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Surgical management of hereditary diffuse gastric cancer

Surgical management of hereditary diffuse gastric cancer
Literature review current through: Jan 2024.
This topic last updated: Dec 13, 2023.

INTRODUCTION — Diffuse gastric carcinoma (DGC) is a highly invasive tumor that is characterized by a late presentation and poor prognosis [1]. An inherited form of DGC, hereditary diffuse gastric cancer (HDGC), can be caused by pathogenic variants in the cadherin-1 (CDH1) gene [2-4] or the alpha catenin (CTNNA1) gene [5].

The lifetime risk of developing gastric cancer for carriers of a CDH1 pathogenic variant from HDGC families is high. By the 2010 HDGC clinical criteria, 70 percent of males and 56 percent of females will develop gastric cancer by age 80 [6]; by the less stringent 2015 HDGC clinical criteria, 42 percent of males and 33 percent of females will develop gastric cancer by age 80 [7,8]. As such, prophylactic total gastrectomy is often recommended at an early age [9-14].

The surgical management of HDGC will be reviewed here. The genetics and pathogenesis of HDGC, as well as issues related to screening for HDGC and surveillance for breast and other cancers in CDH1 mutation carriers, are discussed separately. (See "Hereditary diffuse gastric cancer" and "Gastric cancer: Pathology and molecular pathogenesis", section on 'Hereditary diffuse gastric cancer'.)

INDICATIONS FOR PROPHYLACTIC TOTAL GASTRECTOMY — The management strategy for suspected or confirmed hereditary diffuse gastric cancer (HDGC) is outlined briefly below but discussed in detail elsewhere (algorithm 1). (See "Hereditary diffuse gastric cancer", section on 'Management of CDH1 variant carriers'.)

CDH1 pathogenic variant carrier from HDGC family – Prophylactic total gastrectomy is the recommended approach [15-17]. (See "Hereditary diffuse gastric cancer", section on 'Diffuse gastric cancer in the family'.)

CDH1 pathogenic variant carrier not from HDGC family – With the inclusion of CDH1 on many multigene cancer panels [18-20], individuals may be identified as having a CDH1 pathogenic variant but may not have a personal or family history of diffuse gastric cancer [21]. For such individuals, endoscopic surveillance rather than upfront prophylactic total gastrectomy is generally the preferred approach, but patients may seek individualized evaluation at an experienced center for consideration of prophylactic total gastrectomy [16-18,20-22]. (See "Hereditary diffuse gastric cancer", section on 'No family history of diffuse gastric cancer'.)

CDH1 variant of unknown significance carrier – Endoscopic surveillance rather than upfront prophylactic total gastrectomy is generally the preferred approach [16,23,24]. (See "Hereditary diffuse gastric cancer", section on 'Variants of uncertain significance or HDGC-like families'.)

HDGC-like family member and first-degree relative – HDGC-like families are defined as fulfilling HDGC genetic testing criteria but having no identified CDH1 or CTNNA1 pathogenic variant. Such families must have at least one confirmed case of diffuse gastric cancer and another gastric cancer or lobular breast cancer in first-degree or second-degree relatives. Endoscopic surveillance rather than upfront prophylactic total gastrectomy is generally the preferred approach [16].

CTNNA1 pathogenic variant carrier – The role of gastrectomy for carriers of the CTNNA1 pathogenic variant is less well established, and the decision about prophylactic total gastrectomy versus endoscopic surveillance is individualized and is influenced by the penetrance of diffuse gastric cancer in the family. (See "Hereditary diffuse gastric cancer", section on 'Carriers of CTNNA1 pathogenic or likely pathogenic variants'.)

