Appendiceal carcinoids in Crohn ’ s disease

Department of Medicine (Gastroenterology), University of British Columbia, Vancouver, British Columbia Correspondence and reprints: Dr Hugh Freeman, Gastroenterology, ACU F-137, UBC Hospital, 2211 Wesbrook Mall, Vancouver, British Columbia V6T 1W5. Telephone 604-822-7216, fax 604-822-7236 Received for publication July 2, 2002. Accepted October 18, 2002 HJ Freeman. Appendiceal carcinoids in Crohn’s disease. Can J Gastroenterol 2002;17(1):43-46.

E arlier studies have suggested that patients with Crohn's dis- ease may have an increased colon cancer risk (1-3).In Canada, cohort and population-based studies from British Columbia (4) and Manitoba (5), respectively, have also confirmed this enhanced colon cancer risk in Crohn's disease.In addition, the coexistence of other intestinal neoplasms, including carcinoids, has been described (6)(7)(8)(9)(10)(11)(12), including a report from Alberta that provided the initial Canadian description of ileal carcinoids in Crohn's disease (13).Because most appendiceal carcinoids are discovered coincidentally during the pathological examination of the appendix for other causes, their clinical relevance, if detected during the course of Crohn's disease, is unknown.
Some have speculated that the association of Crohn's disease and carcinoid tumours, although uncommon, is more fre-quent than currently appreciated (9) and may be more than fortuitous (13).In part, this could be related to similarities in clinical presentation with diarrhea or partial bowel obstruction, as well as pathological changes of fibrosis and thickening of the intestinal wall.Indeed, carcinoid tumours, especially if located in the ileum, may completely mimic Crohn's disease (14,15).In contrast, others have argued against an increased risk for carcinoids in Crohn's disease based on clinical experience (16).
Over the past 20 years, a single clinician database for Crohn's disease, now with 1000 consecutive patients, was developed, with a mean follow-up period of over 10 years.In this series, 441 patients to date have undergone an intestinal resection during their clinical course.Although appendiceal carcinoids in Crohn's disease have been noted, a review of reported pathological studies from this single clinical practice revealed three additional new cases, including an advanced lesion that had extended into serosal fat.In Crohn's disease, endoscopic studies, other imaging evaluations and resections including the ileocecal region are relatively common, and as a result, the detection and pathological definition of coexistent carcinoids may be facilitated.The detection of carcinoids in Crohn's disease could also affect critical management decision, so this limited experience in Crohn's disease was evaluated.

Case one
A 25-year-old woman was evaluated in 1971 for abdominal pain, diarrhea and weight loss.Endoscopic and barium contrast studies showed small and large intestinal involvement with Crohn's disease, including ulceration with stricture formation in both the midjejunum and the distal 60 cm of the terminal ileum.Biopsies of the proximal jejunum and the colorectum revealed granulomatous inflammation.In 1977, a side-to-side ileocolonic bypass was done, and, in 1979, a 30 cm strictured jejunal segment was resected, showing granuloma formation.In 1982, a right hemicolectomy with resection of the distal 24 cm of ileum and the bypassed segment was done; transmural acute and chronic inflammatory changes with granulomas and fibrosis were recorded.In 1984, anemia with bleeding developed; ulceration in the neoterminal ileum was visualized and another ileocolonic resection was done, including the anastomosis and 20 cm of distal ileum.In 1989, a review of her resected specimens showed a small carcinoid tumour in the distal appendix.In 1999, two jejunal strictures (total length, 42 cm) and the anastomosis were resected.From then to September 2002, treatment included oral 5-aminosalicylate, oral budesonide and parenteral nutrition.

Case two
A 19-year-old woman first developed abdominal pain, fever and diarrhea in 1984.Her examination revealed abdominal tenderness, anal tags and a tender anal fissure.Erythema nodosum was present in both lower extremities.Barium studies of the upper and lower gastrointestinal tract showed changes consistent with Crohn's disease of the colon, and colonoscopy revealed focal areas of ulceration and granulomatous inflammation.In 1985 and 1986, episodes of abdominal pain and diarrhea were treated with steroids.In 1988, perianal fistulae were treated with multiple perianal fistulotomies.In 1989, severe anorectal pain with fever and weight loss developed.Anorectal stenosis with ulceration and multiple draining fistulous tracts were present.Oral metronidazole was given, resulting in a reduction in fistula drainage, but after several weeks a painful lower extremity peripheral neuropathy developed so the medication was terminated.In 1990, a loop ileostomy was done.Drainage persisted, and after eight months a large perineal ulcer developed.In 1991, a total proctocolectomy and a distal ileal resection were done.Active granulomatous inflammation was present throughout the entire resected specimen.In addition, a small carcinoid tumour of the distal appendix was detected with extension beyond the appendix, including focal penetration into serosal fat.There was no metastatic disease or evidence for retroperitoneal fibrosis.Except for a short hospitalization in 1997 for an ileostomy obstruction that spontaneously resolved, she has remained well to September 2002 with no recurrent disease.

