primary adenocarcinoma in an enterocutaneous fistula associated with...

Primary adenocarcinoma inan enterocutaneous fistula

associated withCrohn’s disease

Luis T Ying MD, David J Hurlbut MD FRCPC, William T Depew MD FRCPC,Alexander H Boag MD FRCPC, Kenneth Taguchi MD FRCS

Can J Gastroenterol Vol 12 No 4 May/June 1998 265

LT Ying, DJ Hurlbut, WT Depew, AH Boag, K Taguchi. Pri-mary adenocarcinoma in an enterocutaneous fistula associatedwith Crohn’s disease. Can J Gastroenterol 1998;12(4):265-269.Increasing numbers of intestinal adenocarcinomas in patientswith Crohn’s disease have been reported, but the strength of thisassociation still needs to be elucidated. Adenocarcinoma has alsobeen documented in different types of fistulous tracts associatedwith Crohn’s disease. The first case of well-differentiated muci-nous adenocarcinoma involving only enterocutaneous fistulae isreported in a patient with long-standing Crohn’s disease compli-cated by persistent abdominal wall fistulous tracts. The malignantlesion arose from neoplastic transformation of columnar epithe-lium lining portions of the fistulae occurring as a result of eitherre-epithelialization of these inflammatory tracts or mural implan-tation of mucosal tissue secondary to prior ulceration. The patienthas remained disease-free eight years after surgical resection of thetumour. Even though intestinal carcinoma is not as strongly asso-ciated with Crohn’s disease as with ulcerative colitis, intestinalcarcinoma should be considered in the setting of long-standingdisease, previous intestinal exclusion surgeries and complicationssuch as enterocutaneous or other types of fistulous tracts. Theprognosis of such patients may be excellent with early diagnosisand treatment.

Key Words: Adenocarcinoma, Crohn’s disease, Enterocutaneous

fistulae, Fistulous tracts

Adénocarcinome primaire dans une fistuleentérocutanée associée à la maladie de Crohn

RÉSUMÉ : Le nombre d’adénocarcinomes intestinaux est enhausse chez les patients atteints de maladie de Crohn, mais lanature de ce lien doit être éclaircie. L’adénocarcinome a aussi étédocumenté dans différents types de fistules associées à la maladiede Crohn. Le premier cas d’adénocarcinome mucineux biendifférencié mettant en cause une fistule entérocutanée seulementest signalé chez un patient souffrant de longue date d’une maladiede Crohn compliquée de fistules abdominales persistantes. Lalésion cancéreuse tire son origine de la transformation néoplasiquede l’épithélium cylindrique tapissant certaines portions desfistules, par suite, soit d’une ré-épithélialisation des ces canauxinflammatoires, soit de l’implantation murale de tissus muqueuxsecondaire à une ulcération. Le patient est resté bien pendant huitans suivant la résection chirurgicale de la tumeur. Bien que lecancer de l’intestin ne soit pas associé aussi souvent à la maladie deCrohn qu’à la colite ulcéreuse, il faut songer à ce diagnostic dans lecontexte d’une maladie chronique, d’antécédents de chirurgiesintestinales et de complications, telles fistules entérocutanées ouautres. Le pronostic peut être excellent chez ces patients si lediagnostic et le traitement se font sans délai.

This paper was a winning entry in the ‘Consultations in Gastroenterology’ Case Study Competition that was initiated and funded with thegenerous sponsorship of Astra Canada and is endorsed by the Canadian Association of Gastroenterology

Departments of Medicine, Pathology and Surgery, Queen’s University, Kingston, OntarioCorrespondence and reprints: Dr William T Depew, Hotel Dieu Hospital, 166 Brock Street, Kingston, Ontario K7L 5G2.

Telephone 613-544-3310, fax 613-544-3114, e-mail [email protected]

CONSULTATIONS IN GASTROENTEROLOGY

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Crohn’s disease was first described as a distinct clinicaland pathological entity in 1932 (1). The first reports of

Crohn’s disease patients who subsequently developed cancerof the large or small intestine were published in 1948 and1956, respectively (2,3). Since then, the number of reportedcases has increased significantly, but it is still unclearwhether patients with Crohn’s disease are at higher risk ofdeveloping intestinal malignancies. There have also been re-ported cases of adenocarcinoma in enterocolonic, enteroves-icular, enterovesiculocutaneous, rectovaginal and perinealfistulae associated with Crohn’s disease (4-8). To date onlyfive cases of adenocarcinoma in enterocutaneous fistulaehave been reported, but in all these cases the carcinoma in-volved both the fistulous tract as well as segments of eithercontiguous small or large bowel (5,8,9). In this paper we de-scribe the first case of mucinous adenocarcinoma that origi-nated from and remained confined to an enterocutaneousfistula in a patient with Crohn’s disease.

