Treatment involves EGD and colonoscopic removal of polyps (probably all those >0.5 or 1 cm in diameter) (185). Clearing of all polyps is preferable but not always possible. Colectomy is sometimes necessary to control colonic polyps and should be considered if colonoscopic management is difficult and especially if neoplastic change is found in colonic polyps. Intussusception is the primary complication of small bowel polyps, starting at a young age, and continuing throughout life (188). Surveillance and treatment of the small bowel are based in large part on prevention of this complication. In the recent study by van Lier et al. (188), the initial episode of intussusception occurred at a median age of 16 years (range, 3–50 years), with 50% of first episodes presenting by age 20 years. Of all intussusceptions, 80% presented as an acute abdomen and the average polyp size causing this complication was 3.5 cm (range, 15–60 cm). When small bowel intussusceptions occur, surgery is often necessary and should include careful examination of the entire small bowel to eliminate all significant polyps. Intraoperative endoscopy is often a helpful adjunct to accomplish extensive polyp removal. This is also an appropriate time to examine and remove gastric and duodenal polyps of significant size (201). The advent of video capsule endoscopy, double balloon enteroscopy, and CT enterography is changing diagnostic and management approaches to PJS by allowing earlier detection of polyps and nonoperative removal in many cases (202, 203, 204, 205).
Chemoprevention approaches to decrease polyp burden in PJS are under study but not yet a reality. PJS polyps exhibit overexpression of COX-2, suggesting that COX-2 inhibitors may be useful in reducing polyps (206). Hyperactivation of the mammalian target of rapamycin has been associated with PJS. In addition, inhibition of mammalian target of rapamycin in a PJS mouse model has demonstrated decreased polyp burden (207). Everolimus, a mammalian target of rapamycin inhibitor, is under study as a potential agent for treatment of PJS (182).
JPS is an autosomal-dominantly inherited condition where multiple juvenile polyps are found in the colorectum (98%), stomach (14%), jejunum and ileum (7%), and duodenum (7%) (183, 208, 209, 210). The incidence of JPS is between 1 in 100,000 and 1 in 160,000 individuals (210). The polyps in JPS vary in size from small sessile nodules to pedunculated lesions that are ≥3 cm in diameter. Most large polyps are pedunculated, but small polyps, especially those in the stomach, are sessile. Grossly, most polyps exhibit a surface that is smooth, rounded, reddish colored, and without fissures or lobulations; large polyps may appear to be multilobulated. A white exudate is often seen on the polyp surface. On cut section, there are cystic spaces filled with mucin. Microscopically, there is abundant lamina propria with benign but often elongated and cystically dilated glands and lack of a smooth muscle core. Excess chronic inflammatory cells are sometimes present. The epithelial lining of the surface and cysts is nondysplastic and reflects the area of the GI tract where the polyp is located. Polyps begin to appear in the first decade of life, and dozens to many hundreds of polyps are present in the fully developed syndrome. Most patients develop symptoms in the first two decades of life. The average age at diagnosis is 18.5 years but may be later. Rectal bleeding with anemia is the most common presenting symptom, followed by abdominal pain, diarrhea, passage of tissue per rectum, and intussusception (183, 208). The majority of colonic polyps, 70% in one study, occurred in the proximal colon (210).
The generally accepted clinical criteria for JPS include: (i) at least five juvenile polyps in the colorectum; (ii) juvenile polyps in other parts of the GI tract; or (iii) any number of juvenile polyps in a person with a known family history of juvenile polyps (210).
Genetic testing is particularly important in JPS, both to confirm the diagnosis in a proband and to test relatives. Testing is also important to separate JPS from other conditions in which juvenile polyps form, especially CS and Bannayan–Riley–Ruvalcaba syndrome. Once a disease-causing mutation is identified in a patient with JPS, other family members should undergo mutation-specific testing to determine whether the disease is present or absent so that appropriate surveillance can be undertaken.
