AUTHOR AND EDITOR INFORMATION

Section 1 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

INTRODUCTION

Section 2 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Background

Chromoblastomycosis is a chronic fungal infection of the skin and the subcutaneous tissue caused by traumatic inoculation of a specific group of dematiaceous fungi (usually Fonsecaea pedrosoi, Phialophora verrucosa, Cladosporium carrionii, or Fonsecaea compacta) through the skin.¹

Several cases of infection by Exophiala species have appeared in the literature.² Chromoblastomycosis is classified among the subcutaneous mycoses and is ubiquitous; however, the prevalence is higher in rural populations in countries with a tropical or subtropical climate, such as Madagascar in Africa and Brazil in South America.

Nomenclature

Since its identification in the early 1910s, the name of the disease has been frequently misused to encompass other infections caused by dematiaceous fungi. More recently, the advent of immunosuppressive therapies and diseases brought more confusion because of the identification of new agents and clinical settings. With the introduction of the concept of phaeohyphomycosis by McGinnis in 1983,³ differentiation among these diseases became more obvious. The features of chromoblastomycosis are distinctive enough to consider it an independent clinical entity. The infection should not be confused with mycoses, such as mycetoma or phaeohyphomycosis, caused by other dematiaceous fungi.

Nowadays, the term chromoblastomycosis is restricted to the cases in which sclerotic cells are present in tissue. Sclerotic cells, also known as Medlar bodies, are globe-shaped, cigar-colored, thick-walled structures that are 4-12 µm in diameter (see Media File 1). Medlar first described them in 1915.⁴ These structures multiply by septation, and they induce a purulent and granulomatous inflammatory reaction in tissue (see Histologic Findings).

In 1992,⁵ the International Society for Human and Animal Mycology (ISHAM) recommended that the best name to define the disease was chromoblastomycosis, which Terra et al coined in 1922.⁶

History

Contrary to what appears in some textbooks, chromoblastomycosis was first described by Max Rudolph in 1914 and not by Lane⁷ or Medlar⁴ in 1915. In 1987, Castro and Castro⁸ reported that Max Rudolph, a German physician living in Brazil, published a preliminary communication where the first 6 cases of the disease were described. Rudolph was also able to isolate a dark-colored fungus from 4 of 6 patients; this fungus grew in culture as a dark grey-to-black–colored furlike colony. Rudolph believed this fungus to be a type of blastomycete, and he successfully inoculated the disease in 4 white rats and 2 monkeys. Surprisingly, he did not describe the histologic aspects of the disease or the pathognomonic sclerotic cells, which both Lane and Medlar described 1 year later.

In 1928, Hoffman⁹ mentioned that in Cuba in 1908 Guiteras had observed 10 cases of a disease known as chapa in which the clinical aspects resembled those of chromoblastomycosis. Unfortunately, those cases were not published. In 1920, 2 Brazilian physicians, Pedroso and Gomes,¹⁰ published 4 cases that had been under observation for many years, the first one since 1911. According to them, all 4 cases were caused by P verrucosa. Two years later, in 1922, Brumpt¹¹ concluded that the agents isolated by Pedroso and Gomes could not be classified as Phialophora species, and he coined the denomination Hormodendrum pedrosoi, later renamed F pedrosoi by Negroni¹² in 1936. By 1930, new cases had been described outside the American continent in France, Sumatra, and Poland.¹³

Four different genera are now widely accepted to cause chromoblastomycosis: F pedrosoi, P verrucosa, C carrionii, and F compacta.¹⁴ Rare cases of chromoblastomycosis caused by Rhinocladiella aquaspersa and Exophiala species have also been reported, allowing the inclusion of these species among those that cause the disease.^{15, 16, 17, 18, 19}

Pathophysiology

The infection usually results from a traumatic cutaneous injury that is often not remembered or realized by the patient. The agents often gain entry into the human body by contact with wood splinters or thorns.

