Review
Hereditary Diffuse Gastric Cancer: Diagnosis and Management

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Hereditary diffuse gastric cancer (HDGC) is a familial cancer syndrome defined by germline mutation of the E-cadherin gene (CDH-1). The cumulative risk for advanced gastric cancer in HDGC is 67% in men and 83% in women by 80 years of age. Early HDGC is characterized by multiple microscopic foci of intramucosal signet-ring cell carcinoma. The time to progression of these foci appears to be variable and currently is not predictable—the carcinoma foci may remain confined to the mucosa for many years. The management options for mutation carriers include prophylactic gastrectomy or surveillance gastroscopy. The only extensive published surveillance experience used chromogastroscopy, which detected early HDGC foci not visible on white-light endoscopy. The use of new techniques such as confocal microscopy, spectroscopy, or autofluorescence may prove useful, but have not been studied in HDGC. In patients up to 20 years of age, the risk for gastric cancer is less than 1%; this risk is outweighed by the mortality and morbidity associated with total gastrectomy. It is therefore recommended that genetic testing should occur at 16 years of age and that annual surveillance chromogastroscopy also should begin at age 16 in identified CDH-1 mutation carriers. After 20 years of age, delaying prophylactic gastrectomy carries significant risk, particularly if the alternative is surveillance by white-light gastroscopy. Surveillance chromogastroscopy (Congo red/methylene blue technique) should be considered for individuals younger than 20 years and patients unwilling to undergo prophylactic gastrectomy. Sufficient evidence for an increased risk for lobular breast cancer in CDH-1 carriers exists to justify breast screening in female carriers older than 35 years of age, however, evidence is insufficient to recommend prophylactic mastectomy.

Section snippets

Search Strategy and Generation of Consensus Guidelines

This article represents a comprehensive review of the literature on HDGC and germline E-cadherin mutations sourced through PubMed. The management approach presented is the consensus of the authors and other members of the New Zealand HDGC Group, based on the literature and collective clinical experience caring for HDGC patients.

Hereditary Diffuse Gastric Cancer Families and CDH-1 Mutations

It is our practice to restrict the diagnosis of HDGC to families with identified CDH-1 mutations. Families that fulfill the IGCLC criteria5 but have no detected CDH-1 mutation are designated familial diffuse gastric cancer.

HDGC is a relatively rare cancer syndrome. To date, germline CDH-1 mutations have been described in 45 families and 5 individual cases of gastric carcinoma (Table 1).1, 2, 3, 4, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 Family A is the largest known HDGC kindred with 40

Hereditary Diffuse Gastric Cancer Penetrance

The penetrance of CDH-1 germline mutations in HDGC is relatively high. The lifetime cumulative risk for advanced gastric cancer has been estimated to be 67% in men and 83% in women, with a mean age at diagnosis of 40 years (range, 14–85 y).20 Although currently there is no evidence for lower penetrance mutations in the CDH-1 coding sequence, polymorphisms in the CDH-1 promoter are associated with an increased risk for apparently sporadic diffuse gastric cancer in some populations.36 There is no

Malignancies Associated With Hereditary Diffuse Gastric Cancer

Diffuse-type gastric adenocarcinoma (Lauren38 classification) with signet-ring cells (SRCs) is the predominant cancer in carriers of germline CDH-1 mutations.4 In advanced stages, HDGC is indistinguishable from advanced sporadic diffuse gastric carcinoma. A mixed-type38 carcinoma at the gastroesophageal junction has been described in 1 CDH-1 mutation carrier.16 Intestinal-type gastric carcinoma is not part of the HDGC syndrome.5, 39 The clear association with diffuse-type gastric carcinoma is a

The Histopathology of Early Stage Hereditary Diffuse Gastric Cancer

Early stage HDGC is characterized by the presence of multiple foci of diffuse type T1a46, 47 signet-ring cell carcinoma confined to the superficial gastric mucosa with no nodal metastases (Figure 2).22, 24, 25 In addition, in situ SRC carcinoma with Pagetoid spread has been described in some early stage HDGC stomachs.26

The foci of intramucosal carcinoma contain mitotically inactive SRCs. Many foci also contain smaller, poorly differentiated cells, with little or no intracytoplasmic mucin. The

The Natural History of Hereditary Diffuse Gastric Cancer: A Long Indolent Phase?

