October.indd

V. Healy M.Jeffers F.B.V. Keane* and O.N. Tucker*
*Department of Surgery and Department of Pathology, The Adelaide and Meath Hospital, Tallaght, Dublin 24, Ireland
Correspondence to: F.B.V. Keane, Department of Surgery, The Adelaide and Meath Hospital, Tallaght, Dublin 24, Ireland

Introduction

Case series

Discussion

References

Granulomatous inflammation of the appendix is uncommon. It can be caused by a variety of conditions, including systemic disorders such as Crohn’s disease and sarcoidosis, and infections such as mycobacterium tuberculosis, yersinia pseudotuberculosis, parasites and fungi. Granulomatous appendicitis as an isolated pathological entity unassociated with systemic disease is rare. Isolated granulomatous inflammation of the appendix of unknown aetiology, otherwise known as idiopathic granulomatous appendicitis is extremely rare. Patients with this condition present with the typical signs and symptoms of acute appendicitis. We present a series of patients with isolated granulomatous inflammation of the appendix, and discuss the difficulties encountered in the management of this condition

Keywords: Granuloma, appendicitis
Surg J R Coll Surg Edinb Irel., 1 October 2003, 286-289

INTRODUCTION
Granulomatous appendicitis is uncommon. It is defined as the presence of granulomatous inflammation in the wall of the appendix. Various causes have been described including infections by fungi, yersinia pseudotuberculosis, mycobacterium tuberculosis, blastomycosis, histoplasma capsulatum, schistosomiasis, actinomycosis, campylobacter, toxoplasma, brucella, candidiasis and some parasites.^1-4 Other causes include foreign bodies, obstruction secondary to a faecolith, mucocele, tumour, and in rare cases, diverticulitis.^5,6 Systemic conditions such as Crohn’s disease and sarcoidosis can be associated with granulomatous inflammation of the appendix.^7-9 The lesions of Crohn’s disease, tuberculosis, sarcoidosis and yersinia can be difficult to differentiate on routine histological examination and may require additional investigations to establish the diagnosis. Idiopathic granulomatous appendicitis, defined as granulomatous inflammation of unknown aetiology confined to the vermiform appendix, is a rare occurance.^9-11 Patients present with the typical symptoms and signs of acute appendicitis.^12,13 In the presence of granulomatous appendicitis it is important to exclude systemic causes of granulomatous inflammation by appropriate investigations and long-term follow-up. We present six cases of isolated granulomatous inflammation of the appendix that were dealt with in our service during a three and a half year period from July 1998 to January 2002.

CASE SERIES
During the first three and a half years since the relocation of the Adelaide and Meath Hospital, our pathology department received 859 appendicectomy specimens with histologically confirmed changes of inflammation. Six of the 859 appendicectomy specimens had findings consistent with granulomatous appendicitis (0.7%).

All six patients presented with pain in the right lower quadrant of the abdomen, associated with systemic complaints of anorexia (50%), nausea (50%), and pyrexia (100%). The male to female ratio was 5:1. The median age of the patients was 27 years (range 18-37 years). Consistent with previously published case reports, five of the six patients (83%) in our series presented with a protracted pre-operative course describing abdominal pain for more than one week, with two patients having symptoms for 10 days.9 A diagnosis of acute appendicitis was suspected pre-operatively in all six patients.

All patients had a palpable mass in the right iliac fossa when anaesthetised. An open appendicectomy was performed in the other three patients (50%) through a standard Lanz incision. Exploratory laparoscopy was performed in three patients (50%). Laparoscopic appendicectomy was successful in only one patient. Conversion to the standard open procedure was performed when laparoscopy demonstrated free turbid peritoneal fluid associated with a large inflammatory mass in the right iliac fossa in one patient, and features suggestive of Crohn’s ileitis in the second patient. At operation, an inflammatory mass was present in all patients (100%). Intra-operative findings included peri-appendiceal abscess formation (83%) and marked thickening of the appendix (83%). Specimens for microbiological assessment were taken intraoperatively in all patients. There was gangrene of the distal appendix in five patients (83%), and perforation of the appendiceal tip in four patients (67%). The caecum and terminal ileum were grossly normal in five patients (83%). In these patients an appendicectomy alone was performed. In one patient, a right hemicolectomy was performed with resection of the distal terminal ileum as the intra-operative findings suggested Crohn’s disease.

