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Colorectal Cancer and Colon Cancer Screening
Stephen P. Laird, MD, MS, and Neil W. Toribara, MD, PhD
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Colorectal Cancer And Colon Cancer Screening
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1. What is colorectal cancer (CRC)? CRC includes both colon and rectal cancer. Over 95% of the primary cancers arising in the large bowel are adenocarcinomas; the remainder are lymphomas, malignant carcinoids, leiomyosarcomas, and Kaposi sarcomas. Several variants of adenocarcinomas have been described. These include signet-ring carcinomas, mucinous or colloid carcinomas, and scirrhous carcinomas. As a general rule, poorly differentiated adenocarcinomas tend to be more aggressive, metastasize earlier, and have a poorer prognosis than well-differentiated tumors. 2. How does the pathophysiology of rectal cancer differ from cancer elsewhere in the colon? The rectum is relatively immobile, lacks a serosal covering, and is located largely behind the peritoneal reflection, surrounded by perirectal fat. As a result, rectal cancers more commonly spread contiguously via direct extension into local structures, whereas colon cancer more commonly spreads via lymphatics and hematogenously. Thus, rectal cancers that have spread beyond the mucosa are treated with surgery and adjuvant radiation with or without chemotherapy, whereas colon cancers are treated with surgery and chemotherapy rather than radiation. Some evidence such as distribution of malignancies within the colon in hereditary nonpolyposis colorectal cancer (HNPCC) and differing cellular surface markers also suggests that biological differences may play a role. 3. How common is colorectal cancer? Cancer is the second leading cause of death in the United States (after cardiovascular disease), and CRC is the second leading cause of death from malignancies (after lung cancer). The lifetime risk of developing CRC is 1 in 18 (5.5%) in women and 1 in 17 (5.9%) in men and is influenced by hereditary and lifestyle factors. The incidence is estimated at 147,000 new cases per year, with an estimated 49,960 deaths in 2008. The incidence of CRC peaked in the mid 1980s and has slowly declined since that time, reflecting the effects of increased availability of colonoscopy, gradual acceptance of CRC screening, and the lag time between polyp formation and malignant transformation. 4. Do the genetic defects leading to sporadic CRC differ from those in genetic syndromes associated with colon cancer? Yes. It appears that all CRC develops from previously normal mucosa by an accumulation of genetic abnormalities, although the methods by which these abnormalities accumulate differ. In most sporadic CRC and familial adenomatous polyposis (FAP) syndrome, genetic abnormalities accumulate via loss of large pieces of DNA, known as loss of heterozygosity (LOH). The most common acquisition sequence of genetic abnormalities is thought to be APC, ras, p53, and DCC, although the order of allelic deletion is not as important as the cumulative loss of DNA or LOH. There is some evidence for a distinct hyperplastic polyp-serrated adenoma-carcinoma pathway having a genetic signature distinct from the more common tubular adenoma pathway described earlier. Translating this knowledge into a practical stool-based DNA test, in which DNA isolated from a stool sample is tested for a panel of mutations in genes commonly involved in colonic carcinogenesis, has proved to be difficult, although efforts are still ongoing. In HNPCC and a small minority of sporadic CRCs, the abnormalities accrue through accumulation of point mutations, which cannot be corrected because of defects in the DNA repair system. 5. Describe the natural sequence from colon adenoma to colon cancer. In one of the major milestones in gastroenterology, the 2004 National Polyp Study showed that removal of colonic adenomas during colonoscopy prevented subsequent development of colorectal cancer, showing that colonic adenomas are a vital step, which can be interrupted, in the carcinogenic progression of sporadic CRC. The prevalence curves for adenomas and colorectal cancers parallel each other, with the adenoma curve shifted 5 to 10 years earlier than carcinomas. This suggests that the time needed for an adenoma to develop into cancer is 5 to 10 years, thus giving a significant window of time to discover and remove premalignant lesions. There is accumulating evidence that there is a second pathway to the development of CRC in which some hyperplastic polyps (previously thought to be benign lesions without malignant potential) may develop into serrated adenomas, which are adenomas with a distinct histology and probably a distinct array of genetic abnormalities (BRAF mutations, extensive DNA methylation, and microsatellite instability). These serrated adenomas have a potential for malignant transformation equal to or perhaps greater than tubular adenomas.
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6. How prevalent are colonic adenomas among the U.S. population? The prevalence of adenomatous polyps appears to be highly dependent on the population studied. Two colonoscopic studies in asymptomatic populations have reported rates of 23% to 25% prevalence in male and female patients between the ages of 50 and 82 years. Two other studies involving only men in Department of Veterans Affairs Medical Centers had prevalence rates of approximately 40% and small studies have suggested prevalences of 50% or greater in some populations. 7. Where in the colon are polyps most commonly located? Autopsy series have shown a relatively even distribution of adenomas throughout the colon, although larger polyps have a distal predominance, as expected from the distribution of CRCs. Recently, there has been an increased interest in flat or nonpolypoid neoplasms whose prevalence may be as high 10%. These are more difficult to detect during standard endoscopy and, in the case of sessile serrated adenomas, which have both a predominant right colon distribution and malignant potential, may be significant contributors to missed or interval cancers (CRCs arising between screening or surveillance colonoscopies). 8. Give the mean age of onset and describe the anatomic distribution of CRC. True sporadic CRCs occur at a mean age of 69; approximately 60% are distal to the splenic flexure (thus theoretically within the reach of a flexible sigmoidoscope). However, some studies have suggested that older patients and blacks appear to have an increased proportion of CRCs in the right colon. 9. How are malignant polyps defined? How are they clinically managed? Pathologists prefer the term severe dysplasia for adenomas with a focus of carcinoma in situ or intramucosal carcinoma, because complete endoscopic removal is curative. The term malignant polyp is reserved for the approximately 5% of adenomas in which a focus of carcinoma has invaded beyond the muscularis mucosa into the submucosa, where lymphatic spread with metastasis is possible. A malignant polyp has at least one of the following characteristics:
• Poorly differentiated cancer • Invasion of veins or lymphatics • Extension of the carcinoma to less than 2 mm of the margin • Invasion of submucosa of the bowel wall When malignant polyps are found, consideration should be given to early re-endoscopy and/or local surgical resection. Endoscopic removal of a malignant polyp is associated with a 10% to 25% relapse rate. 10. How is colon cancer staged, and how does this affect prognosis? Although the overall 5-year survival is about 62% in the United States, there are significant differences among ethnic groups. Although histology and syndromes (HNPCC colorectal cancers have a better prognosis stage for stage than sporadic CRCs) have some effect, the best single determinant of prognosis is stage at diagnosis. The two most widely used staging methods are the Duke’s and TNM (tumor, node, metastasis) systems. Both give essentially equivalent information for prognostic purposes. The Duke’s system is simpler and still widely used by gastroenterologists and surgeons, whereas TNM staging is used more widely among oncologists and pathologists (Table 46-1).
Table 46-1. Duke’s Classification Versus Tumor, Node, Metastasis (TMN) Staging DUKE’S CLASSIFICATION*
5-YEAR SURVIVAL (%)
Stage A Limited to mucosa
95 to 100
Stage B1 Into muscularis propria Stage B2 Through serosa
80 to 85 75
5-YEAR SURVIVAL (%)
TMN STAGING† Stage 0 Carcinoma in situ Stage I Tumor invades submucosa Tumor invades muscularis propria Stage II Tumor invades through muscularis propria into serosa or pericolonic/perirectal tissue Tumor perforates or directly invades other organs
Tis N0 M0
100
T1 N0 M0 T2 N0 M0
95 80
T3 N0 M0 T4 N0 M0
Continued
Chapter 46 Colorectal Cancer And Colon Cancer Screening
Table 46-1 Duke’s Classification Versus Tumor, Node, Metastasis (TMN) Staging—Cont’d DUKE’S CLASSIFICATION*
5-YEAR SURVIVAL (%)
Stage C1 1 to 4 regional nodes positive Stage C2 >4 regional nodes positive
65 42
Stage D‡ Distant metastases
5
5-YEAR SURVIVAL (%)
TMN STAGING† Stage III Any perforation with nodal metastases N1: 1 to 3 nodes N2: ≥4 nodes N3: Any lymph node along named vascular trunk Stage IV Any invasion of bowel wall with or without lymph node metastases but with evidence of distant metastases
TX N1 M0 TX N2 M0 TX N3 M0
TX NX M1
*Gastrointestinal Study Group Modification. † American Joint Committee on Cancer. ‡ Included only in the Turnbull modification of Duke’s classification.
