Background

These colon polyps have a definite increased risk to become malignant. The polyps may be asymptomatic but also may present with bleeding leading to unexplained anemia.

OUTLINE

Epidemiology
Disease Associations
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
SYNONYMS	Colon polyp, adenoma
PREVALENCE	Ranging from 12% in a study of unselected patients and up to 30% in autopsy studies
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.
AGE-RANGE AND MEDIAN	<40 years-20-30% >60 years-40-50%
SEX (MALE:FEMALE)	Equal
GEOGRAPHIC DISTRIBUTION	Worldwide
FIBER
Dietary fiber and distal colorectal adenoma in men. Platz EA, Giovannucci E, Rimm EB, Rockett HR, Stampfer MJ, Colditz GA, Willett WC. Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts 02115, USA.	Cancer Epidemiol Biomarkers Prev 1997 Sep;6(9):661-70 Abstract quote We evaluated the relation of specific sources and components of fiber with diagnosis of distal colon (n = 531) or rectal (n = 159) adenomatous polyps or hyperplastic (n = 327) polyps in the Health Professionals Follow-up Study. We studied 16,448 men free of cancer or polyps in 1986, who underwent endoscopy in 1986-1994, and who provided diet and medical history. Relative risks (RRs) and 95% confidence intervals (CIs) adjusted using multiple logistic regression were calculated. We observed a modest reduced risk of distal colon adenoma with increasing intake of fiber from fruit (P-trend = 0.03) but not cereals or vegetables. The RR comparing the highest (median, 8.4 g/day) to lowest (1.3 g/day) quintile of fruit fiber intake was 0.81 (95% CI, 0.59-1.11). Soluble fiber, but not insoluble fiber, appeared to be inversely associated with distal colon adenoma (P-trend = 0.007). Comparing extreme quintiles (9.4 versus 3.4 g/day soluble fiber), the RR was 0.69 (95% CI, 0.46-1.03). Polyps detected in 1986 or later among men also with a negative endoscopy before 1986 may be considered to be "incident," with diet report corresponding more closely to time of polyp development. For "incident" cases (n = 130), the relation between soluble fiber and distal colon adenoma was strengthened (extreme quintiles RR, 0.27; 95% CI, 0.11-0.66; P-trend = 0.003), whereas for "prevalent" cases (n = 401), we found no association. No consistent relation between fiber and rectal adenomas or hyperplastic polyps was observed. These results suggest that soluble fiber may be particularly important in reducing risk of adenomatous polyps of the distal colon and support national dietary guidelines of increasing fruit consumption.
SMOKING
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.

 

DISEASE ASSOCIATIONS	CHARACTERIZATION
CARCINOID TUMORS
Microcarcinoids in Large Intestinal Adenomas. Pulitzer M, Xu R, Suriawinata AA, Waye JD, Harpaz N. *Department of Pathology, Division of Gastrointestinal Pathology, The Mount Sinai School of Medicine double daggerHenry D. Janowitz Division of Gastroenterology, The Mount Sinai Medical Center, New York, NY daggerDepartment of Pathology, Dartmouth-Hitchcock Medical Center, Lebanon, NH.	Am J Surg Pathol. 2006 Dec;30(12):1531-1536. Abstract quote Composite adenoma-carcinoid tumors are rare colorectal lesions consisting of intermingled adenomatous and carcinoid components. Unlike other mixed endocrine-glandular colorectal neoplasms, which are generally malignant, their glandular component is histologically benign and their natural history is favorable. We present 4 cases of colonic adenomas containing microcarcinoids, a hitherto undescribed lesion that is either a precursor of composite adenoma-carcinoids or a related but independent entity. The cases, identified among our surgical and consultation files, were endoscopically routine sessile polyps removed from 4 otherwise normal individuals, 3 from the cecum and 1 from the distal colon. The microcarcinoids were 0.5 to 1.5 mm in size and situated within the basal lamina propria, where they interposed between the crypts and muscularis mucosae without disturbing the overall polyp architecture. Histologically, they consisted of collections of low-grade epithelial cells arranged in nests, cords, tubules, and irregular clusters and characterized by eosinophilic, granular, or clear cytoplasm and by round central nuclei with stippled or dusty chromatin. Endocrine differentiation of the microcarcinoids was confirmed by the expression of 3 or more of the following: Grimelius argyrophil, chromogranin, synaptophysin, neuron-specific enolase and somatostatin. No mitotic figures or MIB-1 or p53 positivity were observed. The glandular component of the polyps was unremarkable in 3 cases, but 1 polyp, in addition to a microcarcinoid, showed a diffuse pattern of mixed adenomatous-endocrine differentiation. The patients' clinical course was benign on the basis of 2 years' median follow-up (range, 6 mo to 10 y). Two patients with incomplete polypectomies underwent hemicolectomy revealing no residual endocrine neoplasia. Awareness of microcarcinoids in colonic adenomas should help avert potential diagnostic pitfalls posed by their pleomorphism, basal location, and infiltrative patterns, and may help clarify their natural history and possible relationship to composite glandular-carcinoid tumors.
Familial polyposis	Familial adenomatous polyposis (FAP) Gardner syndrome Hereditary nonpolyposis colorectal cancer (HNPCC)
The prevalence of colonic polyps in acromegaly: a colonoscopic and pathological study in 103 patients. Delhougne B, Deneux C, Abs R, Chanson P, Fierens H, Laurent-Puig P, Duysburgh I, Stevenaert A, Tabarin A, Delwaide J. Department of Gastroenterology, University of Liege, Belgium.	J Clin Endocrinol Metab 1995 Nov;80(11):3223-6 Abstract quote Patients with acromegaly are reported to be at risk of developing adenomatous colonic polyps, which are considered to be preneoplastic lesions. This assumption is, however, usually drawn from results obtained in rather small series of patients or without a control group. We, therefore, undertook a prospective colonoscopic and pathological study comprising 103 acromegalic patients and 138 nonacromegalic control subjects referred for irritable bowel syndrome. The prevalence of adenomatous colonic polyps was significantly increased in acromegalic patients compared to that in control subjects (22.3% vs. 8.0%; P = 0.0024). The significance was similarly present in male acromegalic patients (28.6% vs. 5.5% in male control subjects; P = 0.0026), but was absent in female acromegalic patients. The prevalence of colonic polyps was also significantly increased in the group of acromegalic patients under 55 yr of age (20.0% vs. 3.0% in the control group of the same age; P = 0.0026). Other characteristics of adenomatous colonic polyps in acromegaly were the multiplicity and the presence proximal to the splenic flexure. No difference in the duration of acromegaly was found between patients with or without adenomatous polyps. The prevalence of hyperplastic colonic polyps was also significantly increased to 24.3% in acromegalic patients vs 4.4% in control subjects (P < 0.001). In conclusion, in view of the increased incidence of adenomatous colonic polyps, colonoscopy should be part of the follow-up examination in acromegaly.
MALAKOPLAKIA
Malakoplakia and colonic adenoma: a rare association. Rizzo E, Sandmeier D, Hack I, Matter M, Bouzourene H. Institute of Pathology and Surgical Department, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.	Ann Diagn Pathol. 2004 Dec;8(6):364-6. Abstract quote We report the case of a 73-year-old woman who presented respectively a caecal adenocarcinoma, two high-grade dysplastic tubulo-villous adenomas of the right colon, and a well differentiated adenocarcinoma developed on a high-grade dysplastic tubulo-villous adenoma of the left colon. One of the right colonic adenomas was ulcerated and showed typical foci of malakoplakia in the lamina propria. Malakoplakia is a histiocytic inflammatory response that may be associated with inflammatory and infectious diseases, immunosuppressive therapy, or colorectal carcinoma. Association of malakoplakia with colonic adenoma is rare; only three cases have been described in the literature thus far. To verify if this association is more common than usually suspected, we reviewed 100 colonic adenomas measuring at least 2 cm. No other case of malakoplakia associated with adenoma was found. The patient did not suffer from any other inflammatory or infectious disease and she was not under any medication or immunosuppressive therapy. Our observation confirms the isolated association of malakoplakia and colonic adenomas and the rarity of this association.

