Dysplasia in Chronic Ulcerative Colitis: Implications for Colonoscopic Surveillance Barry A. Taylor, M.D., John H. Pemberton, M.D., Herschel A. Carpenter, M.D., Kenneth E. Levin, M.D., Kenneth W. Schroeder, M.D., David R. Welling, M.D., Michael P. Spencer, M.D., Alan R. Zinsmeister, Ph.D. From the Section of Colon a n d Rectal Surge~'y, Section of Surgical Pathology, Division of Gastroenterology a n d Internal Medicine, a n d Section of Biostatistics, Mayo Clinic a n d Mayo Foundation, Rochester, Minnesota Mucosal dysplasia has been used as a marker for patients with chronic ulcerative colitis considered to be most at risk of developing cancer, and its identification is the basis for colonoscopic surveillance programs. To evaluate the reliability of this premise, colectomy specimens from two groups of patients who had undergone surgery for chronic ulcerative colitis (50 with cancer and 50 without) were retrieved. The groups were matched by age, sex, duration of disease, disease extent, and symptoms at the time of surgery. Using a standard technique of multiple random biopsies, we utilized the standard colonoscopic biopsy forceps to obtain four biopsies from mucosa that was not macroscopically suspicious for dysplasia or cancer in eight defined regions in each of the 100 colon specimens. This technique mimicked exactly the methods used in our clinical surveillance program. Ml 3,200 biopsies were evaluated blindly by one pathologist for presence and grade of dysplasia. Twenty-six percent of colons with an established cancer harbored no dysplasia in any biopsy from any region in the colon. While an overall association between the presence of cancer and high-grade dysplasia was detected (relative risk = 9.00; 95 percent CI of 2.73-29.67), the sensitivity and specificity of random colonic biopsies to detect concomitant carcinoma were 0.74 and 0.74, respectively. These findings prompt concern that reliance on random biopsies, obtained during colonoscopic surveillance, may be misplaced. [Key words: Ulcerative colitis; Cancer risk; Surveillance; Dysplasia]

plasia of the colonic mucosa. 4 If p r e c a n c e r could be d i a g n o s e d with confidence, then prophylactic rather than therapeutic surgery c o u l d b e performed. Morson and Pang 4 d e s c r i b e d dysplasia of the r e c t u m in patients with a p r o x i m a l cancer and r e c o m m e n d e d regular rectal biopsies as an aid to cancer control in patients with CUC. H o w e v e r , dysplasia can be a focal lesion, and the r e c t u m m a y b e spared this change even in the p r e s e n c e of a proximal cancer. 5' 6 Because c o l o n o s c o p y provides access to the entire large bowel, facilitating the search for dysplasia, c o l o n o s c o p y surveillance has altered f u n d a m e n t a l l y the way in w h i c h patients with CUC are managed. I n d e e d , in patients without severe s y m p t o m s , p r o c t o c o l e c t o m y is usually not r e c o m m e n d e d unless dysplasia is detected. This p h i l o s o p h y has persisted despite the current popularity of m o r e physiologic operations such as restorative p r o c t o c o l e c t o m y (ileal p o u c h - a n a l anastomosis) .7, Because dysplasia is focal, it m a y not even be d e t e c t e d by extensive c o l o n o s c o p i c biopsies, and established cancers m a y be m i s s e d entirely. 9'1~ Ransohoff et aL 11 c o m p a r e d the distribution of dysplasia in patients with cancer c o m p l i c a t i n g colitis with that in patients without cancer and f o u n d that only 73 p e r c e n t of patients had dysplasia at a site distant from the tumor. F u r t h e r m o r e , in the 22 patients they r e p o r t e d without cancer, dysplasia was found in 27 percent. However, the applicability of this study to clinical practice is limited b e c a u s e the authors e x a m i n e d w h o l e tissue sections and r e p o r t e d each region according to the highest grade of dysplasia detectable a n y w h e r e within that region. We instead investigated the distribution of dys-

Taylor BA, PembertonJH, Carpenter HA, Levin KE, Schroeder KW, Welling DR, Spencer MP, Zinsmeister AR. Dysplasia in chronic ulcerative colitis: implications for colonoscopic surveillance. Dis Colon Rectum 1992;35: 950-956. hronic ulcerative colitis (CUC) carries an increased risk of colonic malignancy. 1 3 Such a malignancy m a y be p r e c e d e d b y p r e c a n c e r or dys-