11. Describe the workup for CRC after the initial diagnosis. Surgical removal of the cancer remains the only curative therapy. Before surgery, visualization of the entire bowel, preferably by full colonoscopy, is indicated to exclude synchronous lesions (either adenomas or cancers) that may influence the operation. Preoperative laboratory tests should include complete blood count, blood chemistry panel-20, and carcinoembryonic antigen (CEA). If the CEA level is elevated at the time of diagnosis (approximately 60% of cases), it provides a convenient method for assessing effectiveness of the surgery and detecting early recurrences. Preoperative abdominal computed tomography (CT) scan and chest radiograph are useful in looking for metastatic disease. In rectal cancers, preoperative staging with transrectal ultrasound helps to determine the utility of adjunct radiation therapy. 12. What surgical margins are recommended? Most surgeons attempt to include at least 5 cm on either side of the tumor within the resection block, although margins as small as 2 cm may be acceptable in the distal rectum to preserve sphincter function. 13. Describe the recommended schedule of colonoscopic follow-up after surgery. If a preoperative colonoscopy clears the remainder of the colon of polyps or synchronous malignancy and the surgical margins are tumor free, colonoscopy before 1 to 3 years after resection is probably not indicated. The risk for developing metachronous neoplasms in a post malignancy resection patient is about the same as for a patient with an adenoma of unfavorable histology; therefore, intervals between colonoscopic screening exams should be similar, every 3 to 5 years. 14. Are there any effective blood tests to screen for CRC? Serum tests to diagnose CRC are limited by the inherent problem that markers produced by malignant cells are hardest to detect in the early, small tumors that have the best prognosis. To date, no putative serum markers of CRC have sufficient sensitivity or specificity to warrant use as primary screening modalities. CEA, the most widely used CRC tumor marker, is therefore useful only to assess efficacy of surgery or monitoring for recurrences in cancers already known to be CEA positive. Even this use has been challenged by those who believe that the clinical benefit of diagnosing recurrences is minimal. (Caveat: Because CEA is excreted in the bile, elevated levels may be difficult to interpret in the presence of biliary obstruction or hepatic dysfunction.) A reasonable surveillance approach in CEA-positive tumors is to check CEA levels every 2 months for the first 6 months, every 4 months for up to 2 years, and then every 6 months for up to 5 years. 15. List the risk factors for developing CRC. Age, diet, environment, personal history of colonic neoplasm, family history of colonic neoplasm, familial colon cancer syndromes, and inflammatory bowel disease. 16. What is the effect of age on the risk of developing CRC? The risk of developing CRC increases with age, starting at about age 40 and roughly doubling with each decade. Below age 40, the incidence of CRC is less than 6 in 100,000; however, by age 80 the incidence is approximately 500 per 100,000 in men and 400 per 100,000 in women. Because over 90% of colorectal cancers occur after age 50, most screening programs have arbitrarily chosen this as a starting age. 17. Discuss the effect of diet on the risk for developing CRC. Diet is thought to account for the major differences in the incidence rates of CRC worldwide. Although epidemiologic studies and animal models suggest that a high-fat, low-fiber diet (typical of Western nations) increases the risk
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of developing CRC, prospective trials of low-fat, high-fiber diets have shown no significant effect. Similarly, other micronutrients, such as folate, reducing agents (vitamins C and E), beta-carotene, and eicosanoids, showed promise in experimental conditions but either failed to yield positive results in controlled trials or still are under investigation. Calcium supplementation is the only dietary intervention that has shown a positive, albeit modest, effect in humans, using adenomas as a surrogate marker for the development of CRC. 18. Do environmental factors increase the risk for developing CRC? The risk of developing CRC is directly related to environmental factors. This effect is evident in comparing the rates of CRC in populations emigrating from a region with a low rate to a region with a high rate. For example, the incidence of colon cancer in the Japanese (low incidence) emigrating to the United States (high incidence) led to a 10-fold increase in incidence over a single generation, much too fast to be a selection phenomenon. In general, the United States and Western European nations have a higher rate of CRC than developing nations. 19. Which adenoma features are associated with a greater malignant potential? Adenomatous polyps are considered premalignant lesions, but the actual risk of neoplastic transformation is unknown. Large size, villous architecture, and dysplasia are features of adenomas that have a higher risk of developing a carcinoma within a given polyp. Some researchers believe that serrated adenomas may have an increased rate and risk of malignant transformation, although there is insufficient evidence to state this definitively. 20. What are the recommendations for CRC screening in people at average risk for CRC? Men and women at average risk should be offered screening for CRC and adenomatous polyps at age 50 years. Options for CRC screening include:
• Fecal occult blood test (FOBT) • Flexible sigmoidoscopy • FOBT and flexible sigmoidoscopy • Colonoscopy Stool DNA testing and CT colonography are two methods that appear to have a great deal of promise, although their utility in everyday clinical practice has yet to be defined. It is important to differentiate between screening modalities that are primarily effective at detecting CRCs, those that can detect both cancers and their precursor lesions, and those that can detect CRCs and identify and remove polyps. Each approach has its advantages and disadvantages, and each person should make an informed decision regarding their preference. 21. Give the current guidelines for surveillance colonoscopy in patients with a history of adenomatous polyps. A periodic surveillance program should be customized according to adequacy of the preparation and endoscopic findings. Colonoscopy Findings One or two tubular adenomas Large sessile (>2 cm) adenoma Inadequate colon preparation Large (>1 cm) adenoma, villous histology, or dysplasia
Next Colonoscopy 5 years 3 to 6 months Repeat within 3 to 6 months 3 years
22. Who is considered to be at increased risk for developing CRC? People at increased risk are defined as those individuals who have a personal history of CRC or an adenomatous polyp, a predisposing illness for CRC such as inflammatory bowel disease (IBD), a first-degree relative (parent, sibling, child) with CRC or an adenomatous polyp, or a gene carrier for familial colon cancer syndromes. The risk of developing CRC is increased approximately 2-fold if a first-degree relative has been diagnosed with CRC over age 65. The younger the age at which the relative was diagnosed, the higher is the risk. The risk also rises if more than one first-degree relative has been diagnosed with CRC. Perhaps more significant, the same risk seems to apply if first-degree relatives were found to have adenomatous polyps. Evidence suggests a slightly increased risk (approximately 1.5-fold) if third-degree relatives (e.g., cousins) have been diagnosed with CRC. 23. Which method of CRC screening is recommended for individuals at increased risk of developing CRC? Colonoscopy is the only recommended screening modality in this patient population.
Chapter 46 Colorectal Cancer And Colon Cancer Screening
24. List the familial colon cancer syndromes. • FAP and Gardner’s syndrome (FAP with extracolonic manifestations) • Hamartomatous polyp syndromes: Peutz-Jeghers syndrome (PJS) and juvenile polyposis syndrome (JPS) •. HNPCC 25. What tests are available for hereditary CRC? Diagnosis of an APC germline mutation is based on one of several DNA-based tests:
• Sequencing of the entire genome (95% sensitive) • Combination of confirmation strand gel electrophoresis screening and protein truncation testing (80% to 90% sensitive)
• Protein truncation alone (80% sensitive) • Linkage analysis (98% sensitive in most families with the FAP mutation) There are more than 228 germline mutations and more than 47 polymorphisms in the seven MMR genes associated with HNPCC. These multiple mutations have limited the development of inexpensive diagnostic assays for HNPCC and diagnosis is now based on direct DNA sequencing. Patients with JPS and their family members are appropriate candidates for genetic testing for germline mutations MAD4 and BMP1A using direct DNA sequencing. The only clearly identified gene mutation in PJS is STK11/LKB1, which leads to 40% to 60% of cases and can be diagnosed by mutation analysis of STK11. Candidate mutations associated with common familial colon cancer have not been characterized well enough to warrant routine genetic testing (Table 46-2).
Table 46-2. Features of Colon Cancer Syndromes SPORADIC CRC
HNPCC
FAP
ATTENUATED FAP
JPS
PJS
69
44
39
49
34
46
Lifetime 1:18 (F) 1:17 (M) Few polyps
1:2000
1:10,000
1:9000
1:100,000
1:200,000
Few polyps, proximal distribution
>100 polyps in teens
≈30 polyps with proximal distribution
>2 P-J polyps in GI tract
Gene abnormality
Multiple
APC (>90%), ? MYH (≈5%)
APC (>90%), ? MYH (≈5%)
Mode of inheritance
?
