Background

This is a common pathological finding in the gastrointestinal tract. These polyps are common in the distal colon of elderly patients and are benign. Recently, a syndrome of hyperplastic polyposis has been described which may be associated with an increase in malignancy. In addition, there is increasing evidence that some hyperplastic polyps may harbor genetic changes that may be preneoplastic changes.

OUTLINE

Epidemiology
Pathogenesis
Laboratory/Radiologic/Other Diagnostic Testing
Gross Appearance and Clinical Variants
Histopathological Features and Variants
Special Stains/ Immunohistochemistry/ Electron Microscopy
Differential Diagnosis
Prognosis
Treatment
Commonly Used Terms
Internet Links

EPIDEMIOLOGY	CHARACTERIZATION
Colonic polyps in an unselected population: prevalence, characteristics, and associations. Cannon-Albright LA, Bishop DT, Samowitz W, DiSario JA, Lee R, Burt RW. Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City.	Am J Gastroenterol 1994 Jun;89(6):827-31 Abstract quote OBJECTIVES: To provide a proctosigmoidoscopic review of a very large set of unselected control subjects, providing an unbiased view of colonic polyps in the general population. METHODS: Sigmoidoscopic data from 406 sequentially recruited subjects were analyzed. Participation rates were over 85%, and subjects were thus free of the usual selection bias. RESULTS: Thirty-eight percent of screened individuals were found to have distal colonic polyps. Adenomas were found in 12%, and hyperplastic polyps were found in 30% of screened individuals. Adenomas were more prevalent in males and in older individuals. Hyperplastic prevalence did not differ significantly by gender or age. Synchronous adenomatous and hyperplastic polyps occurred in 3% of screened individuals, but these lesions were not associated. CONCLUSIONS: Distal colonic adenomatous and hyperplastic polyps are very common in the general population and are not associated. The high frequency of these polyps raises questions about the feasibility of biopsy for all polyps, and suggests that further study is needed to determine the appropriate indications for subsequent colonoscopy.
Diet, alcohol, and smoking and the occurrence of hyperplastic polyps of the colon and rectum (United States). Kearney J, Giovannucci E, Rimm EB, Stampfer MJ, Colditz GA, Ascherio A, Bleday R, Willett WC. Department of Nutrition, Harvard School of Public Health, Boston, MA, USA.	Cancer Causes Control 1995 Jan;6(1):45-56 Abstract quote Hyperplastic polyps of the colon reveal a geographic distribution similar to that of colorectal cancer and adenomatous polyps. However, unlike adenomas--known precursors of colorectal cancer--little is known about the etiology or clinical significance of the hyperplastic polyp. In this prospective study, we set out to determine the main dietary and other lifestyle factors in the United States that might be associated with this lesion. Hyperplastic polyps of the distal colon and rectum were diagnosed in 219 of 12,922 men of the Health Professionals Follow-up Study having had an endoscopic procedure between 1986 and 1992, and 175 of 15,339 women of the Nurses' Health Study who had undergone an endoscopy for a variety of reasons between 1980 and 1990. After adjusting for age, family history of colon cancer, history of previous endoscopy, and total energy intake using multiple logistic regression, those consuming 30 g or more of alcohol per day were at increased risk relative to nondrinkers among men (relative risk [RR] = 1.69; 95 percent confidence interval [CI] = 1.01-2.80) and women (RR = 1.79, CI = 1.02-3.15). Current smoking also was found to be associated strongly positively with hyperplastic polyps in men (RR = 2.45, CI = 1.59-3.75) and women (RR = 1.96, CI = 1.16-2.86). High intake of folate was associated inversely with risk in both men (RR = 0.74, CI = 0.49-1.11, between high and low intakes of folate) and women (RR = 0.45, CI = 0.28-0.74, between high and low intakes of folate). Among macronutrients, a suggestive increase in risk existed with intake of animal fat, although this was attenuated in the full multivariate model (RR[men] = 1.48, CI = 0.94-2.41, and RR[women] = 1.22, CI = 0.77-1.94) between high and low quantities of animal fat intake. These prospective data provide evidence of associations between low folate intake, alcohol consumption, and current cigarette smoking, and risk of hyperplastic polyps of the distal colon and rectum. These same factors also have been found to be related to adenoma and cancer of the colon. The hyperplastic polyp is an indicator of populations at high risk for colorectal carcinoma, and it also may serve as a marker for factors that influence neoplastic evolution.
A case-control study of dietary intake and other lifestyle risk factors for hyperplastic polyps. Martinez ME, McPherson RS, Levin B, Glober GA. Human Nutrition Center, University of Texas-Houston Health Science Center, School of Public Health, USA.	Gastroenterology 1997 Aug;113(2):423-9 Abstract quote BACKGROUND & AIMS: Despite the high prevalence of the hyperplastic polyp, little is known about its etiology. The aim of this study was to assess the relationship between diet and other lifestyle factors and the presence of colorectal hyperplastic polyps. METHODS: Information on diet and other known or suspected risk factors for colorectal cancer or adenoma was collected among 81 subjects with hyperplastic polyps and 480 controls. RESULTS: The multivariate-adjusted odds ratio (OR) for hyperplastic polyps for individuals in the upper vs. the lower quartile was 0.30 (95% confidence interval [CI], 0.10-0.88) for dietary fiber, 0.32 (95% CI, 0.11-0.96) for dietary calcium, 0.90 (95% CI, 0.27-2.95) for total fat, and 2.02 (95% CI, 1.05-3.91) for alcohol consumption. Compared with individuals in the lower category, those in the upper category of body mass index had a higher risk for hyperplastic polyps (OR, 4.50; 95% CI, 1.84-10.97). Cigarette smoking was associated with a higher risk (OR, 1.97; 95% CI, 1.02-3.81 for > 20 pack-years vs. never), whereas an inverse association was seen for use of aspirin and other nonsteroidal anti-inflammatory drugs (OR, 0.29; 95% CI, 0.12-0.67 for once per day or more vs. never). CONCLUSIONS: Hyperplastic polyps share common lifestyle risk factors with colorectal adenomas and carcinomas.
Colorectal adenomatous and hyperplastic polyps: smoking and N-acetyltransferase 2 polymorphisms. Potter JD, Bigler J, Fosdick L, Bostick RM, Kampman E, Chen C, Louis TA, Grambsch P. Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.	Cancer Epidemiol Biomarkers Prev 1999 Jan;8(1):69-75 Abstract quote Arylamine N-acetyltransferase 2 (NAT2) is involved in both the detoxification and bioactivation of carcinogenic arylamines and other mutagens. This enzyme is polymorphic, and the fast and slow phenotypes are thought to be risk factors for colon and bladder cancer, respectively. Here, we report on a case-control study of adenomatous and hyperplastic polyps, with particular attention to tobacco smoking, a known risk factor for adenomas, and polymorphisms of NAT2. All participants underwent complete colonoscopy and were subsequently divided into case and control groups on the basis of pathology. Cases were diagnosed with confirmed adenomas (n = 527) or hyperplastic polyps (n = 200); controls (n = 633) had no history of colonic neoplasia and no polyps at colonoscopy. NAT2 genotype was determined using an oligonucleotide ligation assay and fast, intermediate, or slow phenotype imputed. Multivariate-adjusted odds ratios (ORs) and 95% confidence intervals were computed using logistic regression adjusting for age, sex, nonsteroidal anti-inflammatory drug use, and hormone replacement therapy use. Smoking was associated with an increased risk of adenomas [current versus never smoking OR = 2.0 (95% confidence interval, 1.4-2.9)] and hyperplastic polyps [current versus never smoking OR = 4.1 (2.6-6.5)]. NAT2 status among adenomatous polyp patients and hyperplastic polyp patients, respectively, showed ORs of 1.1 (0.8-1.4) and 1.2 (0.8-1.6; intermediate versus slow) and 1.1 (0.6-1.9) and 0.9 (0.4-1.9; fast versus slow). There were no differences in risk when adenoma patients were stratified on multiplicity, size, or histopathological subtype of polyps. Never-smokers showed no variation in risk across acetylator status for either species of polyp, whereas current smokers showed ORs of 2.0 (1.2-3.2) and 2.3 (1.4-3.9) for adenomas and 3.9 (2.1-7.1) and 4.9 (2.6-9.4) for hyperplastic polyps for slow and intermediate/fast NAT2, respectively, compared with slow-NAT2 never-smokers. Risks of both multiple [OR = 4.3 (2.1-8.8)] and large [OR = 3.8 (1.9-7.5)] adenomas were somewhat elevated in current smokers with an intermediate/fast phenotype compared with smokers with a slow NAT2 phenotype, but the interaction was not statistically significant. Risk of hyperplastic polyps and adenomatous polyps is strongly related to smoking. There is little suggestion of interaction between NAT2 status and smoking and no relationship with NAT2 genotype alone.

