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Small cell cancer of the bladder: pathology, diagnosis, treatment and prognosis

Bulletin du Cancer. Volume 96, Numéro 6, 10030-44, juin 2009, Electronic journal of oncology

DOI : 10.1684/bdc.2009.0883

Summary

Auteur(s) : N Ismaili, S Arifi, A Flechon, O El Mesbahi, J-Y Blay, J-P Droz, H Errihani , Department of medical oncology, national institute of oncology Sidi-Mohamed-Ben-Abdellah, avenue Allal-El-Fassi, 10000 Rabat, Maroc, Department of medical oncology, centre Léon-Bérard, 28, rue Laennec, Lyon-69008, France, Department of medical oncology, Hassan-II hospital, Fez, Maroc, Unité de jour d’oncologie médicale multidisciplinaire, pavillon E, hôpital Édouard-Herriot, 5, place d’Arsonval, 69003 Lyon, France.

Illustrations

ARTICLE

Auteur(s) : N Ismaili^1,2, S Arifi^3,4, A Flechon², O El Mesbahi³, J-Y Blay⁴, J-P Droz², H Errihani¹

¹Department of medical oncology, national institute of oncology Sidi-Mohamed-Ben-Abdellah, avenue Allal-El-Fassi, 10000 Rabat, Maroc
²Department of medical oncology, centre Léon-Bérard, 28, rue Laennec, Lyon-69008, France
³Department of medical oncology, Hassan-II hospital, Fez, Maroc
⁴Unité de jour d’oncologie médicale multidisciplinaire, pavillon E, hôpital Édouard-Herriot, 5, place d’Arsonval, 69003 Lyon, France

Article reçu le 8 Janvier 2009, accepté le 5 Mars 2009

Introduction

Small cell carcinoma (SCC) affects most commonly in the lung. Extrapulmonary SCC was reported to occur in various organs, including the breast, the larynx, the esophagus, the stomach, the intestine, the cervix, the prostate, the urinary bladder and the kidney [1-6]. Genitourinary tract SCC is uncommon [6]. Small cell carcinoma of the bladder (SCCB) represents 0.7% of all bladder tumours [7-12]. The first case was reported in 1981 [13]. To date 882 cases arising in the urinary bladder have been described in the reviewed literature.

Current knowledge of this disease is limited and was based mainly on retrospective investigations. Only 12 authors have described SCCB series of more than 20 patients [6, 8, 10, 11, 14-21]. In 56% of theses cases, the tumour has been a mixture of SCC with one or more of the following: transitional cell carcinoma (TCC), adenocarcinoma and squamous cell carcinoma [7-12, 17, 19, 20].

SCCB is a poorly understood neuroendocrine epithelial tumour associated with a more aggressive behaviour and poorer outcome than bladder TCC. It is mostly diagnosed at advanced stage and generally believed to have a high metastatic potential.

The cause of primary SCCB is unknown. However, several hypotheses were proposed to explain the origin of SCC in the bladder. The most important hypotheses were:

– malignant transformation of bladder neuroendocrine cells gives rise to bladder SCC. This hypothesis was supported by the fact that neuroendocrine cells were found previously in the urinary bladder [22];
– SCCB arises from multipotent stem cells present in the urinary bladder [7];
– SCCB arises from urothelial metaplastic changes [13, 23]. Treatment of SCCB disease is extrapolated from the treatment of SCLC.

The aim of this review is to improve our understanding of the epidemiology, clinical features, diagnosis, pathologic features, histogenesis, molecular genetics, staging, treatment, and prognosis of SCCB.

Papers reviewed were identified by a search on the database PubMed using the terms “bladder cancer”, “rare tumour” and “small cell carcinoma”. Additional papers identified from SCOPUS database, important case reports, and relevant literature reviews were included. Only and all papers published in English were considered. The research was performed since January 1980 up to January 2009.

Epidemiology

Bladder cancer is the second most common genitourinary malignancy after prostate cancer. Worldwide, it is the fourth most common cancer in men and the eighth most common cancer in women [24]. Each year, over 73,000 new cases are reported in Europe and over 56,000 new cases in United States [24]. Up to 95% of urinary bladder tumours are of epithelial origin, from which 90% are TCC [25]. Small cell cancer of the bladder is an extremely rare malignancy with a mean incidence of 0.7% and a range between 0.35 and 1.8% [7-12]. Cramer et al. initially described the disease in 1981 [13]. Since then, 882 cases of SCCB have been diagnosed and reported in the literature up to January 2009. The demographic features of SCCB are similar to those seen in patients with TCC (table 1). The majority of patients are male, with a mean sex ratio equal to 5:1, and a range between 1:1 to 16:1 [7-12, 15, 17, 18, 20, 21, 26, 27]. Most patients are in the sixth to seventh decade. Mean age at time of first diagnosis is 67; ranging between 66 to 68 years (the extreme ages are: 32 and 91) [10, 15, 17, 18]. As with TCC, most patients have a history of tobacco use [9, 12, 17, 19] (65–79%). White patients represent the vast majority of cases (74 to 97% of cases). [10, 18, 19].
Table 1 Demographics and clinical characteristics of SCCB patients according to the studies published in the English literature.

