Haffner Michael C, Weier Christopher, Xu Meng Meng, Vaghasia Ajay, Gürel Bora, Gümüşkaya Berrak, Esopi David M, Fedor Helen, Tan Hsueh-Li, Kulac Ibrahim, Hicks Jessica, Isaacs William B, Lotan Tamara L, Nelson William G, Yegnasubramanian Srinivasan, De Marzo Angelo M
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.
J Pathol. 2016 Jan;238(1):31-41. doi: 10.1002/path.4628. Epub 2015 Oct 14.
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.
前列腺癌通常表现为形态上不同的肿瘤病灶，且经常在诸如高级别前列腺上皮内瘤变（HGPIN）等假定的前驱性病变附近被发现。虽然有一些证据表明这些病变可能有关联，并存在于病理和形态学的连续统一体中，但单个肿瘤内前驱性病变与浸润性癌之间精确的克隆和时间关系仍不明确。在此，我们使用分子遗传学、细胞遗传学和组织学分析来描绘具有不同形态和分子特征的HGPIN与癌病灶之间的克隆、时间和空间关系。首先，在确认先前的发现，即与ERG阳性癌相关的大部分HGPIN病灶存在ERG重排和过表达的同时，我们发现此类HGPIN腺体的一个重要亚群仅表现出部分ERG阳性。这表明此类ERG阳性的HGPIN细胞要么迅速浸润形成腺癌，要么代表已以逆行方式部分浸润导管和腺泡空间的癌细胞。为了阐明这些可能性，我们使用ERG表达状态和TMPRSS2-ERG基因组断点作为克隆性的标志物，并使用PTEN缺失状态来追踪克隆相关病变的时间演变。我们证实形态上不同的HGPIN和附近的浸润性癌病灶是克隆相关的。此外，我们发现相当一部分ERG阳性、PTEN阴性的HGPIN和导管内癌（IDC-P）病灶很可能克隆起源于相邻的PTEN阴性腺癌，这表明此类PTEN阴性的HGPIN和IDC-P病灶源自附近的浸润性腺癌，而非导致其发生。这些数据表明浸润性腺癌可通过癌细胞对良性腺体的逆行定植在形态上模仿HGPIN。在浸润性腺癌附近的导管内癌也观察到了类似的克隆关系。这些发现代表了一种可能被低估的已有浸润性前列腺癌的指标，对前列腺癌的诊断和风险分层具有重要意义。