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Supported in part by Research Grant DK37990 from the National Institutes of Health and by the Mayo Foundation. Address reprint requests to Dr. Pemberton: Section of Colon and Rectal Surgery, Mayo Clinic, 200 First Street Southwest, Rochester, Minnesota 55905. 950

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DYSPLASIA AND CANCER IN COLITIS

plasia and its association with established cancer in the colectomy specimens from 50 ulcerative colitis patients with a cancer and from 50 matched ulcerative colitis patients without cancer, using a sampling technique designed to mimic the colonoscopic methods used in clinical surveillance of patients with CUC. The aims were to determine whether mucosal dysplasia was associated with the presence of a colorectal cancer in patients with chronic ulcerative colitis and to evaluate the sensitivity and specificity of biopsies obtained using standard colonoscopic surveillance techniques.

MATERIALS AND METHODS Selection of Patients: Cancer Cases The medical histories of all patients diagnosed as having chronic ulcerative colitis and colorectal carcinoma in the Mayo Clinic surgical diagnostic index between 1960 and 1986 were reviewed (diagnostic codes: chronic ulcerative colitis and colorectal carcinoma). One hundred candidate patients, all of whom had undergone proctocolectomy or total abdominal colectomy, were identified. Those patients who had undergone bypass procedures, whose tumors were unresectable, or who had less than a total abdominal colectomy were excluded. These demographic and clinical details for the 100 patients were abstracted from the medical history: age, sex, duration of disease, steroid dependence, indications for surgery, presence or absence of associated conditions, extent of disease, symptoms at the time of surgery, and site(s) of cancer. Duration of disease was defined (in years) as the time between the onset of symptoms attributed to CUC (as stated by the patient at initial assessment) and colectomy. Steroid dependence was quantified from the clinical record over the three years immediately before surgery. Colitis was considered to have affected the whole colon if any method of assessment of its extent (radiology, colonoscopy with biopsies, or subsequent gross histology) suggested involvement proximal to the distal transverse colon. Severity of colitis symptoms at the time of surgery was based on the average number of bowel movements per 24 hours as reported by the patient. The presence of associated conditions (e.g., ankylosing spondylitis, cutaneous vasculitis, or sclerosing cholangitis) was assessed after a review of the medical history.

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Selection of Patients: Noncancer Controls The surgical diagnostic index was also screened for the same period of time to provide control patients (diagnostic code: CUC only). Approximately 600 medical histories were examined, and patients were excluded if they either had not come to surgery or had undergone less than a proctocolectomy or total abdominal colectomy. Demographic and clinical details of 450 patients were used to match potential control patients with each of the cancer patients. The matching criteria were age, sex, duration and extent of CUC, and symptoms. If multiple controls matched a given cancer patient, the control with the closest clinic registration number was chosen to provide similar durations of follow-up. Fifty cancer patients who h a d a m a t c h e d n o n c a n c e r control w e r e selected to provide a uniform distribution of cancers throughout each of eight defined regions of the colon and rectum, because cancers complicating CUC tend to occur relatively evenly through the colorecturn. 12-~4 The 50 CUC patients with a colorectal carcinoma and 50 CUC patients without a carcinoma composed the study group (N = 100).

Pathologic Material All 100 colectomy specimens were retrieved and examined. Each specimen was complet e. Each individual colon specimen was pinned on a mounting board, and using a s t a n d a r d colonoscopic biopsy forceps (2.4 mm), four biopsies were obtained from each of eight defined regions in each specimen (cecum, ascending colon, proximal transverse colon, distal transverse colon, proximal descending colon, distal descending colon, sigmoid colon, and upper rectum). This method, therefore, mimicked exactly the biopsy technique used in our institution for patients with CUC undergoing surveillance. Thus, 32 biopsies were obtained per patient. Furthermore, we did not biopsy the cancer in the 50 colectomy specimens with CUC and cancer. Otherwise, mucosal irregularities and raised lesions w e r e biopsied as they would have been clinically. The four biopsies from the same region in each specimen were placed together in one paraffin block. A double ribbon of sections from each block was placed on a single glass slide and stained with hematoxylin and eosin. Each slide was identified o n l y b y a number (between i and 100) and a region