CASE PRESENTATIONA 55-year-old male was initially diagnosed with Crohn’s ilei-tis in 1965, at age 23. He underwent segmental ileal resec-tion in 1970 and 1972 to treat active disease refractory tomedical therapy. A total of 62 cm of terminal ileum was re-moved. In 1972, he developed two anterior abdominal wallfistulae with persistent mild drainage of a serous material.One was located in the midline, just caudal to the umbilicus,and the other in the right peri-umbilical area. The drainagefrom these fistulae fluctuated in concert with his Crohn’sdisease activity. Maintenance therapy with sulfasalazine pro-vided acceptable control of the disease. By 1974, one of thefistulae had healed, but in that year he developed a third fis-tula located in the left upper abdominal quadrant, fromwhich there was draining of fecal and purulent materialalong with passage of gas. A fistulogram revealed a connec-tion to the small bowel. The drainage settled spontaneouslyand the patient declined any further investigative or thera-peutic efforts. He remained on sulfasalazine thereafter. Atherapeutic trial with metronidazole to close the fistulae in1981 was discontinued soon after initiation due to adverseeffects. For most of the 1980s, the patient’s clinical coursewas relatively unremarkable with only infrequent mildsymptoms that occurred whenever he was noncompliantwith his medication.

In 1989 the patient experienced a severe exacerbation ofhis disease, with worsening diarrhea, intense abdominalcramps, fever, chills and an approximately 8 kg weight loss.Over a period of three months he also developed an inflam-matory lesion on his anterior abdominal wall at the site ofone of his fistulae, from which profuse drainage of fecal andpurulent material occurred through six fistulous tracts (Fig-ure 1). Barium enema and fistulogram showed a small ente-rocolonic fistula between the terminal ileum and sigmoidcolon, as well as multiple interconnecting sinus tracts withinthe inflammatory abdominal wall mass that communicatedwith the enterocolonic fistula (Figure 2). Small bowelfollow-through did not reveal obstruction. Treatments with

metronidazole and azathioprine were attempted for onemonth, but these were discontinued due to gastrointestinaladverse effects and sepsis, respectively. The patient’s sys-temic and gastrointestinal symptoms gradually improvedwith sulfasalazine, but the draining abdominal wall lesiondid not change. Surgery to excise the inflammatory mass andtracts, as well as the involved segment of small bowel and theenterocutaneous fistula, was preformed.

Pathological examination of the surgical specimen re-vealed well-differentiated mucinous adenocarcinoma withinand around the fistulous tracts, primarily within the abdomi-nal wall mass (Figure 3). No small bowel mucosal origin foradenocarcinoma was identified. Multiple fistulous tractswere lined by columnar epithelium with areas of neoplastictransition to infiltrating adenocarcinoma within subserosaland abdominal wall tissues. All four mesenteric lymph nodeswere negative for adenocarcinoma. Ancillary resection of asmaller nondraining inflammatory mass in the left upper ab-dominal quadrant did not show any malignant lesion.

At eight years after surgery, the patient is tumour-free andhas no evidence of fistula recurrence. His Crohn’s disease hasbeen quiescent.

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DISCUSSIONSince Crohn’s disease was initially described in 1932, in-creasing numbers of cases of adenocarcinoma of the largeand small bowel in patients with this disease have been re-ported. The extent of the association between Crohn’s dis-ease and intestinal adenocarcinoma is still not entirely clear.The relative risk of colorectal cancer in patients with Crohn’sdisease has been calculated to range from 4.3 to 26.6 (10-12), and estimates of the relative risk of small bowel adeno-carcinoma have ranged from six to 320 times that in a nor-mal population (12-15). Five large population-based epide-miological studies involving 3747 patients with Crohn’sdisease documented 21 cases of colorectal and seven cases ofsmall bowel cancer, with relative risks ranging from 0.89 to2.5 for colorectal malignancies and up to 50 for small bowel

malignancies (16-21). Two of these population-based stud-ies involving 468 patients did not document any case ofsmall bowel cancer in the cohort of Crohn’s disease patients(17,18). The inconsistency in the relative risk of colorectaladenocarcinoma in Crohn’s disease may be due, in part, toreferral bias in studies originating from tertiary care referralcentres, which can generate an overestimation of this asso-ciation. The relative risk of small bowel malignancy seems tobe significantly higher in Crohn’s disease patients than inthe general population, but caution must be applied to theinterpretation of these data. Small bowel cancer is not acommon condition; therefore, the publication of a relativelysmall number of cases in patients with Crohn’s disease mayresult in high relative risk estimates.

