GRANULOMATOUS COLITIS AND ATYPICAL ULCERATIVE COLITIS

GASTROENTEROLOGY Copyright 1966 by The Williams & Wilkin. Co. Vol. 50, No.2 Printed in U.S.A. GRANULOMATOUS COLITIS AND ATYPICAL ULCERATIVE COLITIS Histological features, behavior, and prognosis K. LEWIN, M.B., AND J. D. SWALES, M.B. Gordon Hospital and Vincent Square Laboratories, Westminster Hospital, London, England Secondary involvement of the colon in primary Crohn's disease of the ileum was first described by Colp in 1934 1 and subsequently confirmed by other workers.2-4 Later, it became recognized that a histological picture similar to that seen in regional ileitis could arise de novo in the colon. Thus Wells 5 described a form of regional colitis with fibrosis, noncaseating tubercles, multinucleated giant cells, and designated it "Crohn's disease of the colon." This name has become generally accepted in the British literature,6-1o although Crohn and Yarnis ll refer to it as "granulomatous colitis" and Harris et alp use the term "cicatrizing colitis." Radiologically, the typical appearances of "segmental colitis" and "granulomatous colitis" have been described by Wolf and Marshak 13 and Marshak et aj.14 It was our impression that, while many patients with a granulomatous histological lesion do exhibit a clinical picture suggestive of Crohn's disease of the large bowel, a number are symptomatically indistinguishable from ulcerative colitis. Accord- Received June 14, 1965. Accepted October 20, 1965. Address requests for reprints to: Dr. Klaus Lewin, Vincent Square Laboratories, Vlestminster Hospital, Vauxhall Bridge Road, London, S.W.!, England. The authors wish to thank Mr. S. O. Aylett, the late Dr. E. R. Cullinan, Mr. R. W. Raven, and Dr. R. D. Tonkin, for permission to study case records of patients under their care. They are also indebted to Dr. I. M. P. Dawson for allowing them to study pathological material from his department. Finally, they are grateful to both Dr. Dawson and Dr. Tonkin for their constructive criticism and advice. 211 ingly, we have reviewed in retrospect the clinical picture of 48 cases of primary inflammatory disease of the colon which showed some or all of the histological features of Crohn's disease treated by total or partial colectomy in this hospital. Contrary to most studies, criteria for our selection are histological and not clinical. In addition we have studied the prognostic value of the pathological features of these cases. Pathology, Classification, and Selection of Material During the last 8 years approximately 260 patients were treated surgically at this hospital for Crohn's disease of the colon or for ulcerative colitis. Our study concerns those patients who showed some or all the pathological features previously described as primary Crohn's disease of the colon, granulomatous colitis, or "ulcerative colitis with giant cell systems." A further six patients with similar features who had been treated prior to 1957 were added to this group. The proportion of patients encountered before 1957 showing this picture is considerably less, as the diagnosis was not considered so frequently and the records are less complete. In order to understand the difficulties sometimes encountered in the diagnosis of ulcerative colitis and Crohn's disease, it is helpful to describe briefly the typical pathology of each condi-. tion. Ulcerative colitis. At the Gordon Hospital we recognize three stages in the course of this disease: acute, which may become fulminating; chronic active; and quiescent. These may overlap. The latter represents

212 LEWIN AND SWALES Vol. 50, No.2, < ~. ".. -.. ' - ~.. ',... /,. _ -'"~.... ~ of.. FIG. 1. Acute ulcerative colitis showing mucosal erosion and ulceration, vascular dilation, and superficial inflammation. Disease is limited to the mucosa and superficial submucosa (H &E. X30). the burnt out stage of the disease. The condition usually starts distally as a proctocolitis and spreads towards the cecum. There are no skip areas. The outstanding histological features are: mucosal erosion or ulceration, marked vascular dilation, and a nonspecific chronic inflammation limited to the mucosa and the superficial submucosa (fig. 1). In fulminating cases, however, the process extends through the full thickness of the bowel wall. The inflammatory cells consist predominantly of lymphocytes and plasma cells. There may be a superficial polymorphonuclear infiltration in association with tissue destruction, but this is probably due to secondary bacterial infection. The mucosal destruction varies from superficial erosions to full thickness ulceration. Crypt abscesses are frequent but of little diagnostic value in our experience because they occur in most inflammatory conditions of the bowel. In chronic active ulcerative colitis there is evidence of healing in addition to the above mentioned features. Thus re-epithelialization of the ulcerated areas produces a thinned mucosa with distorted glands (figs. 2 and 3), and re-epithelialization of the mucosal tags produces pseudopolyps. Grohn's disease. This disease is frequently segmental although the whole colon can be affected. Skip areas are common. 111icroscopic appearance: In contrast with ulcerative colitis, the two distinguishing features of this condition are transmural inflammation and thickening of the bowel wall (fig. 4). The latter is initially due to submucous edema but later due to fibrosis. The inflammatory exudate.. consists of lymphocytes, often with prominent follicle formation; plasma cells; and sarcoidlike granulomata. These latter are probably the most useful individual features in the diagnosis of Crohn's disease but they are not always found

