Table of Contents  

Venyo and Maloney: Literature review of small cell carcinoma of the urinary bladder

Introduction

Small cell carcinoma of the urinary bladder is an uncommon, aggressive and poorly differentiated neuroendocrine tumour that has similar behavioural characteristics to small cell carcinoma of the lung.1 Gilligan et al.1 reported that although small cell carcinoma has been classified as an isolated entity, the results of a molecular study by Cheng et al.2 indicate that small cell carcinoma and urothelial carcinoma are derived from the same clonal population. Gilligan et al.1 reported that small cell carcinoma of the urinary bladder has frequently been found in association with other histological forms of bladder cancer. Cheng et al.3 reported on a sample of 66 cases of small cell carcinoma of the urinary bladder, of which 44 (67%) were associated with other types of tumours and 38 (58%) were associated with elements of urothelial carcinoma.

This paper reviews the literature on small cell carcinoma of the urinary bladder and provides a discussion of the topic.

Epidemiology

Sved et al.4 and Koay et al.5 reported that between 1991 and 2005 the annual incidence of small cell carcinoma of the urinary bladder increased from 0.05 to 0.14 cases per 100 000. Nevertheless, small cell carcinoma accounts for less than 1% of all urinary bladder malignancies worldwide.

Cheng et al.3 reported that a history of smoking is associated with the development of small cell carcinoma of the urinary bladder, and Koay et al.5 reported that the prevalence of small cell carcinoma of urinary bladder is higher in whites than in non-whites (91% vs. 9%). Koay et al.5 also found that men are more frequently affected than women (76% vs. 24%), the median age at diagnosis is 73 years and patient survival varies substantially depending upon the presence or absence of distant metastases at the time of initial diagnosis but the median overall survival is 11 months.

Small cell carcinoma of the urinary bladder is rare, accounting for only 0.5–1.0% of all bladder malignancies, and affected individuals show no age, sex or clinical differences from those with the usual type of urothelial carcinoma.6

Aetiology

Gaisa et al.7 reported that at least some cases of small cell carcinoma of the urinary bladder arise from urothelial carcinoma in situ, whereas Shahab8 reported that small cell carcinoma of the urinary bladder may arise from totipotent stem cells in the submucosa.

Clinical features

It has been suggested that the clinical features of small cell carcinoma of the urinary bladder are similar to those of other bladder tumours, and reflect the presence of a mass.1 It has also been suggested that the tumour normally infiltrates the wall of the urinary bladder, leading to either ulceration or bleeding, and that most patients present with locally advanced disease or metastatic disease.1

Koay et al.5 reported that, of a sample of 642 patients presenting with small cell carcinoma of the urinary bladder, 12% had stage I disease, 32% stage II disease, 14% stage III disease and 36% stage IV disease at the time of presentation; the remaining 6% of the tumours were unstaged.

It has been stated by Koay et al.5 that most patients with small cell carcinoma of the urinary bladder in the USA present with poorly differentiated (33% of patients) or undifferentiated tumours (43%), and the most common sites for tumours to form in the urinary bladder are the lateral wall (16%) and the the dome (10%), although they can occur anywhere. Twenty-four per cent of patients in a study reported by Koay et al.5 had distant metastases at the time of initial diagnosis and a further 5% had multiple lymph node metastases that were stage N2 or N3. Paraneoplastic syndromes can occur, but not as commonly as with small cell carcinoma of the lung.1,9

It has also been stated that in the majority of cases (65%) small cell carcinoma of the urinary bladder is advanced by the time of diagnosis or soon after.6 Occasionally, it may be associated with hypercalcaemia and ectopic production of adrenocorticotropic hormone (ACTH). A diagnosis of small cell carcinoma of the urinary bladder should be made whenever a tumour includes a significant component of small cell because the prognosis will be affected by this component.6 This disease is aggressive and metastases of the regional lymph nodes and the peritoneal cavity develop rapidly; median survival is reported to be 11 months.5,6 Small cell carcinoma of the urinary bladder rarely co-exists with tumour cells that exhibit skeletal muscle differentiation10 and in this case 5-year survival ranges from 8% to 16%.3

Pathology

Gross findings

Jiang and Cheng11 reported that small cell carcinoma of the urinary bladder has a polypoid, or nodular, appearance and frequently has an ulcerated surface. Gross examination reveals a solid tumour that originates from the mucosa and often penetrates deeply into the wall of the urinary bladder.

