Morphologic, Molecular and Clinical Features of Aggressive Variant Prostate Cancer

Abstract

The term aggressive variant prostate cancer (AVPCa) refers to androgen receptor (AR)-independent anaplastic forms of prostate cancer (PCa), clinically characterized by a rapidly progressive disease course. This involves hormone refractoriness and metastasis in visceral sites. Morphologically, AVPCa is made up of solid sheets of cells devoid of pleomorphism, with round and enlarged nuclei with prominent nucleoli and slightly basophilic cytoplasm. The cells do not show the typical architectural features of prostatic adenocarcinoma and mimic the undifferentiated carcinoma of other organs and locations. The final diagnosis is based on the immunohistochemical expression of markers usually seen in the prostate, such as prostate-specific membrane antigen (PSMA). A subset of AVPCa can also express neuroendocrine (NE) markers such as chromogranin A, synaptophysin and CD56. This letter subset represents an intermediate part of the spectrum of NE tumors which ranges from small cell to large cell carcinoma. All such tumors can develop following potent androgen receptor pathway inhibition. This means that castration-resistant prostate cancer (CRPCa) transdifferentiates and becomes a treatment-related NE PCa in a clonally divergent manner. The tumors that do not show NE differentiation might harbor somatic and/or germline alterations in the DNA repair pathway. The identification of these subtypes has direct clinical relevance with regard to the potential benefit of platinum-based chemotherapy, poly (ADP-ribose) polymerase inhibitors and likely further therapies.

Keywords: aggressive variant; aggressive variant prostate cancer; anaplastic prostate cancer; neuroendocrine prostate cancer; prostate cancer.

Figure 1

Morphologic appearances of aggressive variant prostate cancer (from a patient identified by feature no. 7 of the list by Aparicio et al [8] and Vlachostergios et al [5]; see text) (A) (hematoxylin and eosin stain, H&E) (bar: 100 microns) and urothelial carcinoma of high grade with a GATA3 immunostaining expression (B; insert) (H&E stain). The immunohistochemical expression of prostate-specific membrane antigen (PSMA) in the same case of aggressive variant prostate cancer shown in 1a (C). Acinar adenocarcinoma of the prostate (D) (H&E stain).

Figure 2

Morphologic appearance of aggressive variant prostate cancer (A) (H&E stain) (bar: 100 microns). The immunohistochemical expression of PSMA (B) as well as chromogranin A (C) and synaptophysin (D) in the same case of aggressive variant prostate cancer shown in (A) (from a patient identified by feature no. 6 of the list by by Aparicio et al [8] and Vlachostergios et al [5]; see text).

Figure 3

Morphologic appearance of aggressive variant prostate cancer in a bone metastasis (A) (H&E stain) (bar: 70 microns). The immunohistochemical expression of PSMA (B) as well as NKX3.1 (C) and prostein (D) in the same case of aggressive variant prostate cancer shown in A (from a patient identified by feature no. 3 of the list by Aparicio et al [8] and Vlachostergios et al [5]; see text).

Figure 4

“A generalized overview of prostate cancer (PCa) progression, metastasis, drug resistance and neuroendocrine differentiation (NED). The illustration describes PCa development from normal epithelial cells (Basal, Luminal and NE cells) to prostatic intraepithelial neoplasia (PIN) to localized- and invasive adenocarcinoma. The cartoon depicts several therapeutic regimens used for the treatment of PCa including surgical resection, radiotherapy and androgen deprivation therapy (ADT). After the initial response to ADT, the majority of the patients relapse with resistance to ADT leading to castration resistant prostate cancer (CRPC) with or without metastasis. These patients are further treated with the next-generation ADTs, enzalutamide or abiraterone. During the course of CRPC treatment, about 30% of PCa patients develop a more aggressive and fatal form of the disease called t-NEPC that has very limited therapeutic responses”. Reproduction from [14] Patel GK, Chugh N, and Tripathi M. Cancers (Basel), 2019, under the Creative Commons Attribution License Attribution 4.0 International (CC BY 4.0).

Figure 5

Small cell carcinoma of the prostate (A) (H&E stain) (bar: 70 microns). High grade PCa with Paneth cell-like rich areas (arrows) (B) (H&E stain). Carcinosarcoma (C) (H&E stain9 and pleomorphic carcinoma of the prostate (D) (H&E stain).