Mycetoma is caused by fungi (eumycetoma), bacteria (actinomycetoma), or combinations. Eumycetoma is most frequently caused by Madurella mycetomatis,¹⁴ which is present in soil and gains cutaneous entry after minor trauma, which has led to the term “Madura foot.” However, metagenomic studies demonstrate diversity of implicated pathogens.¹⁵

Populations of tropical/subtropical regions in the mycetoma belt (latitudes 15° S -30° N) are primarily affected (Figure 1).¹⁶ Sudan has the largest reported mycetoma burden;¹⁷ other endemic regions include Senegal,¹⁸ India,¹⁹ Mexico,²⁰ Brazil, and Argentina.²¹ Men in their 30s-40s are most frequently affected, likely related to agriculture occupations.²² Risk factors include walking barefoot or wearing footwear without sufficient coverage.

In an epidemiologic study (2020),²³ eumycetoma and actinomycetoma were reported beyond tropical endemic areas of the mycetoma belt, to the US (57 cases), Italy (8), China (9), and Australia (5). There are eumycetoma cases in Mexican patients who migrate to the US.^24–26 In a US epidemiologic study¹³ of implantation mycoses (2017–2021), there were 238 eumycetoma cases (5.2 per 1,000,000), with highest prevalence in the Midwest and more commonly among immunosuppressed patients. There was a female predominance for eumycetoma in the US in contrast to international settings, possibly due to different care-seeking behaviors.²¹

The classic triad of disease includes slow, progressive subcutaneous swelling, multiple discharging sinuses, and macroscopic granules.²⁷ Lower extremities are most frequently affected, with painless plaques demonstrating woody swelling and communicating sinuses, with the latter draining purulent material and granular grains (black-fungal, red-bacterial, white/yellow-fungal or bacterial) (Figure 2).²⁸ Clinical variants include nodules without sinuses, cysts,²⁹ and verrucous plaques.^30,31 If left untreated, infection may spread via fascial planes to involve muscle or bone.^28,32

Ultrasound may distinguish eumycetoma from other subcutaneous masses, and between eumycetoma (black grains produce sharp hyperechoic foci) and actinomycetoma (grains less distinct and seen at bottom of lesions).^33,34 Sensitivity and specificity for ultrasound examination of eumycetoma were 94.3% and 50%, respectively, in a cross-sectional study³⁵ of 222 patients suspected of fungal mycetoma caused by Madurella mycetomatis. Sinus material may be obtained via ultrasound-guided fine needle aspiration for histopathologic examination, which is required for definitive diagnosis (Figure 3).³⁶ Tissue fungal culture identifies the causative organism. Magnetic resonance imaging (MRI) may assess for extent of soft tissue involvement.^37,38 The “dot-in-circle” sign on MRI refers to small, round-shaped hyperintense lesions with small central focus correlating to granulomata-containing grains (Figure 4).³⁹ X-ray and computed tomography (CT) may assess for bone involvement.

Chromoblastomycosis is a chronic granulomatous infection most frequently caused by Fonsecaea and Cladophialophora spp. and acquired through traumatic inoculation.

Chromoblastomycosis most commonly occurs in tropical and subtropical regions, and most frequently affects agricultural workers, though not limited to this population (Figure 5). In a review⁷ of 7,740 chromoblastomycosis cases (1914–2020), cases were most common in South America, Africa, Central America and Mexico, and Asia. Men (81.7%) were frequently affected with mean age 57.1 years.

In a US epidemiologic study¹³ of implantation mycoses (2017–2021), there were 667 chromoblastomycosis and phaeohyphomycotic abscess cases (14.7 per 1,000,000), with highest prevalence in the Northeast and more commonly among immunosuppressed patients.

Chromoblastomycosis most frequently affects lower extremities, followed by upper extremities, and head/neck. In early disease stages, chromoblastomycosis may present as a small verrucous papule following trauma (Figure 6). Lesions enlarge over time, forming hypertrophic and verrucous plaques, sometimes associated with pruritus and pain. Black dots with “cayenne pepper” appearance may be present on the surface (Figure 7).⁴⁰ In the aforementioned study of 7,740 chromoblastomycosis patients, the most common morphologies were verruciform, tumorous, and plaque-like.⁷ Only one lesion type was present in 63.2% of patients, while combinations were observed in 36.8%. In the US, chromoblastomycosis typically presents as small to moderate sized plaques with heavy scale-crust, unlike the tumoral masses and large verrucous plaques more typical of long-neglected lesions in endemic regions (Figure 8).⁴¹ Chromoblastomycosis lesions may clinically and histopathologically mimic squamous cell carcinoma.⁴²