Microscopic findings

With regard to the microscopic findings, Cheng et al.3 reported that 68% are usually admixed with classic urothelial carcinomas or adenocarcinomas of the urinary bladder. The histological features of small cell carcinoma of the urinary bladder are the same as those of small cell carcinoma in other organs.11 Microscopic examination of small cell carcinoma of the urinary bladder reveals sheets and nests of loosely cohesive, small, round or oval cells with very scant cytoplasm (Figure 1). The cell nuclei of the tumour are typically hyperchromatic with coarsely granular chromatin, and nuclei moulding can almost invariably be seen. Figures 1 to 7 show haematoxylin and eosin-stained sections of a muscle-invasive small cell carcinoma of the urinary bladder at different magnification. The tumour shown in these figures consists of sheets of small dark pleomorphic cells with scant cytoplasm and finely stippled nuclear chromatin. In Figure 1, some pink strands of detrusor muscle are apparent, confirming the tumour had invaded the muscle and was therefore at least stage pT2. In addition, the tumour was solid and contained no other elements (e.g. there were no elements of transitional cell carcinoma, squamous cell carcinoma or adenocarcinoma). Mitosis is present, the nucleoli are absent or small and tumour necrosis is present.11 Cytological examination of the urine specimen of patients suffering from small cell carcinoma of the urinary bladder often reveals single and loosely cohesive clusters of tumour cells with typical small cell carcinoma morphology.

FIGURE 1

Haematoxylin and eosin staining at × 100 magnification. The tumour consists of sheets of small dark pleomorphic cells with scant cytoplasm and finely stippled nuclear chromatin. There are some pink strands of detrusor muscle confirming the tumour to be at least a stage pT2.

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FIGURE 2

Haematoxylin and eosin staining at × 400 magnification.

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FIGURE 3

An additional view of haematoxylin and eosin staining of the tumour in Figure 1 at × 400 magnification.

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FIGURE 4

Haematoxylin and eosin staining at × 200 magnification.

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FIGURE 5

An additional view of haematoxylin and eosin staining of the tumour in Figure 4 at × 400 magnification.

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FIGURE 6

An additional view of haematoxylin and eosin staining of the tumour in Figure 4 at × 400 magnification.

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FIGURE 7

An additional view of haematoxylin and eosin staining at of the tumour in Figure 4 × 400 magnification.

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Cytology

Cytological examination of urine specimens from patients with small cell carcinoma of the urinary bladder shows numerous tumour cells in loose clusters. The cells tend to be larger than lymphocytes and show scant cytoplasm. The nuclei tend to be eccentric with evenly dispersed, but coarse, chromatin and the nucleoli tend to be indistinct.6

Immunohistochemistry

Immunohistochemistry is a useful tool in the diagnosis of small cell carcinoma of the urinary bladder because neuroendocrine markers, including chromogranin A, synaptophysin, CD56 and neuron-specific enolase, are quite often focal or diffusely positive. Figure 8 shows positive immunohistochemical staining of the muscle-invasive small cell carcinoma of the urinary bladder for CD56. Figures 9 and 10 show positive immunohistochemical staining for synaptophysin at ×200 magnification (Figure 9) and ×400 magnification (Figure 10).

FIGURE 8

Immunohistochemistry for small cell neuroendocrine marker CD56 at × 400 magnification.

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FIGURE 9

Immunohistochemical staining of small cell carcinoma showing positive staining for synaptophysin at × 200 magnification.

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FIGURE 10

Immunohistochemical staining of small cell carcinoma showing positive staining for synaptophysin at × 400 magnification.

