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Year : 2011  |  Volume : 7  |  Issue : 4  |  Page : 493-496

Primary mixed small cell neuroendocrine-adenocarcinoma of the urinary bladder

Department of Pathology, Maulana Azad Medical College, New Delhi- 110002, India

Date of Web Publication19-Jan-2012

Correspondence Address:
Neha Singh
Department of Pathology, Maulana Azad Medical College, New Delhi - 110002
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0973-1482.92015

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How to cite this article:
Singh N, Khurana N, Singh M, Arora P. Primary mixed small cell neuroendocrine-adenocarcinoma of the urinary bladder. J Can Res Ther 2011;7:493-6

How to cite this URL:
Singh N, Khurana N, Singh M, Arora P. Primary mixed small cell neuroendocrine-adenocarcinoma of the urinary bladder. J Can Res Ther [serial online] 2011 [cited 2022 Jan 26];7:493-6. Available from: https://www.cancerjournal.net/text.asp?2011/7/4/493/92015


Primary small cell carcinoma as well as primary adenocarcinoma of the urinary bladder are rare and each comprise less than 2% of bladder tumors. [1],[2] Majority of these cases exist as mixed forms with the predominant component being urothelial carcinoma. Even though very rare, there have been case reports of existence of small cell carcinoma or adenocarcinomas in the bladder. [1],[3],[4] We report one such case in a 51-year-old male and a pertinent literature review.

A 51-year-old male presented with hematuria and dysuria for five months. CT scan showed an irregular polypoidal mass arising from the dome and projecting into the lumen of the bladder.

A partial cystectomy was performed and the tumor was resected along a 1 cm circumferential margin. We received a well circumscribed nodule measuring 7 × 4 × 3 cm. The mucosal aspect of the nodule was markedly congested with areas of fungation [Figure 1]. The cut section was greyish white, solid with necrotic areas.
Figure 1: Gross photograph of the solitary polypoidal tumor with congestion, fungation and surface ulceration

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Histopathological examination revealed predominance of sheets and nests of a uniform population of small round oat like cells with areas of necrosis [Figure 2]. These cells had high N/C ratio, scanty eosinophilic cytoplasm, stippled chromatin and inconspicuous nucleoli with a mitotic rate of 2-3/HPF. Also seen were few microscopic foci showing focal areas with a papillary and glandular configuration [Figure 3]. The cells in these foci were larger, with moderate amount of pale eosinophilic cytoplasm, vesicular nuclei and 1-2 nucleoli. The distinction between the predominant small round cell component and the focal adenocarcinoma like areas was apparent on H and E stained sections, indicating a mixed high-grade malignant tumor. No urothelial elements were identified even on extensive sampling of the tumor. The surrounding bladder mucosa appeared microscopically unremarkable, with no evidence of dysplasia, further indicating that the tumor was a primary mixed small cell-adenocarcinoma of the bladder and not a divergent differentiation in a urothelial carcinoma. The tumor was infiltrating up to the outer half of the muscle coat of the bladder (stage T2b).
Figure 2: Predominant component composed of sheets of small round cells, with intervening fibrous septae

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Figure 3: High power view of the papillae lined by cells with high N/C ratio, vesicular nuclei and moderate eosinophilic cytoplasm

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Immunohistochemistry(IHC) revealed the minor glandular components to be strongly positive for epithelial membrane antigen (EMA) and cytokeratin (CK) [Figure 4], while the predominant small round cell component strongly expressed EMA, neuron specific enolase (NSE) and synaptophysin [Figure 5], indicating a neuroendocrine (NE) differentiation. Hence a diagnosis of a primary mixed small cell NE - adenocarcinoma of the bladder was rendered.
Figure 4: Small cell component showing positivity for synaptophysin and NSE

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Figure 5: CK and EMA were strongly positive in glandular areas, while the small cell component was negative

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Urothelial carcinomas account for the majority of carcinomas arising in the urinary bladder. They can demonstrate a wide spectrum of differentiations ranging from squamous, glandular, NE, sarcomatoid or lymphoepithelioma like elements. Primary small cell NE carcinomas of the bladder are rare and comprise only 2% of bladder tumors. They may either present as a pure small cell carcinoma or in conjunction with other tumors. Most of the cases in literature are reported as small cell NE carcinomas mixed with non small cell components such as urothelial or glandular. [1],[2]

Pure primary adenocarcinoma of the bladder is also very rare and accounts for 1-2% of bladder tumors. These tumors often show enteric differentiation with well formed glandular elements and extracellular mucin, which renders it difficult to distinguish them from contiguous spread from an intestinal primary. [1] In some cases, the glandular component may be represented by more cellular and cytologically less differentiated areas. The present case showed focal glandular formations with a predominant papillary architecture. There was no extracellular mucin, signet ring cells or glands resembling the colonic mucosa.

