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Because of the recent emergence of CT colonography (CTC) as a potential screening tool, the natural history of small colorectal polyps (< 10 mm) has become a critical issue. The primary reason for this is that CTC is highly likely to be both a clinically effective and cost-effective approach to population screening if only large polyps (≥ 10 mm) necessitate referral for polypectomy. On the other hand, if the neoplastic risk of small subcentimeter polyps is deemed to be high enough to warrant invasive colonoscopy in all cases, the utility of CTC as an intermediate filter is significantly weakened. To underscore the importance of this issue and the perceived dearth of scientific data, the American Gastroenterological Association (AGA) recently expressed the need for funding of a “long-term study of the natural history of the small polyp.” Indeed, there are some longitudinal CTC studies already under way to address this question.

However, a reverent look into the past reveals that this score was actually settled more than 40 years ago in the landmark article by Welin et al. [1] titled “The Rates and Patterns of Growth of 375 Tumors of the Large Intestine and Rectum Observed Serially by Double Contrast Enema Study (Malmö Technique).” In fact, this prescient work from 1963 not only establishes the legitimacy of the 10-mm threshold for polypectomy, it also lays the groundwork for the concept of the advanced adenoma, which only decades later would become a central tenet of colorectal screening. In what could be termed a dose of noble irony, the double-contrast barium enema, which has effectively provided the scientific proof needed to support the utility of CTC screening, is also being laid to rest by the ascendancy of this novel colorectal imaging study.

In their visionary paper, Welin and colleagues [1] analyzed data from more than 21,000 double-contrast barium enema studies performed over a 10-year period. From this large study population, two or more serial barium enema studies evaluated a total of 375 unresected colorectal tumors in 303 patients, with a mean follow-up interval of 30 months. Of these 375 lesions, 136 were ultimately resected with pathologic evaluation, and 239 remained under observation. After one strips away the complex growth modeling used by the authors (which is admittedly beyond my ken), the core results are striking; most notably, the growth rates for benign polyps were exceedingly slow (Fig. 1A, 1B, 1C). In fact, the authors conclude that “most of the benign adenomatous polyps and the unresected tumors (most of which are probably benign adenomatous polyps) grew so slowly that they could not have achieved a significant size during the longest human life span.” With regard to polyp size, the authors found that a 10-mm diameter was indeed a critical threshold for predicting future growth and commented that “tumors smaller than 10 mm in diameter and appearing benign roentgenographically may be observed safely by serial double-contrast enema studies.” In the context of potential widespread screening with CTC, these prophetic remarks border on the clairvoyant with regard to the hot-button issues of today [2, 3].

Subsequent works by other researchers have essentially recapitulated the findings of Welin et al [1]. In a natural history study of large polyps (≥ 10 mm), also using the barium enema for longitudinal evaluation, Stryker et al. [4] reinforced the practice of removing large lesions. Interestingly, the cumulative risk of cancer for large polyps at 5 and 10 years was less than 3% and 10%, respectively, suggesting that even large lesions are perhaps not as ominous as commonly believed. Stryker et al. did not address small polyps and their natural history, which is unfortunate because there is actually little debate on the appropriate management of large polyps.

Several longitudinal endoscopic trials have followed small unresected polyps, with findings that mirror Welin et al. [1]. Hofstad et al. [5] performed serial colonoscopy on subcentimeter polyps and found that only one (0.5%) of 189 lesions eclipsed the 10-mm threshold after 1 year. In a follow-up study by Hofstad et al. [6] at the 3-year mark, most polyps remained stable or had regressed in size, and there was an overall tendency to net regression among the medium-sized (5-9 mm) polyps. Longitudinal trials using flexible sigmoidoscopy have also shown the stability of smaller polyps over time [7-9]. In one study that used serial sigmoidoscopy for polyps up to 15 mm in size over a 3- to 5-year period, Knoernschild [7] reported a significant increase in polyp size in only 4% of patients.

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Fig. 1A —A polyp of the descending colon 5 mm in width in 65-year-old man showed no change in size or marginal configuration during three double-contrast study observations over 6.5 years. March 19, 1955. (Reprinted with permission from [1])

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Fig. 1B —A polyp of the descending colon 5 mm in width in 65-year-old man showed no change in size or marginal configuration during three double-contrast study observations over 6.5 years. June 23, 1960. (Reprinted with permission from [1])

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Fig. 1C —A polyp of the descending colon 5 mm in width in 65-year-old man showed no change in size or marginal configuration during three double-contrast study observations over 6.5 years. November 27, 1961. (Reprinted with permission from [1])

Finally, the high observed adenoma detection rates at surveillance in the National Polyp Study, in conjunction with the low observed colorectal cancer incidence, could only be explained by regression of adenomas [10]. On review of this cumulative body of data, one cannot help but wonder if the call for more research on the natural history of small polyps merely serves as a smokescreen that is effectively stalling CTC implementation. Even in the face of longitudinal data that support the concept of noninvasive follow-up for small polyps, and without any compelling evidence to the contrary, there are still those who contend that referral to invasive colonoscopy for polypectomy is indicated for these lesions [11, 12]. Of course, to place such importance on the issue of small polyps is to miss the true goals and benefits of colorectal screening.

In addition to effectively showing the indolent and often idle nature of benign colorectal polyps, Welin and colleagues [1] issued a number of other noteworthy observations. Although nearly all proven cancers in their study showed a more rapid growth rate compared with benign lesions, the estimated doubling times were still relatively long, often approximately 1,000 days. Even the fastest growing cancer required 100 days to increase its diameter by only 2.5 mm, whereas the slower growing cancers might have required well over half the maximum human life span to attain a diameter of 6 cm. Because fewer than 0.1% of subcentimeter adenomas harbor malignancy [13], the issue of cancer growth rates is less relevant to CTC screening because nearly all malignant tumors are large enough to be readily detectable and warrant referral to invasive colonoscopy.

Other interesting observations revolve around the relationship of the histology of adenomas and their resultant behavior. It would appear that H. J. Spjut, one of the pathologists involved in the Welin et al. [1] study, presaged the awareness and clinical significance of tubulovillous adenomas and of advanced adenomas in general by describing a polyp variant that he termed a “villoglandular polyp.” Importantly, the authors found that the villous and villoglandular (tubulovillous) adenomas typically grew much faster than the remaining adenomas (i.e., those with simple tubular histology) and were more likely to attain a large size. Of course, we now recognize these lesions as “advanced adenomas” and regard them as the primary target for screening [14]. The behavior of small tubular adenomas in this study was so benign that the authors thought it supported an existing concept that such lesions were essentially hamartomas with no malignant potential. Although there has been some renewed interest in emphasizing the benign nature of subcentimeter tubular adenomas [15, 16], it may be worthwhile to go one step further and reconsider the notion that these lesions may have virtually no direct clinical significance.

On a personal note, I recently had the pleasure of meeting with a coauthor of the Welin et al. [1] study, James Youker, during a visiting professorship at the Medical College of Wisconsin. During my grand rounds presentation, I stressed the importance of investigating and confirming the natural history of small polyps with regard to the ultimate role of CTC for screening. Of course, it was only later, after reading the 1963 publication, that I realized this esteemed member in the audience had long since shown this concept.

Somewhat forgotten, perhaps because it was well before its time, this landmark article showed a number of important concepts that were either rediscovered in the colonoscopic era (e.g., the advanced adenoma as the target for screening) or remain under somewhat unnecessary debate (e.g., the natural history of small benign polyps). This work serves as an important reminder that it behooves us to be aware of and embrace the efforts of our predecessors. I for one believe that we owe these authors a debt of gratitude for their farsighted research.