NCCN Categories of Evidence and Consensus

Category 1: The recommendation is based on high-level evidence (e.g., randomized controlled trials) and there is uniform NCCN consensus.

Category 2A: The recommendation is based on lower-level evidence and there is uniform NCCN consensus.

Category 2B: The recommendation is based on lower-level evidence and there is nonuniform NCCN consensus (but no major disagreement).

Category 3: The recommendation is based on any level of evidence but reflects major disagreement.

Colonoscopy

Colonoscopy is the most complete screening procedure, allowing the entire large bowel to be examined and polyps to be removed in one session. It is currently the preferred screening method and also the required procedure for confirming positive findings from other tests. Colonoscopy is also considered the current gold standard for assessing the efficacy of other screening methods. Although no randomized controlled trials directly show mortality reduction with colonoscopy, findings from case-control and cohort studies show significant impact of colonoscopy and polypectomy on CRC incidence, estimated at a more than 50% reduction.^4–6

View Full Size

NCCN Clinical Practice Guidelines in Oncology: Colorectal Cancer Screening

Version 1.2010, 10-23-09 ©2010 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 8, 1; 10.6004/jnccn.2010.0003

View Full Size

NCCN Clinical Practice Guidelines in Oncology: Colorectal Cancer Screening

Version 1.2010, 10-23-09 ©2010 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 8, 1; 10.6004/jnccn.2010.0003

View Full Size

NCCN Clinical Practice Guidelines in Oncology: Colorectal Cancer Screening

Version 1.2010, 10-23-09 ©2010 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 8, 1; 10.6004/jnccn.2010.0003

View Full Size

NCCN Clinical Practice Guidelines in Oncology: Colorectal Cancer Screening

Version 1.2010, 10-23-09 ©2010 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 8, 1; 10.6004/jnccn.2010.0003

View Full Size

NCCN Clinical Practice Guidelines in Oncology: Colorectal Cancer Screening

Version 1.2010, 10-23-09 ©2010 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 8, 1; 10.6004/jnccn.2010.0003

View Full Size

NCCN Clinical Practice Guidelines in Oncology: Colorectal Cancer Screening

Version 1.2010, 10-23-09 ©2010 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 8, 1; 10.6004/jnccn.2010.0003

View Full Size

NCCN Clinical Practice Guidelines in Oncology: Colorectal Cancer Screening

Version 1.2010, 10-23-09 ©2010 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 8, 1; 10.6004/jnccn.2010.0003

View Full Size

NCCN Clinical Practice Guidelines in Oncology: Colorectal Cancer Screening

Version 1.2010, 10-23-09 ©2010 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 8, 1; 10.6004/jnccn.2010.0003

View Full Size

NCCN Clinical Practice Guidelines in Oncology: Colorectal Cancer Screening

Version 1.2010, 10-23-09 ©2010 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 8, 1; 10.6004/jnccn.2010.0003

View Full Size

NCCN Clinical Practice Guidelines in Oncology: Colorectal Cancer Screening

Version 1.2010, 10-23-09 ©2010 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 8, 1; 10.6004/jnccn.2010.0003

View Full Size

NCCN Clinical Practice Guidelines in Oncology: Colorectal Cancer Screening

Version 1.2010, 10-23-09 ©2010 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 8, 1; 10.6004/jnccn.2010.0003

View Full Size

NCCN Clinical Practice Guidelines in Oncology: Colorectal Cancer Screening

Version 1.2010, 10-23-09 ©2010 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 8, 1; 10.6004/jnccn.2010.0003

View Full Size

NCCN Clinical Practice Guidelines in Oncology: Colorectal Cancer Screening

Version 1.2010, 10-23-09 ©2010 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 8, 1; 10.6004/jnccn.2010.0003

View Full Size

NCCN Clinical Practice Guidelines in Oncology: Colorectal Cancer Screening

Version 1.2010, 10-23-09 ©2010 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 8, 1; 10.6004/jnccn.2010.0003

View Full Size

NCCN Clinical Practice Guidelines in Oncology: Colorectal Cancer Screening

Version 1.2010, 10-23-09 ©2010 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 8, 1; 10.6004/jnccn.2010.0003

View Full Size

NCCN Clinical Practice Guidelines in Oncology: Colorectal Cancer Screening

Version 1.2010, 10-23-09 ©2010 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 8, 1; 10.6004/jnccn.2010.0003

View Full Size

NCCN Clinical Practice Guidelines in Oncology: Colorectal Cancer Screening

Clinical trials: The NCCN believes that the best management for any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. All recommendations are category 2A unless otherwise noted.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 8, 1; 10.6004/jnccn.2010.0003

In a recent Canadian case-control study that matched each of 10,292 individuals who died of CRC to 5 controls, colonoscopy was associated with lower mortality from left-sided CRC (adjusted conditional odds ratio [OR], 0.33; 95% CI, 0.28–0.39) but not right-sided (OR, 0.99; CI, 0.86–1.14).⁷ Part of this finding may be related to significant variation in the quality of this widely used procedure within the community, which can lead to variable effectiveness.^8,9 The quality indicators of colonoscopy (e.g., withdrawal times) and minimum requirements of a colonoscopy report are listed on pages 16 and 17. Recommendations made by the panel are based on the premise of complete, high-quality colonoscopies, as reflected by colonoscopy to cecum, rectal retroflexion, excellent preparation or endoscopic clearing of residual stool, sufficient distention and full 360° view of front and back side of all folds, withdrawal time longer than 10 minutes, and complete excision of polyps (may require extra snare/biopsy or cautery after initial polypectomy).

An optimal screening protocol should have an interval during which there is a low likelihood of developing cancer and be cost-effective based on the duration of risk reduction after an initial negative colonoscopy. The general consensus is that a 10-year interval is appropriate for most individuals (averagerisk), although shorter intervals may be indicated depending on the completeness and quality of the colonoscopy. The panel emphasizes the importance of family history in the screening scheme. Individual risk factors, the number or characteristics of polyps found, and physician judgment should also be included in the interval determination. A 1996 study reported that 27% of individuals had adenomatous polyps identified on repeat colonoscopy a mean of 66 months after an initial negative colonoscopy.¹⁰ Only 1 of 154 individuals had a polyp 1 cm or larger. These results suggest that an interval of repeat colonoscopy after an initial negative colonoscopy beyond 5 years is safe.

