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Colorectal Neoplasia Long-standing (28 years) colonic inflammatory bowel preventing colorectal cancer. The U.S. Preventive Services Task disease (Crohn disease and ulcerative colitis) is associated with Force updated their guidelines in 2015 to include the use of about a 2.7-fold increased risk; the risk depends on the sever- low-dose aspirin (81 mg/d) for preventing colorectal cancer ity and extent of bowel involvement. Patients with ureterocolic and cardiovascular disease in individuals aged 50 to 59 years anastomoses after bladder surgery and adult survivors of who are at increased risk for cardiovascular disease, have a life childhood malignancy who received abdominal radiation are expectancy of 10 years, and are willing to take aspirin for also at increased risk for colorectal cancer. 10 years. See MKSAP 19 General Internal Medicine 2 for a more Modifiable risk factors include diets high in red and pro- detailed discussion of aspirin use in primary prevention. cessed meat; low intake of fruits, vegetables, fiber, and dairy; Studies of other NSAIDs for prevention of colon cancer use of alcohol and tobacco; type 2 diabetes mellitus; sedentary and adenomas have also yielded positive results; however, lifestyle; and obesity. benefits of aspirin and other NSAIDs must be weighed against harms, especially gastrointestinal bleeding. Some evidence suggests that selective cyclooxygenase-2 e Nonmodifiable risk factors for colorectal cancer include inhibitors prevent recurrent adenomas and decrease the inci- age (250 years), male sex, Black race, and personal or dence of advanced lesions; however, the associated increased family history of colorectal cancer. cardiovascular risk confounds a recommendation of their use e Modifiable risk factors for colorectal cancer include for chemoprevention. diets high in red and processed meat; low intake of fruits, vegetables, fiber, and dairy; use of alcohol and e The US. Preventive Services Task Force recommends the tobacco; type 2 diabetes mellitus; sedentary lifestyle; use of low-dose aspirin for preventing colorectal cancer and and obesity. cardiovascular disease in individuals aged 50 to 59 years who are at increased risk for cardiovascular disease. Chemoprevention Substantial epidemiologic and experimental data suggest that aspirin prevents colorectal cancer. Cohort and case-control Screening studies, for example, show that aspirin use is associated with Screening individuals at average risk is discussed in MKSAP 19 a 30% decreased risk for colorectal cancer. Randomized con- General Internal Medicine 2. trolled trials, however, have shown that aspirin decreases the Screening strategies for individuals at increased risk for risk for recurrent adenomas but has less clear benefit in colorectal cancer are described in Table 24.

Long-standing (28 years) colonic inflammatory bowel preventing colorectal cancer. The U.S. Preventive Services Task disease (Crohn disease and ulcerative colitis) is associated with Force updated their guidelines in 2015 to include the use of about a 2.7-fold increased risk; the risk depends on the sever- low-dose aspirin (81 mg/d) for preventing colorectal cancer ity and extent of bowel involvement. Patients with ureterocolic and cardiovascular disease in individuals aged 50 to 59 years anastomoses after bladder surgery and adult survivors of who are at increased risk for cardiovascular disease, have a life childhood malignancy who received abdominal radiation are expectancy of 10 years, and are willing to take aspirin for also at increased risk for colorectal cancer. 10 years. See MKSAP 19 General Internal Medicine 2 for a more Modifiable risk factors include diets high in red and pro- detailed discussion of aspirin use in primary prevention. cessed meat; low intake of fruits, vegetables, fiber, and dairy; Studies of other NSAIDs for prevention of colon cancer use of alcohol and tobacco; type 2 diabetes mellitus; sedentary and adenomas have also yielded positive results; however, lifestyle; and obesity. benefits of aspirin and other NSAIDs must be weighed against harms, especially gastrointestinal bleeding. Some evidence suggests that selective cyclooxygenase-2 e Nonmodifiable risk factors for colorectal cancer include inhibitors prevent recurrent adenomas and decrease the inci- age (250 years), male sex, Black race, and personal or dence of advanced lesions; however, the associated increased family history of colorectal cancer. cardiovascular risk confounds a recommendation of their use e Modifiable risk factors for colorectal cancer include for chemoprevention. diets high in red and processed meat; low intake of fruits, vegetables, fiber, and dairy; use of alcohol and e The US. Preventive Services Task Force recommends the tobacco; type 2 diabetes mellitus; sedentary lifestyle; use of low-dose aspirin for preventing colorectal cancer and and obesity. cardiovascular disease in individuals aged 50 to 59 years who are at increased risk for cardiovascular disease. Chemoprevention Substantial epidemiologic and experimental data suggest that aspirin prevents colorectal cancer. Cohort and case-control Screening studies, for example, show that aspirin use is associated with Screening individuals at average risk is discussed in MKSAP 19 a 30% decreased risk for colorectal cancer. Randomized con- General Internal Medicine 2. trolled trials, however, have shown that aspirin decreases the Screening strategies for individuals at increased risk for risk for recurrent adenomas but has less clear benefit in colorectal cancer are described in Table 24. TABLE 24. Screening for Colorectal Cancer in Individuals at Elevated Risk

