prostatic small cell carcinoma

Small-cell carcinoma that is primary in the prostate is a rare, extremely aggressive tumour that often presents with disseminated disease.

Incidence estimates range from 0.3% to 1% of all prostatic carcinomas. In about one-half of cases, the carcinoma is pure small-cell carcinoma, and in the other half it is admixed with prostatic acinar adenocarcinoma.

An intriguing and important aspect of prostatic small-cell carcinoma diagnosis is that, in one-third of patients, there was an initial diagnosis of adenocarcinoma, followed by therapy, usually hormonal, in turn followed at a median of 25 months (range 1 month to 25 years) by a subsequent diagnosis of small-cell carcinoma.

There are significant differences between the clinical features of prostatic small-cell carcinoma and those of prostatic acinar adenocarcinoma. Distinctive clinical features include a lower percentage of men who present with an elevated serum PSA level, despite presentation at advanced stages, the propensity for rapid and widespread metastasis, with visceral involvement, lack of hormonal responsiveness, and short survival.

Most patients are aged 65–72 years (range 24–92 years). The most frequent presenting symptoms are related to bladder outlet obstruction and disseminated disease.

In a few cases, paraneoplastic syndromes have been reported; these include Cushing’s syndrome [most common—owing to tumoral adrenocorticotropic hormone (ACTH) production], hypercalcaemia, syndrome of inappropriate antidiuretic hormone hypersecretion, hyperparathyroidism, thyrotoxicosis, hyperglucagonaemia, Eaton–Lambert syndrome, and limbic encephalitis.

The presence of such paraneoplastic syndromes in a patient with prostatic carcinoma should prompt a search, at the histological level, for a small-cell carcinoma element, but these syndromes are not specific for the small-cell histological type. One-third to two-thirds of patients with prostatic small-cell carcinoma present with an elevated serum PSA level; this elevation could be attributable to an admixed adenocarcinomatous component. The digital rectal examination is often suspicious for malignancy, with an enlarged, irregular and stony-hard prostate. Another dramatic difference from prostatic acinar adenocarcinoma is that 92% of prostatic small-cell carcinoma patients have advanced disease at presentation, and three-quarters of patients have metastatic disease.

The sites of clinically evident metastasis are also different, with spread to the viscera, including the liver and lung, being much more common in prostatic small-cell carcinoma. Also, widespread dissemination and metastatic deposits in unusual locations (such as the omentum, vocal cords, temporal bone, axillary lymph node, epididymis, pericardium, and soft tissue) are more often seen with prostatic small-cell carcinoma than with prostatic acinar adenocarcinoma. Finally, the relatively low volume of osseous disease in the presence of visceral metastases should lead one to suspect small-cell carcinoma.

Grossly, there is usually extensive involvement of the prostate, sometimes with replacement of the entire prostate by tumour. At autopsy, cut surfaces are grey–whitish and nodular, and extraprostatic extension into seminal vesicles, periprostatic soft tissue and the bladder can be visualized. Microscopically, prostatic small-cell carcinoma is identical to its more common counterpart in the lung, except that admixture with adenocarcinoma is much more frequent in the prostate.

Histologically, prostatic small-cell carcinoma grows as sheets, with ribbons, nesting, bizarre giant cells, palisading along fibrous bands and rosette-like structures being occasionally noted.122 The polygonal, round or spindled tumour cells exhibit only scanty cytoplasm, with hyperchromatic nuclei, ‘salt and pepper’ stippled chromatin, and inconspicuous nucleoli.

Nuclear moulding can be evident. Both individual cell necrosis, manifested by karryorhectic debris, and large areas of geographical necrosis can be seen. Encrustation of vessels with DNA (the Azzopardi phenomenon) can also be appreciated. Crush artefact is present in most cases.

Mitoses are readily found. Cytologically, prostatic small-cell carcinoma has been diagnosed in pleural fluid and urine specimens.

The acinar adenocarcinoma component in mixed small-cell adenocarcinoma in the prostate is variable in grade and extent. The glandular component varies from focal to 70% of the tumour volume.

In most cases, particularly those where adenocarcinoma preceded a diagnosis of small-cell carcinoma,110 the histological grade of the adenocarcinoma portion is low-grade, but high-grade Gleason pattern 4 has been reported in about one-third of cases.

In two-thirds of cases, the malignant epithelium of the adenocarcinoma and small-cell carcinoma merge directly into each other. In one-third of cases, there is physical separation of the two components.

In metastatic deposits derived from primary mixed small-cell carcinoma–adenocarcinoma, the small-cell carcinoma element is often found, although both components can be seen. Rare examples of admixture of small-cell carcinoma with malignant cells other than adenocarcinoma include coexistence with Paneth cell-like change, squamous cells, and a spindle cell sarcomatoid component.

The immunophenotypic profile of prostatic small-cell carcinoma can be valuable in confirmation of the diagnosis. Epithelial and neuroendocrine differentiation is best demonstrated by applying a panel of antibodies, as no single marker is 100% sensitive.

The prostatic markers PSA, PSAP, PSMA and prostein (P501S) are identified in only a minority of small-cell carcinoma cases, and so these immunostains can be non-contributory in establishing a prostatic origin for a rare metastatic small-cell carcinoma of unknown primary origin.

The adenocarcinomatous component of mixed small-cell carcinoma–adenocarcinoma is positive for PSA and PSAP in almost all cases. Immunohistochemical evidence of biosynthesis of a variety of hormones can be obtained, including ACTH, calcitonin–serotonin, parathormone, antidiuretic hormone, gastrin, vasoactive intestinal peptide, bombesin, somatostatin, and thyrotropin, although these are not used for tissue diagnosis.

Expression of these bioactive molecules by prostatic small-cell carcinoma can result in elevated serum levels in some cases, and production of a paraneoplastic syndrome in a few cases. One should note that prostatic small-cell carcinoma expresses thyroid transcription factor-1 (TTF-1), such that this marker is not useful in the distinction of prostatic and lung small-cell carcinoma.

CD56, TTF-1 and CD44 positivity in immunohistochemistry favours small-cell carcinoma of the prostate over a poorly differentiated adenocarcinoma of the prostate.

ERG gene rearrangements are common in small-cell carcinoma of the prostate (at 47–86%) and can be diagnostically helpful.

Fluorescence in-situ hybridization analyses have demonstrated that these rearrangements are found only in prostatic small-cell carcinoma, and not in small-cell carcinoma from the urinary bladder or lung.

The outcome for patients with small-cell carcinoma of the prostate is dismal, with a median average survival of 9–17 months. These are highly proliferative tumours that generate early, widespread metastases. The neoplasms are not responsive to hormonal therapy. There may be an initial response to cisplatin-based chemotherapy and radiotherapy, but the outcome is not markedly improved with this therapy.

Patient age, sex, primary tumour size and stage are not determinants of survival.

Grading

It was the consensus that small cell carcinoma of the prostate has unique histological, immunohistochemical, and clinical features.

Comparable to its more common pulmonary counterpart, chemotherapy is the mainstay of therapy for prostatic small cell carcinomas.

These clinicopathologic features differ from those associated with Gleason pattern 5 prostatic acinar carcinoma, such that small cell carcinoma should not be assigned a Gleason grade.

References

 Histological variants of prostatic carcinoma and their significance. Humphrey PA. Histopathology. 2012 Jan;60(1):59-74. PMID: 22212078