Febl'um'Y 1966 ULCERATIVE COLITIS AND CROHN 'S DISEASE 213 FIG. 2. Colon in chronic active ulcerative colitis showing regenerated mucosa which is thinned and distorted (H & E, X 30). FIG. 3. Colon in chronic active ulcerative colitis. High power magnification showing epithelial r egeneration and distorted glands (H & E, X 100). (see group 2 below). The fully formed granuloma consists of collections of epitheloid cells and multinucleated giant cells predominantly of the Langhans type without any accompanying caseation. Sometimes the granulomata are poorly formed and consist of loose follicles made up of epitheloid cells only. The inflammation is not confined to the mucosa and extends through all coats. Ulceration of the mucosa

214 LEWIN AND SWALES Vol. 50, No.2 FIG. 4. Colon in Crohn's disease, showing marked submucosal thickening, transmural inftammation;and a fissure on the left (H & E, X 10). is not a pronounced feature but fissuring is common and characteristic (fig. 5). In conclusion, the outstanding differences between the two conditions are shown in table l. Although the classical histological appearances appear to be well demarcated, we found that it was not always possible to fit cases into one group or the other. For example, we came across cases of ulcerative colitis in which inflammation was not limited to the mucosa and superficial submucosa, but extended into the subserosa and was occasionally associated with fibrosis. Similar difficulties were encountered in some cases of Crohn's disease of the large bowel. Therefore, on the basis of histology, after excluding all cases of typical ulcerative colitis, the remaining 48 cases were divided into three groups as follows: Group 1. "Typical granulomatous colitis" (16 cases). Group 1 represents histological appearances enumerated above (figs. 4 and 5), including the sarcoidlike granulomata. Group 2. "Atypical granulomatous colitis" (13 cases). This group is similar to group 1 but is lacking one or other of the features mentioned, especially sarcoidlike granulomata and, in the majority of cases, the submucous thickening. In all patients there was a chronic inflammation of the subserosal tissues. Group 3. "Atypical ulcerative colitis" (19 cases) (fig. 6). Group 3 resembles

Febl'uw'Y 1966 ULCERATIVE COLITIS AND CROHN'S DISEASE 215 FIG. 5. Colon in Crohn's disease showing pronounced fissuring (H & E, X 10). chronic active ulcerative colitis but with nonspecific chronic inflammation or fibrosis of the subserosa. This group also includes one case of chronic active ulcerative colitis. with numerous foreign body giant cells. T he macroscopic findings in the colon were not on the whole useful in classification although they did give a rough indication of the group to which t he specimen belonged. Clinical Findings Sex and age distribution. There were 27 women and 21 men members in the series, with a mean age of onset of the disease of 31.2 years. This figure is broadly comparable with that for typical ulcerative colitis 10 and for small intestinal Crohn's disease with colonic involvement,9 but substantially less than that previously recorded for primary Crohn's disease of the colon. 9 Duration of symptoms. The mean duration of symptoms prior to colectomy was 6 years so that, on the average, the course of the patient's illness was followed for a period of just under 10 years as the mean follow-up period was 3 years and 8 months after colectomy. Clinical featttres. These are listed in table 2. It will be noted that no mention is made of the anal lesions said to be char-, acteristic features of the disease by Lockhart-Mummery and Morson. 15 These were not a conspicuous feature as far as we could assess retrospectively. Complications. As our study was primarily concerned with the predictive value