MLH1, MSH2, MSH6, PMS2, PMS1 Autosomal dominant
≈100s in colon, scattered elsewhere in GI tract MADH4/ SMA4 and BMPRIA (53%)
Autosomal dominant
Autosomal dominant
Autosomal dominant
Autosomal dominant
FEATURES Average age of CRC (yr) Incidence Colon polyps
STK11/ LKB1 (≈55%)
CRC, colorectal cancer; HNPCC, hereditary nonpolyposis colorectal cancer; FAP, familial adenomatous polyposis; JPS, juvenile polyposis syndrome; PJS, Peutz-Jeghers syndrome.
26. What is the recommended surveillance for people with a family history of CRC who do not fit the genetic profiles? • People with a first-degree relative with CRC or adenomatous polyp diagnosed at age younger than 60 years or two first-degree relatives with CRC diagnosed at any age should have a screening colonoscopy starting at age 40 years or 10 years younger than the earliest diagnosis in the family (whichever is first), and repeated every 5 years. • People with a first-degree relative with CRC or adenomatous polyp diagnosed at age older than 60 years or two second-degree relatives (grandparent, aunt, or uncle) with CRC should be screened as average-risk persons but beginning at age 40 years. • People with one second-degree relative with CRC should be screened as average risk.
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27. How do FAP and Gardner syndrome increase the risk of CRC? FAP and Gardner syndrome are inherited in an autosomal dominant manner with their phenotypic expression dependent on the location of the mutation in their APC gene. Their fully expressed forms are characterized by the development of hundreds to thousands of colonic adenomas. One hundred percent of patients expressing this phenotype develop CRC without colectomy. Most patients begin developing adenomas in their teens, and screening in families with a known proband should start at that time. One third of FAP cases arise as de novo mutations. The increased risk of CRC is thought to be due to the sheer number of adenomatous polyps; each polyp has the same risk of malignant transformation as an ordinary sporadic adenoma. 28. How are FAP and Gardner syndrome diagnosed? The APC gene is responsible for both FAP and Gardner syndrome. Most disease-causing mutations result in premature stop codons, which give rise to truncated proteins. Commercial tests are available to detect truncated proteins and to directly sequence the gene. The results can be used for accurate screening of affected kindreds. Members of FAP kindreds who have not developed adenomas by age 40 have not inherited the polyposis phenotype. The position of the mutation gives rise to the phenotype of the FAP. For example, mutations in the extreme beginning or end of the APC gene can cause an attenuated form of FAP, which is characterized by fewer adenomas (1 to 100) with a right-sided predominance. 29. In addition to colonoscopy, what other tests should be considered in FAP? Patients with FAP are at increased risk of extracolonic tumors, including thyroid cancer, pancreatic cancer, duodenal and ampullary cancer, and gastric cancer; therefore, periodic thyroid function tests, liver function tests, and upper gastrointestinal tract screening with both forward and side-viewing endoscopes are recommended. 30. What is the role of NSAIDs in treating FAP? Both sulindac and celecoxib decrease the number of adenomas in patients with FAP, but neither is associated with complete regression. Therefore, chemoprevention cannot replace prophylactic colectomy, although the timing of the colectomy may be delayed. 31. How do hamartomatous polyp syndromes affect the risk of developing CRC? Along with PJS and JPS, the differential diagnosis includes Cowden disease and the Bannayan-Ruvalcaba-Riley syndrome. Phenotypic features of hamartomatous syndromes display considerable overlap. Emerging understanding of the germline mutations may provide more accurate distinctions between these. Hamartomatous polyp syndromes appear to be associated with a slightly increased risk of developing CRC, although nowhere near the risk associated with APC syndromes. 32. What is HNPCC? HNPCC is an autosomal dominant inherited disease in which colon cancer is caused by inactivation of one of the proteins involved in DNA proofreading (usually hMSH2 or hMLH1) leading to early onset of colon cancers and extracolonic cancers (e.g., endometrial, ovarian, gastric, urinary tract, renal cell, biliary, and gallbladder). Colon cancer arises from discrete adenomas, which rapidly accumulate point mutations, resulting in a markedly accelerated progression from adenoma to carcinoma. Because the term nonpolyposis is misleading and the recognition that some members of these kindreds may develop cancers other than CRC, there has been a trend toward calling this entity by its original designation, Lynch syndrome. 33. How is HNPCC diagnosed? Diagnosis is based on either the Amsterdam criteria, the Amsterdam criteria II, or the Bethesda guidelines. The more stringent Amsterdam criteria increase the chances of finding a germline mutation in either MSH2 or MLH1 from 25% to 86%. The Bethesda guidelines are more sensitive but less specific than the Amsterdam criteria. Interestingly, there are a significant number of families fitting the Amsterdam criteria who do not appear to have abnormalities in the mismatch repair genes. These families should be screened endoscopically as outlined in the following section (Table 46-3 and Box 46-1).
Table 46-3. Amsterdam Criteria AMSTERDAM CRITERIA*
AMSTERDAM CRITERIA II
1. One member diagnosed with CRC before age 50 years 2. Two affected generations 3. Three affected relatives, one of them a FDR of the other two 4. Exclude FAP 5. Pathologic confirmation
1. At least three affected relatives with an HNPCCassociated cancer 2. One of whom is an FDR of the other two 3. At least two successive generations 4. One member diagnosed with CRC before age 50 years 5. Exclude FAP 6. Pathologic confirmation
CRC, colorectal cancer; FAP, familial adenomatous polyposis; FDR, first-degree relative; HNPCC, hereditary nonpolyposis colorectal cancer. *All criteria must be met.
CHAPTER 46 COLORECTAL CANCER AND COLON CANCER SCREENING
Box 46-1. Revised Bethesda Guidelines (Meeting any listed feature is sufficient to proceed with testing for microsatellite instability.) 1. Colorectal cancer diagnosed in a patient who is younger than 50 years of age 2. Presence of synchronous, metachronous colorectal or other HNPCC-associated tumors1 regardless of age 3. Colorectal cancer with the MSI-H histology diagnosed in a patient who is younger than 60 years old2 4. Colorectal cancer diagnosed in one or more first-degree relatives with an HNPCC-related tumor, with one of the cancers being diagnosed younger than age 50 years. 5. Colorectal cancer diagnosed in two or more first-or second-degree relatives with HNPCC-related tumors, regardless of age. 1 Colorectal, endometrial, stomach, ovarian, pancreas, ureter and renal pelvis, biliary tract, and brain (usually glioblastoma as seen in Turcot syndrome) tumors, sebaceous gland adenomas and keratoacanthomas in Muir-Torre syndrome, and carcinoma of the small bowel. 2 MSI-H (microsatellite instability-high tumors) refers to changes in two or more of the five NCI-recommended panels of microsatellite markers; histology features include presence of tumor-infiltrating lymphocytes, Crohn-like lymphocytic reaction, mucinous/signet ring differentiation, or medullary growth pattern.