Long-standing (28 years) colonic inflammatory bowel preventing colorectal cancer. The U.S. Preventive Services Task disease (Crohn disease and ulcerative colitis) is associated with Force updated their guidelines in 2015 to include the use of about a 2.7-fold increased risk; the risk depends on the sever- low-dose aspirin (81 mg/d) for preventing colorectal cancer ity and extent of bowel involvement. Patients with ureterocolic and cardiovascular disease in individuals aged 50 to 59 years anastomoses after bladder surgery and adult survivors of who are at increased risk for cardiovascular disease, have a life childhood malignancy who received abdominal radiation are expectancy of 10 years, and are willing to take aspirin for also at increased risk for colorectal cancer. 10 years. See MKSAP 19 General Internal Medicine 2 for a more Modifiable risk factors include diets high in red and pro- detailed discussion of aspirin use in primary prevention. cessed meat; low intake of fruits, vegetables, fiber, and dairy; Studies of other NSAIDs for prevention of colon cancer use of alcohol and tobacco; type 2 diabetes mellitus; sedentary and adenomas have also yielded positive results; however, lifestyle; and obesity. benefits of aspirin and other NSAIDs must be weighed against harms, especially gastrointestinal bleeding. Some evidence suggests that selective cyclooxygenase-2 e Nonmodifiable risk factors for colorectal cancer include inhibitors prevent recurrent adenomas and decrease the inci- age (250 years), male sex, Black race, and personal or dence of advanced lesions; however, the associated increased family history of colorectal cancer. cardiovascular risk confounds a recommendation of their use e Modifiable risk factors for colorectal cancer include for chemoprevention. diets high in red and processed meat; low intake of fruits, vegetables, fiber, and dairy; use of alcohol and e The US. Preventive Services Task Force recommends the tobacco; type 2 diabetes mellitus; sedentary lifestyle; use of low-dose aspirin for preventing colorectal cancer and and obesity. cardiovascular disease in individuals aged 50 to 59 years who are at increased risk for cardiovascular disease. Chemoprevention Substantial epidemiologic and experimental data suggest that aspirin prevents colorectal cancer. Cohort and case-control Screening studies, for example, show that aspirin use is associated with Screening individuals at average risk is discussed in MKSAP 19 a 30% decreased risk for colorectal cancer. Randomized con- General Internal Medicine 2. trolled trials, however, have shown that aspirin decreases the Screening strategies for individuals at increased risk for risk for recurrent adenomas but has less clear benefit in colorectal cancer are described in Table 24. TABLE 24. Screening for Colorectal Cancer in Individuals at Elevated Risk Risk Category Criteria Screening Recommendations (Age; Modality; Interval) | Increased Family history of CRC:

Long-standing (28 years) colonic inflammatory bowel preventing colorectal cancer. The U.S. Preventive Services Task disease (Crohn disease and ulcerative colitis) is associated with Force updated their guidelines in 2015 to include the use of about a 2.7-fold increased risk; the risk depends on the sever- low-dose aspirin (81 mg/d) for preventing colorectal cancer ity and extent of bowel involvement. Patients with ureterocolic and cardiovascular disease in individuals aged 50 to 59 years anastomoses after bladder surgery and adult survivors of who are at increased risk for cardiovascular disease, have a life childhood malignancy who received abdominal radiation are expectancy of 10 years, and are willing to take aspirin for also at increased risk for colorectal cancer. 10 years. See MKSAP 19 General Internal Medicine 2 for a more Modifiable risk factors include diets high in red and pro- detailed discussion of aspirin use in primary prevention. cessed meat; low intake of fruits, vegetables, fiber, and dairy; Studies of other NSAIDs for prevention of colon cancer use of alcohol and tobacco; type 2 diabetes mellitus; sedentary and adenomas have also yielded positive results; however, lifestyle; and obesity. benefits of aspirin and other NSAIDs must be weighed against harms, especially gastrointestinal bleeding. Some evidence suggests that selective cyclooxygenase-2 e Nonmodifiable risk factors for colorectal cancer include inhibitors prevent recurrent adenomas and decrease the inci- age (250 years), male sex, Black race, and personal or dence of advanced lesions; however, the associated increased family history of colorectal cancer. cardiovascular risk confounds a recommendation of their use e Modifiable risk factors for colorectal cancer include for chemoprevention. diets high in red and processed meat; low intake of fruits, vegetables, fiber, and dairy; use of alcohol and e The US. Preventive Services Task Force recommends the tobacco; type 2 diabetes mellitus; sedentary lifestyle; use of low-dose aspirin for preventing colorectal cancer and and obesity. cardiovascular disease in individuals aged 50 to 59 years who are at increased risk for cardiovascular disease. Chemoprevention Substantial epidemiologic and experimental data suggest that aspirin prevents colorectal cancer. Cohort and case-control Screening studies, for example, show that aspirin use is associated with Screening individuals at average risk is discussed in MKSAP 19 a 30% decreased risk for colorectal cancer. Randomized con- General Internal Medicine 2. trolled trials, however, have shown that aspirin decreases the Screening strategies for individuals at increased risk for risk for recurrent adenomas but has less clear benefit in colorectal cancer are described in Table 24. TABLE 24. Screening for Colorectal Cancer in Individuals at Elevated Risk Risk Category Criteria Screening Recommendations (Age; Modality; Interval) | Increased Family history of CRC: CRC diagnosed in FDR age <60 years Begin at age 40 years or 10 years earlier than age of youngest FDR at | or 22 FDRs at any age diagnosis, whichever comes first; colonoscopy; repeat every 5 years*

Risk Category Criteria Screening Recommendations (Age; Modality; Interval) | Increased Family history of CRC: CRC diagnosed in FDR age <60 years Begin at age 40 years or 10 years earlier than age of youngest FDR at | or 22 FDRs at any age diagnosis, whichever comes first; colonoscopy; repeat every 5 years* CRC diagnosed in FDR age 260 years = Begin at age 40 years; any modality; repeat every 10 years* Personal history of CRC Perform at time of diagnosis; colonoscopy; repeat at 1 year, 3 years, and, if normal, every 5 years thereafter until risks outweigh benefit of continued screening Adult patients with cystic fibrosis Cystic Fibrosis Foundation recommends beginning CRC screening at age 40 years in individuals with cystic fibrosis, with continued rescreening every 5 years High Familial adenomatous polyposis Begin at age 10-12 years; flexible sigmoidoscopy or colonoscopy; repeat every 1-2 years until colectomy Lynch syndrome Begin at age 20-25 years or 10 years earlier than youngest cancer in family; colonoscopy; repeat every 1-2 years Inflammatory bowel disease (Crohn Begin after 8 years of chronic colitis; colonoscopy with biopsies; repeat disease or ulcerative colitis) every 1-2 years CRC = colorectal cancer; FDR = first-degree relative (parent, sibling, or child). alf baseline examination is normal.

