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• W2017205280 abstract "Background & Aims: The flat adenoma may be a more aggressive pathway in colorectal carcinogenesis. Sessile adenomas from the National Polyp Study cohort were reclassified histopathologically as flat or polypoid and compared with initial and surveillance pathology. Methods: A total of 933 sessile adenomas detected during 1980–1990 were reclassified as follows: (1) adenoma thickness (AT): ≤1.3 mm, and (2) adenoma ratio (AR): adenoma thickness <2× normal mucosa thickness. Logistic regression was used to assess whether flat adenomas had an effect on risk for high-grade dysplasia initially, and a Cox proportional hazards model assessed the risk for advanced adenomas at surveillance. Results: The analysis encompassed 8401 person-years of follow-up evaluation. AT and AR measures of adenoma flatness were 95% concordant. By the AT measure, flat adenomas (n = 474) represented 27% of all baseline adenomas. Flat adenomas were found to be no more likely to exhibit high-grade dysplasia than sessile (polypoid) or pedunculated adenomas, the odds ratio for high-grade dysplasia was 1.91 (95% confidence interval [CI], 0.66–5.47; P = 0.23) for sessile (polypoid) vs. flat adenomas and 1.78 (95% CI, 0.63–5.02; P = 0.28) for pedunculated vs. flat adenomas adjusted for size, villous component, and location, and corrected for correlation of risk within an individual patient. Patients with flat adenomas at initial colonoscopy were not at greater risk for advanced adenomas at surveillance compared with those with polypoid adenomas only, the odds ratio was 0.76 (95% CI, 0.4–1.42; P = .39), adjusted for multiplicity, age, and family history of colorectal cancer. Conclusions: Flat adenomas identified in the National Polyp Study cohort at baseline were not associated with a higher risk for high-grade dysplasia initially, or for advanced adenomas at surveillance. Background & Aims: The flat adenoma may be a more aggressive pathway in colorectal carcinogenesis. Sessile adenomas from the National Polyp Study cohort were reclassified histopathologically as flat or polypoid and compared with initial and surveillance pathology. Methods: A total of 933 sessile adenomas detected during 1980–1990 were reclassified as follows: (1) adenoma thickness (AT): ≤1.3 mm, and (2) adenoma ratio (AR): adenoma thickness <2× normal mucosa thickness. Logistic regression was used to assess whether flat adenomas had an effect on risk for high-grade dysplasia initially, and a Cox proportional hazards model assessed the risk for advanced adenomas at surveillance. Results: The analysis encompassed 8401 person-years of follow-up evaluation. AT and AR measures of adenoma flatness were 95% concordant. By the AT measure, flat adenomas (n = 474) represented 27% of all baseline adenomas. Flat adenomas were found to be no more likely to exhibit high-grade dysplasia than sessile (polypoid) or pedunculated adenomas, the odds ratio for high-grade dysplasia was 1.91 (95% confidence interval [CI], 0.66–5.47; P = 0.23) for sessile (polypoid) vs. flat adenomas and 1.78 (95% CI, 0.63–5.02; P = 0.28) for pedunculated vs. flat adenomas adjusted for size, villous component, and location, and corrected for correlation of risk within an individual patient. Patients with flat adenomas at initial colonoscopy were not at greater risk for advanced adenomas at surveillance compared with those with polypoid adenomas only, the odds ratio was 0.76 (95% CI, 0.4–1.42; P = .39), adjusted for multiplicity, age, and family history of colorectal cancer. Conclusions: Flat adenomas identified in the National Polyp Study cohort at baseline were not associated with a higher risk for high-grade dysplasia initially, or for advanced adenomas at surveillance. The National Polyp Study, a multicenter, randomized, clinical trial, was initiated in 1980 to determine appropriate surveillance intervals for patients discovered to have one or more colorectal adenomas.1Winawer S.J. Zauber A.G. O’Brien M.J. Ho M.N. Gottlieb L.S. Sternberg S.S. Waye J.D. Bond J.H. Schapiro M. Stewart E.T. Panish J. Ackroyd F. Kurtz R.C. Shike M. National Polyp Study WorkgroupRandomized comparison of surveillance intervals after colonoscopic removal of newly diagnosed adenomatous polyps.N Engl J Med. 1993; 328: 901-906Crossref PubMed Scopus (891) Google Scholar This study provided empiric clinical evidence in support of the adenoma-carcinoma sequence by showing a greater than 75% reduction in the expected incidence of colorectal carcinoma in the surveilled cohort compared with the general population.2Winawer S.J. Zauber A.G. Ho M.N. O’Brien M.J. Gottlieb L.S. Sternberg S.S. Waye J.D. Schapiro M. Bond J.H. Panish J.F. Ackroyd F. Stewart E.T. National Polyp Study WorkgroupPrevention of colorectal cancer by colonoscopic polypectomy.N Engl J Med. 1993; 329: 1977-1981Crossref PubMed Scopus (3941) Google Scholar Study endoscopists, all of whom were experienced and skilled, performed all colonoscopies pertaining to the study. Furthermore, the protocol required that all lesions regardless of diminutive size be removed and that the entire colon be cleared. All lesions were classified at endoscopy according to the protocol as either pedunculated or sessile. Characterization of certain colorectal adenomas as flat originated with Muto et al.3Muto T. Kamiya J. Sawada T. Konishi F. Sugihara K. Kubota Y. Adachi M. Agawa S. Saito Y. Morioka Y. Small flat adenoma of the large bowel with special reference to its clinicopathologic features.Dis Colon Rectum. 