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Some authors12,13 have stated that a definitive diagnosis of small cell carcinoma of the urinary bladder can be achieved based on morphology alone as immunohistochemisty frequently fails to identify the markers mentioned previously. A cocktail of cytokeratin markers is quite often non-reactive; however, a combination of low-molecular-weight cytokeratin, CAM5.2 and epithelial membrane antigen (EMA) is mostly positive.

Documented immunohistochemical positive stains in small cell carcinoma of the urinary bladder include:

  • EMA and CAM5.2 (which result in a visible dot-like perinuclear pattern);

  • neuron-specific enolase and synaptophysin, both of which frequently express neuroendocrine features;14

  • variable c-Kit (27% of small cell carcinomas of the urinary bladder are positive for c-Kit expression),15 chromogranin (weak/focal if present), cytokeratin 716 and thyroid transcription factor 1.17

Pernick6 stated that neuroendocrine stains are of questionable value to many researchers for the diagnosis of small cell carcinoma of the urinary bladder as this is based on a morphological diagnosis. It has been documented that immunohistochemical stains for various markers such as carcinoembryonic antigen marker, cytokeratin 20 marker and human papillomavirus (HPV) marker are negative for small cell carcinoma.8

Electron microscopy

Electron microscopic examination of small cell carcinoma of urinary bladder tissue may reveal only few dense core granules.6

Detection of human papillomavirus DNA and the expression of p16, retinoblastoma protein and p53 proteins in small cell carcinoma

Human papillomavirus has been implicated as an aetiological agent for the development of primary small cell carcinoma of the uterine cervix.18 It has been demonstrated that the HPV E6 and E7 oncoproteins are able to inactivate the tumour-suppressing functions of p53 and retinoblastoma protein (Rb). With regard to squamous cell carcinoma and adenocarcinoma of the cervix, HPV infection is also associated with overexpression of p16, a cyclin-dependent kinase inhibitor.18 Wang and Lu18 reported on 22 cases of primary small cell carcinoma of the uterine cervix that were subjected to broad-spectrum HPV DNA amplification and typing and were immunohistochemically examined to test for the expression of p16, Rb and p53 proteins. The results showed that HPV DNA was detected in every case (100%) and 18 cases (82%) were found to harbour HPV type 18. The tumour cells in 20 of the cases (91%) exhibited strong nuclear staining for p16, which was associated with a complete loss of Rb nuclear staining in 16 cases (73%), and the p53 protein was essentially undetectable in all cases. HPV DNA was not detected in nine colorectal and eight urinary bladder small cell carcinoma samples that were included in the study for comparison. While similar p16 and Rb expression patterns were observed in these HPV-negative colorectal and urinary bladder small cell carcinoma samples, a different expression pattern for p53 was noted, in which strong nuclear staining was seen in 8 of the 17 cases (47%, P = 0.0004 compared with cervical tumours). Wang and Lu18 reported that these observations indicate that different mechanisms are involved in the pathogenesis of small cell carcinomas of the uterine cervix compared with colorectal small cell carcinomas or small cell carcinomas of the urinary bladder. These observations also support the suggestion that overexpression of nuclear p16 serves as an indication of Rb malfunction in tumour cells, which may or may not result from high-risk HPV infection. The aforementioned results of protein expression may relate only to carcinomas of the cervix; however, the small sample size of small cell carcinomas of the bladder does not allow for a definite conclusion to be reached.

