Yield of Advanced Adenoma and Cancer Based on Polyp Size Detected at Screening Flexible Sigmoidoscopy

GASTROENTEROLOGY 2006;131:1683 1689 Yield of Advanced Adenoma and Cancer Based on Polyp Size Detected at Screening Flexible Sigmoidoscopy ROBERT E. SCHOEN,*, JOEL L. WEISSFELD, PAUL F. PINSKY, and THOMAS RILEY *Department of Medicine and Department of Epidemiology and the University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania; Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Bethesda, Maryland; and Information Management Services, Inc, Rockville, Maryland See editorial on page 2006. Background & Aims: Observational screening of the colon with subsequent referral for colonoscopy raises questions about the threshold of polyp size that necessitates referral. To examine the yield at colonoscopy when a given size lesion is observed, we assessed the yield of advanced adenoma and cancer at colonoscopy based on the size of the abnormality detected at flexible sigmoidoscopy (FSG). Methods: We used data from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, a randomized, controlled, community-based study of FSG. Results: Subsequent colonoscopy was performed on 10,850 subjects (60.4% male; mean age, 62.9 years) with a polyp visualized on screening FSG. For women with a polyp 0.5 0.9 cm on FSG (n 1426), the yield in the distal colon on colonoscopy was 0.6% for cancer (number needed to screen [NNS] 166) and 14.5% for advanced adenoma (NNS 7). In men (n 2183), the yield was 0.7% (NNS 142) for cancer and 15.9% (NNS 6) for advanced adenoma. Among persons with polyps 0.5 0.9 cm identified on FSG, 5.5% (198/3609) had distal advanced adenomas that measured 1.0 cm but had villous histology or high-grade dysplasia, and 9.9% (357/3609) had adenomas 1 cm. Conclusions: The yield for a distal advanced adenomatous lesion when a polyp 0.5 0.9 cm is observed at FSG is substantial and is due to the presence of advanced histology in polyps 1 cm and to detection of polyps that measure 1.0 cm on colonoscopy. Establishing thresholds for observation versus evaluation will require careful assessment of the overall yield. New methods for screening the colon for polyps and cancer are in development. Some of the new technology is observational, such as computerized tomographic (CT) colonography or virtual colonoscopy 1 or lower profile, less invasive colonoscopes such as the Aer-O-Scope, 2 in that polyps are visualized, but the therapeutic intervention to remove polyps requires referral for standard colonoscopy. From a costeffectiveness standpoint, the greater the likelihood that a subject is to be referred for a subsequent colonoscopy, the less cost-effective the initial observational screen will be because 2 procedures are required. The negative effect on cost-effectiveness for colonoscopy referral can be strong. 3 There is general agreement that, when a polyp 1.0 cm is found, 4 6 subjects should be sent for colonoscopy. There is much greater uncertainty about the role of colonoscopy when polyps 1.0 cm are found. For example, in an attempt to limit colonoscopy use after abnormal virtual colonoscopy, the Working Group on Virtual Colonoscopy recommends a threshold. According to their guideline, it is reasonable to defer colonoscopy when polyps 6 9 mm in size are encountered during a virtual examination if fewer than 3 polyps are present. As an alternative, a repeat virtual colonoscopy at an interval of up to 3 years is recommended. 4 The rationale for not proceeding with immediate colonoscopy is that cross-sectional studies examining large numbers of small adenomas have demonstrated that the prevalence of cancer is much lower in smaller lesions as compared with lesions 1.0 cm. 4 The data suggest that polyps in the 6- to 9-mm range harbor invasive cancer in 1% of cases and high-grade dysplasia in approximately 4%. 7 In a recent article, advanced histology was seen in 4.2% of polyps 9 mm and cancer in 0.2%. 