Barrett Esophagus with Progression to Adenocarcinoma in Multiple Family Members with Attenuated Familial Polyposis

Attenuated familial polyposis (AFAP) is a subset of familial adenomatous polyposis (FAP) that has a relatively benign disease course. AFAP is characterized by no more than 100 colorectal polyps and has a tendency toward rectal sparing, a 20–25-year delay in the onset of adenomatosis and bowel symptoms, a 10–15-year delay in the development of colorectal cancer, and death caused by colorectal cancer in 15–20 years. Extracolonic involvement is limited. Although gastric polyps and duodenal adenomas are frequent, esophageal involvement has not been reported in the literature, to our knowledge. We report a case of AFAP with esophageal mucosal disease that progressed from metaplasia to malignancy.

Case Report

A 41-year-old white male with a family history of FAP presented for gastroenterologic evaluation. Multiple family members had tested positive for exon 4 deletions in the 5′ end of the adenomatous polyposis coli (APC) gene. The patient's colonoscopic examination revealed multiple polyps (<100) ranging in size from 2 mm to 1 cm throughout the entire colon. Biopsies of the polyps revealed tubular adenomas. A diagnosis of AFAP was made. Surveillance esophagogastroduodenoscopy showed a distal esophageal lesion 37 cm from the incisors, overlying an area suspicious for Barrett esophagus. An endoscopic ultrasound confirmed a T2NxMx lesion. The patient underwent a transhiatal esophagectomy and colectomy. Pathology of the resected esophageal lesion revealed an invasive, well-differentiated T2N1aMx adenocarcinoma in the background of Barrett esophagus.

The patient likely inherited this mutation from his 65-year-old father, who tested positive for it, as did the patient's 2 brothers: a 43-year-old with 10–20 polyps on colonoscopy, and a 33-year-old with 70–80 polyps on colonoscopy. A biopsy of the patient's father revealed Barrett mucosa with extensive low-grade dysplasia. Barrett esophagus was found during an endoscopic examination of the patient's younger brother and was confirmed via biopsies. The patient's older brother had endoscopic findings suggestive of Barrett esophagus, although biopsies revealed severe esophagitis with no metaplastic changes.

Discussion

AFAP is an autosomal dominant, genetically transmitted disease characterized by no more than 100 colorectal adenomas with a predisposition for colorectal cancer. AFAP has a predilection for right-sided colonic adenomas with delayed adenoma expression and limited extracolonic involvement.¹ Because AFAP is not a well-defined disease entity, diagnostic criteria and methods of investigation vary; therefore, the true incidence and prevalence of the disease are unknown.¹ In AFAP, polyps are detected at a mean age of 40–45 years, and colorectal carcinoma develops at a mean age of 55–57 years; in contrast, bowel involvement is delayed by 20–25 years in AFAP.^2–4 Although gastric and duodenal adenomas are frequently encountered, involvement of esophageal mucosa is especially rare.^2,5–8 To the best of our knowledge, our case is the first report of esophageal adenocarcinoma in a patient with AFAP; however, even more intriguing is the manifestation of Barrett esophagus in multiple family members of the patient.

Standard clinical diagnosis of typical or classical FAP is based on the identification of more than 100 colorectal adenomatous polyps. Extraintestinal features of FAP are summarized in Table 1.⁹

Table 1.

Extraintestinal Features in Familial Adenomatous Polyposis

Benign lesions	Malignant lesions
Congenital hypertrophy of the retinal pigment epithelium (70–80%)	Thyroid cancer (2–3%)
Epidermoid cysts (50%)	Brain tumors (<1%)
Osteomas (50–90%)	Hepatoblastomas Desmoid tumors (10–15%)
Supernumerary teeth (11–27%)
Adrenal gland adenomas (7–13%)

Reproduced with permission from Vasen HF, et al.⁹

Clinical diagnosis of AFAP is more difficult. Recently, diagnostic criteria for AFAP have been proposed by 2 groups: Nielsen and associates and Knudsen and colleagues.^10,11 According to Nielsen and coworkers, AFAP should meet at least 1 of the following criteria: 2 patients in the same family with 10–99 adenomas who are older than 30 years of age; or 1 patient with 10–99 adenomas who is older than 30 years of age and has a first-degree relative with colorectal cancer and several adenomas.¹⁰ Knudsen and coworkers proposed the following criteria for AFAP: a dominant mode of inheritance and 3–99 colorectal adenomas in a patient 20 years of age or older.¹¹ In both sets of criteria, family members should not have more than 100 adenomas before 30 years of age. Our patient fulfilled both sets of criteria for AFAP.

