Crohn's Disease of the Colon

Transcription

1 GASTROENTEROLOGY 76: , 1979 CLINICAL CONFERENCE Crohn's Disease of the Colon DAVID M. BULL, M.D., Moderator PARTICIPANTS: MARK A. PEPPERCORN, M.D., DONALD J. GLOTZER, M.D., NORMAN JOFFE, M.D., HARVEY GOLDMAN, M.D., and WILLIAM SILEN, M.D. Departments of Medicine, Surgery, Radiology, and Pathology, Beth Israel Hospital and Harvard Medical School, Boston, Massachusetts Dr. David M. Bull (Moderator): Crohn's disease continues to challenge the gastroenterologist and the surgeon to bring relief of symptoms and to restore function. Despite the lack of specific therapy, an intimate familiarity with the natural history of the disease, its complications, and available modalities of treatment can bring about satisfactory results in the majority of patients. Our goal in this discussion is to present some of our current concepts of diagnosis and treatment of the disease. Case History A 20-yr-old dental student was admitted to the hospital for the first time in February, with diarrhea, abdominal cramps, and weight loss of several weeks duration (Table 1). Physical examination yielded normal results except for evidence of recent weight loss and a large indolent posterior anal ulcer and an anterior anal fissure. Sigmoidoscopic examination otherwise showed no abnormalities in the terminal 25 cm of rectosigmoid. Segmental inflammatory disease of the sigmoid, descending, transverse, and ascending colon was demonstrated on a barium enema with the ascending colon being the most severely involved. The terminal ileum appeared to be normal. A diagnosis of Crohn's colitis was made, and the patient was begun on sulfasalazine in increasing amounts up to 8 g/day. Because of continued diarrhea, abdominal cramps. and weight loss. prednisone, 60 mg/day was added. However. clinically significant diabetes mellitus developed and required reduction of the prednisone dose to 10 tng daily. Azathioprine, 200 mg/day (3 mg/kilo), was added but had to be reduced because of nausea and anorexia. After reduction of the dose of azathioprine to 150 mg/day, the patient began to improve. Received August 15, Accepted October 18, Address requests for reprints to: Dr. David M. Bull, Gastroenterology Unit, Beth Israel Hospital, 330 Brookline Avenue, Boston. Massachusetts The authors extend their appreciation to Dr. Franz J. Ingelfinger for his critical review of the content of this conference, and to Ms. Nelsie Assad for preparation of the manuscript by the American Gastroenterological Association /79/ $02.00 In September (7 mo after onset of symptoms). increasing rectal pain during defecation. an increase in purulent rectal discharge. and fever as high as 103 F developed. He was noted to have induration of the right buttock with a tender. fluctuant area 1 in. from the anus. Incision and drainage of an ischiorectal abscess yielded 100 ml of pus. The patient then became afebrile. It was felt that medical management had failed. and subtotal colectomy with ileostomy was carried out in September, leaving the rectum in situ. Histologic examination showed segmental colonic inflammatory disease which was most marked on the right side. without ileal involvement. The postoperative course was uncomplicated, and corticosteroids were discontinued before discharge. The patient improved progressively and was able to return to dental school. In May, 1967, an elective resection of the rectum was performed because of continued drainage from multiple fistulous openings in the perineum and a large non healing anal ulcer. The patient remained well except for failure of the perineal wound to heal despite careful local management. In December. 1967, he had an excision of the external portion of a persistent perineal sinus to provide more open drainage. Pathologic examination of the specimen showed only granulation tissue and fibrosis. In August, 1968, a still persisting perineal sinus opening :was enlarged under local anesthesia. and the cavity was curetted, but healing still did not take place. A contrast radiographic study outlined a tract which extended upward to the level of the fourth sacral segment. In July, 1969, the patient underwent an unroofing of the perineal sinus with excision of the coccyx. A number of hairs were found within the depths of the cavity. The resultant large wound granulated well and by March. 1970, had virtually healed. At this time. however, the patient had some abdominal cramps. a low-grade fever, and increasing induration and tenderness of the abdominal wall just cephalad and lateral to the ileostomy. The external aspect of the ileal stoma was normal. but digital examination revealed stenosis of the prestomal ileum just below the peritoneal level. Radiographic studies disclosed an abnormal segment of ileum typical of regional enteritis proximal to the ileostomy. The patient was treated with sulfasalazine for 3 wks without effect. The addition of azathioprine to the therapy was also ineffec-

2 608 CLINICAL CONFERENCE GASTROENTEROLOGY Vol. 76, No.3 Table 1. February September, 1966 September, 1966 May, 1967 December, 1967 August, 1968 July, 1969 March,1970 September, 1970 March, Clinical Course of Patient with Crohn's Colitis Presentation: diarrhea, cramps, and weight loss; and failure of medical therapy Incision and drainage of ischiorectal abscess. Subtotal colectomy leaving rectum in situ Proctectomy for persistent and progressive fistulas and activation of disease Drainage of persistent perineal sinus Repeat drainage of persistent perineal sinus Wide unroofing of perineal sinus with coccygeal resection Recurrent Crohn's disease of neoterminal ileum; no effect of sulfasalazine and azathioprine; Lv. hyperalimentation; peristomal abscess and fistula; and ileal resection and relocation of ileostomy Abscess adjacent to neo-ileostomy incised and drained Unroofing of persistent para-ileostomy abscess containing foreign bodies (silk sutures) Patient entirely well and working tive; fever and peristomal pain and tenderness developed. The perineal wound regressed into an indolent looking 3 X 4 cm wound lined by unhealthy granulation tissue. Because of his inability to eat, the patient was treated briefly with Lv. hyperalimentation. An abscess and fistula formed lateral to the ileostomy, and an abdominal exploration was performed in late March, The patient was found to have a large para-ileostomy abscess occupying the retroperitoneum and the abdominal wall lateral to the ileostomy. A localized area of ileitis just proximal to the stoma was resected with construction of a new ileostomy in the left lower quadrant. The site of the ileostomy and adjacent abscess was exteriorized. The postoperative course was uneventful. The perineal wound healed within a few weeks of the abdominal operation and has remained healed. In September, 1970, the patient was readmitted because of increasing tenderness just above the new ileostomy. A small para-ileostomy abscess was noted and drained. Contrast study showed a tract that extended cephalad and medially but did not communicate with the intestine. Gastrointestinal series showed no evidence of ileitis. The sinus tract was treated with daily irrigations and dressings over which the ileostomy appliance was placed. The terminal ileum remained normal by X-ray and endoscopy. Repeated X-ray studies of the sinus tract failed to show a communication with the bowel. On several occasions silk sutures extruded through the tract during irrigations. In March, 1972, because of increasing induration and tenderness, the patient underwent unroofing of a large para-ileostomy abscess extending into the peritoneal cavity. At its innermost extent, two silk sutures were found and removed. Histologic examination disclosed foreign body giant cells but no granulomas. In retrospect, it is likely that the persistent para-ileostomy sinus was caused by infected silk sutures used to ligate mesenteric vessels during ileostomy revision. After removal of the foreign bodies, the para-ileostomy cavity healed. The patient has remained well for the 6 yr since that time. Diagnosis of Crohn's Disease Moderator: Physical