Genomic alterations

Terracciano et al.19 reported that small cell carcinoma of the urinary bladder shows abundant genomic abnormalities, typically more than 10, similar to small cell carcinomas of other organs.19 Terracciano et al.19 also reported that the most frequent changes occurring in small cell carcinoma of the urinary bladder are deletions of 10q, 4q, 5q and 13q and gains in 8q, 5p, 6p and 20q. They also showed that small cell carcinoma has been caused by acquisitions of genomic alterations in a typical invasive urothelial carcinoma. In addition, genomic DNA amplifications are identified in many loci where oncogenes are located.19

Differential diagnosis

It has been suggested that the following tumours should be considered in the differential diagnosis of small cell carcinoma of the urinary bladder:6

  • High-grade urothelial carcinoma that, by definition, should lack any appreciable small cell component such as p63+ or synaptophysin. A limited immunohistochemical panel including pan-cytokeratin, synaptophysin and p63 can discriminate high-grade neuroendocrine carcinoma and small cell carcinoma from high-grade urothelial carcinoma.20

  • Lymphoma, in which tumour cells are smaller and positive for CD45 and B- or T-cell markers.6

  • Metastatic small cell carcinoma, in which there is usually no associated urothelial carcinoma.6

Treatment

Gilligan et al.1 stated that there is currently no consensus regarding the treatment of small cell carcinoma of the urinary bladder because there are no randomized clinical trials on which definitive recommendations could be made for the management of patients. However, the results of several retrospective studies and one prospective phase II study provide some insight into the therapeutic approach to the management of small cell carcinoma of the urinary bladder.1,2124

Localized disease

Some authors3,4,25,26 have reported that patients with small cell carcinoma of the urinary bladder are likely to have a poor prognosis, even when it is evident that the disease is localized, as a result of the potential development of disseminated disease. However, some studies1,21 have shown that small cell carcinoma of the bladder responds to the same chemotherapy procedures that are used for the management of small cell carcinoma of the lung and that some patients can achieve lasting complete remission. Some of these studies1,21 have also reported that combination or aggressive systemic chemotherapy, followed by local therapy (cystectomy or radiotherapy), may increase the long-term survival rate among who present with clinically localized disease.1,21

Cystectomy may or may not be accompanied by adjuvant chemotherapy, but cystectomy alone is associated with a relatively poor prognosis.4,22,23 Siefker-Radtke et al.23 reported a retrospective series of 25 patients with small cell carcinoma of the urinary bladder who initially underwent cystectomy between 1985 and 2002. They reported that the 5-year cancer-specific survival was 36%, and 7 of these 25 patients received postoperative adjuvant chemotherapy; nevertheless, their outcome was not better than the outcome of those patients who did not receive postoperative adjuvant chemotherapy.

Choong et al.22 reported a series of 44 patients with small cell carcinoma of the urinary bladder who were treated between 1975 and 2003. They reported that 7 out of 17 patients (41%) were cured following radical cystectomy alone. They also reported that the patients who received perioperative chemotherapy, instead of surgery alone, were more likely to be cured irrespective of whether they had stage II (100% vs. 71%), stage III (50% versus 13%) or stage IV (20% versus 0%) disease. In relation to the Choong et al.22 study, Gilligan et al.1 commented that the number of patients treated was too small to make the conclusions valid.

Cheng et al.3 reported on 64 patients, of whom 59% underwent cystectomy while the remainder did not. The study found that there was no difference in the survival outcome of the two groups in that the 1- and 5-year survival rates were 57% and 16%, respectively, in the cystectomy group in comparison with 55% and 18%, respectively, in the group without cystectomy.

Sved et al.4 reported on the analysis of published literature on a number of patients with small cell carcinoma of the urinary bladder. Of 20 patients who underwent cystectomy alone, 11 died as a result of their carcinomas, four were in complete remission, one was continuing to live with the disease and four were lost to follow-up. The study also reported that, of the 23 patients who underwent cystectomy with chemotherapy and radiotherapy, six died as a result of their carcinomas, 11 were in complete remission and six were continuing to live with the disease. The summary of the outcome of small cell carcinoma of the urinary bladder treatment was detailed by Sved et al.4 as follows:

  • Twenty patients underwent cystectomy alone and their mean survival was 12.9 months.

  • Eighteen patients underwent cystectomy and chemotherapy and their mean survival was 27 months.

  • Five patients underwent cystectomy and radiotherapy and their mean survival was 29.2 months.

  • Two patients underwent cystectomy and chemotherapy/radiotherapy and their mean survival was 6 months.

