BJUI. Small cell carcinoma of the urinary bladder: a 15-year retrospective review of treatment and survival in the Anglian Cancer Network

Transcription

1 . JOURNAL COMPILATION 2008 BJU INTERNATIONAL Urological Oncology SMALL CELL CARCINOMA OF THE URINARY BLADDER MUKESH et al. BJUI BJU INTERNATIONAL Small cell carcinoma of the urinary bladder: a 15-year retrospective review of treatment and survival in the Anglian Cancer Network Mukesh Mukesh, Natalie Cook, Abigail E. Hollingdale, Nicola L. Ainsworth and Simon G. Russell Department of Oncology, Addenbrooke s Hospital NHS Trust, Cambridge, UK Accepted for publication 12 August 2008 Study Type Therapy (case series) Level of Evidence 4 OBJECTIVE To report the clinical experience and management of patients with small cell carcinoma (SCC) of the bladder, treated in the Anglia Cancer network from 1992 to 2007, and to review published studies, as SCC is a rare condition, accounting for <1% of all bladder tumours, and there is no established treatment strategy for managing these patients. PATIENTS AND METHODS We analysed retrospectively data from all patients diagnosed with SCC of the urinary bladder between 1992 and 2007, with an emphasis on stage, treatment and overall survival. RESULTS Twenty patients were identified with primary bladder SCC (male: female ratio 3:1; mean age 68 years; mean follow-up 15.8 months). Nine patients (45%) had extensive-stage disease at diagnosis. Four patients received best supportive care, three had a radical cystectomy, one radical radiotherapy and six sequential chemoradiotherapy. In all, 13 patients were treated with chemotherapy, with six receiving cyclophosphamide, doxorubicin and vincristine, three receiving carboplatin and etoposide, and the remainder receiving alternative platinum-based regimens. For 12 patients with assessable disease, six had a complete response, three a partial response and three had progressive disease after chemotherapy. No patient received prophylactic cranial irradiation (PCI). At the time of analysis, 14 (70%) patients had died, with one (5%) developing brain metastasis. The median survival was 33 months for patients receiving chemotherapy, vs 3 months with no chemotherapy. CONCLUSIONS SCC of the bladder tends to occur in an older population, more commonly in men. It is an aggressive tumour with a propensity for early metastasis. The response rate to chemotherapy is high but the overall prognosis is poor. Brain secondaries are less common than for SCC of the lung and currently the role of PCI is unclear. As there is no standard of care for these patients, they are treated according to local protocols. Further efforts should be made to develop more effective treatments and the role of PCI should be assessed in the setting of a clinical trial, in conjunction with other extrapulmonary SCCs. KEYWORDS small cell carcinoma, bladder cancer, neuroendocrine tumour INTRODUCTION Small cell carcinoma (SCC) is a distinct histological and biological disease entity which not only arises from the lung but also from a wide range of extrapulmonary sites, including the urinary bladder, prostate, oesophagus, stomach, colon and rectum, salivary glands, larynx and skin. SCC is also referred to as oat-cell carcinoma or smallcell neuroendocrine carcinoma, and is characterized by an aggressive clinical course, early metastatic spread and high diseaserelated mortality rates. The urinary bladder is the most common site for genitourinary extrapulmonary SCC, accounting for <1% of all primary bladder tumours [1 5]. Since the first published case in 1981, it has been described in several series and case reports [1 3,6 12]. However, because of the relative rarity of the tumour, there is no standard approach for managing SCC of the bladder. In previously published studies, different combinations of surgery, radiotherapy (RT) and chemotherapy were used. We report our clinical experience of treating 20 patients in the Anglian Cancer Network, with an emphasis on management, and we review previously published reports on SCC of the bladder. PATIENTS AND METHODS All cases of bladder cancer with SCC, neuroendocrine tumour and oat cell carcinoma histology in the Anglian cancer network from 1992 to 2007 were retrospectively reviewed. Twenty patients were identified and data were obtained from clinical notes for patient demographics, smoking history, performance status (PS), stage (limited vs extensive), treatment received and outcome. The length of followup was based on data extracted from the clinical notes and correspondence. Survival was estimated as the time from the diagnosis JOURNAL COMPILATION 2008 BJU INTERNATIONAL 103, doi: /j x x 747