 

PATHOGENESIS	CHARACTERIZATION
Molecular Pathways suggest at least some polyps are clonal lesions	J Clin Pathol 1999;52:59. Genes, Chromosom Cancer 1995;14:182–8. Cancer Res 1993;53:1895–8. Loss of genetic material on chromosome 1p as evidenced by LOH occurs early in colorectal cancer development and has been found in occasional hyperplastic polyps
GENETIC ALTERATIONS
BRAF and KRAS Mutations in Hyperplastic Polyps and Serrated Adenomas of the Colorectum: Relationship to Histology and CpG Island Methylation Status. Yang S, Farraye FA, Mack C, Posnik O, O'brien MJ. From the *Department of Pathology and daggerSection of Gastroenterology, Boston Medical Center, Boston, MA.	Am J Surg Pathol. 2004 Nov;28(11):1452-1459. Abstract quote   The aim of this study was to test the hypothesis that mutations of the oncogenes BRAF or KRAS are early events in the putative serrated polyp neoplasia pathway and more advanced pathology is associated with acquired mutator and suppressor gene inactivation by CpG island methylation of promoter regions. We assayed 79 sporadic hyperplastic polyps (HPs) classified according to the schema of Torlakovic et al and 25 serrated adenomas (SAs) for BRAF and KRAS mutations and related the findings to histologic characteristics and CpG island methylation phenotype (CIMP). Mutations at exon 15, codon 599, of BRAF were assayed using an allele-specific PCR (AS-PCR) technique and confirmed in a sample of AS-PCR- positive cases by direct sequencing of exon 15. AS-PCR-negative HPs and SAs were also sequenced on exon 15 and exon 11 to detect additional mutations. PCR-RFLP was used to assay KRAS codon 12 and 13 mutations, and these mutations were further validated by direct sequencing of the KRAS gene. BRAF599 mutations were identified in a total of 55 HPs (69.6%) and KRAS mutations in a total of 13 (16.5%). BRAF599 mutations occurred with similar frequencies among microvesicular serrated polyp (76.3%) and serrated polyp with abnormal proliferation (82.1%) subtypes but less frequently in goblet cell serrated polyps (23.1%). Conversely, KRAS mutations were most frequent in goblet cell serrated polyp (46.2%) and less frequent in microvesicular serrated polyp (13.2%) and serrated polyp with abnormal proliferation (7.1%). BRAF599 and KRAS mutations were present in 15 (60.0%) and 7 (28.0%) of SAs, respectively. BRAF 599 mutation and KRAS were mutually exclusive findings in the polyps studied and one or the other occurred in 68 of 79 (86.1%) HPs and 22 of 25 (88.0%) SAs. CpG island methylation involving 2 or more genes (CIMP-H) was present in 80.0% of SAs, 75% serrated polyp with abnormal proliferations, 47.4% of microvesicular serrated polyps, and 15.4% of goblet cell serrated polyps. SAs were significantly more likely to be CIMP-H than HPs (odds ratio 3.7; 95% confidence interval, 1.27-10.86; P = 0.017). A similar high frequency of KRAS or BRAF mutations across the histologic spectrum of the serrated polyps assayed suggests that these are early events in the serrated polyp neoplasia pathway. In contrast, the association of higher levels of CpG island methylation with more advanced histologic changes suggests that CpG island methylation plays a role in serrated polyp progression toward colorectal carcinoma.
Hyperplastic (serrated) polyps of the colorectum: relationship of CpG island methylator phenotype and K-ras mutation to location and histologic subtype. O'Brien MJ, Yang S, Clebanoff JL, Mulcahy E, Farraye FA, Amorosino M, Swan N. Department of Pathology, Boston Medical Center, Boston, MA 02118, USA.	Am J Surg Pathol. 2004 Apr;28(4):423-34. Abstract quote We investigated the frequency of promoter region CpG island methylation (CIM) of hMLH1, MGMT, MINT1, MINT2, and p16 and K-ras mutations in a total of 79 hyperplastic (serrated) polyps (HPs) from 75 patients and correlated the molecular profiles to polyp location in the colorectum, histologic variation, and other factors. Methylation-specific PCR (MS-PCR) was used to assay CIM status. HPs that showed CIM of one or more or two or more of the genes assayed were classified as CpG island methylator phenotype (CIMP) and CIMP-high (CIMP-H), respectively. PCR restriction fragment length polymorphism was used to assay K-ras codon 12 and 13 mutations. Logistic regression indicated a statistically significant trend for increasing odds for CIMP (P = 0.002) and CIMP-H (P < 0.001) according to proximity to the cecum or distance from the rectum. Conversely, K-ras codon 12 mutation was present in 13 of 40 (32.5%) distally located HPs compared with 2 of 39 (5.1%) proximal HPs (P = 0.006). Histologic subtype distribution varied by proximal and distal locations. Frequency of CIMP in serrated polyps with abnormal proliferation (SPAPs), differed significantly from goblet cell serrated polyps (GCSPs) (24 of 26, 92.3% vs. 6 of 13, 46.2%) (P = 0.003) and microvesicular serrated polyps (MVSPs) (26 of 38, 68.4%) (P = 0.03). Frequency of K-ras mutation in GCSPs (7 of 13, 54%) differed from that of MVSPs (6 of 38, 16%) (P = 0.01) and SPAPs (2 of 26, 8%) (P = 0.003). Location in the colorectum and histologic subtype were major determinants of the molecular profile of HPs. The molecular findings of CIMP and K-ras mutations appear to encompass most if not all HPs; CIMP profiles suggest that SPAP is the most advanced morphologic variant. We postulate that MVSP and GCSP may be precursor lesions that, if proximally located or larger, can progress to SPAP. Frequent K-ras mutations and infrequent CIMP distinguish the distal GCSP variant.
