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Inherited Colorectal Cancer Syndromes

C. Neal Ellis, M.D.

Introduction

Colorectal cancer is one of the major causes of cancer deaths in both men and women in westernized societies. In the United States alone, there are 140,000 new cases and 50,000 deaths annually. It is estimated that 5% to 10% of patients with colorectal cancer have an inherited germline mutation that predisposes them to cancer. 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]).

DIAGNOSIS

An inherited colorectal cancer syndrome should be suspected in patients with either an unusually large number of colon polyps or in patients with a colorectal cancer and a history of a previous colorectal cancer or extracolonic malignancy that is associated with inherited colorectal cancer syndromes, particularly if they occurred at an unusually young age. As important as the patient’s medical history is the family medical history. As a rule, the likelihood of an inherited cancer syndrome increases as the number of affected individuals and generations increases and the age of the affected individuals decreases. Despite the importance of the family medical history, it is frequently omitted or inaccurate. The family medical history is usually obtained at the initial physician encounter and is incorrect in 10% to 30%. The most accurate means of obtaining a family medical history is with a questionnaire that the patient and the patient’s family complete and return later.

GENETIC COUNSELING

The initial management of any patient with a suspected inherited cancer syndrome is genetic counseling. Genetic counseling should be performed by a trained individual who can investigate the family medical history, resolve any ambiguities, and construct a pedigree. After examination of the pedigree, if indicated, the patient can be educated about the natural history of the disease, the implications of a hereditary disease for the patient’s family, and issues of employment and insurance. Optimal management of hereditary cancer syndromes requires a lifetime of aggressive surveillance and screening. The best outcomes are obtained when the patient is educated about the disease, participates in the decision making process, and is fully compliant with the treatment plans.

GENETIC TESTING

The role of genetic testing in the diagnosis of an inherited cancer syndrome is often misunderstood. The diagnosis of these syndromes is made on the basis of a patient’s history and clinical examination and the family medical history. Although the discovery of a genetic defect by genetic testing can provide valuable diagnostic and prognostic information for a patient and the patient’s family, the failure to identify an abnormality does not mean that one is not present and does not exclude the diagnosis of an inherited cancer syndrome.

If a specific genetic mutation can be identified in an affected family member, genetic testing for that specific defect can be offered to other members of the family who are at risk for inheriting the defect. In this circumstance, discovery of the abnormality in a patient who has yet to exhibit the disease can indicate the need for early and frequent screening for the manifestations of the disease and the possibility of passing the defect to the patient’s offspring. A family member who can be conclusively proved not to have inherited the defect that is associated with the increased risk of malignancy in the family is at no greater risk for cancer than the general population and does not need aggressive screening for cancer, nor is there a potential for that person’s children to inherit
the defect.1

FAMILIAL ADENOMATOUS POLYPOSIS (FAP) AND ATTENUATED FAMILIAL ADENOMATOUS POLYPOSIS (aFAP)

FAP is a syndrome characterized by the presence of over 100 colonic adenomas. Review of the family medical history usually reveals an autosomal dominant pattern of inheritance, although up to 30% of patients appear to develop the disease from a new APC mutation. 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 with a greater number of polyps and an earlier age of onset. For patients affected by FAP, adenomatous polyps are present in 15% of patients by 10 years of age, 50% at age 15 years, and 75% by 20 years of age. The lifetime risk of colorectal malignancy in patients with FAP is nearly 100% with a median age of 39 years. However, 7% of affected patients develop cancer before age 21 years.2,3

In contrast to patients with FAP, those with aFAP have an average of 30 polyps with the polyps more likely to be right colonic. The onset is also later, with the polyps developing after 25 years of age.6 As with FAP, the lifetime risk of colorectal malignancy in patients with aFAP is nearly 100%, but the median age of cancer diagnosis is 59 years.2 As with FAP, the family medical history will reveals an autosomal dominant pattern of inheritance.

MYH-ASSOCIATED POLYPOSIS

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 obvious. Whereas 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. 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.4 A comparison of the clinical features of FAP, aFAP, and MAP is
shown in Table 1.

MANAGEMENT

As discussed earlier, the initial management of any suspected inherited cancer syndrome is genetic counseling. Management options include aggressive screening regimens, chemopreventive agents, and prophylactic surgery. Regardless of the treatment modality chosen, a lifetime of surveillance is needed.