34. Outline the screening recommendation for patients with HNPCC. Screening with colonoscopy for all members of the family should begin at age 20 to 25 years, repeated semiannually until age 40, and then yearly thereafter. Some individuals with known mutations may elect to have a subtotal colectomy before developing malignancies. 35. What is MYH-associated polyposis (MAP)? MYH polyposis is a recently described autosomal recessive polyposis syndrome that is phenotypically similar to attenuated FAP (15 to 500 adenomas) but does not have an APC germline mutation. This biallelic germline mutation causes nucleotide transversion G:C → T:A in the APC gene. MYH is a protein that acts synergistically with two other proteins, OGG1 and MTH1, in the base excision repair pathway to repair DNA replication errors caused by oxidative stress. These mutations have been demonstrated in both adenomas and carcinomas. It is unknown what percentage of patients with polyposis syndrome have this mutation. 36. What is microsatellite instability (MSI)? Microsatellites are short repeated DNA sequences (up to 10 nucleotides in length) that are susceptible to somatic mutation by misalignment. Ordinarily, this mismatch in the number of repeats is repaired by the DNA proofreading complex (which includes MSH2, MLH1, MSH6, MLH3, PMS1, and PMS2, the so-called mismatch repair genes). When this complex is inactivated (usually by changes in MSH2 or MLH1), mismatched bases, including the commonly occurring microsatellite repeat misalignments, cannot be repaired, leading to a rapid accumulation of genome-wide mutations. MSI is observed in approximately 85% of HNPCC colon cancers and 15% of sporadic colon cancers. As MSI is thought to be common in the malignant transformation of serrated but not tubular adenomas, the former lesions may be responsible for many of the MSI-positive sporadic cancers. The commonly accepted method for detecting MSI is by using a standard panel of five microsatellites, with abnormalities in two or more constituting the MSI-high (MSI-H) phenotype commonly associated with HNPCC. It appears that MSI-positive CRCs have a better prognosis stage-for-stage compared with microsatellite stable cancers; however, they may not respond as well to 5-FU–based chemotherapy. This argues for MSI testing becoming a routine part of the workup for newly diagnosed CRC cases. 37. How does inflammatory bowel disease (IBD) affect the risk of developing CRC? Patients with chronic IBD have an increased risk of developing colorectal cancer, particularly those with chronic ulcerative colitis (CUC). Please see Chapter 43 for colonoscopy screening recommendations in ulcerative colitis. 38. Which two clinical conditions should raise suspicion for the presence of colon cancer? An unexplained iron deficiency anemia or sepsis with Streptococcus bovis as the pathogen should trigger investigation for colorectal cancer. 39. Is FOBT effective in detecting colon polyps and cancer? Yes. Even in the absence of iron deficiency anemia, FOBT has been shown to decrease mortality by 15% to 30% in three large randomized, controlled trials using guaiac-based methods. Immunologic methods for testing human hemoglobin have shown some promise for increasing specificity but have not been widely used because of increased cost. Only large polyps (greater than 1.5 cm in diameter) and cancers bleed enough to be detected routinely by FOBT. Thus, although FOBT screening can reduce mortality from CRC by discovering malignancies at earlier, curable stages, it is considerably less effective in detecting adenomas, whose removal prior to malignant transformation is a much more cost-effective strategy.
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40. Does a program of periodic sigmoidoscopy decrease mortality from CRC? Yes. The magnitude of this decrease is determined by a number of factors, including distribution of CRCs, extent of the exam, predictive value of the procedure for lesions beyond the extent of the exam, and number of patients undergoing screening. Colonoscopic studies have shown that patients with adenomas within the reach of the flexible sigmoidoscope have an increased risk of significant lesions (large adenomas, adenomas with villous histology, and cancers) in the proximal colon and should have a full colonoscopy. With this strategy, one can detect approximately 80% of significant lesions with an examination to the splenic flexure and two thirds of significant lesions if only the descending colon is reached. However, the same data suggest that one half of significant lesions in the proximal colon have no sentinel lesions within the reach of a flexible sigmoidoscope and would be missed during screening. 41. What is the sensitivity and specificity of an air contrast barium enema? Carefully performed, air contrast barium enemas have sensitivities and specificities in the 90% range; however, in most centers the figures are considerably lower, perhaps because modern ultrasound-, CT-, or MRI-based procedures have become more fashionable. 42. How effective is CT colonography (CTC) as a screening test? Also known as virtual colonoscopy, CTC is an evolving technology for CRC screening. The problem to date with CTC as a screening option was the variability of the earlier multicenter trial results. Unpublished data from the 2005 National CT Colonography Trial (ACRIN 6664) showed 90% sensitivity and 86% specificity for adenomas larger than 1 cm. For smaller polyps of 6 mm or larger, the sensitivity and specificity were 78% and 88%, respectively. These preliminary results suggest CTC may be a viable option for CRC screening in selected populations (incomplete or failed colonoscopy, high risk for sedation, patient preference if at average risk for CRC). Nevertheless, this would suggest a 14% falsepositive rate resulting in inappropriate referral for colonoscopy. Additional data from the ACRIN 6664 trial should answer questions regarding patient preferences and cost-effectiveness of CTC compared to optical colonoscopy (OC). Ultimately, cost-effectiveness will hinge on how smaller polyps are managed. The American College of Radiology (ACR) recommends polyps of 5 mm or smaller not be reported at all and that patients with two polyps of 6 to 9 mm be offered the option of CTC follow-up in 3 years or OC with polypectomy. Many are concerned this could lead to the underdiagnosis of important colonic adenoma findings with delayed surveillance, as well as a concern regarding the ethics of incomplete disclosure with patients. In one study of 6000 consecutive polyps found on OC, 12% of polyps 5 to 10 mm had advanced histology and 1% were cancerous. In another retrospective study using the new ACR guidelines, one-third of all patients with high-risk findings (3% of total patients) with a recommended surveillance interval of 3 years would have been told after CTC that they are normal and to come back in 5 to 10 years. CTC has poorer sensitivity than colonoscopy in the detection of flat or depressed lesions. Flat polyps have been reported to be significantly more likely to contain high-grade dysplasia than protuberant polyps. How this affects the overall acceptance of CTC as a viable screening modality remains to be seen. 43. Can CRC be prevented with medicines (chemoprevention)? Because we cannot prevent CRCs by elimination of causative factors, the possibility of chemoprevention has generated considerable enthusiasm. NSAIDs, including sulindac and aspirin, have shown promise in both experimental models and epidemiologic studies. Recent studies have shown protective effects; however, maximum efficacy requires higher doses (more than 14 tablets/wk), which markedly increase the risk of gastrointestinal tract toxicity and potential bleeding. Aspirin use for adenoma prevention at present can only be recommended for those at increased risk for adenoma formation who have no history of ulcer disease or stroke. Sulindac decreases the number and size of adenomas in patients with FAP but does not completely prevent progression to cancer. Its efficacy in sporadic adenomas is unclear, although preliminary results of a trial using a combination of sulindac and DMFO (dimethylfluoroornithine) have shown significant promise at doses that may lower the potential gastrointestinal tract toxicity. Selective cyclooxygenase-2 inhibitors, which have a much lower gastrointestinal toxicity profile, are more effective than sulindac for FAP. Randomized, double-blind prospective studies have shown both rofecoxib and celecoxib to be effective at also decreasing sporadic adenoma recurrence, although only the latter is currently available.
Bibliography 1. AGA Institute Position on CT Colonography. Gastroenterology 2006;131:1627–8. 2. Banerjee S, Van Dam J. CT Colonography for colon cancer screening. Gastrointest Endosc 2006;63:121–33. 3. Bresalier RS. Malignant neoplasms of the large intestine. In: Feldman M, Friedman LS, Brandt L, editors. Sleisenger and Fordtran’s Gastrointestinal and Liver Disease. Philadelphia: WB Saunders; 2006. pp. 2760–810. 4. Butterly LF, Chase MP, Pohl H, et al. Prevalence of clinically important histology in small adenomas. Clin Gastroenterol Hepatol 2006;4:343–8. 5. Cole BF, Baron JA, Sandler RS, et al. Folic acid for the prevention of colorectal adenomas: A randomized clinical trial. JAMA 2007;297:2351–9. 6. Cotton PB, Durkalski VL, Benoit CP, et al. Computed tomographic colonography (virtual colonoscopy): A multicenter comparison with standard colonoscopy for detection of colorectal neoplasia. JAMA 2004;291:1713–9.
