Meta-analysis: cancer risk of low-grade dysplasia in chronic ulcerative colitis

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1 Alimentary Pharmacology & Therapeutics Meta-analysis: cancer risk of low-grade dysplasia in chronic ulcerative colitis T. THOMAS*, K. A. ABRAMS, R.J.ROBINSON*&J.F.MAYBERRY* *Department of Gastroenterology, Digestive Diseases Centre, Leicester General Hospital, Gwendolen Road, Leicester, LE4 5PW; Centre for Biostatistics and Genetic Epidemiology, Department of Health Sciences, University of Leicester, 22-28, Princess Road West, Leicester, LE1 6TP, UK Correspondence to: Dr R. Robinson, Digestive Diseases Centre, Leicester General Hospital, Gwendolen Road, Leicester, LE4 5PW. Publication data Submitted 03 August 2006 First decision 31 August 2006 Resubmitted 13 October 2006 Resubmitted 27 November 2006 Resubmitted 15 December 2006 Resubmitted 18 December 2006 Accepted 20 December 2006 SUMMARY Background The cancer risk of low-grade dysplasia (LGD) in chronic ulcerative colitis is variable and its management remain contentious. Aim To determine the risk of cancer or any advanced lesion once LGD is diagnosed. Methods A MEDLINE, EMBASE and Pub Med search was conducted using the key words surveillance, colorectal cancer, low-grade dysplasia and ulcerative colitis. A random effects model of meta-analysis was used. Results Twenty surveillance studies had 508 flat LGD or LGD with dysplasiaassociated lesion or mass. An average of 4.3 colonoscopies was performed patient post-lgd diagnosis (range: 3 7.6). An average of 18 biopsies taken per colonoscopy (range: 9 24) detected 73 advanced lesions (cancer or high-grade dysplasia) pre-operatively. The cancer incidence was 14 of 1000 (95% CI: ) person years duration (pyd) and the incidence of any advanced lesion was 30 of 1000 pyd (95% CI: 12 76). When LGD is detected on surveillance there is a ninefold risk of developing cancer (OR: 9.0, 95% CI: ) and 12-fold risk of developing any advanced lesion (OR: 11.9, 95% CI: ). Conclusions The risk of developing cancer in patients with LGD is high. These estimates are valuable for decision-making when LGD is encountered on surveillance. Aliment Pharmacol Ther 25, ª 2007 The Authors 657 doi: /j x

2 658 T. THOMAS et al. INTRODUCTION Ulcerative colitis (UC) is a chronic relapsing inflammatory bowel disease of uncertain etiology. Although prevalent world wide it predominantly affects North Americans and Europeans. 1 Chronic colitis predisposes to colorectal cancer and the risk increases with time. 2 Progression from inflammation to colorectal cancer is supposed to follow a sequence from colitis without dysplasia, low-grade dysplasia (LGD), high-grade dysplasia and eventually carcinoma. 3 However, recent reports have suggested that LGD can progress to colorectal cancer without the intermediate stage of highgrade dysplasia. 4 Therefore, LGD can be considered as the definitive interventional point where prophylactic colectomy for colorectal cancer in chronic UC can be instituted. The optimum management of LGD in patients with UC remains contentious. Some advocate intensive colonoscopic surveillance while others recommend early colectomy. Patients with sporadic adenomas or adenoma like mass (ALM: raised or polypoidal dysplasia without surrounding flat dysplasia) can be successfully treated with endoscopic polypectomy or endomucosal resection. Surveys have shown that adoption of any particular approach may be influenced by a physician s individual perception and lacunae in our current knowledge of the disease. 5, 6 This conundrum is due to many factors: variable and uncertain natural history of the disease, difficulty in histological interpretation during the active phase of colitis and wide inter-observer variability in the histological diagnosis of dysplasia even among expert pathologists. 