the muscle wall, with 57% dying from the disease at a mean of 23 months. Majority of the cases showed lack of immunoreactivity for RB1 protein (12/32) and E-cadherin (8/30). The lack of E-cadherin in PUC may contribute to the discohesion of the tumor cells and to the aggressive nature of this variant.
•• Li Q, Assel M, Benfante NE, Pietzak JE, Herr HW, Donat M, et al. The impact of plasmacytoid variant histology on the survival of patients with urothelial carcinoma of bladder after radical cystectomy. Eur Urol Focus. 2019;5(1):104–8. https://doi.org/10.1016/j.euf.2017.06.013 One of the largest retrospective study of patients with plasmacytoid urothelial carcinoma (PCV) (98 patients) who underwent radical cystectomy compared to a large cohort (1312 patients ) with pure UC. The study found that patients with PCV UC were more likely to have advanced tumor stage (p=0.001), positive lymph nodes (p=0.038), and receive neoadjuvant chemotherapy than those with pure UC (46% vs 22%, p<0.0001). The rate of positive soft tissue surgical margins was over five times greater in the PCV UC group compared with the pure UC group, with median OS for pure UC being 8yr versus PCV patients of 3.8 yr. On multivariable analysis the association between PCV and OS was not significant. The authors conclude that patients with PCV features have a higher disease burden at RC compared with those with pure UC. However, PCV was not an independent predictor of survival after RC on multivariable analysis, suggesting that PCV histology should not be used as an independent prognostic factor.
Lopez-Beltran A, Requena MJ, Montironi R, Blanca A, Cheng L. Plasmacytoid urothelial carcinoma of the bladder. Hum Pathol. 2009;40:1023–8. https://doi.org/10.1016/j.humpath.2009.01.001.
Nigwekar P, Tamboli P, Amin MB, Osunkoya AO, Ben-Dor D, Amin MB. Plasmacytoid urothelial carcinoma: detailed analysis of morphology with clinicopathological correlation in 17 cases. Am J Surg Pathol. 2009;33:417–24. https://doi.org/10.1097/PAS.0b013e318186c45e.
• Perrino CM, Eble J, Kao C, Whaley RD, Cheng L, Idrees M, et al. Plasmacytoid/diffuse urothelial carcinoma: a single-institution immunohistochemical and molecular study of 69 patients. Hum Pathol. 2019;90:27–36. https://doi.org/10.1016/j.humpath.2019.04.012 Study of a large cohort of plasmacytoid urothelial carcinoma (PUC), with the identification of 3 distinct morphological subtypes of PUC: classic, desmoplastic and pleomorphic. This study reaffirms the previous studies regarding the immunohistochemistochemical profile of these tumors with a frequent loss of E-cadherin. They reported worst clinical behavior for tumors in the desmoplastic subgroup. This study also raises the issue of whether some tumors classified as UC with rhabdoid morphology may actually fall into the pleomorphic subtype of PUC. However, more studies are required to validate this finding.
•• Al-Ahmadie HA, Iyer G, Lee BH, Scott SN, Mehra R, Bagrodia A, et al. Frequent somatic CDH1 loss-of-function mutations in plasmacytoid variant bladder cancer. Nat Genet. 2016;48:356–8. https://doi.org/10.1038/ng.3503 This study documents CDH1 alterations as pathognomonic of plasmacytoid UC (PUC). In a study of 31 cases of PUC, 97% showed alterations in the CDH1 gene. 84% showed truncating somatic mutations in CDH1 gene with all cases showing loss of protein expression of E-cadherin by immunohistochemistry. Also using two urothelial cell lines with CRISPR/Cas9-mediated knockout of CDH1, the authors were able to demonstrate increased tumor cell migration, which helps explain the invasive properties characteristic of plasmacytoid urothelial carcinoma. These alterations were not seen in non plasmacytoid urothelial carcinoma. In addition the similarities in the pattern of co-altered genes within the plasmacytoid and non plasmacytoid UC suggest a common cell of origin.
Cancer Genome Atlas Research Network. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature. 2014;507:315–22. https://doi.org/10.1038/nature12965.
Keck B, Wach S, Kunath F, Bertz S, Taubert H, Lehmann J, et al. Nuclear E-cadherin expression is associated with the loss of membranous E-cadherin, plasmacytoid differentiation and reduced overall survival in urothelial carcinoma of the bladder. Ann Surg Oncol. 2013;20:2440–5. https://doi.org/10.1245/s10434-013-3075-6.
