Lobomycosis

INTRODUCTION — Lobomycosis is a chronic fungal infection of the skin and subcutaneous tissue that primarily occurs in tropical climates of Latin America. The causative organism is Lacazia loboi (formerly Loboa loboi), a dimorphic fungus found in soil, vegetation, and water. Infection occurs through traumatic implantation of the fungus into the skin.

The most common presentation in humans consists of slow-growing, keloid-like papules, nodules, or plaques in a localized area on exposed skin (picture 1A-C). Other manifestations of lobomycosis include ulcerated, infiltrative, verrucous, gumma-like, multifocal, and disseminated lesions.

Although lobomycosis is the accepted term for this disorder, a variety of other names have been used to refer to lobomycosis [1]. Examples include Jorge Lobo's disease, Jorge Lobo mycosis, Jorge Lobo blastomycosis, Amazonic pseudolepromatous blastomycosis, miraip or piraip ("burning" in the Tupi language), Caiabi leprosy, and lacaziosis.

The clinical features, diagnosis, and management of lobomycosis will be reviewed here.

ETIOLOGY AND TRANSMISSION — The taxonomy of the fungus that causes lobomycosis has changed multiple times since the first description of the disease [2-7]. The general consensus is that L. loboi is the preferred nomenclature [8]. L. loboi is a dimorphic fungus that may exist in a saprophytic phase in soil, vegetation, and water [9]. Molecular analyses have demonstrated a relationship between L. loboi and other fungal members of the order Onygenales, including Paracoccidioides brasiliensis [10]. Attempts to culture L. loboi in vitro have failed.

Traumatic inoculation into the dermis is the most likely mode for the development of lobomycosis in humans, a concept that is supported by a report of lobomycosis that may have resulted from handling of L. loboi-infected mice [11] and a report of lobomycosis in a laboratory scientist transmitted through experimental inoculation [12]. In addition, patients have reported the development of symptoms following snakebites, insect bites, or stingray stings [9,13]. Lobomycosis does not appear to spread through human to human transmission.

L. loboi appears to have a long incubation period. The time period from inoculation to the development of a skin lesion is estimated to be one to two years [11,14].

Lobomycosis-like disease is a granulomatous disease of dolphins that was previously considered an expanding ecologic niche for lobomycosis [15]. The proposed etiologic agent for lobomycosis-like disease is Paracoccidioides ceti, which would distinguish this disease from lobomycosis [15].

PATHOGENESIS — After inoculation into the dermis, lobomycosis replicates slowly within macrophages [16]. Preserved cellular immunity is probably necessary to hinder persistence and progression of the disease.

Cytokines with suppressive effects on cellular immunity, particularly transforming growth factor-beta 1 (TGF-beta 1) and interleukin-10 (IL-10) may play key roles in the pathogenesis of lobomycosis. In a study that evaluated the expression of TGF-beta 1, IL-10, tumor necrosis factor-alpha (TNF-alpha), and inducible nitric oxide synthase (iNOS) in lesional skin from 16 patients with lobomycosis, TGF-beta 1 and IL-10 were the most frequently expressed cytokines [17]. In contrast, expression of TNF-alpha, a proinflammatory cytokine, and iNOS, a marker of cellular immune response, was less prominent. Relevant immunosuppressive actions of TGF-beta may include suppression of phagocytic activity of macrophages and inhibition of nitric oxide and gamma interferon expression [17-19].

In addition, a study that used real-time polymerase chain reaction to assess expression of various cytokines in lesions of lobomycosis and healthy control skin found upregulation of regulatory T cell markers in lesional skin, suggesting that dominance of regulatory T cell activity in infected skin may contribute to persistent infection [20]. Regulatory T cells might inhibit Th-dependent, protective responses to intracellular fungi.

The possibility that impaired cellular immunity increases susceptibility to lobomycosis is also suggested by studies that utilized skin tests to assess immunologic function. Frequent absence of positive reactions to dinitrochlorobenzene sensitization, and reduced likelihood for positive skin reactions to Staphylococcus, Streptococcus, Trichophyton, and Candida antigens, have been detected in patients with lobomycosis [16,21]. Further study is necessary to clarify the role of the immune system in this disease.

In addition to its immunosuppressive effects, TGF-beta may influence the clinical manifestations of lobomycosis. The profibrotic properties of TGF-beta may contribute to the classic keloid-like appearance of lobomycosis [22].

