March 19, 2008
Gastric Adenocarcinoma Arising From Fundic Gland Polyps in a Patient With Familial Adenomatous Polyposis Syndrome
By Garrean, Sean Hering, Justin; Saied, Abdul; Jani, Jigna; Espat, N Joseph
Familial adenomatous polyposis (FAP) is a rare hereditary syndrome characterized by multiple colorectal polyps and early development of colorectal cancer. Although FAP uniformly involves the large bowel, it may also produce lesions in the stomach and upper intestinal tract. Fundic gland polyps are the most common gastric lesion in FAP. In the general population, these polyps are considered benign and have no malignant potential. However, in FAP patients, fundic gland polyps have been occasionally recognized as precursor lesions from which invasive cancer may develop. Herein, we present a case of gastric adenocarcinoma arising from fundic gland polyps in an FAP patient. We also review reported cases of gastric cancer in FAP and FAP variant patients in an effort to better understand the pathology, clinical course, and optimal screening and treatment strategies for this disease manifestation. FAMILIAL ADENOMATOUS POLYPOSIS (FAP) is a rare autosomal dominant syndrome caused by a germline mutation in the tumor suppressor gene adenomatosis polyposis coli (APC) on chromosome 5q.' Clinically, FAP is characterized by greater than a hundred adenomatous polyps in the colon and rectum with a predisposition to early colorectal cancer development. In addition to colorectal lesions, FAP frequently produces upper gastrointestinal tract disease. Indeed, with the emergence of prophylactic colectomy as standard of care in FAP, disease burden and mortality from extracolonic gastrointestinal tract disease is increasing.2
A 61-year-old Caucasian male with history of FAP, for which he underwent two partial colectomies several years ago at an outside hospital, presented to our institution for evaluation of gastric polyps and bleeding. Over the preceding months, the patient had suffered from intermittent bouts of hematochezia, requiring transfusion of approximately two units of blood/week. Upper endoscopy during these episodes revealed multiple bleeding polyps in the stomach. Several nonhemorrhagic polyps were also seen in the residual rectum and sigmoid colon on lower endoscopy.
Whereas the rectosigmoid remnant harbored the greatest potential for malignancy, the most immediate threat to the patient's life was hemorrhaging from gastric polyps. Consequently, surgical removal of the portion of the stomach containing the bleeding polyps was offered as primary therapy, with the recommendation that the patient later undergo completion proctosigmoidectomy.
An esophagogastroduodenoscopy (EGD) was performed on the operating table before laparotomy. The exam showed a mucin-filled gastric cardia and fundus with multiple polyps extending from the gastroesophageal junction to the antrum. After EGD, a midline laparotomy was performed. The stomach was noted to be massively dilated to a longitudinal diameter of 52 cm. A pyloromyotomy was made to determine both the etiology of the gastric distention and the level of gastric resection required to encompass the bleeding diathesis (Fig. 1). Inside the pylorus, two large fronds of gastric polyps were found draping through the pylorus into the duodenum (Fig. 2). Once removed, no polyps could be seen or palpated in either D2 or D3 segments of the duodenum.
FIG. 1. Pyloromyotomy revealed diffuse polyps carpeting the entire stomach.
Attention was next turned to the stomach and defining the level of resection. Diffuse polyps covered the entire stomach from the gastroesophageal junction to the pylorus. Due to the risk of bleeding from any point in the stomach, the decision was made to undertake a total gastrectomy. In addition, given the patient's FAP status and potential risk for malignancy, a nodal dissection was performed in standard D2, spleen-sparing fashion. A Roux-en-Y esophagojejunostomy was subsequently fashioned to restore alimentary tract continuity.
Upon opening the specimen on the back table, diffuse polyps were noted throughout the stomach. Several of these polyps measured greater than 3 cm in diameter. The stomach was sent to pathology for gross and microscopic analysis. Grossly, the stomach contained multiple diffuse polyps with barely identifiable normal mucosa. The largest of these polyps was near the gastric cardia and measured 4.5 x 4.5 x 4 cm and had a mildly necrotic center. Two additional large polyps were noted near the pylorus and measured 4 x 3.5 x 3 cm and 3 x 3 x 2.5 cm respectively.
FIG. 2. Two large fronds of polyps were found draping through the pylorus into the duodenum. No duodenal lesions were noted.
Microscopically, the majority of polyps were fundic gland polyps characterized by foveolar hyperplasia and simple cystically dilated glands. The three largest polyps showed adenomatous changes, including mucin depletion, increased nuclear size and chromaticity, stratification of nuclei, and areas of highly atypical glands with cribiform architecture confined to the mucosal layer. Of note, several foci of malignant cells invading the muscularis propria were identified within the adenomatous regions of the large polyps. Taken together, these features were diagnostic of multifocal adenocarcinoma arising in situ from dysplastic areas of the fundic gland polyps.
FAP is a rare but increasingly recognized hereditary polyposis syndrome of the colon caused by a germline mutation of the APC tumor suppressor gene on chromosome 5q. Clinically, FAP represents a spectrum of disease with variable manifestations and severity. FAP and its variant syndromes all share the common feature of polyposis of the colon and early colorectal cancer development. In addition, numerous extracolonic manifestations frequently occur in these syndromes. Polyps and malignancy may arise anywhere in the upper gastrointestinal tract distal to the esophagus.
