Chromoblastomycosis

Clinics in Dermatology (2012) 30, 403–408

Chromoblastomycosis Edoardo Torres-Guerrero, MD a , Rafael Isa-Isa, MD b , Mariel Isa, MD b , Roberto Arenas, MD a,⁎ Mycology Section, Department of Dermatology, “Dr. Manuel Gea Gonzalez” General Hospital, Calzada de Tlalpan 4800, Colonia Sección XVI, Mexico, DF 14080, Mexico b Instituto Dermatológico y Cirugía de Piel “Dr. Huberto Bogaert Díaz,” Santo Domingo, Dominican Republic a

Abstract Chromoblastomycosis is a chronic, subcutaneous mycosis, characterized by verrucous nodular lesions, usually involving the legs and mainly caused by Fonsecaea, Phialophora, and Cladophialophora spp. The characteristic finding on direct examination or biopsy specimen is the presence of fumagoid cells or Medlar bodies. Chromoblastomycosis can be refractory to medical treatment. Therapeutic options include oral itraconazole, terbinafine, or 5-fluocytosine, alone or combined with surgery or cryosurgery. © 2012 Elsevier Inc. All rights reserved.

Introduction

History

Chromoblastomycosis (formerly chromomycosis) is a chronic, progressive, subcutaneous mycosis caused by pheoid or dematiaceous fungi. The latter is a group of pigmented black fungi, which belong mainly to the Fonsecaea, Phialophora, and Cladophialophora spp. All of the causative agents generate the same parasitic forms, known as fumagoid cells or Medlar bodies. These are dark, oval thick walled cells with septation or binary fission. 1-5 Chromoblastomycosis is characterized by warty nodular lesions, usually involving the legs. 1 Most patients have a history of trauma caused by wood or vegetation, and more than 80% are agricultural workers, who often go barefoot (Figures 1-7). 1

Chromoblastomycosis was first noted in Brazil in 1911 by de Moraes Pedroso, but it was not reported until 1920 by Pedroso and Gomes. In 1914, Max Rudolph emphasized the clinicopathologic features, and Medlar and Lane reported the first North American case in Boston in 1915. At that time, the isolated fungus was called Phialophora verrucosa. In 1922, Pedroso’s original culture was restudied and different types of reproduction were noted, including Hormodendrum, Phialophora, and Acrotheca. As a result of these findings, the fungus was renamed Hormodendrum pedrosoi. In 1936, Carrion, in Puerto Rico, described a third organism, Hormodendrum compactum. 2,3 The use of heat in the treatment of chromoblastomycosis was first suggested by Silva in 1958. After this discovery, several clinicians in Japan experimented with thermotherapy, corroborating the successful use of pocket warmers. 4 In 2005, the genus Fonsecaea was reviewed, and Fonsecaea monophora has been described from molecular analysis of isolates, most of them originally identified as Fonsecaea pedrosoi. More recently, a new species has been described similar to the last ones, Fonsecaea nubica, 6 using multilocus

⁎ Corresponding author. Tel.: +55 4000 3058; fax: +55 4000 3058. E-mail address: [email protected] (R. Arenas). 0738-081X/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.clindermatol.2011.09.011

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Fig. 1

Chromoblastomycosis, a verrucose plaque.

molecular data including amplified fragment length polymorphism profiles, sequences of the ribosomal internal transcribed spacers, and partial sequences of the cell division cycle (cdc42), β-tubulin (tub1) and actin (act1).

Fig. 3 Chromoblastomycosis, verrucose and sporotrichoid nodular lesions.

cases are from Madagascar (the most important focus in the world), but many cases have been reported from Gabon, Mexico, Brazil, Costa Rica, Puerto Rico, Venezuela, Cuba,

Epidemiology Chromoblastomycosis has a worldwide distribution and is frequently seen in tropical and subtropical climates. Most

Fig. 2

Chromoblastomycosis, a typical case on the leg.

Fig. 4

Chromoblastomycosis, facial lesions.

Chromoblastomycosis

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Fig. 7 Fig. 5 Fumagoid cells or sclerotic or Medlar bodies (hematoxylin and eosin, original magnification ×40).