7, 8 Data on the natural history of the disease are largely based on prospective and retrospective cohort studies. The variable results in cancer incidence rates reflect the heterogeneity between studies in terms of different patient populations, extent of colitis, number of surveillance biopsies taken and duration of surveillance. Based on these studies some centres have adopted a conservative approach 9 where as others advocate colectomy. 10 Guidelines published by the British and American Societies of Gastroenterology address these problems to a certain extent. 11, 12 A randomised prospective multicentre study comparing continuing surveillance vs. colectomy at LGD diagnosis with colorectal cancer related deaths, quality of life and death from all causes, as primary outcome measures would be ideal to resolve this debate. Lennard-Jones et al. points out the overwhelming problems associated with such a study in terms of ethical and practical difficulties. 13 An acceptable compromise would be a meta-analysis of all surveillance studies to analyse the incidence and the relative risk of LGD progressing to an advanced lesion, i.e. high-grade dysplasia or colorectal cancer. AIMS AND METHODS The aim of this meta-analysis was to determine the incidence of cancer and the relative risk of developing cancer in patients with LGD in chronic UC undergoing surveillance. We also aimed to determine the incidence of LGD in chronic ulcerative colitis and the positive predictive value of LGD for concurrent cancer and progression to cancer. The guidelines produced by the NHS Centre for Reviews and dissemination York University were followed for the meta-analysis. 14 Identification of studies MEDLINE (1966 to July 2005), EMBASE (1986 to July 2005) and a PubMed were searched using the keywords ulcerative colitis, dysplasia, colorectal cancer, and surveillance. In addition, the references lists of the original articles and relevant review articles were scrutinized to identify studies missed on the initial search. The studies to be included in the analysis were reviewed un-blinded by two authors (TT and RJR). Studies were included based on a predefined inclusion criterion. The following data were recorded on a proforma (Appendix A): type and year of study, number of patients with ulcerative colitis, number of patients with low-grade dysplasia and dysplasia-associated lesion or mass (DALM), duration of study, duration of follow-up in patient years, number of colonoscopies per patient, mean number of surveillance biopsies per colonoscopy, number of patients progressing to an advanced lesion, i.e. colorectal cancer (CRC) or highgrade dysplasia or DALM, cancer stage, number of deaths as a result of CRC and time taken to progress form LGD to CRC. In studies published prior to 1983 (classification of dysplasia was changed in 1983) 15 where dysplasia was classified as mild, moderate and severe, only cases with mild dysplasia were considered as low-grade and included in the analysis. Studies where more than one pathologist reviewed histology, we included the reviewed results in the analysis.

3 META-ANALYSIS: CANCER RISK OF LGD IN CHRONIC UC 659 Inclusion criteria Studies in the English language where the study population (histologically proven UC and LGD), interventions (surveillance colonoscopy or colectomy) and outcomes (CRC, high-grade dysplasia or DALM at colectomy and or surveillance) were clearly defined and documented were included in the analysis. Exclusion criteria The following types of studies were excluded from the analysis: (i) Studies with data only on colorectal cancer in colitis. (ii) Studies involving only high-grade dysplasia. (iii) Studies which included predominantly indeterminate and Crohn s colitis in a combined analysis. (iv) Studies using magnifying chromendoscopy for detecting dysplasia. (v) Studies with inadequate follow-up data (outcome data in the subgroup of patients with LGD in terms of progression to DALM, high-grade dysplasia or cancer was not documented in the studies). Data extraction One author (TT) read each