Anatomic Pathology / LARGE COLORECTAL ADENOMAS AND PATHOLOGIC EVALUATION

336 Am J Clin Pathol 2001;116:336-340 © American Society of Clinical Pathologists

Large Colorectal Adenomas

An Approach to Pathologic Evaluation

Elizabeth D. Euscher, MD,1 Theodore H. Niemann, MD,1 Joel G. Lucas, MD,1

Amy M. Kurokawa,2 and Wendy L. Frankel, MD1

Key Words: Villous adenoma; Adenomatous polyp; Colorectal polyp

A b s t r a c t

Adenomatous polyps are common neoplasticlesions of the large intestine. The risk of carcinomaincreases with polyp size. Small polyps are typicallytotally embedded for histologic examination, but nostandard method for sampling large, grossly benignpolyps has been established. We reviewed grosslynoninvasive adenomas 2.5 cm or larger to determinethe percentage that contained high-grade dysplasia(HGD) and invasive cancer (IC). Based on thesefindings, we suggest an approach to evaluating largeadenomas. Forty-three colon resections met theinclusion criteria (no previous diagnosis of cancer, nogross evidence of invasion, and totally embeddedpolyp). Twelve (28%) had HGD with 3% (1 of 33slides) to 100% (4 of 4 slides) containing HGD. Five(12%) had IC with 4% (3 of 72 slides) to 42% (5 of 12slides) containing IC. All cases with IC had HGD inother slides. Probability studies showed that in themajority of cases, polyps would need to be entirelyembedded to have an estimated probability of 95% ormore of detecting either HGD or IC. Therefore, grosslynoninvasive adenomas should be routinely entirelyembedded.

Adenomatous polyps are common neoplastic lesions inthe large intestine, with the incidence ranging from 12% in astudy of unselected patients1 up to 30% in autopsy studies.2

Adenomas are considered precursor lesions to invasivecolorectal cancer, and the presence of high-grade dysplasia isa step toward invasive carcinoma.3 High-grade dysplasia hasbeen reported in up to 35% of villous adenomas that aregreater than 1 cm in size.2 The likelihood of encounteringinvasive cancer increases with increasing polyp size andapproaches 85% in sessile polyps larger than 4 cm.4 Carci-noma invasive to the submucosa has the potential to follow abiologically aggressive course.5,6 In endoscopically removedsessile polyps with submucosal invasion, there is a 14%chance of recurrence or lymph node metastasis.6,7

Small polyps are typically entirely removed endoscopi-cally. Endoscopic polypectomy alone may not be adequatetherapy, and a colon resection may be necessary when invasivecancer is found less than 0.2 cm from the stalk resectionmargin, when lymphovascular space invasion is present,and/or if the tumor is poorly differentiated.6-8 In addition, if anadenoma cannot be totally removed endoscopically, a limitedcolon resection may be necessary to excise the entire polyp.Optimal sampling of large adenomas without known carci-noma or grossly identifiable invasion has not been studiedsystematically, although the literature suggests thoroughsectioning of large polyps to detect a malignant focus.9,10

Some pathologists use a 1-cassette-per-centimeter rule whensubmitting large adenomas, while others totally embed alladenomas. We evaluated colon resection specimens containingpolyps 2.5 cm or larger without gross evidence of invasion todetermine the percentage of polyps that contained high-gradedysplasia and/or invasive carcinoma, and we determined anapproach to the pathologic evaluation of large adenomatouspolyps without grossly apparent invasive carcinoma.

Anatomic Pathology / ORIGINAL ARTICLE

Am J Clin Pathol 2001;116:336-340 337© American Society of Clinical Pathologists

Materials and Methods

The Ohio State University Department of Pathology(Columbus, OH) case files from January 1985 to January1999 were searched for segmental colectomies performed toresect adenomas that could not be entirely removed endo-scopically. Inclusion criteria included a size of 2.5 cm orlarger, absence of a biopsy-proven diagnosis of cancer in thepolyp, and no evidence of gross invasion ❚ Image 1❚ . Grossmalignant features were apparent extension into or throughthe bowel wall. Cases were included in which it was specifi-cally stated or presumed that the polyp was totally embedded.