  • Twelve patients underwent partial cystectomy and/or chemotherapy/radiotherapy and their mean survival was 34.9 months.

  • Thirteen patients underwent chemotherapy alone and their mean survival was 6.5 months.

  • Fifteen patients underwent chemotherapy plus radiotherapy and their mean survival was 32.9 months.

  • Forty patients underwent radiotherapy alone and their mean survival was 7.8 months.

  • Twenty-eight patients underwent transurethral resection of the bladder tumour alone and their mean survival was 8.6 months.

A number of studies4,24,25,2730 have reported on the use of neoadjuvant chemotherapy followed by cystectomy or radiotherapy in responders. However, Gilligan et al.1 stated that there are no definitive data which indicate whether cystectomy and radiation therapy improves the outcome compared with chemotherapy alone, or whether there is any difference in the outcome with cystectomy alone versus radiation therapy alone.

In relation to neoadjuvant chemotherapy plus cystectomy, Siefker-Radtke et al.24 reported a phase II study which included 18 patients with clinically localized small cell carcinoma of the urinary bladder who had either cT2 (stage II) or cT3b (stage III) disease. The study reported that the patients were initially treated with four cycles of chemotherapy, in which a combination of ifosfamide and doxorubicin was alternated with a combination of etoposide plus cisplatin. During subsequent cystectomy, 14 out of the 18 patients (78%) had either no evidence of residual disease or only carcinoma in situ and the median overall survival was 58 months; at the time of reporting the study results, 13 out of the 18 patients were alive and disease free.

In another study, Siefker-Radtke et al.23 reported that, among patients who initially underwent cystectomy for small cell carcinoma, the 5-year cancer-specific survival was higher for those who also received preoperative chemotherapy than for those who did not (78% and 36%, respectively); in addition, no cancer-related deaths were observed beyond 2 years in those who had also received preoperative chemotheraphy. Likewise, Quek et al.25 reported that 14 patients who received either preoperative or postoperative chemotherapy alongside cystectomy had significantly longer overall survival (P = 0.051) and relapse-free survival (P = 0.003) than the 11 patients who underwent cystectomy alone. Nevertheless, there were only two long-term survivors among the 25 patients in this study.

With regard to neoadjuvant chemotherapy plus radiotherapy, some authors27,2932 have used radiotherapy as an alternative to cystectomy. Bex et al.29 reported on a sample of 17 patients with small cell carcinoma of the urinary bladder who underwent transurethral resection of the tumour and were then treated with platinum-based chemotherapy followed by radiotherapy. They reported that a complete local response was achieved in 15 of the 17 patients (88%); the overall survival was 33 months and seven patients remained disease free; however, four patients developed local recurrence. Lohrisch et al.32 reported on a sample of 10 patients who underwent chemoradiation for small cell carcinoma of the urinary bladder in which they observed a 70% disease-free survival rate at the 2- and 5-year mark, and five patients were alive at the time of publication of the article in 1999.

Metastatic disease

Siefker-Radtke et al.24 and Mukesh et al.27 reported that metastatic small cell carcinoma of the urinary bladder is highly responsive to chemotherapy regimens similar to those used in the treatment of small cell carcinoma of the lung. Siefker-Radtke et al.24 and Ismaili et al.33 reported a median survival of approximately 7–13 months for those presenting with small cell carcinoma of the urinary bladder, which was treated using chemotherapy. However, Gilligan et al.1 reported that these responses were generally transient and most patients relapsed. Gilligan et al.1 stated that the most commonly reported treatment is etoposide in combination with cisplatin or carboplatin; however, numerous other treatments have been reported, as listed by Kelly et al.21 including:

  • platinum compounds (cisplatin, carboplatin)

  • podophyllotoxins (etoposide, teniposide)

  • camptothecins (irinotecans, topotecan)

  • alkylating agents (ifosfamide, cyclophosphamide)

  • anthracyclines (doxorubicin, epirubicin, amrubicin)

  • taxanes (paclitaxel, docetaxel)

  • vincristine

  • other less frequently used drugs with single-agent activity (nitrosoureas, methotrexate, gemcitabine and vinorelbine).

