Beyond the usual suspects - disseminated cryptococcosis presenting as molluscoid skin lesions: A case report

Abstract

BACKGROUND

Cryptococcosis is an infection caused by Cryptococcus species, an invasive fungus. The fungus is transmitted through the inhalation of spores, and causes opportunistic infection that affects the central nervous system, lungs, and skin. Soil, fruits, wood, and bird excreta commonly harbor the fungus. Two cryptococcal species are known to cause infection in humans. Cryptococcus neoformans is known to affect immunocompromised individuals, whereas C. gattii develops disease in immunocompetent individuals.

CASE SUMMARY

We report a case of disseminated cryptococcosis presenting as molluscoid skin lesions, followed by meningo-encephalitis.

CONCLUSION

Collaboration and communication among interdisciplinary teams is essential in the diagnosis of cryptococcosis. Any nonhealing skin lesion should be biopsied for histopathology. Although cryptococcosis is known to have a high case fatality ratio, in our patient, histopathological examination of skin lesions prompted the timely initiation of therapy, and hence, a favorable outcome was achieved.

Key Words: Cryptococcus; Cryptococcosis; Molluscoid lesions; Meningoencephalitis; Histopathology; Case report

Core Tip: Cryptococcal skin lesions are uncommon and may present as erythema, plaque, ulcer or nodule. Very rarely, the skin lesions may present as cellulitis or as molluscoid lesions. Disseminated disease presenting with molluscoid skin lesions is rare. In our patient, lesions presented on the face, many days before clinical onset of meningo-encephalitis. Collaboration and communication among interdisciplinary teams in a healthcare setting can lead to improved patient outcomes. The role of histopathology in the diagnostic process is essential.

INTRODUCTION

In 2022, the World Health Organization (WHO) listed Cryptococcus as a top fungal priority pathogen. Cryptococcal skin lesions are uncommon and may present as erythema, plaque, ulcer or nodule. Very rarely, the skin lesions may present as cellulitis or as molluscoid lesions.

CASE PRESENTATION

Chief complaints

A 57-year-old gentleman from an urban area presented with multiple molluscoid lesions on the face (Figure 1) for 15 days and headache for 10 days.

Figure 1 Molluscoid lesions on face.

History of present illness

He was a known diabetic and hypertensive on treatment. No history of exposure to pets or birds was known.

History of past illness

He was a known diabetic and hypertensive on treatment.

Personal and family history

The patient hails from urban area, with no history of exposure to pets or birds.

Physical examination

On examination, neck rigidity was noticed. Breath sounds were clear and the abdomen was soft and non-tender.

Laboratory examinations

A 4 mm skin punch biopsy was examined for histopathology. This revealed a crusted epidermal surface with pseudoepitheliomatous hyperplasia. Epidermal neutrophil exocytosis with small vesicles was present. On closer examination, the vesicles were packed with colonies of round yeast cells. The dermis was also densely infiltrated by round yeast forms bearing a thick capsule (Figure 2), in an edematous background associated with histiocytes, neutrophils and smaller numbers of lymphocytes and eosinophils. Periodic acid Schiff (PAS) and Grocott’s methenamine silver (GMS) stains revealed round yeast forms with narrow based, tear-drop-shaped budding. A mucicarmine stain highlighted a thick, pink capsule (Figure 3).

Figure 2 Hematoxylin and eosin 400 ×: Round to ovoid yeast forms 5-15 μm in diameter with a thick capsule.

Figure 3 Special stains under oil immersion: Mucicarmine highlights the characteristic gelatinous capsule (blue arrowheads), useful to differentiate from Blastomyces. Grocott’s methenamine silver stain highlights the characteristic narrow based “Teardrop shaped” budding (orange arrowheads), useful to differentiate from Blastomyces and Histoplasma. GMS: Grocott’s methenamine silver.

Cerebrospinal fluid (CSF) analysis was performed and showed a raised leukocyte count of 180 cells/mm³ with 80% lymphocytes. CSF microprotein was raised at 95 mg/dL (reference range 0 mg/dL to 50 mg/dL), with a normal CSF glucose level. CSF Adenosine Deaminase was within normal range. Cryptococcal antigen was positive.

His routine investigations showed low serum magnesium (1.1 mg/dL) and hypokalemia, which was treated. His enzyme-linked immunosorbent assay serology for viral markers (human immunodeficiency virus [HIV], hepatitis B surface antigen, hepatitis C virus) was negative.