Diagnosis is confirmed through identification of sclerotic bodies (thick-walled cells [4–12μm in diameter] resembling copper pennies), also known as muriform cells or medlar bodies, seen on potassium hydroxide (KOH) preparation with microscopy or skin biopsy with histopathology (Figures 9, 10).⁴³ Skin biopsy is preferentially performed in an affected area with visible black dots.⁴⁴ Skin scraping is typically sufficient due to the robust nature of medlar bodies.⁴⁵ Skin scrapings may be used for early and long-standing lesions.⁴⁵ Tissue fungal culture identifies the causative organism.⁴⁴ In a retrospective review of chromoblastomycosis cases (1989–2018) in Brazil, average time to diagnosis was nine years.⁴⁶

Paracoccidioidomycosis is caused by dimorphic fungi of the genus Paracoccidioides, which are soil saprophytes.⁴⁷ Infection occurs via inhalation of conidia, with hematogenous spread to other organs, including the skin.⁴⁸ Direct cutaneous or mucosal inoculation is rare.^49,50 Paracoccidioidomycosis is classified into acute-subacute (juvenile) and chronic (adult) forms. Most cases (74–96%) are chronic,⁵¹ and are classified into unifocal form (single organ involvement—typically lungs), and multiple form, (multiple organ involvement—typically skin, mucosa, and lungs).⁴⁹

Paracoccidioidomycosis is endemic to tropical and subtropical regions of South and Central America (Figure 5). Infection is associated with exposure to rural environments and agricultural activity, with higher risk in people working in coffee, sugar cane, corn, and tobacco plantations.^52,53 Men in their 30s-50s are most frequently affected in the chronic form,⁵¹ and 90% are smokers, with disease risk 14 times higher among smokers vs. non-smokers.^54,55 Adolescents of both sexes are most frequently affected in the acute-subacute form.⁵¹

Brazil has the highest proportion of cases (80%),⁵⁶ with incidence rising in the northern region (Amazon) due to new settlements and concurrent deforestation.^51,57–59 Urban cases of paracoccidioidomycosis may be increasing.⁶⁰

The lungs are most frequently involved (90%), followed by upper respiratory tract mucosa and skin.⁵¹ Mucosal lesions are painful, erythematous ulcers with ragged borders and hemorrhagic spots.⁶¹ In a retrospective study of 161 paracoccidioidomycosis patients, 60.2% presented with oral lesions, most commonly mulberry-like ulcers and gingival hemorrhagic spots (Figure 11),⁶² and 27.8% presented with skin involvement. Cutaneous lesions usually present as erythematous papules or ulcers/vegetations with fine granulations and hemorrhagic spots, most commonly involving the face, extremities, and trunk (Figure 12).⁶³ There is a rare sarcoidosis-like form (Figure 13).⁶⁴

Most symptoms involve the phagocytic-mononuclear system and frequently include generalized lymphadenopathy and hepatosplenomegaly.⁵¹ Cutaneous lesions are present in 16.3% of cases.⁶⁵

Direct microscopy with KOH of tissue samples or skin scrapings demonstrates large yeasts (10–30μm) with a thick, birefringent cell wall with multiple buds resembling a “mariner’s wheel” or “Mickey Mouse Ears.”^8,66,67 Histopathologic examination with Gomori’s methenamine silver (GMS) stain aids in organism identification (Figure 14). Tissue fungal culture identifies the causative organism. Serologic testing is used to monitor response to therapy.⁶⁶ Chest CT is recommended to evaluate for pulmonary involvement.⁴⁷

Sporotrichosis is caused by the dimorphic fungal genus Sporothrix spp. The most common species vary by region, including Sporothrix schenckii (North America, Australia, South Africa),⁶⁸ Sporothrix globosa (Asia),^68,69 and Sporothrix brasiliensis (Brazil).^70,71 Transmission varies by species, with the classical route defined as traumatic inoculation of soil or plant material for Sporothrix schenckii, and the emerging route defined as inoculation through a bite, scratch or contact with respiratory droplets (sneezing, licking) from infected cat for Sporothrix brasiliensis.⁷² In feline sporotrichosis, transmission to humans may occur via contact with infected animal secretions without trauma.