Authors (reference)	N^o	Sex ratio	Age (range)	Smoking history (%)	White race (%)	Symptoms (%)	SCCB/all bladder cancers (%)	Pure histology (%)	Stages (N^o)
Blomjous et al. 1989 [7]	18	2.6: 1	69 (50-81)	-	-	Hematuria, Dysuria	0.48%	44.4%	T2 (N = 5), T3 (N = 8), T4 (N = 5)
Holmang et al. 1995 [8]	25	2.5:1	71.2 (54-87)	-	-	Hematuria	0.7%	40% (pure)	T2 (N = 7), T3 (N = 10), T4 (N = 2) IVM+ (N = 6)
Lohrisch et al. 1999 [9]	14	1:1	–	79%	–	Hematuria (100%), Local pain (36%)	0.35%	50% (pure)	LD (N = 11), ED (N = 2)
Iczkowski et al. 1999 [15]	46	6.7:1	67 (32-91)	–	–	–	–	–	T1 (n = 1), T2 (n = 5), T3 (n = 30), T4 (n = 8), Tx (n = 2)
Siefker-Radtke et al. 2004 (MD Anderson) [18]	88	3.3:1	68 (31-87)	–	88%	Hematuria	–	79.5% (SCC predominant)	Tis (N = 1) T1 (N = 3), T2 (N = 36), T3_T4a (N = 25), T4b/N+/M+ (N = 23)
Cheng et al. 2004 [17]	64	3.3:1	66 (36-35)	65%	–	Hematuria (88%)	–	32% (pure)	T1 (N = 1), T2 (N = 30), T3 (N = 29), T4 (N = 4)
Mangar et al. 2004 [26]	14	6 :1	74 (54-91)	–	–	Hematuria (93%)	–	–	T3 (N = 8), T3N1 (N = 1), T4 (N = 2), IVM+ (N = 3)
Choong et al. 2005 [10] (Mayo Clinic)	44	3:1	66.9 (47-88)	–	97.7%	Hematuria (68.2%) Incidental finding (18%) Urinary obstruction (6.8%) Dysuria (2.3%) Abdominal pain (2.3%) Urinary tract infection (2.3%) Ectopic ACTH secretion (2.3%)	0.5%	61.4% (pure)	II (N = 12), III (N = 13), IV (N = 19)
Abrahams et al. 2005 [19]	51	4:1	67 (39-87)	–	74%	Haematuria (63%), Dysuria (12%), Abdominal pain (2%), Urinary obstruction (2%), Weight loss (2%), Urinary tract infection (2%)	–	12% (pure)	I (N = 2), II (N = 18), II (N = 10), IV (N = 11), Unknown (N = 10)
Bex et al. 2005 [20]	25	11.5:1	64 (40-90)	–	–	–	–	56% (pure)	LD (N = 17), ED (N = 8)
Quek et al. 2005 [11]	25	3:1	68 (40-82)	–	–	–	1%	70%	I/II (N = 4), III (N = 2), IV (N+ or M+) [N = 19]
Mukesh et al. 2008 [21]	20	3:1	68	–	–	–	–	–	LD (N = 11) ED (N = 9)
Ismaili et al. 2008 [12]	14	16:1	60.5 (45-78)	78.5%	–	–	1.8%	35.7% (pure)	II (N = 4), III (N = 5), IVM0 (N = 5)
Bex et al. 2009 [27]	17	16:1	62 (44-78)	-	-	-	-	50% (pure)	LD (N = 17): T2 (N = 14), T3 (N = 2), T4a (N = 1)

Clinical features and diagnosis

Gross hematuria is the most common symptom in SCCB, which was noted in 63 to 88% of the cases [10, 17, 19] (table 1). Dysuria has been reported as the second most common symptom [18]. Urinary obstruction, abdominal pain, urinary tract infection and weigh loss have been reported occasionally [9, 10]. Rare cases of paraneoplastic syndromes such as ectopic ACTH secretion and hypercalcaemia were also reported [28]. Diagnosis of SCCB is mainly accomplished via cystoscopy and transurethral resection of the bladder tumour (TURBT) [29]. Immunohistochemical staining is extremely helpful in establishing the diagnosis (see chapter of Immunohistochemical features).

