Hereditary diffuse stomach carcinoma

The description of a familial clustering of diffuse hereditary gastric carcinoma in Maori families was first described by Jones et al. in 1964 (Treese 2021). Guilford et al. were the first to prove the underlying mutation in 1998.

Diffuse hereditary gastric carcinoma (HDGC) is a rare, autosomal dominant hereditary tumor syndrome with 70 - 80 % penetrance (Wolf 2010).

To date, 3 major hereditary syndromes of the stomach have been described, all of which are inherited in an autosomal dominant manner:

- Hereditary diffuse gastric carcinoma (HDGC)

- Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS)

- Familial intestinal gastric carcinoma (FIGC) (Gullo 2020)

At an expert consensus conference in 2020 (International Gastric Linkage Consortium = IGCLC), clinical groups were defined for the first time for hereditary diffuse gastric carcinoma:

- Detected mutation in the CDH1 gene, but only clinically conspicuous with a lobular breast carcinoma (HLBC)

- No mutation detectable with clinically fulfilled familial HDGC criteria (HDGC-like). This group comprises approx. 50 % (Treese 2021)

A germline mutation diagnosis should always be offered in the event that:

1. gastric carcinoma has occurred in at least two first- or second-degree family members, with diffuse gastric carcinoma in at least one case.

2. there is a patient in the family with diffuse gastric carcinoma before the age of 40.

3. both diffuse gastric carcinoma and lobular breast carcinoma have occurred in the family, at least one case of which occurred before the age of 50 (2019 guideline).

Testing can be considered in the following cases:

1. occurrence of a bilateral lobular breast carcinoma before the age of 50 or if at least two lobular breast carcinomas occurred in the family before the age of 50.

2. personal or family history of cleft lip/palate and diffuse gastric carcinoma.

3. histological evidence of an in situ signet ring carcinoma and / or a pagetoid spread of signet ring cells. These histopathological findings practically never occur in sporadic cases (2019 guideline).

Of the patients who develop gastric carcinoma, only 1 - 3 % have a germline mutation (2019 guideline).

The incidence of HDGC is 5 / 100,000 live births. The distribution varies worldwide, e.g. Portugal and Italy are countries with a high incidence, while countries with a low incidence include the UK and the USA (Treese 2021).

- A mutation of the E- cadherin gene, the so-called CDH1 mutation (Herold 2022), is found in 25 - 50 % of cases

- Only rarely is there a mutation in the CTNNA1 gene (Treese 2021).

Carriers of the genetic defect have an up to 80-fold increased risk of developing gastric carcinoma (Hüneburg 2014).

There is an autosomal dominant inheritance with penetrance for the occurrence of gastric carcinoma in 56% of women and 70% of men (Treese 2021).

Diffuse gastric carcinoma does not usually grow into the lumen, but infiltrates the stomach wall at an early stage. Individual signet ring cells, sometimes arranged as nests, are found beneath the non-neoplastic epithelium. These develop preferentially in the fundus and corpus (Hollstein 2022).

The age of manifestation of HDGC is variable. Although individual cases have been described before the age of 18, the risk is considered to be extremely low (Guidelines 2019).

The average age of onset for mutation carriers is around 38 years (Hollstein 2022).

The symptoms of the disease are non-specific for a long time. Only at an advanced stage do specific symptoms appear, such as:

- Abdominal pain

- Difficulty swallowing

- loss of appetite

- nausea

- vomiting

- Postprandial feeling of fullness

- Weight loss (Kaura 2018)

The diagnosis of HDGC includes endoscopic sonography, esophagogastroduodenoscopy (OGD), biopsies, CT thorax and abdomen as well as the detection of the gene mutation (Hollstein 2022).

HDGC is classified according to Lauren:

- Intestinal type: clearly demarcated

- Diffuse type: infiltrative growth

- Mixed type: the clinical behavior corresponds to carcinomas of the diffuse type (Berger 2023)

Histologically one finds:

- Multifocal growth

- Detection of signet ring cells (Treese 2021)

- Linitis plastica (typical thickening of the stomach wall) (Kaura 2018)

- Early lymph node metastasis

- Women have up to a 60% risk of additionally developing lobular breast cancer (Hollstein 2022)

Guideline-compliant surgical and systemic treatment of carcinoma (Treese 2021)

Despite decreasing Helicobacter pylori infection rates, gastric cancer remains the fourth most common cause of death from tumors worldwide (Treese 2021).

The prognosis of HDGC is rather unfavorable due to early lymph node metastasis (Hollstein 2022). The diagnosis can usually only be made at an advanced stage, as there are no or only non-specific symptoms for a long time. The 5-year survival rate at a late stage is < 30 % (Kaura 2018).

Follow-up care

In the case of curatively treated HDGC patients, an additional breast cancer screening should be carried out once a year during follow-up care. Alternatively, they can also be offered a bilateral mastectomy (Treese 2021).

It is recommended that confirmed carriers of a CDH1 mutation undergo a prophylactic gastrectomy from the age of 20 (2019 guidelines). Alternatively, a gastroscopy can be performed at least once a year in expert centers (Treese 2021).

Genetic counseling should be recommended for all people at risk from the age of 18 (Guidelines 2019).

If the pathogenic variant is known in the family, prenatal testing for high-risk pregnancies is possible (Kaura 2018).