examination and radiography established the diagnosis of Crohn's colitis in this case. Dr. Joffe, would you present the initial x ray findings and comment on the early radiographic features of Crohn's colitis? Dr. Norman Joffe: Review of the barium enema performed in 1966 indicates that extensive changes of inflammatory bowel disease are present. There is predominant involvement of the right colon with segmental areas of abnormality in the transverse, descending, and sigmoid colon. The intervening segments of the colon and the rectum appear normal. The terminal ileum and visualized portion of the distal ileum are also normal in appearance. More specifically, the abnormal segments of colon exhibit asymmetric narrowing of the lumen with a "cobblestone" appearance due to a combination of longitudinal ulcerations and transverse fissuring. No gross fistulous tracts are detected. The overall radiographic findings are most consistent with Crohn's colitis. The differentiation of various forms of inflammatory disease of the colon is best made by a consideration of the collective clinical, radiologic, gross distributional, and histopathological features. Although the two radiographic findings most suggestive of Crohn's colitis, fistula formation and concomitant disease of the small bowel, are not present in this case, almost all of the other characteristic findings such as predominant right-sided disease, segmental distribution, "skip" lesions, rectal sparing, asymmetric involvement of the bowel contour, and longitudinal ulcerations with transverse fissures are demonstrated. Moreover, the presence of these findings indicates a severe or advanced stage of the disease. The earliest radiologic manifestations of Crohn's colitis and the best radiographic technique to demonstrate them remain topics of controversy. Marshak' states that the earliest changes consist of multiple, small, irregular nodules along the contours of the bowel, sometimes associated with thickening of the folds and/or tiny ulcerations. The changes may involve a single short segment or multiple segments in the form of skip lesions; occasionally, the process is diffuse. He believes that the conventional singlecontrast barium enema is the method of choice and emphasizes that the early findings are often best visualized on the postevacuation radiographs. Other authors/- 5 impressed by the fact that gross pathological examination of surgical specimens and colonos copy frequently reveal more extensive disease than predicted by the conventional barium enema, recommend the routine use of primary double-con-

3 March 1979 CLINICAL CONFERENCE 609 trast studies of the colon for the evaluation of suspected inflammatory bowel disease. According to Morson and Dawson,6 the earliest macroscopic signs of Crohn's colitis recognized by endoscopy or pathological examination of surgical specimens consist of tiny "aphthous ulcers" with intervening normal or edematous mucosa. These tiny ulcers probably result from mucosal necrosis overlying enlarged lymphoid follicles and are rarely demonstrated by the conventional single-contrast barium enema. The erroneous conclusion has therefore been reached that such small lesions cannot be detected radiographically. In fact, these discrete "aphthous ulcers" are clearly visible on high-quality double-contrast enemas.'-6 They are best seen en face as a central fleck of barium surrounded by a narrow, translucent halo in an area of otherwise normal-appearing mucosa. The well-defined translucent halo which surrounds each ulcer is of great help in differentiating true ulcers from artefacts due to flocculation or precipitation of poor barium suspensions. Although discrete aphthous ulcers are not specific for Crohn's disease, they are very common in this entity, and their appearance is quite different from the fine, uniform granularity seen in early idiopathic ulcerative colitis. In a recent study from England,6 aphthoid ulceration was demonstrated in 40 of 91 (44%) patients with Crohn's colitis. In approximately 50% of the patients these tiny ulcers were the only or the predominant sign of the disease; in the others, they were associated with more severe changes elsewhere in the colon and were helpful in making a more accurate assessment of the extent of colonic involvement. Recognition of these discrete ulcers in areas of otherwise normal mucosa may precede the development of more flagrant changes of Crohn's colitis by weeks" or years." The more widespread use of high-quality double-contrast enemas in the United States will provide useful information, one hopes, concerning the incidence, nature, and significance of these aphthous ulcers in the pathogenesis of Crohn's colitis, and lead to increased accuracy in the radiographic detection of early changes in this disease. An early radiographic finding which deserves emphasis is that described by Ettinger'0 as "focal" granulomatous colitis. This abnormality may be seen in conventional or double-contrast barium enemas and consists of an isolated, small ( cm) eccentric, tumor-like contour defect. This fii!-ding may represent the only radiographic evidence of colonic involvement, or it may occur in association with more obvious segmental disease elsewhere in the colon. ll We have recently discussed this radiologic sign of focal Crohn's colitis and have shown that the small isolated nodular contour defects correspond pathologically to sharply localized ulcers of variable depth associated with pronounced edema and inflammation of the adjacent mucosa and submucosa. ll In our experience they are more common than is generally recognized, and when present, aid significantly in determining the nature and/or extent of Crohn's disease of the colon. Moderator: Dr. Goldman, would you please comment on the distinguishing pathologic features of Crohn's colitis and present the findings in this case? Dr. Harvey Goldman: In distinguishing ulcerative colitis and Crohn's disease of the colon, the pathologist is not dependent solely on the microscopic sections as may be true in neoplasms and some specific infections. In inflammatory bowel disease, the macroscopic and distributional features are also important. It is often forgotten that in Crohn's disease limited to the small bowel, distinctive histologic features such as granulomas or fissures are present in less than 50% of the cases. '2 A variety of other less specific features of inflammation or repair have been noted, but no single feature is present in every case of regional enteritis. Ultimately, the diagnosis of Crohn's disease of the small intestine is determined by the demonstration of an inflammatory disorder without a known or apparent etiology. It would seem reasonable to expect that specific histologic features may also be absent in some cases of Crohn's disease of the colon. In our collected series '3 of 176 cases of inflammatory disease of the colon, a highly significant association between certain distributional features, fissures, and granulomas was observed and served to define the cases of Crohn's disease. These observations formed the basis for our overall use of combined distributional and histopathological criteria in the diagnosis of ulcerative colitis and Crohn's disease of the colon. Granulomas and/or intramural fissures, representing the only specific microscopic features of Crahn's disease, were present in 80 cases, including 51 with and 29 without characteristic gross or distributional features. There were 23 additional patients without such specific histologic features but in whom the distribution of the lesion was indicative of Crohn's disease, including those with proven concomitant ulcerating disease of the ileum or segmental colonic involvement. The histologic features of these 23 cases were otherwise similar to the 73 cases judged by our combined criteria to represent ulcerative colitis. Thus, of the 103 cases of Crohn's disease of the colon in our study, the,diagnosis was determined by both distinctive distributional and microscopic features in 50%, by specific microscopic features alone in 28%, and by distributional features alone in 22%.

