Case 5 -

Gastrointestinal Basidiobolomycosis Wade S. Samowitz University of Utah Medical Center Salt Lake City, UT

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Clinical Summary: A 57 year old insulin-dependent diabetic man presented at an outside institution with lower abdominal pain, anorexia, fatigue, low grade fevers and constipation. The WBC count was 16,400/µl with 8% eosinophils. CT showed an 18 cm mass involving the transverse colon and stomach. Left colon biopsy showed "active colitis with epithelioid granulomas." The presumptive diagnosis was Crohn's disease and treatment with mesalamine was begun. Subsequent enlargement of the mass prompted surgical resection of a segment of colon and part of the greater curvature of the stomach. Histologic interpretation was "diverticular disease with perforation and foreign body reaction." The patient was discharged but was then admitted to our institution because of an enlarging mass now involving the pancreatic tail and left kidney. Slides from the initial operation were reviewed at our institution. Pathologic findings: The wall of the bowel is involved by numerous necrotizing, and occasional non-necrotizing, granulomas. There are also large areas of necrosis with both eosinophils and neutrophils which are ringed by giant cells. Numerous eosinophils are present both within and outside of the granulomas; associated with the eosinophil infiltration are Charcot-Leyden crystals. The mucosa of the bowel is relatively unaffected by this granulomatous process. Large, thin-walled, irregularly branched fungal hyphae with occasional septae are present within the granulomas and in areas of necrosis. These are surrounded by a thick eosinophilic cuff, the Splendore-Hoeppli phenomenon. Case 5 - Figure 1 Submucosa granuloma with hyphal form with Splendore-Hoeppli phenomenon. Case 5 - Figure 2 Large area of necrosis in muscularis propria and submucosa ringed by giant cells. Case 5 - Figure 3 Giant cells and pallisading histiocytes at the edge of the area of necrosis. Case 5 - Figure 4 Hyphae (both longitudinal and in cross-section) with Splendore-Hoeppli phenomenon. Case 5 - Figure 5 Hyphae with Splendore-Hoeppli phenomenon. Case 5 - Figure 6 Prominent eosinophil infiltrates. Case 5 - Figure 7 Cross-section of hyphal element with Splendore-Hoeppli phenomenon at bottom of photomicrograph; numerous Charcot-Leyden crystals above the fungus. Case 5 - Figure 8 Numerous hyphae with Splendore-Hoeppli phenomenon. Diagnosis: Gastrointestinal Basidiobolomycosis Discussion: Gastrointestinal Basidiobolomycosis is an extremely rare disease, with 8 cases reported from the United States, mostly in residents of Arizona [1]. World-wide a little over 20 cases in total (including the 8 from the US) have been reported, including cases from Nigeria, Brazil, Kuwait, Iran, Saudi Arabia and the Netherlands [2, 3, 4, 5, 6, 7]. The etiologic agent of this disease is Basidiobolus ranarum. Like the agents of Mucormycosis (here defined as infections due to fungi belonging to the order Mucorales), which it histologically resembles, it is a member of the class Zygomycetes; however, it belongs to the order Entomophthorales rather than Mucorales. Basidiobolus ranarum and another member of Entomophthorales, Conidiobolus coronatus, are more commonly associated with skin and soft tissue infections in individuals from tropical areas of Africa, South America, and Asia. Infection due to B. ranarum and C. coronatus typically occurs in immunocompetent individuals. B. ranarum is found in decaying plants and soil and as a commensal in the intestinal tracts of many animals, including frogs, toads, turtles, chameleons, horses and dogs [8]. Skin and soft tissue infection due to this agent is thought to be due to traumatic implantation [9]. The mode of transmission of gastrointestinal disease is uncertain, although a case control study of cases in the US postulated ingestion of soil, animal feces, or food contaminated by these substances [1]. This study also suggested that therapy with ranitidine and duration of residence in Arizona were risk factors for the disease. The clinical presentation of gastrointestinal Basidiobolomycosis includes abdominal pain, fever, constipation, anorexia and weight loss; rarely nausea