World J. Surg. 22, 364 –369, 1998

WORLD Journal of

SURGERY © 1998 by the Socie´te´ Internationale de Chirurgie

Factors Determining Recurrence following Surgery for Crohn’s Disease Bruce G. Wolff, M.D. Department of Colon and Rectal Surgery, Mayo Clinic, 200 First Street Southwest, Rochester, Minnesota 55905, USA Abstract. Many factors have been examined in an attempt to define groups at higher risk for recurrence or recrudescence of Crohn’s disease. Among these factors are age and onset of disease, gender, site of disease, number of resections, symptomatic status at the time of surgery, length of small bowel resection, fistulizing versus obstructive forms of disease, proximal margin length, microscopic margin histology, strictureplasty, and number of sites of disease, as well as the presence of colonic only disease, the presence of granulomas, blood transfusions, family history, and prophylactic treatment. To date, only proctocolectomy with Brooke ileostomy versus other procedures for colonic only disease, and prophylactic treatment have been shown with some degree of confidence to lead to a lower recurrence rate after surgery for Crohn’s disease.

Crohn’s disease represents one of the greatest challenges facing the gastrointestinal surgeon today. The simple fact is that we, as surgeons, are dealing with only a part of the puzzle— groping in the dark not only with the results but also with only a part of the pattern of a disease. Since 1932 the disorder has eluded etiologic delineation and defied medical and surgical therapeutic measures, the balance of which have been based on empiric concepts and observation rather than modern scientific methodology. The various etiologic candidates, whether immunologic, infectious, genetic, or other theories, or various combinations thereof, must be known before realistically and intelligently we can adequately address the problem of recurrence in Crohn’s disease after surgical resection, which occurs, depending on the definition, in 40% to 90% of cases. The only consistent factor in Crohn’s disease is its inconsistency. Why certain manifestations occur in some patients with certain forms of the disease and why there is a response or nonresponse to various therapies continue to be a source of enigmatic frustration. Nevertheless, progress has been made, and in general a reasonable approach to the surgical management of Crohn’s disease can be based on 65 years of trial and error. Crohn’s disease was first approached similarly to colorectal carcinoma; and associated factors such as length of resection margin, perforation versus nonperforation, location of disease, and so on were the earliest variables examined in the hopes of determining surgical efficacy. Indeed, the term “recurrence” has been used and adapted from a neoplastic context and is largely inappropriate. We now know that gross total resection does not lead to a surgical “cure,” as may occur in the neoplastic sense. The Correspondence to: Bruce G. Wolff, M.D.

term “recrudescence” seems to be more apt in the light of well defined evidence of subclinical and microscopic abnormalities in otherwise grossly normal-appearing mucosa throughout the gastrointestinal tract in patients with Crohn’s disease. Such recrudescence or “recurrence” (because this is the customary term, I continue to use it) has been defined in the past in a number of ways, ranging from the minimal changes of ulceration and granularity in mucosa without symptoms, to symptomatic recurrence plus objective evidence of such changes, and even to the need to resume medication or the need for re-resection. It is my goal to examine the historical factors in recurrence of Crohn’s disease in the light of what is known of its “natural” history and show the effects of this accumulated knowledge on present-day surgical management of Crohn’s disease. A number of factors have been studied in regard to recurrence of Crohn’s disease after surgery. Briefly, these factors are sex and family history of the patient, age of disease onset, symptomatic status, presence of granulomas, length of surgical margins, and presence of microscopic disease at the surgical margin. Other factors include the fistulizing versus the obstructive form of the disease, site of the disease in the intestine, and the number of sites involved. The number of previous operations and the length of the disease segment resected have also received attention. The type of operation (i.e., ileostomy versus anastomosis), number of anastomoses, and blood transfusions have also been studied. Perhaps the newest factor that must be considered is prophylactic treatment after resection. Various endpoints that have been used may lead to conflicting and confusing results; as most studies have relied on endoscopic or radiologic recurrence, with or without symptoms, these endpoints are used as the optimum and are thus, perhaps arbitrarily, given more weight. Age and Onset of Disease A bimodal distribution of Crohn’s disease occurring with peaks around 20 years of age and again around 65 to 70 years of age, has been accepted for many years. Naturally, patients with early onset of disease are followed longer and therefore ultimately have a higher risk for recurrence. In the OMGE Multinational Inflammatory Bowel Disease Survey [1] 154 patients who had undergone surgery for Crohn’s disease were closely followed; 77 had a recurrence and were matched with 77 who did not. Risk of recurrence was found to be higher in patients under 20 years of

