Summary Adenocarcinoma of the large intestine can no longer be considered one disease but rather a family of diseases with different precursor lesions, different molecular pathways, and different ...end-stage carcinomas with varying prognoses. Approximately 60% of colorectal carcinomas arise from conventional adenomas via the suppressor pathway leading to microsatellite stable carcinomas. These carcinomas represent the pathway that has been the target of screening and prevention programs to date. However, approximately 35% of carcinomas arise along the serrated pathway developing from the precursor lesion known as the sessile serrated adenoma (also referred to as the sessile serrated polyp). Sessile serrated adenomas/polyps lead to carcinomas with extensive CpG island promoter methylation (CpG island methylated phenotype positive carcinomas), which can be either microsatellite instable high or microsatellite stable. The remaining 5% of carcinomas arise from conventional adenomas in patients with germ line mutations of mismatch repair genes (Lynch syndrome), leading to CpG island methylated phenotype negative microsatellite instable carcinomas. Carcinomas arising from sessile serrated adenomas/polyps are not prevented by removing conventional adenomas and hence may be missed in routine screening programs. In addition, a subset of these lesions may potentially progress rapidly to carcinoma; hence, it is likely that these lesions will require a different screening strategy from that used for conventional adenomas. This article reviews the various pathways to colorectal carcinoma with emphasis on the serrated pathway and evaluates the implications of this pathway for colorectal carcinomas screening programs.
Background The prevalence of sessile serrated adenomas and/or polyps (SSA/Ps) is uncertain. Objective To determine the prevalence of SSA/Ps and SSA/Ps with cytologic dysplasia (SSA/P-CD) by using a ...colonoscopist with a high lesion detection rate and an expert in serrated lesion pathology. Design Retrospective screening colonoscopy study. Setting Academic endoscopy unit. Patients A total of 1910 average risk, asymptomatic patients aged ≥50 years underwent screening colonoscopy between August 2005 and April 2012 by a single colonoscopist with a high lesion detection rate. Interventions Slides of all lesions in the serrated class proximal to the sigmoid colon and all rectal and sigmoid colon serrated lesions >5 mm in size were reviewed by an experienced GI pathologist. Main Outcome Measurements Prevalence of SSA/Ps, defined as the proportion of patients with ≥1 SSA/P. Results There were 1910 patients, of whom 389 had 656 lesions in the serrated class. Review by the experienced GI pathologist determined a prevalence of SSA/Ps without cytologic dysplasia of 7.4% and SSA/Ps-CD of 0.6% (total SSA/P prevalence 8.1%). SSA/Ps and SSA/Ps-CD comprised 5.6% and 0.3%, respectively, of all resected polyps. The mean size of SSA/Ps was 7.13 mm (standard deviation SD 4.66), and 51 of 77 (66.2%) polyps ≥10 mm in the serrated class were SSA/Ps. Limitations Retrospective design. Conclusion A colonoscopist with a high lesion detection rate and an experienced pathologist identified a high prevalence (8.1%) of SSA/Ps in a screening population. SSA/Ps are more common than previously believed.
Epidemiologic and preclinical data suggest that higher intake and serum levels of vitamin D and higher intake of calcium reduce the risk of colorectal neoplasia. To further study the chemopreventive ...potential of these nutrients, we conducted a randomized, double-blind, placebo-controlled trial of supplementation with vitamin D, calcium, or both for the prevention of colorectal adenomas.
We recruited patients with recently diagnosed adenomas and no known colorectal polyps remaining after complete colonoscopy. We randomly assigned 2259 participants to receive daily vitamin D3 (1000 IU), calcium as carbonate (1200 mg), both, or neither in a partial 2×2 factorial design. Women could elect to receive calcium plus random assignment to vitamin D or placebo. Follow-up colonoscopy was anticipated to be performed 3 or 5 years after the baseline examinations, according to the endoscopist's recommendation. The primary end point was adenomas diagnosed in the interval from randomization through the anticipated surveillance colonoscopy.
Participants who were randomly assigned to receive vitamin D had a mean net increase in serum 25-hydroxyvitamin D levels of 7.83 ng per milliliter, relative to participants given placebo. Overall, 43% of participants had one or more adenomas diagnosed during follow-up. The adjusted risk ratios for recurrent adenomas were 0.99 (95% confidence interval CI, 0.89 to 1.09) with vitamin D versus no vitamin D, 0.95 (95% CI, 0.85 to 1.06) with calcium versus no calcium, and 0.93 (95% CI, 0.80 to 1.08) with both agents versus neither agent. The findings for advanced adenomas were similar. There were few serious adverse events.
Daily supplementation with vitamin D3 (1000 IU), calcium (1200 mg), or both after removal of colorectal adenomas did not significantly reduce the risk of recurrent colorectal adenomas over a period of 3 to 5 years. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00153816.).