Siefker-Radtke et al.24 reported 12 patients who presented with stage IV disease, five wth only lymph node involvement and seven with involvement of other sites, with or without lymph node disease. They reported that the patients were treated with a chemotherapy regimen in which cycles of ifosfamide plus doxorubicin were alternated with cycles of etoposide plus cisplatin. Three of the patients who originally had lymph node metastases showed complete remission following chemotherapy and underwent surgical consolidation. The overall median survival for this cohort of patients was 13 months. One of the patients remained disease free 28 months following the original treatment. Other studies22,33,34 have reported either very small numbers of patients treated by chemotherapy and/or used different chemotherapeutic treatments for different patients and therefore it is difficult to estimate response rates and comparative outcomes for different treatments.

Brain metastases

Accoording to Gilligan et al.,1 brain metastases are a frequent complication of small cell carcinomas of the lung but there are only limited data regarding the frequency of brain metastases in patients with small cell carcinoma of the urinary bladder.

Siefker-Radtke et al.24 reported brain metastases in 8 out of 16 patients (50%) with stage III or IV small cell carcinoma of the bladder but none of the 14 patients with stage II disease. Ismaili et al.33 reported that 2 out of 12 relapsing patients (17%) who were treated between 1996 and 2007 had central nervous system involvement; however, a number of larger studies observed a lower prevalence of brain metastases in cases of small cell carcinoma of the urinary bladder.23,27,35 Gilligan et al.,1 in a pooled analysis of 15 series in which the sites of the metastatic disease were identified, found that 37 out of 342 patients had developed brain metastases [11%; 95% confidence interval (CI) 7.5–14.1%].

Gilligan et al.1 reported that prophylactic cranial irradiation decreases the incidence of brain metastases and prolongs survival in patients with small cell carcinoma of the lung; thus, prophylactic cranial irradiation is generally given to patients with small cell lung cancer patients in whom spread of the disease is limited and response to initial therapy is good. Gilligan et al.1 also stated that there are no data evaluating this approach for patients with small cell carcinoma of the urinary bladder.

In conclusion, the treatment for small cell carcinoma of the urinary bladder may be summarized generally as follows:

  • Radical cystectomy should be performed except in the presence of metastatic disease, in which case systemic therapy would be required.36

  • There is a high response rate to chemotherapy, which is similar to the treatment used for lung tumours. However, the overall prognosis is still poor.27

Discussion

Since the report of the first case of small cell carcinoma of the urinary bladder in 1981,37 the majority of patients diagnosed with this rare disease have been male. The male to female ratio is 7.6:1 and the disease typically presents between the ages of 60 and 80 years.3739

Several studies4043 have reported that most patients who present with small cell carcinoma of the lung or other extrapulmonary sites have a history of extensive smoking. Nevertheless, most patients with small cell carcinoma of the urinary bladder are non-smokers. Kayler et al.44 stated that it is unclear whether tobacco contributes to disease progression in view of the paucity of information regarding small cell carcinoma of the bladder.

Mills et al.14 reported that the majority of small cell carcinomas of the urinary bladder have histological patterns consistent with transitional cell carcinoma, squamous cell carcinoma or spindle cell carcinoma.

Atkin et al.45 conducted a cytogenetic study to illustrate that small cell carcinomas of the urinary bladder display rearrangement of the long arms of chromosomes 6, 9, 11, 3 and 18, with hypertriploid DNA and expression of p53.

Pearse46 reported that immunohistochemical studies have revealed the existence of neurosecretory granules in the majority of small cell carcinomas of the urinary bladder, which led some researchers to form the opinion that small cell carcinomas of the urinary bladder are derived from neuroendocrine precursor and decarboxylation cells. However, other studies37,42,47 have suggested a multipotential stem cell origin, which would account for the minor component of admixed non-small cell carcinoma which is commonly seen in these tumours. Partanen et al.48 reported that small cell carcinoma of the urinary bladder rarely demonstrated ectopic hormone production. Grignon et al.49 reported hyperphosphataemia without hypercalcaemia prior to tumour resection, which suggested that humoral production disturbed phosphate metabolism; however, the phosphate level returned to normal following resection. Reyes and Soneru41 reported that the association between small cell carcinoma of the urinary bladder and hypercalcaemia was attributed to skeletal metastasis.