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Fig. 1. Recurrence of Crohn’s disease according to site of disease.

Fig. 2. Recurrence of Crohn’s disease according to number of resections.

age, both at the onset of the disease [risk factor (RF) 2.2:1.0] and at the age of their operation (RF 2.7:1.0). In an epidemiologic study from Sweden, the 10-year cumulative recurrence rate for patients age #25 years at the time of operation was 55%, which was significantly higher than in patients from the same area aged .40 years (40%) [2]. Several other similar studies have not confirmed this observation, making the age of onset of disease [3] and the age at first operation as risks factor still a matter of controversy.

words, terminal ileal disease) and true ileocolitis. Is the recurrence rate for terminal ileal disease ending at the ileocecal valve different from that of small bowel disease occurring more proximally in the small bowel? In our own study [9] almost 90% of patients enrolled had terminal ileal disease, which is by far the most common presentation of Crohn’s disease.

Gender A few studies have suggested that either men [4] or women [5, 6] have higher recurrence rate after surgery. Many other studies have not found gender to be a risk factor for developing recurrent disease after surgery [3]. Site of Disease Traditionally, three main sites of gastrointestinal involvement have been discussed as clinical patterns [7]. Most studies have demonstrated that the risk of recurrence was highest for ileocolonic disease and lowest for colonic disease only, with smallbowel-only disease having an intermediate prognosis. Such clinical patterns are useful to a point and must be considered with other factors. An example is that of colonic disease where the type of operation clearly affects outcome and recurrence rates, as is discussed further. The results from our own recent prospective randomized trial [Wolff et al., unpublished data] in which patients were randomized to mesalamine treatment postoperatively versus placebo after removal of all clinically obvious disease is a group with close and accurate follow-up (Fig. 1). The results from this study echo those reported by Farmer et al. [8] in that large-bowelonly disease has the lowest recurrence rate. Crohn’s colitis only, without small bowel involvement, has had the lowest recurrence rate in most studies. More recently, with the move toward subtotal colectomy with ileorectostomy and segmental colectomy, this risk has increased and is an example of how the type of operation (proctocolectomy versus subtotal or segmental colectomy) can influence recurrence rates. Again the use of “site of disease” as a factor for recurrence is of limited value in that in many studies there has not been a distinction between small bowel (in other

Number of Resections It has been reported in the literature [10] that patients who have one recurrence of Crohn’s disease are likely to have an increased rate of recurrence after their second resection. Most of the studies that have reported this phenomenon have used crude recurrence rates and have only a small number of patients at risk for the second recurrence. The largest series [11, 12] using cumulative recurrence rates have shown no difference in recurrence rate after the second resection. Our own study [11] shows that there is the suggestion of a slight increase in the risk of recurrence in patients who have had more than one resection versus patients who have had one resection only, but this difference did not reach significance (Fig. 2). Again, data supporting number of previous resections as a risk factor for recurrence are not plentiful. Such a parameter is of even more limited potential as a predictor with the advent of strictureplasty and with the performance, in many series, of resections (approximately 60%) concomitantly with strictureplasty. Symptomatic Status at the Time of Surgery Because chronicity of Crohn’s disease with failure of medical management is by far the most common indication for surgery, the degree of symptoms preoperatively has been difficult to correlate with postoperative recurrence rates. Having said this, one study describing recurrence rates after primary excisional surgery [13] did not show a difference in recurrence rates between patients undergoing emergency or urgent procedures compared with those having elective operations. Nevertheless, one wonders if early surgery for Crohn’s disease before severe symptoms occur would affect subsequent recurrence. This is an attractive proposition, as it would lead to operations in patients with better nutritional status, easier operations, and perhaps patients not yet on high doses of antiinflammatory agents, thereby minimizing risk. Such

