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Small cell carcinoma of the urinary bladder
A clinicopathologic analysis of 64 patients
Article first published online: 9 JUL 2004
Copyright © 2004 American Cancer Society
Volume 101, Issue 5, pages 957–962, 1 September 2004
How to Cite
Cheng, L., Pan, C.-X., Yang, X. J., Lopez-Beltran, A., MacLennan, G. T., Lin, H., Kuzel, T. M., Papavero, V., Tretiakova, M., Nigro, K., Koch, M. O. and Eble, J. N. (2004), Small cell carcinoma of the urinary bladder. Cancer, 101: 957–962. doi: 10.1002/cncr.20456
- Issue published online: 18 AUG 2004
- Article first published online: 9 JUL 2004
- Manuscript Accepted: 25 MAY 2004
- Manuscript Revised: 19 MAY 2004
- Manuscript Received: 23 FEB 2004
- urinary bladder;
- small cell carcinoma;
Small cell carcinoma of the urinary bladder is an uncommon tumor that has been described in case reports or small series. Herein, the authors report a series of 64 patients with small cell carcinoma of the urinary bladder.
Histologic slides and medical records from 64 patients with small cell carcinoma of the urinary bladder were reviewed for morphologic, demographic, and clinical data. All patients fulfilled the criteria established for small cell carcinoma according to the World Health Organization classification system. The 2002 tumor, lymph node, and metastasis (TNM) system was used for pathologic staging. The correlations of various clinicopathologic characteristics with survival were analyzed.
Patients ranged in age from 36 years to 85 years (mean age, 66 years). The male-to-female ratio was 3.3:1.0. Among patients with clinical information available, 65% had a history of cigarette smoking, and 88% presented with hematuria. All but one patient had muscle-invasive disease at presentation. Thirty-eight patients (59%) underwent cystectomy. Sixty-six percent of patients had lymph node metastasis at the time of cystectomy. Twenty patients (32%) had pure small cell carcinoma, and 44 patients (68%) had small cell carcinoma with other histologic types (35 patients had urothelial carcinoma, 4 patients had adenocarcinoma, 2 patients had sarcomatoid urothelial carcinoma, and 3 patients had both adenocarcinoma and urothelial carcinoma). With a mean follow-up of 21 months, 68% of patients died of bladder carcinoma. None of the clinicopathologic parameters studied (age, gender, presenting symptoms, smoking history, the presence of a nonsmall cell carcinoma component, chemotherapy, or radiation therapy) were associated with survival. No significant survival difference was found between patients who did and did not undergo cystectomy (P = 0.65). Patients who had organ-confined disease had marginally better survival compared with patients who had nonorgan-confined disease (P = 0.06). The overall, 1-year, 18-month, 3-year, and 5-year disease-specific survival rates were 56%, 41%, 23%, and 16%, respectively.
The prognosis for patients with small cell carcinoma of the urinary bladder remains poor, even though the overall survival for patients with bladder carcinoma has improved significantly over the last decade. Cancer 2004. © 2004 American Cancer Society.
Small cell carcinoma of the urinary bladder is encountered rarely and accounts for < 1% of all urinary bladder carcinomas.1, 2 Current knowledge of this disease is limited and is based mainly on small series and case reports that were published more than a decade ago.1–16 In this series of 64 patients, we studied the clinical and pathologic features of small cell carcinoma of the urinary bladder and their impact on patient survival.
MATERIALS AND METHODS
Sixty-four patients with small cell carcinoma of the urinary bladder were identified from 5 institutions, including Indiana University Hospital (Indianapolis, IN), Northwestern Memorial Hospital (Chicago, IL), Cordoba University (Cordoba, Spain), Case Western Reserve University (Cleveland, OH), and the University of Chicago Hospitals (Chicago, IL). These patients were diagnosed between 1990 and 2003. Patient follow-up was obtained from the medical records and from referring clinicians and pathologists. Death was determined by chart reviews or was verified through cancer registries. Histologic slides were reviewed, and the tumors fulfilled the criteria established for small cell carcinoma according to the World Health Organization (WHO) classification system.17 The 2002 tumor, lymph node, and metastasis (TNM) classification system was used for pathologic staging.18
A Cox proportional hazards model was used to analyze survival outcome with continuous covariates. Log-rank tests were used to analyze the survival outcomes among different groups, and Kaplan–Meier survival curves were plotted for the groups. One patient who died 2 days after surgery was excluded from the survival analysis. The Fisher exact test was used to compare the difference in frequency of categorical clinicopathologic parameters among different groups. SAS software (version 8.2) was used for the statistical analysis. All statistical tests were two-sided, and P values ≤ 0.05 were considered statistically significant.
