Deciphering hydroa vacciniforme

In this issue of Blood, Cohen et al describe a series of hydroa vacciniforme (HV)–like lymphoproliferative disorder (HV-LPD) cases in whites; they confirm that HV-LPD is an Epstein-Barr virus (EBV)–related lymphoproliferation with earlier disease onset and lower EBV DNA levels in blood with a lower risk of developing a systemic disease when compared with nonwhites.¹ 

HV was originally described in western countries as a benign photodermatosis characterized by light-induced vesicles that evolve to crusts and leave varicelliform scars after healing.²  Systemic symptoms are not observed and the disease often resolves spontaneously in adolescence or young adulthood. A similar, but clinically more severe, disorder has been described mainly in children from Latin America and Asia.^3-5  These patients often present with marked facial edema, multiple vesicles, large necrotizing ulcers, and severe scarring in sun-exposed and nonexposed skin areas accompanied by systemic symptoms including fever, lymphadenopathy, and hepatosplenomegaly. Later studies demonstrated that these lesions, which were termed “severe” HV to distinguish them from the more benign “classic” form described in western countries, were associated with EBV infection of T and/or natural killer (NK) cells and often showed monoclonal rearrangements of the T-cell receptor genes; therefore, the term “HV-like lymphoma” was suggested.^6,7  Based on these distinctive features, HV-like lymphoma was incorporated for the first time in the 2008 World Health Organization (WHO) classification of lymphomas as a subgroup of EBV⁺ T-cell lymphoproliferative disorders of childhood. Nevertheless, due to the broad clinical spectrum of the disease and the lack of reliable morphological and molecular criteria to predict its clinical behavior, the term HV-like lymphoproliferative disorder was proposed to avoid the designation as lymphoma, and was incorporated into the revised fourth edition of the WHO lymphoma classification.⁸ 

Because “classic” HV in western countries is very rare and considered a benign, self-limited photodermatosis, the skin lesions are rarely biopsied; and therefore, T-cell clonality or EBV status has not been thoroughly investigated. Nevertheless, it has been assumed that “classic” HV in western countries might belong to the same disease spectrum as cases from Latin America and Asia; however, data are sparse to corroborate this assumption. In the current study, Cohen et al confirm that HV in white patients from the United States and England is, in fact, an EBV-associated lymphoproliferative disorder affecting T and/or NK cells, but occurring in younger patients with a more benign clinical presentation and evolution when compared with nonwhites. Most white patients in this series had an indolent clinical course with or without treatment and irrespective of the demonstration of T-cell clonality, although whites were less likely to develop T-cell clones. This finding highlights the fact that the demonstration of a T-cell clone is not predictive of an aggressive course in patients suffering from HV-LPD, and should not be used as evidence for a malignant lymphoid proliferation.⁴  In contrast, nonwhites present often with more severe cutaneous lesions, systemic symptoms, leukopenia, and high levels of EBV DNA in blood and may progress to a full-blown T- or NK-cell lymphoma/leukemia or develop hemophagocytic syndrome. Although patients with HV-LPD and systemic symptoms might have a temporary response to immunomodulators like thalidomide, corticosteroids, or hydroxychloroquine, only hematopoietic stem cell transplantation has been shown to be curative.⁹ 

The differences in clinical severity and the significantly higher incidence of HV-LPD in patients of distinct ethnic origin are in line with other observations concerning EBV-associated T- and NK-cell lymphoproliferations, such as extranodal NK/T-cell lymphoma, nasal type, the prototypic EBV-associated disorder in Asians and Hispanics. This and the more indolent disease in whites indicate that genetic background and/or environmental differences might be responsible for the spectrum of clinical presentations observed in this disorder. The model suggests that patients with a particular genetic background after primary EBV infection can develop a chronic state characterized by the persistent presence of EBV-infected cytotoxic T cells and/or NK cells that, in response to inflammatory stimuli, such as sun exposure or mosquito bites, are recruited locally and lead to subsequent tissue damage. Additional genetic, immunological, or environmental events might be responsible for the more aggressive clinical behavior in a fraction of these patients (see figure).

Another interesting aspect of the study was the upregulation of interferon-γ (IFN-γ) and multiple genes that encode chemokines including CXCL11 (I-TAC), CXCL10 (IP10), CXCL9 (MIG), and CCL4 (MIP1β), which attract activated monocytes, T cells, and NK cells, demonstrated by RNA sequencing in the skin lesion of 1 white patient. However, this was shown to be a local phenomenon, as the mean serum levels of cytokines tested in HV-LPD patients were similar to healthy controls, in contrast to patients with chronic active EBV infection, systemic form. Nevertheless, the observed local chemokine upregulation in the lesional skin of HV-LPD suggests that these chemokines, and potentially polymorphisms in genes encoding for chemokines and their receptors, might contribute to the severity of this EBV-associated disease, warranting further investigation.¹⁰  Future studies should address this question by comparing the chemokine profile from skin lesions of “classic” HV patients vs the more severe forms and whites vs nonwhites.

In conclusion, this study demonstrates that HV-LPD in whites is an EBV-associated disorder with rather indolent clinical behavior and good response to reduction of sun exposure only. The question of whether “classic” HV without EBV association exists at all remains. It is probably time to rename this disease as HV EBV-associated LPD, encompassing the broad clinical spectrum that can be encountered in this enigmatic disease.