The average age of patients in the combined series shown in Table 2 was 32 years (range, 15–47 y). The presence of foci of stage T1a carcinoma in all of these cases contrasts markedly with the estimated penetrance of advanced disease in CDH-1 mutation carriers at this age. At 30 years the cumulative risk estimate of advanced disease in both men and women is approximately 4%.20 Even allowing for an extended time lag for progression from these early HDGC foci, the penetrance for advanced disease

Presymptomatic CDH-1 Genetic Testing

Informed consent and genetic counseling form the cornerstone of any familial cancer protocol. The American Society of Clinical Oncology recommends that an individual should not be tested for a cancer predisposition gene unless there is a reasonably high likelihood of detecting a disease-causing mutation and the result is intended to influence medical management.53

IGCLC criteria require confirmed diffuse gastric cancer in a minimum of 2 first- or second-degree relatives on the same side of the

Minimum Age for Genetic Screening and Interventions in Hereditary Diffuse Gastric Cancer

The international view on predictive genetic testing in children and adolescents is underpinned by the philosophies of nonmalevolence and autonomy.55 Therefore, testing should be performed only in situations in which there is clear benefit to the child or adolescent through surveillance or medical intervention. More recently, as collective experience has widened, this view has been challenged, acknowledging that many of the previously held concerns, although valid, were theoretical and did not

Gastroscopic Surveillance

For gastroscopic surveillance to be considered it must be able to detect early SRC carcinoma (T1), preferably when still confined to the superficial lamina propria (T1a) and before invasion into the submucosa (T1b).47 In this respect routine white-light gastroscopy is not a sufficiently sensitive surveillance method because diffuse gastric cancer, even at a late stage, often infiltrates beneath the surface epithelium without ulceration or major distortion of pit pattern.27 Multiple random

Screening for Lobular Breast Cancer and Other Malignancies

Our opinion is that there is sufficient evidence of an increased risk for breast carcinoma to warrant breast screening in HDGC.68, 69 Compared with ductal carcinoma, lobular carcinoma can be difficult to detect mammographically because of its diffuse growth pattern and relative lack of microcalcification.70 Ultrasound is more sensitive than mammography in the detection of sporadic lobular carcinoma.71 Our surveillance protocol is based on that used in BRCA mutation,68 and involves a clinical

Other Management: Lifestyle Changes

Surveillance should be accompanied by advice to minimize known gastric cancer risk factors such as smoking and the intake of salted, cured, and preserved foods, and to increase fresh fruit and vegetable intake.72 If H pylori is present it should be eradicated. Although this organism does not appear to play a major role in HDGC,22, 24, 25 it is possible it may modify disease risk.23 Of the 17 gastrectomies we have performed on CDH-1 mutation carriers, all have had foci of SRC carcinoma but only

Staging, D1/D2 Dissection, and Type of Reconstruction

Patients with surveillance-detected disease are staged with computed tomography scanning and/or endoscopic ultrasound in the same manner as for sporadic gastric malignancy. D2 dissection with preservation of the spleen and pancreas is our standard surgical approach. The controversy surrounding the increased mortality risk vs survival benefit in D2 vs D1 resection for gastric cancer has been subject to extensive review.73 It is our opinion that D2 resection when performed without resection of

Conclusions

The flow chart in Figure 3 summarizes the overall strategy for the management of HDGC. This approach has 3 main differences from the existing IGCLC guidelines5, 23: (1) we propose specific age guidelines for genetic testing, surveillance gastroscopy, and prophylactic gastrectomy; (2) we use chromogastroscopic surveillance; and (3) we consider there is sufficient evidence to recommend breast screening (which must include breast ultrasound) but not prophylactic mastectomy. These differences have

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    Supported by a grant from the New Zealand Health Research Council. Dr Charlton’s research was supported by the Bay of Plenty Medical Research Trust, New Zealand.

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