Indications for Total Gastrectomy and Outcomes of Minimally Invasive and Open Gastrectomies | Breast Cancer | JN Learning | AMA Ed Hub [Skip to Content]
[Skip to Content Landing]

Indications for Total Gastrectomy in CDH1 Mutation Carriers and Outcomes of Risk-Reducing Minimally Invasive and Open Gastrectomies

Educational Objective To identify the association between signet ring cell cancer and associated germline CDH1 variants in those who undergo total gastrectomy according to family history.
1 Credit CME
Key Points

Question  What is the likelihood of signet ring cell cancer in patients with a germline CDH1 variant who undergo total gastrectomy according to family history?

Findings  In this cohort study of 101 patients who underwent total gastrectomy, signet ring cell cancer was identified in the surgical specimens of 89% of patients with a family history of gastric cancer and 67% of patients lacking family history.

Meaning  Total gastrectomy may be warranted for patients with CDH1 variants and a family history of gastric cancer and may be appropriate for those without a family history.

Abstract

Importance  CDH1 variants are increasingly identified on commercially available multigene panel tests, calling for data to inform counseling of individuals without a family history of gastric cancer.

Objectives  To assess association between CDH1 variant pathogenicity or family history of gastric or lobular breast cancer and identification of signet ring cell cancer and to describe outcomes of risk-reducing minimally invasive and open total gastrectomy.

Design, Setting, and Participants  This cohort study was performed from January 1, 2006, to January 1, 2020, in 181 patients with CDH1 germline variants from a single institution.

Interventions  Genetic counseling, esophagogastroduodenoscopy, and possible total gastrectomy.

Main Outcomes and Measures  CDH1 variant classification, family cancer history, findings of signet ring cell carcinoma at esophagogastroduodenoscopy and surgery, postoperative events and weight changes, and follow-up.

Results  Of 181 individuals with CDH1 germline variants (mean [SD] age at time of testing, 44 [15] years; 126 [70%] female), 165 harbored a pathogenic or likely pathogenic variant. Of these patients, 101 underwent open (n = 58) or minimally invasive (n = 43) total gastrectomy. Anastomotic leaks that required drainage were infrequent (n = 3), and median long-term weight loss was 20% (interquartile range [IQR], 10%-23%). In those undergoing minimally invasive operations, more lymph nodes were retrieved (median, 28 [IQR, 20-34] vs 15 [IQR, 9-19]; P < .001) and the hospital stay was 1 day shorter (median, 6 [IQR, 5-7] vs 7 [IQR, 6-7] days; P = .04). Signet ring cell cancer was identified in the surgical specimens of 85 of 95 patients (89%) with a family history of gastric cancer and 4 of 6 patients (67%) who lacked a family history. Among the latter 6 patients, 4 had a personal or family history of lobular breast cancer, including 2 with signet ring cell cancer. Of the 16 patients with pathogenic or likely pathogenic CDH1 variants who presented with locally advanced or metastatic gastric cancer, 3 (19%) had no family history of gastric cancer or personal or family history of lobular breast cancer.

Conclusions and Relevance  Total gastrectomy may be warranted for patients with pathogenic or likely pathogenic CDH1 variants and a family history of gastric or lobular breast cancer and may be appropriate for those without a family history. A minimally invasive approach is feasible and may be preferred for selected patients.

Sign in to take quiz and track your certificates

Buy This Activity

JN Learning™ is the home for CME and MOC from the JAMA Network. Search by specialty or US state and earn AMA PRA Category 1 CME Credit™ from articles, audio, Clinical Challenges and more. Learn more about CME/MOC

CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.

Article Information

Accepted for Publication: May 23, 2020.

Corresponding Authors: Vivian E. Strong, MD, Gastric and Mixed Tumor Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065 (strongv@mskcc.org); Zsofia K. Stadler, MD, Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, 122 E 70th St, New York, NY 10065 (stadlerz@mskcc.org).

Published Online: September 30, 2020. doi:10.1001/jamasurg.2020.3356

Author Contributions: Drs Stadler and Strong contributed equally to this work. Dr Strong had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Vos, Salo-Mullen, Tang, Janjigian, Stadler, Strong.

Acquisition, analysis, or interpretation of data: Vos, Salo-Mullen, Tang, Schattner, Yoon, Gerdes, Markowitz, Mandelker, Offitt, Coit, Stadler, Strong.

Drafting of the manuscript: Vos, Salo-Mullen, Offitt, Stadler.

Critical revision of the manuscript for important intellectual content: Salo-Mullen, Tang, Schattner, Yoon, Gerdes, Markowitz, Mandelker, Janjigian, Coit, Stadler, Strong.

Statistical analysis: Vos.