216 LEWIN AND SWALES Vol. 50, N o. f? TABLE 1. Comparison of Crohn's disease and ulcerative colitis Pathological features Distribution Diffuse Segmental Skip areas Bowel wall Crohn's disease Sometimes Usually + Fibrous thickening Cobblestoning + Inflammation Distribution Reaction Destruction Lymph nodes (sarcoidlike granulomata) Transmural Sarcoidlike granulomata, lymphocytes, plasma cells. Fibrosis Fissuring +, ulceration ± +, (Not necessarily enlarged) Ulcera tive coli tis Usually Sometimes Never Not thickened Mucosa and superficial submucosa Lymphocytes and plasma cells. No fibrosis Ulceration + of the pathological colonic changes, two complications are of particular importance, viz. recurrence of the disease in the small and large intestines postoperatively, and the formation of fistulae. So far as can be ascertained, no patient diagnosed as having primary large intestinal disease subsequently developed a small intestinal lesion with one possible exception. This patient had,a lesion involving the ascending colon, which was treated by right hemicolectomy and ileotransverse anastomosis. Subsequently, the disease recurred at the anastomotic site, and involved the ileum to a small extent. No patient who had a partial colectomy subsequently required further colonic resection, although several patients had mild symptoms of pain and diarrhea which were not sufficient to warrant further operation. This is in marked contrast to three cases of involvement of the colon which proved at operation to be associated with an extensive ileitis and which, for this reason, were discarded in the initial selection of patients from our series. All these required subsequent small intestinal resection. It will be noted that several patients had, in fact, a small degree of terminal ileal involvement. There can of course be no absolute certainty that this was not the primary lesion. However, only those cases with terminal ileal involvement were included in which the ileal lesion was in direct continuity with a more extensive lesion of the ascending colon. A total of 22 patients had fistulae at some time in the course of their disease. The 14 preoperative fistulae included seven fistulae-in-ano, four recto vaginal fistulae, two ileocolic fistulae, and one colocolic fistula. Postoperatively, eight patients had fecal fistulae from the anastomotic site and six patients had anorectal fistulae lasting for more than 4 months. To assess whether this represented an increased incidence as compared with histologically typical ulcerative colitis, a group of 48 colitics was selected who were matched for age and sex. All these had been treated by total colectomy. Only one had a preoperative fistula and there was only one patient who had a postoperative fistula lasting for a period of more than 4 months. This difference in the incidence of fistulae is statistically highly significant. The relative frequency of fistulae in the three histological groups is shown in table 3. While fistulae tended to occur more frequently in patients with the classical Crohn type of inflammation, (group 1), the difference between the proportion of each group which developed fistulae is not statistically significant at the 0.05 level. The other pre- and postoperative complications a re listed in table 2. The arthritis was variable in distribution, but on the whole tended to conform to that described in association with ulcerative colitis, i.e. with involvement of the larger joints. 16 One patient had an arthritis of the hand identical with rheumatoid arthritis which preceded her colitis by 4 years, and the

February 1966 ULCERATIVE COLITIS AND CROHN'S DISEASE 217 FIG. 6. A, Colon in "atypical ulcerative colitis," showing severe ulceration and subserosal fibrosis (H & E, X 30). B, High power magnification of same showing muscle coats above and subserosal fibrosis underneath (H & E, X 80).

