The FAP-associated gene is located on chromosome 5q22 and is called APC
for adenomatous polyposis coli (1
has 15 exons (Fig. 12.1
) and encodes a protein of 2,843 amino acids (2
). The large size of the gene may account for the high frequency of new mutations that occur in it. Germ-line mutations in APC
account for most cases of classical FAP (2
). Attenuated FAP (AFAP), in which smaller numbers of polyps are found, is less frequently associated with detectable APC
). Every cell in an FAP patient contains one inactive APC
allele; an alteration in the other allele gives rise to intestinal tumors. Inactivation of the second allele occurs in the earliest recognizable phase of the tumors, including some lesions containing as few as two adenomatous crypts, confirming that inactivation of the second APC
allele occurs early in neoplastic development.
germ-line mutations are most commonly single base pair (bp) changes leading to termination codons or small (1 to 4 bp) deletions, insertions, or splice-altering mutations causing translational frameshifts and subsequent downstream stop codons (2
). Less commonly, large gene deletions or duplications occur (8
). Mutations are located throughout the length of the APC
The first clue to the function of the APC protein came when immunoprecipitation experiments showed that anti-APC antibodies precipitated &bgr;-catenin (9
). APC and &bgr;-catenin are part of a complex signaling pathway, the Wnt pathway, which
controls many cellular processes including proliferation, differentiation, apoptosis, and body patterning during development. Under normal circumstances, APC acts a negative regulator of &bgr;-catenin. APC forms a complex with GSK3B, CSNK1A1, and AXIN, which binds to &bgr;-catenin, phosphorylates it, and induces its degradation (10
). When normal APC function is lost, &bgr;-catenin accumulates in the cytoplasm, translocates into the nucleus, and binds to the transcription factor T-cell factor (TCF)/lymphoid enhancing factor (LEF). TCF/LEF, in turn, regulates a number of downstream target genes including c-MYC, cyclin D1, CD44, and BMP4 (10
). APC also stabilizes microtubules and plays a role in cellular migration and cytoskeletal organization (15
). The absence of APC results in abnormal mitosis and development of chromosomal instability (18
TABLE 12.1 CLASSIFICATION OF INTESTINAL POLYPOSES
Familial adenomatous polyposis and its variants
Basal cell nevus syndrome
Hereditary mixed polyposis
NF type 1
Familial colorectal cancer type X syndrome
Hereditary mixed polyposis
NF, neurofibromatosis; MEN, multiple endocrine neoplasia.
Patients with FAP exhibit considerable phenotypic variability of their colonic and extracolonic lesions. Mutations in specific regions of APC
produce different clinical phenotypes, and the length of the truncated gene product influences the severity of the colonic disease and the presence of eye lesions or desmoid tumors (Fig. 12.1
). Three FAP phenotypes have been suggested. Mild or AFAP is characterized by lower polyp numbers (<100) and later age of disease onset. These patients have an elevated risk for colorectal cancer development, although it is less than that of individuals with classical or severe FAP phenotypes. The AFAP phenotype has been associated with germ-line APC
mutations before codon 157, after codon 1595, or in the alternatively spliced fragment of exon 9 (6
). Classical FAP is characterized by greater than 100 adenomatous polyps and onset at or slightly after puberty. This phenotype is associated with mutations at the 5′ end of the gene between codon 168 and 1550/1580 and excluding codon 1309 (20
). Severe FAP is characterized by polyps numbering in excess of 2000, and an earlier age of onset, and is associated with mutations between codons 1250 and 1464, and especially codon 1309 (21
). Survival in this group of patients is lower than that for other FAP phenotypes (25
FIG. 12.1 The APC gene with its 15 exons shown as blue boxes. Mutations occurring within the part of the gene designated by the red line result in a CHRPE-negative phenotype. Those occurring in the area designated by the yellow line are associated with CHRPE lesions. The yellow arrow indicates the region of the gene in which mutations begin to result in the appearance of CHRPE lesions. The orange area of the gene is associated with formation of desmoid tumors. Mutations in the green and purple areas result in the attenuated APC and full-blown APC phenotypes, respectively.
Some extraintestinal manifestations of FAP are also associated with specific APC
). The presence of congenital hypertrophy of the retinal pigment epithelium
(CHRPE) appears to be limited to individuals with germ-line mutations between codons 311 and 1465. Desmoid tumors occur in patients with mutations downstream of codon 1400.
