HV is an extremely rare disease, with an estimated prevalence of approximately 0.34 cases per 100,000 in one study.⁸ HVLL has a relatively limited geographical distribution and has been mainly described in Central and South America (Peru, Guatemala, Bolivia), Mexico, and Asia (China, Japan), with recent cases reported in India, where the incidence of other EBV-associated malignancies such as NK/T-cell lymphoma are more frequent than in other latitudes, suggesting a genetic predisposition to develop these diseases in the indigenous population combined with an endemic EBV infection.^{9,10,11,12,13,14,15,16,17,18,19,20} In the Peruvian studies, approximately 50% of patients come from the southern region of Peru, correlating to the higher prevalence of EBV infection in that area.¹⁷

It is unclear whether HVLL arises de novo or belongs to a part of the spectrum of classic HV, which is characterized by severe photodermatosis during childhood that typically remits by adolescence.^16,18,21 The fact that both entities are associated with EBV and that T-cell clonality is the main criterion for distinguishing HVLL from HV favors the latter hypothesis.^9,22,23,24 However, while classic HV has been described in Western populations, it usually presents in a self-limited form and progression to HVLL has yet to be reported.¹⁸

It has been postulated that chronic EBV infection in HV patients with particular genetic predispositions followed by subsequent environmental triggers can lead to malignant transformation of lymphocytes characterized by persistent clonal populations with a cytotoxic T-cell or NK-cell phenotype. In HVLL, well-described triggers include inflammatory stimuli secondary to mosquito bites or sunlight exposure. Initially, affected individuals may develop a self-limiting disease with local recurrence upon additional insults. Eventually, the disease may spread to additional body sites and assume a more aggressive behavior when other genetic alterations or environmental events occur.^16,21

HV and HVLL occur in both males and females with no gender predilection. Males with HV may have a later onset and longer duration than females. Although HV and HVLL are more common in children, some patients have persistent disease well into adulthood, with the initial diagnosis made as late as the fourth decade of life.^8,15 Patients with typical HV usually have sporadic itchy erythematous eruptions in a sun-exposed distribution that occur shortly (minutes to hours) after sun exposure, most likely due to ultraviolet A (UVA). The eruptions progress to papules, vesicles, crusts, and eventually to vacciniform (pox-like) scars after several weeks. Severe forms of HV may have conjunctival and corneal ulceration and scarring.^8,25

Marked facial edema is the typical clinical presentation in HVLL, often with persistent eyelid compromise, which may be unilateral or bilateral. The periorbital swelling can be prominent and may be the first clinical manifestation. Additional cutaneous lesions are characterized by papules and vesicles, with crusts, large ulcerations, and severe scarring.¹⁵ The lesions are chronic (lasting months to years) and prone to recurrence, often characterized by temporal heterogeneity, from papules with crusts to well-formed scars in the same area (Fig. 20-1). Both sun-exposed and -nonexposed body sites can be involved, typically with lesions on the face as well as on the upper and lower extremities. Although it is not entirely clear whether the lesions in HVLL are exacerbated by sun exposure, symptoms appear to be highly associated with hypersensitivity to mosquito bites (HMB), which is an EBV⁺ lymphoproliferative disorder with NK-cell lymphocytosis.^{4,12,16,18,26}

Extracutaneous involvement is common in severe HV and HVLL. Hepatosplenomegaly and lymphadenopathy are the most frequently observed signs during the late phase of the disease, with associated general symptoms such as fever, weight loss, and asthenia.^{4,9,12,16,17,18} Laboratory findings show high lactate dehydrogenase (LDH) levels, and elevation of the liver enzymes can be seen in one-third of the patients.⁹ Progression to systemic HVLL with bone marrow infiltration is rare, but can occur 10 to 15 years after initial diagnosis.²⁷ Involvement of other extracutaneous sites, such as the lung, kidney, larynx, parotid, and spinal cord, has also been reported.^9,17