Unique challenges of risk-reducing surgery for hereditary diffuse gastric cancer syndrome: a narrative review

Abstract

The common use of genetic testing has reinvigorated discussions surrounding enhanced cancer surveillance, chemoprevention, and preventive surgery strategies due to increasing recognition of pathogenic germline genetic variants. Prophylactic surgery for hereditary cancer syndromes can significantly reduce the risk of developing cancer. Hereditary diffuse gastric cancer (HDGC), characterized by high penetrance and an autosomal dominant inheritance pattern, is causally linked to germline mutations in the CDH1tumor suppressor gene. Risk-reducing total gastrectomy is currently recommended in patients with pathogenic and likely pathogenic CDH1 variants; however, the physical and psychosocial sequelae of complete stomach removal are substantial and need to be investigated further. In this review, we address the risks and benefits of prophylactic total gastrectomy for HDGC in the context of prophylactic surgery for other highly penetrant cancer syndromes.

Introduction

The subject of surgery for the prevention of cancer is a more common topic of medical discussion in recent decades with the advent of widespread genetic testing. Increased prevalence of next-generation sequencing has reduced the cost of genome sequencing and provided broader access to healthcare providers and patients (^{Rehder et al., 2021}); however, the ability to detect germline variants associated with hereditary cancer risk with a simple blood or saliva test has presented new challenges for clinicians and patients alike. Clinicians now must be familiar with the interpretation of genetic testing and the clinical risks associated with specific gene variants. Unfortunately, the receipt of genetic testing results without pretest counseling can cause unnecessary anxiety and confusion for patients regarding the next steps in management. Thus, a multidisciplinary approach to the clinical management of hereditary cancer syndrome begins with genetic counseling. Affected individuals require explanations of estimated disease penetrance, implications for family members, and counseling on the physical and psychosocial implications of enhanced cancer surveillance, chemoprevention, and preventive surgery.

Currently, prophylactic surgery is recommended for cancer prevention in individuals with high-risk cancer predisposition syndromes such as hereditary diffuse gastric cancer (HDGC), familial adenomatous polyposis (FAP), hereditary breast and ovarian cancer, and hereditary medullary thyroid cancer. The most frequent cause of HDGC is a germline pathogenic or likely pathogenic variant in the CDH1 tumor suppressor gene, which encodes the cell adhesion protein E-cadherin (^{Guilford et al., 1998}). Individuals with a CDH1 variant have an increased lifetime risk of early onset diffuse-type gastric and lobular breast cancers that range from 33 to 42% and 42 to 55%, respectively (^{Roberts et al., 2019; Xicola et al., 2019}). Consensus guidelines recommend risk-reducing total gastrectomy for patients with pathogenic or likely pathogenic CDH1 variants and a family history of diffuse gastric cancer (^{Blair et al., 2020}). Although total gastrectomy removes at-risk gastric mucosa, the life-changing consequences of this major operation, such as weight loss and lifelong micronutrient supplementation, must be underscored. Furthermore, patients should be fully informed prior to proceeding with prophylactic surgery over enhanced surveillance given the imminent changes in lifestyle post-surgery. In this review, we will address the benefits and risks of surgery for cancer prevention in patients with HDGC and discuss outcomes of total gastrectomy relative to other operations for cancer prophylaxis.

Genetic testing in hereditary diffuse gastric cancer

Advances in medical genetics and the availability of cost-effective multigene panel testing have accelerated genetic testing, which in turn has likely increased the frequency of diagnosis of germline CDH1 variants. HDGC exhibits an autosomal dominant inheritance pattern. The International Gastric Cancer Linkage Consortium recently developed updated clinical practice guidelines and genetic testing criteria for HDGC outlined in Table 1 (^{Blair et al., 2020}). Genetic counseling should be offered prior to genetic testing given the lifelong implications of the results. All testing should be performed at certified diagnostic laboratories. A pathogenic variant detected in the proband should prompt cascade genetic testing in the family (^{Whitaker et al., 2021}). A newly identified variant of undetermined significance should be explored with functional analyses to assess pathogenicity, however, recent work by ^{Garcia-Pelaez et al. (2023}) demonstrated missense variants of unknown significance were not associated with HDGC-like phenotypes (i.e. diffuse gastric cancer, lobular breast cancer, and cleft lip/palate) (^{Sugimoto et al., 2015}).