1985; 28: 847-851Crossref PubMed Scopus (449) Google Scholar in a report published in 1985. These adenomas were described as “sessile, sometimes nearly flat,” “slightly elevated,” and as having “an adenomatous component almost twice as thick as the surrounding mucosa.” Initial and later reports by Muto et al.3Muto T. Kamiya J. Sawada T. Konishi F. Sugihara K. Kubota Y. Adachi M. Agawa S. Saito Y. Morioka Y. Small flat adenoma of the large bowel with special reference to its clinicopathologic features.Dis Colon Rectum. 1985; 28: 847-851Crossref PubMed Scopus (449) Google Scholar and Adachi et al.4Adachi M. Muto T. Okinaga K. Morioka Y. Clinicopathologic features of the flat adenoma.Dis Colon Rectum. 1991; 34: 981-986Crossref PubMed Scopus (134) Google Scholar suggested that even small flat lesions had increased risk relative to polypoid (protruded) neoplasms of harboring high-grade dysplasia and progressing to invasive adenocarcinoma. Although some reports from Western centers appeared to corroborate these findings,5Hart A.R. Kudo S. Mackay E.H. Mayberry J.F. Atkin W.S. Flat adenomas exist in asymptomatic people important implications for colorectal cancer screening programmes.Gut. 1998; 43: 229-231Crossref PubMed Scopus (88) Google Scholar, 6Wolber R.A. Owen D.A. Flat adenomas of the colon.Hum Pathol. 1991; 22: 17-24Google Scholar others questioned whether flat adenomas showed exceptional propensity toward the development of high-grade dysplasia or malignant degeneration.7Lanspa S.J. Rouse J. Smyrk T. Watson P. Jenkins J.X. Lynch H.T. Epidemiological characteristics of the flat adenoma of Muto.Dis Colon Rectum. 1992; 35: 543-546Crossref PubMed Scopus (92) Google Scholar Several definitions of flat adenoma are in current use. The most widely accepted, derived from the original report by Muto et al.,3Muto T. Kamiya J. Sawada T. Konishi F. Sugihara K. Kubota Y. Adachi M. Agawa S. Saito Y. Morioka Y. Small flat adenoma of the large bowel with special reference to its clinicopathologic features.Dis Colon Rectum. 1985; 28: 847-851Crossref PubMed Scopus (449) Google Scholar characterizes a flat adenoma as a nonpolypoid adenoma of height no more than twice that of the adjoining mucosa. Wolber and Owen6Wolber R.A. Owen D.A. Flat adenomas of the colon.Hum Pathol. 1991; 22: 17-24Google Scholar emphasized that a flat adenoma showed radial or lateral extension of the dysplastic epithelium on the surface mucosa without vertical extension to the crypt bases (Figure 1). Cairns et al.8Cairns A. Dixon M.F. Rembacken B. Finan P.J. Axon A.T.R. Quirke P. Flat adenomas—a distinct biological entity and a new definition.Gut. 1999; 44: TH566Google Scholar suggested a quantitative measurement of the adenoma thickness or height and reported that a thickness of ≤1.3 mm encompassed 92% of adenomas that were flat by the Muto et al.3Muto T. Kamiya J. Sawada T. Konishi F. Sugihara K. Kubota Y. Adachi M. Agawa S. Saito Y. Morioka Y. Small flat adenoma of the large bowel with special reference to its clinicopathologic features.Dis Colon Rectum. 1985; 28: 847-851Crossref PubMed Scopus (449) Google Scholar definition. Finally, a strictly endoscopic definition9Sawada T. Hojo K. Moriya Y. Colonoscopic management of focal and early colorectal carcinoma.Ballieres Clin Gastroenterol. 1989; 3: 627-645Abstract Full Text PDF PubMed Scopus (32) Google Scholar stated that a flat adenoma should show mucosal elevation with a flat or slightly rounded surface and a height of less than half the greatest diameter of the lesion. Given the widely accepted definitions of flat adenoma and their potential applicability to archived histologic sections of resected adenomas we decided to reclassify all of the National Polyp Study baseline adenomas that had been classified originally as sessile at endoscopy. Grade of dysplasia and histologic classification, using prospectively defined criteria, had been assigned by a review group of 3 pathologists.10O’Brien M.J. Winawer S.J. Zauber A.G. Gottlieb L.S. Sternberg S.S. Diaz B. Dickersin G.R. Ewing S. Geller S. Kasimian D. Komorowsksi R. Szporn A. National Polyp Study WorkgroupPatient and polyp characteristics associated with high grade dysplasia in colorectal adenomas.Gastroenterology. 