Imperiale et al.¹¹ reported on 2436 individuals with no adenomas at baseline colonoscopy. No cancers were found at rescreening at a mean of 5.3 years later. Adenomas were identified in 16%, and only 1.3% had advanced adenomas. The authors recommended a rescreening interval of 5 years or longer. Lieberman et al.¹² reported that advanced adenomas were found in only 2.4% of individuals on repeat colonoscopy within 5.5 years after a baseline normal colonoscopy. In this study, individuals with adenomatous polyps smaller than 1 cm at baseline also had a low rate of developing advanced neoplasia.

Further studies have evaluated the durability of risk reduction 10 years after an endoscopic evaluation. In an early study evaluating the value of rigid sigmoidoscopy for CRC screening, individuals who underwent rigid sigmoidoscopy within 10 years before being diagnosed with colon cancer were compared with a cohort of matched controls.¹³ The negative association was 0.41 risk reduction (95% CI, 0.25–0.69) in the proctosigmoidoscopy group. In a population-based retrospective analysis using a physician billing claims database of individuals who underwent a screening colonoscopy, Singh et al.¹⁴ also assessed the time that risk reduction persists after colonoscopy. They compared incidence of CRC among patients in the surveillance cohort with that in the general population. A negative colonoscopy was associated with a standardized incidence ratio of 0.28 (95% CI, 0.09–0.65) at 10 years.

A similar study calculated the adjusted relative risk for CRC among subjects who had a previous negative colonoscopy;¹⁵ the adjusted OR was 0.26 (95% CI, 0.16–0.40). The low risk was seen even if the colonoscopy had been performed up to 20 or more years previously. In a study of 564 participants, Robertson et al.¹⁶ recently reported that combining results of 2 prior colonoscopies can help predict the likelihood of high-risk findings (advanced adenomas or cancers) on the third screen.

Flexible Sigmoidoscopy

Flexible sigmoidoscopy followed by colonoscopic polypectomy significantly reduced mortality risk in earlier case-control studies.^6,17 Currently, 4 randomized studies are ongoing in the United States and Europe.^18–21 Compared with colonoscopy, this technique requires no sedation and less bowel preparation, but is limited to examination of the lower half of the colon tract. Flexible sigmoidoscopy should be performed using a scope 60 cm or longer. Polyps identified should be biopsied by trained personnel to determine if they are hyperplastic, adenomatous, or sessile serrated polyps (SSP; flat adenomas are unusual and may be missed during colonoscopy). Patients with lesions larger than 1 cm should be referred directly for a colonoscopy, because these lesions are almost always adenomas associated with a risk for proximal colonic neoplasms.

Double-Contrast Barium Enema

The availability of and physicians' experience with double-contrast barium enema are decreasing. This technique is typically only used as an alternative for patients who cannot undergo colonoscopy.

CT Colonography

CT colonography (CTC; see page 17), also known as virtual colonoscopy, is evolving as a promising technique for CRC screening. CTC has the advantages of being noninvasive and not requiring sedation, and the risk for test-related complications is very low. However, a positive finding requires a colonoscopy, and extra-colonic findings—which are present in up to 16% of patients—pose a dilemma.^22,23 These findings require further investigation and have a potential for benefit and harm. Data are currently insufficient to determine the clinical impact of these findings.

The recently completed National CT Colonography Trial (ACRIN 6664) organized by the American College of Radiology assessed the accuracy of CTC in detecting polyps or cancers measuring 10 mm or more.²⁴ Among the 2531 patients participating in the study, 128 large adenomas or carcinomas were found in 109. CTC detected polyps or cancers in 90% of patients who had lesions measuring 10 mm or larger found with colonoscopy. There were 18 lesions found on CTC, but not colonoscopy, for which a subsequent colonoscopy was performed; 5 of these lesions were confirmed to include 4 adenomas and 1 inflammatory polyp. CTC performance in this study was better than that reported in earlier studies^25,26 and similar to what was reported by Pickhardt et al.²⁷

In 2005, 2 meta-analysis reviewed the performance of CTC for detecting colorectal polyps.^28,29 In one meta-analysis, CTC showed high average sensitivity (93%) and specificity (97%), both of which decreased to 86% when medium polyps were included in the analysis. The sensitivity of CTC was heterogenous but improved as the polyp size increased in another meta-analysis (48% for polyps < 6 mm, 70% for those 6–9 mm, and 85% for those > 9 mm). The specificity was uniform (92%) for detection of all the polyps. Kim et al.³⁰ compared CTC with colonoscopy for detecting advanced neoplasia. Although this study was not randomized, detection rates were comparable between the groups (3.2% for CTC and 3.4% for colonoscopy).

The technical aspects of CTC, including imaging, preprocedure preparation, use of stool tagging, and expertise of the interpreter, differ among studies and have not been standardized. Long-term follow-up studies of patients screened with CTC are not yet available.

The issue of radiation exposure also requires consideration. The reported dose of radiation exposure during CTC is approximately 10 mSv. The precise risk from life-long screening cannot be estimated, but experts have suggested that 1 additional person in 1000 would develop cancer in a lifetime after being exposed to radiation at the dose used for CTC.³¹

Available data indicate that CTC may be useful for detecting larger polyps. However, this technique is still evolving in terms of screening intervals, polyp size leading to referral for colonoscopy, and protocol for evaluating extracolonic lesions. The best evidence currently available seems to support repeating the procedure every 5 years and referring patients with identified polyps larger than 5 mm to colonoscopy. The panel views colonoscopy as the preferred screening modality, and there is no consensus on the use of CTC as a primary screening tool.

Fecal Occult Blood Test

Two fecal occult blood tests (FOBT) are currently available: guaiac-based and immunochemical. These may be used alone annually or in combination with flexible sigmoidoscopy. Based on the pseudoperoxidase activity of heme in human blood, guaiac FOBT is the most common stool test for CRC screening. A meta-analysis of 4 randomized controlled trials involving more than 320,000 participants showed a 16% reduction in relative risk for CRC death with guaiac FOBT screening (95% CI, 0.78–0.90).³² In a study of approximately 8000 candidates, Allison et al.³³ showed that the sensitivity of different guaiac FOBT for detecting cancer ranged from 37% to 79%. The technique currently recommended is Hemoccult II SENSA, which is the most sensitive and reader-friendly. One major disadvantage of the guaiac FOBT is that it may miss tumors that bleed in smaller amounts, intermittently, or not at all. To compensate for intermittent bleeding, guaiac FOBTs should be performed on 3 successive stool specimens obtained while the patient adheres to a prescribed diet. Another limitation is the high false-positive rate resulting from reaction with non-human heme in food and blood from the upper gastrointestinal tract.