15. Surveillance of the GI tract in affected or at-risk JPS patients should include screening for colon, stomach, and small bowel cancers (strong recommendation, very low quality of evidence).
16. Colectomy and IRA or proctocolectomy and IPAA is indicated for polyp-related symptoms, or when the polyps cannot be managed endoscopically (strong recommendation, low quality of evidence).
17. Cardiovascular examination for and evaluation for hereditary hemorrhagic telangiectasia should be considered for SMAD4 mutation carriers (conditional recommendation, very low quality of evidence).
JPS mutation carriers have a very high risk for colon cancer and an increased risk for gastric, duodenal, and pancreatic cancers (Tables 5 and 7). The cancer risk in JPS is believed to arise from adenomatous tissue within the juvenile polyp, as up to 50% of juvenile polyps in JPS contain areas of adenomatous change. The risk of colon cancer is 17–22% by age 35 years and approaches 68% by age 60 years (183, 220). The mean age of colon cancer is 34 years, with a range of 15 to 68 years. Gastric cancer risk is 30% in those with SMAD4 mutations (183, 210). The median age of upper GI carcinoma is 58 years, with a range of 21 to 73 years (221, 222).
CS and its variants, including Bannayan–Riley–Ruvalcaba syndrome and PTEN hamartoma tumor syndrome (PHTS), have been associated with a broad range of clinical phenotypes. Colonic polyps are found in up to 95% of CS patients undergoing colonoscopy (224, 225). Polyps are few to numerous (even hundreds) and are distributed throughout the colon. The natural history of polyps is not well characterized, although polyps may occur at a young age. Hamartomatous polyps are the most common histologic type, occurring in up to 29% in one study (224). Polyp types include juvenile polyps, ganglioneuromas, adenomas, and inflammatory polyps (224, 226, 227), and less commonly leiomyomas, lipomas, and lymphoid polyps (228). Hyperplastic polyps have also been reported as an association, but have not been observed in all studies (224, 227). The majority of CS patients have multiple synchronous histologic types at colonoscopy.
Several investigations report the frequent finding of multiple hamartomatous polyps in the stomach, duodenum, and small bowel (183, 224, 229). Similar to the colon, histologies include hamartomas, hyperplastic polyps (different from colonic hyperplastic polyps), ganglioneuromas, adenomas, and inflammatory polyps. An upper GI study of 10 phosphate and tensin homolog (PTEN) mutation-positive patients found all 10 to have multiple hyperplastic gastric polyps and 3 to have multiple hamartomatous polyps in that location (227). One patient had a single hamartomatous polyp in the duodenum whereas three had adenomatous polyps. There are reports of gastric and colon cancers in CS patients (183, 230).
18. Surveillance in affected or at-risk CS patients should include screening for colon, stomach, small bowel, thyroid, breast, uterine, kidney, and skin (melanoma) cancers (conditional recommendation, low quality of evidence).
Management of PHTS involves prevention and early detection of the associated cancers through surveillance. Colon cancer has not been associated with CS historically (183), although recent studies have indeed shown increased risk for this malignancy. One multicenter study found 13% of PTEN mutation carriers to have colon cancer, all younger than 50 years of age (224). Investigations have now indicated a 9 to 16% lifetime risk for large bowel cancer (225, 235, 236). It is uncertain whether colon malignancy arises from adenomatous and/or hamartomatous polyps in PHTS, although there is little doubt as to the increased risk and possibility of young age onset.
Even though HMPS linked to a locus on chromosome 15q13.3–q14 in a number of families, which includes the CRAC1 gene, the etiology remains elusive. Recently, a duplication 40 kb upstream of the GREM1 gene locus at chromosome 15 was found in two individuals with HMPS. The authors hypothesized that this duplication interacts with the GREM1 promoter causing increased GREM1 expression, resulting in a predisposition to multiple colorectal polyps.