Case three
A 16-year-old female patient first developed abdominal pain and diarrhea in 1984.Barium radiographic studies of the upper and lower gastrointestinal tracts revealed a 7 cm distal ileal stricture, consistent with Crohn's disease.In 1985, a perianal abscess was drained.In 1986, a small bowel obstruction resolved with corticosteroids.Flexible sigmoidoscopy showed focal linear colonic ulcers.Multiple anal fistulae and perineal sinus tracts were also excised, and granulomatous inflammation was present.In 1997, abdominal pain with diarrhea led to further evaluation.Endoscopic studies showed scattered aphthoid mucosal ulcers, inflammatory changes and granulomas.The patient's symptoms resolved completely with budesonide.In March 2002, the patient developed abdominal pain, diarrhea and weight loss despite 5-aminosalicylate and budesonide.A barium study showed two distal ileal strictures, which were then resected.The pathological evaluation showed granulomatous inflammation, and sections through the midportion of the appendix revealed a cluster of carcinoid cells typical of a microscopic carcinoid (Figures 1 and 2).In September 2002, she was well on oral 5-aminosalicylate alone.

DISCUSSION
Previous investigations have suggested an increased risk of intestinal cancer in Crohn's disease (1-3), including cohortand population-based studies from both British Columbia and Manitoba (4,5).Carcinoids in Crohn's disease also occur (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)), but it is not clear whether the risk for this tumour type is increased, especially because these are only a very small fraction of all intestinal tumours (17).While the coexistence of carcinoid tumours and Crohn's disease may be rare, their detection may be very important, because these neoplasms have been shown to clinically simulate Crohn's disease, particularly if there is ileal involvement (8,14,15).Moreover, similar complications (eg, retroperitoneal fibrosis) may occur in both disorders (18,19).In addition, most carcinoids in patients with Crohn's disease have been rarely suspected clinically, and so their unanticipated detection during surgery might potentially alter management.Finally, neuroendocrine modulation of immunologically mediated molecular events in inflammatory bowel disease might conceivably result, particularly if a coexistent carcinoid secretes a kinin or another potent peptide that affects the action of an inflammatory mediator (20)(21)(22).
In Crohn's disease, patients are frequently (and sometimes repeatedly) evaluated with endoscopic and other imaging modalities.In addition, a high percentage of patients with Crohn's disease undergo ileocolonic resection, providing additional tissues that may facilitate other diagnoses, including unsuspected carcinoid tumours.In this study, a systematic evaluation of a Crohn's disease clinical database for pathologically confirmed carcinoid tumours was done.In 1000 consecutive patients followed for an extended mean period of approximately 10 years, 441 had intestinal resective surgery, and three carcinoid tumours were defined.These were all located in the appendix of resected specimens for Crohn's disease.
Appendiceal carcinoids occurring concomitantly in Crohn's disease appear to be rarely recorded in the world literature.The first report of these coexistent conditions was in a child in 1981 (6).Since then, another six reports of appendiceal carcinoids have been described in Crohn's disease, all in adults (7)(8)(9)(10)(11)(12).Of these, only one described the involvement of the adjacent ileum and cecum, so it could not be determined whether the carcinoid in this specific report originated in the appendix and was an advanced lesion at the time of detection (8).In the present series, three new cases of appendiceal carcinoid tumours were detected.None was suspected before surgical intervention.Of these, two were macroscopically detectable lesions and, pathologically, one had already invaded through the serosal fat.To date, this patient has remained well over 10 years after removal with no evidence of metastatic disease, implying that the resection done for Crohn's disease, as in other cases localized to the appendix alone, was sufficient.The third case was a microscopically detected lesion only appreciated after 'routine' sectioning of the appendix from the ileocolic resection specimen.These findings also further emphasize that the pathological evaluations in this study were on resected tissues from patients obtained in the course of a 'routine', but focused, clinical practice.It is not known whether additional early carcinoids would have been detected with systematic and more extensive tissue sampling.Because over 50% of the patients in this study have not required an intestinal resection to date, it is conceivable that more carcinoids will eventually be detected.
In this series, an appendiceal carcinoid was detected in 0.3% of patients with Crohn's disease.Although the precise definition of carcinoid risk is difficult to establish, these results are at least comparable with the only other similarly large, but multiphysician, series that described a 0.2% risk for carcinoids in 3326 patients with both ulcerative colitis and Crohn's disease.As in the present study, these occurred primarily in the appendix without systemic features of the typical carcinoid syndrome (16).Although the authors of that report thought that their results did not support an increased risk for carcinoid tumours in inflammatory bowel disease, recent pathological studies have clarified the magnitude of carcinoid risk in resected appendicitis (0.24%) and autopsy studies of noninflamed appendixes (0.03%) (12).Similar data have been reported in an older referral-based population from the Mayo Clinic by Moertel et al (23), who examined the rates of detection of appendiceal carcinoids for a variety of surgical indications (0.32%) as well as their autopsy experience (0.026%).Although controlled data on the risk of carcinoids are not available, these results imply that there may be as much as a 10-fold increased risk of carcinoid tumour development, at least in the appendix, in patients with Crohn's disease, compared to autopsy data from referral-based populations (23).Additional studies, defining the site of carcinoid tumour formation, are needed to further elucidate this observation in patients with inflammatory bowel diseases.In this series, it is conceivable that carcinoid tumour incidence is even higher because fewer than 50% have had an intestinal resection.
No case here displayed clinical features of the carcinoid syndrome; however, pathological evidence for an invasive carcinoid tumour was reported in the second case, suggesting a potential for this development.Others have suggested that a right hemicolectomy is justified in young patients with tumours over 2.0 cm in size with a low risk of operative morbidity or mortality; however, vascular involvement and invasion of the mesoappendix are also features that may favour a more radical approach (24).Although the patient from case two has remained well and additional treatment has not been required, the unanticipated detection of a carcinoid during surgical resection could potentially alter medical or surgical management.Future studies are needed to determine whether the peptide hormones synthesized and secreted by carcinoids can affect the inflammatory process (20)(21)(22) and either intensify or ameliorate disease activity.