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an alternative is frequently discussed, but there have been no studies to date. Length of Small Bowel Resection Several studies have indicated that the resection of lengthy segments of diseased bowel leads to more frequent recurrence of the disease [3, 4, 14 –16]. Small bowel resection has generally received more cautious treatment than colon resection in regard to length of resection. In our study of the natural history of Crohn’s disease after small bowel resection, we found no difference in recurrence rate in patients having ,30 cm of diseased small bowel resected compared to those having $30 cm resected [Wolff et al., unpublished data]. From a slightly different perspective, this finding is similar to that of a study by Trnka et al. [17], which showed that there was no difference in the length of diseased ileum in a relatively small group of patients who developed a recurrence from a similar group who did not develop recurrence. Fistulizing versus Obstructive Forms of Disease Greenstein et al. [18] reviewed 770 patients in which two clinical forms of Crohn’s disease emerge: those with a fistulizing pattern and those with an obstructive form. The recurrence rate of those patients with a fistulizing form was significantly higher than those with the nonfistulizing or obstructive type (p , 0.00001). In a further discussion of these data [19] Sachar stated that “clinically, any studies of the natural history of Crohn’s disease and any clinical trials for postoperative prophylaxis against recurrence should take into account these inherently different clinical patterns.” In a recent review from Germany [20] 793 cases of resection or strictureplasty in 689 patients with Crohn’s disease from a large, single tertiary care facility underwent multivariate analysis. One parameter that was independently associated with the risk for relaparotomy was enterocutaneous fistula. Other types of fistula, including enteroenteric fistulas in the abdomen, actually decreased the risk of site-specific recurrence in this study. The latter result is consistent with our finding that the obstructive form of the disease led to a higher recurrence rate than the fistulizing form in our prospective trial [Wolff et al., unpublished data]. This difference was not significant perhaps owing to the small number of patients. Recently there has been a tendency to discount the recurrence potential of fistulizing disease over the obstructive or nonfistulizing forms. Proximal Margin Length A long-term retrospective study done by Krause et al. [21] compared two groups of patients: one with a “radical” resection of $10 cm of disease-free margins incorporated into the resection versus ,10 cm of uninvolved bowel. They found after a lengthy follow-up of more than 14 years that the longer margins gave a lower recurrence rate (31%) and a better quality of life when compared with the nonradical resection recurrence rate (83%). This report has undergone a great deal of scrutiny, and has caused much discussion over the years. A similar retrospective review [1] reported a similar result in that a margin of normal tissue of ,4 cm led to a 10 times higher recurrence rate. This included histologically positive margins as well. In contrast, another study

Fig. 3. Recurrence versus margin histology.

from Uppsala [22] showed that the length of disease-free resection margins did not influence the risk of recurrence in a univariate or multivariate analysis in 353 patients undergoing a “curative” resection from 1969 to 1986. The only prospective study addressing this issue has been done at the Cleveland Clinic [23] in which patients undergoing ileocolic resection were randomly assigned to two groups in which the proximal margin was either 2 cm or 12 cm from the macroscopically involved disease. There was no significant difference in recurrence rate in the 56 patients undergoing extended resection in contrast to the 75 patients undergoing limited resection, although the recurrence rate in the extended group was lower (18% vs. 25%). This study, along with the retrospective studies that have been done, suffer from having small numbers and the possibility of a type II statistical error being present. This includes our own study, which did not show a significant difference between a proximal margin length of ,5 cm versus a $5 cm margin (Fig. 3). Microscopic Margin Histology The presence of microscopic changes of Crohn’s disease or of nonspecific inflammatory changes at the margin of the resection have been as controversial as the length of the resection margins. Retrospective studies have yielded opposing results, with several papers showing a benefit to having microscopically disease-free margins [24 –27]. Other studies [28 –35] and the Fazio et al. study quoted above [23] have shown no difference in recurrence rates based on microscopic changes at the resection margin. The proximal histology at the margin of resection was examined in our prospective randomized trial comparing nonspecific changes versus normal features on light microscopy (Fig. 4), and no difference in recurrence rate was found. Again, as in many other studies, the possibility of not detecting a true difference due to the small numbers in each group is possible. Most surgeons today accept an observed grossly negative margin of 1 or 2 cm, and a few rely on frozen section margins. Although studying such a phenomenon in a large number of patients might show some difference (i.e., a lower recurrence rate) with negative margins or increasing length of resection, the theoretic benefit of a lower recurrence rate is outweighed by the

