Subcutaneous entomophthoromycosis in an immunocompetent individual: a localised forearm swelling

Abstract

A man in his 80s with no known comorbidities presented with diffuse swelling on the dorsal aspect of his right forearm for 3 months. Clinical features were suggestive of soft tissue sarcoma of the right forearm. A high resolution CT scan of the thorax showed allergic bronchopulmonary aspergillosis associated with mild mediastinal lymphadenopathy. MRI of the right upper limb showed a suspicious neoplastic/infective aetiology. A core biopsy of the right arm swelling found a granuloma with no malignancy features so an incisional biopsy of the lesion was carried out. This indicated granulomatous inflammation with excessive giant cell reaction and focal panniculitis with the possibility of a mycotic lesion. Bronchoalveolar lavage was negative for tuberculosis and fungal infection. After a multidisciplinary team discussion, the patient was started on antifungal medication. There was a marked reduction in both the size and consistency of the swelling after several weeks of oral itraconazole and potassium iodide solution. The purpose of this report is to increase the awareness of this uncommon treatable condition which, if misdiagnosed, could result in an inappropriate intervention.

Background

Zygomycosis is an infection caused by fungi belonging to the phylum Zygomycota which includes two fungal orders: Mucorales and Entomophthorales.¹ The former causes mucormycosis in immunocompromised individuals and the latter causes entomophthoromycosis in immunocompetent individuals. Entomophthorales is a saprophytic group of fungi which is subdivided into two distinct groups: subcutaneous zygomycosis is caused by Basidiobolus ranarum and rhinofacial zygomycosis is caused by Conidiobolus coronatus. Basidiobolomycosis is a chronic subcutaneous infection of the trunk and limbs due to Basidiobolus ranarum¹ (see table 1 for taxonomic classification). Subcutaneous fungal infection is rare among immunocompetent individuals. Subcutaneous zygomycosis is a subcutaneous infection that is largely restricted to tropical areas of Africa, Asia and South America. It is usually seen as the formation of firm and non-tender swellings, generally on the extremities, trunk and rarely on other parts of the body.² It can also resemble soft tissue tumours.³

Table 1.

Taxonomic classification of Basidiobolus ranarum

Kingdom	Fungi
Phylum	Basidiobolomycota
Class	Basidiobolomycetes Doweld, 2001
Order	Basidiobolales
Family	Basidiobolaceae
Genus	Basidiobolus Eidam, 1886
Species	Basidiobolus ranarum Eidam, 1886

We present a rare case of subcutaneous entomophthoromycosis in an immunocompetent individual which occurred as a localised forearm swelling. The clinical features, diagnosis, treatment and follow-up of the patient are discussed.

Case presentation

A man in his 80s with no known comorbidities presented to the general surgery outpatient department with complaints of diffuse swelling on the dorsal aspect of the right forearm (figure 1, figure 2). It was insidious in onset and had gradually progressed to the present size over the previous 3 months. There was no history of trauma, fever, loss of weight, loss of appetite or swelling elsewhere in the body. On general examination, his vital signs were stable. Local examination showed a swelling about 15×11 cm on the dorsal aspect of the right forearm just below the elbow crease. The skin was hyperpigmented and there was induration of the skin. The subcutaneous tissue lesion had a bosselated surface and irregular borders with tattooing over the swelling. Distal pulses were felt. Regional node enlargement was present. Forearm pronation and supination were normal except for the presence of a 30 degree flexion deformity. Systemic examination was normal.

Figure 1.

Clinical photograph showing a diffuse swelling of about 15×13 cm on the dorsal aspect of the right forearm in the supinated position with the presence of tattooing.

Figure 2.

Chest X-ray showing consolidatory changes. Note the perihilar cystic areas predominantly on the right side and a nodule of 1 cm in the left lower zone.