 

PATHOGENESIS	CHARACTERIZATION
ADENOMA-CARCINOMA SEQUENCE
Inherited or acquired mutations of cancer suppressor genes in normal colon	APC Mismatch of repair genes
Methylation abnormalities leads to mucosa at risk	APC Beta-catenin MSH2
Protooncogene mutation leads to adenoma	K-ras Homozygous loss of additional cancer suppressor genes (p53 and LOH at 18q21
Additional mutations and gross chromosomal alterations leads to carcinoma	Many genes
GENES INVOLVED
APOPTOSIS
Apoptosis Index and Apoptosis-Related Antigen Expression in Serrated Adenoma of the Colorectum The Saw-Toothed Structure May Be Related to Inhibition of Apoptosis Hisashi Tateyama, M.D. ; Wenxin Li, M.D. ; Emiko Takahashi, M.D. ; Yasuo Miura, D.V.M. ; Hiroshi Sugiura, M.D. ; Tadaaki Eimoto, M.D. From the Department of Pathology (H.T., W.L., E.T., Y.M., T.E.), Nagoya City University Medical School, Nagoya, and the Department of Pathology (H.S.), Kasugai Municipal Hospital, Kasugai, Aichi, Japan.	Am J Surg Pathol 2002;26:249-256 Abstract quote Serrated adenoma of the colorectum is a recently proposed entity characterized by a saw-toothed structure of hyperplastic polyp and cytologic atypia of tubular adenoma. To clarify the role of apoptosis in morphogenesis of serrated adenoma, we investigated apoptotic indices and expression of apoptosis-related antigens in the tumor cells. Thirty-eight serrated adenomas were examined by the nick-end DNA labeling method and immunostained for CD95 (Fas), bcl-2, bax, and p53. Thirty-seven hyperplastic polyps, 48 tubular adenomas, and 16 sections containing normal colonic mucosa were similarly examined for comparison. The apoptotic indices in the upper and middle zones of the crypts of serrated adenomas and hyperplastic polyps were lower than those of normal colon mucosa and tubular adenomas with statistically significant differences. The CD95 expression was diffusely observed throughout the epithelium of normal crypts and tubular adenomas, whereas it was reduced in serrated adenomas and hyperplastic polyps. The bcl-2 expression was confined to the basal crypts in the latter two lesions but was diffuse throughout the neoplastic epithelium in tubular adenomas. The bax expression was increased in serrated adenomas and tubular adenomas but was decreased in hyperplastic polyps. Overexpression of p53 protein was observed in 50% of serrated adenomas, none of hyperplastic polyps, and 14% of tubular adenomas. These findings suggest that inhibition of apoptosis is caused by reduced CD95 expression in serrated adenomas and hyperplastic polyps, which may induce the characteristic saw-toothed structure in these lesions. Based on the similarities and differences between serrated adenoma and hyperplastic polyp observed in the present study, a progression from the latter to the former lesion may be postulated.
APC gene (5q21)	APC is regarded as a Gatekeeper gene APC protein binds to microtubule bundles and promotes cell migration and adhesion APC protein binds to cytoskeletal protein beta-catenin which is bound to E-cadherin Beta-catenin binds to T cell factor-lymphoid enhancer factor (Tcf-Lef) proteins-this binding leads to stimulation of cell proliferation and inhibition of apoptosis When APC binds to beta-catenin, it starts degradation of it, leading to inhibition of beta-catenin:Tcf signalling pathway Mutations in the APC gene reduce the affinity of APC protein for beta-catenin Net result is loss of intercellular contact and increased cytoplasmic pool of beta-catenin
Germline APC Mutation on the beta-Catenin Binding Site Is Associated with a Decreased Apoptotic Level in Colorectal Adenomas. Venesio T, Balsamo A, Scordamaglia A, Bertolaso M, Arrigoni A, Sprujevnik T, Rossini FP, Risio M. Unit of Pathology, Institute for Cancer Research and Treatment (IRCC) (TV, AB, AS, MB, MR), Candiolo-Torino, Italy.	Mod Pathol 2003 Jan;16(1):57-65 Abstract quote Germline mutations in APC tumor suppressor gene are responsible for familial adenomatous polyposis (FAP). A major role of these genetic changes is the constitutive activation of beta-catenin-Tcf-4 mediated transcription of nuclear target genes, but other cellular functions can be misregulated. To assess how different APC mutations can drive the early steps of colonic tumorigenesis, we studied the effect of 10 different germline-truncating alterations on the phenotype of the corresponding adenomas. A significant reduction of apoptosis, uncoupled with an increased c-myc and cyclin-D1 expression, was seen with a frameshift mutation on codon 1383, in the 20-aa repeats of the beta-catenin degradation domain, independent of a somatic alteration on the wild-type allele. The decreased apoptotic level was associated with a higher incidence of cancerization. No other APC mutation was linked with a similar effect, even in presence of a somatic allelic loss. These findings suggest that mutations in critical sites of the beta-catenin degradation domain of APC gene can convey a selective advantage to the colonic neoplastic clones by altering the apoptotic surveillance rather than enhancing the beta-catenin-Tcf-4 transcription of growth-promoting genes.
HNPCC genes	HNPCC is considered the caretaker genes These are human mismatch repair genes and consist of 4 genes hMSH2 HMLH1 hPMS1 hPMS2 Involved in genetic proofreading during DNA replication
Genetic alterations in serrated adenomas: Comparison to conventional adenomas and hyperplastic polyps Franz Fogt, MD, Dr Med, MRCPath Thomas Brien, MD Charlotte A. Brown, PhD Christopher J. Hartmann, BS Robert L. Zimmerman, MD Robert D. Odze, MD, FRCP	Hum Pathol 2002;33:87-91. Abstract quote Serrated adenoma is a recently described entity characterized by the presence of a hyperplastic (serrated) growth pattern combined with cytologic features of dysplasia. In contrast to conventional (nonserrated) adenomas, the molecular features of serrated adenomas have been poorly studied. Thus, it remains unclear if serrated adenomas are simply a morphologic variant of conventional adenomas or represent a different biologic entity. In this study, 46 serrated adenomas from 39 patients, 32 conventional (nonserrated) adenomas from 31 patients, and 18 hyperplastic polyps from 16 patients were evaluated for loss of heterozygosity (LOH) of APC, p53, p16, and 3p and for K-ras mutations of codons 12, 13, and 61 by polymerase chain reaction (PCR) analysis. Serrated adenomas demonstrated LOH of at least one genetic locus in 32.6% of cases. LOH of the APC gene, 3p, p53, and p16 was seen in 19.4%, 14.2%, 9.3%, and 13.8% of cases, respectively. K-ras mutations were observed in 18% of cases. Similar to serrated adenomas, conventional adenomas demonstrated at least one LOH event in 37.5% of cases and K-ras mutations in another 19% of cases. LOH of APC, 3p, p53, and p16 was observed in 22%, 33%, 5.8%, and 13.4% of cases, respectively. There were no significant differences in either the total number of genetic events or the presence of LOH of any of the individual markers between serrated adenomas and conventional adenomas. However, hyperplastic polyps showed LOH in 22% of cases and a single K-ras mutation (11%). The prevalence of LOH in hyperplastic polyps was lower than both serrated adenomas and conventional adenomas (P < .05). These results support the hypothesis that serrated adenomas represent a biologically similar morphologic variant of conventional adenomas.
METHYLATION ABNORMALITIES
K-ras (12p12)	Most frequent activated oncogene, mutated in 50% of adenomas >1 cm
DCC (18q21) (Deleted in Colon CA)	Expression is reduced or absent in 70-75% of cancers
p53 (17p)	Variable losses in adenomas
SERRATED POLYP NEOPLASIA
Comparison of Microsatellite Instability, CpG Island Methylation Phenotype, BRAF and KRAS Status in Serrated Polyps and Traditional Adenomas Indicates Separate Pathways to Distinct Colorectal Carcinoma End Points. O'brien MJ, Yang S, Mack C, Xu H, Huang CS, Mulcahy E, Amorosino M, Farraye FA. *Departments of Pathology and Laboratory Medicine daggerSection of Gastroenterology, Department of Medicine, Boston University Medical Center, Boston, MA.	Am J Surg Pathol. 2006 Dec;30(12):1491-1501. Abstract quote The aim of this study was to compare BRAF and KRAS, CpG island methylator phenotype (CIMP), and microsatellite instability (MSI) status in each of the histologic categories, including end-point carcinomas with residual adenoma, of the serrated polyp neoplasia pathway and the traditional (nonserrated) adenoma-carcinoma sequence. Deoxyribonucleic acid (DNA) was extracted from the selected samples and assayed for BRAF, KRAS2 codon12, 13, CIMP using markers hMLH1, MGMT, MINT1, MINT2, p16, and MSI using an assay for BAT25 and BAT26. A BRAF mutation was present in 82% of serrated carcinomas (SCas), 62% of serrated adenomas (SAs), 83% of serrated polyps with abnormal proliferation (SPAPs-syn. sessile serrated adenoma [SSA]), 76% of microvesicular serrated polyps (MVSPs), and was not found in any of the histologic categories of the traditional adenoma-carcinoma sequence. KRAS2 mutations were found in 43% of the goblet cell serrated polyp (GCSP) category, 13% of MVSPs, 7% of SPAPs, and 24% of SAs; in 26% of large traditional adenoma (lTAs) compared with small traditional adenomas (sTAs) (0/30; P<0.005) and in 37.3% of traditional carcinomas (TCa). CIMP-H (>1 marker positive) was significantly more frequent in SPAP, SA, and SCa compared with MVSP (P<0.05); CIMP-H was present in 10% of sTAs but was found more frequently in lTA (44.4%; OR 7.2; P=0.007) and TCa (38.9%; OR 5.8; P=0.007). Higher CIMP levels (4 or more markers positive) were significantly more frequent in advanced categories of the serrated pathway (SAs [31%] and SCas [30%]) compared with lTAs [0%] and TCAs [3.4%] (OR 12.2; P=0.02). MSI-H was identified only in the adenocarcinoma component of SCas (9/11) or in the contiguous SAs (3/7). The findings indicate that a BRAF mutation is a specific marker for a serrated polyp pathway that has its origin in a hyperplastic polyp (MVSP) and a potential end point as MSI carcinoma. CIMP-High (CIMP-H) develops early in this sequence and MSI-H develops late. The data provided a less complete picture of a second serrated pathway, identified by a KRAS2 mutation in SAs, but showed that the progressive stages of both iterations of the serrated neoplasia pathway are separate and distinct from those of the traditional adenoma-carcinoma sequence.
Progressive methylation during the serrated neoplasia pathway of the colorectum. Dong SM, Lee EJ, Jeon ES, Park CK, Kim KM. 1Research Institute, National Cancer Center, Goyang, Gyeonggi, Korea.	Mod Pathol. 2004 Sep 24; [Epub ahead of print] Abstract quote Serrated adenoma is a recently described entity characterized by having combined architectural features of hyperplastic polyps and classical adenoma. To understand the role of gene regulation in the progression of the serrated neoplasia pathway, we examined the methylation profiles of the promoter regions of 19 genes, DNA ploidy, and mutator phenotype status. In all, 40 sporadic, classical serrated adenomas were pathologically reviewed and divided into four pathologic groups according to their histologic grades. Methylation-specific PCR was performed using primers for p16, hMLH1, RASSF1A, APC, HIC-1, DAPK, MGMT, SLC5A8, RB1, H-Cadherin, E-Cadherin, TIMP3, PTEN, THBS1, LKB1, p14, p15, FHIT, and VHL. Dual flow-cytometric analyses using cytokeratin and DAPI and MSI studies using BAT26 were also performed. Methylation was observed in 2.5-82.5% (mean 33.9%) of the CpG islands in the promoter regions of 16 genes. The tumors with higher histologic grades, including carcinomas, showed more extensive methylation compared to those with lower grades, and serrated adenomas in the right colon showed more frequent methylation than those in the left (P<0.05). Tumor-specific promoter methylation of SLC5A8 was observed in 33 (82.5%) of the serrated adenomas. Aneuploidization with near-diploid DNA indices was detected in four out of 28 cases examined (14.3%); two were low-grade serrated adenomas and two were carcinomas in the left colon. The high mutator phenotype was not observed in any of the cases examined. Our results indicate that: (1) aberrant, widespread methylation of CpG islands increases with the histological progression of serrated adenomas; (2) methylation of SLC5A8 is an early event; and (3) additional methylation of the p16, p14, MGMT, TIMP3, and FHIT genes are important tumorigenic steps in the serrated neoplasia pathway.