Chapter 46 Colorectal Cancer And Colon Cancer Screening 7. Das D, Arber N, Jankowski J. Chemoprevention of colorectal cancer. Digestion 2007;76:51–67. 8. East JE, Saunders BP, Jass JR. Sporadic and syndromic hyperplastic polyps and serrated adenomas of the colon: Classification, molecular genetics, natural history, and clinical management. Gastroenterol Clin N Am 2008;37:25–46. 9. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer J Clin 2008;58:71–96. 10. Johnson CD, Harmsen W, Wilson L, et al. Prospective blinded evaluation of computed tomographic colonoscopy for screen detection of colorectal polyps. Gastro 2003;125:311–9. 11. Levin B, Lieberman DA, McFarland B, et al. Screening and surveillance for the early detection of colorectal cancer and adenomatous polyps 2008: A joint guideline for the American Cancer Society, the U.S. Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology. Gastroenterology 2008;134:1570–95. 12. Lieberman DA, Weiss DG, Bond JH, et al. Use of colonoscopy to screen asymptomatic adults for colorectal cancer. Veterans Affairs Cooperative Study Group 380. N Engl J Med 2000;343:162–8. 13. Lieberman D, Moravec M, Holub J, et al. Polyp size and advanced histology in patients undergoing colonoscopy screening: Implications for CT colonography. Gastroenterology 2008;135:1100–5. 14. Lynch HT, de la Chapelle A. Hereditary colorectal cancer. N Engl J Med 2003;348:919–32. 15. Mavranezouli I, East JE, Taylor SA. CT colonography and cost-effectiveness. Eur Radiol 2008;18:2485–97. 16. Oono Y, Fu K, Nakamura H, et al. Progression of a sessile serrated adenoma to an early invasive cancer within 8 months. Dig Dis Sci 2008; 54:906–9. 17. Pickhardt PJ, Choi JR, Inku H, et al. Computed tomographic virtual colonoscopy to screen for colorectal neoplasia in asymptomatic adults. N Engl J Med 2003;349:2191–200. 18. Pineau BC, Paskett ED, Chen GJ, et al. Virtual colonoscopy using oral contrast compared with colonoscopy for the detection of patients with colorectal polyps. Gastro 2003;125:304–10. 19. Ransohoff DF, Sandler RS. Screening for colorectal cancer. N Engl J Med 2002;346:40–4. 20. Rockey DC, Georgsson MA. Mass screening with CT colonography. Clin Gastroenterol Hepatol 2005;3:S37–41. 21. Rustgi A. Hereditary gastrointestinal polyposis and non polyposis syndromes. N Engl J Med 1994;331:1694–702. 22. Sandler RS, Halabi JA, Baron, et al. A randomized trial of aspirin to prevent colorectal adenomas in patients with previous colorectal cancer. N Engl J Med 2003;348:883–90. 23. Soetikno RM, Kaltenbach T, Rouse RV, et al. Prevalence of nonpolypoid (flat and depressed) colorectal neoplasms in asymptomatic and symptomatic adults. JAMA 2008;299:1027–35. 24. Tuma R. Drugs to prevent colon cancer show promise, but hurdles remain for chemoprevention. J Natl Cancer Inst 2008;400:764–6. 25. Umar A, Boland CR, Terdiman JP, et al. Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst 2004;96:261–8. 26. Vasen HF, Moslein G, Alonso A, et al. Guidelines for the clinical management of familial adenomatous polyposis (FAP). Gut 2008;57:704–13. 27. Vijan S, Hwang I, Inadomi J, et al. The cost effectiveness of CT colonography in screening for colorectal neoplasia. Am J Gastroenterol 2007;102:380–90. 28. Winawer SJ, Zauber AG, Gerdes H, et al. Risk of colorectal cancer in the families of patients with adenomatous polyps. N Engl J Med 1996;334:82–7.
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1. What is colorectal cancer (CRC)? CRC includes both colon and rectal cancer. Over 95% of the primary cancers arising in the large bowel are adenocarcinomas; the remainder are lymphomas, malignant carcinoids, leiomyosarcomas, and Kaposi sarcomas. Several variants of adenocarcinomas have been described. These include signet-ring carcinomas, mucinous or colloid carcinomas, and scirrhous carcinomas. As a general rule, poorly differentiated adenocarcinomas tend to be more aggressive, metastasize earlier, and have a poorer prognosis than well-differentiated tumors. 2. How does the pathophysiology of rectal cancer differ from cancer elsewhere in the colon? The rectum is relatively immobile, lacks a serosal covering, and is located largely behind the peritoneal reflection, surrounded by perirectal fat. As a result, rectal cancers more commonly spread contiguously via direct extension into local structures, whereas colon cancer more commonly spreads via lymphatics and hematogenously. Thus, rectal cancers that have spread beyond the mucosa are treated with surgery and adjuvant radiation with or without chemotherapy, whereas colon cancers are treated with surgery and chemotherapy rather than radiation. Some evidence such as distribution of malignancies within the colon in hereditary nonpolyposis colorectal cancer (HNPCC) and differing cellular surface markers also suggests that biological differences may play a role. 3. How common is colorectal cancer? Cancer is the second leading cause of death in the United States (after cardiovascular disease), and CRC is the second leading cause of death from malignancies (after lung cancer). The lifetime risk of developing CRC is 1 in 18 (5.5%) in women and 1 in 17 (5.9%) in men and is influenced by hereditary and lifestyle factors. The incidence is estimated at 147,000 new cases per year, with an estimated 49,960 deaths in 2008. The incidence of CRC peaked in the mid 1980s and has slowly declined since that time, reflecting the effects of increased availability of colonoscopy, gradual acceptance of CRC screening, and the lag time between polyp formation and malignant transformation. 4. Do the genetic defects leading to sporadic CRC differ from those in genetic syndromes associated with colon cancer? Yes. It appears that all CRC develops from previously normal mucosa by an accumulation of genetic abnormalities, although the methods by which these abnormalities accumulate differ. In most sporadic CRC and familial adenomatous polyposis (FAP) syndrome, genetic abnormalities accumulate via loss of large pieces of DNA, known as loss of heterozygosity (LOH). The most common acquisition sequence of genetic abnormalities is thought to be APC, ras, p53, and DCC, although the order of allelic deletion is not as important as the cumulative loss of DNA or LOH. There is some evidence for a distinct hyperplastic polyp-serrated adenoma-carcinoma pathway having a genetic signature distinct from the more common tubular adenoma pathway described earlier. Translating this knowledge into a practical stool-based DNA test, in which DNA isolated from a stool sample is tested for a panel of mutations in genes commonly involved in colonic carcinogenesis, has proved to be difficult, although efforts are still ongoing. In HNPCC and a small minority of sporadic CRCs, the abnormalities accrue through accumulation of point mutations, which cannot be corrected because of defects in the DNA repair system. 5. Describe the natural sequence from colon adenoma to colon cancer. In one of the major milestones in gastroenterology, the 2004 National Polyp Study showed that removal of colonic adenomas during colonoscopy prevented subsequent development of colorectal cancer, showing that colonic adenomas are a vital step, which can be interrupted, in the carcinogenic progression of sporadic CRC. The prevalence curves for adenomas and colorectal cancers parallel each other, with the adenoma curve shifted 5 to 10 years earlier than carcinomas. This suggests that the time needed for an adenoma to develop into cancer is 5 to 10 years, thus giving a significant window of time to discover and remove premalignant lesions. There is accumulating evidence that there is a second pathway to the development of CRC in which some hyperplastic polyps (previously thought to be benign lesions without malignant potential) may develop into serrated adenomas, which are adenomas with a distinct histology and probably a distinct array of genetic abnormalities (BRAF mutations, extensive DNA methylation, and microsatellite instability). These serrated adenomas have a potential for malignant transformation equal to or perhaps greater than tubular adenomas.
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6. How prevalent are colonic adenomas among the U.S. population? The prevalence of adenomatous polyps appears to be highly dependent on the population studied. Two colonoscopic studies in asymptomatic populations have reported rates of 23% to 25% prevalence in male and female patients between the ages of 50 and 82 years. Two other studies involving only men in Department of Veterans Affairs Medical Centers had prevalence rates of approximately 40% and small studies have suggested prevalences of 50% or greater in some populations. 7. Where in the colon are polyps most commonly located? Autopsy series have shown a relatively even distribution of adenomas throughout the colon, although larger polyps have a distal predominance, as expected from the distribution of CRCs. Recently, there has been an increased interest in flat or nonpolypoid neoplasms whose prevalence may be as high 10%. These are more difficult to detect during standard endoscopy and, in the case of sessile serrated adenomas, which have both a predominant right colon distribution and malignant potential, may be significant contributors to missed or interval cancers (CRCs arising between screening or surveillance colonoscopies). 8. Give the mean age of onset and describe the anatomic distribution of CRC. True sporadic CRCs occur at a mean age of 69; approximately 60% are distal to the splenic flexure (thus theoretically within the reach of a flexible sigmoidoscope). However, some studies have suggested that older patients and blacks appear to have an increased proportion of CRCs in the right colon. 9. How are malignant polyps defined? How are they clinically managed? Pathologists prefer the term severe dysplasia for adenomas with a focus of carcinoma in situ or intramucosal carcinoma, because complete endoscopic removal is curative. The term malignant polyp is reserved for the approximately 5% of adenomas in which a focus of carcinoma has invaded beyond the muscularis mucosa into the submucosa, where lymphatic spread with metastasis is possible. A malignant polyp has at least one of the following characteristics:
• Poorly differentiated cancer • Invasion of veins or lymphatics • Extension of the carcinoma to less than 2 mm of the margin • Invasion of submucosa of the bowel wall When malignant polyps are found, consideration should be given to early re-endoscopy and/or local surgical resection. Endoscopic removal of a malignant polyp is associated with a 10% to 25% relapse rate. 10. How is colon cancer staged, and how does this affect prognosis? Although the overall 5-year survival is about 62% in the United States, there are significant differences among ethnic groups. Although histology and syndromes (HNPCC colorectal cancers have a better prognosis stage for stage than sporadic CRCs) have some effect, the best single determinant of prognosis is stage at diagnosis. The two most widely used staging methods are the Duke’s and TNM (tumor, node, metastasis) systems. Both give essentially equivalent information for prognostic purposes. The Duke’s system is simpler and still widely used by gastroenterologists and surgeons, whereas TNM staging is used more widely among oncologists and pathologists (Table 46-1).
