Androgen-deprivation therapy-induced aggressive prostate cancer with neuroendocrine differentiation

Abstract

Most prostate cancers (PCas) are classified as acinar type (conventional) adenocarcinoma which are composed of tumor cells with luminal differentiation including the expression of androgen receptor (AR) and prostate-specific antigen (PSA). There are also scattered neuroendocrine (NE) cells in every case of adenocarcinoma. The NE cells are quiesecent, do not express AR or PSA, and their function remains unclear. We have demonstrated that IL8-CXCR2-P53 pathway provides a growth-inhibitory signal and keeps the NE cells in benign prostate and adenocarcinoma quiescent. Interestingly, some patients with a history of adenocarcinoma recur with small cell neuroendocrine carcinoma (SCNC) after hormonal therapy, and such tumors are composed of pure NE cells that are highly proliferative and aggressive, due to P53 mutation and inactivation of the IL8-CXCR2-P53 pathway. The incidence of SCNC will likely increase due to the widespread use of novel drugs that further inhibit AR function or intratumoral androgen synthesis. A phase II trial has demonstrated that platinum-based chemotherapy may be useful for such therapy-induced tumors.

Figure 1

Histologic features of benign prostate gland, high grade PIN, adenocarcinoma and SCNC. (a) A high power view of benign prostate gland showing an inner luminal cell layer (long arrow) and an outer basal cell layer (short arrow). (b) High grade PIN showing malignant luminal cells without invasion of the stroma. (c) Prostatic adenocarcinoma showing proliferation of small, compact malignant glands (arrow). (d) SCNC which is composed of pure NE tumor cells without glandular formation. NE: neuroendocrine; PIN: prostatic intraepithelial neoplasia; SCNC: small cell neuroendocrine carcinoma.

Figure 2

Immunohistochemical characteristics of prostatic adenocarcinoma vs SCNC. Adenocarcinoma expresses luminal differentiation markers AR and PSA. Tumor cells are negative for NE marker CgA. SCNC is negative for AR and PSA, but expresses CgA. AR: androgen receptor; CgA: chromogranin A; NE: neuroendocrine; PSA: prostate-specific antigen; SCNC: small cell neuroendocrine carcinoma.

Figure 3

Some treated prostate cancers have classic morphology for SCNC, but not typical IHC profile. The case demonstrates histologic features of SCNC in that tumor cells do not form glandular structures. They are small with scant cytoplasm, darkly-stained nuclei with homogeneous chromatin pattern and no nucleoli. However, the tumor cells still express luminal differentiation markers AR and PSA and negative for NE marker CgA. AR: androgen receptor; CgA: chromogranin A; H and E: hematoxylin and eosin; IHC: immunohistochemistry; NE: neuroendocrine; PSA: prostate-specific antigen; SCNC: small cell neuroendocrine carcinoma.