TIMING OF PROPHYLACTIC TOTAL GASTRECTOMY — Prophylactic gastrectomy is often advised as early as age 20. However, patients recommended for prophylactic gastrectomy may refuse or wish to postpone surgery. For patients who wish to delay prophylactic total gastrectomy, age, fertility considerations, family phenotypes (especially the age of onset of clinical cancer in probands), and preexisting nutritional disorders should also be taken into account. The estimated risk of neoplastic disease and the anticipated reduction in risk that is achieved through surgical intervention should be weighed against the negative outcomes of surgery, including complications associated with total gastrectomy and gastrointestinal reconstruction. (See "Postgastrectomy complications".)

Age — Patient age, especially at both extremes, should be a consideration in any discussion of prophylactic total gastrectomy. As with other inherited cancer susceptibility syndromes, the age at which a prophylactic procedure is recommended should be based upon the presence of a known pathogenic mutation and the age of onset of disease in the pedigree [25]. The potential physical and psychological ramifications of a total gastrectomy should be balanced with the penetrance pattern of a particular kindred.

Young patients — Prophylactic gastrectomy is often advised as early as age 20 [16,26]. Although the mean age of onset of diffuse gastric cancer documented in the literature is approximately 38, there are certain kindreds in which the mean age of onset is much younger [27]. Early prophylactic total gastrectomy may be justified in such kindreds due to the observation that disease tends to develop at a younger age in successive generations of affected individuals, a phenomenon referred to as genetic anticipation. Some suggest timing total gastrectomy in CDH1 mutation carriers at an age that is five years younger than that of the youngest family member who developed gastric cancer [28,29].

Older patients — Older patients are less likely to benefit from a prophylactic gastrectomy than younger patients because of a shorter life expectancy and a higher perioperative risk.

Although the upper age limit for performing prophylactic gastrectomy is not well defined, some guidelines recommend that patients who are older than 70 years should not undergo such a procedure, as their mortality from the procedure may outweigh their mortality from gastric cancer [16].

Decisions about prophylactic gastrectomy in middle-aged and older patients who are younger than 70 years should be individualized based upon their comorbidities and the age of gastric cancer onset in their respective kindred. If the onset of disease in the family is early, older patients may live out their natural life expectancy without ever developing gastric cancer.

Eating disorders — As patients can be expected to lose 10 to 15 percent of their body weight following total gastrectomy, those with eating disorders such as bulimia and anorexia nervosa are at high risk of developing physical and/or psychological complications after surgery [30,31]. Thus, the potential risk of gastric cancer must be weighed against the severity of eating disorders before a prophylactic gastrectomy is carried out.

We do not perform total gastrectomy in patients who are malnourished, actively losing weight, or who have a body mass index less than 18 to 20 kg/m2. In addition, for any patient with a known or suspected eating disorder, we pursue psychiatric assessment and close collaboration with an established multidisciplinary eating disorder treatment team to give the patient the best chance of achieving long-term healthy weight control. (See 'Nutritional evaluation and counseling' below.)

Women of childbearing age — Total gastrectomy is known to cause weight loss, and low body weight is a known risk factor for female infertility (see "Female infertility: Treatments", section on 'Low body weight'). Nevertheless, gastric surgery does not preclude future pregnancy. At least three pregnancies following prophylactic total gastrectomy have been described [32]. All three delivered normal infants at term. In addition, over 150 pregnancies after gastrectomy for various other indications have also been reported [32-34].

Thus, for those of childbearing age, the risk of infertility must be balanced against the risk of developing a likely fatal cancer. Given that this cancer can strike in childbearing years and has high fatality, people are waiting longer before birthing their first child, and that there is no good evidence that the surgery impacts fertility, we do not advise delaying prophylactic total gastrectomy (eg, until having all desired children or after having at least one child).

For those who become pregnant after gastric surgery, appropriate monitoring and supplementation for nutritional deficiencies is required to avoid maternal anemia and fetal malformation (eg, neural tube defects from folate deficiency). An interval of 6 to 12 months is recommended between prophylactic total gastrectomy and future pregnancy. (See "Fertility and pregnancy after bariatric surgery", section on 'Micronutrient supplementation'.)

