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Fundic Gland Polyposis With High-Grade Dysplasia in a Child With Attenuated Familial Adenomatous Polyposis and Familial Gastric Cancer

2001; Lippincott Williams & Wilkins; Volume: 32; Issue: 2 Linguagem: Inglês

10.1097/00005176-200102000-00026

1536-4801

Thomas M. Attard, Francis M. Giardiello, Pedram Argani, Carmen Cuffari,

Colorectal Cancer Treatments and Studies

Familial adenomatous polyposis (FAP) is an autosomal dominant disorder caused by germline mutations in the adenomatous polyposis coli (APC) gene located on chromosome 5q21. FAP is characterized by the development of hundreds of colorectal adenomas in young adults. If prophylactic colectomy is not performed, patients will develop colorectal cancer by the sixth decade of life (1). In comparison, genotype–phenotype correlation studies have reported that mutations in the extreme 5´ and 3´ end of the APC gene and complete deletions of the APC gene locus are variably associated with a less severe phenotype of FAP termed “attenuated familial adenomatous polyposis” (AFAP) (2,3). The clinical characteristics of AFAP include fewer than 100 colorectal adenomas at presentation (oligopolyposis), notable phenotypic variations within pedigrees, and a delayed onset of colorectal cancer (more than 12 years) compared with classic FAP (4–6). In addition to colorectal adenomas, patients with FAP can have upper gastrointestinal tract polyps. Periampullary carcinoma is the most common extracolonic malignancy (7) and is the current focus of screening through serial esophagogastroduodenoscopies. Although fundic gland polyps are common in patients with FAP and AFAP and in nonsyndromic patients (8), they are generally considered benign (9,10). Recent case reports and histopathologic observations have suggested a premalignant potential in fundic gland polyps (11). Herein, we describe the first pediatric patient with AFAP and a strong family history of gastric carcinoma, who had fundic gland polyps with severe dysplastic changes requiring prophylactic gastrectomy. CASE REPORT The patient is an 11-year-old white girl with AFAP who was referred to the Johns Hopkins Hospital for surveillance esophagogastroduodenoscopy and colonoscopy. At presentation, she was asymptomatic and her physical examination findings were normal. The family pedigree is described in Figure 1 and is relevant for AFAP and gastric adenocarcinoma both presenting at 30 to 40 years of age.FIG. 1.: Five-generation pedigree affected by attenuated familial adenomatous polyposis.She was diagnosed with AFAP at age 9. A screening upper and lower endoscopy showed multiple, biopsy-proven hyperplastic fundic gland polyps with no microscopic signs of dysplasia, and a single adenomatous sigmoid colon polyp, respectively. A second surveillance endoscopic examination was performed at age 10. Biopsies taken from the fundic gland polyps were once again noted to be hyperplastic and without signs of dysplasia. On colonoscopy, a solitary adenomatous polyp was identified and excised from the descending colon. We performed her third esophagogastroduodenoscopy at age 11; it showed multiple (more than 50) pedunculated polyps in the gastric fundus. Four randomly selected polyps were endoscopically snared, cauterized, and recovered for histologic evaluation. The antrum and the duodenum, including the periampullary region, appeared normal. At colonoscopy, a single, broad-based sigmoid polyp measuring less than 0.5 cm was removed by snare cautery without complication. Multiple hematoxylin-and-eosin—stained sections were obtained from each gastric polyp resected. All showed the classic histologic features of fundic gland polyps, including groups of cystically dilated fundic-type glands lined by attenuated chief and parietal cells, and outpouchings (“budding”) at their periphery (Fig. 2). The overlying epithelium showed loss of mucin and nucleomegaly consistent with low-grade dysplasia. One focus showed striking epithelial crowding with a nearly cribriform pattern associated with marked nucleomegaly, irregular nuclear contours, and prominent nucleoli consistent with high-grade dysplasia (see Fig. 2). The sigmoid polyp was a tubular adenoma.FIG. 2.: (A) Intermediate-power view of a resected fundic gland polyp, showing cystically dilated fundic gland