Screening

Endoscopy is the screening method most commonly chosen for patients at risk for a polyposis syndrome. The initial examination should be performed at 12 years of age for patients at risk for FAP. Complete colonoscopy has been recommended by some, and others, given the predilection for rectal and left colonic polyps in FAP, others have recommended flexible proctosigmoidoscopy. Annual flexible proctosigmoidoscopy is the method of choice for subsequent examinations.4,5 Screening should be continued until polyps develop or should be life long for those with a proven APC gene abnormality. For patients at risk for FAP whose genetic status is unknown, if no polyps have been identified by age 50 years, it is reasonable to conclude that these patients did not inherit the genetic defect and that annual screening can be discontinued, although they still need screening for colorectal cancer as recommended for the general population.5

For individuals whose family history suggests aFAP, complete colonoscopy is the procedure of choice because of the likelihood of right colonic polyposis. Screening examination should begin at age 20 years and be performed every 1 to 2 years.5 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.

Extracolonic Manifestations

When a patient is known to have a polyposis syndrome from either the clinical findings of colon polyps or genetic testing, the possibility of extracolonic manifestations must be considered. The most common extracolonic manifestations are shown in table 2.  It can be anticipated that duodenal polyps will develop in 80% to 90% of patients with an APC mutation.  All patients should have esophago-gastro-duodenoscopy 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 re-examined in 5 years. Patients with Stage II disease need a 3 year follow-up, while Stage III demands a 1 year exam. Stage IV disease is an indication for strong consideration of duodenectomy.6

There is no consensus regarding screening for desmoid tumors. However, it is appropriate to consider their potential presence when a polyposis syndrome is identified. Desmoid tumors can be staged according to clinical characteristics. Stage I desmoids are asymptomatic, small (less than 10 centimeters in maximum dimension) and found incidentally either during laparotomy or on CT scan. It is unlikely that these tumors will enlarge and cause problems. Management options include observation, or nonsteroidal anti-inflammatory medications (NSAID). 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.7

Stage II desmoids are symptomatic,10 centimeters 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.7
Stage III desmoids are symptomatic and 11 to 20 centimeters in maximum dimension, or asymptomatic and slowly increasing in size (less than 50 percent increase in diameter in 6 months). Management options for these lesions include NSAID, tamoxifen, raloxifene, and vinblastin/methotrexate. Antisarcoma chemotherapy (adriamycin/ dacarbazine) can be given if the tumor continues to grow despite the less toxic agents.7

Stage IV desmoids are symptomatic, greater than 20 cm maximum diameter, or demonstrate rapid growth (greater than 50 percent increase in diameter within 6 months). Anti-sarcoma chemotherapy, and radiation are usually employed to management these tumors. Desmoids which 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.7

Chemoprevention

Several clinical trials have shown that the nonsteroidal anti-inflammatory drugs (NSAIDs) sulindac, celecoxib, and aspirin can reduce the number and size of colorectal adenomas in patients with FAP. What is unclear is whether suppression of the polyps will prevent progression to colorectal cancer. Given the case reports of cancer occurring in patients with FAP whose polyps were suppressed with sulindac, chemoprevention cannot be recommended as primary therapy for intestinal polyposis. It can be considered for the special circumstance where surgical therapy has been declined or has an unacceptably high risk of complications.

Surgery

Surgery is the primary therapeutic modality in the management of colonic polyposis syndromes. Selection of the appropriate timing of the intervention and the choice of the surgical procedure to be performed must take into account the manifestations of the disease in the patient and the patient’s family. It has been recommended that surgery be performed at age 12 to 15 years for patients with severe disease by clinical examination. Surgery can be delayed until age 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 that 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).8 The advantages of a TAC include a single-stage procedure with a low risk of surgical complications, restored bowel continuity with superior functional results compared with the other surgical options, and the avoidance of a proctectomy with the potential for damage to the pelvic nerves and severe urinary and sexual dysfunction. 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. It appears that 10 to 12 cm of remaining rectum is the optimal remnant, having an adequate reservoir capacity and an acceptable 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. Clinical factors can be used to predict the likelihood that 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 greater than 3 cm in size, and a cancer anywhere in the colon are clinical findings associated with an increased risk of subsequent malignancy in the remaining rectum.9 

Given the risk of subsequent neoplasia after TAC, many surgeons recommend IPAA for most patients with polyposis. With preservation of the anal transition zone, bowel function after IPAA is comparable to that after TAC, but the risk of subsequent neoplasia in the anal transition zone is reported to be as high as 30%. Complete rectal mucosectomy decreases this risk significantly but does not remove it entirely and is associated with diminished bowel function and an increased surgical complication risk. The 20% to 40% risk of surgical complications is the major disadvantage of IPAA. Another perceived disadvantage of IPAA is the usual need for temporary fecal diversion and a subsequent procedure to close the stoma. 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. Damage to the pelvic autonomic nerves results in vaginal dryness and dyspareunia in 25% to 30% of  women. Despite these disadvantages, IPAA is the procedure of choice for patients with an unacceptably high risk of neoplasia after TAC or those with a increased risk of developing desmoid tumors.

