Hydroa vacciniforme-like lymphoproliferative disorder in Korea

Hydroa vacciniforme-like lymphoproliferative disorder (HVLPD) is a rare Epstein–Barr virus (EBV)-associated lymphoproliferative disease. The disease course of HVLPD varies from an indolent course to progression to aggressive lymphoma. We investigated the characteristics of HVLPD in Korean patients. HVLPD patients at Seoul National University Hospital between 1988 and 2019 were retrospectively analyzed. This study included 26 HVLPD patients who all presented with recurrent papulovesicular and necrotic eruption on the face, neck, and extremities. EBV was detected from the skin tissues of all patients. HVLPD was diagnosed during childhood (age < 18 years) in seven patients (26.9%) and in adulthood (age ≥ 18 years) in 19 cases (73.1%). The median age at diagnosis was 24.0 years (range 7–70 years). HVLPD has various clinical courses, from an indolent course to progression to systemic lymphoma. Fourteen patients (53.8%) developed lymphoma: systemic EBV-positive T-cell lymphoma (n = 9, 34.6%); extranodal natural killer/T-cell lymphoma, nasal type (n = 3, 11.5%); aggressive natural killer/T-cell leukemia (n = 1, 3.8%); and EBV-positive Hodgkin lymphoma (n = 1, 3.8%). Mortality due to HVLPD occurred in five patients (26.3%) in the adult group, while it was one patient (14.3%) in the child group. As lymphoma progression and mortality occur not only in childhood but also in adulthood, adult-onset cases may need more careful monitoring.

Histopathologic features, immunohistochemical findings, in situ hybridization, and molecular studies. The histopathologic features of cutaneous tissue were similar in all patients. Dense and diffuse infiltration of atypical lymphocytes was seen in the dermis and subcutaneous fat (Fig. 2). Epidermal necrosis, vesiculation, subepidermal edema, and perivascular and periappendageal atypical lymphocytic infiltration were found. The proliferated atypical lymphocytes were of small to intermediate size, with enlarged, round to oval nuclei. There were an inflammatory background with lymphocytes, eosinophils, histiocytes and plasma cells.
The immunohistochemistry results and molecular study findings are summarized in Table 2. EBV-encoded small nonpolyadenylated RNA (EBER) was positive in all patients. EBER-positive cells were predominantly seen in the perivascular and periappendageal area in the dermis and subcutaneous fat. Detection of monoclonal T-cell receptor γ gene rearrangements was performed in 13 patients. Among them, four patients (30.8%) showed these rearrangements.  In the child group, one patient showed remission (14.3%) and three patients had partial remission and recurrence (42.9%). The disease progressed to systemic lymphoma or leukemia in three patients (42.9%), two of whom had a diagnosis of systemic EBV-positive (EBV+) T-cell lymphoma of childhood and one of whom had aggressive NK/T-cell leukemia. The mortality rate of HVLPD in the child group was 14.3% (1/7). The cause of death was aggressive NK/T-cell leukemia.
In the adult group, remission was noted in two patients (10.5%) and partial remission was observed in six patients (31.6%). Eleven cases (57.9%) were associated with systemic lymphoma, of which seven (36.8%) progressed to systemic EBV+ T-cell lymphoma; 3 (15.8%) to extranodal NK/T-cell lymphoma, nasal type; and 1 (5.3%) to EBV+ Hodgkin lymphoma. The mortality rate of HVLPD in the adult group was 31.6% (6 of 19). When we excluded the case of breast cancer death, the rate of disease-specific death was 26.3% (5 of 19) in the adult group. The causes of death were progression to systemic EBV+ T-cell lymphoma in four patients and extranodal NK/T-cell lymphoma, nasal type, in one patient.
Progression to lymphoma and mortality in relation to age at diagnosis, disease onset, and disease duration. We compared the rates of HVLPD progression to lymphoma and disease-related mortality between patients diagnosed during childhood and those diagnosed during adulthood. Although the rates of both were higher among those diagnosed during adulthood, the differences were not statistically significant (p = 0.665

Anatomic location of cutaneous manifestations
Sun-exposed area 26 (100) Non-sun-exposed area 7 (26.9) www.nature.com/scientificreports/ for progression and p = 1.000 for mortality). We further analyzed these parameters according to whether disease onset occurred in childhood (age < 18 years) or adulthood (age ≥ 18 years). There was no difference between the two groups with regard to either progression to lymphoma or disease-related mortality (p = 1.000 and p = 0.645, respectively). Additionally, we evaluated the effect of the period from disease onset to first diagnosis, comparing patients with a disease duration of < 10 years and those with a duration of ≥ 10 years. There were no differences in the rate of progression to lymphoma or disease-related mortality (p = 1.000 and p = 0.218, respectively) in relation to disease duration before first diagnosis.

