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.

中文翻译：

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高级别浆液性癌前驱病变的形态和分子异质性。

浆液性输卵管上皮内癌（STIC）是大多数盆腔高级别浆液性癌（HGSC）病例的输卵管前驱病变。迄今为止，STIC 和不太典型的假定前体病变（称为浆液性输卵管上皮内病变）的形态、分子和临床异质性尚未得到很好的表征。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中发现的偶发性 STIC（无并发癌）女性的临床管理。本研究分析了 171 个 STIC 和 21 个浆液性输卵管上皮内病变的形态和分子特征。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 拷贝数变化。我们将所有前驱病变分为 2 种形态亚型，一种具有平坦表面 (Flat)，另一种以出芽、松散粘附或分离 (BLAD) 形态为特征。根据 8 名妇科病理学家小组的病理检查，我们发现 87 个 BLAD、96 个扁平病变和 9 个不确定病变。与扁平病变相比，BLAD 病变更常诊断为 STIC（P<0.0001），并且与 HGSC 同时发现（P<0.0001）。BLAD形态的特征还包括较高的Ki-67增殖指数（P<0.0001）、上皮分层的存在（P<0.0001）和淋巴细胞密度增加（P<0.0001）。BLAD 病变在 HGSC 典型的 CCNE1 或 CMYC 位点处也表现出更频繁的 DNA 拷贝数增加/扩增 (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。在 BLAD 和扁平病变之间没有观察到患者年龄、种系 BRCA1/2 突变的存在或 p53 染色模式之间的相关性。这些发现表明，输卵管前体病变在形态和分子上具有异质性，为进一步研究 HGSC 起始的发病机制和确定预测不良患者预后的组织学特征奠定了基础。