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Surgical management of hereditary diffuse gastric cancer

Pamela Hebbard, MD, FRCS
Section Editor
David I Soybel, MD
Deputy Editor
Wenliang Chen, MD, PhD


Diffuse gastric carcinoma (DGC) is a highly invasive tumor that is characterized by a late presentation and poor prognosis. Diffuse gastric cancer represents approximately 5 percent of all invasive gastric cancers. An inherited form of DGC, hereditary diffuse gastric cancer (HDGC) can be caused by mutations in the E-cadherin (CDH1) gene [1-3] or the alpha-E-catenin (CTNNA1) gene [4].

Since the lifetime risk of developing gastric cancer for CDH1 mutation carriers from HDGC families is very high (70 percent for men and 56 percent for women), prophylactic total gastrectomy is often recommended for them at an early age [5-10].

The surgical management of HDGC will be reviewed here. The genetics and pathogenesis of HDGC, as well as issues related to screening for HDGC and surveillance for breast and other cancers in CDH1 mutation carriers, are discussed separately. (See "Hereditary diffuse gastric cancer" and "Pathology and molecular pathogenesis of gastric cancer", section on 'Diffuse type cancers'.)


For patients from a hereditary diffuse gastric cancer (HDGC) family who have tested positive for a pathogenic germline CDH1 mutation, we recommend a prophylactic total gastrectomy to reduce the risk of developing invasive gastric cancer. For patients with a CDH1 mutation but who are not from an HDGC family, we recommend individualized evaluation at an experienced center before prophylactic total gastrectomy is offered.

CDH1 mutation carriers from HDGC families — Asymptomatic patients with a family history of HDGC and CDH1 mutations have a high probability of developing signet ring cell adenocarcinoma of the stomach that cannot be diagnosed on endoscopy. When symptoms arise, the diagnosis can be made by endoscopy, but such patients may already have metastases and decreased survival. Thus, surveillance endoscopy is of limited value, and prophylactic total gastrectomy is recommended for patients with family history of HDGC and CDH1 mutations [11].