4 610 CLINICAL CONFERENCE GASTROENTEROLOGY Vol. 76, No. 3 In the evaluation of a surgical specimen, gross inspection should serve to confirm or amend the results of radiographic and endoscopic examinations and to identify cases with distinctive macroscopic features which, if confirmed microscopically, are indicative of Crohn's disease: (a) extensive and ulcerative disease of the ileum; (b) fistulas, sinuses, or intramural fissures; (c) segmental disease, including skip areas, spared rectum, or focal small aphthous ulcers. Cases with ulcerative colitis may have areas of uneven severity, simulating skip lesions or a spared rectum.14 In such instances, microscopic sections will reveal a diffuse, albeit milder, abnormality. Intramural fissures are best detected grossly by viewing the bowel wall underlying areas of ulceration in profile. Such areas should be checked histologically to distinguish between the characteristic isolated fissures of Crohn's disease and the cracks that may be seen in thinned out portions of the wall in toxic megacolon.'s Numerous histologic features other than fissures and granulomas have been mentioned in the past as potentially discriminating criteria between ulcerative colitis and Crohn's disease. We have noted, however, that many features (crypt abscesses, inflammatory pseudopolyps and submucosal lymphoid nodules, edema, and fibrosis) occur with equal frequency in the two disorders. We have also observed no differences in the presence of regenerative, metaplastic, or atrophic glands, or the character of the inflammation (other than granulomas). Unlike Crohn's disease of the small bowel, muscular hypertrophy is not found in most cases of Crohn's colitis. Indeed, when significant hypertrophy is present, one must suspect diverticular disease. Serosal inflammation, including many lymphoid aggregates in the outer portion of the bowel wall, is clearly more common in Crohn's disease, but serosal inflammation can be found in many cases of ulcerative colitis with deep ulcerations. The demonstration of preservation of mucous cells in the mucosal crypts has been described by others as a reliable and common feature in Crohn's disease!6.17 This feature appears to be the microscopic representation of the focal Crohn's lesion, correlating with gross segmental or skip lesions. In summary, the diagnosis of ulcerative colitis depends on the total demonstration of continuous involvement limited to the rectum and c ~ l othe n, absence of fistulas or fissures, and. an entirely of the small bowel, all of the features need not be and usually are not present in an individual case. The ileocolectomy specimen in this case consisted of 15 cm of ileum and 95 cm of colon. The ileum showed some prominence of the mesenteric fat, but there were no mucosal ulcerations or other alterations. Focal irregular and longitudinal ulcerations together with inflammatory pseudopolyps were present throughout the colon, cecum, and appendix; the lesions were more marked in the right portion and were separated in many areas by normal mucosa. There were no fistulas or strictures. Microscopically, the ulcers were limited to the submucosa, with associated submucosal edema, inflammation with lymphoid nodules and lymphatic dilatation. There was focal serosal inflammation\ and numerous granulomas without necrosis were observed in the submucosa and serosa. There was no muscular hypertrophy, and no intramural fissures were seen. The distal few centimeters and resection margin of colon were free of gross or microscopic diseilse. The rectum, removed 8 mo later, contained a 4.5 X 2.5 discrete nlcer just above the anal verge. Tiny ulcers and mucosal polyps were present more proximally, separated by areas of normal mucosa. The ulcers extended into the submucosa, and submucosal granulomas were noted both in the ulcerated areas and in other areas of grossly' intact mucosa. The pathologic diagnosis of Crohn's disease in this patient was based on the demonstration of a segmental distribution of the colonic lesions and the presence on microscopic examination of focal ulcers and granulomas.. Moderator: Dr. Goldman, would you discuss the use of mucosal biopsies in the assessment of inflammatory bowel disease? Dr. Harvey Goldman: Mucosal biopsy specimens of the rectum and colon, obtained at sigmoidoscopy and colonoscopy, may provide important information. The specimens may serve to: (a) confirm or document the presence of a suspected colitis; (b) detect or exclude other specific causes of colitis; (c) assist in the diagnosis of the particular form of colitis, whether ulcerative or Crohn's; (d) determine the extent, activity, severity, or response to therapy of the colitis, whatever the type; and (e) identify epithelial dysplasia or carcinoma. As indicated previously, the diagnosis of the particular form of colitis is determined by the combined gross, including distributional, and histopathological features. In this regard, nonspecific inflammatory reaction on ~ i s t o lex amination. Crohn's disease of the colon is desig considered the sale determinant; rather, they may o g i the c superficial mucosal biopsy specimens cannot be nated if anyone or more of the following is present: assist in an individual case. It must be remembered (a) focal or segmental involvement of the ileum or that the biopsy contains a sample of only the mucosa and at most the upper portion of the sub colon; (b) fistulas or fissures; and (c) granulomas on histologic examination. As is true of C'rohn's disease mucosa. Therefore, certain important criteria such

5 March 1979 CLINICAL CONFERENCE 611 as intramural fissures or prominent serosal inflammation cannot be employed. The available patterns17 that can be safely discerned are: (a) a normal biopsy; (b) a diffuse colitis or proctitis. characterized by a definite alteration of the surface and crypt epithelium (i.e., degeneration. regeneration. metaplasia, or atrophy); (c) a focal colitis or proctitis. meaning that some portion of the biopsy is normal; and (d) the presence of granulomas. which may occur in either a normal area or in an area of inflammation. Crohn's disease would be supported or determined by the presence of a normal biopsy as confirmation of a spared rectum or other skip area. the appearance of a focal colitis. or the finding of granulomas. A focal proctitis or colitis does not occur in ulcerative colitis; it would identify a case of Crohn's disease, provided other specific infectious and allergic disorders have been excluded. Only the appearance of a diffuse proctitis or colitis can be considered consistent with ulcerative colitis. Crohn's disease. however. may also show areas with diffuse alteration. Therefore, given biopsy specimens that show diffuse colitis. the diagnosis must rest on other examinations. In the past. too much effort has been expended in comparing mucosal biopsy specimens with radiographic and endoscopic modalities. Rather. all information should be used in a collective and not a competitive fashion. The use of mucosal biopsies to determine the extent or degree of activity of a colitis, whatever its type, has been achieving increasing attention. Clearly, more experience is needed, but such biopsies may prove useful in determining the response to medical treatment. the extent of planned surgery, and the probability of clinical recurrence. Biopsies have remained the essential tool in the evaluation of suspicious masses or strictures and in the overall detection of carcinoma. More recently, biopsies have been sought in high risk patients to detect severe epithelial dysplasia, as a marker of concomitant or future carcinoma.'8 Their uses and interpretation in such cases have been dealt with extensively in several recent articles. '9-23 Medical Management of Crohn's Disease of the Colon Moderator: Symptomatic management and supportive care of the physical and emotional needs of the patient are the keystones of treatment of Crohn's disease, however severe. The sicker the patient, the more imperative is thoughtful general management, including careful attention to fluid and electrolyte balance. correction of anemia, and provision of adequate nutrition. Dr. Peppercorn, without minimizing the critical