Histopathology

Macroscopically, SCCB produces large polypoid ulcerated and deeply invasive tumour. The tumour tended to be located on the lateral bladder wall (15.7%), on the posterior bladder wall (8%), on the trigone (2%), on the ureteral orifice (2%), on the anterior wall (2%) and on the dome of bladder (2%) [19]. Histologically, SCCB are identical to SCC of the lung. Therefore, the diagnosis is based on the criteria established by the WHO classification system, which are identical to those for SCLC.

Pathologic diagnosis using light microscopy

Histological studies of SCCB sections when stained with hematoxylin and eosin showed: morphological characteristics of SCC as packed cells having scant cytoplasm containing few organelles. Tumours composed of nests of small round malignant cells with pyknotic round to oval nuclei and evenly dispersed “salt and pepper chromatin” (figures 1 and 2) [19]

The mitotic rate was variable. The tumours were broadly categorized into those that had more than 10 mitotic figures, 10 high-power fields (HPF): 57% of the cases and those with fewer than 10, 10 HPF: 43% of the cases. Tumour rosettes were seen in 23.5% of the cases. Tumour necrosis, either punctuate or geographical, were present in the majority of the cases. Crush artefact (Azzopardi effect) was found in 78.4% of the cases. Vascular invasion was present in 16.7% of the cases [19]. The percentage of “pure” SCC was different in the reported series, and ranged between 12 and 61.4%. In most reports, the authors showed a higher incidence of mixed small cell carcinoma. Overall, the mean percentage of pure SCCB obtained by the analysis of the most important published series is equal to 44% [7-12, 17, 19, 20, 27]. In Abrahams et al. studies’, mixtures of SCC with TCC was present in 70% of the cases, while mixtures of SCC with adenocarcinoma and squamous carcinoma was present only in 8 and 10% of the cases respectively [19]. In the same series, urothelial carcinoma in situ was present in 20% of the cases [19].

Immunohistochemical features

Immunohistochemistry was reported to be helpful for SCCB diagnosis in 8 published papers. The immunohistochemical features of SCCB are summarized in table 2. Tests using the staining of the small cell component of the tumour by the following antibody markers: NSE, chromogranin, synaptophysin serotonin, cytokeratin, S-100 protein, EGFR, C-kit and TTF1. When the light microscope is used for diagnosis of SCCB, the most efficient markers are neuron-specific enolase (the test is positive at a rate of 88.5%), synaptophysin (72.4%), and chromogranin (50%) with strong and intense staining of the cytoplasm of the SCC cells [7, 14, 15, 19]. SCCB are positively stained with the following epithelial markers: CAM 5.2 with strong and focally intense cytoplasmic dot-like reactivity in 41% of the cases [7, 15, 19], CK7 in 59% of cases and EMA in 77.7% of the cases. These last three markers support the urothelial origin of SCCB [7, 30]. Immunohistochemical staining of EGFR and C-kit showed weak cytoplasmic staining in 30 and 27% of the cases, respectively [19, 31, 32]. TTF-1 expression in SCCB was found in 40% of the tumours, demonstrating that this marker is expressed in SCC other than those of pulmonary origin [30, 32].
Table 2 Small cell carcinoma of the urinary bladder: immunohistochemical findings according to 8 studies [7, 14, 15, 19, 30-33].

Antibody	N^o positive / N^o tested	Percentage positive (mean)
Neuroendocrin markers
NSE [7, 14, 15, 19]	1/4, 15/18, 43/46, 10/10 (69/88)	25%, 83%, 93%, 100% (88.5%)
Synaptophysin [7, 15, 19]	12 / 18, 16 / 23, 35 / 46 (63 / 87)	66.6%, 70%, 76% (72.4%)
Serotonin [14]	7 / 9	78%
Chromogranin [7, 14, 15, 19]	4 /18, 9 / 30, 30 / 46, 8 / 9 (51 / 103)	22%-30%-65%-89% (50%)
Epithelial markers
Cytokeratin [7, 14]	7 / 10, 14 / 18 (21 / 28)	70-77% (75%)
EMA [7]	14 / 18	77.7%
CK7 [30]	26 / 44	59%
CAM 5.2 [7, 15, 19]	22 / 46, 9 / 18, 14 / 21 (35 / 85)	47%-50%-66.6% (41%)
Other markers
TTF1 [30, 33]	2 / 4, 17 / 44 (19 / 48)	39%-50% (40%)
S-100 protein [14]	4 / 10	40%
EGFR [19, 31]	14 / 52, 4 / 11	27%, 36% (28.6%)
C-kit [19, 32]	2 / 7, 14 / 52 (19 / 59)	22%, 27% (27%)
CD44v6 [15]	3 / 44	7%

Molecular genetics

The study of the molecular genetics of SCCB is difficult because of the rarity of these tumours. Genetic alterations in SCCB have been the subject of some studies. A comparative genomic hybridization (CGH) study has demonstrated chromosomal deletions at 10q, 4q, 5q and 13q [34, 35]. These regions are frequently deleted in human tumours and known to carry some tumour suppressor genes, PTEN locates to 10q23, and the retinoblastoma gene locates to 13q14 [36]. Gains of DNA sequences have been reported at 5p, 6p, 8q and 20q [34, 35]. But no clear single genetic lesion has been characterized.