The fecal immunochemical test (FIT), approved by the FDA in 2001, directly detects human globin within hemoglobin. Unlike guaiac FOBT, FIT does not require dietary restrictions and a single testing sample is sufficient. However, sensitivity (25%–72%) and specificity (59%–97%) vary widely, as illustrated by a recent German study that assessed 6 different FIT methods on 1319 participants.³⁴ Comparative studies generally show that detection rates for FIT are comparable, if not superior, to guaiac FOBT depending on the test used. For example, in the study by Allison et al.,³³ FIT had a sensitivity of 69% for cancer, which was between that for Hemoccult II and Hemoccult II Sensa. An update study by the same group showed that a newer FIT had a higher sensitivity for detecting cancer than Hemoccult Sensa (82% vs. 64%). A recent Dutch randomized study also showed that FIT had higher detection rates for advanced neoplasia (2.4%) than guaiac FOBT (1.1%), although both were less reliable than flexible sigmoidoscopy (8.0%).³⁵

To ensure adequate follow-up, health care professionals should coordinate FOBT testing so that patients with positive results enter the health care system in a responsible way. FOBT of a single specimen obtained at digital rectal examination is not recommended because of exceptionally low sensitivity.^36,37

Stool DNA Test

Stool DNA test is an emerging screening tool for CRC. It detects the presence of known DNA alterations during colorectal carcinogenesis in tumor cells sloughed into stool. Early proof-of-principle tests involving single-target markers such as K-ras produced less than 40% sensitivity.³⁸ To improve sensitivity, newer tests with multipanel markers were developed. In a large multicenter study of 4404 patients, eligible subjects submitted 1 stool specimen for DNA analysis, underwent standard Hemoccult II testing, and then had a colonoscopy.³⁹ In a subgroup analysis, the multitarget DNA assay SDT-1 (21 mutations) detected 52% of CRC compared with 13% by Hemoccult at specificities of 94% and 95%, respectively. The SDT-1 assay did not perform as well in another large multicenter, prospective, triple-blinded trial that also assessed a second-generation combination test: SDT-2 (APC, K-ras, and vimentin methylation).⁴⁰ A total of 3764 average-risk healthy adults underwent screening colonoscopy, Hemoccult, Hemoccult Sensa, SDT-1, and SDT-2. The sensitivities of SDT-1 and Hemoccult Sensa were very similar for screen-relevant neoplasms (20% and 21%, respectively), whereas the sensitivity of SDT-2 was 40%.

For individuals unwilling or unable to have screening colonoscopy, increasing evidence shows that a stool DNA test may provide a valuable noninvasive option. However, stool DNA has not yet been approved by the FDA and is currently not considered a first-line screening tool. More research is also necessary to determine the optimal testing interval.

Average Risk

Individuals at average risk for developing CRC are those 50 years or older with no history of adenoma, CRC, or inflammatory bowel disease, and a negative family history.

Increased Risk

Individuals with personal history of adenomas/SSP, CRC, or inflammatory bowel disease, and those with a positive family history of CRC or advanced adenomas are considered at increased risk for developing CRC.

High-Risk Syndromes

Individuals with family history of Lynch syndrome (also known as hereditary nonpolyposis colorectal cancer [HNPCC]), or personal or family history of polyposis syndromes are considered high-risk.

Interpretation of Findings

Colonoscopy is indicated as follow-up of abnormal findings from other screening modalities, such as stool tests, flexible sigmoidoscopy (biopsy-proven adenoma), CTC, and double-contrast barium enema. During colonoscopy, any polyps found should be removed, and follow-up strategies should be based on the endoscopic and pathologic findings. Special attention should be given to polyps on the right side of the colon tract, because these tend to be associated with microsatellite instability (MSI) and hence greater cancer risk that warrants additional surveillance.

Adenoma/Adenomatous Polyps: Adenomas or adenomatous polyps (most often found to be tubular), the most common form of polyps, are associated with an increased risk for CRC (see Individuals at Increased Risk, opposite column). Villous adenomas have a greater chance of harboring cancer and having adenomas or cancer found on follow-up.

SSP and Flat Adenoma: SSP, also known as sessile serrated adenomas, are rare forms of polyps associated with adenocarcinoma. The pathologic classification is currently controversial and guidelines for screening these polyps are not clearly established. Patients with SSP may need more frequent screening than those with hyperplastic polyps. Pending additional data, individuals with SSP should be treated following the same guidelines for those with adenomas.

Flat adenomas are unusual and can be easily missed during colonoscopy because they are not protruding from the colon wall.⁴¹ More prospective studies are required to clarify their contribution to CRC risk. Meanwhile, all identified flat adenomas should be removed and patients should undergo routine post-adenoma follow-up.

Hyperplastic Polyps: A large body of literature indicates that hyperplastic polyps are not associated with significantly increased risk for CRC, and supports the recommendation that persons with hyperplastic polyps be screened as average risk. Recent literature, however, suggests that a small subset of persons with multiple or large hyperplastic polyps—the hyperplastic polyposis syndrome (HPP; see page 42 for definition)—have a 26% to 70% risk for developing CRC.^42–44 Most of these had concomitant adenomas or SSP.⁴⁵ Additionally, evidence suggests that some cancers with extensive DNA methylation and MSI might derive from hyperplastic polyps.⁴⁶

Based on these observations, all hyperplastic polyps larger than 5 mm should be removed during the initial colonoscopy and polypectomy session, and patients should undergo colonoscopy every 1 to 3 years thereafter. Ideally, all detected polyps should be removed, but this is not always possible. Removed polyps should also be examined for degree of dysplasia and histologic features of SSP. HPP is rarely reported to be inherited, and the risk for developing CRC in individuals with affected relatives remains unclear.

Personal History of Adenoma/SSP

Individuals with adenomas are at increased risk for developing recurrent adenomas and CRC. To minimize risk for developing CRC, a surveillance program is recommended after screening colonoscopy and complete polypectomy.⁴⁷ For patients with a completely resected adenomatous polyp, the surveillance schedule depends on risk for recurrence, which is in turn related to the number of adenomatous polyps and their size and histology.

Low-risk adenomas are tubular, 2 or fewer in number, and smaller than 1 cm. In this group, colonoscopy should be repeated within 5 years. Emerging data suggest that longer intervals are usually appropriate. If this examination is normal, colonoscopy should be repeated every 5 to 10 years.

Advanced or multiple adenomas (3–10 polyps, ≥ 10 mm, with > 25% villous histology or high-grade dysplasia) have been associated with increased risk. High-grade dysplasia is defined as an adenoma that shows features of severe dysplasia (marked reduction of interglandular stromas with complex irregularity of glands, papillary infolding, and cytogenetic abnormalities) or carcinoma in situ (severe architectural disturbance of glands along with cytologic features of dysplasia).⁴⁸ Carcinoma in situ is a term previously used by pathologists to describe colon polyps and cancer, and is currently being replaced by the term high-grade dysplasia. A study by Golembeski et al.⁴⁹ showed that identification of villous architecture and high-grade dysplasia is associated with poor reproducibility among pathologists.