TABLE 2. Clinical and pathological picture of those patients treated at Gordon Hospital for primary inflammatory disease of the colon Pertinent data Total Clinical ulcerative colitis Clinical Crohn's disease Clinical features Sex Male 21 8 13 Female 27 8 19 Mean age of onset 31.4 yr 31.6 yr 31.4 yr Mean duration of symptoms before 5.8 yr 4 yr 6.7 yr colectomy Degree of toxicity:a Severely ill 11 5 6 Moderately ill 16 3 13 Not ill 19 7 12 Bleeding on admission.37 14 of 16 23 of 32 Investigations Sigmoidoscopy: Normal 14 2 of 14~ 12 of 27 Ulcerative colitis 20 12 of 14 8 of 27 Suggestive of Crohn's 7 o of 14 7 of 27 Blood: Hemoglobin 11.5 g /l00 ml 11.7 g /l00 ml 11.35 g/ l00 ml White blood cell average 8600/ mm 3 9200/ mm 3 8400/ mm 3 Erythrocyte sedimentation rate 36 mm/hr 37 mm/hr 36 mm/ hr Pre- and postoperative complications Arthritis 10 5 5 Pelvic mass 4 0 4 Erythema nodosum 3 0 3 Carcinoma rectum 3 2 1 Stricture 11 5 6 Fistulae 22 0 22 Response to steroids Number treated 19 10 9 N umber responding well initially 11 8 3 Nature of surgical operation Partial colectomy 17 3 14 Total colectomy 31 13 18 Histological features d Ileal involvement Granulomatous 7 of 31 1 of 12 6 of 19 Nonspecific 9 of 26 4 of 12 5 of 14 Lymph node involvement Granulomatous 15 of 30 4 of 11 11 of 19 Atypical 3 of 30 1 of 11 2 of 19 Muscle involvement Hypertrophy 26 9 of 16 17 of 32 Destruction 8 3 of 16 5 of 32 Fissures 16 3 of 16 13 of 32 a Details not available on two patients. ~ Although both patients had a normal sigmoidoscopic appearance at the time of operation, one had a nonspecific inflammation suggestive of ulcerative colitis on biopsy, and the other patient had previously shown appearances suggestive of ulcerative colitis. Significant difference between the two clinical groups at the 0.05 level. d None of these differences between the two groups is significant at the 0.05 level. 218

February 1966 ULCERATIVE COLITIS AND CROHN'S DISEASE 219 arthritis may be considered a coincidental finding. In all the other cases, the arthritis followed the onset of the colitis. Of particular importance is the high incidence of rectal carcinoma in this series. All three patients who developed a rectal carcinoma following colectomy belonged to histological group 3 (atypical ulcerative colitis). Radiology. A substantial number of patients in our study appeared to be indistinguishable from classical ulcerative colitis in all respects apart from the pathological appearances. In order to determine whether the radiological appearances might have provided some clue as to the pathological nature of these cases, the barium enema films were studied in the 40 patients in whom they were available. The appearances associated with the pathological changes of primary Crohn's disease of the colon have been previously described. 13,14 Briefly, these are: (a) a localized constricting lesion in the bowel, (b) the presence of "skip areas," and (c) "spiking" of barium -associated pathologically with transverse fissures. Some or all of these features were found in 16 cases. Of these seven cases had a classical Crohn type of inflammation, (group 1), five had the appearance of atypical Crohn's disease (group 2), and four had the appearance of atypical ulcerative colitis (group 3). The difference between these proportions is not significant, although there is a tendency for a radiological diagnosis of Crohn's disease of the colon to be made more often where the histological lesion is the classical Crohn's type of inflammation. At the same time, however, 24 of our cases were considered radiologically to be ulcerative colitis and of these, seven developed persistent external fistulae at some stage in the disease. As no single feature could be found which correlated significantly with the pathological groups reviewed, we combined the two features upon which the diagnosis of Crohn's disease of the colon could be made, i.e. the presence of persistent fistulae and the characteristic radiological abnormalities. It was then possible to allocate the patients clinically into one Histological group TABLE 3. Clinical behavior of histological groups Group 1 (16) Group 2 (13) I Group 3 (19)! Typical granulomatous g atous ulcer:;tt,lve ~!~~l~~. Atypic.al colitis colitis cob tis No. of patients 9 7 6 with fistulae Clinical ulcera- 2 4 10 tive colitis (no persistent fistulae) Clinical Crohn's 14 9 9 disease (22 wi th fistulae) of two groups. The smaller consisted of 16 patients symptomatically and radiologically indistinguishable from classical ulcerative colitis, in whom a diagnosis of Crohn's disease was purely histological. The larger group of 32 (clinical Crohn's disease) deviated from the clinical picture of ulcerative colitis, either by having preoperative or persistent postoperative fistulae, or by exhibiting atypical radiological features. The histological classification of these groups is shown in table 3. Significantly more cases of clinical Crohn's disease showed the histological changes of classical Crohn's disease (group 1, P 0.05). Likewise, significantly more case of clinical ulcerative colitis showed the histological appearances of atypical ulcerative colitis (group 3). Discussion One feature not brought out by previous studies 15 17 is that a significant number of patients with a histological picture suggesting Crohn's disease of the colon have a clinical presentation indistinguishable from ulcerative colitis. In some reviews, where the method of selection is clinical, the impression is gained that the histological picture of granulomatous colitis is confined to those patients whose clinical course suggests primary Crohn's disease of the colon. Our impression was that this conclusion

