Vanessa Blair

Hereditary diffuse gastric cancer: updated consensus guidelines for clinical management and directions for future research

25–30% of families fulfilling the criteria for hereditary diffuse gastric cancer have germline mutations of the CDH1 (E-cadherin) gene. In light of new data and advancement of technologies, a multidisciplinary workshop was convened to discuss genetic testing, surgery, endoscopy and pathology reporting. The updated recommendations include broadening of CDH1 testing criteria such that: histological confirmation of diffuse gastric criteria is only required for one family member; inclusion of individuals with diffuse gastric cancer before the age of 40 years without a family history; and inclusion of individuals and families with diagnoses of both diffuse gastric cancer (including one before the age of 50 years) and lobular breast cancer. Testing is considered appropriate from the age of consent following counselling and discussion with a multidisciplinary team. In addition to direct sequencing, large genomic rearrangements should be sought. Annual mammography and breast MRI from the age of 35 years is recommended for women due to the increased risk for lobular breast cancer. In mutation positive individuals prophylactic total gastrectomy at a centre of excellence should be strongly considered. Protocolised endoscopic surveillance in centres with endoscopists and pathologists experienced with these patients is recommended for: those opting not to have gastrectomy, those with mutations of undetermined significance, and in those families for whom no germline mutation is yet identified. The systematic histological study of prophylactic gastrectomies almost universally shows pre-invasive lesions including in situ signet ring carcinoma with pagetoid spread of signet ring cells. Expert histopathological confirmation of these early lesions is recommended.

Hereditary diffuse gastric cancer: updated clinical guidelines with an emphasis on germline CDH1 mutation carriers

Germline CDH1 mutations confer a high lifetime risk of developing diffuse gastric (DGC) and lobular breast cancer (LBC). A multidisciplinary workshop was organised to discuss genetic testing, surgery, surveillance strategies, pathology reporting and the patients perspective on multiple aspects, including diet post gastrectomy. The updated guidelines include revised CDH1 testing criteria (taking into account first-degree and second-degree relatives): (1) families with two or more patients with gastric cancer at any age, one confirmed DGC; (2) individuals with DGC before the age of 40 and (3) families with diagnoses of both DGC and LBC (one diagnosis before the age of 50). Additionally, CDH1 testing could be considered in patients with bilateral or familial LBC before the age of 50, patients with DGC and cleft lip/palate, and those with precursor lesions for signet ring cell carcinoma. Given the high mortality associated with invasive disease, prophylactic total gastrectomy at a centre of expertise is advised for individuals with pathogenic CDH1 mutations. Breast cancer surveillance with annual breast MRI starting at age 30 for women with a CDH1 mutation is recommended. Standardised endoscopic surveillance in experienced centres is recommended for those opting not to have gastrectomy at the current time, those with CDH1 variants of uncertain significance and those that fulfil hereditary DGC criteria without germline CDH1 mutations. Expert histopathological confirmation of (early) signet ring cell carcinoma is recommended. The impact of gastrectomy and mastectomy should not be underestimated; these can have severe consequences on a psychological, physiological and metabolic level. Nutritional problems should be carefully monitored.

Hereditary diffuse gastric cancer: predominance of multiple foci of signet ring cell carcinoma in distal stomach and transitional zone

Background and aims: Germline mutations in the CDH-1/E-cadherin gene are, to date, the only known cause of hereditary diffuse gastric cancer (HDGC). While two recent series of prophylactic gastrectomy described microscopic foci of signet ring cell carcinoma in sample sections from 10 macroscopically normal stomachs, whole stomach phenotype has not been mapped. We aimed to describe the size and distribution of foci in relation to mucosal zones and anatomical location. Methods: Six patients (from three HDGC kindred) were referred for total gastrectomy via three different referral pathways. Following fixation, five stomachs were completely blocked and one extensively sampled. Histopathology was mapped to a mucosal photograph of each stomach, enabling precise localisation of carcinoma foci, benign pathology, and mucosal zones. Results: There were 4–318 microscopic foci of intramucosal signet ring cell adenocarcinoma in the six macroscopically normal stomachs (foci size 0.1–10 mm in diameter). The distal third of the stomach contained 48% of total foci (range 29–75%). The body-antral transitional zone occupied 7.7% of mucosal area (range 3.6–11.8) but had 37% of foci (range 10%–75%). The largest foci were found in the transitional zone and foci density was five times greater in the transitional zone than in body or antral type mucosa. Conclusions: In germline CDH-1 mutation carriers, multiple microscopic foci of intramucosal signet ring cell carcinoma show a predilection for the distal stomach and the body-antral transitional zone. Targeting the transitional zone would maximise the likelihood of finding foci in macroscopically normal gastrectomies, and particular attention should be paid to this area during endoscopy.

Chromoendoscopic surveillance in hereditary diffuse gastric cancer: an alternative to prophylactic gastrectomy?