2 MUKESH ET AL. of bladder SCC to death, the last follow-up appointment or the last contact via correspondence with the GP. Living patients were censored at the date of last follow-up. The survival curves were constructed using the Kaplan-Meier technique. Patients were staged in the same manner as the Veterans Administration Lung Group staging for SCC of the lung [13]. A limited stage included tumour confined to the bladder and regional lymph nodes, which can be encompassed within the RT field, and extensive disease included all other patients. For the review of previous reports, Medline was searched using the keywords small cell, neuroendocrine and bladder, with manual searching of journals and review papers. RESULTS Table 1 lists the characteristics for all 20 patients; primary SCC of the bladder had a male predominance (male: female ratio 3:1), and the mean (range) age at diagnosis was 68 (52 88) years. Among patients with retrievable clinical histories, 10 of 15 gave a history of cigarette smoking. More than half of the patients had a PS of 0 1 at the time of diagnosis. Eleven patients had limited-stage disease at the time of diagnosis and nine had extensive disease. The sites of disease for extensive stage were pelvic lymph nodes (three patients), and one each in the liver, mediastinum, pelvic lymph nodes and bone, ascites, liver and lung, and kidney. All patients were treated at the discretion of their clinician (Table 2). Four patients received best supportive care and 13 received chemotherapy (seven with limited disease and six with extensive disease). Different chemotherapy regimens were used, with cyclophosphamide, doxorubicin and vincristine (CAV) being the most common (six patients); other regimes were carboplatin + etoposide (PE, in three), adriamycin, cyclophosphamide and etoposide (ACE, in one), gemcitabine and carboplatin (GC, in one), carboplatin and vincristine (CV, one) and cisplatin, methotrexate and vinblastine (CMV, in one). For 12 patients with assessable disease six had a complete response, three a partial response and three had progressive disease during chemotherapy. Three patients had radical cystectomy with one receiving neoadjuvant and one adjuvant chemotherapy. The patient with radical cystectomy alone had a pelvic relapse treated with RT. Six patients received sequential chemo-rt and one patient received RT alone. None of these patients relapsed locally in the pelvis. No patients received prophylactic cranial irradiation (PCI). With a mean follow-up of 15.8 months, 14 of 20 (70%) patients had died, half within a year of diagnosis, and the overall median survival was 10 months (Fig. 1a). One patient developed brain metastases as the site of disease progression. Irrespective of the clinical stage, the median survival for patients after chemotherapy was 33 months, vs 3 months for patients who received no chemotherapy (hazard ratio 0.26, P = 0.005; Fig. 1b). All six patients still alive had received chemotherapy, with a maximum and minimum follow-up of 60 and 6 months, respectively. DISCUSSION Primary SCC of the bladder is a rare tumour, but unlike urothelial carcinoma it behaves aggressively and is similar to its pulmonary counterpart, with a 25% 2-year survival and 8% 5-year survival [14]. It is a disease of advancing age and, like SCC of the lung, is associated with cigarette smoking. It is more common in men, as seen in the present series and previous studies [1 4,7 12,15 20]. Most of the patients in the present series were in the sixth and seventh decade of life and twothirds had a history of cigarette smoking, which is comparable to findings in other studies [1 4,7 12,15 20]. The origin of extrapulmonary SCC is uncertain but different theories have been postulated, including its derivation from the amine precursor uptake and decarboxylation system, metaplasia from other high-grade