 

LABORATORY/ RADIOLOGIC	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.
In vivo identification of colonic dysplasia using fluorescence endoscopic imaging. Wang TD, Crawford JM, Feld MS, Wang Y, Itzkan I, Van Dam J. G.R. Harrison Spectroscopy Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.	Gastrointest Endosc 1999 Apr;49(4 Pt 1):447-55 Abstract quote BACKGROUND: Previous in vitro studies showed that autofluorescence images of colonic mucosa collected endoscopically can be used to detect dysplasia with high sensitivity. This method is extended to the collection of fluorescence images of adenomatous polyps in vivo. METHODS: Fluorescence images were collected during colonoscopy in 30 patients. A total of 12 adenomatous and 6 hyperplastic polyps were identified. A fiberoptic excitation probe, located in the instrument channel of the colonoscope, delivered 300 mW of near-ultraviolet light at lambdaex = 351 and 364 nm. Mucosal fluorescence in the spectral bandwidth between 400 and 700 nm was imaged, processed, and displayed with various likelihoods of associated dysplasia. RESULTS: Adenomatous polyps exhibited decreased fluorescence intensity compared with adjacent mucosa with normal appearance. With the fluorescence threshold set to 80% of the average intensity of normal mucosa, a sensitivity of 83% for dysplasia identification was achieved. All hyperplastic polyps were correctly identified as being non-dysplastic. Optimal identification of dysplastic regions was obtained with the colonoscope oriented at a near-normal angle of incidence to the polyps. At higher angles of incidence, artifacts caused by illumination shadows were introduced. CONCLUSIONS: The dysplasia associated with adenomatous polyps can be identified in vivo by fluorescence imaging with high sensitivity, thus demonstrating the potential to guide endoscopic procurement of biopsy specimens.

 

GROSS APPEARANCE/CLINICAL VARIANTS	CHARACTERIZATION
Tubular adenomas	May be polypoid and sessile attached with a stalk
Villous adenomas	Sessile with cauliflower-like masses
Tubulovillous adenomas	Appearance intermediate between the two
Diminutive colonic polyps: histopathology, spatial distribution, concomitant significant lesions, and treatment complications. Weston AP, Campbell DR. Division of Gastroenterology, University of Kansas School of Medicine, Kansas City.	Am J Gastroenterol 1995 Jan;90(1):24-8 Abstract quote OBJECTIVES: Our objectives in this study were to determine diminutive colonic polyp histology, distribution, frequency of significant synchronous neoplastic lesions, and treatment complications. METHODS: We evaluated consecutive colonoscopic examinations in which one or more diminutive polyps were detected over a 36-month period; these examinations had been entered into an endoscopy database at the time of colonoscopy. RESULTS: A total of 1964 diminutive polyps were found and removed in 753 colonoscopies; 1525 were removed by hot biopsy, 436 were removed by cold biopsy, and three were removed by snare. Of the diminutive polyps, 40.7% were adenomatous, 37.2% were hyperplastic, 17.9% were mucosal tags or lymphoid aggregates, and 4.3% were mixed; 0.26% contained atypia, and none were cancerous. In the right colon and transverse colon, diminutive polyps were more likely to be neoplastic (p < 0.0001), but in the left colon they were more likely to be nonneoplastic (p < 0.0001). The prevalence of synchronous neoplastic lesions was 21.5%. No perforations were seen; however, significant hemorrhages occurred in six cases in which hot biopsy was used. The risk of a significant hemorrhage from hot biopsy of diminutive polyps was 0.39%. The risk of hot biopsy-induced hemorrhage was significantly higher in the right colon than in the transverse colon and left colon (p < 0.05). The risk in the cecum was 1.33%; in the ascending colon it was 1.03%, and for the remainder of the colon it was 0.24%. CONCLUSIONS: Most diminutive polyps proximal to the left colon are neoplastic. The decision to use the hot biopsy or cold biopsy technique to eradicate diminutive polyps should take into account the location of the polyp because of the significantly increased risk of hemorrhage with hot biopsies in the right colon.