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Table 1. Biopsy Classification of Dysplasia in Inflammatory Bowel Disease (Modified from Riddell eta/. is) Negative Normal mucosa Inactive (quiescent) colitis Active colitis Indefinite Probably negative (probably inflammatory) Unknown Probably positive (probably dysplastic) Positive Low-grade dysplasia High-grade dysplasia

Dis Colon Rectum, October 1992

associated diseases). Interaction terms of dysplasia with the matching variables were also evaluated in the logistic model. This primary analysis considered dysplasia at any site; similar analyse s considered right, left, and rectosigmoid regions individually for the presence of cancer and/or dysplasia. The grade of dysplasia was analyzed by determining the maximum grade over the four biopsies at each of the sites, and the median value (over the eight sites) was computed for each subject. The observed sensitivity and specificity were used to calculate the positive predictive value: PV =

of the colorectum. All 100 slides from each region were pooled and completely mixed together into a random sequence. All 800 slides were examined in a random order for the presence and grade of dysplasia by a single histopathologist (H.A.C.), who was kept unaware of any clinical details or macroscopic findings. The randomization served to eliminate the potential bias that might have been introduced by reading the biopsies case by case. Reports were issued in accordance with guidelines established by the Inflammatory Bowel Disease-Dysplasia Morphology Group in 198315 (Table 1). As defined in that publication, "probably present" was considered to be present on analysis of data, and "probably absent" was considered to be absent. Each region for each colon was reported on the basis of the highest category of dysplasia present within any of its four biopsies.

Statistical A n a l y s i s The histologic review of biopsies provided a graded score for each region sampled. This was converted to a vector of binary outcomes (0,1) corresponding to the presence or absence of dysplasia within each of the eight regions of the colon sampled (present = "present, high grade," "present, low grade," or "probably present"; absent = "probably absent" or "absent'). Initially, dysplasia in any of the eight regions sampled was considered to indicate the overall presence of dysplasia. A conditional logistic regression analysis for matched case-control data 16 was then used to estimate the relative risk (of cancer) in patients with dysplasia relative to those without (i.e., dysplasia was considered as the "exposure" variable). Other clinical variables not included in the matching were considered as possible confounding variables (e.g.,

(prey) (sensitivity) (1 - p r e v ) x (1 - s p e c i f i c i t y ) ' + (prev)(sensitivity)

assuming prevalence ( p r e v ) rates for cancer of 3 to 5 percent among patients with CUC. 17

RESULTS Comparability of Groups (Table 2) Sixty-eight of the 100 patients (68 percent) were men and 32 (32 percent) were women. Ages at the Table 2. Comparability of Patients with CUC and Cancer and Those with CUC Alone (Control)

Median age in years (25th, 75th percentiles) Sex (% males) Median duration of disease in years (25th, 75th percentiles) Extent of CUC % Left-sided only Pancolitis Bowel movements/day % Normal % __10/day % Steroid usage (during three years prior to colectomy) Type of procedure % Proctocolectomy % Total colectomy Associated diseases % Arthritis % Ankylosing spondylitis % Skin lesions % Liver disease

CUC and Cancer

CUC Alone

37 (33, 48)

39 (33, 46)

68 15 (12, 19)

68 14 (11, 18)

4 96

4 96

14 28 44 14 32

10 32 40 18 72

72 28

88 12

16 4 10 20

8 2 12 10

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time of colectomy ranged between 22 and 75 years, with a median of 38 years. The matching yielded two groups of patients with very similar distributions of age at colectomy, sex, duration of disease before colectomy, extent of disease, and severity of symptoms at the time of surgery. Furthermore, the prevalence of associated conditions, such as ankylosing spondylitis, cutaneous manifestations of inflammatory bowel disease, and liver disease, was similar for the two groups. The only difference between the groups was a lower rate of steroid use in the cancer group (32 percent) compared with the control group (72 percent) (P < 0.05). Only 14 percent of controls and 6 percent of cancer patients were eni;olled in any surveillance screening program at the time of colectomy. Thus, only eight percent of controls and 10 percent of cancer patients were operated upon because dysplasia was found preoperatively. Importantly, the indication for surgery was n o t a criterion used in the selection of patients for the two groups.

