Risk-reducing prophylactic total gastrectomy may be warranted for patients with pathogenic or likely pathogenic CDH1 variants and a family history of gastric cancer or lobular breast cancer.
Moreover, it should be considered for patients with CDH1 variants who do not have a family history of disease since they also have a quantifiable risk of developing signet ring cell cancer.
Our findings, published recently in JAMA Surgery, suggest that family history is not a reliable determinant of signet ring cell cancer risk. Further, while esophagogastroduodenoscopy (EGD) may identify signet ring cell cancer in some patients with CDH1 mutations, it is not adequate for long-term surveillance of diffuse gastric cancer in this patient population. (1)
Our study is the largest reported single-institution series of patients with gastric cancers harboring germline CDH1 mutations and the only study to date that describes a large cohort of these patients who underwent minimally invasive, risk-reducing total gastrectomy. We retrospectively examined associations between variant pathogenicity or family history of gastric of lobular breast cancer and a diagnosis of diffuse gastric cancer or the identification of signet ring cell cancer via EGD or in surgical specimens. We also assessed pathological and surgical outcomes for patients who had open or minimally invasive risk-reducing total gastrectomies. (1)
Among 181 patients with CDH1 germline variants seen at Memorial Sloan Kettering Cancer Center (MSK) between 2006 and 2020, 165 harbored a pathogenic or likely pathogenic mutation. Signet ring cell cancer was found in the surgical specimens of 85 of 95 patients (89 percent) who had a family history of gastric cancer, confirming the appropriateness of offering these patients prophylactic gastrectomy. (1)
Notably, we also identified signet ring cell cancer in four of six patients (67 percent) with CDH1 variants who lacked a family history of gastric cancer. Four of the six patients had a personal or family history of lobular breast cancer, including two with signet ring cell cancer. (1)
Among 16 patients with locally advanced or metastatic gastric cancer driven by pathogenic or likely pathogenic CDH1 variants, three (19%) had no family history of gastric cancer or personal or family history of lobular breast cancer. (1)
As CDH1 mutations are increasingly identified on commercially available multigene panel tests, individuals without a family history of gastric cancer should receive counseling on the potential risks and benefits of surgery. The decision to have total gastrectomy requires balancing the potential for preventing invasive diffuse gastric cancer with the morbidity and recovery associated with the surgery, which affect long-term eating habits and weight loss.
Hereditary Diffuse Gastric Cancer
Gastric cancer is the third leading cause of cancer deaths globally. (2) In 2020 there will be an estimated 27,600 new cases and 11,010 deaths in the United States. (3) Most gastric cancers, about 90 percent of cases, are sporadic. Of the remaining about 10 percent of familial cases, one to three percent arise from germline mutations. (4), (5)
Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant cancer predisposition syndrome caused mostly by loss-of-function germline mutation of CDH1, a tumor suppressor gene. (6), (7) It encodes for E-cadherin, a protein that mediates cell-cell adhesion and influences epithelial structure and cell invasion. (8) Individuals with HDGC harboring a CDH1 mutation have an estimated lifetime risk of diffuse gastric cancer of 70 percent for men and 56 percent for women. The latter also have a 42 percent lifetime risk of lobular breast cancer. (9)
Diffuse gastric cancer is characterized by poorly cohesive cells called signet ring cells. Signet ring cell carcinoma (SRCC) has been found in zero to 64 percent of patients with CDH1 mutations via EGD. (10), (11), (12), (13), (14), (15), (16), (17) However, given that it is found in the surgical specimens of 77 to 100 percent of patients who undergo risk-reducing total gastrectomy, EGD is insufficient for surveillance. (10), (11), (12), (14), (15), (16), (18), (19), (20), (21)
Due to the lack of effective surveillance options and the multifocal biology of signet ring cell cancer in HDGC, risk-reducing gastrectomy is recommended for patients with pathogenic or likely pathogenic germline CDH1 variants. (22)
We retrospectively analyzed medical records for 181 patients with germline CDH1 mutations seen at MSK between 2006 and 2020. All patients received genetic counseling at MSK or an outside institution, and most patients had received genetic testing before their referral to MSK. Indications for genetic testing included a personal diagnosis of gastric cancer and a family history of gastric or breast cancer in a first-, second-, or third-degree relative.
Clinical CDH1 germline analysis was performed using Sanger sequencing, multiplex ligation-dependent probe amplification, and next-generation sequencing. Zsofia K. Stadler, MD, a board-certified molecular geneticist and member of our Clinical Genetics Service, classified the CDH1 variants according to the American College of Medical Genetics and Genomics criteria. (23)
Surgical decision-making was guided by the specific CDH1 mutation and its classification, family history of cancer, age, comorbidities, social infrastructure and support, EGD findings, and biopsy results. Four board-certified gastroenterologists with experience in hereditary gastric cancer performed surveillance EGDs and collected about 25 biopsies for each patient throughout all stomach segments. Total gastrectomy was discouraged in patients under 21 years of age and in patients with substantial comorbidities. (1)
Total gastrectomies were all performed at MSK through Roux-en-Y reconstruction by dedicated gastric cancer surgeons Vivian E. Strong, MD, FACS and Daniel G. Coit, MD, FACS. Surgeons selected an open, laparoscopic, or robotic surgical approach, according to their expertise and discretion. Preoperative EGD results informed the extent of lymphadenectomy. A pathologist evaluated intraoperative frozen sections of the proximal and distal margins for esophageal squamous and duodenal mucosa to confirm complete mucosal resection. A dedicated gastrointestinal pathologist performed a postoperative pathological evaluation, including mapping the entire gastric mucosa and annotating anatomical sites. Patients were monitored closely after surgery. (1)
We graded postoperative events according to the Clavien-Dindo system, with grades 1 and 2 considered to be minor, and grades 3 to 5 considered to be major. (24) We defined early events as those occurring within 30 days of surgery and late events between 30 and 90 days.