The fungi most commonly reported as causing chromoblastomycosis are F pedrosoi, C carrionii, and P verrucosa. A small number of cases due to F compacta, R aquaspersa, and different species of Exophiala have also been reported. In 2007, Chaetomium funicola was identified as a cause of chromoblastomycosis in Panama.²⁰

Several authors have demonstrated that a number of different dematiaceous fungi can be isolated from nature. In 1937, Conant²¹ demonstrated that a fungus called Cadophora americana, which was isolated from timber, was actually the same organism as P verrucosa. Later isolations were obtained in several countries from materials, such as plants, palm trees, grass, and soil.¹⁸ C carrionii has been isolated from cactaceae, both from the thorns and from the medullae, in Venezuela.²² C carrionii is the most common agent of chromoblastomycosis in that country, and trauma due to plants is believed to inoculate the skin with the fungus. The fungal cells in human tissue present with the same features as those observed in the inner portions of the plants.

The lesions develop slowly at the site of implantation, producing a warty nodule, which tends to be limited to the skin and the subcutaneous tissue. Over the years, the nodule grows centripetally. In many instances, the central parts of the lesion heal, leaving ivory-colored scars. The disease tends to spread to neighboring healthy skin, forming plaques, which, at times, can involve a whole limb. When nodular lesions predominate over the plaques, the disease assumes a typical cauliflower aspect. Both lymphatic dissemination and cutaneous dissemination have been described.

Frequency

International

The disease has been described worldwide, but the incidence is greater in tropical and subtropical regions located between 30° N and 30° S.²³

An estimated 20% of cases are found in temperate climates, such as in Japan,²⁴ Canada,²⁵ Finland,^{26, 27} and Romania and Czechoslovakia.¹³ This disorder most commonly affects male agricultural workers in rural regions of North America, Central America, and South America, but it does occur worldwide, including Europe, England, India, South Africa, and Australia. The highest incidence of chromoblastomycosis in the world is in the African country of Madagascar, and a large number of cases have been reported in Japan. A survey in the Brazilian Amazon disclosed an extremely high incidence of chromoblastomycosis (1.6 cases per 10,000 population) in a village called Monte Negro, in the state of Rondonia.

Countries with the highest number of cases are Madagascar and Brazil. Several different African and Latin American countries, such as Gabon, Colombia, Venezuela, Cuba, the Dominican Republic, and Mexico, also have high prevalence rates.

F pedrosoi infection is most commonly observed in humid climates, whereas C carrionii infection is normally found in dry areas.

Farming is the most common occupation in patients with chromoblastomycosis.²⁸

Mortality/Morbidity

• Mortality due to chromoblastomycosis is a rare event.
• Morbidity relates directly to the severity of the disease. Initially, in the papule or nodule phase, the disease is asymptomatic. When the nodules coalesce, forming large plaques and sometimes involving the whole limb, complications may appear.
• Common complications include ulceration, lymphedema, and secondary infection.

Race

No racial predilection is reported.

Sex

Most series reports indicate a clear male predominance, although a small number of reports describe similar male-to-female ratios.

• Approximately 70% of cases are seen in men. The explanation for this male predominance is not clear, but men are assumed to be more commonly involved in agricultural work and are more prone to inflict injuries on themselves, thereby causing self-inoculation, rather than women who are supposedly more dedicated to house jobs.
• The possible inhibitory effect of female hormones on the growth of fungi may partially explain the relatively low number of cases in females.

Age

Patients with the disease are most commonly aged 30-50 years.

• The period between inoculation and disease development is believed to last years, explaining the scarcity of children with chromoblastomycosis.
• The disease is rarely found in children exposed to the same environmental conditions as adults.

CLINICAL

Section 3 of 12  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

History

Patients usually do not report discomfort, and they tend to not seek medical care until secondary infection or elephantiasis ensues.

Physical

The disease appears at the site of a previous often unnoticed or unremembered trauma to the skin. After several years, a small, raised, erythematous, asymptomatic papule develops. As the lesion develops over years, it assumes a scaly and infiltrated aspect, generally leading to either of the 2 most common clinical variants: nodular or plaque. In both types, the surface is verrucous, and lesions spread laterally to contiguous healthy tissue.

In general, the disease remains localized to the area of the initial infection or neighboring skin, but lymphatic and hematogenous dissemination may occur, producing metastatic lesions away from the primary site. The nodular type of lesion normally develops into verrucous, pedunculated, cauliflowerlike florets, while the plaque type spreads peripherally, with an active, raised border, leaving a central healed area with atrophic and yellowish scar tissue.

On the surface of both types of clinical variants, numerous black dots may be observed where the causative organisms are preferentially found. Hemopurulent material covering small ulcerations is commonly observed.

