Management of a CDH1 mutation carrier

E. Strong (ed.). Gastric cancer. Principles and practice. Springer (2015)

This should be carried out through a multidisciplinary team that includes but is not limited to a genetic counsellor, geneticist, gastroenterologist, surgeon, dietician and psychologist. Patients are counselled to have a prophylactic gastrectomy at the earliest achievable time. Given the high penetrance of disease and variable natural history of disease this is usually recommended for mutation carriers in their early 20s. Some patients prefer to delay gastrectomy and the only other option is endoscopic surveillance although there are significant deficiencies in this methodology at this point in time.


Early GC in HDGC usually consists of small foci of SRCs, which are usually submillimetre, intramucosal and multifocal, making it difficult to identify at routine white light endoscopy (Fig. 6.2). Case reports exist of patients who have presented with extensive DGC despite normal endoscopy with negative biopsies [113]. Multiple groups have also published series of patients undergoing prophylactic gastrectomy for CDH1 mutations, who despite normal investigations presurgery had multiple independent foci of T1a SRCC identified at pathological assessment [8, 45, 55, 66, 70, 112, 113, 127].

Gastric cancer. Principles and practice (2015) 6.2

Fig. 6.2. Signet ring cells (SRCs) with 0.3 mm mucosal focus found at prophylactic gastrectomy in a CDH1 mutation carrier (female, 26). a Low power view (H&E 50x) and b) high power view (H&E 400x) of boxed area

Current recommendations for endoscopic surveillance in patients with mutation who decline prophylactic gastrectomy, or who are less than 20 years of age, suggest that this should be performed under a research protocol if at all possible to allow evaluation of new endoscopic modalities and to allow investigation of the natural history of HDGC [7]. Endoscopy should be performed at least annually to investigate any clinically significant lesions, ideally at a centre with experience with HDGC. The entire gastric mucosa should be inspected and photographed and any suspicious lesion should be biopsied. In addition, a minimum of 30 random biopsies is recommended from the different anatomic areas of the stomach. These include: prepyloric, antrum, transitional zone, body, fundus and cardia to maximise the likelihood of finding microscopic foci of SRCs [7]. Patients should be made aware that because of the small size and multifocal nature of early SRC lesions it is likely that early lesions will not be detected by random biopsies.

There is a reported propensity of SRCC lesions at the antral–corpus or body–antral junction but this has not been independently validated. Charlton et al. examined six gastrectomy specimens and reported that the distal third of the stomach contained 48% of total foci [66]. The body–antral transitional zone, which occupied 7.7% of the mucosal area, contained 37% foci, and had the largest foci. They concluded that targeting the transition zone would maximise the likelihood of finding microscopic foci of SRCs in HDGC patients. This has not been replicated in other studies. Carniero et al. found no anatomical clustering in nine gastrectomy specimens [111]. Rogers et al. and Barber et al. examining eight gastrectomy specimens each noted a higher prevalence of foci of SRCs in the proximal stomach [49, 127]. As yet the reasons behind the different anatomical clustering of lesions have not been identified, and may represent the different ethnic and geographic origins of the patients, and differing environmental exposures. On the basis of current evidence, anatomical targeting of otherwise normal mucosa cannot be recommended; hence multiple biopsies of all areas of the stomach are suggested in addition to targeted biopsies of obvious lesions.

Chromoendoscopic techniques have also been trialled as a method of improving endoscopic surveillance. Using a methylene blue and congo red technique Shaw et al. were able to identify foci of carcinoma > 4 mm not visualised on white light endoscopy [128]. These results have not been replicated in another study [50], and due to concerns of carcinogenic potential of both congo red and methylene blue these are not recommended [129, 130]. At this time chromoendoscopy cannot be recommended outside a clinical trial.