malignancies, and the most widely accepted view of its origin from a multipotential stem cell with the ability to differentiate into various tissue types [2,9,14,21,22]. This view is supported by the recent report of Cheng et al. [23] who showed an identical pattern of allelic loss in coexisting SCC and urothelial carcinoma, suggesting a common progenitor cell of origin. The most common presentation of SCC of the bladder is macroscopic haematuria [1 3,8,10,11]. Other symptoms include local irritation and pain, and less frequently paraneoplastic syndrome including TABLE 1 Characteristics of the 20 patients with SCC of the bladder Characteristic N (%) Age, years (30) (25) >70 9 (45) Gender Male 15 (75) Female 5 (25) PS (55) >1 6 (30) Unknown 3 (15) Stage Limited 11 (55) Extensive 9 (45) Smoking history Smoker 10 (50) Non-smoker 5 (25) Unknown 5 (25) Limited disease, TXN0-1M0; extensive disease, TXN2-3M0 or TXNXM1. FIG. 1. Kaplan-Meier survival curves for a, overall survival and b, for those treated with chemotherapy or not. a % survival b % survival Survival in SC Bladder Survival, months Chemo 90 No Chemo Survival, months 748 JOURNAL COMPILATION 2008 BJU INTERNATIONAL

3 SMALL CELL CARCINOMA OF THE URINARY BLADDER TABLE 2 The details and outcome for each patient Patient PS Stage* Treatment Site of extensive stage Relapse site/cause of death Outcome at (months) 1 0 L Neoadjuvant PE then radical cystectomy Alive (60) 2 0 E CAV then radical bladder RT Pelvic lymph nodes Alive (21) 3 0 L PE then radical bladder RT Alive (6) 4 1 E CAV Bone + pelvic lymph nodes Alive (12) 5 0 L CAV then radical RT Alive (23) 6 0 L CAV then radical RT Alive (40) 7 1 E CAV then radical RT Pelvic lymph nodes Brain Dead (21) 8 1 L ACE then radical RT GI perforation Dead (33) 9 1 E CMV Malignant ascites Dead (10) 10 2 L PE Pulmonary embolism Dead (6) 11 3 E GC Liver + lung Dead (3) 12 L Radical RT to bladder Bone Dead (2) 13 3 E Palliative RT to bladder Liver Dead (3) 14 L Best supportive care Dead (1) 15 2 E Best supportive care Pelvic lymph nodes Dead (3) 16 2 L Radical cystectomy Pelvis; treated with RT Dead (39) 17 2 E Best supportive care Kidney Dead (5) 18 0 L Radical cystectomy + block dissection Pelvis Dead (10) R hemipelvis then adjuvant CV 19 E CAV Mediastinum Dead (18) 20 1 L Best supportive care MI Dead (1) *L, limited; E, extensive. hyponatraemia, hypokalaemia, hypercalcaemia and Cushing s syndrome [2,8,10,15,17,24,25]. At cystoscopy bladder SCC cannot be differentiated from TCC. SCC of the bladder commonly occurs on the lateral walls (54%), followed by the posterior wall (20%), trigone (10%), dome (8%) and anterior wall (8%) [2,14]. On light microscopy the most common cellular pattern is diffuse sheets of cells with marked hypercellularity, necrosis and mitosis, producing a starry sky appearance [2,11,15,17,18,20,21,26,27]. As the cells are fragile, squash artefact is common, resulting in small blue streaks. The deposition of basophilic material around blood vessels (the Azzopardi phenomenon) is also seen. Most cases express neural markers, commonly neurone-specific enolase, on immunohistochemistry, although it lacks specificity. The other commonly used neural markers, chromogranin A and synaptophysin, are positive in half the cases [4,22]. Epithelial marker antigen and carcinoembryonic antigen are commonly expressed epithelial markers [4]. Cytokeratin (CAM 5.2) is expressed in a quarter of bladder SCC, and its distinctive punctate perinuclear staining pattern aids in differentiating it from highgrade urothelial tumours, where the pattern is membrane staining [28]. The two differential diagnoses of SCC of the bladder are highgrade TCC and lymphoma. The distinctive characteristics of TCC are nesting of large cells with cytoplasmic pleomorphism, anisonucleosis and prominent nucleoli. Lymphoma usually lack mitotic figures and the background usually lacks nuclear debris. Immunocytochemical studies are helpful in differentiating TCC from SCC of the bladder. Chromogranin A is positive in half of the cases with SCC but only 5% of urothelial carcinoma, CD44v6 is positive in 7% of SCC and 60% of urothelial tumours [29]. Cytokeratin 20 is positive in 46 73% of urothelial tumours and is negative in SCC tumours. In keeping with other