SPS, previously referred to as hyperplastic polyposis syndrome, is a rare condition currently defined by clinical criteria and characterized by a predisposition to serrated polyps and an increased risk of CRC (237, 238, 239). Originally, hyperplastic polyps were the only lesion included in the diagnostic criteria for hyperplastic polyposis (240). In addition to hyperplastic polyps, other serrated polyps including sessile serrated polyps and traditional serrated adenomas may also be found, and hence the preferred term serrated polyposis syndrome (241).
The updated World Health Organization (WHO) diagnostic criteria for SPS include any one of the following: (i) at least five serrated polyps proximal to the sigmoid colon with two or more of them >10 mm in diameter, (ii) any number of serrated polyps proximal to the sigmoid colon in an individual who has a FDR with SPS, or (iii) >20 serrated polyps of any size, but distributed throughout the colon (242). The true prevalence of SPS is not known, but had been previously estimated to be 1:100,000 based on a large screening colonoscopy study of 50,148 participants in which 28 subjects (0.06%) were found to have the syndrome. (243). More recent studies have evaluated the prevalence of SPS based on the WHO criteria. The National Health Service Bowel Cancer Screening Programme (NHSBCSP) reviewed all pathology and colonoscopy records for guaiac fecal occult blood test-positive patients presenting for index screening colonoscopy (244). Out of 755 patients, 5 (0.66%) met SPS criteria 1 and/or 3 (244). Therefore, 1 in 151 patients in the NHSBCSP met SPS criteria during their index colonoscopy, a much higher rate than previous reports of SPS in the general population (244). In a study from Barcelona, the prevalence of SPS in patients undergoing colonoscopy after a positive fecal immunochemical testing was 8 out of 2,355 (0.34%) (245).
Although the genetic etiology of SPS remains unknown, 3 patients were found to meet diagnostic criteria for SPS in a series of 17 biallelic MUTYH mutation carriers (18%) (136). Conversely, only one biallelic MUTYH mutation carrier was observed in a study of 126 patients with SPS (0.8%) (246). In both studies, the patients who met criteria for SPS also reported a history of adenomas. These observations indicate some overlap in the presentation (and potentially the pathogenesis) of MAP and serrated polyposis. Although data are currently limited, it may be reasonable to consider genetic testing for MUTYH mutations in patients with SPS, particularly if adenomas are concurrently seen.
Although the mechanisms are not entirely clear, there seems to be a strong association between smoking and SPS (247). In a small study of 32 SPS patients, the rate of current smoking was 47%, and this was significantly higher than the rate in colonoscopy controls (17%) and population controls (12%) (247). In another study of patients with multiple serrated polyps, many of whom met criteria for SPS, 51 of 88 (58%) were ever smokers (248). It is speculated that smoking, although not the cause of SPS, does intensify the phenotypic expression and therefore may be a modifiable risk factor for colorectal lesions(247).
Various studies have shown that a family history of colorectal and other cancers is common and even increased in patients with SPS. Some have suggested that this supports a hereditary etiology to SPS (249, 250). However, nongenetic causes, referral bias, and chance occurrence should not be overlooked as substantial factors in these studies (251).
19. Patients with serrated polyposis should undergo colonoscopies every 1–3 years with attempted removal of all polyps >5 mm diameter (conditional recommendation, low quality of evidence).
