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Review
. 2024 Mar 8;16(6):1097.
doi: 10.3390/cancers16061097.

Intraductal Carcinoma of the Prostate versus Simulants: A Differential Diagnosis Growing in Clinical Impact

Steven Christopher Smith  1 , Sara E Wobker  2
Affiliations
Review

Intraductal Carcinoma of the Prostate versus Simulants: A Differential Diagnosis Growing in Clinical Impact

Steven Christopher Smith et al. Cancers (Basel). .

Abstract

Despite its first recognition even longer ago, in the past nearly 20 years, intraductal carcinoma of the prostate has become a standard histopathologic reporting parameter conveying a strong negative prognostic factor for prostatic adenocarcinoma. When seen at biopsy, intraductal carcinoma of the prostate is associated with risk for aggressive prostatectomy outcomes, including frequently high-grade, high-stage, high-volume disease, with increased risk for recurrence and progression. Multiple organizations, including the uropathology subspecialty societies to the World Health Organization, recognize and recommend reporting the presence of intraductal carcinoma, whether sampled in "pure" form or present with concomitant invasive adenocarcinoma. Moreover, emerging scholarship relates intraductal carcinoma to higher prevalence of homologous recombination repair deficiency mutations in prostatic adenocarcinoma, whether somatic or germline, which serve as indications for approved targeted therapies. Taken together, this is a diagnosis for the histopathologist not to miss. In view of these elevated stakes and the opportunity to further precision medicine, this review details neoplastic and non-neoplastic simulants in the differential diagnosis of intraductal carcinoma of the prostate.

Keywords: cribriform pattern; gleason grading; grade groups; intraductal carcinoma of the prostate; prostate cancer.

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Conflict of interest statement

The author (S.C.S.) reports royalties for Consulting and Authorship from Elsevier Publishing/Amirsys. The author (S.E.W.) reports royalties for Authorship from Wolters Kluwer.

Figures

Figure 1
Figure 1
Patterns of high-grade prostatic intraepithelial neoplasia (HGPIN). (A) Classic examples of HGPIN demonstrate a tufted appearance, with areas of focal accentuation of pseudostratified columnar luminal epithelial cells showing atypia in the form of nucleomegaly, nuclear hyperchromasia, and nucleoli (200×). (B) An infrequent pattern of HGPIN is that of inverted HGPIN, where an acinus is involved by a neoplastic epithelium with a tufted or micropapillary configuration, but where the nucleoli are located adluminally, lifted off the basement membrane, rather than more basally (200×). (C) Flat HGPIN is a less prevalent pattern where a flat, lower cuboidal atypical epithelium is present, rather than the usual tall, columnar cells, with tufted or micropapillary architecture. This pattern is principally notable due to its potential simulation of invasive carcinoma (400×). (D) As is the case for all HGPIN variants, in flat HGPIN, positive staining for basal cells (p63 nuclear/HMWCK cytoplasm, brown chromogen) and variable overexpression of AMACR (red chromogen) can readily be demonstrated by multiplex immunohistochemistry (400×).
Figure 2
Figure 2
Conventional HGPIN immunophenotype. (A) A focus of HGPIN demonstrates at low power larger nuclei and hyperchromatic amphophilic cytoplasm (lower half field) as compared to atrophic ducts and acini (upper half of the field) (100×). (B) Retained expression of p63 nuclear/HMWCK cytoplasmic positive peripheral basal cells (brown chromogen) is characteristic, as frequently is overexpression of AMACR (red chromogen) (100×). (C) Recent studies have established that HGPIN retains expression of PTEN (brown chromogen, cytoplasmic and membranous expression), which is distinctive in the differential diagnosis versus intraductal carcinoma (100×).
Figure 3
Figure 3
The role of PTEN in the differential diagnosis of florid HGPIN and atypical intraductal proliferations (AIPs). (A) A focus showing three tangentially sectioned acini of florid HGPIN raises consideration of atypical intraductal proliferations due to the density and complexity of the epithelial proliferations (40×). (B) The intraductal nature of these three HGPIN acini is confirmed with p63 nuclear/HMWCK cytoplasmic (brown chromogen) peripheral basal cell staining, with mild overexpression of AMACR (red chromogen) (40×). (C) This focus demonstrates retained PTEN expression (brown chromogen), favoring interpretation as florid HGPIN rather than AIP or intraductal carcinoma (40×). (D) In contrast, this dense, lumen spanning, but unusually small intraductal focus (asterisked) shows loss of expression of PTEN (brown chromogen) in the lesional cells, with internal positive control benign ductal cells (left) strongly positive, favoring interpretation as an AIP (200×). (E) An anatomically adjacent core biopsy to the site of (D) demonstrates invasive carcinoma, also PTEN negative (double asterisk, right lower field), as compared to strongly retained expression in benign adjacent ducts (single asterisk). Carcinoma, particularly higher grades, shows frequent loss of PTEN (200×). (F) PTEN is also strongly retained in this reactive/metaplastic ductal focus (asterisk), where inflammation might simulate necrosis and induce reactive nuclear atypia (200×).
Figure 4
Figure 4
Cancerization of prostatic ducts by urothelial carcinoma. (A) In this focus from a transurethral resection of the prostate, urothelial carcinoma in situ has cancerized and expanded a periurethral gland duct. The dense, lumen spanning pattern and nuclear atypia might raise consideration of intraductal carcinoma (200×). (B) Multiplex PIN cocktail staining (p63 nuclear/HMWCK cytoplasmic, brown chromogen; AMACR red chromogen) can easily distinguish urothelial carcinoma in situ involving prostatic ducts because of its characteristic p63/HMWCK double positive and AMACR variable expression pattern. This phenotype is distinctive from the p63/HMWCK negative and AMACR positive phenotype of intraductal carcinoma (200×).
Figure 5
Figure 5
Adenoid Cystic (Basal Cell) Carcinoma of the prostate. (A) Adenoid cystic carcinoma of the prostate demonstrates an infiltrative neoplasm with solid (basal cell pattern, upper right) or cribriform (adenoid cystic pattern, lower left) growth, composed of cells with high nucleocytoplasmic ratios. These patterns might engender consideration of solid or cribriform intraductal carcinoma (100×). (B) By multiplex PIN cocktail staining, adenoid cystic carcinoma shows diffuse nuclear p63 and cytoplasmic HMWCK (both brown chromogen), while AMACR (red chromogen) is negative (200×).
Figure 6
Figure 6
Benign processes that may simulate intraductal carcinoma. (A) Clear cell cribriform hyperplasia shows a pattern of exuberant, benign growth demonstrating cribriform, arching, and Roman bridges-like architecture, occurring with some frequency in the base/central zone of the prostate. Fortunately, the degree of nuclear atypia seen in such foci is very mild, most unlike intraductal carcinoma and cribriform invasive carcinoma (200×). (B) Basal cell hyperplasia with urothelial metaplasia, frequently present in varying proportions together, may simulate the dense solid pattern of intraductal carcinoma, and may show a branching configuration reminiscent of the branching patters of ducts expanded by intraductal carcinoma. The uniformity of the hyperplastic nuclei, the “streaming” look of spindled cells, and the lack of nuclear atypia beyond grooves, are distinctive from intraductal carcinoma (200×).
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