Molecular evidence that invasive adenocarcinoma can mimic prostatic intraepithelial neoplasia (PIN) and intraductal carcinoma through retrograde glandular colonization.
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.
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA.
Michael C
MC
Haffner
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA.
Christopher
C
Weier
Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, USA.
Meng Meng
MM
Xu
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA.
Ajay
A
Vaghasia
Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA.
Bora
B
Gürel
Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA.
Berrak
B
Gümüşkaya
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA.
David M
DM
Esopi
Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA.
Helen
H
Fedor
Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA.
Hsueh-Li
HL
Tan
Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA.
Ibrahim
I
Kulac
Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA.
Jessica
J
Hicks
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA.|Brady Urological Institute, Johns Hopkins University, Baltimore, Maryland, USA.
William B
WB
Isaacs
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA.|Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA.
Tamara L
TL
Lotan
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.
William G
WG
Nelson
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA.
Srinivasan
S
Yegnasubramanian
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.
Angelo M
AM
De Marzo
D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology*; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D003937:Diagnosis, Differential; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D009361:Neoplasm Invasiveness; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000235:genetics; D019048:Prostatic Intraepithelial Neoplasia / Q000235:genetics / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology*; D015534:Trans-Activators / Q000235:genetics; D000071230:Transcriptional Regulator ERG
C072312:ERG protein, human; D015514:Oncogene Proteins, Fusion; C515553:TMPRSS2-ERG fusion protein, human; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
ERG; PTEN; clonality; ductal spreading; prostate cancer; prostatic intraepithelial neoplasia