Because studies have used 1 cm as the standard measure, data are lacking on the relative significance of intermediate-sized adenomas (5–10 mm). Individuals with high-risk adenomas are recommended to repeat colonoscopy within 3 years. Subsequent surveillance colonoscopies are recommended within 5 years, depending on colonoscopic findings. Longer intervals are recommended for persons with normal follow-up colonoscopies. Reassessing risk, including contributing medical and personal factors, number and characteristics of adenomas, and family history, is appropriate at each interval before and after procedures.

Individuals with more than 10 cumulative adenomas are recommended to undergo evaluation for a polyposis syndrome, although only a small fraction of those with no family history and low adenoma burden will have a defined hereditary syndrome. Fewer than 10 polyps may infrequently be associated with an inherited polyposis syndrome, especially in patients younger than 40 years or with a strong family history. Hence, a detailed family history is crucial in patients with multiple adenomas. Individual management is emphasized.

Polypectomy of large sessile polyps is associated with a high rate of recurrence, attributed to the presence of residual adenoma tissue at polypectomy.⁵⁰ Hence, follow-up colonoscopy within 2 to 6 months is appropriate, or when polypectomy is incomplete or involves removal of large sessile polyps.

The NCCN Clinical Practice Guidelines in Oncology: Colon Cancer (to view the most recent version of these guidelines, visit the NCCN Web site at www.NCCN.org) provide suggestions for management if a malignant polyp is found at colonoscopy.

Personal History of CRC

Individuals with a personal history of CRC who underwent colonic resection with curative intent are at increased risk for recurrent adenomas and cancer. The recommendation for intensive surveillance immediately after resection is based on studies that found a high recurrence rate in the 4 to 5 years after CRC resections.^51–54

An analysis of 3278 patients with resected stage II and III CRC found that recurrence rate is especially high in the immediate 5 years after surgery, suggesting that intense surveillance be considered during that period (Intergroup 0089 study).⁵¹ However, the studies did not exclude patients with Lynch syndrome who are at greater than 30% risk for synchronous and metachronous cancers. The guidelines recommend a complete colonoscopy preoperatively and at 1 year after surgery (within 3–6 months if preoperative colonoscopy was incomplete). If this examination is normal, colonoscopy should be repeated in 2 to 3 years. Shorter intervals (1–3 years) are recommended if adenomas or SSP are found. Subsequent colonoscopic intervals are individualized and generally should not exceed 5 years.

Patients with rectal cancer should also undergo periodic rigid or flexible sigmoidoscopy of the rectal anastomosis to identify local recurrence. Expert opinion supports repeat evaluation every 3 to 6 months for the first 2 to 3 years. The usefulness of routine endoscopic ultrasound for early surveillance is not defined.

Inflammatory Bowel Disease

Individuals with a personal history of inflammatory bowel disease are known to be at increased risk for developing CRC. Screening with colonoscopy every 1 to 2 years should be initiated 8 to 10 years after the onset of symptoms and be performed by an endoscopist who is familiar with the appearance of ulcerative colitis or Crohn's disease. When the disease is clinically quiescent, multiple 4-quadrant biopsies (every 10 cm with ≥ 30 samples) should be taken for histologic examination using large-cup forceps. Strictures, particularly those in ulcerative colitis, that are suggestive should be evaluated thoroughly using biopsy and brush cytology. Any masses, including so-called “dysplasia-associated” lesions, are of extreme concern. Endoscopic polypectomy should be performed when appropriate with biopsies of surrounding mucosa to assess dysplasia.

Interpretation of dysplasia or intraepithelial neoplasia can be difficult. Pathologists experienced in interpreting inflammatory bowel disease lesions should evaluate biopsies. Most findings of high-grade, multifocal, or repeat low-grade dysplasia place patients with ulcerative colitis at high-risk for developing CRC. Prophylactic proctocolectomy with ileoanal anastomosis is preferred. These individuals should be referred to a surgeon experienced in inflammatory bowel disease to discuss surgical options. See page 18 for common colorectal resections.

Family History

Family history is the most important risk factor for CRC. A detailed family history must be obtained, including first-degree relatives (parents, siblings, and offspring), second-degree relatives (aunts, uncles, grandparents, and half-siblings), and other relatives with cancer (cousins, great-grandparents, nieces, and nephews). Sometimes a great deal of information can be obtained by looking at first cousins. Grandchildren are often not old enough to manifest any of the clinical phenotypes of cancer syndromes.

For each relative, current age and age at diagnosis of any cancer; availability of a tumor sample; or date, age, and cause of death are very important in discerning whether relatives were at risk for developing cancer, how long they were at risk, and what type of cancer they had. It is particularly important to note the occurrence of multiple primary tumors. Other inherited conditions and birth defects should be included in this family history. Ethnicity and country of origin are also important.

Positive Family History: Individuals with 1 or more first-degree relative diagnosed with CRC are at increased risk for developing the malignancy (see page 15). Colonoscopy every 5 years beginning at 40 years of age is recommended for those with a first-degree relative diagnosed with CRC between 50 and 60 years. If the relative was diagnosed at 60 years of age or older, screening should begin at 50 years and repeated every 5 years. The same screening schedule is recommended for individuals who have 2 second-degree relatives diagnosed with CRC at any age.

For individuals with 1 first-degree relative diagnosed with CRC before 50 years of age or 2 diagnosed with CRC at any age, screening colonoscopy is recommended beginning at 40 years, or 10 years before earliest CRC in family, whichever is earlier. Screening interval will depend on other family history but should be between every 3 and 5 years. Additionally, this family history (or if any of the revised Bethesda criteria are met) suggests the possibility of Lynch syndrome (page 22), and immunohistochemical (IHC)/MSI testing on the colon tumor of the youngest affected family member is warranted.

Having a first-degree relative with advanced adenomas may confer similar CRC risk as having one with CRC. Similarly, having one with early-onset adenomas (< 40 years of age) may confer similar CRC risk as having one with early-onset CRC (< 50 years of age).

Persons who have a second-degree or any number of third-degree relatives with CRC, or individuals with a first-degree relative with nonadvanced adenomas are screened as average-risk individuals, with colonoscopy as the preferred method. However, individualized risk assessment is recommended and should include a careful family history to determine whether a familial clustering of cancers is present in the extended family.