In this paper we report the first case of adenocarcinoma

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involving enterocutaneous fistulae only, in a patient withlong-standing Crohn’s disease complicated by persistentabdominal wall fistulous tracts. Our review of the literaturerevealed only two cases of carcinoma of enterovesiculocuta-neous fistulae (5,8) and three similar cases involving entero-cutaneous fistulae in patients with Crohn’s disease (8,9)(Table 1). When he was diagnosed with adenocarcinoma,our patient had a 24-year history of Crohn’s disease and a17-year history of persistent abdominal wall enterocutane-ous fistulae. This time lag for the development of a malig-nant lesion is consistent with that in previously reportedcases. Except for one case – which did not include details re-garding the duration of Crohn’s disease before the diagnosisof the carcinomatous fistula – all lesions occurred more than10 years after the initial diagnosis. In one case, the patienthad Crohn’s disease for 38 years. For small bowel adenocarci-noma, Hawker et al (22) documented a mean delay of19.2 years, with a range of up to 47 years.

There is no uniformity in the anatomical location of dis-ease among the reported cases. Including this case, two pa-tients had ileitis, one had ileocolitis and one had colitisprimarily. In the previously reported five cases, the malig-nant lesion was not confined to the enterocutaneous fistula;it also involved the surrounding inflamed segments of bowel.These observations support the notion that intestinal can-cers in Crohn’s disease occur at sites of intestinal involve-ment (23). In one case, the tumour originated from anexcluded segment of small intestine (8). It has been postu-lated that bypass or defunction with bacterial stasis in suchsegments has a carcinogenic effect (24). There have beenmany published reports of intestinal carcinoma arising insurgically bypassed bowel (22,24), but the most importantcontributing factor to carcinoma development in patientswith excluded intestine may be the long duration of Crohn’sdisease, rather than the excluded bowel (8,24). As intestinalexclusion surgeries have become increasingly infrequent as a

therapeutic modality in the treatment of Crohn’s disease inrecent decades, the proportion of carcinoma in excludedsmall intestine in Crohn’s disease has fallen dramatically(8,24).

In contrast to the patients in the five reports of adenocar-cinoma of enterocutaneous fistulae associated with Crohn’sdisease, our patient had a malignant lesion confined to thefistulous tracts, with no direct involvement of the communi-cating segment of small bowel. Adenocarcinoma most likelyarose from neoplastic transformation of columnar epitheliallining portions of the fistulae occurring as a result of eitherre-epithelialization of inflammatory tracts from the smallbowel mucosa or mural implantation of viable mucosal tissuesecondary to prior ulceration. Chronic fistulous tracts inCrohn’s disease can re-epithelialize, which would precludepermanent healing (25). The absence of small bowel muco-sal and mural involvement supports the negative mesentericnode status observed.

CONCLUSIONSEven though intestinal carcinoma is not as strongly associ-ated with Crohn’s disease as with ulcerative colitis, intesti-nal carcinoma must be considered in the setting of long-standing disease, previous intestinal exclusion surgeries andcomplications such as enterocutaneous or other types of fis-tulous tracts. If accurate diagnosis is made without delay, theprognosis of these patients after appropriate treatment maybe excellent.

REFERENCES1. Crohn BB, Ginzburg L, Oppenheimer GD. Regional ileitis:

a pathological and clinical entity. JAMA 1932;99:1323-9.2. Warren S, Sommers SC. Cicatrizing enteritis (regional ileitis) as a

pathologic entity: an analysis of 120 cases. Am J Pathol1948;24:475-501.

3. Ginzburg L, Schneider KM, Dreizin DH, Levinson C. Carcinoma ofthe jejunum occurring in a case of regional enteritis. Surgery1956;39:347-51.

268 Can J Gastroenterol Vol 12 No 4 May/June 1998

Ying et al

TABLE 1Summary of clinical data on six patients with adenocarcinoma of enterocutaneous fistulae associated with Crohn’s disease

Age(years)/sex

Duration ofdisease(years)

Areas ofdisease Fistula

Etiology offistula

Areas of tumourinvolvement

Treatment oftumour Clinical course

Case 1 70/F 38 Ileum Enterovesiculo-cutaneous

Post-pig-tailcatheter

Terminal ileum, ascendingcolon, fistula, peri-umbilicaland perivesicular soft tissue

Surgery No recurrence at12 month F/U

Case 2 86/F >10 N/A Enterocutaneous N/A Excluded small bowel N/A N/A

Case 3 N/A >10 N/A Enterovesiculo-cutaneous

N/A N/A N/A N/A

Case 4 50/F 30 Ileum/colon

Enterocutaneous Postsurgery Fistulous tract and involvedsigmoid colon

Surgery andradiation

Died two years afterdiagnosis

Case 5 30/M “Longhistory”

Colon Enterocutaneous Postsurgery Fistulous tract and colon Surgery Died six months aftersurgeries from renal

amyloidosis

Currentcase

47/M 24 Ileum Enterocutaneous Postsurgery Fistulous tract Surgery No recurrence ateight years F/U

F Female; F/U Follow-up; M Male; NA Not available

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4. Greenstein AJ, Janovitz HD. Cancer in Crohn’s disease. The danger ofa by-passed loop. Am J Gastroenterol 1975;64:122-4.

