Submit Your Article CMED MEACR meeting
Home Print this page Email this page Users Online: 649
Home About us Editorial board Search Ahead of print Current issue Archives Submit article Instructions Subscribe Contacts Login 


 
 Table of Contents  
REVIEW ARTICLE
Year : 2015  |  Volume : 4  |  Issue : 4  |  Page : 487-491

Changing trends in the management of small cell carcinoma of urinary bladder


Department of Radiotherapy, PGIMER, Chandigarh, India

Date of Web Publication2-Jul-2015

Correspondence Address:
Dr. Anshuma Bansal
Assistant Professor, Department of Radiotherapy, PGIMER, Chandigarh - 160 012
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2278-0513.157939

Rights and Permissions
  Abstract 

Small cell carcinoma (SCC) of the urinary bladder is a rare presentation, accounting for <1% of all bladder carcinomas. It has been considered as an aggressive variant of bladder carcinoma, with high incidence of distant relapse. Though cisplatin-based chemotherapy is considered the gold standard approach for this variety of bladder tumor, the role of radical cystectomy and radiotherapy cannot be neglected, due to its frequent association with transitional cell carcinoma. Different management strategies have been adopted by oncologists worldwide, in an effort to obtain survival benefits. Recently, neoadjuvant chemotherapy before surgery has been tried and the results are encouraging. This review article particularly focuses on the treatment evolution of SCC of bladder, various treatment options and their effects on the outcome, so that an optimal management can be planned for individual cases.

Keywords: Management, small cell carcinoma, urinary bladder


How to cite this article:
Bansal A. Changing trends in the management of small cell carcinoma of urinary bladder. Clin Cancer Investig J 2015;4:487-91

How to cite this URL:
Bansal A. Changing trends in the management of small cell carcinoma of urinary bladder. Clin Cancer Investig J [serial online] 2015 [cited 2020 Jul 16];4:487-91. Available from: http://www.ccij-online.org/text.asp?2015/4/4/487/157939


  Introduction Top


Small cell carcinoma (SCC) is one of the histopathological subtypes that demonstrates aggressive clinical behavior and most commonly arises in the lung. Though rare, it can occur at extrapulmonary sites also, such as the gastrointestinal tract, salivary gland, uterine cervix, and urinary tract. Extrapulmonary SCC comprises 4% of all SCCs. [1] Its incidence in the bladder is reported to be 0.3-0.7% of all primary carcinomas of the urinary bladder. [1] SCCs of urinary bladder (SCCB) share histopathological and immunohistochemical features with their pulmonary counterpart. The prognosis is poor due to local or distant metastases, and usually the muscle of the bladder is invaded. Definitive treatment strategy has not been defined yet, due to the availability of small case series or reports only. We carried out a literature search from January 1981 to February 2014, through the PubMed/Medline central database at National Center for Biotechnology Information website (http://www.ncbi.nlm.nih.gov/pmc) using the search terms "SCC," "urinary bladder," "management." This review article focuses on presentation, diagnostic workup, the treatment options for SCCB, and their effects on the disease outcome so that an optimal management can be planned for individual cases.


  Discussion Top


Background

Small cell carcinoma of the bladder is a rare, poorly differentiated neuroendocrine epithelial tumor with a mean frequency of 0.7%. [1] It was first described in 1981 by Cramer et al. [2] Majority of the patients are male, with male:female ratio of 5:1. It is found in sixth to seventh decade of life. Like transitional cell carcinoma (TCC), SCCB is often associated with a smoking history in 65-79% of the cases. It is associated with a more aggressive behavior and poorer outcome than bladder TCC. It is frequently found combined with other histological forms: TCC, adenocarcinoma and squamous cell carcinoma. [3] It is mostly diagnosed at an advanced stage and has higher metastatic potential, still it is considered as less aggressive than its pulmonary counterpart. [4]

Pathogenesis

Risk factors are unknown, but there is a hypothesis for bladder localizations that these tumors are usually found in smokers, patients affected by longstanding cystitis, those with bladder lithiasis, and those with augmented cystoplasty. [5]

Several hypotheses have been proposed to explain the origin of SCC in the bladder. According to the first hypothesis, the malignant transformation of bladder neuroendocrine cells (which were previously found in the bladder) gives rise to bladder SCC. Second, SCCB arises from urothelial metaplastic changes. Third and most important theory suggests the origin of SCCB from a multipotential common stem cell that has the ability to differentiate into various cell types. [5] This may explain the coexistence of SCCB with TCC, and the heterogeneity of the immunohistochemical staining (cytokeratin [CK] and endocrine markers).