It is now well established that SPS is associated with an increased risk for CRC (252). The specific lifetime risk of colorectal in SPS is not well defined as most study cohorts to date are relatively small, phenotypically diverse, and subject to referral bias. It has been estimated that the lifetime CRC risk is >50%, although this is likely an overestimate (243). CRC was diagnosed in 5 of 77 (6.5%) SPS patients after a median follow-up time of 1.3 years (253). Four out of five of these CRCs were found in serrated polyps <20 mm (253). Boparai et al. (253) estimated that the 5-year risk of CRC under surveillance was 7%. In two large descriptive studies of SPS patients, the majority of index cases displayed a pancolonic distribution of polyps (89–96%), the presence of adenomas (78–80%), a diagnosis of CRC (31–42%) and a mean age at diagnosis of 48 years (250, 254). In a smaller prospective series of 13 hyperplastic polyposis syndrome patients, 5 (71%) of the 7 CRCs reported were located in the right colon (237). In another retrospective study of 77 patients with SPS, 22 (28.6%) were diagnosed with CRC at their baseline colonoscopy. Five (6.5%) more patients developed CRC while being followed for hyperplastic polyposis syndrome (253). Synchronous adenomas are found in the majority of patients with SPS (248, 252). Conventional adenomas were more frequently found in patients with CRC than those without (254). In a study of CRCs from SPS patients, 18 of 39 (46%) had the BRAF V600E mutation, 2 of 40 (5.0%) had KRAS mutations, and 17 of 45 (38%) had loss of immunohistochemistry expression of MLH1 and PMS2 (255).
There are no available studies regarding the effectiveness of surveillance in SPS. Based on the reported colon cancer risks, colonoscopy and polypectomy is recommended for individuals who fulfill the WHO definition of SPS. Complete clearance of all polyps ≥1 cm should be done when possible. Subsequent colonoscopy intervals should be determined by the number and size of polyps, as well as the number of concurrent adenomas, but generally should be performed every 1–3 years.
20. Indications for surgery for SPS include an inability to control the growth of serrated polyps, or the development of cancer. Colectomy and IRA is a reasonable option given the risks of metachronous neoplasia (conditional recommendation, low quality of evidence).
21. There is no evidence to support extracolonic cancer surveillance for SPS at this time. Screening recommendations for family members are currently unclear pending further data and should be individualized based on results of baseline evaluations in family members (conditional recommendation, very low quality of evidence).
The data on extracolonic cancers in SPS are insufficient at this time, although Win et al. (250) reported an increased risk of colorectal and pancreas cancer in relatives of patients with SPS. However, PC was not found in any of the 115 patients with SPS in a study by Kalady et al. (249). In a larger study of 105 patients with SPS and 341 FDRs, no increased risk of extracolonic malignancies were seen in patients or their relatives (257). Hazewinkel et al. (257) concluded that extracolonic cancer in SPS and their FDRs is not increased compared with the general population.
Familial cases of SPS have been reported, although infrequently in most studies. However, a recent prospective study of 78 FDRs of patients with SPS found that the incidence of SPS was 32% (258). Only one of these relatives was diagnosed with CRC during screening colonoscopy (258). Other studies have reported a family history of CRCs in 50–59% of FDRs of patients with SPS (241, 248). In one of these studies, only 2 (5%) of the 38 probands with SPS reported a family history of SPS (241). In a recent study, Boparai et al. (259) FDRs of serrated polyposis patients had five times the incidence of CRC, suggestive of a hereditary disorder.
Surveillance recommendations for individuals with a family history of serrated polyposis are currently unclear, pending further data. It is reasonable to screen FDRs at the youngest age of onset of serrated polyposis diagnosis (after the exclusion of other genetic causes), and subsequently per colonoscopic findings (248). The frequency and age of initiation of colonoscopic screening in at-risk family members of patients with SPS is less clear. Oquinena et al. (258) recommended that colonoscopy in FDRs start at age 35 years (or 10 years before the youngest age of SPS onset in the family, whichever comes first) and then every 3–5 years if no polyps are found. If the FDRs are found to meet SPS criteria 1 or 3, annual surveillance should be performed or every 2 years if only SPS criteria 2 is met (258). On the contrary, the National Comprehensive Cancer Network (NCCN) recommends that FDRs should have colonoscopy at the earliest of the following: (i) age 40 years, (ii) same age as the youngest SPS diagnosis in the family, and (iii) 10 years before CRC in the family in a patient with SPS (260). Further work is ongoing to better define the cancer risks in probands and their relatives so that accurate risk stratification and risk recommendations can be made regarding SPS.
