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Molecular evidence that invasive adenocarcinoma can mimic prostatic intraepithelial neoplasia (PIN) and intraductal carcinoma through retrograde glandular colonization.
J Pathol. 2016 Jan; 238(1):31-41.JP

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.

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Authors+Show Affiliations

Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA.

Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA.

Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, USA.

Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA.

Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA.

Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA.

Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA.

Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA.

Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA.

Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA.

Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA.

Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. Brady Urological Institute, Johns Hopkins University, Baltimore, Maryland, USA.

Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA.

Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA. Brady Urological Institute, Johns Hopkins University, Baltimore, Maryland, USA.

Yegnasubramanian S

Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA.

Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA. Brady Urological Institute, Johns Hopkins University, Baltimore, Maryland, USA.

MeSH

AdenocarcinomaCarcinoma, Intraductal, NoninfiltratingCell Line, TumorDiagnosis, DifferentialHumansImmunohistochemistryIn Situ Hybridization, FluorescenceMaleNeoplasm InvasivenessOncogene Proteins, FusionPTEN PhosphohydrolaseProstatic Intraepithelial NeoplasiaProstatic NeoplasmsTrans-ActivatorsTranscriptional Regulator ERG

Pub Type(s)

Journal Article

Research Support, N.I.H., Extramural

Research Support, Non-U.S. Gov't

Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

26331372

Citation

Haffner, Michael C., et al. "Molecular Evidence That Invasive Adenocarcinoma Can Mimic Prostatic Intraepithelial Neoplasia (PIN) and Intraductal Carcinoma Through Retrograde Glandular Colonization." The Journal of Pathology, vol. 238, no. 1, 2016, pp. 31-41.

Haffner MC, Weier C, Xu MM, et al. Molecular evidence that invasive adenocarcinoma can mimic prostatic intraepithelial neoplasia (PIN) and intraductal carcinoma through retrograde glandular colonization. J Pathol. 2016;238(1):31-41.

Haffner, M. C., Weier, C., Xu, M. M., Vaghasia, A., Gürel, B., Gümüşkaya, B., Esopi, D. M., Fedor, H., Tan, H. L., Kulac, I., Hicks, J., Isaacs, W. B., Lotan, T. L., Nelson, W. G., Yegnasubramanian, S., & De Marzo, A. M. (2016). Molecular evidence that invasive adenocarcinoma can mimic prostatic intraepithelial neoplasia (PIN) and intraductal carcinoma through retrograde glandular colonization. The Journal of Pathology, 238(1), 31-41. https://doi.org/10.1002/path.4628

Haffner MC, et al. Molecular Evidence That Invasive Adenocarcinoma Can Mimic Prostatic Intraepithelial Neoplasia (PIN) and Intraductal Carcinoma Through Retrograde Glandular Colonization. J Pathol. 2016;238(1):31-41. PubMed PMID: 26331372.

* Article titles in AMA citation format should be in sentence-case

TY - JOUR T1 - Molecular evidence that invasive adenocarcinoma can mimic prostatic intraepithelial neoplasia (PIN) and intraductal carcinoma through retrograde glandular colonization. AU - Haffner,Michael C, AU - Weier,Christopher, AU - Xu,Meng Meng, AU - Vaghasia,Ajay, AU - Gürel,Bora, AU - Gümüşkaya,Berrak, AU - Esopi,David M, AU - Fedor,Helen, AU - Tan,Hsueh-Li, AU - Kulac,Ibrahim, AU - Hicks,Jessica, AU - Isaacs,William B, AU - Lotan,Tamara L, AU - Nelson,William G, AU - Yegnasubramanian,Srinivasan, AU - De Marzo,Angelo M, Y1 - 2015/10/14/ PY - 2015/03/24/received PY - 2015/07/28/revised PY - 2015/08/10/accepted PY - 2015/9/3/entrez PY - 2015/9/4/pubmed PY - 2016/5/24/medline KW - ERG KW - PTEN KW - clonality KW - ductal spreading KW - prostate cancer KW - prostatic intraepithelial neoplasia SP - 31 EP - 41 JF - The Journal of pathology JO - J Pathol VL - 238 IS - 1 N2 - 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. SN - 1096-9896 UR - https://www.unboundmedicine.com/medline/citation/26331372/Molecular_evidence_that_invasive_adenocarcinoma_can_mimic_prostatic_intraepithelial_neoplasia__PIN__and_intraductal_carcinoma_through_retrograde_glandular_colonization_ DB - PRIME DP - Unbound Medicine ER -