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that a large anastomosis (side-to-side) leads to a lower recurrence rate than the more narrow-lumen (end-to-end) types [42, 43]. Granulomas The presence of granulomas on histologic inspection of diseased segments of bowel occurs in about 60% of cases [44]. Whether the presence of granulomas in the resected specimen signifies more aggressive or more severe disease with a higher recurrence rate has not been borne out, particularly in reference to small bowel disease [17], although a nonsignificant higher rate of recurrence in patient’s with ileocolitis and granulomas has been reported [17]. Other studies have not confirmed this tendency [45– 47]. Variability in the histologic review of the surgical specimens may account for this discrepancy. Fig. 4. Recurrence versus margin histology.

Blood Transfusions inherent disadvantage of losing the function of presumably normal small bowel. Strictureplasty and Number of Sites of Disease Logically, the number of sites of involvement of Crohn’s disease would lead one to believe such patients would have an increased rate of recurrence. This type of patient (multiple sites) benefits from strictureplasty, which frequently incorporates resection as well. It is interesting to note that from several large studies the rate of symptomatic recurrence after strictureplasty seems no higher than the rates reported for gross resection of all disease, even though by definition there is residual disease present with strictureplasty [36] (Table 1). Colonic-Only Disease Goligher reported a series of 207 patients who underwent resection for Crohn’s disease of the large intestine. He found that there was a significantly higher recurrence rate in patients undergoing subtotal colectomy and ileorectal anastomosis than in those having proctocolectomy and ileostomy [37]. This observation has been noted in another series [38] as well. A high recurrence rate has also been noted for segmental colectomy [39]. Even though our series of patients [9] with colonic-only disease was small (n 5 34), there was a significantly lower risk in the group of patients having a total proctocolectomy versus another procedure (e.g., segmental resection, ileorectal anastomosis, or abdominoperineal resection with colostomy in multivariate analysis) (Fig. 5). Creation of a stoma versus an anastomosis in general leads to a lower recurrence rate; and in at least one multivariate analysis in one series [40] the number of anastomoses was the most significant prognostic factor for recurrence (p 5 0.001) followed by inflammation at the resection margins (p , 0.05). This finding leads to the suggestion that the type of anastomosis, particularly ileocolonic anastomosis (viz., end-to-end vs. side-to-side) affects the recurrence rate. Cameron et al., from Johns Hopkins University, retrospectively looked at end-to-end versus end-to-side anastomosis and found no difference in the recurrence rate [41]. The presence in stool or intestinal chyme of a potential cofactor influencing recurrence is under consideration, and it may well be

