Affiliations of authors: N. J. Hawkins, School of Pathology, University of New South Wales (NSW), Sydney, Australia; R. L. Ward, School of Medicine, University of NSW, Sydney, and Department of Medical Oncology, St. Vincent's Hospital, Darlinghurst, Sydney, Australia.
Correspondence to: Robyn Lynne Ward, MBBS, Ph.D., Department of Medical Oncology, St. Vincent's Hospital, Victoria St., Darlinghurst, 2010, Sydney, Australia (e-mail: r.ward{at}garvan.unsw.edu.au).
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ABSTRACT |
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INTRODUCTION |
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There has been increasing recognition that hyperplastic (metaplastic) colorectal polyps may indeed be neoplastic lesions (21) because they contain genetic changes also seen in colorectal cancer, including mutations of K-ras (22,23) and MSI (12,24). It has also been recognized that some otherwise typical hyperplastic lesions can show focal dysplasia, a phenomenon referred to variously as a serrated adenoma or as mixed hyperplastic/adenomatous polyps (25). More recently, right-sided hyperplastic polyps have been suggested as a potential precursor lesion of sporadic cancers showing MSI (26,27).
In this study, we examined the frequency of benign epithelial lesions in a group of individuals with sporadic colorectal cancers showing MSI, as well as in a matched control group of individuals with cancers showing microsatellite stability (MSS). The study included both conventional adenomas (tubular, tubulovillous, villous, or flat) and serrated polyps (hyperplastic polyps, serrated adenomas, or mixed hyperplastic/adenomatous polyps). We also assessed the frequency of hMLH1 loss and of hMLH1 promoter methylation in these lesions. In this way, we sought evidence to support the hypothesis that many sporadic colorectal carcinomas with MSI arise from pre-existing hyperplastic polyps or serrated adenomas.
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PATIENTS AND METHODS |
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Patients were drawn from a prospective series of 355 individuals who had undergone curative resection of colorectal carcinoma at St. Vincent's Hospital, Sydney, Australia, from January 1993 to the end of March 2000. Written informed consent was obtained from all individuals, and the study was approved by the St. Vincent's Campus Human Research Ethics Committee. All tumors in this series (n = 382) had been examined for hMLH1 protein expression and MSI (28). Family histories of colorectal cancer and of other malignancies were obtained by interview and were verified against information obtained from death certificates and medical records.
A subgroup of patients with sporadic cancers (index cancers) that showed MSI was identified from this cohort. These patients had at least one carcinoma that showed both MSI and loss of hMLH1, as determined by immunohistochemical analysis. Four individuals were excluded from this test group because it was likely that they had a germline hMLH1 defect, on the basis of either a documented germline mutation (one person), a family history that fulfilled the Amsterdam criteria (29) (two people), or a first colorectal cancer occurring at less than 50 years of age (one person). On this basis, a total of 29 individuals (19 females and 10 males) were identified in the group with sporadic cancers with MSI; their mean age at diagnosis was 76.1 years. Of the 29 sporadic cancers with MSI in these case subjects, 25 (86%) were right-sided (cecum, n = 9; ascending colon, n = 11; and transverse colon, n = 5), while only four case subjects (14%) had lesions distal to the splenic flexure (descending colon, n = 3; and sigmoid colon, n = 1).
A control group of 29 individuals with index cancers showing MSS was then selected from those case subjects in the original cohort who were known to have a cancer that retained hMLH1 expression and MSS. For each case subject with sporadic cancer with MSI, a matched control subject with cancer with MSS was selected who was of the same sex and age (±2 years) and had a tumor at the same site (same or adjacent segment; cecum, ascending, transverse, sigmoid, rectum) as the case subject. All potential control subjects with MSS had been previously assigned a randomly generated number, and the suitable control case subject with the highest number was chosen as the matched pair. There was no statistically significant difference in the extent of the tumor spread (30) (different Dukes' stages) between the two groups (subjects with sporadic cancer showing MSI: stage A [n = 3], stage B [n = 17], stage C [n = 7], and stage D [n = 2]; control subjects with cancer showing MSS: stage A [n = 5], stage B [n = 10], stage C [n = 10], and stage D [n = 4]; P = .32). Likewise, the age distributions of the two groups were very similar: For patients with sporadic cancers showing MSI, the mean age ± standard deviation was 76.1 ± 8.5 years; for control patients with cancers showing MSS, it was 75.9 ± 8.1 years).
