Granulornatous ( Crohn ' s ) appendicitis

H BINDER, HJ FREEMAN. Granulomatous (Crohn's) appendicitis. Can J Gastroenterol 1991;5(3):112-117. Four patients with Crohn's disease limited initially to the appendix, treated by appendectomy and seen at the University of British Columbia H ospital, Vancouver, during 1980-90 are described. In all patients the initial diagnosis was based on the presence of an appendiceal granulomatous inflammatory process, while other causes such as sarcoidosis, tuberculosis and bacterial gut pathogens were excluc.led. While post appendectomy complications, including enterocutaneous fistula, <lid not occur, symptomatic recurrence was later observed in three patients fou r to 24 months following appendiceal resection. This recurrence was associated with a diagnosis of recurrent Crohn's d isease and histological findings of granulomas e lsewhere in the gastrointestinal tract. In conclusion, a 'reagent gra<lc' population of patients with Crohn's disease limited to the appendix was seen. A high frequency of recurrent disease was defined, indicating that isolated granulomarous appendicitis may be the initial and sole presenting feature ofCrohn's disease.

I N 1932, CROI IN ET AL ( 1) EMPI IASIZED in their first description of regional ileitis that "the process never transcends the li mits of Bauhin 's val ve, anJ the appendix is always free from gu ilt and c hanges".Since that time, it has become increasingly recogn ized that Crohn's d isease may involve any site within the gastrointestinal tract from the mouth to the anus.Although cont iguous involvement of the appenJ1x vermiform is occurs, isolated Crohn's disease of the appendix a ppears to be rare.
During the course of a retrospective review of patient files fur t he 10 year period from l 980 to 1990, four patient~ with features typical of C rohn's di ease init iall y li mited to the appendix anJ cha rac terized by grnn ul oma tous inflamma tion we re found.ln this report, the presentation and subsequent clinical course following appendectomy of these four are detailed, and the litera• cure experience on ch is uncommon condition is reviewed.

PATIENTS AND METHODS
The records of C rohn's disea,e patients een during the 10 year period from 1980 to 1990 at the authors' hospital were reviewed.All patient, were seen and fo llowed by a single gastroenterologist (HF) .In an effon to describe a 'reagent grade' population with Crohn 's disease for this report, only patients with granulomatous  pain recu rred with diarrhea.Examinat io n revealed righ t lower q uadrant tenderness.Fihrcoptic colonoscopy and rectal biopsy were normal, and stool stud ies fo r parasites and bacteria l cultures were negative.Ultrasound and computed tomography scan of the abdo men and pelvis were no rmal, but ba rium rad iographic stud ies of the small bowel showed rigidity, cobbleston ing and li near ulce ration in the dista l 7 to 8 cm of the term inal ileum (Figure 3).T he patien t was treated with oral me tronidazole 250 mg qiJ fo r three mo nths.Symptoms resolved and she has rema ined well with an nual follow-up fo r the past three years.Ca se 2: A 28-ycar-old female was admitted in December L989 with fever and severe lower abdominal pain for less than 12 h.Duri ng the previo us month , the pat ient h ad noticed vague abdomina l discomfo rt, malaise a nd intermittent constipatio n .Examination suggested nn ac ute a bdo me n and laboratory investigations revea led a white blood cell count of 23.0xl0 9 /L.
Chest and abdomina l x-rays were no rmal.laparotomy showed a perforated thickened appendix with pe ri tonit is.Appen<lecromy was done; h istological feat ures simihu ro those in case l were prescm, with acllle-on-chron ic granulomarous inflammation and multinudeated giam cells (Figure 4 ).
Following surgery, th e patient developed recurrent lower abdominal pain.Additiona l studies were normal, incl uding abdom inal and pelvic ultrasou nd, hari um radiograph ic invest igation of the sma ll intestine and serological studies for Yersinia species.
Colo noscopy and colorectal mucosa!biopsies were normal.Fecal studies for parasites and bacterial cu ltures were negat ive.T he patient's abdom inal pain resolved spontaneously and no treatment was prescribed.One year later, she remains free from symptoms.Case 3 : A 22-year-old female was admi t te d in August 198 1 t o t h e gynecological service of anothe r teaching hospital with feve r and righ t lo wer quadrant abdominal pai n fo r IO J ays.
C hesr and abdom inal x-rays as well as cervical, feca l, urine and hlood cultures were negative.Pelvic inflammatory Jb-Figure 2) Appendiceal mucosa!clusters of e/)ithelioid cells (case I) Figure 3) Small bowel barium radiograph with ilea/ narrowing and ulceration ( case I) •, ' • ...  ease was suspected a nJ treatment with intravenous cefoxitin commenced; the fever recurred, however, and laparotomy 12 days later detected appendicitis with a localized appendiceal a bscess.., , ;a. ,.. Fecal studies for parasite~ and bacterial cultures were negat ive.Flexible sigmoidoscopy and rectal biopsy were normal.Barium radiographic studies of the upper gastrointestinal tract, including the remaining small bowel, were normal.The symptoms resolved completely with added dietary fibre.As the histo logical find ings in the rcsected ileum from l 982 were typical fo r C rohn's disease, the previous appendectomy sections from 198 1 were also CAN J GASTROENTEROL VOL 5 NO 3 M AY/JUNE 199 1 Granulomatous appendicitis reviewed; granu loma~ with mu ltinucleated giant cells were detec ted that had not previously been reported (Figure 5) .
C ase 4: A 22-year-old male was admitted in November l 984 with a one month history of worsening righ t lower quadrant abdominal pain.There was no d iarrhea or weight loss.Laboratory investigations revea led a white cell coun t of 13.0xl0 9 /L.C h est and abdom inal xrays were normal.Because appendici tis was suspected, laparotomy was Jone, and an e n la rged, inflamed appendix was resec ted.A lt h m igh the surgeo n suspected that C ro hn's disease involving the append ix a lone might be present, examination of the small and la rge intestine was normal.Mic roscopic examination of the appendix revealed a marked acute and c h ron ic inflammatory cell reaction, with multiple noncaseating granu lomas containi ng mulcinucleated gian t cells (Figure 6).The patiem's postoperative course was uncomplicated and he remained free from symptoms for two years.
In 1986, fatigue, abdominal pain and diarrhea (up to th ree to fou r nonbloody stoob daily fo r two months) developed.Fecal c ultures were negative.Barium rad iographs of the upper and lower gastrointestinal tracts were normal.S igmoidoscopy was normal, but a rectal biopsy revealed foca l granulomarous inflammation.The patient was treated with su lphasalazine 0. 5 g qid for six months; symptoms resolved anJ the patient ceased pha rmacological therapy.In Ju ly 1988, abdominal pain , dia rrhea and fatigue recurred with a we igh t loss of 10 kg.Examination revealed oral a phthous ulcers.Fecal tudies for parasites and bacterial cultures as well as Clostridium difficile cytotox in were negative.Upper gastrointestinal trace fibreoptic endoscopy revealed a single focal gastric mucosa!erosion in the prepyloric antrum, wh ile flexible sigmoidoscopy showed patchy mucosa!hyperem ia.Gast ric, duodena l and colonic mucosa I biopsies confirmed the presence of inflammatory changes in the gast ric antrum and colon, with scattered mucosa!granulomas containing mul t inucleated giant cells (Figures 7,8), A Figure 7) Endoscopic ga~tric biopsy with mucosa/ epitlielioid cell m1crogranuloma ( case 4) lactose-free diet was recommended with oral 5-amino a licylate 800 mg bid.Symptoms resolved within two weeks, and the patient has remained free from symptoms for t he past 10 months.

