Clinical Relevance of the Small Colorectal Polyp

Adenomatous colorectal polyps (adenomas) are not like sunflowers. If you plant sunflower seeds, small sunflowers of equal size and shape soon emerge. Then, in a very predictable linear way, all small ones grow to medium-sized and then fully grown flowers. Colorectal adenomatous polyps, however, behave quite differently. Large numbers of small simple tubular adenomas develop in large numbers of people - according to autopsy studies, over 30 % of the population over age 50 have these lesions [1]. However, unlike sunflowers, only a small fraction of these polyps grow to become large adenomas with advanced pathologic (premalignant) features. While it is obvious that all large adenomas at one time were small, the great majority of small adenomas, nevertheless, never grow, advance, and turn cancerous.

Current evidence indicates that over 95 % of colorectal cancers in Western countries arise in adenomatous polyps which develop and grow slowly in the colon over many years before they turn malignant [2]. Remarkable advances in our understanding of the molecular genetic basis for this adenoma-carcinoma sequence help explain the fact that most small adenomas have little clinical significance. Colonic carcinogenesis is a nonlinear, multistep process occurring over many years resulting from the progressive accumulation of genetic mutations and chromosomal deletions [3]. As some neoplasms slowly proceed from normal-appearing mucosa through small, medium, and large benign adenomas, and finally to invasive cancer and metastases, genetic changes are found in increasing number. An adenomatous polyp is a monoclonal derivative of a single epithelial stem cell that either inherits or acquires the first of these many genetic alterations. Each additional genetic insult - probably caused by noxious environmental carcinogenic factors - leads to a new clone of daughter cells with a growth advantage which allows it to take over the developing polyp. The reason most small simple tubular adenomas stay small and remain clinically benign is because they never develop the additional genetic alterations - oncogene mutations and tumor suppressor gene alterations - needed to make them advance.

A large volume of scientific data indicates that clinicians need to shift their attention away from simply finding and harvesting all diminutive colorectal adenomas toward strategies which allow the reliable detection of the much less common, but much more dangerous advanced adenoma. As defined by many studies, including the US National Polyp Study, an advanced adenoma is one which is ≥ 1cm in size or contains high-grade dysplasia or appreciable villous tissue. When screening colonoscopy is performed in average-risk asymptomatic individuals over age 50, the prevalence of advanced adenomas ranges from 6 to 9 % [4] [5] .

In this issue of Endoscopy , Kulling and co-workers report that whether or not a diminutive (≤ 5 mm) polyp has clinically insignificant histology can be predicted from patient characteristics and endoscopic findings, obviating the need for expensive biopsy and histopathologic examination in many cases [6]. A total of 1681 polyps resected in 494 patients were grouped into adenomas with advanced pathologic features (appreciable villous component, severe dysplasia, or early cancer) or insignificant polyps (nonadenomas or simple tubular adenomas with low-grade dysplasia). They found that a small (≤ 5 mm) right-sided polyp in a young patient (< 60 years of age) has only a 3.8 % risk for containing advanced adenomatous tissue. Polyps in patients of age ≥ 60, the presence of anemia, polyp size of > 10 mm, or left-sided location, as single or combined parameters, had a maximum predictive value of 75.4 % for being advanced adenomas. They concluded that costly histopathologic examination of small polyps in the low-risk group may not be required since it does not provide any clinically relevant additional information.

