September 2005

Fig.3

Fig.4

Fig.5

Fig.6

Fig.7

Pathology: Histologic examination revealed necrotizing granulomatous inflammation with abundant yeast and broad-based, branching hyphal phase organisms (Figs.3 and 4). GMS stain confirmed the presence of fungal organisms.

Mycology: Culture on blood agar revealed wooly dense colonies that covered the agar plate within 48 hours (Figure 5). Lactophenol cotton blue staining of the colonies revealed broad, non-septate hyphae measuring 6-15 µm and rhizoids (rootlike hyphae) at the branching points of sporangiophores (Figs 6,7 provided by Beatriz Tapia, M.D.)

Discussion: typically seen with Rhizopus infections_. Most commonly, it is an opportunistic infection seen in patients with underlying risk factors including: 1) immunocompromised state from lymphoproliferative disorders, corticosteroid use, and in high-risk newborns, 2) metabolic disorders, especially diabetic ketoacidosis, and 3) tissue breakdown such as burns or trauma. A key factor in the pathogenesis is a neutropenic state, since normal functioning neutrophils are the main host defense against mucormycosis.

Clinical manifestations are based upon the five main tissue sites involved: 1) rhinocerebral, 2) pulmonary, 3) disseminated, 4) gastrointestinal, and 5) cutaneous. In most cases, mucormycosis is characterized by a rapidly evolving course with angioinvasion, tissue destruction and necrosis. Rhinocerebral disease is the most commonly involved site, with the majority occurring in the setting of diabetic ketoacidosis and immunosuppression. Infection originates in the paranasal sinuses after inhalation of fungal spores and spreads to neighboring tissue. Pulmonary infection can occur as an extension of rhinocerebral disease and can lead to disseminated disease. Most infections occur in profoundly neutropenic patients, especially those with hematologic malignancies. Disseminated disease is associated with an extremely high mortality.

Cutaneous and soft tissue disease can occur either from primary inoculation of the skin or secondary to a disseminated infection. Primary skin infections are usually preceded by a violation of the protective skin barrier either by trauma, excessive perspiration or thermal injuries_. In addition, there have been numerous reported cases of cutaneous mycotic infections associated with contaminated tape in both normal and immunocompromised hosts4,5,6,7. These include cases in which Rhizopus infections developed in normal hosts after elasticized adhesive (Elastoplast) dressing was used at the wound closure site following orthopedic and thoracic surgery4,5. Similar to our case, Rhizopus has been reported in a neutropenic patient receiving chemotherapy for acute myelogenous leukemia, who developed a purpuric tender lesion around her IV site where an occlusive dressing had been placed. The patient's lesion resolved after 3 weeks of therapy with amphotericin B.6

Cutaneous infections are classified as either superficial or gangrenous. Superficial infections have a gradual onset and slow progression, often without systemic symptoms such as fever. These lesions start as pustules with rare ulceration or eschar formation3. Specifically, lesions associated with elasticized tape often begin as erythematous, raised plaques that evolve into vesicles and then pustules. The lesions are frequently confused with contact dermatitis due to the association with tape application4. Gangrenous cutaneous infections present with rapid onset erythematous macules that coalesce and form ulcers and eschars that are painful and invade underlying tissue, resulting in a fulminant course that must be treated promptly with aggressive surgical and medical treatment3.

Diagnosis is made by histopathological examination and fungal tissue culture. Rhizopus has broad (10-20 µm diameter) non-septate hyphae which branch irregularly at 90°, best seen with Gomori's methenamine silver (GMS) stain. The fungus often is seen invading blood vessels, causing thrombosis and infarction. Precise identification of the species is accomplished by fungal tissue culture and subsequent Lactophenol Cotton Blue staining of the colonies.
Appropriate work-up for patients with suspected cutaneous Rhizopus infection includes blood culture; wet mount of sputum or bronchial secretions; head, paranasal, chest and abdominal CT scanning; and tissue biopsy for a bedside touch preparation, H&E, and culture. A bedside touch preparation can be used to make a rapid, 45 minute diagnosis by PAS staining8. This is essential for rapidly evolving gangrenous cases that are life-threatening and require emergent surgical excision.

Treatment involves a combined approach of surgical debridement of devitalized tissue and prompt medical therapy with amphotericin B. In general, therapeutic doses range from 1 to 1.5 mg/kg/d and a total dose of 2 to 4 g is necessary for resolution of infection. Lipid formulations are associated with less toxicity and can be administered at higher doses of up to 10 mg/kg/d. Other anti-fungals, including the azoles, which our patient had been taking prior to diagnosis, are generally ineffective in treating mucormycosis8. Adjunctive therapy includes correcting the neutropenic state of the patient either by withholding immunosuppressives or adding G-CSF or GM-CSF. Recovery of neutrophil function has been reported to decrease the duration and improve the outcome of infection. Due to the difficulty of eradicating infection in necrotic tissue, surgical debridement is critical.

Prognosis of primary cutaneous mucormycosis is significantly better than rhinocerebral, pulmonary or disseminated Rhizopus infections1. The associated mortality is significantly less and most patients recover if treated promptly.

References:

1. Gonzalez CE, Rinaldi MG, Sugar AM. Zycomycosis. Infect Dis Clin N Am 2002;16:895-914. 2. Adam RD, Hunter G, DiTomasso J, Comerci, Jr. G. Mucormycosis: Emerging Prominence of Cutaneous Infections. Clinical Infectious Diseases 1994;19:67-76.

3. Hicks WL, Nowels K, Troxel J. Primary Cutaneous Mucormycosis. American Journal of Otolaryngology 1995;16:265-268.

4. Mead JH, Lupton GP, Odom, RB. Cutaneous Rhizopus Infection. JAMA 1979: 242: 272-274.

5. Hammond DE, Winkelmann RK. Cutaneous Phycomycosis. Arch Dermatol 1979:115:990-992.

6. Khardori N, Hayat S, Rolston K, Bodey G. Cutaneous Rhizopus and Aspergillus Infections in Five Patients With Cancer. Arch Dermatol 1979:125:952-956.

7. Gartenberg G, Bottone EJ, Keusch GT, Weitzman I. Hospital-acquired Mucormycosis of Skin and Subcutaneous Tissue. NEJM 1978;299:1115-1118.

8. Rubin AI, Grossman ME. Bull's eye cutaneous infarct of zygomycosis: A bedside diagnosis confirmed by touch preparation. J Am Acad Dermatol 2004: 51: 996-1001.

This case was presented by Drs.Grace D. Bandow and Lisa Xu.

Presented by Dr. Beatriz Tapia