Familial adenomatous polyposis (FAP) is a rare genetic disorder with autosomal dominant inheritance, defined by numerous adenomatous polyps, which inevitably progress to colorectal carcinoma unless detected and managed early. Greater than 70% of patients with this syndrome also develop extraintestinal manifestations, such as multiple osteomas, dental abnormalities, and a variety of other lesions located throughout the body. These manifestations have historically been subcategorized as Gardner syndrome, Turcot syndrome, or gastric adenocarcinoma and proximal polyposis of the stomach. Recent studies, however, correlate the severity of gastrointestinal disease and the prominence of extraintestinal findings to specific mutations within the adenomatous polyposis coli gene (APC), supporting a spectrum of disease as opposed to subcategorization. Advances in immunohistochemical and molecular techniques shed new light on the origin, classification, and progression risk of different entities associated with FAP.
To provide a comprehensive clinicopathologic review of neoplastic and nonneoplastic entities associated with FAP syndrome, with emphasis on recent developments in immunohistochemical and molecular profiles of extraintestinal manifestations in the thyroid, skin, soft tissue, bone, central nervous system, liver, and pancreas, and the subsequent changes in classification schemes and risk stratification.
This review will be based on peer-reviewed literature and the authors' experiences.
In this review we will provide an update on the clinicopathologic manifestations, immunohistochemical profiles, molecular features, and prognosis of entities seen in FAP, with a focus on routine recognition and appropriate workup of extraintestinal manifestations.
Familial adenomatous polyposis (FAP) syndrome is an autosomal dominant disease defined by numerous adenomatous polyps of the gastrointestinal (GI) mucosa, and a distinct set of extraintestinal lesions involving various organs.1,2 Classically, the number of gastrointestinal polyps correlates with increasing age. Ultimately, hundreds to thousands of polyps can develop in the colon.3,4 A variety of terms have been used to describe the disorder affecting individuals with an adenomatous polyposis coli (APC)–associated polyposis condition: familial adenomatous polyposis, attenuated familial adenomatous polyposis, the recently described gastric adenocarcinoma and proximal polyposis of the stomach, as well as Gardner syndrome and Turcot syndrome.2,4 It is important to note that classifications made to distinguish different varieties of extraintestinal symptomatology, such as Gardner and Turcot syndromes, should no longer be used as both of these syndromes are now known to be a part of the FAP spectrum.5 An average individual with classic FAP will develop colorectal carcinoma (CRC) around the age of 40 years if treatment is not provided.5 Some people have a variant of the disorder, called attenuated FAP, in which polyp growth is delayed, with an average CRC onset at 55 years of age.2 Extraintestinal manifestations of the disease may occur in attenuated FAP; however, this occurs far less commonly than in the classical form of FAP.5
The incidence of FAP is approximately 1 in 7000 to 1 in 30,000 births.6 It is a high penetrance autosomal dominant disease that affects men and women equally and exhibits variable expressivity.6 Most affected individuals have a family history of FAP syndrome; however, a significant subset (approximately 20%–30%) of cases arise from de novo mutations.3 The severity of both intestinal and extraintestinal disease has been found to correspond with the specific regions of the APC gene that are mutated.2
In the 1950s, Dr Eldon Gardner investigated the history of families affected by FAP and defined Gardner syndrome as the association of intestinal polyps, extracolonic growths, osteomas, and skin manifestations.7 A wide array of FAP-associated findings have since been described including bone abnormalities, thyroid and pancreatic cancers, odontomaxillary complications, and desmoid fibromatosis tumors.8–12 Gardner syndrome is now of historical interest rather than clinical significance, as these extraintestinal growths are known to be correlated more with mutation location in the APC gene, rather than occurring together in specific families.5 We provide a review of gastrointestinal features and an in-depth update on clinicopathologic manifestations, immunohistochemical profiles, molecular features, screening and surveillance, and prognoses of extraintestinal entities of FAP. Furthermore, this review helps pathologists with practical information relevant to the recognition and workup of these cases.
