Mucormycosis - A catastrophic mycotic lesion

INTRODUCTION

Mucormycosis is an opportunistic fulminating mycotic infection caused by saprophytic fungal elements of class zygomycetes, widely distributed in environment. The class of zygomycetes is divided into two orders: Mucorales and Entomophthorales. The order Mucorales is responsible for an acute angioinvasive infection, mucormycosis, affecting immunocompromised patients.¹According to literature, nearly 50% of mucormycosispatients have the medical history of diabetes mellitus, as a susceptible factor.² Zygomycosis is the third foremost cause of invasive fungal infection after candidiasis and aspergillosis.³

The source of mucormycosis is exogenous, as these organisms are common inhabitants of soil, bread mold, rotten fruit and vegetables, continuouslydischarge spores into the atmosphere.⁴ These fungal spores may be inhaled, ingested or may enter human body through open wound.^4,5

It is one of the rapidly progressing lethal mycoticinfections in humans which usually begins in the nasal mucosa and paranasal sinuses.⁶ This fungus invades the arteries forming thrombi,blocking blood vessels that reduce blood supply causing necrosis of hard and soft tissues.⁶ Hard palate is commonly affected as it is in close proximity to the nasal cavity and paranasal sinuses. Mucormycosis of the hard palate is generally seen as necrotic ulceration or sloughing of the palatal mucosa.⁷ We report a case of mucormycosis involving the palate in a known case of diabetes mellitus and liver cirrhosis, sustained with road traffic accident.

Description of the case

A 48 year old male patient was admitted to an eye hospital with a chief complaint of swelling around the eyes, double vision and facial pain. Over the past 15 days patient met with road traffic accident, lost his maxillary incisors & was treated by local doctor. Unfortunately the patient failed to respond for treatment.He was referred to our institution for Oral examination and opinion. Patient was a known diabetic since 5 years and on medication. Past medical reports revealed liver cirrhosis. Patient was poorly built, debilitated and disoriented.

On extra-oral examination, diffuse swelling of faceextending superiorly from supra-orbital line till the line joining angle of mouth and gonial angle inferiorly noticed bilaterally. Also patient was unable to open both of his eyes due to periorbital edema.(fig-1)

Intra-oral findings revealed loss of maxillary anterior teeth, Greyish black necrotic eschar on hard and soft palate extending anterolaterally from palatal marginal gingiva of all the maxillary teeth including sockets of accidentally lost maxillary anterior teeth and posteriorly till soft palate involving uvula, with palatal perforation on right side of hard palate. (fig-2) OPG radiograph was non contributory. CT scan images demonstrated bilateral central and lateral incisors and left premolar edentulous status, bilateral mucosal thickening involving all the sinuses. Soft tissue attenuation showing heterogeneous contrast enhancement and reported as suggestive of chronic sinusitis/fungal sinusitis? (fig-3,4)

Based on the history and clinical presentation, a provisional diagnosis of Mucormycosis was given with a differential diagnosis of Wegener’s granulomatosis, Midline lethal granuloma and Aspergillosis.

Incisional biopsy was performed and submitted for histopathological examination.

For medical management the patient was referred to Victoria Hospital, Bangalore.

On gross examination, multiple bits of grayish brown, irregular shaped, soft and fragile necrotic tissue with bony spicules were observed.(fig-5)

Blood investigations revealed RBS of 432mg/ dl, Bilirubin level 3.3 mg/dl, ESR 32 mm/hr, Haemoglobin 8.9 g/dl, HIV was Non-reactive, clinical side KOH test showed no fungal hyphae and the culture report was negative for fungal elements.(Table:1)

H & E stained sections revealed variable amount of necrosis in the involved tissue.Inflammatory cells, chiefly neutrophils located peripheral to necrotic tissue. The organism appeared large, aseptate hyphae with branching at right angle and round to ovoid sporangia. (fig-6,7,8) Organisms were more enhanced in Per-iodic acid Schiff stain and Grocott’sGomori’s silver methanamine stain. (fig-9,10,11) Correlating with clinical features and histopathological findings, diagnosis of Mucormycosis of Palate was given.

Discussion

The first well-documented case of disease in humans was published by the German pathologist Paltauf in 1885.⁸ It was a systemic infection with gastric and rhinocerebral involvement, which Paltauf described as “Mycosis Mucorina”. The disease name “mucormycosis” was subsequently used by the American pathologist R. D. Baker to signify a mycosis caused by certain members of Mucorales.^9,10 Infection arises through inhalation of spores and contamination of the traumatized tissue, ingestion and direct inoculation.¹¹ Furthermore, it has been suggested that vascular ruptures in alveolar socket during dental extraction can create a portal of entry for fungi into the maxillofacial regions.¹² In present case since patient sustained with road traffic accident there could be the possibility of contamination of traumatized tissue.