Presence of Dysplasia (Table 3) Among the patients with CUC who had a concomitant cancer, 37 of 50 (74 percent) had dysplasia while 13 of 50 (26 percent) had n o e v i d e n c e of dysplasia, of any grade, anywhere on any biopsy.

Table 3. Incidence of Dysplasia in Patients with CUC and Cancer (Cancer) and Patients with CUC Alone (Controls) Patient Groups Dysplasia

Cancer (%)

Controls (%)

Present Absent

74 26

26 74

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Moreover, dysplasia was also detected in 26 percent of c o n t r o l s . Thus, the presence of dysplasia had a sensitivity of 74 percent and a specificity of 74 percent for concurrent cancer.

Association of Dysplasia and Cancer Risk A significant association (P < 0.001) w a s detected between the presence of dysplasia at any site and the presence of established cancer; 37 of 50 cancer patients had dysplasia somewhere within their biopsies, compared with 13 of 50 control patients. The estimated overall relative risk of cancer anywhere in the colon in patients with dysplasia (Table 4) was 9.0 (95 percent CI of 2.7-29.7), indicating that patients with dysplasia were approximately 3 to 30 times as likely to have cancer somewhere in the colon.

Association o f R e g i o n a l Dysplasia and Cancer When the three regional sites for dysplasia (right colon, left colon, and rectum) were analyzed simultaneously, the relative risk for cancer (anywhere) was significantly elevated for right-sided dysplasia (relative risk = 6.4; P < 0.05) and leftsided dysplasia (relative risk = 6.8; P < 0.05), but not for rectal dysplasia (1.2; P > 0.05) (Table 4). G r a d e o f Dysplasia and Association w i t h Cancer ( T a b l e 5 ) Similar results were obtained when the presence of dysplasia was defined as only "present, high grade." There were 16 cancer patients (32 percent) with evidence of high-grade dysplasia, compared with a single control patient (2 percent). In general, in this group of 100 colon specimens, al-

Table 4. Relative Risk of Having a Cancer Somewhere in the Large Bowel by Site of Dysplasia Relative Risk of Cancer (95% Confidence Interval) Dysplasia (anywhere) Right-sided dysplasia Left-sided dysplasia Rectal dysplasia

9.0* 6.4* 6.8* 1.2

(2.7, 29.7) (1.6, 24.8) (1.1,41.2) (0.2, 6.7)

No. of Pairs1Cancer

Control

Both

27 24 19 17

3 3 2 3

10 3 6 0

* P < 0.05. ? The number of matched sets (1 case: 1 control) of the 50 total where the cancer patient had dysplasia for the specified region and the matched control did not (Cancer), the control patient had dysplasia in the specified region and the cancer patient did not (Control), or both members of the pair had dysplasia in that region (Both).

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Dis Colon Rectum, October 1992

Table 5. Association Between Grade of Dysplasia (Worst Score) and Presence or Absence of Cancer Dysplasia Absent

Cancer Control

Probably Absent

Probably Present

Present, Low Grade

Present, High Grade

n

(%)

n

(%)

n

(%)

n

(%)

n

(%)

12 32

(24) (64)

1 5

(2) (10)

4 4

(8) (8)

17 8

(34) (16)

16 1

(32) (2)

though dysplasia of a n y grade was never found frequently, it was more common and tended to be of a higher grade in patients with an established cancer than in those without a cancer. In all but one pair of matched cases and controls, the median grade of dysplasia (over all eight sites) for the cancer patients was greater than or equal to the value in its matched control. However, fully 54 percent of the patients with cancer had less than 5 of 32 biopsies positive for dysplasia. Predictive Value The positive predictive value of a study depends upon the prevalence in the population of the disorder sought by the test. The prevalence of cancer in patients with CUC is reported to vary between 3 percent and 5 percenO 7 The positive predictive value of colonoscopy, therefore, varies between 8 percent and 13 percent. DISCUSSION The principal finding was that 26 percent of CUC patients with cancer had no evidence of dysplasia detected in multiple endoscopic biopsy specimens from anywhere in the colon. These data support and extend those of Ransohoff e t aL 11 We used a technique, however, that differed fundamentally from theirs; that is, biopsies were obtained randomly from eight defined regions of each specimen, utilizing standard endoscopy biopsy forceps in a fashion mimicking surveillance colonoscopy techniques performed clinically. Ransohoff e t al. 1~ found a similar incidence of dysplasia in colectomy specimens (73 percent) but a higher incidence of high-grade dysplasia (50 percent).~l In addition to the problem of interpreting biopsy specimens, a possible explanation for this divergent finding is that Ransohoff e t al. used whole tissue blocks and surveyed individual regions within each colectomy specimen. The num-

