Case Report Urol Int 1992:48:95-98

Departments of Urology and Pathology, Medical School, University of Vienna, Austria

Keywords Bladder Small cell carcinoma Immunohistochemistry Neuron-specific enolase

Primary Small Cell Carcinoma of the Urinary Bladder Report of a Case with Immunohistochemical Analyses

Abstract A case of primary small cell carcinoma of the urinary bladder is reported. The light-microscopic diagnosis was supported by immunoreactivity for HISL-19 (marker for peptide-hormone-producing cells) and for neuron-specific enolase (NSE), demonstrating the neuroendocrine differentiation of this rare bladder tumor. Serum NSE, which was significantly elevated, can be a marker for dis­ ease extent and response to therapy.

Introduction While small cell carcinomas have been described in many extrapulmonary sites, primary origin of this tumor type in the urinary bladder seems to be rare. In this report, we describe the light-microscopic and immunohisto­ chemical findings of a case with primary small cell carci­ noma of the urinary bladder. A short review of the litera­ ture is given, and the possible histogenesis of this unusual neoplasm is considered.

Case Report A 55-year-old woman was first seen in our hospital in September 1986 with a 6-month history of urinary bladder irritability and microhematuria. Following cystoscopy, a suspect area was seen on the cranial bladder wall. Excisional biopsy was performed, and the pathological diagnosis revealed inflamed bladder mucosa. Lavage cytology showed no tum or cells. In November 1987, the patient was

Received: December 3. 1990 Accepted after revision: March 18,1991

readmitted for rebiopsy because a control lavage cytology showed urothelial carcinoma cells of medium differentiation; pathological examination of the biopsy again showed nonspecific chronical cysti­ tis. One year later, in August 1988, a control cystoscopy detected a large tumor on the right bladder wall. The tumor was resected. Because of infiltration of the whole bladder wall, a radical resection was not possible. Histopathological diagnosis revealed an invasive small cell carcinoma. Immunohistochemistry showed positivity for antibodies directed against neuron-specific enolase (NSE) as well as for HISL-19 anti­ body. No primary tum or outside the urinary bladder could be detected. The investigations included X-ray examination of the chest and the entire alimentary tract and full lung tomograms. Both iso­ tope bone scan and computerized tomography (CT) scan of the brain were inconspicuous. An excretory urogram revealed hydronephrosis and -ureter on the right side. A CT scan of the lung showed no evi­ dence of a neoplasm. On pelvic CT examination, and 8 X 4 cm mass was seen on the right bladder wall with perivesical infiltration (fig. 1). Laboratory examination, including blood chemistry, serum electro­ lytes and urine analysis were normal. The serum level of NSE was elevated to 48.8 ng/ml, which supported the diagnosis of a neuroen­ docrine neoplasm. Upon laparotomy, iliac staging lymphadcnectomy revealed no positive lymph nodes in the histological examina-

Dr. Karl Höbarth Urologischc Universitätsklinik Wien Allgemeines Krankenhaus Alser Strasse 4. A - 1090 Wien (Austria)

© 1992 S. Karger AG. Basel 0042-1138/92/0481-0095 $2.75/0

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K. Hobarlha F. Wrbah J. Hofbauera

Fig. 1. CT image of the bladder demon­ strates intraluminal bladder mass infiltrating the perivesical adipose tissue.

Pathological Features For histological routine diagnosis, the surgical specimen was fixed in 8% formalin and embedded in paraffin. Sections were stained by conventional methods with hematoxylin and eosin and Giemsa stain. For immunohistochcmistry, deparaffinized sections were stained with antibodies to lu-5 (monoclonal. 1:80, Franke et al. [ 1]), common leukocyte antigen (monoclonal CLA, 1:20, Dakopatts, Denmark), NSE (polyclonal NSE, 1:80, Dakopatts, Denmark) and HISL-19 (monoclonal, 1:4,000, Srikanta et al. [2]), using either the indirect peroxidase method [3] for monoclonal antibodies or the peroxidaseantiperoxidase technique [4] for polyclonal antibodies, respectively. Negative controls performed by omission of the respective first anti­ body revealed consistently negative results. Light-Microscopic Findings. The tumor was predominantly com­ posed of monotonous sheets and nests of densely packed small cells with scanty cytoplasm and hyperchromatic nuclei, and it penetrated the bladder wall into the surrounding adipose tissue. Frequently, spots of tumor necrosis were seen (fig. 2). Immunohistochemical Findings. The murine monoclonal anti­ body lu-5, which recognizes an epitope which is present in most cytokeratin polypeptides in epithelium-derived cell lines, revealed strong positivity, confirming the epithelial derivation of this neoplasm (fig. 3). A large cell anaplastic lymphoma was excluded by CLA ne­ gativity. Additionally, antibodies directed against NSE, a marker for neuroendocrine tumors, as well as HISL-19, a monoclonal anti­ body directed against peptide-hormone-producing cells, showed po­ sitivity in nearly all tumor cells in typical patterns of immunoreaction (fig. 4, 5).