Dominican Republic, India, and Australia. Chromoblastomycosis has been diagnosed in several countries in Europe. 5 Between 1955 and 1980, 290 cases were reported in Japan, and 249 of these were caused by F pedrosoi. 2 Chromoblastomycosis affects mainly men aged between 30 and 60 years, who likely acquire the infection by traumatic inoculation while working. Most patients live in rural areas (farmers, wood cutters, latex gatherers, and others), and all races seem to be susceptible. 2 Chromoblastomycosis is uncommon in women or children aged younger than 15 years. 5

Etiology and pathogenesis Several species of Hyphomycetes of the Dematiaceae family have been isolated. The most frequent etiologic agents are: F pedrosoi, F compacta, Phialophora verrucosa, Cladophialophora carrionii, and Rhinocladiella aquaspersa (Table 1). These agents are slow-growing fungi with low virulence and a high tolerance to heat (40°-42ºC). 1

Lesion after treatment with cryosurgery and itraconazole.

The pathogenesis of chromoblastomycosis is not fully understood. A genetic susceptibility is suggested by the development of several cases in a family, although this has never been proved. 7,8 A defect in acquired cellular immunity has been postulated, but a chronic infection in immunocompetent mice has been developed by intraperitoneal inoculation. An imbalance between protective type 1 T-helper cell and less efficient type 2 T-helper cell responses has been noted. The humoral immune response involves immunoglobulin (Ig) M and IgA. High levels of IgM antibodies are the result of constant antigenic stimulation due to slow fungal degradation. Because chromoblastomycosis does not affect mucosal epithelia, the elevated levels of IgA may represent only a marker of the immune status of patients. 9 The pathogenesis of long-term complications may be explained by the following hypothesis: transforming growth factor-β has a double effect that induces fibrosis and immunosuppression in affected skin. 10 Depending on the host response, a tuberculoid or suppurative granuloma can be observed. Antimelanin antibodies are produced during human infection. 11,12 Melanin is a virulence factor. It is a negatively charged hydrophobic high-molecular-weight pigment with hydroquinone groups that is formed by the oxidative polymerization of phenolic or indolic compounds. Melanin interferes with complement activation, reducing the susceptibility of pigmented fungi to antifungal agents. Melanin production by F pedrosoi involves the formation of melanosomelike compartments and participates in the intracellular Table 1

Agents causing chromoblastomycosis

Fonsecaea pedrosoi Fonsecaea compacta Fonsecaea monophora Phialophora verrucosa Cladophialophora carrionii Cladophialophora yegresii Rhinocladiella aquaspersa Exophiala jeanselmei Fig. 6

Abdominal chromoblastomycosis, verrucose plaque.

406 storage and regulation of calcium and iron ions. F pedrosoi melanin has a protective effect by its direct interaction with nitric oxide (NO). It acts as a trap for the unpaired electron of NO, protecting the fungus against oxidative damage. This mechanism does not allow macrophages or other phagocytes to clear fungal elements and could partly explain the recalcitrant, chronic course of chromoblastomycosis. 12

Etiologic agents The agents of chromoblastomycosis are common soil saprophytes of decaying wood and plants. They penetrate through a skin abrasion and spread by contiguity. These fungi have also been isolated in wood from sauna baths in Finland, which corroborates their resistance to high temperatures. F pedrosoi is the most important agent in tropical zones of Latin America, with a high frequency in rural populations in Cuba, Puerto Rico, and the Dominican Republic. It is also the most common etiologic agent in Mexico. C carrionii is found in arid and semiarid zones, such as the Lara, Falcon, Bariquisimeto, and Maracaibo states in Venezuela, and also in Australia, South Africa, and Mexico. P verrucosa is found in lowlands under the same conditions as F pedrosoi. It has been isolated only once in Mexico, but there are scattered reports from Moscow, the Japanese islands, and other parts of the world. 5 F compacta has been isolated less than 12 times in the world. This species was identified in tropical Central America and in North America. Fonsecaea spp are particularly common in southern China. F monophora is a new species segregated from F pedrosoi, and it is the predominant etiologic agent of chromoblastomycosis in southern China. C yegresii is a newly introduced species, similar to C carrionii, which originates in cactus plants but is less virulent. The occurrence of C carrionii and C yegresii in association with xerophytes has been proved, but their environmental route is still unknown. 7 Exophiala jeanselmei and species of the genus Rhinocladiella have been infrequently associated with systemic infection. Only isolated cases of infection of the lung, brain, peritoneum, and esophagus have been reported. 13 These infections are associated with a wide range of underlying conditions, including immunodeficiency, cancer, agranulocytosis, therapy with immunosuppressive drugs (corticosteroids), and AIDS. In addition, many of the risk factors for nosocomial fungemia are usually present, including postoperative status, central venous catheters, the use of broadspectrum antibiotics, and neutropenia. 13

Clinical features The incubation period is unknown. A history of injury or traumatic inoculation is not always present. 2 The lesions are

