Hydroa vacciniforme L56.8

Bazin 1862

Rare, benign, lymphoproliferative disease (EBV-associated light dermatosis) with pathologically increased photosensitivity and intermittent development of itchy and burning erythema, vesicles and blisters, papules, urticarial plaques and consecutive scars in solar areas of the skin (Quintanilla-Martinez L et al. 2019; Huggins RH et al. 2009; Sangueza M et al. 2013).

Hydroa vacciniforme was originally described as a benign disease in European countries, as there were no systemic symptoms and the disease resolved spontaneously in adolescence or young adulthood (Quintanilla-Martinez L et al. 2019).

However, a more severe and disfiguring form known as hydroa-vacciniform-like lymphoproliferative disease, EBV-induced (HV-LPD) has been reported in children from Latin America and Asia. This is associated with chronic EBV infection and is listed in the WHO classification of lymphomas as a subgroup of EBV+ T-cell lymphoproliferative disorders of childhood (Quintanilla-Martinez L et al. 2019).

Some authors define hydroa vacciniforme as a cutaneous variant of Epstein-Barr virus (EBV)-associated T/NK lymphoproliferative disorders (LPDs) (Iwatsuki K et al. 2019).

Prevalence: 0.1-0.5/100,000 inhabitants/year. Hydroa vacciniforme occurs more frequently in people with darker skin color (Asian and South American populations). Familial cases have been described but are rare.

Ultraviolet radiation: Although ultraviolet radiation generally triggers the clinical symptoms, the exact pathomechanism leading to this "photodermatosis" is unknown. Disease-specific lesions can be induced by photoprovocation with repeated monochromatic or broadband UV radiation (Huggins RH et al. 2009).

Hydroa vacciniforme and EBV: Viral infections probably play a comorbid role. Associations with an Epstein-Barr virus infection have been described (serologic EBV detection and PCR detection of EBV antigen in lesional tissue), as well as (much more rarely) with a herpes simplex virus infection. Based on these findings, hydroa vacciniforme (HV) is now classified by many authors as a (benign) cutaneous variant subgroup of Epstein-Barr virus (EBV)-associated T/NK lymphoproliferative diseases (LPDs).

From these associations it can be concluded that UV is probably not the only causative factor. Hydroa vacciniforme-like lymphoproliferates may also occur at UV-averse sites, further supporting a multifactorial etiology.

Hydroa vacciniforme and hydroa-vacciniforme-like lymphoproliferative disease (HV-LPD): In contrast to the relatively bland course of classic hydroa vacciniforme, the differences in clinical severity and incidence between patient populations in hydroa-vacciniforme-like lymphoproliferative disease (HV-LPD) and hydroa-vacciniforme-like lymphoma suggest a combination of genetic, immunologic, and/or environmental events. Since hydroa-vacciniforme-like lymphoproliferative disease occurs primarily in Asian and South American populations, this entity is thought to have a specific genetic background predisposing it to develop a chronic EBV infection after the initial infection.

In response to inflammatory stimuli (e.g. UV exposure, insect bites), lesional EBV-infected cytotoxic T cells and/or NK cells are recruited. There is evidence of upregulation of interferon-gamma, as well as several genes encoding various chemokines (CXCL9, CXCL10, CXCL11 and CCL4)(Quintanilla-Martinez L et al. 2019).

Hydroa vacciniforme is considered a childhood disease with a bimodal incidence in early childhood (1 to 7 years) and around or after puberty (12 to 16 years).

The disease typically occurs seasonally, usually a few hours after sun exposure in the spring or summer months (Gupta G et al. 2000). Isolated cases in infancy and adulthood have been reported.

There is no confirmed gender preference.

Hydroa-vacciniforme lesions typically begin as symmetrical, itchy or burning erythematous grouped erythema in sun-exposed areas of the skin such as the face and back of the hands. The lesions typically appear within a few hours of sun exposure. After a few hours, red papules or plaques develop, surrounded by pale or hemorrhagic vesicles and blisters. After a few days, crusting occurs. The lesions heal over several weeks with the formation of blisters up to 2.0 cm in size, sometimes bifurcated, with serous or hemorrhagic contents.