importance of these general aspects of treatment which are outside the scope of today's clinical conference. may I ask you to discuss in particular the pharmacologic agents available for treatment of Crohn's disease, and to comment specifically on the treatment this patient received? Dr. Mark Peppercorn: The medical management of this patient is typical of that employed in many such patients with Crohn's disease. Although sulfasalazine and corticosteroids have been widely used in the treatment of Crohn's disease, their efficacy in this disease has not been proven until recently. This is in contrast to their established benefit in ulcerative colitis. Recent results from the National Cooperative Crohn's Disease Study2' demonstrate the efficacy of sulfasalazine over placebo in actively symptomatic Crohn's disease treated for 4 mo. Prednisone was also effective in such patients treated for 4 mo. There was no response to prednisone in the few patients with disease limited to the colon although the same group responded to sulfasalazine. Conversely, very recent data from this continuing study2s show that active disease limited to the ileum responded to prednisone over placebo, but not to sulfasalazine. Based on studies which confirm previous clinical impressions, I would approach the drug therapy of our patient in much the same manner as was done. In the absence of fulminant symptoms sulfasalazine is a good initial choice. Patients seem to do best when started on a low dose with gradual increase over several days to a maximal dose of 4 g/day. In the event of lack of response to sulfasalazine over a 3- or 4-wk period, a corticosteroid such as prednisone would be added at a dose of mg/day depending on the severity of symptoms. Although the patient apparently responded to this regimen. clinically significant diabetes mellitus developed presumably related to the high dose steroid therapy. Side effects are not uncommon with both of these medications. Although this patient had no apparent reaction to sulfasalazine despite the high doses, the frequency of side effects is generally reported to be about 20%. Recent work on the metabolism of sulfasalazine has shed some light on the possible mode of its action. Studies in germ-free and conventional rats have established that the intestinal bacterial flora is solely responsible for the breakdown of sulfasalazine to its two principal metabolites, sulfapyridine and 5-aminosalicylate. 26 The role of the flora in the drug's metabolism has been confirmed in patients,27 and distribution studies 28 reveal that the parent drug is extensively degraded in the colon. The salicylate moiety is excreted primarily in the feces while sulfapyridine is absorbed, further metabolized by the liver and excreted in the urine. These findings sug-

6 612 CLINICAL CONFERENCE GASTROENTEROLOGY Vol. 76, NO.3 gest that the efficacy of the parent drug, sulfasalazine, may be due to the fact that it serves to deliver one or both of its active metabolites to diseased areas of the bowel. 29 This speculation has led to a recent investigation 3o in which patients with ulcerative proctitis were randomly treated with enemas containing either sulfasalazine, 5-aminosalicylate, or sulfapyridine. This preliminary study concludes that 5-aminosalicylate and sulfasalazine but not sulfapyridine are effective locally. These results suggest that 5-aminosalicylate may be the active moiety in sulfasalazine. These studies, along with the observations that the common adverse reactions to sulfasalazine such as headache, nausea, and anorexia may be related to the serum sulfapyridine level,31 could lead to the development of a less toxic but equally effective drug. Because of the development of diabetes, prednisone had to be tapered in this patient and azathioprine was added. Although azathioprine and related drugs are commonly used in Crohn's disease, the role, if any, for these drugs remains in doubt. Although a number of uncontrolled studies reported glowing results of treatment with azathioprine, the National Cooperative Crohn's Disease Study found no beneficial effect of azathioprine alone in patients with actively symptomatic Crohn's disease over the 4 mo period of the study.24 This conclusion has been challenged by Present et al.,32 who used 6-mercaptopurine (6-MP) in a controlled double-blind manner in a group of patients with Crohn's disease refractory to sulfasalazine and/or corticosteroids. A statistically significant improvement was noted in the 6-MP group as compared to the placebo. Present et al. pointed out that the therapeutic response noted in their patients could take up to 4-6 mo, a period which was beyond the time frame of the National Crohn's Study. I am forced to conclude that the role of immunosuppressive therapy in Crohn's disease is still unclear and that further long-term studies are needed. Although the efficacy of azathioprine as a single agent can be questioned, it seems to have a steroidsparing effect in both Crohn's disease and ulcerative colitis ' Thus the drug may be useful in minimizing the side effects of corticosteroids such as the diabetes which occurred in this patient. Surgical Management of Crohn's Disease of the Colon Moderator: Dr. Glotzer, would you comment on the surgical management of this patient and the indications for operation in colonic Crohn's disease? Dr. Donald J. Glotzer: Most of the troublesome complications encountered in colonic Crohn's dis- ease and its surgical treatment occurred in this one patient. Nonetheless, he is now in excellent health and working, an outcome which is by no means unique in contrast to frequently expressed pessimism about prognosis in colonic Crohn's disease. When this patient came to operation, he had received the gamut of available agents known to be effective for the nonoperative treatment of his disease.,dr. Peppercorn has indicated that the conduct of treatment was rational even as judged by 1978 standards. Obviously, the ineffectiveness of medical therapy in this particular case is not a measure of the overall value of nonoperative management. Surgical treatment was utilized as part of a therapeutic continuum rather than as a competitive modality of treatment. Whether the indication for operation in this patient should be considered the development of perirectal complications or failure of nonoperative management is a moot point. Failure of medical management should always be implicit in the indications for operation in both Crohn's disease of the colon and ulcerative colitis because of the destructive nature of the operations and the threat of recurrence. The indications for operation in colonic inflammatory disease are listed in Table 2. These are, for the most part, similar in ulcerative colitis and Crohn's disease of the colon, but there are some differences worthy of discussion. Perirectal abscesses and fistulas are rare in ulcerative colitis but occur frequently in Crohn's disease of the colon. These are often so extensive and destructive that they are rather frequent indications for operation, as was the case in this patient. Similarly, enteric fistulas frequently lead to operation in colonic Crohn's disease but do not occur in ulcerative colitis. Although it was initially thought that toxic megacolon and cancer did not occur in Crohn's disease,35 it has now become clear that each may complicate this disease. Farmer et al."6 found that toxic megacolon was the indication for operation in 20% of patients operated upon for what they termed the colonic pattern of Crohn's disease of the colon. With regard to complicating cancer in colonic Crohn's disease, Weedon et al. 37 have found a 20-fold increased risk of colonorectal cancer (P < 0.001) compared to that expected in the general population. However, because this risk amounts to only about 3% after 20 yrs exposure to the disease, it does not seem to be sufficient to warrant prophylactic colectomy in longstanding disease. Neither would it mandate removal of a functionally isolated rectal stump, contrary to proper management in ulcerative colitis. Clearly, however, a number of patients are removed from cancer risk in colonic Crohn's disease by operations made necessary by other complications.