paper and extracted data using a predefined review form (Appendix A). Definitions (i) Prevalent cancer or LGD: Cancer or LGD found within 6 months of initiating surveillance either on colonoscopy or colectomy. (ii) Incident cancer or LGD: Cancer or LGD found at colectomy or colonoscopy after 6 months of initiating surveillance. LGD found at colectomy in patients with no dysplasia or indefinite for dysplasia was also considered incident LGD. (iii) Advanced lesions: Flat LGD was considered to progress to an advanced lesion if high-grade dysplasia, CRC or DALM was detected on surveillance. LGD in the presence of DALM was considered to progress to an advance lesion if HGD or CRC was detected on surveillance. Statistical analysis All statistical analyses were done using STATA (Statacorp, Texas, Version 9.0, 1997) meta-analysis 16, 17 programmes. The heterogeneity between studies was calculated using the Chi-square test for homogeneity (Q-value) and a value of < 0.05 was considered statistically significant. 18 As there were significant heterogeneity between the studies a random model of meta-analysis was used as described by DeSimion and Laird. 19 Overall the pooled estimate, with the 95% confidence intervals of the incidence of cancer, any advanced lesion and LGD was obtained using the random effects model of meta-analysis and the logs odds or log incidence scales were used as appropriate. Changes in log incidence over time were calculated using the mixed effects meta-regression technique. 20 The size of the circles in are inversely proportional to the variance associated with the log incidence rates in each study (the larger the circle the smaller the study) and the regression line was estimated using the mixed effect meta-regression techniques. Follow-up in patient years duration (pyd) was extracted from the articles. When the follow-up in pyd was not specifically documented it was calculated using the mean median follow-up duration and the total number of patients with LGD. Begg s test 21 and Egger s test 22 was used to determine publication bias. RESULTS From an explosion of abstracts, 776 relevant abstracts were reviewed. Of the 776 abstracts 52 articles were scrutinized in depth. Thirty-two studies did not full fill 3, 4, the predefined exclusion criteria. Hence 20 studies 8 10, were included in the final analysis (Table 1). Overall analysis The study analysed 508 patients with LGD (477 patients with flgd and 31 patients with LGD in the presence of DALM) in more than 2677 patients with chronic ulcerative colitis (the total number of patients with UC was not specified in 3 studies 4, 10, 25 ) who were enrolled into a colorectal cancer surveillance programme (average duration of colitis prior to entry into the study was 12 years). Overall an average of 3.6 colonoscopies were done per patient (range: ) in 17 studies 3, 8, 9, 23, 24, over a mean surveillance period of 12 years (9713 colonoscopies for 2677 patients) and an average of 18 biopsies (range: 9 24) were taken per colonoscopy. The average age of patients with LGD from 11 studies 3, 4, 8 10, 24, 25, 27, 29, 30, 35 was 42 years (range,

4 660 T. THOMAS et al. Author Year flgd + DALM (n) Follow-up in pyd for LGD AL on Col or Sur Befritis Biasco No data 4 0 Blackstone No data 0 4 Brostrom No data 2 0 Connell No data 8 0 Hata No data 0 0 Jonsson No data 4 0 Lashner No data 6 0 Leidenius No data 0 0 Lennard J* Lim Lindberg No data 0 13 Lofberg No data 3 0 Lynch Nugent No data 4 2 Rosenstock No data 0 1 Rozen Ullman T** Ullman T Woolrich No data 5 1 AL on Col at initial diagnosis or for NPLGD Table 1. Table showing the various studies with outcome data on patients with LGD detected on surveillance for chronic ulcerative colitis pyd, patient years duration; AL, advanced lesions; LGD, low-grade dysplasia; DALM, dysplasia-associated lesion or mass; NPLGD, nonprogressive flat LGD or DALM; Col, colectomy; Sur, surveillance colonoscopy. * Follow-up in pyd