Imaging examinations

Magnetic resonance imaging of the brain showed multiple diffusely scattered discrete to conglomerating foci of altered signal intensity in bilateral para-ventricular white matter, peri-trigonal region and bilateral basal ganglia.

MULTIDISCIPLINARY EXPERT CONSULTATION

Joint care was provided by expert dermatology and neurology teams.

FINAL DIAGNOSIS

A final diagnosis of disseminated cryptococcosis was established.

TREATMENT

The patient started on IV liposomal amphotericin B (liposomal) 200 mg IV daily and oral Flucytosine 1500 mg every 6 hours plus supportive diabetic/antihypertensive care.

OUTCOME AND FOLLOW-UP

After 14 days of treatment initiation, the patient’s overall condition improved. His skin lesions regressed and dried off and his headache diminished. His treatment continued with oral antifungal Fluconazole 200 mg once daily for 4 months. At present, after 7 weeks of initial presentation, he is conscious, alert, his headache is resolved, and he is able to do his routine chores and has resumed his job.

DISCUSSION

Cryptococcus was established as a fungus causing central nervous system and pulmonary manifestations in the early 1950’s, with the first ever case report emerging from the Indian subcontinent in 1952 by Balkrishna Rao and Lilauwala[1]. Cryptococcus as a cause of cutaneous lesions was first reported by Mukthabai et al[2] in 1970. The genitourinary system, cardiovascular system, eyes, bones, and gastrointestinal tract can also be affected. Cutaneous cryptococcosis has two clinical forms. Primary localized cutaneous cryptococcosis occurs after direct inoculation of the fungus into the skin following an injury. Disseminated cryptococcosis, however, occurs through inhalation or hematogenous spread from any organ[1-4].

Cutaneous cryptococcosis can present with a variety of lesions ranging from erythema, plaque, nodule, ulcer, and even cellulitis. Molluscoid lesions (waxy papules with umbilicated center and a cheesy core) have rarely been reported. Manifestations of cutaneous lesions reported in the literature are summarized in Table 1[2,5-15].

Table 1 Key presentations of cutaneous Cryptococcosis in other case reports.

Ref.	Patient age, gender	Cutaneous manifestations	Associated disease(s)	Remarks
Pepe et al[5], 2025	73, male	Multiple non-healing ulceronecrotic lesions with haemorrhagic bullae on right arm. Largest lesion size 4 cm × 3 cm. Painful	RA, hypertension, congestive heart failure, chronic obstructive pulmonary disease. HIV-negative	Patient was taking corticosteroids long-term for RA
Jain et al[6], 2025	93, male	Ulcer on chest for 6 months. Painful	Squamous cell carcinoma, scalp. HIV-negative	Tumor was treated with local wide excision. No treatment history of chemotherapy, radiotherapy, or immunosuppressant therapy
Jalkh et al[7], 2025	46, male	Solitary facial nodule for 2 weeks. Lesion initially diagnosed as keratoacanthoma. Pain not mentioned	HIV-positive. Previous history of pulmonary tuberculosis	On anti-retroviral treatment for 11 years
Ahuja et al[8], 2024	48, female	Hyperpigmented firm plaque on left thigh for 2 months. Painless	Membranous glomerulonephritis, hypertension. HIV-negative	Patient was on oral prednisolone and rituximab
Gencebay et al[9], 2024	56, female	Ulcerated erythematous lesion on lower abdomen for 6 months. Pain not mentioned	MS. Bowen’s disease on forehead	Patient was on disease-modifying therapy fingolimod for MS
Premjith et al[10], 2022	40, female	Non-healing cutaneous ulcer on right thumb of size 15 cm × 1.0 cm with necrotic floor for 3 months. Painless	HIV-positive	History of thorn prick 2 weeks prior to onset
Han et al[11], 2017	63, male	Cellulitis left forearm for 3 weeks. Painless	Chronic kidney disease, HIV-negative	Patient was on oral steroid therapy
Yang et al[12], 2016	33, male	Red nodular plaque of size 15 cm × 1 cm on left upper eyelid. Painless	HIV-negative	Cryptococcus neoformans was isolated in cultures from skin and lung
Pan et al[13], 2013	62, male	Soft swellings on forehead, left elbow, right chest wall for 3 weeks. Painless	Chronic lymphocytic leukemia on chemotherapy	Patient had pneumonia and osteolytic lesions in right frontal bone and right 9th rib, thought to be cryptococcal osteomyelitis
Kumar et al[14], 2005	Three cases: Two male and one female	Subcutaneous swellings in right abdominal flank, occipital region and left anterior upper thigh respectively. Pain not mentioned	All 3 cases were HIV negative	Cryptococcus found on fine needle aspiration smears
Bilimoria et al[15], 1980	35, male	Ulcers on face, leg, shoulder. Painless	Hodgkin disease. HIV not mentioned	No CNS, lung manifestations
Mukthabai et al[2], 1970		Reported 3 cases of cutaneous cryptococcosis	Details not available	Quoted reference in Bilimoria et al[15], 1980, manuscript in IJDVL