7 March 1979 CLINICAL CONFERENCE 613 With regard to failure of medical management, some. physicians might have persisted with nonoperative treatment in this patient longer than we did, despite the severe perirectal complications, because of their belief that prognosis after operation of Crohn's colitis is poor. Although, in absolute terms, failure of medical management would mandate operation, in practical terms, this judgment is somewhat subjective. Therefore, if the postoperative prognosis in Crohn's colitis indeed were substantially different from that of ulcerative colitis, the proper trade-off of disability of disease vs. treatment might be different in the two diseases because ulcerative colitis is commonly considered to be cured by a colectomy. A valid comparison of the postoperative courses of Crohn's disease of the colon and ulcerative colitis requires careful definition of the populations having each disease and a precise definition of recurrence. Follow-up studies of this type carried out by my colleagues, including Dr. Goldman, and myself have led to somewhat surprising and perhaps controversial conclusions. I3 The determination of populations at risk and the definition of recurrent disease are not major problems in those patients who have lesions that can be encompassed by resection and anastomosis. Such a segmental distribution of disease within the intestine lending itself to this type of operation virtually defines such cases as Crohn's disease. Recurrent disease can also be rigorously defined in these patients by the development of unequivocal X-ray changes or by pathologically confirmed disease when reoperation is required. We have observed recurrence of disease in almost 75% of patients after anastomotic procedures for Crohn's colitis and ileocolitis,i3 and thus we agree with those who cite a high rate of recurrence after such operations in Crohn's disease of the colon. Despite the high recurrence rate, however, I believe that an anastomotic procedure is the operation of choice when anatomically feasible because it may avoid ileostomy altogether in a few patients and may postpone its construction for long periods in others. The years of life and maturation without an ileostomy provided by an anastomotic procedure may allow these patients, who are frequently quite young, to cope with a more radical procedure at a later time. The real difficulty in the comparison of ulcerative colitis and Crohn's disease is the determination of their respective courses after colectomy and ileostomy. We have found that over 50% of patients with inflammatory disease of the colon had one or more of the commonly accepted clinical, distributional and histologic features of Crohn's disease listed in Table 3 and were therefore considered to have Crohn's colitis or ileocolitis. I3 Before our review, the Table 2. Indications for Operation in Colonic Inflammatory Bowel Disease 1) Intractability-failure of nonoperative management a) Retardation of growth and maturation in children b) Inability to work or to function socially despite optimal management (failure of corticosteroids, sulfasalazine, and?azathioprine) c) Complications of chronic corticosteroid treatment 2) Fulminating colitis or toxic megacolon which fails to respond promptly to therapy 3) Perforation 4) Unremitting hemorrhage (uncommon) 5) Carcinoma, high statistical probability of carcinoma, or pre cancer on biopsy (in some cases) 6) Stricture a) Obstructive symptoms in Crohn's disease and in ulcerative colitis (rare) b) Unresolved differential diagnosis with carcinoma 7) Anal and perianal complications a) Stricture (rare) b) Severe and destructive abscesses and fistulas failing to respond to local surgical therapy and systemic management 8) Unremitting cutaneous and systemic complications (arthritis, uveitis, liver disease, pyoderma, and erythema nodosum) (rare) majority of patients who proved to have Crohn's disease of the colon had been considered to have ulcerative colitis. Therefore, we feel that valid retrospective studies of prognosis in Crohn's disease require careful study and review of material on the entire population of patients with inflammatory bowel disease and should not rely on the previous clinical and pathological diagnoses. A second major problem in determining the risk of recurrence after ileostomy lies in the definition of recurrence. The ileostomy itself may give rise to conditions other than recurrence which may require reoperation. The scope of such reoperations (or ileostomy revisions) can range from an excision of a cutaneous cicatrix to a major intraabdominal procedure requiring ileal resection. Ileostomy revision may be required for obstruction, prolapse, recession, skin irritation, or other purely mechanical problems as well as for an inflammatory condition. Ileitis can result from partial obstruction, from poorly defined Table 3. Clinical, Distributional and Histologic Features Leading to Diagnosis of Crohn's Disease of the Colon 1) Associated extensive small bowel involvement or classical regional enteritis 2) Predominantly right-sided colitis 3) Enteroenteric or enterocutaneous fistulas; large and complex perianal fistulas; large indolent anal lesions 4) Normal rectum by sigmoidoscopy 5) Clearly segmental disease 6) Presence of fissures and/or granulomas on histologic examination

8 614 CLINICAL CONFERENCE GASTROENTEROLOGY Vol. 76. No.3 entities such as prestomal or post colectomy ileitis or true recurrent Crohn's disease as illustrated by this patient; pathologic findings in such cases may range from trivial and nonspecific to those typical of Crohn's disease. For these reasons in our follow-up studies we have avoided making the often necessarily subjective and arbitrary distinctions between these various entities and have simply compared the numbers of ileostomy revisions in ulcerative colitis and Crahn's disease. Using this approach, we have found that although ileostomy revisions of all types were necessary in 40% of patients with Crohn's colitis or ileocolitis and 30% of those with ulcerative colitis, this difference was not statistically significant. There was also no significant difference in the frequency of those revisions which required resection of ileum for obstruction, bleeding or fistula and thus could be construed as having been done for recurrent disease (32% Crohn's disease vs. 23% ulcerative colitis). Moreover, a simple enumeration of the percent of patients needing reoperation after ileostomy cannot by itself describe the long-term prognosis after operation. We have shown (Figure 1) that the risk of requiring a revision in a given postoperative year in Crohn's disease and ulcerative colitis is essentially the same after the first two postoperative years.13 No patient in the series developed short bowel syndrome resulting in severe nutritional problems even though a number with both Crohn's disease and ulcerative colitis required multiple revisions. Our patient today remained well after his revision for what was obviously recurrent disease. I believe that an important reason for our rather favorable view of the outcome of operation for Crohn's disease of the colon lies in the fact that we have studied all of the patients in the population subject to the risk of recurrence. We believe that the denominator of the fraction, recurrence/those at risk, is much too small in those series reporting very high rates of recurrence. 