Investigations

Laboratory investigations showed haemoglobin 11.3 g/dL, total leucocyte count 13 010 /mm³ and platelets 300 000/μL. Fasting blood sugar was 100 mg/dL, postprandial blood sugar 130 mg/dL and glycosylated haemoglobin was 4.9%. Liver function tests, renal function tests, serum electrolytes and the coagulation profile were within normal limits. Serology for HIV, hepatitis B and hepatitis C was non-reactive and the COVID-19 RT-PCR routine was negative. A chest x-ray showed consolidatory changes, with perihilar cystic areas predominantly on the right side and a nodule of 1 cm in the left lower zone. An x-ray of the right forearm was normal (figure 2, figure 3). Ultrasound of the abdomen showed no significant abnormality. From the history and clinical examination, the patient was suspected to have soft tissue sarcoma of the right forearm with pulmonary metastasis. A core biopsy from the right arm swelling showed granuloma. Sputum for gram stain and acid-fast bacilli was negative. Mantoux was negative. The erythrocyte sedimentation rate was 42 mm/hour. A high resolution CT scan of the thorax showed central cystic and cylindrical bronchiectasis with mucocele formation, features that could represent allergic bronchopulmonary aspergillosis associated with mild mediastinal lymph adenopathy (figure 4). MRI scan of the right upper limb showed suspicion of the proximal forearm and elbow with involvement brachioradialis, superficial and deep subcutaneous plane and cuticular region neoplastic lesion/infective lesion (myositis) anterior aspect of distal forearm, elbow and proximal forearm. Laxity of the triceps tendon (close to the osseous tendon junction) with subcutaneous oedema was also seen (figure 5).

Figure 3.

X-ray of the right forearm: (A) anteroposterior view; (B) lateral view.

Figure 4.

(A, B) High resolution CT scan of the thorax showing central cystic and cylindrical bronchiectasis with mucocele formation, features which could represent allergic bronchopulmonary aspergillosis associated with mild mediastinal lymph nodes.

Figure 5.

MRI of the rght upper limb showing suspicious neoplastic aetiology/infective aetiology (myositis) of the anterior aspect of the distal forearm, elbow and proximal forearm together with laxity of the triceps tendon with subcutaneous oedema.

A core biopsy of the right arm swelling was found to be consistent with granuloma with no features suggestive of malignancy. An incisional biopsy of the lesion was therefore performed under local anaesthesia to rule out tuberculosis/fungal infection/malignancy. Following the incisional biopsy, suturing was used to close the wound. Histopathology showed granulomatous inflammation with excessive giant cell reaction and focal panniculitis with the possibility of a mycotic lesion of the right arm swelling. Micropathological examination showed that the deeper dermis and subcutaneous tissue were completely replaced with a granulomatous reaction consisting of foreign body and Langhan giant cells, eosinophils and lymphocytes. The fungal elements were seen as unstained tubes and haloes with eosin-stained thin walls and infrequent septa surrounded by Splendore–Hoeppli material. Hyphae agents were also seen within the giant cells. In the Periodic acid–Schiff (PAS) stained section the hyphal wall was stained pink (figure 6).

Figure 6.

(A) Granulomatous inflammation with excessive giant cell reaction and focal panniculitis. (B) Hollow tube-like structures suggestive of basidiobolomycosis (Periodic acid–Schiff stain; magnification 40x).

Treatment

The case was discussed with a multidisciplinary team involving a general surgeon, pathologist and dermatologist and antifungal treatment with itraconazole capsules 100 mg twice daily and potassium iodide solution 30 mL three times a day for 3 months was started (figure 4).

Before starting treatment, a liver function test and thyroid function test were performed which showed normal values. During treatment the patient developed coryza-like symptoms due to potassium iodide which were resolved following the administration of an antihistamine and he then tolerated both medications well.

Outcome and follow-up

During follow-up the swelling gradually decreased in size (figure 7) along with a change in consistency. The sutures were removed on postoperative day 14. His forearm movements of pronation and supination were normal. He was able to flex and extend his arm to the full extent. Liver function and thyroid function tests were carried out monthly during follow-up and found to be normal. The clinical course was satisfactory and treatment with itraconazole and potassium iodide was successful.

Figure 7.

Postoperative photographs showing swelling over the right forearm in the supine position of (A) 14×11.3 cm on 27 March 2021, (B) 10×8.32 cm on 9 April 2021 and (C) 8×5.6 cm on 26 April 2021.

Discussion

Zygomycosis is an infection caused by fungi belonging to the phylum Zygomycota which includes two fungal orders, Mucorales and Entomophthorales.⁴ The former causes mucormycosis and the latter causes entomophthoromycosis. Entomophthoromycosis is an uncommon sporadic slowly progressive subcutaneous infection which includes two distinct forms:⁵

• subcutaneous zygomycosis usually caused by Basidiobolus spp (basiodiobolomycosis); and

• rhinofacial zygomycosis caused by Conidiobolus spp (conidiobolomycosis).

Pathogenic isolates of Basidiobolus are Basidiobolus ranarum and, for Conidiobolus, are Conidiobolus coronatus and Conidiobolus incongruus.^{6 7} Subcutaneous zygomycosis is caused by Basidiobolus ranarum.