in 38 patients. ** Two patients had colectomy for refractory disease ). The average duration of colitis at the diagnosis of LGD from 16 studies 3, 4, 8 10, 23 30, 32, 35, 36 was 17 years (range: 11 23). PostLGD diagnosis an average of 4.3 colonoscopies 4, 8 10, 25 (range: 3 7.6) were performed patient from 8 27, 30 studies (1225 colonoscopies in 288 patients) to detect seventy-three advanced lesions preoperatively during surveillance (HGD: 47, colorectal cancers: 18, DALM: 8). Thirteen of the 47 patients with pre-operative high-grade dysplasia had cancer on operative histology, three had low-grade dysplasia, three had no dysplasia, data were not available on three patients and the remaining 25 had persistent high- grade dysplasia. Overall 31 CRCs (Appendix B) were detected of which 55% were early cancers (Dukes A or B). In 98 cases, colectomy was performed within 6 months of initial diagnosis or for nonprogressive LGD. In 25 of 98 (25.5%) of cases colorectal cancer was detected on operative histology (concurrent CRC) and in addition 11 of 98 (11%) had concurrent high-grade dysplasia. Thus, overall 36 of 98 (37%) of patients with LGD on surveillance had a co-existing advanced lesion. INCIDENCE OF COLORECTAL CANCER AND ADVANCED LESIONS IN LGD Seven of the 20 studies 4, 8 10, 25, 27, 30 reported the duration of follow-up (mean duration or follow-up in patient years) postlgd (including DALM) diagnosis (involving more than 1000 patients with ulcerative colitis undergoing surveillance and 239 patients with LGD followed up for pyd). Figure 1 shows the Forrest plot of the cancer incidence rates from these studies. The overall cancer incidence rate from was 14 of 1000 pyd (95% CI: five of 1000 to 34 of 1000) and the overall incidence rate of any advanced lesion (HGD, CRC or DALM) was 30 of 1000 pyd (95% CI: 12 of of 1000) (Figure 2). Two 8, 27 of the seven studies included are from the same centre and 29 patients have been double reported. However, excluding the earlier study 27 from this centre does not significantly alter the incidence rate for cancer (cancer incidence rate 16 of 1000 pyd, 95% CI: six of 1000 to 42 of 1000). A mixed effect meta-analysis regression showed that only the number of biopsies taken per colonoscopy

5 META-ANALYSIS: CANCER RISK OF LGD IN CHRONIC UC 661 Lennard J, 1990 Lynch, 1994 Rozen, 1995 Ulman T, 2002 Figure 1. Forrest plot showing the incidence of colorectal cancer in patients with lowgrade dysplasia undergoing surveillance. The numbers , 0.002, 0.02, and 0.2 on the x-axis denotes 0.2 of 1000, 2 of 1000, 20 of 1000 and 200 of 1000, respectively. Befritis, 2002 Lim, 2003 Ulman T, 2003 Combined Cancer Incidence/1000 patient years duration of follow up Lennard J, 1990 Lynch, 1994 Rozen, 1995 Figure 2. Forrest plot showing the incidence of any advance lesion (colorectal cancer, highgrade dysplasia or dysplasiaassociated lesion or mass) in patients with LGD undergoing surveillance. (0.0006, 0.006, 0.06 on the x-axis denotes 0.6 of 1000, 6 of 1000 and 60 of 1000, respectively). Ulman T, 2002 Befritis, 2002 Lim, 2003 Ulman T, 2003 Combined Incidence of Advanced Lesions/1000 patient years duration of follow up had a statistically significant influence on the incidence rates of advanced lesions (P = 0.002) whereas the duration of colitis prior to the diagnosis of LGD (P = 0.27), number of pathologists reviewing histology (P = 0.72) and the number of surveillance colonoscopies done per patient (P = 0.54) did not have a statistically significant influence on the cancer incidence rates. When the overall risk from studies was plotted against the midpoint of each study (Figures 5 and 6) there was a significantly increased trend in the incidence rates of cancer (P = 0.002) and advanced lesions from 1987 to the present date (P = 0.05). Cancer incidence and the incidence of advanced lesions increased by 13% and 11% per year of study, respectively. Using overall incidence rates, Begg s test was