Urothelial Carcinoma: Divergent Differentiation and Morphologic Subtypes

Abstract

Urothelial carcinoma (UC) is known to encompass a wide spectrum of morphologic features and molecular alterations. Approximately 15% to 25% of invasive UC exhibits histomorphologic features in the form of "divergent differentiation" along other epithelial lineages, or different "subtypes" of urothelial or sarcomatoid differentiation. It is recommended that the percentage of divergent differentiation and or subtype(s) be reported whenever possible. Recent advances in molecular biology have led to a better understanding of the molecular underpinning of these morphologic variations. In this review, we highlight histologic characteristics of the divergent differentiation and subtypes recognized by the latest version of WHO classification, with updates on their molecular and clinical features.

Keywords: Divergent differentiation; Subtype; Urothelial carcinoma.

Fig. 1.

Squamous differentiation of urothelial carcinoma (UC) and squamous cell carcinoma of the bladder. (A-B) Examples of squamous differentiation with transition from adjacent conventional urothelial carcinoma in the bladder. (C-D) Pure squamous cell carcinoma can also occur in the bladder. (E) In rare cases, the carcinoma is associated with high-risk human papillomavirus (HPV), with basaloid morphology (high-power view in inset) and positive RNA in situ hybridization for high-risk HPV (F).

Fig. 2.

Glandular differentiation of UC and pure adenocarcinoma of the bladder. (A-B) Examples of glandular differentiation with transition from adjacent conventional urothelial carcinoma in the bladder. (C-D) Rarely, pure adenocarcinoma can also occur in the bladder. The example in these figures shows resemblance to adenocarcinoma of gastrointestinal origin with acinar and cribriform architecture which is lined by pseudostratified epithelium.

Fig. 3.

Adenocarcinomas of Müllerian type in urinary bladder. (A-B) Examples of clear cell adenocarcinoma (CCA) that shows tubulocystic pattern (A) with hyalinized papillary cores or solid sheet-like growth patterns (B). Nuclear hobnailing and prominent cytological atypia are shown in the high-power view (insets). The tumor cells are typically positive for PAX8 (C) and may be positive for HNF1ß (D). (E) Another example of CCA demonstrates microcystic/glandular growth pattern and absence of ARID1A expression by immunohistochemistry (F), which corresponds to ARID1A mutation.

Fig. 4.

Neuroendocrine carcinoma of urinary bladder. (A) Small cell carcinoma (SmCC) of urinary bladder exhibits characteristic small cells with high nuclear to cytoplasmic ratio, nuclear molding, abundant mitotic figures and necrosis that is virtually identical SmCC in the lung. The tumor cells are classically positive for neuroendocrine markers including synaptophysin (B left), chromogranin (B right), and INSM1 (C left), and exhibit loss of RB expression (C right). (D-E) Large cell neuroendocrine carcinoma (LCNEC) exhibits variable architectural patterns; the example in (D) shows solid and vaguely rosette-like growth pattern, while the example in (E) exhibits prominent glandular architecture. LCNEC usually contains large high grade polygonal tumor cells with variable amounts cytoplasm and prominent nucleoli (D inset). The tumor cells are positive for neuroendocrine markers such as synaptophysin (F left) and chromogranin (F right) in more variable degrees.

Fig. 5.

UC with trophoblastic differentiation. (A) Example of clusters of syncytiotrophoblasts in the background of conventional UC, with IHC evidence of β-HCG expression in (B).

Fig. 6.

Micropapillary urothelial carcinoma (MPUC). (A-B) Examples of classic MPUC exhibit multiple small clusters of tumor cells with reversal of polarity, embedded in a back-to-back lacunar/retraction space and lacking a true fibrovascular cores. (C) MPUC may exist with conventional UC. (D) IHC for HER2neu demonstrates overexpression of HER2, which corresponds to amplification of ERBB2 gene in the MPUC area; note that the adjacent UC-NOS only shows weak membranous expression.

Fig. 7.

Plasmacytoid urothelial carcinoma (PUC). (A-B) Examples of PUC that shows infiltrative growth of discohesive single or small clusters of cells that resemble plasma cells. The tumor cells are typically positive for GATA-3 (C) but shows abnormal expression of E-cadherin (D), which corresponds to alteration of CDH1 gene. (E) PUC has high rate of lymph node metastasis. (F) IHC for E-cadherin demonstrates absence of expression in PUC involving lymph node.

Fig. 8.

(A) Nested subtype of UC (NVUC) in superficial lamina propria of urinary bladder shows confluent nests and cordlike growth with cystitis cystica-like areas. Note the morphologic resemblance to benign or non-neoplastic entities such as proliferative cystitis and von Brunn nest hyperplasia. (B-C) NVUC characteristically exhibits deceptively bland cytology, jagged tumor-stroma interface and minimal desmoplastic response. (D) Large nested subtype consists of large irregular and infiltrating nests, and may associate with stromal reaction and has an overall bland histologic feature. (E) Lymphoepithelioma-like urothelial carcinoma (LELC) consists of syncytial growth of high-grade epithelial cells in the background of dense lymphoplasmacytic infiltrate. The tumor cells harbor large pleomorphic nuclei, vesicular chromatin, prominent nucleoli, and ill-defined cytoplasmic borders, and are evident by pan-cytokeratin staining (F). (G) Lipid-rich urothelial carcinoma demonstrates large neoplastic cells with optically clear empty multivacuolated cells resembling lipoblasts. (H) Example of giant cell urothelial carcinoma with loosely cohesive nests or single cells of anaplastic giant cells.

Fig. 9.

Sarcomatoid urothelial carcinoma exhibits mesenchymal differentiation, most commonly with spindled appearance (A, B). Myxoid stromal change may be observed in various degrees (C). Heterologous elements/differentiation may occur; examples here include (D) rhabdomyosarcomatous differentiation and (E) angiosarcomatoid differentaition. (F) Poorly-differentiated urothelial carcinoma remains in the 2022 WHO classification to encompasses undifferentiated carcinoma with osteoclastic giant cells and any other tumors in which a substantial component of the neoplasm does not show a definitive line of differentiation.