1990; 98: 371-379Crossref PubMed Scopus (737) Google Scholar Thus, an opportunity was presented, within the framework of a randomized clinical trial, to test the hypothesis that flat adenomas, as defined, more frequently exhibited high-grade dysplasia and were associated more strongly with advanced adenomas at follow-up evaluation than polypoid adenomas. Patients evaluated for enrollment had been referred for colonoscopy to 1 of 7 participating clinical centers in the United States for initial colonoscopy or polypectomy between November 1980 and February 1990.1Winawer S.J. Zauber A.G. O’Brien M.J. Ho M.N. Gottlieb L.S. Sternberg S.S. Waye J.D. Bond J.H. Schapiro M. Stewart E.T. Panish J. Ackroyd F. Kurtz R.C. Shike M. National Polyp Study WorkgroupRandomized comparison of surveillance intervals after colonoscopic removal of newly diagnosed adenomatous polyps.N Engl J Med. 1993; 328: 901-906Crossref PubMed Scopus (891) Google Scholar Those patients who had a family or personal history of familial polyposis or inflammatory bowel disease, or a history of polypectomy or colorectal cancer, were excluded from the study. Randomized patients had at least one histologically documented adenoma of the colon or rectum and had undergone a colonoscopy reaching to the cecum with complete removal of all identified polyps. The study compared more frequent surveillance colonoscopy (1 and 3 yr after initial colonoscopy) with less frequent surveillance colonoscopy (3 yr after initial colonoscopy). Patients assigned to either arm also were offered surveillance colonoscopy at 6 years. For this report, the data from both arms of the randomized trial were pooled to analyze the association of flat adenomas and high-grade dysplasia at baseline and with advanced adenomas at surveillance. An advanced adenoma was defined as an adenoma that was larger than 1.0 cm or an adenoma that exhibited high-grade dysplasia or invasive cancer.1Winawer S.J. Zauber A.G. O’Brien M.J. Ho M.N. Gottlieb L.S. Sternberg S.S. Waye J.D. Bond J.H. Schapiro M. Stewart E.T. Panish J. Ackroyd F. Kurtz R.C. Shike M. National Polyp Study WorkgroupRandomized comparison of surveillance intervals after colonoscopic removal of newly diagnosed adenomatous polyps.N Engl J Med. 1993; 328: 901-906Crossref PubMed Scopus (891) Google Scholar Dysplasia grade already had been determined prospectively by a 3-person pathology review team that had reviewed serial sections of each polyp obtained from the participating institutions and coded consecutively on an individual case basis for simultaneous examination on a multiheaded microscope.1Winawer S.J. Zauber A.G. O’Brien M.J. Ho M.N. Gottlieb L.S. Sternberg S.S. Waye J.D. Bond J.H. Schapiro M. Stewart E.T. Panish J. Ackroyd F. Kurtz R.C. Shike M. National Polyp Study WorkgroupRandomized comparison of surveillance intervals after colonoscopic removal of newly diagnosed adenomatous polyps.N Engl J Med. 1993; 328: 901-906Crossref PubMed Scopus (891) Google Scholar The criteria for histologic classification of dysplasia level have been described previously in detail.10O’Brien M.J. Winawer S.J. Zauber A.G. Gottlieb L.S. Sternberg S.S. Diaz B. Dickersin G.R. Ewing S. Geller S. Kasimian D. Komorowsksi R. Szporn A. National Polyp Study WorkgroupPatient and polyp characteristics associated with high grade dysplasia in colorectal adenomas.Gastroenterology. 1990; 98: 371-379Crossref PubMed Scopus (737) Google Scholar Four categories (mild, moderate, severe, and carcinoma in situ) initially were described; for analysis these were collapsed into 2 groups, low grade (mild/moderate dysplasia) and high grade (severe dysplasia/carcinoma in situ). The concordance in the assignment of categories as low grade or high grade between local review and pathology review committee exceeded 90%. Study endoscopists had classified each polyp as sessile or pedunculated at colonoscopy according to the study protocol. For this study, all baseline sessile adenomas were reclassified as flat or polypoid by 2 measurements—adenoma thickness (AT) or height, and adenoma/mucosa thickness ratio (AR). Each slide was placed on a lightbox and viewed through a 7× magnification lens that had a 0.1-mm calibrated micrometer (Figure 1). Adenomas with an AT measurement of ≤1.3 mm or AR ≤2 were classified as flat. Radial or lateral growth of adenomatous epithelium over normal crypts also was noted when present (Figure 1). Slides that could not be classified because of orientation or tissue fragmentation were considered nonevaluable. The observer (M.J.O.) was unaware of previously assigned dysplasia grade and patient outcome. The overall frequency of flat adenomas for each method was determined as well as the concordance of the 2 measures. The study assessed whether flat adenomas were more likely to have high-grade dysplasia compared with sessile nonflat or pedunculated adenomas and assessed whether flat adenoma(s) at baseline colonoscopy were predictive for the detection of advanced adenomas at surveillance colonoscopy. The general estimating equation approach for logistic regression11Diggle P.J. Liang K.