Small cell bladder cancers (SCCB) are a relatively rare, but highly aggressive disease.1 Given the lack of randomized prospective trials, retrospective studies and few prospective series support the treatment decisions. A multimodality approach, which combines chemotherapy with radiation or surgery, is often proposed to patients with localized disease. The use of chemotherapy has been associated with better outcome and platinum-based regimens are usually recommended, based on the known sensitivity of small cell lung cancer (SCLC) to these agents.

Our recent study analyzed 384 patients with nonmetastatic SCCB included in the U.S. Surveillance, Epidemiology and End Results (SEER) database, in order to investigate the impact of chemotherapy, surgery, and radiotherapy on overall survival.2 Chemotherapy (neo-adjuvant, perioperative or adjuvant) was associated with a better outcome. In addition, patients with T2 disease treated with chemosurgery showed better survival compared to those who underwent chemoradiation.

Our analysis has several intrinsic limits and this last observation might be related to confounder factors that cannot be adjusted in multivariable analysis or might reflect the possible clinical downstaging of patients who received radiotherapy. However, our data might also support the assumption that SCCB exhibits different tumor biology and clinical behavior compared to SCLC. In fact, concomitant chemoradiotherapy plus prophylactic cranial irradiation, rather than chemo-surgery, is usually recommended as the best treatment option for SCLC, based on the notion that this neoplasm is highly aggressive and disseminates early3.

Shen and colleagues have recently performed deep molecular profiling of SCCB.4 These neoplasms harbor frequent genetic aberrations, involving TP53, RB1, PIK3CA, ERCC2, ARID1A, and EP300, which have been implicated in neuroendocrine differentiation and urothelial bladder cancer.4 These findings are consistent with those of previous studies and suggest that the small cell component is often the result of divergent differentiation from a single common progenitor.5-7 Therefore, lineage switching, rather than an independent progression, is probably the predominant mechanism of development of SCCB.8 A similar divergent clonal evolution has been widely described in pretreated castration-resistant neuroendocrine prostate cancer.9 However, lineage switching may also occur in the context of de novo disease without the selective pressure of treatments.

Although all small cell tumors share organ-independent common molecular and pathologic features, the biology of SCCB still probably recalls their primary origin. SCCB is aggressive, undifferentiated neoplasms, which retain site-specific alterations and show neuroendocrine features. Response to chemotherapy, surgery or radiotherapy is dependent on the driving aberrations that occur in each specific framework. Platinum-based chemotherapy is active, but SCCB should not be invariably associated with SCLC. For example, the uninspiring results obtained with immune checkpoint inhibitors for the latter should not discourage from investigating the activity of immunotherapy for the systemic treatment of SCBC.10,11

In the lack of a deep personalized molecular characterization, a multimodality approach focused on the site of origin is probably the best treatment choice for patients with SCCB. “The apple doesn’t fall far from the tree”: until otherwise proven, genitourinary imprinting guides the evolution of these small cell tumors.

Fig.1. Origin of SCCB. Several studies suggest that lineage switching from urothelial precursors is the predominant mechanism of development of SCCB.

Academic Unit of Medical Oncology Genova

Written by: Carlo Cattrini, MD, Elisa Zanardi, Alessandra Rubagotti, PhD, Francesco Boccardo, MD, Academic Unit of Medical Oncology, San Martino Polyclinic Hospital, Genoa, Italy

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