EPIDEMIOLOGY — The overall prevalence of lobomycosis is low [23]. The frequency of the disease varies based upon geographic location. Tropical regions of South America and Central America are the primary locales for lobomycosis. In particular, areas of dense forests with high annual rainfall (>20 cm per year) and warm, humid environments (average temperature >24°C) are the sites of greatest predilection for the disease [24].

Lobomycosis was first reported in 1931 by Jorge Lobo in Recife, Brazil, and continues to occur in Brazil [25,26]. Examples of other South American and Central American countries in which lobomycosis has been reported include Colombia [27-29], Suriname [30], Venezuela [9,31-35], Guyana, French Guiana [36-38], Ecuador [39], Peru [40-42], Bolivia [43], Panama [44,45], Costa Rica [46], and Mexico. Although most cases of lobomycosis occur in such tropical climates (eg, by the year 2000, only 3 of 465 reported human cases had occurred outside of the Amazon region [47]), lobomycosis occasionally has been reported elsewhere. Reports have emerged from the United States [48], Canada [49], France [50], the Netherlands [51], Germany [52], Greece [53], and South Africa [9].

Lobomycosis occurs more frequently in men than in women and is most common in adults between the ages of 40 and 70 years [54]. In a retrospective study of patients with lobomycosis in the state of Acre, Amazon region, Brazil, 219 of 249 patients (88 percent) were male [54]. In endemic areas, lobomycosis most often occurs as an occupational infection and occasionally as a recreational infection in individuals exposed to harsh outdoor environments, such as forest workers, farmers, hunters, and fishermen [55].

CLINICAL FEATURES — The initial lesion of lobomycosis is a superficial or deep-seated papule. Because of the prolonged incubation period, the papule may appear months to years after inoculation. Over the course of subsequent months to years, the area of involvement expands contiguously, leading to the formation of single or multiple monomorphic or polymorphic plaques or nodules that often resemble scars or keloids (picture 1A-C) [47]. The surface of the plaques and nodules is usually smooth, shiny, and intact, and the color usually ranges from skin colored to red-brown or wine-red. Telangiectasias may be present.

Lobomycosis may also demonstrate a variety of other clinical characteristics, including dyschromia, ulceration, and infiltrative, verrucous, or gumma-like lesions (picture 2) [56,57]. Dyschromia is common, and varies from hyperpigmentation to hypopigmentation and even achromia. Ulcers are most likely secondary to trauma and may be particularly likely to occur in sites of moist, macerated skin. Infiltrative lesions may resemble tuberculoid leprosy or burn scars (picture 3) [55]. Verrucous lobomycosis results from exophytic growth and may occur in longstanding disease, particularly on the lower extremities.

Gumma-like lobomycosis is a rare presentation that presents as macular lesions with turgid borders, which evolve to form pustules, yellow exudate, and eventual scarring. This gumma-like phenomenon can occur several times in the same lesion and is associated with spontaneous resolution of the involved lesion [58].

Most often, the cutaneous manifestations of lobomycosis are limited to a localized area on a site of exposed skin. The most common sites are the pinna, upper limbs, and lower limbs [1,59]. However, multifocal (multiple sites of involvement on a single limb) and disseminated presentations may also occur. In a retrospective study of 249 patients with lobomycosis in Brazil, localized, multifocal, and disseminated cutaneous lesions of lobomycosis were present in 61, 22, and 16 percent of patients, respectively [54]. Regional lymph node enlargement, which may represent lymphatic spread of the fungus, is estimated to occur in 10 to 25 percent of patients [60,61].

Skin involvement from lobomycosis is usually asymptomatic. However, patients with extensive involvement may experience pruritus or dysesthesia.

HISTOPATHOLOGY — The major histologic findings of lobomycosis are located in the epidermis and dermis. Although the epidermis may be normal or atrophic, transepidermal elimination of the fungus may be associated with acanthosis, hyperkeratosis, spongiosis, neutrophil collections, and hyperplastic follicular infundibula in some areas (picture 4) [62,63]. In addition, ulcerated or verrucous presentations of lobomycosis will exhibit epidermal ulceration or significant epithelial hyperplasia consistent with these clinical presentations.

The dermis exhibits a dense histiocytic dermal infiltrate composed of large numbers of epithelioid cells, multinucleated giant cells, and Langhans cells. Granulomas may or may not be present. In some cases, aggregates of large xanthomatous histiocytes with clear or finely granular eosinophilic cytoplasm (pseudo-Gaucher cells) are present [62]. There is often a thin zone of collagen immediately beneath the epidermis that is spared from the inflammatory process in the dermis, a finding referred to as a Grenz zone or Unna band.

