Hydroa-vacciniforme like lymphoma, EBV-induced (HVLL) C84.-

Hydroa-vacciniform-like EBV-induced lymphoma (HVLL) and systemic EBV-positive T-cell lymphoproliferative disease (LPD) in childhood were first included in the World Health Organization (WHO) classification of tumors of hematopoietic and lymphoid tissues in the subgroup of EBV-positive T-cell LPD in childhood in 2008 (Quintanilla-Martinez L et al. 2008).

In children from indigenous populations in Mexico, Peru and Asia (Quintanilla-Martinez L et al. 2008), a special group of UV-induced, vesicopapular rashes mimicking hydroa vacciniforme (HV-like) was identified. These hydroa vacciniforme-like lymphoproliferations present with pronounced facial edema, vesicles, crusts and large ulcers, with severe scarring and disfigurement in sun-exposed, but also in non-sun-exposed skin areas. Patients generally also exhibit systemic symptoms such as fever, weight loss and asthenia. Hepatosplenomegaly and lymphadenopathy are frequently observed in the acute phase. An unusual hypersensitivity to mosquito bites (HMB) has also been noted in this clientele (Doeden K et al. 2008) (see below Severe insect bite allergy, EBV-induced).

As panniculitis and/or vasculitis were the predominant histologic features, this disease was initially termed "scarring vasculitic panniculitis (ESVP)", later also referred to as "severe hydroa vacciforme". It was later recognized that they were associated with EBV infection and often showed monoclonal rearrangements of the T-cell receptor (TCR) genes. The term "HV-like lymphoma" was therefore proposed for this clinical symptomatology (Iwatsuki KX et al.1999).

Hydroa-vacciniform-like EBV-induced lymphoma (HVLL) is defined as an EBV-positive cutaneous T-cell lymphoma with a hydroa-vacciniform-like clinical aspect occurring in children and less frequently in young adults. A hyperergic local and systemic reaction to insect bites is often associated.

Clinically, patients present with facial edema and recurrent vesiculopapular rashes, followed by severe ulceration and massive crusting. Although the skin lesions are not exclusively limited to sun-exposed areas and do not only occur after sun exposure, as is the case with the skin lesions of hydroa vacciniforme , there is a seasonal increase in occurrence in summer. Patients also exhibit systemic symptoms such as fever, weight loss and asthenia as well as hepatosplenomegaly and generalized lymphadenopathy.

Lymphoid cell predominantly C D3+ (few scattered CD20+ cells), perivascular but also periadnexial dermal but also subcutaneous infiltrate often with angiodestructive features. The intensity of the infiltrate and the atypia of the lymphocytes vary. Cytological atypia characterized by large cells with irregular nuclei, conspicuous nucleoli and abundant clear cytoplasm is not uncommon, occasionally also spongiotic vesicles without epidermotropism.

Proliferation of cytotoxic TCR-αβ T cells with expression of ^CD8+, β ^F1+ and ^TIA-1+ and negativity for CD4 and CD56 is detectable in around 50 % of cases. Around 10% of cases may be double negative for CD4/CD8 and β F1 but positive for TCR-γ. The lymphoid infiltrate tends to involve the subcutaneous tissue, giving the aspect of panniculitic T-cell lymphoma (SPTCL). Eosinophilia is not uncommon. Half of the infiltrates show a variable number of+ CD30 cells. LMP1 is occasionally positive

ISH and molecular analysis: EBER1 probe showed numerous ^EBER+ cells in all cases. In most cases, however, the number of EBER+ ^cells represented only a subpopulation of the CD3+ infiltrating cells. The number of EBER+ ^cells is similar in cases with T and NK cell phenotypes. EBER+ ^cells are predominantly ^CD56+, less frequently ^CD8+.