 

HISTOLOGICAL TYPES	CHARACTERIZATION
GENERAL	Lined by a stratified layer of hyperchromatic columnar cells Dysplasia ranging from mild to severe is present
To step or not to step: an approach to clinically diagnosed polyps with no initial pathologic finding. Nash JW, Niemann T, Marsh WL, Frankel WL. Department of Pathology, Ohio State University Hospitals, Columbus, USA.	Am J Clin Pathol 2002 Mar;117(3):419-23 Abstract quote. We determined whether there were additional diagnostic findings in additional level sections performed on polyps with no pathologic diagnosis (NPD) or those in which only lymphoid aggregates (LAs) were seen initially and determined the level at which findings were identified. All colorectal biopsy specimens submitted with a clinical diagnosis of polyp during a 6-month period were included (N = 733). Initially, 3 level sections were cut for each polyp, and if a cause for the polyp was found, no additional levels were evaluated. If LAs or no cause for the polyp was found, 5 additional levels through each block were examined. Any diagnostic findings and the level at which they were identified were recorded. A discrete cause for the polyp was identified in routine levels in 574 cases (78.3%). Deeper levels were performed in 159: 23 for clarification of a suspected diagnosis, 38 for LAs, and 98 for NPD. Findings were identified in 31 (22.8%) of 136 stepped for LA or NPD with neoplastic findings in 13 (9.6%). Most diagnoses were identified in levels 4 or 5, but tubular adenomas were found in levels 7 and 8. These results support level sectioning specimens submitted as polyps with NPD or LAs on initial sections.
Deeper examination of negative colorectal biopsies. Wu ML, Dry SM, Lassman CR. Department of Pathology and Laboratory Medicine, University of California Los Angeles School of Medicine, USA.	Am J Clin Pathol 2002 Mar;117(3):424-8 Abstract quote Initial histologic sections of specimens from colorectal biopsies of putative lesions may lack polyps. These sections may contain lymphoid aggregates that seemingly correlate with endoscopic findings; however; additional sections might contain polyps. We reviewed 83 specimens from colorectal biopsies of putative lesions for which initial sections lacked polyps. Our objectives were to determine the incidence of polyps within additional sections and to determine whether the presence of lymphoid aggregates within initial sections excludes the presence of polyps within additional sections. Eight specimens (10%) contained polyps (5 adenomatous, 3 hyperplastic), which remained histologically occult until examination to depths of approximately 120 to 380 microm. Five polyps (62%) were associated with lymphoid aggregates that were present within initial sections. We conclude that additional sections may contain surprisingly large numbers of polyps and that lymphoid aggregates present within initial sections fail to exclude the presence of polyps within additional sections.
Tubular adenomas	>75% of polyp consists of tubular architecture
Villous adenomas	>50% of polyp consists of villous architecture
Tubulovillous adenomas	20-50% contains villous architecture
Accuracy of pathologic interpretation of colorectal polyps by general pathologists in community practice. Rex DK, Alikhan M, Cummings O, Ulbright TM. Departments of Medicine, Gastroenterology, and Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.	Gastrointest Endosc 1999 Oct;50(4):468-74 Abstract quote BACKGROUND: The histologic features of colorectal polyps often guide colonoscopic surveillance and the need for surgical intervention. Our objective was to evaluate the pathologic interpretation of colorectal polyps by general pathologists in community practice. METHODS: Twenty histologic slides of colorectal polyps were reviewed by 20 randomly selected general pathologists in community practice. There were 5 malignant polyps, 9 adenomas, and 6 miscellaneous polyps. RESULTS: Cancer was correctly identified in 91% of readings and adenoma in 94%. The grade of differentiation of cancer was provided in 55% of readings, and comment regarding whether the resection margin was free of cancer was made by 50% of pathologists. Tubular adenoma was called tubulovillous or villous in 35% of readings, but tubulovillous or villous adenoma was seldom (2%) called tubular. High-grade dysplasia was correctly identified in 47% of 60 readings, was called invasive cancer in 22%, and was missed in 31%. Among miscellaneous polyps, hyperplastic polyp was correctly recognized in 75% of cases, and inflammatory polyp and juvenile polyp each were recognized by 16 of 20 pathologists (80%). Peutz-Jeghers hamartoma was identified by 4 of 20 pathologists (20%), and the polypoid phase of solitary rectal ulcer syndrome was recognized by 2 pathologists (10%). CONCLUSION: Areas of strength with regard to interpretation of colon polyps by general pathologists in community practice included identification of cancer, adenoma, and certain non-neoplastic polyps (e.g., inflammatory and juvenile polyps). Areas of weakness included lack of comment on cancer differentiation and proximity to the resection line, erroneous identification of high-grade dysplasia, and identification of rare lesions. The results of this study suggest areas on which to focus continuing education and continuous quality improvement efforts with regard to polyp interpretation.
Large Colorectal Adenomas An Approach to Pathologic Evaluation Elizabeth D. Euscher, MD Theodore H. Niemann, MD Joel G. Lucas, MD Amy M. Kurokawa and Wendy L. Frankel, MD	Am J Clin Pathol 2001;116:336-340 Abstract quote Adenomatous polyps are common neoplastic lesions of the large intestine. The risk of carcinoma increases with polyp size. Small polyps are typically totally embedded for histologic examination, but no standard method for sampling large, grossly benign polyps has been established. We reviewed grossly noninvasive adenomas 2.5 cm or larger to determine the percentage that contained high-grade dysplasia (HGD) and invasive cancer (IC). Based on these findings, we suggest an approach to evaluating large adenomas. Forty-three colon resections met the inclusion criteria (no previous diagnosis of cancer, no gross evidence of invasion, and totally embedded polyp). Twelve (28%) had HGD with 3% (1 of 33 slides) to 100% (4 of 4 slides) containing HGD. Five (12%) had IC with 4% (3 of 72 slides) to 42% (5 of 12 slides) containing IC. All cases with IC had HGD in other slides. Probability studies showed that in the majority of cases, polyps would need to be entirely embedded to have an estimated probability of 95% or more of detecting either HGD or IC. Therefore, grossly noninvasive adenomas should be routinely entirely embedded.
VARIANTS
CAUTERY CHANGES
The effect of electrothermal cautery-assisted resection of diminutive colonic polyps on histopathologic diagnosis. Goldstein NS, Watts JC, Neill JS, Vogel LM, Barkel D, Kadro O, Priest S, Klein S Department of Anatomic Pathology, William Beaumont Hospital, 3601 W Thirteen Miles Rd, Royal Oak, MI 48073, USA.	Am J Clin Pathol 2001 Mar;115(3):356-61 Abstract quote We examined diminutive colonic polyps to identify relationships between thermal electrocoagulation or resection trauma cytologic artifacts, type of thermal electrocoagulation, polyp size, and the interobserver variation among 3 pathologists. The 3 pathologists independently evaluated 119 colonic polyps 5 mm or less in maximum dimension for diagnosis and degree of thermal electrocoagulation or resection trauma cytologic artifacts. The maximum dimension of the polyps and type of thermal electrocoagulation were recorded. The average percentage of polyps in which a definitive diagnosis could not be made because of cytologic artifacts was 16.5% (range, 11.8%-19.3%). Decreasing polyp size was associated linearly with the inability to make a definitive diagnosis owing to cytologic artifacts. Polyps smaller than 2 mm significantly more often could not be definitively diagnosed by at least 1 pathologist owing to cytologic artifacts, including some polyps that were excised without thermal electrocautery. Interobserver variation increased with decreasing polyp dimension. Two millimeters seems to represent a cut point, below which the likelihood that a definitive diagnosis can be made can be increased if thermal electrocoagulation is used. This small size seems to make them especially susceptible to cytologically injurious forces.
EOSINOPHILIA
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.
FLAT ADENOMAS
Histologic classification of endoscopically removed flat colorectal polyps: a multicentric study. Rubio CA, Kato Y, Hirota T, Muto T. Department of Pathology, Gastrointestinal Pathology Research Laboratory, Karolinska Institute, Stockholm, Sweden.	Jpn J Cancer Res 1996 Aug;87(8):849-55 Abstract quote A total of 594 flat colorectal polyps, removed at endoscopy, were histologically classified into non-neoplastic (n = 49) and neoplastic (n = 545) polyps. Non-neoplastic polyps were subdivided into metaplastic (n = 45) and hyperplastic (n = 4), whereas neoplastic polyps were subdivided into adenomas (n = 481), intramucosal carcinomas (n = 28) and invasive adenocarcinomas (n = 36). Several adenoma phenotypes were discerned: tubular (n = 375), serrated (n = 59), villous (n = 39), mixed (n = 7) and fenestrated (n = 1). Intramucosal carcinomas were subdivided into tubular (n = 26) and serrated (n = 2), and invasive adenocarcinomas into tubular (n = 32), serrated (n = 3) and fenestrated (n = 1). The microscopic characteristics of each histologic phenotype described in this communication are defined and illustrated.
MULTINUCLEATED EPITHELIAL GIANT CELLS