The hallmark of FAP is the development of hundreds to thousands of adenomatous polyps (Figure 1, A and B) in the colon and rectum, which often arise by adolescence, with an almost inevitable progression to CRC by the fourth decade of life, which is significantly younger than in sporadic CRCs.13 Approximately 70% to 80% of tumors in total occur on the left side of the colon.13 While FAP is most widely recognized for the adenomatous polyps after which it is named, patients have a higher risk than the general population of developing other intestinal and extraintestinal manifestations such as gastric fundic gland polyps (FGPs), duodenal polyps, congenital hypertrophy of retinal pigment epithelium (CHRPE), fibromas, fibromatosis, nasal angiofibromas, thyroid carcinomas, hepatoblastomas (HBs), brain tumors, and pancreatobiliary tumors.5,13
The presence of colorectal adenomatous polyposis is the main feature of FAP. Adenomatous polyps develop throughout the colorectum starting in childhood and adolescence. By age 15 years, approximately 50% of patients with FAP have colorectal adenomas, and the percentage increases to 95% by age 35 years.1 The lifetime risk of CRC is almost 100%. If these adenomatous polyps are left untreated, transformation to invasive carcinoma is almost inevitable, with patients presenting between the ages of 35 and 40 years on average.14
Macroscopically, classic FAP demonstrates numerous sessile adenomatous polyps carpeting the colonic mucosa (Figure 1, A and B). Each polyp generally measures 1 cm or less. Microscopically, polyps in FAP show various histologic features, similar to those present in their sporadic counterparts (Figure 1, C).2 Morphology of polyps in a single colectomy resection specimen may range from hyperplastic polyp, to tubular adenoma (Figure 1, C) (with or without high-grade dysplasia), to invasive adenocarcinoma within a single colectomy resection specimen. In fact, it is not uncommon to see several foci of invasive adenocarcinoma in 1 colorectomy specimen. Attenuated FAP shows this same range of histopathologic features; however, there are typically fewer polyps and occasional areas with macroscopically normal mucosa.2
The duodenum is the second most common site for the adenomatous polyps of FAP to arise, and it occurs in 30% to 70% of patients with FAP. Duodenal/periampullary carcinoma is the second leading cause of death in patients with FAP, after colorectal cancer, with the lifetime risk of development of duodenal malignancy similar to that of CRC at approximately 100%.15 Of the 4 duodenal parts, duodenal adenomas of FAP most commonly arise in the second and third (vertical and horizontal) parts.16 While several grading systems have been described to measure the severity of duodenal polyposis, the Spigelman system, which describes 5 stages from 0 to IV, is still the most commonly used system. The Spigelman staging system assigns points on the basis of size (1–4, 5–10, >10 mm), number (1–4, 5–20, >20), histology (villous, tubular, tubulovillous), and degree of dysplasia (low-grade, high-grade). Increased stage correlates with an increased risk for progression to duodenal cancer (Figure 1, D and E). Stage I reflects mild disease.16 Stage II is associated with a 2% risk of duodenal cancer, stage III disease is associated with a 3% risk, and stage IV is associated with a 30% risk.15 Of patients with duodenal disease, 80% present with stage II or stage III disease; the remaining 20% present with stage I or stage IV. Similar to polyposis in other locations, there is often progression of disease. Within 10 years of presentation, for 40% to 70% of FAP patients with duodenal involvement, the disease will advance in stage. The risk of stage III or stage IV duodenal polyposis exponentially increases after the age of 40 years. By the age of 70 years, approximately 50% will develop stage IV duodenal polyposis.1,15,16 Patients with FAP have a 100- to 330-fold increase in their risk of developing duodenal carcinoma in comparison to unaffected individuals.15,17,18
The periampullary polyps and adenocarcinomas (Figure 1, D and E) that occur in patients with FAP have the same histologic features as those present in patients without FAP. One can appreciate invasive adenocarcinoma involving pancreatic duct and common bile duct at the ampulla of Vater in this case (Figure 1, D and E).
In contrast to duodenal polyps, polyps found in the stomach are more likely to be benign FGPs located in the fundus and the body of the stomach than adenomas. The percentage of FAP patients with this manifestation has been found to range widely, with most studies noting that FGPs occur in anywhere from 30% to 88% of patients with familial polyposis syndrome, in comparison to just 5.9% of the general adult population undergoing endoscopy.19 Fundic gland polyps appear to affect men and women with FAP equally and, as expected, tend to present earlier (commonly between 30 and 40 years of age) than the peak incidence in the general population.20,21 In addition, while FGPs are isolated in 60% of sporadic cases, between 40% and 80% of patients with FAP-associated FGPs have more than 100 polyps, occasionally reaching into the thousands.22 Up to 50% of FAP-associated FGPs develop low-grade foveolar dysplasia, a rare (<15%) occurrence in sporadic FGPs.22 Gastric adenomas, which can be found throughout the stomach, only account for approximately 10% of gastric polyps.15,16 Interestingly, in Japan, where the general population has an increased risk of gastric cancer, adenomatous stomach polyps occur more frequently in patients with FAP than in FAP patients living in Western countries. Japanese patients with FAP were also found to have a 3 to 4 times higher gastric cancer rate than the general Japanese population.23,24 In contrast, person-year analysis revealed that patients with FAP in the United States do not have a significantly higher risk of gastric malignancy.1,18
HEAD AND NECK MANIFESTATIONS
Osteomas are an important extraintestinal component of FAP. They are found in 65% to 80% of patients with FAP. They can range in presentation from slight thickening in the bone to a large mass affecting any part of the skeleton.26 The frontal bones are the most frequent site of involvement.27 However, osteomas can affect the mandible, maxilla, and long bones as well.28,29 Exostosis osteomas, also called peripheral osteomas, can be palpable, but are typically detected by routine radiography.30,31 Central and lobulated osteomas can occur in the maxilla and mandible. Central osteomas are characteristically located near the roots of the anterior mandibular teeth. Lobulated osteomas are most commonly found at the mandibular angle and arise from the surface of the bone.31
Sections of the osteoma usually show anastomosing, irregular trabeculae or solid, sclerotic nidus of woven bone with variable mineralization and with fibrous stroma identifiable at low magnification (Figure 2, A and B).
