1 INTRODUCTION

Familial adenomatous polyposis (FAP) is a rare autosomal dominant inherited condition characterized by colorectal polyposis and adenocarcinomas that are caused by germline variants in the adenomatous polyposis coli (APC OMIM *611731) gene. Variants at the terminal 5′ and 3′ ends of the APC are associated with an attenuated form of FAP (AFAP), which is associated with a significant risk of developing colorectal adenocarcinoma (Aghabozorgi et al., 2019; Spirio et al., 1993). It is worth mentioning that genotype–phenotype correlations for upper gastrointestinal FAP need to be investigated, because duodenal and gastric cancers remain life-threatening even after the risk of colorectal neoplasms is eradicated. Fundic gland polyposis in the body and fundus of the stomach is frequently observed by upper endoscopy in these patients, while gastric adenomatous lesions are less common (Burt, 2003; Kawase et al., 2009). Fundic gland polyps have a lower malignant potential, and a few case reports have mentioned that gastric adenocarcinoma is associated with fundic gland polyposis in patients with FAP (Hofgärtner et al., 1999; Zwick et al., 1997).

Gastric polyps generally arise from the foveolar or glandular compartments. Fundic gland polyps are usually sporadic, whereas fundic gland polyposis can develop in FAP patients. These polyps sometimes show dysplastic changes, characterized by nuclear enlargement, crowding, stratification, and hyperchromasia in the foveolar epithelium overlying the fundic gland polyps (Shibata et al., 2013). On the other hand, pyloric gland adenoma is a rare neoplastic proliferation of pyloric glands and is observed in 6% of FAP patients (Wood, Salaria, Cruise, Giardiello, & Montgomery, 2014). These dysplastic lesions reportedly have genetic KRAS (OMIM *190070) alterations; however, although there have been several studies on molecular alterations of gastric dysplastic lesion, there have been no reports on the molecular alterations of gastric carcinoma in patients with FAP (Hackeng et al., 2017). We herein report a case of gastric adenocarcinoma and pyloric gland adenoma arising in fundic gland polyposis in an FAP patient. These tumors were endoscopically resected and thoroughly investigated by immunohistochemical and genetic analyses.

2 MATERIALS AND METHODS

2.2 Clinical report

A Japanese woman was diagnosed with FAP and underwent a total colectomy at 36 years of age. The pathological examination revealed multiple colorectal adenomas with several early cancers presenting AFAP. A desmoid tumor was found 2 years later and was treated with chemotherapy (vinblastine and methotrexate).

During follow-up, upper gastrointestinal endoscopy demonstrated gastric fundic gland polyposis, which had been examined annually since then. A reddish large polyp and a few whitish flat polyps were observed in her stomach at 48 years of age. Magnifying endoscopy showed that the microsurface pattern of these areas was slightly irregular and that the microvascular pattern was irregular. Biopsy of the large polyp showed a tubular adenoma with focal high-grade dysplasia, and thus this lesion was subsequently resected by endoscopic submucosal dissection (tumor 1, Figure 1a,b). Histologically, the completely resected tumor contained multiple microscopic foci of intramucosal tubular adenocarcinoma within tubular adenoma (Figure 1c,d, Figure S1). Later, the white flat polyps were treated with endoscopic mucosal resections at 12 and 18 month after the first treatment, respectively (tumors 2 and 3, Figure 1e,f). These tumors were histologically pyloric gland adenomas with low- to high-grade dysplasia (Figure 1g,h, Figure S2). Multiple pink-colored polyps were also found and were histologically diagnosed as fundic gland polyps with foveolar hyperplasia (Figure S3). Stool antigen and blood antibody test for Helicobacter pylori were both negative.

The patient's family history was significant, as her mother had died of colorectal carcinoma. Her son and daughter underwent colonoscopy and both were found to have a small number of adenomatous polyps (Figure 2a). Gastroduodenoscopy examinations also showed multiple fundic gland polyps in the fundus and body of the stomach of her son and daughter.

Based on the family history of the patient, which was strongly indicative of an autosomal dominant pattern of inheritance of colorectal neoplasms, and after genetic counseling, a genetic analysis of the APC was performed using peripheral blood specimens of the family members (Figure 2b).

3 RESULTS

Polymerase chain reaction and direct sequencing were conducted and a frame shift variant, NM_000038.5(APC): c.5782delC (p.Gln1928fs*42), was found in exon 15 of the APC in tested family members. This is quite a rare variant (Lagarde et al., 2020), given the fact that only one case with this variant has been deposited in the International Society for Gastrointestinal Hereditary Tumor (InSight) variant database (https://www.insight-group.org/variants/databases/) and that no cases have been reported in the ClinVar database.

A histopathological examination showed that both adenocarcinoma and pyloric gland adenoma were of the gastric type, based on their histology and immunohistochemical profile (i.e., positive immunoreactivity for MUC5AC and MUC6, but negative immunoreactivity for MUC2 and CDX2) (Figure 1, File S1, Figure S1). This profile further indicated that these tumors were of mixed pyloric and foveolar type. To investigate whether these tumors were derived from the similar genetic pathway, a genetic analysis using next-generation sequencing (NGS) was performed. The detailed results are shown in the Table S3. KRAS mutations were found in the neoplastic tumors (i.e., both adenocarcinoma and pyloric gland adenomas), but not in the fundic gland polyps (Table 1). The mutation alleles were different among the tumors (i.e., KRAS p.Gly12Ala, p.Gly12Arg, and p.Gly12Asp) indicating that the tumorigenesis may have been different. Adenocarcinoma was focally stained with p53 immunohistochemistry (File S1, Figure S1). NGS also confirmed the identical germline variant of the APC in all samples examined.