The dermis also contains abundant fungal structures of L. loboi located within or outside of dermal macrophages (picture 5A). The fungal structures are round with birefringent membranes and thick walls containing melanin, and are best visualized with a silver stain or periodic acid-Schiff (PAS) stain (picture 5B). Each yeast cell approximates 6 to 12 micrometers in diameter. The fungus reproduces with simple gemmulation without exporulation, resulting in blastoconidia with chain-like or rosary-bead-like configurations [23].

Additional histologic findings of lobomycosis include lymphocytes in small to moderate numbers in the dermis (with a CD4:CD8 ratio of approximately 3:2), few or absent neutrophils, striking fibrosis, and asteroid bodies (star-shaped eosinophilic bodies within giant cells) [47,64].

DIAGNOSIS — The diagnosis of lobomycosis is often made years to decades after exposure, a phenomenon likely secondary to the slow progression of the disease and its often asymptomatic nature [48,54]. In general, a diagnosis of lobomycosis should be considered in patients living in endemic areas who present with single or multiple keloid-like skin lesions located in cutaneous sites of predilection for this infection (eg, pinna, extremities, and other areas of exposed skin). Rarely, lobomycosis is diagnosed outside of an endemic area. (See 'Epidemiology' above.)

The diagnostic evaluation of patients with lobomycosis consists of both a clinical and microscopic examination. Although the clinical findings can suggest a diagnosis of lobomycosis, confirmation of the diagnosis requires microscopic visualization of fungal cells consistent with L. loboi.

Clinical evaluation — The clinical evaluation of patients with lobomycosis should include a history of the course of lesion development (lobomycosis typically progresses slowly over the course of years) and a full skin examination to determine the extent of disease. In addition, palpation of regional lymph nodes and the tissue between the site of infection and regional lymph nodes should be performed. The detection of enlarged lymph nodes in the absence of another cause for lymphadenopathy in a patient with cutaneous lobomycosis supports a biopsy to assess for L. loboi within lymph nodes. (See 'Clinical features' above.)

Microscopic confirmation — A skin biopsy is the gold standard procedure for confirming a diagnosis of lobomycosis [55]. A specific antigen to confirm the presence of L. loboi in tissue has not been identified and the organism cannot be cultured in vitro.

Skin biopsy — A sample for histologic examination can be obtained through a punch biopsy or surgical excision. Visualization of structures consistent with L. loboi in the dermis confirms the diagnosis. The fungal forms are best visualized with a silver stain or periodic acid-Schiff (PAS) stain. (See "Skin biopsy techniques", section on 'Biopsy site preparation'.)

Characteristic features of lobomycosis include round yeast-like cells (approximately 6 x 13.5 x 11 micrometers) with a birefringent membrane and thick wall containing melanin (picture 5A-B). Individual fungal cells may be connected by short tubular projections forming 2 to 10 cell chains [55]. A dense, dermal histiocytic infiltrate also is present. (See 'Histopathology' above.)

Other techniques — Although a skin biopsy that demonstrates L. loboi in the dermis is the gold standard for confirming a diagnosis of lobomycosis, a biopsy is not always feasible, particularly in resource-limited settings. Limited data from case reports and a case series suggest that L. loboi may also be detected through fast and simple epidermal sampling techniques, such as a potassium hydroxide (KOH) preparation or exfoliative cytology. Transepidermal elimination of L. loboi from the dermis may account for the ability to detect L. loboi with these techniques [62]:

●Potassium hydroxide preparation – In a potassium hydroxide (KOH) preparation, the surface of a lesion is scraped with a scalpel blade followed by placement on a glass slide with KOH. Microscopic examination is performed after the KOH solution dissolves epidermal keratinocytes [65]. (See "Office-based dermatologic diagnostic procedures", section on 'Potassium hydroxide preparation'.)

The punch smear technique is an alternative approach that allows for assessment for L. loboi in the dermis. A 1 or 2 mm punch biopsy is taken from a skin lesion and placed on a glass slide. The epidermal portion of the specimen is removed with a scalpel. KOH is then placed on the specimen. After approximately 10 minutes, the specimen is crushed with a second glass slide. A coverslip is then placed on each slide, and both slides are examined with a microscope.