Nasal angiofibromas have been described in some patients with FAP, and mutational studies (which are further discussed below) indicate they could be part of the syndrome.32,33 It is a histologically benign but locally aggressive vascular tumor that grows in the back of the nasal cavity. It most commonly affects adolescent males and may grow into fissures of the skull and may spread to adjacent structures. Patients with nasopharyngeal angiofibroma usually present with 1-sided nasal obstruction and recurrent bleeding.32,33
Nasal angiofibromas display an intricate mixture of stellate and staghorn blood vessels with variable vessel wall thickness ranging from single layer of endothelium to variable smooth muscle cell layers. Irregular fibrous stroma—loose, edematous to dense, or acellular—can be seen (Figure 2, C and D).34
Dental abnormalities are found in 30% to 75% of patients with FAP.31 These abnormalities include impacted or unerupted teeth, tooth ankylosis, congenitally missing teeth, supernumerary teeth (Figure 3, A), hypercementosis, and compound odontomas.30,31 Ankylosis in particular can be difficult to treat, as it can lead to difficulty in extraction.31
An APC gene (Figure 3, B) mutation in exon 15, namely, 4292-4293-Del GA, causing FAP in a family, was recently described in association with supernumerary teeth (Figure 3, A) and odontoma.35 Furthermore, RNA sequencing analysis of human supernumerary teeth suggests that the APC gene is the key gene involved in the development of supernumerary teeth in humans.35 Interestingly, the APC gene (Figure 3, B) was also found to play an important role in the tooth development of mice.35
Congenital Hypertrophy of Retinal Pigment Epithelium
CHRPE, which may be present at birth, is the most common and earliest extraintestinal manifestation of FAP populations.36,37 It is clinically described as at least 1 darkly pigmented lesion with a halo in the retina and may be present bilaterally.38 The size and shape (oval, round, coffee bean) of the lesion may be variable but most lesions are similar in size to the optic disc.39 CHRPE has no malignant potential.40 Blair and Trempe41 first described CHRPE in 1980. Mutations in the codons between 463 and 1387 of the APC gene are usually found in these patients.36,37,42,43 CHRPE has a prevalence of 90% in patients with FAP and the associated APC mutations, while it is only seen in 1.2% to 4.4% of the general population.44 Therefore, its presence is a harbinger for FAP, and the physician should reflexively screen for FAP when discovered.45
Normal retinal pigment epithelium (RPE) cells have prominent apical melanosomes and basal nuclei.46 In CHRPE, a normal Bruch membrane and choriocapillaris are seen associated with hypertrophic RPE cells.46 These pigmented areas are thickened and packed with melanosomes both apically and basally. Atrophic, thinned RPE cells can be identified in depigmented areas of a CHRPE lesion.46
The histologic features of FAP-associated thyroid cancers were initially described by Harach et al,47 with 70% to 90% of cases showing features of cribriform-morular variant of papillary thyroid carcinoma (CMV-PTC), an extremely rare variant accounting only for less than 1% of all PTCs in the general population.48 The reported lifetime risk of developing thyroid cancer in patients with FAP approaches 2%. However, recent works suggest a significantly higher prevalence of 12% in patients screened with ultrasonography.49 In the FAP population, thyroid carcinoma is often bilateral and multifocal compared to unifocal tumor in sporadic CMV-PTC. Most FAP patients with thyroid cancers bear germline mutations of the APC gene in exon 15.50,51 CMV-PTC behaves like classical PTC, with approximately 10% of cases presenting as metastatic disease.48
At present, the World Health Organization (WHO) lists CMV-PTC in both its familial and sporadic presentation as separate entities; however, it is controversial whether this tumor is a variant of papillary thyroid carcinoma or a distinct category of thyroid carcinoma.10 This debate is due to the fact that this entity does not follow general BRAF and RAS subtypes used in molecular classification of thyroid tumors.10
Most CMV-PTCs are well circumscribed or encapsulated, solid with some cystic areas, and white. They have a mean size of about 2.5 cm and are generally multifocal (Figure 4, A), and they can be found throughout the thyroid gland (Figure 4, A).52–56 Meanwhile, CMV-PTC in nonsyndromic patients tends to present as a single lesion.10 In both patient populations, tumors may have different architectural patterns including follicular, cribriform (Figure 4, B through D), papillary, trabecular, or solid.47 Cribriform patterns (Figure 4, B through D) are formed by anastomosing bars and arches of cells without fibrovascular stroma (Figure 5, A and B), often merging with tubular (glandlike) follicles.56 Nonarborizing papillary and pseudopapillary structures are lined by cells (Figure 5, A through C), which vary from cuboidal to columnar, and may exhibit stratification (Figure 5, A through C).10,56 Literature suggests an absence of nuclear features in CMV-PTC, which are typically present in classic PTC. Cells generally contain moderate to abundant cytoplasm (Figure 5, A and B). Nodular squamoid whorls (morules) (Figure 4, C and D), which are one of the hallmarks of CMV-PTC, generally have an oval shape with no keratinization. Cells within these morules may demonstrate distinct nuclear clearings, termed peculiar nuclear inclusions (Figure 4, C and D).56
