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Colorectal cancer is one of the major causes of cancer deaths in both men and women. It is estimated that 5 to 10% of patients with colorectal cancer have an inherited germline mutation that predisposes them to cancer. Hereditary colorectal cancer syndromes can be divided into those associated with colonic polyposis – familial adenomatous polyposis (FAP), attenuated familial adenomatous polyposis (aFAP), and MYH associated polyposis (MAP), and those not associated with colonic polyposis – hereditary nonpolyposis colon cancer (HNPCC). The hereditary polyposes are usually easier to diagnose than HNPCC, but their higher penetrance and variable phenotype pose some difficult problems in management and surveillance. The timing and type of surgical intervention, the management of desmoid risk, the treatment of rectal or pouch neoplasia, and the management of duodenal neoplasia are all questions that must be addressed in patients with FAP or MAP.
Clinically, hereditary colorectal cancer syndromes can be divided into those associated with colonic polyposis (familial adenomatous polyposis [FAP], attenuated familial adenomatous polyposis [aFAP], and MYH-associated polyposis [MAP]) and those not associated with colonic polyposis (hereditary nonpolyposis colon cancer [HNPCC]). Treatment options for these patients include multiple aggressive screening regimens, chemopreventive medications, and prophylactic surgery. Selection of the appropriate management approach is best made using information obtained from the patient's clinical examination, the family medical history, and genetic evaluation.
Classical FAP is defined by the presence of over 100 synchronous colorectal adenomas. Review of the family medical history will usually reveal an autosomal dominant pattern of inheritance, although up to 30% of patients appear to develop the disease from a new adenomatous polyposis coli (APC) mutation.1 Although all areas of the colon are involved in the fully developed syndrome, there appears to be a predilection for the rectum and left colon. Adenomatous polyps are present in 15% of FAP by 10 years of age, 50% at age 15 years, and 75% by 20 years of age. The lifetime risk of colorectal malignancy in untreated patients with FAP is near 100% with a median age of 39 years. However, 7% of affected patients will develop cancer before age 21 years.2,3,4,5
In contrast to patients with FAP, those with attenuated FAP have less than 100 synchronous adenomas (an average of 30) with the polyps more likely to be right-sided. The onset is also later with the polyps developing after 25 years of age.6 Like FAP, the lifetime risk of colorectal malignancy in untreated patients with aFAP is near 100%, but the median age of cancer diagnosis is 59 years.2,7 Also like FAP, the family medical history will usually reveal an autosomal dominant pattern of inheritance.
It is usually impossible to distinguish MAP from FAP and aFAP clinically in an individual patient. On evaluation of the family medical history however, the distinction is usually obvious. Although FAP and aFAP have an autosomal dominant pattern of inheritance, MAP is inherited in an autosomal recessive manner. The number of polyps in MAP is variable, having a reported range of 5 to 750, with a median of ~50 polyps, and 36% of patients having over 100 polyps.8,9 To date, patients with MAP have been diagnosed at a median age of 48 years with a range of 13 to 65 years. Colorectal cancer has been present at diagnosis in 48% at a mean age of 50 years and a range of 30 to 65 years. The cancers are usually left-sided, with multiple colorectal cancers present in 24% of the patients at diagnosis.9
Any APC mutation can result in FAP or one of its clinical variants. The variants of FAP are distinguished by the number of polyps (aFAP) or by the extracolonic manifestations (Gardner's syndrome, Turcot's syndrome). The clinical significance of the extracolonic manifestations can range from a benign asymptomatic marker (congenital hypertrophy of the retinal pigmented epithelium [CHRPE]), to a cosmetic problem (osteomas), to a lesion with significant malignant potential or morbidity (gastroduodenal adenomas, desmoids) as shown in Table Table11.
Duodenal adenomatous polyps develop in 80 to 90% of patients with FAP with a 12% risk of duodenal or periampullary cancer, which will occur an average of 16 years after the diagnosis of FAP.10,11,12,13,14 Adenomas can also develop in the jejunum and ileum, but the malignant potential of these lesions is low.15
Gastric polyps are also present in the majority of patients with FAP. Most commonly these are small sessile lesions that on histologic evaluation are composed of dilated fundic glands. These polyps are considered to be hamartomas with no malignant potential.16,17,18,19,20 Gastric adenomas are found in 10% of patients with FAP, but there seems to be regional differences in the incidence of the lesions with these neoplasms being much more common in Japanese compared with non-Japanese patients.11,16,21
Desmoid tumors are tumors of fibroaponeurotic tissue with an incidence of 12 to 38% in patients with FAP.22,23,24,25 An increased risk of desmoids has been described in premenopausal women, and during pregnancy, or following abdominal trauma or surgery.26,27,28,29,30,31 Desmoids usually present within 2 to 3 years of the precipitating event and are located intraabdominally in 80% of patients, within the abdominal wall in 18% of patients, or extraabdominally in 2% of patients.30,32 There are multiple desmoids in 5 to 38% of patients.31,32,33 In contrast to sporadic desmoids, those associated with FAP have a variable clinical course. Although 47% will remain stable or grow slowly after diagnosis, 10% will regress completely, 29% will undergo cycles of growth and regression and 10% will grow rapidly.32 Symptoms related to intraabdominal desmoids can include abdominal pain, obstruction of the small intestine or ureters, or occlusion of the mesenteric blood vessels with resultant intestinal ischemia, perforation, and sepsis. Surgery for a desmoid-related complication will be required in 27% of patients with an intraabdominal desmoid.34,35
Extracolonic manifestations have also been associated with MYH mutations and include 2 reported cases of gastric cancer (1 at 17 years of age) and 2 cases of duodenal polyps. Congential hypertrophy of the retinal pigment epithelium (CHRPE) and osteomas have also been reported.9,36,37
The initial management of a suspected inherited cancer syndrome is genetic counseling. Subsequent management options include aggressive screening regimens, chemoprevention, and prophylactic surgery. Regardless of the initial treatment modality chosen, a lifetime of surveillance is needed.