5. Schoenfeld PS, Butler JA, Denobile J. Adenocarcinoma in anenterovesiculocutaneous fistula. Am J Gastroenterol 1996;91:608-9.

6. Buchmann P, Allan RN, Thompson H, Alexander-Williams J.Carcinoma in a rectovaginal fistula in a patient with Crohn’s disease.Am J Surg 1980;140:462-3.

7. Chaikhouni A, Regueyra FI, Stevens JR. Adenocarcinoma in perinealfistulas of Crohn’s disease. Dis Colon Rectum 1981;24:639-43.

8. Ribeiro MB, Greenstein AJ, Heimann TM, Yamazaki Y, Aufses AH Jr.Adenocarcinoma of the small intestine in Crohn’s disease. SurgGynecol Obstet 1991;173:343-9.

9. Lightdale CJ, Sternberg SS, Posner G, Sherlock P. Carcinomacomplicating Crohn’s disease. Report of seven cases and review of theliterature. Am J Med 1975;59:262-8.

10. Weedon DD, Shorter RG, Ilstrup DM, et al. Crohn’s disease andcancer. N Engl J Med 1973;289:1099-102.

11. Gyde SN, Prior P, MacCartney JC, et al. Malignancy in Crohn’sdisease. Gut 1980;21:1024-9.

12. Greenstein AJ, Sachar D, Smith H, et al. A comparison of cancer riskin Crohn’s disease and ulcerative colitis. Cancer 1981;48:2742-5.

13. Hoffman JP, Taft DA, Wheelis RF, Walker JH. Adenocarcinoma inregional enteritis of the small intestine. Arch Surg 1977;112:606-11.

14. Korelitz B. Carcinoma of the intestinal tract in Crohn’s disease: resultsof a survey conducted by National Foundation for Ileitis and Colitis.Am J Gastroenterol 1983;78:44-6. (Edit)

15. Fresko D, Lazarus DD, Dotan J, Reingold M. Early presentation ofcarcinoma of the small bowel in Crohn’s disease (Crohn’s carcinoma):

case reports and review of the literature. Gastroenterology1982;82:783-9.

16. Ekbom A, Helmick C, Zack M, Adami H-O. Increased risk of largebowel cancer in Crohn’s disease with colonic involvement. Lancet1990;336:357-9.

17. Gollop JH, Phillips SF, Melton JH III, Zinsmeister AR. Epidemiologicaspects of Crohn’s disease: a population-based study in OlmstedCounty, Minnesota, 1943-1982. Gut 1988;29:49-56.

18. Fireman Z, Grossman A, Lilos P, et al. Intestinal cancer in patientswith Crohn’s disease. A population study in Central Israel. Scand JGastroenterol 1989;24:346-50.

19. Munkholm P, Langholz E, Davidsen M, Binder V. Intestinal cancerrisk and mortality in patients with Crohn’s disease. Gastroenterology1993;105:1716-23.

20. Persson P-G, Karlen P, Bernell O, et al. Crohn’s disease and cancer:a population-based cohort study. Gastroenterology 1994;107:1675-9.

21. Ekbom A, Helmick C, Zack M, Adami H-O. Extracolonicmalignancies in inflammatory bowel disease. Cancer 1991;67:2015-9.

22. Hawker PC, Gyde SN, Thompson H, Allan RN. Adenocarcinomaof the small intestine complicating Crohn’s disease. Gut1982;23:188-93.

23. Michelassi F, Testa G, Pomidor WJ, et al. Adenocarcinomacomplicating Crohn’s disease. Dis Colon Rectum 1993;36:654-61.

24. Greenstein AJ, Sachar D, Pucillo A, et al. Cancer in Crohn’s diseaseafter diversionary surgery: A report of seven carcinomas occurring inexcluded small bowel. Am J Surg 1978;135:86-90.

25. Lewin KJ, Riddell RH, Weinstein WM. Gastrointestinal Pathologyand its Clinical Implications. New York: Igaku-Shoin, 1992:887.

Can J Gastroenterol Vol 12 No 4 May/June 1998 269

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