Small cell carcinoma of the bladder

INTRODUCTION — Small cell carcinoma (SCC) of the bladder is an aggressive, poorly differentiated neuroendocrine neoplasm that is similar to SCC of the lung in clinical behavior.

Although SCC is classified as a discrete entity, molecular studies have indicated that SCC is derived from the same clonal population as urothelial carcinoma (also known as transitional cell carcinoma) [1]. Bladder SCC is frequently found in conjunction with other histologic forms of bladder cancer [2-4]. As an example, in a series of 64 cases, 44 (68 percent) had other tumor types present, including elements of urothelial cancer in 38 cases (58 percent of the total series) [2]. Similarly, another series of 51 cases of SCC reported that elements of urothelial carcinoma, adenocarcinoma, and squamous cell carcinoma were seen in 70, 8, and 10 percent of the cases, respectively [3].

SCC of the bladder will be reviewed here. Extrapulmonary SCC at other sites is discussed separately. (See "Extrapulmonary small cell cancer".)

EPIDEMIOLOGY — SCC of the bladder is a rare neoplasm. For example, in the United States, it accounts for roughly 500 new cases annually. The incidence of SCC of the bladder may be increasing, based upon Surveillance, Epidemiology, and End Results (SEER)-Medicare data from the United States where the incidence rose from 0.05 to 0.14 cases per 100,000 population between 1991 and 2005 [5], but this still represents fewer than 1 percent of all bladder tumors [6].

Analyses of patients with SCC of the bladder from two databases (SEER and the National Cancer Database) noted the following [5,7]:

●Men are affected more commonly than women (76 versus 24 percent).

●The median age at diagnosis is 73 years, with older adults (age >75 years) having a poorer prognosis.

●Median overall survival varies substantially based on the stage of disease. Median overall survival is approximately 11 months across the entire population [5] and 21 months for those with localized SCC [7].

A past history of smoking has been associated with SCC of the bladder [2].

MOLECULAR BASIS OF DISEASE — Some molecular studies indicate that SCC is derived from the same clonal population as urothelial carcinoma. Despite this, emerging data suggest that the genetics of SCC of the bladder are different from that of conventional urothelial-derived cancer, with a distinct molecular phenotype and involved pathways.

Notable genetic and molecular findings in SCC of the bladder include:

●Frequent loss of heterozygosity at 3p25-26, which encompasses the von Hippel-Lindau (VHL) tumor suppressor gene [8].

●Telomerase reverse transcriptase (TERT) promoter mutations are common, occurring in 100 percent of cases in one observational study [9].

●More common or higher expression of progestin receptor, c-kit, topoisomerase 2, tubulin 3, ribonucleotide reductase subunit M1, and topoisomerase 1 [10]. Conversely, expression of nectin 4 in SCC of the bladder is rarely detected [11].

●Epigenetic alterations are noted to be important, with methylation silencing of the promoter for tumor suppressor genes including mut L homolog 1 (MLH1) and O-6-methylguanine DNA methyltransferase (MGMT) [10].

●Deletions at 10q, 4q, 5q, and 13q, with candidate genes including phosphatase and tensin homolog (PTEN) loss (10q23) and retinoblastoma (RB) loss (13q14) [12]. Fibroblast growth factor receptor mutations and translocations do not appear to be common in SCC.

Overexpression of actionable mutations such as c-kit [10], epidermal growth factor receptor (EGFR) [13], and somatostatin receptors [14] has also been noted in a substantial proportion of SCC of the bladder tissues. It is unknown whether targeting these alterations will improve clinical outcomes.

CLINICAL PRESENTATION — The clinical features of SCC of the bladder are similar to those of other bladder tumors and reflect the presence of a mass.

In a Rare Cancer Network series of 107 patients, the following presenting symptoms were observed [15]:

●Hematuria (86 percent)

●Ureteral obstruction and acute renal failure (13 percent)

●Dysuria and frequency (29 percent)

●Hematospermia (n = 1)

●Recurrent urinary tract infections (n = 1)

In another series, the diagnosis of SCC was incidentally made in 7 percent of patients during surveillance cystoscopy following a prior diagnosis of urothelial carcinoma. SCC is sometimes identified during surgery for a bladder tumor whose histology initially appeared to be urothelial based upon transurethral resection of bladder tumor (TURBT). Paraneoplastic syndromes can occur but are less common than with SCC of the lung [16]. (See "Clinical manifestations of lung cancer", section on 'Paraneoplastic phenomena'.)

DIAGNOSTIC WORKUP — The workup of SCC of the bladder mirrors that for other bladder cancers. (See "Clinical presentation, diagnosis, and staging of bladder cancer", section on 'Initial evaluation'.)

On cystoscopy, the most common sites involved tend to be the lateral wall or the bladder dome, although any area of the bladder can be involved.