Immunohistochemical staining is helpful not only in distinguishing this variant, but also in highlighting its unique molecular classification among thyroid carcinomas. Strong nuclear and cytoplasmic staining for β-catenin (Figure 5, D; Figure 6, A and B) is a hallmark of this tumor type, and positivity can overrule doubts that the pathologist may encounter on hematoxylin-eosin examination.10 Tumor cells are typically positive for thyroid transcription factor-1 (TTF-1) and negative for calcitonin and thyroglobulin immunostains. While most of these lesions demonstrate a low Ki-67 proliferative index, often less than 5%, the cribriform-morular variant of thyroid carcinoma displaying poorly differentiated carcinoma features may have a proliferative index of up to 60%.57,58 Tumor cells demonstrate nuclear positivity for estrogen (Figure 6, C) and progesterone (Figure 6, D) receptors. P63, carcinoembryonic antigen (CEA), CD117, Wilms tumor protein (WT1), calretinin, cytokeratin 20, epidermal growth factor receptor, and c-kit (CD117) stains should show negativity in tumor cells.10 Morules have a distinctive staining pattern, which distinguishes these nests from early squamous metaplasia. They are positive for β-catenin (Figure 5, D; Figure 6, A and B), AE1/AE3, E-cadherin, bcl-2, CA 19.9, and cyclin D1, and negative for TTF-1, thyroglobulin, calcitonin, CEA, 34βE12, vimentin, and CA 125 stains.10
SKIN AND SOFT TISSUE MANIFESTATIONS
Dermatologic examination of patients with FAP is likely to lead to the identification of an array of benign skin tumors including epidermal cyst, fibroma, fibromatosis, lipoma, and pilomatricoma.59 Given that these benign skin tumors are also prevalent in the general population, they may be less diagnostically relevant unless there is a high clinical suspicion for FAP syndrome. One study, which performed whole-skin examination on 56 adult APC mutation carriers and 116 control patients, found at least 1 FAP-associated skin lesion in nearly half of all patients with FAP, whereas these skin findings were only found on examination of a third of control patients.59
Patients with FAP may have skin findings such as skin tumors or epidermal inclusion cysts, and therefore a full body examination is necessary.60 In a study conducted by Leppard and Bussey,61 169 members of 15 families with what was previously known as Gardner syndrome were found to have epidermoid cysts that were not pilar or steatocystoma in origin. While these cysts are very common in non-FAP patients and can occur anywhere on the body, they may be a subtle clue in patients with FAP, as the presence of these cysts frequently predates the appearance of intestinal polyps.62 Cysts are often asymptomatic, but may present with pruritus, inflammation, and rupture. In patients with FAP, they may occur in less common locations such as the face or extremities, tend to occur near puberty, and are present in 50% to 65% of patients.60 Histology of epidermal cysts in patients with FAP is often like that seen in nonsyndromic patients; however, pilomatricoma-like changes have been reported in the epidermal cysts of patients with FAP.63
The 2013 WHO classification of soft tissue tumors includes Gardner-associated fibroma (GAF) as a benign soft tissue lesion associated with FAP.64 The defining feature of GAF is its role as a precursor of desmoid fibromatosis. GAF characteristically involves the superficial and deep soft tissues of the paraspinal region, back, chest wall, head and neck, or extremities,65 and mainly occurs in the first 2 decades of life. GAF is a lesion specific to patients with FAP and occasionally acts as a disease-defining entity, serving as the first substantial sign to identify families and individuals with FAP.65
GAF is described, histologically and cytologically, as a paucicellular, dense fibrocollagenous proliferation (Figure 7, A through D) with small bland fibroblasts distributed throughout haphazardly arranged bundles of collagen (Figure 7, A through D). Slender, cleftlike spaces between the collagen bundles impart a “cracked” appearance (Figure 7, A and B). Lesions may have a plaquelike growth pattern with infiltration and entrapment of surrounding structures.65
Desmoid-type fibromatosis is a fibroblastic tumor of intermediate malignant potential with a locally destructive growth pattern and frequent recurrences.12 It represents the third most common cause of death in individuals with FAP.66 While most cases occur in a nonsyndromic setting, lesions that show germline mutations in APC are seen at a higher frequency in patients with FAP than in the general population.12 When FAP associated, it has been found that these lesions are also more likely to reoccur.12 The site of origin is a very important feature in this tumor and may help delineate syndromic versus sporadic cases. Abdominal wall fibromatosis originates from musculoaponeurotic elements and grows with a diffuse growth pattern into regional adipose and fibrous tissues. Extraabdominal fibromatosis is observed in the head, neck, and the extremities and often leads to functional disability and severe tissue destruction.12 Intraabdominal fibromatosis (mesenteric fibromatosis), the most common subtype associated with FAP syndrome, has the same biological features as other types of fibromatosis, but the growth pattern of large gastrointestinal stromal tumors,12 with the potential to infiltrate into the intestinal mucosa or the retroperitoneal space. Major differential diagnoses include gastrointestinal stromal tumors and dedifferentiated liposarcomas, as well as other types of benign or low-grade malignant mesenchymal tumors with spindle cell morphology.12 Owing to locally aggressive tumor growth and frequent recurrences, fibromatosis can cause major clinical and therapeutic problems, such as bowel obstruction.