Endoscopy is the screening method most commonly chosen for patients at risk for a polyposis syndrome (Table 2). For individuals whose family history or APC gene mutation suggests FAP, the initial examination should be performed at 10 to 12 years of age. Complete colonoscopy has been recommended by some, whereas others, given the predilection for rectal and left colonic polyps in FAP, have recommended flexible proctosigmoidoscopy.1 Annual flexible proctosigmoidoscopy is the method of choice for subsequent examinations. Screening should be continued until adenomas are diagnosed. If no polyps have been identified by age 25 years in patients at risk for FAP by family history and whose genetic status is unknown, it is reasonable to conclude that their chance of inheriting an APC mutation is slim and the frequency of screening can be reduced.
For individuals whose family history or APC mutation suggests aFAP, complete colonoscopy is the screening procedure of choice because of the predominance of right colonic polyposis in aFAP.1,6 Screening should begin at age 20 years and be performed every 1 to 2 years. There is no consensus on when to discontinue screening examinations, but given the natural history of aFAP, it would seem that screening of the healthy individual should continue into the eighth decade of life.
No guidelines for the screening of patients with MAP have been proposed. However, given the clinical features of MAP, it would seem appropriate to follow a screening protocol similar to that used for aFAP.
Once a patient is known to have a polyposis syndrome by either the clinical findings of colon polyps or by genetic testing, the possibility of extracolonic manifestations must be considered. All patients should have esophagogastroduodenoscopy starting at age 20 years and continuing at intervals determined by the findings of the previous examination. The findings in the duodenum are expressed according to the Spigelman Staging System (Table 3), which integrates adenoma size, number, histology, and degree of dysplasia. Patients with stage 0 or I disease can be reexamined in 5 years. Patients with stage II disease need a 3-year follow-up; stage III demands a 1-year exam. Stage IV disease is an indication for strong consideration of duodenectomy.13
There is no consensus regarding screening for desmoid tumors. However, it is appropriate to consider their potential presence when a polyposis syndrome is identified. Patients with an increased risk for desmoids include those with an APC mutation 5′ of codon 1400, those with >30% affected family members suffering from desmoids, those having reoperative surgery, and those with an extraabdominal desmoid already.
Desmoid tumors can be staged according to clinical characteristics.38 Stage I desmoids are asymptomatic, small (<10 cm in maximum dimension) and found incidentally during laparotomy or on computed tomography (CT) scan. It is unlikely that these tumors will enlarge and cause problems. Management options include observation, or nonsteroidal antiinflammatory drugs (NSAIDs). If a stage I desmoid is found incidentally at surgery and it is easily resectable without the removal of a significant amount of bowel, resection is appropriate.39,40
Stage II desmoids are symptomatic, 10 cm or less in greatest diameter, and have no evidence of enlargement. Symptomatic desmoids require treatment. If they are resectable with minimal sequelae, then resection is best. If the tumor is unresectable, the addition of tamoxifen or raloxifene to a NSAID offers the possibility of a quicker and more consistent response with low risk of side effects.41,42
Stage III desmoids are symptomatic and 11 to 20 cm in maximum dimension, or asymptomatic and slowly increasing in size (<50% increase in diameter in 6 months). Management options for these lesions include NSAID, tamoxifen, raloxifene, and vinblastine/methotrexate. Antisarcoma chemotherapy (adriamycin/ dacarbazine) can be given if the tumor continues to grow despite the less toxic agents.43,44,45
Stage IV desmoids are symptomatic, >20 cm maximum diameter, or demonstrate rapid growth (>50% increase in diameter within 6 months). Antisarcoma chemotherapy and radiation are usually employed in the management of these tumors. Desmoids that cause life-threatening complications such as sepsis, perforation, or hemorrhage are also classified as stage IV tumors. Management usually requires emergent, major exenterative surgery likely to result in significant loss of bowel and long-term morbidity.46,47
Several clinical trials have shown that the NSAIDS, sulindac, celecoxib, and aspirin can reduce the number and size of colorectal adenomas in patients with FAP.48,49,50,51 It is unclear, however, if suppression of the polyps will prevent colorectal cancer. Given the case reports of cancer occurring in patients with FAP whose polyps were suppressed with sulindac,52 chemoprevention cannot be recommended as primary therapy for intestinal polyposis. It can be considered for special circumstances, where surgical therapy has been declined or has an unacceptably high risk of complications, or when polyposis develops in an ileal pouch and surgery means an end ileostomy.
