Colorectal Cancer ____________________________________________________________________________
age with repeat screening every 10 years. Increased risk with greater extent of family history warrants room for clinical judgment in favor of even earlier screening based on family history, and shortening the frequency of screening interval to every five years. There is no empirical or logical support to initiate colorectal cancer screening 10 years younger in age than the family member with youngest age of colorectal cancer detection [91; 117]. Other Genetic Factors In addition to FAP and Lynch syndrome, several rare genetic syndromes confer an increased risk for colorectal cancer, including [91; 97]: • Peutz-Jeghers syndrome: STK11/LKB1 gene • Juvenile polyposis syndrome: SMAD4/DPC4 and BMPR1A genes • Cowden syndrome: PTEN gene • Ruvalcaba-Myhre-Smith syndrome: PTEN gene • Hereditary mixed polyposis syndrome Factors that Suggest Hereditary Colorectal Cancer Predisposition Syndrome With the exception of autosomal recessive inheritance with MYH -associated polyposis, all gene mutations known to cause colorectal cancer predisposition are inherited in an autosomal dominant fashion [114]. Thus, family characteristics consistent with autosomal dominant inheritance of cancer predisposition are important to identify because they indicate high risk and possibly the presence of a cancer-predisposing mutation [90]. Factors that suggest a hereditary colorectal cancer predisposi- tion syndrome include [112; 114]: • Vertical transmission (i.e., presence of a genetic predisposition in sequential generations) of cancer predisposition in autosomal dominant conditions • Inheritance risk of 50% for both men and women because when a parent carries an autosomal dominant genetic predisposition, each child has a 50% chance of inheriting the predisposition regardless of sex • Other clinical characteristics: ‒ Cancers with an earlier age of onset than sporadic (non-genetic) cases ‒ Predisposition to other cancers, such as endometrial cancer ‒ Two or more primary cancers in a single individual, including multiple primary cancers of the same type (e.g., two separate primary colorectal cancers) or primary cancer of different types (e.g., colorectal and endometrial cancer) ‒ Presence of non-neoplastic extracolonic features, as with congenital retinal pigment epithelium hypertrophy and desmoids in FAP
‒ Uncommon tumors such as adrenocortical, sebaceous carcinoma, ampullary, and small bowel ‒ The presence of multiple polyps, even when family history appears negative
Oligopolyposis (i.e., polyp count greater than expected) can involve as few as 10 to 15 polyps, and the diverse pathology of polyps requires careful attention to polyp count and histology to determine whether genetic testing and/or further clinical evaluation is appropriate [112]. Genetic Testing As discussed, many genes associated with inherited colorectal cancer syndromes have been identified, and genetic testing is available for diagnosis and is the accepted standard of clinical care. Genetic testing of asymptomatic persons without colorec- tal cancer symptoms or precursors (adenomatous polyps) is performed to identify increased probability of developing colorectal cancer. Positive findings should lead to diagnostic testing to investigate the presence of occult cancer, followed by treatment if cancer or precursors are found. The intent is to prevent the development of colorectal cancer or increase the likelihood of curative outcome afforded by early detection. Patients can also use this information for decisions related to family planning, work, or retirement. Disease-causing mutations can be found in most families affected by one of the inherited syndromes, and once a muta- tion is found in an index case of the family, relatives can be tested for the presence or absence of that mutation with near- 100% accuracy. Cancer screening and management is then based on the genetic testing results [118]. Clinical issues somewhat unique to genetic testing include genetic counseling and informed consent for genetic testing. Genetic screening for inherited colorectal cancer syndromes can be hampered by patient or proband resistance, but con- sent to testing is greatly improved with coordination between the pathologist, referring surgeon or oncologist, and a cancer genetics counselor [99; 118]. Clinical criteria used to identify candidates for genetic testing to determine the presence of an inherited susceptibility to colorectal cancer include [91; 97; 104]: • A strong family history of colorectal cancer and/or polyps • Multiple primary cancers in a patient with colorectal cancer • Family history of other cancers consistent with known inherited syndromes causing a high risk of colorectal cancer • Early age at colorectal cancer diagnosis
32
MDAZ2326
Powered by FlippingBook