Disseminated Gastrointestinal Basidiobolomycosis: A Case Report with Review of Diagnostic Clues

Introduction Basidiobolomycosis is a rare fungal infection caused by an environmental saprophyte, Basidiobolus ranarum. It usually presents as a chronic subcutaneous infection; however, few cases of gastrointestinal involvement have been reported. The exact transmission route of gastrointestinal cases is not clear, and diagnosis always requires a high index of suspicion because it tends to mimic other inflammatory and neoplastic conditions. Case Report. A 31-year-old immunocompetent woman presented with abdominal pain and an advanced colon mass. She was completely well until about 1.5 years ago, when she underwent bariatric surgery. One year after surgery, chronic abdominal pain developed. A colonoscopy showed an ulcerative lesion in the descending colon, and the biopsy was in favor of ulcerative colitis. Despite immunosuppressive treatment, there was no improvement, and with worsening symptoms, more investigations revealed advanced colon mass with entrapment of the stomach and pancreas. Colonic mucosa biopsy and trucut biopsy of the mass showed just necrosis and acute inflammation; thus, she underwent exploratory laparotomy with colectomy, partial gastrectomy, distal pancreatectomy, and left nephrectomy. On pathologic examination, there was granulomatous inflammation plus the Splendore–Hoeppli phenomenon around fungal hyphae, which was diagnostic for gastrointestinal basidiobolomycosis. Previous pathology slides were reviewed and revealed a tiny focus of basidiobolomycosis. After 6 months of treatment with itraconazole, she is relatively well without any clinical or radiologic abnormalities. Conclusion Our case highlights the significance of suspicion for basidiobolomycosis in ulcerative and necrotic lesions with increased eosinophils, especially in the presence of abdominal mass and systemic eosinophilia.


Introduction
Basidiobolomycosis is a rare fungal infection caused by the fungus Basidiobolus ranarum of the Entomophthorales family.Tis fungus is an environmental saprophyte found in soil and decaying vegetable materials, especially in tropical and subtropical areas.Basidiobolomycosis mainly afects immunocompetent individuals as a chronic subcutaneous infection.
Gastrointestinal involvement is extremely rare [1,2].Te diagnosis of gastrointestinal basidiobolomycosis (GIB) is always confusing and requires a high index of suspicion because it tends to mimic other non-neoplastic and also neoplastic conditions, even on histopathologic evaluation.Te exact transmission route is also not clear in some cases [2,3].In the reported case of GIB, misdiagnosis with infammatory bowel disease led to disseminated visceral involvement.
A 31-year-old woman from the north of Iran was transferred to Abu Ali Sina Hospital, Shiraz, Iran, to be evaluated for advanced colon mass.She was completely well until about 1.5 years ago, when she underwent bariatric surgery for morbid obesity (BMI: 50.1).One year after surgery, she presented with intermittent, generalized, and progressive abdominal pain and fever, which lasted for a month.Tere was no history of nausea, vomiting, or diarrhea.
A colonoscopy showed an ulcerative lesion in the descending colon, and a biopsy was in favor of ulcerative colitis.Despite treatment with immunosuppressant drugs, there was no improvement after 6 months, and with worsening of symptoms, more investigations by computed tomography (CT) revealed a large complex new malignantlooking abdominal mass encasing the transverse colon, stomach, tail of pancreas, and left kidney (Figure 1).A repeated colonoscopic biopsy and trucut biopsy of the mass showed ulceration, necrosis, and an acute infammatory reaction.
A physical examination on admission showed a lowgrade fever (37.9 °C) and abdominal tenderness.Laboratory data showed mild leukocytosis, mild anemia, and eosinophilia with increased erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP).Other laboratory tests, including urea, creatinine, glucose, and liver function tests, were within normal ranges.According to the clinical and radiologic data and also based on the previous histologic diagnosis of ulcerative colitis, she underwent exploratory laparotomy in our center with a preoperation diagnosis of advanced colon malignancy, which showed extensive involvement of the visceral organs (Figure 2(a)).
Te specimens of total colectomy, hemigastrectomy, distal pancreatectomy, splenectomy, and left nephrectomy were sent for pathologic examination.Te macroscopic evaluation revealed two well-demarcated, rubbery, creamy masses.Te largest mass was 17 × 15 × 10 cm found in the submucosa of the colon and pancreas with attachment to the stomach (Figure 2(b)).Histologic examination of the mentioned masses and pancreas revealed acute and chronic infammatory changes with a predominantly granulomatous reaction and a rise in the eosinophilic count.Basidiobolomycosis infection was suspected based on macroscopic mass formation and the presence of broad, thin-walled, and aseptate hyphae, in addition to the Splendore-Hoeppli phenomenon (radiating intensely eosinophilic material) surrounding the fungal hyphae.Special stains for fungal elements, such as Periodic Acid-Schif (PAS) and Grocott's Methenamine Silver (GMS), were also used to confrm the diagnosis (Figure 3).Te colonic mucosa showed focal ulceration and activity without any evidence of chronic colitis.Te specimen was sent to pathology in a 10% formalin solution to rule out cancer, but unfortunately, tissue culture was not performed because there was not enough suspicion for a fungal infection.
Te pathologic slides of the previous biopsies from another center were also reviewed and showed a tiny focus of the Splendore-Hoeppli phenomenon, which was missed due to the unfamiliarity of the pathologists with this clinical entity (Figure 4).
Intravenous antifungal therapy with fuconazole was started, but since the patient could not tolerate it and developed nausea, vomiting, and diarrhea after two days, it was replaced by oral itraconazole for 6 months.In a follow-up visit two weeks later, the patient showed improvement in her symptoms, and during the 6-month follow-up visits, no clinical or radiologic defcits were noted.Table 1 shows the transition of laboratory data from the frst day of admission to recovery time.
We requested and obtained informed consent from the patient for publishing the case report and the accompanying images.Te research was approved by the Ethics Committee of Shiraz University of Medical Sciences (No. IR.SUMS.MED.REC.1400.433).

