Small Cell Carcinoma of the Urinary Bladder: A Clinicopathologic and Immunohistochemical Analysis of 81 Cases

Abstract

Small cell carcinoma (SmCC) of the bladder is a rare disease. We retrospectively studied a large series of bladder SmCC from a single institution. The patients included 69 men and 12 women with a mean age of 68 years. Most bladder SmCC were presented at advanced stage with tumors invading the muscularis propria and beyond (n=77). SmCC was pure in 27 cases and mixed with other histologic types in 54 cases, including urothelial carcinoma (UC) (n=32), UC in situ (n=26), glandular (n=14), micropapillary (n=4), sarcomatoid (n=4), and squamous (n=3), and plasmacytoid (n=1) features. Most SmCC expressed neuroendocrine markers synaptophysin (41/56), chromogranin (26/55), and CD56 (39/41); however, they did not express UC luminal markers CK20 (0/17), GATA3 (1/30), and uroplakin II (1/22). Some SmCC showed focal expression of CK5/6 (9/25), a marker for the basal molecular subtype. Furthermore, expression of the retinoblastoma 1(RB1) gene protein was lost in most of the bladder SmCC (2/23). The patient’s survival was significantly associated with cancer stage but did not show significant difference between mixed and pure SmCC. Compared to conventional UC at similar stages, SmCC had a worse prognosis only when patients developed metastatic diseases. In conclusion, bladder SmCC is an aggressive disease which is frequently present at an advanced stage. A fraction of SmCC show a basal molecular subtype, which may underlie its good response to chemotherapy. Inactivation of the RB1 gene may be implicated in the oncogenesis of bladder SmCC.

INTRODUCTION

Bladder cancer is the sixth most common malignancy in the US, with an estimated incidence of 79,030 new cases in 2017 [1]. Approximately 90% of bladder cancers are composed of urothelial carcinoma (UC), and other histologic types, such as squamous cell carcinoma and adenocarcinoma, are far less common [2]. Although most UC are detected at an early stage, about 25% UC are present at an advanced stage – the tumor invades the muscularis propria and/or metastasizes to lymph nodes and other organs [3]. Invasive UC demonstrates a high tendency to develop divergent differentiation, leading to a number of histologic variants, such as micropapillary, nested, plasmacytoid, and sarcomatoid variants [4,5]. Some aggressive UC variants are associated with poor clinical outcome and may require therapeutic approaches that differ from those used for the conventional UC [6]. In spite of their clinical importance, it may be difficult to recognize UC variants, particularly at metastatic sites, as the morphologic features of histologic variants are not limited to bladder UC and can be seen in other carcinomas. Several recent studies have reported that immunohistochemistry is a useful tool to aid the differential diagnosis of UC variants [7,8].

Small cell carcinoma (SmCC) of the bladder is a rare histologic variant and accounts for less than 1% of all bladder malignancies [9–11]. SmCC belongs to a family of neuroendocrine tumors, which also includes large cell neuroendocrine carcinoma, well-differentiated neuroendocrine tumor, and paragangliomas in the bladder [9]. SmCC is by far the most common neuroendocrine tumor in the bladder. Like its more common counterpart in the lungs, bladder SmCC typically expresses neuroendocrine markers, such as synaptophysin, chromogranin, and neuron-specific enolase (NSE), but a lack of expression of these markers does not exclude the diagnosis of SmCC [9]. There have been limited studies about this rare disease, and most studies have been based on small cohorts of patients. Although several large series of bladder SmCC were previously reported, but they were largely focused on clinical and therapeutic aspects of this rare disease [12–13]. Herein we describe a large series of SmCC from a single institution, providing detailed clinicopathologic and immunohistochemical features of this rare disease.

MATERIALS AND METHODS

Patients

After the Institutional Review Board at The University of Texas MD Anderson Cancer Center approved the study, we searched our pathology database from 1992 to 2014 and found 81 cases of SmCC of the urinary bladder. All 81 patients underwent transurethral biopsy or resection of bladder tumor, and 48 patients underwent radical cystectomy. The patients’ archived hematoxylin- and eosin (H&E) stained slides were retrieved from our files and reviewed for pathological analysis, including histologic features, other coexistent histologic variants, pathologic stage, and metastasis to lymph nodes and other organs. Clinical data, including patients’ demographics, treatments, and outcomes, were retrieved from their medical records. The primary tumor pathologic stage was evaluated according to the 2010 American Joint Committee on Cancer TNM criteria: I (T₁N₀M₀), II (T₂N₀M₀), III (T₃N₀M₀ and T_4aN₀M₀), and IV (T_4bN₀M₀, T_anyN_1–3M₀ and T_anyN_anyM₁). [14]. In cases in which cystectomy was not performed, clinical stage was determined based on clinical and radiographic findings.