The duodenum is the most common site of extracolonic polyp formation. Duodenal polyps are adenomas and typically occur in the second and third portion of the duodenum.2, 3 Rates of duodenal adenoma in FAP range from as high as 100 per cent in the Japanese literature to 33 per cent in the Western literature.26 Duodenal and peri-ampullary cancer can also occur and, together with desmoid tumors, represent the second most common cause of mortality in FAP.2 Thus, frequent endoscopic screening (every 2-3 years) and biopsy starting at the age of 20 are recommended. Duodenotomy/polypectomy or even pancreaticoduodenectomy may be indicated if malignancy or diffuse polyposis are found.
TABLE 1. Gastric Cancer Associated with FAP, AFAP, or Gardner's Syndrome: Reported cases in the English Literature
Like the duodenum, the stomach also represents a major site of morbidity and potential mortality in FAP. Gastric polyps often occur in FAP and may be either adenomatous or hyperplastic (i.e., fundic gland polyps). Adenomatous polyps are rare, usually occurring in the antrum and associated with severe duodenal adenomatosis.3 Most cases of gastric adenocarcinoma arise from adenomatous polyps. By contrast, fundic gland polyps are the predominant gastric lesion in FAP. FGPs primarily occur in the body and fundus of the stomach and are characterized histologically by surface and foveolar epithelial hyperplasia and cystically dilated glands.27 Once thought to harbor no malignant potential, FGPs are now recognized as potential precursors for the development of invasive gastric cancer in FAP.23- 27
Although the risk of duodenal cancer is universally increased in FAP, only the Japanese and Korean literature have found an increased prevalence of gastric cancer in FAP (2.1% in Japan and 4.2% in Korea). The rates of gastric cancer in Japanese and Korean FAP patients are 10- and 7-fold higher than in the general population of these countries, respectively.17 By contrast, the incidence of gastric cancer in Western FAP patients is not significantly different from the general population.18 Interestingly, although the rate of duodenal cancer is markedly higher than gastric cancer in the Western literature,14 the trend is reversed in Japan and Korea.17, 18 Gastric cancer occurs more frequently than duodenal cancer in East Asian FAP patients and is much more prevalent in FAP than the general population.17 The reason for this is unknown.
Regardless of its epidemiology, gastric cancer does occur in FAP patients, including those with FGPs only. Five cases of gastric adenocarcinoma arising from FGPs have been reported in the FAP literature. Zwick et al.26 described a patient with attenuated FAP who developed metastatic liver adenocarcinoma secondary to gastric cancer originating from fundic gland polyps. Upper endoscopy and multiple biopsies revealed diffuse fundic gland polyposis; however, gastric cancer remained undetected until postmortem autopsy. The brother of this patient was also afflicted by attenuated FAP.27 He too developed metastastic liver adenocarcinoma from a gastric primary. Despite routine surveillance with upper endoscopy and biopsy, gastric cancer was not found until postmortem autopsy as well. Of note, dysplastic changes were recognized in some FGPs obtained during endoscopy and biopsy. Based on these two patients, the authors concluded that current screening guidelines for gastric polyposis may be insufficient. They suggested a more aggressive approach, including complete excision of representative FGPs and thorough histologic examination. In addition, the authors proposed that prophylactic gastrectomy may be an appropriate treatment option for patients with high grade dysplasia or large FGPs (>7 mm), though furthermore study is obviously needed.
The present findings of our patient support the conclusions made by these authors. Despite routine endoscopic surveillance, our patient developed gastric adenocarcinoma in FGPs. As in the aforementioned studies, only the largest polyps (>3 cm) contained invasive cancer, suggesting that size is a significant factor correlating with the malignant potential of these lesions. Unlike other cases in the literature, our patient presented with hemorrhage, enabling the detection and treatment of gastric cancer before widespread metastasis. Thus, FGPs in FAP pose a definitive risk of malignant transformation. Aggressive screening with complete excision of large polyps and careful histological examination should be performed in all patients. The potential role of prophylactic gastrectomy in patients with diffuse FGPs, high grade dysplasia or large lesions requires furthermore exploration.
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SEAN GARREAN, M.D.,* JUSTIN HERING, M.D.,* ABDUL SAIED, M.D.,* JIGNA JANI, M.D.,[dagger]
N. JOSEPH ESPAT, M.D., M.S., F.A.C.S.[double dagger]
From the Departments of * Surgery and [dagger] Pathology, University of Illinois at Chicago, Chicago, Illinois, and
the [double dagger] Department of Surgical Oncology, Roger Williams Medical Center, Providence, Rhode Island
Address correspondence and reprint requests to N. Joseph Espat, M.D., M.S., F.A.C.S., Roger Williams Medical Center, Professor and Chief Surgical Oncology, 825 Chalkstone Avenue, Providence, RI 02908. E-mail: [email protected]
Copyright Southeastern Surgical Congress Jan 2008
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