Differences in phenotypic expression of FAP also exist within individual families (26
). This suggests that the nature of the inherited genetic defect is only one parameter determining patient phenotype. These differences may be due to modifier genes or epigenetic factors. Additionally, inactivation of APC
may provide affected cells with a proliferative growth advantage allowing the colon to then acquire additional genetic abnormalities, thereby facilitating disease progression. Environmental factors may also be important. Bile from FAP patients appears to be more mutagenic than that from non-FAP patients (28
), perhaps inducing secondary changes both in APC
and other genes in the adenoma-carcinoma sequence (see Chapter 14
). Many manifestations of FAP may be partially controlled by hormonal status and other genetic factors. Data supporting such a postulate include (a) stimulation of polyp growth during puberty, (b) adenoma inhibition by sulindac, (c) the preponderant development of thyroid carcinomas in women (29
), and (d) the association of repeated trauma with development of desmoid tumors (see Chapter 19
Attenuated Adenomatous Polyposis
A less severe form of FAP, known as AFAP, is characterized by a relatively low number of adenomas. AFAP is associated with a germ-line APC
mutation in approximately 10% of affected patients (30
). It is important to note that as many as 25% of patients with an AFAP phenotype do not carry mutations in APC
but in a gene termed MYH
-associated polyposis (MAP) is discussed in another section in this chapter. AFAP differs significantly from classical FAP in that affected individuals have fewer adenomas that tend to cluster on the right side of the colon where they appear flat rather than polypoid. The number of adenomas varies among family members, ranging from 1 or 2 to 100. Upper GI lesions, particularly fundic gland polyps, are almost invariably present. In addition, affected patients exhibit a reduced risk for colorectal cancer compared with those with classical FAP.
The lifetime penetrance of colon cancer is high in AFAP families, however, even among members with relatively few adenomas. When colorectal cancers do develop, they arise later than in classical FAP. The average age of colon cancer onset in AFAP patients is approximately 15 years later than that of patients with classical FAP and approximately 10 years earlier than individuals with sporadic colorectal cancer. Table 12.2
compares classical FAP and AFAP.
FAP is the most frequent genetic polyposis syndrome, affecting approximately 2 to 3 per 100,000 individuals in the general population (31
). It is transmitted as an autosomal dominant disorder with up to 90% penetrance. Fifty percent of the children of an affected individual and a normal individual will inherit the polyposis gene and will develop the disease. Fifteen to twenty percent of patients with FAP have no familial history and represent spontaneous new mutations (34
). FAP occurs in all ethnic groups, and males and females are equally affected.
TABLE 12.2 COMPARISON OF FAP AND AFAP COLORECTAL CANCER SYNDROMES
Number of colonic adenomas
Sometimes thousands; usually more than 100
Usually 1-50; seldom more than 100
Invisible to polypoid adenomas
Flat or slightly elevated plaques
Polypoid or sessile
Location of colonic adenomas
Throughout the colon
Predominantly located proximal to splenic flexure
Location of colon cancer
Throughout the colon
Predominantly located proximal to splenic flexure
Average age of cancer onset
Fundic gland polyps
Almost invariably present
Periampullary carcinoma, papillary thyroid carcinoma, sarcomas, brain tumors, and small bowel cancer
FAP, familial adenomatous polyposis; AFAP, attenuated FAP.
Adenomas are not present at birth in FAP patients. Most affected individuals remain asymptomatic until puberty, at which time the polyps begin to appear. In untreated, unscreened patients, the mean age of polyp development is 24.5 years, symptom onset is 33 years, polyp diagnosis is 35.8 years, cancer diagnosis is at 39.2 years, and death from cancer averages a mean of 42 years (35
). Young patients present with a small number of polyps, the number of which progressively increases with time. Eventually, the entire length of the colon becomes carpeted with adenomas. By the time a patient comes to colectomy, he or she may have hundreds to tens of thousands of polyps. Progression to cancer is inevitable; by age 30, approximately 75% of FAP patients will have developed colon carcinoma unless a prophylactic colectomy is performed. Most untreated patients die of cancer by the fifth decade of life.