Presentation

Clinical features of SCCB are similar to bladder TCC. Gross hematuria is the most common presentation seen in 63-88% cases. [6] Dysuria is the second most common symptom. Urinary obstruction, abdominal pain, urinary tract infection, and weight loss are reported occasionally. Rare cases of paraneoplastic syndromes such as ectopic ACTH secretion and hypercalcemia have also been reported.

Confirmation of diagnosis

Diagnosis is obtained via histopathological examination of specimens obtained by cystoscopy and transurethral resection of bladder tumor. Light microscopy shows the tumor composed of nests of small round malignant cells with pyknotic round to oval nuclei and evenly dispersed "salt and pepper chromatin." Mitotic rate is high (>10 mitotic figures ⁄ 10 high power fields) in 57% of the cases. [7] Tumor rosettes, tumor necrosis, vascular invasion are the other features that can be found in light microscopy.

Immunohistochemistry is extremely helpful in establishing the diagnosis.

Neuron-specific enolase, chromogranin, and synaptophysin are the markers found positive in 88.5%, 50%, and 72.4% cases, respectively. [8] Other markers are serotonin, CK, S-100 protein, TTF1, endothelial growth factor receptor (EGFR), and c-KIT. SCCB are also stained with the epithelial markers: CAM 5.2, CK7, and EMA, supporting the urothelial origin of SCCB.

Extent of disease

Pelvic and abdomen computed tomography helps in determining bladder mass and the locoregional extension of the disease, outside the bladder wall and in the pelvic lymph nodes. Bone scan is recommended in those with advanced disease to rule out distant bone metastasis.

Staging

More than 95% of patients are diagnosed at muscle invasive stage T2 or more. The most frequent sites of metastasis are pelvic and retroperitoneal lymph nodes (28.6-53%), liver (23.8-47%), bone (23.8-33%), brain (7.9%), and lung (9.5-13%). [9] As for bladder TCC, the tumor, node, metastasis staging system is commonly used for SCCB.

Differential diagnosis

Direct invasion of the bladder by SCC of the prostate can sometimes be confused with primary SCCB. But, prostatic SCC is typically negative for PSA. Metastatic SCCB from another primary, like small cell carcinoma lung cancer (SCLC), can be the other differential diagnosis. Metastatic SCLC may not be distinguishable histologically from a primary SCCB; however, the presence of TCC component (including TCC in situ) would support a diagnosis of bladder SCC. Primary lymphomas of the bladder can also sometimes have histological similarity to SCCB, but lymphomas are positive for leukocyte common antigen and negative for keratin and neuroendocrine markers.

Management

Because of the rarity of SCCB, there is no standard treatment of the disease. SCCB is an aggressive tumor. About 90% of patients are at stage II or more and 25% are at stage IV at diagnosis. [9] Many treatments have been tried, but the optimal management of these tumors has multimodality therapy, which includes surgery, chemotherapy, and radiation. [10] The treatment options include either the radical cystectomy followed by adjuvant treatment or the bladder preservation protocols.


  Role of surgery Top


It has been a debated issue whether receiving radical cystectomy provides a better overall survival (OS) for bladder SCC patients. In contrast to SCLC, radical resection is performed in 60-70% of the cases of SCCB. Surgery is favored because of the frequent combination of SCCB with TCC. Literature review [4],[9],[11] suggests that surgery is favorable, but the 5-year OS after radical resection alone in SCCB ranges from 20% to 36% only [Table 1], thereby concluding that surgery alone is not appropriate to achieve cure for patients with SCCB.
Table 1: Outcome of small cell carcinoma bladder with surgery alone

Click here to view


However, in a multi-institutional review of 64 patients with localized SCCB, [12] the efficacy of cystectomy has been questioned, as no survival difference was found between 38 patients undergoing radical cystectomy and those without surgery, receiving radical radiation (10 patients) or chemotherapy alone (23 patients). 5-year survival was 16% with surgery and 18% in the later group.