Inflammatory bowel disease (Crohn Begin after 8 years of chronic colitis; colonoscopy with biopsies; repeat disease or ulcerative colitis) every 1-2 years CRC = colorectal cancer; FDR = first-degree relative (parent, sibling, or child). alf baseline examination is normal. Data from Rex DK, Boland CR, Dominitz JA, et al. Colorectal cancer screening: recommendations for physicians and patients from the U.S. multi-society task force on colorectal cancer. Gastroenterology. 2017;153:307-323. [PMID: 28600072] doi:10.1053/j.gastro.2017.05.013; Syngal S, Brand RE, Church JM, et al.; American College of Gastroenterology. ACG clinical guideline: genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol. 2015 Feb;110(2):223-62; quiz 263. [PMID: 25645574]; Rubin DT, Ananthakrishnan AN, Siegel CA, et al. ACG clinical guideline: ulcerative colitis in adults. Am J Gastroenterol. 2019; 114:384-413. [PMID: 30840605] doi:10.14309/ajg.0000000000000152. 46

Colorectal Neoplasia TABLE 25. Classification of Colorectal Polyps into local tissues, lymph node involvement, and evidence of metastasis (TNM system). Cross-sectional imaging of the chest, Adenomatous Polyps? abdomen, and pelvis is used for staging in the initial evalua- Tubular adenoma tion after diagnosis. Management of colon cancer depends on Tubulovillous adenoma stage, evidence of microsatellite instability, and presence of Villous adenoma specific mutations, including KRAS/NRAS and BRAF. Serrated Lesions For staging and treatment of colorectal cancer, see MKSAP 19 Oncology. Hyperplastic polyp Favorable characteristics include stage I to II cancer and Sessile serrated polyp with or without cytologic dysplasia lack of angiolymphatic involvement. Endoscopic resection of Traditional serrated adenoma polyps can be curative, and negative margins after removal are Other a favorable sign. Malignant sessile or flat polyps are associated Hamartomatous polyp with higher risk for recurrence and local or distant spread. Inflammatory polyp With or without high-grade dysplasia. e Colorectal cancer is usually diagnosed by colonoscopy with biopsy.

Serrated Lesions For staging and treatment of colorectal cancer, see MKSAP 19 Oncology. Hyperplastic polyp Favorable characteristics include stage I to II cancer and Sessile serrated polyp with or without cytologic dysplasia lack of angiolymphatic involvement. Endoscopic resection of Traditional serrated adenoma polyps can be curative, and negative margins after removal are Other a favorable sign. Malignant sessile or flat polyps are associated Hamartomatous polyp with higher risk for recurrence and local or distant spread. Inflammatory polyp With or without high-grade dysplasia. e Colorectal cancer is usually diagnosed by colonoscopy with biopsy. e Cross-sectional imaging of the chest, abdomen, and Because adenomas are an intermediary step in the progres- pelvis is used for staging in the initial evaluation after sion from normal colonic mucosa to colon cancer, identification diagnosis. and management of adenomatous polyps are critical. Adenomas can be found throughout the colon. They are classified by mor- phology, histology, and degree of dysplasia (Table 25). Adenomas Surveillance with any degree of villous histology or high-grade dysplasia have greater malignant potential. Risk is also increased in pol- Surveillance for colorectal cancer after screening or polypec- yps larger than 1 cm. The progression of adenoma to carci- tomy is based on baseline examination findings (Table 26).

e Cross-sectional imaging of the chest, abdomen, and Because adenomas are an intermediary step in the progres- pelvis is used for staging in the initial evaluation after sion from normal colonic mucosa to colon cancer, identification diagnosis. and management of adenomatous polyps are critical. Adenomas can be found throughout the colon. They are classified by mor- phology, histology, and degree of dysplasia (Table 25). Adenomas Surveillance with any degree of villous histology or high-grade dysplasia have greater malignant potential. Risk is also increased in pol- Surveillance for colorectal cancer after screening or polypec- yps larger than 1 cm. The progression of adenoma to carci- tomy is based on baseline examination findings (Table 26). noma takes approximately 8 to 10 years. Key quality indicators for screening colonoscopy include ade- quate bowel preparation, preparation sufficient to identify polyps Hereditary Colorectal 6 mm or larger, visualization of the entire colon to the cecum, Cancer Syndromes adenoma detection rate, and longer duration of colonoscopy. Several hereditary syndromes are associated with colorectal cancer (Table 27). e Screening colonoscopy is recommended to begin at age 40 years or 10 years earlier than the age of the youngest Lynch Syndrome first-degree relative diagnosed with colorectal cancer Lynch syndrome is characterized by germline mutations in the

