Diffuse gastric cancer is one of three major histological types of gastric cancer, the other ones being intestinal-type and mixed gastric cancer. Familial clustering of diffuse gastric cancer may sometimes be attributed to an inherited predisposition for this disease, and it is then referred to as hereditary diffuse gastric cancer (HDGC). HDGC patients have a very high lifetime risk of developing diffuse gastric cancer and are thus recommended for prophylactic total gastrectomy. This measure turns their poor prognosis into an excellent one.
Patients suffering from diffuse gastric cancer tend to remain asymptomatic for prolonged periods of time. Epigastric pain, nausea, and early satiety are among the first symptoms triggered by this type of cancer, but they are frequently dismissed by the patient and the physician. Furthermore, they are most suggestive of common disorders like dyspepsia, gastric ulcer, and other forms of gastritis, so if therapeutic measures are taken, patients are usually prescribed antacids and proton pump inhibitors. Patients with gastric cancer don't typically respond to such treatment. It is of utmost importance to pay attention to these symptoms and the patients' response to therapy, and a family history of gastric cancer should warrant clarifying imaging and genetic studies despite the low incidence of HDGC.
The presence of a palpable mass in the upper abdomen is another symptom of advanced-stage diffuse gastric cancer. Over the course of the disease, loss of appetite becomes more pronounced and patients are losing weight. Metastatic disease may accelerate the loss of weight, and may also cause additional symptoms. Diffuse gastric cancer most commonly metastasizes to regional lymph nodes, to the peritoneum and viscera. Peritoneal carcinomatosis is generally associated with ascites.
Familial anamnesis is the basis of HDGC diagnosis. While diagnostic criteria for HDGC include the documentation of diffuse gastric cancer in at least two relatives of first or second degree, as defined in the Summary section, this cancer predisposition syndrome may also be suspected if there is only one such relative diagnosed before the age of 40, if there is a family history of gastric cancer and breast cancer, and even in the absence of a positive family history if the patient at hand is younger than 50 years and is diagnosed with diffuse gastric cancer and lobular breast cancer .
Techniques employed to diagnose diffuse gastric cancer in HDGC patients don't differ from those applied to diagnose the sporadic disease. Briefly, endoscopy is carried out to visualize the inner surface of the stomach and to collect tissue samples for subsequent histological examination. Diffuse gastric cancer may be below lesions of the gastric mucosa, but the surface of the mucous membrane may also appear intact . Endoscopic sonography and tomographic techniques may provide valuable information to determine the site of biopsy if there are no superficial lesions, but it is possible that neither approach yields pathological findings during early stages of the disease. The most common finding in images is a diffuse thickening of the gastric wall. Positron emission tomography/computed tomography is recommended for tumor staging .
Biopsies have to be carried out and histological studies are required to confirm the diagnosis of diffuse gastric cancer, but the histological assessment of the subtype of gastric cancer may not be necessary in members of families known to be affected by HDGC. Be that as it may, diffuse gastric is characterized by poorly cohesive, diffusely infiltrating cells that may form irregular microtrabeculae or abortive glands  . Tumor cells may be embedded in abundant fibrous tissue, a phenomenon referred to as tumor-embedding desmoplasia, or samples may be of higher cellularity with scarce stroma. High cellularity is commonly observed in anaplastic diffuse gastric cancer, where cytokeratin-positive tumor cells are pleomorphic and carry highly atypical nuclei and prominent nucleoli .
Although patients who are found to suffer from diffuse gastric cancer and who have a positive family history may be diagnosed with HDGC, genetic studies should be carried out in a complementary manner. The identification of the underlying mutation is the prerequisite for an adequate family workup and thus for the prevention of gastric cancerogenesis in relatives who carry this mutation. If CDH1 mutations cannot be detected, other genes may be sequenced, e.g., BRCA1 and BRCA2 in case of concurrent breast cancer, MLH1, MSH2, MSH6, and PMS2, SMAD4 and BMPR1A, or STK11 if anamnestic or clinical data suggest Lynch syndrome, juvenile polyposis syndrome, or Peutz-Jeghers syndrome, respectively .