and vomiting and lower gastrointestinal tract bleeding may be seen [8]. Abdominal masses, usually involving the colon, are present. These masses may also involve the stomach, duodenum, liver, biliary system and pancreas. Most patients exhibit a peripheral eosinophilia. The histologic appearance of gastrointestinal Basidiobolomycosis is quite distinctive [10]. It is typically a mural disease with marked wall thickening; the mucosa is much less involved, although it often shows focally increased eosinophils. Numerous granulomas are present in the wall of the bowel and subserosa, surrounding areas of necrosis or abscesses composed of eosinophils, neutrophils or both. Prominent eosinophil infiltrates outside of the granulomas are also commonly present, and Charcot-Leyden crystals may be seen. Within the granulomas hyphal forms surrounded by a thick eosinophilic cuff (Splendore-Hoeppli phenomenon) are present. These hyphae are large (8-40 um in width), thin-walled, irregularly branched, and contain occasional septae. Hyphal walls can be seen on H and E, and typically do not stain well with fungal stains like GMS or PAS. The differential diagnosis includes Crohn's disease [11] and Mucormycosis. A predominantly mural, granulomatous disease like gastrointestinal Basidiobolomycosis could be confused with Crohn's disease. Besides the lack of fungi in Crohn's disease, mucosal disease is usually more prominent than in Basidiobolomycosis. Mucormycosis usually occurs in immunodeficient individuals or in uncontrolled diabetics. Mucormycosis also typically shows prominent vascular invasion and tissue necrosis and lacks the well-formed granulomas and the Splendore-Hoeppli phenomenon seen with B. ranarum. C. coronatus (and other species like C. incongruus) may appear histologically identical to B. ranarum. Visceral involvement is very rare with Conidiobolomycosis and some individuals with disseminated disease are immunocompromised. Culture and/or serum antibodies can distinguish Basidiobolomycosis from Conidiobolomycosis. As with most other infectious organisms, culture is extremely important. B. ranarum has a characteristic beaked zygospore [8]. Also, the organism forcibly ejects spores that may then be seen on the cover of the Petri dish [8, 12]. Since B. ranarum does not survive at 4 degrees Centigrade, culture of fresh tissue is imperative. Treatment of gastrointestinal Basidiobolomycosis usually involves a combination of surgical resection and prolonged antifungal therapy [9]. The organism is often resistant to amphotericin B, but is usually responsive to itraconazole. Lack of or inappropriate treatment often leads to a fatal outcome [11]; appropriate therapy appears to be associated with a good outcome [1]. This patient was initially treated with the liposomal form of amphotericin B without a response. Subsequent testing revealed resistance to amphotericin but susceptibility to itriconazole. Itriconazole thereapy led to defervescence and resolution of leukocytosis and peripheral eosinophilia. A right hemicolectomy was performed due to persistence of the mass and colonic obstruction. The patient was discharged on long-term itriconazole. References Lyon GM, Smilack JD, Komatsu KK, et al. Gastrointestinal basidiobolomycosis in Arizona: clinical and epidemiological characteristics and review of the literature. 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Archives of pathology & laboratory medicine 2009 Dec; 133(12): 1938-42. Zavasky DM, Samowitz W, Loftus T, Segal H, Carroll K. Gastrointestinal zygomycotic infection caused by Basidiobolus ranarum: case report and review. Clin Infect Dis 1999 Jun; 28(6): 1244-8. Pfaller MA, Diekema DJ. Unusual fungal and pseudofungal infections of humans. Journal of clinical microbiology 2005 Apr; 43(4): 1495-504. Yousef OM, Smilack JD, Kerr DM, et al. Gastrointestinal basidiobolomycosis. Morphologic findings in a cluster of six cases. American journal of clinical pathology 1999 Nov; 112(5): 610-6. Pasha TM, Leighton JA, Smilack JD, et al. Basidiobolomycosis: an unusual fungal infection mimicking inflammatory bowel disease. Gastroenterology 1997 Jan; 112(1): 250-4. Gugnani HC. A review of zygomycosis due to Basidiobolus ranarum. European journal of epidemiology 1999 Nov; 15(10): 923-9.