Pathogenesis

Little is known about the pathogenesis of SCCB. The cellular origin of SCCB is still controversial. It has been suggested that SCCB arise from the terminally differentiated endocrine cells, however this theory fails to explain the mixed histological patterns that are commonly seen. A second theory proposes that SCCB arise from a metaplasia of other high-grade malignancies [13, 23]. And a third theory suggests that the origin of SCCB may be a multipotential common stem cell that has the ability to differentiate into various cell types depending on the influence of specific transformation or progression-related gene. This may explain the coexistence of SCCB with TCC, and the heterogeneity of the immunohistochemical staining (cytokeratin and endocrine markers) [37, 38]. Furthermore Terracciano et al. reported that both SCC and TCC tumor areas showed the same DNA alterations, and there were no aberrations present in the TCC area that were not also present in the coexistent SCC [34]. These findings support the mulitipotential stem cell theory.

Differential diagnosis

SCC of the prostate, metastatic SCC, and lymphoma must differentiate small cell cancer of the bladder histologically from direct invasion of the bladder. Prostatic SCC contains an adenocarcinomatous component in more than 50% of the cases, and this component will react immunocytochemically for prostate-specific antigen and prostatic acid phosphatase [14]. Separation from pure prostatic SCC however would require clinical correlation, because theses tumours rarely react positively with prostatic markers [14]. Similarly metastatic SCC from another source, usually from the lung, may not be distinguishable histologically from a primary SCCB; however, the presence of TCC component (including TCC in situ) would support a primary origin in the bladder. Differentiation of SCC from lymphoma may be possible by immunohistochimestry. Lymphoma shows positive immunostaining for leukocyte common antigen (LCA), and negative immunostaining for keratin and neuroendocrin markers.

Staging

Between 70 and 80% of bladder TCC are low-grade, non muscle-invasive at the first time of diagnosis, either as an exophytic papillary lesion (Ta) or with invasion into lamina propria (T1) [39]. By contrast, most SCCB are at advanced stage, typically with muscularis propria invasion or extravesical extension [10, 15, 17-19]. Therefore, distant metastasis needs to be diagnosed to decide the adequate treatment.

According an extended investigation of 88 patients, only 4.5% (4 patients) were diagnosed at superficial stage of the disease, while 40.1% (N = 36) were diagnosed at stage T2, 28.3% (N = 25) were diagnosed at stage T3-T4a (stage III) and 26.1% (N = 23) were diagnosed at stage T4b-M+ (stage IV). Similar findings were observed in three others larges series: the first showed 93% of the patients diagnosed at stage II or above [15], the second reported only one patient stage I among 64 cases [17], while the third reported all of the 44 cases at stage II or above [10] (tables 1 and 3). Theses data suggests that the current TNM staging system used for bladder TCC may not be appropriate for SCCB. In SCLC, the treatment strategy and prognosis of the disease are best oriented by the two-stage system: “limited” (T1-4N0-1M0) and “extensive” (TxNxM1 or TxN2-3M0). This staging system is more commonly used in practice. The limited stage concerns those patients with cancer confined to an area that can be encompassed within a single radiation field. The extensive stage includes cases where the disease cannot be covered within one radiation filed. We propose that SCCB be staged using a two-stage system similar to that used in SCLC as was proposed by Bex et al. [20, 27], Lohrisch et al. [9], and Pan et al. [40]. In contrast with SCLC, more than half of the patients with SCCB undergo local or locoregional resection [8, 10-12, 17, 18]. The mixture of SCC with TCC can explain the role of surgery in this disease. In fact, 60% of the patients having SCCB and were long-term survivor’s developed TCC, 24 to 26 months after they were treated by curative radiotherapy and chemotherapy. These patients were treated by surgery (TURBT or radical cystectomy) [9]. Therefore, surgical treatment should be considered in the management of limited disease in combination with other modalities.