Background: Hereditary diffuse gastric cancer (HDGC) is defined by germline mutations in the E-cadherin gene, CDH-1. The first family in which CDH-1 mutations were identified was a large Maori kindred, where lifetime penetrance is 70%. Prophylactic gastrectomy is an unacceptable option for many mutation carriers. The results of annual chromoendoscopic surveillance using the methylene blue/congo red technique in 33 mutation carriers over a five year period are described. Patients and methods: Thirty three confirmed CDH-1 mutation carriers (18 males, 15 females), median age 32 years (range 14–69), were enrolled in 1999–2003. Medical records, endoscopy, and pathology were reviewed retrospectively. Results: Over five years, 99 surveillance endoscopies were performed, of which 93 were chromo-dye enhanced. Sixty nine chromoendoscopies were normal. In 24 procedures, 1–6 pale areas/stomach (size 2–10 mm) were detected post chromo-dye application (totalling 56 pale lesions). One biopsy was taken from each pale lesion: 23 lesions (41%) showed signet ring cell carcinoma (10 patients), 10 lesions (18%) gastritis (four patients), and 23 (41%) normal mucosa (10 patients). No chromo-dyes were used in six procedures with macroscopic lesions (two HDGC, four ulceration). Total gastrectomies from patients with carcinoma were macroscopically normal but pathological mapping showed multiple microscopic foci of early signet ring cell carcinoma. Correlation of chromoendoscopic and gastrectomy findings showed that congo red/methylene blue detected carcinoma foci 4–10 mm in size but not foci <4 mm. Conclusions: The use of chromoendoscopy following normal white light gastroscopy facilitated detection of early gastric carcinoma foci not visible with white light gastroscopy. If these findings are validated in other HDGC kindred, chromogastroscopy represents an improved surveillance technique that can be safely considered alongside prophylactic gastrectomy.

Hereditary diffuse gastric cancer: translation of CDH1 germline mutations into clinical practice

Hereditary diffuse gastric cancer (HDGC) is the only known cancer syndrome that is dominated by gastric adenocarcinoma. HDGC is caused by germline mutation of the CDH1 gene that encodes the cell adhesion protein E-cadherin. Mutation carriers have a more than 70% lifetime risk of developing DGC and an elevated risk of lobular breast cancer. Intestinaltype gastric cancer is not part of the syndrome. Clinical management of HDGC involves predictive genetic testing beginning at or near 16 years of age. It is recommended that mutation carriers undergo prophylactic gastrectomy after about 20 years of age. Anatomical mapping has demonstrated that mutation carriers develop multifocal stage T1a signet ring cell carcinomas, with up to several hundred foci being observed in single stomachs. These foci develop following the somatic inactivation of the second CDH1 allele by mechanisms that include DNA promoter hypermethylation.

Destabilized Adhesion in the Gastric Proliferative Zone and c-Src Kinase Activation Mark the Development of Early Diffuse Gastric Cancer

The initial development of diffuse gastric cancer (DGC) is poorly understood. The study of E-cadherin (CDH1) germ line mutation carriers predisposed to DGC provides a rare opportunity to elucidate the genetic and biological events surrounding disease initiation. Samples from various stages of hereditary and sporadic DGC were investigated to determine general mechanisms underlying early DGC development. Paraffin-embedded tissues from 13 CDH1 mutation carriers and from 10 sporadic early DGC cases were analyzed. Immunofluorescence and immunohistochemistry using differentiation, proliferation, and adhesion markers showed that DGC initiation seems to occur at the proliferative zone (the upper neck) of the gastric epithelium and correlates with absent or reduced expression of junctional proteins (beta-actin, p120, Lin-7). Slow proliferation of neoplastic cells at the upper gastric neck leads to the formation of intramucosal signet-ring cell carcinoma (SRCC) displaying differentiated features. As shown by immunolabeling, invasion from SRCC lesions beyond the gastric mucosa is associated with poor differentiation, increased proliferation, activation of the c-Src system, and an epithelial-mesenchymal transition. Our results provide a molecular description of the early development of DGC and explain the relationship between the two main DGC types, poorly differentiated carcinoma and SRCC: both share their origin, but SRCC develops following cancer cell differentiation and seems relatively indolent in its intramucosal stage.

A short guide to hereditary diffuse gastric cancer

Hereditary diffuse gastric cancer (HDGC) is the only known predisposition syndrome dominated by carcinoma of the stomach and with a recognised genetic cause. Germline mutations in the E-cadherin gene (CDH1) co-segregate with the disease in about half of the families with multiple diffuse gastric cancer. In these families, identification of the CDH1 mutation allows for clinical measures to be taken. Importantly, clinical intervention is likely to be therapeutic and associated with tolerable morbidity. This review is thus aimed at providing a current overview of the clinical management and the underlying biology of HDGC.

Cancer in Māori: lessons from prostate, colorectal and gastric cancer and progress in hereditary stomach cancer in New Zealand

Persisting ethnic disparities in cancer incidence and outcomes exist between Māori and non‐Māori in Aotearoa/New Zealand. It is difficult to disentangle the complex interplay of environmental and genetic factors that contribute to the variation in cancer statistics between these two groups. In Māori, the sites of highest cancer incidence are the prostate in men, breast in women and lung in both – the next most common cancers in Māori are colorectal and stomach cancer. This paper discusses colorectal, prostate and stomach cancer in Māori to illustrate selected issues that impact on cancer care. Colorectal cancer is discussed to illustrate the importance of accurate cancer statistics to focus management strategies. Prostate cancer in Māori is reviewed – an area where cultural factors impact on care delivery. Sporadic stomach cancer in New Zealand is used to show how sub‐classification of different types of cancer can be important and illustrate the breadth of putative causal factors. Then follows an overview of developments in hereditary gastric cancer in New Zealand in the last 15 years, showing how successful clinical and research partnerships can improve patient outcomes. One example is the Kimi Hauora Clinic, which provides support to cancer patients, mutation carriers and their families, helping them navigate the interface with the many health‐care professionals involved in the multidisciplinary care of cancer patients in the 21st century.

Familial Gastric Cancer: Genetics, Diagnosis, and Management

This article focuses on the diagnosis and management of familial gastric cancer, particularly hereditary diffuse gastric cancer (HDGC). First, existing consensus guidelines are discussed and then the pathology and genetics of HDGC are reviewed. Second, patient management is covered, including surveillance gastroscopy, prophylactic total gastrectomy, and management of the risk of breast cancer.