Patient Presentation
A 39-year-old man was admitted to undergo systemic chemotherapy for acute myelocytic leukemia. Following completion of chemotherapy, he developed an anticipated, progressive cytopenia requiring multiple packed red blood cell and platelet transfusions. Soon thereafter, few necrotic slightly atrophic plaques developed on the upper chest wall (see photo above). Cutaneous biopsies and cultures were performed. Subsequent chest X-ray revealed bilateral pulmonary infiltrates while bronchoscopy with bronchial lavage showed no significant findings.

What is Your Diagnosis?

Diagnosis: Cutaneous Aspergillosis
A spergillus is a saprophytic hyaline mold that is a frequent opportunistic pathogen.1 Aspergillosis and candidiasis are the two most common systemic mycoses found in neutropenic patients and the incidence of Aspergillus infections has risen dramatically in the last two decades.2-4 Aspergillus spores are airborne and ubiquitous in our surroundings but do not typically affect immunocompetent hosts.5

Of the Aspergillus species, A. fumigatus and A. flavus are the most common, with
A. fumigatus being responsible for approximately 90% of pulmonary infections attributed to fungus.4,5 Local portals of entry, including burns, trauma, intravenous catheters and surgical sites, may allow primary cutaneous aspergillosis to occur.2,3

Secondary cutaneous aspergillosis may occur following inhalation of conidia with resultant lung infection and dissemination to the skin. Infection with Aspergillus is not uncommon in immunocompromised individuals, especially neutropenic patients with underlying malignancies or undergoing chemotherapy, as well as individuals with HIV.2 The cost of treating these infections, which are often fatal, represents a tremendous burden on our healthcare system.4,6

Clinical Presentation
The clinical presentation of cutaneous aspergillosis can be variable but most commonly includes papules and necrotic papulonodules or necrotic ulcers. The clinical appearance of necrosis is due to the organism’s ability to invade and thrombose blood vessels. Fever, tenderness and wound induration can herald a post-operative Aspergillus wound infection.3 Hepatomegaly and jaundice have been reported as an unusual presentation with hepatic involvement.7

Diagnosis
Physical examination of ulceronecrotic lesions in an immunocompetent or neutropenic individual should lead one to consider an infectious etiology. Tissue biopsy and culture serve to identify the infectious agent and appropriate antimicrobial treatment. On routine culture media Aspergillus forms powdery to granular colonies that vary in color from white to greenish-black depending on the species.1,4 Cultures from sputum or bronchial washings are known to have a low sensitivity but high positive predictive value.4 Further blood culture and radiographic examination may be warranted based on the extent of disease. Chest radiographs are often normal even in the setting of life-threatening pulmonary disease but may show an aspergilloma or “fungus ball.”4,8

Histology
Histologic examination of cutaneous aspergillosis demonstrates multiple septate hyphae with characteristic branching at approximately 45° angles. This is useful in distinguishing from the 90° branching seen in zygomycoses. Additionally, the presence of septae confirms Aspergillus, as opposed to the non-septated hyphae seen in zygomycoses.1 Vascular invasion is also characteristic of Aspergillus.3 Although diagnosis can usually be made with hematoxylin/eosin staining, subsequent staining with PAS or Gomori-methenamine-silver (GMS) may help identify smaller hyphae.

Differential Diagnosis
The presence of an ulceronecrotic lesion in a neutropenic patient suggests an infectious etiology. Thus, a host of infectious causes must be considered, including aspergillosis, candidiasis, cryptococcosis, zygomycoses and various bacterial causes.

Treatment
There are several anti-fungal agents to choose from in the treatment of cutaneous and disseminated aspergillosis, including amphotericin B (AmBisome), itraconazole (Sporanox), voriconazole (VFEND) and caspofungin (Cancidas).

Some authors have advocated amphotericin B as the agent of choice in immunosuppressed patients.3 However, voriconazole has been shown to have a better response rate, improved survival rate, fewer side effects and lower cost compared to amphotericin B in the treatment of invasive aspergillosis.9,10 Another randomized trial determined voriconazole to be an acceptable alternative to amphotericin B for empirical therapy in patients with fever and neutropenia, and voriconazole has the advantages of good oral bioavailability and central nervous system penetration.4,11

Caspofungin, from the echinocandin class of anti-fungal compounds, has the advantage of being better tolerated than amphotericin B, although there is little experience in using this agent in the pediatric population.12,13 While minimum inhibitory concentrations for various anti-fungal medications are often discussed in the literature, there are potential discrepancies between in vitro resistance and in vivo efficacy.4,14

There is also evidence to support surgical methods in the treatment of aspergillosis. Aggressive therapy combining a surgical approach with amphotericin B or itraconazole offers a 3-year survival rate of 82% in pediatric patients on chemotherapy who get invasive pulmonary aspergillosis.15