e Screening colonoscopy is recommended to begin at age 40 years or 10 years earlier than the age of the youngest Lynch Syndrome first-degree relative diagnosed with colorectal cancer Lynch syndrome is characterized by germline mutations in the before age 60 years. mismatch repair genes (MLH1, MSH2, MSH6, PMS2) or the epithelial cell adhesion molecule gene (EPCAM), leading to an ¢ Colorectal cancer screening is recommended to begin at increased risk for neoplasia of the colon and other organs. The age 40 years for any patient with two first-degree relatives previous name for this syndrome, hereditary nonpolyposis diagnosed with colorectal cancer after age 60 years. colorectal cancer, is no longer used because the syndrome is ¢ Colonoscopy is recommended for patients with Lynch associated with colorectal polyps as well as extracolonic can- syndrome at age 20 to 25 years or 10 years earlier than cers. The syndrome follows an autosomal dominant inherit- youngest age at which cancer was diagnosed in the family. ance pattern, and new mutations are rare. In persons with Lynch syndrome, the lifetime risk for colorectal cancer depends on the location of the gene Clinical Presentation mutation; the risk can be as high as 50% to 80%. Colorectal cancer may be asymptomatic or may present with Colorectal cancer in Lynch syndrome is more likely in iron deficiency anemia, gastrointestinal bleeding, altered the proximal colon and can display characteristic patho- bowel habits, abdominal pain, colonic obstruction, and weight logic features, such as tumor-infiltrating lymphocytes loss in more advanced cases. and medullary growth pattern. Colorectal tumors in Lynch syndrome result from microsatellite instability that can be assessed using polymerase chain reaction or Diagnosis and Staging immunohistochemistry (see Pathogenesis). All colorectal Colorectal cancer is usually diagnosed by colonoscopy with cancers should be screened for Lynch syndrome genetic biopsy. Staging is based on tumor size and extent of invasion mutations or microsatellite instability.

before age 60 years. mismatch repair genes (MLH1, MSH2, MSH6, PMS2) or the epithelial cell adhesion molecule gene (EPCAM), leading to an ¢ Colorectal cancer screening is recommended to begin at increased risk for neoplasia of the colon and other organs. The age 40 years for any patient with two first-degree relatives previous name for this syndrome, hereditary nonpolyposis diagnosed with colorectal cancer after age 60 years. colorectal cancer, is no longer used because the syndrome is ¢ Colonoscopy is recommended for patients with Lynch associated with colorectal polyps as well as extracolonic can- syndrome at age 20 to 25 years or 10 years earlier than cers. The syndrome follows an autosomal dominant inherit- youngest age at which cancer was diagnosed in the family. ance pattern, and new mutations are rare. In persons with Lynch syndrome, the lifetime risk for colorectal cancer depends on the location of the gene Clinical Presentation mutation; the risk can be as high as 50% to 80%. Colorectal cancer may be asymptomatic or may present with Colorectal cancer in Lynch syndrome is more likely in iron deficiency anemia, gastrointestinal bleeding, altered the proximal colon and can display characteristic patho- bowel habits, abdominal pain, colonic obstruction, and weight logic features, such as tumor-infiltrating lymphocytes loss in more advanced cases. and medullary growth pattern. Colorectal tumors in Lynch syndrome result from microsatellite instability that can be assessed using polymerase chain reaction or Diagnosis and Staging immunohistochemistry (see Pathogenesis). All colorectal Colorectal cancer is usually diagnosed by colonoscopy with cancers should be screened for Lynch syndrome genetic biopsy. Staging is based on tumor size and extent of invasion mutations or microsatellite instability. 47

Colorectal Neoplasia TABLE 26. Surveillance for Colorectal Cancer After Screening or Polypectomy Adenomatous Polyps Interval to Next Colonoscopy 1-2 tubular adenomas <10 mm 7-10 years 3-4 tubular adenomas <10 mm 3-5 years 5-10 tubular adenomas <10 mm, adenoma =10 mm, adenoma with villous component, 3 years or adenoma with high-grade dysplasia >10 adenomas? on single examination 1 year | Piecemeal resection of adenoma >20 mm 6 months, then 1 year later, then 3 years after second examination Serrated Polyps Interval to Next Colonoscopy $20 HP in rectum or sigmoid colon <10 or $20 HP proximal to sigmoid colon <10 mm 10 years 1-2 SSP <10 mm in size 5-10 years 3-4 SSP <10 mm in size or HP>10 mm 3-5 years 5-10 SSP <10 mm in size, SSP =>10 mm, or SSP with dysplasia 3 years Serrated polyposis syndrome 1 year HP = hyperplastic polyps; SSP = sessile serrated polyps; TSA = traditional serrated adenomas. | *Consideration for genetic testing based on adenoma burden, age, and family history. Data from Gupta S, Lieberman D, Anderson JC, et al. Recommendations for follow-up after colonoscopy and polypectomy: a consensus update by the US Multi-society Task Force on Colorectal Cancer. Gastroenterology. 2020;158:1131-1153.e5. [PMID: 32044092] doi:10.1053/j.gastro.2019.10.026.

