Utility of PTEN and ERG immunostaining for distinguishing high-grade PIN from intraductal carcinoma of the prostate on needle biopsy

Abstract

Intraductal carcinoma of the prostate and high-grade prostatic intraepithelial neoplasia (PIN) have markedly different implications for patient care but can be difficult to distinguish in needle biopsies. In radical prostatectomies, we demonstrated that PTEN and ERG immunostaining may be helpful to resolve this differential diagnosis. Here, we tested whether these markers are diagnostically useful in the needle biopsy setting. Separate or combined immunostains were applied to biopsies containing morphologically identified intraductal carcinoma, PIN, or borderline intraductal proliferations more concerning than PIN but falling short of morphologic criteria for intraductal carcinoma. Intraductal carcinoma occurring with concurrent invasive tumor showed the highest rate of PTEN loss, with 76% (38/50) lacking PTEN and 58% (29/50) expressing ERG. Of biopsies containing isolated intraductal carcinoma, 61% (20/33) showed PTEN loss and 30% (10/33) expressed ERG. Of the borderline intraductal proliferations, 52% (11/21) showed PTEN loss and 27% (4/15) expressed ERG. Of the borderline cases with PTEN loss, 64% (7/11) had carcinoma in a subsequent needle biopsy specimen, compared with 50% (5/10) of PTEN-intact cases. In contrast, none of the PIN cases showed PTEN loss or ERG expression (0/19). On needle biopsy, PTEN loss is common in morphologically identified intraductal carcinoma yet is very rare in high-grade PIN. Borderline intraductal proliferations, especially those with PTEN loss, have a high rate of carcinoma on resampling. If confirmed in larger prospective studies, these results suggest that PTEN and ERG immunostaining may provide a useful ancillary assay to distinguish intraductal carcinoma from high-grade PIN in this setting.

Figure 1. PTEN loss and ERG expression are common in morphologically diagnosed intraductal carcinoma of the prostate on needle biopsy

(A) Dense cribriform to solid architecture in isolated intraductal carcinoma case (arrows, 200× magnification). (B) Quadruple immunostain for PTEN (brown), ERG (purple) and basal cells (red) on case in (A) demonstrates PTEN loss in intraductal carcinoma (arrow) compared to nearby benign gland (arrowhead). ERG is expressed in nuclei of intraductal proliferation, although it is less intense than nearby endothelial cells (gray arrow). (C) Dense cribriform intraductal carcinoma with nearby invasive carcinoma (200× magnification). (D) Quadruple immunostain for PTEN (brown), ERG (purple) and basal cells (red) on case in (C) demonstrates PTEN loss and ERG expression in intraductal carcinoma cells (inset) relative to entrapped benign cells (inset, arrowhead). The surrounding invasive carcinoma is concordant with the intraductal carcinoma for these markers. (E) Intraductal carcinoma with marked cytological atypia (200× magnification). Although this case does not show dense cribriform or solid intraductal proliferation, it qualifies as intraductal carcinoma due to the presence of atypical nuclei (arrow) greater than 6 × the size of surrounding benign nuclei (arrowhead). (F) Quadruple immunostain for PTEN (brown), ERG (purple) and basal cells (red) on case in (E) demonstrates PTEN loss in intraductal carcinoma cells (arrow) relative to nearby benign glands (arrowhead). ERG is also expressed in this case.

Figure 2. PTEN loss and ERG expression are not seen in morphologically diagnosed high grade PIN on needle biopsy

(A) High grade PIN with tufted architecture (arrow, 200× magnification). Nuclear enlargement and nucleoli are apparent at 20× magnification (arrow) compared to surrounding benign glands (arrowhead). Nucleoli are easily visible (inset). (B) Quadruple immunostain for PTEN (brown), ERG (purple) and basal cells (red) on case in (A) demonstrates intact PTEN and absence of ERG staining. (C) High grade PIN with micropapillary architecture. This case contained concurrent invasive adenocarcinoma. (D) Quadruple immunostain for PTEN (brown), ERG (purple) and basal cells (red) on case in (C) demonstrates intact PTEN and absence of ERG staining.

Figure 3. PTEN and ERG expression in borderline intraepithelial proliferations more concerning the PIN, but insufficient for a diagnosis of intraductal carcinoma using current morphologic criteria

(A) Borderline proliferation with loose cribriform architecture, unusual for PIN, but insufficient for diagnosis of intraductal carcinoma (100× magnification). (B) Quadruple immunostain for PTEN (brown), ERG (purple) and basal cells (red) on case in (A) demonstrates PTEN loss relative to adjacent benign cells (inset shows involved gland from different area of core; arrowhead demonstrates nearby benign gland) and diffuse expression of ERG. (C) Borderline proliferation with substantial cytologic atypia (arrow) but lacking sufficient atypia to qualify as intraductal carcinoma (630× magnification). (D) Quadruple immunostain for PTEN (brown), ERG (purple) and basal cells (red) on case in (C) demonstrates pagetoid spread of PTEN-negative, ERG-positive cells (arrow). (E) Borderline proliferation (200× magnification) with dense cribriform architecture which is highly suspicious for intraductal carcinoma but insufficiently represented at the edge of the needle core. (F) Quadruple immunostain for PTEN (brown), ERG (purple) and basal cells (red) on case in (E) demonstrates retention of PTEN and lack of ERG expression in the proliferation.