Department of Pathology, Centro Hospitalar São João, Porto, Portugal; Department of Pathology, Faculty of Medicine, University of Porto, Porto, Portugal; Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal; Institute for Research Innovation in Health (i3S), University of Porto, Porto, Portugal.
Department of General Surgery, Centro Hospitalar São João, Porto, Portugal; Department of General Surgery, Faculty of Medicine, University of Porto, Porto, Portugal; Department of General Surgery, High Risk Consultation of Digestive Tumors, Centro Hospitalar São João, Porto, Portugal.
Gastrointest Endosc. 2018 Jun;87(6):1566-1575. doi: 10.1016/j.gie.2018.02.008. Epub 2018 Feb 15.
The time course for the development of clinically significant hereditary diffuse gastric cancer (HDGC) is unpredictable. Little is known about the progression from preclinical, indolent lesions to widely invasive, aggressive phenotypes. Gastroendoscopy often fails to detect early lesions, and risk-reducing/prophylactic total gastrectomy (PTG) is the only curative approach. We present an HDGC family with early-onset disease in which clinical and histologic findings provided insight into the understanding of different HDGC phenotypes.
The proband was diagnosed at age 18 years with widely invasive, metastatic DGC. CDH1 genetic testing identified a pathogenic, germline CDH1 variant (c.1901C>T, p.Ala634Val). Thirty family members were tested, and 15 CDH1 carriers were identified.
Six family members had PTG, with negative preoperative workup. The proband's 14-year-old sister is the youngest patient, reported to date, to have PTG after negative preoperative biopsy sampling. Intramucosal HDGC foci were detected in all PTG specimens (1-33). In contrast to the "indolent" phenotype of these foci, the aggressive DGC from the proband showed pleomorphic cells, absent E-cadherin expression, increased proliferation (Ki-67 index), and activation of oncogenic events (p53, pSrc and pStat3 overexpression). All family members had Helicobacter pylori gastritis. Cag-A-positive strains were detected in all specimens, except in the proband's sister.
HDGC is a heterogeneous disease regarding clinical behavior, endoscopic findings, histopathologic features, and immunophenotypic/molecular profile. The presence of bizarre, pleomorphic cells in endoscopic biopsy specimens is suggestive of advanced disease and should prompt clinical intervention. The involvement of a full multidisciplinary team is essential for the management of these patients.
临床显著遗传性弥漫型胃癌（HDGC）的发展时间不可预测。人们对从临床前、惰性病变向广泛侵袭性、侵袭性表型进展知之甚少。胃肠内窥镜检查常常无法检测到早期病变，而降低风险/预防性全胃切除术（PTG）是唯一的治愈方法。我们报告了一个 HDGC 家族，其疾病具有早发性，临床和组织学发现为理解不同的 HDGC 表型提供了线索。
先证者 18 岁时被诊断为广泛侵袭性、转移性 DGC。CDH1 基因检测发现了一种致病性的、种系 CDH1 变体（c.1901C>T，p.Ala634Val）。对 30 名家庭成员进行了检测，发现了 15 名 CDH1 携带者。
6 名家庭成员接受了 PTG，术前检查均为阴性。先证者 14 岁的妹妹是迄今为止报告的接受 PTG 的最年轻患者，她的术前活检样本为阴性。所有 PTG 标本中均检测到黏膜内 HDGC 灶（1-33 个）。与这些病灶的“惰性”表型相反，先证者的侵袭性 DGC 表现出多形性细胞，E-钙黏蛋白表达缺失，增殖增加（Ki-67 指数），以及致癌事件的激活（p53、pSrc 和 pStat3 过表达）。所有家族成员均患有幽门螺杆菌胃炎。除先证者的妹妹外，所有标本均检测到 Cag-A 阳性株。
HDGC 在临床行为、内镜表现、组织病理学特征以及免疫表型/分子谱方面是一种异质性疾病。内镜活检标本中存在奇异的、多形性细胞提示疾病处于晚期，应促使临床干预。充分发挥多学科团队的作用对于这些患者的管理至关重要。
