Familial Adenomatous Polyposis
Total Page：16
File Type：pdf, Size：1020Kb
78 Review Article Familial Adenomatous Polyposis Alexia Waller1 Sarah Findeis2 Michael J. Lee3 1 Department of Pathology, Baylor University Medical Center, Dallas, Address for correspondence MichaelJ.Lee,MD,Departmentof Texas, United States Pathology and Cell Biology, Columbia University Medical Center, 630 2 School of Medicine and Dentistry, Pennsylvania State University, West 168th St. VC14-215, New York, NY 10032, United States Hershey, Pennsylvania, United States (e-mail: [email protected]). 3 Department of Pathology and Cell Biology, Columbia University MedicalCenter,NewYork,NewYork,UnitedStates J Pediatr Genet 2016;5:78–83. Abstract Familial adenomatous polyposis (FAP), caused by a germline mutation in the adenoma- tous polyposis coli (APC) gene on chromosome 5q21, is an autosomal dominant disorder Keywords characterized by hundreds to thousands of adenomas throughout the gastrointestinal ► familial adenomatous tract. A variety of extraintestinal manifestations, including thyroid, soft tissue, and brain polyposis tumors, may also be present. These patients inevitably develop colorectal carcinoma by ► Turcot syndrome the fourth decade of life. In this review, the pathology, epidemiology, and genetic ► Gardner syndrome features of FAP are discussed. Introduction ampulla of Vater can obstruct bile flow and pancreaticobiliary enzymes, leading to acute pancreatitis.5 Familial adenomatous polyposis (FAP) is an autosomal domi- The diagnosis of FAP is not particularly challenging, since nant disorder, caused by an inherited mutation in the adeno- symptomatic patients will undergo colonoscopic evaluation matous polyposis coli (APC) gene on 5q21, with a frequency and the endoscopic impression is fairly unique. After molec- that ranges from 1 in 6,850 to 29,000 people. Approximately ular confirmation, family members should be placed under 10 to 30% of patients will develop FAP spontaneously without the appropriate screening protocol. Children of FAP patients a family history.1 There is often genotypic variation, as should be screened by genetic testing and begin flexible mutations can occur at several different sites in the gene, sigmoidoscopy by age 10 years, with annual subsequent leading to divergent phenotypes. Environmental and dietary exams.6 One of the most cost-effective methods for FAP factors are also thought to contribute to the variation in screening is a fundoscopic examination looking for congenital clinical expression.2 hypertrophy of the retinal pigment epithelium (CHRPE). This FAP patients usually have greater than 100 gastrointestinal is seen in up to 90% of FAP patients, even including infants.7 In polyps, often in the range of thousands (►Fig. 1). Although addition to gastrointestinal polyps and malignancy, other adenomas are usually absent until puberty, the number and associated pathologic findings include hepatoblastomas, size of adenomas increase drastically until the gastrointesti- desmoid tumors, and brain cancer, which can be fatal. There- nal tract becomes completely filled by these dysplastic fore, even a prophylactic colectomy is not completely effective polyps. By the age of 30 years, almost three-quarters of in reducing these patients’ mortality risk.8 afflicted patients develop colorectal carcinoma, and the 3 fi average age of death is 42 years. The rst and second most Pathologic Features common causes of FAP-related mortality are metastatic colorectal carcinoma and desmoid tumors, respectively.4 FAP is characterized by hundreds of adenomas throughout Common symptoms include abdominal pain, diarrhea, hem- the luminal gastrointestinal tract that develop during early atochezia, and melena. Patients may also present with severe adolescence. Starting from the caudal end of the tract and dehydration due to electrolyte imbalances and depletion working downward, fundic gland polyps (FGPs) are benign from diarrhea and mucous discharge. Adenomas at the lesions commonly seen within the stomach; however, up to received Issue Theme Hereditary Cancer Copyright © 2016 by Georg Thieme DOI http://dx.doi.org/ July 15, 2015 Syndromes in Children; Guest Editors: Verlag KG, Stuttgart · New York 10.1055/s-0036-1579760. accepted after revision Nicole D. Riddle, MD, and Raul S. ISSN 2146-4596. August 10, 2015 Gonzalez, MD published online March 15, 2016 Familial Adenomatous Polyposis Waller et al. 79 Fig. 1 Colectomy specimen from a patient with FAP, showing innumerable tubular adenomas. (Photograph courtesy of Robert Weir, PA.) 25% of FGPs in FAP patients harbor foveolar dysplasia.9 tions than bile from non-FAP patients, potentially affecting Sporadic and FAP-associated FGPs also demonstrate differ- the APC gene or other genes in the progression of dysplasia to ences at the