Patients with SCCB should be considered as having limited stage if the disease is restricted to the bladder or locoregional lymph nodes within the pelvis that can either completely be resected or be encompassed within one radiation filed. These patients should be offered a local treatment with surgery and/or radiotherapy with chemotherapy. On the other hand, patients with non-regional lymph nodes involvement (retroperitoneal lymph nodes or distant lymph nodes) or with distant metastasis should be considered to have extensive stage disease. Systemic chemotherapy is the treatment of choice for these patients.

Based on two larges studies, the most frequents sites of metastasis were pelvic and retroperitoneal lymph nodes (28.6-53%), liver (23.8-47%), bone (23.8-33%), brain (7.9-16%) and lung (9.5-13%) [10, 18]. Metastasis from SCCB to the skin, adrenal gland and thyroid gland were also reported [10, 41]. Consequently, after histological diagnosis and before any local treatment, the staging workup for SCCB should include computed tomography scans of the pelvis, abdomen chest and brain, and bone scan in analogy to SCLC. Three prospective studies examined the use of positron emission tomography with 18-fluoro-2-deoxyglucose (PET-FDG) in staging of primary SCLC [42-44]. Theses studies showed that the sensitivity of PET ranged from 89 to 100%, and its specificity ranged from 78 to 95%. Theses data suggested that total-body PET may be useful in the staging of SCLC and can be considered in the staging of SCCB especially for those patients for whom localised curative treatment was considered.
Table 3 Table summarizes treatment strategy and outcome of SCCB.

Authors	N^o	Stages (N^o)	Management (N^o)	Median OS (months)		2-year survival (%)		3-y survival (%)	5-y survival (%)		Difference between the groups
Blomjous et al. 1989 [7]	18	T2 (N = 5) T3 (N = 8) T4 (N = 5)	TURBT → RT → CT (N = 2) TURBT → CT (N = 1) RC → CT (N = 1) CT → RC (N = 1)	9	NR	27.7	60	–	–		Median survival = NR with CT versus 7 months without CT
TURBT → RT(N = 9) RC (N = 3) None (N = 1)	7	15.4
Holmang et al. 1995 [8]	25	T2 (N = 7); T3 (N = 10); T4 (N = 2) IVM+ (N = 6)	S + RT (N = 18); CT (N = 2); None (5)	–		–		–	20		–
Lohrisch et al. 1999 [9]	14	LD (N = 9); ED (N = 1)	CT → RT (N = 8); CT→ RC (N = 1) ; CT→ C (N = 1)	41		70		–	50	70	CT > no CT
LD (N = 2); ED (N = 2)	RT (N = 2); None (N = 2)	–		0		0
Bastus et al. 1999 [45]	5	T2 (N = 1); T3 (N = 3); T3N1 (N = 1)	CT → RT (N = 5)	NR		80		–
Siefker-Radtke et al. 2004 (MD Anderson) [18]	46	T2 (N = 13); T3-T4a (N = 8)	CT→ RC (N = 21)	NR		–		–	78		CT → RC > RC, P = 0.026
T2 (N = 12); T3-T4a (N = 7); Unknown (N = 6)	RC (N = 25)	23		–		–	36
Cheng et al. 2004 [17]	64	T1 (N = 1); T2 (N = 30); T3 (N = 29); T4 (N = 4)	RC(N = 38); RT(N = 10); CT(N = 23)	15		–		–	16		RC versus no RC, P = NS
Mangar et al. 2004 [26]	14	T3 (N = 8) ; T3N1 (N = 1) ; T4 (2) IVM+ (3)	CT → RT (N = 1) ; RT (N = 3) ; RC (N = 2);	5	21	–		—	–		Survival with radical cystectomy and RT > no radical treatment
PRT (5); None (N = 3)
Choong et al. 2005 (Mayo Clinic) [10]	44	II (N = 12)	RC (N = 7); NCT → RC (N = 1); PC (N = 3)	NR		–		–	25	63	Survival of stage II > III, P < 0.001; Survival of stage II > IV, P < 0.001; Survival of stage III versus IV, P = 0.3
III (N = 13)	RC (N = 8); RC → CT (N = 2)	24		–		–	15
IV (N = 19)	RC→CT (N = 10); RC (N = 2); CT (N = 5)	12		–		–	10
Bex et al. 2005 [20]	25	10 LD, 3 ED	CT (N = 13) → RT (N = 8)	8 (2-84)	15	–		–			CT > no CT, P = 0.003
LD (N = 7); ED (N = 5)	RT (N = 5); C (N = 3); P (N = 4)	4
Quek et al. 2005 [11]	25	I/II (N = 4) III (N = 2) IV N+ ou M+ (19)	RC → ACT (N = 13) ; NCT→ RC (N = 1) ; RC (N = 11)	13		30%		–	0		Survival of mixed SCCB > Pure SCCB, P = 0.06
Mukesh et al. 2008 [21]	20	LD (N = 11) ; ED (N = 9)	CT (N = 13): CT → RT (6); RC → CT (7)	33		–		–	–		CT > no CT
CT (N = 7): BSC (N = 4); RC (N = 4); RT (N = 1)	3
Ismaili et al. 2008 [12]	14	II (N = 4), III (N = 5), IVM0 (N = 5)	RC→CT (N = 4); RC (N = 5); CT→RC (N = 2); CT (N = 1); RCT (N = 1); None (N = 1)	29.5		58%		–	–		Survival of mixed SCCB > Pure SCCB, P = 0.01, CT + Surgery > Surgery
Bex et al. 2009 [27]	17	LD (N = 17): T2 (N = 14); T3 (N = 2); and T4a (N = 1)	CT→RT (60: 56-70 Gy) (N = 17); Salvage RC (N = 3)	32.5 (4-87)		56%		47%	36%		–