lined by chief and parietal cells. The surface mucous neck cells at the upper right are normal (arrow); at the upper left, dysplasia is evident (double arrow). (Hematoxylin and eosin, ×160) (B) High-power view of focus of high-grade dysplasia in mucous neck cells of fundic gland polyp, consisting of glandular crowding, loss of mucin, nucleomegaly, nuclear contour irregularity, and prominent nucleoli. Residual parietal cells and dilated gland are seen at the bottom (arrow). Hematoxylin and eosin, ×400.Figure 2: ContinuedIn view of the malignant potential of the gastric polyps and the family history of gastric carcinoma (see Fig. 1), our patient underwent a total gastrectomy, Roux-en-Y esophagojejunostomy, and Hunt-Lawrence pouch creation. The resected stomach showed striking polyposis limited to the gastric fundus (Fig. 3). Extensive sectioning revealed innumerable fundic gland polyps, most of which demonstrated low-grade dysplasia of the surface mucinous epithelium. Another single focus of high-grade dysplasia was also identified. The nonpolypoid mucosa was unremarkable, with no evidence of dysplasia in the surface epithelium. No invasive carcinoma was identified, and all 10 resected lymph nodes were free of tumor. There were no intra-or postoperative complications. She was discharged home on postoperative day 8. Since discharge, she has been weaned off all analgesic medications, and her only complaints include mild symptoms consistent with dumping syndrome.FIG. 3.: Gross photograph of the resected stomach. The specimen shows striking carpet-like polyposis limited to the gastric fundus. The uninvolved antrum is to the lower right (arrow).DISCUSSION In comparison to FAP, patients with AFAP have fewer than 100 polypoid colonic adenomas, which are mostly right-sided. The adenomas are occasionally described as flat rather than polypoid lesions, leading to the initial description as “hereditary flat adenoma syndrome”(7). Colorectal cancer tends to be of later onset compared with FAP. Annual surveillance sigmoidoscopy is recommended from puberty, but less frequently in patients with negative protein truncation testing (PTT) when affected persons in the family have positive PTT. However, given the propensity for right-sided lesions, a complete colonoscopy is indicated in patients with AFAP. In patients with AFAP, fundic gland polyps and duodenal adenomas are more prominent than colonic polyps (6,12). Esophagogastroduodenoscopy with both a front-and side-viewing endoscope is indicated at the time of diagnosis. The frequency of surveillance endoscopies is determined by the size and histology of periampullary polyps. There are no specific recommendations pertaining to the management of fundic gland polyps noted on upper endoscopy (13). The malignant potential of fundic gland polyps remains controversial, especially in children, because of the paucity of publications addressing the incidence of either sporadic or syndromic gastric polyps. Further, high-grade dysplasia and overt malignancy of the stomach is rare in the pediatric population. Our patient is the first reported case of a child with AFAP and high-grade dysplasia in fundic gland polyps that required a prophylactic gastrectomy. Moreover, her family pedigree shows this prominent phenotype in successive generations. In the pedigree (see Fig. 1), patient 403 had 10 colonic adenomas in the ascending and transverse colon. Adenocarcinoma of the colon developed at age 63 and was resected. Although fundic gland polyps were recognized at age 72, she died of metastatic stomach cancer at age 75. Patient 402 died at age 49 of metastatic gastric carcinoma and tested negative for mutations of the APC gene by PTT. No polyps were noted in the colon at autopsy. Patient 505, our patient's mother, had adenomatous gastric polyps with high-grade dysplasia diagnosed at age 38 and required a prophylactic gastrectomy. In comparison, our patient (604) had multiple fundic gland polyps that were identified during screening endoscopy performed at 9, 10, and again at 11 years of age. The polyps obtained at her last endoscopy (age 11) showed high-grade dysplasia. The family fulfills the criteria for AFAP. The affected family members had relatively few (less than 100), predominantly right-sided colorectal adenomatous polyps. Moreover, all patients had prominent