| *Consideration for genetic testing based on adenoma burden, age, and family history. Data from Gupta S, Lieberman D, Anderson JC, et al. Recommendations for follow-up after colonoscopy and polypectomy: a consensus update by the US Multi-society Task Force on Colorectal Cancer. Gastroenterology. 2020;158:1131-1153.e5. [PMID: 32044092] doi:10.1053/j.gastro.2019.10.026. Lynch syndrome should be suspected in patients with Adenomatous Polyposis Syndromes synchronous (occurring within 6 months of the primary Familial Adenomatous Polyposis tumor diagnosis) or metachronous (occurring more than Familial adenomatous polyposis (FAP) is an inherited disorder 6 months after the primary tumor diagnosis) colorectal can- characterized by multiple (usually >100) adenomatous colon cers, colorectal cancer before age 50 years, occurrence of mul- polyps. FAP is caused by germline APC mutations that are tiple Lynch syndrome-associated cancers, or a family history inherited in an autosomal dominant pattern, although de novo of multiple cancers associated with Lynch syndrome. Clinical mutations occur in about 25% of cases. Adenomas in classic criteria to evaluate for Lynch syndrome include the Amsterdam FAP are more numerous in the distal colon than in the proxi- and Bethesda criteria (Table 28) as well as newer models, such mal colon. Adenoma and cancer develop in 100% of classic FAP as the PREdiction Model for gene Mutations 5 (PREMM;). The cases if surgery is not performed. The average age of colorectal Amsterdam II criteria are specific but not sensitive for the cancer onset is 39 years, with a risk of 93% by age 50 years. An diagnosis of Lynch syndrome, whereas the Bethesda criteria attenuated form of FAP (AFAP) causes fewer polyps (<100 syn- have good sensitivity but poor specificity. Given the limitations chronous polyps) with more proximal colonic distribution. of the clinical criteria and predictive models, genetic coun- The risk for colon cancer in patients with AFAP is about 70% seling and testing should be offered to patients with a personal by age 80 years, with an average age at onset of 58 years. and/or family history consistent with Lynch syndrome as well Both FAP and AFAP are associated with extracolonic as to patients whose tumor shows evidence of microsatellite intestinal manifestations (Figure 26). Duodenal adenomas instability or loss of mismatch repair protein expression. When require surveillance because the lifetime risk for duodenal a mutation is identified in a family, first-degree relatives should adenocarcinoma is estimated at 4%. Fundic gland polyps of the be tested and surveillance instituted. stomach do not have malignant potential but can mask the Screening recommendations for colorectal cancer in presence of gastric adenomas and cancer; risk for gastric can- patients with Lynch syndrome are described in Table 24. Risk- cer is less than 1%. Patients are also at risk for desmoid tumors, reducing total hysterectomy and bilateral salpingo-oophorec- especially after abdominal surgery, and for papillary thyroid tomy should be considered starting at age 40 to 45 years after cancer. Nonmalignant findings include extra teeth, sebaceous childbearing is completed in women who carry Lynch syn- or epidermoid cysts, osteomas, and congenital hypertrophy of drome mutations. the retinal pigmented epithelium. Screening with upper endoscopy for stomach and small- In classic FAP mutation carriers, screening with sigmoid- bowel cancers can be considered starting at age 30 to 35 years oscopy or colonoscopy should begin at age 10 to 12 years and and repeated every 2 to 5 years. Testing and treatment for be repeated every 1 to 2 years. Screening in patients with AFAP Helicobacter pylori are also recommended in patients at risk can be delayed until age 20 to 25 years and should be per- for or with Lynch syndrome to decrease the likelihood of gas- formed with colonoscopy. For individuals with FAP and AFAP, tric cancer. screening with upper endoscopy should begin at age 25 to

Lynch syndrome should be suspected in patients with Adenomatous Polyposis Syndromes synchronous (occurring within 6 months of the primary Familial Adenomatous Polyposis tumor diagnosis) or metachronous (occurring more than Familial adenomatous polyposis (FAP) is an inherited disorder 6 months after the primary tumor diagnosis) colorectal can- characterized by multiple (usually >100) adenomatous colon cers, colorectal cancer before age 50 years, occurrence of mul- polyps. FAP is caused by germline APC mutations that are tiple Lynch syndrome-associated cancers, or a family history inherited in an autosomal dominant pattern, although de novo of multiple cancers associated with Lynch syndrome. Clinical mutations occur in about 25% of cases. Adenomas in classic criteria to evaluate for Lynch syndrome include the Amsterdam FAP are more numerous in the distal colon than in the proxi- and Bethesda criteria (Table 28) as well as newer models, such mal colon. Adenoma and cancer develop in 100% of classic FAP as the PREdiction Model for gene Mutations 5 (PREMM;). The cases if surgery is not performed. The average age of colorectal Amsterdam II criteria are specific but not sensitive for the cancer onset is 39 years, with a risk of 93% by age 50 years. An diagnosis of Lynch syndrome, whereas the Bethesda criteria attenuated form of FAP (AFAP) causes fewer polyps (<100 syn- have good sensitivity but poor specificity. Given the limitations chronous polyps) with more proximal colonic distribution. of the clinical criteria and predictive models, genetic coun- The risk for colon cancer in patients with AFAP is about 70% seling and testing should be offered to patients with a personal by age 80 years, with an average age at onset of 58 years. and/or family history consistent with Lynch syndrome as well Both FAP and AFAP are associated with extracolonic as to patients whose tumor shows evidence of microsatellite intestinal manifestations (Figure 26). Duodenal adenomas instability or loss of mismatch repair protein expression. When require surveillance because the lifetime risk for duodenal a mutation is identified in a family, first-degree relatives should adenocarcinoma is estimated at 4%. Fundic gland polyps of the be tested and surveillance instituted. stomach do not have malignant potential but can mask the Screening recommendations for colorectal cancer in presence of gastric adenomas and cancer; risk for gastric can- patients with Lynch syndrome are described in Table 24. Risk- cer is less than 1%. Patients are also at risk for desmoid tumors, reducing total hysterectomy and bilateral salpingo-oophorec- especially after abdominal surgery, and for papillary thyroid tomy should be considered starting at age 40 to 45 years after cancer. Nonmalignant findings include extra teeth, sebaceous childbearing is completed in women who carry Lynch syn- or epidermoid cysts, osteomas, and congenital hypertrophy of drome mutations. the retinal pigmented epithelium. Screening with upper endoscopy for stomach and small- In classic FAP mutation carriers, screening with sigmoid- bowel cancers can be considered starting at age 30 to 35 years oscopy or colonoscopy should begin at age 10 to 12 years and and repeated every 2 to 5 years. Testing and treatment for be repeated every 1 to 2 years. Screening in patients with AFAP Helicobacter pylori are also recommended in patients at risk can be delayed until age 20 to 25 years and should be per- for or with Lynch syndrome to decrease the likelihood of gas- formed with colonoscopy. For individuals with FAP and AFAP, tric cancer. screening with upper endoscopy should begin at age 25 to 48

