Hydroa vacciniforme-like lymphoproliferative disorder D82.

Hydroa-vacciniform-like lymphoproliferative disease (HV-LPD) is a cutaneous form of a chronic, Epstein-Barr virus-positive (EBV+) T/NK lymphoproliferative, childhood-onset, photosensitive disease (see photodermatoses below) that is associated with the risk of developing a complicating systemic lymphoma (Jaffe ESösend et al. 2017).

Note: The following terms were previously used to describe HV-LPD:

• Hydroa vacciniforme-like eruption (HVLL)
• Edematous scarring vasculitic panniculitis
• Severe hydroa vacciniforme

The nomenclature and definition has since been changed from "Hydroa vacciniforme-like eruption" to "Hydroa-vacciniforme-like lymphoproliferative disease, EBV-induced (HV-LPD)" due to the clear pathogenetic association with a symptom-causing "chronic active EBV infection" (CAEBV).

Hydroa vacciniforme-like lymphoproliferative disorder (HV-LPD) is a very rare, childhood-onset, Epstein-Barr virus-associated lymphoproliferative and photosensitive disease that occurs mainly in the indigenous population of Latin America and Asia and is associated with a high EBV viral load. In Central Europe and North America, this severe variant of hydro vacciniforme is only very rarely observed.

Hydroa-vacciniforme-like lymphoproliferative disease (HV-LPD) is very rare in Western countries. Most studies describe recurrent, solar-induced skin lesions with T-cell or NK-cell phenotypes in children and adolescents from Asian and Latin American countries.

HV-LPD is associated with chronic EBV infection (CAEBV) and persists in genetically predisposed populations. This explains the almost exclusive occurrence of the disease in the Asian and South American population (Zhang G et al. 2013).

Mainly children and young adults are affected (age: 2 - 20 years; median 8 years). The clinical course of HV-LPD is variable; a seasonal and recurrent occurrence of lesions in spring or summer is characteristic. The duration of the disease is up to 10-15 years (Guo N et al. 2019).

Mainly on sun-exposed areas such as the face, neck, extensor sides of the upper extremities (especially forearms). Manifestations on areas of skin not exposed to the sun are rarer.

Clinical manifestations are initially mainly on sun-exposed areas (face, upper extremities on the extensor side), less frequently also in areas that have not been exposed to the sun (e.g. abdomen and back - this pattern is more likely to be seen as a sign of disease progression), red, extensive edema, vesicles, blisters and plaques, extensive crusty ulcerations and smaller, flat, skin-colored or pigmented scars. The course is recurrent after UV exposure with a tendency to heal with strict sun protection

Some patients have a history of a severe hyperergic reaction to insect bites (see below Severe insect bite allergy, EBV-induced).

The skin changes are associated to varying degrees with systemic symptoms such as fever, weight loss, asthenia, arthralgias, lymphadenopathies, hepatosplenomegaly and/or elevated liver enzymes (see DD: Hydroa vacciniforme).

LDH is significantly elevated; a positive EBV DNA blood load is characteristic. Both LDH and EBV DNA levels are important indicators of lymphoma development. They also reflect the efficiency of treatment (decrease in LDH and EBV DNA levels during successful therapy).

Histologically, a deep perivasal and periadnexal infiltrate of atypical small to medium-sized lymphoid cells with enlarged, irregularly configured nuclei and conspicuous nucleoli is found penetrating the dermis and subcutaneous fatty tissue. In addition, small lymphocytes, plasma cells, histocytes and varying degrees of eosinophil infiltrates are also found.

Progressions of the disease are characterized by dense, diffuse, atypical, medium-sized or large lymphoid cells. The mitotic rate is then significantly increased. Thrombotic angioinvasions with vascular destruction are rare.

Immunohistochemical examinations and EBER: The cutaneous lymphoid cells are 100% positive for CD3 and TIA1. They partially express CD30. EBER can always be detected by in situ hybridization. EBER-bearing cells were mainly concentrated around blood vessels and adnexa in the dermis.

• Around 1/3 of patients also have ^CD8+ T cells, but no ^CD4+ or ^CD56+ cells.
• Around 1/3 of patients initially have ^CD4+ T cells but no ^CD8+ T cells or CD56+ ^cells.
• Around 1/3 of patients have ^CD56+ cells but no ^CD4+ or ^CD8+ T cells, which indicates an NK cell phenotype.

There are therefore 3 different immunohistological phenotypes:

• the CD4+ phenotype
• the CD8+ phenotype and
• the NK cell phenotype.

However, their clinical course shows no differences. The NK- phenotype is not more aggressive than the T-cell phenotype. All phenotypes have a similar incidence of complicative expression of systemic lymphoma.

