Cytoplasmic PTEN Protein Loss Distinguishes Intraductal Carcinoma of the Prostate from High Grade Prostatic Intraepithelial Neoplasia

1] Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, USA [2] Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
Modern Pathology (Impact Factor: 6.19). 12/2012; 26(4). DOI: 10.1038/modpathol.2012.201
Source: PubMed


Intraductal carcinoma of the prostate is a marker of aggressive disease. However, intraductal carcinoma exists on a morphologic continuum with high-grade prostatic intraepithelial neoplasia (PIN) and distinguishing intraductal carcinoma from PIN is a common diagnostic dilemma with significant clinical implications. We evaluated whether immunostains for PTEN and ERG can sensitively identify intraductal carcinoma and accurately distinguish it from high-grade PIN. A combined immunostain for PTEN, ERG, p63 and CK903 was developed and validated. Radical prostatectomy specimens with lesions meeting criteria for intraductal carcinoma (n=45), intraductal cribriform proliferations falling short of intraductal carcinoma (n=15), and PIN lesions (n=39) were retrospectively identified and assessed for PTEN and ERG. Cytoplasmic PTEN loss was identified in 84% (38/45) of the intraductal carcinoma and 100% (15/15) of intraductal cribriform proliferation cases. In contrast, cytoplasmic PTEN loss was never observed in PIN (0/39; P<0.0001). Of the 53 cases of intraductal carcinoma or intraductal cribriform proliferation with cytoplasmic PTEN loss, it was homogeneously lost in 42 cases (79%). Weak, focal nuclear positivity for PTEN was retained in 31 of these 42 cases (74%). ERG expression was identified in 58% (26/45) of intraductal carcinoma and 67% (10/15) of intraductal cribriform proliferations compared with 13% (5/39) of PIN. Concordance between the PTEN/ERG status of the intraductal carcinoma lesions and the concurrent invasive carcinoma was high (>95% and P<0.0001 for each), and substantially less for PIN and the concurrent invasive tumor (83% for PTEN and 67% for ERG; P=NS for each). Cytoplasmic PTEN loss occurs in the majority of intraductal carcinoma and intraductal cribriform proliferation cases. Cytoplasmic PTEN loss was never observed in PIN (100% specificity). Our study identifies PTEN loss as a potentially useful marker to distinguish intraductal carcinoma from PIN and provides a plausible molecular explanation for why intraductal carcinoma is associated with poor prognosis.Modern Pathology advance online publication, 7 December 2012; doi:10.1038/modpathol.2012.201.

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Article: Cytoplasmic PTEN Protein Loss Distinguishes Intraductal Carcinoma of the Prostate from High Grade Prostatic Intraepithelial Neoplasia

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    • "Loss of PTEN, a tumor suppressor, occurs in up to 70% of invasive prostatic carcinomas and is uncommon in HGPIN.28,29 Using immunohistochemistry, cytoplasmic loss of PTEN was identified in 84% of IDC-P and was not identified in any cases of HGPIN (0/39).7 "
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    ABSTRACT: Intraductal carcinoma of the prostate (IDC-P) is defined as a proliferation of prostate adenocarcinoma cells distending and spanning the lumen of pre-existing benign prostatic ducts and acini, with at least focal preservation of basal cells. Studies demonstrate that IDC-P is strongly associated with high-grade (Gleason grades 4/5), large-volume invasive prostate cancers. In addition, recent genetic studies indicate that IDC-P represents intraductal spread of invasive carcinoma, rather than a precursor lesion. Some of the architectural patterns in IDC-P exhibit architectural overlap with one of the main differential diagnoses, high-grade prostatic intraepithelial neoplasia (HGPIN). In these instances, additional diagnostic criteria for IDC-P, including marked nuclear pleomorphism, non-focal comedonecrosis (>1 duct showing comedonecrosis), markedly distended normal ducts/acini, positive nuclear staining for ERG, and cytoplasmic loss of PTEN by immunohistochemistry, can help make the distinction. This distinction between IDC-P and HGPIN is of critical importance because IDC-P has an almost constant association with invasive carcinoma and has negative clinical implications, including shorter relapse-free survival, early biochemical relapse, and metastatic failure rate after radiotherapy. Therefore, IDC-P should be reported in prostate biopsies and radical prostatectomies, regardless of the presence of an invasive component. This article will review the history, diagnostic criteria, molecular genetics, and clinical significance of IDC-P.
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    • "Using the same highly validated IHC assay that we used in the present study, we previously found a rate of 17% of loss of PTEN20. However, in a more recent study in which 39 cases of PIN, that were spatially separate from invasive carcinoma lesions, were analyzed we found a rate of 0%; conversely, in lesions diagnosed as intraductal carcinoma of the prostate, which appears in most cases to represent intra-ductal spread of already invasive adenocarcinoma lesions, we found a very high rate of PTEN loss36. Additional studies using a variety of molecular and in situ analyzes will be required to sort out the issue of molecular alteration timing in human PIN lesions. "
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    ABSTRACT: Background ERG rearrangements and PTEN loss are two of the most common genetic alterations in prostate cancer. However, there is still significant controversy regarding the order of events of these two changes during the carcinogenic process. We used IHC to determine ERG and PTEN status and calculated the fraction of cases with homogeneous/heterogeneous ERG and PTEN staining in a given tumor. Methods and Results Using a single standard tissue section from the index tumor from radical prostatectomies (N= 77), enriched for relatively high grade and stage tumors, we examined ERG and PTEN status by IHC. We determined whether ERG or PTEN staining was homogeneous (all tumor cells staining positive) or heterogeneous (focal tumor cell staining) in a given tumor focus. 57% (N=44/77) of tumor foci showed ERG positivity, with 93% of these (N=41/44) cases showing homogeneous ERG staining in which all tumor cells stained positively. 53% (N=41/77) of tumor foci showed PTEN loss, and of these, 66% (N=27/41) showed heterogeneous PTEN loss. In ERG homogeneously positive cases, any PTEN loss occurred in 56 % (N=23/41) of cases, and of these, 65% (N=15/23) showed heterogeneous loss. In ERG negative tumors, 51.5% (N=17/33) showed PTEN loss, and of these, 64.7% (N=11/17) showed heterogeneous PTEN loss. In a subset of cases, genomic deletions of PTEN were verified by FISH in regions with PTEN protein loss as compared to regions with intact PTEN protein, which did not show PTEN genomic loss. Conclusions These results support the concept that PTEN loss tends to occur as a subclonal event within a given established prostatic carcinoma clone after ERG gene fusion. The combination of ERG and PTEN IHC staining can be used as a simple test to ascertain PTEN and ERG gene rearrangement status within a given prostate cancer in either a research or clinical setting.
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