The comprehensive review of gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) from diagnosis and treatment

Abstract Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) was first proposed by Wothley et al. in 2012 as a rare familial gastric cancer syndrome associated with an autosomal dominant form of inheritance. GAPPS is characterized by gastric basal gland polyposis from the hilum to the body of the stomach. Li et al. in 2016 showed that the cause of the disease is a point mutation in the promotor 1B region of the APC gene, and genetic testing was used to confirm the diagnosis. If the patient has already developed gastric cancer, treatment should be based on the usual treatment for gastric cancer. If no distant metastases exist, a good prognosis can be expected by performing a total gastrectomy. On the other hand, patients with distant metastasis have a poor prognosis. In the case of dysplasia, prophylactic total gastrectomy is recommended, but because it is highly invasive and postoperative postgastrectomy syndrome must be considered, the decision should be made with careful consideration of the patient's background. Therefore, there are no guidelines for screening for GAPPS, the timing of prophylactic total gastrectomy, or methods of endoscopic surveillance. Because GAPPS is a rare disease, its natural history is still unclear. Further case series are needed to elucidate the molecular biology and clinicopathological features of GAPPS and to establish clinical management, including diagnosis, treatment, and surveillance. In this review, we provide an overview of GAPPS, its clinical management, and its problems, which will be useful for the treatment of GAPPS.

cases are caused by inactivating germline mutations in the CDH1 tumor suppressor gene, which encodes E-cadherin, a transmembrane protein that is localized to the adherence junctions in epithelial tissues and has functions in cell-to-cell adhesion. The pathogenesis of HDGC has been clarified by the results of many clinical and basic studies to date and has already been published as a medical guideline, establishing clinical indices for diagnosis, treatment, and surveillance. 3 Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) is a new hereditary gastrointestinal (GI) polyposis clinically characterized by Worthley et al. 5 in 2012. Furthermore, in 2016, Li et al. 6 reported that the cause of GAPPS is a point mutation in the promoter 1B region of the APC gene, and genetic diagnosis has shown an important role in the diagnosis of GAPPS. With the spread of the disease concept, the number of reports of GAPPS has been gradually increasing. GAPPS is diagnosed by genetic diagnosis before the onset of GC, and cases of prophylactic total gastrectomy are increasing. Although surgical techniques have improved, the postoperative complication rate and mortality rate of total gastrectomy have remained high over the past decade. 7 The mechanisms and natural history of gastric carcinogenesis are still unclear because GAPPS is a rare tumor. Furthermore, the clinical management of GAPPS, including screening, surveillance, and the timing of prophylactic total gastrectomy before the development of gastric cancer, remains unclear. This review will summarize the clinical management of GAPPS in terms of diagnosis, treatment, and surveillance and will hopefully be useful in the practice of GAPPS, which is expected to increase in number in the future.

| DIAG NOS IS
The first paper reporting GAPPS proposed the following clinical diagnostic criteria: (1) gastric polyps restricted to the gastric body and fundus with no duodenal or colorectal polyposis; (2) index case: >100 polyps carpeting the proximal stomach, first-degree relative of another case: >30 polyps; (3) predominantly fundic gland polyps (FGPs), some with regions of dysplasia (or a family member with either dysplastic FGPs or gastric adenocarcinoma); (4) autosomal pattern of inheritance; (5) exclusion of other gastric polyposis syndromes and the use of proton pump inhibitors (PPIs). 5 Endoscopic findings of massive gastric polyposis with suspected GAPPS may resemble polyposis as part of other gastric or gastrointestinal polyposis syndromes. The entire fundic gland area from the fundus to the middle of the body is densely populated with "carpet-like" FGPs several millimeters in size. As shown in Figure 1, the characteristic finding that FGP is not present in the antrum on upper GI endoscopy is a point that can facilitate differential diagnosis to other GI polyposis syndromes such as MUTYH-associated polyposis, Peutz-Jeghers syndrome, and familial adenomatous polyposis (FAP). However, GAPPS is also characterized by the lack of characteristic findings in endoscopic morphology, color tone, by NBI imaging. Therefore, FGPs cannot be diagnosed by macroscopic findings alone due to the similarity with other GI polyposis syndromes. Previously, diagnosis of GAPPS largely depend on clinical and endoscopic findings as described above. Multi-cancer gene panels for genetic testing are useful to rule out germline variants associated with other gastric polyposis syndromes, which include the above polyposis-disposition genes and known hereditary gastric cancer predisposition syndromes. Notably, germline point mutations in the APC promoter 1B were recently identified and co-segregated with GAPPS in six families (one Australian and five North American families). 6

| TRE ATMENT
If GAPPS has already developed GC, proceed with treatment in the same manner as for general gastric cancer. On the other hand, if not already developed with GC, current guidelines on endoscopic surveillance or timing of prophylactic gastrectomy largely depend on expert opinions due to rare diseases.

