Low-grade dysplasia in ulcerative colitis

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tumorigenesis. ~ In particular, the enuciation by Shamsuddin et al. 2 that histological and immunohistochemicai alterations in the human mucosa distal from tumors may be due to exposure to carcinogenic agents may anticipate the observation of chemically induced rodent aberrant crypt loci by Bird. 3 However, the heterogeneity of the alterations documented by Shamsuddin, as well as the heterogeneity of aberrant crypt foci, emphasize the theme of the editorial4; that to understand the relationships among these readily detectable abnormalities to progression of the disease as well as to the more subtle histological abnormalities, biochemical and molecular measurements must better define the nature of the lesions and subsets thereof. A start in this direction has been made by Pretlow et al. as well as others. 5-s It is also true, however, that Bird, 3 Roncucci et al., 9 and Pretlow et al. 1° referred to a distinct morphological entity in unsectioned mucosa; their operational definition is carefully reiterated in the second sentence of the editorial. 4 Whereas these structures may encompass some of the features previously noted in sectioned tissue, the recognition of these larger, more readily identifiable structures was a new contribution leading to, among other things, the ability to microdissect the tissue for further biochemical and molecular characterization. Indeed, Bird and Pretlow tt have discussed a similar issue and strongly argued that the term aberrant crypt foci be used only to refer to the lesions identified by the methodology described to avoid confusion in the literature. Thus, to the question posed by Shamsuddin, "is aberrant abnormal?," in this context, the answer is no; aberrant crypt focus is a descriptive noun that is not equivalent to the adjective "abnormal" used in describing the histology of crypts in the mucosa. LEONARD H. AUGENLICHT, Ph.D. Albert Einstein Cancer Center 111 East 2IOth Street Bronx, New York 10467 1. Shamsuddin AKM. Is aberrant abnormal? Gastroenterology 1995; 108:1609. 2. Shamsuddin AKM, Weiss L, Phelps PC, Trump BF. Colon epithelium. IV. Human colon carcinogenesis. Changes in human colon mucosa adjacent to and remote from carcinomas of the colon. J Nat Cancer Inst 1981;66:413-419. 3. Bird RP. Observation and quantification of aberrant crypts in the murine colon treated with a colon carcinogen: preliminary findings. Cancer Lett 1987;37:147-151. 4. Augenlicht L. Adhesion molecules, cellular differentiation, and colonic crypt architecture. Gastroenterology 1 9 9 4 ; 1 0 7 : 1 8 9 4 1898. 5. Pretlow TP, Brasitus TA, Fulton NC, Cheyer C, Kaplan EL. K-ras mutations in putative preneopiastic lesions in human colon. J Nat Cancer Inst 1993;85:2004-2007. 6. Shivapurkar N, Tang Z, Ferreira A, Nasim S, Garett C, Alabaster O. Sequential analysis of K-ras mutations in aberrant crypt foci and colonic tumors induced by azoxymethane in Fischer-344 rats on high-risk diet. Carcinogenesis 1994;15:775-778. 7. Jen J, Powell SM, Papadopoulos N, Smith KJ, Hamilton SR, Vogelstein B, Kinzler KW. Molecular determinants of dysplasia in colorectal lesions. Cancer Res 1994;54:5523-5526. 8. Smith AJ, Stern HS, Penner M, Hay K, Mitri A, Bapat BV, Gallinger S. Somatic APC and K-ras codon 12 mutations in aberrant crypt foci from human colons. Cancer Res 1994;54:5527-5530. 9. Roncucci L, Medline A, Bruce WR. Classification of aberrant crypt foci and microadenomas in human colon. Cancer Epidemiol Biomarkers Prev 1991;1:57-60. 10. Pretlow TP, Barrow BJ, Ashton WS, O'Riordan MA, Pretlow TG, Jurcisek JA, Stellato TA. Aberrant crypts: putative preneoplastic

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foci in human colonic mucosa. Cancer Res 1991;51:15641567. 11. Bird RP, Pretlow TP. Letter to the editor. Cancer Res 1992; 52:4291-4292.