Histopathologic Analysis
Benign epithelial lesions were defined as focal epithelial lesions of colorectal mucosa showing polypoid morphology and/or epithelial dysplasia, without invasion of underlying muscularis mucosa. They were identified from archival blocks of paraffin-embedded tissue and were compared with pathologic descriptions of the original resection specimen. Polypoid foci of essentially normal epithelium and minute foci of hyperplastic epithelium in association with mucosal inflammation were excluded from further analysis. Two pathologists then independently classified the remaining lesions as either "serrated polyps" (indicating both hyperplastic polyps and serrated adenomas) or conventional adenomas (tubular, tubulovillous, villous, or flat). Serrated polyps were characterized by a typical serrated morphology that was visible at least superficially within gland lumina (Fig. 1, A). The term "serrated adenoma" described any benign lesion with a serrated architecture and epithelial dysplasia. As such, the term encompassed lesions sometimes referred to as mixed hyperplastic/adenomatous polyps. Benign dysplastic lesions without evidence of serrated architecture were classified as conventional adenomas.
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Detection of hMLH1 was performed on paraffin-embedded tissues with the use of an anti-hMLH1 monoclonal antibody (#554072; Becton Dickinson, Franklin Lakes, NJ), as described previously (28). Staining was considered assessable when nuclear staining was seen in either stromal or germinal follicle lymphocytes or in normal epithelial cells in the base of crypts. The absence of staining of all cells in one or more crypts was considered indicative of hMLH1 loss only when the basal cells of the crypt were assessable (as evidenced by adjacent muscularis mucosae) and when positive staining for hMLH1 was present in adjacent stromal cells or in crypt epithelium. Immunohistochemical analysis and interpretation were performed after the investigators were blinded to the clinical status of the patient and the microsatellite status of each lesion.
DNA Extraction
Preparation of DNA from fresh and paraffin-embedded tissues was performed as described previously (28). If hMLH1-negative glands represented less than half of all tissue within a section, then the negative glands were microdissected with the use of a stereomicroscope. After extraction of paraffin by xylene and ethanol, DNA was extracted with a Qiamp Tissue kit (Qiagen, Hilden, Germany), according to the instructions of the manufacturer. DNA obtained by microdissection was insufficient for bisulfite treatment and was assessed only for MSI.
Analysis of MSI
Polymerase chain reaction (PCR) amplification of microsatellite loci was performed as described previously (31). The markers used in this study were Bat25, Bat26, D5S346, D2S123, and D17S250 (32). A lesion was considered to show a high degree of MSI if two or more of the markers demonstrated instability.
Assessment of hMLH1 Promoter Methylation
Bisulfite modification of DNA was performed as described previously (33), and DNA was resin purified, treated with 0.3 M NaOH (5 minutes at room temperature), and precipitated. Methylation-specific PCR (20) was performed on bisulfite-modified DNA with the use of AmpliTaq (Perkin-Elmer, Boston, MA) preincubated with Taqstart antibody (Clontech Laboratories Inc., Palo Alto, CA). Methylation-specific primer amplicons were digested with BstU1 (New England Biolabs Inc., Beverly, MA) to confirm methylated DNA. As was the case with microsatellite analysis, all assays were performed without knowledge of the clinicopathologic or genetic features of the case.
Statistical Analysis
Categorical variables were compared with the use of the chi-square test or Fisher's exact test as appropriate. The Wilcoxon rank-sum test was used for analysis of the frequency of benign lesions. Conditional logistic regression was used to predict the presence of benign lesions based on the microsatellite status of the primary cancer, and the estimated odds ratio (OR), 95% confidence intervals (CIs), and P values were reported. A two-sided probability value of less than .05 was considered to be statistically significant. All data were analyzed with the use of the SPSS statistical software V9.0 (SPSS Inc., Chicago, IL).
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RESULTS |
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Overall, 281 benign proliferative lesions were identified from 40 of the 58 individuals in this study. These benign lesions were found in 23 of the 29 individuals in the group with sporadic cancer showing MSI and in 17 of the 29 individuals in the control group with cancer showing MSS (Table 1). The majority of these lesions were derived from the right colon, including 110 hyperplastic polyps, 14 serrated adenomas, and 127 conventional adenomas. Only eight hyperplastic polyps, one serrated adenoma, and 21 conventional adenomas were found distal to the splenic flexure, reflecting the use of right hemicolectomy for the resection of most cancers in this study.
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With respect to conventional adenomas, there was no statistically significant difference in the number of lesions between the two groups (P = .52, MannWhitney test), and the likelihood of harboring one or more conventional adenomas was essentially the same (14 of 29 individuals with MSI versus 15 of 29 individuals with MSS).
