Gastric Adenocarcinoma and Dysplasia in Fundic Gland Polyps of a Patient With Attenuated Adenomatous Polyposis Coli

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1 GASTROENTEROLOGY 1997;113: CASE REPORTS Gastric Adenocarcinoma and Dysplasia in Fundic Gland Polyps of a Patient With Attenuated Adenomatous Polyposis Coli A. ZWICK,* M. MUNIR,* C. K. RYAN, J. GIAN, R. W. BURT, M. LEPPERT, x L. SPIRIO, x and W. Y. CHEY* *William B. and Sheila Konar Center for Digestive and Liver Diseases and Departments of Medicine and Pathology, University of Rochester Medical Center, Rochester, New York; and Division of Gastroenterology and x Department of Human Genetics, University of Utah College of Medicine, Salt Lake City, Utah Gastric adenocarcinoma has been previously recoga adenomatous polyposis and was eventually found to belong to nized as a potential complication of familial adenomafirst kindred with a known mutation of AAPC. 1 She had her tous polyposis coli (APC) and attenuated forms of APC screening colonoscopy at that time, which revealed three (AAPC). This tumor has only been reported to originate adenomatous polyps. Subsequently, she underwent four surfrom adenomatous polyps of the gastric mucosa in veillance colonoscopies over the next 7 years. One to two ade- these clinical conditions. There have been no previous nomatous polyps were removed at each procedure. She had case reports of gastric adenocarcinoma arising from remained asymptomatic until 1980, when colonoscopy showed the more commonly found fundic gland polyps associated multiple polyps that were larger than those previously recase with AAPC or APC. We report the first definitive moved. At that time, she was advised to undergo total procto- of gastric adenocarcinoma arising from a hyper- colectomy with continent ileostomy, which was performed in plastic polyp of the fundis of a patient with AAPC. November The resected colon showed a total of 26 adenomatous polyps ranging from 0.5 to 1 cm, without eviamilial adenomatous polyposis coli (APC) and attenu- forms of APC (AAPC) are autosomal dominantly the time of colectomy, have multiple polyps were found in dence of malignancy or regional lymph node involvement. At Fated inherited conditions associated with the development of her stomach. The patient next presented to her primary care numerous adenomatous polyps within the colon. These physician in September 1994 with complaints of epigastric syndromes are now known to arise from mutations of the pain not relieved by cimetidine. Upper gastrointestinal endos- APC gene, found on the long arm of chromosome 5. 1 The copy showed gastric polyposis with representative biopsy specigastric lesions are predominantly hyperplastic in nature mens showing fundic gland polyps. and are known as fundic gland polyps in the collective By early November 1994, she was complaining of nausea literature. Less commonly, adenomatous polyps are and pain in the right upper quadrant and lower back. Abdomi- found. 2 9 The frequency of a specific histological polyp nal ultrasonography showed multiple cystic and solid masses type is strongly related to location within the stomach, and nodules in the liver. Liver function tests showed elevations in plasma levels of aspartate aminotransferase to 54 IU/L, g- with fundic gland polyps predominantly found in the body glutamyltransferase to 291 IU/L, and alkaline phosphatase to and fundus and adenomas more common in the antrum IU/L. Her hematocrit was 33%. Subsequent computerized The development of gastric carcinoma however, has been tomography scan of the abdomen and pelvis showed wideassociated exclusively with gastric adenomas. 11,12 Tradi- spread, multiple, large combined cystic and solid masses tionally, fundic gland polyps have been thought to have within the large polypoid mass along the left lateral and anteno potential for malignant transformation. 9,13 16 Although rior wall of the gastric fundus. Initial attempts of a computerstudied histologically in several series, these polyps have ized tomography guided liver biopsy of a representative nodonly rarely shown evidence of dysplasia but never frank ule failed to reach a definitive diagnosis. malignancy. 10,13,14,17 We report the first definitive case of The patient was then referred to Strong Memorial Hospital gastric adenocarcinoma arising from a fundic gland polyp. in mid-november 1994 for diagnostic evaluation and treat- Case Report Abbreviations used in this paper: AAPC, attenuated adenomatous Patient History and Diagnostic Work-up polyposis coli; APC, adenomatous polyposis coli; EM, electron mi- A 49-year-old married woman was initially evaluated croscopy by the American Gastroenterological Association at the age of 29 (in 1974) for a family history of familial /97/$3.00

