Yesterday, we found another case of stomach cancer in a young man, an unmarried 25-year-old woman, gastric signet ring cell carcinoma with peritoneal metastasis, which is the most malignant stomach cancer, and the prognosis is very bad.
And this phenomenon is not an isolated phenomenon, now there are more and more stomach cancers in young people, relevant studies have shown that the number of stomach cancer cases under the age of 30 has almost doubled compared with 20 years ago.
You don't have to be too nervous when you see this data, in fact, most of the stomach cancers that young people suffer from are diffuse gastric cancer, a type of gastric cancer with obvious genetic predisposition. This type of stomach cancer accounts for only about 1-3% of all stomach cancers and is a relatively rare disease.
For example, in this young case yesterday, his father, grandfather, and uncle all died of stomach cancer. And it is rare to encounter such a tragic case in clinical practice.
The famous Napoleonic family, which we are familiar with, has many people who died of stomach cancer, including Napoleon himself. Also probably belongs to this type.
Today, let's briefly talk about hereditary gastric cancer.
1. The difference between familial aggregation and hereditary nature of gastric cancer
It is generally believed that familial clustering means that there are multiple people in the family who suffer from gastric cancer one after another, but there are not necessarily genetic factors, and most of them are related to similar dietary habits and Helicobacter pylori infection.
About 5%~10% of gastric cancer patients have familial clustering.
Some experts also believe that the category of familial cluster gastric cancer should include familial hereditary gastric cancer.
Familial hereditary gastric cancer is an autosomal dominant disease (or hereditary tumor syndrome), and most of the more clear pathogenic gene variants are inherited downward with the family, mainly including three major syndromes:
遗传性弥漫型胃癌（HDGC）、
胃腺癌伴近端多发息肉（GAPPS）、
家族性肠型胃癌（FIGC）；
In addition, familial hereditary gastric cancer also includes gastrointestinal genetic syndromes with gastric cancer as the secondary manifestation, such as Lynch syndrome, juvenile polyposis syndrome (JPS), melanopolyposis syndrome (PJS), familial adenomatous polyposis (FAP), etc., which are mainly manifested by familial hereditary colorectal cancer, and have a high risk of gastric cancer.
2. Hereditary diffuse gastric cancer
Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant syndrome, characterized by the high incidence of diffuse gastric cancer and breast lobular carcinoma, mostly caused by inactivating mutations in the tumor suppressor gene CDH1, and a small proportion of HDGC families have abnormal CTNNA1 gene.
Clinicopathological features of HDGC
1) Autosomal dominant inheritance is incomplete penetrance, and the penetrance of mutant genes is 70%~80%;
2) The age of onset is early, the literature reports that the age of onset is 14~84 years old, the average age is 38 years old, and there are characteristics of early onset, which may be 5~6 years earlier than the previous generation;
3) Poor tumor differentiation: the pathological types are mainly poorly differentiated adenocarcinoma and signet ring cell carcinoma, and the Lauren classification is mostly diffuse;
4) Difficulty in early diagnosis by endoscopy: it is manifested as submucosal invasion and scattered distribution, and it is often difficult to obtain tumor tissue under gastroscopy, so it is necessary to collect random and multi-point materials and send them for pathological examination;
5) Mostly accompanied by extragastric tumors: the most common are colon cancer and female breast cancer, and other extragastric tumors include esophageal cancer, liver cancer, lung cancer, leukemia, endometrial cancer and prostate cancer.
In 2020, the IGCLC released the latest HDGC genetic testing criteria, which are subdivided into family diagnostic criteria and individual diagnostic criteria:
Pedigree diagnostic criteria
1) Regardless of age, there were 2 cases of gastric cancer in the family, and at least 1 case was diagnosed with diffuse gastric cancer (DGC);
2) Regardless of age, there is one or more cases of DGC in the family, and one or more cases of lobular carcinoma (LBC) before the age of 70;
3) At least 2 cases of LBC before the age of 50 years were developed in the family.
Individual diagnostic criteria
1) DGC before the age of 50;
2) 1 case of DGC in Māori regardless of age;
3) Regardless of age, the first-degree relatives of DGC patients have a personal or family history of cleft lip/palate;
4）70岁之前患DGC和LBC；
5) Bilateral LBC before the age of 70;
6) Family members < 50 years of age, gastric biopsy reveals in situ signet ring cells and/or Paget-like spread of signet ring cells.
3. Familial intestinal gastric cancer
Familial intestinal gastric cancer (FIGC) is an autosomal dominant form of intestinal gastric cancer without polyposis. Precancerous lesions of intestinal gastric cancer include chronic atrophic gastritis, intestinal metaplasia, and dysplasia, and no specific genetic variants have been identified.
Clinical diagnostic criteria
1) At least 3 cases of intestinal gastric cancer in the family, and 1 case was a first-degree relative of the other two people;
2) At least one of the relatives diagnosed with intestinal gastric cancer was < 50 years old;
3) Two consecutive generations of onset.