Observational studies suggest a strong association between smoking and SPS. Independent studies have reported significant smoking history in patients with SPS, leading to the assumption that smoking may be a modifiable risk factor in the pathogenic pathway of colorectal lesions (248, 250).
The known hereditary syndromes associated with an increased risk for developing PC along with their relative risk for developing PC are shown in Table 12. PC is one of the key cancers used in determining whether a patient’s family history warrants genetic risk evaluation for hereditary breast and ovarian cancer syndrome according to the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast and Ovarian (3). Referral for genetic assessment for FAMMM syndrome should be considered in a PC patient with a personal or family history of melanoma or multiple dysplastic nevi (261). Patients who meet the aforementioned criteria for LS, PJS, or FAP may also be at increased risk for PC. Consideration for genetic counseling for testing for hereditary pancreatitis is based on expert opinion and warranted for PC patients with a personal history of at least 2 attacks of acute pancreatitis of unknown etiology, a family history of pancreatitis, or early-age onset chronic pancreatitis (262, 263).
The risk for development of PC in those patients with an inherited predisposition for PC development is shown in Table 12. The risk is highest in hereditary pancreatitis (53-fold risk) (264), PJS (132-fold risk) (197), and FAMMM families with a known CDKN2A mutation (13- to 39-fold risk) (265, 266, 267). The risk is not as great for BRCA1 (˜2-fold) (268), BRCA2 (3- to 9-fold) (269, 270), LS (9- to 11-fold) (71, 271), and ATM (˜3-fold) (272) mutation carriers based on registry data. There are currently no data available on the risk of developing PC in PALB2 mutation carriers.
Familial pancreatic cancer (FPC) has been defined by consensus opinion as families with ≥2 FDRs relatives who do not meet criteria for a known PC-associated hereditary syndrome (262). Case reports first demonstrated families with an excess number of PC cases. Best estimates from case–control and cohort studies suggest that up to 10% of PC patients will have a first- or second-degree relative with PC (273, 274). The risk for developing PC in FPC kindreds is dependent on the number of FDRs as shown in Table 12. Segregation analysis of families with multiple PC cases has shown an autosomal-dominant inheritance pattern and a 32% lifetime risk for PC development at age 85 years (275). The prospective risk for PC development in individuals with FPC is related to the number of FDRs with PC in the kindred. Those with one or two PC-affected FDRs had a risk ranging from 4- to 7-fold, although whereas those with ≥3 PC-affected FDRs had a risk ranging from 17 to 32-fold (262, 276, 277). The complexity in cancer risk assessment has led to the development of a risk prediction model (PancPRO) to provide more detailed risk estimates for individuals from FPC kindreds that take into account the ages at diagnosis, family size, and the relationship between family members (278).
In attempts to discover the cause of their PC susceptibility, studies have been performed on familial FPC kindreds for known candidate genes that fall into two groups: (i) genes that cause inherited disorders that are associated with increased risk of PC development (e.g., BRCA1, BRCA2, and CDKN2A) even in the absence of meeting criteria for these hereditary syndromes (279, 280, 281) and (ii) recently described genes such as palladin (PALLD) (282), ATM (283), and PALB2 (284, 285) that were discovered by whole genome sequencing or linkage analysis of FPC kindred(s). As shown in Table 13, results vary depending on the study population with mutations, for example, in BRCA1 ranging from 0 to 6% (281, 286), BRCA2 ranging from 0 to 6% (281, 287, 288), CDKN2A ranging from 0 to 20% (280, 281, 288), and PALB2 ranging from 0 to 5% (281, 285, 288). PALLD was found to be the susceptibility mutation in a large well-characterized family at the University of Washington (282); however, subsequent studies have not found this gene to be responsible for other FPC families (289, 290). Results from a recent study found ATM mutations in 2.4% of FPC families (283). Known genetic mutations are responsible for ˜20% of the familial clustering of pancreatic cancer. Thus, in the majority of cases, the responsible inherited factor(s) accounting for the increased number of PC cases in these kindreds have not been identified.
