Consideration of a novel surgical approach in the management of gastric adenocarcinoma and proximal polyposis syndrome

Graphical Abstract

Introduction

Gastric adenocarcinoma and proximal polyposis syndrome (GAPPS) is a rare genetic disorder characterized by an autosomal dominant genetic predisposition to develop gastric polyposis, which is associated with a higher risk of dysplasia and gastric adenocarcinoma.¹ Genetic analysis of affected families has linked GAPPS to a point variant in APC promoter 1B.² Of importance, in contrast to other gastric-polyposis or cancer-predisposition syndromes, the phenotype of APC promoter 1B variant–associated gastric polyposis includes polyps restricted to the proximal stomach, with no evidence of colorectal or duodenal disease. This unique phenotype is secondary to the differential expression of the 1B promoter in gastric mucosa compared to other anatomic sites.³ Because of the consistent distribution of fundic gland polyps to the proximal stomach in patients with GAPPS, proximal gastrectomy with double-tract reconstruction can be considered a favorable alternative to total gastrectomy in patients with GAPPS who are recommended for risk-reducing gastrectomy. The double-tract reconstruction technique may result in better postoperative quality of life, compared with total gastrectomy, and it allows for endoscopic surveillance of the distal stomach and duodenum. Here, we present the case of a patient with GAPPS with high-grade dysplasia who underwent robot-assisted proximal gastrectomy and double-tract reconstruction. This case demonstrates that knowledge of genotype-phenotype associations may help to inform surgical decision-making and allow for more-tailored surgical interventions.

Case Report

A healthy 58-year-old man with no known medical or surgical history initially presented for evaluation of prolonged fatigue after recovering from symptomatic COVID-19 infection. He was found to be anemic, and he was evaluated by upper and lower endoscopy. Upper endoscopy identified diffuse proximal gastric polyposis; the remainder of his stomach and duodenum appeared normal (Figure 1). Complete colonoscopy to the terminal ileum identified 2 subcentimeter benign polyps. Biopsy specimens from sampled fundic gland gastric polyps were determined to contain high-grade dysplasia. The patient was referred for assessment of genetic cancer risk and noted that his mother had undergone gastric surgery at age 64 for reported polyps, but that she had not been diagnosed with cancer. The patient reported that his mother is currently alive and has no evidence of gastric disease. The patient underwent genetic testing with a multigene panel (Ambry Genetics, CancerNext-Expanded), which initially revealed 3 variants of unknown significance: APC (c.−191T>G), CHEK2 (p.S356L), and PMS2 (c.779_782delCCinsTG). The APC variant was reclassified as likely pathogenic and was further characterized as a substitution in the APC 1B promoter region upstream of the first translated codon. The patient’s clinical findings and genetic results were consistent with GAPPS.

Figure 1.

Preoperative esophagogastroduodenoscopy showing extensive gastric polyposis of the gastric fundus (A) and proximal gastric body (B), but the distal body (C), antrum (D), and duodenum (E, F) are not affected.

The patient was referred for consideration of a risk-reducing total gastrectomy. In discussions with the patient about the risks, benefits, alternatives, and expectations of a total gastrectomy, the patient was hesitant about the lifestyle and nutritional challenges that can arise following a total gastrectomy. After a discussion of alternative management options with the patient and in a multidisciplinary setting, the patient opted for a partial gastrectomy and underwent robot-assisted proximal gastrectomy with double-tract reconstruction. By use of intraoperative gastroscopy, the distal transection margin was confirmed, and a proximal gastrectomy was completed with no visible polyps remaining. Reconstruction was completed using the double-tract method—a Roux-en-Y esophagojejunostomy and an end-to-side gastrojejunostomy were formed—which permitted future endoscopic surveillance of the distal stomach and duodenum (Figure 2).

Figure 2.

Schematic representation of double-tract reconstruction after proximal gastrectomy. The gastric remnant and duodenum remain accessible for endoscopic surveillance. (Made using biorender.com.)