In all cases, further risk evaluation and counseling as outlined on page 19 are required for patients who meet the criteria for an inherited CRC syndrome.

Molecular Workup

Genetic testing for Lynch syndrome is somewhat complicated because several different genes contribute to its development. MSI and IHC analysis of CRC specimens are frequently first used to identify individuals who might have Lynch syndrome (page 25).⁶⁴ IHC analysis is used to detect the protein expression of the 4 MMR genes in tumor tissue. If one of the genes is not expressed, then underlying dysfunction of that gene is indicated. Both MSI and IHC have false-negative rates of 5% to 10%. Some studies have shown that both IHC and MSI are cost-effective and useful for selecting high-risk patients who may have MLH1, MSH2, and MSH6 germline mutations.^65,66 However, conclusive data are not yet available on which strategy is optimal.^67–71

MSI analysis of colon cancer tissue is very sensitive but less specific than IHC testing. The classical Bethesda guidelines provide several criteria for testing colorectal tumors for MSI.⁷² The National Cancer Institute introduced the revised Bethesda guidelines in 2002 (see page 26) to clarify selection criteria for the MSI testing.⁷³ Bethesda guidelines are useful for determining which individuals should have MSI testing, leading to subsequent identification of MLH1 and MSH2 germline mutations. One study reported that MLH1 and MSH2 mutations were detected in 65% of patients with MSI of the colon cancer tissue who met the Bethesda criteria.⁷⁴

MSI test is particularly helpful when the family history is not strongly suggestive of Lynch syndrome. Families that meet the minimal criteria for consideration, such as diagnosis before the age of 50 years (but meet no other criteria), may not represent the disorder. Microsatellite stable tumors arising within a patient with disease onset at a young age is unlikely to represent the disorder. Proceeding with genetic testing in this setting will probably not yield informative results.

IHC analysis is usually performed for family members who meet the Amsterdam criteria I or II (page 27), because there is a 50% to 92% chance of identifying a mutation in 1 of the 4 MMR genes in these individuals.⁶⁴ The first version of the minimum criteria for clinical definition of HNPCC was introduced in 1991 (Amsterdam criteria), and these criteria were modified in 1999 (Amsterdam II criteria).⁷⁵ MMR gene mutations are found in 88% of patients with MSI-positive tumors and who meet the Amsterdam criteria.⁷⁶ Among patients with MSI-negative tumors, only 29% were found to have germline MMR gene mutations.

Genetic Testing

Some centers now perform IHC (and sometimes MSI) testing on all CRCs to determine which patients should undergo genetic testing for Lynch syndrome. The cost-effectiveness of this approach is uncertain. If Lynch syndrome is suspected based on the extended pedigree, an analysis of the tumor block for MSI provides diagnostic information and guidance on the likelihood of informative predictive testing. Screening for MSI is cost-effective for patients with newly diagnosed CRC and for the siblings and children of mutation carriers.⁷⁷

Mutations found within a family provide an opportunity to perform predictive testing for at-risk family members, which can prevent many unnecessary procedures. Genetic testing should be considered for at-risk family members when the family mutation is known (page 23). At-risk family members can be defined as first-degree relatives of an affected individual and/or proband. If a first-degree relative is unavailable or unwilling to be tested, more distant relatives should be offered testing for the known family mutation.

If the familial mutation is not known in an individual who meets the revised Bethesda guidelines, the management plan depends on the results of IHC staining and/or MSI analysis as outlined in page 22. Almost all tumors arising within the context of Lynch syndrome are microsatellite unstable. If tumor is available from the affected relative and shows abnormal IHC and/or high MSI, genetic testing for mutations should be considered (page 23). Testing should proceed in the following order: the gene mostly likely mutated according to IHC results (if available), MLH1 or MSH2, then MSH6 or PMS2. Those with normal IHC and/or low/stable MSI but do not meet the more stringent Amsterdam criteria should be monitored with colonoscopy based on individual risk assessment. If they meet the Amsterdam criteria or if tumor from an affected family member is not available, then genetic testing for MMR mutations is recommended.

Because of the challenges that exist with using MSI testing and IHC staining of tumor tissue, several computer models have been developed to predict detection of a priori risk for Lynch syndrome mutation.^78–80

For individuals who do not meet the revised Bethesda guidelines or Amsterdam criteria, individualized management should be considered based on the severity of family history.

Many other issues are involved in genetic counseling of individuals undergoing presymptomatic testing for cancer susceptibility. Many individuals elect not to undergo testing, and these individuals must be counselled to continue with increased surveillance.

Surveillance and Treatment Options

Individuals with Lynch syndrome are at an increased lifetime risk for developing CRC compared with the general population (80% vs. 6%, respectively), endometrial cancer (20%–60% vs. 3%, respectively), and other cancers (page 28).^81,82 Screening study data in the literature mainly concern colon and endometrial cancers. More data are needed to evaluate the risk and benefits of extracolonic cancer screening. If Lynch syndrome can be confirmed, colonoscopy is advised to start between ages 20 and 25 years, or 10 years younger than the youngest age at diagnosis in the family, whichever comes first, and be repeated every 1 to 2 years. This recommendation is based on a systematic review of data between 1996 and 2006 on the reduction in cancer incidence and mortality using colonoscopy.⁶³ For women, referral to a gynecologic oncologist should be considered to screen for endometrial and ovarian cancers. Total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAH/BSO) is an option for women who have completed childbearing. Because patients are also at increased risk for gastric and duodenal cancer, upper gastrointestinal endoscopy every 1 to 3 years based on findings starting at age 25 to 30 years should be considered.⁸³ The endoscopy session should include side-viewing examination for ampullary cancers. Annual urinalysis, which provides relative ease and low cost compared with other tests, should also be considered to screen for urothelial cancers. Because of the current lack of data, annual history and physical examination is appropriate for screening of other cancers (e.g., brain, pancreatic).

If there are no pathologic findings, continued screening is recommended. If the patient is not a candidate for routine screening, subtotal colectomy may be considered. This important feature often arises clinically because some people cannot undergo a colonoscopy or decline to have one on a regular basis.

Patients with confirmed adenocarcinoma should be treated following the appropriate NCCN disease-specific guidelines (see the NCCN Clinical Practice Guidelines in Oncology Table of Contents at www.NCCN.org).

For patients with adenomas, recommendations include endoscopic polypectomy with a follow-up colonoscopy every 1 to 2 years. This option depends on the tumor location and characteristics, surgical risk, and patient preference. If the adenomas identified cannot be endoscopically resected, or high-grade dysplasia is identified, total abdominal colectomy with an ileorectal anastomosis (IRA) is recommended (page 18). Because surgical management is evolving, the option of segmental or extended segmental colectomy is based on individual considerations and discussion of risks. These patients should be followed up with endoscopic rectal examination every 1 to 2 years.