The immunosuppressive effect of blood transfusions is well known [48, 49], and at least two studies [50, 51] have shown a reduction in recurrence rate in patients who received a transfusion during the perioperative period. A later study by Sutherland et al. [52] did not show such an effect. Although it is interesting to speculate on the topic, this factor is dictated by patient and operative circumstances rather than as a prophylactic maneuver, as the well known risks of transfusion, though low, can be disastrous. Family History Many studies have suggested that multiple members of the same family may be afflicted with inflammatory bowel disease (IBD), either Crohn’s or ulcerative colitis. A recent study [53] suggests that approximately 10% of IBD patients have affected family members with Crohn’s disease. To date, there is no information as to whether such afflicted family members have a higher rate of recurrence after surgery than patients with nonfamilial Crohn’s disease. Prophylactic Treatment A number of prospective randomized trials have now shown a reduction in recurrence of Crohn’s disease with certain agents (mesalamine, metronidazole, Salazopyrin) [9, 54 –57] when given after resective surgery for Crohn’s disease in which all obvious disease has been removed. Conclusions There remains a great deal of discussion and controversy regarding the traditional factors of recurrence. The only factors that have been studied in a prospective randomized fashion are the study comparing length of proximal margins [23], which found no difference, and the various studies with drugs used prophylactically after surgical resection, which have shown a benefit to treatment over placebo. Not all have shown a significant difference. The only variable that is unquestioned is that of proctocolectomy and Brooke ileostomy in colonic-only disease versus segmental resection or ileorectostomy, with which the recurrence rates are clearly much higher. In this setting, quality of life issues must be considered as well as extent of disease.

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Table 1. Results with strictureplasty. Total operations

No. of strictureplasties

Concomitant resection (%)

Perioperative complications (%)

Recurrent symptoms (%)

Author/Location

Date

No. of patients

Silverman et al., Toronto Pritchard et al., Lahey Fazio et al., Cleveland Dahn et al., Oxford Alexander-Williams, Birmingham Kendall et al., St. Mark’s Mayo

1989 1990 1989 1989 1987

14 13 50 24 57

16 16 54 30

36 52 225 86 146

93 31 60 62

21 15 16 1 14

26 69 22 46 40

1986 1991

5 35

5 36

26 71

80 66

2 0

100 20

Average follow-up (months) 16 24 8.3 40 6 6 24

enfermedad, ası´ como la presencia de patologı´a restringida al colon, la presencia de granulomas, las trasfusiones de sangre, la historia familiar y el tratamiento profila´ctico. Hasta el momento, so ´lo la proctocolectomı´a con ileostomı´a de Brooke versus otros tipos de procedimientos para enfermedad confinada al colon y el tratamiento profila´ctico, han demostrado con algu ´n grado de confiabilidad, llevar a una menor tasa de recurrencia en pacientes con enfermedad de Crohn que han sido sometidos a operacio ´n.

References

Fig. 5. Recurrence of Crohn’s disease according to operation.

Re´sume´ De nombreux facteurs ont ´ete´ ´etudie´s pour arriver `a de´finir les groupes de maladies de Crohn `a haut risque pour re´cidive ou rechutes. Parmi ceux-la` on trouve l’aˆge et le de´but de la maladie, le sexe, le site de la maladie, le nombre de re´sections, l’e´tat symptomatique au moment de la chirurgie, la longueur de l’intestin re´se´que´, le caracte`re fistulisant ou occlusif de la maladie, la longueur de la marge de re´section proximale, l’histologie de la tranche de section, la stricturoplastie, le nombre de sites de la maladie, ainsi que la pre´sence de maladie colique seule, la pre´sence de granulomes, le nombre de transfusions sanguines, les ante´ce´dents familiaux, et le traitement prophylactique. A ce jour, seule la coloproctectomie avec ile´ostomie de Brooke pour les formes coliques isole´es ainsi qu’un traitement prophylactique de la maladie semblent re´duire le risque de re ´cidive apre `s la chirurgie. Resumen Muchos factores han sido motivo de ana´lisis con el propo ´sito de definir cua´les son los grupos de alto riesgo de desarrollar recurrencia o recrudescencia de la enfermedad de Crohn. Entre tales factores de encuentran la edad, la forma del comienzo de la enfermedad, el sexo, la ubicacio ´n anato ´mica de la enfermedad, el nu ´mero de resecciones, el estado sintoma´tico en el momento de la cirugı´a, la longitud del segmento de intestino resecado, el tipo fistulizante versus el tipo obstructivo de la enfermedad, la longitud del segmento proximal, el aspecto microsco ´pico del margen de seccio ´n, la estenoplastia y el nu ´mero de lugares de ubicacio ´n de la

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