Correct: D

Histology: These prostate chips show glandular structures with areas of papillary formation lined by columnar pseudostratified epithelium. On high power, the epithelial cells have prominent nucleoli.

Discussion: Ductal adenocarcinoma, also called “prostatic duct adenocarcinoma” is accounts for about 3% of all prostate cancer and is most commonly associated with usual acinar adenocarcinoma but it can be pure in 0.2-0.4% of all prostate cancer cases. Ductal adenocarcinoma is characterized by an epithelial lining that is pseudostratified and columnar. The most common location for this tumor is in the large ducts around the prostatic urethra. Because tumor cells are columnar and tall it was originally described as adenocarcinoma with endometrioid features. While the cells are tall with elongated nuclei, most still show large prominent nucleoli as seen in acinar adenocarcinoma; a minority can have very bland cytology. Architecturally, most ductal adenocarcinomas are characterized by papillary formation and cribriform growth. The cribriform growth in ductal adenocarcinoma differs from the cribriform of usual acinar adenocarcinoma in that the cells in ductal adenocarcinoma still preserve the columnar pseudostratified morphology often with slit-like spaces while the acinar is cuboidal with basally located round nuclei and round lumina.
The differential diagnoses of ductal adenocarcinoma include prostatic urethral polyp, hyperplastic benign glands, urethral villous adenomas, PIN, and cribriform acinar adenocarcinoma. Prostatic urethral polyp is a benign entity most frequently found in transurethral resections and is composed of normal benign prostatic glands without any cytologic atypia or the columnar and pseudostratified organization of epithelial cells (see prostatic urethral lesions chapter). Detached fragments of ductal adenocarcinoma may mimic a prostatic urethral polyp. Benign prostatic glands can show exuberant epithelium, especially around the central zone of the prostate and could pose consideration of ductal adenocarcinoma to the unexperienced eye. However, in prostatic gland hyperplasia the cells are identical to normal benign secretory cells. The differential diagnosis with these benign entities can be easily resolved with the use of immunohistochemistry which will highlight the presence of intact basal cells and lack expression of racemase, contrary to ductal adenocarcinoma.
The differential diagnosis with villous adenoma can be challenging given that the adenomatous changes in a lesion with intestinal differentiation can mimic the cytology of ductal adenocarcinoma of the prostate. Furthermore, adenocarcinoma with intestinal differentiation, either spread from colon and rectum or primary from the urethra, can mimic ductal adenocarcinoma of the prostate. The presence of extracellular mucin will favor villous adenoma or adenocarcinoma from colonic origin, which can be confirmed by positive staining for CDX2 and negative staining for prostate markers in the adenocarcinoma with intestinal differentiation. It is also rare for ductal adenocarcinoma of the prostate to have mucinous goblet cells, in contrast to villous adenoma of the prostatic urethra. One must also be aware that ductal adenocarcinoma of the prostate can rarely express CDX2 such that prostate-specific stains such as NKX3.1, P501S, and PSA should be done to differentiate between the two entities if needed.
The differential diagnosis with PIN can be challenging in cases in which the focus of ductal adenocarcinoma is very small in needle biopsies. The presence of true papillary formation, cribriform architecture or comedo necrosis favors ductal adenocarcinoma. If the entire lesion has basal cells highlighted by immunohistochemistry, that rules out invasive ductal adenocarcinoma but still could be intraductal carcinoma with ductal cytology; the vast majority of these cases have associated invasive ductal adenocarcinoma. Finally, the differential diagnosis with adenocarcinoma with cribriform morphology is based in the lack of papillary formation and the tumor cells with more cuboidal shape instead of elongated as seen in ductal carcinoma. Given the presence of cribriform glands, most cases of ductal adenocarcinoma should be graded as Gleason score 4+4=8 (Grade Group 4). When the ductal adenocarcinoma shows solid areas or necrosis, then Gleason pattern 5 is assigned. Ductal adenocarcinoma is positive for prostate-specific in an analogous fashion to acinar adenocarcinoma, including PSA, NKX3.1 and prostein (p501s). When a PIN4 is performed, approximately 30% of cases will show focal positive staining for HMWCK and/or p63 highlighting basal cells. As noted above, this represents an intraductal component of ductal adenocarcinoma.

References
1. Humphrey PA. Histological variants of prostatic carcinoma and their significance. Histopathology. 2012;60(1):59-74.
2. Bostwick DG, Kindrachuk RW, Rouse RV. Prostatic adenocarcinoma with endometrioid features. Clinical, pathologic, and ultrastructural findings. Am J Surg Pathol. 1985;9(8):595-609.
3. Epstein JI, Woodruff JM. Adenocarcinoma of the prostate with endometrioid features. A light microscopic and immunohistochemical study of ten cases. Cancer. 1986;57(1):111-119.