-Y. Zeger S.L. Analysis of longitudinal data. Clarendon Press, Oxford1994Google Scholar was used to assess whether the shape of the adenoma was a risk factor for high-grade dysplasia at the initial colonoscopy and to adjust for confounding variables such as adenoma size (≤0.5 cm, 0.6–1.0 cm, >1.0 cm), histology (tubular, tubulovillous, or villous), and location (proximal, cecum to splenic flexure vs. distal), and to correct for correlation of risk within individual patients. Odds ratios and 95% confidence intervals (CIs) were derived. Analysis of variance was used to compare mean size by adenoma shape. The Cox proportional hazards model was used to assess whether patients with one or more flat adenomas at initial colonoscopy were more likely to have any advanced adenoma at surveillance colonoscopy. Each patient was classified according to whether an advanced adenoma was detected at surveillance and the time since the initial colonoscopy. The hazard ratios for flat adenoma as a risk factor for advanced adenomas at surveillance were calculated with a 95% CI and adjusted for the variables adenoma multiplicity, family history, and age, which previously had been shown to be independent determinants of risk for advanced adenoma on follow-up evaluation.1Winawer S.J. Zauber A.G. O’Brien M.J. Ho M.N. Gottlieb L.S. Sternberg S.S. Waye J.D. Bond J.H. Schapiro M. Stewart E.T. Panish J. Ackroyd F. Kurtz R.C. Shike M. National Polyp Study WorkgroupRandomized comparison of surveillance intervals after colonoscopic removal of newly diagnosed adenomatous polyps.N Engl J Med. 1993; 328: 901-906Crossref PubMed Scopus (891) Google Scholar In addition, the analyses were stratified by the randomization assignment (more frequent and less frequent surveillance colonoscopy) of the randomized trial. SAS 9.0 (SAS Institute, Cary, NC) was used for all analyses. There were 938 patients of the total 1418 patients randomized in the National Polyp Study who had one or more surveillance colonoscopies and are the subjects of the present analysis. These patients had a total of 1750 adenomas at the baseline colonoscopy, which were confirmed and classified histologically and by grade of dysplasia by the pathology review;10O’Brien M.J. Winawer S.J. Zauber A.G. Gottlieb L.S. Sternberg S.S. Diaz B. Dickersin G.R. Ewing S. Geller S. Kasimian D. Komorowsksi R. Szporn A. National Polyp Study WorkgroupPatient and polyp characteristics associated with high grade dysplasia in colorectal adenomas.Gastroenterology. 1990; 98: 371-379Crossref PubMed Scopus (737) Google Scholar 802 (46%) of the baseline adenomas were pedunculated and slides for 15 (1%) were not available. The remaining 933 sessile adenomas were assessed for flatness: 703 (75%) of these were classified using AT and 432 (45%) were classified as flat by the AR measure; of the 423 with both AT and AR measures, 402 (95%) were concordant for flatness. Because of the high level of concordance between the measures but the low evaluability rate for the AR measure, the AT was used as the primary measure for flatness. Overall, 474 (27%) of all the 1750 baseline adenomas (or 31% of the 1505 evaluable adenomas) detected were classified as flat (Table 1).Table 1Histopathologic Reclassification of Baseline Adenomas According to Thickness Measurement (AT) of Sessile AdenomasShapen (%)Flat474 (27)Sessile229 (13)Not evaluable230 (13)Pedunculated802 (46)Missing slides15 Total1750 (100) Open table in a new tab The size of the adenomas varied by shape: the mean size was 0.5 cm for flat, 0.98 cm for sessile (polypoid), 1.22 cm for pedunculated, and 0.50 cm for nonevaluable adenomas (P < 0.001). The location of the adenomas varied by shape with a right-sided location for 43% (204) of flat, 36% (82) of sessile (polypoid), 15% (123) of pedunculated, and 46% (106) of the sessile nonevaluable adenomas (P < 0.001). High-grade dysplasia occurred in 6 (1.3%) flat adenomas compared with 17 (7.4%) sessile (polypoid) adenomas, 80 (10.0%) pedunculated adenomas, and 1 (0.4%) sessile nonevaluable adenomas. The odds ratio for high-grade dysplasia for sessile (polypoid) adenomas compared with flat adenomas was 6.31 (95% CI, 2.40–16.63; P < 0.002) and for pedunculated vs. flat was 8.72 (95% CI, 3.62–20.98; P < 0.0001). However, when stratified by size, there was no statistically significant difference in frequency of high-grade dysplasia among the shape categories (P = 0.13). Table 2 shows the frequency of high-grade dysplasia according to adenoma shape and size category. High-grade dysplasia occurred in 5 (2%) left-sided flat adenomas compared with 1 (0.5%) right-sided flat adenoma (P = 0.24); in 15 (10%) left-sided sessile polypoid adenomas compared with 2 (2%) right-sided sessile polypoid adenomas (P = 0.03); and in 71 (10%) left-sided pedunculated adenomas compared with 9 (7%) right-sided pedunculated adenomas (P = 0.33).Table 2Frequency of High-Grade Dysplasia in Baseline Adenomas According to Adenoma Shape and SizeSizeShapeP valueFlatSessile (polypoid)Pedunculated>1.0 cm1/16 (6%)8/52 (15%)56/351 (16%)0.570.6–1.0 cm4/109 (3.7%)8/120 (6.7%)22/337 (6.5%)0.52≤0.5 cm1/348 (0.3%)1/57 (1.8%)2/114 (1.8%)0.20Total6/473 (1.3%)17/229 (7.4%)80/802 (10.0%)0.0001aP = 0.13 adjusted overall for adenoma size by Mantel-Haenszel procedure.a P = 0.13 adjusted overall for adenoma size by Mantel-Haenszel procedure. Open table in a new tab In a previous report from the National Polyp Study,10O’Brien M.J. Winawer S.J. Zauber A.G. Gottlieb L.S. Sternberg S.S. Diaz B. Dickersin G.R. Ewing S. Geller S. Kasimian D. Komorowsksi R. Szporn A. National Polyp Study WorkgroupPatient and polyp characteristics associated with high grade dysplasia in colorectal adenomas.Gastroenterology. 