Whereas small cell cancer is a common histological variant accounting for 14% of all primitive cancers arising from the lung [1], small cell carcinoma of the bladder (SCCB) is extremely rare and accounts for less than 1% of all cancers arising from the bladder [2, 3]. To our knowledge, 882 cases have been reported in the literature as extra-pulmonary localizations of small cell carcinomas. The first case was described in 1981 by Cramer et al [4]. Small cell carcinoma (SCC) is often, but not always neuroendocrine tumour. The diagnosis of SCCB is based on criteria established by the WHO classification system. Those criteria are identical to those used to diagnose small cell lung cancer (SCLC) [5]. Immunochemical staining can be extremely helpful in establishing the diagnosis. This tumour is associated with a more aggressive behaviour and poorer prognosis than transitional cell bladder carcinoma (TCC), and is mostly diagnosed at advanced stages. Because of the rarity of the disease, no standard treatment had yet been proposed. Treatment algorithms have been extrapolated from the treatment of small cell cancer arising in the lung and often involved chemotherapy regimens using a platinum agent. We conducted a retrospective analysis of all cases of recurrent or metastatic small cell carcinoma of the bladder treated at the Léon-Bérard Cancer Centre over a 12-year period for definition of patient's outcome.

All the files of patients with locally advanced or metastatic carcinoma of the bladder that were treated at the Léon-Bérard Cancer Centre between January 1996 and December 2007, were retrospectively reviewed to select all the cases with metastatic or recurrent small cell disease. Patients were considered to have small cell carcinoma of the bladder if pathological examination of their tumour revealed the presence of any small cell component according to the WHO classification [5]. We considered and analysed each patient medical records for further investigations of demographics, clinical stage, histological results, treatments and outcome. Radiological reports were reviewed to determine the stage of the disease caused by recurrent or metastatic small cell carcinoma of the bladder, at the time of diagnosis, using the 2002 TNM classification for genitourinary tumours. Data about the different treatments used: surgery, chemotherapy and radiotherapy were extracted from each patient medical record. The date and site of recurrence and, if applicable, the date and cause of death were also considered. Survival was analyzed statistically in all patients. Overall survival was calculated from the date of diagnosis of recurrent or metastatic disease to the date of death or to the date of last follow up. We retrospectively compared survival between pure small cell carcinoma group (n = 6) and mixed small cell carcinoma group (n = 9), despite of the fact that the two groups of patients were too small and biased by a variety of different therapies. The Kaplan-Meier method was used to calculate median overall survival. The log-rank test was used to evaluate the differences between the two groups. Approval for the study was obtained from Léon-Bérard Cancer Centre, Lyon, France; Date 16/Jul/2007.

Primary SCCB is a rare disease that accounts for less than 1% of all bladder cancers [2, 3]. The relatively high incidence of 1.8% reported here might reflect a bias due to the fact that our centre mostly recruits patients with metastatic bladder cancer. Primary SCCB was initially described in 1981 by Cramer et al [4]. Since then, 882 cases of SCCB have been published up to January 2009. Pathogenesis was uncertain; however the multipotent stem cell theory applies best to this case [7–9].

When considering histological tests, SCCB is indistinguishable from its pulmonary counterpart. The diagnosis is accomplished via cystoscopy and histological analysis of the transurethral resection of bladder tumour. The diagnoses were based on the criteria established by the WHO classification system, and were identical to those related to the diagnosis of SCLC [5]. Microscopically, the tumour was composed of sheets of uniformly small, round mitotically active cells with overlapping nuclei and evenly distributed chromatin, lacking prominent nucleoli. Nuclear moulding, tumour necrosis and crush artefact were commonly seen [10]. Immunohistochemical staining and analysis showed that the cells expressed the effect of: 1- the markers of neuroendocrine differentiation, including synaptophysin (expressed at a rate of 66.6 to 76%), neuron-specific enolase (25 to 100%), and chromogranin (22 to 89%); 2- the epithelial markers: EMA (77.7%), Cytokeratine7 (59%), and CAM 5.2. 3 (47 to 66.6%); 3- other markers were less commonly expressed: TTF1 (39 to 50%), C-KIT (22 to 27%) and EGFR (27 to 36%) [3, 10–16]. In the present study, we found that most small cell bladder cancers (60%) were mixed with transitional cell carcinoma. In concordance with our results, the mean percentage of mixed SCCB obtained by the analysis of the most important published series was equal to 56% [2, 3, 6, 10, 17–22]. Other teams have shown a higher incidence of pure small cell carcinoma [3, 18, 19, 21].

Small cell bladder cancer was highly aggressive as most of the patients (up to 95%) were diagnosed at advanced stage (Stage II or more), from whom 25% were metastatic and two-thirds developed distant recurrence [18, 20, 23]. Theses finding suggest that the current TNM staging system used for bladder TCC may not be appropriate for SCCB, leading the scientific community to recommend the use of the two staging system (actually in practice): limited and extensive stages in analogy to SCLC [17, 21, 22, 24, 25].

Because small cell carcinoma of the bladder was rare, and due to lack of randomized controlled trials, no standard treatment of this disease was proposed. However, chemotherapy played a prominent role in the management of these tumours. The prognostic of SCCB was poor even in limited stage disease [20]. According to 2 large series, five years survival in all stages ranged between 16 and 25% [18, 20]. In our institution we conducted a retrospective study of 14 localised small cell carcinoma of the urinary bladder. The disease free survival was equal to 5.7 months and the overall survival was equal to 29.5 months. Two years survival was equal to 56% [6]. The prognostic of patients with stage IV disease is very poor. In the Mayo Clinic study, 19 patients were diagnosed with stage IV disease (with or without distant metastasis), only 2 were survivors. The median overall survival for patients with stage IV disease was 11 months and the one year survival rate for theses patients was 36.8%. The results obtained in our series were in concordance with previous Mayo Clinic results and showed a 7.6-month median survival and 33% survival probability at 1 year [18].

Considering the generally poor prognosis of SCCB, novel therapeutic strategies are needed to improve outcomes of patients. Targeted therapies are now established for several diseases, but have not yet been investigated in SCCB. C-KIT protein expression has been reported in 27% of cases of SCCB suggesting the possibility to consider the therapeutic use of STI-571, a small molecule inhibitor of C-KIT kinase activity, in patients with c-kit positive tumours [15]. However, STI-571 has been tried in treatment of SCLC and found to be ineffective [32–34].

Finally, we found that pure small cell carcinoma tended to have poorer outcome than mixed small cell carcinoma of the bladder. The median duration of survival was 9.9 months in the mixed small cell carcinoma group, as compared with 4.6 months in the pure small cell carcinoma group, but the difference was not statistically significant (Log rank test: p = 0.228) (Figure 2). In two series, mixed histology tended to do better than pure neuroendocrine tumour [6, 19].

Small cell carcinoma of the bladder is an uncommon tumour. Recurrent and metastatic disease was associated with very poor prognosis. The pure small cell carcinoma appeared to have poorer outcome than the mixed small cell carcinoma of the bladder. In the absence of prospective studies, the best treatment of this disease cannot be established with certainty. From our study and from the literature, we conclude that platinum-based chemotherapy is the mainstay treatment for recurrent and metastatic disease.