• Borhan WM, Cimino-Mathews AM, Montgomery EA, Epstein JI. Immunohistochemical differentiation of plasmacytoid urothelial carcinoma from secondary carcinoma involvement of the bladder. Am J Surg Pathol. 2017;41:1570–5. https://doi.org/10.1097/PAS.0000000000000922 Comparative immunohistochemistry study using a large cohort of plasmacytoid urothelial carcinoma (PUC), to distinguish from lobular breast carcinoma and signet ring adenocarcinomas of the stomach, which are close morphological differentials of PUC. The authors recommend a panel of mammaglobin, ER and uroplakin II to exclude lobular breast carcinoma, and the use of GATA-3 and uroplakin II to rule out gastric primary.
• Samaratunga H, Delahunt B, Egevad L, Adamson M, Hussey D, Malone G, et al. Pleomorphic giant cell carcinoma of the urinary bladder: an extreme form of tumour dedifferentiation. Histopathology. 2016;68:533–40. https://doi.org/10.1111/his.12785 The largest study to date of this variant of UC, consisting of the clinical, morphological and immunohistochemical profile of 13 cases. 50% of patients with available follow up died within 1 year of diagnosis. The authors documented the presence of admixed conventional UC in 62% of their cases, with similar immunohistochemical profile as the conventional UC. They suggest that this variant represents an extreme form of de-differentiation of UC.
Samaratunga H, Delahunt B. Recently described and unusual variants of urothelial carcinoma of the urinary bladder. Pathology. 2012;44:407–18. https://doi.org/10.1097/PAT.0b013e3283560172.
Lopez-Beltran A, Amin MB, Oliveira PS, Montironi R, Algaba F, McKenney JK, et al. Urothelial carcinoma of the bladder, lipid cell variant: clinicopathologic findings and LOH analysis. Am J Surg Pathol. 2010;34(3):371–6. https://doi.org/10.1097/PAS.0b013e3181cd385b.
Knez VM, Barrow W, Lucia MS, Wilson S, La Rosa FG. Clear cell urothelial carcinoma of the urinary bladder: a case report and review of the literature. J Med Case Rep. 2014;8:275. https://doi.org/10.1186/1752-1947-8-275.
Lopez-Beltran A, Pacelli A, Rothenberg HJ, Wollan PC, Zincke H, Blute ML, et al. Carcinosarcoma and sarcomatoid carcinoma of the bladder: clinicopathological study of 41 cases. J Urol. 1998;159:1497–503. https://doi.org/10.1097/00005392-199805000-00023.
Wright JL, Black PC, Brown GA, Porter MP, Kamat AM, Dinney CP, et al. Differences in survival among patients with sarcomatoid carcinoma, carcinosarcoma and urothelial carcinoma of the bladder. J Urol. 2007;178:2302–6. https://doi.org/10.1016/j.uro.2007.08.038.
Sanfrancesco J, McKenney JK, Leivo MZ, Gupta S, Elson P, Hansel DE. Sarcomatoid urothelial carcinoma of the bladder: analysis of 28 cases with emphasis on clinicopathologic features and markers of epithelial-to-mesenchymal transition. Arch Pathol Lab Med. 2016;140:543–51. https://doi.org/10.5858/arpa.2015-0085-OA.
•• Guo CC, Majewski T, Zhang L, Yao H, Bondaruk J, Wang Y, et al. Dysregulation of EMT drives the progression to clinically aggressive sarcomatoid bladder cancer. Cell Rep. 2019;27(6):1781–93. https://doi.org/10.1016/j.celrep.2019.04.048 The authors report a comprehensive genomic analysis of 28 cases of SARC and 84 cases of conventional urothelial carcinoma (UC), with the TCGA cohort of 408 muscle-invasive bladder cancers serving as the reference. SARCs showed a distinct mutational landscape, with enrichment of TP53, RB1, and PIK3CA mutations. They are related to the basal molecular subtype of conventional UCs and could be divided into epithelial-basal and more clinically aggressive mesenchymal subsets on the basis of TP63 and its target gene expression levels. Other analyses revealed that SARCs are driven by downregulation of homotypic adherence genes and dysregulation of the EMT network, and nearly half exhibit a heavily infiltrated immune phenotype. These findings have important implications for prognostication and the development of more effective therapies for this highly lethal variant of bladder cancer.