1990; 98: 371-379Crossref PubMed Scopus (737) Google Scholar we showed that villous histology and size were independent risk factors for high-grade dysplasia in adenomas. Multivariate analysis showed adjusted odds ratios for high-grade dysplasia in sessile (polypoid) vs. flat adenomas to be 1.91 (95% CI, 0.66–5.47; P = 0.23) and pedunculated vs. flat adenomas to be 1.78 (95% CI, 0.63–5.02; P = 0.28) when controlling for adenoma size, villous histology, and adenoma location, and correcting for correlation of risk within an individual case (Table 3).Table 3Odds Ratio for High-Grade Dysplasia by Adenoma ShapeModelGeneral estimating equation odds ratio95% CI and P valueSessile vs. flat1.910.66–5.47 (P = 0.23)Pedunculated vs. flat1.780.63–5.02 (P = 0.28)NOTE. Estimates from the GEE model adjusted for adenoma size, histology, and location and corrected for correlation of risk for high-grade dysplasia within an individual case. Open table in a new tab NOTE. Estimates from the GEE model adjusted for adenoma size, histology, and location and corrected for correlation of risk for high-grade dysplasia within an individual case. The study patients were grouped by the presence of one or more flat adenomas at baseline: of the 938 patients in the surveillance cohort, 335 (36%) had one or more flat adenomas (average, 1.4 flat adenomas), with 186 (20%) having flat adenomas only and 149 (16%) having flat adenomas along with pedunculated or sessile (polypoid) adenomas. There were 535 patients with no flat adenomas, 410 (44%) with pedunculated adenomas only, and 125 (13%) with sessile (polypoid) and pedunculated adenomas. There were 68 (7%) with only nonevaluable adenomas. Characteristics of study patients with and without flat adenomas at baseline were similar with respect to age (mean, 62 vs. 61) and sex (73% male vs. 71% male). A total of 42 patients developed advanced adenomas during the surveillance period of 5.9 years (average duration).1Winawer S.J. Zauber A.G. O’Brien M.J. Ho M.N. Gottlieb L.S. Sternberg S.S. Waye J.D. Bond J.H. Schapiro M. Stewart E.T. Panish J. Ackroyd F. Kurtz R.C. Shike M. National Polyp Study WorkgroupRandomized comparison of surveillance intervals after colonoscopic removal of newly diagnosed adenomatous polyps.N Engl J Med. 1993; 328: 901-906Crossref PubMed Scopus (891) Google Scholar Comparison of one or more flat adenomas and no flat adenoma groups for risk for advanced adenomas on follow-up evaluation revealed a hazard ratio of 0.76 (95% CI, 0.4–1.42; P = .39). This analysis was adjusted for multiplicity, age, and family history, factors previously shown to be associated independently with advanced adenomas on follow-up evaluation. There were a total of 5 incident cancers in the study, as previously reported,2Winawer S.J. Zauber A.G. Ho M.N. O’Brien M.J. Gottlieb L.S. Sternberg S.S. Waye J.D. Schapiro M. Bond J.H. Panish J.F. Ackroyd F. Stewart E.T. National Polyp Study WorkgroupPrevention of colorectal cancer by colonoscopic polypectomy.N Engl J Med. 1993; 329: 1977-1981Crossref PubMed Scopus (3941) Google Scholar and the endoscopic and pathologic characteristics of these are summarized in Table 4. One of these cancers (case #1) was an invasive adenocarcinoma that developed in a flat adenoma. A second invasive adenocarcinoma measuring 1.5 cm in greatest dimension was a flat, depressed lesion with central ulceration and without evidence of residual adenoma. A third cancer consisted of a small 8-mm sessile adenoma with a focus of invasive adenocarcinoma. The remaining 2 carcinomas were large and polypoid, 2.5 and 1.5 cm, respectively, in greatest dimension and both showed residual tubulovillous adenoma.Table 4Characteristics of 5 Colorectal Adenocarcinomas Detected on Follow-up Colonoscopy in the National Polyp StudyCase12345FU year detected67333Shape/contourFlatSessilePolypoidPolypoidFlat (depressed)Residual adenoma locationTubularTubularTubulovillousTubulovillousNoneSigmoidHep F1TransverseCecumCecumSize0.6 cm0.8 cm2.5 cm1.5 cm1.5 cmAJCC stage (TNM)I (T1NXM0)aEndoscopic resection only.I (T1N0M0)I (T2N0M0)I (T2N0M0)IIA (T3N0M0)Dukes stageAAAABFU, follow up; AJCC, American Joint Committee on Cancer.a Endoscopic resection only. Open table in a new tab FU, follow up; AJCC, American Joint Committee on Cancer. For the present study, we classified as flat those adenomas that had been described as sessile at a time when flat was not in the endoscopist’s lexicon but were found on review of histologic sections to be thin (≤1.3 mm) or less than twice the thickness of the contiguous mucosa. A purely histologic definition of flat adenoma without reference to endoscopic findings would not have been meaningful, as has been pointed out by Samowitz and Burt.12Samowitz W.S. Burt R.L. The non-specificity of histological findings reported for flat adenomas.Hum Pathol. 