Administrative, technical, or material support: Salo-Mullen, Gerdes, Mandelker, Janjigian, Offitt, Coit, Strong.

Supervision: Tang, Schattner, Yoon, Offitt, Coit, Stadler, Strong.

Conflict of Interest Disclosures: Dr Yoon reported partial ownership of Attis Lab outside the submitted work. Dr Janjigian reported receiving personal fees from Eli Lilly, Michael J. Hennessy Associates, Zymeworks Inc, Jounce Therapeutics, Seattle Genetics, Rgenix, AstraZeneca, Daiichi Sankyo, ONO Pharma, Merck & Co Inc, Bristol Myers Squibb, Pfizer, Bayer, and Imugene and receiving research funding from Boehringer Ingelheim, Eli Lilly, Merck & Co Inc, Bristol Myers Squibb, Bayer, and Genentech/Roche outside the submitted work. Dr Stadler reported spouse’s consulting for Genentech/Roche, RegenexBio, Optos, Adverum, Allergan, Regeneron, BioMarin, and Spark Therapeutics outside the submitted work. No other disclosures were reported.

Funding/Support: This study was supported in part by Cancer Center Support Grant P30 CA008748 from the National Institutes of Health/National Cancer Institute.

Role of the Funder/Sponsor: The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: Jessica Moore, MS, Memorial Sloan Kettering Cancer Center, edited the manuscript. She was compensated through her regular salary. Murray F. Brennan, MD, provided critical review to the manuscript. He was not compensated for his work.