DIAGNOSIS — The diagnosis of SCC of the bladder is generally made by histopathological examination of a tissue specimen from a transurethral biopsy or resection of a tumor. The pathology of SCC of the bladder is discussed separately. (See "Pathology of bladder neoplasms", section on 'Small cell carcinoma'.)

STAGING — The staging of SCC of the bladder uses the same tumor, node, metastasis (TNM) system as is used for other bladder cancer (table 1). However, unlike management of urothelial carcinoma, management of SCC of the bladder is the same for stages I, II, and III, so staging is of less importance in this disease. (See "Clinical presentation, diagnosis, and staging of bladder cancer", section on 'Staging'.)

The majority of patients tend to present with advanced disease. In the 2011 Surveillance, Epidemiology, and End Results (SEER) database study, the stage of disease at presentation was [5]:

●Stage I – 12 percent

●Stage II – 32 percent

●Stage III – 14 percent

●Stage IV – 36 percent

Due to the high rate of metastases, the initial evaluation should include computed tomography (CT) and/or magnetic resonance imaging (MRI) of the chest, abdomen, and pelvis. Brain imaging should be considered for patients with advanced-stage disease (T3b, node positive, metastatic).

TREATMENT — There are no randomized clinical trials upon which to base recommendations for the management of SCC of the bladder. However, several retrospective series and one prospective phase II study provide some insights.

Selection of therapy — Unlike urothelial carcinoma of the bladder, the presence or absence of muscle invasion does not affect treatment decisions for SCC because SCC has a much greater propensity to metastasize regardless of T stage. Therefore, the treatment is the same for T1, T2, and T3 tumors.

Our approach depends on whether disease is localized to the bladder or not:

●For patients with SCC of the bladder with localized disease and no evidence of disseminated metastases (stage I, II, or III disease), we suggest neoadjuvant chemotherapy followed by local therapy. However, patients who have already undergone radical cystectomy may be offered adjuvant chemotherapy with the rationale that cure with surgery alone is rare [17,18]. (See 'Neoadjuvant chemotherapy plus definitive local therapy' below.)

●For patients who are surgical candidates, we proceed with radical cystectomy. (See 'Cystectomy alone' below.)

●For patients who are unable to undergo surgery for whatever reason, we offer definitive radiation therapy (RT). (See 'Neoadjuvant chemotherapy plus radiation therapy' below.)

●For patients with SCC of the bladder and evidence of metastatic disease, we administer systemic chemotherapy utilizing a regimen with activity in SCC. Our preference is to use etoposide plus cisplatin (EP). (See 'Metastatic disease' below.)

Disease localized to the bladder — Patients with SCC of the bladder have a poor prognosis, even when disease appears to be localized, due to the development of disseminated disease in a large proportion of cases [2,6,19,20].

Although there are no randomized trials establishing the benefit of perioperative chemotherapy, retrospective data suggest that perioperative chemotherapy improves overall survival (OS) when added to cystectomy for localized small cell bladder cancer. Our preference is to administer neoadjuvant chemotherapy prior to surgery for these patients. For patients who undergo surgery without chemotherapy, which then identifies SCC or a significant component of SCC, we recommend postoperative (adjuvant) chemotherapy, with a platinum and etoposide being our preferred regimen. (See 'Neoadjuvant chemotherapy plus definitive local therapy' below.)

While the role of definitive local therapy (cystectomy or RT) has not been prospectively studied, data from neoadjuvant studies in urothelial cancer suggest that not treating the primary cancer in addition to systemic therapy risks leaving residual cancer incompletely treated.

Neoadjuvant chemotherapy plus definitive local therapy — The most widely reported approach has been to use neoadjuvant chemotherapy using regimens with activity in SCC of the lung [19,21-25]. For patients in whom a response to chemotherapy is achieved, this is followed by locoregional primary tumor-directed treatment using either cystectomy or RT. Patients who progress on or do not respond to neoadjuvant chemotherapy are treated similarly to those who present with metastatic disease. (See 'Metastatic disease' below.)

There are no definitive data to indicate whether radical cystectomy or definitive RT improves the outcome compared with chemotherapy alone, nor whether there is any difference in outcome with cystectomy versus RT. However, retrospective data consistently find multimodal therapy is associated with improved survival. As with muscle-invasive urothelial bladder cancer, we prefer cystectomy with pelvic lymph node dissection to RT following completion of neoadjuvant chemotherapy because of better potential for local cancer control and the probability of occult cancer in the bladder even after response to chemotherapy.