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. 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 those with technical problems that prevent an ileal pouch from reaching the anus.

Postoperative Surveillance

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 are essential for the remainder of the patient’s life. Endoscopy of the rectal remnant or ileal pouch should be performed annually with polyps smaller than 5mm 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. Although the significance of polyps in an ileal pouch is uncertain, it has been suggested that these can be managed with the NSAID sulindac or celecoxib.

HEREDITARY NONPOLYPOSIS COLON CANCER

HNPCC is a syndrome characterized by a very high risk of colorectal cancer without an unusual number of colorectal polyps. HNPCC has an autosomal dominant pattern of inheritance and is associated with 5% to 8% of colorectal cancers.

Diagnosis

The principles for the diagnosis of an inherited cancer syndrome and the roles of genetic counseling and genetic testing that have already been discussed apply to the diagnosis and evaluation of HNPCC. As opposed to the diagnosis of the polyposis syndromes, in which the clinical finding of colonic polyposis is indicative of a hereditary colorectal cancer syndrome, the diagnosis of
HNPCC is based primarily on the family medical history. The most common diagnostic guidelines for HNPCC, the Amsterdam criteria, are shown in Table 4. These criteria were developed to standardize the diagnosis for research purposes and are quite strict. They fail to recognize any of the extracolonic manifestations of HNPCC and have a low sensitivity, especially in families with fewer members. The Bethesda guidelines (Table 5) are much less stringent and take into account extracolonic tumors and several other clinical-pathologic findings in patients with HNPCC. They were developed to identify tumors that were more likely to have microsatellite instability, a classic finding in HNPCC. Although the Bethesda guidelines are more sensitive than the Amsterdam criteria, they are also much less specific.

Management

As discussed earlier, the initial management of any suspected inherited cancer syndrome is genetic counseling. Management options include aggressive screening regimens, chemopreventive agents, and prophylactic surgery. Regardless of the treatment modality chosen, a lifetime of surveillance is needed.

Screening

Because the majority of polyps and cancers in patients with HNPCC are proximal to the splenic flexure of the colon, complete colonoscopy is the screening procedure of choice. Screening should be started at age 20 to 25, or 5 years younger than the youngest affected family member, and be performed every 1 to 2 years for the duration of the patient’s life.5 Endoscopic removal of all polyps, if technically possible, has been shown to reduce the incidence of colorectal cancers in HNPCC families.
Endometrial carcinoma is the most common extracolonic manifestation of HNPCC. mThe cumulative incidence in women with HNPCC who have not had a hysterectomy is 30% to 60%. This has led to the suggestion that screening for endometrial carcinoma is indicated for at-risk women. Screening options include annual endometrial aspirate and/or transvaginal ultrasonography beginning at age 25 to 35 years.

Surgery

Surgical intervention is indicated for patients who are proved or strongly suspected to have HNPCC when they develop either a colon polyp that cannot be managed endoscopically or a colon cancer. With the risk of a metachronous colon cancer being reported to be as high as 40% at 10 years after a segmental resection, most would recommend a TAC.8 Even after TAC, the risk of cancer in the rectal remnant is reported to be 6% to 20%.

For patients with HNPCC who develop rectal cancer, proctocolectomy with ileal pouch anal anastomosis (IPAA) should be performed if sphincter preservation is technically possible and does not violate oncologic principles. If sphincter preservation is not possible, TPC will be necessary. These three surgical options, TAC, IPAA, and TPC, have already been discussed.

Women with germline mutations of the MMR genes also have a 30% to 60% lifetime risk of developing endometrial cancer. It does not seem unreasonable to consider prophylactic hysterectomy and bilateral salpingo- oophorectomy at the time of colectomy for the patient who is postmenopausal or has completed her family.
Postoperative Surveillance
Regardless of the surgical procedure chosen, postoperative
surveillance of any remaining colon and screening for the extracolonic manifestations are essential for the remainder of the patient’s life. Endoscopy of the remaining large bowel should be performed biannually with polyps removed and examined to exclude dysplasia.