Total

50 50

ber of tissue blocks per colectomy specimen and why a particular block was selected for analysis were not specified; the randomness of the biopsies, therefore, may be questioned. A limitation of our study (but also of all colonoscopic surveillance studies) is that a complete set of surveillance biopsies from the large bowel accounts for an estimated 0.05 percent of its total mucosal surface area~8; a potentially huge sampling error obviously exists. Nevertheless, we found a significant association between the presence of dysplasia at any site and the presence of established cancer. The estimated overall relative risk was 9.0 (CI: 2.7-29.7); patients with dysplasia, therefore, were 3 to 30 times as likely to have cancer somewhere in the colon or rectum. Moreover, the grade of dysplasia tended to be higher in CUC patients with cancer than in CUC patients without cancer; 16 cancer patients (32 percent) had high-grade dysplasia, compared with only a single control patient (2 percent). These findings confirm that dysplasia, when it occurs, is a marker for cancer. But because 26 percent of patients with established cancer had no evidence of dysplasia (of any grade) in a n y of their biopsies, high-grade dysplasia is a stronger indicator that a cancer is already present. Moreover, calculating the positive predictive value of colonoscopic surveillance is interesting; the extremely low prevalence of colorectal cancer in a population of CUC patients (5 percent) renders a predictive value of only 13 percent. This observation suggests that colonoscopic surveillance programs may have significant limitations. Our observation that rectal dysplasia was not significantly associated with a more proximal cancer supports those of others 5'6; 66 percent of our patients with proximal cancers had no rectal dysplasia. Sampling the rectum for dysplasia in an attempt to identify a proximal cancer, therefore, is a rather meaningless exercise. While the ultimate usefulness and safety of co-

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DYSPLASIA AND CANCER IN COLITIS

lonoscopic surveillance await results of long-term prospective studies, our study suggests that up to one-quarter of patients d e v e l o p i n g cancer with CUC may do so without d e v e l o p i n g identifiable dysplasia at a site r e m o t e from the actual cancer. Thus, using a prospective policy that advises proct o c o l e c t o m y only u p o n detection of either highgrade dysplasia or dysplasia of any grade, a large proportion of patients may already have an established cancer at the time of surgery. We, therefore, cannot support the conclusion of Rosenstock et al. TM that the absence of dysplasia correlates with the absence of cancer. Furthermore, based on the observation that patients with dysplasia of any grade on surveillance c o l o n o s c o p i c biopsy will be 3 to 30 times m o r e likely to have an established cancer than if they did not have dysplasia, we believe that dysplasia of any grade represents a clear indication for proctocolectomy. Conversely, there is little question that it is quite difficult to advise p r o c t o c o l e c t o m y in the setting of a negative surveillance c o l o n o s c o p y and no symptoms. However, 26 p e r c e n t of CUC patients with an established colorectal cancer did not have c o n c u r r e n t dysplasia detected. Clearly, colonoscopic surveillance in this sizable p r o p o r t i o n of CUC patients may not have identified t h e m ahead of time as being at high risk for d e v e l o p m e n t of cancer. We therefore agree with Collins et aL 19 that the future of c o l o n o s c o p i c biopsy surveillance for dysplasia in CUC patients is c l o u d e d at best and that markers other than mucosal dysplasia should be sought. CONCLUSION The sensitivity and specificity of r a n d o m colonic biopsies to detect the p r e s e n c e of a concomitant cancer of the c o l o n in patients with CUC are low. Because the prevalence of cancer in this same population of CUC patients is likewise low, the predictive value of surveillance c o l o n o s c o p y is poor. Reliance, therefore, on surveillance programs to safely and effectively guide p r o m p t surgical intervention may be misplaced. For patients and physicians who insist u p o n continuing a colonoscopic surveillance program, however, it seems imperative that regular examinations of the entire colon be p e r f o r m e d even in the absence of symptoms or of dysplasia; r e p e a t e d c o l o n o s c o p i e s subject the mucosa to additional biopsies, thus less-

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ening the sampling error. Among patients without dysplasia, however, the findings in this study support more conventional criteria for deciding w h e n to intervene in the course of the disease surgically; these include: 1) total d e g r e e of colonic involvement (pancolitis), 2) duration of disease for more than 10 years, 2 3) chronically active long-standing disease, and 4) disease presenting in c h i l d h o o d or with a severe first attack. 2'9 Failure to operate in these high-risk situations while waiting for dysplasia to be discovered by surveillance c o l o n o s c o p y appears to invite a high risk of d e v e l o p i n g concomitant colorectal carcinoma.