3B 39 Our roughly 50% relative incidence of Crohn's disease of the colon vs. ulcerative colitis in the population of patients with co Ionic inflammatory bowel disease is in accord with more recent prospective analyses.<o A feature of our studies confusing to some is the fact that we have compared rates of revision rather than rates of recurrence for reasons I hope I have made clear. However, we can attempt to estimate a "true" recurrence rate by defining as recurrent disease those cases with grass and radiologic features typical of Crohn's disease (as illustrated by our patient today) or those with granulomas on microscopic examination. With this admittedly imprecise definition, we would have a recurrence rate of about 16% over the 5-36 yr follow-up period of this study (mean 14 yr). This figure is comparable to most found in the literature with the exception of those series with what we believe are spuriously low prevalences of Crohn's disease. Nugent et al.,41 who also analyzed their entire population of patients with colonic inflammatory bowel disease, found a recurrence rate of only 3%, a rate even lower than ours. Thus, since the long-term course of Crohn's disease of the colon after operation is rather favorable, we feel that there is no solid basis for delaying operation in Crohn's disease of the colon beyond that which would be appropriate for a patient with ulcerative colitis. Diagnosis and Management of Complications Moderator: Dr. Peppercorn, our patient had undergone a successful two-stage proctocolectomy and ileostomy and appeared to be doing well. Were there any medical measures that should have been introduced prophylactically to prevent the recurrent disease he developed? Dr. Mark Peppercorn: The decision not to begin any treatment after proctocolectomy and ileostomy in the hope of preventing recurrence can now be supported by data from well-controlled studies. The National Crohn's Disease Study has shown that neither sulfasalazine nor prednisone prevents flare-ups of disease after remission or prevents postoperative recurrence up to 2 yr after operation. 24 Recently, Bergman and Krause have also published results showing that a combination of sulfasalazine and low-dose corticosteroids was not effective in preventing postoperative recurrence of disease. 42 Moderator: Four years after ileostomy, the patient, who, except for the persistent perineal sinus, had fared quite well in the interim, developed symptoms and signs of recurrent disease. One of the problems we would like to discuss is the differentiation of actual recurrence of disease and other inflammatory and mechanical problems to which the stoma is subject. Dr. Joffe, can the radiologist help here? Dr. Norman Joffe: Radiology plays an important role in the evaluation of clinical symptoms which arise after the construction of an ileostomy particularly when such symptoms develop weeks, months, or years after operation. The radiologic procedures employed include a retrograde ileostogram, antegrade barium study of the small bowel, and contrast injections of sinus or fistulous tracts. Any or all of these techniques may provide valuable information concerning the cause and nature of the clinical problem. In our patient, for example, barium studies done in March, 1970, 3.5 yr postoperatively, disclosed typical changes of recurrent Crohn's disease

9 March 1979 CLINICAL CONFERENCE > I-...J ~ CD o Cl: q,, 0.10 I Crohns Disease _ Ulcerafive COlifis _ YEARS Figure 1. Plot of probability per patient year follow-up of ileostomy revisions done because of obstruction, bleeding or fistula which required excision of intestine for correction of problem. Probability derived from number of revisions in given follow-up year divided by number of patients at risk in that year. (From Fawaz KA, et ai, Gastroenterology 71: , 1976). involving the prestomal ileum (Figure 2). In September. 1970, 6 mo after a segment of ileum had been resected and a new ileostomy constructed. a retrograde ileostogram and small bowel examination showed normal appearances of the prestomal ileum (Figure 3A). while injections of the abdominal wall sinus openings (Figure 3B) failed to disclose fistulous communications with the bowel. These findings suggested that the patient's clinical problem at this time was not related to recurrent Crohn's ileitis and this was confirmed by his subsequent course. In patients with a well-functioning ileostomy. barium studies generally show the prestomal ileum to be normal in caliber with intact mucosal folds which extend virtually all the way to the stoma itself. If barium is administered orally, motility of the small bowel is normal. In patients who have symptoms related to a malfunctioning ileostomy, barium studies, performed either retrograde via the stoma or by oral ingestion, may show one of two major types of abnormality: (a) changes due to so-called "ileostomy dysfunction" or (b) prestomal ileitis. The radiologic findings in patients with ileostomy dysfunction secondary to a purely mechanical problem such as stomal stenosis consist of moderate to marked dilatation of the prestomal ileum with dilution of the barium suspension by retained secretions. The circular mucosal folds within this dilated segment are either thickened, few in number and widely-spaced, or there is almost total effacement of the mucosal pattern (Figure 4A). If barium is administered orally there may be a delay in transit time. Digital examination of the stoma may reveal a stenotic ring; however, a distinct stricture is not always demonstrable in patients with this clinical syndrome and radiologic picture. The precise 16 cause of the "ileostomy dysfunction" in such cases is unclear; it may be related to a functional disturbance resulting from diminished propulsive activity of the neoterminal ileum which is unable to handle a particular amount of flow at a given time. 43 In some instances superficial ulceration secondary to the obstructive process is seen. The appearances are not unlike those sometimes found in the colon proximal to an obstructing lesion such as carcinoma, and the pathogenesis of this type of prestomal ileitis may in fact be similar. The possibility of recurrent Crohn's disease of the prestornal ileum must always be considered in the differential diagnosis of stomal dysfunction. Barium studies will typically show changes identical to those seen in Crohn's disease in the nonoperated patient. The prestomal segment appears narrowed and rigid with a "cobblestone" mucosal pattern (Figure 4B); sinus tracts (Figure 2) or fistulae may be demonstrated and there is separation of adjacent small bowel loops (Figure 2) due to marked thickening of the diseased bowel wall and/or adjacent mesentery. Figure 2. Small bowel examination in March, 1970, shows typical changes of Crohn's disease involving segment of prestomal ileum. There is irregular narrowing and rigidity of the diseased area with transverse fissuring on its inferior aspect; a sinus tract (open white arrow) is clearly demonstrated, and there is separation of the adjacent loops of small bowel

