Shedding light on the hydroa vacciniforme-like lymphoproliferative disorder
By Warren R. Heymann, MD, FAAD
Sept. 1, 2021
Vol. 3, No. 35
Hydroa vacciniforme (HV) has always mystified me in every respect — its clinical presentation, pathophysiology, prognosis, and even its name. I understand “vacciniforme” because residual scars may resemble those of smallpox. I was surprised to learn that “hydroa” is derived from the Greek hídrōia (plural) heat spots (literally, sweat eggs), equivalent to hidr(ṓs) sweat + -ōia, plural of ōión egg. (1) Admittedly, for the rare times I have considered the diagnosis of HV, I never conjured an image of “sweat eggs.”
HV is a rare childhood photosensitivity disorder of unknown pathogenesis. Previously, two forms have been recognized: typical HV and severe HV-like eruptions. Typical HV occurs mostly in young children and is characterized by recurrent vesiculopapules on sun-exposed areas. The erythematous vesiculopapules become umbilicated with central necrosis, later healing with small pox–like scars within 1 to 2 weeks. Involvement of the oral mucosa has also been reported. Mild burning, stinging, or pruritus is common within 6 hours of sun exposure, and mild conjunctivitis or keratitis is not uncommon. Rare features include photoonycholysis, earlobe mutilation, and partial absorption of bone. The histopathology of HV reveals intraepidermal vesiculation with reticular degeneration, progressing to confluent epidermal necrosis in later lesions. A dense perivascular lymphohistiocytic infiltrate may be present in the dermis. Direct immunofluorescence is usually negative but may rarely demonstrate scattered granular deposits of C3 at the dermoepidermal junction. Systemic symptoms are generally absent, and the disease tends to resolve spontaneously by early adult life. There is no specific epidemiologic distribution, but most patients have been reported in the United States, United Kingdom, Japan, and Europe. The differential diagnosis includes erythropoietic protoporphyria, polymorphous light eruption, actinic prurigo, and porphyria cutanea tarda. (2)
The precise pathogenesis of HV remains enigmatic. Ultraviolet light plays a role, with both UVB and UVA having been implicated. In-vitro experiments with lymphocytes and fibroblasts suggested a reduced DNA repair defect. Other studies have pointed to photoproducts causing tissue damage either directly or via DNA. (2) The identification of EBV+ lymphocytes by EBER in cases of HV strongly supports an association with EBV infection. Responding to inflammatory stimuli in genetically predisposed patients, EBV-infected cytotoxic T cells and/or NK cells are recruited locally, causing tissue damage via an upregulation of interferon-y and multiple genes that encode chemokines (notably CXCL9, CXCL10, CXCL11, and CCL4). (2,3)
Severe, or atypical, HV-like eruptions have long been recognized, characterized by ulcerative cutaneous lesions on exposed and photoprotected areas, facial edema, fever, and systemic complications, such as liver damage and hematologic abnormalities. These atypical eruptions were reclassified as HV-like lymphoma (HVLL) according to the 2008 World Health Organization lymphoma classification. HVLL is no longer categorized as a subtype of childhood EBV+ T-cell lymphoma and HVLL is now referred to hydroa vacciniforme-like lymphoproliferative disorder (HVLPD) in the 2016 WHO classification, since this disease has distinctive clinicopathological features. HVLPD is a primarily cutaneous disorder with a broad spectrum of clinical aggressiveness and HVLL is considered a syndrome accompanying this disease. Some authors suggest that the HVLPD-NK cell phenotype should be classified as a separate entity. (4)
HVLPD is more common in Asia and Central and South America than the United States or Europe. Patients may progress to EBV-positive T- or NK-cell lymphoma/leukemia or hemophagocytic syndrome. T cells in lesions are often monoclonal. Some patients with HVLPD also have hypersensitivity to mosquito bites with necrosis, elevated levels of immunoglobulin E (IgE), and increased numbers of EBV-positive NK cells in the peripheral blood. Cohen et al reported their 11-year experience in evaluating patients with HVLPD at the Clinical Center of the National Institutes of Health (NIH). They found that white patients generally had a benign course, while 4 of 6 nonwhite patients required hematopoietic stem cell transplantation for their disease. (5)
In their review of 7 Chinese pediatric patients (age range 4 to 15 years), Ren et al reported 4 fatalities, 2 of which were related to the hemophagocytic syndrome. In this series, elevated liver enzymes and LDH were important prognostic factors, while the severity of skin disease, systemic symptoms, viral load, degree of lymphocytic atypia were poor predictors of outcome. (6) In their retrospective review of 41 Chinese patients with HVLPD, Liu et al found that all patients presented with papulovesicular lesions, mainly distributed on sun-exposed areas, with 26 patients showing systemic symptoms. Follow-up data were available for 20 patients — 16 patients were alive, and 4 patients died. Of the 4 deceased patients, 3 had taken a serum EBV DNA test that showed high viral loads. These 3 patients also received chemotherapy. The authors concluded that HVLLPD in Chinese patients shows indolent behavior in most cases, which differs from the aggressive characteristics of HVLLPD in Latin Americans. They contend that patients with high serum EBV DNA loads have an increased risk evolving into aggressive disease and that chemotherapy should not be considered as first-line treatment for most Chinese patients. (7)