This fungal infection usually originates from the nasal mucosa and paranasal sinuses and spreads to oral cavity either by direct invasion or through blood stream. The hyphae form thrombi within the blood vessels thusdecreasing blood supply causing necrosis of the tissue.¹³ Hard palate is usually affected intraorally, because of its close proximity to the nasal fossa and paranasal sinuses.⁵ The fungal hyphae once enter into the blood vessels they can spread to other organs such as cerebrum or lungs leading to fatal condition. In the present case, palatal necrosis was observed with rapid progression of infection in to the orbit resulting in peri-orbital cellulitis. The key risk factors for mucormycosis include uncontrolled diabetes mellitus in ketoacidosis, metabolic acidosis, treatment with corticosteroids, organ or bone marrow transplantation, neutropenia, trauma and burns, malignant hematologic disorders, and deferoxamine therapy in patients receiving hemodialysis.¹⁴

Diabetes mellitus increases susceptibility to infections, reduced blood flow, and cell-mediated immune abnormalities characteristic of diabetes.¹⁵ Hyperglycemia stimulates fungal growth and also reduces chemotactic and phagocytic efficiency which later leads to proliferation of innocuous organisms.¹⁶

The clinical trait of mucormycosis is the rapid onset of tissue necrosis, associated with or without fever. Based on the involvement of a particular anatomical structures and clinical features, mucormycosis can be classified under six forms.⁴

(1) Rhinocerebral, (2) Pulmonary, (3) Cutaneous, (4) Gastrointestinal (5) Disseminated, and (6) Miscellaneous

The most common clinical form of mucormycosis is the Rhinocerebral infection representing about one-third to one-half of the cases reported (Pillsbury and Fischer, 1977).¹⁷ Approximately 70% of cases of rhinocerebralmucormycosis are associated with diabetic patients in ketoacidosis (McNulty, 1982).¹⁸ Mucormycosis in cirrhotic patients with associated diabetes mellitus may reflect compromised immunity of the patient due to diabetes mellitus rather than liver disease, to develop rhinocerebralmucormycosis. Neutropenia is often present in advanced stage of liver disease as a result of accelerated neutrophils apoptosis.¹⁹ Kusaba et al in his study demonstrated that, an altered neutrophils and an accelerated apoptosis exists in cirrhotic patients.²⁰ Liver cirrhosis patients are more susceptible to develop opportunistic infections.¹⁹ Since the present case reveals the medical history of liver cirrhosis which can be considered to be a added risk factor in development of mucormycosis.

As the disease is rapidly progressive, imaging modalities like computetomography (CT) and magnetic resonance imaging (MRI) are useful diagnostic aids to study the involvement of paranasal sinuses, orbital and cerebral spread and also to know the extent of necrosis. The most common finding with CT of the orbit is thickening of the extraocular muscles. CT scanning of the sinuses may exhibit mucosal thickening of sinus wall, air-fluid levels and bony erosion.^2,4 Although evidence of infection of the soft tissues of orbit may sometimes be evident on CT scan, MRI, with its tremendous soft tissueresolution, can demarcate the extension of the disease process better than CT (Fatterpekar et al, 1999).²¹ Patients with early rhinocerebralmucormycosis may have a normal MRI, and if infection is suspected, biopsy of the infected areas should always be performed in high-risk patients.⁴

The diagnosis of mucormycosis is basically made on microscopic examination of tissue sections, which always depends on the evidence of fungal invasion of the tissues. Therefore, the biopsy should be performed from infected tissues site. Involved tissue demonstrates focal areas of infection and may appear nodular or may produce extensive tissue necrosis with accompanying hemorrhage spots. The biopsy specimen must histologically demonstrate the zygomycetes class of fungi, characteristic of broad ribbon-like, thin-walled, aseptate hyphal elements that branch at right angles with frequent angioinvasion. In contrast to the zygomycetes, Aspergillus tends to demonstrate an acute branching pattern and has narrower, more uniform septa. Vascular invasion resulting in necrosis of the infected tissue, and perineural invasion are more advanced features of this infection. It is been suggested that special stain such as GMS or PAS be performed for a better visualization of fungal elements in tissues.^22,23

Culture of organisms from a potentially infected site can result in inaccurate diagnosis, as this causative organism is ubiquitous, found in healthy individuals, and is a quite common laboratory contaminant. Moreover, the organism may be killed during tissue grinding, which is routinely used to process tissue specimens for culture. Fungal elements may be rare as they are often fragmented and additionally, hyphae may be confined to a part of the specimen.Thus, a sterile culture does not rule out the infection. Furthermore, waiting for the results of the fungal culture may delay treatment process.^22,4

Four factors are crucial for treating mucormycosis: rapid diagnosis, correction of predisposing factors if possible, aggressive surgical debridement of infected tissue, and suitable antifungal therapy.¹²

Early diagnosis is important because small, focal lesions can often be surgically excised before they progress to involve adjacent structures. Controlling predisposing factors may help in improving the treatment aspect. In diabetic patients with ketoacidosis, hyperglycemia and acidemia should be corrected.Mucormycosis is rapidly progressive and antifungal therapy alone is often insufficient to control the infection. Treatment includes immediate hospitalization and systemic antifungal therapy. The drug of choice for Mucormycosis is Amphotericin B. The other Supportive therapeutic modalities includes; nutritional supplements,fluid balance and correction of underlying immune abnormalities. Surgical treatment is often necessary to remove the necroseddead tissue.^12,4 In the present case, surgical management like tissue debridement and curettage was carried out frequently. Therefore, debridement of the necrotic tissue should be performed in critical conditions to control further involvement of adjacent structures. In most cases, the infection is relentlessly progressive and results in death unless treatment like surgical debridement and antifungal therapy is initiated promptly.

Prognosis depends on several factors such as infection site, rapidity of diagnosis, type and severity of immunosupression. The mortality rates were nearly 85% in earlier days. After the introduction of combined therapy, more than 80% of the patients can be expected to survive.¹²

Conclusion: Though the clinical forms, microbiology and pathological aspects of mucormycosis are well established, the rarity of the disease leads to difficulties in diagnosis. Therefore dental practitioners should be familiar with the signs and symptoms of the disease. Early diagnosis is necessary to treat patients and limit futher spread of infection; delay can result in a poor prognosis, high morbidity and mortality.