From 1995 to 2002, 1150 patients were identified who had undergone one or more colonoscopy, had paraffin wax blocks of neoplastic colorectal tissue available through the pathology department, and met the criteria for one of several sequential genetic epidemiological studies. One hundred and twenty six of these patients were found to have had hyperplastic polyps. There were 42 women and 84 men. The mean (SD) age at the time of removal of the first hyperplastic polyp was 63.7 (10.8) years. Each patient had an average of 1.17 (0.47) hyperplastic polyps, and in total there were 147 polyps. One hundred and nine patients (87%) had only one hyperplastic polyp, whereas 14 patients (11%) had two. Only three patients (2%) had more than two hyperplastic polyps: two patients each had three and one had four hyperplastic polyps (table 1). Of the 126 patients, 89 patients (71%) had only a left sided hyperplastic polyp, whereas 32 patients (25%) had only a right sided hyperplastic polyp. Four patients (3%) had hyperplastic polyps on both sides of the colon, and one patient had one hyperplastic polyp of unknown location (table 1).
Table 1 Patient demographics and hyperplastic polyp characteristics
One hundred and twenty two patients had a mean (SD) of 3.2 (3.0) adenomas in addition to their hyperplastic polyps. Forty three patients (35%) had only one adenoma, whereas 28 patients (23%) had two adenomas, and 51 patients (42%) had three or more adenomas. Seventy (57%) of the 122 patients with adenomas had only tubular adenomas, whereas the other 52 patients (43%) had adenomas with some villous component (tubulovillous or villous) (table 2). Of the 122 patients with adenomas, 46 patients (38%) had left sided adenomas only, 24 patients (20%) had right sided adenomas only, and 52 patients (43%) had adenomas on both sides of the colon. Sixty nine patients (57%) had had an adenoma before the detection of their first hyperplastic polyp, with an average interval of 4.3 years (range, 1–19). Thirty two patients (26%) had an adenoma after their last hyperplastic polyp, with an average interval of 4.7 years (range, 1–15).
Table 2 Neoplastic lesions in patients with hyperplastic polyps
Of the 122 patients with adenomas, 42 patients (34%) had at least one adenoma with a K-ras mutation. However, of these 42 patients, only three had a hyperplastic polyp with a K-ras mutation, whereas 39 had a hyperplastic polyp with no Ki-ras mutation (table 2). In contrast, 80 patients had adenomas without a K-ras mutation, and 11 of these patients also had a K-ras mutated hyperplastic polyp. Thus, patients with hyperplastic polyps with a K-ras mutation were not more likely to have adenomas with K-ras mutations (OR, 0.48; 95% CI, 0.08 to 1.99). One hundred and twelve patients had at least one adenoma assayed for APC LOH, and 42 of them (38%) had at least one adenoma with APC LOH (table 2).
Of the 126 patients, 26 had a carcinoma. Four patients had only a carcinoma and 22 had both a carcinoma and one or more adenomas. Sixteen carcinomas were in the left colon, nine were in the right colon, and one was located in the small bowel. Twenty three of the 26 carcinomas were assayed with respect to the K-ras gene and eight were found to have a K-ras mutation (table 2). None of the eight patients with K-ras mutated colorectal carcinoma had a hyperplastic polyp with a K-ras mutation. Of the four patients with only a carcinoma and no adenoma, one carcinoma was K-ras mutated; all four had a hyperplastic polyp with no K-ras mutation. APC LOH was detected in three of 21 carcinomas assayed. Among the 21 patients with only left sided hyperplastic polyps and a colorectal carcinoma, 13 had a left sided carcinoma and seven had a right sided carcinoma, whereas one patient had a small bowel carcinoma.
In total, 147 hyperplastic polyps were removed from the 126 patients. One hundred and nine hyperplastic polyps (74%) were found in the left colon, 37 (25%) were removed from the right colon, and one was from an unknown location (table 1). The location by segment was: caecum, eight; ascending colon, 12; transverse colon, 17; descending colon, 15; sigmoid colon, 64; and rectum, 30. One hundred and forty three of the 147 hyperplastic polyps (97%) were assayed for Ki-ras mutation and in 15 (10%) a mutation was detected. These 15 hyperplastic polyps were removed from 14 patients, and they had been located in the rectum in five patients and in the sigmoid colon in 10 patients (table 1). At least one hyperplastic polyp with a K-ras mutation occurred in 7% of all women and 13% of all men, percentages that are not significantly different (p < 0.38; OR, 0.5; 95% CI, 0.1 to 2.0). Fourteen of the 15 mutations occurred within codon 12, namely: nine transitions GGT to GAT, four transversions GGT to GTT, one transversion GGT to GCT; in addition, there was one transversion in codon 13: GCC to GAC.
