Background and Aims

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.

Methods

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.

Results

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.

Conclusions

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.

中文翻译：

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遗传性弥漫性胃癌的表型异质性：一个家庭早期发病的报告

背景和目标

发生具有临床意义的遗传性弥漫性胃癌（HDGC）的时间过程是无法预测的。从临床前惰性病变到广泛侵入性，侵袭性表型的进展知之甚少。胃内镜检查常常无法发现早期病变，降低风险/预防性全胃切除术（PTG）是唯一的治疗方法。我们介绍了一个HDGC家族，具有早期发作的疾病，其中的临床和组织学发现为了解不同的HDGC表型提供了见识。

方法

该先证者在18岁时被诊断为广泛侵入性转移性DGC。CDH1基因检测鉴定出一种致病的种系CDH1变体（c.1901C> T，p.Ala634Val）。测试了30个家庭成员，并确定了15个CDH1携带者。

结果

六名家庭成员患有PTG，术前检查阴性。先证者的14岁姐姐是迄今报道的最小的术前活检样本阴性的PTG患者。在所有PTG标本中都检测到了粘膜内HDGC病灶（1-33）。与这些病灶的“惰性”表型相反，先证者的侵略性DGC显示多形细胞，E-钙粘蛋白表达缺失，增殖（Ki-67指数）增加和致癌事件的激活（p53，pSrc和pStat3过表达） 。所有家庭成员均患有幽门螺杆菌胃炎。在所有标本中均检测到了Cag-A阳性菌株，但先证者的姐妹除外。

结论

HDGC是一种异质性疾病，涉及临床行为，内窥镜检查结果，组织病理学特征和免疫表型/分子特征。内窥镜活检标本中存在奇异的多形性细胞提示晚期疾病，应及时进行临床干预。一个完整的多学科团队的参与对这些患者的治疗至关重要。