Immunohistochemistry

Immunohistochemical staining was performed on routine sections as well as tissue micro array (TMA) sections. TMA consisted of 1-mm SmCC tissue cores (two cores per patient) and was constructed using a manual tissue arrayer (Beecher Instruments, Silver Spring, MD). The following monoclonal antibodies were used for immunostaining: AE1/AE3 (clone AE1/3, 1:100 dilution, Dako, Carpinteria, CA), CAM 5.2 (clone CAM 5.2, 1:50 dilution, BD Biosciences, San Jose, CA), CK7 (clone OV-TL 12/30, 1:100 dilution, Dako), CK5/6 (D5/16B4 clone, 1:50 dilution, Dako), CK14 (LL002 clone, 1:50 dilution; BioGenex, Fremont, CA), CK20 (clone Ks20.8, 1:4000 dilution, Dako), CK903 (clone 34βE12, 1:100 dilution, Dako), synaptophysin (clone 27G12, dilution 1:600, Leica Biosystems, Buffalo Grove, IL), chromogranin (clone LKZH10, 1:4000 dilution, Millipore, San Diego, CA), CD56 (clone 123C3, 1:100 dilution, Life Technologies, Carlsbad, CA), neuron-specific enolase (NSE; clone E-27, 1:3 dilution, Cell Marque, Rocklin, CA), GATA-3 (clone HG3-31, 1:100 dilution, Santa Cruz Biotechnology, Santa Cruz, CA), p63 (clone 4A4, 1:1000 dilution, Santa Cruz Biotechnology), RB1(clone LM95.1, 1:30 dilution; Millipore), thrombomodulin (clone 1009, dilution 1:10, Dako), and uroplakin II (clone BC-21, 1:00 dilution; Biocare, Concord, CA). Briefly, 4-μm-thick sections were deparaffinized in xylene and hydrated in graded alcohol. Immunostaining was performed using a BOND-MAX autostainer (Leica Biosystems, Buffalo Grove, IL). Slides were incubated with the primary antibody and then with a visualization reagent (secondary goat anti-mouse immunoglobulin and horseradish peroxidase linked to a dextran polymer backbone). The slides were then rinsed with distilled water, incubated with a 3,3-diaminobenzidine substrate-chromogen solution, and subjected to Mayer hematoxylin counterstaining. The immunohistochemical slides were evaluated by two pathologists (G.W. and C.C.G.) blinded to patient identity and reported as either positive or negative.

Statistical Analysis

The cancer specific survivals for patients with SmCC at different stages were compared using the Kaplan-Meier method with the Prism 6 software program (GraphPad Software, La Jolla, CA). The cancer specific survivals of bladder SmCC were also compared with a cohort of 89 cases of conventional UC at similar stages that were treated in our institute. The Fisher exact test was used to calculate two-tailed P values. P values less than 0.05 were considered statistically significant.

RESULTS

The patients included 69 men and 12 women (Table 1). The median age of patients was 68 years (range, 34–90 years). The majority of patients initially presented with gross or microscopic hematuria (n=73). Other presenting symptoms included dysuria, increased urinary frequency, and urinary tract infection (Table 1). Cystoscopic examination typically demonstrated ulcerated or fungating lesions. The tumors were most commonly located at the lateral (n=30) and posterior wall (n=20). Nonetheless, the tumors were observed at other locations as well. In 3 cases, the tumors were found in diverticula.

Table 1.