Table 46-1. Duke’s Classification Versus Tumor, Node, Metastasis (TMN) Staging DUKE’S CLASSIFICATION*
5-YEAR SURVIVAL (%)
Stage A Limited to mucosa
95 to 100
Stage B1 Into muscularis propria Stage B2 Through serosa
80 to 85 75
5-YEAR SURVIVAL (%)
TMN STAGING† Stage 0 Carcinoma in situ Stage I Tumor invades submucosa Tumor invades muscularis propria Stage II Tumor invades through muscularis propria into serosa or pericolonic/perirectal tissue Tumor perforates or directly invades other organs
Tis N0 M0
100
T1 N0 M0 T2 N0 M0
95 80
T3 N0 M0 T4 N0 M0
Continued
Chapter 46 Colorectal Cancer And Colon Cancer Screening
Table 46-1 Duke’s Classification Versus Tumor, Node, Metastasis (TMN) Staging—Cont’d DUKE’S CLASSIFICATION*
5-YEAR SURVIVAL (%)
Stage C1 1 to 4 regional nodes positive Stage C2 >4 regional nodes positive
65 42
Stage D‡ Distant metastases
5
5-YEAR SURVIVAL (%)
TMN STAGING† Stage III Any perforation with nodal metastases N1: 1 to 3 nodes N2: ≥4 nodes N3: Any lymph node along named vascular trunk Stage IV Any invasion of bowel wall with or without lymph node metastases but with evidence of distant metastases
TX N1 M0 TX N2 M0 TX N3 M0
TX NX M1
*Gastrointestinal Study Group Modification. † American Joint Committee on Cancer. ‡ Included only in the Turnbull modification of Duke’s classification.
11. Describe the workup for CRC after the initial diagnosis. Surgical removal of the cancer remains the only curative therapy. Before surgery, visualization of the entire bowel, preferably by full colonoscopy, is indicated to exclude synchronous lesions (either adenomas or cancers) that may influence the operation. Preoperative laboratory tests should include complete blood count, blood chemistry panel-20, and carcinoembryonic antigen (CEA). If the CEA level is elevated at the time of diagnosis (approximately 60% of cases), it provides a convenient method for assessing effectiveness of the surgery and detecting early recurrences. Preoperative abdominal computed tomography (CT) scan and chest radiograph are useful in looking for metastatic disease. In rectal cancers, preoperative staging with transrectal ultrasound helps to determine the utility of adjunct radiation therapy. 12. What surgical margins are recommended? Most surgeons attempt to include at least 5 cm on either side of the tumor within the resection block, although margins as small as 2 cm may be acceptable in the distal rectum to preserve sphincter function. 13. Describe the recommended schedule of colonoscopic follow-up after surgery. If a preoperative colonoscopy clears the remainder of the colon of polyps or synchronous malignancy and the surgical margins are tumor free, colonoscopy before 1 to 3 years after resection is probably not indicated. The risk for developing metachronous neoplasms in a post malignancy resection patient is about the same as for a patient with an adenoma of unfavorable histology; therefore, intervals between colonoscopic screening exams should be similar, every 3 to 5 years. 14. Are there any effective blood tests to screen for CRC? Serum tests to diagnose CRC are limited by the inherent problem that markers produced by malignant cells are hardest to detect in the early, small tumors that have the best prognosis. To date, no putative serum markers of CRC have sufficient sensitivity or specificity to warrant use as primary screening modalities. CEA, the most widely used CRC tumor marker, is therefore useful only to assess efficacy of surgery or monitoring for recurrences in cancers already known to be CEA positive. Even this use has been challenged by those who believe that the clinical benefit of diagnosing recurrences is minimal. (Caveat: Because CEA is excreted in the bile, elevated levels may be difficult to interpret in the presence of biliary obstruction or hepatic dysfunction.) A reasonable surveillance approach in CEA-positive tumors is to check CEA levels every 2 months for the first 6 months, every 4 months for up to 2 years, and then every 6 months for up to 5 years. 15. List the risk factors for developing CRC. Age, diet, environment, personal history of colonic neoplasm, family history of colonic neoplasm, familial colon cancer syndromes, and inflammatory bowel disease. 16. What is the effect of age on the risk of developing CRC? The risk of developing CRC increases with age, starting at about age 40 and roughly doubling with each decade. Below age 40, the incidence of CRC is less than 6 in 100,000; however, by age 80 the incidence is approximately 500 per 100,000 in men and 400 per 100,000 in women. Because over 90% of colorectal cancers occur after age 50, most screening programs have arbitrarily chosen this as a starting age. 17. Discuss the effect of diet on the risk for developing CRC. Diet is thought to account for the major differences in the incidence rates of CRC worldwide. Although epidemiologic studies and animal models suggest that a high-fat, low-fiber diet (typical of Western nations) increases the risk
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of developing CRC, prospective trials of low-fat, high-fiber diets have shown no significant effect. Similarly, other micronutrients, such as folate, reducing agents (vitamins C and E), beta-carotene, and eicosanoids, showed promise in experimental conditions but either failed to yield positive results in controlled trials or still are under investigation. Calcium supplementation is the only dietary intervention that has shown a positive, albeit modest, effect in humans, using adenomas as a surrogate marker for the development of CRC. 18. Do environmental factors increase the risk for developing CRC? The risk of developing CRC is directly related to environmental factors. This effect is evident in comparing the rates of CRC in populations emigrating from a region with a low rate to a region with a high rate. For example, the incidence of colon cancer in the Japanese (low incidence) emigrating to the United States (high incidence) led to a 10-fold increase in incidence over a single generation, much too fast to be a selection phenomenon. In general, the United States and Western European nations have a higher rate of CRC than developing nations. 19. Which adenoma features are associated with a greater malignant potential? Adenomatous polyps are considered premalignant lesions, but the actual risk of neoplastic transformation is unknown. Large size, villous architecture, and dysplasia are features of adenomas that have a higher risk of developing a carcinoma within a given polyp. Some researchers believe that serrated adenomas may have an increased rate and risk of malignant transformation, although there is insufficient evidence to state this definitively. 20. What are the recommendations for CRC screening in people at average risk for CRC? Men and women at average risk should be offered screening for CRC and adenomatous polyps at age 50 years. Options for CRC screening include:
• Fecal occult blood test (FOBT) • Flexible sigmoidoscopy • FOBT and flexible sigmoidoscopy • Colonoscopy Stool DNA testing and CT colonography are two methods that appear to have a great deal of promise, although their utility in everyday clinical practice has yet to be defined. It is important to differentiate between screening modalities that are primarily effective at detecting CRCs, those that can detect both cancers and their precursor lesions, and those that can detect CRCs and identify and remove polyps. Each approach has its advantages and disadvantages, and each person should make an informed decision regarding their preference. 21. Give the current guidelines for surveillance colonoscopy in patients with a history of adenomatous polyps. A periodic surveillance program should be customized according to adequacy of the preparation and endoscopic findings. Colonoscopy Findings One or two tubular adenomas Large sessile (>2 cm) adenoma Inadequate colon preparation Large (>1 cm) adenoma, villous histology, or dysplasia
Next Colonoscopy 5 years 3 to 6 months Repeat within 3 to 6 months 3 years
22. Who is considered to be at increased risk for developing CRC? People at increased risk are defined as those individuals who have a personal history of CRC or an adenomatous polyp, a predisposing illness for CRC such as inflammatory bowel disease (IBD), a first-degree relative (parent, sibling, child) with CRC or an adenomatous polyp, or a gene carrier for familial colon cancer syndromes. The risk of developing CRC is increased approximately 2-fold if a first-degree relative has been diagnosed with CRC over age 65. The younger the age at which the relative was diagnosed, the higher is the risk. The risk also rises if more than one first-degree relative has been diagnosed with CRC. Perhaps more significant, the same risk seems to apply if first-degree relatives were found to have adenomatous polyps. Evidence suggests a slightly increased risk (approximately 1.5-fold) if third-degree relatives (e.g., cousins) have been diagnosed with CRC. 23. Which method of CRC screening is recommended for individuals at increased risk of developing CRC? Colonoscopy is the only recommended screening modality in this patient population.