Table 1 summarizes the patient characteristics and clinical findings in 64 patients with small cell carcinoma of the urinary bladder. The mean age at diagnosis was 66 years (range, 36–85 years), and the male-to-female ratio was 3.3:1.0. Among patients with retrievable clinical histories, 65% (19 of 29 patients) gave histories of cigarette smoking; and 88% (29 of 33 patients) presented with macroscopic hematuria. Two patients presented with irritative symptoms, and two patients presented with symptoms of urinary obstruction. None had paraneoplastic syndrome.
|Characteristic||No. of patients (%)|
|<50 yrs||4 (6)|
|50–59 yrs||10 (16)|
|60–70 yrs||21 (33)|
|>70 yrs||29 (45)|
|Hematuria present||29 (45)|
|Hematuria absent||4 (7)|
|Pathologic tumor classification|
|Coexisting nonsmall cell carcinoma component|
The diagnosis of small cell carcinoma was based on the criteria established by the WHO classification system,17 which are identical to the criteria for small cell carcinoma of the lung. The carcinomas were comprised of sheets of small cells separated by delicate fibrovascular stroma (Fig. 1). The cells had uniformly small, round-to-oval, overlapping nuclei with evenly distributed chromatin and lacked prominent nucleoli. The cytoplasm was sparse. Mitotic figures were frequent in all tumors. In some tumors, the diagnosis of small cell carcinoma was made solely on morphologic grounds, even if neuroendocrine differentiation could not be demonstrated by immunohistochemistry or electron microscopy studies, a diagnostic process that is acceptable according to the WHO criteria.19 In the majority of patients (68%), small cell carcinoma coexisted with another carcinoma component, including urothelial carcinoma in 35 patients (55%), adenocarcinoma in 4 patients (6%), sarcomatoid urothelial carcinoma in 2 patients (3%), and both adenocarcinoma and urothelial carcinoma in 3 patients (5%). These nonsmall cell carcinoma components comprised < 10% of the total tumor areas. Except for 1 patient who had Stage I disease, all patients presented with at least locally advanced disease (≥ T2), and 66% of patients had lymph node metastases at the time they underwent cystectomy.
Treatment varied among patients for whom information was available. Thirty-seven patients underwent radical cystectomy, and 1 patient underwent partial cystectomy. Fifty-six percent of patients received chemotherapy. Cisplatin and etoposide combinations and carboplatin/etoposide were the most common regimens. Twenty-five percent of patients received local radiation therapy.
The mean follow-up was 21 months (range, from 2 days [a patient who died after acute myocardial infarction] to 122 months). Long-term survival was noted in 2 patients who underwent cystectomy (113 months and 122 months, respectively). Follow-up information was not available in eight patients. Sixty-eight percent of patients (38 of 56 patients) died of bladder carcinoma. The 1-year, 18-month, 3-year, and 5-year disease-specific survival rates were 56%, 41%, 23%, and 16%, respectively (Fig. 2). None of the clinicopathologic parameters, including age (P = 0.29), gender (P = 0.39), presenting symptoms (P = 0.10), smoking history (P = 0.17), the presence of coexisting nonsmall cell carcinoma component (P = 0.40), chemotherapy (P = 0.92), or radiation therapy (P = 0.53), were associated significantly with survival. No significant survival difference was found between patients who underwent cystectomy and patients who did not undergo cystectomy (Fig. 3). The 1-year and 5-year disease-specific survival rates among patients who underwent cystectomy were 57% and 16%, respectively; and the 1-year and 5-year disease-specific survival rates among patients who did not undergo cystectomy were 55% and 18%, respectively (P = 0.65). Pathologic tumor classification was associated marginally with survival (P = 0.06). The 1-year disease-specific survival rate for patients with organ-confined disease (T1 and T2) and patients with nonorgan-confined disease (T3 and T4) was 58% and 25%, respectively (Fig. 4).
There was no significant difference in survival between patients who underwent cystectomy alone and patients who received combined-modality treatments (P = 0.87). The 1-year disease-specific survival rate among patients who underwent cystectomy only was 45%, compared with 66% among patients who received combination therapy.
Approximately 60,240 individuals (44,640 men and 15,600 women) are expected to develop bladder carcinoma in the United States in 2004.20 Urothelial carcinoma accounts for the vast majority of these tumors. Small cell carcinoma of the urinary bladder is uncommon. Unlike urothelial carcinoma, small cell carcinoma of the urinary bladder behaves aggressively, similar to its pulmonary counterpart, small cell carcinoma of the lung.21 With a mean follow-up of 21 months, 68% of patients in our series died of bladder carcinoma. The 1-year, 3-year, and 5-year disease-specific survival rates were 56%, 23%, and 16%, respectively.