Methylation patterns define two types of hyperplastic polyp associated with colorectal cancer. Wynter CV, Walsh MD, Higuchi T, Leggett BA, Young J, Jass JR. Conjoint Gastroenterology Laboratory, Royal Brisbane and Women's Hospital Research Foundation, Bancroft Centre, Queensland, Australia. Department of Pathology, McGill University, Montreal, Canada. Department of Digestive Surgery, Tokyo Medical and Dental University, Tokyo, Japan.	Gut. 2004 Apr;53(4):573-580 Abstract quote.   Aim: Hyperplastic polyps (HP) of the colorectum have traditionally been regarded as non-neoplastic lesions. Recent data implicate HP in the pathogenesis of colorectal cancers (CRC) characterised by extensive DNA methylation and microsatellite instability. The aim of this study was to identify morphological and molecular features that may characterise subtypes of HP with potential for neoplastic progression. MATERIALS AND METHODS: HP (22) clustering around distal CRC (group I) were compared with HP (58) in subjects with hyperplastic polyposis (group II). DNA methylation was tested in methylated in tumour (MINT) loci (1, 2, 12, 31) and genes HPP1, MGMT, p14(ARF), p16(INK4a), and hMLH1. RESULTS: Group II HP showed significantly more methylation than group I HP at all loci except MINT1 and MGMT. Group I showed the lowest frequency of DNA methylation but the highest frequency of K-ras mutation. Group II HP (termed HP variant) had the morphological features of the recently described "sessile serrated adenomas". Methylation of hMLH1 was found most frequently in group II polyps that included foci of dysplasia (7/10) and in no group I lesions. CONCLUSION: The findings support the existence of morphological and molecular heterogeneity among HP and highlight a subset that is likely to have significant malignant potential.
Lack of association between the C677T MTHFR polymorphism and colorectal hyperplastic polyps. Ulrich CM, Kampman E, Bigler J, Schwartz SM, Chen C, Bostick R, Fosdick L, Beresford SA, Yasui Y, Potter JD. Cancer Prevention Research Program, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.	Cancer Epidemiol Biomarkers Prev 2000 Apr;9(4):427-33 Abstract quote Colorectal hyperplastic polyps are benign lesions that share many risk factors with colorectal adenomas and cancers. Low folate intakes are associated with an increased risk of colon cancer. The enzyme 5,10-methylene-tetrahydrofolate reductase (MTHFR) may be linked to DNA methylation and nucleotide synthesis and thus play a role in the etiology of colorectal neoplasia. We investigated an association between the common MTHFR polymorphism (C677T) and colorectal hyperplastic polyps within the Minnesota Cancer Prevention Research Unit case-control study. Cases (n = 200) were diagnosed with colonoscopically confirmed hyperplastic polyps; controls (n = 645) were derived from the same gastroenterology practice and were polyp-free at colonoscopy. Dietary intakes were estimated from a self-administered food-frequency questionnaire prior to colonoscopy. Multivariate adjusted odds ratios (ORs) and 95% confidence intervals for MTHFR status were 0.8 (0.6-1.2; CT versus CC wild-type) and 0.9 (0.5-1.6; TT versus CC). In subgroup analyses stratified on dietary intakes of folate, vitamin B12, vitamin B6, or methionine, those with the TT genotype and either low intakes of folate or vitamin B6 were at increased risk relative to those with normal or high vitamin intake. However, most 95% confidence intervals included 1.0, and no consistent trends were observed. In contrast to our findings on colorectal adenomas, increasing alcohol consumption was associated with an elevated risk of colorectal hyperplastic polyps, regardless of genotype. The MTHFR (C677T) variant genotype does not appear to be related to risk of colorectal hyperplastic polyps, and there is no convincing evidence that MTHFR shows a different relation to risk, dependent on dietary intakes of nutrients related to its pathway.
Hyperplastic polyps and DNA microsatellite unstable cancers of the colorectum. Jass JR, Young J, Leggett BA. Department of Pathology, The University of Queensland, and Conjoint Gastroenterology Laboratory, Royal Brisbane Hospital, Queensland, Australia.	Histopathology 2000 Oct;37(4):295-301 Abstract quote Although the scientific and clinical rationale for classifying colorectal cancer according to mechanisms underlying genetic instability is well supported, little is known of the early morphogenesis of sporadic cancer showing high levels of DNA microsatellite instability (MSI-H). Evidence is accumulating that the traditional adenoma-carcinoma sequence may not apply to sporadic MSI-H colorectal cancer. The serrated pathway comprising hyperplastic polyps, mixed polyps and serrated adenomas may serve as the missing link. This review relates the recently described CpG island methylator phenotype (CIMP) to the serrated pathway. Two rate-limiting genetic steps may underlie the neoplastic pathway associated with CIMP. A transmembrane receptor expressed by pericryptal myofibroblasts (HPP1) may be implicated in the transition from normal to hyperplasia whereas inactivation of hMLH1 is responsible for the conversion of hyperplasia to dysplasia through loss of DNA mismatch repair. These mechanisms fit with clinical observations relating to sporadic MSI-H colorectal cancer, specifically proximal location, multiplicity, higher frequency among females and rapid evolution of early cancer.
Histomorphometric characteristics and cellular kinetics of colorectal polyps with epithelial serrated proliferation adjacent to carcinoma. Hamatani S, Wada R, Tsujimoto S, Yanagita M, Mitsuda A, Hasegawa C, Kuwahata N, Yokouchi Y, Miura M. Department of Pathology, Ohmori Hospital, Toho University School of Medicine, Ohta-ku, Tokyo 143-8541, Japan.	Oncol Rep 2001 Jan-Feb;8(1):49-55 Abstract quote Four cases of colorectal polyps with epithelial serrated proliferation (CP-ESP) with malignant transformation were studied. In CP-ESP adjacent to carcinoma, if the nuclear size in the surface layer was significantly smaller than those in the bottom and the middle layers of the crypts, the specimen was defined as zone formation positive. If there was no significant difference among the layers, the specimen was defined as zone formation negative. Cell kinetics were evaluated using Ki-67 immunostaining. The CP-ESP regions of cases 1 and 2 showed zone formation with inferior and lateral glandular branching, and were qualitatively hyperplastic on cell kinetics. Cases 3 and 4 showed inferior and lateral glandular branching with no zone formation, and were kinetically neoplastic (adenoma). The histogenesis of hyperplastic polyps with atypia (cases 1 and 2) involves the hyperplastic polyp-carcinoma sequence. In contrast, the development of tubulovillous adenoma or serrated adenoma (cases 3 and 4) may involve the tubulovillous adenoma-carcinoma or serrated adenoma-carcinoma sequence.