●Exfoliative cytology – In exfoliative cytology, scrapings from the surface of a lesion are examined under a microscope without the aid of KOH [66].

Similar to its appearance in skin biopsy specimens, L. loboi detected through these techniques appears as multiple round yeast-like bodies with thick walls that may be connected by small bridges, forming chains.

DIFFERENTIAL DIAGNOSIS — Examples of infectious disorders that can present with nodular or verrucous skin lesions similar to lobomycosis include leprosy (nodular variant), leishmaniasis (lepromatous variant), and some subcutaneous mycoses (eg, sporotrichosis, chromomycosis, and paracoccidioidomycosis). In all cases, a skin biopsy demonstrating fungal cells consistent with L. loboi easily distinguishes lobomycosis from these disorders.

The nodular appearance of lobomycosis also requires differentiation from benign and malignant tumors. Because lobomycosis may closely resemble common keloids (picture 6A-B), clinicians in endemic areas should have a high suspicion for lobomycosis, particularly when a history of skin injury and preceding scar is absent. Unlike lobomycosis, a biopsy of a keloid is characterized by thick, eosinophilic collagen bundles in the dermis. The nodules and plaques of dermatofibrosarcoma protuberans (DFSP) may also resemble lobomycosis (picture 7). DFSP tends to occur on the trunk and proximal extremities and is characterized by pathologic findings of spindle cells in a storiform pattern. (See "Keloids and hypertrophic scars" and "Dermatofibrosarcoma protuberans: Epidemiology, pathogenesis, clinical presentation, diagnosis, and staging".)

TREATMENT — Skin involvement in lobomycosis typically continues to progress without treatment; therefore, treatment is generally indicated to improve quality of life (see 'Prognosis' below). The extent of disease influences the therapeutic approach. For patients with localized, surgically amenable disease, surgical excision is the preferred treatment.

A variety of pharmacologic interventions have been attempted for the treatment of lobomycosis that cannot be surgically excised. However, results of pharmacologic treatments are often disappointing and data on the efficacy of these therapies are limited.

Surgically amenable disease — Patients with localized lobomycosis are best managed with surgery. Wide surgical excision is the preferred first-line treatment. The intent is to remove all infected tissue, leaving the surgical margins clear of disease [67]. Despite this intent, recurrences are common after surgical treatment [9,54]. Surgery must be performed with care because the infection may be transmitted to areas of healthy skin via surgical instruments [55,68].

Other surgical techniques that have been reported effective in individual patients include cryosurgery and electrocauterization [55]. Cryotherapy often requires multiple treatment sessions [67].

Some authors have used pharmacologic therapy in conjunction with surgery in an attempt to reduce the risk for recurrence after surgical procedures [11]. However, the efficacy of such measures in comparison to surgery alone is unclear.

Poor surgical candidates — Treatment of patients with nonsurgically amenable lobomycosis is difficult. There is no reliably effective treatment and treatment failure is common. Data are primarily limited to case reports. No high-quality therapeutic trials have been performed.

Examples of treatment regimens that have been reported to be effective in case reports or other studies include:

●Itraconazole and clofazimine – Treatment of a facial lesion of lobomycosis for one year with itraconazole (100 mg per day) and clofazimine (100 mg per day) was associated with clinical and histopathologic remission [52]. Relapse did not occur during a three-year follow-up period.

●Posaconazole – A patient with lobomycosis involving the ear was treated with oral posaconazole (400 mg twice daily) for 27 months [42]. Significant improvement was evident after four months of treatment. After 24 months, only postinflammatory hyperpigmentation remained. Although a biopsy specimen taken after 27 months showed persistent L. loboi cells, follow-up five years later showed no evidence of clinical recurrence. Posaconazole (400 mg twice daily) was also associated with partial improvement in a patient with disseminated lobomycosis associated with immunosuppression after a renal transplant [69].

●Itraconazole and cryosurgery – A patient who developed a multifocal relapse of lobomycosis after surgery to treat the infection improved following five sessions of liquid nitrogen cryotherapy and oral itraconazole (400 mg per day) [67]. Follow-up at six months revealed almost complete regression of all lesions.