8 Pathologic study of removed lesions, however, may not be equivalent to an evaluation of what is found when a screening test estimates that a lesion of a given size is present. Differences between screening test results and subsequent colonoscopy may be due to measurement differences between the 2 tests or to missed lesions on 1 examination and not the other. As noted in the recent American Gastroenterological Association (AGA) Institute white paper on CT colonography, understanding the relationship of polyp size to clinical outcome is a fundamental question and vital to evaluating the potential impact of virtual colonoscopy on the practice of gastroenterology. 7 To address the yield at colonoscopy when a given size lesion is observed, we utilized data from the sigmoidoscopy examination from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO). We examined the yield of advanced adenoma and cancer based on the size of the lesion identified at sigmoidoscopy. In the PLCO Trial, lesion size at sigmoidoscopy is estimated and recorded, and subjects are referred to their primary care physicians for subsequent management, often for diagnostic colonoscopy. 9 Data from the PLCO Trial can be used to assess the yield from diagnostic colonoscopy after a screening test in this case flexible sigmoidoscopy observes a polyp and estimates a size, but does not assess histology, similar to the situation when observational screening of the colon is performed. Abbreviations used in this paper: FSG, flexible sigmoidoscopy; NNS, number needed to screen; PLCO, Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. 2006 by the AGA Institute 0016-5085/06/$32.00 doi:10.1053/j.gastro.2006.08.025

1684 SCHOEN ET AL GASTROENTEROLOGY Vol. 131, No. 6 Materials and Methods The PLCO Cancer Screening Trial is a multicenter randomized trial sponsored by the National Cancer Institute, which evaluates the effectiveness of early detection of prostate, lung, colorectal, and ovarian cancer. For colorectal cancer, the PLCO Trial tested 60-cm flexible sigmoidoscopy, administered on 2 occasions, at enrollment and 3 years later for those randomized before December 1995, or 5 years later for the others. Participant eligibility criteria relevant to this investigation included the following: (1) age, 55 74 years; (2) no known prior cancer of the colon or rectum; and (3) no colonoscopy, sigmoidoscopy, or barium enema in the past 3 years (for individuals randomized after April 1995). Additional eligibility criteria and information about the PLCO cohort have been previously published. 9,10 Randomization into the PLCO Trial began in November 1993 and was completed in July 2001, with over 154,000 people aged 55 74 years enrolled. Participants were largely recruited via mass mailing of informational brochures and letters of invitation to age-eligible persons identified on public, commercial, or screening center-specific mailing lists. The 10 PLCO Trial centers are located in the following cities: Washington, DC; Detroit, MI; Salt Lake City, UT; Denver, CO; Honolulu, HI; Minneapolis, MN; Marshfield WI; Pittsburgh, PA; St. Louis, MO; and Birmingham, AL. Flexible sigmoidoscopy (FSG) examinations were performed by trained nurses or certified physicians. An FSG examination was considered positive if the examiner noted a polypoid lesion or mass. At sigmoidoscopy, PLCO Trial examiners recorded the location and shape and estimated the size of each of the 4 largest lesions. Lesion size was determined by visual estimation. Lesions were usually not biopsied or removed. Individuals were referred to their personal physicians for evaluation of screendetected abnormalities and were tracked to determine the results of subsequent diagnostic workup. Data on diagnostic follow-up for up to 12 months after the FSG examination were collected using trained medical record abstractors, who recorded the pathology, size, and location of each lesion found. The anatomic site of lesions was recorded as rectum, sigmoid