Paracoccidioidomycosis (PCM) is an endemic systemic mycosis in Latin America, caused by species of the Paracoccidioides brasiliensis complex (P. brasiliensis sensu stricto, P. americana, P. restrepiensis, and P. venezuelensis) and Paracoccidioides lutzii.1,2 These are thermodimorphic fungi that grow as filamentous mycelia at 25–28 °C and as yeasts at 35–37 °C or during parasitism in host tissues.3 Human infection occurs through the inhalation of fungal propagules. In nature, these microorganisms act as soil saprophytes, typically found in humid environments with dense vegetation cover.4

Brazil accounts for approximately 80% of all PCM cases worldwide, with most originating from the South, Southeast, and Midwest regions. The estimated incidence in the country ranges from 1 to 4 cases per 100,000 inhabitants per year.5 However, rates are considerably higher in areas of recent colonization, such as the Amazon region, where they range from 9 to 40 cases per 100,000 inhabitants, and have increased more recently in the states of Tocantins, Pará, and Maranhão.2,6–8 The actual burden of PCM in Brazil remains uncertain, as the disease is not compulsorily reported to the national notification system. Consequently, most available data derive from epidemiological surveys, case series, and hospital records.9–13

The latency period of Paracoccidioides spp. in humans is referred to as PCM infection. When the microorganism is reactivated and begins to cause tissue damage, exhibiting characteristic clinical signs and symptoms, the condition is referred to as PCM disease.4 Paracoccidioidomycoses can present in two primary clinical forms. The most common form is the chronic form, typically occurring in adults aged 30 to 60. It is characterized by predominant pulmonary involvement, often associated with mucocutaneous or cutaneous lesions, and may also progress to compromise the central nervous system and other organs. The second form is the acute/subacute, or juvenile, type, which usually affects children, adolescents, and young adults under 30. This form follows a rapid, disseminated course, characterized by fever, localized or generalized lymphadenopathy, hepatosplenomegaly, gastrointestinal manifestations, skin and bone lesions, and limited or absent pulmonary involvement.4,14

Involvement of the eyelid, genital, and osteoarticular systems in PCM is rare. Most reports of these atypical presentations are limited to isolated case reports, and such sites are consistently underrepresented in large case series. The present study reports a case series of PCM with rare manifestations ‒ specifically eyelid, genital, and osteoarticular involvement ‒ treated at a PCM referral center in the southeastern region of Brazil.

Between 1973 and 2020, 33 patients with rare forms of PCM (eyelid, genital, and osteoarticular) were diagnosed in the state of Espírito Santo, Brazil.

Geographically, most patients originated from rural regions of Espírito Santo, particularly the Southwest Serrana, Central-West, Northwest, and Central Serrana microregions. However, most patients resided in the Metropolitan region at the time of diagnosis, likely reflecting rural-to-urban migration patterns (Table 1).

None of the patients was immunocompromised. Systemic arterial hypertension was the most frequently reported condition (n = 5, 15.2%), followed by schistosomiasis (n = 4, 12.0%) and other helminth infections (n = 4, 12.0%); tuberculosis (n = 2, 6.0%) and diabetes mellitus (n = 1, 3.0%) were less common.

Eyelid

We identified 11 cases of PCM with eyelid involvement over 47-years. All patients were male and presented with the chronic form of the disease, with a mean age of 45.9-years. Most had a history of rural occupational exposure (n = 9, 81.8%), and a high proportion were smokers (n = 8, 72.7%) and alcohol users (n = 8, 72.7%) (Table 1). Regarding self-reported race, 7 patients (63.6%) were brown, 2 (18.2%) were black, 1 (9.1%) was white, and data were unavailable for 1 patient (9.1%).

This involvement was frequently associated with additional cutaneous lesions (n = 10, 90.9%) and respiratory symptoms (n = 8, 72.7%). The description of eyelid lesions was available for 8 patients (72.7%): ulceration was the most frequent presentation (n = 5, 62.5%), followed by verrucous lesions (n = 2, 25.0%) and papules (n = 1, 12.5%). Additionally, 2 patients (18.2%) had conjunctival involvement, described as moriform hyperemia. Some lesions are shown in Fig. 1C and 1D Other reported clinical manifestations included lymphadenomegaly (n = 6, 54.5%), oral mucosa lesions (n = 6, 54.5%), weight loss (n = 5, 45.4%), and fever (n = 4, 36.4%).