Molecular analyses: Molecular analyses showed that monoclonal rearrangements in the TCR genes were detectable in the majority of patients with a T-cell phenotype. These cases are then classified as ^EBV+ T/NK-cell lymphoma based on the monoclonality of the TCR gene rearrangements (WHO classification criterion from 2008).

Hydroa vacciniforme (no evidence of systemic involvement, mainly affects white Europeans)

EBV+ T/NK cell lymphoma: Gradual transitions possible. It is not always possible to distinguish between HV-LPD and systemic EBV+ T/NK-cell lymphoma, as these diseases often have overlapping clinical and pathological features at the time of diagnosis and/or during the course of the disease.

Adequate photoprotection is important!

Most patients with a hydroa-vacciniforme-like lymphoproliferative disease are treated in the early stages with immunomodulating or immunosuppressive therapies externally and, if necessary, internally. This results in a temporary improvement in symptoms at this stage.

If the disease progresses, chemotherapeutic regimes (gemcitabine) may be used in combination with radiotherapy.

At an advanced stage, allogeneic hematopoietic stem cell transplants can also be used successfully (Guo N et al. 2019).

The results vary and range from complete and partial remissions (around 2/3 of patients) to treatment failure with progressive disease progression and development of systemic lymphoma with a poor prognosis.

The 5-year survival rate in larger collectives is 45.0 % (!).

In the early stages, recurrent inflammatory vesicles, papulovesicles, crusts and finally, after several weeks, varioliform scars appear. The course is intermittent, so that a colorful clinical picture with fresh and older lesions can develop. The skin lesions typically heal within 1-2 weeks with varioliform scarring, but recur with the same distribution pattern after a latency period of varying length and renewed UV-provocation.

The majority of patients show this indolent, chronic course.

Progression of the disease is observed in most patients (>80 %) after a period of between 0.2 and 7 years (median: 0.63 years). Progression of the disease is indicated by systemic symptoms such as intermittent fever, asthenia, lymphadenopathies, hepatosplenomegaly and bone marrow infiltration. At this stage of progression, the disease is no longer classified as hydroa-vacciniforme-like lymphoproliferative disease, but as systemic EBV+ T/NK cell lymphoma (Guo N et al. 2019). Cytopenia, elevated lactate dehydrogenase, destructive multi-organ involvement and advanced age are poor prognostic factors. On the skin side, progression is characterized by plaques and facial edema, with deeper extensive ulcers and necrosis.

To date, there is no reliable method for differentiating between hydroa-vacciniform-like lymphoproliferative disease (HV-LPD) and progression to systemic NK/T-cell lymphoma. The presence of a TCR gene rearrangement is not helpful for the diagnosis of lymphoma, as monoclonality is already detectable in the early stages in most cases. Patients with malignant progression usually present with deep ulcers, atypical, medium to large sized cells, severely elevated LDH, prolonged high EBV DNA loads (typically > 1 × 105 copies), severe systemic manifestations, diffuse obliteration of normal nodal architecture by atypical cell infiltration and bone marrow involvement. Older patients tended to develop lymphoma.

1. Chen CC et al. (2020) Hydroa Vacciniforme and Hydroa Vacciniforme-Like Lymphoproliferative Disorder: A Spectrum of Disease Phenotypes Associated with Ultraviolet Irradiation and Chronic Epstein-Barr Virus Infection. Int J Mol Sci 21:9314.
2. Guo N et al. (2019) Clinicopathological categorization of hydroa vacciniforme-like lymphoproliferative disorder: an analysis of prognostic implications and treatment based on 19 cases. Diagn Pathol 14:82.
3. Han B, Hur K, Ohn J, Kim TM, Jeon YK, Kim YC, Mun JH. Hydroa vacciniforme-like lymphoproliferative disorder in Korea. Sci Rep. 2020 Nov 9;10(1):19294.

4. Iwatsuki Ket al. (2019) Hydroa vacciniforme: a distinctive form of Epstein-Barr virus-associated T-cell lymphoproliferative disorders. Eur J Dermatol 29: 21-28.

5. Jaffe ES et al. (2017) Cutaneous EBV-related lymphoproliferative disorders. Semin Diagn Pathol 34:60-75.

6. Wang Mi (2013) Hydroa vacciniforme-like lymphoma of an adult: a case report with review of the literature. Diagn Pathol 8: 72.

7. Zhang G et al. (2013) Nk-/T-cell lymphoma resembling hydroa vacciniforme with positive CD4 marker expression: a diagnostic difficulty. Am J Dermatopathol 35:94-97.