Eruptive lentigines in a child receiving voriconazole after bone marrow transplant

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A 9-year-old Arab girl presented with a history of asymptomatic, progressive, eruptive hyperpigmented macules on the face, followed by the extremities and trunk for 4 months. She had undergone a fully matched bone marrow transplant (BMT) for thalassemia major 6 months prior to visiting us. Soon after BMT, she was started on graft versus host disease (GVHD) prophylaxis with sirolimus and methotrexate. She developed an erythematous maculopapular rash on the trunk and extremities with mild diarrhoea on day 21 post-transplant, suggestive of acute GVHD, which was managed with the addition of systemic corticosteroids (methylprednisolone 1 mg/kg/day in a tapering dose for a month), and she fully recovered. Both sirolimus and methotrexate were stopped after a month. Starting from day 25 post-transplant, she had also been receiving monthly intravenous immunoglobulins for GVHD prophylaxis, and pentamidine (150 mg every 2 weeks), voriconazole (8 mg/kg/day), acyclovir, and penicillin V as prophylaxis against Pneumocystis jirovecii, invasive fungi, Varicella zoster, and pneumococci, respectively.

Cutaneous examination showed diffuse facial hyperpigmentation on an erythematous background with widespread 1-4 mm brown macules on the face, neck, trunk, and extremities [Figures 1a and b] without mucosal or nail involvement. A punch biopsy from a macule on the abdomen revealed epidermal acanthosis with elongated rete ridges and increased basal layer pigmentation. A sparse superficial mixed inflammatory infiltrate with melanin incontinence was seen in the upper dermis [Figure 2a]. Immunohistochemical staining with Melan-A [Figure 2b] demonstrated normal basal melanocyte distribution and presence of melanophages in the upper dermis.

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Figure 1a:

Multiple, eruptive brownish macules of 1-4 mm in size distributed on the neck, trunk, and upper extremities.

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Figure 1b:

Multiple, eruptive brownish macules of 1-4mm in size distributed on the lower extremities.

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Figure 2a:

Epidermal acanthosis with elongation of the rete ridges and increased pigmentation of the basal cell layer and sparse superficial mixed inflammatory cell infiltrate with melanin incontinence in the upper dermis (Haematoxylin & eosin, 200x).

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Figure 2b:

Immunohistochemical staining with Melan-A shows normal distribution of melanocytes along the basal cell layer and the presence of melanophages in the upper dermis (200x).

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She was diagnosed with eruptive lentigines and was adviced to stop voriconazole and was also instructed to maintain a strict photoprotection.

Voriconazole is a second-generation triazole antifungal agent that was approved for invasive aspergillosis in late 2002 and is licensed by the U.S. Food and Drug Administration (FDA) for use in children older than 2 years.¹ Systemic antifungal prophylaxis with voriconazole is strongly recommended for children and adolescents undergoing allogeneic haematopoietic stem cell transplantation (HSCT) during the pre-engraftment period also for those receiving systemic immunosuppression for the treatment of GVHD.² Long-term voriconazole use has been associated with hepatotoxicity, visual disturbances, hormone-related side effects including gynecomastia, alopecia, adrenal insufficiency, hypokalemia, hyponatremia, and phototoxic reactions.³ Voriconazole-induced phototoxicity has been reported in 20-46% of paediatric patients.^4,5 The onset of phototoxic rashes can vary from months to years, depending on the degree of sun exposure.⁵ Patients treated for 6 months or longer have been observed to have a higher risk (46%).⁵ Additional risk factors include higher cumulative dose, white race, and cystic fibrosis.^4,5

Voriconazole-induced phototoxicity typically presents on photo-exposed areas with erythema, cheilitis, skin fragility, vesiculation, pseudoporphyria, lentigines, and actinic keratoses.^4,5 Most phototoxic reactions usually resolve after discontinuation of the drug. Lentigines due to voriconazole are usually seen on photoexposed areas. A possible link between chronic photosensitivity in these patients and the development of aggressive squamous cell carcinoma after continuous use of voriconazole for 3-4 years, particularly in those with concurrent immunosuppression (due to malignancy, primary immunodeficiencies, or post-transplant status), has been reported.^5,6

Differential diagnosis includes eruptive melanocytic naevi in similar settings with immunosuppression, which should be differentiated both clinically and histologically.

Our patient had eruptive generalised lentigines affecting both photoexposed and photoprotected areas 2 months after starting voriconazole. Generalised lentigines in our patient can be attributed to phototoxicity related to voriconazole and immunosuppression related to BMT. Eruptive lentigines have also been reported in patients following phototherapy, topical tacrolimus, chemotherapy, immunosuppressants, and treatment with biologics.^6,7 Patients receiving immunosuppressants have been reported to develop lentigines in both photoexposed and photoprotected areas.^6,7 The exact mechanism responsible for voriconazole-induced phototoxic reactions is not fully understood. Voriconazole phototoxicity may result from Voriconazole N-Oxide (VNO) metabolite forming photoproducts under ultraviolet-B (UVB), generating reactive oxygen species and oxidative DNA damage through the generation of reactive oxygen species (ROS).^5,6 Alternatively, inhibition of CYP450 with voriconazole therapy is thought to possibly increase serum retinol level, a known photosensitiser.^5,6 In addition, immunosuppression and direct stimulation of melanocytes by drugs may also contribute.^6.7 Individual variation in skin response to insults and possibly a “field effect,” where lentiginous hyperpigmentation extends beyond purely UV-exposed skin, cannot be ruled out.

Facial erythema, pigmentation, and lentigines improved 8 months after discontinuation of voriconazole in our patient [Figures 3a and b], supporting voriconazole as the primary cause.

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Figure 3a:

Improvement of skin lesions on the neck, trunk, and upper extremities post stoppage of voriconazole.

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Figure 3b:

Lower extremities showing improvement of the lesions eight months after stopping voriconazole.

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To conclude, patients receiving voriconazole with immunosuppression should be counseled to use strict photoprotection, discontinue the drug if phototoxicity occurs, and those with lentigines and other signs of chronic phototoxicity must be monitored for long-term risks, including non-melanoma skin cancers.