| Endoscopic surveillance
Upper GI endoscopy is useful for the early detection of GAPPS, and endoscopic biopsy at regular intervals is necessary to prevent the development of GC. However, some previous reports questioned prolonged endoscopic surveillance in patients with GAPPS. 10,13 One case of rapid progression to GC with distant metastasis was reported despite frequent endoscopic surveillance. 10 In our case, the rapid progression to GC with distant metastasis was observed in a brief period of 10 months. 14 The micropapillary component was observed in the biopsy specimens, although the proportion was small. Furthermore, sampling in cases of polyposis, which includes FGP with different degrees of dysplasia, is challenging. 13 Clinically, upon adequate sampling by endoscopic biopsy, we face hundreds of heterogeneous polyp lesions that may include FGPs with varying degrees of dysplasia, adenoma, or mixed-histology polyps, raising clinical concerns. The timing of endoscopic surveillance initiation also remains controversial, particularly in young patients. A recent report suggested that the firstdegree relatives of patients with GAPPS with a proven APC mutation should start undergoing endoscopic surveillance at 15 years of age. 15 The interval or starting time of endoscopic surveillance should be flexible according to the disease condition.

| Prophylactic gastrectomy
Total gastrectomy with lymph node dissection is required if GAPPS has already developed GC without distant metastasis. Table 1 summarizes the cases of therapeutic and prophylactic gastrectomy for GAPPS. 5,8,10,14,[16][17][18][19][20][21][22] On the other hand, if not already developed with GC, prophylactic total gastrectomy for GAPPS must be considered very carefully, with caution, and with a fully individualized approach. Repak et al. 10 stated that patients who fulfill the original GAPPS criteria and those with FGP progression to dysplasia should be tested for genetic mutations so that prophylactic gastrectomy can be performed appropriately. Furthermore, Foretova et al. 19 recommended prophylactic total gastrectomy for cases with progressive massive stomach polyposis even without dysplasia. Table 1 summarized the cases who underwent prophylactic total gastrectomy for GAPPS. 8,14,16,[19][20][21][22] Based on these previous reports, the algorithm for GAPPS family members with or without mutation of the 1B promoter of the APC gene is proposed. 15 In early reports, the death of a family member was the main reason for surgery without a genetic test, but in recent reports, preoperative genetic tests are performed to diagnose GAPPS, and prophylactic total gastrectomy has been performed. 14,16,[19][20][21][22] With the spread of minimally invasive surgery, laparoscopic or robotic-assisted total gastrectomy has become popular. 14,16,21 Iwaoka et al. 16 reported from their experience with four GAPPS cases treated by robotic total gastrectomy that there were a large number of polyps, but there was no problem in grasping the stomach wall with forceps. However, total gastrectomy is a complex procedure with a significant risk of postoperative morbidity and mortality. 7,23 Early complications after total gastrectomy, such as esophagojejunal anastomotic leakage, duodenal stump leakage, and pancreatic fistula related to lymphadenectomy, can be fatal. Grossman et al. 20 reported a 10-year-old boy with low-grade dysplasia who underwent prophylactic gastrectomy after a genetic diagnosis. In particular, the impact of prophylactic total gastrectomy on the subsequent growth of pediatric patients needs to be considered.

| PROG NOS IS
Patients who undergo total gastrectomy with or without GC have a better prognosis, whereas patients with the rapid progression to GC with distant metastasis have a worse prognosis. A 41-year-old woman who had been admitted to another hospital for FGP without any symptoms and a rapid progression to gastric adenocarcinoma with multiple liver metastases was observed in a brief period of 10 months and died a year after diagnosis. 14

| CLINIC AL ISSUE S
Gastric polyposis restricted to the gastric body and fundus is suspected to be caused by GAPPS, and detailed family history should be obtained to improve the prognosis through diagnosis and early detection in close relatives. However, the problem with GAPPS is that its natural history is not clear and there is insufficient evidence since the disease concept has not yet been clarified and reports are still rare. In addition, because it is a hereditary disease, genetic counseling is essential. There are many problems to be solved, such as whether or not to perform genetic testing on patients themselves, during gastric adenoma to GC progression may be more contextdependent than colon adenoma progression. The molecular biological mechanism of HDGC was elucidated, the disease concept became popular, and cases were accumulated. As a result, its natural history, diagnostic methods, and treatment strategies were established, leading to the creation of guidelines. 3 Further molecular analysis helps us to define HDGC syndrome by mutations in CDH1 and closely related genes, rather than through clinical criteria that capture families with heterogeneous susceptibility profiles. 27 Like HDGC, the molecular biological mechanism of GAPPS will be clarified in the near future, and it is expected that it will be applied to diagnosis and treatment.
Familial adenomatous polyposis is a genetic disorder that closely resembles GAPPS, and prophylactic total colectomy is performed.
However, after total colectomy, the patient's quality of life is often greatly reduced due to frequent diarrhea, dehydration, bowel obstruction, anal dysfunction, and development of intraperitoneal desmoid tumors. A recent clinical study showed that low-dose aspirin safely suppressed the recurrence of colorectal polyps larger than 5 mm in Japanese patients with FAP. 28 Since FAP and GAPPS have similar pathologies, if the molecular biological characteristics of GAPPS can be elucidated in the future, a therapeutic strategy called chemoprevention may be established for GAPPS.

| CON CLUS ION
Although GAPPS is a rare disease, when we find gastric polyposis confined to the gastric hilum, it is easy to suspect this disease because of the clinical features of GAPPS. At that time, a detailed family history is expected to improve the prognosis by diagnosis and early detection of close relatives. However, since the concept of the disease and the responsible gene have not been reported for some time, the number of cases is small and evidence is lacking. In the future, it is important to systematically accumulate cases by establishing a global registry system.

ACK N OWLED G M ENTS
This work was supported in part by Medical Research Encouragement Prize of the Japan Medical Association.

FU N D I N G I N FO R M ATI O N
The authors declared that no grants were involved in supporting this study.