Colorectal Neoplasia TABLE 27. Hereditary Colorectal Cancer Syndromes | Syndrome Gene(s) Gastrointestinal Other Features | Manifestations Malignant Benign and Other Features | Lynch syndrome MLH1, MSH2, Colon cancer Endometrial cancer Microsatellite instability | EPCAMEMSE: SHG Gastric cance r Ovarian cancer Proximal colon cancer Small-bowel cancer Hepatobiliary cancer Universal screening of all p. : Uri acy colon and endometrial ancreatic cancer rinary tract cancer aanicers | Brain cancer Sebaceous skin adenoma/ cancer FAP APC Colon cancer >100 synchronous polyps Genotype-phenotype . F . correlation Gastric cancer Papillary thyroid cancer

FAP APC Colon cancer >100 synchronous polyps Genotype-phenotype . F . correlation Gastric cancer Papillary thyroid cancer Duodenal/ampullary Brain/central nervous system ; osmes .uanee Fundic stomach gl | ale f | } adenomas | | . Desmoid tumors Pancreatic cancer Epidermal cysts Osteomas Congenital hypertrophy of retinal pigment epithelium Attenuated FAP <100 synchronous colon polyps More proximal distribution

Congenital hypertrophy of retinal pigment epithelium Attenuated FAP <100 synchronous colon polyps More proximal distribution MutYH-associated MutYH Colon cancer Similar to FAP Autosomal recessive polyposis Duodenal cancer inheritance Monoallelic carriers have 1.5- to 2-fold increased colon cancer risk Polymerase POLE Oligo-adenomatous Endometrial cancer Possible microsatellite proofreading- POLD1 polyposis instability on tumor testing associated polyposis Juvenile polyposis SMAD4 Colon cancer Hereditary hemorrhagic syndrome BMPRIA —— telangiectasia Polyp complications: Small-bowel cancer anemia, bleeding prolapse, Pancreatic cancer pain, diarrhea, s intussusception Juvenile polyps

Polyp complications: Small-bowel cancer anemia, bleeding prolapse, Pancreatic cancer pain, diarrhea, s intussusception Juvenile polyps Peutz-Jeghers STK11 Small-bowel cancer Breast cancer Skin changes: syndrome ‘ mucocutaneous Colon cancer Ovarian cancer (SCTAT) pigmentation on lips and Gastric cancer Uterine cancer buccal mucosa Pancreatic cancer Cervical cancer (adenoma Symptoms of polyps: malignum) intussusception, ulceration, Peutz-Jeghers-type ; 4 bleeding, infarction polyps Testicular cancer (Sertoli cell tumor) Lung cancer | PTEN hamartoma PTEN Colon cancer Breast cancer Large head circumference | syndrome Gastric cancer Thyroid cancer Characteristic benign skin | Small bowel cancer Kidney cancer =e i cecal |

PTEN hamartoma PTEN Colon cancer Breast cancer Large head circumference | syndrome Gastric cancer Thyroid cancer Characteristic benign skin | Small bowel cancer Kidney cancer =e i cecal | Gastrointestinal Endometrial cancer hamartomatous polyps Sin (ndlanaztia) | | Serrated polyposis Unknown Colon cancer No current evidence for extra | syndrome colonic surveillance Serrated lesions FAP = familial adenomatous polyposis; SCTAT = sex cord tumor with annular tubules. 49

Colorectal Neoplasia TABLE 28. Criteria for Lynch Syndrome adenomas greater than 6 mm; an increase in the number of polyps; adenoma with high-grade dysplasia; and multiple Amsterdam II Criteria Revised Bethesda Criteria? diminutive polyps, which can prevent identification of adeno- 23 relatives with Lynch- CRC diagnosed at age <50 years mas. The type of surgery depends on the polyp burden in the related tumor rectum. High rectal polyp burden typically necessitates total 22 generations affected Synchronous, metachronous Lynch- proctocolectomy with ileostomy or ileal anal pouch; other- related tumors independent of age wise, subtotal colectomy with ileorectal anastomoses may be 1 cancer diagnosed at CRC with MSI-high-like histologic age < 50 years features? at age <60 years possible. Postsurgical surveillance is yearly sigmoidoscopy for patients with an intact rectum and ileoscopy every 2 years for 1 relative a first-degree CRC diagnosed in individual with relative of the other two 21 first-degree relative with Lynch- those with an ileostomy. related tumor, if one was diagnosed at age <50 years MutYH-Associated Polyposis Familial adenomatous CRC diagnosed in individual with MutYH-associated polyposis (MAP) is an inherited syndrome polyposis excluded 22 first- or second-degree relatives characterized by fewer adenomas than classic FAP. MAP is with Lynch-related tumor, independent of age caused by mutations in the MutYH gene, a component of base

polyps; adenoma with high-grade dysplasia; and multiple Amsterdam II Criteria Revised Bethesda Criteria? diminutive polyps, which can prevent identification of adeno- 23 relatives with Lynch- CRC diagnosed at age <50 years mas. The type of surgery depends on the polyp burden in the related tumor rectum. High rectal polyp burden typically necessitates total 22 generations affected Synchronous, metachronous Lynch- proctocolectomy with ileostomy or ileal anal pouch; other- related tumors independent of age wise, subtotal colectomy with ileorectal anastomoses may be 1 cancer diagnosed at CRC with MSI-high-like histologic age < 50 years features? at age <60 years possible. Postsurgical surveillance is yearly sigmoidoscopy for patients with an intact rectum and ileoscopy every 2 years for 1 relative a first-degree CRC diagnosed in individual with relative of the other two 21 first-degree relative with Lynch- those with an ileostomy. related tumor, if one was diagnosed at age <50 years MutYH-Associated Polyposis Familial adenomatous CRC diagnosed in individual with MutYH-associated polyposis (MAP) is an inherited syndrome polyposis excluded 22 first- or second-degree relatives characterized by fewer adenomas than classic FAP. MAP is with Lynch-related tumor, independent of age caused by mutations in the MutYH gene, a component of base Tumors confirmed by excision repair. In this recessive condition, affected patients pathologic evaluation | inherited two mutated copies from their parents. Most patients

