LEF1 is preferentially expressed in the tubal-peritoneal junctions and is a reliable marker of tubal intraepithelial lesions

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Modern Pathology (2017) 30, 1241–1250

LEF1 is preferentially expressed in the tubal-peritoneal junctions and is a reliable marker of tubal intraepithelial lesions

Schmoeckel E¹, Odai-Afotey AA², Schleißheimer M¹, Rottmann M³, Flesken-Nikitin A², Ellenson LH⁴, Kirchner T¹, Mayr D¹, Nikitin AY².

1 Institute of Pathology, Ludwig Maximilians University, Munich, Germany. 2 Department of Biomedical Sciences and Cornell Stem Cell Program, Cornell University, Ithaca, NY, USA. 3 Institute of Medical Information Processing, Biometry und Epidemiology, Ludwig Maximilians University, Munich, Germany. 4 Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA.

Abstract: Recently it has been reported that serous tubal intraepithelial carcinoma (STIC), the likely precursor of ovarian/extra-uterine high-grade serous carcinoma, are frequently located in the vicinity of tubal-peritoneal junctions,consistent with the cancer-prone features of many epithelial transitional regions. To test if p53 (aka TP53)-signatures and secretory cell outgrowths (SCOUTs) also localize to tubal-peritoneal junctions, we examined these lesions in the fallopian tubes of patients undergoing salpingo-oophorectomy for sporadic high-grade serous carcinomas or as a prophylactic procedure for carriers of familial BRCA1 or 2 mutations. STICs were located closest to the tubal-peritoneal junctions with an average distance of 1.31 mm, while SCOUTs were not detected in the fimbriated end of the fallopian tube. As many epithelial transitional regions contain stem cells, we also determined the expression of stem cell markers in the normal fallopian tube, tubal intraepithelial lesions and high-grade serous carcinomas. Of those, LEF1 was consistently expressed in the tubal-peritoneal junctions and all lesions, independent of p53 status. All SCOUTs demonstrated strong nuclear expression of β-catenin consistent with the LEF1 participation in the canonical WNT pathway. However, β-catenin was preferentially located in the cytoplasm of cells comprising STICs and p53 signatures, suggesting WNT-independent function of LEF1 in those lesions. Both frequency of LEF1 expression and β-catenin nuclear expression correlated with the worst 5-year patient survival, supporting important role of both proteins in high-grade serous carcinoma. Taken together, our findings suggest the existence of stem cell niche within the tubal-peritoneal junctions. Furthermore, they support the notion that the pathogenesis of SCOUTs is distinct from that of STICs and p53 signatures. The location and discrete patterns of LEF1 and β-catenin expression may serve as highly sensitive and reliable ancillary markers for the detection and differential diagnosis of tubal intraepithelial lesions.

LEF1优先表达于输卵管-腹膜连接处，且是输卵管上皮内病变的可靠标记

摘要：输卵管浆液性上皮内癌（STIC）被认为可能是卵巢/子宫外高级别浆液性癌的癌前病变，有研究发现STIC经常位于输卵管 - 腹膜连接处附近，这与许多上皮移行区具有癌变倾向是一致的。针对因散发高级别浆液性癌行输卵管卵巢切除术或家族性BRCA1/2突变携带者预防性手术的患者，我们通过检查其输卵管的p53（又名TP53）印记和分泌细胞过生长（SCOUT）以验证这些病变是否也位于输卵管 - 腹膜连接处。 STIC最接近输卵管 - 腹膜连接处，平均距离为1.31 mm，而输卵管伞端未发现SCOUT。由于许多上皮移行区含有干细胞，因此我们测定了正常输卵管，输卵管上皮内病变和高级浆液性癌中干细胞标志物的表达。其中，LEF1在输卵管 - 腹膜连接处和所有病变中表达，与p53表达无关。所有SCOUTs的β-catenin染色核强阳性表达，并且β-catenin与LEF1参与经典WNT途径。然而，STIC和p53印记中，β-catenin往往呈胞浆阳性，表明这些病变中LEF1发挥非WNT依赖的作用。LEF1表达和β-catenin核表达的阳性率都与患者5年生存率相关，说明两种蛋白在高级浆液性癌中发挥重要的作用。总而言之，我们的研究结果表明在输卵管-腹膜连接处存在干细胞。此外，这些结果支持SCOUTs的发病机制与STICs和p53印记不同的理论。 LEF1和β-catenin表达的位置和方式可作为输卵管上皮内病变检测和鉴别诊断的高灵敏度和可靠的辅助标记。（翻译 宋征）