10 616 CLINICAL CONFERENCE A B Figure 3. A. Retrograde ileostogram performed in September, 1970, shows normal appearance of the prestomal ileum. B. Contrast medium injected via catheter inserted in upper abdominal wall sinus opening (closed white arrow) fills irregular cavity with blind tract extending superiorly and medially; the contrast also extends inferiorly (open white arrow) and "efluxes through the lower abdominal wall sinus opening. No fistulous communication with bowel is demonstrated. Early or mild changes of prestomal Crohn's disease may be more ambiguous, but in my experience narrowing or at least lack of dilatation has been a helpful distinguishing feature from other types of prestomal ileitis which I will now discuss. GASTROENTEROLOGY Vol. 76, No.3 There is in addition to recurrent Crohn's disease and dysfunctional ileitis, a nonspecific type of prestomal ileitis of uncertain origin. This form of "prestomal ileitis" may develop in any patient with an ileostomy regardless of the primary reason for the surgery. The clinical and pathological findings in this type of nonspecific ileitis have been fully described Radiologically, the findings are somewhat similar to those seen in simple "ileostomy dysfunction" in that there is moderate to marked dilatation of the prestomal ileum with dilution of the barium by retained secretions. In addition, however, there are gross inflammatory changes characterized by mucosal and submucosal swelling and occasionally discrete ulcerations or pseudopolyposis may be evident. An example of this type of nonspecific prestomal ileitis is illustrated in Figure 4C. In our experience, the marked dilatation of the inflamed segment is a most helpful differentiating feature from true Crohn's ileitis. In the latter it is distinctly unusual for the diseased segment itself to be markedly dilated. Moderator: Dr. Glotzer, undoubtedly the surgical management of problems related to the ileostomy, including those related to recurrent disease, differ from patient to patient. Could you outline the principles of surgical management and elaborate on the surgical treatment you provided for this patient? Dr. Donald J. Glotzer: With regard to the treatment of obvious recurrent prestomal Crohn's disease such as our patient developed, it is clear that we did him no service by the brief periods of treatment with sulfasalazine and azathioprine. During the delay entailed thereby, a peristomal abscess and fistula developed which made it necessary that the ileostomy be moved to a less desirable location. Because of this and similar experiences, I have come to regard prestomal Crohn's disease as primarily a "surgical" condition, especially in view of the data cited earlier about the favorable long-term course after ileostomy revision. True, some patients with obvious prestomal Crohn's disease may get along without operation for long periods of time. However, others, especially those developing acute symptoms and signs such as abdominal cramps, peristomal pain and tenderness with a stenotic, "cobblestoned" terminal ileum by X-ray examination, may be headed for serious trouble as was the case in our patient today. We feel that we have avoided unnecessary complications and suffering in some such patients by a prompt resection of the diseased ileum, since small perforations and abscesses were found still contained within the mesentery at operation and on subsequent pathologic study. Presumably if these patients had not been operated upon when they were, they would have developed large peristomal

11 March 1979 CLINICAL CONFERENCE 617 B Figure 4. A. Retrograde ileostogram showing typical features of "ileostomy dysfunction" secondary to a stomal stenosis. Proctocolectomy and ileostomy were performed for idiopathic ulcerative colitis. Note markedly dilated prestomal ileum with almost complete effacement of mucosal pattern. Dilution of the barium in this segment was better shown in the ante grade small bowel examination. B. Retrograde ileostogram showing typical changes of Crohn's disease of the prestomal ileum. There are narrowing and rigidity of the diseased segment and typical "cobblestone" mucosal pattern. C. Small bowel examination showing typical features of nonspecific prestomal ileitis. Proctocolectomy and ileostomy were performed for idiopathic ulcerative colitis. Note swollen mucosal folds and superficial ulceration in markedly dilated prestomai segment. Dilution of the barium by retained secretions is well shown. abscesses and fistulas such as was the case in our patient. Patients with ileostomy for Crohn's disease can have problems similar to those occuring after opera- tion for ulcerative colitis. If mechanical, as is usually the case, the problem should be corrected by the appropriate operation, typically a local revision of the ileostomy. In addition, there exist poorly defined entities just discussed by Dr. Joffe and alluded to by myself, variously termed "postcolectomy ileitis," "mucosal ileitis," or "nonspecific prestomal ileitis." These disorders are apparently unrelated to organic or functional obstruction of the ileostomy. KnillJones et a1. 44 described two forms of postcolectomy ileitis: an acute form which was fulminating and usually ended in perforation if not promptly resected as well as a latent form which responded to corticosteroids. The interface between these various entities and inflammation due to obstructive, me-

12 618 CLINICAL CONFERENCE GASTROENTEROLOGY Vol. 76, No.3 chanical problems are not at all clear as far as I am concerned. Each must be differentiated from recurrent Grohn's disease, which I believe generally should be resected for the reasons I have just cited. Before we leave this patient's ileostomy problems, I would like to discuss briefly his peristomal abscess and sinus, which he developed subsequent to his resection for recurrent Grohn's disease. We feared he might have a second recurrence. We have recently seen about a half dozen such patients who were assumed to have had recurrent Grohn's disease with apparent fistulas, who ultimately proved to have sinuses caused by infected sutures. These sinuses Gleared up with removal of the offending fpreign body as they did in our case today, just as in patients without Grohn's disease. Thus, in Grohn's disease, a draining sinus, even a very complicated one, cannot be assumed to be a fistula. Neither can proven fistulas necessarily be assumed to be indicative of recurrence. Patients with Grohn's disease, particularly those with complex operations done in infected sites, are susceptible to the same intrinisically surgical complications as patients with other diseases. Moderator: Dr. Goldman, would you elaborate on Dr. Glotzer's points concerning recurrence? Would you then discuss the pathologic findings and their relationship to the points you made previously concerning diagnosis? Dr. Harvey Goldman: In the study which Dr. Glotzer and I have alluded to,13 we reviewed the ileal segments removed at the time of ileostomy revision in patients with both ulcerative colitis and Grohn's disease. Overall, the group with Grohn's disease had more revisions, bigger resections, and more prominent inflammation, some of which clearly represented true recurrence of disease. However, there was considerable overlap in the two groups, suggesting that many revisions were required for problems other than recurrent disease. Of the 19 revisions in patients with ulcerative colitis, no or minimal nonspecific inflammation was noted in 10, broad ulcers extending into the submucosa in 5 and muscularis externa in 1, and sinus tracts in 3; no revision specimens showed granulomas. Of 35 revisions in patients with Grohn's disease, no or nonspecific inflammation was seen in 16, broad ulcers into the submucosa in 7 and deeper muscle in 4, sinus tracts or