Summary of clinicopathologic features of bladder small cell carcinoma

Features	No. of patients
Sex
Male	69
Female	12
Presenting symptom
Hematuria	73
Dysuria	2
Urinary frequency	1
Urinary tract infection	1
N/A	4
Tumor location
Lateral wall	30
Posterior wall	20
Trigone/neck	12
Anterior wall	11
Dome	5
Diverticulum	3
Tumor histology
Pure	27
Mixed with	54
Urothelial carcinoma	32
Urothelial carcinoma in situ	26
Adenocarcinoma	14
Sarcomatous	4
Micropapillary	4
Squamous	3
Plasmacytoid	1
Primary tumor stage on cystectomy
pT1	2
pT2	28
pT3	18
pT4	0
Anatomic stage
I	5
II	37
III	12
IV	27

Microscopically, the tumors showed sheets and large nests of malignant cells with round-to-oval nuclei, scant cytoplasm, and a high nuclear/cytoplasmic ratio (Fig. 1A), resembling SmCC of the lung. The nuclei showed finely stippled chromatin and numerous mitotic figures but lacked prominent nucleoli. Coagulative necrosis and nuclear molding were commonly seen. Only 1/3 of SmCC were pure (n=27), and the majority was mixed with other histologic types (n=54). Overall, the SmCC component accounted for a mean of 34% (range 5–90%) of the mixed tumor. The most common coexistent histologic types were conventional UC (n=32) (Fig. 1B) and UC in situ (n=26) (Fig. 2A). Other histologic types included adenocarcinoma (n=14) (Fig. 3A), micropapillary (n=4), sarcomatous (n=4) (Fig. 1C), squamous cell carcinoma (n=3) (Fig. 1D), and plasmacytoid (n=1) variants.

Figure 1.

Bladder small cell carcinoma shows various histologic features. Pure small cell carcinoma shows malignant cells with large nuclei and scant cytoplasm (A). Small cell carcinoma coexists with urothelial carcinoma (B), chondrosarcomatous dedifferentiation (C), and squamous cell carcinoma (D). Original magnification (A–D) × 100.

Figure 2.

Bladder small cell carcinoma shows distinct immunohistochemical features from adjacent urothelial carcinoma in situ. Small cell carcinoma coexists with urothelial carcinoma in situ (A). Small cell carcinoma is positive for synaptophysin (B) and negative for CK20 (C) and GATA-3 (D). In contrast, urothelial carcinoma in situ is negative synaptophysin (B) and positive for CK20 (C) and GATA-3 (D). Original magnification (A–D) × 100.

Figure 3.

Bladder small cell carcinoma shows distinct immunohistochemical features from adjacent adenocarcinoma. Small cell carcinoma coexists with adenocarcinoma (A). Small cell carcinoma is positive for synaptophysin (B) and chromogranin (C) and negative for CK20 (D). In contrast, adenocarcinoma is negative for synaptophysin (B) and chromogranin (C) and positive for CK20 (D). Original magnification (A–D) × 100.

Immunohistochemical studies were performed in most cases (Table 2). Most SmCC expressed at least one neuroendocrine markers, including synaptophysin (73%, 41/56) (Fig. 2B), chromogranin (47%, 26/55) (Fig 3B), CD56 (95%, 39/41), and NSE (100%, 4/4). SmCC also expressed various cytokeratins, such as pan-CK (89%, 8/9), CK7 (47%, 9/19), HMWCK (60%, 3/5), and CAM5.2 (100%, 6/6), but the staining signals were often focal and weak. SmCC generally did not express urothelial luminal markers, including CK20 (0/17) (Fig. 2C), GATA3 (1/30) (Fig. 2D), and uroplakin II (1/22). A fraction of SmCC expressed a basal marker CK5/6 (9/25). In addition, only two cases showed nuclear expression of the RB1 gene protein (2/23), indicating the important role of this tumor suppressor gene in the development of SmCC (Fig 4).

Table 2.

Immunohistochemical features of bladder small cell carcinoma

Antibody	Source	Dilution	Number of Cases Tested	Number of Positive Cases
Synaptophysin	Leica Biosystems	1:600	56	41 (73%)
Chromogranin A	Millipore	1:4000	55	26 (47%)
CD56	Life Technologies	1:100	41	39 (95%)
NSE	Cell Marque	1:3	4	4 (100%)
CAM5.2	BD Biosciences	1:50	6	6 (100%)
AE1/AE3	Dako	1:100	9	8 (89%)
CK5/6	Dako	1:50	25	9 (36%)
CK7	Dako	1:100	19	17 (89%)
CK14	BioGenex	1:50	25	0 (0%)
CK20	Dako	1:4000	17	0 (0%)
CK903	Dako	1:100	5	3 (60%)
GATA-3	Santa Cruz	1:100	30	1 (3%)
Uroplakin II	Biocare	1:100	22	1 (5%)
p63	Santa Cruz	1:1000	6	1 (17%)
Thrombomodulin	Dako	1:10	2	0 (0%)
RB1	Millipore	1:30	23	2 (9%)

Figure 4.