  Role of radiotherapy Top


Small cell lung cancer is treated with a combination of radiotherapy (RT) and chemotherapy. In analogy to SCLC, RT either alone or in combination with chemotherapy, has been tried to treat SCCB at a localized stage. The rationale for the use of radiation is that RT following radical surgery helps improve local control rates. Alone or in combination with chemotherapy, RT is used in bladder preservation protocols, or medically inoperable patients, or those not willing for surgery. As shown in [Table 2], the 5-year survival of patients with SCCB treated with radiation ranges from 20% to 70% in various studies in literature. [4],[13],[14] However, most of these studies have utilized chemotherapy either in the neoadjuvant setting or as an adjuvant to radiation therapy. These results confirmed that RT can be curative, but significantly more curative when used in combination with chemotherapy.
Table 2: Outcome of small cell carcinoma bladder with RT in combination with surgery or chemotherapy

Click here to view



  Role of chemotherapy Top


Chemotherapy is the major treatment modality for SCCB. On multivariate analysis, [15] cisplatin chemotherapy is the only predictive factor for survival of SCCB patients (P < 0.0001). In surgically resectable disease, chemotherapy has been tried as neoadjuvant therapy to shrink the tumor prior to local therapy or as adjuvant treatment after surgical resection. In metastatic patients, palliative chemotherapy remains the treatment of choice.


  Neoadjuvant chemotherapy Top


Neoadjuvant chemotherapy (NACT) before surgery in surgically resectable SCCB has been investigated in several retrospective studies. In addition, primary chemotherapy was used in sequence with radiation to increase the efficacy of RT.

The rationale for the use of NACT in SCCB is that SCCB is a highly chemosensitive disease. NACT allows downstaging, which facilitates the surgical techniques. Furthermore, it provides early treatment and control of micrometastatic disease. Besides, the systemic treatment is better tolerated by allowing the preoperative administration of chemotherapy drugs in optimal doses with less toxicity.

Siefker-Radtke et al. in 2004 analyzed a retrospective data [11] of 46 patients with SCCB and found that 5-year survival was significantly better in patients who received NACT prior to surgery, compared to the surgery alone group (76% vs. 36% [P = 0.026]). Same authors in 2009 conducted a prospective phase II trial [16] in 30 patients. Half of them were treated with NACT followed by surgery while others were given chemotherapy alone. The study concluded that the 5-year survival in the operable group was 80%, and the OS was 58 months versus 13.3 months in operable versus inoperable patients, respectively.

Ahsaini et al. [17] reported a rare case of a 54-year-old Arab male native of Moroccan, diagnosed as small cell neuroendocrine carcinomas of the ureter and the bladder with stage T2N0M0. Neoadjuvant alternating doublet chemotherapy with ifosfamide/doxorubicin and etoposide/cisplatin (EP) was given, and nephroureterectomy associated to a cystoprostatectomy was carried out. After 24 months of follow-up, no local or distant metastasis was detected. Based on these data, NACT should be considered as the treatment of choice for surgically resectable SCCB.


  Adjuvant chemotherapy Top


No clear data define the role of adjuvant chemotherapy after primary surgery of invasive SCCB. The Mayo Clinic recommendations propose cystectomy alone for patients with stage II disease, and adjuvant chemotherapy for patients with stages III and IV (M0) disease. However, many institutions who followed the Mayo recommendations of initial cystectomy, reported very poor outcomes and a high likelihood of upstaging. Some authors concluded that adjuvant chemotherapy may provide improved survival compared with cystectomy alone. Bex et al. [14] in his study reported a median survival period of 15 months in patients who received chemotherapy regardless of the tumor stage compared to 4 months median survival period in patients not on chemotherapy.

A recent study published reported that the mean survival of patients treated with local treatment (surgery and/or RT) plus chemotherapy and with chemotherapy alone to be 13.8 and 14.7 months respectively. This emphasizes the fact that chemotherapy is more significant than local treatment. [18]


  Choice of chemotherapy regimen Top


Owing to the rarity of this malignancy, no prospective study has been carried out to establish the efficacy and duration of chemotherapy or the relative efficacy of platinum-etoposide versus other chemotherapeutic regimens. The drugs and regimen of choice to be used in SCCB can be extrapolated from the successful use of these regimens in its pulmonary counterpart that is, in SCLC. In a Japanese phase III study, [19] conducted in patients with extensive stage SCLC, irinotecan/cisplatin (IP) significantly improved median progression free, as well as OS compared with standard EP therapy (median progression-free survival: 6.9 vs. 4.8 months, P < 0.001), (median OS: 12.8 vs. 9.4 months, P = 0.0021) respectively. However, a large North American trial [20] failed to confirm this, according to which both regimens produced comparable efficacy, with less hematologic and greater gastrointestinal toxicity with IP. However, for limited-stage SCLC, four cycles of EP, continue to be the standard of care. [21] Based on these results in SCLC, cisplatin - etoposide continues to be the most common chemotherapy being used in SCCB. [Table 3] shows the list of various first and second line chemotherapy regimens used for the treatment of SCCB.