22. Surveillance of individuals with a genetic predisposition for pancreatic adenocarcinoma should ideally be performed in experienced centers utilizing a multidisciplinary approach and under research conditions. These individuals should be known mutation carriers from hereditary syndromes associated with increased risk of PC (Peutz–Jeghers, hereditary pancreatitis, FAMMM) or members of FPC kindreds with a PC-affected FDR. Because of a lower relative risk for pancreatic adenocarcinoma development in BRCA1, BRCA2, PALB2, ATM, and LS families, surveillance should be limited to mutation carriers with a first- or second-degree relative affected with PC (conditional recommendation; very low quality of evidence).
23. Surveillance for PC should be with endoscopic ultrasound and/or MRI of the pancreas annually starting at age 50 years, or 10 years younger than the earliest age of PC in the family. Patients with PJS should start surveillance at age 35 years (conditional recommendation, very low quality of evidence).
It is not feasible to screen for PC because of its low incidence in the general population with an estimated lifetime risk in the United States of 1.4% in 2013 (291). Expert opinion has recommended that individuals with a relative risk of more than fivefold when compared with the general population warrant consideration for PC surveillance (73, 262, 292), with the aim to detect early pancreatic lesions that can be intervened upon. Two such precursor lesions of PC include intraductal papillary mucinous neoplasms and pancreatic intraepithelial neoplasia (293).
Based on this degree of risk, candidates for PC surveillance are limited at this time to unaffected individuals from pancreatic cancer-prone families who are candidates for pancreatic surgery. Unlike colon cancer, in which colonoscopy has been proven to be an effective screening tool to reduce colon cancer-related mortality, there is no proven strategy for PC (294). As stated in a recent International Cancer of the Pancreas Screening Consortium summit (73), recommendations for screening patients with a family history of PC “are primarily based on evidence of increased risk, rather than a proven efficacy of screening.” In light of these acknowledged limitations in PC screening, expert opinion has repeatedly emphasized the importance of performing PC surveillance in the setting of active peer-reviewed research protocols by experienced centers utilizing a multidisciplinary team approach (73, 262, 292).
Attempts at a unified recommendation for age to commence screening have been unsuccessful with no clear consensus achieved despite being addressed at two international meetings (73, 262). Two recently reported surveillance studies have shown that the majority of significant lesions have been found in older patients (295, 296). Canto et al. (295) reported in their large multicenter surveillance study of high-risk individuals that the prevalence of pancreatic lesions was age related with a significant difference found in the number of lesions detected between patients <50 years old when compared with patients ≥50 years old. Furthermore, all pancreatic lesions with high-grade dysplasia were in patients >65 years of age. Ludwig et al. (296) also reported differences in finding a significant abnormality based on age, with a yield of 35% in those >65 years old as compared with only 3% in those ≤65 years old. Several studies in both the hereditary and sporadic setting have found that smokers have an earlier age of PC diagnosis as compared with nonsmokers (297, 298, 299), but no data exist regarding whether smoking status should affect surveillance strategy.
Endoscopic ultrasound and MRI/magnetic resonance cholangiopancreatography are the preferred imaging modalities for surveillance as they do not involve the use of radiation like CT scanning and are significantly more accurate in finding pancreatic lesions, particularly small cystic lesions, based on data from CAPS3 study (295).
24. Because of the increased risk for PC development when compared with a pancreatic cyst in the sporadic setting, cystic lesion(s) of the pancreas detected during surveillance of a hereditary pancreatic cancer-prone family member requires evaluation by centers experienced in the care of these high-risk individuals. Determining when surgery is required for pancreatic lesions is difficult and is best individualized after multidisciplinary assessment (conditional recommendation, low quality of evidence).