colon, descending colon, splenic flexure, transverse colon, hepatic flexure, ascending colon, or cecum, and, when available, the distance in centimeters to the lesion was documented. Lesion size was recorded from the colonoscopy report. Dates of diagnosis and TNM clinical and pathologic stages were collected for subjects with invasive colorectal cancer. For classification of abnormalities found on subsequent colonoscopy, a lesion in the rectum, sigmoid colon, or descending colon was considered distal. If the anatomic site was not recorded and the distance was, then a lesion at a distance of less than 50 cm into the colon was considered distal. Any lesion with a recorded anatomic location from the splenic flexure to the cecum or a lesion with no recorded location but a distance 50 cm into the colon was considered proximal. Pathologic results were obtained from the local hospital pathologist s report. An adenoma was defined as advanced if it was reported as containing villous features (villous or tubulovillous adenomas), was large ( 1 cm as estimated by the endoscopist at colonoscopy), or had severe dysplasia. Carcinoma in situ was classified as severe dysplasia. To compare the yields at colonoscopy based on polyp size found at FSG, we calculated the number of patients needed to screen (NNS) or the number of patients Table 1. Demographic Characteristics N(%) Sex Male 6548 (60.4) Female 4302 (39.6) Age (y) 55 59 3276 (30.2) 60 64 3440 (31.7) 65 69 2682 (24.7) 70 74 1452 (13.4) Education College graduate 3718 (34.3) Post-high school/some college 3758 (34.6) High school or less 3338 (30.8) Missing 36 (0.3) Race White 9933 (91.5) African American 480 (4.4) Hispanic/Asian/other 437 (4.0) Family history colorectal cancer None 9067 (83.6) First-degree relative 1296 (11.9) Missing/possible 487 (4.5) needing to undergo colonoscopy to detect each of the 2 outcomes of interest, cancer, or advanced adenoma. Results Of 77,465 men and women aged 55 74 years randomized to the intervention group, a baseline screening FSG examination was performed in 64,658 (83.5%). Of these, 15,150 (23.4%) had an abnormal examination suspicious for a polyp or mass. Information on 10,875 (71.8%) who underwent a subsequent diagnostic colonoscopy within 1 year of the abnormal flexible sigmoidoscopy was available. An additional 25 subjects were excluded from this study because the sizes of their polyps were not available, leaving 10,850 subjects who had an abnormal FSG and who underwent a diagnostic colonoscopy within 1 year. Of these, 60.4% were male, and 91.5% were white. The demographic characteristics of this population are reported in Table 1. Nearly 70% had education beyond high school, and 11.9% reported having a first-degree relative with colorectal cancer. Table 2 examines the yield of cancer or advanced adenoma in the distal colon for women and men by 5-year age groupings who had a polyp 1.0 cm detected at screening FSG. Of 602 women with a large polyp on flexible sigmoidoscopy, 38 (6.3%) had cancer and 326 (54.2%) had an advanced adenoma detected in the distal colon. The NNS for cancer was 16 and for advanced adenoma 1.8. The results for men were similar. The yield for cancer was lower for men and women ages 55 59 years compared with those 60 years or older (Table 2). Of the women and men who had a polyp 1.0 cm detected at screening FSG, 15.0% and 14.7% had 1 or more smaller adenomas ( 1.0 cm) detected at colonoscopy, and 23.4% and 20.7% did not have an adenomatous polyp detected at colonoscopy, respectively. For women with the largest lesion measuring 0.5 0.9 cm on FSG (n 1426) (Table 3), the yield of advanced adenoma by 5-year age group ranged from 14% in the ages 55- to 59-year group to 16.2% in the ages 70- to 74-year group. Overall, there