What additional clinical evidence supports the conclusions of Kulling et al. regarding the benign clinical significance of most diminutive colorectal polyps? Many small polyps, especially those located in the left colon, are hyperplastic, not neoplastic Hyperplastic polyps have no malignant potential, and several prospective studies with good pathology control now have shown that when a hyperplastic polyp is found during screening flexible sigmoidoscopy in the left colon, this does not predict an increased prevalence of adenomas in the proximal colon [8]. Therefore, if the only abnormality found during screening sigmoidoscopy is a hyperplastic polyp, no further evaluation or follow-up is indicated. A large volume of accumulating evidence also shows that small (< 1 cm) tubular adenomas have little immediate or long-term clinical significance. For example, long-term post-polypectomy follow-up studies performed at the Mayo Clinic in the US and at St Mark's Hospital in London showed that patients who underwent resection of only one or two small tubular adenomas had no measurable increased risk of developing subsequent colorectal cancer compared with that of the average population [9] [10] . In contrast, patients with large (≥ 1 cm) or multiple (≥ 3) adenomas, or adenomas with villous changes or high-grade dysplasia, had a risk of metachronous cancer that was increased three- to sixfold [11]. The US National Polyp Study also has extensively investigated the clinical significance of the small adenoma. An independent review by expert pathologists at the Mallory Institute, Boston, of 572 diminutive (≤ 5 mm) adenomas resected by colonoscopists in the seven centers of this multicenter study showed that only 0.9 % had high-grade dysplasia [12]. During the trial, 1418 patients with newly diagnosed adenomas had their colons cleared of all synchronous lesions and then were randomized to two equal groups - one to have follow-up colonoscopy surveillance in 1 and 3 years, the second to have only 3-year follow-up examinations. Recurrent adenomas were very common, occurring in 42 % and 32 %, respectively, of these two groups [13]. However, the great majority of these polyps were small tubular adenomas with negligible immediate clinical significance. Undoubtedly, an appreciable fraction of these “recurrent” polyps were actually synchronous lesions which were missed during the index colonoscopy. Advanced adenomas were found in only 3.3 % of each group over 3 years of follow-up. Multivariate analysis of data from both the National Polyp Study and other large postpolypectomy outcomes investigations, have shown that patients are more likely to have advanced adenomas during follow-up colonoscopic surveillance if their index adenomas were multiple (≥ 3), large (≥ 1 cm), or contained the advanced pathologic features of villous tissue, high-grade dysplasia, or invasive carcinoma [14] [15] [16] . In addition to these polyp characteristics, the presence of a significant family history of colorectal cancer (one or more first-degree relatives with the disease) also increased the likelihood of finding an advanced adenoma during follow-up colonoscopy.

Based on these findings, recent polyp surveillance guidelines promulgated by professional digestive disease societies in the US recommend that clinicians assess each patient's risk for developing metachronous advanced adenomas and tailor their follow-up surveillance strategies accordingly [17]. Patients with colorectal adenomas now can be stratified into high- and low-risk groups. After the colon has been satisfactorily cleared of all synchronous adenomas, repeat colonoscopy in 3 years is recommended for patients who are at high risk. These include those who initially have multiple (≥ 3) adenomas, a large (≥ 1 cm) adenoma, an adenoma with the advanced pathologic features of villous change, high-grade dysplasia, or invasive carcinoma, or a first-degree relative with a colorectal cancer. Patients with a low risk of metachronous advanced adenomas include those who initially have only one or two small (< 1 cm) tubular adenomas without high-grade dysplasia or cancer, and no significant family history of colorectal cancer. For these patients, the first follow-up colonoscopy safely can be delayed until at least 5 years, or, for selected older patients or those with substantial co-morbidity, no follow-up may be indicated. Widespread adoption of these new evidence-based recommendations would greatly reduce the cost of postpolypectomy surveillance while still providing patients with adequate protection from subsequent cancer. For example, in a cost-effectiveness modeling analysis, Lieberman concluded that conventional postpolypectomy surveillance still practiced in many centers comprises 19 - 34 % of the total cost of a colorectal cancer screening program [18]. According to his analysis, if surveillance instead focused only on the detection of metachronous advanced adenomas, this percentage cost could be reduced to 11 - 20 %.

In addition to the need to better stratify postpolypectomy risk for advanced adenomas, a related important question is what is the prevalence of right-sided advanced adenomas in patients found to have small tubular adenomas at screening flexible sigmoidoscopy? Should all of these patients undergo colonoscopy to search for advanced adenomas in the proximal colon? Clinically, as well as economically, this is a very important question because 40 - 50 % of patients found to have polyps on screening sigmoidoscopy fall into this group. A number of studies and case series have examined this issue and have reported conflicting results and conclusions. Zarchy & Ershoff found that patients with small (< 1 cm) tubular adenomas in the distal colon had only a 0.8 % prevalence of proximal synchronous advanced adenomas [19]. In contrast, Read et al., in a similar study reported that proximal advanced adenomas were found in 6.9 % of patients with distal adenomas that were < 1 cm in diameter [20]. Schoen et al. found an intermediate prevalence of advanced proximal adenomas of 3 % in those with only distal tubular adenomas < 1 cm in size [21]. Levin et al., in a large study which included a control group of persons who had no adenomas in the distal colon yet subsequently underwent colonoscopy, found that, although the prevalence of advanced adenomas in the proximal colon was the same in those with and without small distal tubular adenomas, each group nevertheless had an appreciable prevalence of proximal advanced adenomas (> 5 %) that would have been missed had colonoscopy not been performed [22]. Lastly, Wallace et al. found no advanced proximal adenomas in 90 patients with a single distal tubular adenoma 1 - 5 mm in diameter, and concluded that these patients were unlikely to benefit from colonoscopy [23].