Secondary infection with bacteria is common, giving the lesion a characteristic ill odor. Secondary infection is believed to be important in the genesis of lymph stasis and consequently of elephantiasis. In old cases, lesions in different stages of development can be found. Extracutaneous spread may occur rarely, due to hematogenic and lymphatic dissemination. Contiguous spread to the underlying bone may produce an osteolytic lesion.²⁹

The sites most commonly affected are the lower extremities, especially the feet. The hands, the arms, and the buttocks are also frequently involved, and sporadic reports mention lesions on the ears, the face, and the breasts.

Causes

The isolation of the causative fungi from nature on several different occasions has added to the demonstration that fungi gain entry into the host's body through traumatic inoculation¹; this finding also confirmed that populations at risk are rural workers who walk barefoot in endemic regions where the causative agents are found.

• A Brazilian study has suggested a link between the occurrence of lesions on the buttocks and the habit of sitting on babaçu (Orbignya phalerata) shells. The authors have failed to isolate the causative fungus from the shells.³⁰ In 2004, Salgado et al³¹ were able to isolate the same F pedrosoi from a thorny bush (Mimosa pudica) and from a chromoblastomycosis patient. The lesion had developed after an accident at the site where those bushes grew.
• On the other hand, in 1994, Zeppenfeldt et al²² demonstrated that certain cactaceae from the Falcon state in Venezuela had fungi not only on their surfaces and thorns but also in the medulla. Not coincidentally, the fungus was identified as C carrionii, which is the most commonly found organism in chromoblastomycosis cases in that country. The histologic characteristics of the fungus in plant tissue resembled that found in humans. Experimental inoculation of C carrionii in goats, performed n Venezuela, demonstrated that although chromoblastomycosis affecting that genus of mammals has never been reported, C carrionii caused cellular reactions in goats identical to those seen in humans at the first stages of infection.³²
• In 1989, Tsuneto et al³³ demonstrated a higher frequency of HLA-A29 in patients with chromoblastomycosis; this finding suggests that genetics might have an influence in the acquisition of the disease.

DIFFERENTIALS

Section 4 of 12  

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Other Problems to be Considered

When clinically presenting as a verrucous plaque, chromoblastomycosis may mimic several dermatoses that also manifest as a verrucous plaque; these conditions include cutaneous leishmaniasis, sporotrichosis, cutaneous tuberculosis or mycobacteriosis, as well as squamous cell carcinoma.
Chromoblastomycosis-induced lymphedema may mimic elephantiasis.

WORKUP

Section 5 of 12  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Lab Studies

• Among the possible laboratory tests to be obtained, direct examination of 10% potassium hydroxide cleared lesion scrapings is by far the most useful. Typical, thick-walled, cigar-colored, sclerotic cells, also known as Medlar bodies, are readily seen. Although these cells are pathognomonic of chromoblastomycosis, they do not give specific information on the agent. Eventually, dematiaceous hyphae can also be observed. Identifying the agent is easier when the specimens collected include the black dots present in the lesions. In 2005, Miranda et al³⁴ suggested the use of vinyl adhesive tape for collecting and identifying some types of deep-seated mycoses in which the infectious agents can be observed in the horny layer of the epidermis in transepidermal elimination events.
• In culture, each causative agent produces a similar pattern, that of a slow-growing, dark, velvety colony with a black obverse. Identification of individual species is handled in the usual manner by observing various characteristics, including conidia production.
• Serologic tests are exclusively used for research matters, and they are not routinely used or available. A recently isolated, highly specific and sensitive immunoblotting method depicted a 54-kd antigen from F pedrosoi³⁵ that may prove to be helpful in the study of the disease.
• An enzyme-linked immunosorbent assay (ELISA) using a somatic antigen of C carrionii was tested to serologically follow cases of chromoblastomycosis due to C carrionii before, during, and after therapy. ELISA proved to be a valuable tool for the diagnosis and follow-up of patients with chromomycosis (due to C carrionii). According to the authors³⁶ in 2005, the use of an ELISA might be useful to establish remission criteria in chromoblastomycosis caused by C carrionii.
• Duplex polymerase chain reaction is a rapid and specific assay for identification of Fonsecaea isolates, mainly for the strains that are difficult to identify using morphologic methods.³⁷