In one retrospective review of 625 patients with localized or locally advanced bladder cancer from the National Cancer Database, the three-year survival rate was higher in patients who underwent neoadjuvant chemotherapy plus cystectomy compared with radical cystectomy (53 versus 35 percent) or treatment for bladder preservation (23 percent) [17]. Although the data are of low quality, they support the use of cystectomy after neoadjuvant chemotherapy [26]. (See "Overview of the initial approach and management of urothelial bladder cancer", section on 'Muscle invasive disease'.)

Neoadjuvant chemotherapy plus cystectomy — The use of neoadjuvant chemotherapy appears to improve survival compared with initial cystectomy.

In a retrospective series from MD Anderson over a 25-year period, 95 patients who were surgical candidates were treated either with neoadjuvant chemotherapy (48 cases) or initial cystectomy (47 cases, 21 of whom received subsequent adjuvant chemotherapy) [24]. A variety of chemotherapy regimens were used as neoadjuvant therapy, with the majority receiving either EP, or ifosfamide plus doxorubicin. The five-year disease-specific survival was significantly longer in patients treated with neoadjuvant chemotherapy (79 versus 20 percent with initial cystectomy). In patients treated with initial cystectomy, adjuvant chemotherapy did not appear to increase OS (median 18 months either with or without adjuvant chemotherapy).

A subsequent prospective phase II study included 18 patients with clinically localized SCC of the bladder who underwent neoadjuvant chemotherapy. Chemotherapy consisted of four cycles of ifosfamide plus doxorubicin alternating with the combination of EP [21]. At cystectomy, 14 of 18 patients (78 percent) either had no evidence of residual disease or only carcinoma in situ. The median OS was 58 months. Thirteen of the 18 patients were alive and disease free.

Small retrospective analyses have suggested that adjuvant therapy may have some activity:

●Retrospective data from the Mayo Clinic reported on 68 patients with small cell bladder cancer treated with cystectomy between 1980 and 2005 [4,27]. The 18 patients receiving postoperative chemotherapy had significantly improved five-year OS compared with patients who did not receive adjuvant chemotherapy (43 versus 20 percent) [27]. Only two patients received neoadjuvant chemotherapy in this cohort.

●In the University of Southern California experience, 25 patients with neuroendocrine bladder cancer getting cystectomy between 1971 and 2004 showed an improved relapse-free survival and OS for those receiving perioperative chemotherapy, which was mostly given in the postoperative setting [19]. Further follow-up and expansion on this cohort showed that perioperative chemotherapy and radiological response to neoadjuvant therapy were associated with better OS, while there was a trend toward better outcome with administration of neoadjuvant therapy (unpublished data).

●A series of 38 patients from the Fox Chase Cancer Center reported that a majority of long-term survivors received neoadjuvant platin-based chemotherapy followed by cystectomy, with pathologic downstaging of disease occurring in 9 of 21 patients (45 percent) [25].

Neoadjuvant chemotherapy plus radiation therapy — RT has been used as an alternative to cystectomy at many centers [22,23,28-30]. In the largest study, 17 patients with SCC of the bladder underwent transurethral resection of their tumor and were then treated with platinum-based chemotherapy followed by RT [22]. A complete local response was achieved in 15 (88 percent). The median OS was 33 months. Four patients eventually had a local recurrence, while seven patients remained disease-free.

Given the lack of prospective data comparing RT with cystectomy in these patients, we generally reserve RT for patients who are not candidates for or refuse cystectomy.

Cystectomy alone — Cystectomy alone for SCC of the bladder is associated with a poor prognosis and a relatively low cure rate [19,24,27].

The role of cystectomy alone is illustrated by an analysis of 64 cases from five university hospitals in the United States and Europe; 59 percent of patients underwent cystectomy, while 41 percent did not [2]. There was no significant difference in survival between patients who underwent cystectomy alone and patients who received combined-modality treatments. The one-year disease-specific survival rate among patients who underwent cystectomy only was 45 percent, compared with 66 percent among patients who received combination therapy. It should be pointed out that this was not a prospective study and that other small retrospective series also support a role for chemotherapy in the perioperative setting. (See 'Neoadjuvant chemotherapy plus cystectomy' above.)

The poor outcome from cystectomy alone was also illustrated by a retrospective series of 25 patients who were initially managed with cystectomy at MD Anderson [18]. The five-year cancer-specific survival was 36 percent. Other series report similar or worse outcomes for cystectomy alone.

Role of prophylactic cranial irradiation — For SCC of the bladder, prophylactic cranial irradiation (PCI) is not routinely recommended because there appears to be a lower incidence of brain metastases in extrapulmonary SCC compared with small cell lung cancer [31,32]. In the absence of data showing benefit from PCI for extrapulmonary SCC, and in view of the documented side effects of whole-brain irradiation, we do not recommend PCI for SCC of the bladder.

However, there should be a low threshold for cranial imaging as part of staging and restaging, when clinically appropriate (high T stage, or symptoms or signs suggestive of central nervous system disease). (See "Extrapulmonary small cell cancer".)