The severity of the skin lesions and the clinical appearance vary between patients and show a broad spectrum. In contrast to classic hydroa vacciniforme, the lesions are larger and deeper and in some cases lead to significant tissue loss and disfigurement. They are not associated with photosensitivity. Systemic symptoms such as fever, lymphadenopathy and/or hepatosplenomegaly are common (especially in patients with severe skin lesions and a T-cell phenotype).

A central aspect of the disease is the long clinical course, which emphasizes the chronic nature of this EBV-induced lymphoproliferative disease. Monoclonality and clonal persistence are not reliable predictors of an aggressive disease or a fatal clinical course. Monoclonality of the TCR-gamma genes can also be detected in "classic" hydroa vacciniforme (Kimura Hito et al. 2012). This finding is also confirmed by other investigators, regardless of whether systemic symptoms are present or not. The number of infiltrating ^EBER+ cells (viral load) also provides no prognostic indication.

In the study by Iwatsuki et al., 5 out of 11 patients diagnosed with severe HV developed systemic NK-/T-cell lymphoma 2 to 14 years after the onset of the disease. Of note, all cases were associated with NK-cell lymphocytosis and/or hemophagocytosis. Two of these cases were classified as "subcutaneous lymphomas" without further specification.

Since the inclusion of HVLL in the WHO lymphoma classification, several controversial questions have been raised that still need to be clarified. It is not known whether HVLL is a true lymphoma from its first clinical manifestation or whether it is a preneoplastic disease with the risk of developing systemic lymphoma. It is also uncertain whether HVLL is a de novo disease or whether it develops in patients with long-standing hydroa vacciniforme.

Classic Hysdro vacciniforme is considered a benign photodermatosis with spontaneous improvement or remission during adolescence in Western countries. These cases are rarely biopsied.

However, Asian studies have shown that the "classic hydroa vacciniforme" occurring in indigenous populations there is also an EBV-associated disease (Iwatsuki KX et al.1999; Cohen JI et al. 2009). Finally, it has not yet been definitively established whether Asian "classical" hydroa vacciniforme corresponds to the same disease that has been described in Western populations and in which no progression to HVLL has been observed (Ruiz-Maldonado R et al.1995). It is generally recommended to use the criterion of monoclonality of the TCR genes for differentiation (Cho KHLee et al. 2004).

1. Barrionuevo C et al. (2002) Hydroa-like cutaneous T-cell lymphoma: a clinicopathologic and molecular genetic study of 16 pediatric cases from Peru, Appl Immunohistochem Mol Morphol 10: 7-14.
2. Cho KHLee et al. (2004) Epstein-Barr virus-associated lymphoproliferative lesions presenting as a hydroa vacciniforme-like eruption: an analysis of six cases, Br J Dermatol 151: 372-380
3. Cohen JI et al. (2009) Epstein-Barr virus-associated lymphoproliferative disease in non-immunocompromised hosts: a status report and summary of an international meeting, September 8-9, 2008. Ann Oncol 20 9: 1472-1482
4. Doeden K et al. (2008) Hydroa-like lymphoma with CD56 expression. J Cutan Pathol 35 5: 488-494
5. Gupta G et al (2000) Hydroa vacciniforme: a clinical and follow-up study of 17 cases, J Am Acad Dermatol 42: 208-213)
6. Iwatsuki KX et al.(1999) The association of latent Epstein-Barr virus infection with hydroa vacciniforme, Br J Dermatol 140: 715-721
7. Kimura Hito et al. (2012) EBV-associated T/NK-cell lymphoproliferative diseases in nonimmunocompromised hosts: prospective analysis of 108 cases. Blood 119: 673-686.
8. Quintanilla-Martinez L et al. (2008) EBV-positive T-cell lymphoproliferative disorders of childhood. WHO Classification of Tumors of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: International Agency for Research on Cancer (IARC): 278-260
9. Ruiz-Maldonado R et al.( 1995) Edematous, scarring vasculitic panniculitis: a new multisystemic disease with malignant potential. J Am Acad Dermatol 32: 37-44)