Adenomas also develop in extracolonic sites, most commonly in the duodenum around the ampulla of Vater. Duodenal adenocarcinomas represent the second most common cancer arising in FAP patients. The lifetime risk for duodenal cancer development in individuals affected by FAP is 3% to 5% (36
). Patients less frequently develop adenomas in the stomach or in other portions of the small intestine. Gastric cancers are more common in FAP patients living in
parts of the world where gastric cancer rates are high. Fifty percent of Japanese FAP patients develop gastric adenomas, and gastric carcinoma is more common in these patients than ampullary cancers. In contrast, Western gene carriers exhibit a higher rate of ampullary than gastric neoplasms (40
Colonic adenomas are often present for years before giving rise to symptoms including rectal bleeding, colicky abdominal pain, diarrhea, and mucous discharge (35
). Seventy-five percent of polyposis patients without cancer have rectal bleeding, and 63% have diarrhea (35
). When symptoms are severe enough to cause concern, two thirds of the patients have already developed a carcinoma. Very rarely, patients develop severe electrolyte depletion as a result of diffuse polyposis (41
). Acute pancreatitis develops secondary to obstruction of the pancreatic duct at the ampulla of Vater by adenomas. Intussusception due to the adenomas may also occur.
Carcinoma invariably develops in FAP patients if the colon is not resected by age 40 or 50. Indeed, FAP is the “experiment of nature” that provides support for the colonic adenoma-carcinoma sequence. Adenomas also represent the precursor for small intestinal cancer, but small intestinal adenomas are less likely to become malignant than are colonic lesions. Adenomas and carcinomas also develop in the retained rectum following colectomy.
Carcinomas develop approximately 6 years after symptom onset. The incidence of carcinoma is approximately 10% in patients observed for 5 years and 50% in those observed for 20 years. Each 10-year age group has a 2.4-fold increase in cancer risk (44
). Multiple cancers are frequent, with synchronous lesions affecting 41% of patients and metachronous lesions affecting 70%. Polyp count and patient age, but not sex, predict cancer risk. Patients with greater than 1,000 polyps have a 2.3 times greater risk of cancer than those with less than 1,000 polyps.
TABLE 12.3 SPIGELMAN CLASSIFICATION FOR DUODENAL POLYPOSIS IN FAP
Polyp size (mm)
Mild (low grade)
Moderate (low grade)
Severe (high grade)
Stage 0, 0 points
Stage I, 1-4 points
Stage II, 5-6 points
Stage III, 7-8 points
Stage IV, 9-12 points
Patients who undergo prophylactic colectomy may still die of other tumors, including ampullary cancers, brain tumors, hepatoblastomas, and desmoid and other tumors.
Many drugs and dietary supplements have been studied as potential chemopreventive agents for adenomas in the setting
of FAP. The nonsteroidal anti-inflammatory drug, sulindac, was the first drug shown to be effective in decreasing polyp numbers in FAP patients (46
). Both sulindac and the COX-2 inhibitor, celecoxib, have now both been studied extensively and show efficacy in reducing polyp burden in FAP patients. Chemoprevention is generally considered in FAP patients who are postcolectomy, especially those with a retained rectum (45
). The role of chemopreventive agents in managing duodenal polyposis is less clear. Sulindac is generally not considered effective in reducing upper GI polyp burden (48
), and results of studies using celecoxib have shown unclear benefits (50
). The use of either of these agents must be weighed against the risk of GI and cardiovascular complications known to occur with the use of these drugs.
TABLE 12.4 RECOMMENDED SURVEILLANCE INTERVALS FOR UPPER ENDOSCOPY IN FAP
Adenoma and Carcinoma Distribution
Adenomas develop throughout the entire colon (Fig. 12.2
) and appendix. They are fairly evenly distributed throughout the large intestine, with a tendency for them to be larger in the sigmoid and the rectum, thereby making the density appear greater in this region (35
). Rarely, the rectum is spared,
especially in AFAP. When extensive, the entire large bowel becomes carpeted with adenomas (Fig. 12.2
). Adenomas show gradations in size and shape from pedunculated tumors 1 cm or more in diameter to smaller, broader-based nodules to tiny lesions 1 mm or less in size. Adenomas tend to be larger in propositi (Figs. 12.2
) than in patients undergoing surveillance (Fig. 12.4
). In classical FAP, the number of polyps ranges from less than 100 (Fig. 12.2
) to greater than 5,000 with an average of 1,000, depending on when one sees the patient (35
). Colorectal carcinomas may be multifocal and more frequently develop on the left side of the colon (56
). Patients with AFAP develop flatter, nonpolypoid adenomas than are seen in classical FAP. They arise throughout the colon, with preferential involvement of the right colon. They also originate in the retained rectum following colectomy.
FIG. 12.3 Resection specimen in a familial adenomatous polyposis (FAP) patient.There is a large fungating tumor present that represented an invasive carcinoma. Numerous pedunculated adenomas are seen in the surrounding mucosa.