Figure 1a: Mural granulomatous inflammation
(Haematoxylin and eosin, magnification x 20)

Figure 1b: Mucosal granulomatous inflammation
(Haematoxylin and eosin, magnification x 100)

Figure 1c: Non-caseating granuloma within germinal centre of lymphoid follicle (Haematoxylin and eosin, magnification x 200)

On gross histological examination, all the appendiceal specimens were (appreciably) enlarged with an average size of 7.2 x 4 x 2cm. All specimens exhibited transmural thickening with fibrosis, acute and chronic inflammatory changes, and multiple non-caseating granulomata (Figure 1). Non-caseating granulomas were found in the mucosa (50%), submucosa (50%), muscularis (67%) and in the serosa (17%) (Figure 1a-b). Epitheliod granulomas with central necrosis typical of yersinia infection were not seen, and serology for yersinia was negative.¹⁴ Three cases (50%) had non-caseating granulomas within the germinal centres of lymphoid follicles (Figure 1c). Occasional mucosal granulomas were identified in the base of the caecum and terminal ileum in the one patient who had a right hemicolectomy. The features and distribution of disease were not suggestive of Crohn’s disease. No foreign bodies, obstructing lesions or parasites were seen. Special stains for acid-fast bacillus and fungi were negative. Culture results obtained from the periappendiceal abscesses demonstrated ß-haemolytic streptococci group C, coagulase negative staphylococci, and bacteroides. A diagnosis of idiopathic granulomatous appendicitis was made in all six cases based on the histological and microbiological findings.

Post-operative complications included one patient who had a persistent pyrexia for two days which responded to antibiotic treatment. There was one superficial wound infection, which required oral antibiotics, and local wound dressings. A third patient developed a right iliac fossa collection measuring 3.5 x 2cm, which settled with conservative management. Postoperative investigations included a small bowel barium meal and follow-through study in one patient, and colonoscopy with multiple biopsies in two patients, which were normal. No evidence of Crohn’s disease was detected. No specific post-operative investigations were performed on the remaining three patients. All patients have been reviewed in the outpatient department, and all remain asymptomatic.

DISCUSSION
Granulomatous inflammation of the appendix is uncommon. In our series, 6 of 859 appendicectomy specimens had findings consistent with granulomatous appendicitis (0.7%). The reported incidence in western countries ranges from 0.14-0.3%, with an incidence of 1.3-2.3% in under-developed countries.¹⁵ Epitheliod granulomas are known to occur in the gastrointestinal tract in association with a number of systemic granulomatous conditions and infections. The higher incidence in the latter countries is believed to be due to the increased incidence of tuberculosis and schistosomiasis.^1,15

The presence of granulomas in an appendix specimen should prompt a search for Crohn’s disease elsewhere in the bowel.¹⁶ Crohn and Ginzberg in 1932 in their initial description of regional ileitis stated that ‘the process never transcends the limits of Bauhin’s valve, and that the appendix is always free from guilt and free from changes’.¹⁷ However, a number of subsequent studies have suggested that the appendix can be involved alone or in association with Crohn’s disease of the ileum or colon.^18-21 It is essential to examine the small bowel, caecum and colon to exclude Crohn’s disease, as there is a reported 25% incidence of appendiceal involvement with concurrent ileal or colonic Crohn’s disease.^7,22 There are a number of similarities and differences between idiopathic granulomatous appendicitis and Crohn’s disease of the appendix that can help differenciate these conditions.²³ Neutrophilic infiltration of crypts with crypt abscesses, mucosal erosion and ulceration, transmural lymphocytic inflammation and mural fibrosis with thickening can occur in both conditions.²⁴ A higher number of granulomas per tissue section is seen in idiopathic granulomatous appendicitis (n=19.7) compared with Crohn’s disease (n=0.3).^24,25 Fistula formation is rare in isolated granulomatous appendicitis, but can occur in 15-20% of patients undergoing appendicectomy for ileocaecal Crohn’s disease.^26-28 Subsequent surgical intervention may be required in patients with Crohn’s disease but is rarely necessary in patients with idiopathic granulomatous appendicitis.