used to determine if the results could be explained by publication bias. Overall publication bias was present (paucity of small studies showing low cancer incidence causing a gap in the base of the graph upper right hand corner in Figure 7) but not statistically significant (Begg s test p = 0.24) RISK OF DEVELOPING CRC HIGH-GRADE DYSPLASIA IN LGD The relative risk of colorectal cancer in patients with LGD compared to patients with no dysplasia on surveillance was determined from 7 8, 9, 26, 29, 33, 36, 37 of the 20 studies (Figure 3). There was a ninefold higher risk of developing CRC once LGD is diagnosed compared with patients having no dysplasia (OR: 9.0, 95% CI: ). Data from eight 8, 9, 26, 29, 32, 33, 36, 37 of

6 662 T. THOMAS et al. Lashner, 1989 Nugent, 1991 Woolrich, 1992 Biasco, 1994 Connel, 1994 Rozen, 1995 Lim, 2003 Combined Odds ratio Figure 3. Forrest plot showing the odds ratio for cancer in patients with low-grade dysplasia in chronic ulcerative colitis undergoing surveillance. Brostrom, 1986 Lashner, 1989 Nugent, 1991 Woolrich, 1992 Biasco, 1994 Connel, 1994 Rozen, 1995 Lim, 2003 Combined Odds ratio Figure 4. Forrest plot showing odds ratio of any advanced lesion in patients with lowgrade dysplasia in chronic ulcerative colitis undergoing surveillance. the 20 studies were used to estimate the relative risk of developing an advanced lesion in patients with LGD (Figure 4). There was a 12-fold higher risk of developing an advanced lesion (HGD or CRC) once LGD is diagnosed compared to no dysplasia (OR: 11.9, 95% CI: ). In terms of absolute risk reduction this equates to 12% and 15% for CRC and advanced lesions respectively. Therefore, the number needed to colonoscope (NNC) was 8 (95% CI 5 25) to detect one CRC and 6 (95% CI: ) to detect one advanced lesion over an average duration of 5.2 years. Metaregression analysis showed that the duration of colitis prior to the first diagnosis of LGD during surveillance had no significant influence on the cancer risk (p = 0.57). INCIDENCE AND PREVALENCE OF LGD IN CHRONIC UC The overall prevalence of both flat low-grade dysplasia (flgd) and LGD in the presence of DALM from 13 3, 9, 23 26, 29, 30, 32, 33, studies was 9.4% (95% CI: ). The overall incidence of LGD (including DALM s) was 21 of 1000 pyd (95% CI: 15 of 1000 to 30 of 1000) from 16 studies. 3, 8, 9, 23, 24, 26 30, Of the 16 studies, four were from the UK, 5 from the USA and 6 from other European Union countries and 1 from Israel. The overall incidence rates for LGD in the UK was 15 of 1000 pyd (95% CI: eight of 1000 to 32 of 1000), in USA, 43 of 1000 pyd (95% CI: 27 of 1000 to 67 of 1000) and in other European Union

7 META-ANALYSIS: CANCER RISK OF LGD IN CHRONIC UC Cancer P = Figure 5. Meta-regression plot showing the trend of cancer incidence rates and the incidence rates of advanced lesions with time. The cancer incidence rate is plotted on the log scale against the study mid points on the x-axis. Incidence (log scale) Study mid-point 1.5 Advanced Lesions P = 0.05 Figure 6. Meta-regression plot showing the trend of cancer incidence rates and the incidence rates of advanced lesions with time. The cancer incidence rate is plotted on the log scale against the study mid points on the x-axis. (log scale) Incidence Study mid-point Begg's funnel plot with pseudo 95% confidence limits -2 P = 0.24 Loginlgd -4 Figure 7. Funnel plot showing no significant publication bias in surveillance studies in patients with LGD in chronic UC SE of: loginlgd countries 15 of 1000 pyd (95% CI 10 of 1000 to 21 of 1000). Mixed effects meta-regression techniques was used to check if the number of biopsies taken per colonoscopy or the number of colonoscopies done per patient during surveillance had a significant influence on the geographical variation in incidence rates. The number of colonoscopies (P = 0.57), number of biopsies done per colonoscopy (P = 0.09) had no significant influence on the incidence rates of LGD.