December 2006 POLYP SIZE AND YIELD 1685 Table 2. Yield of Cancer or Advanced Adenoma in Distal Colon for Persons With a Polyp 1.0 cm at Flexible Sigmoidoscopy Cancer 7 (4.2) 14 (7.7) 10 (6.8) 7 (6.4) 38 (6.3) 16 Advanced adenoma 83 (50.3) 98 (53.8) 83 (56.8) 62 (56.9) 326 (54.2) 1.8 No. in cohort 165 182 146 109 602 Age, y 55 59 60 64 65 69 70 74 All NNS Cancer 14 (4.4) 29 (7.2) 25 (7.8) 11 (6.5) 79 (6.5) 15 Advanced adenoma 175 (55.2) 216 (53.9) 178 (55.3) 94 (55.3) 663 (54.8) 1.8 No. in cohort 317 401 322 170 1210 was a 0.6% rate of cancer and a 14.5% rate of advanced adenoma, for an NNS of 166 for cancer and 7 for advanced adenoma. The corresponding rates for men (n 2183) with the largest lesion measuring 0.5 0.9 cm (Table 3) were 0.7% for cancer and 15.9% for advanced adenoma or an NNS of 142 and 6, respectively. The distal colon cancer and advanced adenoma rates for women with the largest lesion measuring 0.5 cm detected at FSG in women (n 2274) (Table 4) were 0.1% for cancer and 4.1% for advanced adenoma, for an NNS of 1000 for cancer and 24 for advanced adenoma. In men (n 3155) compared with women (Table 4), as seen with lesions in the 0.5- to 0.9-cm range, the rates were somewhat higher, with a 0.3% rate for cancer and 4.9% for advanced adenoma, for an NNS of 333 for cancer and 20 for advanced adenoma. The yield of cancer or advanced adenoma in the distal colon for persons with the largest polyp on FSG measuring 1.0 cm, 0.5 0.9 cm, or 0.5 cm followed the expected progression, with the highest yields for persons with larger polyps, and lower yields as lesion size decreased The presence of multiple polyps in the same size range on FSG did not appreciably change the diagnostic yields (data not shown). The yields based on findings in the entire colon (Table 5), as opposed to findings limited to the distal colon, were higher. This is as one would expect because lesions in the proximal colon are included in the outcome results. The yield of cancer for persons with the largest lesion detected in the 0.5- to 0.9-cm range at FSG for women and men, respectively, were 0.8% and 0.9%, for an NNS of 125 and 111, respectively. The advanced adenoma rates ranged between 16% and 21% with an NNS of 6 and 5, respectively. For persons with lesions 0.5 cm, the NNS for cancer in women was 250 and in men 167. The advanced adenoma NNS was 15 in women and 11 in men. The determinants of advanced lesions were similar in women and men. Some polyps met more than 1 of the criterion for advanced adenoma. Table 6 describes persons with at least 1 advanced distal adenoma on subsequent diagnostic colonoscopy according to the characteristics of the largest polyp at FSG. For persons with the largest polyp on FSG measuring 0.1 0.4 cm and 0.5 0.9 cm, respectively, the most advanced adenoma was large ( 1.0 cm) in 59.2% and 64.3% and not large ( 1.0 cm) but villous or with high-grade dysplasia in 40.8% and 35.7%. Among 3609 persons (1426 women and 2183 men) at FSG with the largest polyp between 0.5 and 0.9 cm, 5.5% (198/3609) had an adenoma at colonoscopy 1.0 cm but with villous histology or high-grade dysplasia, and 9.9% (357/3609) had a large adenoma, measuring 1 cm in size. To examine in greater detail the relationship between polyp size at sigmoidoscopy to that found at colonoscopy, we compared polyp size in subjects with both a single distal lesion at FSG and a single distal lesion (adenomatous and nonadenomatous) at colonoscopy (n 1795, Table 7). For polyps whose size measured between 5 and 7 mm at FSG (Table 7), 72.1% 77% measured no more than 3 mm larger (or less than 8 10 mm, respectively) at colonoscopy. Conversely, in 23% 27.9%, a polyp 4 mm larger or more (or 9 11 mm, respectively) was detected at colonoscopy. For example, for 6-mm polyps at sigmoidoscopy, 72.1% measured 9 mm at colonoscopy, but 27.9% measured 10 mm, including 12.3% measuring 11 mm or greater. Table 3. Yield of Cancer or Advanced Adenoma in Distal Colon for Persons Whose Largest Polyp is 0.5 0.9 cm at Flexible Sigmoidoscopy Cancer 4 (1.0) 4 (0.9) 0 (0) 0 (0) 8 (0.6) 166 Advanced adenoma 54 (14.0) 68 (14.7) 50 (13.8) 35 (16.2) 207 (14.5) 7 No. in cohort 386 462 362 216 1426 Cancer 4 (0.6) 5 (0.7) 4 (0.7) 2 (0.8) 15 (0.7) 142 Advanced adenoma 107 (16.0) 115 (16.4) 83 (15.1) 43 (16.2) 348 (15.9) 6 No. in cohort 667 700 551 265 2183