polyps; adenoma with high-grade dysplasia; and multiple Amsterdam II Criteria Revised Bethesda Criteria? diminutive polyps, which can prevent identification of adeno- 23 relatives with Lynch- CRC diagnosed at age <50 years mas. The type of surgery depends on the polyp burden in the related tumor rectum. High rectal polyp burden typically necessitates total 22 generations affected Synchronous, metachronous Lynch- proctocolectomy with ileostomy or ileal anal pouch; other- related tumors independent of age wise, subtotal colectomy with ileorectal anastomoses may be 1 cancer diagnosed at CRC with MSI-high-like histologic age < 50 years features? at age <60 years possible. Postsurgical surveillance is yearly sigmoidoscopy for patients with an intact rectum and ileoscopy every 2 years for 1 relative a first-degree CRC diagnosed in individual with relative of the other two 21 first-degree relative with Lynch- those with an ileostomy. related tumor, if one was diagnosed at age <50 years MutYH-Associated Polyposis Familial adenomatous CRC diagnosed in individual with MutYH-associated polyposis (MAP) is an inherited syndrome polyposis excluded 22 first- or second-degree relatives characterized by fewer adenomas than classic FAP. MAP is with Lynch-related tumor, independent of age caused by mutations in the MutYH gene, a component of base Tumors confirmed by excision repair. In this recessive condition, affected patients pathologic evaluation | inherited two mutated copies from their parents. Most patients Lynch-related tumors include colorectal, endometrial, gastric, ovarian, pancreatic, have 20 to 99 adenomatous colon polyps. Some individuals can ureter and renal pelvis, biliary tract, brain, and small bowel cancer. Also included develop cancer with only a few or no synchronous adenomas. are sebaceous gland adenomas and keratocanthomas in Muir-Torre syndrome. Mean age at cancer onset is about 52 years. In addition, patients CRC = colorectal cancer; MSI = microsatellite instability. with MAP can have other polyp types, including serrated “Tumors should be tested for MSI, or genetic testing may be considered if criteria are met. lesions and hyperplastic polyps. Duodenal cancer risk in MAP

Lynch-related tumors include colorectal, endometrial, gastric, ovarian, pancreatic, have 20 to 99 adenomatous colon polyps. Some individuals can ureter and renal pelvis, biliary tract, brain, and small bowel cancer. Also included develop cancer with only a few or no synchronous adenomas. are sebaceous gland adenomas and keratocanthomas in Muir-Torre syndrome. Mean age at cancer onset is about 52 years. In addition, patients CRC = colorectal cancer; MSI = microsatellite instability. with MAP can have other polyp types, including serrated “Tumors should be tested for MSI, or genetic testing may be considered if criteria are met. lesions and hyperplastic polyps. Duodenal cancer risk in MAP ®>MSI-high-like histologic features include presence of tumor infiltrating lymphocytes, is estimated at 4%, and surveillance with upper endoscopy is Crohn-like lymphocytic reaction, mucinous or signet-ring differentiation, and similar to that indicated in patients with FAP. Surgical manage- medullary growth pattern. ment of the colon is also similar to that of FAP.

®>MSI-high-like histologic features include presence of tumor infiltrating lymphocytes, is estimated at 4%, and surveillance with upper endoscopy is Crohn-like lymphocytic reaction, mucinous or signet-ring differentiation, and similar to that indicated in patients with FAP. Surgical manage- medullary growth pattern. ment of the colon is also similar to that of FAP. 30 years and include visualization of the papilla with a duo- Other Adenomatous Polyposis Syndromes denoscope. Fundic gland polyps in the stomach should be Several recently described rare polyposis syndromes are inher- randomly sampled. Surveillance of the upper gastrointestinal ited in an autosomal dominant manner. Polymerase proof- tract is determined by duodenal findings. Annual thyroid reading associated polyposis appears to have features of both ultrasonography is also recommended. FAP and Lynch syndrome and is caused by mutations in poly- Colectomy is the treatment of choice for classic FAP and merase proofreading genes POLE and POLD1. Endometrial may be pursued in patients with AFAP. Absolute indications cancer has been described in this syndrome, and tumor testing for surgery include cancer and significant symptoms, such shows microsatellite instability. Mutations in GREM1 have as rectal bleeding. Relative indications include multiple also been associated with hereditary polyposis. Management FIGURE 26. Intestinal features of familial adenomatous polyposis (FAP). Duodenal adenomas can also develop, especially involving the ampulla of Vater, and evolve into

30 years and include visualization of the papilla with a duo- Other Adenomatous Polyposis Syndromes denoscope. Fundic gland polyps in the stomach should be Several recently described rare polyposis syndromes are inher- randomly sampled. Surveillance of the upper gastrointestinal ited in an autosomal dominant manner. Polymerase proof- tract is determined by duodenal findings. Annual thyroid reading associated polyposis appears to have features of both ultrasonography is also recommended. FAP and Lynch syndrome and is caused by mutations in poly- Colectomy is the treatment of choice for classic FAP and merase proofreading genes POLE and POLD1. Endometrial may be pursued in patients with AFAP. Absolute indications cancer has been described in this syndrome, and tumor testing for surgery include cancer and significant symptoms, such shows microsatellite instability. Mutations in GREM1 have as rectal bleeding. Relative indications include multiple also been associated with hereditary polyposis. Management FIGURE 26. Intestinal features of familial adenomatous polyposis (FAP). Duodenal adenomas can also develop, especially involving the ampulla of Vater, and evolve into adenocarcinoma (left). If a patient with FAP has had surgery and has an ileorectal anastomosis, rectal polyps can develop in the remaining rectum (center). Numerous fundic gland polyps of the stomach can develop in FAP; these polyps have minimal malignant potential but can obscure the presence of gastric adenomas (right, arrows). 50