Discussion
Hydroa vacciniforme is a rare photodermatosis originally described by Bazin 14 . Although the pathogenesis of hydroa vacciniforme is not clearly established, sensitivity to UVB or UVA has been suggested as a pathologic mechanism 15 . In 1996, Cho et al. first suggested an association with EBV and recurrent necrotic papulovesicular eruptions of the face 10 . As most cases with hydroa vacciniforme manifestations have shown the presence of EBV, the question about the existence of classic hydroa vacciniforme without EBV infection remains unresolved 16 . Therefore, Quintanilla-Martinez and Fend suggested renaming the disease as hydroa vacciniforme EBV-associated lymphoproliferative disorder to encompass the broad clinical spectrum 16 . HVLPD has been given various names, including hydroa vacciniforme-like lymphoma and EBV-associated vesiculopapular eruption on the face. In 2008, the WHO classification introduced 2 T-cell lymphoproliferative disorders associated with EBV in children: hydroa vacciniforme-like lymphoma and systemic EBV+ lymphoproliferative disease of childhood 17 . In 2016, the 4th WHO classification reclassified the disease into two groups: HVLPD and systemic EBV+ T-cell lymphoma of childhood (Table 3) 18 .
The EBV-associated T-and NK-cell lymphoproliferative diseases include EBV-associated hemophagocytic lymphohistiocytosis (HLH); CAEBV of T-and NK-cell type; systemic EBV+ T-cell lymphoma of childhood; aggressive NK-cell leukemia; extranodal NK/T-cell lymphoma, nasal type; and primary EBV+ nodal NK/T-cell lymphoma (Table 4) 19,20 . Primary EBV+ nodal NK/T-cell lymphoma is a new provisional entity defined as peripheral T-cell lymphoma with primary nodal presentation without nasal involvement 20 . Although splenomegaly and hepatic involvement can occur in 73% and 60% of the patients, skin and gastrointestinal involvement are rare 21 . EBV-associated HLH is a life-threatening inflammatory disease with symptoms including high fever, cytopenia, hypofibrinogenemia, elevated serum transaminases, hyperbilirubinemia, prolonged prothrombin time, and hyponatremia; it may occur as a primary condition or secondary to other conditions 19 . Secondary EBV-associated HLH may accompany CAEBV of T-and NK-cell type. HVLPD is classified as a cutaneous form of CAEBV of T-and NK-cell type. CAEBV of T-and NK-cell types has a broad range of clinical manifestations from indolent cutaneous form to a more severe systemic form 20   www.nature.com/scientificreports/ disease characterized by systemic neoplastic proliferation of NK-cells 19 . It occurs in young to middle-aged adults. Extranodal NK/T-cell lymphoma, nasal type, is EBV+ aggressive lymphoma and occurs mainly in middle-aged adults. It occurs in 70-80% of all cases and primarily involves the nasal and nasopharyngeal region. Skin lesion presents as nodular ulcerative lesions, and gastrointestinal tract, testis and mucous membrane are involved 19 .
Systemic EBV+ T-cell lymphoma of childhood is a more rapidly progressive and fatal disease, characterized  Table 3. Change of definition of hydroa vacciniforme and hydroa vacciniforme-like lymphoproliferative disease.