Patients with FAP have up to an 800-fold increased risk of fibromatosis when compared with the general population.66 They have a 16% cumulative risk of developing fibromatosis in the 10 years after colectomy, with the peak incidence of presentation occurring 1 to 3 years following colorectal surgery.12,66
Although the microscopic appearance of mesenteric fibromatosis is often characteristic and easily identified, small tissue samples, desmin positivity of muscle fibers that have been displaced by the locally aggressive lesion, and/or high cellularity may lead to misdiagnosis. Grossly, mesenteric fibromatosis is usually a white, firm, solid, infiltrative mass (Figure 8, A). The microscopic hallmark is a diffuse growth of uniform, elongated spindle cells in a collagenous to myxoid stroma (Figure 8, B and C). Bundles of collagen with a keloidal or glassy appearance are a common feature of mesenteric fibromatosis (Figure 8, B and C; Figure 8, D: nuclear expression of β-catenin).12,66 Dilated and thin-walled blood vessels are often surrounded by paucicellular areas. Lesions frequently infiltrate into surrounding tissue.66 In extraabdominal fibromatosis, the infiltrating lesion often entraps local structures and skeletal muscle fibers. Scattered clusters of atrophic skeletal muscle may be mistakenly interpreted as giant cell reaction (Figure 8, B inset). Cytologically, fibromatosis shows bland spindle cells with long, fusiform nuclei and metachromatic matrix material (Figure 9, A through C). Immunohistochemically, the spindle cells are almost always positive for vimentin and at least partially positive for smooth muscle actin; however, this staining is not specific. Desmin and S100 immunostains are rarely expressed.12 The Ki-67 proliferative index is typically below 1%. Nuclear expression of β-catenin (Figure 8, D) is an important diagnostic feature that is found in 90% to 95% of cases. It is worthwhile to note that a range of staining intensity has been demonstrated.12
CENTRAL NERVOUS SYSTEM MANIFESTATIONS
FAP patients with APC gene mutations between codons 697 and 1224 are exposed to a 3-fold increased risk of brain tumors in general, and a 13-fold increased risk of medulloblastoma, when compared with FAP patients with other APC gene mutations.67 The incidence of medulloblastomas in patients with FAP is greatest before the age of 20 years.67 The combination of colonic polyposis and central nervous system (CNS) tumors was historically included in the designation of Turcot syndrome, but this distinction is no longer preferred.5 Like Gardner syndrome, Turcot syndrome was once thought to be its own clinical entity; however, it is now assumed that all individuals with FAP are at increased risk for brain tumors, albeit a relatively low lifetime risk.5 This observation has implications ranging from genetic counseling for individuals with FAP to potentially impacting the risk-benefit assessment for surveillance of brain tumors within this subpopulation.67 Activation of the Wnt signaling pathway and intranuclear localization of β-catenin appear to be present in a subset of patients with medulloblastoma that have a better prognosis.68,69 While increased risk of glioblastomas and astrocytic tumors is generally associated with the germline mutations of mismatch repair genes seen in Lynch syndrome, astrocytomas have also been found to occur in the setting of FAP, albeit rarely.70 Other CNS neoplasms found less commonly in association with FAP include ependymomas and pituitary adenomas.67,71
Four histologic variants of medulloblastoma, including medulloblastoma with extensive nodularity, desmoplastic nodular, anaplastic, and large cell, are globally accepted. Medulloblastoma is considered a small round blue cell tumor (Figure 10, A and B) with densely packed areas of mitotically active, basophilic cells with a high nuclear to cytoplasmic ratio (Figure 10, A and B).72 Both medulloblastoma with extensive nodularity and the desmoplastic nodular variant of medulloblastoma are considered to have more favorable prognosis than classic medulloblastoma.73 Medulloblastomas are usually positive cytoplasmically for S100 immunostain (Figure 10, C) and have a very high Ki-67 proliferative index (Figure 10, D).
MANIFESTATIONS OF THE HEPATOBILIARY SYSTEM
Hepatoblastoma is the most common pediatric liver malignancy with an estimated incidence of 1 per 100,000 children. Hepatoblastoma occurs in patients younger than 15 years of age, and primarily affects children during the first 3 years of life, with a 2:1 male to female ratio.74,75 Hepatoblastomas are thought to originate from hepatic progenitor cells that undergo malignant transformation during embryogenesis. The Wnt/β-catenin signaling pathway plays a central role in the pathogenesis of HBs.76 In several tumor subtypes, this pathway is constitutively activated owing to “loss of function” mutations of the APC genes (at the 5′ end of the gene),75 leading to inefficient β-catenin degradation and its intracellular localization. Somatic APC mutations leading to HB are rare but have been reported.77–79 Patients with FAP carrying a germline APC mutation have a 750- to 7500-fold increased risk of HB development in comparison to the normal population.80–82 Importantly, given the high proportion (10%–25%) of de novo germline mutations occurring in the APC gene, a child presenting with HB may be the child's first manifestation of FAP and may even be the first manifestation of FAP in the family.75,83
Hepatoblastoma is typically a solitary, well-demarcated mass arising in noncirrhotic liver parenchyma (Figure 11, A).84 As is seen in hepatocellular carcinoma, hemorrhage, necrosis, and bile staining may be prominent.85 Hepatoblastoma can be variable in size, and it often presents at a late stage, and with nonspecific symptoms. Multinodular tumors may contain different histologic components and should be adequately sampled. Most HBs express α-fetoprotein.86 Histologic classifications include epithelial or mixed-epithelial (Figure 11, A through C) histologic subtype (∼50%), mixed epithelial-mesenchymal (∼45%), and anaplastic (undifferentiated) variants.86 Although any subtype may occur in the setting of FAP, mixed epithelial (fetal and embryonal cells) (Figure 11, A through C) histologic subtype is the most common variant of HB in FAP.86 The epithelial type consists of fetal hepatocytes, embryonic hepatocytes, or both. Fetal epithelial-type exhibits cords of small hepatocytes that resemble adult liver cells.86 Cytoplasmic lipid and glycogen give zones of cells a pale appearance, rendering a “light-and-dark” pattern to fetal areas at low power (Figure 11, A through C).