 

LABORATORY/ RADIOLOGIC/OTHER

CHARACTERIZATION

Significance of distal polyps detected with flexible sigmoidoscopy in asymptomatic patients. Matter SE, Campbell DR. Division of Gastroenterology, University of Kansas School of Medicine, Kansas City 66160-7350.

Arch Intern Med 1992 Sep;152(9):1776-80 Abstract quote BACKGROUND--Colorectal cancer is a frequent cause of death from cancer. To reduce the mortality associated with this disease, regular flexible sigmoidoscopy is recommended. However, the significance of diminutive polyps (adenomatous or hyperplastic) detected during flexible sigmoidoscopy remains controversial, as does the appropriate endoscope length (35 vs 60 cm) for colorectal cancer screening. METHODS--One hundred one consecutive patients with no history of colonic disease, gastrointestinal tract symptoms, or positive results of fecal occult blood testing underwent flexible sigmoidoscopy as part of a colorectal cancer screening program. All patients with distal polyps detected during flexible sigmoidoscopy underwent colonoscopy. RESULTS--More than 25% of these asymptomatic, predominantly male subjects had colonic neoplasms or polyps detected. Fifty percent more lesions could be detected with a 60-cm sigmoidoscope than with a 35-cm sigmoidoscope, and detection of any distal polyp, whether adenomatous or hyperplastic, was associated with at least one proximal colon adenoma in 20% of patients. "Extended flexible sigmoidoscopy" for colorectal cancer screening was well tolerated by patients, as evidenced by insertion to the hepatic flexure in 25% of patients, and provided significantly more information than could be obtained with a 35-cm sigmoidoscope. CONCLUSIONS--Colorectal cancer screening should be performed with a 60-cm flexible sigmoidoscope, and distal colonic polyps or neoplasms will be detected in 25% of asymptomatic patients.