fundic gland polyposis. Although fundic gland polyps were initially considered pathognomonic for FAP, they are often recognized as a sporadic finding during endoscopy. In a recent series, fundic gland polyps accounted for 17% of all gastric polyps identified (8). These polyps have been associated with the prolonged use of proton pump inhibitors (more than 32 months) (14) and are noted to regress in size after the discontinuation of therapy, thereby suggesting a role for hypergastrinemia. Circulating trophic mediators produced by colorectal adenomas have been postulated to contribute to fundic gland polyposis in patients with FAP. Interestingly, these fundic gland polyps have been observed to regress after prophylactic colectomy (15). Fundic gland polyps occurring in FAP patients tend to be multiple, are diagnosed at an earlier age, and show a higher male-to-female ratio than those in sporadic cases. Histologically, they are identical to sporadic cases (9,10), although they have a greater propensity to develop dysplastic changes (16). Fundic gland polyps are described as hyperplastic, regenerative, or cystic hamartomas and are generally considered to lack malignant potential. The authors of a recent study suggested that dysplastic changes can occur in fundic gland polyps on exposure to an as yet undefined carcinogenic stimulus present in FAP or AFAP (17). A family pedigree with AFAP and malignant transformation of fundic gland polyps has been previously reported (11). A member of this pedigree had numerous gastric fundic gland polyps with high-grade dysplasia, necessitating gastrectomy (11,18). Recently, another family member died at age 45 with metastatic adenocarcinoma of the stomach associated with a large fundic gland polyp. In this patient, the diagnosis was established only at autopsy despite serial endoscopic evaluations since age 26 years (19). Interestingly, Friedl et al. (20) reported two families with 3´ mutations of the APC gene with mild colonic involvement consistent with AFAP. Notably, one subject required stomach resection at a young age, and another subject developed adenocarcinoma of the stomach at an advanced age. In comparison, the family members presented in this report are at a greater risk for gastric adenocarcinoma (patients 204, 303, 401, 402, 403, 404, 501) rather than colorectal or periampullary duodenal cancer. In addition, either gastric adenocarcinoma or high-grade dysplasia developed in association with fundic gland polyps in multiple generations (see Fig. 1). Our patient is the youngest patient reported to date who was diagnosed with high-grade dysplasia in association with fundic gland polyps. Serial endoscopic studies would suggest that either high-grade dysplasia developed over the span of 11 months, or that the diagnosis was missed on an earlier endoscopy. The former study provided mucosal biopsies as opposed to polypectomies. In both instances, questions are raised as to what the standard of care should be for screening patients with either AFAP or FAP and a predilection to fundic gland polyposis and gastric cancer. Although observational bias could account for the recognition of severe dysplasia in successive generations of the pedigree, genetic anticipation cannot be ruled out. We suggest that all patients with AFAP and multiple fundic gland polyps undergo annual surveillance endoscopy. Consideration should be given to polypectomy as opposed to simple mucosal biopsies, especially in patients with a family history of fundic gland dysplasia or gastric carcinoma. Logic dictates that larger polyps might be more likely to harbor dysplastic, proliferative epithelium and hence should be selectively excised. However, in our patient, high-grade dysplasia was present in the scattered polyps that were indistinguishable from the numerous polyps surrounding them. Hence, dysplasia is not always limited to large polyps, and endoscopic sampling must be thorough. In patients with high-grade dysplasia, complete gastrectomy should be recommended. Interestingly, APC germline mutations were not identified by PTT in the affected persons, raising the possibility of nontruncating APC mutations or alternative gene mutations as the cause. Further genetic analysis of this family may allow the identification of a novel mutation, possibly unrelated to the APC locus.