Hereditary forms of colorectal cancer are characterized by family history, young age at disease onset, and the presence of other tumors. Given the incidence of de novo mutations, however, AFAP cannot be ruled out in the absence of a positive family history, which is particularly important when assessing a patient with a low polyp burden.

Tumor suppressor genes produce proteins that inhibit tumor formation by regulating mitotic activity and providing inhibitory cell cycle control. The APC gene is a tumor suppressor gene located on chromosome 5q31.^12,13 APC produces a 2,843 amino acid protein that forms a cytoplasmic complex with glycogen synthase kinase-3 β, β-catenin, and axin. β-catenin activates transcription of genes that regulate cellular growth and proliferation, such as c-myc. Wnt signaling proteins are extracellular signaling molecules that help to regulate tissue development throughout the organism. These signaling proteins are closely associated with the APC-β-catenin pathway. Reduced levels of β-catenin inhibit Wnt expression. When APC is mutated, β-catenin levels rise, activating Wnt. Overexpression of Wnt leads to activation of genes that drive cell proliferation and tumor formation. APC gene mutations associated with AFAP have mainly been detected in 3 regions: the 5′ end (the first 5 exons), exon 9, and the distal 3′ end of the gene. A germline APC truncation mutation is responsible for autosomal dominant inheritance; however, de novo germline mutations occur in 20–30% of cases.

Although AFAP is usually characterized by fewer than 100 colorectal polyps, several researchers have described kindred in whom the number of polyps far exceeds this criterion.^3,5,6,14 The penetrance of colorectal cancer remains high in patients with AFAP, but the exact incidence and lifetime risk remain unknown. Extracolonic involvement is usually limited to the upper gastrointestinal tract in the form of gastric fundic polyps and duodenal adenomas.^1,2,5,6,15 As with FAP, upper gastrointestinal cancers do not appear to be a prominent feature in AFAP. This finding was documented in a study by Soravia and associates, who reported only 1 case of duodenal cancer among 79 patients.² Another series reported 2 cases of periampullary or duodenal cancers among 132 patients, 1 case of periampullary carcinoma among 16 patients, and 1 case of adenocarcinoma of the stomach (in a 71-year-old patient) among 9 patients.^7,16 Desmoid tumors have been described in the literature, particularly in patients with mutations at the 3′ end of the gene. Congenital hypertrophy of the retinal pigment epithelium has not been reported until now. Osteomas, epidermoid cysts, and papillary thyroid carcinomas have been reported only sporadically.

Conclusion

To date, AFAP remains a poorly understood entity, and no specific guidelines have been established for its surveillance and treatment.¹⁵ There is a general consensus that yearly colonoscopies comprise standard-of-care treatment, given the development of polyps proximal to the splenic flexure.¹⁷ Endoscopy is recommended starting at 20–25 years of age. Due to the late onset of polyposis in AFAP— contrary to classic FAP—no upper age limit has been set for surveillance.^17,18 Dye spraying during colonoscopy is recommended to differentiate AFAP from FAP.^19,20 AFAP is somewhat difficult to classify as a separate entity due to varied disease expression in individuals with identical mutations. Unlike classic FAP mutations, mutations causing AFAP have reduced or variable penetrance, which may be the reason for this variable expression.^15,21 External factors, such as hormones, growth factors, and environmental exposure, could also be vital factors determining the phenotypic expression of AFAP.

It would be interesting to determine whether our patient's kindred actually have a unique mutation that accounts for their unusual esophageal involvement. It is also likely that they had similar exposure to the previously mentioned external factors. Close follow-up of the patient's siblings is required to monitor development of esophageal neoplasms; in fact, 1 sibling already had Barrett epithelium. Further research is needed to provide more substantiated evidence of AFAP's potential direct association with Barrett epithelium, the progression to adenocarcinoma, and whether prophylactic resection is warranted. We hope that our case helps to provide insight into understanding AFAP, an uncommon and intriguing disease.