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Molecular evidence that invasive adenocarcinoma can mimic prostatic intraepithelial neoplasia (PIN) and intraductal carcinoma through retrograde glandular colonization.

ABSTRACT: Prostate cancer often manifests as morphologically distinct tumour foci and is frequently found adjacent to presumed precursor lesions such as high-grade prostatic intraepithelial neoplasia (HGPIN). While there is some evidence to suggest that these lesions can be related and exist on a pathological and morphological continuum, the precise clonal and temporal relationships between precursor lesions and invasive cancers within individual tumours remain undefined. Here, we used molecular genetic, cytogenetic, and histological analyses to delineate clonal, temporal, and spatial relationships between HGPIN and cancer lesions with distinct morphological and molecular features. First, while confirming the previous finding that a substantial fraction of HGPIN lesions associated with ERG-positive cancers share rearrangements and overexpression of ERG, we found that a significant subset of such HGPIN glands exhibit only partial positivity for ERG. This suggests that such ERG-positive HGPIN cells either rapidly invade to form adenocarcinoma or represent cancer cells that have partially invaded the ductal and acinar space in a retrograde manner. To clarify these possibilities, we used ERG expression status and TMPRSS2-ERG genomic breakpoints as markers of clonality, and PTEN deletion status to track temporal evolution of clonally related lesions. We confirmed that morphologically distinct HGPIN and nearby invasive cancer lesions are clonally related. Further, we found that a significant fraction of ERG-positive, PTEN-negative HGPIN and intraductal carcinoma (IDC-P) lesions are most likely clonally derived from adjacent PTEN-negative adenocarcinomas, indicating that such PTEN-negative HGPIN and IDC-P lesions arise from, rather than give rise to, the nearby invasive adenocarcinoma. These data suggest that invasive adenocarcinoma can morphologically mimic HGPIN through retrograde colonization of benign glands with cancer cells. Similar clonal relationships were also seen for intraductal carcinoma adjacent to invasive adenocarcinoma. These findings represent a potentially undervalued indicator of pre-existing invasive prostate cancer and have significant implications for prostate cancer diagnosis and risk stratification.

SUBMITTER: Haffner MC

PROVIDER: S-EPMC4715537 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Molecular evidence that invasive adenocarcinoma can mimic prostatic intraepithelial neoplasia (PIN) and intraductal carcinoma through retrograde glandular colonization.

Haffner Michael C MC Weier Christopher C Xu Meng Meng MM Vaghasia Ajay A Gürel Bora B Gümüşkaya Berrak B Esopi David M DM Fedor Helen H Tan Hsueh-Li HL Kulac Ibrahim I Hicks Jessica J Isaacs William B WB Lotan Tamara L TL Nelson William G WG Yegnasubramanian Srinivasan S De Marzo Angelo M AM

The Journal of pathology 20151014 1

Prostate cancer often manifests as morphologically distinct tumour foci and is frequently found adjacent to presumed precursor lesions such as high-grade prostatic intraepithelial neoplasia (HGPIN). While there is some evidence to suggest that these lesions can be related and exist on a pathological and morphological continuum, the precise clonal and temporal relationships between precursor lesions and invasive cancers within individual tumours remain undefined. Here, we used molecular genetic, ...[more]