Variants, Family History, and Presentation with Diffuse Gastric Cancer
In total, we identified 181 patients with germline CDH1 variants. The mean age was 44 years, and 70 percent of patients were female. Twenty patients presented with metastatic or locally advanced diffuse gastric cancer, with a mean age at diagnosis of 46 years. Sixteen of those 20 patients had a pathogenic or likely pathogenic variant: three did not have a family history of gastric cancer or personal or family history of lobular breast cancer. Five of these patients with advanced disease underwent curative-intent gastrectomy, and the remaining 15 received palliative chemotherapy. (1)
Three of four patients who presented with gastric cancer with a variant of uncertain significance did not have a family history. (1)
Asymptomatic Patients Presenting for Total Gastrectomy
A total of 101 asymptomatic patients with a pathogenic or likely pathogenic CDH1 variant underwent total gastrectomy: 43 had minimally invasive surgery, and 58 had open surgery. Six of the 101 patients had no first-, second-, or third-degree relative family history of gastric cancer: four had a personal or family history of invasive lobular breast cancer, and two had evidence of signet ring cell cancer at preoperative EGD with gastric biopsy. (1)
Signet Ring Cell Cancer at EGD and Surgery
Among 101 asymptomatic patients who underwent surgery, signet ring cell cancer was found on preoperative EGD in 23 patients (24 percent). Notably, it was found in the surgical specimens of 88 patients (87 percent): 86 patients had a stage 1a tumor (pT1a), and two had cancer invading the submucosa (pT1b). In all cases, lymph nodes tested negative. (1)
Among 78 patients with a negative preoperative EGD, 66 patients (85 percent) had signet ring cell cancer in their surgical specimen and 12 patients (15 percent) did not. All positive preoperative EGD findings were confirmed via surgical pathology analysis. Accordingly, the sensitivity of EGD for identifying gastric cancer in the surgical specimen was 26 percent, and the specificity was 100 percent, indicating that gastrectomy in patients with positive EGD findings is required.
Signet ring cell cancer was more common among patients with a family history of gastric cancer compared to patients without a family history, found in 85 of 95 patients (89 percent) versus four of six patients (67 percent), but this comparison was not statistically significant given the limited sample size. (1)
Signet ring cell cancer was more commonly found in patients with a pathogenic variant than in patients with a likely pathogenic variant (72 of 78 patients, or 92 percent versus eight of 12 patients or 67 percent, p = 0.009).
Follow-up and Management
None of the 101 asymptomatic patients who underwent gastrectomy developed recurrent or invasive gastric cancer at a median follow-up of 16 months (interquartile range [IQR], 6 to 43 months). However, all five patients who presented with invasive diffuse gastric cancer experienced recurrence at a median of 18 months (IQR, 14 to 29 months). Four of the five patients died of gastric cancer, with a median time to death of 32 months (IQR, 23 to 42 months). The remaining patient had locally advanced ypT3N2 gastric cancer and lived more than six years post gastrectomy. (1) The poor outcomes in patients who presented with locally advanced or metastatic gastric cancer confirm the substantial risks of failing to intervene.
Surgical and Patient Outcomes
Patient demographics, including body mass index, were comparable between the minimally invasive and open surgery groups. As expected with minimally invasive surgery, operative time was significantly longer, length of hospital stay was significantly shorter, and the number of lymph nodes retrieved was significantly higher. (1)
Minimally invasive surgery allowed experienced surgeons to perform extended lymphadenectomy in patients with positive biopsy results for signet ring cell cancer. Note that extended lymphadenectomy is not essential for asymptomatic patients with CDH1 variants undergoing prophylactic gastrectomy since lymph node metastasis has not been reported in this patient population. (22)
The early postoperative event rate of 28 percent for our cohort was within the 10 to 48 percent range previously reported by other institutions in case series of 10 and 23 patients with CDH1 variants who underwent total gastrectomy. (10), (12) However, our rate of anastomotic leaks was three percent versus 9 percent, late postoperative event rates were lower at 20 percent versus 35 percent, and median weight loss was similar at 20 percent versus 19 percent, by comparison. Other series of total gastrectomy in patients with CDH1 have not described postoperative events. (1)
For 79 patients with available post-discharge weight data, the median long-term weight loss was 20 percent (IQR, 10 to 23 percent). Weight loss varied with preoperative body mass index, with the greatest loss of 28 percent at two years among obese patients, followed by 18 percent for overweight patients and 14 percent for normal-weight patients. Despite this substantial weight loss, only one patient was underweight at follow-up.
Improving Outcomes for Patients with Gastric Cancers and Predispositions
The present study adds to our previous report published in 2017, in which none of the 41 patients who received prophylactic gastrectomy developed gastric cancer recurrence at a median follow-up of 16 months, and 85 percent of patients surveyed rated their outcomes as being as good or better than they expected. (21)
We will continue to analyze the genetic status and surgical results for patients with HDGC at MSK with a view to improving outcomes. We do not recommend total gastrectomy to patients with variants of unknown significance; we encourage them to continue follow up with genetics counseling for updates on new variants that may be classified as pathogenic.
MSK is the highest-volume referral center for gastric cancer in the United States, caring for over 200 patients annually. Our multidisciplinary stomach cancer experts collaborate to develop individualized treatment plans for patients with rare and common cancers. We are committed to helping our patients achieve their best possible outcomes.