Barrett esophagus and the "indefinite for dysplasia" category.
Article Type: Letter to the editor
Authors: Al-Abbadi, Mousa A.
Murthy, Ravindra
Youngberg, George A.
Pub Date: 12/01/2009
Publication: Name: Archives of Pathology & Laboratory Medicine Publisher: College of American Pathologists Audience: Academic; Professional Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2009 College of American Pathologists ISSN: 1543-2165
Issue: Date: Dec, 2009 Source Volume: 133 Source Issue: 12
Accession Number: 230246899
Full Text: To the Editor.--We read with interest the outstanding review article by Dr Odze (1) published in the Archives of Pathology & Laboratory Medicine in 2008 about Barrett esophagus. The article provided us, practicing pathologists, a much needed tool to use when we need guidance concerning questions that arise about Barrett esophagus. In the article, an evidence-based review was outlined regarding the diagnosis, classification, histologic differentiation, criteria of precursor lesion "dysplasia," and additional new adjunct markers for dysplasia and carcinoma. In the review, the precursor lesions were divided into 3 categories: (1) negative for dysplasia, (2) indefinite for dysplasia, and (3) positive for dysplasia. The dysplasia classification was thoroughly described histologically and in our practice we always try to use these 3 categories. However, and interestingly enough in the same year, Wang and Sampliner2 wrote an update on the practice guidelines dealing with Barrett esophagus diagnosis, surveillance, and therapy. The article represented the recommendations of the practice parameters committee of the American College of Gastroenterology, which was published in the American Journal of Gastroenterology.Actually,thearticle was sent to us by our staff gastroenterologist (R.M.) following frequent questions and discussions regarding the second category "indefinite for dysplasia" because the practice parameters article does not include or even mention the category of indefinite for dysplasia. We are writing this letter to Dr Odze and the gastrointestinal pathology community at large to address this specific issue. As far as the indefinite for dysplasia category, we always face the following questions from our gastroenterologists: "What should we do as far as follow up?" and "What should we tell the patient?" We suggest that communication with the American College of Gastroenterology be established trying to unify these definitions and clarify follow-up guidelines. A similar approach was successfully used by the American Society for Colposcopy and Cervical Pathology in establishing clear guidelines for management of cervical lesions.

Mousa A. Al-Abbadi, MD

Department of Pathology and Laboratory Medicine

Ravindra Murthy, MD

Department of Internal Medicine

James H. Quillen VA Medical Center

Mountain Home, TN 37684

George A. Youngberg, MD

Department of Pathology

James H. Quillen College of Medicine

Johnson City, TN 37684

(1.) Odze RD. Update on the diagnosis and treatment of Barrett esophagus and related neoplastic precursor lesions. Arch Pathol Lab Med. 2008; 132(10):1577-1585.

(2.) Wang KK, Sampliner RE. The Practice Parameters Committee of the American College of Gastroenterology. Am J Gastroenterol. 2008; 103(3):788-797. ********

In Reply.--I thank Drs Al-Abbadi, Murthy, and Youngberg for their interest and kind comments regarding my recently published review article titled "Update on the Diagnosis and Treatment of Barrett Esophagus and Related Neoplastic Precursor Lesions." (1) Drs Al-Abbadi, Murthy, and Youngberg raise an important, and often neglected, issue in dysplasia pathology related not only to Barrett esophagus (BE) but to other chronic inflammatory disorders of the gastrointestinal tract tract (GI) as well, such as inflammatory bowel disease: the fact that some "atypical" cases simply defy accurate classification as either negative or positive for dysplasia, and, thus, are termed "indefinite." Wang and Sampliner, (2) in the updated 2008 guidelines for the diagnosis, surveillance, and therapy of BE, did not include specific guidelines for the management of patients with a biopsy considered indefinite for dysplasia. I also believe that this is a glaring omission; one that incorrectly assumes that pathologists are always capable of distinguishing negative from positive cases, which, of course, we know is simply not true. Oddly enough, many gastroenterologists either believe that pathologists are only rarely incapable of making a definitive diagnosis or feel that the indefinite category should be lumped together with biopsies that are considered negative for dysplasia. In my opinion, both of these assumptions are incorrect and are often related to a generalized lack of awareness among gastroenterologists regarding the difficulties in diagnosing dysplasia in the GI tract. As pathologists, we are keenly aware of cases that defy accurate interpretation despite a careful and meticulous evaluation of the specimen. Regarding natural history, no study has evaluated, specifically, the natural history or outcome of indefinite cases, but several have provided such data within the context of a larger dysplasia study. For instance, Montgomery et al (3) showed that 4 of 22 cases (18%), considered indefinite for dysplasia by most of 12 GI pathologists, developed cancer within a median follow-up period of 96 months. This was similar to the value (15%) of low-grade dysplasia cases in that study.