8 664 T. THOMAS et al. Concurrent CRC only (%) Concurrent HGDCRC (%) Progression to CRC only (%) Overall Only flgd* LGD+DALM Progression to any advanced lesion (%) * The positive predictive value for flgd for progression to only CRC cannot be accurately determined. Table 2. Table showing the positive predictive value of LGD (flgd and LGD in the presence of DALM) for concurrent cancer at colectomy and progression to cancer and advanced lesions preoperatively LGD AS A PREDICTOR OF ADVANCED LESIONS The positive predictive value (PPV) of LGD and LGD in the presence of DALM for concurrent advanced lesions and progression to advanced lesions cancer from 21 studies are given in Table 2. Overall the positive predictive value for LGD including DALM (number of cases of advanced lesions on colectomy at initial diagnosis or for nonprogressive lesions total number of cases who had colectomy at initial diagnosis or nonprogressive lesions) for concurrent advanced lesions was 37% (36 of 98) and the overall PPV for LGD for progression to an advanced lesion preoperatively was 18% (73 of 410). When only cancers are considered the overall PPV for concurrent cancer was 25.5% (25 of 98) and PPV for progression to cancer was 7.6% (31 of 410). When only flgd are considered 18 of the 81 patients whom had colectomy either at initial diagnosis or for nonprogressive LGD had cancer at colectomy giving a PPV for flgd of 22%. In 58 of the remaining 396 cases of flgd progressed to an advanced lesion (CRC, HGD, or DALM) giving a PPV of 14.6% for LGD for progression to an advanced lesion. With respect to LGD in the presence of DALM, 7 of the 17 patients in 15 studies had an advanced lesion on colectomy either at initial diagnosis or for nonprogrerssive disease giving a PPV of 41% for LGD in the presence of DALM for concurrent advanced lesions and 9 of the remaining 14 patients progressed CRC or HGD giving a 64% PPV for LGD in the presence of DALM for progression to an advanced lesion. DISCUSSION This is the first meta-analysis of cancer incidence rates when LGD is found on surveillance. This also the first comprehensive systematic review in the last 10 years since Bernstein et al. reported the cancer rate in any dysplasia from 10 surveillance studies in patients with chronic UC. 38 This relatively small meta-analysis, in the absence of large randomised multi-centre trials provides useful estimates of cancer risk and the risk of any advanced lesion in patients diagnosed with LGD on surveillance. The pooled estimates take into account the study heterogeneity as they are based on the random effects model. The methods used have made assumptions, and must be interpreted with caution. We accept the pitfalls of such an analysis. The incidence rate of any advanced lesion was estimated at 30 of 1000 pyd and that of cancer at 14 of 1000 pyd from seven studies. Compared with Eaden et al. meta-analysis 2 there is a fourfold increase in the cancer incidence rate and a 10-fold rise in the incidence rate of any advanced lesion once LGD is diagnosed on surveillance. The estimated cancer risk may be an underestimate for the following reasons: Firstly, the number of surveillance biopsies postlgd diagnosis is an important (especially for flat depressed lesions) determinant of the cancer incidence rates. Rubin et al. has estimated that 33 surveillance biopsies are required to detect dysplasia with 90% confidence. 39 However, questionnaire surveys in UK have shown that surveillance practice is not uniform and only a few gastroenterologists performing more than 20 biopsies during surveillance. 40 Therefore, sampling bias has a significant influence on the cancer incidence rates as confirmed later in our metaregression analysis. Secondly, the operator s ability to detect dysplasia is another important variable. The drawbacks of conventional surveillance compared with surveillance following dye spraying and magnification has been recently reported. Rutter et al. has shown that targeted biopsies following dye spraying significantly increases the chances of detecting dysplasia when compared to conventional surveillance. In the same study dysplasia was not detected in 2900