220 LEWIN AND SWALES Vol. 50, No.2 was not entirely correct, and the present review tends to confirm our belief. Comes and Stecher 10 make no comment on the close histological resemblance of some cases of granulomatous colitis to ulcerative colitis and speak of primary Crohn's disease of the colon as though it were always a well defined entity. This is, indeed, the position of the majority of workers,9, 15, 18, 19 although it has been claimed that fundamentally both these diseases are identical.2 0-22 The group of cases reviewed here shows a complete histological spectrum between a typical Crohn's type of inflammation involving the large intestine, and a picture that resembles ulcerative colitis, apart from some submucosal and serosal inflammation and fibrosis. It was expected that these histological differences would be paralleled by differences in the clinical course. This expectation was only partly realized. Thus, a greater number of cases with a typical granulomatous process in the bowel developed fistulae at some time during their illness, as compared with cases which had a closer histological resemblance to ulcerative colitis (table 3). However, there was considerable overlap in the clinical behavior of the histological groups and the difference is not statistically significant. If other features which suggest clinical Crohn's disease rather than ulcerative colitis are taken into account, then the histological picture becomes significantly correlated with the clinical disease (table 3). The 16 cases reviewed here which were clinically indistinguishable from ulcerative colitis warrant more detailed examination. It might be argued that these are cases of ulcerative colitis with some atypical histological features or that they are Crohn's disease with atypical clinical presentation. Against the first proposition is the fact that two of these cases showed the pathological appearance of classical Crohn's disease described above. Likewise, eight cases which clinically resembled primary Crohn's disease of the colon had the same histological picture of atypical ulcerative colitis seen in 10 out of the 16 "colitislike" cases. It is possible that the three histological groups are not entities, but merely represent different parts of the same pathological spectrum. For the second hypothesis, that these are all variants of Crohn's disease, it might be argued that the clinical resemblance of some of our cases to ulcerative colitis is only a superficial one; that, as not all the clinical features of Crohn's disease are found in a given case, it would be expected that there would be a certain proportion of cases in whom few or none of the clinical features of Crohn's disease would be present. This point is invalid for two reasons: First, the proportion of these cases resembling ulcerative colitis clinically (33%) is too large for these cases to be discarded as atypical; and second, it would mislead the clinician to refer to these cases as Crohn's disease, when the clinical course is characteristic of ulcerative colitis. The only justifiable grounds for referring to this group as Crohn's disease of the colon would be if the etiology of Crohn's disease were known to be identical with the etiology of both groups of disorders. From the practical point of view, the finding of these atypical histological appearances in the colon of a patient apparently suffering from ulcerative colitis does not in general affect the long term prognosis (with the exception of predisposition to neoplasm which will be discussed later). The most that can be said is that there is an increased risk of postoperative fistula formation, and that this risk is greatest in those cases that show the typical granulomatous picture defined above (group 1). It is important to note, however, that in our series, once the fistulae had healed after the operation, there was no tendency for further fistulae to form. This is in marked contrast to regional ileitis. Possibly, this is attributable to the absence of small intestinal recurrences in our series, with the one possible exception of an anastomotic recurrence referred to above. This observation has also be~n made by Comes and Stecher10 but is not in accordance with the observations of Lindner 17 and Lockhart-Mummery and Morson. 9,15 This difference may be more apparent than real. All cases were