A number of studies have suggested that granulomatous inflammation of the appendix can be an isolated process unrelated to the presence of, or subsequent development of Crohn’s disease.^23,24,29 Richards et al. (1997) retrospectively reviewed 1133 consecutive appendicectomy specimens over a six-year period, and identified seven patients with isolated granulomatous appendicitis.³⁰ Following a mean follow-up period of seven years no case had evidence of Crohn’s disease. The authors concluded that isolated granulomatous appendicitis, without small bowel or caecal involvement, may not represent true Crohn’s disease. They proposed that appendicectomy alone can be performed in these patients with minimal morbidity. Similarly, Wettergren (1991) examined 6051 appendiceal specimens over a five-year period and encountered six patients (0.1%) with epitheliod granulomas.³¹ On subsequent follow-up for 9 to 11 years (median 9.5 years) all the patients remained free of gastrointestinal symptoms. Others have suggested that even in the presence of proven primary Crohn’s disease of the appendix there is a favourable long-term prognosis after simple appendectomy, despite a 10-14% incidence of recurrence as granulomatous ileocolitis.^7,9,20

Other causes of granulomatous appendicitis need to be considered. Sarcoidosis can manifest as acute appendicitis.^4,8,32 The Kveim test is positive in 80% of patients with this condition.³³ Mycobacterium tuberculosis is diagnosed by tissue culture, demonstration of acid-fast bacilli, positive tuberculin skin tests, with evidence of pulmonary or additional systemic involvement. Yersinia pseudotuberculosis can cause enteric infections with granulomatous lesions of the mesenteric lymph nodes, terminal ileitis, and/or appendicitis.^14,34

It can be detected by cold enrichment culture techniques, serology, and histologically. Microscopically, typical yersinia granulomas are large, stellate or geographically shaped, and partly palisading with central necrosis. Warthin-Starry stains can be used to demonstrate yersinial microorganisms.¹⁴ This condition has a chronic, mild and benign course. It is usually self-limiting and does not require specific treatment. In our series, granulomas were demonstrated within lymphoid germinal centres in three of our patients (50%) which raises the possibility of toxoplasma infection. This is usually seen in cervical lymph nodes, but rare cases of toxoplasmosis presenting as appendicitis have been recorded.¹ However, toxoplasma was not demonstrated in any of our patients.

Idiopathic granulomatous appendicitis presents most commonly with a protracted period of abdominal complaints, as demonstrated in our patient group.⁹ Pre-operative investigations by imaging techniques, such as abdominal ultrasound can demonstrate a markedly thickened appendiceal wall.^20,35,36 Intra-operatively the appendix is thickened and enlarged.⁹ Appendicectomy alone can be performed with minimal morbidity.³⁰ The exclusion of other causes of granulomatous inflammation is essential.¹¹ In our patient series no causative factors were identified. A diagnosis of idiopathic granulomatous appendicitis was concluded in all six patients.

In conclusion, isolated granulomatous appendicitis is rare. Systemic and infectious causes of granulomatous inflammation of the appendix must be excluded with appropriate investigations prior to a diagnosis of idiopathic granulomatous appendicitis. The prognosis of idiopathic granulomatous appendicitis appears to be favourable but careful long-term follow-up of the patients is essential.

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Royal College of Surgeons in Ireland

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