1995; 26: 571-573Abstract Full Text PDF PubMed Scopus (13) Google Scholar The National Polyp Study endoscopy protocol required, however, that the shape of all polyps encountered, whether pedunculated or sessile, be documented, thus permitting this retrospective reclassification. It is not possible to assert that these flat adenomas are the equivalent in all respects of those that might have been identified by a prospectively applied endoscopic classification of flatness using more modern endoscopy equipment and techniques, or that some proportion of flat adenomas by such definition were not overlooked. Nonetheless, the flat adenomas identified here can be said to have substantial equivalence with those of the original Muto et al.3Muto T. Kamiya J. Sawada T. Konishi F. Sugihara K. Kubota Y. Adachi M. Agawa S. Saito Y. Morioka Y. Small flat adenoma of the large bowel with special reference to its clinicopathologic features.Dis Colon Rectum. 1985; 28: 847-851Crossref PubMed Scopus (449) Google Scholar report that described them as “sessile, sometimes nearly flat adenomas with an adenomatous component almost [sic] twice the thickness of the surrounding mucosa.” The present study’s definition also would not include some of the lesions encompassed by the endoscopic description of a flat adenoma as an elevated lesion with a height of less than half its diameter,9Sawada T. Hojo K. Moriya Y. Colonoscopic management of focal and early colorectal carcinoma.Ballieres Clin Gastroenterol. 1989; 3: 627-645Abstract Full Text PDF PubMed Scopus (32) Google Scholar, 13Fujii T. Rembacken B.J. Dixon M.F. Yoshida S. Axon A.T.R. Flat adenomas in the United Kingdom are treatable cancers being missed?.Endoscopy. 1998; 30: 437-443Crossref PubMed Scopus (204) Google Scholar notably larger lesions in which the height could exceed several millimeters; such lesions would be unlikely to have been overlooked by the study endoscopists, however, and would have been classified as sessile (nonflat). The present analysis of adenomas removed from an adenoma-bearing, geographically representative U.S. cohort suggests that flat adenomas are common—36% of patients had one or more flat adenomas, representing at least 27% of all adenomas removed. These statistics bear comparison with those of Saitoh et al.,14Saitoh Y. Waxman I. West A.B. Popnikolov N.K. Gatalica S. Watari J. Obara T. Kohgo Y. Pashricha P.J. Prevalence and distinctive biologic features of flat colorectal adenomas in a North American population.Gastroenterology. 2001; 120: 1657-1665Abstract Full Text Full Text PDF PubMed Scopus (357) Google Scholar who recently reported finding flat or depressed lesions in 22.7% of 211 patients who underwent colonoscopy for suspected colorectal neoplasms at a Texas medical center and of the total of 136 adenomas harvested 39.7% were flat or depressed. Lanspa et al.7Lanspa S.J. Rouse J. Smyrk T. Watson P. Jenkins J.X. Lynch H.T. Epidemiological characteristics of the flat adenoma of Muto.Dis Colon Rectum. 1992; 35: 543-546Crossref PubMed Scopus (92) Google Scholar previously had reported a relative frequency rate of 51% of flat adenomas among adenomas removed from a Midwestern U.S. cohort, using a colonoscopic definition of flatness applied prospectively. Fujii et al.13Fujii T. Rembacken B.J. Dixon M.F. Yoshida S. Axon A.T.R. Flat adenomas in the United Kingdom are treatable cancers being missed?.Endoscopy. 1998; 30: 437-443Crossref PubMed Scopus (204) Google Scholar and Rembacken et al.,15Rembacken B.J. Fujii T. Cairns A. Dixon M.F. Yoshida S. Chalmers D.M. Axon A.T.R. Flat and depressed colonic neoplasms a prospective study of 1000 colonoscopies in the UK.Lancet. 2000; 355: 1211-1214Abstract Full Text Full Text PDF PubMed Scopus (619) Google Scholar in prospective surveys of patients in the United Kingdom referred for colonoscopy, reported the relative frequency of flat adenomas among harvested adenomas as 36% and 38%, respectively. Thus, the relative frequency of flat adenomas in the National Polyp Study is quite similar to that reported from surveys of adenoma bearers in which flat adenomas were sought prospectively using state-of-the-art endoscopy equipment and chromoendoscopy techniques.13Fujii T. Rembacken B.J. Dixon M.F. Yoshida S. Axon A.T.R. Flat adenomas in the United Kingdom are treatable cancers being missed?.Endoscopy. 1998; 30: 437-443Crossref PubMed Scopus (204) Google Scholar, 14Saitoh Y. Waxman I. West A.B. Popnikolov N.K. Gatalica S. Watari J. Obara T. Kohgo Y. Pashricha P.J. Prevalence and distinctive biologic features of flat colorectal adenomas in a North American population.Gastroenterology. 2001; 120: 1657-1665Abstract Full Text Full Text PDF PubMed Scopus (357) Google Scholar, 15Rembacken B.J. Fujii T. Cairns A. Dixon M.F. Yoshida S. Chalmers D.M. Axon A.T.R. Flat and depressed colonic neoplasms a prospective study of 1000 colonoscopies in the UK.Lancet. 2000; 355: 1211-1214Abstract Full Text Full Text PDF PubMed Scopus (619) Google Scholar The original report from Muto et al.3Muto T. Kamiya J. Sawada T. Konishi F. Sugihara K. Kubota Y. Adachi M. Agawa S. Saito Y. Morioka Y. Small flat adenoma of the large bowel with special reference to its clinicopathologic features.Dis Colon Rectum. 1985; 28: 847-851Crossref PubMed Scopus (449) Google Scholar indicated a high-grade dysplasia rate of 42% in flat adenomas; a later report of a larger number of cases from the same group4Adachi M. Muto T. Okinaga K. Morioka Y. Clinicopathologic features of the flat adenoma.Dis Colon Rectum. 