Hereditary Diffuse Gastric Cancers

Hereditary diffuse gastric cancer is a rare syndrome that can be caused by inheriting a mutation in the CDH1 gene.

Key Facts

The vast majority of gastric cancer cases are not due to inherited genes from one’s parents. Only about 10% of gastric cancers are thought to be related to inherited genes.
An individual who inherits a mutation in the CDH1 gene from his/her mother or father is at significantly increased risk of developing diffuse gastric cancer. Women are also at increased risk of developing lobular breast cancer.
Prophylactic total gastrectomy is often recommended for individuals with germline CDH1 mutation. This procedure should be performed at high-volume referral centers

Background

Gastric cancer is the third highest cause of cancer death worldwide with over one million new cases diagnosed annually leading to more than 750,000 deaths. The incidence is twice as high in males compared to females. The major risk factor of gastric cancer is infection with Helicobacter pylori (H. pylori), which can colonize the stomach early in life and cause chronic inflammation that over years or decades leads to gastric cancer. H. pylori infection and gastric cancer incidence vary widely in different regions with the highest rates in East Asia, Eastern Europe, and South America. H. pylori infection and gastric cancer are relatively uncommon in the United States.

Types of Gastric Cancer

In 1965, a pathologist named Lauren described two distinct histological subtypes of gastric cancer:

Intestinal
Diffuse

The intestinal type generally forms an obvious mass when viewed by endoscopy. The diffuse type has single cells or poorly cohesive cells that infiltrate the gastric wall, making early lesions more difficult to identify on endoscopy, and progressive disease can ultimately lead to linitis plastica (a.k.a “leather bottle” stomach).

Causes of Hereditary Gastric Cancer (HDGC)

While around 90% of gastric cancer cases arise sporadically, the remaining 10% are seen in familial clustering and considered to be hereditary in nature.

Early onset familial gastric cancer was first described in three families of Maori descent from New Zealand in 1964. In 1998, Parry Guilford and colleagues published their study of early onset diffuse gastric cancer in a large Maori family in New Zealand. They carried out genetic studies and found an inherited mutation in the CDH1 gene was the cause of gastric cancer in this family. This group subsequently identified additional germline mutations in the CDH1 gene associated with familial gastric cancer. Hundreds of CDH1 germline mutations have subsequently been identified in diffuse gastric cancer families in multiple different countries.

The original estimates of lifetime risk of developing hereditary diffuse gastric cancer (HDGC) in individuals with germline CDH1 mutation were up to 70% or greater. However, this estimate was based on families with high burden of HDGC amongst multiple family members. As additional families with less cases of gastric cancer have been examined, the risk estimates for hereditary diffuse gastric cancer in the setting of germline CDH1 mutation have declined. Currently, the lifetime risk of HDGC in individuals with germline CDH1 mutation is estimated at 37-42% for men and 25-33% for women. Females with germline CDH1 mutation also carry a 39-55% risk of developing lobular breast cancer.

Diagnosis of Hereditary Gastric Cancer

Pathological evaluation of prophylactic gastrectomy specimens in HDGC patients has been characterized by one or more microscopic infiltrates of diffuse gastric cancer that underlie normal appearing mucosa. This feature limits the use of conventional endoscopy as a potentially screening modality in high-risk patients that carry germline mutations in the CDH1 gene. However, non-hereditary diffuse type gastric cancer is often detected in Japan and South Korea, which generally screen individuals with endoscopy every 2 years beginning at age 40.

Treatment for Hereditary Gastric Cancer

Individuals with germline CDH1 mutations face difficult decisions with respect to cancer screening and risk reducing surgeries. They benefit most from evaluation at referral centers with expertise in this rare condition.

Prophylactic Total Gastrectomy

After an individual with germline CDH1 mutation has undergone multidisciplinary evaluation at a referral center, prophylactic (preventative) total gastrectomy can be offered starting at 20 years old. The rates of morbidity and even mortality following total gastrectomy correlate with surgeon volume and institution volume. Thus, prophylactic total gastrectomies are best performed at high-volume gastric cancer referral centers.

Avoiding Anastomotic Leaks and Strictures

The creation of the anastomosis, or connection, between the esophagus and the small bowel after total gastrectomy can be technically demanding, and reconstruction-related complications such as leak and stricture account for a significant proportion of post-operative morbidity.