Multinucleated epithelial giant cells in colorectal polyps: a potential mimic of viropathic and/or dysplastic changes. Kambham N, Troxell M, Longacre TA. Department of Pathology, Stanford University, Stanford, CA 94305, USA.	Am J Surg Pathol. 2005 Jul;29(7):912-9. Abstract quote   Multinucleated epithelial giant cells (MEG) simulating viral cytopathic effect and/or dysplasia have been reported in the esophagus in association with inflammation, but the occurrence of similar cells in the colon has not been documented. Twenty-three colon specimens (22 biopsies and 1 partial colectomy) featuring MEG from 21 patients were evaluated for a variety of histologic features and correlated with clinical, endoscopic, and follow-up data. Patients included 9 males and 12 females (mean age, 64.9 years; range, 45-86 years). Eleven cases were obtained from 10 asymptomatic patients undergoing surveillance biopsies. Presenting symptoms in the remaining patients were dyspepsia, anemia, abdominal pain, and hematochezia. Over half (13 of 23) of the specimens were from descending and rectosigmoid colon, and almost all were visualized as polyps on endoscopy. Microscopically, all but 1 of the cases featured multiple MEG (range, 6 to >50 cells per biopsy) in the base and mid crypt zones of inflamed polyps with serrated architecture. Immunohistochemical stains for CMV, HSV, adenovirus, EBV, and polyoma virus were negative and no viral particles were identified on ultrastructural examination. Nuclear staining for hMLH1 and hMSH2, markers of microsatellite instability, was similar in distribution to adjacent serrated crypts, but reduced staining intensity was noted in occasional multinucleated cells. Expression of Ki-67 and cleaved caspase 3 was consistent with a quiescent or low proliferative state. Clinical follow-up was available for 9 patients (mean duration, 22.7 months). One patient died of heart failure; all others were well at last follow-up. Bizarre MEG may occasionally be seen within the crypts of inflamed polyps with serrated architecture, raising concern for dysplasia or viral infection. Immunohistochemical and ultrastructural studies fail to establish a viral etiology, and follow-up does not indicate clinically aggressive disease. These changes appear to represent a nonspecific, possibly degenerative response to inflammation and injury, and should be distinguished from dysplasia.
SERRATED ADENOMA
"Filiform" Serrated Adenomas: A Clinicopathologic and Immunophenotypic Study of 18 Cases. Yantiss RK, Oh KY, Chen YT, Redston M, Odze RD. *Weill Medical College of Cornell University, New York, NY †Brigham and Womenʼs Hospital, Boston, MA.	Am J Surg Pathol. 2007 Aug;31(8):1238-1245. Abstract quote In this study, we describe a previously uncharacterized type of adenomatous polyp of the colorectum that shows prominent, thin, elongated projections of neoplastic epithelium with a serrated contour, which we have termed "filiform serrated adenoma" (SA). Routinely processed polypectomy specimens from 18 patients with filiform SA and 23 controls with traditional (nonfiliform) SA were evaluated for their clinical and pathologic features, and immunohistochemically stained for a variety of markers (O-methylguanine methyltransferase, MLH1, MSH2, CDX2, nuclear beta-catenin, p53, and Ki-67) designed to evaluate their molecular and proliferative characteristics. DNA was extracted from the paraffin-embedded materials, amplified by polymerase chain reaction, and analyzed for microsatellite instability, BRAF, K-ras, and p53 mutational status. Five cases contained sufficient non-neoplastic tissue for dissection and DNA extraction, allowing analysis of loss of heterozygosity. The study group consisted of 7 males and 11 females of mean age 64 years (range: 42 to 89 y). All 18 filiform SAs were located in the left colon, including 15 (83%) that occurred in the rectum, compared with 43% of the control group (P=0.03). Filiform SAs were also larger (1.6 cm) than SAs (mean: 1.2 cm, P=0.02), but no other clinical differences were noted. Most (56%) filiform SAs contained marked stromal edema and tall nonmucinous cells with abundant eosinophilic cytoplasm (61%). High-grade dysplasia was present in 4/18 (22%) cases. Four (22%) filiform SAs also contained nonserrated adenomatous elements with a villous (3 cases) or tubular (1 case) growth pattern. Two (11%) cases contained adjacent areas of sessile SAs and 4 (22%) had hyperplastic areas. None of the polyps in the control group showed stromal edema, high-grade dysplasia, or mixed elements. Polyps in both groups demonstrated comparable staining patterns for O-methylguanine methyltransferase, MLH-1, MSH-2, CDX2, beta-catenin, and Ki-67, and none showed increased nuclear p53 expression. Low-frequency microsatellite instability was present in 5/12 (42%) filiform SAs, 7/12 (58%) were microsatellite stable. Mitogen-activated protein kinase pathway abnormalities were present in 71% of the cases [7/14 (50%) with BRAF and 3/14 (21%) with K-ras mutations]. Four cases showed silent p53 mutations upon direct sequencing and 4 revealed loss of heterozygosity at the loci evaluated, including 1 at D5S346 [adenomatous polyposis coli (APC) gene], 1 at D17S250 (p53 gene), and 2 at MYCL (chromosome 1p34). We conclude that filiform SA potentially represents an unusual variant of SA with a predilection for the left colon, particularly the rectum.
Serrated Pathway and APC (Conventional)-Type Colorectal Polyps Molecular-Morphologic Correlations, Genetic Pathways, and Implications for Classification Neal S. Goldstein, MD	Am J Clin Pathol 2006;125:146-153 Abstract quote This review addresses the genetic mutations and cell signaling pathway alterations in colorectal premalignant polyps, focusing on the link between molecular changes and morphologic features. Biallelic APC (adenomatous polyposis coli) mutations are directly responsible for the specific and characteristic cytologic features of dysplastic cells in conventional tubular adenomas. Sessile serrated adenomas (SSAs) are the precursor lesions of the serrated neoplasia pathway. The BRAF activating mutation and hypermethylation of SLC5A8, which mediates short chain fatty acid transport, may be the important events in the genesis of SSAs. Intracellular butyrate inhibits histone deacetylase, allowing histone hyperacetylation and, eventually, transcriptional activation of specific genes. Decreased p21(WAF1/CIP1) and activation of the mitogen-activated protein kinase pathway may be the key intermediary alterations. Progressive loss of cell cycle control and decreased and altered cytoplasmic differentiation produce the characteristic constellation of morphologic changes of SSAs and traditional serrated adenomas.
Small Colonic Microsatellite Unstable Adenocarcinomas and High-Grade Epithelial Dysplasias in Sessile Serrated Adenoma Polypectomy Specimens A Study of Eight Cases Neal S. Goldstein, MD	Am J Clin Pathol 2006;125:132-145 Abstract quote Eight sessile serrated adenoma (SSA), right colon polypectomies with focal invasive adenocarcinoma or high-grade dysplasia were studied to identify features indicating a high risk of transformation and characterize the morphologic features of serrated dysplasia; 6 cases had invasive adenocarcinoma; 2 were high-grade dysplasia. All 8 were microsatellite unstable-high and had absent hMLH1 nuclear immunoreactivity. The mean patient age at polypectomy was 69.5 years (range, 57.1-83.9 years). Mean polyp maximum dimension was 8.5 mm (range, 6-12 mm). The majority of each polyp was nonmalignant SSA. All 8 cases had an abrupt transition from benign to high-grade in situ or invasive malignancy. In the 6 invasive adenocarcinomas, the neoplasm extended directly down into the submucosa without lateral intramucosal spread. The mean maximum dimension of the invasive adenocarcinoma was 2.9 mm (range, 2-4 mm). All 8 cases had high-grade serrated-type dysplasia. The nonmalignant SSAs had marked expansion of the proliferative zone. Crypts adjacent to malignancy had moderately enlarged nuclei, irregular nuclear membranes, and overly prominent nucleoli. SSA crypts were lined by a variety of gastric-type cells; no cell type predominated. Foci of adjacent crypts had similar cytologic features. Small proximal SSAs can transform into adenocarcinoma without a component of adenomatous dysplasia.
Serrated Polyps of the Large Intestine A Morphologic and Molecular Review of an Evolving Concept Dale C. Snover, MD, etal.	Am J Clin Pathol 2005;124:380-391 Abstract quote Serrated polyps of the large intestine, including traditional hyperplastic polyps, traditional serrated adenomas, and more recently described sessile serrated adenomas, have gained increased recognition in recent years because of growing evidence that one of these lesions, the sessile serrated adenoma, might be the precursor lesion for some cases of microsatellite unstable colorectal carcinoma. Nevertheless, there has been some reluctance to embrace the concept of sessile serrated adenoma, and numerous diagnostic challenges exist. This article, which grew out of the Roger C. Haggitt Gastrointestinal Pathology Society Forum presented in Vancouver, Canada, March 6, 2004, as part of the annual meeting of the United States–Canadian Academy of Pathology, reviews the morphologic and molecular evidence for the concept of various polyps in the general category of serrated polyps of the large intestine, in particular the lesion known as the sessile serrated adenoma, and provides a conceptual framework for diagnosis of these lesions.