 

GROSS APPEARANCE/ CLINICAL VARIANTS	CHARACTERIZATION
General
VARIANTS
Hyperplastic Polyposis-Definition	Histopathology 1980:4:155–70. WHO International Classification of Tumors (3rd edition): Pathology and genetics of tumors of the digestive system. Berlin: Springer-Verlag, 2000: 135–6. Am J Surg Pathol 1987;11:323–7. 1. At least five histologically diagnosed hyperplastic polyps proximal to the sigmoid colon, of which two are greater than 10 mm in diameter, or 2. Any number of hyperplastic polyps occurring proximal to the sigmoid colon in an individual who has a first-degree relative with hyperplastic polyposis, or 3. Greater than 30 hyperplastic polyps of any size but distributed throughout the colon.
Hyperplastic Polyposis Association With Colorectal Cancer	Am J Surg Pathol 2001;25:177-184 Twelve patients were identified, seven of whom had developed colorectal cancer Most polyps were hyperplastic 11 patients also had polyps containing dysplasia as either serrated adenomas, mixed polyps, or traditional adenomas Mean percentage of dysplastic polyps in patients with cancer was 35%, and in patients without cancer, 11% (p < 0.05) Microsatellite instability (MSI): 3 of 47 hyperplastic polyps 2/8 serrated adenomas Kras was mutated: 8/47 hyperplastic polyps 2/8 serrated adenomas No polyps showed loss of heterozygosity of chromosomes 5q, 1p, or 18q 2/7 cancers showed a high level of MSI Conclusion: Condition is associated with a high risk of colorectal cancer Hyperplastic polyps are the dominant type of polyp, but most cases have some dysplastic epithelium A higher proportion of dysplastic polyps is associated with increased cancer risk Clonal genetic changes are observed in some hyperplastic polyps and serrated adenomas.

 