Recurrent manifestations and forms of healing can exist in parallel, resulting in a polymorphic appearance. Disfiguring mutilations of the nose and auricles are possible. Ophthalmologic complications in the form of recurrent keratoconjunctivitis have also been described (Mortazavi H et al. 2015). In severe cases, fever reactions and disorders of the general condition may occur.

In contrast, patients with hydroa-vacciniforme-like lymphoproliferative disease (HV-LPD ) present with marked facial oedema, multiple vesicles, large necrotizing ulcers and severe scarring in light-spread and non-light-spread areas. At the same time, patients often suffer from systemic symptoms such as high fever, lymphadenopathy and hepatosplenomegaly. In addition, EBV-related complications such as hypersensitivity to insect bites, hemophagocytic syndrome and other features of a chronically active EBV infection are common (Iwatsuki K et al. 2006).

Hydroa-vacciniforme lesions show characteristic spongiotic vesiculation with fibrin and acute inflammatory cells, confluent epidermal and focal upper dermal necrosis and marked reticular keratinocyte degeneration. Early lesions may show a lymphohistiocytic infiltrate of variable density mixed with neutrophils. The lymphoid infiltrate shows in situ hybridization positivity for EBV RNA (Gruber-Wackernagel A et al. 2014).

Direct immunofluorescence microscopy shows no specific patterns. Occasionally, subepidermal granular deposition of C3 was detected.

In addition to the characteristic histological features of classic lesions, hydroa-vacciniforme-like lymphoproliferative disease (HV-LPD) shows atypical, perivascular but also diffuse In addition to the characteristic histological features of classic lesions, the lesions of hydroa-vacciniform-like lymphoproliferative disease (HV-LPD) show diffuse atypical, perivascular but also diffuse lymphocytic infiltrates (pleomorphic nuclei, irregular nuclear borders, hyperchromasia). Signs of vasculitis with angiotropism are also detectable. Occasionally also lymphocytic epidermotropism.

The diagnosis of classical hydroa vacciniforme is based on clinical and histopathologic findings. The following laboratory tests are helpful in differentiating between a hydroa vacciniforme and a hydroa vacciniforme-like lymphoproliferative disease/lymphoma:

• Hematologic and liver profiles
• Percentage of NK lymphocyte subset
• T-cell receptor gene rearrangement
• Anti-EBV antibody titers
• EBV DNA load in peripheral blood.
• Patients with hydroa-vacciniforme-like lymphoma often have elevated hepatic transaminases, leukopenia, thrombocytopenia, elevated NK lymphocytes, monoclonal T-cell receptor gene rearrangements and a high circulating EBV DNA load (Iwatsuki K et al. 2006).

Furthermore:

• Photoprovocation especially with UVA (e.g. 3 times 1-1.5 MED UVA1 at intervals of 24 hours)
• Porphyrins in stool and serum (exclusion of porphyria).

Erythropoietic porphyria (detection of porphyrins in stool and urine; erythrocyte fluorescence)

Hepatic por phyria (detection of porphyrins in blood and urine)

Erythema (exudativum) multiforme (exanthematic course; cocard form of efflorescences)

Actinic prurigo (rare light dermatosis, extensive lichenified foci)

Vesicular polymorphous light dermatosis

Bullous lupus erythematosus (rare, mainly on non-light-exposed areas, histo)

Bullous impetigo (large, flaccid blisters on a reddened surface, with initially clear, then whitish-grey, creamy purulent contents)

Actinic prurigo

Systemic lupus erythematosus (flat red plaques, typical histology and immunohistology, positive ANA and DNA-Ak).

Hydroavacciniforme-like lymphoproliferative disease: In contrast to classic (benign) hydro vacciniforme, patients with hydroa vacciniforme-like lymphoproliferative disease (very rare in Europe) present with marked facial edema, multiple vesicles, large necrotizing ulcers and severe scarring in light-spread and non-light-spread skin areas. Patients often suffer from systemic symptoms such as high fever, lymphadenopathy and hepatosplenomegaly. In addition, patients often present with EBV-related complications such as hypersensitivity to mosquito bites, hemophagocytic syndrome and chronic active EBV infection (Iwatsuki K et al. 2006).