When an individual tests negative for a known familial Lynch syndrome mutation and has no symptoms, they are no longer at a heightened cancer risk based on the mutation identified in their family. This does not mean they are at zero risk; rather they are at average risk, and routine screening is recommended.

Diagnosis: Classical Versus Attenuated FAP

Diagnosis of classical FAP is based on the presence of more than 100 polyps, or fewer polyps at younger ages, especially in patients with a family history of FAP.⁸⁴ When fully developed, patients exhibit hundreds to thousands of colonic adenomas. The life-time risk for cancer in individuals with classic FAP approaches 100% by 50 years of age. Most of the resulting cancers occur in the left colon. Family members are increasingly being diagnosed at adolescence through genetic testing for their specific familial mutation or through sigmoidoscopic screening in the second decade of life. Because cancer incidence rises dramatically early in the third decade, prophylactic proctocolectomy is usually indicated in the second decade.

Attenuated FAP is a recognized variant of FAP characterized by a later onset of disease and fewer adenomas, typically fewer than 100.⁸⁴ These adenomas are more prone to occur in the right colon and may take the form of diminutive sessile adenomas.⁸⁵ Phenotypic expression is often variable within families. The onset of CRC is typically delayed, but the incidence of cancer rises sharply after the age of 40 years and approaches 70% by 80 years of age.

Management of FAP includes early screening and colectomy or proctocolectomy after the onset of polyposis. Genetic testing can guide management of cancer risk in patients and their family members. It is important to note the distinction between individuals with a personal history of FAP and individuals who are considered at high risk based on a family history of FAP (but no symptoms or findings). This distinction makes a significant difference in clinical management. Again, at-risk family members can be defined as first-degree relatives of an affected individual and/or proband. If a first-degree relative is unavailable or unwilling to be tested, more distant relatives should be offered testing for the known family mutation.

Fundic gland polyps (FGP) occur in most patients with FAP, classical and attenuated, and often are too numerous to count. In FAP, FGPs usually have biallelic inactivation of the APC gene, and often display foci of dysplasia or microadenomas of the foveolar epithelium.⁸⁶ However, malignant progression in FGPs is uncommon and the lifetime risk for gastric cancer in patients with FAP in Western countries is reported to range from 0.5% to 1%. Endoscopic biopsies of FGP are not routinely recommended. However, the recommendation is to observe carefully for polyps that stand out because they have an irregular shape or texture or are large, suggesting adenomas. Removal of polyps in the antrum or immediate preantrum is also recommended, if possible. These are less common and often adenomas.

Surgical Options

Three different surgical options are available for individuals with classical and attenuated FAP (page 34).⁸⁷ The prime factors when choosing an operation for FAP are the personal and familial phenotype, including the rectal polyp burden and whether colon or rectal cancer is present at diagnosis (page 18). In patients presenting with the classical FAP phenotype, proctocolectomy, if possible, is the preferred procedure because it prevents both colon and rectal cancer.

Total Proctocolectomy With Ileal Pouch Anal Anastomosis: Total proctocolectomy with ileal pouch anal anastomosis (IPAA), usually with a temporary loop ileostomy, is offered to patients with classical FAP, those with attenuated FAP with severe phenotypes resulting in carpeting of the rectum, those with curable colon or rectal cancer complicating the polyposis, and those who underwent IRA and now have an unstable rectum in terms of polyp number, size, or histology. The operation is generally not offered to patients with incurable cancer, those with an intra-abdominal desmoid or low rectal cancer, or patients who have an anatomic, physiologic, or pathologic contraindication to an IPAA.

The advantages of this operation are that the risks for developing rectal cancer are negligible and a permanent stoma is not needed. The disadvantages are that it is a complex operation, a temporary stoma is usually needed, and it is associated with a small risk for bladder and sexual dysfunction after proctectomy. Bowel function, although usually reasonable, is also somewhat unpredictable. The ileal pouch requires surveillance, and the area of the IPAA should still be examined because of the imperfect nature of mucosectomy. The remaining controversy over performing total abdominal colectomy with IRA versus total proctocolectomy with IPAA centers on issues of relative quality of life.^88–93 A modest reduction in life expectancy is expected in patients with classical FAP with rectal preservation.^94,95 Proctoscopic examination of a retained rectum is indicated annually.

Total Abdominal Colectomy With IRA: A total abdominal colectomy with IRA is a fairly quick and straightforward operation with an overall low morbidity rate, and generally results in good bowel function. Most patients have 3 to 4 bowel movements per day after this procedure, and the risk for urgency, seepage, or fecal incontinence is low. Without proctectomy, no risk exists for bladder or sexual function problems, and even a temporary stoma is obviated. The major disadvantages of total abdominal colectomy with IRA are high risk for rectal cancer development and associated morbidity and mortality, frequent need to undergo subsequent proctectomy because of severe rectal polyposis, and real need for regular endoscopic surveillance of the retained rectum (every 6–12 months).

In a review of 659 patients in the Dutch-Scandinavian collaborative national polyposis registries who underwent colectomy with IRA, Vasen et al.⁹⁶ found a high rate of advanced and fatal rectal cancers even though 88% of the patients underwent a diagnostic proctoscopy within 18 months of presentation. The investigators estimated that 12.5% of patients undergoing this procedure would die of rectal cancer by 65 years of age even if compliant with endoscopic screening. They concluded that proctocolectomy is the preferred procedure for most patients with the classical FAP phenotype, although some controversy remains. They and others also observed that patients could not be reliably selected for colectomy based on genotype alone. However, studies have reported that the risk for rectal cancer development associated with total abdominal colectomy and IRA has declined since the 1980s when IPAA first became available for high-risk patients with severe polyposis.^97,98

However, IRA is the preferred surgery for most patients with attenuated FAP who have either rectal-sparing or endoscopically manageable rectal polyposis. It is not recommended for patients with curable colon or rectal cancer or those with extensive rectal or colonic polyposis. Patients and families must be absolutely reliable in attending follow-up endoscopic examinations. The risk to the rectal stump rises considerably after the age of 50 years, and if the rectum becomes unstable a proctectomy with either an IPAA or end ileostomy is recommended.⁹⁹

Total Proctocolectomy With Ileostomy: A total proctocolectomy with end ileostomy is rarely indicated as a prophylactic procedure because good options are available that do not involve a permanent stoma, which has implications for the patient and family. Fear of a permanent stoma may make family members reluctant to undergo screening. The operation removes all risk of colon and rectal cancer, but is associated with the risk for bladder or sexual function disorders. This operation may be offered to patients with a low, locally advanced rectal cancer, those who cannot have an ileal pouch because of a desmoid tumor, those with a poorly functioning ileal pouch, and those who have a contraindication for an IPAA (e.g., concomitant Crohn's disease, poor sphincter function).

