Histologic Variants of Urothelial Carcinoma: Morphology, Molecular Features and Clinical Implications

Abstract

Bladder cancer is a heterogeneous disease including conventional urothelial carcinoma (UC) and its histologic variants, and non-urothelial carcinoma, including squamous and glandular neoplasms. Urothelial carcinoma accounts for the majority of bladder cancer cases, but morphologic variants are common and include nested, microcystic, micropapillary, lymphoepithelioma-like, plasmacytoid, sarcomatoid, giant cell, undifferentiated, clear cell and lipoid. Certain variants of UC tend to be associated with a poor prognosis and have diagnostic and potential treatment implications that make the identification of variant histology crucial to clinical decision making. While there is still uncertainty regarding the prognostic implications of many of these variants, identifying and reporting variant histology is important to develop our understanding of their biology. Unique molecular features accompany many of these morphologic variants and to better understand these tumors, we review the molecular and clinical implications of histologic variants of bladder cancer. Major efforts are underway to include variant histology and divergent differentiation of UC in clinical trials to develop evidence based approaches to treatment. The purpose of this article is to review the current literature on variant histology of urothelial cancer and to highlight molecular findings and the clinical relevance of these tumors.

Accounting for B cell behaviour and sampling bias yields a superior predictor of anti-PD-L1 response in bladder cancer

“…Bladder cancer is divided into three disease states: non-muscle invasive, muscle-invasive, and metastatic. There are also several variants within these categories, both in terms of histology and gene expression, with different clinical significance 59 .…”

“…UC can be further subdivided into papillary and non-papillary carcinomas. Non-papillary carcinomas can exhibit variable spectrum of histological features, including squamous differentiation 59,60 .…”

Current Management of Localized Muscle-Invasive Bladder Cancer: A Consensus Guideline from the Genitourinary Medical Oncologists of Canada

“…Approximately, 10-25% of bladder cancers have a component of variant histology [47][48][49][50]. The World Health Organization and International Consultation on Bladder Cancer recognizes more than 10 unique histologic variants in bladder cancer [46,51], summarized in Table 3.…”

A phase II trial of durvalumab and tremelimumab in metastatic, non‐urothelial carcinoma of the urinary tract

“…The heterogeneity of tumors arising in the urothelial tract is reflected by the presence of divergent differentiation and variant morphologies. [1][2][3] While two thirds of these cancers are classified as pure urothelial carcinoma (UC), the remaining third exhibit some element of non-UC histology including squamous cell carcinoma (SCC), adenocarcinoma (ADC), and small cell/neuroendocrine carcinoma (NE). 4 The SCC and ADC histologies (including those of urachal origin) are considered chemotherapy resistant, unlike NE, which is initially chemotherapy sensitive but almost uniformly progresses after treatment.…”

“…The heterogeneity of tumors arising in the urothelial tract is reflected by the presence of divergent differentiation and variant morphologies 1–3 . While two thirds of these cancers are classified as pure urothelial carcinoma (UC), the remaining third exhibit some element of non‐UC histology including squamous cell carcinoma (SCC), adenocarcinoma (ADC), and small cell/neuroendocrine carcinoma (NE) 4 .…”