Serrated lesions of the colorectum are the precursors of perhaps one-third of colorectal cancers (CRCs). Cancers arising in serrated lesions are usually in the proximal colon, and account for a ...disproportionate fraction of cancer identified after colonoscopy. We sought to provide guidance for the clinical management of serrated colorectal lesions based on current evidence and expert opinion regarding definitions, classification, and significance of serrated lesions. A consensus conference was held over 2 days reviewing the topic of serrated lesions from the perspectives of histology, molecular biology, epidemiology, clinical aspects, and serrated polyposis. Serrated lesions should be classified pathologically according to the World Health Organization criteria as hyperplastic polyp, sessile serrated adenoma/polyp (SSA/P) with or without cytological dysplasia, or traditional serrated adenoma (TSA). SSA/P and TSA are premalignant lesions, but SSA/P is the principal serrated precursor of CRCs. Serrated lesions have a distinct endoscopic appearance, and several lines of evidence suggest that on average they are more difficult to detect than conventional adenomatous polyps. Effective colonoscopy requires an endoscopist trained in the endoscopic appearance of serrated lesions. We recommend that all serrated lesions proximal to the sigmoid colon and all serrated lesions in the rectosigmoid > 5 mm in size, be completely removed. Recommendations are made for post-polypectomy surveillance of serrated lesions and for surveillance of serrated polyposis patients and their relatives.
Premalignant polyps of the large intestine are common specimens in surgical pathology. They consist of several different subtypes identifiable by histological criteria that are associated with ...different molecular characteristics and with the development of different types of colorectal carcinoma. The most common of these is the conventional adenoma, which most commonly leads to carcinomas with a low degree of methylation (CIMP-L) that are microsatellite stable. In Lynch syndrome patients these polyps lead to CIMP-L carcinomas that are microsatellite instable. The second most common is the sessile serrated adenoma, which leads to carcinomas with a high degree of methylation (CIMP-H) that may be either microsatellite stable or instable. The least common premalignant polyp is the traditional serrated adenoma, which can lead to either CIMP-L or CIMP-H carcinomas, most often microsatellite stable. This paper will review the histological features of these lesions, discuss problems in diagnosis and discuss the role of histology in management.
•Microsatellite stable (MSS) colorectal carcinomas with a low degree of methylation (CIMP_L) arise in conventional adenoma•Prognostic factors in malignant adenomas include grade, vascular invasion, tumor budding, invasion depth and margin.•Sporadic microsatellite instable tumors arise in sessile serrated adenoma (SSA). These show a high degree of methylation.•CIMP-high MSS tumors usually arise in SSA although some may arise in traditional serrated adenomas.•Carcinomas arising in sessile and traditional serrated adenomas are preceded by the development of cytological dysplasia in these lesions
The precursor lesion for the ~30% of colon carcinomas developing along the serrated pathway was first described in detail in 1996, and was named sessile serrated adenoma in 2003. Although the entity ...itself was controversial initially, over time the concept of a serrated pathway initiated by this lesion has become well accepted in the medical community. The name sessile serrated adenoma, however, has been controversial since the beginning and continues to be controversial. Alternative names, including serrated polyp with abnormal proliferation, sessile serrated polyp and, most recently, sessile serrated lesion, have been proposed. Despite the fact that the term sessile serrated lesion was adopted by the World Health Organization in 2019, none of these terms has received universal acceptance. In this article, arguments for and against adopting the term sessile serrated lesion are discussed in detail.
Background & Aims Sessile serrated adenomas/polyps (SSA/Ps) and traditional serrated adenomas (TSAs) are now distinguished from hyperplastic polyps and recognized as precursors to colorectal cancer ...(CRC). We studied CRC risks associated with serrated polyps. Methods By using Danish databases (1977–2009), we conducted a nationwide population-based, case-control study nested within individuals who had received colonoscopies (n = 272,342), and identified 2045 CRC cases and 8105 CRC-free individuals (controls). For each case and control, we identified the first colorectal polyp(s) that underwent a biopsy or were excised during or after the initial colonoscopy, and obtained tissue blocks for hyperplastic lesions. Four expert pathologists reviewed these lesions using current terminology for serrated polyps. We used logistic regression to compute odds ratios (ORs) to associate the risk of CRC with polyp type and estimated the absolute risks by multiplying the risk in patients with no polyps by these ORs. Results Seventy-nine cases and 142 controls had SSA/Ps (OR, 3.07; 95% confidence interval CI, 2.30–4.10). SSA/Ps with cytology markers of dysplasia were associated with a particularly high OR (4.76; 95% CI, 2.59–8.73). Women with SSA/P had a higher risk for CRC than men with SSA/P (OR for women, 5.05; 95% CI, 3.05–8.37 vs OR for men, 2.18; 95% CI, 1.24–3.82); patients with SSA/P proximal to the splenic flexure had the highest risk for CRC (OR, 12.42; 95% CI, 4.88–31.58). The OR for CRC was 4.84 in the 14 cases vs 17 controls with TSAs (95% CI, 2.36–9.93), 2.51 in the 757 cases vs 1698 controls with conventional adenomas (95% CI, 2.25–2.80), and 1.30 in the 55 cases vs 235 controls with hyperplastic polyps (95% CI, 0.96–1.77). The 10-year risk for CRC was 4.4% for patients with SSA/P with dysplasia, 4.5% for patients with TSAs, and 2.3% for patients with conventional adenomas. Conclusion Patients with SSA/P or TSA are at increased risk for CRC; their level of risk is similar to or higher than that of patients with conventional adenomas.