As indicated in the original 1983 article on dysplasia in inflammatory bowel disease, which was then adopted to the BE classification in 1988, it is well known that some cases show atypical cytologic changes considered too severe to be termed negative but fall short of the criteria for true dysplasia. In my experience, there are 3 main reasons for being indefinite about a particular atypical focus. The first, and most common, is when the atypical focus is situated in an area of mucosa with active inflammation and/or ulceration. In this setting, and particularly adjacent to the neosquamocolumnar junction, reactive epithelial changes may mimic some of the features of low-grade dysplasia, by showing an increase in nuclear size, hyperchromaticity, stratification, increased mitoses, mucin depletion, and, in some instances, slight loss of cell polarity. Although some adjunctive techniques, such as application of a-methylacyl coenzyme A racemase immunohistochemistry, (4) may be useful to help distinguish regeneration from dysplasia in this setting, ultimately, we rely heavily on the histologic features in biopsy specimens. Second, and less commonly, biopsies may be difficult to interpret due to technical reasons, such as tangential sectioning, inappropriately thick tissue sections, poor orientation of the specimen, scant tissue, artifactual disassociation of the surface epithelium from the lamina propria, or even marked cautery artifact, which is especially common in endoscopic mucosal resection specimens. Third, some cases may show deep crypt cytologic changes of dysplasia but show surface maturation, which is usually considered a histologic feature of regeneration. However, recent data have shown that dysplasia begins in the crypt bases and progresses to the surface with time, so many of these indefinite cases in fact represent early "crypt dysplasia." (5,6) Of course, interpretation of dysplasia is also highly dependent on the experience of the pathologist and his or her level of awareness of the wide spectrum of histologic changes that can occur in patients with BE.

My feeling is that it is our job to educate our gastroenterology colleagues, and to press the importance of close cooperation, particularly when dealing with biopsies that are difficult to interpret or show intermediate features between regeneration and dysplasia. Most importantly, many clinicians are unaware of the proper course of management when faced with a patient with a biopsy that is indefinite for dysplasia and how a discussion with a pathologist can help guide them down the right path. For instance, when biopsies are considered indefinite due to the confounding effects of inflammation, the most sensible form of treatment would be to increase the antiinflammatory regimen and rebiopsy the suspicious area (typically in 3-6 months) after the inflammation subsides. However, if biopsies are difficult to interpret due to technical reasons, and if after measures are taken by the pathologist to correct the problem the biopsy is still difficult to interpret, then the most appropriate course of action would be to rebiopsy immediately, rather than wait 3 to 6 months.

Interpretation of dysplasia is not an exact science, and lack of appreciation of this concept by our clinical colleagues may, in some circumstances, lead to inappropriate treatment. Thus, close cooperation between pathologists and clinicians is essential when dealing with dysplasia in the GI tract and particularly when the pathologic changes are difficult to interpret.

Robert D. Odze, MD, FRCPC

Department of Pathology

Brigham and Women's Hospital

Boston, MA 02115

(1.) Odze RD. Update on the diagnosis and treatment of Barrett esophagus and related neoplastic precursor lesions. Arch Pathol Lab Med. 2008; 132(10):1577-1585.

(2.) Wang KK, Sampliner RE. Updated guidelines 2008 for the diagnosis, surveillance, and therapy of Barrett's esophagus. Am J Gastroenterol. 2008; 103(3):788-797.

(3.) Montgomery E, Goldblum JR, Greenson JK, et al. Dysplasia as a predictive marker for invasive carcinoma in Barrett esophagus: a follow-up study based on 138 cases from a diagnostic variability study. Hum Pathol. 2001;32(4):379-388.

(4.) Dorer R, Odze RD. AMACR immunostaining is useful in detecting dysplastic epithelium in Barrett's esophagus, ulcerative colitis and Crohn's disease. Am J Surg Pathol. 2006;30(7):871-877.

(5.) Lomo LC, Blount PL, Sanchez CA, et al. Crypt dysplasia with surface maturation: a clinical, pathologic and molecular study of a Barrett's esophagus cohort. Am J Surg Pathol. 2006;30(4):423-435.

(6.) Zhang X, Huang Q, Goyal R, Odze RD. DNA ploidy abnormalities in basal and superficial regions of the crypts in Barrett's esophagus and associated neoplastic lesions. Am J Surg Pathol. 2008;32(9): 1327-1335.
Gale Copyright: Copyright 2009 Gale, Cengage Learning. All rights reserved.