Immunohistochemical Analysis of Lesions
A total of 38 hyperplastic polyps, 11 serrated adenomas, and 82 conventional adenomas were assessed for hMLH1 loss by immunohistochemistry, as shown in Table 1. Focal loss of hMLH1 expression was seen in 15 serrated polyps (nine hyperplastic polyps and six serrated adenomas) from 10 individuals, all with sporadic cancers with MSI (Table 1
). The hMLH1 loss varied in extent from one gland to the entire lesion (Fig. 2
). While hMLH1 loss was associated with the presence of epithelial dysplasia in serrated adenomas, hMLH1 loss was also seen in nine hyperplastic polyps in the absence of dysplasia (Fig. 2
). There were 13 individuals from the sporadic cancer with MSI group who had a serrated polyp (hyperplastic polyp or serrated adenoma) available for immunohistochemical analysis of hMLH1 expression. Ten of these individuals showed at least focal hMLH1 loss in one or more of their serrated polyps. The clinicopathologic characteristics of these 13 individuals are shown in Table 2
. In contrast, no loss of hMLH1 staining was seen in the six assessable serrated polyps from four individuals in the control group with cancer with MSS (Table 1
). The presence of a sporadic cancer with MSI in any individual in this study was thus statistically significantly associated with focal hMLH1 loss in at least one serrated polyp (P = .02, Fisher's exact test).
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Microsatellite Analysis of Benign Lesions
Microsatellite analysis was attempted on paraffin-embedded material from 45 benign lesions. These lesions included seven lesions from the control group with MSS (four conventional adenomas, two hyperplastic polyps, and one serrated adenoma) and 38 lesions from the group with sporadic cancer with MSI (eight conventional adenomas, 21 hyperplastic polyps, and nine serrated adenomas). Twelve of these lesions showed loss of hMLH1 by immunohistochemistry, while 33 lesions showed normal hMLH1 expression.
Informative results were obtained from 23 lesions. These lesions included 20 lesions from the group with sporadic cancer with MSI (six conventional adenomas from three individuals, eight hyperplastic polyps from five individuals, and six serrated adenomas from four individuals), as well as three lesions from the control group with MSS (one conventional adenoma, one hyperplastic polyp, and one serrated adenoma). Seven of these lesions showed loss of the hMLH1 protein by immunohistochemistry, while 16 lesions showed normal hMLH1 protein expression.
Most of the noninformative samples were from microdissected material and showed no amplification at any loci, presumably because of suboptimal amounts or quality of the DNA template. A further eight lesions showed amplification at less than five markers and were not included in the analysis shown below. However, all were stable at all assessable loci, and all belonged to the hMLH1-positive group. Of the seven informative hMLH1-negative lesions, six showed instability at two or more markers (MSI). With one exception, all of these lesions showed complete loss of hMLH1. The one informative hMLH1-negative lesion without MSI contained a focus of six hMLH1-negative glands within a larger, otherwise entirely positive hyperplastic polyp and represented no more than 10% of the template DNA. All of the 16 assessable hMLH1-positive lesions showed MSS at all five markers.
hMLH1 Promoter Methylation
Of the 29 cancers in this study that showed both MSI and hMLH1 loss by immunohistochemistry, 27 also showed methylation of the hMLH1 promoter. In the two individuals with a cancer not showing hMLH1 promoter methylation, no serrated lesions were found. One of these individuals (a male, 69 years old) had two conventional adenomas, and these adenomas did not show MSI, hMLH1 loss, or promoter methylation.
hMLH1 promoter methylation was assessed from paraffin-embedded tissue from 14 benign lesions. These lesions included nine lesions from the group with sporadic cancer with MSI (six hyperplastic polyps from four individuals, one serrated adenoma from one individual], and two conventional adenomas from two individuals). They also included five lesions (one hyperplastic polyp and four conventional adenomas from three individuals) from the control group with cancer with MSS (Table 3). All of the serrated polyps in the group with sporadic cancer with MSI showed hMLH1 promoter methylation. These polyps included four hyperplastic polyps that were hMLH1 positive by immunohistochemistry as well as two hyperplastic polyps and one serrated adenoma that showed hMLH1 loss. All of the methylated lesions were derived from individuals whose concomitant carcinoma also showed methylation. None of the lesions in the control group showed hMLH1 promoter methylation, and all were positive by hMLH1 immunohistochemistry.
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DISCUSSION |
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These findings support a model for the development of sporadic cancers with MSI as shown in Fig. 3. Since sporadic cancers with MSI are found largely in the right colon, then it seems reasonable to assume that precursor lesions will also be right-sided. On this basis, the model has implications for the biology of right-sided serrated polyps and, more importantly, may critically influence the pathologic assessment and clinical management of these lesions.
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The model for the development of sporadic MSI shown in Fig. 3 is consonant with current knowledge regarding the molecular epidemiology and precursor pathologic lesions of this disease. Unlike conventional adenomas, hyperplastic polyps show a low rate of APC mutation (22,23), consistent with the lower rate of these mutations seen in carcinomas with MSI (6,11,13). Likewise, both serrated adenomas (5%) (35) and carcinomas with MSI (16%) (28) show lower rates of K-ras mutation than conventional adenomas (35%) (36) and carcinomas with MSS (25%40%).