1686 SCHOEN ET AL GASTROENTEROLOGY Vol. 131, No. 6 Table 4. Yield of Cancer or Advanced Adenoma in Distal Colon for Persons Whose Largest Polyp is 0.5 cm at Flexible Sigmoidoscopy Cancer 0 (0) 3 (0.5) 0 (0) 0 (0) 3 (0.1) 1000 Advanced adenoma 36 (4.7) 23 (3.4) 27 (4.9) 8 (2.7) 94 (4.1) 24 No. in cohort 761 669 546 298 2274 Cancer 2 (0.2) 3 (0.3) 3 (0.4) 3 (0.8) 11 (0.3) 333 Advanced adenoma 31 (3.2) 54 (5.3) 46 (6.1) 25 (6.3) 156 (4.9) 20 No. in cohort 980 1026 755 394 3155 Discussion Observational screening for colorectal cancer, such as with virtual colonoscopy, 1 raises important questions about the threshold for further diagnostic testing. The intent of observational screening is to identify higher risk subjects, and to target expensive, invasive testing such as colonoscopy. However, the establishment of a threshold of size for referral to colonoscopy will result in delay in detection and diagnosis of some lesions. For example, The Working Group on Virtual Colonoscopy recommends observing polyps 6 9 mm in size detected at virtual colonoscopy. 4 The implications of deferring evaluation are under study, 11,12 but final results are not expected for several years. We used data from screening FSG and follow-up colonoscopy conducted in conjunction with the PLCO Cancer Screening Trial to evaluate the yield of cancer and advanced adenoma on colonoscopy based on the size of the abnormality observed at FSG. Over 10,000 individuals ages 55 74 years from a geographically diverse population with a paired FSG and colonoscopy could be assessed, and, because of the diversity of pathologists and endoscopists involved, the data reflect real-world, community-based results. Because adenomas 1 cm are more likely to harbor malignancy 13 or to be associated with subsequent risk of malignancy, 14 experts agree that individuals with polyps 1 cm detected on FSG 5,6 or on virtual colonoscopy 4 should proceed to colonoscopy. The wisdom of this policy is borne out by our results, which show that when a polyp 1 cm was detected on FSG, the risk that cancer would be detected in the distal colon was approximately 6.5% for men or women or that only 15 to 16 people would need to undergo colonoscopy to detect cancer in the distal colon. The prevalence of finding an advanced adenoma in the distal colon was nearly 55%, with fewer than 2 subjects needing to undergo colonoscopy to detect an advanced adenoma. The yield for advanced adenoma was not 100%, as one might expect, because polyps identified as 1.0 cm on FSG may measure 1.0 cm at colonoscopy, the polyp detected may Table 5. Yield of Cancer or Advanced Adenoma in Entire Colon For persons whose largest polyp is 0.5 0.9 cm at flexible sigmoidoscopy Cancer 4 (1.0) 5 (1.1) 0 (0) 2 (0.9) 11 (0.8) 125 Advanced adenoma 65 (16.8) 81 (17.5) 59 (16.3) 45 (20.8) 250 (17.5) 6 No. in cohort 386 462 362 216 Cancer 5 (0.8) 5 (0.7) 5 (0.9) 5 (1.9) 20 (0.9) 111 Advanced adenoma 134 (20.1) 140 (20.0) 109 (19.8) 56 (21.1) 439 (20.1) 5 No. in cohort 667 700 551 265 2183 For persons whose largest polyp is 0.5 cm at flexible sigmoidoscopy Cancer 0 (0) 4 (0.6) 4 (0.7) 0 (0) 8 (0.4) 250 Advanced adenoma 50 (6.6) 39 (5.8) 41 (7.5) 17 (5.7) 147 (6.5) 15 No. in cohort 761 669 546 298 2274 Cancer 3 (0.3) 4 (0.4) 4 (0.5) 8 (2.0) 19 (0.6) 167 Advanced adenoma 64 (6.5) 95 (9.3) 84 (11.1) 48 (12.2) 291 (9.2) 11 No. in cohort 980 1026 755 394 3155