The reasons for these conflicting results and conclusions are unclear. Current polyp guidelines, therefore, recommend that the management of a patient found to have one or two small tubular adenomas at flexible sigmoidoscopy should be individualized [17]. Colonoscopy to look for synchronous adenomas may be of little benefit to many patients with only one or two small (< 1 cm) tubular adenomas. However, younger, healthy individuals with this finding may wish to have colonoscopy in an attempt to reduce their risk of subsequent colorectal cancer to even below that of the average-risk population. Older patients, especially those with significant co-morbidity, are not likely to benefit from an intensive colorectal evaluation.

Kulling et al. take a conservative approach to the treatment of diminutive polyps which is also supported by current polyp guidelines [7]. They recommend that, even though small right-sided polyps in a young patient may have clinically insignificant histology and do not require histopathologic examination, they nevertheless should be eradicated whenever they are encountered during colonoscopy. Whether this approach can be supported by the evidence discussed in this editorial remains controversial. Equally controversial is the authors' concern that their conclusions about the need for biopsy of small polyps may not apply to small flat adenomas. Many recent papers describe small flat colorectal adenomas with a purportedly high malignant potential [24]. These reports suggest that such lesions are common, may be missed using conventional colonoscopic techniques, and that they frequently and rapidly degenerate into small flat cancers. Most of the papers describing these flat adenomas come from Japan, although there recently also have been reports of such lesions by colonoscopists in Western Europe [25]. For several reasons, however, there appears to be little evidence in the US that small flat adenomas with a high malignant potential are being missed by expert Western colonoscopists, and there is little evidence to support the notion that they represent an exception to the classic adenoma-carcinoma sequence model of colorectal carcinogenesis. As discussed above, reports from large series of diminutive polyps in the US describe a uniformly low prevalence of high-grade dysplasia [12]. When small flat adenomas have been looked for systematically during colonoscopy in Western countries, lesions with that gross appearance have been found in a sizable minority of patients. However, when these lesions were biopsied or resected, they almost always had clinically insignificant histopathologic features [27]. The most compelling evidence that small flat adenomas with a high malignant potential are not being overlooked by Western colonoscopists using conventional video endoscopic techniques was reported by the US National Polyp Study [28]. During 8 400 person-years of follow-up after colonoscopic polypectomy, only five new cancers were detected in a group of 1418 adenoma patients. This represented a reduced incidence of cancer of 90 % compared with that of two polyp-bearing reference populations. All five of the cancers that were found were early-stage cancers in polypoid adenomas. If small flat adenomas with appreciable malignant potential had been missed during colonoscopy, small flat cancers without associated benign adenomatous tissue should have been detected during this careful follow-up surveillance. Thus, the findings and conclusions in the current paper by Kulling et al. regarding small polyps should be valid, regardless of whether the gross adenoma configuration appears flat or polypoid.