Discussion
We investigated the English literature in the period 1964-2021 via PubMed, Google, and Google Scholar twice, using the following search keywords: basidiobolomycosis and gastrointestinal and Iran.
A young Nigerian boy was the frst known case of GIB, as described by Edington in 1964.Following that, the United States, Saudi Arabia, India, and Iran all had a small number of case reports.All previous Iranian case reports were from the south of the country [7,8]; our case, however, was from a northern province, and to the best of our knowledge, no case of GIB had been reported from that region in English literature until now.
Similar to our situation, every case that has been published has been immunocompetent and has no clear risk factors.Although the patient in our case was an adult female, most cases that have been documented were young boys [8,9].
Ingestion of infected foods is considered the main route of infection, and disturbing gastric mucosal defense due to the use of ranitidine and smoking may facilitate fungal infection after gastric entrance.Using contaminated papers  Case Reports in Medicine for cleaning the skin (e.g., toilet papers) exposure in the work environment are other proposed theories [10][11][12].So far, few cases like ours have been reported with a history of previous surgery, including herniorrhaphy, appendectomy, and laparotomy for peptic ulcer perforation [11,13,14].GIB mostly involves the colon.Abdominal pain, fever, diarrhea or constipation, weight loss, and abdominal mass are the primary clinical manifestations.Cases have also been reported with retroperitoneal fbrosis and ileocecal intussusception [8,15].In most cases, these nonspecifc symptoms and signs result in a misdiagnosis of malignancy, infammatory bowel disease (such as Crohn's disease or ulcerative colitis), tuberculosis, sarcoidosis, etc.In a review by Al Jarie, none of the reported cases had a diagnostic    endoscopic biopsy.Tis misdiagnosis typically causes a delay in diagnosis, followed by an increase in morbidity and mortality [4-6, 16, 17].Peripheral blood eosinophilia is a common laboratory fnding, as increased ESR, anemia, and thrombocytosis [18][19][20].However, the diagnosis of GIB depends on the detection of B. ranarum on a morphological, microbiological (tissue culture), or molecular basis (PCR).Te best results are obtained by using DNA extracted from formalinfxed parafn-embedded lesional tissues.However, this method is not widely used by many health institutions, as well as our center, due to the rarity of basidiobolomycosis infections.Culture on Sabouraud agar at 20-30 °C with incubation for 2-3 days is the gold standard for defnitive diagnosis [20][21][22].However, in most reported cases, similar to ours, the patients had undergone surgical resection with the clinical impression of mass, and therefore the specimens have been transferred to the laboratories in formalin and no cultures have been performed [21,23].
Te main histologic fndings include mixed infammatory cells, especially eosinophilic infltration, granulomatous reactions, broad, thin-walled, and aseptate hyphae, and Splendore-Hoeppli phenomenon (radiating intensely eosinophilic material) around fungal hyphae.Because the Splendore-Hoeppli phenomenon can be caused by a variety of microorganisms and inert substances, special staining for fungal elements, such as PAS and GMS stains, or culture should be used to confrm the presence of fungus [8,10,20].Te other fungal infections with similar morphology to B. ranarum are Conidiobolus coronatus, Conidiobolus incongruous, and Pythium.Tey are separated from B. ranarum by the fact that these fungi afect the head and neck region in immunocompromised patients.Visceral involvement by these fungi has not been reported [21,22].