December 2006 POLYP SIZE AND YIELD 1687 Table 6. Distal Advanced Adenoma Characteristics by Size of Largest Polyp at Flexible Sigmoidoscopy (FSG) Distal advanced adenoma characteristics Large, villous HGD Large, not villous, HGD Villous HGD HGD Total Largest polyp at FSG (cm) 0.1 0.4 50 (20.0%) a 98 (39.2) b 86 (34.4) c 16 (6.4) 250 0.5 0.9 119 (21.4) d 238 (42.9) e 176 (31.7) f 22 (4.0) 555 NOTE. Large is 1 cm. HGD, High-grade dysplasia. a Four of 50 subjects had HGD. b One of 98 subjects had HGD. c One of 86 subjects had HGD. d Eighteen of 119 subjects had HGD. e Ten of 238 subjects had HGD. f Four of 176 subjects had HGD. not be adenomatous, or no polyp may be identified at subsequent colonoscopy. 9 Our primary aim was to examine the yield at colonoscopy based on the size of the largest lesion identified at FSG, with particular emphasis on the yield in persons with at least 1 polyp 0.5 0.9 cm in size. For persons whose largest polyp detected on FSG measured 0.5 0.9 cm, the yield for cancer in the distal colon was 0.6% 0.7% in women and men, with an NNS of 142 to 166. The yield for an advanced adenoma was approximately 15%, with an NNS of only 6 to 7. The yield from the entire colon was higher yet (Table 5). It is important to put these yields in perspective. Studies of screening colonoscopy demonstrate that the prevalence of advanced proximal neoplasia, predominantly advanced adenomas, in those with a negative FSG is approximately 1% 2%. 15,16 In a recent screening colonoscopy study in women, the rate was 3.2%. 17 This translates to an NNS ranging from 30 to 100. That is, in the setting of a negative FSG, there is still a 1% 3% chance that an advanced adenoma or cancer may be present in the proximal colon. The probability of missed advanced proximal neoplasia has led many authors to caution against FSG as a primary screening tool 17 19 and has fueled the preference of colonoscopy over FSG by some organizations. 20 The US Preventive Services Task Force 21 and the gastrointestinal consortium 22 continue to endorse a variety of screening modalities but recognize the enhanced accuracy of colonoscopy. 21 In comparison, the yield of advanced neoplasia after colonoscopy for persons with a polyp no larger than 0.5 0.9 cm at FSG is substantially higher with an NNS to detect advanced neoplasia in the distal colon of 6 7, around 8-fold greater than that for performing a colonoscopy after a negative FSG. Even for persons with diminutive polyps 0.5 cm, the NNS for an advanced lesion in the distal colon was 20 24, approximately 2-fold greater than that for colonoscopy after a negative FSG. It is important to note that the yields we have focused on are yields in the distal colon for lesions seen within the distal colon on FSG. This is to allow a more direct comparison of what was observed to what was found in a similar region of the colon. If one includes in the yield lesions found throughout the colon, the yields are higher. There are a number of reasons for the substantial yield of advanced adenoma and cancer for persons with polyps 1.0 cm on FSG. In 5.5% of people, an adenoma 1 cm was detected, but the adenoma had villous features or high-grade dysplasia. In 9.9%, an adenoma 1 cm was detected. In these latter instances, the size of the lesion may have been underestimated at FSG or overestimated at colonoscopy. The lesion could have been missed, such that the FSG was identifying a different Table 7. Relationship Between Polyp Size at Flexible Sigmoidoscopy and Subsequent Colonoscopy in Subjects With a Single Distal Polyp Size at colonoscopy (mm),n(%) 5 5 6 7 8 9 10 11 All Size at flexible sigmoidoscopy (mm) 5 444 (53.1) 135 (16.2) 48 (5.7) 18 (2.2) 36 (4.3) 4 (0.5) 29 (3.5) 122 (14.6) 836 5 71 (23.9) 91 (30.6) 19 (6.4) 18 (6.1) 18 (6.1) 4 (1.4) 27 (9.1) 49 (16.5) 297 6 17 (13.9) 20 (16.4) 26 (21.3) 14 (11.5) 10 (8.2) 1 (0.8) 19 (15.6) 15 (12.3) 122 7 11 (12.6) 11 (12.6) 8 (9.2) 15 (17.2) 10 (11.5) 1 (1.2) 11 (12.6) 20 (23.0) 87 8 20 (19.8) 13 (12.9) 12 (11.9) 6 (5.9) 16 (15.8) 3 (3.0) 11 (10.9) 20 (19.8) 101 9 4 (36.4) 2 (18.2) 1 (9.1) 1 (9.1) 3 (27.3) 11 10 10 (6.1) 11 (6.7) 11 (6.7) 4 (2.4) 12 (7.3) 4 (2.4) 56 (34.2) 56 (34.2) 164 11 6 (3.4) 5 (2.8) 2 (1.1) 1 (0.6) 3 (1.7) 3 (1.7) 35 (19.8) 122 (68.9) 177 All 579 (32.3) 290 (16.2) 128 (7.1) 76 (4.2) 106 (5.9) 21 (1.2) 191 (10.6) 404 (22.5) 1795 NOTE. N 1795.