Management

Because of the extreme rarity of SCCB, it is difficult to conduct clinical trials; therefore, there is no standard treatment of the disease. The therapeutic strategy recommended for SCCB is generally extrapolated from treatment adopted for SCLC. Small cell cancer of the bladder is an aggressive tumour: up to 90% of patients present with stage II or more, and up to 25% of patients present with stage IV disease; therefore, chemotherapy plays a prominent role in the management of both limited-stage and extensive-stage small-cell bladder carcinoma [18]. table 3 summarizes the most important studies addressing the management of SCCB.

Limited-stage (T1-4 N0-1M0)

Radical resection

Cystectomy is the corn stone of treatment of bladder TCC; therefore radical resection is commonly performed in SCCB [10, 17, 18]. In a review of 88 cases reported by MD Anderson Cancer Centre, 46 patients undergone cystecomy; 21 after neoadjuvant chemotherapy, and 25 without neoadjuvant chemotherapy. Similarly in two other studies, the resection was performed in 38 of 64 patients in the first study, and in 30 of 44 patients in the second [10, 17]. In most time, the patients received other therapeutic modalities such as chemotherapy or/and radiotherapy. In a multi-institutional review of 64 patients with limited-disease, the efficacy of cystectomy has been questioned as no survival difference was found between patient undergoing surgery and those without surgery [17]. The 5-year disease specific survival was 16 versus 18%, respectively, for those receiving cystectomy, and those who did not receive cystectomy [17]. In another study conducted by MD Anderson, the patients who received neoadjuvant chemotherapy have significantly better survival that those patients who did not receive chemotherapy. Theses findings suggest that surgery alone is not appropriate to achieve cure for patients with limited stage (LS) SCCB.

Chemotherapy

Chemotherapy is the major treatment modality for SCCB. In one large series, the authors showed on multivariate analysis that cisplatin chemotherapy is the only predictor factor for survival of SCCB patients (P < 0.0001) [6]. In the LS, chemotherapy is used as neoadjuvant therapy to shrink the tumour prior to local therapy or as adjuvant treatment after surgical resection [10, 18]. A retrospective study of 46 patients treated at the M.D. Anderson Cancer Centre showed a 5-year survival of 78% for patients receiving neoadjuvant chemotherapy followed by cystectomy, versus 36% for patients undergoing cystectomy alone. In the Mayo Clinic Study, the authors have proposed cystectomy for patients with stage II disease and adjuvant treatment for patients with stages III and VI (M0) disease. In addition chemotherapy is used in combination with radiation to increase the efficacy of radiotherapy [9, 20, 27, 44]. The most commonly used regimen for SCCB is cisplatin plus etoposide chemotherapy in analogy to SCLC [10, 27, 18]. Etoposide is administered at 100 to 120 mg/m² intravenously on day 1 to 3, repeated every 3 weeks. Cisplatin is usually given at 70 to 100 mg/m² intravenously on day 1. The MD Anderson group showed that preoperative chemotherapy with a neuroendocrine regimen was more likely to successfully eradicate the small cell component compared to regimens typically used for TCC. In fact, of the 12 patients treated with a neuroendocrine regimen only 2 had SCC present at cystectomy. However, for those 9 patients treated with a TCC regimen (MVAC) 6 had small cell still present at cystectomy [18]. Consequently, this group recommended the protocols used in the neuroendocrine tumours containing etoposide and cisplatin or ifosfamide and doxorubicine for both histological types: pure SCC and mixed SCC of the bladder [46]. Other authors recommended a regimen covering both small cell component and transitional cell component for mixed SCCB: the addition of taxane or ifosfamide to the standard platinum plus etoposide regimen may be considered [40]. Sometimes, cisplatin is substituted with carboplatin because of reduced toxicity profile, easier use and same efficacy [47].