References

• 1 Correa P. Epidemiology of polyps and cancer in the human intestine.  Gastroenterology. 1979;  77 1245-1251
• 2 Bond J H. Clinical evidence for the adenoma-carcinoma sequence, and the management of patients with colorectal adenomas.  Semin Gastrointest Dis. 2000;  11 176-184
• 3 Fearon E R. Molecular genetic studies of the adenoma-carcinoma sequence.  Adv Intern Med. 1994;  39 123-147
• 4 Lieberman D A, Weiss D, Bond J, et al. Use of colonoscopy to screen asymptomatic adults for colorectal cancer.  N Engl J Med. 2000;  343 162-168
• 5 Lieberman D A, Smith F W. Screening for colon malignancy with colonoscopy.  Am J Gastroenterol. 1991;  86 946-951
• 6 Rex D KL, Lehman G A, Ulbright T M, et al. Colonic neoplasia in asymptomatic persons with negative fecal occult blood tests: influence of age, gender, and family history.  Am J Gastroenterol. 1993;  88 825-831
• 7 Külling D, Christ A D, Karaaslan N, et al. Histology may not be necessary for a small right-sided polyp in a young patient.  Endoscopy. 2001;  33 428-432
• 8 Sciallero S, Costantini M, Bertinelli E, et al. Distal hyperplastic polyps do not predict proximal adenomas: results from a multicentric study of colorectal adenomas.  Gastrointest Endosc. 1997;  46 124-130
• 9 Atkin W S, Morson B C, Cuzick J. Long-term risk of colorectal cancer after excision of rectosigmoid adenomas.  N Engl J Med. 1992;  326 658-662
• 10 Spencer R J, Melton LJ I II, Ready R L, et al. Treatment of small colorectal polyps: A population-based study of risk of subsequent carcinoma.  Mayo Clin Proc. 1984;  59 305-310
• 11 Lotfi A M, Spencer R J, Illstrup D M, et al. Colorectal polyps and the risk of subsequent carcinoma.  Mayo Clin Proc. 1986;  61 337-343
• 12 Gottlieb L S, Winawer S J, Sternberg S S, et al. National Polyp Study (NPS): the diminutive colonic polyp (abstract).  Gastrointest Endosc. 1984;  28 143
• 13 Winawer S J, Zauber A G, O'Brien M J, et al. Randomized comparison of surveillance intervals after colonoscopic removal of newly diagnosed adenomatous polyps.  N Engl J Med. 1993;  328 901-906
• 14 Winawer S J. Colon surveillance for neoplasms: appropriate intervals for surveillance.  Gastrointest Endosc. 1999;  49 Suppl S63-66
• 15 Van Stolk R U, Beck G J, Baron J A, et al. Adenoma characteristics at first colonoscopy as predictors of adenoma recurrence and characteristics at follow-up.  Gastroenterology. 1998;  115 13-18
• 16 Zauber A, Winawer S J. Initial management and follow-up surveillance of patients with colorectal adenomas.  Gastroenterol Clin N Am. 1997;  26 85-101
• 17 Bond J H. For the Practice Parameters Committee of the American College of Gastroenterology. Polyp Guideline: diagnosis, treatment and surveillance for patients with colorectal polyps.  Am J Gastroenterol. 2000;  95 3053-3063
• 18 Lieberman D A. Cost-effectiveness model for colon cancer screening.  Gastroenterology. 1995;  109 1781-1786
• 19 Zarchy T M, Ershoff D. Do characteristics of adenomas on flexible sigmoidoscopy predict advanced lesions on baseline colonoscopy?.  Gastroenterology. 1994;  106 1501-1504
• 20 Read T E, Read J D, Butterly L F. Importance of adenomas 5 mm or less in diameter that are detected by sigmoidoscopy.  N Engl J Med. 1997;  336 8-12
• 21 Schoen R E, Corle D, Cranston L, et al. Is colonoscopy needed for the nonadvanced adenoma found on sigmoidoscopy.  Gastroenterology. 1998;  115 533-541
• 22 Levin T, Palitz A, Grossman S, et al. Predicting advanced proximal colonic neoplasia with screening sigmoidoscopy.  JAMA. 1999;  281 1611-1617
• 23 Wallace M B, Kemp J A, Trnka Y M, et al. Is colonoscopy indicated for small adenomas found by screening flexible sigmoidoscopy?.  Ann Intern Med. 1998;  129 273-278
• 24 Muto T, Kamiya M, Zawada T, et al. Small “flat adenoma” of the large bowel with special reference to its clinico-pathologic features.  Dis Colon Rectum. 1985;  28 847
• 25 Rambacken B J, Fujii T, Caims A, et al. Flat and depressed colonic neoplasms: a prospective study of 1000 colonoscopies in the UK.  Lancet. 2000;  355 1211-1214
• 26 Bond J H. Small flat adenomas appear to have little clinical importance in Western countries.  Gastrointest Endosc. 1995;  42 184-186
• 27 Lanspa S J, Rouse J, Smyrk T, et al. Epidemiologic characteristics of the flat adenoma of Muto: a prospective study.  Dis Colon Rectum. 1992;  35 543-549
• 28 Winawer S J, Zauber A G, Ho M N, et al. Prevention of colorectal cancer by colonoscopic polypectomy.  N Engl J Med. 1993;  329 1977-1981