FIG. 12.4 Resection specimen from a patient who was part of a surveillance program. The patient has numerous small nodular lesions only mildly elevated over the mucosal surface. The lesions are smaller in patients undergoing surveillance than those who are not part of surveillance programs.
Pathologic Features of Adenomas
Adenomas and carcinomas in FAP patients grossly resemble their sporadic counterparts. Endoscopically, very small adenomas resemble hyperplastic polyps (Figs. 12.2
). It is only when they become larger that the typical raspberrylike configuration of an adenoma becomes evident. As in sporadic colon cancer, the incidence of malignancy relates to adenoma size.
In the early stages, adenomas consist of small groups of adenomatous tubules. They range from unicryptal, bicryptal, or tricryptal lesions in grossly normal-appearing mucosa (Figs. 12.5
) to the more typical multicryptal grossly visible polyps seen in patients without FAP (Fig. 12.7
). Even in unicryptal adenomas, the entire tubule is completely lined by neoplastic epithelium (Fig. 12.6
). Proliferation throughout the entire length of the adenomatous crypt leads to branching, budding, infolding, and mucosal elevation.
FAP patients develop depressed, flat, or polypoid adenomas (57
) with AFAP patients showing a tendency to develop flat lesions. In contrast to pedunculated adenomas, the whole surface of flat or depressed adenomas lies at or below the level of the normal mucosa (Fig. 12.8
). Polypoid adenomas are those with convex surfaces. Flat adenomas differ endoscopically and histologically from the usual adenoma. They present as slightly elevated plaques of adenomatous mucosa, not more than twice as thick as the adjacent normal mucosa. Further growth is by radial extension of adenomatous epithelium so that the lesions remain flat. When cancer develops, then one sees a reddish depression surrounded by marginal elevations (58
Upper Gastrointestinal Lesions
Nearly all FAP patients have polyps in the upper GI tract, with as many as 90% of patients developing gastric or duodenal adenomas by age 70 (36
). Adenomas develop in the gastric antrum, duodenum, periampullary region, and ileum. However, it is the periampullary region that is most commonly involved, and adenomas tend to cluster at this site. More than 50% of FAP patients who undergo upper endoscopy have a grossly polypoid lesion, 90% of which arise in the periampullary region (59
), suggesting that bile plays a role in their growth (60
). The bile of FAP patients has a greater proportion of chenodeoxycholic and a lower proportion of deoxycholic acid than does the bile of patients without polyposis (60
) and is more mutagenic. Patients also exhibit fecal flora abnormalities resulting in the possible production of carcinogenic compounds.
Periampullary carcinoma is a major cause of death in FAP patients (61
), affecting from 2.9% to 12% of all FAP patients (35
) and causing death in 22.2% of patients following colectomy (62
FIG. 12.5 Cross-sections of the grossly apparently normal mucosa in patients with familial polyposis. Low-power picture showing two foci containing adenomatous glands (A). A unicryptal adenoma is present above the star. A tricryptal adenoma is illustrated by the arrow. A tricryptal adenoma is illustrated in (B).
Duodenal adenomas develop in as many as 100% of patients in Japanese series (62
) and in 50% in Western countries (35
). Duodenal adenomas develop when patients are in their second to fifth decades of life. The average age of FAP patients with adenomas involving the ampulla of Vater is 31.7 years, compared with 59.6 years in those without FAP. Duodenal adenomas vary in size and appearance from microadenomas in a normal-appearing ampulla to sessile polyps measuring 3 cm in diameter (65
). Duodenal adenomas are generally small in screened populations. Over 90% of duodenal adenomas are tubular lesions. Larger lesions may become tubulovillous. FAP-associated duodenal adenomas show a significant increase in the number of Paneth cells (Fig. 12.9
) and endocrine cells per crypt compared to controls. This specialized cell hyperplasia affects the flat mucosa of FAP patients, regardless of the presence or absence of adenomas, and may represent a primary defect in the regulation of duodenal stem cell differentiation in FAP patients (66
FIG. 12.6 Longitudinal section of the mucosa showing the presence of a unicryptal adenoma (arrow). Even the single adenomatous crypts are easily visible.