Among variable diferential diagnoses, infammatory bowel disease is the most critical one.Severe colitis in infammatory bowel disease is usually accompanied by architectural distortion, ulceration, and mixed infammatory cell infltration.Tus, in the absence of a high clinical suspicion for basidiobolomycosis and looking for the fungus, small biopsy specimens without granulomatous reaction may easily be missed as ulcerative colitis.Moreover, superfcial intestinal mucosal biopsies in GIB can show nonspecifc chronic infammation [24].Unfortunately, there is no defnite confrmatory test for infammatory bowel disease, and treatment with immunosuppressive therapy may lead to disseminated fungal infection, as in our case.
Surgical resection of the infected bowel with a wide margin, followed by 6-12 months of systemic antifungal therapy, is the treatment of choice [8,24,25].Itraconazole is  the most commonly used antifungal medication, followed by amphotericin, ketoconazole, and voriconazole.B. ranarum is intrinsically resistant to amphotericin B. voriconazole is a useful and generally well-tolerated drug for treating uncommon fungal infections and should be considered a backup plan in patients with no efective outcomes after being treated with other antifungal drugs.However, with the increasing likelihood of resistant strains, culture and sensitivity tests are necessary to identify the most efective antifungal treatment plan for each individual situation [26][27][28].Long-term medical treatment and follow-up are advised to prevent the recurrence, and the disseminated cases should be treated with debridement and antifungal therapy [25,29,30].
Our patient was initially diagnosed with ulcerative colitis based on clinical presentation and colonoscopic biopsies and was later thought to have advanced colon cancer according to the radiologic assessment.If the pathologists were educated about the histologic characteristics of GIB or observed increased ESR, eosinophilia, and signifcant eosinophil infltration in the colonic tissue, the initial colon biopsy could be suggestive of the disease and prevent misdiagnosis and additional visceral involvement.Moreover, it is recommended that the Middle Eastern countries, who comprise the majority of GIB patients, furnish their laboratories for relevant PCR and fungal culture.

Conclusion
Although a high index of suspicion is required for preoperative diagnosis of GIB, some clinical and paraclinical tips, such as peripheral eosinophilia and abdominal mass formation with eosinophilic infltration in the context of previous intraabdominal intervention, should raise suspicion for the disease and, if put together correctly, could help to solve the puzzle and enable diagnosis.As in our situation, a delayed diagnosis might lead to the infection spreading and necessitating advanced surgery.

Figure 1 :
Figure 1: Abdominal CT scan with contrast shows a huge mass in the transverse colon.

Figure 2 :
Figure 2: Te gross morphology of the case shows extensive visceral involvement (a) in the operation room and (b) after formalin fxation at the pathology department.

Figure 4 :
Figure 4: Review of the previous biopsy showed a tiny focus of the Splendore-Hoeppli phenomenon (arrows) (hematoxylin and eosin ×40).

Table 1 :
Te initial and posttreatment results (after 8 weeks) of the laboratory tests.