series [2,4,7,9 11,19], the present study showed a propensity of SCC of the bladder for early metastatic spread, with nearly half the patients presenting with extensive disease. More than half the patients received chemotherapy; about three-quarters of these patients had some response, i.e. partial or complete, although a quarter progressed whilst on chemotherapy. Seven patients received RT with curative intent and three had radical surgery in the form of cystectomy. The median survival in the series was 10 months. The previously reported median survival for SCC of the bladder in other series was 4 19 months [1,8,9,14]. Factors with prognostic significance are similar to those for SCC of the lung, including extent of disease at diagnosis [3,10], PS and the level of lactate dehydrogenase [7]. There is no significant difference in survival between patients with pure SCC and tumours with mixed histology [1,3]. Metastatic disease predicts a poor outcome and only cisplatin chemotherapy, and not primary surgery, improves survival [5]. This should be interpreted with caution, as a good PS is required for cisplatin-based chemotherapy, and this might explain the association of cisplatin with improved survival. The optimum therapy for patients with SCC of the urinary bladder is difficult to define because of the rarity of the disease and paucity of clinical studies. Given its historical resemblance to SCC of the lung, it has been treated with multimodal treatments, including chemotherapy, chemo-rt, and surgery with or without chemotherapy. The role of chemotherapy is well established in SCC of the lung [30,31] and SCC of the bladder is also a chemosensitive disease. Mackey et al. [5] reported on 180 patients with JOURNAL COMPILATION 2008 BJU INTERNATIONAL 749

4 MUKESH ET AL. genitourinary SCC, assessing variables associated with survival. For bladder SCC, cisplatin-based chemotherapy was the only variable predicting survival in a multivariable analysis in their series. Bex et al. [19], using treatment analogous to that of SCC of the lung, showed a difference in survival of patients who received chemotherapy from those who did not, regardless of tumour stage. The median survival of patients receiving chemotherapy was 15 months, vs 4 months for those who did not (P = 0.003). In a retrospective series of 88 patients [16], those receiving neoadjuvant chemotherapy had a significantly better 5-year survival than those with primary cystectomy (78% vs 36%, P = 0.026). Adjuvant chemotherapy gave no additional survival benefit. Moreover, there were no cancer-related deaths after 2 years in patients who had received neoadjuvant chemotherapy. Quek et al. [7] reported on 20 patients with SCC or mixed histology tumour of the bladder treated with cystectomy. Patients receiving neoadjuvant or adjuvant chemotherapy had significantly better overall and disease-free survival. In the present series, different chemotherapy regimens were used at the discretion of the treating clinician. The median survival was 10 months and there was improved survival in patients receiving chemotherapy, with a median survival of 33 months with chemotherapy vs 3 months without chemotherapy. It is possible that patient selection criteria were a major source of bias. The PS is a known prognostic indicator in SCC of the lung [32] and is likely to be so in SCC of the bladder. Despite the shortcomings of data from a retrospective small series and lack of uniform treatment strategies, the available data strongly suggest a significant survival advantage with chemotherapy. In deciding the optimum local treatment, there are no direct comparisons between cystectomy and radical RT. The role of cystectomy alone in patients with SCC of the bladder is limited. It might be adequate for patients with early-stage disease, as shown in the series from the Mayo clinic, with longterm disease-free survival [1]. They identified eight patients with stage II SCC of the bladder treated with radical cystectomy alone. Six of these patients were disease-free, one had local recurrence and one developed metastatic disease less than a year after surgery. However, as most patients with SCC of the bladder present with disease extension either through the bladder wall or pelvic lymph