PMID: 26331372

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Project description:Targeted pharmacological correction is used extensively in medical practice today. 3,3'-Diindolylmethane (DIM) is known as a substance with various anticancer properties. An interim study of the efficacy of a new drug Infemin on the basis of diindolylmethane (DIM) with improved bioavalability has been conducted.The clinical trial had a multicenter, randomized, placebo-controlled, double-blind design and was carried out in two parallel groups. The interim analysis of data included 21 patients diagnosed with a high-grade prostatic intraepithelial neoplasia (PIN). Group 1 (11 patients) received Infemin in a dose of 900 mg of DIM a day, and group 2 (10 patients) received placebo. To assess the efficacy of therapy, the analysis of morphological index (MI) changes based on the results of histological examinations of prostate biopsy specimens was performed, and a proportion of patients with persistent PIN in 12 months after Infemin initiation was calculated. Researchers also evaluated prostate size, urodynamic parameters (Qmax, Qave, Vres), IPSS, and QoL (quality of life) indices and International Index of Erectile Function (IIEF) at 3, 6, 9, and 12 months after the Infemin administration start.After 12 months of treatment in the Infemin group, MI decreased from 0.50 to 0.08, while in the placebo group, it increased from 0.27 to 0.58; the difference between the groups was statistically significant (p = 0.0003, Mann-Whitney test). In 45.5 % of patients in the Infemin group, a complete regression of PIN was also observed, while in the placebo group, PIN regression was not observed in any patients (p = 0.053, Yates' corrected chi-square). Study results in the Infemin group show improvement of maximal urinary flow rate Qmax (53.3 % increase compared to the initial value); however, the statistical significance was not reached (p = 0.180, Mann-Whitney test) due to the small sample size. Evaluation of other urodynamic parameters, prostate volume, quality of life, symptoms reflecting urination disorder, and erectile dysfunction symptoms did not reveal significant differences between the Infemin and placebo groups either which is probably due to the small sample size.The intermediate results of the 21 patients in this multicenter, randomized, placebo-controlled, double-blind study show that Infemin may be a promising drug candidate in patients with high-grade PIN.www.chictr.org.cnChiCTR-INR-15007496.

Project description:Lo-MYC and Hi-MYC mice develop prostatic intraepithelial neoplasia (PIN) and prostatic adenocarcinoma as a result of MYC overexpression in the mouse prostate. However, prior studies have not determined precisely when, and in which cell types, MYC is induced. Using immunohistochemistry (IHC) to localize MYC expression in Lo-MYC transgenic mice, we show that morphological and molecular alterations characteristic of high grade PIN arise in luminal epithelial cells as soon as MYC overexpression is detected. These changes include increased nuclear and nucleolar size and large scale chromatin remodeling. Mouse PIN cells retained a columnar architecture and abundant cytoplasm and appeared as either a single layer of neoplastic cells or as pseudo-stratified/multilayered structures with open glandular lumina-features highly analogous to human high grade PIN. Also using IHC, we show that the onset of MYC overexpression and PIN development coincided precisely with decreased expression of the homeodomain transcription factor and tumor suppressor, Nkx3.1. Virtually all normal appearing prostate luminal cells expressed high levels of Nkx3.1, but all cells expressing MYC in PIN lesions showed marked reductions in Nkx3.1, implicating MYC as a key factor that represses Nkx3.1 in PIN lesions. To determine the effects of less pronounced overexpression of MYC we generated a new line of mice expressing MYC in the prostate under the transcriptional control of the mouse Nkx3.1 control region. These "Super-Lo-MYC" mice also developed PIN, albeit a less aggressive form. We also identified a histologically defined intermediate step in the progression of mouse PIN into invasive adenocarcinoma. These lesions are characterized by a loss of cell polarity, multi-layering, and cribriform formation, and by a "paradoxical" increase in Nkx3.1 protein. Similar histopathological changes occurred in Hi-MYC mice, albeit with accelerated kinetics. Our results using IHC provide novel insights that support the contention that MYC overexpression is sufficient to transform prostate luminal epithelial cells into PIN cells in vivo. We also identified a novel histopathologically identifiable intermediate step prior to invasion that should facilitate studies of molecular pathway alterations occurring during early progression of prostatic adenocarcinomas.

Dataset Information

Molecular evidence that invasive adenocarcinoma can mimic prostatic intraepithelial neoplasia (PIN) and intraductal carcinoma through retrograde glandular colonization.

Publications

Molecular evidence that invasive adenocarcinoma can mimic prostatic intraepithelial neoplasia (PIN) and intraductal carcinoma through retrograde glandular colonization.

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