Nodular gastric antral vascular ectasia (GAVE) is a reported phenotype of GAVE that has histologic features overlapping with gastric hyperplastic polyps (GHPs), with additional features often seen in ...flat mucosa of GAVE.
To determine if nodular GAVE and GHPs are distinct lesions by evaluating the prevalence of features reported in nodular GAVE in GHPs with or without associated GAVE.
A review of all lesions diagnosed as GHPs between 2014 and 2017 was performed. Slides were analyzed for a number of features including established histologic features of GAVE without knowledge of clinical or endoscopic features.
A total of 90 polyps were analyzed including 18 from patients with GAVE (20%). GAVE polyps were larger than non-GAVE polyps (average size, 1.3 cm versus 0.68 cm; P < .001), with more common extensive ulceration and associated granulation tissue (61.11% n = 11 versus 4.17% n = 3; P = .004), fibrin thrombi (50% n = 9 versus 15% n = 11; P = .003), moderate to marked vascular ectasia (83% n = 15 versus 35% n = 11; P = .001), and fibrohyalinosis (72% n = 13 versus 28% n = 20; P = .001). All polyps showed foveolar hyperplasia and smooth muscle proliferation. There were no features that were exclusively found in GAVE or non-GAVE cases.
Nodular GAVE appears to represent GHPs arising in a background of GAVE, with superimposed features found in flat mucosa of GAVE stomachs. The presence of fibrin thrombi, marked vascular ectasia, fibrohyalinosis, and/or ulceration in a GHP is suggestive but not diagnostic of GAVE, and the absence of these features does not rule out GAVE.
Both annual testing for fecal occult blood and biennial testing significantly reduce mortality from colorectal cancer. However, the effect of screening on the incidence of colorectal cancer remains ...uncertain, despite the diagnosis and removal of precancerous lesions in many persons who undergo screening.
We followed the participants in the Minnesota Colon Cancer Control Study for 18 years. A total of 46,551 people, most of whom were 50 to 80 years old, were enrolled between 1975 and 1978 and randomly assigned to annual screening, biennial screening, or usual care (the control group). Those assigned to the screening groups were asked to prepare and submit two samples from each of three consecutive stools for guaiac-based testing. Those with at least one positive slide in the set of six were offered a diagnostic examination that included colonoscopy. Screening was conducted between 1976 and 1982 and again between 1986 and 1992. Study participants have been followed with respect to newly diagnosed cases of colorectal cancer and deaths. Follow-up has been more than 90 percent complete.
During the 18-year follow-up period, we identified 1359 new cases of colorectal cancer: 417 in the annual-screening group, 435 in the biennial-screening group, and 507 in the control group. The cumulative incidence ratios for colorectal cancer in the screening groups as compared with the control group were 0.80 (95 percent confidence interval, 0.70 to 0.90) and 0.83 (95 percent confidence interval, 0.73 to 0.94) for the annual-screening and biennial-screening groups, respectively. For both screening groups, the number of positive slides was associated with the positive predictive value both for colorectal cancer and for adenomatous polyps at least 1 cm in diameter.
The use of either annual or biennial fecal occult-blood testing significantly reduces the incidence of colorectal cancer.
Background & Aims:
Colonoscopic polypectomy is considered effective for preventing colorectal cancer (CRC), but the incidence of cancer in patients under colonoscopic surveillance has rarely been ...investigated. We determined the incidence of CRC in patients under colonoscopic surveillance and examined the circumstances and risk factors for CRC and adenoma with high-grade dysplasia.
Methods:
Patients were drawn from 3 adenoma chemoprevention trials. All underwent baseline colonoscopy with removal of at least one adenoma and were deemed free of remaining lesions. We identified patients subsequently diagnosed with invasive cancer or adenoma with high-grade dysplasia. The timing, location, and outcome of all cases of cancer and high-grade dysplasia identified are described and risks associated with their development explored.
Results:
CRC was diagnosed in 19 of the 2915 patients over a mean follow-up of 3.7 years (incidence, 1.74 cancers/1000 person-years). The cancers were located in all regions of the colon; 10 were at or proximal to the hepatic flexure. Although most of the cancers (84%) were of early stage, 2 participants died of CRC. Seven patients were diagnosed with adenoma with high-grade dysplasia during follow-up. Older patients and those with a history of more adenomas were at higher risk of being diagnosed with invasive cancer or adenoma with high-grade dysplasia.
Conclusions:
CRC is diagnosed in a clinically important proportion of patients following complete colonoscopy and polypectomy. More precise and representative estimates of CRC incidence and death among patients undergoing surveillance examinations are needed.
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