Cases were reviewed by 2 pathologists (E.D.E., W.L.F.)to classify adenomas as tubular, tubulovillous, or villous andto determine the percentage of slides containing high-gradedysplasia or invasive carcinoma. Adenomas were classifiedbased on the World Health Organization Classification ofTumors: tubular adenoma with dysplastic glands occupyingmore than 80% of the luminal surface; villous adenoma withvillous architecture present in more than 80% of the luminalsurface; and tubulovillous adenoma with a mixture of tubularand villous structures.11 High-grade dysplasia was definedby nuclear stratification and/or cytologic features of carci-noma and irregular cribriform glands without an associateddesmoplastic stromal response.6 Invasive carcinoma wasdefined by extension of malignant glands beyond the level ofthe muscularis mucosa with an associated desmoplasticresponse. Cases were divided into adenomas without high-grade dysplasia, adenomas with high-grade dysplasia, andadenomas with high-grade dysplasia and invasive carcinoma.

Results were analyzed by using the Wilcoxon rank sumtest to determine whether there were significant differences

for polyp size or number of cassettes submitted. The Fisherexact test was used to determine whether there was a rela-tionship between the villous component and invasive cancer.Probability studies were performed to determine how manycassettes would be necessary per centimeter of polyp todetect a focus of high-grade dysplasia or invasive cancer inany single slide. The probability studies evaluated thenumber of cassettes per centimeter of polyp (1-5 cassettes)submitted and determined the number of cases in which anysingle slide with high-grade dysplasia or invasive carcinomawould have been detected with estimated probabilities of70% or more, 80% or more, 90% or more, and 95% or more.To perform this analysis, it was necessary to assume that thechance of cancer or high-grade dysplasia was equal for allcassettes and that the probability for an individual cassettewas constant and unaffected by the previous cassettes.

Results

A total of 43 polyps were identified ranging in size from2.5 to 15.7 cm; the number of blocks submitted per polypranged from 3 to 72 ❚ Table 1❚ . The average number of blocksrequired to totally embed the polyps was 2.7 per centimeter ofadenoma. Nine polyps measured 2.5 cm in maximum dimen-sion; most polyps ranged from 3.0 to 5.0 cm (23 cases). Onepolyp was classified as a tubular adenoma, while 29 were clas-sified as tubulovillous adenomas and 13 as villous adenomas.

No high-grade dysplasia was identified in 31 cases.These polyps ranged from 2.5 to 8.5 cm (mean ± SD, 3.5 ±1.3 cm). Twelve cases contained high-grade dysplasia. Ofthose, 7 had high-grade dysplasia without invasive carci-noma and ranged from 2.5 to 7.2 cm (mean ± SD, 4.5 ± 1.4

❚ Image 1❚ A, Segmental colon resection specimen opened longitudinally to reveal a large adenoma. B, Cross-section of thelarge adenoma without definite invasion.

A B

Euscher et al / LARGE COLORECTAL ADENOMAS AND PATHOLOGIC EVALUATION

338 Am J Clin Pathol 2001;116:336-340 © American Society of Clinical Pathologists

cm). In these cases, 3% (1 of 33 slides) to 100% (4 of 4slides) of slides contained focal high-grade dysplasia. Theremaining 5 cases of high-grade dysplasia contained focalinvasive carcinoma and ranged from 3.0 to 15.7 cm (mean ±SD, 6.4 ± 4.7 cm). In cases in which both high-gradedysplasia and carcinoma were present, 15% (11 of 72 slides)to 92% (11 of 12 slides) had focal high-grade dysplasia, and4% (3 of 72 slides) to 42% (5 of 12 slides) contained focalinvasive carcinoma. In the largest polyp of our series (15.7cm), high-grade dysplasia was present in 15% (11 of 72slides), and invasive cancer was present in only 4% (3 of 72slides). Invasive cancer was not observed in polyps withouthigh-grade dysplasia. No invasive carcinoma was present inpolyps less than 3.0 cm. In cases with invasive carcinoma, noinvasion extended beyond the submucosa, none had lympho-vascular space invasion, and lymph nodes were negative for