Bladder small cell carcinoma lacks expression of the retinoblastoma 1 gene. Original magnification × 200.

Pathologic staging was evaluated on 48 patients who underwent radical cystectomy. The primary tumor invaded the lamina propria (pT1) (n=2), muscularis propria (pT2) (n=28) and perivesical soft tissue (pT3) (n=18). To aid the clinical staging, patients underwent a variety of radiographic imaging evaluations, including computed tomography (CT), positron emission tomography, bone scan scintigraphy, and magnetic resonance imaging (MRI). 55 patents had diseases localized to the bladder, including stage I (n=4), II (n=40), and III (n=11). 26 patients had stage IV diseases with metastases to lymph nodes (n=16) and/or other organs (n=11). The most frequent metastasis organ was the liver (n=7), followed by the bone (n=4), lung (n=2) and brain (n=1). Treatment information was available for 72 patients. Patients received chemotherapy (n=63), cystectomy (n=48), radiation (n=11), and immunotherapy (n=2). Among the patients who underwent cystectomy, 43 patients also had received neoadjuvant chemotherapy before surgery.

Clinical followup was available for 77 patients, and the mean follow-up time was 36 months (range, 1–166 months). 38 patients died in a mean of 16 months (range, 1–96 months), and 39 patients were alive in a mean of 55 months (range, 1–166 months). The cancer specific survival time was significantly associated with the clinical stage (p=0.0017) (Fig. 5A). The outcome of SmCC was also compared with 89 cases of conventional UCa at similar stages that were treated at our institute (Fig. 5B). The median survival time did not show any significant difference between SmCC and UC (29 months vs 24 months) (p=0.2224) in stage I, II, and III patients. However, when the disease developed metastasis (stage IV), SmCC had a significantly poorer median survival time than that of UC (15 months vs 24 months) (p=0.0194). The median survival time did not show any significant difference between pure and mixed SmCC (Fig. 5C) (p=0.8734). The median survival time for the patients who underwent neoadjuvant chemotherapy before cystectomy was 38 months, but the median survival time for patients who did not received neoadjuvant chemotherapy was only 12 months (Fig. 5D). Long-term survival (> 60 months) was observed in 17 patients, who had disease localized to the bladder and received neoadjuvant chemotherapy.

Figure 5.

Kaplan-Meier survival analyses of bladder small cell carcinoma. A. Cancer specific survival is significantly associated with cancer stage. B. Survival is compared between small cell carcinoma (SmCC) and conventional urothelial carcinoma (UC). Cancer specific survival for metastatic SmCC is significantly worse than that for metastatic UC, but there is no significant difference when the tumors are localized. C. Survival does not show significant difference between mixed and pure SmCC. D. Neoadjuvant chemotherapy (NAC) significantly prolongs survival.

DISCUSSION

We retrospectively analyzed a large cohort of bladder SmCC from a single institution and found that bladder SmCC demonstrated distinct clinicopathologic features from the conventional UC. At presentation, over 90% bladder SmCC were at advanced stages with tumors invading the muscularis propria and beyond, and about 1/3 developed metastases to lymph nodes and other organs. The patients’ cancer specific survival showed significant association with cancer stage. About 2/3 bladder SmCC were mixed with other histologic type, most commonly UC or UCIS; however, the patients’ survival did not show a significant difference between pure or mixed SmCC. We also compared the survivals of bladder SmCC and UC at similar stages. Patients with SmCC limited to the bladder achieved a long-term survival after neoadjuvant chemotherapy and radical cystectomy. However, when the disease developed metastasis, bladder SmCC showed a significantly worse survival than conventional UC at similar stages, as the widespread disease could not be eradicated by surgery alone. Our immunohistochemical analysis not only supported the neuroendocrine nature of bladder SmCC but also suggested that a fraction of bladder SmCC belonged to a basal molecular subtype, which might underlie its good response to chemotherapy. We also found that the inactivation of the RB1 gene was highly prevalent in SmCC, indicating an important role in the oncogenesis of bladder SmCC.