The most common findings in surveillance studies are cystic lesions in the pancreas (295, 300). Management of these cysts is unclear as similar to cysts in a nonhereditary setting, most are benign or just have low-grade dysplasia (73, 292). Recent consensus recommendations propose that these patients be followed according to international consensus guidelines for sporadic branch duct intraductal papillary mucinous neoplasms (301), although the majority agreed that surgery should be considered for those branch duct intraductal papillary mucinous neoplasms ≥2 cm in size (73).
It is estimated that there were ∼21,600 new cases of gastric cancer in the United States in 2013 (303). The lifetime risk for gastric cancer is ∼0.9% (303). The majority of gastric cancer cases are sporadic, but familial clustering is present in ∼10% of cases. There are two main types of gastric cancer: diffuse and intestinal. Intestinal-type gastric cancer is a component tumor in LS, familial adenomatous polyposis, and PJS. These syndromes have already been described previously in this guideline, including the risks for gastric cancer, surveillance guidelines for gastric cancer, and genetic testing recommendations, and therefore intestinal forms of gastric cancer will not be discussed in this section.
The only hereditary cancer susceptibility syndrome known to cause diffuse gastric cancer is hereditary diffuse gastric cancer (HDGC). This condition was originally described in three Maori families with autosomal-dominant diffuse gastric cancer in New Zealand in 1964 (304). Approximately 1–3% of diffuse gastric cancers are attributable to HDGC. A genetic evaluation for HDGC is indicated for families having individuals with (i) ≥2 cases of diffuse gastric cancer, with at least one diagnosed at <50 years, (ii) ≥3 cases of documented diffuse cancer in first- or second-degree relatives independent of age of onset; (iii) diffuse gastric cancer diagnosed at <40 years; and (iv) a personal or family history of diffuse gastric cancer and lobular breast cancer with one diagnosed at <50 years (305).
25. Management for patients with HDGC should include (i) prophylactic gastrectomy after age 20 years (>80% risk by age 80 years); (ii) breast cancer surveillance in women beginning at age 35 years with annual mammography and breast MRI and clinical breast examination every 6 months, and (iii) colonoscopy beginning at age 40 years for families that include colon cancer (conditional recommendation, low quality of evidence).
An international consortium study of 11 families with at least 3 cases of diffuse gastric cancer who had tested positive for a CDH1 gene mutation found that the lifetime risk of developing gastric cancer was 67% for males and 83% for females, with a mean age at diagnosis of 38–40 years of age (range, 14–85) (311). Females also had an increased risk of lobular breast cancer with a lifetime risk of 39% (311). A recent analysis by an international consortium suggests that the risk of gastric cancer is 80% for both men and women, and that the risk of lobular breast cancer is 60% in women (312). There is some evidence that individuals with HDGC are also at increased risk for signet ring cell colon cancer, although exact risk estimates are not known (313). There is a high rate of gastric cancer detection at the time of prophylactic gastrectomy. A recent systematic review (305) found that of 220 previously reported patients who tested positive for CDH1 mutations, 76.8% underwent a prophylactic gastrectomy whereas 23.2% declined to undergo prophylactic surgery. Among the 169 patients who underwent surgery, 62.7% had negative preoperative endoscopic biopsies and 12.4% (21) tested positive for cancer in their preoperative screening. No information was available on 42 patients. Following gastrectomy, 87% (147) patients had positive histopathology results (including early lesions such as foci of signet ring cells to advanced lesions such as linitis plastica). Only 10% (17 patients) had negative final pathology and it was not reported in 5 patients. It is important to identify both the esophageal and duodenal mucosa at the ends of the surgical specimen because there has been a report of gastric cancer after prophylactic gastrectomy (314).