•• Priore SF, Schwartz LE, Epstein JI. An expanded immunohistochemical profile of osteoclast-rich undifferentiated carcinomas of the urinary tract. Mod Pathol. 2018;31:984–8. https://doi.org/10.1038/s41379-018-0012-z This is the largest study to date of osteoclast-rich undifferentiated carcinomas of the urinary tract (ORUCUT), which investigates the immunohistochemical profile of these tumors with respect to more specific urothelial markers. This study identified 21 cases of ORUCUT and performed immunohistochemistry for GATA3, uroplakin II, and thrombomodulin along with pancytokeratin (AE1/3) on all cases. Mononuclear cells stained positive in 20 cases (95%) for GATA3 and 19 cases (90%) for thrombomodulin. None of the mononuclear cells were positive for uroplakin II and only three cases showed focal positivity for AE1/3. The osteoclast-like giant cells were negative for GATA3, uroplakin II, thrombomodulin, and AE1/3, providing additional support to a reactive origin for these cells. Additionally, 15 cases (71%) were associated with either in situ or invasive urothelial carcinoma. The findings support a urothelial origin for this tumor.
Paner GP, Cox RM, Richards K, Akki A, Gokden N, Lopez-Beltran A, et al. Pseudoangiosarcomatous urothelial carcinoma of the urinary bladder. Am J Surg Pathol. 2014;38:1251–9. https://doi.org/10.1097/PAS.0000000000000241.
Yildiz P, Behzatoglu K, Hacihasanoglu E, Okcu O, Durak H, Yucetas U. Histological, immunohistochemical features and pathogenesis of pseudoan giosarcomatous urothelial carcinoma. Ann Diagn Pathol. 2017;30:17–20. https://doi.org/10.1016/j.anndiagpath.2017.05.007.
Cox RM, Schneider AG, Sangoi AR, Clingan WJ, Gokden N, McKenney JK. Invasive urothelial carcinoma with chordoid features. A report of 12 distinct cases characterized by prominent myxoid stroma and cordlike epithelial architecture. Am J Surg Pathol. 2009;33:1213–9. https://doi.org/10.1097/PAS.0b013e3181a8ffbe.
Parwani AV, Herawi M, Volmar K, Tsay SH, Epstein JI. Urothelial carcinoma with rhabdoid features: report of 6 cases. Hum Pathol. 2006;37:168–72. https://doi.org/10.1016/j.humpath.2005.10.002.
• Agaimy A, Bertz S, Cheng L, Hes O, Junker K, Keck B, et al. Loss of expression of the SWI/SNF complex is a frequent event undifferentiated/dedif- ferentiated urothelial carcinoma of the urinary tract. Virchows Arch. 2016;469:321–30. https://doi.org/10.1007/s00428-016-1977-y This is the first study exploring SWI/SNF expression in undifferentiated UC of the urinary tract. In this study, the authors analyzed by immunohistochemistry 14 undifferentiated UCs (11 from bladder and 3 from renal pelvis) with a nondescript anaplastic or rhabdoid morphology, using commercially available antibodies against the SWI/SNF components SMARCB1 (INI1), SMARCA2, SMARCA4, SMARCC1, SMARCC2, and ARID1A. All tumors were muscle-invasive (9 were T3-4). A conventional UC component was seen in 57% of the cases. The undifferentiated component expressed pan-cytokeratin AE1/AE3 (13/14), vimentin (8/14) and GATA3 (9/14). Complete loss of at least one SWI/SNF subunit was detected in 10/14 cases (71 %) in the undifferentiated component. SMARCA2 was most frequently lost followed by ARID1A. Their results are similar to studies in other epithelial tumors where the SWI/SNF complex has been implicated in the dedifferentiation process and association with aggressive clinical course.
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•• Robertson AG, Kim J, Al-Ahmadie H, Bellmunt J, Guo G, Cherniack AD, et al. Comprehensive molecular characterization of muscle-invasive bladder cancer. Cell. 2017;171(3):540–56. https://doi.org/10.1016/j.cell.2018.07.036 This study reports a comprehensive analysis of 412 muscle-invasive bladder cancers characterized by multiple TCGA analytical platforms. The study found fifty-eight genes to be significantly mutated, with the overall mutational load to be associated with APOBEC-signature mutagenesis. mRNA expression clustering also identified a poor-survival "neuronal" subtype which is not characterized by small cell or neuroendocrine morphology. Clustering by mRNA, long non-coding RNA (lncRNA), and miRNA expression identified subsets with differential epithelial-mesenchymal transition status, histologic features, and survival. This study identified 5 expression subtypes that have a lot of promise to stratify response to different treatments.
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Aron, M. Variant Histology in Bladder Cancer—Current Understanding of Pathologic Subtypes. Curr Urol Rep 20, 80 (2019). https://doi.org/10.1007/s11934-019-0949-6
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DOI: https://doi.org/10.1007/s11934-019-0949-6