  Bladder Preservation (Chemo Radiation) Versus Cystectomy Plus Chemotherapy Top


In a SEER database (the surveillance, epidemiology, and end results - Medicare database) of 106 patients, analyzed by Koay et al. [22] between 1995 and 2005, there was no difference in terms of OS (19% vs. 26%) (P > 0.05) b/w bladder-sparing approach, versus at least cystectomy with chemotherapy (of whom over 90% received radical cystectomy). A comparison of the bladder-sparing approach with cystectomy alone yielded similar results, and, therefore, the author concluded that cystectomy and bladder-sparing approaches represent two viable strategies.

However, this cannot be generalized and that the results of this study need to be interpreted with caution because bladder-sparing approach has not shown beneficial results in the recent phase two trial done at MD Anderson Cancer Centre. [16] In addition, it is important to note that the patients with localized disease analyzed by Koay et al. [22] had poor outcomes: Median OS in the chemotherapy and nonchemotherapy groups were 23 and 12 months, respectively.


  Targeted therapy Top


Despite the use of multimodality treatment, the outcomes of treating bladder SCC remain poor. Novel targeted agents have been tried to improve survival. The majority of SCCB express vascular EGFR on endothelial cells, the EGFR, the c-KIT, the platelet-derived growth factor receptor, and the fibroblast growth factor receptor. Antiangiogenesis agents and tyrosine kinase inhibitors can be tried in metastatic setting. However, the beneficial effect of these agents in terms of survival has not been proven yet.

Prognosis

The prognosis of SCCB is poor. The five-year survival rate of all stages combined is equal to 19% (16-25%). [10] The 5-year survival rates for patients with stages II, III, and IV were 63.6%, 15.4%, and 10.5%, respectively. Because of the rarity of this disease, no others prognostic factors were identified.


  Conclusion Top


Small cell carcinoma of the urinary tract is a distinct histological and biologic disease entity with an aggressive clinical course. Therapeutic modalities vary from institution to institution. The prognosis in patients with SCCB tumors remains poor but the improvements in systemic multiagent chemotherapy, especially NACT with the aggressive surgical approach or radical RT, can improve the long-term survival. In surgically resectable disease (T1-T4aN0M0), management should include multimodal therapy with chemotherapy followed by radical cystectomy. In case, when surgery is performed first, adjuvant chemotherapy or adjuvant chemo-RT should be indicated. In advanced disease (T4b, N+ or M+), chemotherapy using a platinum agent (cisplatin in suitable patients) is the mainstay of treatment.

 
  References Top

1.
Zhao X, Flynn EA. Small cell carcinoma of the urinary bladder: A rare, aggressive neuroendocrine malignancy. Arch Pathol Lab Med 2012;136:1451-9.  Back to cited text no. 1
    
2.
Cramer SF, Aikawa M, Cebelin M. Neurosecretory granules in small cell invasive carcinoma of the urinary bladder. Cancer 1981;47:724-30.  Back to cited text no. 2
[PUBMED]    
3.
Mazzucchelli R, Morichetti D, Lopez-Beltran A, Cheng L, Scarpelli M, Kirkali Z, et al. Neuroendocrine tumours of the urinary system and male genital organs: Clinical significance. BJU Int 2009;103:1464-70.  Back to cited text no. 3
    
4.
Holmäng S, Borghede G, Johansson SL. Primary small cell carcinoma of the bladder: A report of 25 cases. J Urol 1995;153:1820-2.  Back to cited text no. 4
    
5.
Shahab N. Extrapulmonary small cell carcinoma of the bladder. Semin Oncol 2007;34:15-21.  Back to cited text no. 5
    
6.
Epstein JI, Amin MB, Reuter VE. Bladder Biopsy Interpretation. Philadelphia, PA, USA: Lippincott Williams and Wilkins; 2004.  Back to cited text no. 6
    
7.
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;46:57-63.  Back to cited text no. 7
    
8.
Iczkowski KA, Shanks JH, Allsbrook WC, Lopez-Beltran A, Pantazis CG, Collins TR, 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;35:150-6.  Back to cited text no. 8
    
9.
Choong NW, Quevedo JF, Kaur JS. Small cell carcinoma of the urinary bladder. The Mayo Clinic experience. Cancer 2005;103:1172-8.  Back to cited text no. 9
    