4. Gastric adenocarcinoma with proximal multiple polyps (GAPPS)
Gastric adenocarcinoma with proximal multiple polyps (GAPPS) is a rare gastric polyposis syndrome with a significant risk of gastric adenocarcinoma characterized by autosomal dominant gastric polyposis confined to the proximal stomach (including dysplastic lesions and/or intestinal adenocarcinoma) without duodenal or colorectal polyposis or other inherited gastrointestinal neoplastic syndromes.
Clinical diagnostic criteria
GAPPS is primarily clinical, with diagnostic criteria including:
1) gastric polyps are confined to the fundus and corpus of the stomach without evidence of colorectal or duodenal polyposis;
2) The number of polyps proximal to the stomach > 100, or the number of polyps proximal to first-degree relatives > 30;
3) most of the polyps are located at the bottom of the stomach, and the pathological examination of some polyps shows dysplasia (or family members have a history of gastric polyp dysplasia or gastric adenocarcinoma);
4) autosomal dominant inheritance patterns;
5) Patients who include other hereditary gastric polyposis syndromes and who are using proton pump inhibitors are excluded.
4. Health management and treatment strategies
1. Protocol for healthy carriers of CDH1 mutations
HDGC is an autosomal dominant disorder with high penetrance. The lifetime cumulative risk of gastric cancer in carriers of CDH1 germline-pathogenic or probable pathogenic mutations (hereinafter referred to as pathogenic mutations) is about 37%~42% in males and 25%~33% in females.
Prophylactic total gastrectomy (PTG) is recommended by most guidelines. In general, it is recommended that patients undergo prophylactic surgery at the age of 20~30 years, or reduce the age of the youngest family member by 5 years.
Currently, there are no prophylactic recommendations for CDH1 carriers.
Healthy carriers of CDH1 mutations can be classified into the following categories according to whether they meet the clinical diagnostic criteria for HDGC and whether CDH1 mutations are detected, and there are different recommended strategies:
1) For asymptomatic CDH1 germline pathogenic mutation carriers with a significant family history of cancer, prophylactic resection should carefully consider the patient's wishes, and evaluate the risk of morbidity, surgical safety, and quality of life. Close endoscopic surveillance is recommended for patients who have not undergone prophylactic gastrectomy, and gastroscopy is recommended once a year, including biopsies of 30 random sites, and all patients undergoing monitoring should be fully aware of the limitations of endoscopic monitoring.
2) There is no family history of DGC and HDGC or personal history of LBC, and there is a pathogenic CDH1 mutation or a CDH1 mutation of unknown significance after clinical genetic testing to assess cancer risk.
Health management strategies for individuals who meet the clinical diagnostic criteria for HDGC but are not carriers of the disease-causing mutation of CDH1: for individuals from high-risk families who do not carry the disease-causing mutation, early evidence supports endoscopic screening of first-degree relatives.
1.1 Endoscopic monitoring
The optimal frequency of endoscopic monitoring has not been uniformed, and once a year is recommended. In addition, multiple randomized biopsies are recommended to improve the detection rate.
Indications for endoscopy:
1) Age< 20 years old.
2) Refusal of surgical excision.
3) The detected mutation is not a clear pathogenic mutation or is of unknown significance.
1.2 Prophylactic total gastrectomy
1) Timing of surgery: For patients at risk of HDGC, the patient's age, fertility needs, family phenotype (especially the age of cancer in the proband) and baseline nutritional status should be considered when deciding whether to undergo surgery.
PTG is not recommended for older or younger patients. PTG is usually recommended at the age of 20~30. It is recommended that carriers of the disease-causing CDH1 mutation undergo total gastrectomy at an age 5 years younger than the age of onset of gastric cancer in the youngest family of gastric cancer patients.
However, older patients have a shorter life expectancy, poor perioperative risk tolerance, are less likely to benefit from PTG than younger carriers, and the risk of surgical death exceeds the risk of gastric cancer death, so surgical treatment is not recommended for patients over 70 years old.
Total gastrectomy can cause weight loss, and for women of childbearing age, the risk of infertility must be weighed against the risk of cancer. Women who become pregnant after gastric surgery should be monitored and supplemented appropriately to avoid maternal anemia and fetal abnormalities (eg, neural tube defects due to folate deficiency).
2) Extent of surgical resection: Since the pathogenic variant of CDH1 is present in all gastric tissues, the surgeon must ensure that the entire stomach is removed in the PTG. The distal margins should extend at least 1 cm beyond the pylorus. Frozen sections of the proximal margins should be performed prior to gastrointestinal reconstruction to determine the absence of residual gastric mucosa, as residual may increase the risk of future malignancy.
3) Scope of lymph node dissection: Regular lymph node dissection can be performed without PTG alone, and only D1 (perigastric) lymph node dissection. Because most of these patients have cancer stages that do not exceed pT1a, no lymph node metastases have been reported.