HISTOLOGICAL TYPES	CHARACTERIZATION
General	Hyperplastic goblet cells impart a serrated appearance to the glands None or minimal cytologic atypia
VARIANTS
COLCHICINE EFFECT
Colchicine effect in a colonic hyperplastic polyp. A lesion mimicking serrated adenoma. Torbenson M, Montgomery EA, Iacobuzio-Donahue C, Yardley JH, Wu TT, Abraham SC. Division of Gastrointestinal/Liver Pathology, Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205-2196, USA.	Arch Pathol Lab Med 2002 May;126(5):615-7 Abstract quote Colchicine effect has been described recently in gastrointestinal biopsies, where it can result in accumulation of metaphase mitoses and epithelial disorganization. We describe the case of a colonic hyperplastic polyp with colchicine effect from a 52-year-old woman who was receiving colchicine for primary biliary cirrhosis. Biopsy of the polyp revealed prominent metaphase mitoses and focal loss of nuclear polarity in the surface epithelium, features that mimicked a serrated adenoma. Distinguishing between hyperplastic polyp and serrated adenoma is important because of the different management implications and the increased potential for neoplastic progression in the latter.
MIXED POLYPS
Mixed hyperplastic adenomatous polyps/serrated adenomas	Am J Surg Pathol 1990;14:524–37
Colorectal polyps with extensive absorptive enterocyte differentiation: histologically distinct variant of hyperplastic polyps. Yokoo H, Usman I, Wheaton S, Kampmeier PA. Department of Pathology, Northwestern Memorial Hospital, Chicago, Ill 60611, USA.	Arch Pathol Lab Med 1999 May;123(5):404-10 Abstract quote BACKGROUND: The histologic classification of colorectal polyps is well established. However, practicing pathologists may still occasionally encounter colorectal polyps that are difficult to classify. We studied 6 colorectal polyps that showed uncommon histologic features that have not been described in the English language literature. MATERIALS AND METHODS: The polyps were studied using standard hematoxylin-eosin stain, mucin histochemistry, and electron microscopy. RESULTS: The 6 polyps we studied showed extensive papillary and villous structures with alternating villi and crypts. The villi were lined by well-differentiated absorptive cells, whereas the crypts were lined by immature glandular cells, thus mimicking the histology of the small intestinal mucosa. CONCLUSIONS: These polyps appear to represent a variant of the hyperplastic polyp, in as much as cellular maturation (immature glandular cells differentiate into the mature surface absorptive cells) is the essential feature distinguishing hyperplastic polyps from adenomas.
Stromal eosinophilia in colonic epithelial neoplasms. Moezzi J, Gopalswamy N, Haas RJ Jr, Markert RJ, Suryaprasad S, Bhutani MS. Department of Veterans Affairs Medical Center, and Wright State University School of Medicine, Dayton, Ohio 45428, USA	Am J Gastroenterol 2000 Feb;95(2):520-3 Abstract quote OBJECTIVE: The purpose of this retrospective study was to determine the frequency and intensity of eosinophilic infiltration (or tissue eosinophilia) in the stroma of colonic adenomas, hyperplastic polyps, and colorectal adenocarcinomas. Eosinophilic infiltration in various malignancies has been reported but has not been evaluated in benign colorectal adenomas and hyperplastic polyps. METHODS: We analyzed 488 colonic neoplasms: 176 tubular adenomas, 55 tubulovillous adenomas, 82 villous adenomas, 15 early carcinomas in polyps, 95 invasive adenocarcinomas, and 65 hyperplastic polyps for the presence of eosinophilic infiltration. The eosinophilic infiltration was graded as negative (< or =5%), mild to moderate (>5-40%), or marked (>40%), depending on the percentage of eosinophils relative to total inflammatory cells in the stroma. RESULTS: Mild to moderate eosinophilia was noted in 75% of all adenomas. The transitional zone in all cases of invasive adenocarcinoma (zone between normal tissue and adenocarcinoma) revealed a high percentage of tissue eosinophilia. There was a striking absence of TE in the stroma of invasive adenocarcinomas. Only 5% of hyperplastic polyps had any eosinophilic infiltration. CONCLUSIONS: These data suggest that, in the spectrum of colonic neoplasms, stromal eosinophilia is most prominent in adenomas and seems to decrease with progression through the adenoma-carcinoma sequence. The ramifications of this study may alter management plans and provide some prognostic information for clinical evaluation.
Hyperplastic Polyp with Epithelial Misplacement (Inverted Hyperplastic Polyp): A Clinicopathologic and Immunohistochemical Study of 19 Cases Rhonda K. Yantiss, M.D., Harvey Goldman, M.D. and Robert D. Odze, M.D., F.R.C.P.C. Department of PathologyBeth Israel Deaconess Medical Center (RKY, HG) and Department of Pathology, the Brigham and Women’s Hospital, Harvard Medical School (RDO), Boston, Massachusetts	Mod Pathol 2001;14:869-875 Abstract quote Hyperplastic polyps of the colon are the most common type of benign colonic polyp. Rarely, these polyps may show misplaced epithelium within the submucosa, thereby simulating an adenoma with pseudoinvasion or even an adenocarcinoma. In this study, we describe the clinical, pathologic, and immunophenotypic features of 19 hyperplastic polyps with misplaced epithelium to identify potential diagnostic pitfalls and gain insight into their pathogenesis. Routinely processed polypectomy specimens from 12 patients with 19 hyperplastic polyps containing foci of misplaced epithelium were evaluated for a variety of morphologic features including pattern and extent of submucosal involvement, continuity of the submucosal epithelium with the mucosa, presence of recent or remote hemorrhage, inflammation, association of misplaced epithelium with lymphoid aggregates, inflammation, and defects in the muscularis mucosae. Clinical and endoscopic data were obtained and correlated with the histologic findings. Immunoperoxidase stains (ABC method) for collagen IV (basement membrane marker), MIB-1 (proliferation marker), and E-cadherin (intercellular adhesion protein) were performed in all cases. The study group consisted of five males and seven females ranging in age from to 52 to 73 years (mean: 63 y). All of the polyps were located in the rectum or sigmoid colon, and their mean size was 0.5 cm (range: 0.2 to 1.0 cm). Most showed misplaced epithelium in a lobular (26%) or a mixed pattern consisting of lobules and irregularly distributed crypts (63%) that, upon deeper levels, was almost always continuous with the mucosal portion of the polyps (95%). Defects in the muscularis mucosae and splaying of the muscle fibers around misplaced epithelium were seen in all cases. Lymphoid aggregates were present adjacent to foci of misplaced epithelium in 37% of cases. Fresh hemorrhage, vascular congestion, and hemosiderin deposits were present in 79, 53, and 42% of cases, respectively. Strong and uniform staining of the misplaced epithelium for MIB-1 and E-cadherin was demonstrated in all cases, similar to that seen in the lower third of the mucosal portion of the polyps. A continuous collagen IV basement membrane pattern of staining was noted around all foci of misplaced epithelium. Hyperplastic polyps with misplaced epithelium probably occur secondary to trauma-induced protrusion of glands through breaks in the muscularis mucosae. Pathologists should be aware of this entity to avoid diagnostic confusion with other, more serious lesions, such as adenomas with pseudoinvasion or well-differentiated adenocarcinoma.

 

DIFFERENTIAL DIAGNOSIS	KEY DIFFERENTIATING FEATURES
Lipoma of the colon with overlying hyperplastic epithelium. Radhi JM, Haig TH. Department of Pathology, Royal University Hospital, University of Saskatchewan, Saskatoon.	Can J Gastroenterol 1997 Nov-Dec;11(8):694-5 Abstract quote Lipomas of the colon are submucosal nonepithelial tumours covered by intact or eroded mucosa. A large colonic lipoma present in close proximity to an area of diverticulitis is presented. The lining mucosa in this case exhibited hyperplastic changes, reminiscent of those seen in hyperplastic polyps. The significance of such mucosal changes are highlighted because adenomatous or even carcinomatous transformation, though rare, remains possible.
Serrated adenoma: a clinicopathological, DNA ploidy, and immunohistochemical study. Iwabuchi M, Sasano H, Hiwatashi N, Masuda T, Shimosegawa T, Toyota T, Nagura H. Department of Pathology, Tohoku University School of Medicine, Sendai, Japan.	Anticancer Res 2000 Mar-Apr;20(2B):1141-7 Abstract quote AIMS: Serrated adenoma (SA) is a relatively newly defined entity of colorectal neoplasm. In this study, we examined the cell proliferation, DNA ploidy, and clinicopathological features of SA in order to investigate its biological features. METHODS AND RESULTS: We reviewed 10,532 polypectomy specimens of the colorectum obtained from Japanese cases between 1974 and 1998 at Tohoku University Hospital. In total, 193 cases of SA were detected. We first examined clinical features of these cases by reviewing the charts, and then studied cell proliferation using immunohistochemistry of Ki-67 and topoisomeraseIIa, p53 immunoreactivity and DNA ploidy. Results were subsequently compared with those of tubular adenoma (TA) and hyperplastic polyp (HP). Mean size of SA (8.6 +/- 4.6 mm) was significantly larger than those of TA (7.3 +/- 4.6 mm) and HP (5.6 +/- 3.0 mm). More than 80% of SA were protuberant in macroscopic appearance. SA was located predominantly in the sigmoid colon and rectum. Incidences of concomitant carcinoma in HP, SA and TA were 0.4% (1 out of 263), 4.1% (8 out of 193) and 10.3% (809 out of 7838), respectively. Labeling indices for Ki-67 and topoisomeraseIIa in HP, SA and TA were as follows: Ki-67--24.2%, 30.8%, 39.5% and topoisomeraseIIa--15.3%, 16.1%, 23.9%, respectively. In SA, p53 immunoreactivity was detected in the intramucosal carcinoma co-existing with the serrated component. Two out of the ten SA cases examined demonstrated non-diploid patterns of DNA ploidy. CONCLUSION: SA is a distinct colorectal neoplastic lesion with the potential of malignant transformation similar to that of tubular adenoma.