Discussion Primary small cell carcinomas of the urinary bladder are rare. In our review of the literature, approximately 50 documented cases were found [5-9], Small cell carcino­ mas are usually located in the lung [ 10], (The synonymous term oat cell carcinoma is widely used in the literature.) Cases of primary extrapulmonary occurrence of this tu­ mor are described in several organs, such as the esopha­ gus, pharynx, skin, gastrointestinal tract, uterine cervix, endometrium, prostate, thymus, breast and kidney [11, 12], As typical biological behavior, similar to the small cell carcinomas of the lung, these tumors show early inva­ sion and métastasés as well as a rapid clinical course. The frequency of small cell carcinomas in the urinary bladder is less than 0.5% of all bladder malignancies [7], A prevalence in the 6th—8th decade with a male predomi­ nance can be seen. In the series of Blomjous et al. [7], 89% of patients developed metastasis, and 78% died after a median follow-up period of 7 months. Because of the rapid clinical course, the therapy of choice is cystectomy. The value of adjuvant chemotherapy or radiation therapy is questionable. Small cell carcinomas have the ability to produce dif­ ferent hormonal polypeptides, and they are frequently associated with paraneoplastic syndromes. Although in our case tumor cells showed positivity for HISL-19, revealing features of pcptide-hormone-producing cells, no clinical symptomatology of excessive peptide or amine secretion could be detected. Immunohistochemical stud-


Primary Small Cell Carcinoma

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tion. Therefore, cystectomy and an ileal conduit were performed. Pathological examination of the tumor confirmed the primary diag­ nosis of a small cell carcinoma infiltrating the perivesical space and the distal part of the right ureter. The postoperative period was uneventful and a follow-up period of 15 months showed no evidence of métastasés or tumor recurrence.

Fig. 2. Small cell carcinoma of the uri­ nary bladder (upper part of the figure) infil­ trating the bladder wall. HE. X 592.

Fig. 4. Immunostaining for NSE in a small cell carcinoma of the urinary bladder showing diffuse cytoplasmic staining of tu­ mor cells. Mayer’s hemalum countcrstaining. X 148.

ies suggest that these tumors frequently show neuroendo­ crine differentiation. Like in our case, most of the docu­ mented small cell carcinomas presented positivity for NSE, a marker for neuroendocrine cells and endocrine tumors. NSE is the neuronal form of the glycolytic enzyme enolase, which is localized in the cytosol of neu­ roendocrine cells. It can be a useful marker for neuroen­ docrine tumors [ 13], Serum levels of NSE are significantly raised in most patients with neuroendocrine neoplasmas; they can also be a marker for disease extent and response to therapy of small cell carcinomas [14], As NSE also has been documented in nonneuroendocrine tissues [15], it is not a truly specific marker for small cell carcinomas, but in addition with other neuroendocrine markers and the light-microscopic features it can be helpful for classifying these tumors. The histogenesis of small cell carcinomas arising in the urinary bladder it still not clear. The origin from neoplas­ tic transformation of cells with neuroendocrine differenti­ ation, documented in normal [16] and mctaplastic [17] bladder mucosa, could be possible. On the other hand, tumor derivation from a multipotent mucosal stem cell which represents the precursor of different types of blad­ der cancer cannot be excluded. The fact that our patient showed no clinical evidence of metastases or recurrence after a follow-up of 15 months is unusual for the typical rapid course reported of other small cell carcinomas. NSE can be a useful marker for the follow-up of these neo­ plasms. In our case postoperative serum levels of NSE were within the normal range. Immunohistochemical ex­

Fig. 5. Small cell carcinoma of the uri­ nary bladder: immunostaining for HISL-19 reveals typical granular staining reaction in perinuclear location (arrows). Mayer’s he­ malum counterstaining. X 562.

aminations are helpful to confirm the diagnosis by dem­ onstrating neuroendocrine features. Owing to the limited number of reported cases, the incidence of this tumor arising in the urinary bladder has still not be exactly deter­ mined. Recognition of further examples of this type of carcinoma in the urinary bladder with additional studies and long-term follow-up will clarify the clinical behavior of this rare bladder lesion.