4) Gastrointestinal reconstruction: The ideal method of reconstruction after total gastrectomy is to preserve the continuity of the duodenum and jejunum and to provide a functional pouch to minimize functional and nutritional disorders. After total gastrectomy for HDGC prevention, Roux-en-Y esophageal-jejunostomy tends to be used when available.
2. Protocols for patients with CDH1 mutant gastric cancer
For CDH1 gene mutation carriers, when gastroscopy is confirmed to diagnose signet ring cell carcinoma or diffuse gastric cancer, it is recommended to perform radical total gastrectomy and perioperative treatment according to the stage.
If diagnosed at an advanced stage, follow existing guidelines for gastric cancer with systemic medical therapy.
At present, targeted therapy, immunotherapy and cell therapy for CDH1 and its related pathways are still in the research stage, and patients are encouraged to actively participate in relevant clinical studies.
In addition, the exact background of the discovery of the disease-causing mutation in CDH1 should be considered in clinical practice, including but not limited to the following:
1) Detection of CDH1 pathogenic mutations in probands with HDGC-related tumors [DGC and/or LBC] but a negative family history. In this condition, the proband's tumor may be the first manifestation of HDGC, and a de novo causative mutation has been reported.
2) Detection of CDH1 pathogenic mutations in probands with non-HDGC-related tumors. In this case, the disease-causing mutation in CDH1 may be found incidentally or in an unreported expansion type.
Endoscopic screening regimens are recommended for people who meet both of these conditions.
5. Health management and eugenics of CDH1 mutant families
1. Family health management
Once a family member is identified as a carrier of a disease-causing CDH1 mutation, long-term follow-up is required. If PTG is not considered, gastroscopy should be performed once a year.
However, due to the pathological particularity of HDGC, multifocal nature and the characteristics of the growth of the submucosal lamina in the early stage of the lesion, it is difficult to detect the cancer foci early under endoscopy.
Multi-site biopsy at the gastric antral junction or no less than 28~30 whole gastric biopsy specimens per time can increase the positive rate of early detection of carcinoma in situ and precancerous lesions.
In addition, due to the high incidence of LBC in women with pathogenic mutations in the CDH1 gene, an annual breast clinic and breast magnetic resonance imaging (MRI) may be considered.
There is still controversy about colorectal cancer screening, and colonoscopy every 3~5 years can be considered after the age of 40 or the age of the youngest colorectal cancer patient in the family is reduced by 10 years.
2. Eugenics
CDH1 germline mutation carriers should be followed up for a long time, if PTG is not considered, gastroscopy should be performed once a year, clinical evidence suggests that female carriers with germline mutations in the CDH1 gene have a high incidence of LBC, and it is recommended to have a breast clinic and breast MRI once a year.
In addition, first-degree relatives of CDH1 germline mutation carriers are recommended to undergo CDH1 germline mutation gene screening.
6. Protocols for other gene mutation carriers
Mutation carrier protocols for other genes (such as CTNNA1, STK11, APC, TP53, MMR gene, etc.), including CTNNA1, STK11, APC, PTEN, and germline mutations in mismatch repair (MMR) genes, caused by hereditary gastric cancer have a very low overall incidence rate (<1%).
For CTNNA1 treatment, please refer to the guidelines for the treatment and follow-up screening of CDH1 germline mutations; STK11, APC and PTEN are rare, and it is usually recommended to start at the age of 20 and undergo upper gastrointestinal endoscopic screening every 2~3 years for germline pathogenic mutation carriers.
For Lynch syndrome, the high-incidence tumors are colorectal cancer and endometrial cancer, and the penetrance of gastric cancer is relatively low, so at present, in addition to colonoscopy every 1~2 years, it is recommended to undergo gastroscopy every 3~5 years from the age of 40 for germline pathogenic mutation carriers, in addition to colonoscopy every 1~2 years.
When there is Helicobacter pylori (HP) infection, bacteriotherapy is given at the same time. For patients with risk factors for gastric cancer, such as atrophic gastritis, extensive or incomplete intestinal metaplasia, family history of gastric cancer, and first-generation immigrants (East Asians) from areas with a high incidence of gastric cancer, it is recommended to be screened once every 2~3 years.
In addition, family clusters of gastric cancers are mainly due to Helicobacter pylori infection.
People with Helicobacter pylori infection have a 1-fold increased risk of developing gastric cancer compared with those without infection. At present, the mainland is a country with a high incidence of Helicobacter pylori infection, with an infection rate of up to 50%.
Therefore, the eradication of Helicobacter pylori infection is the focus of primary prevention of gastric cancer.
References:
1. Familial Hereditary Tumor Committee of Chinese Anti-Cancer Association. Expert Consensus on Clinical Diagnosis and Treatment of Familial Hereditary Tumors in China (2021 Edition) (3)—Familial Hereditary Gastric Cancer[J]. Chinese Journal of Clinical Oncology, 2021, 48(24): 1248-1252.