CNS: Central nervous system; HIV: Human immunodeficiency virus; IJDVL: Indian Journal of Dermatology, Venereology and Leprology; MS: Multiple sclerosis; RA: Rheumatoid arthritis.

We noticed that most of the documented cases (including our patient) report painless lesions. Only 2 cases were associated with pain, both were elderly males with ulcerated lesions on arm or chest, and both were HIV-negative. One of the two patients was taking long-term corticosteroids without prescription for rheumatoid arthritis; the other had squamous cell carcinoma on the scalp, treated with local wide excision[5,6].

The largest study reported to date on cutaneous cryptococcosis was by Neuville et al[16], wherein they reviewed cryptococcal skin lesions reported in the National French Registry from 1985 to 2000. They identified 108 cases of cutaneous cryptococcosis registered over a 16-year period, of which 28 cases had primary cutaneous cryptococcosis and 80 had secondary cutaneous cryptococcosis. Of the primary cutaneous cryptococcosis cases, 8 (28.5%) were farmers or gardeners and 20 (71.4%) presented with lesions on hand.

Cryptococcus species are facultative intracellular organisms. The capsule of the fungus comprises polysaccharides glucuronoxylomannan and glucuronoxylomannogalactan, which are significant factors contributing to the virulence of the pathogen. Cryptococcus neoformans and Cryptococcus gatti both spread through inhalation and cause a similar spectrum of illness. The lung is the most common site of pathogen entry. However, meningoencephalitis is the most common clinical manifestation of the infection. With a case fatality ratio of about 12%, cryptococcosis may progress to coma and death. Symptoms such as a cough and dyspnea, have been rarely reported in the literature[3,17].

On histopathology examination, Cryptococcus yeasts are variably sized (round/ovoid 5-15 μm in diameter). The yeasts exhibit a clear, thick refractile mucopolysaccharide capsule surrounding the pale blue nucleus. Characteristic narrow based “tear drop-shaped” budding pattern is useful to differentiate from Blastomyces and Histoplasma. Another important differential diagnosis is cutaneous leishmaniasis caused by Leishmania donovani species, a protozoan parasite. The Leishmania amastigotes replicate within the histiocytes. However, the parasite appears ovoid, is smaller in size (up to 6 μm) and has a characteristic rod-shaped kinetoplast. While the PAS stain highlights the fungi, mucicarmine stain demonstrates the highly characteristic gelatinous capsule a bright pink (useful to differentiate from Blastomyces), whereas the GMS stain reveals the characteristic narrow based tear-drop-shaped budding[17-19].

Cryptococcus was listed as top fungal priority pathogen by WHO in 2022. As per latest treatment guidelines, liposomal amphotericin B 3-4 mg/kg daily and flucytosine 25 mg/kg four times a day is the most optimal induction therapy option for cryptococcal meningitis, disseminated cryptococcosis, and severe isolated pulmonary cryptococcosis in high income settings. However, in low-income settings, patients with HIV-associated cryptococcal meningitis are best treated with liposomal amphotericin B 10 mg/kg as a single-dose, with 14 days of flucytosine 25 mg/kg four times a day and fluconazole 1200 mg daily as induction therapy[3,20].

CONCLUSION

A rare first clinical presentation of disseminated cryptococcosis may be molluscoid skin lesions. In our case, these lesions presented on the face, many days preceding the clinical onset of meningo-encephalitis. Collaboration and communication among interdisciplinary teams in a healthcare setting can lead to improved patient outcomes. The role of histopathology in the diagnostic process is essential.