PREOPERATIVE EVALUATION — Patients contemplating prophylactic total gastrectomy should be evaluated and managed by a multidisciplinary team that includes primary care providers, medical specialists, surgeons, geneticists, nutritionists, and psychologists.

Genetic and family counseling — Hereditary diffuse gastric cancer (HDGC) is inherited in an autosomal dominant fashion, with most cases resulting from germline pathogenic variants in the CDH1 gene [2-4]. HDGC should be suspected in any case of diffuse gastric cancer diagnosed in a patient under the age of 50 years and prompt genetic testing of the patient and family members [13,16]. Specific criteria for genetic testing for CDH1 pathogenic variants in patients with suspected HDGC are addressed elsewhere. (See "Hereditary diffuse gastric cancer", section on 'Genetic counseling and testing'.)

Female members of the kindred should be made aware that the risk for lobular breast cancer is also increased. Females with CDH1 germline pathogenic or likely pathogenic variants have a 43 to 55 percent risk of developing lobular breast cancer by age 80 [7,8]. Most guidelines suggest that mutation carriers be managed as are other females with high-risk inherited conditions such as BRCA mutations [15]. (See "Cancer risks and management of BRCA1/2 carriers without cancer".)

Nutritional evaluation and counseling — Nutritional counseling should be provided by an experienced dietician to educate the patient about potential long-term nutritional deficiencies after total gastrectomy [35]. Micronutrients most commonly depleted after total gastrectomy include several water-soluble vitamins (eg, vitamin B12), fat-soluble vitamins (eg, vitamins A, D, E, and K), and trace minerals, including iron and calcium. A detailed discussion of postgastrectomy nutrient deficiencies is presented elsewhere. (See "Bariatric surgery: Postoperative nutritional management", section on 'Micronutrient management'.)

The patient should also be educated about other postgastrectomy complications, which are expected to occur to a greater or lesser extent in almost everyone who undergoes total gastrectomy [36]. Dietary and medical therapies are usually effective in dealing with most postgastrectomy syndromes. Surgical reintervention is rarely needed. (See "Postgastrectomy complications".)

It is important for the patient to be aware that recovery from prophylactic total gastrectomy and return to a new "normal" eating pattern may take up to one year, during which time they are expected to lose 10 to 20 percent of their body weight [17]. It is advisable that patients speak with others who have undergone this operation and who will be able to act as a source of support during recovery from the operation.

Preoperative imaging and endoscopy — Preoperative preparation for prophylactic total gastrectomy includes abdominal imaging, upper endoscopy, and colonoscopy to ensure there is not an undiagnosed malignancy, as this would markedly change the operative approach. (See 'Patients who have known invasive gastric cancer' below.)

Abdominal imaging — The patient being evaluated for prophylactic gastrectomy should undergo computed tomography (CT) evaluation of the abdomen preoperatively to rule out the presence of a mass or any other signs of malignancy, such as lymphadenopathy, peritoneal carcinomatosis, or liver metastasis [13]. Positron emission tomography (PET) scanning can be performed for further staging, but only if gastric cancer is suspected by CT imaging or endoscopy.

Endoscopy — Preoperative evaluation prior to prophylactic gastrectomy should include upper endoscopy with at least 30 biopsies taken randomly from the antrum, incisura, fundus, and body of the stomach as well as any grossly abnormal (eg, pale) areas [16,37].

For all patients in whom total gastrectomy is anticipated, the gastroesophageal junction should be carefully examined by upper endoscopy, and the presence of Barrett esophagus or hiatal herniation should also be noted. A shortened esophagus will alter the surgical approach and may require extension of the incision into the thorax. If magnifying endoscopy methodology (eg, narrow band imaging, chromoendoscopy) is available, it can be used as a part of the endoscopic evaluation [38]. (See "Barrett's esophagus: Evaluation with optical chromoscopy" and "Chromoendoscopy".)