Lleal and Jejunal Lesions
Adenomas also develop in the ileum and jejunum but to a lesser extent than in the duodenum. As many as 82% of FAP patients develop ileal adenomas (67
). Ileorectal anastomoses, ileostomies, and ileal pouches predispose
the ileal mucosa to become neoplastic (68
). The ileal mucosa undergoes colonic metaplasia, which then gives rise to adenomas. Ileal adenomas resemble duodenal, gastric, and large intestinal adenomas. Ileal adenomas tend to be sessile, measuring 1 to 5 mm in size. Multiple lymphoid polyps also develop in the terminal ileum in FAP patients.
FIG. 12.7 Familial polyposis. Histologic section through the mucosa demonstrating the presence of multiple adenomatous polyps arising on the surface of the mucosa.
FIG. 12.8 Flat adenoma in a patient with attenuated adenomatous polyposis coli (AFAP). Note that the adenomatous glands (center) lie at or below the level of the normal mucosa.
FIG 12.9. Duodenal adenoma in a familial adenomatous polyposis patient showing the presence of adenomatous epithelium and a large number of Paneth cells, as evidenced by the eosinophilic granules within the cytoplasm.
Gastric polyps develop in approximately two thirds of FAP patients (71
). Two different types of polyps arise in the stomach. Antral polyps are usually adenomas, whereas the small polyps arising in the fundus and body are usually fundic gland polyps (see Chapter 4
). Fundic gland polyps affect 25% to 60% of FAP patients.
Fundic gland polyps occur earlier than gastric adenomas, presumably because they originate in the existing fundic mucosa without the requirement for intervening intestinal metaplasia. Most patients with fundic polyps are under age 20. Fundic gland polyps are often multiple and small in diameter, appearing sessile or semisessile. They are histologically identical to sporadic fundic gland polyps (see Chapter 4
) (Fig. 12.10
). The gastric mucosa may be studded with numerous small, sometimes eroded, polyps that may increase in number and size over a several year period. Alternately, they may decrease in size and number or even disappear. Lesions that decrease or disappear may be followed by the appearance of a new crop of polyps (72
). The fundic gland lesions are generally considered to be benign with little or no malignant potential, yet dysplasias and carcinomas have been described in FAP-associated fundic gland polyps (73
) (Fig. 12.10
). Superimposed gastric adenomas may give the false impression of dysplasia arising in a fundic gland polyp.
In Western countries, FAP-associated gastric adenomas and carcinomas are rare, contrasting with the Japanese experience and supporting the role of environmental or other genetic factors in gastric cancer development. Gastric adenomas develop in the antrum in areas of intestinal metaplasia, a histologic requirement for the formation of gastric adenomas. When one compares gastric adenomas with colonic adenomas, the gastric lesions tend to be smaller and more sparsely distributed. In addition, gastric adenomas occur later in life than colonic adenomas. Gastric adenocarcinomas develop in the adenomas.
FAP patients have a high incidence of extraintestinal manifestations, including dental and skin abnormalities and the development of various types of neoplasms (Fig. 12.11
). The dental abnormalities include unerupted teeth, supernumerary
teeth, dentigerous cysts, and mandibular cysts. Subcutaneous lesions include epidermoid cysts, lipomas, fibromas, neurofibromas, and trichoepitheliomas. The latter appear at an early age, even before polyps appear. Those that occur in prepubertal years are strong indicators for the presence of a polyposis syndrome, and to some represent an indicator for regular sigmoidoscopy, even without a history of polyposis. Epidermal inclusion cysts are often multiple. The epidermoid cysts occur anywhere on the body but most are located on the arms, buttocks, legs, face, and occasionally in the testis.
FIG. 12.10 A: Fundic gland polyp in a patient with attenuated FAP. The lesion is similar in appearance to a sporadic fundic gland polyp. B: Low-grade foveolar-type dysplasia is a fundic gland polyp from another patient with FAP.
FIG. 12.11 Diagram of the various manifestations of familial adenomatous polyposis, which is essentially a systemic disorder.
Not surprisingly, patients who carry germ-line mutations in a tumor suppressor gene such as APC
exhibit tumors at sites other than the GI tract. These are summarized in Figure 12.11
. Osteomas commonly occur in the skull or jaw, although they can affect any bone. These benign tumors rarely become malignant. FAP associates with nasopharyngeal angiofibromas (77
). The lesion occurs 25 times more commonly in FAP patients when compared with the general population.
FAP patients also develop a number of endocrine and other neoplasms. Thyroid carcinomas, which occur with increased frequency in FAP patients, are all follicular neoplasms, sometimes containing papillary, cribriform, solid, and spindle cell components. FAP-associated thyroid cancers are commonly multifocal and predominantly affect young women. Since multicentricity is unusual for follicular thyroid tumors, it should alert the pathologist to the possibility of FAP (78
). Soft tissue lesions include fibromas, lipomas, and desmoid tumors.
