Eruptive Cherry Angiomas After Nitrogen Mustard Treatment for Vitiligo

Introduction

Cherry angiomas (CAs), also known as senile angiomas due to their association with aging, are the most common vascular skin tumors. They typically emerge in individuals aged 40 and older and are characterized by a gradual increase in both quantity and size over time. The etiology and pathogenesis of CAs are not yet fully elucidated. Recent studies suggested a potential involvement of HHV-8 in the development of CAs, particularly in individuals with systemic or local immunosuppression.¹ Decreased expression of mir-424 and elevated levels of MEK1 or cyclin E1 in CAs may contribute to abnormal cell proliferation within the tumor.² Additionally, GNAQ- and GNA11-mediated signaling pathways are implicated in the pathogenesis of CAs.³ Eruptive cherry angioma (ECA) refers to the sudden and widespread emergence of cherry angiomas. This condition is relatively uncommon, with only limited reported cases. The presentation of ECA has been found to be associated with advanced age, skin malignancies such as cutaneous melanoma, and chronic iatrogenic immunosuppression. The disruption in skin immune competence, arising from both iatrogenic influences and age-related changes, could potentially serve as a significant predisposing factor in the development of CAs.⁴

In this report, we present a case involving a vitiligo patient, who developed ECA subsequent to the administration of nitrogen mustard at a young age. This case highlights the potential adverse effects associated with NM treatment in individuals with susceptibility, as it may lead to the onset of ECA.

Case Presentation

At the age of 13, a 43-year-old male was diagnosed with vitiligo and received treatment with a nitrogen mustard solution at a local hospital. After using this solution, the patient experienced mild itching and redness in the vitiliginous areas, subsequently leading to the emergence of partial repigmented spots. However, one year later, the patient also observed the development of several red papules near the treated areas, and these papules gradually increased in number over time. As a result of this unforeseen progression, the patient discontinued the two-year vitiligo treatment. At that time, hundreds of papules had already appeared. After discontinuation of nitrogen mustard treatment, a noticeable deceleration in the growth rate of papules was observed. Subsequently, the patient did not pursue specialized treatment for vitiligo or ECA. Notably, the patient has a family history of lupus erythematosus in his father, with no other noteworthy medical history, such as malignancy. Imaging studies of internal organs and detection of HHV-8 revealed no evident abnormalities.

Physical examination revealed over 400 dome-shaped, smooth-surfaced, and ruby-colored papules on his chest, abdomen, back, and proximal extremities. The diameters of these papules ranged from 1 to 5 mm (Figure 1). Dermatoscopy revealed the homogeneous red background containing clustered red lacunae (Figure 2). A biopsy of a chest lesion was performed, revealing dilated vascular spaces in the papillary dermis and superficial dermis. These vessels exhibited erythrocyte congestion, in accordance with the diagnosis of cherry angiomas (Figure 3).

Figure 1 (A and B) Physical examination revealed approximately 400 dome-shaped, smooth-surfaced, and ruby-colored papules on his chest, abdomen, back, and proximal extremities. The diameters of these papules ranged from 1 to 5 mm.

Figure 2 (A and B) The homogeneous red background containing clustered red lacunae (black arrows) was observed.

Figure 3 (A) A biopsy revealed dilated vascular spaces (black arrows) in the papillary dermis and superficial dermis (H&E, 100x). (B) These vessels exhibited erythrocyte congestion (H&E, 400x).

Discussion

In this case, the patient presented with a rare and remarkable condition characterized by the rapid development of hundreds of cherry angioma (CA) lesions at a young age, occurring over just several months. Given the patient’s age, typical age-related factors are unlikely to be contributing to this condition, prompting consideration of immune-related factors as the potential underlying cause. After two years of nitrogen mustard (NM) treatment, the patient rapidly developed numerous CA lesions. Notably, upon discontinuing NM usage, the growth of these lesions appeared to slow down. This observation strongly prompted the suspicion of a potential association between the use of NM and the development of eruptive cherry angioma (ECA). Furthermore, it is plausible that the growth pattern of these lesions post-discontinuation may be influenced by age-related factors.

Ma et al reported a case of ECAs in a vitiligo patient following nitrogen mustard (NM) use, with lesion progression halting upon drug discontinuation.⁵ Similarly, Zhu et al described another case of ECAs and concurrent skin malignancy in a long-term NM user.⁶ Upon comparison, we have identified common features in these patients: a higher number of lesions burden at a younger age, often around or within vitiligo lesions and treatment sites. These reports substantiate the link between ECAs and NM utilization in vitiligo treatment.

NM is a topical chemotherapeutic agent frequently employed in vitiligo treatment. However, its use may lead to contact dermatitis, and prolonged exposure increases the risk of cutaneous malignancies, including basal cell carcinoma (BCC), squamous cell carcinoma (SCC), keratoacanthoma, actinic keratosis, and lentigo maligna.⁶ There are now safer and more effective alternatives for treating vitiligo, such as topical treatments (corticosteroids and calcineurin inhibitors) and phototherapy. Consequently, the utilization of NM in vitiligo treatment has gradually waned. In a study involving human bronchial epithelial cells and pulmonary endothelial cells, exposure to NM vapor led to an upregulation of vascular endothelial growth factor A (VEGF-A) and placental growth factor (PlGF) expression compared to a phosphate-buffered solution (PBS) control.⁷ VEGF-A is known for its pro-angiogenic properties, promoting cell migration and increasing vascular permeability, while PlGF is also capable of inducing angiogenesis. Hence, it is reasonable to propose that the emergence of ECAs in this context could be associated with the heightened expression of VEGF-A and PlGF induced by the use of NM. Furthermore, the possible contribution of external stimuli triggered by NM and the concurrent disruption of the immune system may act as potential initiators.

Conclusion

The use of topical NM has significantly declined due to its potential for cutaneous complications, notably the relatively rare occurrence of ECAs. Physicians must exercise caution when considering NM therapy for vitiligo. Moreover, this case study may offer valuable insights into the etiology and pathogenesis of ECAs.