Sporotrichosis has a global distribution, with endemic areas being Latin America (especially Brazil, Mexico, Colombia), Asia (especially China, India, Japan), and to a lesser extent, US and Australia (Figure 5).⁷³ It is often considered the most prevalent and widespread implantation mycosis worldwide.⁷⁴ Veterinarians and those who work with animals may have increased infection risk.^72,75

An ongoing sporotrichosis epidemic in Rio de Janeiro, Brazil, primarily from feline transmission of Sporothrix brasiliensis, caused an increase in human cases from 759 in 1998–2004 to >4,000 in 2014.⁷⁴ In a case series of 122 sporotrichosis patients infected with Sporothrix brasiliensis, 70.5% were female, which may be related to the high proportion of women working as housewives or cleaners in Brazil with close contact to domesticated cats.⁷⁶

The cutaneous form is most common, including lymphocutaneous (55%) and fixed cutaneous (25%) involvement (Figures 15, 16).⁷⁷ In the lymphocutaneous form, a papulonodular lesion develops days to weeks after inoculation and subsequently ulcerates, often resembling the initial lesion of syphilis and therefore referred to as chancriform (Figure 17). Similar lesions thereafter occur along regional lymphatic channels proximal to the original lesion (nodular lymphangitis). In the cutaneous form, polymorphic skin lesions, including papules, nodules, ulcers, verrucous lesions, and plaques develop following trauma.⁷⁴ Extracutaneous involvement is associated with chronic obstructive pulmonary disease, alcoholism, steroids, AIDS, solid organ transplantation, and TNF-alpha inhibitors, and may include pulmonary, osteoarticular, ophthalmic, and central nervous system infection.^74,78

Tissue fungal culture is the primary diagnostic test.^79–83 Histopathology has low sensitivity, showing only an inflammatory or granulomatous reaction, and rarely oval or spherical yeasts (2–6μm in diameter) sometimes elongated in a cigar shape (Figure 18).⁷⁹ Because organisms may be sparse, immunohistochemistry may enhance sensitivity. Polymerase chain reaction (PCR) is a fast, accurate, and highly sensitive diagnostic method. ⁸⁴ However, immunohistochemistry and PCR are not readily available for sporotrichosis diagnosis in the US.

Emergomycosis is caused by a group of previously unknown dimorphic fungal species that have recently been reclassified to the genus Emergomyces. Emergomyces spp. are found in soil and are likely spread by inhalation of conidia.⁸⁵ It is unknown whether Emergomyces spp. have truly emerged or whether they are now recognized due to increased immunosuppressed, susceptible hosts, and the adoption of molecular identification techniques.⁸⁶

Emergomycosis cases have been reported in North America, Africa, Asia, and Europe.⁸⁷ The most cosmopolitan and widespread species is Es. pasteurianus,⁸⁸ diagnosed in the Netherlands,⁸⁹ Italy,⁹⁰ Spain,⁹¹ France,⁹² India,⁹³ China,^94,95 Uganda,⁹⁶ and South Africa.⁹⁷ Other species include Es. canadensis (North America), Es. orientalis (Asia), Es. europaeus (Europe) and Es. africanus (Southern Africa).^85,87,98,99 Emergomycosis most commonly affects immunosuppressed people, including those with advanced HIV, solid organ transplantation, diabetes mellitus, hematologic malignancy, and those taking immunosuppressants.^{88,100,101,102} The highest burden of cases is among HIV-infected patients in South Africa.¹⁰³

Emergomycosis is now recognized as the most commonly diagnosed dimorphic fungal infection in South Africa.⁸⁶ Recent cases of emergomycosis have been reported in North America, including four cases in immunocompromised patients in the US (Colorado, New Mexico) and Canada (Saskatchewan).¹⁰⁴

Emergomycosis may involve the skin, mucous membranes, lungs, gastrointestinal tract, liver, spleen, bone marrow, lymph nodes, and cervix.^{85,86,88,105–107} In a retrospective study of 55 emergomycosis patients in South Africa, 96% had skin lesions at presentation, and 88% had pulmonary involvement.¹⁰⁸ Cutaneous lesions are typically widespread and polymorphic,¹⁰⁵ and may include umbilicated papules, hyperkeratotic plaques, nodules, verrucous lesions, and ulcerations (Figures 19, Figure 20).^{85,105,106,108,109}