Table 1 - Hereditary diffuse gastric cancer syndrome genetic testing criteria for CDH1 and CTNNA1

Individual criteria
DGC at age < 50
Bilateral LBC at age < 70
History of DGC and LBC both diagnosed at age < 70
DGC (any age) with personal or family history of cleft lip/palate
Gastric in-situ signet ring cells or pagetoid spread of signet ring cells at age < 50

Family criteriaa
≥2 individuals (any age) with gastric cancer, with at least one confirmed DGC
≥2 individuals with LBC at age < 50
≥1 individual with DGC (any age) and ≥1 individual with LBC at age < 70 in different family members

DGC, diffuse gastric cancer; LBC, lobular breast cancer.

^aFamily members must be first- or second-degree blood relatives.

Other candidate gene variants linked to HDGC have been identified in CDH1 variant-negative index cases such as CTNNA1, BRCA2, STK11, SDHB, PRSS1, ATM, MSR1, and PALB2 (^{Hansford et al., 2015}). CTNNA1 is located on chromosome 5 and encodes alpha-catenin, which complexes with the cytoplasmic domain of E-cadherin and is involved in cellular adhesion (^{Sugimoto et al., 2015}). Individuals who test negative for a CDH1 variant should be tested for CTNNA1 as truncating variants in this gene have been causally linked to HDGC (^{Blair et al., 2020}). The diagnosis of an inherited gene variant in otherwise healthy individuals can have life-altering consequences. Clinical decision-making in HDGC is generally focused on cancer risk reduction, in the form of enhanced surveillance or prophylactic surgery.

Enhanced surveillance versus risk-reducing total gastrectomy

Given the current limitations of effective gastric cancer screening modalities, risk-reducing total gastrectomy is often considered the most effective mode of cancer prevention in patients with pathogenic or likely pathogenic germline CDH1 variants. For patients who defer surgery, comprehensive endoscopic surveillance with random and targeted biopsy is performed every 6–12 months. Multiple studies have demonstrated that pathologic analysis of final gastrectomy specimens in most asymptomatic CDH1 carriers have almost complete penetrance at the tissue level and will harbor occult signet ring cell carcinoma foci (^{Rocha et al., 2018; Vos et al., 2020}); however, detection of signet ring cell carcinoma with endoscopic surveillance remains challenging given high false negative rates (^{van Dieren et al., 2020}). Most importantly, the mechanism by which cells transition from occult signet ring cell carcinoma (≤T1a disease) to advanced gastric cancer is not yet understood. The optimal frequency of surveillance endoscopy when occult signet ring cells are detected is not known and often leads to recommendations for total gastrectomy. Although the ability to surgically remove the at-risk organ appears to make the decision clear, the profound lifestyle changes after total gastrectomy should be emphasized and require further long-term study.