A review of literature revealed that coexistence of a primary small cell NE carcinoma and adenocarcinoma, as a mixed tumor of the urinary bladder is a fairly uncommon manifestation of bladder carcinoma, and there have been only a few case reports. In a series of 51 cases of primary small cell carcinomas of the bladder by Abrahams et al, only 8% cases showed a coexistence of small cell carcinoma and adenocarcinoma. [3] Chin et al reported a unique case of a primary mixed adenocarcinoma composed of signet ring cells, glands and mucinous lakes intimately admixed with carcinoid elements. [4] Abenoza et al reported a similar case of a primary mixed adenocarcinoma-NE carcinoma of the urinary bladder. [5]

Some of the small cell carcinomas show NE differentiation, which can be established conclusively by combining ultrastructural and immunohistochemical methods. IHC alone may yield valuable information in demonstrating the NE nature, provided at least NSE and synaptophysin are included in the panel of markers. [6] However, the presence of NE differentiation does not seem to impart any prognostic significance.

Tumors with a small cell component behave very differently from the pure urothelial bladder carcinoma. These tumors are at an advanced stage at initial diagnosis, tend to have a rapidly progressive clinical outcome and a poorer prognosis than do urothelial carcinomas. [2],[7],[8],[9],[10] Since both pure small cell NE or pure adenocarcinoma of the bladder have a poorer prognosis as compared to the conventional urothelial carcinomas, [1] this rare mixed entity is associated with an extremely poor prognosis. [2] These tumors require a radical cystectomy with adjuvant chemotherapy. However in the present case, since the tumor was well circumscribed intraoperatively and grossly was not infiltrating the serosal layer (stage II), a partial cystectomy was performed initially. However once the histologic nature of the tumor was revealed, a completion cystectomy was performed. Following which, the patient was lost to follow up and could not receive chemotherapy.

Abenoza et al reported a very rapidly progressive clinical course with local recurrences and widespread metastasis in their cases, further confirming that these mixed tumors herald a very poor prognosis. A higher rate of lymph node metastasis has been reported in mixed tumors showing two or more variant histological patterns in contrast to conventional urothelial carcinomas and this may clinically reflect as presentation at a more advanced stage, heralding a poor outcome. [5]

Hence it is important to note that the therapy and outcome of these patients may vary considerably depending on the inclusion of a small cell and/or adenocarcinomatous element in their histopathology report, since small cell carcinoma is a leading prognosticator in bladder malignancies. [2] Herein lies the significance of keeping in mind this rare entity and hence performing a thorough sampling of the tumor and judicious use of immunomarkers in cases where there is even the slightest suspicion of a divergent differentiation in bladder tumors.

It is important to be aware of the varied differentiations that can be encountered in the common urothelial carcinomas, because some of them may have prognostic as well as therapeutic implications. In cases which show a small cell component, a meticulous search should be made to look for areas representing non small cell components, since pure forms of small cell carcinomas of the bladder are very rare. The presence of small cells or glandular foci indicates a poorer prognosis and present clinically at a more advanced stage. A thorough sampling of the tumors and judicial use of IHC can help in identifying these divergent areas, which in turn can alter the patient's management and prognosis.

 > References Top

1.Shanks JS, Iczkowski KA. Divergent differentiation in urothelial carcinoma and other bladder subtypes with selected mimics. Histopathology 2009;54:885-900.  Back to cited text no. 1
2.Lopez FV, True LD. How wide is the spectrum of neuroendocrine differentiation of the urinary bladder? Am J Clin Pathol 2007;128:723-5.  Back to cited text no. 2
3.Abrahams NA, Moran C, Reyes AO, Radtke AS, Ayala AG. Small cell carcinoma of the bladder: A contemporary clinicopathologic study of 51 cases. Histopathology 2005;46:57-63.  Back to cited text no. 3
4.Chin NW, Marinescu AM, Fani K. Composite adenocarcinoma and carcinoid tumor of urinary bladder. Urology 1992;40:249-52.   Back to cited text no. 4
5.Abenoza P, Manivel C, Sibley RK. Adenocarcinoma with neuroendocrine differentiation of the urinary bladder. Clinicopathologic, immunohistochemical, and ultrastructural study. Arch Pathol Lab Med 1986;110:1062-6.  Back to cited text no. 5
6.Blomjous CE, Thunnissen FB, Vos W, de Voogt HJ, Meijer CJ. Small cell neuroendocrine carcinoma of the urinary bladder. An immunohistochemical and ultrastructural evaluation of 3 cases with a review of the literature. Virchows Arch A Pathol Anat Histopathol 1988;413:505-12.  Back to cited text no. 6
7.Bui M, Khalbuss WE. Primary small cell neuroendocrine carcinoma of the urinary bladder with coexisting high-grade urothelial carcinoma: A case report with review of literature. Cytojournal 2005;2:18.  Back to cited text no. 7
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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.Capdevila J, Maroto P, Algaba F, Lerma E, Villavicencio H. Mixed transitional cell and small cell carcinoma of the bladder with metastases with neuroendocrine histology only. Case report and bibliography review. Arch Esp Urol 2007;60:306-9.  Back to cited text no. 9
10.Nabi G, Singh I, Ansari MS, Sharma MC, Dogra PN. Primary small cell neuroendocrine carcinoma of urinary bladder: An uncommon entity to be recognized. Int Urol Nephrol 2001;33:637-40.  Back to cited text no. 10


  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]


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