4 DISCUSSION

We reported a case of adenocarcinoma arising in fundic gland polyposis in an FAP patient. Pyloric gland adenomas with low- and high-grade dysplasia were also shown to develop in fundic gland polyps. The differences in these polyps were distinctly discerned based on their endoscopic appearances and histopathological features, and a genetic analysis was conducted to explore their mutational profiles.

Gastric adenocarcinoma is a recently reported cancer risk in Western patients with FAP (Mankaney et al., 2017). A white mucosal patch was reported to be a worrisome endoscopic feature in the stomach of FAP patients (Leone et al., 2019; Walton, Frayling, Clark, & Latchford, 2017). Our patient showed whitish flat mucosal areas in the fundus and body of the stomach. Moreover, the reddish elevated tumor observed in the body of the stomach was primarily treated with endoscopic submucosal dissection and was diagnosed as adenocarcinoma in a background of fundic gland polyps. Magnifying endoscopy showed irregularity in the microvascular pattern. The endoscopic features of these neoplastic lesions had diagnostic value in the determination of adequate treatment.

A pathological examination with immunohistochemistry could reveal that mucin specific antibodies indicated differentiation of neoplasia. MUC6 and MUC5AC positivity indicated gastric-type tumors and the predominance of MUC6 confirmed that the tumor was enriched with glandular cells. Gastric adenocarcinoma is found in the foveolar epithelia covering the fundic gland. Immunohistochemistry is useful for investigating the characteristics of neoplasms (Choi et al., 2018; Mitsui et al., 2019). Pyloric gland adenomas are divided into three types based on the immunohistochemical patterns of MUC6 and MUC5AC positivity; pure pyloric type, predominant foveolar type, and mixed pyloric and foveolar type (Choi et al., 2018). A multicenter study of gastric pyloric adenomas revealed that high-grade transformation, intramucosal adenocarcinoma, and invasive adenocarcinoma were observed within 25.4%, 7.5%, and 9.0% of tumors, respectively. High-grade fundic gland adenoma was frequently found in mixed pyloric and foveolar type. MUC2, CDX2, and CD10 are also useful immunohistochemical markers that can be used to subclassify gastric cancers into the gastric, intestinal, and mixed gastrointestinal types (Mitsui et al., 2019). A case report on gastric cancers in a Japanese FAP patient showed that the tumors were of the gastrointestinal type (Yaguchi et al., 2017). Another case report showed that an FAP patient had a gastric-type adenocarcinoma whereas his pedigree had an intestinal-type adenocarcinoma (Mitsui et al., 2019). The latter carcinoma was observed in an H. pylori-positive patient with atrophic gastritis, representing a possible phenocopy of FAP-associated gastric cancer. The H. pylori status may be associated with the gastric carcinogenesis. Further immunohistochemical analyses may reveal the differentiation phenotype of gastric cancer from FAP patients.

In our study, a genetic analysis revealed a novel finding that gastric carcinoma from fundic gland polyposis in the FAP patient represented the APC-related adenoma-carcinoma sequence. Reported genetic mutations in gastric and colorectal cancers were identified from the COSMIC database (https://cancer.sanger.ac.uk/cosmic/). KRAS and APC mutations were found in 4% and 5% of gastric adenocarcinomas, respectively. These mutations were more frequently observed in colorectal cancer (34% and 48%, respectively) than in the stomach. One of the FAP-derived gastric carcinogenesis is the adenoma-carcinoma sequence, which is commonly seen in colorectal carcinogenesis. The germline APC variant in our patient could cause fundic gland polyposis and acquired KRAS mutation alleles generate gastric neoplasia. The different KRAS mutation alleles indicated that these gastric neoplastic lesions developed from distinct origins. This was followed by acquisition of genetic mutations, such as PIC3CA, which drove gastric carcinogenesis.

The APC germline variant found in our patient and her pedigrees was the frame shift variant (p.Gln1928fs*42), which corresponded to the result that AFAP with gastric cancer possesses the variant at the 3′ distal end of the APC (de Oliveira et al., 2019; Groves et al., 2002). These variants were different from those of gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) (Li et al., 2016). This is a rare variant of familial polyposis and is an autosomal-dominant cancer-predisposition syndrome with massive fundic gland polyposis, which is associated with a significantly high risk of developing gastric adenocarcinoma. Variants in promoter 1B of APC are associated with GAPPS syndrome. Prophylactic gastrectomy is recommended for the patients with this syndrome. However, there are only a few reports about the clinical course of FAP patients after the treatment of gastric lesions (Nakamura et al., 2017). There are no clear clinical recommendations for gastric neoplasms in FAP patients (Campos, Martinez, Sulbaran, Bustamante-Lopez, & Safatle-Ribeiro, 2019). Our patient refused gastrectomy and requested endoscopic resection of the gastric tumors based on the general indications for mucosal gastric cancer. We recommend biannual endoscopic surveillance and endoscopic resection is indicated if a neoplastic polyp is suspected.

We herein reported a case of adenocarcinoma arising in fundic gland polyposis in a patient with FAP, which was successfully treated with endoscopic resection. The endoscopic features were well correlated with the pathological features. Genetic examinations with NGS showed that multifocal gastric neoplasia occurred in the adenoma-carcinoma sequence.

CONFLICT OF INTEREST

The authors declare no conflict of interest in association with the present study.

AUTHOR’S CONTRIBUTION

HTan and KM: study design. HTan: analysis data and draft the manuscript. KT, YK, YM, TI, and TS: endoscopic procedures. YO and YM: genetic analysis (NGS). TK and KA: genetic analysis (Sanger sequence). NU and SK: immunohistochemical study. HTak: pathological analysis. MF and TO: study supervision and review the manuscript.