Fig. 1.

(A) Ulcerated lesions on the prepuce; (B) Vegetative, whitish lesions with an erythematous halo in the balanopreputial sulcus; (C) Eyelid involvement of paracoccidioidomycosis with an extensive lesion on the lower eyelid, presenting a granulomatous, infiltrative, and hemorrhagic aspect, with conjunctival involvement; and (D) Crusted lesion on the lower eyelid. All patients were treated at the Reference Center.

Histopathological analysis demonstrated a 100% diagnostic yield, while direct microscopy of lesion samples was positive in 80.0% of cases (Table 2). Serology was performed in 8 patients, with a positivity rate of 87.5%.

Table 2.

Clinical characteristics, diagnosis and treatment of 33 patients.

Variables		Eyelid form, n = 11 (%)	Genital form, n = 10 (%)	Osteoarticular form, n = 12 (%)
Risk Factors	Alcoholism	8 (72.7)	8 (80)	4 (33.3)
	Smoking	8 (72.7)	7 (70)	5 (41.7)
Involved organs	Lymph nodes	6 (54.5)	5 (50)	8 (66.7)
	Lung	8 (72.7)	10 (100)	5 (41.7)
	CNS	0	1 (10)	0
	Skin lesions	10 (90.9)	6 (60)	8 (66.7)
	Oral mucosa lesions	6 (54.5)	8 (80)	1 (8.3)
	Larynx	3 (27.3)	3 (30)	0
Diagnostic Methods
PCM serology (DID)	Reactive	7 (87.5)	5 (62.5)	8 (88.9)
	Non-reactive	1 (12.5)	3 (37.5)	1 (11)
	NP	3	2	3
Histopathology	Positive	5 (83.3)	10 (100)	10 (83.3)
	NA	1 (16.7)	0	2 (16.7)
	NP	5	0	0
Direct mycological examinations	Positive	4 (80)	3 (75)	3 (60)
	Negative	1 (20)	1 (25)	2 (40)
	NP	6	6	5
PCM treatment	Sulfamethoxazole/ Trimethoprim	9 (81.8)	5 (50)	8 (66.7)
	Amphotericin B	2 (18.2)	5 (50)	10 (83.3)
	Itraconazole	1 (9.1)	1 (10)	4 (33.3)
	Ketoconazole	1 (9.1)	1 (10)	0

NP, No Performed; NA, No Available; CNS, Central Nervous System.

Treatment was also analyzed by affected organ (Table 2). Among patients with eyelid involvement, the most frequently used regimen was trimethoprim–sulfamethoxazole (n = 9, 81.8%), followed by amphotericin B (n = 2, 18.2%), while itraconazole and ketoconazole were each used in 9.1% of cases (n = 1).

In this retrospective study, we analyzed 33 cases of rare PCM presentations involving the eyelids, genital system, and osteoarticular system. Our findings corroborate previously described epidemiological associations for PCM,11,15 and further delineate patterns specific to these underrecognized clinical manifestations, which are often associated with delayed diagnosis.

The mechanisms underlying the localization of Paracoccidioides spp. in unusual sites remain unclear. Hematogenous dissemination from a primary pulmonary focus is the most accepted explanation, supported by the frequent detection of pulmonary lesions in genital and eyelid PCM.10,16 In osteoarticular PCM, both hematogenous spread and direct extension from adjacent foci have been proposed.17 The finding that all genital cases had concomitant pulmonary involvement reinforces this hypothesis and suggests that the genital lesions likely represent secondary dissemination rather than primary inoculation.