Diagnosis is via tissue fungal culture in conjunction with histologic evidence of tissue invasion.¹⁰⁰ Punch or incisional skin biopsies may be used for tissue culture and histopathology.¹⁰⁰ Histopathologic sections demonstrate 2–5μm intracellular (in histiocytes) and extracellular oval yeasts with narrow-based budding and inflammatory change, best visualized with hematoxylin-eosin, periodic acid Schiff (PAS), GMS, and Wright-Giemsa stains (Figure 21).^85,88,101 Histopathology alone is not sufficient for diagnosis, as yeast cells of Es. africanus and Es. orientalis resemble those of Histoplasma capsulatum and Blastomyces dermatitidis, respectively.^85,88,100

Talaromycosis is caused by the fungus Talaromyces marneffei, which is spread via inhalation of spores.¹¹⁰

Talaromycosis is endemic to tropical and subtropical regions of Asia and primarily affects HIV patients.¹¹¹ Patients with other immunosuppressive conditions, including cancer and organ transplantation, may also be affected.¹¹² A total of 24,622 talaromycosis cases were reported in 33 countries by late 2018, with an estimated 288,000 talaromycosis cases globally 1964–2018, and approximately 17,300 cases diagnosed annually.¹¹³

It is estimated that talaromycosis incidence will increase by 35% 2020–2025,¹¹³ due to rising incidence of advanced HIV among newly diagnosed HIV patients in Indonesia, Thailand, Vietnam, and the Philippines.¹¹¹

The main clinical manifestations are painless papules involving the face, neck, and extremities.^114–117 In a retrospective study of 80 HIV patients with disseminated talaromycosis, 71% had cutaneous findings, and 87% of papules had central umbilication (Figure 22). Non-HIV patients less often had skin lesions (44% vs. 71%),^118,119 and had longer time to diagnosis (180 vs. 45 days)¹²⁰ and higher mortality (29% vs. 21%)¹²¹ compared to HIV-coinfected patients. Papules less often have central umbilication in non-HIV-coinfected vs. HIV-coinfected patients.¹²²

Tissue fungal culture is the primary diagnostic test.¹²³ Presumptive diagnosis may be made via microscopy of Wright-stained touch smears from a skin biopsy, showing clear basophilic, oval yeasts with central septation.^124–126 Histopathology with GMS or PAS staining demonstrate round or oval yeast cells within macrophages (Figure 23),¹²⁶ but may resemble that of other fungal diseases associated with parasitized histiocytes, including emergomycosis and histoplasmosis. Antigen detection is an accurate and inexpensive diagnostic option for advanced HIV patients with high fungal burden.¹⁰⁰ An inexpensive, point-of-care immunochromatographic strip test with high sensitivity/specificity using clinical urine specimens was recently developed, which is not yet readily available in the US.¹²⁷

Lobomycosis, also known as lacaziosis or Jorge Lobo’s disease, is caused by the fungus Lacazia loboi, which presumably gains cutaneous entry after minor trauma.¹²⁸ This pathogen is non-cultivable, and taxonomy is therefore debated.^129,130 Dolphins are the only other known host. Recent increase in dolphin varieties infected with Lacazia loboi¹³¹ raises concern for increased geographical distribution of disease in humans.

Lobomycosis primarily occurs in Central and South America, and most commonly affects forest workers, farmers, hunters, manual laborers, and fishermen. There were 907 reported cases globally as of 2022, which is likely an underestimate.¹³⁰

Incidence has increased in Acre, Brazil.^132,133 Cases have been reported in the US and Canada, likely caused by preceding exposure in the Amazon Basin.^134,135

Lobomycosis is characterized by long incubation period (sometimes years) followed by slow, progressive development of painless keloid-like nodules, which may ulcerate or become verrucous (Figure 24).¹⁰ In the localized form, lower extremities are most frequently affected, followed by ears, upper extremities, and head (Figure 25).^136,137 In a retrospective study of 249 lobomycosis cases in Brazil, localized, multifocal, and disseminated cutaneous lesions were observed in 61%, 22%, and 16% of patients, respectively.¹³⁸

Diagnosis is made via skin biopsy with histopathology,¹³⁹ showing isolated round yeast-like cells with a thick wall containing melanin, or in 2–10 cell chains connected via tubular projections (Figure 26).¹³⁹ In scaly lesions, fungal visualization using direct microscopy on lesional scrapings is useful. ^10,140

Fungal skin NTDs have been and continue to be neglected, despite association with substantial morbidity and stigma. Public health efforts are needed to improve surveillance and to increase access to diagnostic tools in endemic regions, since diagnosis is challenging. A high index of suspicion for fungal NTDs based on demographics and clinical presentation is necessary, with adequate tissue biopsy for histological examination and fungal culture. Recognition of cutaneous manifestations and prompt diagnosis is imperative for improved outcomes.