Hydroa vacciniforme
Rare, sporadic, idiopathic photodermatosis characterized by papules, vesicles, and crusts which heal with vacciniform scarring after sunlight exposure. The pathogenesis is unclear although sensitivity of UVB or UVA has been suggested First reported by Bazin 14,15 Hydroa vacciniforme-like lymphoma Proliferation of clonal T cells or, less frequently, NK cells infected by EBV with a latency type 1 profile. It has an indolent clinical course with long periods of recurrent skin lesions in sun-exposed areas that tends to regress spontaneously. After several years, the process may resolve or progress to systemic disease

WHO classification 17
Systemic EBV+ lymphoproliferative disease of childhood Aggressive condition with rapid evolution to multiple-organ failure and death. It has overlapping features with aggressive NK-cell leukemia, but the cells have a T-cell phenotype and clonal TCR rearrangement. It may emerge in a background of chronic EBV infection and progress from a polyclonal, to an oligoclonal, and to a monoclonal EBV-driven proliferation The prognostic factors of progression from HVLPD to systemic lymphoma have not been definitely established. Factors such as high serum EBV DNA loads, Latin American descent, systemic symptoms, adult onset, and chemotherapy were suggested to be associated with a more aggressive disease course 3,10,19,20 . In our database, among 19 adult cases, 11 (57.9%) were associated with systemic lymphoma, and this proportion was higher than that observed among childhood cases. Among these cases, seven progressed to systemic EBV+ T-cell lymphoma; three to extranodal NK/T-cell lymphoma, nasal type; and one to EBV+ Hodgkin lymphoma. Therefore, considering the higher possibility of adverse outcomes, adult-onset cases may also need careful monitoring as in children cases.
There is no established treatment guideline for HVLPD. Stringent sun protection is recommended for all patients using broad-spectrum sunscreens, sun-protecting clothing, and avoidance of sun exposure. Various treatments were tried including hydroxychloroquine, anti-viral drugs (acyclovir and valacyclovir), topical and systemic corticosteroids, and chemotherapy. For systemic HVLPD, although corticosteroids or thalidomide provided temporary improvements, the only curative treatment is hematopoietic stem cell transplantation 23 . A recent report suggested that chemotherapy should not be considered as the first-line treatment as it was associated with poor prognosis in patients with HVLPD 3 . However, chemotherapy may be an effective method to reduce systemic disease burden in an effort to enhance the curative potential of allogeneic bone marrow transplantation, with or without the reduction of EBV viral load 24 . Therefore, its use should be prudently considered in selected cases. Further investigations on which patients can benefit from chemotherapy are warranted.
There are some limitations. Although this study included one of the large cases with three decades data in SNUH, the sample size is small as HVLPD is an extremely rare disease. In addition, a detailed molecular analysis was not performed due to the retrospective study design. Lastly, it was challenging to distinguish between HVLPD and extranodal NK/T-cell lymphoma, nasal type, and primary EBV+ nodal T/NK-cell lymphoma with extranodal involvement as some features are overlapped. However, the diagnosis was made based on clinical and pathologic findings by an experienced dermatologist, pathologist, and oncologist.
In summary, we described 26 cases of HVLPD encountered at our institution during the last three decades. HVLPD seems to have various disease courses. Fourteen patients (53.8%) in the present study had systemic T-cell lymphoma, NK-T cell lymphoma/leukemia, and EBV+ Hodgkin lymphoma. Lymphoma progression and mortality can occur not only in childhood but also in adulthood.

Methods
We retrospectively reviewed cases of HVLPD diagnosed based on clinical and histopathologic features between 1988 and 2019 in the Department of Dermatology of SNUH. Patients who both gave and signed an informed consent to perform a skin biopsy were recruited (In cases of patients under 18 years of age, signed informed consent were given by parents and/or legal guardians). HVLPD was defined according to the revised 4th WHO classification of hematopoietic and lymphoid tumors 1 . Clinical and laboratory data at the time of diagnosis were obtained from medical records.
Histopathologic features, immunohistochemical findings, EBER by in situ hybridization, serum EBV loads, T-cell clonality test using multiplex-PCR for the T-cell receptor γ gene, and results of radiologic imaging studies were reviewed. Photoprovocation tests UVA. A 5 × 5 cm area on the buttock or upper arm was irradiated 3 or 5 times at 24-h intervals (15-20 J/cm 2 ) 9 . This study was approved by the institutional review board of Table 4. Classification of EBV-associated T-and NK-cell lymphoproliferative diseases 19,20 . a A provisional entity.