2 660 ZWICK ET AL. GASTROENTEROLOGY Vol. 113, No. 2 Figure 1. Opened stomach at autopsy; pancreas and duodenum at lower left. Sessile and semipedunculated polyps blanket the entire fundus. Arrow notes approximate location of malignant polyp. mation into a high-grade adenocarcinoma (Figure 3A and B). The carcinoma was composed of highly atypical glands originating in the lamina propria and infiltrating through the muscularis mucosa. A small artery invaded by tumor was identified in this area (Figure 4). The malignant cells constituting the glands possessed abundant, brightly eosinophilic cytoplasm with irregular hyperchromatic nuclei and numerous mitoses, suggestive of origin from a parietal cell line. Electron microscopy (EM) was performed on these cells from tissue removed from the paraffin block, because at the time of postmortem, tissue had not been specifically fixed for EM in glutaraldehyde. Ultrastructurally, the tumor cells were characterized by numerous mitochondria and the absence of secretory granules, but suboptimal fixation precluded more thorough examination. One fundic gland polyp randomly submitted for histological examination was significant for a focus of marked dysplasia; an abnormal tripolar mitoses was identified within the dysplastic glands (Figure 5). Additional findings at autopsy included extensive metastases to the liver, periaortic lymph nodes, peri- toneal surface of the diaphragm, and gastric serosa. There were no tumor masses in the pancreas, adrenals, kidneys, ovaries, uterus, lungs, and heart. Histologically, the metastases were identical in morphology to the primary tumor in the stomach. Suspected as the acute cause of death were antemortem thrombi within the left pulmonary vasculature. Both a rapid urease test (CLO test) and Warthin Starry Silverstein histological stain for Helicobacter pylori were negative in the mucosa of the antrum as well as gastric corpus. ment. She had lost approximately 10 pounds over the prior 10 days because of nausea, vomiting, and abdominal pain. The pertinent physical finding at the time revealed a firm abdomen with tender hepatomegaly, with a span of 20 cm. There was no evidence of splenomegaly or ascites. Cytological examination of the liver by fine-needle aspirate showed a poorly differentiated adenocarcinoma. Upper gastrointestinal endoscopy was performed and showed a normal esophagus and cardia. The fundus and antrum were carpeted with small polyps ranging in size from õ 2 5 mm in diameter. There was a large area of multiple, lobulated, soft polyps collectively forming a mass that occupied approximately 40% of the fundic lumen. Multiple biopsy specimens were obtained from the polyps mucosal surface using 7-mm biopsy forceps. The duodenum showed a few somewhat larger, but similar appearing, polyps from which multiple biopsy specimens were obtained. Histological findings of the biopsy specimens were hyperplasia of fundic glands in the stomach and a tubulovillus adenoma in the duodenum. Clinical Course and Pathology The patient was placed on an adequate analgesic regimen, and the oncology service provided consultation service. It was considered that further diagnostics to find the primary tumor would not change the prognosis significantly, and thus no specific treatment was offered. The patient decided to be on home hospice and died on December 31, An autopsy was performed at the University of Rochester Medical Center. The autopsy was significant for a normal esophagus and small intestine; the patient had undergone a total colectomy in The stomach contained numerous sessile and pedunculated polyps involving the fundus and body (Figure 1). The largest polyp was located in the midfundus along the greater curvature and measured 3.5 cm in greatest dimension. Microscopic examination of the gastric polyps showed simple hyperplasia of fundic glands and microcysts consistent with fundic gland polyposis (Figure 2). The largest fundic gland polyp had undergone partial malignant transfor- Discussion In 1895, Hauser 18 became the first to describe multiple polyps of the gastric antrum and duodenum in a patient with APC at necropsy. Since that time, there have been only sporadic case reports of gastric polyposis in these patients until the Japanese investigators began to carefully document the phenomenon of fundic gland Figure 2. Representative histological sections of the gastric polyps sampled at autopsy. Typical benign fundic gland features are present with simple hyperplasia of glands and surface epithelium and dilated microcysts (H&E; original magnificatio 501).