E. Torres-Guerrero et al. more frequent on the legs (85%). 1 The disease can also involve other exposed areas, such as hands, arms, trunk, buttocks, neck, forearms, and face. Less than 20% of patients develop disseminated lesions affecting both the arms and legs. Initially, the lesion is a small, nonpruriginous, erythematous papule that slowly spreads to the surrounding skin. New lesions develop over months or years in the same area or on over adjacent areas. Lesions progress into an erythematous plaque, with or without scales or ulceration, with a well-defined border and may resemble tinea or psoriasis. Later, the plaque expands centrifugally and develops an irregular verrucous or papillomatous surface. Satellite lesions can be observed. Current clinical classification is based on its variable morphology and the clinical presentation, including nodular, verrucous or vegetant, tumoral, cicatricial, and lymphangitic (sporotrichoid) forms. Mixed lesions are frequent. 2,14 Verrucous lesions look like a cauliflower or are craterlike. They can ulcerate and discharge pus due to secondary infection. Lesions heal with scars and atrophic and achromic areas. Keloid formation is not rare. 1 Lymphadenopathy can be present in patients with secondary bacterial infection. Lymphedema and even elephantiasis may develop in advanced cases. 2 Patients are usually asymptomatic; nevertheless, some facial or disseminated lesions may be pruritic or tender. Lymphatic and hematogenous spread is exceptional, but brown hyphal structures have occasionally been isolated from brain abscesses. Patients with ulcerations or with sclerodermiform or cicatricial lesions can experience incapacitating pain. Chromoblastomycosis does not involve bone or muscle. Often, 5 to 15 or more years may elapse from the onset of the disease until the diagnosis is made. Squamous cell carcinoma may develop in chronic ulcerated lesions. 15

Diagnosis The characteristic finding on direct examination with potassium hydroxide (KOH) is the presence of sclerotic or fumagoid cells (Medlar bodies [Figure 5]). These are doublewalled brown structures with a diameter of 4 to 10 µm that resemble copper pennies. Sometimes, thick and dark hyphae are identified. Cultures can be performed on Sabouraud agar or Sabouraud with antibiotics at 25° to 28ºC. The organism grows slowly (25-30 days). The biopsy specimen shows pseudoepitheliomatous hyperplasia with parakeratosis, spongiosis, and occasionally, abscesses. In the dermis, there is a suppurative or tuberculoid granuloma with lymphocytes, plasma cells, neutrophils, eosinophils, macrophages, and multinucleated giant cells. Fibrosis is present in older cases. Fumagoid cells are found alone or in clusters, both within and outside multinucleated giant cells, and can be identified with hematoxylin and eosin,

Chromoblastomycosis without special stains. 1,2 Transepidermal elimination is possible. Main features of the cultures are: • Phialophora verrucosa produces brownish-gray to dark olive-gray colonies on Sabouraud agar, at 25° to 30°C, and typical phialides with cup-shaped collarettes. • F pedrosoi produces dark brown, dark olive, or black colonies on Sabouraud agar. There are three types of sporulation: Cladosporium, Rhinocladiella, and Phialophora. • F compacta produces olive-black colonies and the same type of sporulation as F pedrosoi. • Cladosporium carrionii colonies are velvety to woolly, dark olive, or nearly black on Sabouraud agar with oval conidia. They usually are of the same size in the same conidial chain. • Rhinocladiella aquaspersa colonies are woolly, dark to olive-gray, with erect conidiophores, and cylindrical, thick-walled, one-celled conidia. 2 There are two new culture media made from tree fruit. The first, Theobroma grandiflorum, is a native Amazonian tree with a slightly fibrous, yellowish mesocarp, containing potassium (34.3 mg/100 g of mesocarp), phosphorus (15.7 mg/100 g), magnesium (13.0 mg/100 g), and amino acids. The second is Bactris gasipaes Kunth, an American palm tree, which contains potassium (289.3 mg/100 g of mesocarp), calcium (24.7 mg/100 g), and magnesium (17.6 mg/100 g) and is rich in fatty acids, including oleic (46.3%), palmitic (38.2%), and palmitoleic (7.4%) acids. By using these natural media, the time required for the induction of sclerotic cells was reduced from about 45 days to only 48 hours, without the addition of other chemical components and without the use of specific temperature conditions or shaking methods. 16 An experimental study with a metabolic antigen (chromomycin test) was conducted for detection of delayed hypersensitivity to F pedrosoi in patients with chromoblastomycosis. The test had a sensitivity of 90% and a specificity of 98.8%. These findings suggest that this antigen can be used as a diagnostic aid and also in epidemiologic studies to determine the prevalence of chromoblastomycosis in endemic areas. 17 The loop-mediated isothermal amplification technique was developed for the rapid detection of pathogenic or allergenic fungi. Genus-specific polymerase chain reaction (PCR) primers for Fonsecaea spp are now available. 18 PCR primers are created from the ribosomal DNA internal transcribed spacer region and the 5.8S ribosomal RNA gene and are used for rapid clinical diagnosis, environmental detection, and in retrospective studies of archived clinical samples. 19