Gilligan et al.1 made the following recommendations for the management of small cell carcinoma of the urinary bladder.

Localized disease

In the case of patients with localized disease, when the tumour has been assessed as stage II or stage III and when the patient's overall condition permits aggressive therapy, Gilligan et al.1 recommend a combined modality approach which includes neoadjuvant chemotherapy using a platinum-based combination, as is used for small cell lung cancer, followed by specific treatment directed towards the primary tumour (for example, cystectomy or radiotherapy; grade 1B).

  • Gilligan et al.1 suggest the use of the combination of cisplatin plus etoposide (grade 2C). They report that this approach has been associated with a higher incidence of long-term, disease-free survival than in historical series treated with cystectomy alone, or cystectomy followed by adjuvant chemotherapy.

  • They also suggested that following neoadjuvant chemotherapy, cystectomy rather than radiotherapy should be performed to treat grade 2C small cell bladder tumour. They further recommend that in the case of patients who are not surgical candidates (e.g. patients with inoperable tumours), radiotherapy should be the alternative method of treatment.

Disseminated disease

In the case of patients with disseminated disease, Gilligan et al.1 recommend systemic chemotherapy using a regimen that is also used to treat advanced small cell carcinoma of the lung (grade 1B).

Brain metastasis

  • Gilligan et al.1 recommend that patients with stage I or stage II disease and brain metastases who achieve complete remission after neoadjuvant chemotherapy plus either cystectomy or radiotherapy should not undergo prophylactic cranial irradiation (grade 2C).

  • For patients with stage III or IV disease who have partial or complete response to the treatment, Gilligan et al.1 recommend prophylactic cranial irradiation as an additional treatment; however, they also state that the advantages and disadvantages should be discussed with the patient.

Gilligan et al.1 also report that although there are no data for patients with small cell carcinoma of the urinary bladder, prophylactic irradiation decreases the incidence of brain metastases and prolongs survival in those with small cell carcinoma of the lung; however, whole-brain irradiation can have substantial neurological side-effects.

Future directions

Ismaili50 reported that:

  1. Although the results of cisplatin-based chemotherapy are promising, most patients die as a result of metastatic disease.

  2. Developments in molecular biology have led to the investigation of new molecules in a large number of tumours including small cell carcinoma of the lung. Overexpression of a number of receptors, including vascular endothelial growth factor receptor (VEGFR) on endothelial cells, epidermal growth factor receptor (EGFR), c-KIT, platelet-derived growth factor receptor (PDGFR) and fibroblast growth factor receptor (FGFR) on tumour cells, has prompted the scientific community to evaluate the efficacy and safety of new molecules that target signalling pathways controlled by proteins such as bevacizumab, sunitinib, sorafenib, pazopanib, Imatinib, cetuximab, erlotinib, gefitinib, lapetinib, everolimus and bortezomib in metastatic small cell cancer of lung.

Puglisi et al.51 based their report on preliminary studies and suggested that targeting angiogenesis would be the most promising strategy for the treatment for small cell carcinoma of the lung. Ismaili50 added that in analogy to small cell carcinoma of the lung, the role of the aforementioned molecules would be the most promising treatment for metastatic small cell carcinoma of the urinary bladder.

A number of studies28,5254 have recommended the following strategies for the treatment of small cell carcinoma of the urinary bladder.

Surgically resectable disease

Neoadjuvant chemotherapy followed by radical resection should be considered the initial treatment of choice in surgically resectable small cell carcinoma of urinary bladder. Some authors23,24 have reported that this can achieve a cure in 78–80% of patients.