The patient tolerated the operation well, and there were no postoperative complications. Final pathology from the surgical specimen identified a negative surgical margin free of polyps (Figure 3A) and with numerous confluence hyperproliferative aberrant pits, fundic gland polyps (Figure 3B), and adenomas, with multifocal low- and high-grade dysplasia (Figure 3C-D). There was no invasive adenocarcinoma, and the resection margins were negative for polyps or dysplasia. Twenty-four lymph nodes were collected; all were free of disease.

Figure 3.

Gross and histopathologic evaluation of the proximal gastrectomy specimen. Gross inspection of the proximal gastrectomy specimen (A) confirmed a proximal region of extensive polyposis (black arrow) with a clear distal margin of normal-appearing mucosa (black star). Discrete fundic gland and adenomatous polyps inspected on hematoxylin and eosin stain revealed benign fundic gland polyps (B) and fundic gland polyps containing low-grade dysplasia (C) and high-grade dysplasia (D).

At the time of publication of this report, the patient was alive and well, and surveillance endoscopy has been completed at 6 to 12-month intervals and has identified only normal mucosa in the remnant stomach and duodenum. The patient is approximately two years out from surgery and reports adequate oral intake with infrequent abdominal discomfort following large meals. He has maintained his weight consistent with his pre-operative status. A daily multivitamin was added post-operatively and there has been no clinical or laboratory evidence of any anticipated nutritional deficiencies. Genetic testing in at-risk family members has since commenced and identified others with the same genetic variant. This retrospective case study was exempt from IRB approval. The investigators in this study obtained informed consent to publish the report from each participant or each participant’s guardian or legal representative.

Discussion

GAPPS is a rare cancer-predisposition syndrome that was initially described by Worthley and colleagues in 2012.¹ In their initial description, the authors detailed 3 distinct families in which some individuals had gastric polyposis with no disease in the distal stomach and some individuals had advanced gastric cancer arising in the proximal stomach with adjacent polyposis. None of the screened individuals had evidence of colorectal polyposis. In their genetic analysis, the investigators excluded coding variants in APC, MUTYH, CDH1, SMAD4, BMPR1A, STK11, and PTEN. Despite a heretofore uncharacterized genetic abnormality in these individuals, the authors indicated that, in each of the included families, “the risk of gastric cancer was sufficient for many clinicians to recommend gastrectomy.”¹ Although GAPPS remains a rare disease, the general recommendation for individuals with the gastric-polyposis phenotype is to undergo a risk-reducing prophylactic total gastrectomy.⁴ As we have gained more insight into the genetic basis of GAPPS, however, the requirement for total gastrectomy appears to be a matter of debate.

In 2016, researchers mapped the loss of the wild-type allele on 5q in fundic gland polyps from individuals affected with GAPPS.² Using Sanger sequencing techniques, the investigators identified variants in the APC promoter 1B that reduced binding of the YY1 transcription factor, thus decreasing the activity of the APC promoter 1B. These APC promoter 1B variants have been further identified in other families with GAPPS.^5–7 APC promoter 1B variant–associated GAPPS is distinct from other gastric-polyposis and cancer-predisposition syndromes. Coding variants in APC and biallelic MUTYH variants—which are diagnostic for classical or attenuated familial adenomatous polyposis syndrome and for MUTYH-associated polyposis, respectively—may cause gastric polyposis, in addition to usually profuse colonic polyps. However, the extent of gastric polyps is generally less severe but more broadly distributed. More so, this also often includes polyps of the duodenum.^{8, 9} In patients with variants in the hamartomatous polyposis genes (SMAD4, BMPR1A, and STK11), gastric polyposis tends to be less severe, with the exception of the rarely observed massive gastric polyposis phenotypic variant, which is seen in some carriers of SMAD4 variants and can encompass the entire distribution of the stomach.¹⁰ Although a risk of gastric cancer is associated with a number of other cancer-susceptibility genes (Lynch syndrome mismatch repair genes, ATM, BRCA1/2, CDH1, CTNNA1, and PALB2), gastric polyposis is not a major component of these syndromes.¹¹