3 August 1997 ADENOCARCINOMA ARISING IN A FUNDIC GLAND POLYP 661 Figure 3. (A) Adenocarcinoma (large arrow, upper left), developing in a fundic gland polyp and infiltratin through the muscularis mucosa into submucosa (small arrows, lower right and left) (H&E; original magnificatio 501). (B) Higher magnificatio of the carcinoma. Malignant glands are composed of cells with abundant, brightly eosinophilic cytoplasm and irregular hyperchromatic nuclei (H&E; original magnificatio 3001). polyposis in their APC patients. 3,4 Western researchers Western and Japanese population may be attributable to in recent years have subsequently begun to report and the overall higher incidence of gastric carcinoma within characterize these lesions with increasing frequency. 9,13 the Japanese population in general. In none of these cases A varied incidence of gastric cancer has been reported has the gastric cancer been found to arise from a fundic in patients with APC. The predominant number of re- gland polyp. Because AAPC has been recognized only in ports have come from Japan, where gastric cancer has recent years, 1 the prevalence of fundic gland polyposis been most frequently shown to arise from preexisting in patients with AAPC has not been extensively investigated. antral adenomas. 15,16 The Japanese Polyposis Center has reported a 2.1% incidence of gastric cancer, all originat- Our case shows adenocarcinoma arising not in a tubular or villous adenoma but in a fundic gland polyp (Figure ing from adenomas, in their patients with APC. 19 Jagelman and DeCosse 11 reported a 0.6% incidence of gastric 3). In addition, a randomly sampled fundic polyp displays adenocarcinoma among 1255 patients with APC compiled from 10 separate non-oriental polyposis registries. mitotic figure (Figure 5 B and C). A tripolar mitosis is within it a focus of significant dysplasia with an abnormal It is felt that the difference in incidence between the a feature often used to support a diagnosis of dysplasia or outright malignancy in a wide array of tumors from different tissues. One may conjecture from this that the carcinoma might have arisen from a similar dysplastic focus in another fundic gland polyp. The morphology of the carcinoma itself is somewhat unusual in that many of the cells were large and on H&E stain, brightly eosinophilic (normal parietal cells are strongly eosinophilic). However, we could not conclusively prove by EM that the tumor was a parietal cell carcinoma. The distinctive ultrastructural features that are diagnostic of parietal cells include abundant mitochondria, the absence of secretory granules, and intracytoplasmic canaliculi with microvilli. EM disclosed that the malignant cells from this patient contained abundant mitochondria and no secretory granules, but because of postmortem artefact and suboptimal fixation, we could not evaluate for the presence of a cana- Figure 4. An example of vascular invasion by the tumor; this vessel is licular system. located just below the malignant fundic gland polyp in the submucosa. Carcinoma infiltratin through stroma (arrow) is noted on the right. Although gastric cancer in APC has only been pre- (H&E; original magnificatio 1125). viously associated with adenomatous polyps, predomi-

4 662 ZWICK ET AL. GASTROENTEROLOGY Vol. 113, No. 2 as to the histological description of a fundic gland polyp. They were described as hyperplastic, 9,14 regenerative, 20 or hamartomatous. 4,21 These polyps are characterized by hyperplasia of surface and foveolar epithelium with shallow pits and cystic dilatations of glands. Fundic gland polyps have only recently been diagnosed as a distinct entity, having formerly been described under a variety of names and referred to as a type of hamartomatous polyp. Endoscopically, they appear as small hemispherical polyps (1 7 mm) located throughout the fundus and body, less commonly occurring in the distal stomach. They routinely appear the same color as normal gastric mucosa but sometimes are paler, occurring in closely spaced groups, bunches, or clusters that can resemble larger polyps. There have been rare reports of occasional dysplasia observed on biopsy specimens of single fundic gland polyps, but this has not been consistently observed in most series. 10,13,14 In an attempt to characterize better the histopathologic and biochemical features of fundic gland polyps in patients with APC, they were compared with those found in non-apc patients. Nishiura et al. 22 compared biopsy specimens from both APC and non-apc patients. They found no significant histological difference between the two groups. This included semiquantitative analysis of different cell populations such as chief cells, parietal cells, and accessory cells. Histochemically, the major difference found was the presence of O-acylated sialic acid in the mucus of foveolar and superficial epithelium of APCassociated polyps compared with non-apc polyps. O- Acylated sialic acid is a substance not usually found in normal fundic gland epithelium but is present in normal colonic mucosal epithelial cells. 22 It is also found in goblet cells of gastric mucosa with intestinal metaplasia and malignant cells of some gastric cancers. It was suggested by the investigators that fundic gland polyps in patients with APC are not simply hyperplastic but represent a form of intestinal metaplasia, with perhaps a stronger tendency toward dysplasia and malignancy than fundic gland polyps of non-apc patients. Nevertheless, it has been reported that fundic gland polyps are innocuous and Figure 5. Fundic gland polyp with focus of dysplasia. (A) Two fundic are not a concern for malignant transformation. 