February 1966 ULCERATIVE COLITIS AND CROHN'S DISEASE 221 excluded from our series whose history or operative findings suggested that the disease had originated in the small intestine. The seven cases which did have involvement of the terminal part of the small intestine in a granulomatous inflammation, had it in a minor degree which was only detectable histologically in the majority of cases. These cases, interestingly enough, showed a marked tendency to postoperative fistula formation. In Lindner's series,t7 10 cases out of 31 described as having "simultaneous involvement of the ileum and colon" suffered a small intestinal relapse. Our experience suggests that these cases were in fact secondary involvement of the colon in regional ileitis. Brooke,7 on the other hand, described two cases out of a total of 59 with initial involvement of the colon in granulomatous disease treated by colectomy, who subsequently developed ileal lesions proximal to the ileostomy. Thus, while subsequent small intestinal involvement may occur it is unusual; possibly our series was too small to include such cases. Among our cases, the group that behaved clinically as ulcerative colitis showed a significantly better response to steroid therapy than the remaining cases. Among the latter only three out of nine treated with steroids responded well initially-a slightly smaller proportion than that noted by Lindner17 (17 out of 31) among his mixed group of primary and secondary Crohn's disease of the colon. Yarnis and Crohn 23 also report a good response to steroids. Surgical treatment was effective in the vast majority of our cases. Thirteen out of 16 of the ulcerative colitislike cases were treated by total colectomy as the diagnosis was never questioned until the histological report came through. One patient died in hepatic failure 6 weeks after the operation, but otherwise recovery was the rule. As might be anticipated, a larger percentage of cases which usually resembled Crohn's disease underwent partial as opposed to total colectomy (14 out of 32). Patients in this group underwent a more difficult postoperative period with prolonged fistula formation, in the majority of cases from the site of the anastomosis. There was no tendency, however, for previously disease-free parts of the colon to become involved to such an extent as to require surgery following resection. This is in accordance with the statement of Yarnis and Crohn 23 that progression of the disease in the colon is the exception not the rule. Associated with this static nature of the inflammatory process is the notable absence of any tendency for fistulae to recur once they had healed up in the postoperative period. One final point is the high incidence of rectal carcinoma in this small series (table 2). In fact, of the five cases followed up for more than 8 years, three developed rectal carcinoma. All these belong to histological group 3. In one case this was a squamous carcinoma occurring in rectal mucosa, which had undergone squamous metaplasia. The other two were adenocarcinomas. It has been observed by Aylett 24 that carcinomas tend to develop in rectal strictures and that the presence of the latter condition is contraindication to ileorectal anastomosis in ulcerative colitis. Possibly our cases, which show greater amounts of fibrosis than are normally seen in ulcerative colitis, are especially prone to carcinoma for this reason. There is as yet no explanation as to why carcinoma should be more likely to occur in areas of fibrosis in the large bowel. In contradistinction it should be noted that carcinomatous change in regional ileitis is rare. Only four patients out of 1600 cases of regional ileitis developed carcinoma of the small bowel.lo Summary A survey was made of the clinical manifestations and postoperative course of 48 patients who had been subjected to total or partial colectomy for "colitis," the inflammatory reaction of which manifested varying degrees of resemblance to Crohn's disease. Criteria of selection for the survey were histological and not clinical. Cases in which the disease was believed to be as-