The risk of metachronous neoplasia in patients with serrated adenoma. Lazarus R, Junttila OE, Karttunen TJ, Makinen MJ. Department of Pathology, University of Oulu, Oulu, Finland.	Am J Clin Pathol. 2005 Mar;123(3):349-59. Abstract quote   Serrated adenomas are the precursors of at least 5.8% of colorectal cancers; otherwise little is known of their clinical significance in comparison with conventional adenomas and hyperplastic polyps. We compared the risk of metachronous lesions in colorectal serrated adenomas, conventional adenomas, and hyperplastic polyps. A consecutive series of patients with colorectal polyps first diagnosed from January 1978 to December 1982 and follow-up specimens to the end of 2000 was reviewed, and 239 polyps fulfilling the selection criteria were chosen as index polyps. The type of polyp seen in follow-up correlated significantly with the type of the initial lesion. Serrated adenomas were estimated to grow faster than conventional adenomas, but the incidence of colorectal cancer did not differ significantly between serrated (2/38 [5%]) and conventional adenomas (2.2%). The results indicate that serrated adenomas are lesions with a significant risk of metachronous serrated adenomas and the development of cancer. We emphasize the need for the proper recognition and management of serrated adenomas.
Histopathological and clinical evaluation of serrated adenomas of the colon and rectum. Bariol C, Hawkins NJ, Turner JJ, Meagher AP, Williams DB, Ward RL. Departments of Medical Oncology (RLW), Anatomical Pathology (JJT), Colorectal Surgery (APM), and Gastroenterology (DBW, CB), St. Vincent's Hospital, Sydney.	Mod Pathol 2003 May;16(5):417-23 Abstract quote We evaluated the diagnostic utility of the histological characteristics ascribed in the literature to serrated adenomas and developed a practical working model to allow their reliable identification. We also documented the frequency and location of serrated adenomas identified in an unselected series of individuals undergoing colonoscopic evaluation, as well as the clinical characteristics of those individuals. One hundred forty consecutive individuals (prospective polyp data set; 97 male, 43 female; age mean: 63.3 y; age range: 29-98 y) with 255 polyps were identified from 919 individuals undergoing colonoscopy. Further polyps previously removed from these individuals were added for the purpose of histological assessment (extended polyp data set, n = 380). All polyps were assessed by two independent examiners for eight selected architectural and cytological features of serrated adenomas. In the prospective polyp data set, 56 patients had 72 hyperplastic polyps, 7 had 9 serrated adenomas, 3 had 4 admixed polyps, and 98 had 170 conventional adenomas. There was no difference in the age, sex, or cancer association of the seven patients with serrated adenomas when compared with the case of other individuals with polyps. The prevalence of serrated adenomas was 9/919 (1%) in our population, with an average size of 5.8 mm. When assessing serrated adenomas histologically, the combination of nuclear dysplasia and serration of >/=20% of crypts provided the most accurate model for detection of these lesions (sensitivity 100%, specificity 97%). Other criteria provided supportive evidence but did not increase the diagnostic yield. The optimum model for the histological identification of the serrated adenoma includes the presence of a serrated architecture in >/=20% of crypts in association with surface epithelial dysplasia.
Morphologic reappraisal of serrated colorectal polyps. Torlakovic E, Skovlund E, Snover DC, Torlakovic G, Nesland JM.	Am J Surg Pathol 2003 Jan;27(1):65-81 Abstract quote The "hyperplastic polyp" is considered a benign lesion with no malignant potential, whereas "serrated adenoma" is a precursor of adenocarcinoma. The morphologic complexity of the serrated adenoma varies from being clearly adenomatous to being difficult to distinguish from hyperplastic polyp, which creates a need for more detailed morphologic analysis of all serrated polyps. We evaluated 24 morphologic variables in 289 serrated polyps from the colon and rectum. Cluster analysis and discriminant analysis were performed. A subset of polyps was immunostained for hMLH1 and hMSH2. Major differences were found between right-sided and left-sided polyps. A distinct group of serrated polyps with abnormal proliferation was identified throughout the colon and rectum. These polyps demonstrated decreased expression of hMHL1 and hMSH2 compared with polyps with normal proliferation. Left-sided serrated polyps with normal proliferation further clustered into three groups: vesicular cell-type, goblet cell-type, and mucin-poor-type. We recommend evaluation of the localization, size, and morphologic features when serrated polyps are included in colorectal carcinogenesis research. Polyps with abnormal proliferation are similar to the polyps in "hyperplastic polyposis" and, because of their decreased expression of hMLH1 and hMSH2, may be the subset of polyps associated with the development of colorectal carcinoma via the microsatellite instability pathway.
Serrated adenomatous polyposis in humans. Torlakovic E, Snover DC. Department of Laboratory Medicine, University of Minnesota Medical School, Minneapolis, USA.	Gastroenterology 1996 Mar;110(3):748-55Abstract quote BACKGROUND & AIMS: Hyperplastic polyposis clinically resembles adenomatous polyposis and has not generally been considered precancerous. However, since the original description, a number of cases associated with adenocarcinoma have been reported. The aim of this study was to reevaluate patients previously diagnosed with hyperplastic polyposis. METHODS: Pathological analysis of polyps in 6 patients with putative hyperplastic polyposis and 4 with associated carcinoma was compared with classic isolated hyperplastic polyps, adenomas, and solitary serrated adenomas. Immunohistochemical study for the detection of p53 protein, blood groups antigens, including Lewis(a) and Lewis(b), and peanut lectin binding was performed. RESULTS: Polyps in our patients were much more similar to serrated adenomas than to hyperplastic polyps and were characterized by large size, prominent architectural distortion, cytologically atypical nuclei, focal nuclear crowding and nuclear dispolarity, and rare upper zone mitotic figures. The polyps in our patients and control serrated adenomas had a decrease or absence of endocrine cells compared with classic hyperplastic polyps and normal colon and similar immunohistochemical reactivity for p53 and Lewis(a) and Lewis(b) antigens. CONCLUSIONS: Our results indicate that the polyps in our patients are serrated adenomas. Serrated adenomatous polyposis has not been described before and should be distinguished from true hyperplastic polyposis given a possible association with adenocarcinoma in the former group.
Small colorectal serrated adenomas: endoscopic findings. Jaramillo E, Watanabe M, Rubio C, Slezak P. Dept. of Diagnostic Radiology, Karolinska Hospital, Stockholm, Sweden.	Endoscopy 1997 Jan;29(1):1-3 Abstract quote BACKGROUND AND STUDY AIMS: Serrated adenomas are a distinct form of colorectal neoplasia. Several reports have indicated that serrated adenomas may give rise to invasive adenocarcinoma. The present study describes the endoscopic findings in 54 colorectal serrated adenomas detected in 35 patients. PATIENTS AND METHODS: Thirty-five of 1225 patients (2.9%) who underwent colonoscopy during 1993 in the gastrointestinal endoscopy section at Karolinska Hospital (22 men, 13 women; mean age 68 years, range 49-84 years) were found to have a total of 182 polyps, including 118 adenomas and 64 hyperplastic polyps at histopathology. Fifty-four of the 118 adenomas (46%) were of the serrated type. In two of the 35 patients, two large exophytic colorectal adenocarcinomas were also present. RESULTS: Twenty-nine of the serrated adenomas (53.5%) were flat, 23 were sessile (42.5%), and two were pedunculated (4%). The mean sizes of the flat and sessile lesions were 3.5 mm (range 2-10 mm) and 5.9 mm (range 2-20 mm), respectively. The endoscopic appearance of serrated adenomas of 5 mm or less (n = 39, 72%) was similar to that of hyperplastic polyps. Forty-two (78%) of the lesions were located in the sigmoid and rectum. Fifty-one lesions showed low-grade dysplasia (including one with microinvasive carcinoma), and the remaining three had high-grade dysplasia. CONCLUSIONS: The study suggests that small polyps with a hyperplastic appearance should not be regarded as innocuous, since they may represent serrated adenomas carrying a malignant potential.
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.
Serrated adenoma of the colorectum: colonoscopic and histologic features. Matsumoto T, Mizuno M, Shimizu M, Manabe T, Iida M, Fujishima M. Division of Gastroenterology, Department of Medicine, Kawasaki Medical School, Kurashiki-City, Okayama, Japan.	Gastrointest Endosc 1999 Jun;49(6):736-42 Abstract quote BACKGROUND: Serrated adenoma is a recently recognized epithelial neoplasm of the colorectum. The aim of this study is to clarify the colonoscopic features of serrated adenomas. METHODS: The endoscopic findings for 52 serrated adenomas of the colorectum were investigated; these were then divided into three groups according to surface features. The histologic type (tubular, tubulovillous or villous) and the incidence of high-grade dysplasia were compared among the three groups. RESULTS: The surface under chromoscopy showed a hyperplastic pattern in 17 lesions, a cerebriform pattern in 18 lesions and a combined pattern in 17 lesions. The tubular type of serrated adenoma was predominant in the hyperplastic pattern group (94%), whereas the tubulovillous or villous histologic types were frequent in the cerebriform pattern (89%) and combined pattern (82%) groups. High-grade dysplasia was found in 18% of the combined pattern adenomas; the incidence was lower in hyperplastic (6%) or cerebriform pattern (0%) adenomas. CONCLUSIONS: Surface features of serrated adenomas have a close correlation with their histologic type. A combined hyperplastic-cerebriform surface pattern under chromoscopy was seen only in serrated adenomas.