References
1.
Guilford  P , Hopkins  J , Harraway  J ,  et al.  E-cadherin germline mutations in familial gastric cancer.   Nature. 1998;392(6674):402-405. doi:10.1038/32918 PubMedGoogle ScholarCrossref
2.
Guilford  PJ , Hopkins  JB , Grady  WM ,  et al.  E-cadherin germline mutations define an inherited cancer syndrome dominated by diffuse gastric cancer.   Hum Mutat. 1999;14(3):249-255. doi:10.1002/(SICI)1098-1004(1999)14:3<249::AID-HUMU8>3.0.CO;2-9 PubMedGoogle ScholarCrossref
3.
Cavallaro  U , Christofori  G .  Cell adhesion and signalling by cadherins and Ig-CAMs in cancer.   Nat Rev Cancer. 2004;4(2):118-132. doi:10.1038/nrc1276 PubMedGoogle ScholarCrossref
4.
Hansford  S , Kaurah  P , Li-Chang  H ,  et al.  Hereditary diffuse gastric cancer syndrome: CDH1 mutations and beyond.   JAMA Oncol. 2015;1(1):23-32. doi:10.1001/jamaoncol.2014.168 PubMedGoogle ScholarCrossref
5.
Hebbard  PC , Macmillan  A , Huntsman  D ,  et al.  Prophylactic total gastrectomy (PTG) for hereditary diffuse gastric cancer (HDGC): the Newfoundland experience with 23 patients.   Ann Surg Oncol. 2009;16(7):1890-1895. doi:10.1245/s10434-009-0471-z PubMedGoogle ScholarCrossref
6.
Chen  Y , Kingham  K , Ford  JM ,  et al.  A prospective study of total gastrectomy for CDH1-positive hereditary diffuse gastric cancer.   Ann Surg Oncol. 2011;18(9):2594-2598. doi:10.1245/s10434-011-1648-9 PubMedGoogle ScholarCrossref
7.
Pandalai  PK , Lauwers  GY , Chung  DC , Patel  D , Yoon  SS .  Prophylactic total gastrectomy for individuals with germline CDH1 mutation.   Surgery. 2011;149(3):347-355. doi:10.1016/j.surg.2010.07.005 PubMedGoogle ScholarCrossref
8.
Shaw  D , Blair  V , Framp  A ,  et al.  Chromoendoscopic surveillance in hereditary diffuse gastric cancer: an alternative to prophylactic gastrectomy?   Gut. 2005;54(4):461-468. doi:10.1136/gut.2004.049171 PubMedGoogle ScholarCrossref
9.
Norton  JA , Ham  CM , Van Dam  J ,  et al.  CDH1 truncating mutations in the E-cadherin gene: an indication for total gastrectomy to treat hereditary diffuse gastric cancer.   Ann Surg. 2007;245(6):873-879. doi:10.1097/01.sla.0000254370.29893.e4 PubMedGoogle ScholarCrossref
10.
Barber  ME , Save  V , Carneiro  F ,  et al.  Histopathological and molecular analysis of gastrectomy specimens from hereditary diffuse gastric cancer patients has implications for endoscopic surveillance of individuals at risk.   J Pathol. 2008;216(3):286-294. doi:10.1002/path.2415 PubMedGoogle ScholarCrossref
11.
Hüneburg  R , Marwitz  T , van Heteren  P ,  et al.  Chromoendoscopy in combination with random biopsies does not improve detection of gastric cancer foci in CDH1 mutation positive patients.   Endosc Int Open. 2016;4(12):E1305-E1310. doi:10.1055/s-0042-112582 PubMedGoogle ScholarCrossref
12.
Jacobs  MF , Dust  H , Koeppe  E ,  et al.  Outcomes of endoscopic surveillance in individuals with genetic predisposition to hereditary diffuse gastric cancer.   Gastroenterology. 2019;157(1):87-96. doi:10.1053/j.gastro.2019.03.047 PubMedGoogle ScholarCrossref
13.
Carneiro  F , Huntsman  DG , Smyrk  TC ,  et al.  Model of the early development of diffuse gastric cancer in E-cadherin mutation carriers and its implications for patient screening.   J Pathol. 2004;203(2):681-687. doi:10.1002/path.1564 PubMedGoogle ScholarCrossref
14.
Charlton  A , Blair  V , Shaw  D , Parry  S , Guilford  P , Martin  IG .  Hereditary diffuse gastric cancer: predominance of multiple foci of signet ring cell carcinoma in distal stomach and transitional zone.   Gut. 2004;53(6):814-820. doi:10.1136/gut.2002.010447 PubMedGoogle ScholarCrossref
15.
Lynch  HT , Kaurah  P , Wirtzfeld  D ,  et al.  Hereditary diffuse gastric cancer: diagnosis, genetic counseling, and prophylactic total gastrectomy.   Cancer. 2008;112(12):2655-2663. doi:10.1002/cncr.23501 PubMedGoogle ScholarCrossref
16.
Strong  VE , Gholami  S , Shah  MA ,  et al.  Total gastrectomy for hereditary diffuse gastric cancer at a single center: postsurgical outcomes in 41 patients.   Ann Surg. 2017;266(6):1006-1012. doi:10.1097/SLA.0000000000002030 PubMedGoogle ScholarCrossref
17.
van der Post  RS , Vogelaar  IP , Carneiro  F ,  et al.  Hereditary diffuse gastric cancer: updated clinical guidelines with an emphasis on germline CDH1 mutation carriers.   J Med Genet. 2015;52(6):361-374. doi:10.1136/jmedgenet-2015-103094 PubMedGoogle ScholarCrossref
18.
Lee  K , Krempely  K , Roberts  ME ,  et al.  Specifications of the ACMG/AMP variant curation guidelines for the analysis of germline CDH1 sequence variants.   Hum Mutat. 2018;39(11):1553-1568. doi:10.1002/humu.23650 PubMedGoogle ScholarCrossref
19.
Rogers  WM , Dobo  E , Norton  JA ,  et al.  Risk-reducing total gastrectomy for germline mutations in E-cadherin (CDH1): pathologic findings with clinical implications.   Am J Surg Pathol. 2008;32(6):799-809. doi:10.1097/PAS.0b013e31815e7f1a PubMedGoogle ScholarCrossref
20.
Dindo  D , Demartines  N , Clavien  PA .  Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey.   Ann Surg. 2004;240(2):205-213. doi:10.1097/01.sla.0000133083.54934.ae PubMedGoogle ScholarCrossref
21.
van der Post  RS , Carneiro  F .  Emerging concepts in gastric neoplasia: heritable gastric cancers and polyposis disorders.   Surg Pathol Clin. 2017;10(4):931-945. doi:10.1016/j.path.2017.07.011 PubMedGoogle ScholarCrossref
22.
Roberts  ME , Ranola  JMO , Marshall  ML ,  et al.  Comparison of CDH1 penetrance estimates in clinically ascertained families vs families ascertained for multiple gastric cancers.   JAMA Oncol. 2019;5(9):1325-1331. doi:10.1001/jamaoncol.2019.1208 PubMedGoogle ScholarCrossref
If you are not a JN Learning subscriber, you can either:
Subscribe to JN Learning for one year
Buy this activity
jn-learning_Modal_Multimedia_LoginSubscribe_Purchase
Close
If you are not a JN Learning subscriber, you can either:
Subscribe to JN Learning for one year
Buy this activity
jn-learning_Modal_Multimedia_LoginSubscribe_Purchase
Close
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right
Close

Name Your Search

Save Search
Close
With a personal account, you can:
  • Track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
jn-learning_Modal_SaveSearch_NoAccess_Purchase
Close

Lookup An Activity

or

Close

My Saved Searches

You currently have no searches saved.

Close

My Saved Courses

You currently have no courses saved.

Close
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right
Close