Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA.
Department of Urology, Weill Cornell Medicine, New York, NY, USA.
J Pathol. 2019 Sep;249(1):79-89. doi: 10.1002/path.5283. Epub 2019 May 24.
Intraductal carcinoma of the prostate (IDC-P) most often appears associated with high-grade invasive prostate carcinoma (PCa), where it is believed to represent retrograde spread. However, IDC-P rarely occurs as an isolated finding at radical prostatectomy or with concurrent low-grade (Grade Group 1) invasive carcinoma. We hypothesized that isolated IDC-P (iIDC-P) in these unusual cases may represent a distinct in situ lesion and molecularly profiled 15 cases. iIDC-P was characterized by copy number alteration (CNA) profiling and targeted next generation sequencing in cases with sufficient tissue (n = 7). Immunohistochemistry for PTEN and ERG was performed on the total cohort (n = 15), where areas of iIDC-P and associated invasive disease were evaluated separately (n = 9). By copy number profiling, iIDC-P alterations were similar to those previously described in high-grade invasive PCa (PTEN, RB1, and CHD1 loss; MYC gain). However, in four cases, targeted sequencing revealed a striking number of activating oncogenic driver mutations in MAPK and PI3K pathway genes, which are extraordinarily rare in conventional PCa. In addition, pathogenic mutations in DNA repair genes were found in two cases of iIDC-P (BRCA2, CHEK2, CDK12) and other known PCa-associated mutations (FOXA1, SPOP) in two cases. Overall, ERG was expressed in 7% (1/15) of the iIDC-P lesions and PTEN was lost in 53% (8/15). Discordance for ERG or PTEN status between IDC-P and the low-grade PCa was observed in five of nine cases, with intact PTEN in the invasive tumor and PTEN loss in IDC-P in four. Despite a CNA profile similar to conventional PCa, iIDC-P is enriched with potentially targetable oncogenic driver mutations in MAPK/PI3K genes. Based on PTEN and ERG status, iIDC-P is not likely a precursor to the associated low-grade invasive PCa, but represents a molecularly unique in situ tumor of unclear clinical significance. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
前列腺导管内癌（IDC-P）通常与高级别浸润性前列腺癌（PCa）相关，被认为是逆行扩散的结果。然而，IDC-P 很少作为根治性前列腺切除术的孤立发现，也很少与同时存在的低级别（G1 级）浸润性癌共存。我们假设这些不常见病例中的孤立 IDC-P（iIDC-P）可能代表一种独特的原位病变，并对 15 例病例进行了分子特征分析。在有足够组织的情况下（n=7），对 iIDC-P 病例进行了拷贝数改变（CNA）分析和靶向二代测序。对整个队列（n=15）进行了 PTEN 和 ERG 的免疫组化检测，其中单独评估了 iIDC-P 和相关浸润性疾病的区域（n=9）。通过拷贝数谱分析，iIDC-P 的改变与先前描述的高级别浸润性 PCa 相似（PTEN、RB1 和 CHD1 缺失；MYC 获得）。然而，在 4 例中，靶向测序显示 MAPK 和 PI3K 通路基因中存在大量激活的致癌驱动突变，这在常规 PCa 中极为罕见。此外，在 2 例 iIDC-P 中发现了 DNA 修复基因的致病性突变（BRCA2、CHEK2、CDK12）和在 2 例中发现了其他已知的 PCa 相关突变（FOXA1、SPOP）。总的来说，在 15 例 iIDC-P 病变中有 7%（1/15）表达 ERG，53%（8/15）缺失 PTEN。在 9 例中有 5 例观察到 IDC-P 和低级别 PCa 的 ERG 或 PTEN 状态不一致，4 例中浸润性肿瘤中 PTEN 完整，而 IDC-P 中 PTEN 缺失。尽管 CNA 谱与常规 PCa 相似，但 iIDC-P 富含 MAPK/PI3K 基因中潜在的可靶向致癌驱动突变。根据 PTEN 和 ERG 状态，iIDC-P 不太可能是相关低级别浸润性 PCa 的前体，而是代表一种分子上独特的原位肿瘤，其临床意义尚不清楚。