Total proctocolectomy with continent ileostomy is offered to patients who are motivated to avoid end ileostomy because they either are not suitable for total proctocolectomy with IPAA or have a poorly functioning IPAA. This is a complex operation with a significant risk for re-operation.

Surveillance After Surgery

For all patients with FAP, proctocolectomy surveillance involves annual physical examination, sigmoidoscopy, and polypectomy. In practice, some patients have few or no recurrent polyps in the rectum and the follow-up interval can probably be cautiously lengthened. Major surveillance in patients with a personal history of FAP or attenuated FAP after colectomy involves the upper gastrointestinal tract. It is recommended that physicians or centers with expertise in FAP manage patients, and that management should be individualized based on genotype, phenotype, and other personal considerations. In patients with retained rectum, polyp ablation can be performed if adenoma burden is low. In the case of attenuated FAP, surveillance involves annual physical and endoscopic examination if colectomy has been performed. Again, if rectal adenomas do not recur, longer follow-up intervals may be safely followed.

APC testing is recommended in the proband for several reasons: it confirms the diagnosis and allows other family members to clarify their risks through mutation-specific testing. Additionally, identifying the location of the APC mutation can be useful in predicting the severity of colonic polyposis generally and the severity of rectal involvement (for FAP) and risks for extracolonic cancers in affected patients.

Most classical and attenuated FAP patients will develop duodenal adenomas that can become cancerous (see Duodenoscopic Findings, opposite column).

Patients with classical FAP also are at elevated risk for developing other extracolonic cancers, which warrants attention during surveillance (page 30).¹⁰⁰ Patients are at heightened risk for thyroid cancer, with a lifetime risk of approximately 2% and female predominance (95%).¹⁰⁰ Peak incidence is in the third decade of life, with a mean age of around 30 years. Yearly thyroid physical examination is recommended and considered adequate for timely diagnosis and treatment. Annual thyroid ultrasound can be used to supplement physical examination. These patients also have an increased risk for intra-abdominal desmoid tumors, most of which present within 5 years of colectomy. Because significant morbidity and mortality are associated with advanced tumors, early diagnosis is likely of benefit.¹⁰¹ If family history of desmoids is present, pelvic CT or MRI every 3 years postcolectomy should be considered, and performed immediately if abdominal symptoms are present. Data on screening for small bowel polyps and cancer are lacking, but adding small bowel visualization to CT or MRI for desmoids can be considered.

The risk for hepatoblastoma is much higher in young children predisposed to FAP.¹⁰² Although the absolute risk is approximately 1.5%, given the lethality of the disease (25% mortality), active screening by liver palpation, ultrasound, and AFP measurements every 3 to 6 months during the first 5 years of life may be considered. The optimal approach would be to perform this screening in a clinical trial.

Medulloblastoma accounts for most brain tumors found in patients with FAP, predominantly in women younger than 20 years.¹⁰³ The incidence of pancreatic cancer in FAP is not well defined and likely very low. Giardiello et al.¹⁰⁴ reported 4 retrospective cases (histology not documented) of 1391 FAP-related subjects. More studies are needed to elucidate the risk and benefit of screening for brain and pancreatic cancers; no specific recommendations are provided other than to undergo annual physical examation.

Duodenoscopic Findings: Duodenal adenomas develop in more than 90% of patients with FAP, and are classified into stages 0 to IV, as defined by Spigelman et al.¹⁰⁵ based on macroscopic and histologic criteria (page 31). Duodenal cancer risk is uncommon in individuals younger than 40 years, and are rare in those younger than 30 years. The cumulative risk for developing severe duodenal polyposis (stage IV) has been estimated to be approximately 40% by 60 years of age.¹⁰⁶ The risk for duodenal cancer increases dramatically with stage IV disease.

Surveillance using end- and side-view duodenoscopy, Spigelman's or other standardized staging system, and extensive biopsy of dense lesions to evaluate advanced histology are recommended starting at age 25 to 30 years, although efficacy of surveillance of these sites has not been shown. More intensive surveillance and/or treatment is required in patients older than 50 years with large or villous adenomas.

Endoscopic treatment options include endoscopic papillectomy, in addition to excision or ablation of resectable large or villous adenomas, and mucosectomy of resectable advanced lesions to potentially avert surgery. The appropriate period for follow-up endoscopy relates to the burden of polyps, varying from every 4 years if no polyps are found to every 6 to 12 months for Spigelman's stage IV polyposis. Surgical evaluation and expert surveillance every 6 to 12 months is recommended for stage IV polyps, invasive carcinoma, and high-grade dysplasia or dense polyposis that cannot be managed endoscopically. Surgical counseling is also advised for those with stage IV polyposis.

Chemoprevention: Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to reduce the incidence and recurrence of colorectal adenomas,^107–109 although long-term follow-up is needed to more precisely determine the role of this type of therapy. Long-term use of sulindac seems to be effective in polyp regression and preventing recurrence of higher-grade adenomas in the retained rectal segment of patients with FAP.¹¹⁰ However, in a randomized, double-blind, placebo-controlled study, sulindac did not prevent the development of adenomas in those with FAP.¹¹¹ NSAIDs are not effective as primary treatment of FAP. Prophylactic colectomy remains the preferred treatment to prevent CRC in patients with FAP. Chemoprevention with NSAIDs can be considered after initial prophylactic surgery for both classical and attenuated FAP as an adjunct to endoscopic surveillance to reduce the rectal polyp burden.

Cyclooxygenase-2 (COX-2) inhibitors are a form of NSAID that have been shown to be overexpressed in colorectal adenomas and cancers. International multicenter studies have been conducted to study the effect of these agents as chemoprevention of colorectal adenomas.^112–115 Results from the Prevention of Colorectal Sporadic Adenomatous Polyps (PreSAP) trial showed that the use of celecoxib, a COX-2 inhibitor, significantly reduced the occurrence of colorectal adenomas within 3 years after polypectomy.¹¹² The Adenoma Prevention with Celecoxib (APC) trial showed that celecoxib significantly lowered the formation of adenomas during a 3-year period in patients at high risk for CRC who had their polyps removed.¹¹⁴ Five-year safety and efficacy results showed that compared with placebo, the reduction in incidence of advanced adenomas over 5 years was 41% for those who received a lower dose of celecoxib compared with 26% in patients who received a higher dose (both P < .0001).¹¹⁶ However, because of the increased risk for cardiovascular events associated with their use, COX-2 inhibitors are not recommended routinely for sporadic adenomas.^117,118

Personal History of Classical FAP

Prophylactic surgery (proctocolectomy or colectomy) remains the primary preferred treatment for this group of individuals (page 30). Surgery is performed either at the onset of polyposis or later, depending on the severity of the familial phenotype and genotype, the extent of polyposis at diagnosis, individual considerations, and local practices and expertise. Proper postsurgical surveillance should be followed. In patients who are younger than 18 years with mild polyposis and without family history of early cancers or genetic disposition, the timing of colectomy can be individualized, but annual colonoscopy is essential.

