Departments of Gynecology and Obstetrics.
Department of Oncology, Division of Quantitative Science, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine.
Am J Surg Pathol. 2024 Apr 1;48(4):475-486. doi: 10.1097/PAS.0000000000002187. Epub 2024 Feb 1.
Serous tubal intraepithelial carcinoma (STIC) is the fallopian tube precursor lesion for most cases of pelvic high-grade serous carcinoma (HGSC). To date, the morphologic, molecular, and clinical heterogeneity of STIC and a less atypical putative precursor lesion, termed serous tubal intraepithelial lesion, has not been well characterized. Better understanding of precursor heterogeneity could impact the clinical management of women with incidental STICs (without concurrent carcinoma) identified in cases of prophylactic or opportunistic salpingectomy. This study analyzed morphologic and molecular features of 171 STICs and 21 serous tubal intraepithelial lesions. We assessed their histologic features, Ki-67 and p53 staining patterns, and genome-wide DNA copy number alterations. We classified all precursor lesions into 2 morphologic subtypes, one with a flat surface (Flat) and the other characterized by budding, loosely adherent, or detached (BLAD) morphology. On the basis of pathology review by a panel of 8 gynecologic pathologists, we found 87 BLAD, 96 Flat, and 9 indeterminate lesions. As compared with Flat lesions, BLAD lesions were more frequently diagnostic of STIC ( P <0.0001) and were found concurrently with HGSC ( P <0.0001). BLAD morphology was also characterized by higher Ki-67 proliferation index ( P <0.0001), presence of epithelial stratification ( P <0.0001), and increased lymphocyte density ( P <0.0001). BLAD lesions also exhibited more frequent DNA copy number gain/amplification at the CCNE1 or CMYC loci canonical to HGSCs ( P <0.0001). Both BLAD morphology and STIC diagnoses are independent risk factors for an elevated Ki-67 proliferation index. No correlation was observed between BLAD and Flat lesions with respect to patient age, presence of germline BRCA1/2 mutation, or p53 staining pattern. These findings suggest that tubal precursor lesions are morphologically and molecularly heterogeneous, laying the foundation for further studies on the pathogenesis of HGSC initiation and identifying histologic features predictive of poor patient outcomes.
输卵管上皮内浆液性癌（STIC）是大多数盆腔高级别浆液性癌（HGSC）的输卵管前体病变。迄今为止，STIC 的形态学、分子学和临床异质性，以及一种不太典型的假定前体病变，即输卵管上皮内病变，尚未得到很好的描述。更好地了解前体异质性可能会影响在预防性或机会性输卵管切除术病例中偶然发现的无伴发癌的 STIC 患者的临床管理。本研究分析了 171 例 STIC 和 21 例输卵管上皮内病变的形态学和分子特征。我们评估了它们的组织学特征、Ki-67 和 p53 染色模式以及全基因组 DNA 拷贝数改变。我们将所有前体病变分为 2 种形态亚型，一种具有平坦表面（Flat），另一种表现为出芽、松散附着或脱落（BLAD）形态。根据 8 位妇科病理学家小组的病理复查，我们发现 87 例 BLAD、96 例 Flat 和 9 例不确定病变。与 Flat 病变相比，BLAD 病变更常被诊断为 STIC（P<0.0001），且常与 HGSC 同时存在（P<0.0001）。BLAD 形态还具有更高的 Ki-67 增殖指数（P<0.0001）、上皮分层（P<0.0001）和淋巴细胞密度增加（P<0.0001）。BLAD 病变还表现出更多的 CCNE1 或 CMYC 基因座的 DNA 拷贝数增益/扩增，这是 HGSCs 的特征（P<0.0001）。BLAD 形态和 STIC 诊断都是 Ki-67 增殖指数升高的独立危险因素。BLAD 和 Flat 病变在患者年龄、是否存在种系 BRCA1/2 突变或 p53 染色模式方面无相关性。这些发现表明输卵管前体病变在形态学和分子学上是异质的，为进一步研究 HGSC 起始的发病机制以及确定预测患者预后不良的组织学特征奠定了基础。