Surgery, preferably prophylactic, is the best way of managing the large intestine in patients with colonic polyposis syndromes. The timing and the choice of surgery must take into account the manifestations of the disease in the patient and their family, and the site of the mutation (if known) (Table 4). APC mutations between codons 1250–1464 are associated with profuse polyposis that always demands a total proctocolectomy. The risk of cancer for patients with more than 1000 adenomas is twice that of patients with fewer polyps.53 In contrast, patients with aFAP (less than 100 synchronous adenomas) can be safely managed with colectomy and ileorectal anastomosis, preserving the rectum for the functional benefits it offers.
With these considerations, it has been recommended that surgery be performed at age 12 to 15 years for patients with severe disease by clinical exam. Surgery can be delayed until ages 18 to 21 for those with less severe disease. For patients whose family medical history or genetic test results reveal an increased risk of desmoid disease, or who are found to have a desmoid tumor on clinical evaluation, surgery should be delayed until they have an increasing number and size of polyps, which cannot be managed endoscopically, or develop polyps with severe dysplasia.
Surgical options include total abdominal colectomy with ileorectostomy (TAC), proctocolectomy with ileal pouch anal reconstruction (IPAA), and total proctocolectomy with Brooke ileostomy (TPC). The indications for each are shown in Table Table55.
The advantages of a TAC include a single-stage procedure with a low risk of surgical complications, preservation of bowel continuity with superior functional results when compared with the other surgical options, and the avoidance of a proctectomy with its potential for damage to the pelvic nerves, decreased fertility, and urinary and sexual dysfunction.53,54,55,56,57,58,59 Bowel function is influenced by the length of the remaining rectum. Longer rectal remnants are associated with better bowel function, but an increased risk of subsequent rectal neoplasia.60 It appears that 15 cm of remaining rectum is the optimal remnant, having an adequate reservoir capacity and low risk of subsequent neoplasia. The risk of subsequent malignancy with 10 to 12 cm of remaining rectum has been reported to be 25 to 37% over 20 years and is the major disadvantage of TAC.60,61 Clinical and genetic factors can be used to predict the likelihood a cancer will develop in the rectal remnant. The presence of over 20 polyps in the rectum or more than 1000 polyps in the colon, a rectal polyp >3 cm in size, or a cancer anywhere in the colon are clinical findings associated with an increased risk of subsequent malignancy in the remaining rectum.62
Given the risk of rectal neoplasia after TAC, many surgeons recommend IPAA for patients with severe (>1000 adenomas) polyposis. With preservation of the anal transition zone, bowel function after IPAA can be similar to that after TAC,59,63,64 but the risk of subsequent neoplasia in the anal transition zone is reported to be as high as 30%.54,65 Complete rectal mucosectomy will decrease this risk by half, but is associated with significantly worse bowel function and an increased surgical complication risk.66,67,68
The 20 to 40% risk of surgical complications is a major disadvantage of IPAA.69,70,71,72,73 Proctectomy is associated with a risk of damage to the pelvic autonomic nerves resulting in impotence and retrograde ejaculation in 2% and 6% of males, respectively.74 Damage to the pelvic autonomic nerves will result in vaginal dryness and dyspareunia in 25 to 30% of women.75,76 Furthermore, IPAA is associated with a drop of 50% in a woman's ability to conceive, a drop not seen with ileorectal anastomosis (IRA).77 Despite these disadvantages, IPAA is the procedure of choice for patients with an unacceptably high risk of rectal cancer after TAC. Although TPC does not have the risk of subsequent neoplasia that is associated with TAC and IPAA with preservation of the anal transition zone, it is almost never performed as the initial procedure for the management of polyposis because of the permanent stoma.76 However, with preoperative counseling, proper selection of a stoma site, and postoperative teaching, a patient with an ileostomy can lead a full and active life. Currently, TPC is reserved for patients with a contraindication to sphincter preservation such as a low rectal cancer, those with poor sphincter function from previous anorectal conditions or obstetric trauma, or for technical problems that prevent an ileal pouch from reaching the anus.
Regardless of the surgical procedure chosen, postoperative surveillance of the rectal remnant after TAC, the ileal pouch after IPAA, and the ileostomy after TPC, and screening for the extracolonic manifestations is essential for the remainder of the patient's life. Endoscopy of the rectal remnant or ileal pouch should be performed annually with polyps <5 mm followed and larger polyps removed without fulguration and examined histologically to exclude dysplasia. For patients who underwent TAC, proctectomy with IPAA can be considered for an increasing number or size of polyps or the development of severe dysplasia.78,79,80 Although the significance of polyps in an ileal pouch is uncertain, it has been suggested that these can be managed with the NSAIDS sulindac or celecoxib.