Granulomatous inflammation is a distinctive form of chronic inflammation produced in response to various infections, autoimmune, toxic, allergic and neoplastic conditions[1]. Fungal granulomas are rare, chronic infections with a very low prevalence rate that often resemble tumors or chronic inflammation, complicating diagnosis. While these infections commonly affect immunocompromised individuals, they can also appear in healthy elderly patients, particularly in tropical areas like India. 

Fungi such as Basidiobolus ranarum, Sporothrix schenckii, and Madurella mycetomatis are frequently seen. A study estimated that over 57 million people suffer from serious fungal diseases[2]. Granulomatous invasive fungal sinusitis was seen in nearly 30% of chronic fungal rhinosinusitis cases[3]. Globally, more than 6.5 million cases of invasive fungal infections are reported annually, with a significant mortality rate[4]. Fungal infections can be difficult to diagnose, although clinicians from various specialties may face this challenge[5].

These deep fungal infections can present to the dermatologist with variable presentations, such as nodulo-pustular lesions, cysts, indurated masses with surface changes such as discharging sinuses or verrucosity and ulcer. The lesions generally remain localized and appear as non-tender nodular edema. As a result, they are frequently misidentified as other benign lesions clinically[6]. The variable clinical presentation can pose diagnostic challenges[7, 8]. Patients may be treated with topical corticosteroids or calcineurin inhibitors. This may result in tinea incognita, a fungal infection with a different clinical presentation that may complicate the clinician even more[9].

Such suspected fungal infections require early evaluation by histopathology, culture aided by imaging studies. Based on which initiation of appropriate therapy to prevent complications.

This is a clinical case of a 74-year-old female patient came with a complaint of swelling over the right thigh since 3 months. The patient was apparently asymptomatic 3 months back, then developed swelling over the right thigh. The swelling was insidious in onset and gradually progressive, and was associated with pain. The pain was throbbing in nature, increased on walking, and was relieved with medication. No complaints of fever, weight loss, appetite loss, or trauma. She had no known allergies or addictions. There was no history of chronic illness, immunosuppression, or long-term medication use, and has no significant family history. 

On examination, diffuse swelling is present over the anterior and posterior aspects of the thigh, extending to the distal one-third of the thigh with a size of 10 x 8 x 2cm.  On palpation, tenderness is present over the swelling. No scars, sinus noted over the swelling, no visible pulsations. The provisional diagnosis was soft tissue sarcoma. Clinically Differential Diagnosis considered are Lipoma, Abscess, and Malignancy.

Investigations:

Fig. 1: Granulomatous lesion containing fungal hyphae (H&E, 10x)

Fig. 2: Under the light microscopy, fungal hyphae seen in a giant cell (H&E,40x)

Fig. 3: Fungal hyphae (arrow) (H&E,40x)

Treatment and follow-up: 

Following histopathological diagnosis, the patient was prescribed itraconazole 200 mg orally once daily for 3 days and on follow-up, there was clinical improvement in the swelling and associated pain, and the patient was reported to be clinically well without significant ongoing symptoms. On subsequent follow-up, clinical improvement in the swelling and associated pain was noted, and the patient was clinically well without significant ongoing symptoms.

The primary cutaneous fungal pathogens can be classified into two groups:  Superficial Fungal Infections and Deep Fungal Infections. Superficial Fungal Infections are characterized by hyphae or pseudo-hyphae and sometimes yeast cells in the keratin layer of the epidermis and the follicles. Organisms causing superficial cutaneous fungal infections do not affect the dermis, except in cases of hair follicle rupture[10]. Deep cutaneous infections affect the dermis and subcutaneous tissue. 

This case shows fungal hyphae-containing granulomas in deep dermis and subcutaneous fat tissue. The deep fungal infections encountered include chromoblastomycosis, sporotrichosis, rhinosporidiosis, mycetoma, histoplasmosis, subcutaneous pheohyphomycosis, mucor-mycosis, hyalohyphomycosis, entomophthoromycosis, penicilliosis and cryptococcosis[11]. This is a case of deep fungal infection involving dermis and subcutaneous fat tissue, characterized by granulomas. The appearance of granulomas in these infections indicates a type IV hypersensitivity response, primarily mediated by CD4+ and CD8+ T-lymphocytes[12].

In the differential diagnosis of granulomatous infection of subcutaneous tissue, include cutaneous TB, Crohn’s disease, sarcoidosis, rheumatoid nodules and subcutaneous granuloma annulare. All these are characterized by granulomas, but in our case, along with granulomas, fungal hyphae were also seen, which helped in making the final diagnosis and excluding other granulomatous infections. 

In the diagnosis of granulomatous inflammation, along with the careful examination of Histopathological sections, use of special stains increases the diagnostic sensitivity. Mycobacterium and fungal infections are the most common cause for granulomatous inflammations, Grocott Methenamine Silver (GMS) stains and Ziehl-Neelsen stain (AFB) are most commonly used special stains for the identification of fungi and acid-fast bacilli. Though culture is the gold standard method for the diagnosis of infectious organism, use molecular diagnostic methods from culture growth or from the fresh or formalin fixed infected tissue improves the specificity and identification of organisms, particularly mycobacteria[13, 14].  

This case highlights the importance of considering subcutaneous fungal infections in the differential diagnosis of chronic soft tissue swelling cases, even in elderly patients without immunosuppression. The histopathological evaluation of granulomatous inflammation is a useful indicator of the diagnosis. A clinical discussion between the clinician and the pathologist enables the appropriate use of necessary laboratory procedures, resulting in accurate and early detection of the disease. Specific therapy helps in the successful care and recovery of the patient without any complications.