Radiotherapy

In general, SCLC is treated with a combination of radiotherapy and chemotherapy. In analogy to SCLC, radiotherapy was used to treat SCCB at LS, either alone or in combination with surgery and/or chemotherapy [8, 9, 20, 27, 45]. Four studies assessed the role of curative radiotherapy in the management of limited stage bladder SCC. The first study concerns 18 patients treated with surgery and radiotherapy. The three other studies concern 5, 10 and 17 patients, respectively treated with sequential chemoradiotherapy. The 5 years survival was equal to 28% in the first study with 5 long survivors having 10.7 years mean survival (ranging between 6 to 18 years) [8]. The 5 years survival was equal to 70% in the third study, with 5 long survivors having 85.6 months mean survival (48 to 138 months) [9], and 36% in the fourth study [27]. The 2 years survival was equal to 80% in the second study [45], and 56% in the fourth study [27]. These results confirmed that radiotherapy could be curative when used in combination with surgery but more curative when used with chemotherapy or both chemotherapy and surgery.

Combined modalities

Different options might be used to achieve a cure for LS SCCB: the first option was the combinations of chemotherapy and radiotherapy in analogy to SCLC which can achieve a cure in 36 to 70% of patients [9, 27]; the second combination is the associations of induction chemotherapy followed by surgery which can achieve a cure in 78% of the patients [18]; the third option was the combination of surgery followed by adjuvant chemotherapy [10, 17]; the fourth option was the combination of surgery followed by chemoradiotherapy.

Extensive stage (TxNxM1 or TxN2-3M0)

Chemotherapy

When SCLC arises outside the thorax the treatment is performed using chemotherapy alone that produces a response rate ranging from 60 to 80% and the median life expectancy ranged from 8 to 13 months [48]. The gold standard chemotherapy for patients with good performance status SCLC is platinum-based regimen, typically cisplatin-etoposide (PE) [49-51]. The PE regimen is the most used in the management of SCCB either in LS or ES [9, 10, 18]. In ES SCLC, irinotecan-cisplatine regimen was shown to be an effective treatment [52, 54]. Other chemotherapy regimens including etoposide-cisplatine alternating protocol either with ifosfamide-doxorubicine or with cyclophosphamide, doxorubicine and vincristin (CAV), as well as single agents, including paclitaxel, irinotecan, topotecan, and doxorubicine, have all been used in SCCB [10, 18]. table 4 summarizes the most used regimen in the management of SCCB in analogy to SCLC.
Table 4 Table summarizes chemotherapeutic regimen used in the management of SCCB.

Regimen	Schedule	Drugs and doses
First line chemotherapy: mixed and pure SCC
EP [10, 20, 27, 49-51]	On day 1 to 3, repeated after 21 days	Etoposide 120 mg/m² on day 1 to 3	Cisplatin 80-100 mg/m², on day 1
IP [52, 53]	On day 1, 8, and 15, repeated every 28 days	Irinotecan 60 mg/m² on days 1, 8 and 15	Cisplatin 60 mg/m² on day 1
VIP [20]	On day 1 to 4, repeated after 21 days	Ifosfamide 1.2 g/m², on day 1 to 4	Etoposide 75 mg/m² on day 1 to 4	Cisplatin 20 mg/m² on day 1 to 4
EP/CAV [27, 49]	Alternative regimen: PE on day 1 to 3 repeated after 42 days and CAV on day 1 repeated after 42 days	Etoposide 100 mg/m² on day 1 to 3	Cisplatin 80 mg/m², on day 1	Cyclophosphamide 800 mg/m²	Doxorubicine 50 mg/m²	Vincristine 1.4 mg/m²
CaE [47]	On day 1 to 3, repeated after 21 days	Carboplatin AUC 5 on day 1	Etoposide 120 mg/m² on day 1 to 3
First line: mixed SCC
MVAC [18]	On day 1, 2, 15, and 22, repeated after 28 days	Methotrexate 30 mg/m² on day 1, 15 and 22	Vinblastine 3 mg/m² on day 2, 15, and 22	Doxorubicine 30 mg/m² on day 2	Cispatin 70 mg/m² on day 2
Second line chemotherapy
Oral topotecan [55, 56]	On day 1 to 5, repeated every 21 days	Topotecan 2.3 mg/m² on day 1 to 5
I.V. topotecan [5, 10]	On day 1 to 5, repeated every 21 days	Topotecan 1.5 mg/m² on day 1 to 5
CAV	On day 1, repeated every 21 days	Cyclophosphamide 800 mg/m²	Doxorubicin 50 mg/m²	Vincristine 1.4 mg/m²
TP [57]	On day 1 to 5, repeated every 21 days	Topotecan 0.75 mg/m² on day 1 to 5	Cisplatin 60 mg/m² on day 1

Radiotherapy

Based on the high efficacy of chemotherapy against metastatic small cell carcinoma, palliative radiotherapy is rarely adopted for palliation of painful metastasis. However, radiotherapy in ES disease is reserved for treatment of brain metastases, for symptomatic bone metastases and for cord compression.