Sequential chemoradiotherapy is the second treatment option and is reported29,32 to have a cure rate of 36–70%.

If surgery was performed first, some studies22,25 suggest that adjuvant chemotherapy or adjuvant chemoradiotherapy should be sought postoperatively.

Advanced disease

In advanced disease, cisplatin chemotherapy should be considered the initial treatment of choice for patients who have an acceptable performance status (e.g. a score of 0–1 on the Zubrod scale) and acceptable renal function (glomerular filtration rate > 60 ml/min). The therapeutic treatment should be centred on the chemotherapy regimen – etoposide plus cisplatin or a sequential protocol of ifosfamide plus doxorubicin on day 1 and etoposide plus cisplatin at day 21. However, in patients who do not have an acceptable performance status or renal function, cisplatin should be replaced by carboplatin with a target area under the concentration versus time curve of 5–6 mg/ml/min.

Prognosis

A number of authors3,22 have reported that the prognosis of small cell carcinoma of the urinary bladder is poor and that the 5-year survival rate for all stages is 19% (CI 16–25%).

Choong et al.22 reported that the 5-year survival rate of patients with stage II, III and IV disease was 63.6%, 15.4% and 10.5%, respectively. Choong et al.22 also reported that the prognosis of patients with advanced disease, stage III or IV, is significantly poorer (P< 0.0001) than that of patients with stage II disease.

Other authors25,33,55 have reported that small cell carcinoma of urinary bladder with pure small cell histology had a poorer prognosis in comparison with tumours which had mixed small cell histology. Ismaili50 stated that, in view of the rarity of the disease, no other prognostic factors had been identified.

Conclusions

Small cell carcinoma of the urinary bladder is an aggressive tumour that typically presents with advanced or disseminated disease. It is rare, accounting for only 0.5–1.0% of all bladder malignancies, and patients show no clinical, age or sex differences from those with typical urothelial carcinoma.

Some cases of small cell carcinoma of the urinary bladder arise from urothelial carcinoma in situ whereas some small cell carcinoma of the urinary bladder may arise from totipotent stem cells in the submucosa. Small cell carcinomas of the urinary bladder are usually large polypoid masses and can occur anywhere in the bladder.

Microscopically, small cell carcinomas of the urinary bladder are seen as loosely cohesive sheets, or nests, of small to intermediate-sized cells with minimal cytoplasm, hyperchromatic nuclei, stippled or coarsely granular chromatin, indistinct nucleoli and no nuclear overlapping. Mitotic activity and necrosis are common and the tumours may co-exist with other forms of in situ or invasive carcinoma.

Co-existence of small cell carcinoma of the urinary bladder with other types of carcinoma is common and immunohistochemistry plays a pivotal role in the diagnosis of small cell carcinoma of urinary bladder using the markers of neuroendocrine tumours.

The strategy to treat small cell carcinoma of the urinary bladder was extrapolated from the strategy used to treat small cell carcinoma of the lung. In cases where the tumour may have to be surgically resected, the treatment should include multimodal therapy with chemotherapy being delivered initially, followed by radical resection or radiotherapy.

Radical cystectomy is the main treatment for small cell carcinoma of the urinary bladder, unless metastatic disease is present, followed by systemic treatment. Response to chemotherapy is good, similar to response to treatment for small cell carcinoma of the lung; however, the overall prognosis remains poor.

In cases where the disease is in the advanced stages, chemotherapy with a platinum agent, such cisplatin in suitable patients, is the mainstay of treatment.

There is currently no consensus regarding the treatment of small cell carcinoma of the urinary bladder; however, Gilligan et al.,1 among others, have made general recommendations for the approach to treatment of this aggressive disease.

Small cell carcinomas of the urinary bladder with pure small cell histology have been shown to have a poorer overall prognosis than small cell carcinomas of the urinary bladder with mixed small cell histology.

There is a dire need for further investigations of small cell carcinomas of the urinary bladder in order to improve our knowledge regarding the diagnosis and treatment of this rare disease.

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