Evolving nodule on the lip of an 11‐year‐old girl

An 11-year-old girl, with known acquired immunodeficiency syndrome, thought to be from vertical transmission of human immunodeficiency virus (HIV), presented with a pink, friable nodule on her upper lip, which had been slowly growing for 4 months (Figure 1). Her disease was stage C3 (CD4+ T cells: 40/mm3; viral load: 332000 copies/mL). She was treated empirically, first with topical mupirocin, and then with oral flucloxacillin (25 mg/kg/day for 7 days), and itraconazole (5 mg/kg/day for 14 days) without improvement. There was no history of local trauma, fever or other symptoms and the remaining physical examination was normal. A punch biopsy was performed (Figure 2). The histopathological examination showed a mixed inflammatory infiltrate, including aggregates of histiocytic cells, with multinucleated giant cells (Figure 2, H&E) containing ovoid, encapsulated, periodic acid-Schiff (PAS)/Grocott methenamine silver (GMS) positive structures in the cytoplasm, suggestive of Cryptococcus neoformans (CN; Figure 3), later confirmed by tissue culture. Blood cultures were negative. The remaining microbiologic studies were negative, including fungal and mycobacterial cultures and polymerase chain reaction (PCR) assays for other opportunistic fungi, mycobacteria, and leishmania. The serum cryptococcal antigen test, chest radiography, abdominal ultrasound and head computed tomography scan were also negative or unremarkable. Since there was no evidence of systemic dissemination, including no central nervous system involvement, a lumbar puncture was not performed. Due to a lack of improvement with itraconazole, fluconazole (12 mg/kg/day) was started, with complete resolution after 2 months. At the same time, antiretroviral therapy (dolutegravir, abacavir and lamivudine) was initiated, but despite the viral load becoming rapidly undetectable, the increase of CD4 count was slow (100/mm3 at 6 months). C. neoformans is a ubiquitous opportunistic fungus, found in soil and pigeon droppings, primarily affecting individuals with defects in T-cell immunity.1, 2 The infection is most frequently acquired via inhalation, causing primary lung infection, with subsequent dissemination to the central nervous system, bones, and skin.2 Extrapulmonary infection is an AIDS-defining illness.3 Primary cutaneous cryptococcosis (PCC) is rare and was the subject of controversy for decades until considered a distinct entity in 2003.4 PCC typically results from direct skin inoculation and is defined by the identification of CN in a skin biopsy or culture, in the absence of systemic dissemination.2, 4 Usually, PCC presents as a single ulcerated nodule in exposed areas, mostly on the hands, but the clinical picture is varied, including vesicles, pustules, acneiform lesions, granulomas or cellulitis-like plaques, which can delay the diagnosis.2 Most cases of cutaneous cryptococcosis occur after hematogenous dissemination, which is known as secondary cutaneous cryptococcosis (SCC), so it is crucial to rule out systemic involvement.4 Histopathology findings range from tuberculoid granulomas with few microorganisms, to large numbers of yeast-like microorganisms, surrounded by mucinous capsular material, without a significant inflammatory response.5 The cell wall of CN stains with PAS, GMS, and Fontana Masson, and the capsule stains with mucicarmine and Alcian Blue. Discrimination of unencapsulated tissue variants of cryptococcus from other fungi, like histoplasma or blastomyces can be achieved using combined stains, direct immunofluorescence and PCR methods.6 Children seem to be less affected by cryptococcosis infections, which has been demonstrated in several pediatric series, published in the last decades. One of the largest series, from Colombia, reported an annual incidence between 0.017 to 0.12 cases per 100,000 children.1 Differences in exposure patterns, strains and degrees of virulence, as well as differences in immune response, may partially explain the lower incidence. On the other hand, serologic studies showed that, in urban areas, exposure and subclinical infection are remarkably common in healthy children.1 These data support the theory that infection occurs early in life, remaining latent and later reactivated in the setting of an immunocompromised status.1 Indeed, cryptococcosis is more common in immunosuppressed and HIV-positive children and, in a large series from South Africa, the majority of affected HIV-positive children had CD4+ T-cell counts lower than 50 cells/uL.1 Series from China, Taiwan, Colombia have shown an unexpected increase in cases of cryptococcosis in immunocompetent children.1 In all series, cases of skin involvement were rare, with neurocryptococcosis and disseminated disease being the most common forms.1 There are no specific recommendations for the treatment of PCC, nor for the pediatric population, so regimens recommended for disseminated disease in adults are used as a reference.1, 3 Classically, cryptococcosis was treated with amphotericin B (0.5–1 mg/kg/day), but azoles are equally effective, better tolerated, and can be administered orally, emerging as a first-line alternative. Fluconazole (12 mg/kg/day) for 6–12 months is the most frequently prescribed treatment but, itraconazole (100–400 mg/day) is an effective alternative, although drug interactions and tolerance profile limit its use.2, 7 Dose and treatment duration may need to be adjusted according to the location of the lesion, disease extension, and immune status. Most cases have a favorable course, but patients with severe immunosuppression have a greater risk of systemic dissemination, CNS involvement and fatal outcomes.7 Cases of PCC in children are extremely rare, however, delayed treatment can result in serious, life-threatening complications. Therefore, dermatologists and pediatricians should be aware of this entity and consider it in lesions refractory to antibiotics. The authors have no conflict of interest to disclose.