Metastatic disease — Metastatic SCC of the bladder is highly responsive to chemotherapy regimens similar to those used in SCC of the lung [21,28]. Median survival is approximately 7 to 13 months [21,33]. However, these responses are generally transient, and most patients eventually relapse.

Although brain metastases are a frequent complication in patients with SCC of the lung, they do not appear to be a common manifestation of metastatic disease among patients with SCC of the bladder [18,28,33-35]. In a pooled analysis of over 340 patients, only 37 (11 percent) were diagnosed with brain metastases [34].

Systemic chemotherapy — Although systemic chemotherapy is the treatment of choice for metastatic disease, there are less data to guide the choice of a preferred regimen.

●Metastatic treatment-naïve SCC – The most commonly administered regimen consists of etoposide plus cisplatin (EP). For patients who are at a high risk for cisplatin-induced toxicity, carboplatin is a reasonable alternative. This preference for EP is extrapolated from the treatment of SCC of the lung. (See "Extensive-stage small cell lung cancer: Initial management".)

The data on chemotherapy for patients with metastatic treatment-naïve SCC are limited. In one prospective trial, 12 patients with stage IV disease at presentation (five with only lymph node involvement and seven with involvement at other sites with or without lymph node disease) were treated with alternating regimens of ifosfamide plus doxorubicin and EP [21]. Three patients had a complete response and underwent surgical consolidation. The median OS for this cohort was 13 months, but one patient remained disease-free for 28 months after the original treatment.

●Relapsed or refractory SCC – For patients who have progressed on EP, the treatment approach should mirror that for patients with SCC of the lung. Although many centers have published their experience, they have reported either very small numbers and/or have used different regimens for different patients, making it very challenging to estimate response rates and outcomes for specific regimens [4,33,36]. (See "Treatment of refractory and relapsed small cell lung cancer".)

Is there a role for immunotherapy? — The role of checkpoint inhibitor immunotherapy in small cell carcinoma of the bladder remains under investigation. Given limited data for this approach, patients are encouraged to participate in clinical trials, where available.

Systemic therapy for SCC of the bladder has been mainly extrapolated from the treatment of small cell lung cancer (SCLC), which incorporates immunotherapy into initial management. Further details on the treatment of SCLC is discussed separately. (See "Limited-stage small cell lung cancer: Initial management" and "Extensive-stage small cell lung cancer: Initial management".)

There are emerging data regarding the use of immunotherapy in SCC of the bladder, such as pembrolizumab in patients with chemotherapy-refractory disease [37], although expression rates of programmed cell death ligand 1 (PD-L1) and tumor-infiltrating lymphocytes are low in this disease [38]. As such, the efficacy of immunotherapy in SCC of the bladder remains to be proven.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Bladder cancer".)

SUMMARY AND RECOMMENDATIONS

●Clinical presentation – Small cell carcinoma (SCC) of the bladder is an aggressive tumor that typically presents with locally advanced or disseminated disease. (See 'Clinical presentation' above.)

●Treatment of localized disease – Our approach to the management of patients with disease localized to the bladder is as follows (see 'Disease localized to the bladder' above)

•Neoadjuvant chemotherapy prior to cystectomy – For patients with localized disease and no evidence of disseminated metastases (stage I, II or III) whose overall condition permits aggressive therapy, we suggest neoadjuvant chemotherapy using a platinum-based combination (Grade 2B). For patients who respond to treatment, we suggest cystectomy (Grade 2C). (See 'Neoadjuvant chemotherapy plus cystectomy' above.)

•No neoadjuvant chemotherapy prior to cystectomy – In patients who did not receive neoadjuvant chemotherapy prior to cystectomy, we suggest adjuvant platinum-based combination chemotherapy if the overall condition of the patient permits (Grade 2C). Our preferred regimen for chemotherapy is cisplatin and etoposide. (See 'Disease localized to the bladder' above.)

•No PCI – Following definitive treatment, we suggest not administering prophylactic cranial irradiation (PCI) for these patients (Grade 2C). (See 'Role of prophylactic cranial irradiation' above.)

●Treatment of metastatic disease – For patients who do not respond to neoadjuvant therapy and for those who present with disseminated disease, we proceed with systemic chemotherapy. (See 'Metastatic disease' above and "Extensive-stage small cell lung cancer: Initial management".)

We suggest the use of regimens that are active in advanced SCC of the lung (Grade 1B), including cisplatin and etoposide for previously untreated patients, and agents including topotecan, anthracyclines, alkylating agents, and vinca alkaloids.

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Timothy Gilligan, MD, and David I Quinn, MBBS (Hons I), PhD, FRACP, FACP, who contributed to earlier versions of this topic review.