Of the fourteen patients who had two hyperplastic polyps, 11 patients had no K-ras mutation in either, one patient had a K-ras mutation in both, and two patients had one hyperplastic polyp with a K-ras mutation and one without. Of the two patients who had three hyperplastic polyps, one patient had no K-ras mutations, and the other patient had only one hyperplastic polyp with a K-ras mutation. The one patient with four hyperplastic polyps had three without a K-ras mutation and one with a K-ras mutation.
The 14 patients with K-ras mutated hyperplastic polyps had an average of 4.1 adenomas, compared with an average of 3.1 adenomas for the 108 patients with hyperplastic polyps that were K-ras normal, a difference that is not significant (p < 0.23).
We sized each hyperplastic polyp based upon the largest of the three dimensions measured by the pathologist. The mean size of the 15 hyperplastic polyps with a K-ras mutation was 3.2 mm. The mean size for the 128 hyperplastic polyps without a k-ras mutation was 3.25 mm (no size was recorded for four), a difference that is not significant (p < 0.9) (table 1).
One hundred and thirty three hyperplastic polyps were assayed for APC LOH, and none of them revealed LOH for the APC gene. The 14 hyperplastic polyps not assayed for APC LOH were from all segments of the colon. In total, 55 hyperplastic polyps were assessed for microsatellite instability: 32 of the 37 hyperplastic polyps from the right colon and 23 of the 109 hyperplastic polyps from the left colon (including all hyperplastic polyps found to have a Ki-ras mutation). These 55 hyperplastic polyps were all microsatellite stable (table 1).
One hundred and forty two hyperplastic polyps had been removed from colons that also yielded at least one adenoma. There was no association between the hyperplastic polyp and the adenoma regarding the colon segment or the side of the colon from which the two lesions were removed. Of these 142 hyperplastic polyps, 68 (48%) had been removed from the same segment as the adenoma, and 73 (52%) had come from a different segment than the adenoma (the location of one hyperplastic polyp was unknown) (table 1). In total, 90 patients had hyperplastic polyps on the left side, and 71 of them had adenomas also on the left side, whereas 19 patients had adenomas only on the right side of the colon. Of the 31 patients with hyperplastic polyps only on the right side of the colon, 26 patients had adenomas on the left side and five patients had adenomas only on the right side. There was no relation between the location of hyperplastic polyps and adenomas (OR, 0.72; 95% CI, 0.19 to 2.27).
In total, 25 patients had a carcinoma of the colon and one had a small bowel carcinoma. Twenty one patients had hyperplastic polyps in the left colon, 14 of whom had a carcinoma in the left side and seven of whom had a carcinoma in the right side. Four patients had hyperplastic polyps only on the right side of the colon, two of whom had a carcinoma in the left side, whereas two had a carcinoma in the right side.
We also identified six additional patients from our entire cohort who had hyperplastic polyps but no colorectal neoplasm (data not shown). These six patients had a total of nine hyperplastic polyps, three of which were K-ras mutated, two from the sigmoid colon and one from the rectum. None of the hyperplastic polyps had APC LOH, and the three with a K-ras mutation were microsatellite stable. Of note, one of the six patients had three hyperplastic polyps: one removed from the ascending colon, and two years later, one removed from the rectum and one from the transverse colon. Only the hyperplastic polyp from the rectum was K-ras mutated.
As a separate evaluation, an independent pathologist with recognised expertise in gastroenterological pathology, who had not been involved with the activities of our study, re-reviewed a subset of haematoxylin and eosin stained slides. The 15 hyperplastic polyps with K-ras mutation were admixed with 15 other hyperplastic polyps without a K-ras mutation. Our expert pathologist reviewed all 30 cases blindly. He could detect no specific histological features unique to those cases with K-ras mutations (fig 2).
Figure 2 A sigmoid hyperplastic polyp with a mutation in the K-ras gene: GGT to GAT in codon 12.