In one retrospective review of adverse events within 90 days of total gastrectomy for 238 non-CDH1 patients with gastric cancer, esophagojejunal anastomotic leak requiring invasive intervention occurred in 11% of patients. Even among the usually younger and healthier CDH1-positive individuals that receive prophylactic total gastrectomy, esophageal anastomotic leak rates between 8-26% have been reported.

Anastomotic stricture rates of up to 21% have been reported following esophagojejunostomy with the highest rates occurring with circular staplers. Dr. Sam Yoon developed a technique for the connection of the esophagus and small bowel, which he described in the Journal of Gastrointestinal Surgery. In his series of 54 patients undergoing prophylactic total gastrectomy, there were no anastomotic leaks and one possible anastomotic stricture.

Eating After Total Gastrectomy

There are clear nutritional consequences following total gastrectomy, and thus routine laboratory testing and long-term follow-up is needed. In our series, the median weight loss was 19% of pre-operative weight and the nadir of weight loss was at 3 months. With long-term follow-up, median weight gain from the lowest weight was only 4%. Routine laboratory work should include a complete blood count (CBC), electrolytes, BUN, creatinine, and liver function tests. Total gastrectomy results in loss of intrinsic factor secretion, significantly impairing vitamin B12 absorption, and predisposes to iron malabsorption and deficiency. Additionally, calcium and vitamin D absorption are also diminished.

For total gastrectomy patients, doctors have always recommended that they take a multivitamin with iron orally and vitamin B12 either by intramuscular injection (1000 mcg monthly) or sublingually (methylcobalamin 1500 mcg daily). For those at risk of calcium deficiency and osteoporosis, one can either increase consumption of calcium rich foods to 1,500 mg/day or take calcium citrate 1,200 to 1,500 mg per day in divided doses. Iron studies should be performed, and ferrous sulfate 200 mg (elemental iron 57 mg) three times per day can be added if there is iron deficiency. Fat malabsorption occurs in about 10% of patients after gastrectomy and is more common when the duodenum is bypassed. This is due to alterations in gastric lipase secretions, exocrine pancreatic insufficiency, altered cholecystokinin release, pancreaticobiliary asynchrony, or small intestinal bacterial overgrowth (SIBO). This can lead to deficiencies in vitamins A, D, E, and K.

Outlook After Surgery

Dr. Sam Yoon, Chief of the Division of Surgical Oncology, recently reported the short and long term outcomes of 54 patients undergoing prophylactic total gastrectomy. This is one of the world’s largest series.

Summary of Short and Long-Term Outcomes in 54 Patients Undergoing Prophylactic Total Gastrectomy:

There were fifty-four patients (35 female, 19 male) with a median age of 41 years (16-70 years) underwent prophylactic total gastrectomy between 2006-2021.
Eight patients (15%) had one or more microscopic foci of diffuse gastric cancer on random biopsies prior to surgery.
Median operative time was 161 minutes, and median hospital stay was 7 days. There were no anastomotic leaks at the connection of the esophagus to the small bowel.
The pathological analysis of the first 10 pts included the entire gastric mucosa and revealed a median of 15 foci of diffuse gastric cancer (range 5-136). The subsequent 44 patients with more limited pathological analysis had a median of 2 foci (range 0-5), and two patients (3.7%) had no foci identified.
Median weight loss was 19%, and the median weight nadir was 3 months after surgery.
In long-term follow-up (median 4.6 years) of 20 patients, median global quality of life (QOL) was 2.0 (very good), the majority had persistent difficulty with certain foods or liquids, and all stated they would again elect PTG over surveillance endoscopy.

Risk of Breast Cancer

Females with germline CDH1 mutation also carry a 39-55% risk of developing lobular breast cancer. Annual surveillance with breast MRI is thus recommended beginning at age 30. Lobular breast cancer often does not form a discrete mass or form microcalcifications so the utility of mammogram is lower than that for infiltrating ductal carcinoma. Bilateral risk-reducing mastectomies can also be considered. Three of the 35 women in our series underwent bilateral risk-reducing mastectomies after their prophylactic total gastrectomy.

Next Steps

Given the rarity of germline CDH1 mutation and the specialized, multi-disciplinary expertise required for treatment, individuals with germline CDH1 mutation are best evaluated and treated at an established referral center, like the one at Columbia. Our Gastric Cancer Program has a multidisciplinary team of genetic counselors, gastroenterologists, dieticians, surgical oncologists, breast surgeons, plastic surgeons, and pathologists.

To make a surgical appointment with the Gastric Care Program, please call us at (212) 305-0273 today or request an appointment online today.