Most published cases of eyelid involvement occur in middle-aged male smokers with the chronic form of the disease and concomitant lung involvement. Active lesions range from localized erythematous patches with madarosis to ulcerative lesions, without a predilection for any specific site.15,18,19 In our study, ulceration was the most frequent clinical manifestation. Given its granulomatous and ulcerative presentation, eyelid PCM may mimic neoplastic or other infectious conditions, such as leishmaniasis, sporotrichosis, and tuberculosis, often leading to diagnostic delay or unnecessary surgical procedures.18 Diagnosis can be established by culture, direct microscopy, or histopathological analysis, with serological methods demonstrating good accuracy for both diagnostic support and monitoring cure.20 With antifungal treatment, lesions typically progress to fibrosis.15

Similarly to eyelid involvement, genital PCM is more frequent in middle-aged males with the chronic form of the disease. A review of 52 cases of urogenital PCM showed that over 90% occurred in males with the chronic form; local edema and pain, typically associated with predominantly ulcerative genital lesions, were the most common manifestations, with a median time from symptom onset to diagnosis of 24-weeks.21 Our data showed that male sex, chronic form, and lung involvement were consistent findings in all patients with the genital form. Those findings align with Severo et al.,10 who reported lung infiltrates on chest radiographs in all 11 cases of genital PCM. In contrast to our findings, in which no single site predominated, the testicle appears to be the most common site in genital PCM, followed by the prostate and penis.21

In contrast, osteoarticular involvement is more often reported in a different patient profile: younger individuals with the acute/subacute form of the disease and less frequent lung involvement. Weight loss, fever, and local pain were the most common signs and symptoms, and unifocal osteomyelitis was the predominant clinical manifestation.21 Radiological studies, including bone radiography, computed tomography, and magnetic resonance imaging, were performed in cases of suspected osteoarticular PCM. Bone lesions in PCM have been well described in the literature, characterized by sharply defined osteolytic lesions without marginal sclerosis and typically without a periosteal reaction.8,17,22 These radiological features are essential for distinguishing PCM from neoplastic and pyogenic osteomyelitis processes.

Although histopathology was frequently employed and remains a valuable diagnostic approach in PCM, it should not be regarded as the most reliable method in all clinical settings. Less invasive techniques, such as serology and direct microscopy, also play a crucial role and may provide accurate results when performed by trained professionals.23 In many healthcare institutions, however, the limited availability of serological assays or specialized microscopy often leads to the preferential use of biopsy, despite its invasive nature. The turnaround time and cost-effectiveness of each method vary depending on local resources: biopsy may be more accessible or financially viable in specific hospitals, while serological tests can yield faster results when available. Direct microscopy, although inexpensive, requires considerable expertise for precise interpretation and remains highly dependent on operator skill.23 In cases with inconclusive histopathological findings, these complementary methods are essential for establishing a diagnosis, particularly for mucocutaneous lesions where biopsy is seldom performed.23,24

Antifungal treatment with amphotericin B, trimethoprim-sulfamethoxazole, or itraconazole should follow the Brazilian guideline recommendations.4 In our series, more than half of the patients required hospitalization and intravenous antifungal therapy, reflecting delayed diagnosis and the severity of these rare disease presentations. Paracoccidioidomycoses often require therapy extending beyond 18-months, with periodic serological monitoring to detect early relapse.4,5,14 The higher relapse rate observed among patients with irregular therapy reinforces the need for long-term follow-up and patient education regarding treatment adherence. Adherence difficulties are common in low-resource settings, where prolonged treatment and drug availability remain significant barriers.25,26

This study has limitations inherent to retrospective medical record analyses, including incomplete or inaccurate data. Nevertheless, it provides epidemiological, clinical, and microbiological insights into rare forms of PCM. Our findings underscore the importance of considering PCM as a differential diagnosis in endemic regions, particularly in the context of diseases such as leishmaniasis, sporotrichosis, tuberculosis, and skin neoplasms. These analyses also highlight trends in the clinical presentation of PCM, which can guide diagnostic reasoning and support a more accurate recognition of conditions that remain underexplored in the current literature.

In conclusion, our findings provide additional insight into the clinical spectrum of PCM in Brazil, particularly regarding rare presentations involving the eyelids, genital system, and osteoarticular system. These results highlight the importance of considering PCM in the differential diagnosis of atypical manifestations in endemic areas. Increased awareness of these uncommon presentations may contribute to earlier recognition and more accurate diagnosis. Furthermore, this study adds to the current understanding of the epidemiological and clinical characteristics of PCM in southeastern Brazil.