REFERENCES 1. Lennard-Jones JE, Morson BC, Ritchie JK, Shoev DC, Williams CB. Cancer in colitis: assessment of the individual risk by clinical and histological criteria. Gastroenterology 1977;73:1280-9. 2. van HeerdenJA, Beart RWJr. Carcinoma of the colon and rectum complicating chronic ulcerative colitis. Dis Colon Rectum 1980;23:155-9. 3. Lennard-Jones JE. Cancer risk in ulcerative colitis: surveillance or surgery. BrJ Surg 1985;72:584-6. 4. Morson BC, Pang LS. Rectal biopsy as an aid to cancer control in ulcerative colitis. Gut 1967;8:423-34. 5. Riddell RH, Morson BC. Value of sigmoidoscopyand biopsy in the detection of carcinoma and premalignant change in ulcerative colitis. Gut 1979;20: 575-80. 6. Dobbins WO III. Current status of the precancer lesion in ulcerative colitis. Gastroenterology 1977; 73:1431-3. 7. Pemberton JH, Kelly KA, Beart RW Jr, Dozois RR, Wolff BG, Ilstrup DM. Ileal pouch-anal anastomosis for chronic ulcerative colitis: long-term results. Ann Surg 1987;206:504-11. 8. Riddell RH. Dysplasia and cancer in ulcerative colitis: a soluble protein? Scand J Gastroenterol 1984; 104:137-49. 9. Fuson JA, Farmer RG, Hawk WA, Sullivan BH. Endoscopic surveillance for cancer in chronic ulcerative colitis. Am J Gastroenterol 1980;73:120-6. 10. Riddell RH. Dysplasia and cancer in inflammatory bowel disease. BrJ Surg 1985;72:S83. 11. Ransohoff DF, Riddell RH, Levin B. Ulcerative colitis and colonic cancer: problems in assessing the diagnostic usefulness of mucosal dysplasia. Dis Colon Rectum 1985;28:383-8. 12. Edling NP, Eklof O. Distribution of malignancy in ulcerative colitis. Gastroenterology 1961;41:465-6. 13. YardleyJH, Ransohoff DF, Riddell RH, Goldman H. Cancer in inflammatory bowel disease: how serious

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is the problem and what should be done about it? Gastroenterology 1983;85:197-200. 14. Dobbins WO III. Dysplasia and malignancy in inflammatory bowel disease. Annu Rev Med 1984; 35:33-48. 15. Riddell RH, Goldman H, Ransohoff DF, et al. Dysplasia in inflammatory bowel disease: standardized classification with provisional clinical applications. Hum Pathol 1983;14:931-68. 16. Breslow NE, Day NE. Statistical methods in cancer research. In: The analysis of case-control studies. Volume 1. IARC Scientific Publications #32. Lyon, 1989, Chapter 7.

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17. Lightdale CJ, Sherlock P. Neoplasia and gastrointestinal malignancy in inflammatory bowel disease. In: Kirsner JB, Shorter RG, eds. Inflammatory bowel disease. Philadelphia: Lea and Febiger, 1988: 281-98. 18. Rosenstock E, Farmer RG, Petras R, Sivak MV, Rankin GB, Sullivan BH. Surveillance for colonic carcinoma in ulcerative colitis. Gastroenterology 1985;89: 1342-6. 19. Collins RH Jr, Feldman M, Fordtran JS. Colon cancer dysplasia and surveillance in patients with ulcerative colitis: a critical review. N Engl J Med 1987;316: 1654-8.

Dysplasia in chronic ulcerative colitis: implications for colonoscopic surveillance.

Mucosal dysplasia has been used as a marker for patients with chronic ulcerative colitis considered to be most at risk of developing cancer, and its i...
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