Prostate cancer (CaP) is the fourth most diagnosed cancer (after breast, lung, and colorectal) worldwide per a World Health Organization (WHO) report; it is also by far the most common genitourinary malignancy [1]. Over 95% of cases are prostatic adenocarcinoma, the vast majority of which are histologically acinar-type and thus prostatic acinar adenocarcinoma (PAA). However, a small number are prostatic ductal adenocarcinoma (PDA). Poorly differentiated adenocarcinoma (either acinar or ductal) with cribriform morphology is increasingly being recognized as its own clinical entity as well: cribriform carcinoma of the prostate (CC-P). Other uncommon cancers of the prostate include neuroendocrine, primary urothelial and stromal, and intraductal carcinoma of the prostate (IDC-P). Our understanding of these less common histologic patterns in prostate cancer has significantly evolved in recent years, and as PDA, ICD-P, and CC-P in particular are associated with poor prognosis compared with PAA, accurate recognition of their hallmarks is paramount for clinical decision-making [2], [3], [4].

PDA is a histologic subtype of prostate adenocarcinoma characterized by papillary structures and/or complex and cribriform glands lined by tall columnar pseudostratified cells and/or prostatic intraepithelial neoplasia (PIN) like growth with an irregular basal cell layer (Fig. 1) [1,5]. It was initially described as “endometrioid carcinoma” by Melicow in 1967 due to its resemblance to endometrial cancer [6]. As it emerges from periurethral ducts or peripheral prostatic ducts, PDA commonly coexists with acinar CaP [7].

IDC-P is a neoplastic epithelial proliferation that extensively occupies the ductal-acinar structures with at least partial preservation of the basal cell layer. It shares features of high-grade prostatic intraepithelial neoplasia (HGPIN) but may display a higher degree of architectural and/or nuclear atypia, glandular overcrowding (>50% cellularity), and necrosis [1] (Fig. 2). IDC-P was initially reported in 1985 [8] but was not recognized as a distinct entity until the fourth edition of the WHO Blue Book in 2016 [9]. There is no specific grading assigned to this entity when it is isolated and noninvasive. However, grading concomitant IDC with invasive carcinoma is controversial [4,10]. If comedonecrosis is present, it is characterized as Gleason 5 [10].

CC-P represents a histologic growth pattern of PAA characterized by small, circular cribriform glands with a contiguous proliferation of cells creating intertwined lumens as well as larger, irregular cribriform glands [11] (Fig. 3). Assigned a Gleason grade 4, CC-P has been shown to have less favorable outcomes than variants with other patterns described as “poorly formed” or “fused” [10]. Unlike other Gleason grade 4 diseases, there is greater inter-rater reproducibility among pathologists when observing CC-P [12].

These histopathological subtypes of CaP have corresponding differences in genetics, prognosis, and responses to treatment. Thus, accurate characterization of the histopathologic type will assist physicians and patients when confronted with critical clinical decisions. This paper reviews the genetic expression patterns and oncologic outcomes of PDA, IDC-P, and CC-P, while also delving into their implications for treatment options.