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Samuel Amukele md, Department of Urology, Long Island Jewish Medical Center, 270-05 76th Avenue, New Hyde Park, New York 11040, USA. E-mail: email@example.com
Abstract Primary neuroendocrine carcinomas of the lower urinary tract are distinctly rare, locally aggressive neoplasms with a high rate of metastasis. We present a case of primary small cell carcinoma of the urethra occurring in a 64-year-old man. The clinical, histological and immunohistochemical features of urethral small cell carcinoma are highlighted with respect to the differential diagnosis of neuroendocrine and other urethral tumors. The possible histogenesis of urethral small cell carcinoma, reported at this location in only a small number of cases, is briefly discussed. We favor an origin from pluripotent epithelial stem cells as one of the possible histogenic pathways.
Primary neuroendocrine carcinomas of the genitourinary tract are rare. They are malignant tumors composed of small cells that display a diffuse growth pattern and express markers of neuroendocrine and epithelial differentiation. Several reported cases contain elements of transitional cell, squamous cell or adenocarcinoma, suggesting derivation from a primitive precursor cell or from metaplastic epithelium.1,2 The differential diagnosis includes a heterogenous group of neoplasms such as neuroblastoma, carcinoid, small cell variant of osteosarcoma, primitive neuroectodermal tumor, Merkel cell tumor and metastatic small cell carcinoma. We report a case of small cell carcinoma (SCC) arising from the proximal urethra, one of the most infrequent locations of primary neuroendocrine carcinoma in the urogenital tract, and describe its clinical presentation and management. There is paucity of existing literature on the clinical course and management of this rare condition.
A 64-year-old male presented with a painless mass on the shaft of the penis, nocturia, hesitancy and postmicturation dribbling of two months duration. Physical examination revealed a firm, immobile mass extending from the proximal third of the penis to the base of the scrotum. A painful hard nodule was present at the glans penis. Digital examination of the prostate was normal. Serum prostate specific antigen was 0.7 ng/mL. Urine cytology showed clusters of tumor cells with hyperchromatic nuclei, scant cytoplasm and molded contours. Abdominal computed tomography (CT) confirmed a heterogenous, 7 × 5 cm mass with a diffuse growth pattern at the base of the penis surrounding and obliterating the urethral lumen (Fig. 1a). Metastases with distinct tumor boundaries and less than 2 cm in size were seen in the adrenals, pancreas, left kidney and inguinal region. Bladder and prostate showed no abnormalities.
Transurethral and excisional biopsies of the mass and glans penis nodule revealed a proliferation of small peppery tumor cells with scant cytoplasm (Fig. 2a,b). Neoplastic cells were immunoreactive for cytokeratin (CK AE1.3), chromogranin, neuron-specific enolase and synaptophysin (Fig. 2c–e), but negative for leukocyte common antigen (LCA), thyroid transcription factor-1 (TTF-1) and p63 antigen. Diagnosis was SCC of the urethra.
The patient was treated with systemic chemotherapy. Six cycles of cisplatin 80 mg/m2 on day 1 as intravenous injection and etoposide (VP-16) 100 mg/m2 on days 1–5 per oral intake every 4 weeks were administered. This led to nearly complete local regression of the tumor (Fig. 1b). Six months after initial presentation, brain and lung metastasis developed and the patient succumbed to his illness 2 months later. There was no recurrence of the tumor at the urethra until very shortly before his death necessitating the insertion of a suprapubic tube. Second-line chemotherapy was not given in light of the rapid recurrence of the tumor, poor patient performance status and the documented low response rates in neuroendocrine tumors.
Most urethral tumors are transitional, squamous, or adenocarcinomas. Urethral SCC is extremely rare with only four cases reported in literature. Histologically, SCC of the urogenital tract resembles neuroendocrine carcinomas arising elswehere, such as SCC of the lung.1 Small, round to oval tumor cells with scant cytoplasm and hyperchromatic peppery nuclei are frequently arranged in a trabecular or sheet-like fashion. On immunohistochemistry, cells are usually positive for markers of neuroendocine differentiation like synaptophysin, neuron-specific enolase, the most constant marker, or chromogranin.1,3 On electron microscopy, neurosecretory granules within the cells have been shown.4 Differential diagnosis of urethral SCC includes several other rare neoplasms. Diagnosis, as in the present case, is based on a combination of clinical, histological and immunohistochemical studies. A negative immunohistochemical reaction with LCA excludes lymphoma. A negative reaction to p63, a commonly expressed antigen in the urothelium, and a positive reaction to chromogranin, a marker with a specificity of 97% in SCC of the bladder, distinguishes urethral SCC from poorly differentiated transitional cell carcinoma.5,6 Carcinoid tumors are distinguished by their more abundant eosinophilic cytoplasm and more round regular nuclei. Primitive neuroectodermal tumors are characterized by larger cell bodies with their cytoplasm spread out in dendritic processes. Negative staining with TTF-1, expressed by pulmonary SCC and the lack of evidence of a primary site on chest CT excludes metastatic SCC from the lung. The lack of clinical involvement of scrotal or penile skin and the absence of punctate paranuclear staining with cytokeratin described as characteristic of Merkel cell carcinoma excludes this rare skin neoplasm.1
The histogenesis of SCC of the urethra remains unknown. However, several observations support the concept of SCC of the urethra originating from urothelial reserve or pluripotent stem cells capable to differentiate along several cell lines. Small cell carcinoma of the urethra has been described as occurring in a synchronous fashion with other urethral tumors. Young et al. reported a case where SCC of the penile urethra contained elements of squamous cell carcinoma.7 Similar cases of synchronous occurrences of SCC, squamous and transitional cell carcinomas have been reported in the bladder, supporting the theory of a common precursor for different neoplasms.2 On the other hand, metaplasia from high-grade transitional cell or other urethral carcinomas would also explain the combined occurrence of SCC and other tumor elements. Neuroendocrine-paracrine cells in paraurethral glands of Littré and in the urethro-prostatic region are considered to be postmitotic cells unable to dedifferentiate and not considered the origin of these rare tumors. The clinical relevance of neoplasms showing neuroendocrine differentiation has been suggested in SCC of the bladder by a more favorable response to chemotherapy.3,8
Extrapulmonary SCC are aggressive neoplasms with a high rate of metastasis. Reviewing the few previously published reports of urethral SCC, regional lymph nodes are often positive for metastases at initial presentation (Table 1). Aggressive surgical management, including the resection of local metastases and adjuvant chemotherapy, seems to be justified for limited disease with prolonged survival being reported. For non-resectable or disseminated disease, systemic chemotherapy is usually considered. Data from retrospective multivariate analyses of patients with bladder SCC show that cisplatin-based chemotherapy is an independent predictor of improved survival.2 The patient in the present case had an initial good response, but progressed later as often seen in SCC of other sites. Because of the rarity of the disease we can not advocate such therapy as the treatment of choice. Early diagnosis, accurate staging and exact histopathological diagnosis are of paramount importance in order to improve the dismal outlook of this neoplasm.
Table 1. Reported cases of primary small cell carcinoma of the urethra