 

PROGNOSIS AND TREATMENT	CHARACTERIZATION
PROGNOSIS
Hyperplastic-like Colon Polyps That Preceded Microsatellite-Unstable Adenocarcinomas Neal S. Goldstein, MD, Punam Bhanot, MD, Eva Odish, HTL(ASCP), and Susan Hunter, SI(ASCP)	Am J Clin Pathol 2003;119:778-796 Abstract quote We compared hyperplastic-like polyps that preceded microsatellite-unstable adenocarcinomas to incidental hyperplastic polyps to identify distinguishing morphologic criteria. The study group included 106 hyperplastic-like, nonadenomatous, serrated polyps, most from the ascending colon in 91 patients; the control group included 106 rectosigmoid hyperplastic polyps from 106 patients in whom adenocarcinoma did not develop. Study group polyps had an expanded crypt proliferative zone, a serrated architectural outline that became apparent in the basilar crypt regions, basilar crypt dilation, inverted crypts, and a predominance of dysmaturational crypts (crypts with minimal cell maturation). In contrast, control group polyps had a proliferative zone confined to the basal crypt region, serrated architecture that became apparent in the superficial crypt region, rare to no basilar crypt dilation, and rare or no dysmaturational crypts. Hyperplastic-like polyps that preceded microsatellite-unstable adenocarcinomas had a distinctive constellation of morphologic features related to altered and decreased cell function and control that resulted in dysmaturational crypts. Dysmaturation constitutes a range of morphologic alterations, some of which overlap with incidental-type innocuous hyperplastic polyps. The morphologic features described herein provide initial guidelines to identify this potentially important subset of premalignant serrated-like polyps.
Sporadic colorectal cancers with microsatellite instability and their possible origin in hyperplastic polyps and serrated adenomas. Hawkins NJ, Ward RL. School of Pathology, University of New South Wales, Sydney, Australia.	J Natl Cancer Inst 2001 Sep 5;93(17):1307-13 Abstract quote BACKGROUND: Microsatellite instability (MSI) is seen in 10%-15% of sporadic colorectal cancers mostly in the right colon, but the precursors of cancers with MSI remain unknown. We examined whether sporadic cancers with MSI arise from pre-existing benign proliferative lesions (such as hyperplastic polyps or serrated adenomas [together denoted as "serrated polyps"]). METHODS: The frequency of benign epithelial lesions (serrated polyps and conventional adenomas) was determined by histologic review of resection specimens from individuals (n = 29) with sporadic colorectal cancer with MSI and from a matched control group (n = 29) with cancer showing microsatellite stability (MSS). MSI status, expression of mismatch repair enzyme (product of the human mut-L homologue 1 [hMLH1] gene), and hMLH1 gene promoter methylation in the benign lesions were determined. Data were analyzed by the chi-square test, by Wilcoxon's rank-sum test, and by conditional logistic regression as appropriate, and a two-sided probability less than.05 was considered to be statistically significant. RESULTS: Individuals with cancers showing MSI were more likely to harbor at least one serrated polyp than individuals with cancers showing MSS (odds ratio = 4.0; 95% confidence interval = 1.1 to 14.2; P =.03), but the frequency of conventional adenomas was the same in both groups (P =.52, Mann-Whitney test). Loss of hMLH1 protein expression was seen in lesions from 10 of 13 patients with MSI, but no loss was seen in lesions from four patients with MSS (P =.02, Fisher's exact test). Loss of hMLH1 protein expression was associated with MSI in assessable lesions. The hMLH1 promoter was methylated in all assessable serrated polyps from patients with cancers showing MSI but in none of the lesions from patients with MSS cancers. CONCLUSIONS: Some right-sided hyperplastic polyps may give rise to sporadic colorectal carcinomas with MSI. Methylation of the hMLH1 gene promoter within neoplastic cell subpopulations may be a critical step in the progression to carcinoma. The frequency with which benign lesions progress to cancer with MSI is unknown.
Distal hyperplastic polyps do not predict proximal adenomas: results from a multicentric study of colorectal adenomas. Sciallero S, Costantini M, Bertinelli E, Castiglione G, Onofri P, Aste H, Casetti T, Mantellini P, Bucchi L, Parri R, Boni L, Bonelli L, Gatteschi B, Lanzanova G, Rinaldi P, Giannini A, Naldoni C, Bruzzi P. Unit of Clinical Epidemiology and Trials, National Institute for Cancer Research, Genon, Italy.	Gastrointest Endosc 1997 Aug;46(2):124-30 Abstract quote BACKGROUND: The association between distal hyperplastic polyps and proximal adenomas is still a matter of debate. We investigated this association while taking into account patient characteristics. METHODS: After exclusion of patients with inflammatory bowel diseases, familial adenomatous polyposis, or any cancer, 3088 eligible consecutive subjects aged 18 to 69 years underwent total colonoscopy in four gastroenterology units. The odds ratios (OR) of having proximal adenomas according to patient characteristics (age, sex, medical center, year of endoscopy, reasons for referral, and distal findings) were estimated in univariate and multivariate analyses. RESULTS: Patients with distal polyps of any type showed an adjusted OR of 2.5 (95% CI [1.9, 3.1] p < .001) of having proximal adenomas as compared with those without distal polyps. When distal adenomas and distal hyperplastic polyps were included in the multivariate model as independent factors, the presence of adenomas significantly increased the risk of proximal adenomas (OR = 2.8: 95% CI [2.2, 3.6] p < .001), whereas the presence of hyperplastic polyps did not (OR = 1.1: 95% CI [0.8, 1.5] p = .64). No association with number, size, or location of distal hyperplastic polyps was seen. CONCLUSIONS: Our data show that the presence of hyperplastic polyps should not be the sole indication for total colonoscopy because they are not associated with proximal adenomas when adjusting for patient characteristics and presence of distal adenomas.