Although the origin of bladder SmCC remains uncertain, there have been several hypotheses about its pathogenesis [15–19]. It has been postulated that bladder SmCC may develop from malignant transformation of Kulchitsky-type neuroendocrine cells in the bladder mucosa, as immunohistochemistry and electromicroscopy have demonstrated the presence of sporadic neuroendocrine cells in the normal urothelial urothelium [15]. Another theory has suggested that bladder SmCC may result from transdifferentiation of conventional UC. Indeed, a recent study demonstrated that microRNA-145 transformed conventional UC cells to pluripotent stem cells with subsequent differentiation into neuroendocrine, glandular, squamous lineages [16]. A third theory proposed that bladder SmCC and UC may share a common clonal origin - a multipotential, undifferentiated cell (or cancer stem cell) based on the fact that most SmCC coexist with conventional UC in the bladder [18]. In the current study, 66% of bladder SmCC were mixed with other carcinomas, most commonly UC (40%) and UCIS (32%), suggestive a close relationship between SmCC and UC. Furthermore, Cheng et al. compared patterns of loss of heterozygosity between SmCC and corresponding UC and found that they shared almost identical patterns of allelic loss, supporting SmCC and UC originate from a common, clonal precursor [19]. Nonetheless, more genetic and molecular studies are needed to explore the oncogenesis of bladder SmCC.

Recent genomic analyses of bladder UC have demonstrated two intrinsic molecular subtypes, luminal and basal, and each subtype is associated with distinct clinical behavior and sensitivity to chemotherapy [20,21]. Basal UC is more aggressive with shorter survival in a chemotherapy-naive setting when compared to luminal UC. However, basal UC is more sensitive to cisplatinum-based chemotherapy and thus the patients with basal UC appeared to benefit more from chemotherapy when compared to luminal UC [22]. Using a small panel of immunohistochemical markers, we successfully separated bladder UC into luminal and basal subtypes, which demonstrated over 90% consistence with the molecular subtypes based on the genomic analysis [23]. In the current study, most SmCC (64%) did not express luminal or basal markers, largely reflecting the dedifferentiated nature of this disease. Among the 10 cases of SmCC that expressed basal or luminal markers, 9 cases expressed the basal marker CK5/6 and only 1 case expressed the luminal marker GATA-3, suggesting that SmCC is likely to evolve from a basal subtype UC. In addition, our limited genomic analysis also supported that most SmCC demonstrated a gene expression profile of the basal subtype (data not shown), which may underlie its good response to chemotherapy.

The RB1 gene encodes a tumor suppressor protein that regulates cell-cycle regulation, senescence, and cell apoptosis [24]. Recent genomic analysis of 110 lung SmCC revealed inactivation of the RB1 gene in nearly all the tumors, sometimes by complex genomic rearrangements [25]. Only two lung SmCC had the wild-type RB1, but they both showed evidence of chromothripsis, leading to overexpression of cyclin D1, revealing an alternative mechanism of RB1 deregulation. Thus, loss of the tumour suppressors RB1 is considered an essential molecular event for the development of lung SmCC. In bladder UC, RB1 mutations were found in 21% of non-muscle-invasive UC and 36% of muscle-invasive UC, suggesting that RB1 mutations are associated with an invasive disease [26,27]. A recent study demonstrated that patients with bladder UC lacking RB1 expression may benefit from forced expression of the RB1 protein using tumor-targeted liposomal delivery method [28]. In the present study, we found that over 90% of bladder SmCC lacked RB1 expression on immunohistochemical analysis, suggesting that inactivation of the RB1 gene is a critical molecular alteration in development of SmCC. Patients with bladder SmCC may be suitable candidates for the RB1-targeted therapy.

Our study demonstrated that the survival of patients with bladder SmCC was significantly associated with cancer stage. Studies have reported that pure SmCC was associated with a worse prognosis than SmCC mixed with other histology [29,30]. In the current study, we did not find any significant difference between pure SmCC and those with mixed histology. We also compared SmCC with conventional UCa at similar stages and found that they had a similar outcome, when the tumors were localized to the bladder and thus likely to be completely resected. However, SmCC had a worse outcome than UC, when the tumors developed metastasis, as they were unlikely to be completely resected. SmCC demonstrated a high sensitivity to cisplatin-based chemotherapy. A previous study from our institute by Lynch et al found neoadjuvant chemotherapy was associated with pathologic downstaging and significantly improved the patient’s survival [12]. In the current study, a long-term survival (> 5 years) was achieved in 16 patients including 7 patients with > 10 years of survival. All these patients had disease localized to the bladder and underwent neoadjuvant chemotherapy followed by radical cystectomy. Although limited by their retrospective nature, our study supports that neoadjuvant chemotherapy followed by radical cystectomy is an effective approach in treating patients with SmCC localized to the bladder.