nodes, surgery alone is unlikely to TABLE 3 Previous reports of cranial relapse in SCC of the bladder Study Cranial relapse, n or n (%) N patients Use of PCI (n) [38] 0 12 No [36] 1 7 Yes (3) [19] 0 25 No [1] 5 (8) 44 No [7] NI 20 [16] 9 (16) 55 No [10] 2 14 No [3] NI 64 [8] 0 14 Yes (2) [11] 2 (9) 22 No Although there were few patients, none of the five who received PCI had cranial relapse. NI, no information. result in a cure. Also, as distant relapse after surgery for organ-confined disease is well documented, clinicians increasingly use chemotherapy in the adjuvant or neoadjuvant setting. Many clinicians have adopted a bladder-sparing strategy of transurethral resection followed by chemo-rt. Chemo-RT is a proven strategy for SCC of the lung [33] and has been used in many case series for SCC of the bladder. In the present series, six patients received sequential chemo- RT, with good survival results and no local relapse in the pelvis. It was first described by Oblon et al. [34] using sequential chemotherapy and RT for SCC of the bladder. Lohrisch et al. [8] analysed retrospectively patients in the British Columbia Cancer Agency; of 10 (eight with T3/4 disease) who received platinum-based chemotherapy, followed by RT in doses of Gy, the 3- and 5-year survival was 70% and 44% in this group. The rate of secondary bladder primary malignancies in surviving patients was 60% at 3 years. None of the patients had small-cell elements on histological examination of their subsequent bladder neoplasm. Bex et al. [19] described 10 patients with limited disease treated with neoadjuvant cisplatin-based chemotherapy; eight had a complete response and proceeded with RT to a dose of 60 Gy. Only one patient developed a local recurrence requiring salvage cystectomy. Bastus et al. [35] reported on four patients with mixed SCC of the bladder treated with sequential cisplatin-based chemotherapy and two-phase RT to the pelvis (45 Gy) and bladder (15 Gy). All four patients had a complete response to chemotherapy and only one relapsed locally after RT. Recently, Lester et al. [36] reported no relapse in the bladder in four patients receiving radical RT after a complete response to chemotherapy. All four patients received four cycles of PE and the RT dose was Gy in fractions. The treatment field involved the whole bladder and any lymph nodes seen on pretreatment CT. Prophylactic pelvic irradiation was not routinely used. One potential drawback of chemo-rt with bladder preservation is the subsequent development of uroepithelial tumours in up to 60% patients in one series, requiring salvage cystectomy [8], although this has not been shown in other series [19,35,36]. No case series have reported a role for adjuvant RT after radical cystectomy, possibly because most relapses are extrapelvic. In pulmonary SCC, brain metastases are common and will emerge in 50 60% of patients over 2 years. PCI is the standard care in patients with SCC of the lung who have a complete response to therapy, with an improvement in both disease-free and overall survival [37]. Relapses in the brain are well documented but the role of PCI in SCC of the bladder is unclear (Table 3) [1,3,7,8,10,11,16,19,36,38]. In the present series of 20 patients, one (5%) relapsed with brain metastasis. In other series [3,7,8,11,16,19,36,38] the cranial relapse rate was 0 16%, and because there are so few patients involved, it is not possible to draw firm conclusions. To our knowledge, no case series have used PCI as a standard treatment, although three patients in the series of Lester et al. [36] were treated with PCI after a complete response to chemotherapy. This decision was made after one of the patients 750 JOURNAL COMPILATION 2008 BJU INTERNATIONAL