Of note, due to the high risk of lobular breast cancer in female HDGC patients, women diagnosed with this inherited gastric cancer predisposition syndrome should be examined for neoplasms of the breast. Female HDGC patients aged 35 years and older should additionally be recommended surveillance for breast cancer .
Treatment of HDGC patients with diffuse gastric cancer doesn't differ from treatment of patients diagnosed with the sporadic disease. The primary treatment of gastric cancer is surgical resection, which is carried out with a curative intent. In this context, total gastrectomy is recommended for all HDGC patients - this measure combines the treatment of an existing neoplasm with the prophylactic removal of the stomach. Due to the tendency of diffuse gastric cancer to spread diffusely, to expand within the gastrointestinal tract via the submucosal and subserosal lymphatics, care should be taken when defining the surgical margins. Biopsies have to be carried out to collect tissue samples from these surgical margins, which should be assessed for the presence of occult tumor cells. Despite all efforts, the risk of recurrence is high and survival rates of patients suffering from diffuse gastric cancer are low .
The outcome may be improved administering adjuvant chemotherapy. Molecular targeted therapies have not yet been approved for diffuse gastric cancer treatment, but may become available as progress is made in the molecular characterization of families affected by HDGC.
Diffuse gastric cancer is associated with an unfavorable prognosis, and HDGC patients are no exception from this rule. However, subtype-specific differences should be considered. Tumor-embedding desmoplasia is assumed to improve the outcome since tumor cells surrounded by fibroblast-rich tissue are less likely to invade blood and lymphatic vessels, and to form metastases. Patients diagnosed with anaplastic diffuse gastric cancer have the poorest prognosis.
Prophylactic gastrectomy significantly improves the prognosis of high-risk individuals . Breast cancer remains an issue, though, in females carrying CDH1 mutations. Although prophylactic mastectomy is not routinely recommended, it may be considered in families with a high incidence of breast cancer .
Contrary to the intestinal type of gastric cancer, which has been associated with Helicobacter pylori infection, dietary habits and life style, diffuse gastric cancer is usually related to chromosomal and gene aberrations . Although both germline mutations and acquired sequence anomalies may contribute to apparently sporadic gastric cancerogenesis, there are certain germline mutations that are associated with a lifetime risk for diffuse gastric cancer of up to 80% . The penetrance of the respective genotypes is incomplete, but they do cause striking familial clustering of the disease and justify the diagnosis of HDGC  . In detail, the following gene mutations may account for HDGC:
The incidence of diffuse gastric cancer approximates 20 per 1,000,000 inhabitants, and while men and women are affected almost equally, patients of African ancestry are more likely to develop this type of cancer than Caucasian individuals . However, the incidence of HDGC has been estimated to <1 per 1,000,000 people, which corresponds to <1% of all cases of gastric cancer . Females carrying HDGC-associated mutations are less likely to develop diffuse gastric cancer than males, but their lifetime risk still amounts to almost 60% .
Sporadic diffuse gastric cancer is typically diagnosed in the elder adult. At the time of diagnosis, most patients are >60 years old . By contrast, the hereditary form of the disease usually manifests before the age of 40, with a considerable variety being observed regarding the age of HDGC patients at the time of diagnosis, even within families . HDGC-associated lobular breast cancer typically arises in women aged 40 years and older .
HDGC patients who are heterozygous for inactivating mutations of tumor suppressor gene CDH1 have inherited one defective allele from one of their parents, but also carry a wild-type allele. It has been speculated that a second hit on this wild-type allele is required for gastric cancerogenesis  . This may also apply to patients who are negative for CDH1 mutations, but who have a family history indicating autosomal dominant inheritance of gastric cancer . In any case, mutation, promoter hypermethylation, and loss of heterozygosity may all lead to silencing of epithelial cadherin  .
Additionally, somatic mutations like those that account for the onset of sporadic diffuse gastric cancer, may be acquired by HDGC patients . They highlight the fact that gastric cancerogenesis is a multistep and multifactorial process that favors the accumulation of genetic anomalies - both in hereditary and sporadic disease .
