Photosensitive Erythema Multiforme and Vandetanib in a Pediatric Patient

Vandetanib is a tyrosine kinase inhibitor that inhibits vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF) receptors and rearranged during transfection (RET). It is FDA-approved for the treatment of symptomatic or progressive metastatic medullary thyroid cancer (MCT) [1]. Reported mucocutaneous complications include photosensitivity, acneiform eruption, dry skin, hand-foot reaction [2], and Stevens-Johnson/toxic epidermal necrolysis syndrome [3]. Photosensitivity is the most characteristic adverse reaction. Inhibition of VEGF and EGF signaling by vandetanib contributes to photosensitivity by impairing keratinocyte survival, skin barrier integrity, and cutaneous repair mechanisms [4]. This photosensitivity can manifest as exaggerated sunburn, erythematous or lichenoid eruption, and less frequently as photoinduced subacute cutaneous lupus erythematosus [2] or photosensitive erythema multiforme (PEM). Photoinduced erythema multiforme (EM) secondary to vandetanib has been rarely reported. To our knowledge, only four cases have been reported in the adult population [5-7] (Table 1). Oral and topical corticosteroids and photoprotective measure- resolution *No change was made in his oncological treatment *No relapse was noted at 1-year follow-up Oral corticosteroids and photoprotective measures- improvement *Vandetanib treatment was stopped and switched to Selpercatinib *No relapse was noted at 1-year follow-up Oral and topical corticosteroids –improvement *Vandetanib treatment was stopped and switched to Cabozantinib Topical corticosteroids and extreme photoprotective measures –resolution *No change was made in her oncological treatment Photoprotective measures, topical corticosteroids– resolution *No change was made in his oncological treatment A 14-year-old boy presented to the dermatology clinic with a pruritic rash. He had a history of MCT and was being treated with vandetanib. He was diagnosed 16 months before presentation in our hospital, after experiencing dyspnea for several months. At diagnosis, he had a diffuse right thyroid mass with retrosternal extension and enlarged lymph nodes encasing and narrowing the trachea. Partial surgical resection was performed. The pathology report showed MCT involving both thyroid lobes as well as diffuse lymph node involvement. Laboratory results showed elevated calcitonin and carcinoembryonic antigen (CEA). A few months later, he was re-operated at another hospital for thyroidectomy and lymph node dissection, followed by thyroid hormone replacement therapy. Genomic evaluation showed RET (NM_020975.6): c.1894_1899delIGAGCTG, p.Glu632_Leu633del, VAF 24%; and CYP2D6 (NM_000106.6): c.506-1G>A, VAF 52%. He was referred to our hospital due to tumor regrowth and recurrent dyspnea. Imaging studies showed diffuse local involvement, esophageal and parapharyngeal invasion, and bony vertebral and lung metastases. Consequently, he started treatment with oral vandetanib 300 mg once a day, with clinical, laboratory, and radiological improvement. The rash appeared 3 weeks after starting vandetanib. At the presentation to the Dermatology department, a physical examination revealed targetoid erythematous papules merging into plaques on sun-exposed areas: face, nape, neck, arms, and hands (Figure 1A). The palms were also involved (Figure 1B), but the mucous membranes were unaltered. The patient denied recent infections, including oral herpes simplex, other medication changes, or systemic symptoms. To evaluate for a lupus-related rash, given the distribution, laboratory workup, including ANA, was performed and returned negative. Additionally, PCR testing for herpes simplex virus was conducted to rule out HSV as a trigger for EM, and results were also negative. Considering the photosensitive distribution in the form of EM, the patient underwent a photo test during vandetanib intake. The photo test revealed a diminished minimal erythemal dose (MED) to UVA (< 2.5 J/cm2) (Figure 1C). The minimal erythema dose (MED) is defined as the lowest dose of ultraviolet (UV) radiation that produces a well-defined erythema (redness) on the skin, typically assessed 16–24 h after exposure. A photoprovocation test was performed by irradiating non-sun-exposed skin with UVA, which produced a red papule after two exposures to 5 J/cm2. A biopsy demonstrated interface dermatitis with abundant dyskeratotic keratinocytes across all epidermal layers, confirming the clinical impression of EM (Figure 1D). A second biopsy from the papules that developed after photoprovocation again indicated EM, establishing the diagnosis of photo-drug–induced EM. The patient was initially treated with topical steroids for a few weeks, which resulted in some improvement, but active lesions persisted. Oral prednisone was added for 2 weeks, leading to further improvement. After phototesting, the patient was advised to adopt stricter photoprotective measures. Within 2 months, his rash resolved, and it was not necessary to discontinue vandetanib. He has remained rash-free for the past year while continuing vandetanib and adhering to strict photoprotection, with follow-up visits every 4–6 months. Written informed consent was obtained from the patient for the publication of his information and images. EM is a mucocutaneous disorder characterized by a polymorphous rash composed of erythematous papules and plaques with a targetoid appearance, predominantly affecting the acral areas. EM is typically triggered by various factors. The most common trigger is the herpes simplex virus. Other triggers include mycoplasma and drugs. There are reports of photo-distributed EM that were triggered by drugs [8]. Four cases of photo-distributed EM induced by vandetanib have been reported in the adult population (Details of the previously reported adult cases and comparison with our pediatric case are summarized in Table 1). These patients were treated with steroids and photoprotective measures with a good response [5, 6], but two of them had to switch to vandetanib because of the rash [5, 7]. Three of the reported cases developed the rash approximately 3 weeks after starting vandetanib [5, 6], whereas one case occurred after five months [7]. Phototesting was performed in two cases, with positive results [6, 7]; it was not conducted in the other two cases [5]. Histopathological evaluation was performed in all cases, showing similar findings [5-7], but a biopsy from the phototest area was only reported in our case and another one of these cases [7]. Our case is unique, as it appears to be the first reported case in the pediatric population, to our knowledge. Additionally, this side effect is distinctive as it is photoinduced. The photo-test showed reduced MED, and the biopsy from the area where the photo provocation was positive showed changes compatible with EM. Importantly, this side effect is preventable. Thus, caregivers must be aware of this side effect and inform patients about the significance of photoprotective measures while taking vandetanib. Caregivers should also recognize that children often face challenges adhering to photoprotective measures due to inconsistent sunscreen use, discomfort with clothing, and peer-related issues. Effective strategies involve multidisciplinary education, caregiver and school engagement, and regular reinforcement, often supported by dermatology consultation [9]. This proactive approach aims to diminish the likelihood of discontinuation of this potentially lifesaving treatment in the future. Moreover, photoprotection in pediatric patients is a primary preventive strategy to reduce the long-term burden of photoaging and skin cancer, and it should be implemented through a combination of behavioral, physical, and topical measures [10]. The authors declare no conflicts of interest. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.