FIG. 12.12 Desmoid tumor in a patient who died of complications from the desmoid. A: Autopsy en bloc resection of the liver, spleen, intestines, and desmoid tumor. One can see that the tumor diffusely infiltrates the abdominal contents and extends up to the liver. Numerous organs were entrapped within this neoplasm, including the biliary tree, large numbers of vessels, and loops of bowel. B: Higher magnification of the neoplasm showing the presence of a fleshy mass with areas of ischemic necrosis.
Desmoid tumors are a locally invasive form of fibromatosis (see Chapter 19
) that affects 9% to 32% of FAP patients (79
), particularly women (81
). Affected patients are often young, with a mean age of 29.8 years (82
). The overall prevalence of these lesions in FAP is 15%, a risk approximately 850 times greater than that of the general population (82
Desmoid tumors tend to involve members of the same family and associate with mutations in exon 15 of APC
). Most patients have undergone a previous colectomy (81
). Hormonal factors such as pregnancy and estrogen use may also play etiologic roles in desmoid development. Although the desmoids can develop on the shoulder girdle, buttocks, and groin, most of the desmoid tumors associated with FAP arise in the abdominal wall or within the abdominal cavity (45
Desmoid tumors represent an adverse prognostic factor in FAP patients because they associate with a high frequency of complications and tumor recurrence. These nonencapsulated, irregular, and infiltrative (Fig. 12.12
), locally aggressive lesions do not metastasize, but they can cause significant intestinal obstruction, ureteral or vascular compression, or other local problems. Extensive mesenteric or retroperitoneal involvement leads to recurrent small bowel obstruction. A staging system
for these lesions was developed in 2005 (84
) (Table 12.5
). Five-year survival for patients with stage I, II, III, and IV intraabdominal desmoid tumors is 95%, 100%, 89%, and 76%, respectively (85
). Death results from vascular compromise, small bowel gangrene, perforation, or intra-abdominal sepsis.
TABLE 12.5 DESMOID TUMOR STAGING SYSTEM
Asymptomatic, <10 cm maximum diameter, not growing
Mildly symptomatic, <10 cm maximum diameter, not growing
Moderately symptomatic or bowel/ureter obstruction, or 10 to 20 cm, or slowly growing
Severely symptomatic, septic complications such as fistula or abscess, or >20 cm, or rapidly growing
Mildly symptomatic = sensation of a mass and pain; no restriction Moderately symptomatic = sensation of a mass and pain; restrictive but not hospitalized
Severely symptomatic = sensation of a mass and pain; restrictive and hospitalized
Currently, first-line treatment for patients with large or growing intra-abdominal desmoid tumors is pharmacologic and includes the nonsteroidal anti-inflammatory drug sulindac, usually in combination with either tamoxifen or toremifene (86
). Patients who do not respond to firstline therapy may be treated with chemotherapy (doxorubicin and dacarbazine or methotrexate and vinblastine) or radiotherapy (90
). The treatment for abdominal wall desmoid tumors is controversial with some authors advocating surgical excision (88
) and others advising against surgery because of the high risk of recurrence (93
FIG. 12.13 Desmoid tumor. A: A highly vascular spindled cell mass is present, which extends up to a large sclerotic vessel but does not invade it. B: Higher magnification showing the haphazard arrangement of the spindled cells.
Histologically, desmoids consist of uniform, mature fibroblasts arranged in intertwining bundles. Mitoses are infrequent and never atypical. The extent of vascularization varies and may be prominent (Fig. 12.13
). This prominent vascular ectasia, which sometimes occurs in FAP patients, is not a feature in non-FAP individuals and may account for intraoperative hemorrhagic complications. The tumor infiltrates the intestinal loops and peritoneum. The arteries and veins become surrounded by tumor, but it does not infiltrate them (Fig. 12.13
). The tumor cells actively produce collagen fibers.
Desmoids in FAP patients contain both germ-line and somatic APC mutations, suggesting that inactivation of this gene plays a role in the development of the lesions (94
). Desmoid tumors also demonstrate deletion of 5q (95
). Desmoid tumors from patients with FAP demonstrate more chromosomal copy number alterations than sporadic desmoid tumors (96
), a finding that supports the hypothesis that loss of APC function results in chromosomal instability (97