DISCUSSION
Granulomarous appendicitis is a distinct but rare clinicopathological entity characteri zed by a granulomatous inflammatory process localized solely to the appendix vermiform is.When fungi, parasites, oreign bodies and obstruction •econdary to fccalith, mucocele or tumour h ave been eli mi:1ated his-colog1cally as ca uses, fewer than I 00 cases have been reported.Various diseases may be responsible, including sa rcoidosis (3) and specific infections, ie, tuberculosis ( 4) and yersiniosis ( 5,6).ln addit ion, isolated Crohn 's disease initially limited to the appendix a nd ca using granulomas solely at this site has been well described .The present report details the authors' acc umulated experie nce (over 10 years) with C rohn's disease initially limited to the appendix a nd treated with appendectomy.A 'reagent grade' population was defined based o n the presence of an appendiceal granulomatous process and the excl usion of other known causes, including infectious agents such as Yersinia enterocolitica (2).The present repo rt indicates that recurrent symptoms and subseq uent detection of Crohn's disease e lsewhere in the gastrointestinal tract, including stomach , small bowel and colorectum, may be frequent.These observ;:i tions are consistent with previous reports of isolated C rohn's disease at other sites such as the oropharynx, and the subsequent observation, occasionally many years later, of more extensi ve Crohn's di ease (37-39).
Appendiceal involvement in patients with Crohn's di:.ease includes a mixed patient group.Acute ('nongranulomatous') appendic itis may precede establishment of a diagnos is of C rohn's disease (40) or, alternatively, Crohn's disease itself may involve the appendix secondarily hy extension nf the gran ulomacous procc~, from contiguous ileum or cecum.Crohn's disease limited to the appendix is much less common and was first descnhed by Meyerding and Bertram in 1953 (7) in a 21-year-old male with right lower quadrant abdominal pain.Since that time, othe r cases have appeared in the li teratu re (8-36); patients are usuall y in the second to third decade of life, tend to be male, and present with right lower quadrant abdominal pai n and, occasionally, a palpable mas .The unc ha racteristi cally long duration of symptoms of acute append icitis noted elsewhere (28), and the difficult separation from more indolent gynecological causes of inflammatory disease, were underlined in the present series of patients.
Previous recommendations for more extensive surgical resection, including ileocolectomy (28), may be based largely on the fear of complications in the postoperative period, including fistulizau on.Despite the suggestion that appendectomy should nm be performed in thi setting (4 1 ), the experience in the present report suggcsb that recognition of Crohn's disease limited co the appendix, even for well trained surgeons, 1s difficu lt.The diagnosis is usually retrospective, establish ed after histological review of surgical sections.Significantly, <1ppendectomy alone in the present patients did not result in any postoperative morbidity or complication such as enterocutaneom fistu la (40).
Collected surgical series of cases suggest chat the vast majority of patient, re ma in asymptomatic followi ng resection of the appendix.This conclusion may be potentiall y misleading since the period of long term fo llow-up for mo,r reported patients appears often to ht limited to less than one year.In the presen t pmients, as in patients with Crohn's disease at other ~ites 'treated surgically', recurrent symptoms and histological evidence of Crohn 's disease were freq uent.Accordingly, clo e follow-up on a regular basis seems appropriate and, if symptoms recur, further evaluation may be warranted.