 

REFERENCES
1.  Berk T, Cohen Z, Bapat B, et al. Negative genetic test results in familial adenomatous polyposis: clinical screening implications. Dis Colon Rectum 1999;42:307–310
2.  Guillen JG, Smith A, Puig-LaCelle J, et al. Gastrointestinal polyposis syndromes. Curr Prob Surg 1999:228–323
3.  Church JM, McGannon E, Burke C, Clark B. Teenagers with familial adenomatous polyposis: what is their risk for colorectal cancer? Dis Colon Rectum 2002;45:887–889
4.  Lipton L, Tomlinson I. The multiple colorectal adenoma phenotype and MYH, a base excision repair gene. Clin Gastroenterol Hepatol 2004;8:633–638
5.  Church J, Lowry A, Simmang C. Practice parameters for the identification and testing of patients at risk for dominantly inherited colorectal cancer—supporting documentation. Dis Colon Rectum 2001;44:1404–1412
6.  Groves CJ, Saunders BP, Spigelman AD, et al. Duodenal cancer in patients with familial adenomatous polyposis (FAP); results of a 10 year prospective study. Gut 2002;50:634-636.
7.  Church J , Berk T, Boman B, Guillem J, Lynch C, Lynch P, Rodriguez-Bigas M, Rusin L,Weber T. Staging intra-abdominal desmoid tumors in familial adenomatous polyposis: A search for a uniform approach to a troubling disease. Dis Colon Rectum 2005; 48:1528-1534.
8.  Church J, Simmang C. Practice parameters for the treatment of patients with dominantly inherited colorectal cancer. Dis Colon Rectum 2003;46:1001-1012
9.  Church J, Burke C, McGannon E, et al. Predicting polyposis severity by proctoscopy: how reliable is it? Dis Colon Rectum 2001;44:1249–1254


Table 1.
 Comparison of Familial Adenomatous Polyposis, Attenuated Familial Adenomatous Polyposis, and MYH-Associated Polyposis

                                                                FAP            aFAP                  MAP             
Number of polyps                          >100     Average 20–30Median _50
Age of onset (yr)<2125–30?
Location of polypsDistal colonProximal colonThroughout
Average age at cancer diagnosis (yr)
 395950
Manner of inheritanceDominantDominantRecessive

Table 2.  Extracolonic Manifestations of FAP and aFAP
 Incidence  (%)                 Significance                                     
Duodenal adenomas80–9012% risk of malignancy
Gastric hamartomas50–70Must exclude gastric adenoma
Desmoids12–3827% risk of complications
HepatoblastomaMost common before age 2 years
Osteomas80Usually less than 1cm in size 

Table 3.  Spigelman Staging for Duodenal Adenomatosis
Scorex 123
No. polyps1-45-20>20
Size (mm) 1-45-10>10
Histologic type TubularTubulovillousVillous
DysplasiaMildModerateSevere
xSpigelman stage I, score 1-4; stage II, score 5-6; stage III, score 7-8; stage IV, score 9-12

Table 4.  Amsterdam Criteria for the Diagnosis of Hereditary Nonpolyposis Colon Cancer
1. At least 3 relatives with histologically proven colorectal cancer; 1 must be a first-degree relative of the other 2.
2. At least 2 successive generations should be affected.                           
3. In 1 of the relatives, colorectal cancer should be diagnosed before age 50 years. 
4. Familial adenomatous polyposis must be excluded. 

Table 5.  Bethesda Guidelines
1. Individuals in families that meet the Amsterdam criteria. 
2. Individuals with 2 hereditary nonpolyposis colon cancer (HNPCC)-related cancers, including synchronous and metachronous colorectal cancers or associated extracolonic cancers (endometrial, ovarian, gastric, hepatobiliary, or small bowel carcinomas or transitional cell carcinoma of the ureter or renal pelvis).
3. Individuals with colorectal cancer and a first-degree relative with colorectal cancer and/or HNPCC-related extracolonic cancer and/or a colorectal adenoma; 1 of the cancers diagnosed at age <45 years, and the adenoma diagnosed at age <40 years.
4. Individuals with colorectal or endometrial cancer diagnosed at age <45
years.                                                                                                                                     
5. Individuals with a signet-ring cell colorectal cancer (composed of >50% signet ring cells) diagnosed at age < 45 years.
6. Individuals with a right-sided colorectal cancer with an undifferentiated pattern on histology (poorly or undifferentiated carcinoma composed of irregular, solid sheets of large eosinophilic cells and containing small gland-like spaces) diagnosed at age <45 years.
7. Individuals with adenomas diagnosed at age <40 years.