The first case of basidiobolomycosis was reported in 1964 in a 6-year-old Nigerian boy.⁷ It is found in the tropical forest of Africa, Asia and India and is also found in decaying substances. Mucorales are causative organisms of acute infection in the diabetic and immunosuppressed host.

The mode of acquisition of the disease remains poorly understood. The portal of entry is believed to be the skin following insect bites, scratches and minor cuts. It is most common in young children as a disease of the skin and subcutaneous tissues involving the thighs and buttocks.⁸ Painless swelling, a woody feel, ability to insinuate fingers under swelling without lymphadenopathy in the absence of systemic signs are some of the characteristic features. These organisms are classified based on the site of involvement as cutaneous, subcutaneous, visceral and disseminated. Sometimes it may present as gastrointestinal symptoms due to gastrointestinal tract involvement with the most common features being abdominal pain and fever. Other variable symptoms include vomiting, diarrhoea, constipation, abdominal distension, haematochezia and jaundice. A mass affecting part of the gastrointestinal tract was observed in almost all patients with gastrointestinal basidiobolomycosis, with the most commonly affected site being the right-sided colon followed by the hepatobiliary system.⁹ Basidiobolomycosis is believed to spread by traumatic implantation of the fungus into the subcutaneous tissues of the thigh, buttock or trunk. Host defence includes macrophages with epithelioid and multinucleate giant cell formations, eosinophils, lymphocytes and plasma cells, leading to chronic granulomatous reactions.¹⁰ The micromorphology of the Entomophthoromycotina is broad hyphae, thin-walled, ribbon-like and mostly aseptate with right or wide-angle branching, with plasma cells, epithelioid cells, multinucleate giant cells and histiocytes. The Splendore–Hoeppli phenomenon can be a histological finding seen in entomophthoromycosis, with eosinophilic hyaline material around hyphae in H&E-stained sections, which is also characteristic of sporotrichosis, blastomycosis and schistosomiasis.¹¹ There is no evidence of angioinvasion and necrosis. These lesions present as painless firm lesions with or without lymphadenopathy. Extracutaneously, the gastrointestinal tract and rhinofacial area may be involved.

The gold standard investigation of choice is histopathological and mycological cultures. Fluorescent dye (Blankophor) wet mount preparation under fluorescent microscopy increases sensitivity. Culture media used include sabouraud dextrose agar, potato dextrose agar or cornmeal agar. Different molecular methods with DNA probes, fungal primers and PCR can be used. Imaging such as CT or MRI is useful in assessing the extent of the therapeutic response and helps surgeons in planning for procedures.¹¹

Treatment for entomophthoromycosis is antifungal therapy with surgical debridement. Potassium iodide, cotrimoxazole, amphotericin B, imidazoles and hyperbaric oxygen are used in treatment, although potassium iodide and azoles remain the main baseline treatment.¹² An early and correct diagnosis helps in achieving a complete cure and prevents unnecessary radical surgery.

The lack of evidence-based treatment for basidiobolomycete infection indicates the need for further investigations in this area. Effective treatments include ketoconazole, itraconazole, fluconazole, potassium iodide and cotrimoxazole. A suggested dose of potassium iodide for children is 30 mg/kg/day for several months. With ketoconazole, itraconazole and fluconazole, liver enzymes must be monitored at least monthly. A reported regimen for cotrimoxazole is 80 mg trimethoprim+400 mg sulfamethoxazole per tablet, two tablets per day in children for 6–8 weeks. In our case, we started the patient on oral itraconazole and oral potassium iodide solution for 3 months which successfully treated the condition.¹³

Patient’s perspective.

I came with swelling over the right forearm for 3 months. Doctors took MRI suspecting cancer followed by a biopsy. The chief doctor explained to me that it is fungal infection which is causing the swelling in the forearm and advised me to take potassium iodide along with itraconazole. As advised by the doctors, I took the medication and followed up with the doctor after getting discharged. The swelling decreased day by day within 3 months and, as told by the doctor, the swelling disappeared.

I am thankful to the chief surgeon and team.

Learning points.

• Physical examination of all systems is important to rule out tuberculosis/malignancy.

• The importance of histopathology and special stain in diagnosing this case.

• Knowledge of antifungal drugs, dosage and side effects.

• Preparation of potassium iodide solution.

• Management of antifungal side effects.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s)