Gastric cancer surveillance may be used before prophylactic gastrectomy and for patients who decline gastrectomy, but the efficacy is uncertain and should be used with caution. Given the penetrance of this condition, it is recommended that these individuals undergo screening every 6–12 months beginning 5–10 years before the earliest cancer diagnosis in the family (313, 314). It is recommended that this is a detailed 30-min endoscopic examination of the gastric mucosa with multiple random biopsies (313, 314). Some studies have shown an improved detection rate of early gastric cancer with indigo-carmine staining or a pH-sensitive congo red dye followed by pentagastrin stimulation (315)
Because of limited data, the breast cancer surveillance guidelines are based on those for women with a BRCA1 or BRCA2 mutation. Given that lobular breast cancers can be difficult to diagnose by clinical examination and mammography, annual MRI is recommended as part of the surveillance regimen. The colonoscopy guidelines are also based on limited evidence at present.
Genetic testing should only be done in the setting of pre- and posttest genetic counseling. Full informed consent should always be part of the process of cancer genetic counseling. Nongenetics professionals should consider offering cancer genetic testing only if they are able to provide or make available adequate genetic education and counseling as well as access to preventive and surveillance options. Otherwise they should consider referring the patient and family for these services. Standards for informed consent that should be adopted in gastroenterology practices are outlined in Table 14.
The advent and commercial availability of next-generation sequencing panels have increased both the complexity and the ease of cancer genetic testing significantly in the past few years. Next-generation sequencing allows for analysis of multiple genes at one time for a lower cost than traditional Sanger sequencing. There are multiple cancer gene panels including anywhere from 6 to 52 genes now offered at a variety of diagnostic laboratories. Some limitations of the new technology include the longer turnaround time (results can take up to 3 months instead of 2–3 weeks) and a higher chance of finding uncertain results (known as variants of uncertain significance) given the large number of genes included. In addition, there are some genes on these panels for which there are very little data available about the associated cancer risks or appropriate management and others for which the cancer risks are so low that the family would be managed based on the cancer history and not the mutation result. In these cases, the results are not useful clinically and can cause confusion for the patient. However, gene panels also may streamline testing for individuals at increased risk for a cancer susceptibility syndrome and reduce greatly the need for sequential tests where multiple diagnoses are under consideration. In general, genetics professionals are using the next-generation sequencing panels for patients with a long list of differential diagnoses (e.g., if testing for >1 possible genetic syndrome) because the panels are much more cost effective and can shorten the diagnostic journey. It is conceivable that gene panels may in a short period of time replace in large part individual genetic tests and that testing for all the syndromes discussed in this guideline will soon be done simultaneously for at-risk patients.
Several well-established hereditary cancer syndromes now exist, each with implications for specific cancer risks in GI and other organ systems. The assessment for cancer susceptibility should be a standard part of patient evaluations in gastroenterology office and endoscopy practices. A systematic and focused family history of cancer and premalignant conditions is the first step and sufficient to screen for ∼10–15% of patients who may need more detailed risk assessment by more extensive family history assessment, genetic counseling, and genetic testing. The underlying genetic etiologies for several syndromes are now well established, and the array of cancer susceptibility genes is continually expanding. Genetic testing is widely available and should be part of standard of care of patients at increased risk for a hereditary cancer syndrome. Mutation carriers and at-risk individuals require intensive surveillance, possibly prophylactic surgery, and family counseling, and management needs to be individualized based on the syndrome under consideration, as well as the specifics of the family history at hand. There is a dire need of organized collaborative international efforts to study benefits of surveillance and surgical strategies in patients with these relatively rare syndromes in order to be able to offer truly evidence-based management recommendations.
This guideline was produced in collaboration with the Practice Parameters Committee of the American College of Gastroenterology. The Committee gives special thanks to Christine Y. Hachem, MD, FACG, who served as guideline monitor for this document. We are grateful to Christine Hachem, Lauren Gerson, and Maria Susano for assistance with guideline development, to Paul Moayyedi for reviewing and grading recommendations, and to Chinedu Ukaegbu for help with drafting of the manuscript tables and assembling reference libraries.
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