Follow-up of patients with hyperplastic polyps of the large bowel. Croizet O, Moreau J, Arany Y, Delvaux M, Rumeau JL, Escourrou J. Department of Gastroenterology, Rangueil Hospital, Toulouse, France.	Gastrointest Endosc 1997 Aug;46(2):119-23 Abstract quote BACKGROUND: Adenomatous colonic polyps are accepted as premalignant lesions. There is controversy regarding the significance of the hyperplastic polyp. The aim of this study was to determine the incidence of further polyps in patients with only hyperplastic polyps on a first colonoscopy in comparison with patients without polyps and with adenomatous polyps. METHODS: Ninety patients had only hyperplastic polyps (group I). These patients were paired according to age and sex with subjects having no polyps (group II) and with patients having adenomas (group III). RESULTS: Fifty-six patients in group I had at least one follow-up examination. New polyps were found in 46.4% in group I versus 15.5% in group II (p < 0.001) and 50% in group III (NS). In group I, 30.7% of new polyps were hyperplastic and 69.3% were adenomas. In fact, 32.2% of group I patients developed further adenomas (mean 1.5 +/- 0.8 adenomas). These adenomas occurred 1 to 4 years after the first polypectomy (mean 2.4 +/- 0.8 years). Most of these adenomas were small and tubular, but 16.6% were villous or had severe dysplasia. CONCLUSION: Patients with hyperplastic polyps were 2.4 times more likely to have further adenomas than were those without polyps.
Colorectal hyperplastic polyps and risk of recurrence of adenomas and hyperplastic polyps. Polyps Prevention Study. Bensen SP, Cole BF, Mott LA, Baron JA, Sandler RS, Haile R.	Lancet 1999 Nov 27;354(9193):1873-4 Abstract quote We examined data from two large colorectal chemoprevention trials for possible associations of hyperplastic polyps and adenomas with subsequent development of these lesions. Hyperplastic polyps do not predict metachronous adenomas.
Risk of advanced proximal neoplasms in asymptomatic adults according to the distal colorectal findings. Imperiale TF, Wagner DR, Lin CY, Larkin GN, Rogge JD, Ransohoff DF. Department of Medicine, Indiana University Medical Center, Indianapolis 46202-5121, USA.	N Engl J Med 2000 Jul 20;343(3):169-74 Abstract quote BACKGROUND AND METHODS: The clinical significance of a distal colorectal polyp is uncertain. We determined the risk of advanced proximal neoplasia, defined as a polyp with villous features, a polyp with high-grade dysplasia, or cancer, among persons with distal hyperplastic or neoplastic polyps as compared with the risk among persons with no distal polyps. We analyzed data from 1994 consecutive asymptomatic adults (age, 50 years or older) who underwent colonoscopic screening for the first time between September 1995 and December 1998 as part of a program sponsored by an employer. The location and histologic features of all polyps were recorded. Colonoscopy to the level of the cecum was completed in 97.0 percent of the patients. RESULTS: Sixty-one patients (3.1 percent) had advanced lesions in the distal colon, including 5 with cancer, and 50 (2.5 percent) had advanced proximal lesions, including 7 with cancer. Twenty-three patients with advanced proximal neoplasms (46 percent) had no distal polyps. The prevalence of advanced proximal neoplasia among patients with no distal polyps was 1.5 percent (23 cases among 1564 persons; 95 percent confidence interval, 0.9 to 2.1 percent). Among patients with distal hyperplastic polyps, those with distal tubular adenomas, and those with advanced distal polyps, the prevalence of advanced proximal neoplasia was 4.0 percent (8 cases among 201 patients), 7.1 percent (12 cases among 168 patients), and 11.5 percent (7 cases among 61 patients), respectively. The relative risk of advanced proximal neoplasia, adjusted for age and sex, was 2.6 for patients with distal hyperplastic polyps, 4.0 for those with distal tubular adenomas, and 6.7 for those with advanced distal polyps, as compared with patients who had no distal polyps. Older age and male sex were associated with an increased risk of advanced proximal neoplasia (relative risk, 1.3 for every five years of age and 3.3 for male sex). CONCLUSIONS: Asymptomatic persons 50 years of age or older who have polyps in the distal colon are more likely to have advanced proximal neoplasia than are persons without distal polyps. However, if colonoscopic screening is performed only in persons with distal polyps, about half the cases of advanced proximal neoplasia will not be detected.
TREATMENT	Surgical removal is curative
Hyperplastic Polyposis	Genes Chromosomes Cancer 1995;12:251–4 Patients should have regular colonoscopic surveillance Colectomy should be considered for those with a high proportion of dysplastic polyps

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