The various faces of hereditary diffuse gastric cancer

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The various faces of hereditary diffuse gastric cancer

Tuesday, 02.10.2018

Authors and affiliations:

Irene Gullo1,2,3,4, Vitor Devezas5,6,7, Manuela Baptista5,6,7, Luzia Garrido8, Sérgio Castedo3,4,8,9,10, Rui Morais11,  Xiaogang Wen3,4,12, Elisabete Rios1,2,3,4, Jorge Pinheiro1,2, Inês Pinto-Ribeiro3,4, Rui M Ferreira3,4, Jonh Preto5, João Santos-Antunes11, Margarida Marques11, Miquel Campos13, Filipe Almeida14, Maria do Céu Espinheira15, Jorge Amil Dias15, Céu Figueiredo2,3,4, Carla Oliveira2,3,4, Eunice Trindade15, Fátima Carneiro1,2,3,4


1Department of Pathology, Centro Hospitalar São João (CHSJ), Porto, Portugal

2Department of Pathology, Faculty of Medicine of the University of Porto (FMUP), Porto, Portugal

3Institute of Molecular Pathology and Immunology at the University of Porto (Ipatimup), Porto, Portugal

4Institute for Research Innovation in Health (i3S), University of Porto, Porto, Portugal

5Department of General Surgery, CHSJ, Porto, Portugal

6Department of General Surgery, FMUP, Porto, Portugal

7Department of General Surgery, High Risk Consultation of Digestive Tumors, CHSJ, Porto, Portugal

8Department of Gastroenterology, CHSJ, Porto, Portugal

9Oncogenetic Consultation, Breast Center, CHSJ, Porto, Portugal

10Department of Genetics, CHSJ, Porto, Portugal

11Department of Genetics, FMUP, Porto, Portugal

12Department of Pathology, Centro Hospitalar Vila Nova de Gaia, Vila Nova de Gaia, Portugal

13Department of Pediatrics, Division of Pediatric Surgery, CHSJ, Porto, Portugal

14Department of Ethics Committee, CHSJ, Porto, Portugal

15Department of Pediatrics, Pediatric Gastroenterology Unit, CHSJ, Porto, Portugal



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 earlyonset 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.


Journal: Gastrointestinal Endoscopy, Volume 87, Issue 6, June 2018, Pages 1566-1575