Differential diagnosis The most important differential diagnoses are verrucous tuberculosis, fixed sporotrichosis, lacaziosis, leishmaniasis, blastomycosis, paracoccidioidomycosis, verrucae, and squamous cell carcinoma. 1,5

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Treatment Chromoblastomycosis is extremely difficult to treat and is often refractory to various therapeutic approaches. Reliable therapies include curettage, electrodesiccation, and cryosurgery. Drug therapy for at least 6 months may result in a favorable clinical response, but relapses during or after therapy are common. In early or small lesions, a wide and deep excision is the treatment of choice. A common approach involves monthly cryosurgery sessions combined with oral itraconazole (300400 mg/d) for 6 to 8 months. In localized forms, the best option is itraconazole (300 mg/d) or terbinafine (250 mg/d), given 3 months before surgical excision and for an additional 6 to 9 months. In patients with disseminated, chronic, or resistant disease, long-term continuous treatment or even monthly pulses are necessary to prevent a relapse. The best results have been achieved with oral 5fluocytosine (100-150 mg/d); however, cultures may remain positive, and the drug is not available in all countries (500mg tablets). Some patients with disease caused by C carrionii have been cured with this regimen. Treatment must be long-term and usually takes twice as much as the time needed to obtain a negative culture. 1 Successful treatments with terbinafine (250-500 mg/d) have been reported, and cure has been achieved in 74.2% of patients after 12 months of treatment. 20 The therapeutic response to oral potassium iodide (1-9 g/d) given for several months is unreliable. Isoniazid has been effective in cases due to C carrionii but not when F pedrosoi is involved. Marked improvement has been reported with vitamin D (calciferol; 600,000 IU once or twice weekly) for 4 to 6 months. 1,5 In these patients, recurrence is common. Oral ketoconazole, for example, does not have a significant effect in the treatment of chromoblastomycosis. Monotherapy with this agent produces moderate improvement in 32% to 47% of cases. Intravenous amphotericin B has been successful in isolated cases, but failures occur often. In addition, the patient must be monitored frequently for nephrotoxicity. The starting dose for amphotericin B therapy is 0.1 to 0.25 mg/kg daily. If toxicity develops, the drug can be given every other day or the dose can be reduced. Alternatively, amphotericin B can be applied intralesionally in a 2% procaine solution weekly for 5 months. 21 Extreme caution must be exercised because an intra-arterial injection can cause distal necrosis of the limb. The response to topical amphotericin B is slow and not very effective. A synergistic action occurs with the combination of amphotericin B and 5-fluocytosine. A common regimen involves 50 mg of intravenous amphotericin B on alternating days plus oral 5-fluocytosine (70-100 mg/kg daily). The combination of amphotericin B and itraconazole is sometimes successful; however, failure to respond to any and all drugs has been reported, especially in longstanding cases. 1,5 Local heat therapy, using pocket warmers for at least 6 months, has also been effective, because temperatures over

408 40° to 42ºC kill the causal fungi. Other therapies used only in isolated cases, include Mohs micrographic surgery, carbon dioxide laser, thiabendazole, and fluconazole. 1,2,5 In vitro studies show that the combination of itraconazole and terbinafine may be effective for F monophora infection if given for 6 to 12 months. 22 Posaconazole has good antifungal activity against a broad spectrum of fungi, including black fungi, and is a potentially useful therapeutic agent for patients with serious systemic mycoses. 23 In an experimental study, treatment with melanin-binding human antibodies completely inhibited the proliferation of conidia and, to a lesser extent, sclerotic cells. The mechanisms by which antibodies against melanin inhibit fungal growth are still unknown, but binding to the cell surface could impair the biologic functions of molecules involved in wall assembly. These results indicate that melanin from F pedrosoi is an immunologically active fungal structure that activates beneficial humoral and cellular responses. 11 We believe, as do other clinical investigators that further trials with new drugs, vaccines, combination therapy, and biologic therapy are needed to determine their therapeutic value in chromoblastomycosis. Currently, only small or limited lesions can be cured with surgical excision or cryosurgery plus itraconazole.

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