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Fig. 3. Strongly positive immunostaining for monoclonal antibody lu-5 in a small cell carcinoma of the urinary bladder. Counterstaining with Mayer’s hemalum. X 148.

1 Franke WW. W inters, von Overbeck J. Gudat F, Heitz PU, Strahli C: Identification of the conserved, conformation-dependent cytokeratin epitope recognized by monoclonal antibody (lu-5). Virchows Arch (A] 1987;411:137-147. 2 Srikanta S. Krisch K, Eisenbarth GS: Novel isletproteins defined by monoclonal islet cell antibody HISL-19: Identification and charac­ terization. Diabetes 1986;35:300-305. 3 Stein H, Gerdes H. Schwab U, Lemke H. Ma­ son TY. Ziegler A, Schienle W. Diehl V: Identi­ fication of Hodgkin and Sternbcrg-Rccd cells as a unique cell type derived from newlydetected small-cell population. Int J Cancer 1982:30:445-459. 4 Sternberger LA, Hardy Ph Jr, Cuculis JJ. Mevcr HG: The unlabelled antibody-enzyme method of immunohistochemistry. Prepara­ tion of soluble antigen-antibody complex (horseradish peroxidase-antihorseradish per­ oxidase) and its use in identification of spiro­ chetes. J Histochcm Cytochem 1970; 18:315— 333. 5 Cramer SF, Alkawa H, Ccbelin M: Neurosecre­ tory granules in small cell invasive carcinoma of the urinary bladder. Cancer 1981 ;47:724— 730.


6 Partanen S, Asikainen U: Oat cell carcinoma of the urinary bladder with ectopic adrenocortico­ tropic hormone production. Hum Pathol 1985; 16:313-315. 7 Blomjous CEM. Vos W, De Voogt HJ. Van der Valk P, Meijer CJLM: Small cell carcinoma of the urinary bladder. A clinicopathologic, mor­ phometric. immunohistochemical and ultrastructural study of 18 cases. Cancer 1989:64: 1347-1357. 8 Mills SE. Wolfe JT III. Weiss MA, Swanson PE, Wick MR. Fowler JE Jr, Young RH: Small cell undifferentiated carcinoma of the urinary' bladder. A light-microscopic, immunocytochemical and ultrastructural study of 12 cases. Am J Urol Pathol 1987;11:606-617. 9 Ordonez NG. Khorsand J. Ayala AG, Sneige N: Oat cell carcinoma of the urinary tract. An immunohistochemical and electron micro­ scopic study. Cancer 1986:58:2519-2530. 10 Bensch KG. Corrin B. Pariente R. Spenger H: Oat-cell carcinoma of the lung: Its origin and relationship to bronchial carcinoid. Cancer 1968:22:1163-1172. 11 Ibrahim NBN, Briggs JC, Corbishley CM: Extrapulmonary oat cell carcinoma. Cancer 1984: 54:1645-1661.

12 Capclla C, Euscbi V, Rosai J: Primary oat cell carcinoma of the kidney. Am J Surg Pathol 1984;8:855-861. 13 Tapia FJ, Polak JM, Barbosa AJA. Bloom SR. Marangos PJ, Dermody C. Pearse AGE: Neu­ ron-specific enolase is produced by neuroendo­ crine tumors. Lancet 1981 ;i:808-811. 14 Carney DN, Marangos PJ. Ihde DC. Bunn PA Jr, Cohen MH, Minna JD, Gazdar AF: Serum neuron-specific enolase: A marker for disease extent and response to therapy of small-ccll lung cancer. Lancet 1982;i:583—585. 15 Haimoto H. Takahashi Y. Koshiwaka T. Nagura H, Kato K: Immunohistochemical local­ isation of y-enolase in normal human tissues other than nervous and neuroendocrine tis­ sues. Lab Invest 1985;52:257-263. 16 Gosling JA. Dixon JS. Humpherson JR: Func­ tional Anatomy of the Urinary'Tract. An Intergrated Text and Color Atlas. New York, Gow­ er, 1983. pp 33-34. 17 Gordon A: Intestinal metaplasia of the urinarytract epithelium. J Pathol Bacteriol 1963:85: 441-444.


Primary Small Cell Carcinoma

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Primary small cell carcinoma of the urinary bladder. Report of a case with immunohistochemical analyses.

A case of primary small cell carcinoma of the urinary bladder is reported. The light-microscopic diagnosis was supported by immunoreactivity for HISL-...
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