Treatment of typical HV consists of strict photoprotection with broad-spectrum sunscreens. Low-dose prophylactic narrowband UVB phototherapy during the spring months may reduce disease severity. Oral antimalarial drugs, azathioprine, thalidomide, cyclosporine, beta-carotene, and fish oil supplementation have been used in HV with varying success. Patients with HV should be followed clinically for the development of atypical features, because lesions of typical HV have been reported to precede NK/T-cell lymphoma by up to 10 years. (2) Currently, there are no therapeutic guidelines for patients with HVLPD. In addition to modalities used for HV, antiviral agents, interferon gamma, corticosteroids (systemic and topical), intravenous immunoglobulin, antibiotics (minocycline), and calcineurin inhibitors have been utilized with varying degrees of success. Chemotherapy and radiotherapy have been shown to offer minimal or no benefit and may worsen the prognosis. (8)
Point to Remember: HVLPD is Epstein-Barr virus-related displaying a spectrum of disease ranging from benign to life-threatening lymphoma. While ultraviolet-light may be involved in its pathogenesis, more research is required to shed light on this disorder.
Our expert’s viewpoint
Ellen J. Kim, MD, FAAD
Professor of Dermatology, Perelman School of Medicine at the University of Pennsylvania
HV and HVLPD are rare disorders one may never see in daily dermatology practice but are important to know about as they vividly illustrate the eternal question: when and how does a skin rash turn into a lymphoma? While we fortunately have more tools to help distinguish between these related disorders (T cell receptor clonality, EBER in situ hybridization, peripheral blood viral load), judicious clinicopathologic correlation remains paramount. (9) The concept of a disease continuum/spectrum is a common framework for evaluating patients for various cutaneous lymphoma subtypes (parapsoriasis/classic patch mycosis fungoides, benign follicular mucinosis/folliculotropic MF, lupus panniculitis/atypical lobular panniculitis/subcutaneous panniculitis-like T-cell lymphoma, cutaneous lymphoid hyperplasia/primary cutaneous marginal zone lymphoma, and the list goes on). Ongoing genomic and epiproteomic work will hopefully further illuminate the mechanism behind disease progression from benign to “atypical/borderline” to definitive cancer in these diverse disorders.
In my U.S.-based cutaneous lymphoma practice, MF is the most common CTCL subtype and has a clinical presentation which is the inverse of HV and HVLPD: patches/plaques in sun protected areas. We routinely prescribe ultraviolet phototherapy (or at-home natural sun exposure “heliotherapy”) as a first line skin-directed treatment for early-stage MF. Thanks to the AAD and dermatologists’ efforts, patients today are well versed in the public health message of sun protection to avoid skin cancer/melanoma, so they are invariably surprised and bemused and ask: “Isn’t the sun bad for your skin?” (Some enterprising patients immediately follow up with a request for a prescription to move to a tropical climate or year-long cruise, doctor’s orders!) Many other cutaneous lymphomas or LPDs actually benefit from sun exposure, but HVLPD stands out as the exception (in addition to actinic reticuloid/chronic actinic dermatitis) requiring aggressive sun protection.
Dr. Kim had disclosed financial relationships with the following to the AAD at the time of publication: Actelion, Galderma USA, Helsinn Healthcare, Kyowa Hakko Kirin Pharma, Inc., Medimmune, Solgenix LLC. Full disclosure information is available at coi.aad.org.
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Cohen JI, Manoli I, Dowdell K, et al. Hydroa vacciniforme-like lymphoproliferative disorder: an EBV disease with a low risk of systemic illness in whites. Blood 2019; 133: 2753-2764.
Ren F, Zhu J, Perry DM, Pruitt L, Elston DM. Hydroa vacciniforme-like lymphoproliferative disorder: a retrospective cohort study of seven pediatric cases. Int J Dermatol 2020; 59: e290-e292.
Liu Y, Ma C, Wang G, Wang L. Hydroa vacciniforme-like lymphoproliferative disorder: Clinicopathologic study of 41 cases. J Am Acad Dermatol 2019; 81: 534-540.
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Chen CC, Chang KC, Medeiros LJ, Lee JY. 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. 2020 Dec 7;21(23):9314. doi: 10.3390/ijms21239314.
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