Positron emission tomography (PET) has been investigated as a potential surveillance method. In one case report fluoro-2-deoxy-D-glucose (FDG)-PET was able to identify early GC in an asymptomatic CDH1 mutation carrier [131]. This has not been replicated in other studies, with reports of patients with negative FDG-PET scans harbouring foci of malignancy at pathological review [8, 24]. Currently no imaging technique is satisfactory for surveillance in HDGC, and should only be included in a research protocol.

The best surveillance includes careful endoscopic examination of the stomach with insufflation and suction of the stomach to ensure no linitus plastica with both targeted and random biopsies of regions representing the entire stomach.

Prophylactic total gastrectomy

Patients who develop symptomatic DGC have a poor 5 year survival of approximately 10% despite current treatments, with the majority dying before the age of 40 [132]. In view of the poor survival once symptomatic and the lack of effective surveillance for mutation carriers, prophylactic gastrectomy is recommended to all mutation carriers. As noted above, although performed with prophylactic intent, most published series find foci of DGC or SRCC in gastrectomy specimens, even in those patients who have undergone extensive presurgical screening, however most show only T1N0 disease [8, 45, 55, 66, 70, 112, 113, 127]. Preoperatively all patients should undergo endoscopy to exclude gross abnormalities, have random biopsies performed and to delineate the gastro–oesophageal junction [126]. CT of the abdomen to exclude lymphadenopathy or other disease in otherwise young patients is not always necessary.

The below discussion is specific to prophylactic gastrectomy and not gastrectomy for established GC (for a discussion on gastrectomy and postoperative management see Part III: Gastric resection and postoperative management). Gastrectomy for HDGC should be performed in a centre with expertise in the surgery and low operative mortality. Gastrectomy must be total, as SRCs can be found throughout the entire stomach and any remnant stomach would maintain the risk for DGC. The proximal resection margin must transect the oesophagus to ensure no gastric mucosa is left behind [133, 134]. In the prophylactic setting, D2 nodal dissection is not necessary as no lymph node metastases have yet been observed, therefore only lymph nodes harvested during the gastric resection should be removed [7, 135]. Currently Roux-en-Y reconstruction in an open procedure should be standard. Any surgeon proposing laparoscopic prophylactic gastrectomy, or alternative surgical reconstruction must be able to reassure the patient with audited data that this does not involve additional risk [7].

Patients need to be counselled about the shortand long-term morbidity and mortality of gastrectomy. This is part of the function of the multidisciplinary team, including genetic counsellor, psychologist, gastroenterologist, gastric surgeon, dietician and specialist nurse. It may also be helpful for patients to discuss the procedure with other individuals who have had the same operation. The early and late complications of gastric resection are documented in detail in Chaps. 20 and 22. In the setting of HDGC and prophylactic gastrectomy, it must be remembered that patients undergoing this procedure are likely to be significantly younger than patients undergoing gastrectomy for sporadic GC, and therefore the long-term consequences of morbidity from the procedure may be different, and potentially greater. In the prophylactic setting mortality from gastrectomy should be no more than 1% [10]. In addition to the mortality risk, patients must be informed about potential operative complications including haemorrhage, anastomotic leak and/ or stricture and anaesthetic complications [126]. The long-term morbidity from total gastrectomy is substantial but often transient with 100% of patients experiencing a variable degree of weight loss, alteration in eating habits, dumping syndrome and nutritional deficiencies in vitamin B12, iron, thiamine and zinc [44]. These must be discussed and managed, emphasising the importance of a dietician. After surgery physical function usually returns to normal by approximately 6 months [7]. Psychological aspects of gastrectomy can have a profound effect on individuals particularly on the issue of body image that may need specific psychological input.

One concern that may affect the timing of prophylactic gastrectomy in female mutation carriers is the preservation of fertility. Patients may wish to postpone gastrectomy until after childbearing is complete. However, there are reports of successful pregnancy following prophylactic gastrectomy for HDGC [136], and after gastrectomy for other reasons [137, 138]. Maternal anaemia was the only significant complication potentially related to the previous gastrectomy, and appropriate monitoring and supplementation for nutritional deficiencies is recommended [136].