There is no significant relationship between the age of the patient and the predominant histologic subtype in HB.87 Most cases (85%–90%), contain both fetal and embryonal derivatives in variable proportions; 20% have stromal derivatives.84
Immunohistochemistry may help differentiate HB from uninvolved liver or other hepatocellular tumors and may also help to accurately diagnose the HB subtype. Glypican 3 (Figure 11, D) can aid the pathologist with classification of HBs, demonstrating a faint pericanalicular staining pattern in well-differentiated fetal HB, in contrast to a coarse, granular cytoplasmic staining in the mitotically active fetal subtype and embryonal cells,87 or the negative pattern in small cell undifferentiated, cholangioblastic, and mesenchymal components.87 While small cell components are usually negative for glypican 3, β-catenin (Figure 11, E) often shows a strong, uniform nuclear staining in the small cells. This contrasts with embryonal and fetal cells, which show cytoplasmic glypican 3 positivity in most instances and variable nuclear β-catenin staining.87 β-Catenin staining is usually associated with strong glutamine synthetase and cyclin D1 staining in HBs.87
Unfortunately, when it comes to differentiating between HB and other tumors affecting the liver, β-catenin cannot be as heavily relied upon. Rare pediatric hepatocellular carcinomas can show strong positive staining, as can nested epithelial-stromal tumors. While most pediatric hepatocellular carcinomas do not show the same intense nuclear staining as HB, there is no reliable immunostain to differentiate hepatocellular carcinoma.87 The high prevalence of HBs with β-catenin mutations and the increased incidence of HBs in FAP families show the important role of an overactivation of wingless/Wnt pathway in the pathogenesis of HBs.84 Saving fresh or frozen HB tissue sample as well as nontumoral liver tissue from these patients will be of great importance for further investigation into prognosis and clinical behavior of these tumors in the setting of FAP syndrome.84,87
Pancreatic malignancies in FAP of exocrine, endocrine, or stromal origin are rare, and a genetic association is disputed. Although the absolute lifetime risk of pancreatic carcinoma in patients with FAP is low, at about 2%, the risk has been estimated to be more than 4 times that of the general population.88 FAP is caused by mutations in the APC gene locus, but most pancreatic carcinomas are associated with other mutations such as KRAS and P53.89–91 Unfortunately, reports on mutations of the APC gene in human pancreatic cancers are limited and have conflicting findings. Neuman et al92 theorized that chromosome 5's APC mutation could be an initiating step for pancreatic carcinomas. Another group of investigators93 reported sporadic mutations of the APC gene in 4 of 10 pancreatic cancers in their series. Seymour et al94 and Ding et al95 found no APC mutations in pancreatic carcinomas. Owing to the rarity of pancreatic malignancies in the setting of FAP, a true linkage is difficult to prove.11
Gallbladder and Bile Ducts
While rare, adenomatous change and malignancy of the gallbladder and bile ducts have been described in the setting of FAP. Owing to the rarity of these lesions, there is a paucity of data investigating their relationship to FAP. Studies involving larger cohorts are required to further research the incidence and prevalence of these pathologic processes in association to FAP. These processes may lead to biliary obstruction in patients with FAP, but the detailed mechanism has not been fully investigated.96,97
The lifetime incidence of adrenal tumors is as high as 15% in patients with FAP, in comparison to the approximate 5% incidence of adrenal tumors seen in the general population.98 The tumors are rarely malignant and routine surveillance is not recommended. Adrenal masses are usually found incidentally on imaging studies performed for other reasons.
MOLECULAR PATHOGENESIS AND ANCILLARY STUDIES
Patients with FAP acquire and accumulate new mutations through enhanced stem cell survival and turnover rate, which occurs at a more rapid rate than in healthy individuals. The APC mutation initiates a neoplastic process by interfering with the Wnt signaling pathway and subsequently disrupting several stages of cell development.99,100 The protein encoded by wild-type APC makes a complex with GSK-3b, Axin, and other cofactors to degrade β-catenin; the mutated APC product loses this ability, which leads to accumulation of β-catenin in the nucleus, followed by activation of the Wnt signaling pathway.101,102 The Wnt signaling pathway is required to maintain normal crypt development.103 In accordance with the 2-hit model of tumorigenesis, the APC wild-type allele is deleted or mutated in most FAP-associated lesions, including colorectal adenoma and carcinoma, gastroduodenal tumors,104 fibromatosis,105 medulloblastomas,106 thyroid carcinomas,107 and HBs.108 Each colorectal adenomatous polyp is a premalignant lesion that may progress to carcinoma in an unpredictable fashion.2 The classically accepted pathway of sporadic CRC has been described as a progression from adenoma to carcinoma in which de novo mutations and instabilities in important genes such as KRAS, APC, and SMAD4 cause development of high-grade adenomas.109 Loss of APC, a tumor suppressor gene, is considered the initial trigger of tumorigenesis in the gastrointestinal system, which may then be followed by additional mutations in KRAS and P53.110 Several studies using mouse models have supported these conclusions, finding that KRAS, P53, and SMAD4 cannot initiate the process of malignancy, which suggests that APC is the initial first step in the process of tumor formation in FAP.111,112 P53 mutation and 17p allele loss are described in 40% and 33% of cases, respectively.113
Frameshift and nonsense mutations account for more than 90% of APC mutations. Only a minority of APC mutations have large deletions that could involve most of or the entire gene.114 More than 700 different deleterious APC gene mutations have been identified, with mutations at codon 1061 (11%) and 1309 (13% to 17%) accounting for approximately 30%.2 The rate of germline mutations leading to a new deleterious APC allele is estimated to be 5 to 9 mutations per million gametes.115 Therefore, it is not uncommon to see sporadic cases occurring in people with no previous family history of FAP, representing up to one-quarter of cases of diagnosed FAP. These de novo APC mutations arise during embryogenesis and do not impose a risk for the patient's siblings. FAP patients with no family history usually present with less severe phenotype. Inherited (germline) mutation in the APC gene has almost complete (90%–100%) penetrance by the age of 40 years. In addition to the abovementioned mutations, gonadal mosaicism has been described in about 10% of new cases of FAP.75,116