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Literature review current through: Nov 2017. | This topic last updated: Nov 13, 2017.
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  1. Guilford P, Hopkins J, Harraway J, et al. E-cadherin germline mutations in familial gastric cancer. Nature 1998; 392:402.
  2. Gayther SA, Gorringe KL, Ramus SJ, et al. Identification of germ-line E-cadherin mutations in gastric cancer families of European origin. Cancer Res 1998; 58:4086.
  3. Grady WM, Willis J, Guilford PJ, et al. Methylation of the CDH1 promoter as the second genetic hit in hereditary diffuse gastric cancer. Nat Genet 2000; 26:16.
  4. Majewski IJ, Kluijt I, Cats A, et al. An α-E-catenin (CTNNA1) mutation in hereditary diffuse gastric cancer. J Pathol 2013; 229:621.
  5. Huntsman DG, Carneiro F, Lewis FR, et al. Early gastric cancer in young, asymptomatic carriers of germ-line E-cadherin mutations. N Engl J Med 2001; 344:1904.
  6. Caldas C, Carneiro F, Lynch HT, et al. Familial gastric cancer: overview and guidelines for management. J Med Genet 1999; 36:873.
  7. 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; 32:799.
  8. 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; 16:1890.
  9. Lynch HT, Kaurah P, Wirtzfeld D, et al. Hereditary diffuse gastric cancer: diagnosis, genetic counseling, and prophylactic total gastrectomy. Cancer 2008; 112:2655.
  10. Pinheiro H, Oliveira C, Seruca R, Carneiro F. Hereditary diffuse gastric cancer - pathophysiology and clinical management. Best Pract Res Clin Gastroenterol 2014; 28:1055.
  11. 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; 18:2594.
  12. 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; 52:361.
  13. Koea JB, Karpeh MS, Brennan MF. Gastric cancer in young patients: demographic, clinicopathological, and prognostic factors in 92 patients. Ann Surg Oncol 2000; 7:346.
  14. Stiekema J, Cats A, Kuijpers A, et al. Surgical treatment results of intestinal and diffuse type gastric cancer. Implications for a differentiated therapeutic approach? Eur J Surg Oncol 2013; 39:686.
  15. LaDuca H, Stuenkel AJ, Dolinsky JS, et al. Utilization of multigene panels in hereditary cancer predisposition testing: analysis of more than 2,000 patients. Genet Med 2014; 16:830.
  16. Kurian AW, Hare EE, Mills MA, et al. Clinical evaluation of a multiple-gene sequencing panel for hereditary cancer risk assessment. J Clin Oncol 2014; 32:2001.
  17. Johnston JJ, Rubinstein WS, Facio FM, et al. Secondary variants in individuals undergoing exome sequencing: screening of 572 individuals identifies high-penetrance mutations in cancer-susceptibility genes. Am J Hum Genet 2012; 91:97.
  18. Kaurah P, MacMillan A, Boyd N, et al. Founder and recurrent CDH1 mutations in families with hereditary diffuse gastric cancer. JAMA 2007; 297:2360.
  19. Pharoah PD, Guilford P, Caldas C, International Gastric Cancer Linkage Consortium. Incidence of gastric cancer and breast cancer in CDH1 (E-cadherin) mutation carriers from hereditary diffuse gastric cancer families. Gastroenterology 2001; 121:1348.
  20. Cisco RM, Ford JM, Norton JA. Hereditary diffuse gastric cancer: implications of genetic testing for screening and prophylactic surgery. Cancer 2008; 113:1850.
  21. Blair V, Martin I, Shaw D, et al. Hereditary diffuse gastric cancer: diagnosis and management. Clin Gastroenterol Hepatol 2006; 4:262.
  22. Lewis FR, Mellinger JD, Hayashi A, et al. Prophylactic total gastrectomy for familial gastric cancer. Surgery 2001; 130:612.
  23. Liedman B, Andersson H, Bosaeus I, et al. Changes in body composition after gastrectomy: results of a controlled, prospective clinical trial. World J Surg 1997; 21:416.
  24. Kaurah P, Fitzgerald R, Dwerryhouse S, Huntsman DG. Pregnancy after prophylactic total gastrectomy. Fam Cancer 2010; 9:331.
  26. PISANI BJ. Term gestation following total gastrectomy. J Am Geriatr Soc 1958; 6:99.
  27. Adams JF. The clinical and metabolic consequences of total gastrectomy. 3. Notes on metabolic functions, deficiency states, changes in intestinal histology, and radiology. Scand J Gastroenterol 1968; 3:152.
  28. Eagon JC, Miedema BW, Kelly KA. Postgastrectomy syndromes. Surg Clin North Am 1992; 72:445.
  29. Lynch HT, Silva E, Wirtzfeld D, et al. Hereditary diffuse gastric cancer: prophylactic surgical oncology implications. Surg Clin North Am 2008; 88:759.
  30. Kadowaki S, Tanaka K, Toyoda H, et al. Ease of early gastric cancer demarcation recognition: a comparison of four magnifying endoscopy methods. J Gastroenterol Hepatol 2009; 24:1625.
  31. Fitzgerald RC, Hardwick R, Huntsman D, et al. Hereditary diffuse gastric cancer: updated consensus guidelines for clinical management and directions for future research. J Med Genet 2010; 47:436.
  32. Kluijt I, Siemerink EJ, Ausems MG, et al. CDH1-related hereditary diffuse gastric cancer syndrome: clinical variations and implications for counseling. Int J Cancer 2012; 131:367.
  33. Li J, McBean E, Li X, et al. Laparoscopic prophylactic total gastrectomy with linear stapler side-to-side esophagojejunal anastomosis for hereditary diffuse gastric cancer syndrome in 2 siblings. Surg Laparosc Endosc Percutan Tech 2013; 23:e124.
  34. Roviello F, Rossi S, Marrelli D, et al. Number of lymph node metastases and its prognostic significance in early gastric cancer: a multicenter Italian study. J Surg Oncol 2006; 94:275.
  35. Lehnert T, Buhl K. Techniques of reconstruction after total gastrectomy for cancer. Br J Surg 2004; 91:528.
  36. Gertler R, Rosenberg R, Feith M, et al. Pouch vs. no pouch following total gastrectomy: meta-analysis and systematic review. Am J Gastroenterol 2009; 104:2838.
  37. Fein M, Fuchs KH, Thalheimer A, et al. Long-term benefits of Roux-en-Y pouch reconstruction after total gastrectomy: a randomized trial. Ann Surg 2008; 247:759.
  38. Newman EA, Mulholland MW. Prophylactic gastrectomy for hereditary diffuse gastric cancer syndrome. J Am Coll Surg 2006; 202:612.
  39. Hallowell N, Lawton J, Badger S, et al. The Psychosocial Impact of Undergoing Prophylactic Total Gastrectomy (PTG) to Manage the Risk of Hereditary Diffuse Gastric Cancer (HDGC). J Genet Couns 2017; 26:752.
  40. 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; 266:1006.
  41. Muir J, Aronson M, Esplen MJ, et al. Prophylactic Total Gastrectomy: a Prospective Cohort Study of Long-Term Impact on Quality of Life. J Gastrointest Surg 2016; 20:1950.
  42. Huntsman, D, University of British Columbia, 2008, personal communication.
  43. Worster E, Liu X, Richardson S, et al. The impact of prophylactic total gastrectomy on health-related quality of life: a prospective cohort study. Ann Surg 2014; 260:87.
  44. Lim YC, di Pietro M, O'Donovan M, et al. Prospective cohort study assessing outcomes of patients from families fulfilling criteria for hereditary diffuse gastric cancer undergoing endoscopic surveillance. Gastrointest Endosc 2014; 80:78.
  45. Fujita H, Lennerz JK, Chung DC, et al. Endoscopic surveillance of patients with hereditary diffuse gastric cancer: biopsy recommendations after topographic distribution of cancer foci in a series of 10 CDH1-mutated gastrectomies. Am J Surg Pathol 2012; 36:1709.