Encyclopedia of Pathology

Living Edition
| Editors: J.H.J.M. van Krieken

Hydroa-Vacciniforme like Lymphoproliferative Disorder

  • Atsuko NakazawaEmail author
Living reference work entry
DOI: https://doi.org/10.1007/978-3-319-28845-1_3881-1

Synonyms

Definition

Hydroa vacciniforme (HV)-like lymphoproliferative disorder (HV-like LPD) is a chronic EBV-positive cutaneous T-cell lymphoproliferative disorder of childhood, associated with the risk of developing systemic lymphoma. HV-like LPD is a polyclonal or (most often) monoclonal disorder of T-cells and/or NK cells, regardless of the presence or absence of systemic symptoms and the severity of the skin lesions. Classic HV, severe HV, and HV-like cutaneous T-cell lymphoma constitute a continuous spectrum of EBV-associated HV-like LPD (Quintanilla-Martinezz et al. 2013, 2017).

Clinical Features

  • Incidence

    HV-like LPD is rare and occurs mainly in children and adolescents from Latin America and East Asia. It is rare in adults. There is a seasonal increased occurrence during the summer (Quintanilla-Martinezz et al. 2013).

  • Age

    The median age of the time of diagnosis is 8 years (range: 1–15 years) (Quintanilla-Martinezz et al. 2013.

  • Sex

    The male to female ratio is slightly elevated (2.3,1) (Quintanilla-Martinezz et al. 2013).

  • Site

    Although lesions most commonly involved face, dorsal surface of the hands, and earlobes, skin lesions are not exclusively limited to sun-exposed areas. Half of the patients presented with disseminated dermatosis and systemic symptoms, such as fever, wasting, lymphadenopathy, and hepatosplenomegaly. Twenty percent of the patients also have hypersensitivity to mosquito bite, which usually associates with a proliferation of EBV-infected NK cells (Quintanilla-Martinezz et al. 2013).

  • Treatment

    Currently, no standard treatment has been established. Chemotherapy and/or radiotherapy have been shown to be of little or no benefit. Immunomodulating therapies, such as predonisolone, cyclosporine A, interferon alfa, chloroquine, and thalidomide, have been shown to result in temporary remission or improvement of symptoms (Barrionuevo et al. 2002; Kimura et al. 2012; Beltran et al. 2014). In indolent cases, a conservative treatment is recommended, whereas hematopoietic stem cell transplantation has been introduced as a curative therapy in more advanced cases (Kimura et al. 2012).

  • Outcome

    The clinical course is variable, and some patients are alive with recurrent skin lesions for 9–13 years, while less than 50% of patients died of organ failure or systemic lymphoma including a nasal-type NK/T-cell lymphoma and a peripheral T-cell lymphoma, NOS (Quintanilla-Martinezz et al. 2013). Some patients present with a very indolent course, with localized skin lesions in sun-exposed areas and no systemic symptoms (classic HV)(Iwatsuki et al. 2006). EBV-infected lymphocyte subsets, anti-EBV antibody titres, EBV DNA load, T-cell clonality, the amount of EBV-positive cells, and/or the density of the infiltrate do not predict the outcome. Late onset (onset age > 9 years) and EBV reactivation are both related to more severe phenotypes of the disease (Quintanilla-Martinezz et al. 2013; Miyake et al. 2015).

Macroscopy

Skin lesions include edema, papules, blisters, crusts, and ulcers, and heal as vacciniforme-like scars (Barrionuevo et al. 2002). Multiple vesiculopapules with umbilication and crust are characteristics in addition to prominent swelling of the face, lips, and eyelids (Fig. 1).
Fig. 1

Hydroa-vacciniforme-like lymphoproliferative disorder. Ulcerated subcutaneous nodule with a hemorrhagic crust in the arm. The patient also shows papulovesicular eruptions with hemorrhagic crust on the face, earlobes and lower legs (courtesy of Prof. Miho Maeda)

Microscopy

The lymphoid infiltrate is predominantly in the dermis and sometimes extended deep into the subcutaneous tissue (Figs. 2 and 3). The infiltrate is mainly located around adnexa and blood vessels, often with angiocentric/angiodestructive features (Fig. 4) (Magana et al. 1998). The intensity and atypia of the lymphocytes varies from case to case. The neoplastic cells are generally small to medium-sized, without significant atypia (Fig. 5). The characteristic histological feature of HV is an intraepidermal spongiotic vesicle without epidermotropism, whereas the overlying epidermis is frequently ulcerated in severe case (Quintanilla-Martinezz et al. 2013).
Fig. 2

Hydroa-vacciniforme-like lymphoproliferative disorder. Skin biopsy from the left lower leg lesion shows a dense lymphoid infiltrate from dermis to hypodermis

Fig. 3

Hydroa-vacciniforme-like lymphoproliferative disorder. Subcutaneous lymphoid infiltration is nodular/angiocentric or panniculitis-like pattern