Different types of APC germline mutations appear to cause different phenotypic impacts.117 For example, mutations near codon 1300 have been associated with the highest risk of CRC development, compared to mutations at other locations.117,118 Mutations in the codons between 463 and 1387 of the APC gene are usually found in the cases of CHRPE associated with FAP.36,37,43 Mutations at the 3′ end of the APC gene are highly associated with aggressive fibromatosis in these patients.12 Patients with APC gene mutations between codons 697 and 1224 are exposed to a 3-fold increased risk of brain tumors in general, and a 13-fold increased risk of medulloblastoma.73
Screening for at-risk members of families affected by FAP by genetic testing is the standard of care.14 If a patient is suspected of having a gastrointestinal cancer syndrome, the workup should begin with a thorough history and physical examination. Family history elicited should include any first- or second-degree relatives with history of cancers, gastrointestinal polyps, as well as their age at diagnosis and any relevant genetic testing. Familial history of extracolonic manifestations of FAP such as CHRPE, epidermal cysts, osteomas, thyroid cancer, desmoid tumors, HB, medulloblastoma, and duodenal/ampullary adenomas should be also included.13 The criteria for APC-gene testing mainly confirms the diagnosis of FAP and presymptomatic diagnosis of individuals aged 10 years or older at risk for this syndrome. Currently, most laboratories use sequencing for mutation analysis and some additional tests for large-segment rearrangements. Testing for at-risk population starts with first testing an affected member of the family to determine whether a detectable mutation is present in the pedigree119 and if a mutation is observed in an affected family member, then at-risk relatives can get true positive or negative test results. If a mutation is not identified in an affected individual, then testing at-risk relatives would not help and should not be conducted because the results will usually be inconclusive (in this situation, a negative test result for an at-risk person may be a false-negative result because the laboratory technology may not be able to identify a mutation, if one is present).120 When an affected family member is not available for testing, evaluation of an at-risk individual may only be given if the affected gene is found in another at-risk family member. In patients with classic or the attenuated FAP phenotype, in which no mutation in the APC gene has been found, MYH gene testing should be considered.120
Among individuals with multiple colorectal adenomas in whom an APC pathogenic germline variant has been excluded, biallelic MUTYH pathogenic variants are found in 7% to 13% of patients with more than 100 adenomas and in 14% to 40% of patients with 10 to 99 adenomas.121,122 MUTYH-associated polyposis is estimated to account for less than 1 percent of all CRCs.121
SCREENING AND SURVEILLANCE
Patients with pathogenic APC mutations should be screened for FAP-associated tumors. More specific decisions, such as age at initial screening and frequency of screening, should be carefully made on the basis of each patient's personal and family history.13,49,123 Individuals with first-degree relatives known to have FAP, patients with more than 10 to 20 intestinal polyps, and/or patients with colorectal adenomas in combination with extraintestinal manifestations associated with FAP are at high risk for FAP and testing should be discussed.13,49,123
Upper Gastrointestinal Tract
Although upper gastrointestinal tract screening has not been shown to decrease mortality, it is still recommended for patients with classic FAP considering the high incidence and prevalence of malignancies in the stomach and duodenum.124,125 The development of symptoms or signs indicative of upper gastrointestinal or pancreatic abnormalities should prompt evaluation, with focus on the ampullary region.124–126
For patients who do not first develop symptoms, upper endoscopy should be started either at the onset of colonic polyposis or between the ages of 25 and 30 years. A family history of early-onset gastric or duodenal cancers should also prompt earlier screening.127 Repeated screening endoscopies should be performed every 3 to 5 years in individuals without duodenal adenomas.13
Fundic gland polyps are very common findings in the body or fundus of stomach in patients with FAP and have low risk of progression toward malignancy. Polyps should be biopsied or resected completely to assess for dysplasia. Low-grade dysplasia is common in FGPs, but surgery should be reserved for high-grade dysplasia or malignancy.13 Antral polyps are generally adenomatous, and complete endoscopic resection is recommended.3 The presence of nondysplastic FGPs should not alter the frequency of recommended screening intervals.18,23
Duodenal polyps and adenomas can be found in more than half of the patients with FAP. Most patients with duodenal involvement will develop duodenal carcinoma.125,128 Total resection or sampling of duodenal polyps should be done at the time of initial discovery and on each subsequent follow-up.128 Polyps identified at the ampulla of Vater should be endoscopically sampled on initial discovery. Essentially, in patients with FAP, even mucosal folds with an abnormal appearance should be biopsied.129,130 Management of histologically confirmed high-grade dysplasia in the periampullary region is controversial, and the decision between surgery, ablative therapy, and watchful waiting should be made on an individual basis, considering various factors including the size and number of adenomas as well as patient's age. Recent studies have supported the utility of endoscopic ampullectomy in such cases, demonstrating only minimal procedure-associated morbidities.131 Proper follow-up surveillance is imperative given the likelihood of recurrence in patients with FAP.131
The frequency of surveillance varies based on the severity of duodenal polyposis.123 The suggested surveillance based on the Spigelman stage of duodenal polyposis is as follows: stage 0, every 4 years; stage I, every 2 to 3 years; stage II, every 1 to 3 years; stage III, every 6 to 12 months; stage IV, assuming duodenectomy has not yet been performed, every 6 months.123
Lower Gastrointestinal Tract