●Multiple drug therapy for multibacillary leprosy – Observations suggesting improvement in concomitant lobomycosis in patients undergoing multiple drug therapy (MDT) for leprosy led to investigation of MDT for lobomycosis. In an unblinded study (n = 120), patients with lobomycosis were alternately assigned to one of two groups (MDT for four years or MDT plus itraconazole [100 mg twice daily] for four years) [70]. MDT consisted of a monthly regimen of 600 mg of rifampin, 300 mg of clofazimine, and 100 mg of dapsone and daily treatment with 50 mg of clofazimine and 100 mg of dapsone. Surgical excision was also performed. Patients who did not adhere to therapy over time were reclassified as controls. Overall, response rates were similar in the two treatment groups, with improvement occurring in 52 of 80 patients (65 percent) and cure occurring in 20 (25 percent). The likelihood of cure was greater than the control group for both the MDT and MDT plus itraconazole groups (1.8, 95% CI 1.2-2.8 and 1.9, 95% CI 1.2-3, respectively). Some of the limitations of this study include the lack of randomization and a high rate of treatment discontinuation in the MDT plus itraconazole group.

●Trimethoprim-sulfamethoxazole – A combination of surgical excision and a five-month course of trimethoprim-sulfamethoxazole (160/800 mg given twice daily) was associated with marked improvement of lobomycosis on the ear. No clinical signs of recurrence were detected at a follow-up visit at six months.

Treatments with ketoconazole [43,71,72], amphotericin B [73], sulfa compounds [74,75], clofazimine alone [76-78], 5-fluorocytosine, and additional combination drug regimens have been attempted, but responses have been incomplete or poor. A complete response of lobomycosis has been reported in a dolphin treated with oral miconazole [79].

An incidental finding of favorable responses of lobomycosis among 10 patients treated for concomitant leprosy in a dermatology department in Brazil may aid in the search for effective treatments for lobomycosis [54]. The patients noted softening and/or reduced pruritus in lobomycosis lesions during treatment for multibacillary leprosy (rifampicin, clofazimine, and dapsone).

PROGNOSIS — The clinical course of lobomycosis is characterized by slow, progressive involvement of the skin and subcutaneous tissue. Lymph node involvement may be present. Although involvement of internal organs does not occur, extensive or disseminated skin disease can cause local tissue destruction and physical disability. Spontaneous resolution is rare [80].

Squamous cell carcinoma is a rare complication of lobomycosis. A few case reports document the development of squamous cell carcinoma in sites of longstanding lobomycosis [81,82].

FOLLOW-UP — Long-term follow-up is mandatory since there is a high relapse rate in lobomycosis [23].

SUMMARY AND RECOMMENDATIONS

●Etiology and transmission – Lobomycosis is a chronic fungal infection of the skin and subcutaneous tissue that may affect humans and dolphins. Lacazia loboi, a dimorphic fungus found in soil, vegetation, and water, is the causative agent. Traumatic implantation of the fungus into the skin is considered the most likely mode of transmission. (See 'Etiology and transmission' above.)

●Epidemiology – Lobomycosis most frequently occurs in tropical climates of South America and Central America. Lobomycosis is occasionally diagnosed elsewhere. (See 'Epidemiology' above.)

●Clinical features:

•Course – Lobomycosis is characterized by a slow and progressive clinical course. The initial skin lesion often does not appear until one to two years after inoculation. (See 'Clinical features' above.)

•Skin findings – The initial skin lesion of lobomycosis is usually a papule that expands to form keloid-like nodules or plaques (picture 1A-C). Ulcerated, infiltrative, verrucous, and gumma-like presentations also may occur. The most common sites for lesion development are the pinna, upper limbs, and lower limbs. Localized lobomycosis is most common, but multifocal and disseminated presentations may occur. (See 'Clinical features' above.)

●Diagnosis – A diagnosis of lobomycosis is confirmed by recognition of fungal cells consistent with L. loboi in the skin (picture 5B). Skin biopsy is the gold standard test. L. loboi may also be detected through superficial epidermal sampling techniques. (See 'Diagnosis' above.)

●Treatment – The treatment of lobomycosis can be challenging:

•Surgery feasible – For patients with localized disease that is surgically amenable, we suggest surgical excision as the first-line treatment (Grade 2C). Alternative surgical therapies that may be beneficial are cryotherapy and electrocauterization. (See 'Surgically amenable disease' above.)

•Surgery not feasible – The treatment of lobomycosis that cannot be surgically managed is particularly difficult. A variety of pharmacologic treatments have been attempted with mixed results. Data on the efficacy of these treatments are limited and the optimum approach to pharmacologic treatment of lobomycosis is unclear. (See 'Poor surgical candidates' above.)