10.
Naturale RT, Maclennan GT. Small cell carcinoma of the bladder. J Urol 2006;176:781.  Back to cited text no. 10
    
11.
Siefker-Radtke AO, Dinney CP, Abrahams NA, Moran C, Shen Y, Pisters LL, 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;172:481-4.  Back to cited text no. 11
    
12.
Cheng L, Pan CX, Yang XJ, Lopez-Beltran A, MacLennan GT, Lin H, et al. Small cell carcinoma of the urinary bladder: A clinicopathologic analysis of 64 patients. Cancer 2004;101:957-62.  Back to cited text no. 12
    
13.
Lohrisch C, Murray N, Pickles T, Sullivan L. Small cell carcinoma of the bladder: Long term outcome with integrated chemoradiation. Cancer 1999;86:2346-52.  Back to cited text no. 13
    
14.
Bex A, Nieuwenhuijzen JA, Kerst M, Pos F, van Boven H, Meinhardt W, 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;65:295-9.  Back to cited text no. 14
    
15.
Mackey JR, Au HJ, Hugh J, Venner P. Genitourinary small cell carcinoma: Determination of clinical and therapeutic factors associated with survival. J Urol 1998;159:1624-9.  Back to cited text no. 15
    
16.
Siefker-Radtke AO, Kamat AM, Grossman HB, Williams DL, Qiao W, Thall PF, et al. Phase II clinical trial of neoadjuvant alternating doublet chemotherapy with ifosfamide/doxorubicin and etoposide/cisplatin in small-cell urothelial cancer. J Clin Oncol 2009;27:2592-7.  Back to cited text no. 16
    
17.
Ahsaini M, Riyach O, Tazi MF, El Fassi MJ, Farih MH, Elfatmi H, et al. Small cell neuroendocrine carcinoma of the urinary tract successfully managed with neoadjuvant chemotherapy. Case Rep Urol 2013;2013:598325.  Back to cited text no. 17
    
18.
Ismaili N, Heudel PE, Elkarak F, Kaikani W, Bajard A, Ismaili M, et al. Outcome of recurrent and metastatic small cell carcinoma of the bladder. BMC Urol 2009;9:4.  Back to cited text no. 18
    
19.
Lara PN Jr, Chansky K, Shibata T, Fukuda H, Tamura T, Crowley J, et al. Common arm comparative outcomes analysis of phase 3 trials of cisplatin + irinotecan versus cisplatin + etoposide in extensive stage small cell lung cancer: Final patient-level results from Japan Clinical Oncology Group 9511 and Southwest Oncology Group 0124. Cancer 2010;116:5710-5.  Back to cited text no. 19
    
20.
Lara PN Jr, Natale R, Crowley J, Lenz HJ, Redman MW, Carleton JE, et al. Phase III trial of irinotecan/cisplatin compared with etoposide/cisplatin in extensive-stage small-cell lung cancer: Clinical and pharmacogenomic results from SWOG S0124. J Clin Oncol 2009;27:2530-5.  Back to cited text no. 20
    
21.
Kubota K, Hida T, Ishikura S, Mizusawa J, Nishio M, Kawahara M, et al. Etoposide and cisplatin versus irinotecan and cisplatin in patients with limited-stage small-cell lung cancer treated with etoposide and cisplatin plus concurrent accelerated hyperfractionated thoracic radiotherapy (JCOG0202): A randomised phase 3 study. Lancet Oncol 2014;15:106-13.  Back to cited text no. 21
    
22.
Koay EJ, Teh BS, Paulino AC, Butler EB. Treatment trends and outcomes of small-cell carcinoma of the bladder. Int J Radiat Oncol Biol Phys 2012;83:64-70.  Back to cited text no. 22
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3]


This article has been cited by
1 Primary small cell carcinoma of the urinary bladder in association with bilharziasis: A case report from Egypt
Omar Hamdy,Khalid Atallah,Amira K. El-Hawary,Gehad Saleh,Gena M. Abdelazeem,Islam H. Metwally
Current Medicine Research and Practice. 2017;
[Pubmed] | [DOI]



 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

 
  In this article
Abstract
Introduction
Discussion
Role of surgery
Role of radiotherapy
Role of chemotherapy
Neoadjuvant chem...
Adjuvant chemoth...
Choice of chemot...
Targeted therapy
Conclusion
Bladder Preserva...
References
Article Tables

 Article Access Statistics
    Viewed4547    
    Printed58    
    Emailed4    
    PDF Downloaded18    
    Comments [Add]    
    Cited by others 1    

Recommend this journal