metastatic carcinoma. The size of polyps in each category isshown in Table 1. There was a trend to increasing polyp sizewith high-grade dysplasia and invasive carcinoma. A statisti-cally significant difference in both tumor size and number ofcassettes was seen between the group without high-gradedysplasia or invasive cancer and the group with high-gradedysplasia and invasive cancer but not between other groups.While villous adenomas had high-grade dysplasia and inva-sive carcinoma present more frequently than tubulovillousadenomas, no significant relationship was found between thediagnosis of either villous adenoma or tubulovillousadenoma and the presence of high-grade dysplasia and/orcancer by using the Fisher exact test (P = .66).

Results of the probability studies are summarized in❚ Table 2❚ and ❚ Table 3❚ . If 1 cassette per centimeter had beensubmitted in the 12 cases with high-grade dysplasia, only 5

❚ Table 1❚Polyp Size and the Presence of High-Grade Dysplasia and Invasive Carcinoma in Adenomas

Size (cm)

Slides With Slides With Range Mean ± SD* High-Grade Dysplasia† Invasive Carcinoma†

Adenoma (n = 31) 2.5-8.5 3.5 ± 1.3 — —High-grade dysplasia (n = 7) 2.5-7.2 4.5 ± 1.4 3 (1/33)-100 (4/4) —High-grade dysplasia and invasive carcinoma (n = 5) 3.0-15.7 6.4 ± 4.7 15 (11/72)-92 (11/12) 4 (3/72)-42 (5/12)

* P = .08 for adenoma vs high-grade dysplasia; P = .30 for high-grade dysplasia vs high-grade dysplasia and invasive carcinoma; and P = .02 for adenoma vs high-gradedysplasia and invasive carcinoma (Wilcoxon rank sum test).

† Data are given as percentage (number of slides with dysplasia or carcinoma/total number of slides).

❚ Table 2❚Frequency and Percentage of Cases (n = 12) in Which at Least One Cassette With High-Grade Dysplasia Would Have BeenDetected*

Probability

No. of Cassettes per Centimeter 70% or More 80% or More 90% or More 95% or More

1 7 (58) 6 (50) 6 (50) 5 (42)2 11 (92) 8 (67) 7 (58) 6 (50)3 11 (92) 11 (92) 9 (75) 9 (75)4 11 (92) 11 (92) 11 (92) 10 (83)5 12 (100) 11 (92) 11 (92) 11 (92)

* Data are given as number (percentage).

❚ Table 3❚Frequency and Percentage of Cases (n = 5) in Which at Least One Cassette With Invasive Carcinoma Would Have Been Detected*

Probability

No. of Cassettes per Centimeter 70% or More 80% or More 90% or More 95% or More

1 2 (40) 2 (40) 1 (20) 1 (20)2 2 (40) 3 (60) 2 (40) 2 (40)3 5 (100) 4 (80) 3 (60) 2 (40)4 5 (100) 5 (100) 4 (80) 4 (80)5 5 (100) 5 (100) 5 (100) 4 (80)

* Data are given as number (percentage).

Anatomic Pathology / ORIGINAL ARTICLE

Am J Clin Pathol 2001;116:336-340 339© American Society of Clinical Pathologists

of 12 cases would have an estimated probability of 95% ormore of detecting high-grade dysplasia in any 1 slide. Forcases with invasive carcinoma, if 1 cassette per centimeterhad been submitted, only 1 of 5 cases would have had anestimated probability of 95% or more of detecting invasivecarcinoma in any 1 slide. By increasing the number ofcassettes per centimeter, more cases approach an estimatedprobability of 95% or more of detecting both high-gradedysplasia and invasive carcinoma.