 

SPECIAL STAINS/ IMMUNO- HISTOCHEMISTRY/ OTHER	CHARACTERIZATION
Expression of E-cadherin-associated molecules (alpha-, beta-, and gamma-catenins and p120) in colorectal polyps. Valizadeh A, Karayiannakis AJ, el-Hariry I, Kmiot W, Pignatelli M. Department of Histopathology, Royal Postgraduate Medical School, London, United Kingdom	Am J Pathol 1997 Jun;150(6):1977-84 Abstract quote E-cadherin and its associated cytoplasmic proteins alpha-, beta-, and gamma-catenin and p120 protein play a crucial role in the maintenance of normal tissue architecture. Perturbation in any of these molecules results in loss of intercellular adhesion and cell transformation. In this study, we have used immunohistochemistry to localize E-cadherin, alpha-, beta-, and gamma-catenin, and p120 in paraffin-embedded tissues from 60 patients with colonic polyps. Specimens consisted of 20 samples each from hyperplastic, inflammatory, and sporadic adenomatous polyps. Ten histologically normal colonic samples were also studied. Normal colonic epithelial cells showed strong E-cadherin/ catenin/p120 immunostaining at the cell-cell junction. In 65% (13/20) of adenomatous polyps, beta-catenin showed abnormal nuclear localization with increased expression and loss of membranous staining compared with the adjacent normal mucosa. In two cases (10%), gamma-catenin was seen in the nuclei. Heterogeneous p120 immunoreactivity was observed in four cases (20%), of which two also showed beta-catenin nuclear localization. Preserved membranous alpha-catenin staining was seen in all cases. E-cadherin was down-regulated in 6 of 20 (30%) adenomas with loss of cell surface staining in 3 cases. All hyperplastic and 40% (8/20) of inflammatory polyps showed weak E-cadherin expression on the surface epithelium. Similar changes in p120 expression were seen in all hyperplastic and 20% (4/20) of inflammatory polyps. There were no concomitant changes in alpha-, beta-, or gamma-catenin expression. These results indicate that changes in catenin expression and cellular localization occur early in dysplastic colonic lesions.
Aberrant expression of MUC5AC and MUC6 gastric mucin genes in colorectal polyps. Bartman AE, Sanderson SJ, Ewing SL, Niehans GA, Wiehr CL, Evans MK, Ho SB. Department of Medicine, Veterans Affairs Medical Center and the University of Minnesota, Minneapolis, USA.	Int J Cancer 1999 Jan 18;80(2):210-8 Abstract quote Altered mucin glycosylation and the de novo appearance of gastric mucin antigens have been described in colonic adenomas. The purpose of our study was to determine if expression of the gastric mucin genes MUC5AC and MUC6 occurs in colorectal adenomas and whether this correlates with histopathologic criteria of malignant potential. Immunohistochemical staining using antibodies against MUC5AC and MUC6 tandem repeat synthetic peptides was performed on specimens of normal colon mucosa (n = 26), hyperplastic polyps (n = 9) and adenomatous polyps (n = 111). Mucin mRNA levels were determined using RNase protection assays using riboprobes corresponding to unique non-repetitive sequences. MUC5AC and MUC6 staining were rarely detected and of low intensity in normal colon and hyperplastic polyps. The number of immunoreactive polyps and intensity of MUC5AC and MUC6 staining were greatest in larger adenomas of moderate villous histology and dysplasia. MUC5AC and MUC6 staining tended to decrease in highly villous polyps with severe dysplasia. Increased MUC5AC mRNA levels were found in 26/45 of adenomas tested compared with 0/9 normal colon specimens. MUC6 mRNA levels were found in 20/45 of adenomas compared with 1/9 normal colon specimens. MUC5AC and MUC6 mRNA were present more frequently and at higher levels in polyps with intermediate stages of size, villous histology and dysplasia. We conclude that aberrant expression of MUC5AC and MUC6 mucin genes is likely responsible for an expanded repertoire of mucin antigen expression in colorectal neoplasia.

 

DIFFERENTIAL DIAGNOSIS	KEY DIFFERENTIATING FEATURES
PSEUDOINVASION
Utility of MMP-1, p53, E-Cadherin, and Collagen IV Immunohistochemical Stains in the Differential Diagnosis of Adenomas With Misplaced Epithelium versus Adenomas With Invasive Adenocarcinoma Rhonda K. Yantiss, M.D. ; Marcus W. Bosenberg, M.D. , Ph.D. ; Donald A. Antonioli, M.D. ; Robert D. Odze, M.D. , F.R.C.P.C. From the Departments of Pathology (R.K.Y.), UMass Memorial Health Care, Worcester, and Brigham and Women's Hospital (M.W.B., R.D.O.) and Beth Israel Deaconess Medical Center (D.A.A.), Boston, Massachusetts, U.S.A.	Am J Surg Pathol 2002;26:206-215 Abstract quote Adenomas with misplaced epithelium in the submucosa of the polyp stalk (“pseudoinvasion”) may be difficult to distinguish from adenomas that harbor invasive adenocarcinoma by morphologic analysis. Recently, several epithelial and stromal proteins, such as matrix metalloproteinase-1 (MMP-1), p53, E-cadherin, and collagen IV, have been shown to be altered in colonic adenocarcinomas in comparison with adenomas and normal colonic mucosa. Therefore, the purpose of this study was to evaluate the diagnostic use of several epithelial (p53, E-cadherin) and stromal (MMP-1, collagen IV) markers in distinguishing adenomas with misplaced epithelium from those with invasive adenocarcinoma. Routinely processed polypectomy specimens from 23 patients with an adenoma with misplaced epithelium (male/female ratio 12/11; mean age 65 years) and 23 patients with an adenocarcinoma arising in an adenoma (male/female ratio 13/10; mean age 63 years) were immunohistochemically stained (avidin-biotin complex method) for monoclonal antibodies to MMP-1 (epithelial and stromal cell collagenase), p53 (tumor suppression gene), E-cadherin (intercellular adhesion protein), and collagen IV (basement membrane collagen component), and the results were compared between the two polyp groups. Where appropriate, immunopositivity was evaluated in the epithelium (MMP-1, p53, E-cadherin), stroma (MMP-1), and/or basement membrane (collagen IV). Cases were considered positive if an increase (MMP-1, p53) or decrease (E-cadherin, collagen IV) in either the intensity or proportion of cells staining was noted in the submucosal epithelial component compared with the intramucosal portion of the polyp head for each individual polyp. In adenomas with invasive adenocarcinoma, MMP-1 staining of the stroma surrounding submucosal epithelium and p53 nuclear staining within the epithelium were increased in 21 (91%) and 14 (61%) cases, respectively, whereas decreased or discontinuous E-cadherin and collagen IV staining was noted in 15 (65%) and 22 (96%) cases, respectively. All these values were significantly different (p < 0.005) from those observed in adenomas with misplaced epithelium [MMP-1, 11 of 23 (48%); p53, 1 of 23 (4%); E-cadherin, 0 of 23 (0%); collagen IV, 0/23 (0%)]. Furthermore, in three diagnostically difficult cases that contained foci of misplaced epithelium with high-grade dysplasia, the immunohistochemical results confirmed the impression that the lesions represented epithelial misplacement rather than invasive adenocarcinoma. In conclusion, the degree and/or pattern of MMP-1, p53, E-cadherin, and collagen IV staining in the submucosal epithelial elements in comparison with the intramucosal adenomatous tissue may help distinguish adenomas with misplaced epithelium from those with invasive adenocarcinoma.