Investigators have also observed methylation of APC promoter 1A in individuals with GAPPS, individuals with sporadic fundic gland polyps, and individuals with normal stomachs, which indicates that APC promoter 1B may play a more important role, compared with 1A, in the gastric mucosa and account for the gastric-limited disease observed in patients with GAPPS.² This finding further supports the unique phenotype of proximal gastric polyposis. Given the distribution of gastric fundic glands along the fundus and the body of the stomach, the proposed role of APC promoter 1B appears to be consistent with observations in patients with GAPPS that polyposis and resultant dysplasia and carcinoma are relegated to the proximal and mid stomach, and not the distal stomach. These observations provide a rationale for resecting the proximal stomach only and leaving behind functional distal stomach for reconstruction.

Proximal gastrectomy with double-tract reconstruction was initially described in the 1980s,¹² but, owing to concerns related to intractable reflux esophagitis and anastomotic strictures historically associated with proximal gastrectomies, this technique has not been widely adopted. With the increasing rates of proximal early gastric cancer detected in Asia, there has been renewed interest in proximal gastrectomy with double-tract reconstruction, particularly using a minimally invasive surgery approach.¹³ Quality of life is adversely affected in all patients who undergo gastric surgery for cancer¹⁴; novel reconstruction strategies may provide improvements in quality of life, improve nutritional status, and help maintain adequate enteral nutrition and weight. Results from a small cohort of patients who underwent laparoscopic proximal gastrectomy with double-tract reconstruction for early gastric cancer showed much lower rates of complications, compared with those for total gastrectomy. The authors observed reflux in 2 of 46 patients and esophageal stenosis in 2 of 46 patients. No patients had reflux esophagitis diagnosed by endoscopy at 3 months.¹³ Although the study cohort was small and nonrandomized, outcomes from this study were better than those in historic controls and certainly warrant further investigation. The KLASS 05 trial is currently investigating laparoscopic proximal gastrectomy with double-tract reconstruction, compared with laparoscopic total gastrectomy, for early upper gastric cancer; short-term data show no difference in surgical outcomes and incidence of short-term reflux symptoms.¹⁵ These data suggest that preservation of the distal stomach by means of double-tract reconstruction is not associated with a higher risk of reflux symptoms, compared with laparoscopic total gastrectomy, and that concerns over such symptoms should not be the key deterrent to performing this operation.

Guidelines on management of GAPPS are provided by the National Comprehensive Cancer Network (NCCN) based on the estimated lifetime risk of gastric cancer of 13%.¹⁶ Current NCCN guidelines propose annual upper endoscopy starting at age 15 and consideration for risk-reducing total gastrectomy for those individuals with a diagnosis of GAPPS.¹⁷ Proximal gastrectomy with double tract reconstruction is not discussed in current NCCN guidelines and it is critical to note that proximal gastrectomy with double-tract reconstruction leaves distal gastric mucosa in situ, thus leaving behind potential for recurrent polyp formation and dysplasia. Ongoing surveillance of the distal stomach remains necessary and we currently perform surveillance endoscopy yearly in these patients. For those patients that elect for risk-reducing total gastrectomy, there is no current recommendation for regular surveillance.

Conclusions

GAPPS is a rare genetic syndrome characterized by proximal polyposis of the stomach without polyposis in other regions of the gastrointestinal tract. Because APC promoter 1B–associated GAPPS results in a predictable phenotype with a consistent area of distribution, risk-reducing prophylactic total gastrectomy may not be the ideal approach to management. In contrast, proximal gastrectomy with double-tract reconstruction preserves the distal stomach and allows for better nutrition without an undue risk of reflux esophagitis. In addition, this approach allows for endoscopic surveillance of the distal stomach to evaluate for recurrent polyposis. Although GAPPS remains rare, our case report highlights the importance of elucidating the underlying genetic etiology of gastric polyposis, as the recognition of APC promoter 1B–associated GAPPS may have implications for surgical decision-making. Appropriately selected individuals with GAPPS who present for risk-reducing prophylactic gastrectomy could be considered for proximal gastrectomy with double-tract reconstruction as a viable alternative to total gastrectomy.