It is important to differentiate SmCC from other malignant neoplasms in the bladder. Poorly differentiated UC may show solid sheets of immature cells with large nuclei and scant cytoplasm, mimicking SmCC, but it shows a distinct immunohistochemical profile from SmCC. As demonstrated in the current study, bladder most SmCC express neuroendocrine markers, such as chromogranin, synaptophysin, and CD56, but not urothelial markers, such as uroplakin II, GATA-3, and CK20. In contrast, UC usually expressed urothelial markers but not neuroendocrine markers. Metastatic SmCC from other organs, particularly those from the prostate, may also involve the bladder. Bladder SmCC frequently co-exists with other malignant histologies, particularly UC and UCIS. In our study, 66% of bladder SmCC were accompanied by other histologic types of carcinoma, most frequently UC (40%) and UCIS (32%). However, prostatic SmCC often arise in the setting of prostatic adenocarcinoma with an elevated level of prostatic specific antigen (PSA). Our previous study found that prostatic SmCC frequently demonstrated the TMPRSS2-ERG fusion while this gene fusion was not detected in bladder SmCC [31]. Another recent study reported that bladder SmCC often showed mutations in the TERT promoter but these mutations were not present in SmCC or neuroendocrine carcinomas of other organs [32]. Lymphoma and melanoma occasionally involves the bladder but they express lymphocytic and melanocytic markers. Additionally they lack expressions of either epithelial or neuroendocrine markers.

Although we reported a large series of bladder SmCC with detailed clinicopathologic and immunohistochemical analysis, there were some limitations in our study. First, there was a high variability in the number of cases that were analyzed with each immunostain, as a large number of cases in our study were referral and consultation cases from different hospitals, where immunohistochemistry was not uniformly performed. There might be a potential bias in selection of immunohistochemistry, as the cases were not stained with the same antibodies. Second, only a limited number of the immunohistochemical markers for the molecular classification were tested in our study. However, our recent study found that the immunohistochemical expressions of only two markers, luminal (GATA3) and basal (CK5/6), were sufficient to identify the molecular subtypes of bladder cancer with over 90% accuracy [23]. Finally, our immunohistochemical methods were not uniform, as they were performed on routine histologic sections as well as on TMAs. As TMAs examine only a small fraction of the tumor that is analyzed using routine sections, it has been questioned whether TMA cores could adequately assess biomarkers that exhibited tissue heterogeneity. However, several groups have demonstrated strong correlations between TMA and routine sections. In most instances, two 0.6-mm cores could adequately represent the staining that is observed on routine sections [33,34]. Nonetheless, additional independent immunohistochemical study may be needed to verify the findings of our study.

In conclusion, SmCC of the bladder is an aggressive disease which usually presents at an advanced stage with frequent metastases. Most bladder SmCC are mixed with UC and other histologic types, suggestive that they might share a common clonal origin. When the disease is localized to the bladder, SmCC does not have a significantly different clinical outcome from conventional UCa. Indeed, neoadjuvant chemotherapy followed by radical cystectomy can lead to a long-term survival in patients who have SmCC limited to the bladder. However, when the disease develops metastasis, SmCC shows a significantly worse prognosis than UC. Although most SmCC do not express luminal or basal markers, a small fraction shows a basal molecular subtype, which may underlie its good response to chemotherapy. The prevalence of the RB1 gene dysfunction in bladder SmCC suggests that it plays an important role in its oncogenesis and may be a potential therapeutic target for this aggressive disease.

Highlights.

• Report one of the largest cohorts of bladder small cell carcinomas

• Provide detailed pathologic and clinical analyses of this rare disease

• Highlight the immunohistochemical features of bladder small cell carcinoma

• Compare its outcome with that of conventional urothelial carcinoma at similar stage

• Discuss how to differentiate bladder small cell carcinoma from its mimics