Chapter 46 Colorectal Cancer And Colon Cancer Screening
24. List the familial colon cancer syndromes. • FAP and Gardner’s syndrome (FAP with extracolonic manifestations) • Hamartomatous polyp syndromes: Peutz-Jeghers syndrome (PJS) and juvenile polyposis syndrome (JPS) •. HNPCC 25. What tests are available for hereditary CRC? Diagnosis of an APC germline mutation is based on one of several DNA-based tests:
• Sequencing of the entire genome (95% sensitive) • Combination of confirmation strand gel electrophoresis screening and protein truncation testing (80% to 90% sensitive)
• Protein truncation alone (80% sensitive) • Linkage analysis (98% sensitive in most families with the FAP mutation) There are more than 228 germline mutations and more than 47 polymorphisms in the seven MMR genes associated with HNPCC. These multiple mutations have limited the development of inexpensive diagnostic assays for HNPCC and diagnosis is now based on direct DNA sequencing. Patients with JPS and their family members are appropriate candidates for genetic testing for germline mutations MAD4 and BMP1A using direct DNA sequencing. The only clearly identified gene mutation in PJS is STK11/LKB1, which leads to 40% to 60% of cases and can be diagnosed by mutation analysis of STK11. Candidate mutations associated with common familial colon cancer have not been characterized well enough to warrant routine genetic testing (Table 46-2).
Table 46-2. Features of Colon Cancer Syndromes SPORADIC CRC
HNPCC
FAP
ATTENUATED FAP
JPS
PJS
69
44
39
49
34
46
Lifetime 1:18 (F) 1:17 (M) Few polyps
1:2000
1:10,000
1:9000
1:100,000
1:200,000
Few polyps, proximal distribution
>100 polyps in teens
≈30 polyps with proximal distribution
>2 P-J polyps in GI tract
Gene abnormality
Multiple
APC (>90%), ? MYH (≈5%)
APC (>90%), ? MYH (≈5%)
Mode of inheritance
?
MLH1, MSH2, MSH6, PMS2, PMS1 Autosomal dominant
≈100s in colon, scattered elsewhere in GI tract MADH4/ SMA4 and BMPRIA (53%)
Autosomal dominant
Autosomal dominant
Autosomal dominant
Autosomal dominant
FEATURES Average age of CRC (yr) Incidence Colon polyps
STK11/ LKB1 (≈55%)
CRC, colorectal cancer; HNPCC, hereditary nonpolyposis colorectal cancer; FAP, familial adenomatous polyposis; JPS, juvenile polyposis syndrome; PJS, Peutz-Jeghers syndrome.
26. What is the recommended surveillance for people with a family history of CRC who do not fit the genetic profiles? • People with a first-degree relative with CRC or adenomatous polyp diagnosed at age younger than 60 years or two first-degree relatives with CRC diagnosed at any age should have a screening colonoscopy starting at age 40 years or 10 years younger than the earliest diagnosis in the family (whichever is first), and repeated every 5 years. • People with a first-degree relative with CRC or adenomatous polyp diagnosed at age older than 60 years or two second-degree relatives (grandparent, aunt, or uncle) with CRC should be screened as average-risk persons but beginning at age 40 years. • People with one second-degree relative with CRC should be screened as average risk.
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27. How do FAP and Gardner syndrome increase the risk of CRC? FAP and Gardner syndrome are inherited in an autosomal dominant manner with their phenotypic expression dependent on the location of the mutation in their APC gene. Their fully expressed forms are characterized by the development of hundreds to thousands of colonic adenomas. One hundred percent of patients expressing this phenotype develop CRC without colectomy. Most patients begin developing adenomas in their teens, and screening in families with a known proband should start at that time. One third of FAP cases arise as de novo mutations. The increased risk of CRC is thought to be due to the sheer number of adenomatous polyps; each polyp has the same risk of malignant transformation as an ordinary sporadic adenoma. 28. How are FAP and Gardner syndrome diagnosed? The APC gene is responsible for both FAP and Gardner syndrome. Most disease-causing mutations result in premature stop codons, which give rise to truncated proteins. Commercial tests are available to detect truncated proteins and to directly sequence the gene. The results can be used for accurate screening of affected kindreds. Members of FAP kindreds who have not developed adenomas by age 40 have not inherited the polyposis phenotype. The position of the mutation gives rise to the phenotype of the FAP. For example, mutations in the extreme beginning or end of the APC gene can cause an attenuated form of FAP, which is characterized by fewer adenomas (1 to 100) with a right-sided predominance. 29. In addition to colonoscopy, what other tests should be considered in FAP? Patients with FAP are at increased risk of extracolonic tumors, including thyroid cancer, pancreatic cancer, duodenal and ampullary cancer, and gastric cancer; therefore, periodic thyroid function tests, liver function tests, and upper gastrointestinal tract screening with both forward and side-viewing endoscopes are recommended. 30. What is the role of NSAIDs in treating FAP? Both sulindac and celecoxib decrease the number of adenomas in patients with FAP, but neither is associated with complete regression. Therefore, chemoprevention cannot replace prophylactic colectomy, although the timing of the colectomy may be delayed. 31. How do hamartomatous polyp syndromes affect the risk of developing CRC? Along with PJS and JPS, the differential diagnosis includes Cowden disease and the Bannayan-Ruvalcaba-Riley syndrome. Phenotypic features of hamartomatous syndromes display considerable overlap. Emerging understanding of the germline mutations may provide more accurate distinctions between these. Hamartomatous polyp syndromes appear to be associated with a slightly increased risk of developing CRC, although nowhere near the risk associated with APC syndromes. 32. What is HNPCC? HNPCC is an autosomal dominant inherited disease in which colon cancer is caused by inactivation of one of the proteins involved in DNA proofreading (usually hMSH2 or hMLH1) leading to early onset of colon cancers and extracolonic cancers (e.g., endometrial, ovarian, gastric, urinary tract, renal cell, biliary, and gallbladder). Colon cancer arises from discrete adenomas, which rapidly accumulate point mutations, resulting in a markedly accelerated progression from adenoma to carcinoma. Because the term nonpolyposis is misleading and the recognition that some members of these kindreds may develop cancers other than CRC, there has been a trend toward calling this entity by its original designation, Lynch syndrome. 33. How is HNPCC diagnosed? Diagnosis is based on either the Amsterdam criteria, the Amsterdam criteria II, or the Bethesda guidelines. The more stringent Amsterdam criteria increase the chances of finding a germline mutation in either MSH2 or MLH1 from 25% to 86%. The Bethesda guidelines are more sensitive but less specific than the Amsterdam criteria. Interestingly, there are a significant number of families fitting the Amsterdam criteria who do not appear to have abnormalities in the mismatch repair genes. These families should be screened endoscopically as outlined in the following section (Table 46-3 and Box 46-1).
Table 46-3. Amsterdam Criteria AMSTERDAM CRITERIA*
AMSTERDAM CRITERIA II
1. One member diagnosed with CRC before age 50 years 2. Two affected generations 3. Three affected relatives, one of them a FDR of the other two 4. Exclude FAP 5. Pathologic confirmation
1. At least three affected relatives with an HNPCCassociated cancer 2. One of whom is an FDR of the other two 3. At least two successive generations 4. One member diagnosed with CRC before age 50 years 5. Exclude FAP 6. Pathologic confirmation
CRC, colorectal cancer; FAP, familial adenomatous polyposis; FDR, first-degree relative; HNPCC, hereditary nonpolyposis colorectal cancer. *All criteria must be met.