5 SMALL CELL CARCINOMA OF THE URINARY BLADDER developed brain metastases. It can be postulated that brain metastases are uncommon in extrapulmonary SCC. This is supported by other case series assessing brain metastases in extrapulmonary SCC. Ku et al. [39] reported on 22 patients with oesophageal carcinoma, of whom only one developed a cranial relapse. Soto et al. [40] identified 18 patients with limited-stage extrapulmonary SCC treated with chemotherapy and RT; none received PCI and only one developed a cranial relapse. In conclusion, SCC of the bladder is a rare, aggressive malignancy, and mostly affects elderly men with a smoking history. Patients usually have a poor PS and significant comorbidities, which limits their treatment options. The prognosis is influenced by the disease extent at diagnosis, PS and the use of chemotherapy. With the paucity of evidencebased data about SCC of the bladder, it is difficult to define the best treatment strategy. For small-volume disease limited to the bladder, cystectomy alone might be sufficient. For limited-stage patients with a significant tumour burden, chemotherapy should be offered in the adjuvant or neoadjuvant setting. The use of platinum-based regimens has a favourable prognosis. With the high risk of systemic relapse for this disease, a bladderconserving approach with sequential chemo- RT is an attractive option. Due to the risk of local relapse or development of subsequent uroepithelial tumours, a regular cystoscopic follow-up is needed with a view to salvage cystectomy. For patients with extensive disease, palliative chemotherapy should be offered, analogous to lung SCC. There is currently no evidence for the use of PCI in these patients. Further research is needed to develop more effective therapies and to define the role of PCI for extrapulmonary SCC. CONFLICT OF INTEREST None declared. REFERENCES 1 Choong NW, Quevedo JF, Kaur JS. Small cell carcinoma of the urinary bladder. The Mayo Clinic experience. Cancer 2005; 103: Blomjous CE, Vos W, De Voogt HJ, Van der Valk P, Meijer CJ. Small cell carcinoma of the urinary bladder. A clinicopathologic, morphometric, immunohistochemical, and ultrastructural study of 18 cases. Cancer 1989; 64: Cheng L, Pan CX, Yang XJ et al. Small cell carcinoma of the urinary bladder: a clinicopathologic analysis of 64 patients. Cancer 2004; 101: Trias I, Algaba F, Condom E et al. Small cell carcinoma of the urinary bladder. Presentation of 23 cases and review of 134 published cases. Eur Urol 2001; 39: Mackey JR, Au HJ, Hugh J, Venner P. Genitourinary small cell carcinoma: determination of clinical and therapeutic factors associated with survival. J Urol 1998; 159: Cramer SF, Aikawa M, Cebelin M. Neurosecretory granules in small cell invasive carcinoma of the urinary bladder. Cancer 1981; 47: Quek ML, Nichols PW, Yamzon J et al. Radical cystectomy for primary neuroendocrine tumors of the bladder: the University of Southern California experience. J Urol 2005; 174: Lohrisch C, Murray N, Pickles T, Sullivan L. Small cell carcinoma of the bladder: long term outcome with integrated chemoradiation. Cancer 1999; 86: Holmang S, Borghede G, Johansson SL. Primary small cell carcinoma of the bladder: a report of 25 cases. J Urol 1995; 153: Mangar SA, Logue JP, Shanks JH, Cooper RA, Cowan RA, Wylie JP. Smallcell carcinoma of the urinary bladder: 10- year experience. Clin Oncol 2004; 16: Grignon DJ, Ro JY, Ayala AG et al. Small cell carcinoma of the urinary bladder. A clinicopathologic analysis of 22 cases. Cancer 1992; 69: Swanson PE, Brooks R, Pearse H, Stenzel P. Small cell carcinoma of urinary bladder. Urology 1988; 32: Zelen M. Keynote address on biostatistics and data retrieval, part 3. Cancer Chemother Rep 1973; 4: Abbas F, Civantos F, Benedetto P, Soloway MS. Small cell carcinoma of the bladder and prostate. Urology 1995; 46: Mills SE, Wolfe JT, Weiss MA et al. Small cell undifferentiated carcinoma of the urinary bladder. A light-microscopic, immunocytochemical, and ultrastructural study of 12 cases. Am J Surg Pathol 1987; 11: Siefker-Radtke AO, Dinney CP, Abrahams NA et al. Evidence supporting preoperative chemotherapy for small cell carcinoma of the bladder: a retrospective review of the M. D. Anderson cancer experience. J Urol 2004; 172: Soriano P, Navarro S, Gil M, Llombart- Bosch A. Small-cell carcinoma of the urinary bladder. A clinico-pathological study of ten cases. Virchows Arch 2004; 445: Ali SZ, Reuter VE, Zakowski MF. Small cell neuroendocrine carcinoma of the urinary bladder. A clinicopathologic study with emphasis on cytologic features. Cancer 1997; 79: Bex A, Nieuwenhuijzen JA, Kerst M et al. Small cell carcinoma of bladder: a single-center prospective study of 25 cases treated in analogy to small cell lung cancer. Urology 2005; 65: Abrahams NA, Moran