Rare presentation of cutaneous cryptococcosis in advanced HIV

Abstract

Cryptococcus neoformans is an encapsulated yeast which causes opportunistic infection in the context of immunosuppression, including advanced HIV infection. Cryptococcal infection is systemic and can result in a fatal meningoencephalitis. Cutaneous lesions occur in 15% of those with systemic cryptococcosis and may be the first indicator of infection. Identification of these lesions may therefore expedite diagnosis and access to treatment. Cutaneous lesions typically present as papulonodular molluscum-like lesions; however, may vary significantly in appearance. We describe a rare case of extraneuronal cryptococcal infection manifesting as large subcutaneous tumours in a patient with advanced HIV-related immune deficiency.

Background

Cryptococcosis is the most common systemic fungal infection associated with advanced HIV and can cause a fatal meningoencephalitis; therefore, early detection of disseminated disease is vital.¹ Cutaneous lesions may be the first sign of dissemination and correct identification can expedite access to treatment.² Their appearance may be atypical, emphasising the importance of histopathological diagnosis.²

Case presentation

A 47-year-old HIV-positive man attended an outpatient appointment, having disengaged with HIV care several years previously. He was generally well but reported the emergence of a painless subcutaneous mass in his left axilla (figure 1) 2 weeks previously and subsequently three similar lesions appeared on his right loin (figure 2), left flank and lower chest (figure 3).

Figure 1.

Skin lesion left axilla.

Figure 2.

Skin lesion in right axilla.

Figure 3.

Skin lesions on torso.

An erythematous subcutaneous non-tender, firm, mobile tumour (11 cm × 6 cm) was noted in his left axilla, A further flesh-coloured lesion (10 cm × 2 cm) was seen in the right loin. Similar lesions were also seen over lower chest and left flank.

Examination was otherwise normal. He had no other medical history and took no prescribed medications.

Investigations

The above investigations (table 1) excluded pulmonary disease and central nervous system dissemination of cryptococcus.

Table 1.

Essential investigation results

Investigations	Results
FBC, U&E, LFT	Normal
CD4 count	39 cells/μL
HIV viral load	24 674/mL
TPPA	Positive
RPR titre	1:256
Serum cryptococcal antigen	Positive in 1:640 titre
Induced sputum	Negative for PCP, acid fast bacilli, bacterial and fungal microscopy and culture
CT brain	Normal
CSF analyses	Opening pressure 15 cm H2O Acellular Protein 0.34 g/L Cryptococcal antigen negative Viral PCR negative India Ink negative Bacterial and fungal culture no growth
CT chest	Normal

CSF, Cerebrospinal fluid; FBC, Full blood count; LFT, liver function tests; PCP, pneumocystis carinii pneumonia; RPR, Rapid plasma reagin; TPPA, Treponema pallidum particle agglutination assay; U&E, Urea and electrolytes.

Skin biopsy of the left flank mass was performed and histopathological analysis demonstrated findings suggest cutaneous cryptococcosis (figures 4 and 5), which was confirmed when culture grew Cryptococcus neoformans var grubii. Treponema immunohistochemistry stain was negative.

Figure 4.

H&E photomicrograph showing subcutaneous lymphohistiocytic infiltrate with numerous yeasts evident within histiocytes and giant cells as well as within the interstitium.

Figure 5.

The Mucicarmine stain of the skin biopsy highlights the thick capsule of the Cryptococcus.

Differential diagnosis

Syphilitic gumma, lipoma, panniculitis, erythema nodosum and Kaposi sarcoma.

Treatment

Treatment for possible cryptococcal meningitis with liposomal amphotericin and flucytosine was initiated following the positive serum cryptococcal antigen result, as per BHIVA guideline recommendations.³ Following negative CSF analysis, treatment was switched to fluconazole 400 mg once daily and highly active antiretroviral therapy (HAART) was initiated. The patient was reviewed 2 weeks later with the positive skin biopsy result, at which point the fluconazole dose was increased to 400 mg twice daily and continued until complete resolution of skin lesions at 7 weeks. He continued to receive fluconazole 400 mg once daily as prophylaxis until CD4 raise to >200 cells/μL. He was treated for late latent syphilis with benzathine penicillin.

Outcome and follow-up

Patient currently on his regular HIV clinic follow-up.

Discussion

Cryptococcus neoformans is an encapsulated yeast which causes opportunistic infection in immunosuppression and is found in avian droppings worldwide. On histology, the organism has a thick mucoid capsule that is characteristically mucicarmine positive (figure 5) distinguishing it from histologically similar fungal organisms, including histoplasma and blastomycosis.

Prior to the advent of HAART, C. neoformans occurred in 5%–10% of HIV-positive individuals.⁴ Incidence has decreased, but remains a major burden to global health, with approximately 1 million cases occurring annually worldwide.⁵ Primary infection normally occurs in the lungs following inhalation, and then disseminates haematogenously.⁶ It is a neurotropic organism, causing meningoencephalitis, associated with a high mortality. Extracranial manifestations include hepatitis, osteomyelitis, prostatitis, pyelonephritis, skin lesions and peritonitis.

Cutaneous cryptococcosis is usually associated with disseminated infection in advanced HIV, occurring in 15% of those with systemic involvement.⁷ Rarely primary cutaneous cryptococcus infection may occur in immunocompetent individuals via injury and inoculation of the organism.² Identifying cutaneous cryptococcal lesions can be crucial in diagnosing dissemination prior to the emergence of meningoencephalitits. Lesions vary in appearance, commonly presenting as papulonodular molluscum-like lesions with an umbilicated centre and most often over face.^{3 8} Acneiform, nodular, herpetiform, ulcerated and lesions mimicking cellulitis are also recorded.⁶ Prior to the HIV epidemic, there were isolated case reports of cryptococcosis among immunosuppressed people presenting as gummatous lesions, subcutaneous abscesses or tumour-like swellings with or without sinus formation.⁹ However, lesions similar to those seen in our patient are rare, and an online database search yielded no reports of cutaneous disease presenting as a subcutaneous tumour without neurological or pulmonary involvement in an immune-deficient HIV-positive individual.

Learning points.

• Cryptococcosis is the most common systemic fungal infection in advanced HIV and can manifest as cutaneous lesions in 10%–20% cases of disseminated disease.

• These may have an atypical appearance, re-emphasising the importance of biopsy and histopathological diagnosis.

• Screening for disseminated cryptococcus with serum cryptococcal antigen and a search for potential sites of dissemination should be carried out in all individuals with advanced HIV to pre-empt the development of potentially fatal meningoencephalitis.