1991; 34: 981-986Crossref PubMed Scopus (134) Google Scholar reported the high-grade dysplasia rate to be 13.3%, a lower figure but still more than twice the rate of 6.1% reported for all adenomas in the National Polyp Study database.9Sawada T. Hojo K. Moriya Y. Colonoscopic management of focal and early colorectal carcinoma.Ballieres Clin Gastroenterol. 1989; 3: 627-645Abstract Full Text PDF PubMed Scopus (32) Google Scholar Furthermore, the latter rate of high-grade dysplasia4Adachi M. Muto T. Okinaga K. Morioka Y. Clinicopathologic features of the flat adenoma.Dis Colon Rectum. 1991; 34: 981-986Crossref PubMed Scopus (134) Google Scholar in flat adenomas was derived from a notably high-risk cohort of adenoma-bearing patients, 38% of whom had a history of colorectal carcinoma and an additional 28% of whom had a previous history of colorectal adenomas. A more recent study from the University of Tokyo16Watanabe T. Sawada T. Kubota Y. Adachi M. Saito Y. Masaki T. Muto T. Malignant potential in flat elevations.Dis Colon Rectum. 1993; 36: 548-553Crossref PubMed Scopus (55) Google Scholar reported a series of 99 colonoscopically removed flat lesions that measured up to 1 cm in diameter. The rate of high-grade dysplasia among the flat adenomas ≤5 mm in diameter was 0%, whereas the rate among the adenomas 6–10 mm in diameter (44 cases) was 15.8%. Among the 18 flat adenomas reported by Lanspa et al.,7Lanspa S.J. Rouse J. Smyrk T. Watson P. Jenkins J.X. Lynch H.T. Epidemiological characteristics of the flat adenoma of Muto.Dis Colon Rectum. 1992; 35: 543-546Crossref PubMed Scopus (92) Google Scholar none showed high-grade dysplasia. In the past, differences in the rates of high-grade dysplasia in flat adenomas among reported series have been attributed in part to variation in classification criteria, particularly between Japanese and Western studies.17Rozen P. Brazowski E. Flat colorectal neoplasia identification, pathogenesis and clinical significance.Dig Liver Dis. 2003; 35: 135-137Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar A strength of the present study is that the histologic classification criteria are the equivalent of the current World Health Organization classification and were developed prospectively and applied before the classification of the adenomas as flat or nonflat. Furthermore, monitoring of local vs. review center classification of dysplasia during the course of the National Polyp Study showed a high level of reproducibility for this classification with a concordance level in the assignment of high-grade (vs. low-grade) dysplasia that exceeded 90%. The present analysis provided no evidence that high-grade dysplasia is more frequent in flat adenomas than in pedunculated or sessile (polypoid) adenomas of equivalent size. A comparison of crude high-grade dysplasia rates among the 3 shape categories appeared to show statistically significant lower rates in flat adenomas compared with both sessile nonflat and pedunculated adenomas. However, an adjusted or stratified analysis (Table 2) showed this result to be attributable to disproportionate representation of the smallest size category among the flat adenomas (i.e., confounding by size). The study corroborated the several reports that have noted that, in common with sessile (polypoid) and pedunculated adenomas, the risk for high-grade dysplasia in flat adenomas increases with adenoma size.13Fujii T. Rembacken B.J. Dixon M.F. Yoshida S. Axon A.T.R. Flat adenomas in the United Kingdom are treatable cancers being missed?.Endoscopy. 1998; 30: 437-443Crossref PubMed Scopus (204) Google Scholar, 16Watanabe T. Sawada T. Kubota Y. Adachi M. Saito Y. Masaki T. Muto T. Malignant potential in flat elevations.Dis Colon Rectum. 1993; 36: 548-553Crossref PubMed Scopus (55) Google Scholar The current observations thus point to flat adenomas as an entity encompassed by existing morphologic concepts of the adenoma-carcinoma sequence. The findings indicate a low rate of high-grade dysplasia among adenomas smaller than 1 cm and appear to contradict the suggestion that the rate of progression of adenoma to malignancy is greater in flat adenomas. The study also has been able to show, within the framework of a randomized clinical trial, that the risk for metachronous advanced adenomas among patients with one or more flat index adenomas does not differ from that of patients with sessile or pedunculated adenomas only. There is persuasive documentation in the literature that a central depression identifies flat lesions that may harbor high-grade dysplasia or early invasive adenocarcinoma.19Kudo S. Tamara S. Nakajimo T.T. Hirota S. Asano M. Ito O. Kusaka H. Depressed type of colorectal cancer.Endoscopy. 1995; 27: 54-57Crossref PubMed Scopus (119) Google Scholar, 20Minamoto T. Sawagushi K. Mai M. Yamashita N. Sugimara T. Esumi H. Infrequent K-ras activation in superficial-type (flat) colorectal adenomas and adenocarcinomas.Cancer Res. 1994; 54: 2841-2844PubMed Google Scholar These lesions appear to be relatively uncommon,13Fujii T. Rembacken B.J. Dixon M.F. Yoshida S. Axon A.T.R. Flat adenomas in the United Kingdom are treatable cancers being missed?.Endoscopy. 