The optimal timing of prophylactic gastrectomy is unknown. However, in most kindreds it is thought the risk of GC before age 20 is less than 1%, and therefore, the mortality risk from the surgery is higher than the risk reduction from surgery before the age of 20 [10]. At present, consensus recommendations are for surgery to occur after the age of 20, although the earliest onset of GC in each family must be considered [7]. There is no absolute contraindication to prophylactic total gastrectomy in the setting of HDGC.

The importance of comprehensive pathological review of the gastrectomy specimen cannot be understated. This is shown by the publication of a case initially reported as showing nonpenetrance, and the discussion of publication bias accounting for lack of similar cases being published [139, 140]. The specimen was subsequently reviewed in more detail and four foci of b) intramucosal carcinoma and three foci of in situ carcinoma were identified [139]. Processing and reporting of gastrectomy specimens should follow specific guidelines, including full specimen photography to allow for accurate mapping of any foci of carcinoma. Figure 6.3 shows a gas trectomy specimen with the location of invasive foci of SRCs identified. The pathology report should document status of the margins, any features of invasive carcinoma including site, histological subtype, lymphatic, venous or neural invasion, precursor lesions, and features of the non-neoplastic mucosa, including H. pylori, intestinal metaplasia, and gastritis [7]. If there are lymph nodes in the specimen, they should also be sampled. If the entire stomach is not sampled, and no evidence of carcinoma is found, this should be reported as no carcinoma found in the proportion of mucosa examined, not negative for carcinoma [7].

Follow-up postgastrectomy is essential to monitor for nutritional deficiencies or other late presenting side effects [134].

Gastric cancer. Principles and practice (2015) 6.3a

Gastric cancer. Principles and practice (2015) 6.3b

Fig. 6.3. Prophylactic gastrectomy specimen from a CDH1 mutation carrier (female, 22). a Stomach map diagram demonstrating location of foci of invasive signet ring cells (SRCs) within mucosa (M), large dot represents 10 mm focus with invasion into submucosa (SM). b) Low power (H&E 50x). c) High power (H&E 400x)

Breast cancer surveillance

The cumulative lifetime risk of LBC for female CDH1 mutation carriers is thought to be 60% by age 80 [7]. Screening for breast cancer is recommended to begin at age 35, although the exact age that risk starts increasing is unknown. Screening for LBC should include monthly self-examinations, 6th monthly examinations by a physician and annual mammography and MRI from the age of 35 [7, 18, 134]. MRI is recommended as lobular breast cancer may be missed on mammogram [141]. Prophylactic mastectomy has been performed in some women with CDH1 mutations, but its role in HDGC is still uncertain [48, 142]. Most LBCs are oestrogen receptor positive, but there is insufficient evidence to recommend chemoprevention with tamoxifen as yet [7, 142].

Knowledge Gaps

Our understanding of the biology of HDGC has significant gaps that impact on the management of patients. A better understanding of the additional factors that influence penetrance, both environmental and genetic, will help in determining which patients require total gastrectomy and the timing of gastrectomy. Understanding the rate of progression of SRCC to DGC would have implications for timing of surgery for patients but at this point it appears quite variable from patient to patient.

Current methods for surveillance for GC are insensitive, necessitating prophylactic gastrectomy in asymptomatic patients. Improved surveillance methods may allow for gastrectomy to be postponed, thereby postponing the morbidity and mortality risk associated with the procedure. In addition, for LBC, the information available to guide surveillance, potential chemotherapeutic strategies, and the utility of surgical prophylaxis is limited. These are all areas where improved knowledge has potential in alter patient treatment and outcome. Equally, the knowledge on risks of other cancers, in particular colorectal cancer, in HDGC is limited. Therefore, it is unknown whether screening for extra-gastric malignancies, in particular colorectal cancer, needs to be more intensive in HDGC families than what is offered to the general population.

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