GASTRECTOMY AND RECONSTRUCTION — Prophylactic total gastrectomy should be performed by a surgeon who is familiar with hereditary diffuse gastric cancer (HDGC) and performs the procedure on a regular basis.

Margins of resection — Because the CDH1 pathogenic variant is present in all gastric tissues, the surgeon must be sure to remove the entire stomach during prophylactic gastrectomy. The distal margin of resection should be carried to duodenal mucosa least 1 cm beyond the pylorus [6]. Before gastrointestinal reconstruction, frozen section should be obtained of the proximal margin to confirm squamous esophageal mucosa and a lack of residual gastric mucosa, which increases the risk for future malignancy.

In a review of 29 prophylactic gastrectomies, three patients required reintervention due to incomplete removal of proximal gastric mucosa [39]. In another study of 44 cases, intraoperative frozen section of the proximal margin identified residual gastric mucosa in two patients and occult malignancy in one [17].

Minimally invasive versus open gastrectomy — Prophylactic total gastrectomy in otherwise asymptomatic patients may be an ideal situation for the minimally invasive approach since perigastric lymph node harvest is not necessarily needed in the absence of invasive disease [40]. (See 'Extent of lymph node dissection' below.)

At experienced centers, minimally invasive prophylactic total gastrectomy has been used to treat asymptomatic carriers of a CDH1 pathogenic variant with a family history of HDGC in up to 40 percent of cases [17,41]. Compared with open surgery, minimally invasive prophylactic total gastrectomy was associated with longer operative time but shorter hospital stay and greater lymph node recovery [17]. Nevertheless, minimally invasive surgery impacts mostly short-term rather than long-term outcomes. Thus, the surgical approach is not as important as the experience of the surgeon.

The techniques of minimally invasive gastrectomy are discussed elsewhere. (See "Laparoscopic gastrectomy for cancer".)

Extent of lymph node dissection — In the absence of a confirmed invasive malignancy, the approaches to lymph node dissection for prophylactic gastrectomy vary greatly by surgeon preference:

We perform a conservative harvest of perigastric nodal tissue along the greater and lesser curves of the stomach but preserve the omentum. Such a practice provides reasonable nodal sampling in case an occult malignancy is found on final pathology but does not expose the patient to unnecessary harm that may be associated with a more extensive lymph node dissection.

Some surgeons do not perform a formal lymph node dissection, taking only those lymph nodes that are harvested during the course of gastric resection. This approach may be reasonable because the majority of these patients will have no more than pT1a cancers (table 1), from which no lymph node metastases have been reported [26].

Other surgeons advocate a D1 (perigastric nodes plus omentum) or D1+ (D1 plus left/right gastric artery and hepatic artery nodes) lymph node dissection with prophylactic gastrectomy just in case T1b or higher-stage disease is found on final pathology [16]. Preoperative upper endoscopy cannot exclude pT1b lesions (table 1), which carry a higher risk of lymph node metastases (17 to 28 percent of cases depending on depth of submucosal invasion [42]). (See "Early gastric cancer: Epidemiology, clinical manifestations, diagnosis, and staging".)

In any case, a D2 lymph node dissection is not performed in the absence of confirmed malignancy, due to higher associated morbidities [16]. The approaches to therapeutic lymph node dissection (eg, D1 versus D2) for invasive gastric cancer patients are controversial and are discussed in another topic. (See "Surgical management of invasive gastric cancer", section on 'Extent of lymph node dissection'.)

Reconstruction — Following total gastrectomy for any indication, the ideal method of reconstruction preserves duodenal and jejunal continuity and provides a functional reservoir to minimize functional and nutritional disturbances [36,43,44]. Gastrointestinal reconstruction following total gastrectomy is not standardized. The various techniques for reconstruction following total gastrectomy are discussed elsewhere. (See "Total gastrectomy and gastrointestinal reconstruction", section on 'Gastrointestinal reconstruction'.)