Imaging Studies

• Bone involvement is not a typical finding in chromoblastomycosis. Long-lasting lesions may lead indirectly to bone changes, making it necessary to evaluate possible bone compromise with regular radiography, especially when lesions are old, located at sites with scarce subcutaneous tissue, or associated with lymphedema.
• Lymphoscintigraphy has been used to evaluate lymphedema, but it is not routinely used.³⁸

Histologic Findings

In cutaneous lesions, the cigar-colored fungi are easily seen in hematoxylin and eosin–stained sections. No special stains are needed. The typical finding is a pseudoepitheliomatous hyperplasia of the epidermis with a diffuse, lymphomononuclear inflammatory infiltrate in the dermis. The tissue response to the fungus is typically mixed.

True and pure abscesses or microabscesses, granulomas, granulomatous reactions, and abscesses surrounded by a granulomatous reaction with giant cells may be seen in the same section.³⁹ Inside the giant cells, brown-colored, thick-walled fungal cells may be seen. These muriform fungal cells may be single, 2-celled, or multiple-celled; this feature is a result of multiplication by splitting rather than budding.

Transepidermal elimination of the fungal cells is the histologic counterpart of the black dots clinically evident in chromoblastomycosis lesions. An unusual dermal response has been described by Jawitz et al⁴⁰ in 2007, consisting of dermal effacement by a spindle cell proliferation arranged in sweeping fascicles.

Staging

Staging of the disease is especially useful for academic matters. Because treatment is still difficult, several papers in the literature describe the results obtained with different therapeutic methods. Unfortunately, most papers are single case reports, and follow-up tends to be short. The lack of uniformity in staging contributes to the low reproducibility of the proposed regimens.

In 1999, Castro devised an elegant, clinically based, physician friendly index to stage chromoblastomycosis. The severity index is based on the extension of the diseased area, the number of lesions, the presence of complications (eg, lymphedema, ulceration, secondary infection), and the unresponsiveness to previous treatments. According to this scoring system, patients are classified as having mild (up to 3 points), moderate (4-6 points), or severe (7-10 points) disease.

• Scoring system for staging chromoblastomycosis
• • Area of lesions: Small lesions up to 25 cm² are 1 point. Medium lesions larger than 25 cm² and smaller than 100 cm² are 2 points. Lesions larger than 100 cm² are 3 points.
  • Number of lesions: A single lesion is 1 point. One to 5 lesions is 2 points. More than 5 lesions or metastatic lesions is 3 points.
  • Complications (1 point for each complication present): Lymphedema is 1 point. Ulceration is 1 point. Secondary infection is 1 point.
  • Resistance to previous treatment or previous unsuccessful treatment is 1 point.

TREATMENT

Section 6 of 12  

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Medical Care

One of the most characteristic features of chromoblastomycosis is its refractoriness to treatment. Treatment options include oral itraconazole (as monotherapy or with oral 5-FC), locally applied heat therapy, and cryosurgery.

• Several authors indicate itraconazole as the best choice of therapy.^{18, 41, 42} Daily doses range from 200-400 mg, and results vary greatly. Adverse effects are not common, but efficacy is not as high as one would desire. Severe cases should be treated for several years. The authors' experience in treating more than 25 patients with varying degrees of severity for up to 5 years shows that itraconazole produces dramatic improvement after a few months of therapy; however, a complete cure is rarely reached, especially in severe cases. These results might be because of the predominantly fungistatic mechanism of action of the drug. In numerous cases, drug withdrawal led to relapse.
• Although few studies have been published, the association of itraconazole and 5-FC is promising.⁴³ As with 5-FC and amphotericin B, itraconazole and 5-FC produce a synergistic effect. Multidrug therapy for chromoblastomycosis seems to be an interesting approach and may also be used with cryosurgery.
• In 1996, Esterre et al⁴⁴ presented interesting results when using terbinafine to treat more than 100 patients in Madagascar. Similar to that of itraconazole, the drug presented below optimal results, it is exceedingly expensive, and treatment lasts several months. To date, no reports on the association of terbinafine and itraconazole or terbinafine and 5-FC have appeared in the literature.
• Posaconazole (Noxafil), a new triazole derivative, has been experimentally used to treat chromoblastomycosis. Posaconazole has recently received approval from the US Food and Drug Administration for prophylaxis against invasive Aspergillus and Candida infections in patients at high risk because of severe immunosuppression.
• • The results of isolated cases suggest that outcomes may be slightly superior to those obtained by itraconazole or terbinafine (Unpublished data on file, Dr. Shikanai-Yasuda, Department of Infectious Diseases, Univ. São Paulo).
  • According to Keating⁴⁵ in 2005, posaconazole at 800 mg/d was associated with an overall success rate of 82% in persons with refractory chromoblastomycosis.
• Heat therapy is another treatment. Especially in Japan, the use of pocket warmers has proven successful in the treatment of a limited number of cases. Apparently, an increase in skin temperature somehow impairs fungal development.⁴⁶