1998; 30: 437-443Crossref PubMed Scopus (204) Google Scholar, 15Rembacken B.J. Fujii T. Cairns A. Dixon M.F. Yoshida S. Chalmers D.M. Axon A.T.R. Flat and depressed colonic neoplasms a prospective study of 1000 colonoscopies in the UK.Lancet. 2000; 355: 1211-1214Abstract Full Text Full Text PDF PubMed Scopus (619) Google Scholar however, and the present study did not address this phenomenon. The molecular genetic changes underlying flat adenomas also are not addressed in the present study. Several investigators have noted that K-ras mutations are infrequent in these adenomas compared with their polypoid counterparts and have suggested the possibility of a distinctive molecular pathway in flat adenomas.20Minamoto T. Sawagushi K. Mai M. Yamashita N. Sugimara T. Esumi H. Infrequent K-ras activation in superficial-type (flat) colorectal adenomas and adenocarcinomas.Cancer Res. 1994; 54: 2841-2844PubMed Google Scholar, 21Yamagata S. Muto T. Uchida Y. Masaki T. Higuchi Y. Sawada T. Hirooka T. Polypoid growth and K-ras codon 12 mutation in colorectal cancer.Cancer. 1995; 75: 953-957Crossref PubMed Scopus (87) Google Scholar Some investigators14Saitoh Y. Waxman I. West A.B. Popnikolov N.K. Gatalica S. Watari J. Obara T. Kohgo Y. Pashricha P.J. Prevalence and distinctive biologic features of flat colorectal adenomas in a North American population.Gastroenterology. 2001; 120: 1657-1665Abstract Full Text Full Text PDF PubMed Scopus (357) Google Scholar, 15Rembacken B.J. Fujii T. Cairns A. Dixon M.F. Yoshida S. Chalmers D.M. Axon A.T.R. Flat and depressed colonic neoplasms a prospective study of 1000 colonoscopies in the UK.Lancet. 2000; 355: 1211-1214Abstract Full Text Full Text PDF PubMed Scopus (619) Google Scholar have speculated that bringing to bear the equivalent of Japanese endoscopists’ experience in detecting flat mucosal lesions and perhaps the use of dye spraying would have enhanced the colorectal cancer incidence reduction achieved in the National Polyp Study from the observed 76%–90%2Winawer S.J. Zauber A.G. Ho M.N. O’Brien M.J. Gottlieb L.S. Sternberg S.S. Waye J.D. Schapiro M. Bond J.H. Panish J.F. Ackroyd F. Stewart E.T. National Polyp Study WorkgroupPrevention of colorectal cancer by colonoscopic polypectomy.N Engl J Med. 1993; 329: 1977-1981Crossref PubMed Scopus (3941) Google Scholar to 100%. Adenomas, irrespective of shape, and particularly smaller adenomas, may be missed by a single colonoscopy performed by a single examiner as shown by Hixson et al.22Hixson L.J. Fennerty M.B. Sampliner R.E. McGee D. Garewal H. Prospective study of the frequency and size distribution of polyps missed by colonoscopy.J Natl Cancer Inst. 1990; 82: 1769-1772Crossref PubMed Scopus (312) Google Scholar and Rex et al.23Rex D.K. Cummings O.W. Helper D.F. Nowak T.V. McGill J.M. Chiao G.Z. Kwo P.Y. Gottlieb K.T. Ikenberry S.O. Gress F.G. Lehman G.A. Born L.J. 5-year incidence of adenomas after negative colonoscopy in asymptomatic average-risk persons.Gastroenterology. 1996; 111: 1768-1781Abstract Full Text Full Text PDF Scopus (151) Google Scholar in back-to-back-colonoscopy studies. Rex et al.23Rex D.K. Cummings O.W. Helper D.F. Nowak T.V. McGill J.M. Chiao G.Z. Kwo P.Y. Gottlieb K.T. Ikenberry S.O. Gress F.G. Lehman G.A. Born L.J. 5-year incidence of adenomas after negative colonoscopy in asymptomatic average-risk persons.Gastroenterology. 1996; 111: 1768-1781Abstract Full Text Full Text PDF Scopus (151) Google Scholar reported that 24% of adenomas overall, 6% of adenomas sized 1.0 cm or larger, and 25% of adenomas smaller than 1 cm are overlooked in a single examination. The diversity of shape of potentially overlooked adenomas is reflected in the 5 incident cancers reported in the National Polyp Study, which included proportionate representation of pedunculated, sessile, and flat cancers by current definitions. The characteristics of these incident cancers, however, do not negate the intuition that small rather than large neoplasms and flat rather than elevated or polypoid lesions may be overlooked more easily at endoscopy. The present study findings are consistent with the hypothesis that when colonoscopies were performed in the National Polyp Study, flat adenomas frequently were perceived and classified as sessile and not disproportionately overlooked by the study endoscopists. The data analysis indicates that risk for progression to malignancy in such flat adenomas is no greater than in polypoid adenomas and that patients with flat adenomas at initial colonoscopy are not at greater risk for metachronous advanced adenomas. The study findings also emphasize the observed efficacy of colorectal cancer reduction in the National Polyp Study using standard colonoscopy and removal of all mucosal lesions regardless of size.24Zauber A.G. O’Brien M.J. Winawer S.J. On finding flat adenomas is the search worth the gain?.Gastroenterology. 2002; 122: 839Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar Nonetheless, awareness of flat and depressed adenomas and cancers, as currently defined, and training in their recognition, can only serve to enhance the proven efficacy of colonoscopic resection of adenomas in the prevention of colorectal carcinoma." @default.
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