Patients diagnosed with diffuse gastric cancer who have a family history of the disease should be tested for mutations in the CDH1 gene and possibly in other genes. Once the underlying gene defect is identified in a family affected by HDGC, genetic tests should be carried out in all family members. HDGC is inherited in an autosomal dominant manner, so all carriers of the respective mutation are at high risk of developing gastric cancer. Unfortunately, surveillance by means of periodic screenings has proven ineffective to detect diffuse gastric cancer in early stages of the disease, so prophylactic total gastrectomy is advised for these patients  . Gastrectomy is not recommended for asymptomatic patients originating from families in which no germline mutation has been detected .
In case the causal mutation cannot be identified, members of families affected by HDGC are recommended for regular endoscopic surveillance to detect premalignant changes in the gastric wall. Individuals at risk should be examined from the age of 40, or from an age five years younger than the earliest diagnosis in a family member. Screenings according to the so-called "Cambridge protocol" comprise the careful inspection of the gastric mucosa, insufflation and desufflation of the stomach to assess flexibility, and biopsies of mucosal lesions and/or 30 random biopsies from all regions of the stomach .
Gastric cancer is one of the most common cancers worldwide and familial clustering is observed in about 10% of all cases  . Increased familial incidence of gastric cancer may be due to inherited gastric cancer predisposition syndromes like HDGC, Lynch syndrome , juvenile polyposis syndrome , and Peutz-Jeghers syndrome , but also familial adenomatous polyposis  and Li-Fraumeni syndrome . In Lynch syndrome, juvenile polyposis syndrome, and Peutz-Jeghers syndrome, the lifetime risk of gastric cancer is >20%; in familial adenomatous polyposis and Li-Fraumeni syndrome, it is <10% . It is beyond the scope of this article to discuss the similarities and differences in etiology and pathogenesis of neoplasms in all those syndromes, but it shall be mentioned that there may be a genotypic overlap between them and HDGC.
Genetic studies are highly recommended for the diagnosis of gastric cancer predisposition syndromes, but causal gene mutations cannot be detected in all patients. In fact, the underlying gene defect is identified in less than a third of those 10% of cases of gastric cancer mentioned above . Thus, sequence anomalies in determined genes are not exclusion criteria for the diagnosis of HDGC. According to the current guidelines, HDGC patients have at least two relatives of first or second degree who have been diagnosed with diffuse gastric cancer, with at least one of them being diagnosed before the age of 50; or at least three relatives of first or second degree who have been diagnosed with diffuse gastric cancer, regardless of their age at diagnosis .
Gastric cancer is one of the most common cancers worldwide. There are distinct types of gastric cancer, with one of them being diffuse gastric cancer. In this context, "diffuse" refers to the characteristic growth behavior of this type of tumor. It diffusely infiltrates the stomach wall, which causes gastric wall thickening and loss of flexibility. Diffuse gastric cancers are unlikely to grow as discrete, solid masses, and their are associated with a poor prognosis.
Some patients who develop diffuse gastric cancer have a family history of the disease, i.e., there are several relatives who have at some point also been diagnosed with this type of cancer. They may suffer from hereditary diffuse gastric cancer, which is an inherited gastric cancer predisposition syndrome associated with a lifetime risk for diffuse gastric cancer of up to 80%. About a third of these patients carries a mutation in the CDH1 gene, but little is known about the underlying gene defect in the remaining two thirds of patients. In any case, knowledge regarding the causal mutation allows for a detailed family workup and the identification of relatives at risk.
Because it is very difficult to diagnose diffuse gastric cancer during early stages of the disease, and because patients suffering from this type of cancer tend to remain asymptomatic for prolonged periods of time, individuals carrying a CDH1 mutation are recommended for prophylactic total gastrectomy. This means that the only chance to avoid the onset of diffuse gastric cancer in predisposed people is the surgical removal of the entire stomach before tumor growth starts.