CHAPTER 46 COLORECTAL CANCER AND COLON CANCER SCREENING
Box 46-1. Revised Bethesda Guidelines (Meeting any listed feature is sufficient to proceed with testing for microsatellite instability.) 1. Colorectal cancer diagnosed in a patient who is younger than 50 years of age 2. Presence of synchronous, metachronous colorectal or other HNPCC-associated tumors1 regardless of age 3. Colorectal cancer with the MSI-H histology diagnosed in a patient who is younger than 60 years old2 4. Colorectal cancer diagnosed in one or more first-degree relatives with an HNPCC-related tumor, with one of the cancers being diagnosed younger than age 50 years. 5. Colorectal cancer diagnosed in two or more first-or second-degree relatives with HNPCC-related tumors, regardless of age. 1 Colorectal, endometrial, stomach, ovarian, pancreas, ureter and renal pelvis, biliary tract, and brain (usually glioblastoma as seen in Turcot syndrome) tumors, sebaceous gland adenomas and keratoacanthomas in Muir-Torre syndrome, and carcinoma of the small bowel. 2 MSI-H (microsatellite instability-high tumors) refers to changes in two or more of the five NCI-recommended panels of microsatellite markers; histology features include presence of tumor-infiltrating lymphocytes, Crohn-like lymphocytic reaction, mucinous/signet ring differentiation, or medullary growth pattern.
34. Outline the screening recommendation for patients with HNPCC. Screening with colonoscopy for all members of the family should begin at age 20 to 25 years, repeated semiannually until age 40, and then yearly thereafter. Some individuals with known mutations may elect to have a subtotal colectomy before developing malignancies. 35. What is MYH-associated polyposis (MAP)? MYH polyposis is a recently described autosomal recessive polyposis syndrome that is phenotypically similar to attenuated FAP (15 to 500 adenomas) but does not have an APC germline mutation. This biallelic germline mutation causes nucleotide transversion G:C → T:A in the APC gene. MYH is a protein that acts synergistically with two other proteins, OGG1 and MTH1, in the base excision repair pathway to repair DNA replication errors caused by oxidative stress. These mutations have been demonstrated in both adenomas and carcinomas. It is unknown what percentage of patients with polyposis syndrome have this mutation. 36. What is microsatellite instability (MSI)? Microsatellites are short repeated DNA sequences (up to 10 nucleotides in length) that are susceptible to somatic mutation by misalignment. Ordinarily, this mismatch in the number of repeats is repaired by the DNA proofreading complex (which includes MSH2, MLH1, MSH6, MLH3, PMS1, and PMS2, the so-called mismatch repair genes). When this complex is inactivated (usually by changes in MSH2 or MLH1), mismatched bases, including the commonly occurring microsatellite repeat misalignments, cannot be repaired, leading to a rapid accumulation of genome-wide mutations. MSI is observed in approximately 85% of HNPCC colon cancers and 15% of sporadic colon cancers. As MSI is thought to be common in the malignant transformation of serrated but not tubular adenomas, the former lesions may be responsible for many of the MSI-positive sporadic cancers. The commonly accepted method for detecting MSI is by using a standard panel of five microsatellites, with abnormalities in two or more constituting the MSI-high (MSI-H) phenotype commonly associated with HNPCC. It appears that MSI-positive CRCs have a better prognosis stage-for-stage compared with microsatellite stable cancers; however, they may not respond as well to 5-FU–based chemotherapy. This argues for MSI testing becoming a routine part of the workup for newly diagnosed CRC cases. 37. How does inflammatory bowel disease (IBD) affect the risk of developing CRC? Patients with chronic IBD have an increased risk of developing colorectal cancer, particularly those with chronic ulcerative colitis (CUC). Please see Chapter 43 for colonoscopy screening recommendations in ulcerative colitis. 38. Which two clinical conditions should raise suspicion for the presence of colon cancer? An unexplained iron deficiency anemia or sepsis with Streptococcus bovis as the pathogen should trigger investigation for colorectal cancer. 39. Is FOBT effective in detecting colon polyps and cancer? Yes. Even in the absence of iron deficiency anemia, FOBT has been shown to decrease mortality by 15% to 30% in three large randomized, controlled trials using guaiac-based methods. Immunologic methods for testing human hemoglobin have shown some promise for increasing specificity but have not been widely used because of increased cost. Only large polyps (greater than 1.5 cm in diameter) and cancers bleed enough to be detected routinely by FOBT. Thus, although FOBT screening can reduce mortality from CRC by discovering malignancies at earlier, curable stages, it is considerably less effective in detecting adenomas, whose removal prior to malignant transformation is a much more cost-effective strategy.
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Chapter 46 Colorectal Cancer And Colon Cancer Screening
40. Does a program of periodic sigmoidoscopy decrease mortality from CRC? Yes. The magnitude of this decrease is determined by a number of factors, including distribution of CRCs, extent of the exam, predictive value of the procedure for lesions beyond the extent of the exam, and number of patients undergoing screening. Colonoscopic studies have shown that patients with adenomas within the reach of the flexible sigmoidoscope have an increased risk of significant lesions (large adenomas, adenomas with villous histology, and cancers) in the proximal colon and should have a full colonoscopy. With this strategy, one can detect approximately 80% of significant lesions with an examination to the splenic flexure and two thirds of significant lesions if only the descending colon is reached. However, the same data suggest that one half of significant lesions in the proximal colon have no sentinel lesions within the reach of a flexible sigmoidoscope and would be missed during screening. 41. What is the sensitivity and specificity of an air contrast barium enema? Carefully performed, air contrast barium enemas have sensitivities and specificities in the 90% range; however, in most centers the figures are considerably lower, perhaps because modern ultrasound-, CT-, or MRI-based procedures have become more fashionable. 42. How effective is CT colonography (CTC) as a screening test? Also known as virtual colonoscopy, CTC is an evolving technology for CRC screening. The problem to date with CTC as a screening option was the variability of the earlier multicenter trial results. Unpublished data from the 2005 National CT Colonography Trial (ACRIN 6664) showed 90% sensitivity and 86% specificity for adenomas larger than 1 cm. For smaller polyps of 6 mm or larger, the sensitivity and specificity were 78% and 88%, respectively. These preliminary results suggest CTC may be a viable option for CRC screening in selected populations (incomplete or failed colonoscopy, high risk for sedation, patient preference if at average risk for CRC). Nevertheless, this would suggest a 14% falsepositive rate resulting in inappropriate referral for colonoscopy. Additional data from the ACRIN 6664 trial should answer questions regarding patient preferences and cost-effectiveness of CTC compared to optical colonoscopy (OC). Ultimately, cost-effectiveness will hinge on how smaller polyps are managed. The American College of Radiology (ACR) recommends polyps of 5 mm or smaller not be reported at all and that patients with two polyps of 6 to 9 mm be offered the option of CTC follow-up in 3 years or OC with polypectomy. Many are concerned this could lead to the underdiagnosis of important colonic adenoma findings with delayed surveillance, as well as a concern regarding the ethics of incomplete disclosure with patients. In one study of 6000 consecutive polyps found on OC, 12% of polyps 5 to 10 mm had advanced histology and 1% were cancerous. In another retrospective study using the new ACR guidelines, one-third of all patients with high-risk findings (3% of total patients) with a recommended surveillance interval of 3 years would have been told after CTC that they are normal and to come back in 5 to 10 years. CTC has poorer sensitivity than colonoscopy in the detection of flat or depressed lesions. Flat polyps have been reported to be significantly more likely to contain high-grade dysplasia than protuberant polyps. How this affects the overall acceptance of CTC as a viable screening modality remains to be seen. 43. Can CRC be prevented with medicines (chemoprevention)? Because we cannot prevent CRCs by elimination of causative factors, the possibility of chemoprevention has generated considerable enthusiasm. NSAIDs, including sulindac and aspirin, have shown promise in both experimental models and epidemiologic studies. Recent studies have shown protective effects; however, maximum efficacy requires higher doses (more than 14 tablets/wk), which markedly increase the risk of gastrointestinal tract toxicity and potential bleeding. Aspirin use for adenoma prevention at present can only be recommended for those at increased risk for adenoma formation who have no history of ulcer disease or stroke. Sulindac decreases the number and size of adenomas in patients with FAP but does not completely prevent progression to cancer. Its efficacy in sporadic adenomas is unclear, although preliminary results of a trial using a combination of sulindac and DMFO (dimethylfluoroornithine) have shown significant promise at doses that may lower the potential gastrointestinal tract toxicity. Selective cyclooxygenase-2 inhibitors, which have a much lower gastrointestinal toxicity profile, are more effective than sulindac for FAP. Randomized, double-blind prospective studies have shown both rofecoxib and celecoxib to be effective at also decreasing sporadic adenoma recurrence, although only the latter is currently available.
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