Colorectal Neoplasia FIGURE 29. Peutz-Jeghers syndrome is associated with distinctive mucocutaneous pigmentations. The pigmented lesions occur most commonly on the lips and perioral region but can also occur on the nose, perianal area, and genitals. FIGURE 27. Endoscopic view of juvenile polyps (arrows) in the colon of a patient with juvenile polyposis syndrome. Juvenile polyps can have an erythematous and waxy appearance. Multiple juvenile polyps (+5 polyps) are found in the colon (98%), stomach (14%), and small bowel (14%) of patients with guidelines are not established, but management of colonic JPS (Figure 27). Sporadic juvenile polyps can be found in up to polyps follows similar principles as for other adenomatous 1% of children and are not considered syndromic. The average polyp syndromes. age at JPS diagnosis is 18.5 years, and rectal bleeding is the most common symptom. Hamartomatous Polyposis Syndromes PJS is caused by mutations in the STK11 (LKB1) gene. Its Hamartomas are polyps caused by overgrowth of normal tis- incidence is approximately 1 in 200,000 live births. PJS hamar- sue. Three primary syndromes are associated with hamarto tomas are found primarily in the small bowel but can also mas in the gastrointestinal tract: juvenile polyposis syndrome develop in the stomach and colon (Figure 28). PJS is also char- (JPS), Peutz-Jeghers syndrome (PJS), and PTEN hamartoma acterized by hyperpigmented mucocutaneous macules on the syndrome (also known as Cowden syndrome). lips and buccal mucosa (Figure 29). Small-bowel hamartomas JPS is caused by mutations in the BMPR1A and SMAD4 develop at a young age in patients with PJS and may present genes. Its incidence is approximately 1 in 130,000 live births. with intussusception, obstruction, and bleeding.

FIGURE 29. Peutz-Jeghers syndrome is associated with distinctive mucocutaneous pigmentations. The pigmented lesions occur most commonly on the lips and perioral region but can also occur on the nose, perianal area, and genitals. FIGURE 27. Endoscopic view of juvenile polyps (arrows) in the colon of a patient with juvenile polyposis syndrome. Juvenile polyps can have an erythematous and waxy appearance. Multiple juvenile polyps (+5 polyps) are found in the colon (98%), stomach (14%), and small bowel (14%) of patients with guidelines are not established, but management of colonic JPS (Figure 27). Sporadic juvenile polyps can be found in up to polyps follows similar principles as for other adenomatous 1% of children and are not considered syndromic. The average polyp syndromes. age at JPS diagnosis is 18.5 years, and rectal bleeding is the most common symptom. Hamartomatous Polyposis Syndromes PJS is caused by mutations in the STK11 (LKB1) gene. Its Hamartomas are polyps caused by overgrowth of normal tis- incidence is approximately 1 in 200,000 live births. PJS hamar- sue. Three primary syndromes are associated with hamarto tomas are found primarily in the small bowel but can also mas in the gastrointestinal tract: juvenile polyposis syndrome develop in the stomach and colon (Figure 28). PJS is also char- (JPS), Peutz-Jeghers syndrome (PJS), and PTEN hamartoma acterized by hyperpigmented mucocutaneous macules on the syndrome (also known as Cowden syndrome). lips and buccal mucosa (Figure 29). Small-bowel hamartomas JPS is caused by mutations in the BMPR1A and SMAD4 develop at a young age in patients with PJS and may present genes. Its incidence is approximately 1 in 130,000 live births. with intussusception, obstruction, and bleeding. FIGURE 28. Peutz-Jeghers syndrome (PJS) polyps. Capsule endoscopy showing a PJS hamartomatous polyp in the small intestine (/e/t); polyps in the small intestine can cause bleeding and/or obstructions. Colonoscopy showing a hamartomatous polyp in the colon of a patient with PJS (right).

FIGURE 29. Peutz-Jeghers syndrome is associated with distinctive mucocutaneous pigmentations. The pigmented lesions occur most commonly on the lips and perioral region but can also occur on the nose, perianal area, and genitals. FIGURE 27. Endoscopic view of juvenile polyps (arrows) in the colon of a patient with juvenile polyposis syndrome. Juvenile polyps can have an erythematous and waxy appearance. Multiple juvenile polyps (+5 polyps) are found in the colon (98%), stomach (14%), and small bowel (14%) of patients with guidelines are not established, but management of colonic JPS (Figure 27). Sporadic juvenile polyps can be found in up to polyps follows similar principles as for other adenomatous 1% of children and are not considered syndromic. The average polyp syndromes. age at JPS diagnosis is 18.5 years, and rectal bleeding is the most common symptom. Hamartomatous Polyposis Syndromes PJS is caused by mutations in the STK11 (LKB1) gene. Its Hamartomas are polyps caused by overgrowth of normal tis- incidence is approximately 1 in 200,000 live births. PJS hamar- sue. Three primary syndromes are associated with hamarto tomas are found primarily in the small bowel but can also mas in the gastrointestinal tract: juvenile polyposis syndrome develop in the stomach and colon (Figure 28). PJS is also char- (JPS), Peutz-Jeghers syndrome (PJS), and PTEN hamartoma acterized by hyperpigmented mucocutaneous macules on the syndrome (also known as Cowden syndrome). lips and buccal mucosa (Figure 29). Small-bowel hamartomas JPS is caused by mutations in the BMPR1A and SMAD4 develop at a young age in patients with PJS and may present genes. Its incidence is approximately 1 in 130,000 live births. with intussusception, obstruction, and bleeding. FIGURE 28. Peutz-Jeghers syndrome (PJS) polyps. Capsule endoscopy showing a PJS hamartomatous polyp in the small intestine (/e/t); polyps in the small intestine can cause bleeding and/or obstructions. Colonoscopy showing a hamartomatous polyp in the colon of a patient with PJS (right). 51