Progressive or relapsing disease

In analogy to SCLC, the likelihood of response to further chemotherapy can be predicted on the basis of the response to previous therapy and the duration of free interval. Patients who did not respond to previous therapy or who relapsed within 3 months are judged refractory. For patients with sensitive disease, the same induction regimen can be used for treatment. Second-line regimens, such as single-agent topotecan (either intravenous or oral) or the combination of CAV can be used if the first line regimen is not considered appropriate [54-56].

Therapeutic approaches for the future

Considering the generally poor prognosis of SCC of the urinary bladder, novel therapeutic strategies are needed, to improve outcomes of patients. Given to the known log-linear or near linear dose-response curves of numerous chemotherapy drugs, chemotherapy dose intensification strategies could improve outcomes in a chemosensitive disease like SCLC and SCCB. In SCLC, the use of hematopoietic stem cells leads to investigate HDC since the 1980s in a multiples phase II studies. This strategy produced high complete response rate, even in patients with relapsed or refractory disease. Most of the studies considered “late intensification” strategy, where only responding patients were treated and often using multiple sequential high-dose cycles of chemotherapy [58-64]. Elias et al. [65 reported excellent results in 36 patients with LS. All had responded to previous standard CT, and 29 were in complete remission. They received HDC followed by chest and prophylactic cranial radiotherapy. Five years survival was 41%. Fletcher et al. [66] reported a 56% 4-year survival among 30 patients with LS treated with HDC given after 2 cycles of conventional chemotherapy. One randomized trial suggested an improvement in median survival among patients with LS (14 versus 19 months). But, this difference was not significant [67]. A European Group for Blood and Marrow Transplantation study, including 69 patients, tested three cycles of HDC (ICE) administered at 28 days intervals in previously untreated patients [68, 69]. The CR rates were 70 and 36% in-patient with LS and ES, respectively. Two years survival was, 32 and 5% in patients with LS and ES, respectively. Despite theses promising results, the benefit of HDC with autologous hematopoietic stem cell transplantation (AHSCT) in SCLC is still uncertain, in the absence of large randomized trials. One study assessed the role of HDC in extrapulmonary SCC at extensive stage. Three of the seven patients investigated remain relapse-free, leading the authors to encourage further investigation in this population [70]. To our knowledge, no reports cite the use of high-dose chemotherapy for treating SCCB. Clinical trials are needed to determine whether patients with SCCB might benefit from high-dose approach. 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 [32]. Moreover development of new agents, based on our understanding of the molecular biology of these tumours, is needed. So the identification of novel diagnostic therapeutic targets should be more effective.

Prognosis

The prognosis of SCCB is poor. The overall 5-year survival rate in all stages is 19% (16 to 25%) [10, 17]. Based on one large study, the 5-year survival rates for patients with stages II, III, and IV were 63.6, 15.4, and 10.5% respectively (the difference of survival was significant between stages II and III, and between stages II and IV, P < 0.0001) (table 3). In another study, the 1-year disease-specific survival rates for patients with organ-confined tumours (T1 and T2) and for patients with more widespread disease (T3 and T4) were 58 and 25%, respectively (P = 0.06) [17]. Theses data suggest that patients with stage II disease have better outcome than patients with stages III-IV disease. In addition, pure small cell histology was shown to have poorer outcome than the mixed small cell histology [10, 12]. In one study, the authors demonstrated that median duration of survival was significantly higher in patients with mixed small cell histology (median survival was 34 months in mixed SCC versus 9.5 months in pure SCC, P = 0.01) (table 3) [12]. Because of the rarity of this disease, no others prognostic factors were identified up to now.

Summary

Primary SCCB is a very rare and aggressive tumour. In the absence of prospective studies, the best treatment for this tumour cannot be established for certain. For limited stage diseases, the management should include combined modalities with chemotherapy and radical surgery and/or radical radiotherapy. For extensive stage disease, the chemotherapy using a platinum agent is the mainstay treatment. Pure small cell histology shows to have worsened prognosis than the mixed small cell histology. Further investigations are needed to improve our knowledge in the diagnosis and treatment of this rare disease.

Acknowledgments

We sincerely thank Mohammed Ismaili, professor of microbiology at Moulay-Ismail University, Meknes, Morocco.

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