In terms of known morphologic changes, indirect evidence in support of this model has come from case reports of focal hMLH1 loss and MSI within hyperplastic polyps and serrated adenomas (37) and from similar findings in the setting of the hyperplastic polyposis syndrome (38). The term "serrated neoplasia pathway" has been used to describe this apparent morphologic continuum of tumor progression (26,27,39).
However, while the model predicts the presence of transitional forms, such as contiguous hyperplastic polyps or serrated adenomas, in the evolution of sporadic cancer with MSI, such lesions are only seldomly reported. There may be several explanations for this. Benign neoplasms showing MSI are said to show more rapid progression (40), and increasingly dysplastic clones may quickly destroy or replace any pre-existent serrated polyp, even before the lesion becomes clearly invasive. This possibility may explain our finding in this study of several adenomas with apparently conventional morphology that showed MLH1 loss and that abutted sporadic cancers with MSI. Furthermore, the pathologic concept of the "serrated adenoma" is a recent one, and these lesions may not be reported in routine practice but rather may be designated as conventional adenomas. It is noteworthy that, in two recent and large prospective studies of the colonoscopic detection of neoplastic lesions (41,42), no serrated adenomas were identified from the 5115 individuals examined. Finally, the malignant potential suggested for right-sided hyperplastic polyps and serrated adenomas may have been obscured by the presence, in far greater numbers, of their essentially benign left-sided counterparts (43).
The diagnosis of the hyperplastic polyposis syndrome (HPS) is based on the finding of a considerable number of hyperplastic polyps (>20) that are often larger than sporadic hyperplastic polyps (>510 mm) and that are distributed widely in the colon and rectum (44). Two cases from the group with sporadic cancer with MSI in this study (Table 2, patients 14 and 22) clearly fulfill these criteria, with 30 and 52 hyperplastic polyps, respectively. Both of these case patients showed MLH1 loss in at least one of their serrated polyps. It is interesting that both individuals were male and, at 58 years of age (patient 22) and 68 years of age (patient 14), were the youngest and fifth youngest individuals, respectively, in the test group with sporadic cancer with MSI. Four other case subjects from the group with sporadic cancer with MSI also showed a moderate number of hyperplastic polyps or serrated adenomas (Table 2
; patients 12, 21, 27, and 38), which, however, was not enough for a diagnosis of HPS. These individuals were all older than 75 years, and three of the four were women. It is possible that at least some of the cases of HPS reported previously in the literature were in fact typical cases of sporadic cancers with MSI arising in a setting of multiple hyperplastic polyps. As such, it is possible that HPS represents a conglomeration of several diseases, each with a distinct pathobiology (31).
Traditionally, hyperplastic polyps have been regarded as the "Cinderellas of colorectal pathology" (21), with no malignant potential, and current practice guidelines (45) suggest that they can be safely ignored. The findings of this study suggest that this prevailing paradigm may need to be reconsidered and that right-sided serrated polyps could be viewed as potential precursors of colonic carcinoma. If this hypothesis is accepted, then two clinical implications are immediately apparent. First, pathologists must reassess their reporting practices with regard to hyperplastic polyps and serrated adenomas of the right colon, since they may be biomarkers of the future development of a sporadic cancer with MSI. Secondly, endoscopists should view right-sided hyperplastic polyps with the same consideration as they would apply to conventional adenomas at this site.
This study is unable to answer the important question of how frequently right-sided serrated lesions progress to sporadic colorectal cancer with MSI, because of the strong ascertainment bias of this study. However, it is worth noting that 10 of the 29 individuals in this study with a sporadic cancer with MSI harbored at least one separate serrated polyp with focal hMLH1 loss and that, if not removed, this could plausibly have progressed to a further cancer within 1 year to several years. Prospective studies are needed to determine the real risk of malignant progression in these lesions and the most effective way of identifying those particular hyperplastic polyps with malignant potential.
In summary, we present data that suggest that hyperplastic polyps and serrated adenomas in the right colon are the precursors of sporadic microsatellite-unstable colorectal carcinomas. The recognition of this possibility has important implications for research on the key genetic changes underpinning tumor progression in this group of cancers. Accurate determination of the risk of developing carcinomas from right-sided serrated polyps and the screening implications of the detection of such lesions will only be determined in large prospective studies that recognize the unique biologic significance and malignant potential of these lesions.
We thank Yan Yu, Kay Fong Cheong, Elisa Mokany, and Su Ku (all from the Department of Medical Oncology, St. Vincent's Hospital, Sidney, Australia) for technical assistance. We are also grateful to Dr. Jenny Turner (Department of Anatomical Pathology, St. Vincent's Hospital) for providing initial histopathologic assessment of these cases and access to archival material and to Dr. Adrienne Morey (Department of Anatomical Pathology, St. Vincent's Hospital) for reviewing the histologic materials.
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Manuscript received January 12, 2001; revised July 10, 2001; accepted July 12, 2001.
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