Personal History of Attenuated FAP

Treating patients with a personal history consistent with attenuated FAP varies depending on the patient's age and adenoma burden (page 35). For young patients younger than 21 years with a small adenoma burden, colonoscopy and polypectomy are recommended every 1 to 2 years with appropriate surgical evaluation and counseling. In patients aged 21 years and older with small adenomas, colectomy and IRA are alternative treatment options to colonoscopy and polypectomy. Patients older than 40 years should strongly consider colectomy and IRA. Even patients older than 40 years with what seems to be an endoscopically manageable adenoma burden, particularly if responsive to a chemopreventative agent such as sulindac or celecoxib, may choose to defer consideration of colectomy. For those who have significant polyposis that is not manageable with polypectomy, colectomy with IRA is preferred, but IPAA is an option. Annual physical examination is recommended, and NSAIDs may be considered as chemoprevention. Surveillance of the rectum and upper gastrointestinal tract is similar to that for classical FAP.

Family History of Classical FAP

Management of individuals with a family history of FAP depends on whether the familial mutation is known or unknown. Individuals who have a family history of FAP have 2 possible situations: known specific mutation that has caused familial polyposis or family history of polyposis with no known familial mutation.

Familial Mutation Known:

Genetic Counseling: When the mutation responsible for FAP within a family is known, screening can be appropriately directed to those at highest risk and APC testing can be considered for at-risk family members. At-risk individuals should be provided counseling so that they are able to make informed decisions about the implications of genetic testing and on their own management.

Genetic Testing: Genetic testing for the APC gene in individuals with familial polyposis should be considered before or at the age of screening. The age at which to begin screening should be based on symptoms, family phenotype, and other individual considerations. Fatal CRC is rare before 18 years of age.

If an APC gene mutation is found, individuals have virtually a 100% probability that they will eventually develop familial polyposis. Truncating mutation of the APC gene is detectable in approximately 80% of patients with FAP using protein-truncating tests.^119,120 These patients need to undergo flexible sigmoidoscopy or colonoscopy every 12 months, beginning at 10 to 15 years of age.

If an individual at risk is found not to carry the APC gene mutation responsible for familial polyposis in the family, screening as an average-risk individual is recommended.

No Genetic Testing: Some people who undergo genetic counseling decide, for one reason or another, not to undergo genetic testing, which influences how their screening is managed. These individuals are considered to be potentially at risk and should be offered annual flexible sigmoidoscopy or colonoscopy beginning at age 10 to 15 years until they are 24 years of age. Then, if results continue to be negative, screening is scaled down to every 2 years until 34 years of age, every 3 years until 44 years of age, and every 3 to 5 years thereafter. Substituting colonoscopy every 5 years should be considered beginning at age 20 years because of the possibility that the patient may have attenuated FAP.

Screening is recommended so often for these individuals for several reasons. First, adenomas may begin to develop in adolescence. Most people with classic FAP present with polyps before 25 years of age, so annual screening with sigmoidoscopy will detect FAP in most of these patients. Less often, people with FAP will not develop polyps until a later age. The probability of FAP in a person without any polyps on annual screening begins to decrease with age around this time, so that screening does not need to be as frequent between 24 and 34 years of age and can be even less frequent between 34 and 44 years of age. However, even this recommended screening schedule is more rigorous than screening guidelines for the general population, because serial negative examinations up to 35 years of age do not exclude the diagnosis of FAP. Individuals with attenuated polyposis may not present until a later age and may have fewer polyps than those with classic FAP, but enhanced screening is still warranted.

Familial Mutation Unknown: In some families, mutations cannot be found with available testing technology, recognizing that the sensitivity to identify APC gene mutations is currently only approximately 80%. In other families, affected individuals have died or are not immediately available. Under these circumstances, APC testing should be considered for at-risk family members. If the mutation responsible for FAP within a family is not found, it is important to remember the limitations of interpreting a gene test in a presymptomatic individual. Evaluating presymptomatic individuals at risk in these families presents a difficult problem, because the mutation responsible for FAP within the family is not known. Certainly, a positive test in a presymptomatic person is informative even when the familial mutation has not been previously identified. But interpreting a test in which “no mutation is found” in a presymptomatic person is not the same as a “negative test.”

The best approach in this situation is to attempt to identify the APC mutation in an affected family member, even if the available person is not a first-degree relative. Without this information, genetic testing in an unaffected individual offers less precision in estimating a person's risk. If a mutation is found, they should be managed similar to those with known familial mutations. FAP is only excluded in a person at risk whose genetic testing results indicate no mutation is found when a mutation has been previously identified in an affected family member (a “true-negative” test result). Physicians have recognized this particular issue as a source of confusion and misinterpretation. Thus, it is critical that patients receive appropriate genetic counseling to avoid false-negative interpretations of test results.¹²¹ MYH testing should be considered if APC gene mutation is negative and family history is consistent with a recessive inheritance.

Surveillance for these at-risk individuals who are not tested or have no mutation found after testing is identical to that in untested individuals with known familial mutation (see No Genetic Testing, page 55). Again, if polyposis is detected, then individuals should be managed the same as those with personal history of classical FAP.

Family History of Attenuated FAP

The same genetic counseling, testing, and surveillance considerations discussed previously for patients with a classical FAP family history apply to patients with a family history of attenuated FAP, except for the endoscopy approach (pages 36 and 37). Individuals with attenuated polyposis may not present until a later age and may have fewer polyps than those with classical FAP. However, enhanced screening is still warranted for these patients. The recommended endoscopic schedule involves colonoscopy beginning in late teens, with repeat examinations every 2 to 3 years. Thus, the late onset and right colon involvement is accommodated, in contrast to classical FAP. These recommendations apply to patients who have known gene familial mutations, those not tested, and those for whom a familial mutation is not known. Individuals should continue with screening until adenomas are found, at which point they should be managed as patients with personal history of attenuated FAP.