9 META-ANALYSIS: CANCER RISK OF LGD IN CHRONIC UC 665 non-targeted biopsies. 41 High magnification colonoscopy in addition to dye spraying has a high predictive value in detecting both non-neoplastic and neoplastic lesions. 42 Chromendoscopy detects new neoplasia missed on conventional colonoscopy in 10% of patients and has a higher chance of detecting intraepithelial neoplasia in flat lesions compared with conventional colonoscopy. 43 These studies further highlight the possibility of missing LGD because of sampling bias. Thirdly, only 145 of 482 (30%) patients in our analysis (excluding 26 of 508 patients who had colectomy at initial diagnosis) had colectomy either for progression to an advanced lesion or for nonprogressive LGD. Considering the possibility of sampling bias and the drawbacks of nontargeted surveillance the number of concurrent cancers in noncolectomised patients remain uncertain. Finally, the presence of ongoing inflammation and the degree of inflammation significantly correlates with the development of dysplasia and cancer. 44 The risk of CRC in UC is reduced by 80% in patients on longterm 5-aminosalycilates. 2 The impact of 5-aminosalycilates on the incidence rate of any advanced lesion could not be determined in this analysis because medication status in the subgroup of patients with LGD was not clearly documented in the selected studies. We have also shown that once LGD is diagnosed during surveillance there is a ninefold increase in the risk of developing cancer and a 12-fold increase in risk from any advanced lesion compared to patients with no dysplasia. Lynch et al. has pointed out that 75% of patients will have some form of dysplasia if surveyed long enough. 27. With these figures in mind colectomy for patients with flat LGD seems a reasonable practice as in some Scandinavian centres. 45 In contrast to the above argument Tine et al. in a recent retrospective study found that six of eight patients (75%) with flat LGD did not progress to an advanced lesion after a median surveillance period of 17.8 years. 46 One can argue that 6 monthly intensive surveillance is the least one should offer these patients and colectomy considered for persistent nonprogressive LGD although there is no clear consensus regarding this strategy. Patients with chronic colitis found to have DALMs on surveillance should be offered a colectomy. However, it is also important to determine whether polypoidal or raised dysplastic lesions found on surveillance are sporadic adenomas or associated with colitis (DALM or ALM) since sporadic adenomas found outside an area of inflammation could safely be removed by polypectomy. A similar approach has been considered for ALM or even for genuine DALMs. 25, 47 We have also shown a significant increased trend in incidence of cancer with time. Our meta-regression showed the number of surveillance biopsies had a significant influence on the incidence of any advanced lesions (P = 0.002) and highlights the importance of adhering to an intensive surveillance protocol. As the inter-observer variation between pathologists for LGD is high one would expect this to influence the overall incidence rates of cancer in LGD as in the St Marks study. 33 The problem with accurate histological interpretation of LGD is to differentiate it from regenerative epithelium in the presence of underlying inflammation. 48 Repeat sampling after high doses 5-ASAs can potentially circumvent this problem to certain extent in the same way as high dose proton pump inhibitors in patients with LGD in Barrett s epithelium. Although our meta-regression analysis showed no significant influence of this variable on the overall incidence rates of either cancer or an advanced lesion this should be interpreted with extreme caution as only 2 8, 29 of the seven studies included in the analysis had more than one pathologist reviewing histology. The true influence of histological interpretation can only be assessed if the cancer incidence rate in studies where two or more pathologist s interpreted histology is compared to studies where only one pathologist was involved in histological interpretation of LGD. The numbers in this meta-analysis are small for any useful comparison. This is the first study to estimate the number needed to colonoscope (NNC) to detect an advanced lesion or cancer (any stage) once LGD (flat or DALM) is detected on surveillance. This was estimated to be 6 and 8, respectively over a mean duration of 5.2 years. The NNC for LGD with DALM s could not be calculated separately because of the paucity of data. We suspect this to be lower for DALM than the above estimate. These estimates are valuable in calculating the cost effectiveness and the cost benefit of cancer surveillance when LGD is detected. To date similar data are not available for useful comparison of invasive cancer surveillance programmes in Barrett s oesophagus or nondysplastic chronic ulcerative colitis. This will contribute to a difficult but informed management strategy when LGD is found on surveillance.