The American College of Gastroenterology and the National Comprehensive Cancer Network (NCCN) recommend annual sigmoidoscopy beginning at the age of 10 to 12 years for patients with a genetic diagnosis of FAP, or at-risk family members who have not undergone genetic testing.13,132 If colorectal polyps are found on sigmoidoscopy, a full colonoscopy should be performed. The number, size, and distribution of polyps as well as the age of the patient should be considered during the colonoscopy to evaluate the extent of polyposis in colorectum and the plan for colectomy.15 Several polyps should be sampled for evaluation of dysplasia. Patients need to undergo annual screening with colonoscopy and even in the absence of colorectal adenomas in endoscopy, this screening should be performed every year throughout life.125 As a colectomy will not eliminate the risk for malignancy (tumors may arise from remaining segments of the intestinal system including perianally or in the ileal pouch), surveillance should not be neglected in patients who are status post colectomy. While the incidence of ileal cancer is low (with development of ileal adenoma and adenocarcinoma at 10-year follow-up found to be 45% and 1%, respectively),127 the incidence of rectal cancer in patients where the rectum is not fully removed remains high without adequate follow-up surveillance. Most of these patients will ultimately require rectal resection.13,127 Screening for these patients should involve endoscopy of the rectum or ileum at least every other year.13 A discontinuation of intensive testing has been suggested only for the first-degree relatives of affected patients who have not had adenomas detected on previous examinations, or for members of families with similarly negative examination findings and without an identified pathogenic APC mutation.125
Screening for CHRPE with slit lamp and indirect ophthalmoscopy is highly recommended in patients with FAP.123 A study conducted by Nusliha et al45 found this method to be highly sensitive and specific for the screening of CHRPE in patients suspected of having or with FAP. Slit lamp and indirect ophthalmoscopy is minimally invasive, does not require advanced ophthalmologic skills to perform, and has a high sensitivity.13,45 NCCN guidelines recommend that individuals presenting with CHPRE should be screened for FAP.123
Beginning between the ages of 15 and 20 years, it is recommended that patients with FAP be screened with an annual ultrasonography of the thyroid.13 Physical examination alone is not a sufficient method of screening for malignancy in patients with FAP, as highlighted in multiple studies. One study investigating screening methods in patients with FAP found that none of the 5 patients who were ultimately given a diagnosis of thyroid cancer were suspected of having thyroid disease on the basis of clinical history and physical examination alone.133 A second study prospectively screened 205 patients with FAP, using ultrasonography, which revealed 1 or more thyroid nodules in approximately one-half of patients. Most of these nodules were suspicious, and approximately one-third of the study subjects required fine-needle aspiration biopsy.134
Patients with FAP should be questioned regularly regarding neurologic symptoms. In addition, a periodic head magnetic resonance imaging scan is recommended for patients with a first-degree relative or a positive family history for CNS malignancy. A set frequency for screening has not been established, but intervals between 1 and 3 years are common, which is often decided upon on an individual basis taking into account related symptoms, patient age, and family.123
Performing an abdominal computed tomography scan to assess for fibromatosis is recommended for the following patients: before colectomy in patients with a history of fibromatosis or an APC mutation beyond codon 1444135 ; patients with a palpable abdominal mass on physical examination; and patients with symptoms suggestive of abdominal organ obstruction.135,136
Screening for HB is controversial owing to the low risk and uncertain effectiveness of screening.137 There is not yet consensus among experts on whether all patients with FAP should be screened for HB, thus the decision is currently made on a case-by-case basis.123 However, in patients with an established family history of HB, genetic testing for FAP is recommended during infancy, as this genetic testing may be useful to determine if liver screening is warranted.13 Infants with genetic testing positive for FAP should then be screened with serum α-fetoprotein and ultrasonography every 6 months. While the first 5 years of life are the most critical for screening, it is generally recommended until the patient is between the ages of 10 and 15 years.13,137,138 Given that serum α-fetoprotein is only elevated in approximately two-thirds of patients with HB,13 a combination of physical examination, α-fetoprotein level testing, routine liver function tests, and abdominal ultrasonography should be used for screening of children with FAP.13,138
Gallbladder and Biliary Tract
Annual liver function tests are recommended as a method to screen for biliary tumors, although the sensitivity of this approach is unknown.123 Further evaluation should be done only for symptoms or given an abnormal liver function test result. This evaluation is in addition to upper endoscopy every 1 to 3 years, as discussed above.
Screening colonoscopy with timely treatment of identified lesions has led to a 55% reduction in CRC as the first presenting sign that patients are affected by FAP. This has led to improvement in cumulative survival for patients with FAP.106,132,139 Despite impressive strides to improve mortality, individuals with FAP who receive proper follow-up still have up to an 80% risk of developing CRC, presenting on average by the age of 56 years.13,132 In one series, 30% of patients with a colectomy (without proctectomy) developed rectal cancer before 60 years of age, and those who developed rectal cancer had an average mortality of 25%.140 Regardless of colectomy, patients continue to be at risk for upper gastrointestinal cancers and mesenteric desmoids, resulting in postsurgical morbidity or reduced lifespan for patients with FAP.140
FAP syndrome is an inherited syndrome that arises from mutations in the APC gene and produces adenomatoid polyposis spanning the tubular gastrointestinal tract as well as a constellation of extraintestinal lesions. Benign extraintestinal tumors include osteomas, dental abnormalities, skin lesions, desmoid fibromatosis, CHRPE, adrenal adenomas, and nasopharyngeal angiofibromas; and extraintestinal malignancies include malignant neoplasms of the thyroid, pancreas, liver, CNS, gallbladder, and biliary tract. In addition to the endoscopic screening and diagnostic workups that are now routine for these patients, screening and workup of extraintestinal manifestations and malignancies for patients with pathogenic APC mutations should not be overlooked. Screening for FAP-associated tumors should be done for people with a pathogenic APC mutation. Decisions for screening of CRC and other FAP-associated tumors for these patients should be carefully made on the basis of their personal and family history of adenomas and malignancy.
The authors have no relevant financial interest in the products or companies described in this article.
Drs Dinarvand and Davaro contributed equally to this manuscript.