Surgical Care

Cryosurgery with liquid nitrogen can be used to treat chromoblastomycosis, especially localized lesions. Several reports have appeared in the literature showing that the method has been used on almost every continent with good results.

Freezing time in one study varied from 30 seconds to 4 minutes, and the number of cycles varied from 1 to more than 40. All localized lesions responded extremely well to treatment, with no relapse for as long as 15 years, a follow-up period unparalleled in the literature. Three patients with generalized lesions attained clinical and mycologic remission for as long as 26 months, and 3 had significant improvement without cure.⁴⁷

MEDICATION

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Overall results of the various treatments in one Mexican study were as follows: 31% of the conditions were cured, 57% improved, and 12% did not respond to treatment. Optimal results were obtained with cryosurgery for small lesions; itraconazole for large ones; and, in some cases, the combination of both.⁴⁸

Chromoblastomycosis may also be cured by prolonged topical application of tolerable heat from pocket warmers. It may take as long as 6 months or more.⁴⁹

Drug Category: Antifungals

Mechanism of action usually involves inhibiting pathways (eg, enzymes, substrates, transport) necessary for sterol/cell membrane synthesis or altering the permeability of the cell membrane (polyenes) of the fungal cell.

FOLLOW-UP

Section 8 of 12  

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Further Inpatient Care

• Lymphedema and secondary infection or ulcerated lesions are common complications of chromoblastomycosis on the lower limbs.
• • Physiotherapy and lymphatic drainage are useful in preventing lymphedema.
  • Ulcers and secondary infection are dealt with by appropriate nursing care. Oral antibiotics may be used.

Complications

• The most common complications are ulceration; secondary infection; and lymphedema, leading to elephantiasis.
• Rare cases of malignant transformation (squamous cell carcinoma) of chromoblastomycosis have been documented in the literature.

Prognosis

• The prognosis tends to be good, especially for small and localized lesions. When the affected area is large, as in severe cases, cure is difficult, although control is easily achieved.
• Cicatricial and unaesthetic scars are the rule after the disease is eliminated.

MISCELLANEOUS

Section 9 of 12  

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• References

Medical/Legal Pitfalls

• No medical/legal pitfalls are of interest.

ACKNOWLEDGMENTS

Section 10 of 12  

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The authors and editors of eMedicine gratefully acknowledge the contributions of previous author, Luiz Guilherme M Castro, MD, to the development and writing of this article.

MULTIMEDIA

Section 11 of 12  

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• Differentials
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• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Media file 1:  Sclerotic cells on a potassium hydroxide preparation.
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Media file 2:  Micromorphology of Cladosporium carrionii (left) and Fonsecaea pedrosoi (right), the 2 most commonly isolated agents in chromoblastomycosis.
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Media file 3:  Chromoblastomycosis, tumoral form. Chronic disease led to elephantiasis and involvement of the entire lower limb.
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Media file 4:  Plaque lesion on the foot. The verrucous aspect of the lesion differentiates it from other infectious dermatoses that may present as a verrucous lesion, namely, cutaneous leishmaniasis, sporotrichosis, cutaneous tuberculosis, and cutaneous mycobacteriosis.
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Media file 5:  Culture of Fonsecaea pedrosoi on Sabouraud agar. The black velvety colony has the same macroscopic appearance as the colonies of other chromoblastomycosis-causing agents (eg, Cladosporium carrionii, Fonsecaea compacta, Phialophora verrucosa, Rhinocladiella aquaspersa, Exophiala species).
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Media file 6:  Hematoxylin and eosin–stained section shows typical sclerotic cells inside an abscess. Sclerotic cells present as round, thick-walled, cigar-colored structures.
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REFERENCES

Section 12 of 12

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Article Last Updated: Feb 11, 2008