Following total gastrectomy for hereditary diffuse gastric cancer, we prefer to use a Roux-en-Y esophagojejunostomy with pouch reconstruction when feasible (figure 1). Jejunal pouch reconstruction may provide some quality-of-life benefits in the short term [44,45] but is not universally endorsed. A temporary feeding jejunostomy tube may be placed for postoperative nutritional support in patients who are expected to have a complicated or delayed recovery.

Pathology — The surgical specimen of a prophylactic total gastrectomy should be analyzed following a specific institutional protocol. Both the World Health Organization (WHO) and Lauren classifications should be reported [46,47]. Most lesions in HDGC are tiny foci of typical signet cells confined to the superficial lamina propria, rather than infiltrating the muscularis mucosae. By contrast, advanced HDGC predominantly presents as linitis plastica [16]. (See "Gastric cancer: Pathology and molecular pathogenesis".)

OUTCOMES — Prophylactic total gastrectomy performed for carriers of a CDH1 pathogenic or likely pathogenic variant carries a perioperative mortality rate of 0 to 2.5 percent [12,17,48], a perioperative morbidity of rate of about 30 percent [17,48], and a long-term morbidity rate of about 20 percent [17,48].

For patients presenting with a clinically detected cancer, the outcome is significantly reduced. More specifically, a retrospective study of 99 pathogenic CDH1 variant carriers within the FREGAT (FRench Eso-GAsTric tumor) network reported that the prognosis of the index patients is dismal, with a median survival of 12 (7.6 to 16.4) months because peritoneal carcinomatosis was present in 71 percent at diagnosis. Among the 77 nonindex patients who underwent prophylactic total gastrectomy, cancer was detected on specimens in 54.5 percent (n = 42, all pT1a), of which 59.5 percent had no cancer detected on preoperative endoscopy (n = 25) [49].

Major complications after total gastrectomy include surgical site infection, anastomotic leak and sepsis, and late esophageal stricture [30,50]. The major potential long-term morbidities associated with total gastrectomy include some degree of malabsorption, dumping syndrome, diarrhea, and a 10 to 20 percent decrease in body weight [17,31,50]. (See "Postgastrectomy complications".)

Studies of patient-reported outcomes and attitudes in patients having undergone prophylactic gastrectomy have shown favorable physical and psychological recovery from the procedure, with the majority of patients generally feeling positive about their decision [48,51-53]. In reported series, only 6 to 10 percent of patients report worse quality of life after the procedure or regret their decision to have surgery [48,54].

PATIENTS WHO DEFER OR REFUSE SURGERY — For patients at risk for hereditary diffuse gastric carcinoma (HDGC) who refuse or wish to delay prophylactic total gastrectomy, we suggest close endoscopic surveillance.

The suggested endoscopic protocol, based on limited data, calls for annual white-light high-definition endoscopic examination with 28 to 30 biopsies (three to five from cardia, five from fundus, 10 from body, five from transition zone, and five from antrum) evaluating for intramucosal signet ring cell carcinoma (SRCC) [6,16,55].

However, patients must be fully educated about the shortcomings of this approach. The theoretical number of biopsies necessary to discover one focus of SRCC was estimated at 1768 (range 50 to 5832) at a 90 percent detection rate [56]. Further, multiple mucosal biopsies have failed to identify SRCC that lies beneath an intact mucosal lining in many carriers of a CDH1 pathogenic variant who are undergoing prophylactic total gastrectomy [9,11-13]. We suggest periodically revisiting the option of surgery with patients who initially declined it as they may reconsider when life circumstances permit [52]. (See "Hereditary diffuse gastric cancer", section on 'Endoscopic assessment'.)