9,12,14,23 25 polyps; the one on the left contains a dysplastic focus (outlined by However, it is not certain whether fundic gland polyps arrows). (B) Higher power view of the dysplastic area showing an abnormal mitotic figur (arrow). (C ) High-power view of the tripolar nantly arising from the antrum, the majority of gastric polyps belong to the fundic gland type. This is the most common gastric lesion in APC as well as AAPC, with a reported prevalence of 27% 73% in APC. 4,9,13,15 However, there has been no agreement among investigators of patients with AAPC 1 are also as innocuous as those mitosis (arrow) (H&E; original magnifications A, 501; B, 3001; C, in patients with APC. More careful and extensive surveys 4001). for these patients are needed. Frequent endoscopic surveillance has been recommended if adenomas of the stomach and/or the duodenum are identified, but is generally recommended at longer intervals if only fundic gland polyps are found. Based on the findings of our patients, the known and potential biochemical differences of AAPC-associated fundic gland

5 August 1997 ADENOCARCINOMA ARISING IN A FUNDIC GLAND POLYP 663 Gastroduodenal polyps in patients with familial adenomatous polyposis. Dis Colon Rectum 1992; 35: Sarre RG, Frost AG, Jagelman DG, Petras RE, Sivak MV, McGan- non E. Gastric and duodenal polyps in familial adenomatous polyposis: a prospective study of the nature and prevalence of upper gastrointestinal polyps. Gut 1987; 28: Kurtz RC, Sternberg SS, Miller HH, DeCosse JJ. Upper gastroin- polyps and the occasional finding of dysplasia within these polyps, we suggest that the presence of fundic gland polyposis in AAPC patients may not be a completely benign process as previously suggested. Based on the unique findings of this patient, we also suggest that larger fundic gland polyps (those ú7 mm in diameter) testinal neoplasia in familial polyposis. Dig Dis Sci 1987; 32: be completely excised and examined histologically for the indolent presence of dysplasia or malignant transforgastroenteric lesions in familial adenomatous coli. Acta Pathol 15. Watanabe H, Enjoji M, Yao T, Iida M, Ohsosto K. Accompanying mation. This suggested recommendation obviously needs Jpn 1977; 27: more study. 16. Ohsoto K, Watanabe H, Itoh H, Yao T, Nishimura M. Simultane- ous occurrence of multiple gastric carcinomas and familial polyposis of the colon. Jpn J Surg 1974; 4: References 17. Goodman AJ, Dundas SAC, Scholefiel JH, Johnson BF. Gastric carcinoma and familial adenomatous polyposis (FAP). Int J Colon 1. Spirio L, Olschwang S, Groden J, Robertson M, Samowitz W, Joslyn G, Gelbert L, Thliveris A, Carlson M, Otterud B, Lynch H, Dis 1988; 3: Watson P, Lynch P, Laurent-Puig P, Burt R, Hughes JP, Gilles T, 18. Hauser G. Ueber polyposis intestinal adenomatosa und dereu Leppert M, White R. 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Pathol 1978; 9: Nishiura M, Hirota T, Itabashi M, Oshio K, Yamada T, Oguro Y. 5. Bulow S, Lauraifsen KB, Johansen A, Svendsen LB, Sondergaard A clinical and histopathological study of gastric polyps in familial JO. Gastroduodenal polyps in familial polyposis coli. Dis Colon polyposis coli. Am J Gastroenterol 1984; 79: Rectum 1985; 28: Watanabe H, Jass JR, Sobin LH. WHO histological typing of 6. Jarvinsen H, Nyberg M, Peltoralleo P. Upper gastrointestinal tract esophageal and gastric tumours. 2nd ed. New York: Springerpolyps in familial adenomatous coli. Gut 1983; 24: Verlag, 1990: Sivak MV, Jagelman DG. Upper gastrointestinal endoscopy in 24. Ming SC. Epithelial polyps of the stomach. In: Ming SC, Goldman polyposis syndromes: familial polyposis coli and Gardner s syn- H, eds. Pathology of the gastrointestinal tract. Philadelphia: drome. Gastrointest Endosc 1984; 30: Saunders, 1992: Burt RW, Berenson MM, Lee RG, Tolman KL, Freston JW, Gardner 25. Iida M, Yao T, Itoh H, Watanabe H, Kohrogi N, Shigematus A, ES. Upper gastrointestinal polyps in Gardner s syndrome. Gastro- Iwashita A, Fujishima M. Natural history of fundic gland polyposis enterology 1984; 86: in patients with familial adenomatous coli/gardner s syndrome. 9. Ranzi T, Castagnone D, Velio D, Velio P, Bianchi P, Polli EE. Gastroenterology 1985; 89: Gastric and duodenal polyps in familial polyposis coli. Gut 1981; 22: Received May 13, Accepted April 15, Domizio P, Talbot JC, Spigelman AD, Williams CB, Phillips RKS. Address requests for reprints to: William Y. Chey, M.D., Konar Upper gastrointestinal pathology in familial adenomatous polypo- Center for Digestive and Liver Diseases, Box 646, University of Rochsis: results from a prospective study of 102 patients. J Clin ester Medical Center, 601 Elmwood Avenue, Rochester, New York Pathol 1990; 43: Fax: (716) Jagelman DG, DeCosse JJ. Upper gastrointestinal cancer in famil- The authors thank David Anderson (husband) for his graceful coopial adenomatous polyposis. Lancet 1988; 1: eration that made this investigation possible, Pat Faiello for prepara- 12. Church JM, McGannon E, Hull-Boiner S, Sivak MV, Van Stolk tion of the manuscript, and the histology laboratory, Department of R, Jagelman DG, Fazio VW, Oakley JR, Lavery IC, Milsom JW. Pathology, for technical help.