The most worrying complication is the transformation of benign hydroa vacciniforme into hydroa-vacciniforme-like lymphoma. Due to the aggressive and sometimes fatal clinical course of hydroa-vacciniforme-like lymphoma, prolonged follow-up of at least 10 years after diagnosis is required, even if the disease initially shows remission (Sangueza M et al. 2013).

There are no sheared treatment methods that have proven to be successful in the long term.

Strict sun protection with broad-spectrum sunscreens (UVA and UVB protection), opaque clothing, tinted windows and avoidance of the midday sun is necessary to prevent recurrences of the disease.

In the acute stage, short-term glucocorticoid extenders such as prednicarbate (e.g. Dermatop cream).

It is important to protect the skin and eyes from light.

"Hardening" with narrow-band UVB light or exposure to low-dose prophylactic narrow-band UVB light during the spring months should reduce the severity of the disease (Ketterer R et al. 1994).

Therapeutic approaches with chloroquine have been described, but are not convincing; likewise therapeutic approaches with pyridoxine (600mg/day).

Other therapeutic agents listed with varying degrees of success are: azathioprine, cyclosporine, thalidomide, beta-carotene and oral fish oils.

In severe cases, systemic glucocorticoids (50-75 mg prednisone p.o.) are recommended.
A trial with beta-carotene appears useful.

Rare manifestations include eye involvement.

Frequent annual recurrences in spring. Spontaneous resolution possible post-puberty.

In contrast, patients with hydroa vacciniforme-like lymphoma present with marked facial edema, multiple vesicles, large necrotizing ulcers and severe scarring in light-spread and non-light-spread areas. Patients often present with systemic symptoms such as high fever, lymphadenopathy and hepatosplenomegaly. In addition, patients often present with EBV-related complications such as hypersensitivity to mosquito bites, hemophagocytic syndrome and chronic active EBV infection (Iwatsuki K et al. 2006).

The exact pathogenesis of Hydroa vacciniforme is still unclear. Sensitivity to ultraviolet B light is undisputed. It is disputed whether UVB or UVA is the trigger. However, the chromophore that leads to UV-induced damage in Hydroa vacciniforme is unclear. In vitro studies with lymphocytes and fibroblasts indicate a reduced DNA repair mechanism. Other studies have indicated that photoproducts cause tissue damage either directly or via perceptive DNA (Gupta G et al. 2000).

Psychosocial component: Patients with hydroa vacciniforme suffer significant psychosocial and emotional distress. According to studies, the most commonly perceived impairment is the restriction of daily activities and living conditions required to minimize the disease. In addition, the disfigurement caused by permanent scarring has a restrictive impact on patients' lives. The clinical course of hydroa-vacciniforme-like lymphoma is aggressive and associated with high mortality, especially when extracutaneous involvement occurs (Sangueza M et al. 2013).

Sun protection: It is important that patients are educated about the need to strictly protect themselves from the sun during midday hours and to use adequate sun protection. Sunscreen should cover a broad spectrum (UVA and UVB). It is also important to educate patients that windows do not filter UVA light and that precautions to avoid sun exposure are also needed indoors.

The exact pathogenesis of Hydroa vacciniforme is still unclear. Some studies suggest that sensitivity to ultraviolet B light (UVB) is the cause; other studies point to triggering by longer wavelengths (UVA spectrum). The chromophore that leads to UV-induced damage in Hydroa vacciniforme is still unknown. In vitro studies with lymphocytes and fibroblasts have implicated a reduced DNA repair defect. Other studies indicated that photoproducts cause tissue damage either directly or via perceptive DNA (Gupta G et al. 2000).

In contrast to the relatively bland course of classical hydroa vacciniforme, the differences in clinical severity and incidence between patient populations in"hydroa vacciniforme-like lymphoproliferative disease" suggest a combination of genetic (Asian and South American populations), immunologic and/or environmental events. In addition, some studies have shown upregulation of interferon-gamma and several genes encoding chemokines, including CXCL9, CXCL10, CXCL11 and CCL4, in patients' serum levels.

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