Clinicopathologic and Immunohistochemical Study of Combined Small Cell Carcinoma and Urothelial Carcinoma Molecular Subtype

Muscle invasive bladder cancer, an aggressive disease with heterogeneous molecular profiles, has recently been subclassified into three major molecular subtypes -basal, luminal and “p53-like” urothelial carcinomas (UCas), which bear prognostic and therapeutic implication. Similar to breast cancer, basal and luminal subtype UCas are designated by basal (CK5/14) and luminal (CK20) markers. The “p53-like” subtype presents with wild-type p53 gene with upregulated p53 pathways and is implicated in chemoresistance. Urinary bladder is one of the most common primary sites of extrapulmonary small cell carcinoma (SmCC). Bladder SmCC frequently coexists with UCa; however, the relation of SmCC with specific UCa molecular subtypes has not been studied. The aim of this study is to investigate the clinicopathology and immunophenotypes of the combined SmCC and UCa molecular subtypes. A total of 22 combined SmCC and UCa cases were studied for the clinicopathology and immunohistochemical (IHC) profiles by luminal and basal cell markers as well as Her2/Neu and p53. Our results demonstrated that all the urinary bladder SmCCs were associated with high grade UCas. They were more commonly seen in older male patients with a smoking history and had a poor prognosis. Based on the reported molecular subtyping, the UCas could be immunohistochemically subclassified into luminal, basal, dual and null types, which showed different clinicopathologic and IHC features. Compared to non-SmCC associated UCa, the subtypes of UCa in the combined SmCCs and UCas were characterized by: 1) Although overall luminal type was still relatively more common in men, basal marker-expressing subtypes were significantly increased in incidence and were more common in women. 2) Her2/Neu overexpression was more commonly observed in luminal than basal cell marker-expressing UCas. 3) IHC overexpression of p53 was common in all the subtypes, with UCas and SmCCs sharing the same p53 expression pattern. Although limited by relatively a small number of cases, the results of this study will enhance our understanding of the combined SmCC and UCa entity and potentially lead to a future therapeutic management.