1688 SCHOEN ET AL GASTROENTEROLOGY Vol. 131, No. 6 lesion than that detected at colonoscopy, or the large lesion, although detected in the distal colon by colonoscopy, was actually beyond the reach of the FSG and was not the same lesion because of the shortening of the colon at colonoscopy (by accordioning or sleeving of the bowel onto the colonoscope). It is likely that all of these reasons contributed to the observed large adenoma rate in the distal colon. Missed lesions are unlikely to be the sole explanation because the proportion of subjects with large distal adenomas correlated to the size of the lesion identified at FSG (data not shown) and was not randomly distributed. However, the advanced adenoma and cancer yields detected here are significant enough so that misclassification of size on the order of 10% or 20% 23 would have only a small impact on the overall yield or NNS. Previous studies suggest that polyps 6 9 mm harbor invasive cancer 1% of the time and high-grade dysplasia in approximately 4%. 7 Our data are not comparable because we are not evaluating pathologic results observed in polyps of given size removed at colonoscopy. Rather than using the polyp as the unit of analysis, we are using the patient as the unit of analysis and assessing colonoscopy outcomes in patients classified according to the largest polyp discovered at sigmoidoscopy. Our data emphasize, for example, that the yield at colonoscopy in an individual found to have a polyp of an estimated size of 0.6 cm during an observational examination is not necessarily the same as the pathologic diagnosis attached to a 0.6-cm polyp removed at colonoscopy. One must use caution when directly translating the yield on colonoscopy from a polyp 0.5 0.9 cm observed on sigmoidoscopy to the yield seen with a similar size polyp by a different observational technology. For example, because virtual colonoscopy is prone to false-positive examinations because of stool, 24 it is possible that the yield on virtual colonoscopy for observed similar sized lesions would be lower than that of sigmoidoscopy. Alternatively, because virtual colonoscopy visualizes the entire colon, lesions beyond the reach of sigmoidoscopy are identifiable, and virtual colonoscopy may more correctly identify subjects with large lesions. In the PLCO Trial, in nearly 20% of cases, colonoscopy could not confirm an abnormality detected on FSG, generally a small polyp. 9 Whether these examination results are false positive sigmoidoscopy examination results or false negative colonoscopy examination results is indeterminable, 25 but they reflect inherent limitations in using colonoscopy as the gold standard. 1 Nonetheless, the large size of this cohort, with its broad geographic representation, and involvement of a huge cadre of FSG examiners and colonoscopists, makes these results representative of expected yields in the community setting. 9 Little is known about the natural history of advanced adenomas. 26,27 Although they are now commonly utilized as an end point for evaluating screening, this is in part because they are much more common than invasive cancer, and the nature of prevention is to identify lesions likely to become cancer. However, if advanced adenomas are unlikely to progress to invasive cancer, or do so on average over a prolonged period of time, then strategies to maximize their detection may be overly aggressive. In conclusion, the yield for cancer and advanced adenoma within the distal colon in persons with a polyp measuring no larger than 0.5 0.9 cm on FSG is substantial, regardless of age or gender, when compared, for example, to the yield for proximal lesions after a negative FSG. This result is due to the presence of advanced histology in polyps 1 cm and to detection of polyps that measure 1.0 cm on colonoscopy. Had we observed polyps in the 5- to 9-mm range in the PLCO Trial, we would have missed a considerable number of advanced distal and proximal lesions. In the United Kingdom 5 and in the Italian FSG screening trial, 6 biopsies of polyps 6 9 mm are performed, and the decision to proceed to colonoscopy is contingent on the histology. Whether that strategy would have been sufficient to detect these advanced lesions is unknown. However, histologic sampling is not possible with observational screening. Assessment of the yield for advanced lesions across all colorectal cancer screening activities, including yield on surveillance examinations after a previous history of adenomatous polyps, yield after a negative examination, and yield after an observational screening test identifies an abnormality requires careful scrutiny. Putting these yields in perspective is essential toward developing a cogent, logical, and prioritized approach to colorectal cancer prevention. Our data suggest that care must be taken in establishing the threshold for observation versus evaluation. References 1. Pickhardt PJ, Choi JR, Hwang I, Butler JA, Puckett ML, Hildebrandt HA, Wong RK, Nugent PA, Mysliwiec PA, Schindler WR. Computed tomographic virtual colonoscopy to screen for colorectal neoplasia in asymptomatic adults (see comment). N Engl J Med 2003; 349:2191 2200. 2. Vucelic B, Rex D, Pulanic R, Pfefer J, Hrstic I, Levin B, Halpern Z, Arber N. The Aer-O-Scope: proof of concept of a pneumatic, skill independent, self-propelling, self-navigating colonoscope. Gastroenterology 2006;130:2248 2249. 3. Ladabaum U, Song K, Fendrick AM. Colorectal neoplasia screening with virtual colonoscopy: when, at what cost, and with what national impact? Clin Gastroenterol Hepatol 2004;2:554 563. 4. Zalis ME, Barish MA, Choi JR, Dachman AH, Fenlon HM, Ferrucci JT, Glick SN, Laghi A, Macari M, McFarland EG, Morrin MM, Pickhardt PJ, Soto J, Yee J, Working Group on Virtual Colonoscopy. CT colonography reporting and data system: a consensus proposal (review; 36 references). Radiology 2005;236:3 9. 5. UK Flexible Sigmoidoscopy Screening Trial Investigators. Single flexible sigmoidoscopy screening to prevent colorectal cancer: baseline findings of a UK multicentre randomised trial (comment). Lancet 2002;359:1291 1300. 6. 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