Sequelae of risk-reducing total gastrectomy

Mortality after total gastrectomy is rare in expert centers (^{Strong et al., 2017; Vos et al., 2020}). Immediate postoperative complications are infrequent and associated with higher surgical volume. The most common operative risks are bleeding, anastomotic leak, surgical site infection, and duodenal stump leak (^{Strong et al., 2017; van der Kaaij et al., 2018; Vos et al., 2020}). Nausea and bile reflux are also commonly reported in the immediate postoperative period, yet often improve with medical therapy and lifestyle changes (^{Liu and Lopez, 2022}). Unlike BRCA1/2 variant carriers who undergo risk-reducing bilateral mastectomy, total gastrectomy imparts significant dietary restrictions that require major lifestyle changes and intensive counseling by a registered dietitian. Activities of daily living must be altered to ensure adequate time to eat small, frequent meals and to maintain hydration. Post-total gastrectomy, some patients have reported difficulties returning to work due to such lifestyle changes, particularly in individuals whose jobs require long shifts with limited breaks (^{Hallowell et al., 2017}). Almost all patients lose weight after total gastrectomy due to the restrictive and malabsorptive nature of the procedure, however, most return to a normal BMI (18.5–24.9 kg/m²) by 1-year post-gastrectomy (^{Strong et al., 2017}). Parenteral supplementation or enteral nutrition via jejunal tube placement is rarely needed (^{Dann et al., 2015}). Dysphagia after gastrectomy requires additional workup with esophagogastroduodenoscopy and esophagram to rule out esophageal dysmotility, esophagojejunal anastomotic stricture, disease progression, or esophageal spasm (^{Nath et al., 2016; Hawkins et al., 2021}). Operative re-intervention is rare after prophylactic total gastrectomy. If an anastomotic leak at the esophagojejunostomy is suspected, an esophagram with water soluble contrast is performed and an esophageal stent is placed if a leak is detected. Other long-term complications requiring operative intervention are incisional hernia repair, internal hernia, abscess drainage, and wound debridement (^{Vos et al., 2020}).

Early and late dumping syndrome are common post-gastrectomy sequelae. Early dumping, defined as rapid emptying of contents into the roux-limb, causes vasomotor symptoms, abdominal pain, nausea, and diarrhea approximately 10–30 min after a meal versus late dumping results in hypoglycemia and vasomotor symptoms 2–4 h after food ingestion (^{Davis and Ripley, 2017}). Dumping syndrome is ameliorated by avoiding added sugars, thoroughly chewing food, separating fluid from solid intake, and eating soluble fiber (^{Liu and Lopez, 2022}). Most symptoms of dumping can be avoided with proper dietary counseling.

Psychosocial impact of risk-reducing total gastrectomy

Risk-reducing total gastrectomy imparts significant psychosocial costs that warrant further investigation. Relief of cancer anxiety is one obvious benefit of individuals undergoing prophylactic total gastrectomy. Interestingly, multiple studies have shown that quality of life scores decrease immediately post-gastrectomy, but often return to baseline by 6–12 months (^{Worster et al., 2014; Muir et al., 2016}). Additionally, global health status scores were reportedly similar in CDH1 patients after prophylactic total gastrectomy when compared to the general population (^{Kaurah et al., 2019}); however, certain symptoms can persist at 24 months post-total gastrectomy, such as diarrhea, fatigue, reflux, and dietary restrictions, emphasizing the long-term sequelae of this prophylactic surgery (^{Worster et al., 2014}). Chronic gastrointestinal symptoms and fatigue after total gastrectomy may also prohibit patients from returning to work full-time. This may lead not only to psychosocial distress but also financial consequences (^{Hallowell et al., 2017}). Conflicting data exist regarding changes in body image after total gastrectomy (^{Worster et al., 2014; Muir et al., 2016}). One qualitative survey found significant post-surgical weight loss affected body image, particularly in men (^{Hallowell et al., 2017}). In the same study by ^{Hallowell et al. (2017}), patients also reported that fatigue and dietary restrictions had a negative impact on relationships and the ability to socialize post-total gastrectomy. Despite the negative sequelae of total gastrectomy, most patients do not endorse long-term regret after surgery (^{Muir et al., 2016}); however, pathologic absence of cancer in the gastrectomy specimen and the occurrence of post-surgical complications have been associated with decision regret post-total gastrectomy (^{Gamble et al., 2023}).

Challenges of prophylactic surgery for cancer prevention in other hereditary syndromes

Given the paucity of data on the long-term consequences of prophylactic gastrectomy, providers must utilize lessons learned from other highly penetrant hereditary diseases such as FAP, hereditary breast and ovarian cancer, and hereditary medullary thyroid cancer for clinical guidance. Individuals with FAP, an autosomal dominant inherited disease, will develop hundreds to thousands of polyps in the colorectum and cancer by age 40 if left untreated (^{Yen et al., 1993; Lynch and de la Chapelle, 2003}). Surgical removal of the colon and rectum via total proctocolectomy with ileal pouch-anal anastomosis (IPAA) or ileorectal anastomosis is the standard of care in patients with FAP. Significant alteration of gastrointestinal anatomy at a young age and consequent lifestyle changes require management from a multidisciplinary team. Common surgical sequelae of IPAA and ileorectal anastomosis such as frequent stools, incontinence, and poor pouch function are associated with lower quality-of-life scores (^{Durno et al., 2012}). Like gastrectomy patients, overall quality of life was comparable to the general population on validated surveys, however, functional impairment at work due to persistent gastrointestinal symptoms negatively impacted mental health (^{Wolf et al., 2011; Durno et al., 2012}).