Low-Grade Dysplasia in Ulcerative Colitis Dear Sir: In their editorial, Drs. Vemulapalli and Lance state "contrary to Axon's opinion, the inescapable conclusion is that low-grade dysplasia diagnosed by the St. Mark's pathologists indicated a high risk of malignant progression within a few years. ''1 The editorial by Vemulapalli and Lance was stimulated by the report by Connell et al. in the same issue of GASTROENTEROLOGY. 2 In it, the St. Mark's group revised their criteria for the diagnosis of low-grade dysplasia along the lines of the Inflammatory Bowel Disease Morphology Study Group report 3 and then reassessed their surveillance group retrospectively in the knowledge that this condition had previously been overdiagnosed. As a result, excluding dysplasia-associated masses or lesions, they accepted only 9 patients as having lowgrade dysplasia of the 51 previously diagnosed (Tables 4 and 6 in their report). The diagnosis of dysplasia is not straightforward; even experienced pathologists disagree substantially as to whether or not biopsy specimens show dysplastic change. 4'5 To be clinically useful, a histopathologic diagnosis must have biological significance and be reproducible. In drawing their conclusion that low-grade dysplasia denotes a high risk for progression to highgrade dysplasia and cancer, Vemulapalli and Lance seem to accept that pathologists can consistently recognize and agree on its diagnosis. The data presented in the St. Mark's study do not support this conclusion. Whereas the histological review by two highly experienced gastrointestinal pathologists yielded an overall agreement of 77%, the K coefficient is only 0.54 because there is a relatively high level of chance agreement on the diagnosis of "no dysplasia." More than two thirds of the allocations by both pathologists fall into the "negative for dysplasia" category, and agreement on this relatively straightforward diagnosis was reached in 199 of 301 biopsy specimens. However, inspection of the diagnoses given to the remaining 102 biopsy specimens shows wide and important discrepancies. Thus, of 47 biopsy specimens diagnosed as low-grade dysplasia by one or other pathologists, they agreed in less than half (20 of 47). Indeed, Connell et al. draw attention to these disagreements in the discussion. Only by examining the biopsy specimens together could the pathologists reach a consensus diagnosis, which was used in validating the predictive value of low-grade dysplasia. The inevitable conclusion from this study is that, working independently, even experienced pathologists cannot reproducibly diagnose low-grade dysplasia, and its predictive value is thereby compromised. The statement by Vemulapalli and Lance that % confirmed diagnosis of low grade dysplasia will increasingly be taken as an indication for early colectomy" begs the all-important question "who is to confirm the diagnosis?" Few if any centers can match the expertise of the St. Mark's pathologists, but it seems that even they have to debate a diagnosis of low-grade dysplasia through a double-headed microscope before it carried predictive value. Apart from the diagnostic problems of low-grade dysplasia, its clinical significance is far from clear. Approximately 30% of cancers in ulcerative colitis are unassociated with dysplasia in the rest of the colon6; conversely, most patients with dysplasia do not have cancer] -9 In a review of 11 large prospective colonoscopic studies, 9 73 cancers in all were discovered in 1656 patients (4.4%), whereas 26

May 1995

cancers were found in the subgroup of 303 patients (8.3%). If dysplasia-associated masses or lesions are excluded on the grounds that biopsy specimens in these cases may have been taken from a superficial part of the cancer itself, the percentage of cancers found in this latter group decreases to 6%. Thus, the incidence of cancer in the two groups is similar. There is no reason why pathologists should not change the criteria for the diagnosis of dysplasia. Indeed, the figures above suggest that a reappraisal is badly needed if the diagnosis is to have clinical relevance. Their message is, however, that they have overdiagnosed the condition by a factor of 5.7 in previous years. Neither is it unreasonable for them to review their biopsy specimens (previously reported) in light of their new standards. In doing so, however, their report is subject to the pitfalls of a retrospective study. In their prospective study 4 years ago ~° assessing much of the same data, they stated "the biopsy specimens have not been regarded for the purpose of this analysis because clinical decisions were governed by the pathological report at the time." This is the way most other studies have been reported to date. Until prospective studies using the revised criteria have been reported, the statement in your editorial will remain speculative. ANTHONY AXON MICHAEL DIXON