molecular level. Sporadic FGPs often show carcinoma. Others have postulated that the hormonal or somatic mutations in the β-catenin gene at exon 3. This environmental milieu may influence FAP manifestations mutation is not seen within FGPs of FAP patients. Instead, due to a strong predilection of thyroid cancer in female FAP the common genetic mutation in this latter group is a second patients and desmoid tumors (abdominal fibromatosis) dis- – somatic APC hit on top of a germline APC mutation. While covered after trauma.15 17 there are similarities in the mutational pathways between A common extraintestinal lesion in FAP patients is CHRPE. sporadic and FAP-associated FGPs, there are clear differences This benign finding occurs in approximately 70 to 80% of in the initial mutation.10 patients and is often present at birth. It is asymptomatic and – Adenomas can be seen in the small intestine, with approx- does not demonstrate progression into a malignancy.18 20 imately two-thirds located in the periampullary region.4,11 CHRPE can be visualized on fundoscopic examination of the Progression of adenomas in the small intestine to adenocar- eye. Bilateral, multiple CHRPEs are a specific feature for FAP, cinoma is the third leading cause of mortality in FAP patients. with 95 to 100% specificity.21 It is an excellent diagnostic The pathognomonic feature of FAP is the presence of modality for testing family members before moving to hundreds of adenomas within the colon and rectum. The genetic testing. The histologic features of CHRPE demonstrate rectum is almost always involved, and the length of the large hypertrophy of the retinal pigmented epithelium (RPE) with intestine is carpeted by adenomas. There is variation in size cells that are up to twice as large as normal RPE cells. These and shape, ranging from less than 1 mm to greater than 1 cm RPE cells are filled with melanin granules and lose their in size. The number of polyps can be less than 100 to more nuclear basal polarity. Electron microscopy shows that the than 5,000. The adenomas are histologically similar to spon- pigmented cells of a CHRPE contain melanosomes rather than taneous tubular adenomas, with elongated, hyperchromatic lipofuscin.22 nuclei lining the crypts. There is no surface maturation, and Thyroid cancer is also associated with FAP. The most some adenomas may focally demonstrate fingerlike villous common thyroid cancer among FAP patients is papillary extensions. Rather than the typical polypoid configuration, thyroid carcinoma. They are often multifocal and confined some adenomas are flat and can grow in a horizontal fashion. to one thyroid lobe. From a prognosis standpoint, FAP- A proctocolectomy is necessary, since the adenomas invari- associated thyroid cancers behave nonaggressively, with a ably progress to colorectal carcinoma by the age of 35 to low incidence of metastatic disease and mortality rates 40 years. These cancers are more likely to be seen on the left within a decade; sometimes, they appear as a rare variant, – side of the colon.12 14 known as cribriform-morular papillary thyroid carcinoma, – that is almost always seen only in patients with FAP.23 27 Nongastrointestinal Diseases Papillary thyroid carcinomas demonstrate a characteristic papillary architecture with pathognominic cytologic features There is extensive phenotypic diversity in FAP patients. such as nuclear clearing, pseudostratification, nuclear Lesions may involve several organs outside the gastrointesti- grooves, and pseudoinclusions.28 nal tract. Along with the initial mutation, there are likely Desmoid tumors, or fibromatosis, are a rare tumor caused additional factors that contribute to these variations. Bile by mutations in the β-catenin gene.29 They are typically from FAP patients has been theorized to cause more muta- present in the abdomen and can involve the mesentery or Journal of Pediatric Genetics Vol. 5 No. 2/2016 80 Familial Adenomatous Polyposis Waller et al. abdominal wall; less commonly, they are seen within the medulloblastoma with extensive nodularity, desmoplastic limbs.30 Approximately 15% of FAP patients have desmoid nodular, anaplastic, and large cell. Classic medulloblastomas tumors.31 These tumors are locally invasive and are the are the most common form and are characterized by sheets of second leading cause of death among FAP patients.4 This is densely packed, small, mitotically active, basophilic cells with due to the numerous complications that can occur from the high nuclear-to-cytoplasmic ratio. Medulloblastoma with locally aggressive nature of these tumors or the surgical extensive nodularity has an expanded lobular architecture interventions necessary to remove these lesions, which do because of reticulin-free zones and a streaming pattern not always succeed in removing the entire