Demographically, the clinical features of our patients with small cell carcinoma of the urinary bladder were similar to those of patients with urothelial carcinoma.22–25 Most of our patients were in the sixth to seventh decade of life, males predominated, and many had a history of cigarette smoking. The most common presentation was macroscopic hematuria. Similar to the findings in other studies,1, 3, 4 most of our patients presented with advanced-stage disease. In the patients we studied, all but one had muscle-invasive disease (≥ T2) at presentation. None of the clinicopathologic parameters, including age (P = 0.29), gender (P = 0.39), presenting symptoms (P = 0.10), smoking history (P = 0.17), the presence of a coexisting nonsmall cell carcinoma component (P = 0.40), cystectomy (P = 0.65), chemotherapy (P = 0.92), or radiation therapy (P = 0.53), were associated with survival. Organ-confined small cell carcinoma of the urinary bladder was associated with marginally better survival compared with was more widespread disease. The 1-year disease-specific survival rates for patients with organ-confined tumors (T1 and T2) and for patients with more widespread disease (T3 and T4) were 58% and 25%, respectively (P = 0.06). The absence of a significant correlation may be attributed to the small sample size and the lack of uniform treatment.
The frequent association of small cell carcinoma of the urinary bladder with urothelial carcinoma suggests that small cell carcinoma may originate from a urothelial stem cell rather than from a specific neuroendocrine precursor cell.12 In 1981, Cramer et al. proposed that small cell carcinoma of the urinary bladder originates from metaplastic urothelium.16 We found that most small cell carcinomas of the urinary bladder (69%) were admixed with other histologic types of carcinoma. The combination of small cell carcinoma-urothelial carcinoma was most frequent. Components other than small cell carcinoma usually comprise only a minor portion of the tumor. Regardless of the make-up of the tumor, the presence of small cell carcinoma portends a poor outcome. We found no significant difference in survival between patients with pure small cell carcinoma and patients who had tumors with mixed histology (P = 0.40). For practical purposes, it seems appropriate to classify the tumors with mixed histologic patterns as small cell carcinoma rather than urothelial carcinoma or adenocarcinoma with neuroendocrine differentiation. However, nonsmall cell carcinoma components comprised < 10% of the total tumor mass in tumors with mixed histologic pattern in this series. Whether the presence of a minor component of small cell carcinoma in a neoplasm comprised predominantly of urothelial carcinoma substantially worsens the prognosis has not been ascertained.
The poor prognosis for patients with small cell carcinoma of the urinary bladder warrants aggressive treatment. Several patients with long-term survival have been reported after treatment with combined modalities of therapy.3, 14, 15, 26, 27 Surgery alone occasionally produces long-term survival if the tumor truly is localized to the bladder.2, 13 In our study, the cystectomy group had unfavorable outcomes, similar to patients who did not undergo cystectomy, although occasional long-term survival was observed in our patients, similar to the findings of other investigators. Two of our patients survived for > 9 years after cystectomy. The 1-year and 5-year disease-specific survival rates among patients who underwent cystectomy were 57% and 16%, respectively, compared with 55% and 18%, respectively, among patients who did not undergo cystectomy. Similarly, chemotherapy and radiation therapy appear to be ineffective in altering the clinical course. No significant survival advantage was found in patients who were treated by radiation or chemotherapy in the current study. Among 8 patients who received radiation therapy, Abbas et al. reported a median survival of only 4.5 months.28 In meta-analyses by other investigators, cystectomy and chemotherapy appeared to confer a more favorable prognosis.12, 29
In conclusion, the prognosis for patients with small cell carcinoma of the urinary bladder remains poor, even though the overall survival for patients with bladder carcinoma has improved significantly over the last decade.24 Improvement in survival may depend on the identification of new molecular markers for use in early diagnosis and for novel targeted therapies.30
- 7Small 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: 150–156., , , et al.
- 12Small cell carcinoma of the urinary bladder: a report of two cases with complete remission and a comprehensive literature review with emphasis on therapeutic decisions. J Urol Pathol. 1996; 5: 1–19., , , et al.
- 17WHO histologic typing of urinary bladder tumors. Berlin: Springer, 1999., , .
- 18GreeneFL, PageDL, FlemmingID, et al., editors. AJCC staging manual, 6th ed. New York: Springer-Verlag, 2002.
- 19World Health Organization classification of tumours: pathology and genetics of tumours of the urinary system and male genital organs. Lyon: IARC Press, 2004., , , .
- 30C-kit expression in small cell carcinoma of the urinary bladder: prognostic and therapeutic implications. Mod Pathol. In press., , , et al.