How Wide Is the Spectrum of Neuroendocrine Carcinoma of the Urinary Bladder?

Abstract

Better characterization of the clinical outcome and response to therapy of extrapulmonary neuroendocrine (NE) carcinomas is an ongoing effort. However, this endeavor is belabored with notable challenges: (1) These carcinomas are rare. With the exception of the histologically distinctive and clinically indolent carcinoid (also termed well-differentiated neuroendocrine carcinoma by some investigators), NE carcinomas typically represent far fewer than 1% of carcinomas of solid organs. Consequently, most single centers have difficulty assembling a large series in a sufficiently short time so that a clinical outcome analysis is meaningful.1,2 (2) These carcinomas are not as well defined histologically as one might assume. The histologic definition is a bit fuzzy and, accordingly, subject to observer variability. The following questions can be raised when this issue is considered: • Are tumor architecture (an organoid growth pattern) and cytologic appearance (a finely clumped pattern of chromatin and inconspicuous nucleoli) of sufficient sensitivity and specificity to unequivocally identify a small cell NE carcinoma that will express NE tissue biomarkers—chromogranin and/or synaptophysin— if immunostained? • Or, should we demand immunohistochemical verification of an NE phenotype before accepting a tumor as an NE carcinoma? • And how should we classify carcinomas that are not pure NE carcinomas but that have an NE component and a component with a phenotype common to the organ of origin, eg, urothelial carcinoma with NE differentiation? • Furthermore, should we accept as NE carcinomas tumors that are composed of cells that have the histologic and cytologic appearance of undifferentiated non–small cell carcinomas but that express chromogranin and/or synaptophysin, such as large cell NE carcinomas of the lung?3 In this issue of the Journal, Alijo Serrano et al4 motivate us to raise these questions in their report of a small series of NE carcinomas of the urinary bladder. Their article confirms already published data that small cell NE carcinomas of the urinary bladder are often of high stage at initial diagnosis, tend to have a more rapidly progressive course than do “conventional” urothelial carcinomas, and express the NE markers chromogranin and synaptophysin, in addition to other markers expressed by NE carcinomas and non-NE carcinomas, such as thyroid transcription factor (TTF)-1 and CD57. In exploring the questions raised by this article, we limit our focus to the topic of the study by Alijo Serrano et al4—NE carcinomas of the urinary bladder. Let us now address the issues we raised.