2020-42 / October 19
Contributors: Liwei Jia

A man in his mid 60s had a prior history of prostatic adenocarcinoma (Gleason score 5+5=10, involving 12 cores). His PSA level initially declined to undetectable after introducing treatment with abiraterone + prednisone 1.5 years ago. He now presents with rising PSA level and has evidence of new bone metastases identifiable on CT imaging. A TURP was performed to relieve his urinary symptoms.


1. What is the correct diagnosis?

a. Prostatic acinar adenocarcinoma, Gleason score 5+3=8 (Grade Group 4)

b. Prostatic acinar adenocarcinoma with metastatic small cell carcinoma

c. Mixed prostatic acinar adenocarcinoma with small cell carcinoma

d. Prostatic acinar adenocarcinoma with neuroendocrine differentiation

1. Mixed prostatic acinar adenocarcinoma with small cell carcinoma

The 2016 World Health Organization genitourinary tumor classification includes neuroendocrine (NE) cells in usual prostate cancer, prostatic adenocarcinoma with Paneth cell-like NE differentiation, well-differentiated NE tumor (carcinoid), small cell NE carcinoma, and large cell NE carcinoma, as well as other tumors that do not fit neatly into these categories. The use of “neuroendocrine differentiation” in usual prostatic adenocarcinoma or Paneth cell-like change is discouraged as in undiscerning hands it may be still be interpreted as high-grade NE carcinoma.

High grade neuroendocrine prostatic carcinoma (NEPC) is a rare disease, only accounting for approximately 1% of primary prostate cancers (de novo NEPC), whereas the incidence of treatment-emergent neuroendocrine prostate cancer is 25-30% in castrate-resistant prostate cancers (CRPC). Unlike prostate acinar adenocarcinoma, high grade NEPCs are very aggressive with median cancer-specific survival less than 2 years. In contrast to CRPC, which tends to produce osseous metastases, NEPC typically disseminates to variable visceral organs such as lung and liver. Emerging evidence suggests that NEPC develops as a transdifferentiation from prostatic adenocarcinoma, in response to androgen deprivation therapy and/or treatment with inhibitors targeting AR signaling pathways, since AR signaling is required for epithelial cell differentiation during prostate development. Supportive molecular evidence for this theory is that genomic rearrangement of the ERG gene occurs with similar frequency (~50% of cases) in adenocarcinoma and SCNC of the prostate. Conventionally, neuroendocrine prostate cancers have been managed clinically with cisplatin-based chemotherapy regimens. Hence, an appropriate classification of NEPC cases can have a transformative impact on patient treatment.

Small cell carcinoma (SmCC) is the most common form of NEPC. Histologically, SmCC across the various anatomic sites share morphologic features, exhibiting small cells with prominent, hyperchromatic nuclei and limited, eosinophilic granular cytoplasm, salt-and-pepper chromatin, and a high proliferative rate. The immunoprofile of NEPC includes the expression of neuroendocrine markers such as synaptophysin (SYP),chromogranin A (CHGA), insulinoma-associated protein 1 (INSM1) and neuron-specific enolase (NSE), as well as absent AR, PSA, and NKX3.1 expression. Importantly, morphology should be the gold standard in the diagnosis of NEPC. IHC study can provide supportive evidence to aid in the diagnosis. However, the diagnosis should not rely upon IHC studies, as there are significant variations from case to case in terms of IHC patterns. It is generally difficult to determine the origin of metastatic SmCC based on morphology or immunoprofile of the tumor. Expression of ERG, AR, and PSA by IHC in SmCC, if possible, would suggest prostate origin. Similarly, positive ERG rearrangement by FISH confirms prostate origin. However, negative results of IHC of prostatic markers or ERG gene rearrangement are not useful. Clinical and radiologic findings are usually the most important evidence in determining the primary site of metastatic SmCC.

Epstein JI, Amin MB, Beltran H, et al. Proposed Morphologic Classification of Prostate Cancer With Neuroendocrine Differentiation. Am J Surg Pathol. 2014; 38(6):756-767.

Santoni M, Conti A, Burattini L, et al. Neuroendocrine differentiation in prostate cancer: novel morphological insights and future therapeutic perspectives. Biochim Biophys Acta. 2014;1846:630–637.

Grigore AD, Ben-Jacob E, Farach-Carson MC. Prostate cancer and neuroendocrine differentiation: more neuronal, less endocrine? Front Oncol. 2015;5:37.

Lipianskaya J, Cohen A, Chen CJ, et al. Androgen-deprivation therapy-induced aggressive prostate cancer with neuroendocrine differentiation. Asian J Androl. 2014; 16(4):541-544.

Komiya A, Yasuda K, Watanabe A, et al. The prognostic significance of loss of the androgen receptor and neuroendocrine differentiation in prostate biopsy specimens among castration-resistant prostate cancer patients. Mol Clin Oncol. 2013; 1:257-262.

Liwei Jia, MD PhD
UT Southwestern Medical Center


prostate, neuroendocrine carcinoma, small cell carcinoma