 

PROGNOSIS AND TREATMENT	CHARACTERIZATION
PROGNOSIS	Malignancy risk is dependent upon several factors: Tubular adenomatous polyps<1cm have low risk of cancer High risk of cancer in sessile villous adenomas >4cm in diameter Severe dysplasia is often found in villous areas
Colonic dysplasia	Pathol Annu. 1981;16:181-213. Gastroenterology. 1990;98:371-379. Presence of high-grade dysplasia is a step toward invasive carcinoma. High-grade dysplasia has been reported in up to 35% of villous adenomas that are greater than 1 cm in size. The likelihood of encountering invasive cancer increases with increasing polyp size and approaches 85% in sessile polyps larger than 4 cm
Recurrence/Metastasis	Hum Pathol. 1994;25:1160-1171 Am J Surg Pathol. 1983;7:613-623 In endoscopically removed sessile polyps with submucosal invasion, there is a 14% chance of recurrence or lymph node metastasis.
Correlation of polypoid lesions in the distal colorectum and proximal colon in asymptomatic screening subjects. Nusko G, Altendorf-Hofmann A, Hermanek P, Ell C, Hahn EG. Department of Medicine I, University of Erlangen, Germany. .	Eur J Gastroenterol Hepatol 1996 Apr;8(4):351-4 Abstract quote OBJECTIVE: Knowledge of a possible correlation between distal polyps found at screening sigmoidoscopy and proximal colonic lesions is important for deciding whether to perform total colonoscopy or not. PATIENTS: A prospective analysis of 2439 consecutive patients with colorectal polyps. Of these, 304 were asymptomatic subjects who underwent complete colonoscopy for screening and were found to have adenomatous or hyperplastic polyps in the distal colorectum. RESULTS: Ten (15%) out of 65 patients with distal hyperplastic polyps only and 86 (36%) out of 239 with distal adenomatous polyps were found to have adenomatous polyps in the proximal colon as well (P < 0.001). The frequency of synchronous proximal adenomas in patients with small (< or = 5 mm) or large distal adenomas (> 5 mm) was comparable (37% and 35%, respectively). However, patients with small distal adenomas had significantly smaller proximal adenomas (P = 0.004) containing less villous component (P = 0.017) than those with large distal adenomas. Neither the patient's age nor the presence of multiple distal adenomas increased the prevalence of proximal adenomas. CONCLUSION: Hyperplastic polyps found on rectosigmoidoscopy do not indicate a need for a complete colorectal examination, as 15% of patients with distal hyperplastic polyps will have proximal adenomatous polyps, a figure that is comparable with that of asymptomatic patients having no distal polyps, either hyperplastic or adenomatous. When only small distal adenomas are found at screening sigmoidoscopy in asymptomatic persons the decision to do a total colonoscopy should be based on individual considerations, as in such cases only small polyps are to be expected in the proximal colon.
Growth of colorectal polyps: redetection and evaluation of unresected polyps for a period of three years. Hofstad B, Vatn MH, Andersen SN, Huitfeldt HS, Rognum T, Larsen S, Osnes M. Medical Department, Ullevaal Hospital, Oslo, Norway	Gut 1996 Sep;39(3):449-56 Abstract quote BACKGROUND, AIMS, AND PATIENTS: In a prospective follow up and intervention study of colorectal polyps, leaving all polyps less than 10 mm in situ for three years, analysis of redetection rate, growth, and new polyp formation was carried out in 116 patients undergoing annual colonoscopy. The findings in relation to growth and new polyp formation were applied to 58 subjects who received placebo. RESULTS: Redetection rate varied from 75-90% for each year, and was highest in the rectum and sigmoid colon. There was no net change in size of all polyps in the placebo group, however, polyps less than 5 mm showed a tendency to net growth, and polyps 5-9 mm a tendency to net regression in size, both for adenomas and hyperplastic polyps. This pattern was verified by computerised image analysis. Patients between 50 and 60 years showed evidence of adenoma size increase compared with the older patients, and the same was true for those with multiple adenomas (four to five) compared with those with a single adenoma. The new adenomas were significantly smaller and 71% were located in the right side of the colon. Patients with multiple adenomas had more new polyps at all the follow up examinations than patients with a single adenoma. One patient developed an invasive colorectal carcinoma, which may be evolved from a previously overlooked polyp. Two polyps, showing intramucosal carcinoma after follow up for three years, were completely removed, as judged by endoscopy and histological examination. CONCLUSIONS: The results show that follow up of unresected colorectal polyps up to 9 mm is safe. The consistency of growth retardation of medium sized polyps suggests extended intervals between the endoscopic follow up examinations, but the increased number of new polyps in the proximal colon indicates total colonoscopy as the examination of choice. The growth retardation of the medium sized polyps may partly explain the discrepancy between the prevalence of polyps and the incidence of colorectal cancer.
Lack of spontaneous regression of tubular adenomas in two years of follow-up. Bersentes K, Fennerty MB, Sampliner RE, Garewal HS. Department of Internal Medicine, Arizona Health Sciences Center and Tucson Veterans Affairs Medical Center, 85723, USA.	Am J Gastroenterol 1997 Jul;92(7):1117-20 Abstract quote OBJECTIVE: Change in colon polyp size over time has not been well characterized. It has been inferred that some polyps will increase in size, leading to an increased risk of progressing to cancer, whereas other polyps may spontaneously regress. To develop a better understanding of the natural history of colon polyps, we prospectively investigated change in polyp size over a 2-yr period. METHODS: Patients were enrolled if they had an endoscopically detected proximal rectal or sigmoid polyp measuring 3-9 mm. The index polyp site was then permanently marked with an adjacent India ink tattoo to allow definitive future localization of the polyp. Patients underwent flexible sigmoidoscopy at 6-month intervals, and at each examination, the polyp size was carefully measured with open biopsy forceps. After a maximum of 2 yr, each polyp was removed and the histology determined. RESULTS: Thirty polyps were followed in 26 patients who completed the study. Twelve polyps were tubular adenomas (TA), one was tubulovillous, 14 were hyperplastic polyps (HP), two had no pathological diagnosis, and one was a leiomyoma. HP were more likely to decrease in size than were TA. Three polyps demonstrated fast growth rates (2-4 mm/yr), and all were TA. Two polyps were removed early because their size had reached 1 cm or more. Both of those polyps were TA. No polyps regressed completely during the 2 yr of the study; neither did we find consistent linear growth rates. CONCLUSIONS: In contrast to prior reports, in this study, after polyps had been definitively localized with India ink, we observed no complete polyp regressions.
Prospective determination of distal colon findings in average-risk patients with proximal colon cancer. Rex DK, Chak A, Vasudeva R, Gross T, Lieberman D, Bhattacharya I, Sack E, Wiersema M, Farraye F, Wallace M, Barrido D, Cravens E, Zeabart L, Bjorkman D, Lemmel T, Buckley S. Department of Medicine, Division of Gastroenterology/ Hepatology, Indiana University School of Medicine, Indianapolis, USA.	Gastrointest Endosc 1999 Jun;49(6):727-30 Abstract quote BACKGROUND: Recent guidelines indicate that colonoscopy and sigmoidoscopy are both acceptable options for screening average-risk patients for colorectal cancer. Retrospective studies have found that a majority of patients with cancer proximal to the splenic flexure have a normal screening flexible sigmoidoscopy. METHODS: This was a multicenter, prospective description of colonoscopic findings and family history in consecutive patients with proximal colon cancer. RESULTS: Among 116 prospectively identified average-risk patients with cancer proximal to the splenic flexure, 40 (34.5%) had neoplasia distal to the splenic flexure. The prevalence of patients with adenomas greater than or equal to 1 cm, with only one tubular adenoma less than 1 cm, and with only hyperplastic polyps were 16.4%, 8.6%, and 6.9%, respectively. CONCLUSIONS: Most average-risk patients with cancer proximal to the splenic flexure will have a normal screening flexible sigmoidoscopy. These patients have an unexpectedly high prevalence of large distal adenomas, but the prevalence of both single small tubular adenomas and hyperplastic polyps alone is similar to that expected during screening of the general population. Clinicians and payers should continue to seek methods to improve the cost-effectiveness and availability of screening colonoscopy in average-risk persons.
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	Complete removal In general, an invasive adenocarcinom that arises within the polyp can be adequately treated if the following are true: It is a pedunculated polyp and the adenocarcinoma is superficial and does not approach the margins of excision across the base of the stalk, no vascular or lymphatic invasion, and carcinoma is not poorly differentiation If the invasive adenocarcinoma is arising within a sessile poly, polypectomy is inadequate treatment and further surgery is needed

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Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.

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