222 LEWIN AND SWALES Vol. 50, No. 2 sociated with extensive regional ileitis were excluded. Histologically, the cases showed a spectrum between a typical Crohn's type of inflammation and a picture resembling ulcerative colitis with serosal involvement. Clinically, the cases fell into two groups, those which resembled ulcerative colitis (16 cases) and those which resembled Crohn's disease of the large bowel (32 cases). There was a tendency for cases to conform to their histological picture but the number of exceptions made prognostication difficult. Fistulae tended to persist postoperatively for longer periods than in classical ulcerative colitis, but once postoperative fistulae had healed in these disorders no further fistulae formation occurred. A limited resection of localized disease where performed proved to be adequate. A surprising high incidence of rectal carcinoma was observed (three out of five patients followed up for more than 8 years). This occurred exclusively in the cases which presented the appearances of histologically atypical ulcerative colitis. From this study, it is concluded that the term primary Crohn's disease of the colon is probably not an entirely adequate designation for all patients with this histological picture, since many patients with this histological spectrum are clinically indistinguishable from ulcerative colitis. Subsequent small intestinal recurrence did not occur in our series, and thus the prognosis of Crohn's disease of the colon is inarkedly different from that of regional ileitis. REFERENCES 1. Colp, R. 1934. A case of nonspecific granuloma of the terminal ileum and the caecum. Surg. Clin. N. Amer.1I,: 443-449. 2. Donchess, J. C., and S. Warren. 1934. Chronic cicatrizing enteritis with involvement of the caecum and the colon. Arch. Path. (Chicago) 18: 22-29. 3. Brown, F. W., J. A. Bargen, and H. M. Webster. 1934. Chronic inflammatory lesions of the small intestine (regional enteritis). Amer. J. Dig. Dis. 1: 426-431. 4. Crohn, B. B., and B. D. Rosenak. 1936. A combined form of ileitis and colitis. J. A. M. A. 106: 1-5. 5. Wells, C. 1952. Ulcerative colitis and Crohn's disease. Ann. Roy. ColI. Surg. Eng. 11: 105-120. 6. Dukes, C. E., and H. E. Lockhart-Mummery. 1957. Practical points in the pathology and surgical treatment of ulcerative colitis. Brit. J. Surg. 45: 25-36. 7. Brooke, B. N. 1959. Granulomatous disease of the intestine. Lancet 2: 745. 8. Watkinson, G., H. Thompson, and J. C. Goligher. 1960. Right sided or segmental ulcerative colitis. Brit. J. Surg. 47: 337-351. 9. Lockhart-Mummery, H. E., and B. C. Morson. 1960. Crohn's disease (regional enteritis) of the large intestine and its distinction from ulcerative colitis. Gut 1: 87-105. 10. Cornes, J. S., and M. Stecher. 1961. Primary Crohn's disease of the colon and rectum. Gut 2: 189-201. 11. Crohn, B. B., and H. Yarnis. 1958. Regional ileitis, Ed. 2. Grune & Stratton, Inc., New York. 12. Harris, F. 1., G. H. Bell, and H. Brunn. 1933. Chronic cicatrizing enteritis; regional ileitis (Crohn). A new surgical entity. Surg. Gynec. Obstet. 57: 637-{)45. 13. Wolf, B. S., and R. N. Marshak. 1962. Granulomatous colitis (Crohn's disease of the colon): roentgen feature. Amer. J. Roentgen. 88: 662-670. 14. Marshak, R. H., B. S. Wolf, and J. Eliasoph. 1959. Segmental colitis. Radiology 73: 707-716. 15. Lockhart-Mummery, H. E., and B. C. Morson. 1964'. Crohn's disease of the large intestine. Gut 5: 493-509. 16. McEwen, L., C. Lingg, J. B. Kusner, and J. A. Spencer. 1962. Arthritis accompanying ulcerative colitis. Amer. J. Med. 33: 923-941. 17. Lindner, A. E., R. H. Marshak, B. S. Wold, and H. D. Janowitz. 1963. Granulomatous colitis: A clinical study. New Eng. J. Med. 269: 379-385. 18. Rappaport, H., F. H. Burgoyne, and H. F. Smetana. 1951. The pathology of regional enteritis. Milit. Surg. 109 : 463--502, 19. Warren, S., and S. C. Sommers. 1948. Cicatrizing enteritis (regional ileitis) as a pathologic entity: analysis of 120 cases. Amer. J. Path. 24 : 475-501. 20. Lumb, G. 1951. Cicatrizing enterocolitis. Brit. J. Surg. 39: 233-243. 21. Lumb, G., and R. H. B. Protheroe. 1958. Ulcerative colitis. A pathologic study of 152

Februa1'Y 1966 ULCERATIVE COLITIS AND CROHN'S DISEASE 223 surgical specimens. Gastroenterology 34: 381-407. 22. Goldgraber, M. B., J. B. Kirsner, and W. L. Palmer. 1958. The histopathology of chronic ulcerative colitis and its pathogenic implications, p. 935-943. In Proceedings of the world congress of gastroenterology, Washington, D. C., Vol. 2. The Williams & Wilkins Company, Baltimore, 1959. 23. Yarnis, H., and B. B. Crohn. 1960. Segmental (ulcerative) colitis. Gastroenterology 38: 721-728. 24. Aylett, S. O. 1964. Cancer risk in ulcerative colitis. Lancet 2: 820-821.