Occasionally a patient followed endoscopically for HDGC will have a biopsy that is positive for intramucosal SRCC but lack endoscopic evidence of erosion, a disturbed vascular and pit pattern, or histopathologic signs of invasion into or beyond the muscularis mucosa (T1a). We typically advise such patients to undergo prophylactic total gastrectomy because accurate local staging is difficult with HDGC. For those who still wish to forego gastrectomy after appropriate counselling, guidelines recommend repeating endoscopic surveillance at six-month intervals [16].

PATIENTS WHO HAVE KNOWN INVASIVE GASTRIC CANCER — Patients with a family history of hereditary diffuse gastric cancer who have biopsy-proven invasive gastric cancer should be staged and managed according to guidelines set for nonhereditary gastric cancer and should undergo a therapeutic (as opposed to prophylactic) total gastrectomy with appropriate levels of lymph node dissection.

The indications for and techniques of gastrectomy in patients with proven gastric cancer are discussed elsewhere. (See "Surgical management of invasive gastric cancer".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Gastric cancer" and "Society guideline links: Gastric surgery for cancer".)

SUMMARY AND RECOMMENDATIONS

Definition – Hereditary diffuse gastric cancer (HDGC) is an inherited form of diffuse type gastric cancer, which results from a germline pathogenic or likely pathogenic variant of the cadherin-1 (CDH1) gene or the alpha catenin (CTNNA-1) gene. (See 'Introduction' above.)

Management – The management of asymptomatic individuals with either a pathologic variant of the CDH1 or CTNNA-1 gene and/or a family history of diffuse gastric cancer is discussed (algorithm 1). (See 'Indications for prophylactic total gastrectomy' above and "Hereditary diffuse gastric cancer", section on 'Management of CDH1 variant carriers'.):

Timing of surgery – The optimal timing of prophylactic total gastrectomy for patients at risk of developing HDGC is as early as age 20. However, a patient's age, fertility considerations, family phenotype (especially the age of onset of clinical cancer in probands), and preexisting nutritional disorders should also be taken into account when making a decision for surgery. (See 'Timing of prophylactic total gastrectomy' above.)

Preoperative workup – Preoperative computed tomography (CT) imaging and upper and lower endoscopy are carried out to exclude occult malignancy. Upper endoscopy is also used to assess the location of the gastroesophageal junction to determine the best surgical approach. (See 'Preoperative imaging and endoscopy' above.)

Surgical techniques:

Gastrectomy – During prophylactic total gastrectomy, the surgeon must ensure that the entire stomach is removed. The proximal (esophageal) and distal (duodenal) margin must be checked by frozen section to ensure that it is free from any residual gastric tissue. (See 'Margins of resection' above.)

Lymphadenectomy – The extent of lymph node dissection required for asymptomatic patients undergoing prophylactic total gastrectomy is controversial. We perform a conservative nodal sampling of perigastric nodes but preserve the omentum. (See 'Extent of lymph node dissection' above.)

Reconstruction – Following total gastrectomy in patients undergoing prophylactic gastrectomy, gastrointestinal reconstruction is not standardized. Jejunal pouch reconstruction may provide short-term quality-of-life benefits and is our preferred method of reconstruction following prophylactic total gastrectomy for HDGC. (See 'Reconstruction' above and "Total gastrectomy and gastrointestinal reconstruction", section on 'Gastrointestinal reconstruction'.)

Surgical outcomes – Prophylactic total gastrectomy performed for CDH1 mutations carries a perioperative mortality rate of 0 to 2.5 percent, a perioperative morbidity rate of about 30 percent, and a long-term morbidity rate of about 20 percent. The majority of patients show physical and psychological recovery from the procedure at 12 months after surgery and feel positive about their decision to have surgery. (See 'Outcomes' above and "Total gastrectomy and gastrointestinal reconstruction", section on 'Perioperative morbidity and mortality' and "Postgastrectomy complications".)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Debrah Wirtzfeld, MD, MSc, FRCSC, FACS, who contributed to an earlier version of this topic review.

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Topic 8041 Version 31.0

References

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