Accelerated photocarcinogenesis and multifocal squamous cell carcinomas associated with voriconazole and human papillomavirus in HIV – case report

Introduction

Voriconazole is an antifungal used in the management of invasive fungal infections. It has phototoxic and carcinogenic effects, particularly in the immunosuppressed population. Non-melanoma skin cancer (NMSC) is increased in the same population and can be associated with human papillomavirus (HPV). We report a case of multifocal HPV-associated squamous cell carcinomas (SCC) in a 68-year-old male HIV-positive patient on intermittent long-term voriconazole for invasive aspergillosis.

Case

The patient was diagnosed with HIV in September 1985 when HIV testing first became available; however, he most likely acquired the infection a few years earlier. He was a long-term non-progressor and only started antiretroviral therapy in March 2003 when his CD4 count dropped below 200 cells/mm³. His CD4 nadir of 80 cells/mm³ was reached later that year. He developed multiple HIV-related comorbidities including peripheral neuropathy, pulmonary TB, cryptosporidiosis and recurrent invasive aspergillosis affecting the sinuses, lungs and brain. He received courses of voriconazole from 2003–2014. It was switched to itraconazole due to phototoxicity.

Dermatologically he had multiple actinic keratoses, Bowen’s disease and SCCs treated with cryotherapy, surgery and photodynamic therapy. He re-presented in May 2021 with multiple SCCs of the head, neck and limbs (Figures 1 and 2)OPEN IN VIEWER

Figure 1.

Squamous cell carcinoma and extensive field-cancerisation of the skin.

OPEN IN VIEWER

Figure 2.

Squamous cell carcinoma of the left ear with cutaneous horn.

. Histology showed scattered multinucleated tumour cells, koilocytosis and mounds of parakeratosis, suggesting HPV-related SCC. His antiretroviral was Biktarvy (bictegravir/emtricitabine/tenofovir) and his viral load was undetectable. His last CD4 count in 2016 was 260 cells/mm³. He reported moderate lifetime sun exposure.

Owing to the large number of SCCs our patient was referred to Plastic Surgery and required multiple excisions. Unfortunately, he was found to have metastases and his health deteriorated before further surgery and immunotherapy could be considered. In March 2022, he died in ICU from aspiration pneumonia and metastatic SCC.

Discussion

Voriconazole is an azole antifungal used in the treatment of invasive aspergillosis and other serious fungal infections, as well as prophylaxis of fungal infections in haematopoietic stem cell transplant patients. ¹ Due to its interaction with CYP450 enzymes, voriconazole has multiple drug interactions. It has several serious dermatological side effects, including phototoxicity and photocarcinogenesis. Stevens-Johnson syndrome and toxic epidermal necrolysis have also been reported. ¹

The mechanism of voriconazole phototoxicity is unknown but there are some proposed mechanisms of action. First, due to the similarity of side effects with retinoids, such as photosensitivity, erythema and dryness, it has been proposed that inhibition of CYP450 enzymes by voriconazole leads to increased blood retinoid levels. ² However, studies measuring blood retinoid levels with voriconazole use have yielded conflicting results.^3,4 Furthermore, retinoids are not associated with either photo-ageing or skin cancer. Indeed retinoids have been used in NMSC prophylaxis. Alternatively, voriconazole is metabolised to voriconazole N-oxide (VNO) in the liver by CYP2C19, CYP2C9 and CYP3A4. VNO has stronger UVA and UVB absorbance compared to voriconazole. ⁵ It is conceived that VNO is generated in the epidermis by keratinocyte expression of many CYP450 enzymes, where it accumulates and causes oxidative stress. ⁶

The association between voriconazole and SCC is well-established in the transplant literature. The most recent systematic review and meta-analysis analysed eight studies (>3000 patients) of either lung transplant or stem cell transplant cases and found a significant association between voriconazole and SCC development. ⁷ Longer duration and increased dose of voriconazole increased the risk of SCC but there was no association with BCC development. A recent US-based cohort study following nearly 10,000 lung transplant patients, also confirmed an association between voriconazole and increased SCC risk, independent of UV exposure, with no such association found with BCC development. ⁸ Voriconazole-related SCCs are claimed to be more aggressive than non-voriconazole related SCCs. ⁹

Only one other case report exists of SCC associated with voriconazole in a patient with HIV. A 49-year-old man diagnosed with HIV in 1994 received voriconazole intermittently over a period of 3 years before developing multifocal SCC in 2007. ¹⁰

HIV is a known risk factor for the development of NMSC. SCC risk in HIV is associated with more severe immunosuppression, with those with lower CD4 nadirs having a greater risk of SCC. ¹¹ Our patient had a CD4 nadir of 80 cells/mm3, and despite many years of ART, his CD4 count remained at only just over 200. Furthermore, HPV is known to be associated with SCC, with an increase in prevalence found in tumours from immunocompromised patients compared with immunocompetent patients. ¹² The impact of HPV vaccination is unknown. Tumours from our patient revealed evidence of HPV. It is likely that in combination with the phototoxic and carcinogenic effects of voriconazole, chronic immunosuppression and HPV infection resulted in the dramatic, multifocal SCC development.

A particular challenge of this case was the long-term nature of the increased risk of SCC development. Our patient developed multifocal SCCs several years after stopping voriconazole. This highlights the need for long-term follow up of these patients. Ultimately, it would be sensible to consider alternative antifungals for long-term use in HIV patients, such as itraconazole or posaconazole.