Discussion

Colonic polyps are common specimens encountered in apathology practice. It is well established that adenomasrepresent precursor lesions to invasive colonic carcinoma.This is supported by the presence of a spectrum of histologicchanges in adenomas that range from low-grade dysplasia tofrankly invasive carcinoma.6 When high-grade dysplasia ispresent, there is a strong association with the presence ofinvasive carcinoma,12,13 and once carcinoma is invasive intothe submucosa, there is a 14% risk for metastasis.6-8

Small polyps can be removed totally via endoscope andtypically are embedded entirely in 1 or 2 cassettes for micro-scopic evaluation. Many colonic polyps can be removedendoscopically; however, polyps that are too large for endo-scopic polypectomy may require a segmental colon resec-tion. When polyps contain areas of necrosis, ulceration, orgross extension into the muscularis, sampling can be directedto these areas. However, polyps can become large yet retain abenign appearance. In some cases, no obvious areas of inva-sion may be present even if the polyp contains focally inva-sive carcinoma. Therefore, extensive sampling is required toexclude invasive cancer since this may alter prognosis andfuture therapy. While some pathologists follow the generalrule of submitting 1 section per centimeter of large polyps assuggested for other types of tumors, and many pathologiststotally embed all polyps, there is no well-established litera-ture to support these practice patterns.

The incidence of high-grade dysplasia and invasive carci-noma has been shown to increase with increasing polyp sizeand increasing percentage of villous component.4,9,10 The riskof invasive carcinoma is 18% in polyps larger than 1.5 cm,14

and it remains approximately 18% in polyps measuring up to2.5 cm.14 However, the risk of carcinoma has been reported ashigh as 42% in polyps greater than 2.5 cm.14 Because of thesefindings, and since smaller polyps are easily totally embeddedin a few cassettes, we chose polyps 2.5 cm or larger withoutgross evidence of invasion to help determine an approach forpathologists to the sampling of large polyps.

We found invasive carcinoma in 5 (12%) of 43 cases.No invasive cancer was detected in polyps smaller than 3 cm.In the 16 polyps that were 4 cm or larger, invasive carcinoma

was detected in 3 (19%). In a previous study of 65 polyps 4cm or larger, the incidence of invasive cancer was 85%.4 Alikely explanation for the much lower rate of invasive cancerin our series is that we specifically excluded polyps when thegross examination suggested the presence of invasive carci-noma. We found that adenomas with invasive carcinomawere significantly larger than adenomas without either inva-sive carcinoma or high-grade dysplasia. While villousadenomas more frequently had high-grade dysplasia and/orinvasive carcinoma present, there was no statistically signifi-cant association between villous architecture and the pres-ence of high-grade dysplasia or invasive carcinoma.

Since 12 (28%) of the benign-appearing polyps in ourstudy contained high-grade dysplasia, and 5 (12%) containedinvasive carcinoma, it is evident that gross examination aloneis not sufficient to predict the presence of high-gradedysplasia or invasive carcinoma. Increasing adenoma sizewas associated with invasive cancer and high-gradedysplasia. However, size alone could not predict the presenceof high-grade dysplasia.

The strongest predictor for the presence of invasivecarcinoma is high-grade dysplasia, and every effort shouldbe made to detect its presence. However, it is the invasivecarcinoma that has biologic significance. From our proba-bility studies, it is evident that 1 cassette per centimeter ofpolyp is insufficient to detect either high-grade dysplasia orinvasive carcinoma. The number of cases with an estimatedprobability of 95% or more of detecting high-grade dysplasiaor invasive carcinoma increases with the number of cassettessubmitted per centimeter. Theoretically, in some cases, 5cassettes per centimeter would be required to detect eitherhigh-grade dysplasia or invasive carcinoma with an esti-mated probability of 95% or more. In practice, however,most of the adenomas were totally embedded in fewer (3/cmon average) cassettes. Therefore, totally embedding large,benign-appearing adenomas is necessary to have the bestpossibility of detecting invasive carcinoma.

From the 1Department of Pathology and 2Center for Biostatistics,Ohio State University, Columbus.

Address reprint requests to Dr Frankel: Dept of Pathology,The Ohio State University, 416A Doan Hall, 410 W 10th St,Columbus, OH 43202.

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