A 69 year-old man was admitted with urinary urgency and hematuria.  Previously diagnosed prostatic adenocarcinoma (Gleason Grade 4 + 3; T3b, N1, Stage IV) had been treated two years earlier with radical prostatectomy and postoperative hormonal therapy; the patient has since been clinically recurrence free with no serologically detectable PSA.  Cystoscopy performed following the present admission demonstrated an ulcerated invasive tumor, consistent with a bladder primary.  Transurethral resection was performed. 

The TURBT specimen was comprised of multiple fragments of extensively myo-invasive tumor without an intact overlying urothelial surface.  The histologic composition was monomorphous, the appearance uniform from area to area, and the following immunohistochemical results obtained:  synaptophysin (shown), chromogranin A and pankeratin, positive; CK7, CK20, PSA, and PSAP, negative.

LARGE CELL NEUROENDOCRINE CARCINOMA (LCNEC) OF THE PROSTATE

Discussion

The incidence, and significance, of neuroendocrine differentiation in prostatic carcinoma varies with its definition.  Isolated neuroendocrine cells, identified initially with silver stains and more recently immunohistochemically, may be found in the large majority of otherwise typical prostatic adenocarcinomas.  This finding, independent of histologic grade, is likely of minimal, if any, clinical significance.  A more clinically relevant classification of prostatic neuroendocrine neoplasia comprises a spectrum of malignancies similar to that in the lung and other extrapulmonary sites:  carcinoid tumor or carcinoid-like neoplasms, small cell, and large cell neuroendocrine carcinoma.  Prostatic carcinoids are curiosities, usually comprising case reports, and characterized by indolent behavior.  Small cell carcinoma is the most widely recognized variant, often emerging in the setting of previously treated conventional adenocarcinoma.  Large cell neuroendocrine carcinoma is, until recently, the least appreciated and most poorly defined.

The typical morphology of LCNEC is that of trabeculae, solid aggregates and coalescent sheets of intermediate to large cells with moderately abundant cytoplasm, hyperchromatic nuclei with coarse chromatin, variably prominent nucleoli, high mitotic activity and inapparent glandular differentiation unless admixed with a co-existent component of acinar adenocarcinoma; peripheral palisading and organoid configurations may be focally present.  Similar to small cell carcinoma, designation of a Gleason grade is not appropriate for LCNEC.  Neuroendocrine differentiation is variably manifest by CD56 (NCAM), CD57 (Leu-7), chromogranin A, and synaptophysin reactivity.  Since there is often a loss of PSA and PSAP expression with progressive neuroendocrine differentiation, the cytokeratin profile (CK7 and CK20 negative), which is typically the opposite of urothelial malignancies, is further supportive of prostatic origin.  In addition, LCNEC is frequently admixed with residual prostatic adenocarcinoma of the usual  type, which may demonstrate the histologic effects of hormone ablative therapy but retains PSA and PSAP reactivity.  Morphology aside, pankeratin staining excludes paraganglioma of the urinary bladder from differential diagnostic consideration.

In a recent study, LCNEC typically presented as a de-differentiated recurrence of previously treated conventional prostatic adenocarcinoma, usually following long- term hormonal therapy, but rare cases may arise de novo.  The emergence of LCNEC is prognostically ominous, characterized by poor therapeutic response and a mean survival of seven months. 

Submitted by the Pathologists of St. Jude's Hospital, Fullerton, California.

Shirin Farahmand, M.D.
Patrick Fitzgibbons, M.D.
Howard Friedberg, M.D.
Victor Lee, M.D., PhD.
Cynthia Miller, M.D.
Jay Packer, M.D.

REFERENCES

Evans, A., et al. Large Cell Neuroendocrine Carcinoma of Prostate. Am J Surg Pathol. 2006; 30: 684-693.

Sant’ Agnese, P. Neuroendocrine Differentiation in Human Prostatic Carcinoma. Hum Pathol. 1992; 23: 287-296.

COMMENTS
Beautiful case and photography. Thanks for the great discussion!