fissures without granulomas in 2, and granulomas in 6. Thus, about 50% of the Grohn's cases had no ileitis, and only a small proportion of the total (those with granulomas) could be interpreted as representing disease recurrence. We are wary of ascribing the other cases to recurrence, since identical pathological alterations were noted in the patients with tilcerative colitis. Since granulomas do not occur in all cases of Grahn's disease, however, some of the revi- sions with less specific abnormalities may represent recurrence even though we cannot distinguish them. In such cases, as in the original colonic specimen, the pathologist should seek evidence of focal involvement or intramural fissures at areas away from the stoma. In the case under discussion, the resected ileal segment measured 20 cm in length, the proximal 5.5 cm of which were free of gross or microscopic disease. The remaining mucosa showed a finely polypoid or cobblestone appearance, and histologic examination revealed tiny ulcers extending into the submucosa. A transmural sinus tract was present 6 cm from the distal end which represented the fistulous tract; and, surrounding the stoma, there was a 6 X 3.5 X 3 cm mass of inflammatory tissue. Granulomas without necrosis were found in the mesenteric lymph nodes. A pathologic diagnosis of recurrent Grohn's disease was based on the presence of granulomas and was supported by demonstration of a fistulous tract away from the stoma. Moderator: The final complication this patient had was his persistent perineal sinus. Dr. Glotzer, would you discuss the pathogenesis and treatment of this entity? Dr. Donald ]. Glotzer: Depending upon the definition of persistence,46 a persistent perineal sinus affects as many as 60% of patients after proctectomy for inflammatory bowel disease. I would estimate that 5-10% of patients have this complication. Disability caused by a persistent perineal sinus may range from nuisance and inconvenience to major sepsis. Persistent perineal sinus is much more frequent after proctectomy for inflammatory bowel disease than after operation for cancer, in which the excision of tissue and resultant defect is, paradoxically, more extensive. In our experience, healing of the perineal sinus after proctectomy for cancer is usually complete in 6-8 wk, whereas complete healing rarely occurs before 5 or 6 mo in patients with inflammatory bowel disease.'7 Persistent perineal sinus is said to be more common in Grohn's disease than in ulcerative colitis, but a study by Irwin and Goligher 48 does not seem to substantiate this contention. Because of the frequency of perineal sinus in inflammatory bowel disease and its failure to respond to treatment, there is a tendency to view it as a part of the disease rather than as the problem in wound healing which we believe that it is. If the patient has Grohn's disease, it is even more likely that the perineal sinus will be regarded as an inevitable and hopeless consequence of a mysterious disease, in accordance with a general nihilistic approach to treatment. This belief gives rise to treatment with local and systemic antibiotics and topical agents and even

13 March 1979 CLINICAL CONFERENCE 619 such irrational maneuvers as the instillation of nitrogen mustard into the sinus. This problem in wound healing is very much analogous to the problem of a thoracic empyema in which there is not only inadequate dependent drainage but also a surrounding rigid bony structure (the thoracic cage) which does not allow obliteration of the infected space. The thoracic surgeon solves the problem of empyema by removing ribs to provide wide drainage and in extreme cases by thoracoplasty to obliterate the space. In a persistent perineal sinus there is also a small opening into a large cavity with rigid walls supported by the bony pelvis. Chronic infection prevents the obliteration of this space which would normally occur by descent of the pelvic peritoneum, backward shift of the urogenital structures and upward movement of the soft tissues of the perineum as shown in Figure 5. In the patient under discussion, we ultimately performed a corrective operation which Dr. William Silen and I have described 47 which entails unroofing the cavity by excising the coccyx or even the distal 2 sacral segments. Using this approach, we have observed complete healing in 18 of 20 such patients with only minor persistence in the others. This patient's sinus, which had persisted for over 2 yr, healed promptly after unroofing. We and others have begun to take advantage of our understanding of this special problem in wound healing by closing the perineal wound primarily in suitable patients. We have used suction catheters to hasten descent of the closed pelvic peritoneum and thus obliterate the space. 47 Others 4B 49 have not closed the pelvic peritoneum at all and have achieved the same goal. This patient, with perineal fistula and abscess, would not have been suitable for primary closure because sepsis would have precluded primary healing, but many other patients with inflammatory bowel disease are candidates for this approach. Besides preventing the perineal sinus, it is gratifying to have such patients leave the hospital with a completely healed perineum, thus avoiding all the morbidity of conventional management of such open wounds. Dr. David M. Bull: Although information concerning pathogenetic mechanisms in Crohn's disease and ulcerative colitis is essentially nonexistent, I shall mention some areas of current immunologic research interest that may eventually pay dividends. Shorter et al., employing short-term tissue culture of colonic epithelial cells, have made several important observations: (a) lymphocytes from patients with ulcerative colitis and Crohn's disease are capable of killing colonic epithelial cells in vitro;50 (b) lymphocytes from normal individuals are cytotoxic for colonic epithelial cells when cultured in the presence ";"7"" Figure 5. Conceptual diagram of mode of healing of perineal wound. Top panel depicts boundaries of rectal excision. Middle panel shows closed pelvic peritoneum tenting over large pelvic space left by the excision of the rectum. Bottom panel pictures obliteration of this space mainly by descent of the pelvic peritoneum and by backward shift of the urogenital structures. Some upward shift of the soft tissue of the perineum also contributes. (From Silen, William, and Glotzer, Donald J.: The prevention and treatment of the persistent perineal sinus. Surgery 75: , 1974). of serum from patients with ulcerative colitis or Crohn's disease,51 a reaction resembling antibodydependent cellular cytotoxicity (ADCC); and (c) the cell responsible for destruction of colonic epithelial cells is the "K" or "null" lymphocyte," which is also the ADCC-active cell. The fact that ADCC reactions against viral antigens can result in the destruction of virus-infected cells 53 provides a potential link between this kind of cytotoxicity and current studies of a possible viral etiologic agent in Crohn's disease Lymphocytes from patients with ulcerative colitis and Crohn's disease also are immunologically specifically reactive with the enterobacterial common antigen component of E. coli 014,56.57 which in turn is antigenically related to intestinal cell membranes. These immunologic relationships between patients' lymphocytes and the intestinal mucosa, while far from definitive, are at present the most promising