Similarly, risk-reducing bilateral prophylactic mastectomy (BPM) is recommended for BRCA1/2 carriers at risk of hereditary breast and ovarian cancer. Cumulative breast and ovarian cancer risk by age 80 was 72% and 44%, respectively in BRCA1 carriers compared to 69% and 17% in BRCA2 carriers (^{Kuchenbaecker et al., 2017}). Although BPM most effectively eliminates cancer risk, removal of healthy breasts is not without risk of surgical complications such as skin necrosis, wound infection, hematoma, and seroma formation (^{Carbine et al., 2018}). Psychosocial outcomes of BPM include a reduction in overall anxiety; however, body image and feelings of femininity have been shown to be adversely affected (^{McCarthy et al., 2017; Carbine et al., 2018}). Risk-reducing salpingo-oophorectomy (RRSO) can also result in premature menopause with lasting effects. One study found that the majority (68.9%) of women had moderate or severe menopausal symptoms up to almost 8 years post-RRSO and half reported urogenital symptoms such as burning, dyspareunia, and dysuria (^{Stuursma et al., 2018}). Furthermore, the consequences of prophylactic mastectomy and oophorectomy can have lasting impacts on patients’ physical and mental well being requiring close follow-up care.

Another hereditary cancer syndrome requiring surgery for cancer interception is hereditary medullary thyroid cancer. Germline mutations in the REarranged during Transfection (RET) proto-oncogene exhibit an autosomal dominant inheritance pattern and lead to multiple endocrine neoplasia type 2 (MEN2), a hereditary cancer syndrome comprised of medullary thyroid cancer, pheochromocytoma, and primary hyperparathyroidism. Nearly all MEN2 patients develop early-onset medullary thyroid cancer challenging surgeons to determine at what age (rather than whether) to perform total thyroidectomy (^{van Treijen et al., 2022}). The timing of surgery is dependent on each individual’s specific RET mutation risk category developed by the American Thyroid Association (ATA), in addition to calcitonin levels (^{van Treijen et al., 2022}). Total thyroidectomy should be performed at specialized centers with experienced pediatric surgeons within the first year of life for individuals with the highest ATA risk category (^{van Treijen et al., 2022}). Additionally, one study showed disease remission significantly improved in patients who underwent thyroidectomy before the age of one (^{Castinetti et al., 2019}). This emphasizes the importance and challenges of early detection of RET mutations in individuals at such a young age. The high cure rate of medullary thyroid cancer is thought to outweigh the risk of surgical complications such as hypoparathyroidism, bleeding, and rarely laryngeal nerve injury. Unlike patients who undergo total gastrectomy, prophylactic total thyroidectomy imparts few lifestyle changes including lifelong thyroid hormone replacement therapy and possibly calcium supplementation if the parathyroids are compromised.

Conclusion

Germline variants in CDH1 are likely to be identified more frequently with the widespread availability of germline genetic testing. Risk-reducing surgery for gastric cancer prevention has the potential to remove the stomach and prevent the development of advanced cancer; however, the physical and psychosocial costs of prophylactic surgery must be addressed when counseling individuals about cancer risk-reduction. Further research is needed to provide insight into the long-term sequelae of prophylactic total gastrectomy for HDGC and other hereditary cancer syndromes. Until achievements are made in cancer prevention strategies that do not require surgery, a multidisciplinary team approach to clinical management is critical prior to any surgical intervention.

Acknowledgements

This study was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute.

Conflicts of interest

There are no conflicts of interest.