Centre for Digestive Diseases The General Infim~zaU at Leeds Great George Street Leeds LS1 3EX, England 1. Vemulapalli R, Lance P. Cancer surveillance in ulcerative colitis: more of the same or progress? Gastroenterology 1994;107: 1196-1199. 2. Connell WR, Lennard-Jones JE, Williams CB, Talbot IC, Price AB, Wilkinson KH. Factors affecting the outcome of endoscopic surveillance for cancer in ulcerative colitis. Gastroenterology 1994;107:934-944. 3. Riddeil RH, Goldman H, Ransohoff DF, Appelman HD, Fenoglio CM, Haggitt RC, Ahren C, Correa P, Hamilton SR, Morson BD, Sommers SC, Yardley JH. Dysplasia in inflammatory bowel disease: standardised classification with provisional clinical applications. Hum Pathol 1 9 8 3 ; 1 4 : 9 3 1 - 9 6 8 . 4. Dixon MF, Brown LJR, Gilmour HM, et al. Observer variation in the assessment of dysplasia in ulcerative colitis. Histopathology 1988; 1 3 : 3 8 5 - 3 9 7 . 5. Melville DM, Jass JR, Shepherd NA, Northover JMA, Capellaro D, Richman PI, Lennard-Jones JE, Ritchie JK, Andersen SN. Dysplasia and deoxyribonucleic acid aneuploidy in the assessment of precancerous changes in chronic ulcerative colitis. Observer variation and correlations. Gastroenterology 1 9 8 8 ; 9 5 : 6 6 8 - 6 7 5 . 6. Brostrom O, Lofberg R, Ost A, Reichard H. Cancer surveillance of patients with longstanding ulcerative colitis: a clinical, endoscopical and histological study. Gut 1986; 2 7 : 1 4 0 8 - 1 4 1 3 . 7. Lennard-Jones JE, Ritchie JK, Morson BC, Williams CB. Cancer surveillance in ulcerative colitis: experience over 15 years. Lancet 1983; 2 : 1 4 9 - 1 5 2 . 8. ManningAP, Butgim OR, Dixon MF, Axon ATR. Screening by colon-

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oscopy for colonic epithelial dysplasia in inflammatory bowel disease. Gut 1987; 2 8 : 1 4 8 9 - 1 4 9 4 . 9. Axon ATR. Cancer surveillance in ulcerative colitis--a time for reappraisal. Gut 1 9 9 4 ; 3 5 : 5 8 7 - 5 8 9 . 10. Lennard-Jones JE, Melville DM, Morson BC, Ritchie JK, Williams GB. Precancer and cancer in extensive ulcerative colitis: findings among 401 patients over 22 years. Gut 1990; 3 1 : 8 0 0 - 8 0 6 . Reply. W e are interested in the comments ofDrs. Axon and Dixon about the editorial that accompanied our report (Gastroenterology 1994; 107:934-944). In our report, we drew attention to the variability between experienced observers in the diagnosis of dysplasia. However, of the total of 301 biopsy specimens we examined, there was agreement on the absence of dysplasia in 199 and on the presence of dysplasia in 40. In their letter, the correspondents regard as "chance agreement" the diagnosis of no dysplasia in 199 biopsy specimens. They comment that the diagnosis of no dysplasia is "relatively straightforward." W e disagree; it is all too easy to describe epithelial atypia as dysplastic when the features are due to regeneration following inflammation and may lead to lack of specificity, which is one of our major concerns. In their statement that "most patients with dysplasia do not have cancer," they quote as evidence our data published in the same year as the consensus report (Hum Pathol 1983; 14:931-968) on the definition of dysplasia. Our findings at that time were subject to the tow threshold for diagnosis of dysplasia to which we now draw attention. They also quote their own report in which a finding of low-grade dysplasia was not found to be useful, presumably due to the fact that their own threshold for this diagnosis was also low. A low threshold for diagnosis of dysplasia leads to high sensitivity but low specificity. The higher threshold that we now use increases the specificity and thus the clinical significance of low-grade dysplasia. The difficulties in the definition of dysplasia suggest that if a pathologist has any doubt whether dysplasia is present or absent in a biopsy specimen, it is helpful to ask for the independent opinion of a colleague followed by discussion of the findings. In our experience, it is more common for dysplasia to be overdiagnosed than for pathologists not to recognize it. W e agree that prospective studies using current criteria for diagnosis of dysplasia are needed. In our opinion, dysplasia is still a useful clinical marker if its limitations are appreciated. Hopefully, the chromosomal and genetic markers of a neoplastic tendency that are now being assessed will complement and improve upon the purely histological technique generally available at present. JOHN E. LENNARD-JONES IAN C. TALBOT

St. Mark's Hospital City Road London EC1V 2PS, England ASHLEY B. PRICE

Department of Pathology Northwick Park Hospital Watford Road Harrow HA 1 3 UJ, England