10 666 T. THOMAS et al. We attempted to determine the incidence of LGD in chronic ulcerative colitis. The incidence data is possibly contaminated by the prevalence data and therefore should be interpreted with caution. Where possible prevalent LGD has been excluded when incident figures are calculated. We have shown that there is a geographical variation in the incidence of LGD with an incidence of 12 of 1000 pyd in Europe, of 28 of 1000 pyd in the US and 15 of 1000 pyd in UK. This geographical variation may represent a true population difference with genetic, environmental and dietary factors playing a role. This is difficult to prove without comparative trials between continents and to date there is no evidence to suggest this. The relatively low incidence of LGD in Europe may be a reflection of more aggressive medical therapy or a policy of early colectomies in some Scandinavian countries. 45 An alternative explanation for the high incidence in USA may be the more intensive surveillance protocols in some American centres. American surveillance studies on an average do more biopsies per colonoscopy than either European or British studies. However, our metaregression analysis showed that influence of biopsies per colonoscopy on LGD incidence rates were not significant. We acknowledge that there is selection bias in our inclusion criteria in that non-english language publications have been excluded. It is also possible that some relevant studies may have eluded our search. The other obvious drawback is that unpublished data has not been included in our analysis. It is possible that many of the unpublished data are small studies showing low incidence of cancer rates. The overall positive predictive value of LGD for concurrent cancer was 25.5% and for progression to CRC was 7.6%. This compares to Bernstein et al. results of 19% and 8%, respectively. 39 However, the predictive value of DALM for any concurrent advanced lesion and progression to any advanced lesion was 41% and 64%, respectively. These figures are in keeping with other studies. 29, 39 Low-grade dysplasia in the presence of DALM constitutes a high risk of CRC and is an indication for colectomy. Patients should be made aware of the risk and routinely advised to undergo colectomy if these lesions are detected. On the other hand, there is a one in four chance of any concurrent advanced lesions when only flat LGD is found on surveillance and a lesser risk of progressing to an advanced lesion. These figures allow both the gastroenterologists and patients to make informed choices regarding colectomy in the presence of such lesions. To conclude we have shown that there is a high incidence of CRC or any advanced lesion in the presence of LGD and an increased trend of cancer incidence over time. We have also given useful figures for the number needed to colonoscope to detect CRC or any advanced lesion once LGD is diagnosed on surveillance. Low-grade dysplasia in the presence of DALM has a high positive predictive value for concurrent CRC and progression to any advanced lesion. Flat LGDs has a positive predictive value of 22% for harbouring concurrent CRC and 14.6% PPV for progression to any advanced lesion. The decision regarding continuing surveillance, colectomy, endoscopic polypectomy or endomucosal resection (for sporadic adenomas and ALMs) should be an informed one involving a multidisiplinary team. Cancer risk estimates in our meta-analysis will contribute significantly to this decision-making process. APPENDIX A Type of Study Country where study done Total number of patients with UC undergoing surveillance Duration of follow-up in patients with ulcerative colitis in patient years duration Total number of patients with low-grade dysplasia Duration of follow-up in patients with LGD in pyd Mean number of surveillance colonoscopies Mean number of biopsies per colonoscopy Duration of colitis when LGD detected Mean age of patients when LGD detected Number of pathologists reviewing histology Number of patients with cancer HGD on immediate colectomy (within 6 months of diagnosis of LGD) Number of patients with cancer HGD among patients had colectomy for persistent LGD Number of patients progressing to CRC pre-operatively Number of patients progressing to HGD DALM preoperatively Operative histology no dysplasia LGD DALM HGD Cancer Stage of CRC Dukes A Dukes B Dukes C Dukes D

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