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Hydroa Vacciniforme, EBV, and Lymphoma
Hydroa vacciniforme (HV) is a rare form of photosensitivity disorder in children or adolescence and is frequently associated with Epstein–Barr virus (EBV) infection, whereas HV-like lymphoproliferative disorders (HVLPD) describe a spectrum of EBV-associated T-cell or natural killer (NK)-cell lymphoproliferations with HV-like cutaneous manifestations, including EBV-positive HV, atypical HV, and HV-like lymphoma.
1.1. Hydroa Vacciniforme
Hydroa vacciniforme (HV), first described in 1862, is a rare idiopathic photosensitive cutaneous disorder. Photodermatoses are a heterogeneous group of cutaneous disorders involving abnormal reactions to sunlight, usually caused or aggravated by ultraviolet (UV) components. Initially, HV was believed to be a photodermatosis, intermediate in severity between hydroa aestivale and xeroderma pigmentosum. Currently, HV is classified within the group of immunologically mediated (idiopathic) photodermatoses. The prevalence of HV is 0.5 cases per 100,000 people in the Scottish population. In the United States, HV constitutes 0.37% of all patients with photodermatoses and is more prevalent in non-white, non-black patients. In most cases, HV occurs in childhood with a bimodal distribution of early childhood (1–7 years old) and around or after puberty (12–16 years old). Classically, HV is characterized by chronic recurrent papulovesicles or vesiculobullous eruptions on sun-exposed areas after sunlight exposure, and is usually self-limited in adolescents or young adults. Patients may be sensitive to one kind of sunlight or to a wider range of wavelengths. Some studies suggest that UVB is the causal agent, whereas other studies report that longer wavelengths in the UVA spectrum are the more likely cause. HV is seasonal and occurs typically in the summer.
1.2. Hydroa Vacciniforme-Like Lymphoproliferative Disorders
Patients with atypical or severe HV can present with eruptions similarly to those of patients with classic HV in the early phase of the disease, but recurrent cutaneous eruptions become more severe with age, progressing to involve both sun-protected and sun-exposed areas with facial swelling, ulcers, scarring, fever, hepatitis, hematologic abnormalities, and lymphadenopathy. After a protracted clinical course with many recurrences, a subset of patients with atypical or severe HV may develop a systemic and often fatal EBV-positive T cell or NK cell lymphoma, although development of lymphoma is uncommon. Regarding this phenomenon, the 2008 edition of the World Health Organization (WHO) classification of hematopoietic and lymphoid tumors described the HV-like lymphoma (HVLL) mostly carrying clonal rearrangements of the T-cell receptor (TCR) genes and monoclonal Epstein–Barr virus (EBV). However, because of the inability to predict which patients will behave in an indolent fashion versus those patients who will develop overt lymphoma, the new designation hydroa vacciniforme-like lymphoproliferative disorder (HVLPD) was established in the 2016 edition of the WHO classification. This term encompasses chronic HV-like EBV-positive lymphoproliferative disorders of childhood with an increased risk of developing systemic lymphoma. By definition, HVLPD should include EBV-positive HV subtypes, particularly atypical or severe HV cases, and HVLL with a broad spectrum of clinical severity and a long disease course. HVLPD occurs mainly in children in Asia and Latin America without a significant sex bias, and the median age at diagnosis is 8 years (range: 1–15 years).
In the early phase of the disease, patients with HVLPD present with cutaneous disorders involving sun-exposed areas characterized by chronic papulovesicular skin lesions, ulcers, and scarring with an indolent behavior, similar to classic HV. However, some patients experience a long course of recurrences with disease extending to sun-protected skin areas, and progressing to systemic manifestations, including fever, hepatitis, lymphadenopathy, hepatosplenomegaly, and hemophagocytic syndrome. Non-white patients with HVLPD are more likely to develop systemic disease than white patients. Moreover, HVLPD may persist for dozens of years and over time about 15% of patients with HVLPD will develop HVLL with a higher mortality rate. HVLL is predominantly reported in Latin America (Peru, Mexico, and Guatemala) and Asia (Korea, Japan, and Taiwan), and rarely occurs in whites. In Taiwan, Lee et al. reported that HVLL constitutes 1% of all primary cutaneous lymphomas.
2. Pathological Features and Immunochemical Profiles
Histopathological features of HV can vary according to clinical stage and the severity of different lesions. In early stages of HV, characteristic histologic features in the skin include intraepidermal spongiotic vesiculation, varying degrees of lymphocytic infiltrate in the upper dermis (Figure 2) and areas of keratinocyte necrosis. A histologic hallmark of HV, suggested by Iwatsuki et al., is a dense perivascular lymphocytic infiltration with reticulated degeneration of the epidermis. The histologic features of classic HV and atypical/severe HV are essentially indistinguishable, such as reticulated epidermal degeneration and dense perivascular infiltration of mainly T cells, although the lymphoid infiltrate is often more dense and extensive, and extends deeply into subcutaneous tissue in atypical/severe HV. Moreover, the clinical manifestations often deviate from the pathological features. Even with clinical features of aggressive disease or systemic involvement, lymphoid cells often show minimal or mild atypia (Figure1). Thus, the diagnosis of HV versus HVLPD relies greatly on a careful history, physical examination, and phototesting, whereas histopathologic examination and laboratory tests are helpful in ruling out other photodermatoses.
Notably, in situ hybridization for EBER in skin biopsy specimens shows positive cells in over 95% of patients with classic HV and atypical/severe HV and 100% patients with HVLPD. Immunohistochemically, expression of CD5, CD7, CD43, and CD25 is variable, whereas CD57 is negative. The lymphoid infiltrate is composed most frequently of cytotoxic CD8+ T cells, but in one-third of cases the infiltrate is derived from CD56+ NK cells. The T cells can be positive for either T-cell receptor αβ or γδ. The Ki-67 index is variable, and can be very low or as high as 50%.
Monoclonal rearrangement of TRG and/or TRB is regarded as a useful tool for distinguishing classic HV from severe HV . In a large cohort study of HVLPD, 88% of patients carried monoclonal T-cell receptor gene rearrangements. Xie et al. further recommended that clonal rearrangements of the T-cell receptor genes is a prognostic indicator. In their study all patients with monoclonal T-cell receptor gene rearrangements died . In our previous study, all classic HV patients showed no evidence of a monoclonal T-cell population in the initial skin specimens. Thus, T-cell monoclonality would be unusual in classic HV and might be an important clue to herald progression to atypical HV or HVLL, especially combined with an atypical or aggressive clinical presentation. Notably, a subset of HV-like eruptions is one of the clinical manifestations of chronic active EBV infection (CAEBV), and clinicopathologic survey with fulfillment of diagnostic criteria is the key to reach the diagnosis of CAEBV. Direct immunofluorescence is usually nonspecific, although there are a few reports describing granular deposition of C3 below the basement membrane and in the dermal papillae.