Fig. 4

Hydroa-vacciniforme-like lymphoproliferative disorder. Dense lymphoid infiltrate surrounding adnexa and blood vessels is observed in the dermis of the ulcer edge

Fig. 5

Hydroa-vacciniforme-like lymphoproliferative disorder. The infiltrate is composed of small to medium-sized lymphocytes without marked atypia

Immunophenotype

Most cases have a CD8-positive T-cell phenotype; however, one third of the cases have a NK-cell phenotype with double negative for CD4/CD8 and homogeneously CD56-positive. Rare cases present a γδ phenotype. The lymphoid cells, regardless of cell-type derivation, are positive for cytotoxic markers, such as granzyme B and TIA-1 (Fig. 6). LMP1 is negative by immunohistochemistry in the majority of cases but not all cases reported (Iwatsuki et al. 2006; Quintanilla-Martinezz et al. 2013).
Fig. 6

Hydroa-vacciniforme-like lymphoproliferative disorder. The neoplastic cells are positive for CD3 (a), CD8 (b), and granzyme B (c). Most of lymphoid cells are positive for EBV-encoded small RNA (EBER) by in situ hybridization (d)

Molecular Features

In situ hybridization for EBV-encoded small RNA (EBER) is positive; however, the amount of EBER-positive cells represents only a subpopulation of the CD3-positive infiltrating cells. EBER-positive cells concentrated mainly around the blood vessels and adnexa in the dermis, in the subcutaneous tissue, and in the basal epithelial layer in cases with intraepidermal vesicles. Most cases with T-cell phenotype have clonal rearrangements of the TCR genes, while NK-cell phenotype cases show a polyclonal rearrangement of the TCR genes. EBV is monoclonal by terminal repeat analysis (Iwatsuki et al. 2006; Kimura et al. 2012; Quintanilla-Martinezz et al. 2013).

Differential Diagnosis

Morphologically, HV-like LPD can mimic subcutaneous panniculitis-like T-cell lymphoma (SPTCL), primary cutaneous γδ T-cell lymphoma, or cutaneous involvement by an extranodal NK/T-cell lymphoma of the nasal type. Without clinical information, the differential diagnoses with the latter might be impossible because the morphology and phenotype of the neoplastic cells are indistinguishable.

References and Further Reading

  1. Barrionuevo, C., Anderson, V. M., Zevallos-Giampietri, E., et al. (2002). Hydroa-like cutaneous T-cell lymphoma: A clinicopathologic and molecular genetic study of 16 pediatric cases from Peru. Applied Immunohistochemistry & Molecular Morphology, 10, 7–14.CrossRefGoogle Scholar
  2. Beltran, B. E., Maza, I. N., CB, M.–. A., et al. (2014). Thalidomide for the treatment of hydroa vacciniforme-like lymphoma: Report of four pediatric cases from Peru. American Journal of Hematology, 89, 1160–1161.CrossRefGoogle Scholar
  3. Iwatsuki, K., Satoh, M., Yamamoto, T., et al. (2006). Pathogenic link between hydroa vacciniforme and Epstein-Barr virus–associated hematologic disorders. Archives of Dermatology, 142, 587–595.CrossRefGoogle Scholar
  4. Kimura, H., Ito, Y., Kawabe, S., et al. (2012). EBV-associated T/NK-cell lymphoproliferative diseases in nonimmunocompromised hosts: Prospective analysis of 108 cases. Blood, 119, 673–686.CrossRefGoogle Scholar
  5. Magana, M., Sangüeza, P., Gil-Beristain, J., et al. (1998). Angiocentric cutaneous T-cell lymphoma of childhood (hydroa-like lymphoma): A distinctive type of cutaneous T-cell lymphoma. Journal of the American Academy of Dermatology, 38, 574–579.CrossRefGoogle Scholar
  6. Miyake, T., Yamamoto, T., Hirai, Y., et al. (2015). Survival rates and prognostic factors of Epstein-Barr virus-associated hydroa vacciniforme and hypersensitivity to mosquito bites. The British Journal of Dermatology, 172(1), 56–63.CrossRefGoogle Scholar
  7. Quintanilla-Martinezz, L., Ridaura, C., Nagl, F., et al. (2013). Hydroa vacciniforme-like lymphoma: A chronic EBV+ lymphoproliferative disorder with risk to develop a systemic lymphoma. Blood, 122, 3101–3110.CrossRefGoogle Scholar
  8. Quintanilla-Martinezz L, Ko Y-H, Kimura H, et al (2017) Hydroa vacciniforme-like lymphoproliferative disorder. In S. H. Swerdlow, E. Campo, N. L. Harris, et al. (Eds.), WHO classification of Tumours of Haematopoietic and lymphoid tissues (revised 4th ed., pp. 360–362). Lyon: IARC.Google Scholar

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Clinical ResearchSaitama Children’s Medical CenterSaitamaJapan