C, Reyes AO, Siefker-Radtke A, Ayala AG. Small cell carcinoma of the bladder: a contemporary clinicopathological study of 51 cases. Histopathology 2005; 46: Christopher ME, Seftel AD, Sorenson K, Resnick MI. Small cell carcinoma of the genitourinary tract: an immunohistochemical, electron microscopic and clinicopathological study. J Urol 1991; 146: Van Hoeven KH, Artymyshyn RL. Cytology of small cell carcinoma of the urinary bladder. Diagn Cytopathol 1996; 14: Cheng L, Jones TD, McCarthy RP et al. Molecular genetic evidence for a common clonal origin of urinary bladder small cell carcinoma and coexisting urothelial carcinoma. Am J Pathol 2005; 166: Reyes CV, Soneru I. Small cell carcinoma of the urinary bladder with hypercalcemia. Cancer 1985; 56: Partanen S, Asikainen U. Oat cell carcinoma of the urinary bladder with ectopic adrenocorticotropic hormone production. Hum Pathol 1985; 16: Podesta AH, True LD. Small cell carcinoma of the bladder. Report of five cases with immunohistochemistry and review of the literature with evaluation of prognosis according to stage. Cancer 1989; 64: Abenoza P, Manivel C, Sibley RK. Adenocarcinoma with neuroendocrine JOURNAL COMPILATION 2008 BJU INTERNATIONAL 751

6 MUKESH ET AL. differentiation of the urinary bladder. Clinicopathologic, immunohistochemical, and ultrastructural study. Arch Pathol Lab Med 1986; 110: Cheng C, Nicholson A, Lowe DG, Kirby RS. Oat cell carcinoma of urinary bladder. Urology 1992; 39: Iczkowski KA, Shanks JH, Allsbrook WC et al. Small cell carcinoma of urinary bladder is differentiated from urothelial carcinoma by chromogranin expression, absence of CD44 variant 6 expression, a unique pattern of cytokeratin expression, and more intense gamma-enolase expression. Histopathology 1999; 35: Agra Y, Pelayo M, Sacristan M, Sacristan A, Serra C, Bonfill X. Chemotherapy versus best supportive care for extensive small cell lung cancer. Cochrane Lung Cancer Group. Cochrane Database Syst Rev 2003; (4): CD Thatcher N, Clark PI, Girling DJ et al. Comparison of oral etoposide and standard intravenous multidrug chemotherapy for small-cell lung cancer: a stopped multicentre randomised trial. Lancet 1996; 348: Bremnes RM, Sundstrom S, Aasebo U et al. The value of prognostic factors in small cell lung cancer: results from a randomised multicenter study with minimum 5 year follow-up. Lung Cancer 2003; 39: Pignon JP, Arriagada R, Ihde DC et al. A meta-analysis of thoracic radiotherapy for small-cell lung cancer. N Engl J Med 1992; 327: Oblon DJ, Parsons JT, Zander DS, Wajsman Z. Bladder preservation and durable complete remission of small cell carcinoma of the bladder with systemic chemotherapy and adjuvant radiation therapy. Cancer 1993; 71: Bastus R, Caballero JM, Gonzalez G et al. Small cell carcinoma of the urinary bladder treated with chemotherapy and radiotherapy: results in five cases. Eur Urol 1999; 3: Lester JF, Hudson E, Barber JB. Bladder preservation in small cell carcinoma of the urinary bladder: an institutional experience and review of the literature. Clin Oncol 2006; 18: Auperin A, Arriagada R, Pignon JP et al. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group. N Engl J Med 1999; 341: Asmis TR, Reaume MN, Dahrouge S, Malone S. Genitourinary small cell carcinoma: a retrospective review of treatment and survival patterns at The Ottawa Hospital Regional Cancer Center. BJU Int 2006; 97: Ku GY, Minsky BD, Rusch VW, Bains M, Kelsen DP, Ilson DH. Small-cell carcinoma of the esophagus and gastroesophageal junction: review of the Memorial Sloan-Kettering experience. Ann Oncol 2008; 19: Soto DE, Eisbruch A. Limited-stage extrapulmonary small cell carcinoma. Outcomes after modern chemotherapy and radiotherapy. Cancer 2007; 13: Correspondence: Mukesh Mukesh, Clinical Oncology, Addenbrooke s Hospital NHS Trust, Cambridge CB2 0QQ, UK. drmukesh12@doctors.net.uk Abbreviations: SCC, small cell carcinoma; RT, radiotherapy; PS, performance status; PCI, prophylactic cranial irradiation; CAV, cyclophosphamide, doxorubicin and vincristine; PE, carboplatin and etoposide; ACE, adriamycin, cyclophosphamide and etoposide; GC, gemcitabine and carboplatin; CV, carboplatin and vincristine; CMV, cisplatin, methotrexate and vinblastine. 752 JOURNAL COMPILATION 2008 BJU INTERNATIONAL