Clinicopathological categorization of hydroa vacciniforme-like lymphoproliferative disorder: an analysis of prognostic implications and treatment based on 19 cases

Hydroa vacciniforme-like lymphoproliferative disorder (HV-LPD) was nominated and introduced into the 4th revised edition of the WHO classification of Tumors of Hematopoietic and Lymphoid Tissues [1]. HV-LPD is a cutaneous form of Epstein-Barr Virus-positive (EBV+) T/NK lymphoproliferative disease, which occurs in childhood and carries the risk of systemic lymphoma [2, 3]. Other terms have been used previously to describe HV-LPD, including hydroa vacciniforme-like eruption, edematous scarring vasculitic panniculitis, classic and severe hydroa vacciniforme, hydroa-like cutaneous T-cell lymphoma, and hydroa vacciniforme-like lymphoma (HVLL) [3]. The term HVLL was included the 2008 WHO classification of peripheral mature T-cell lymphoma [4]. The nomenclature and definition changed from HVLL to lymphoproliferative disorder, due to its relationship with chronic active EBV (CAEBV) infections and its clinical course.

HV-LPD is extremely rare. It manifests as recurrent skin lesions infiltrated with T cells or NK cells. It is mostly found in children and young adults from Asian and Latin American countries. It is associated with CAEBV infections. It might persist only in genetically predisposed individuals [5‐7].

The clinical course of HV-LPD is variable; it lasts up to 10–15 years [8, 9]. In the early stage, skin lesions tend to occur on sun-exposed areas. Lesions comprise recurrent papulovesicles, crusts, and eventually, vacciniform (pox-like) scars, after several weeks. In the late stage, this disorder involves areas unexposed to the sun and becomes more aggressive. Deep ulcerations, necrosis, and facial edema are common. Severe systemic manifestations might be present, such as intermittent fever, lymph node enlargement, and hepatosplenomegaly. When systemic dissemination occurs (hepatosplenomegaly, lymphadenopathy, and bone marrow infiltration), it is best classified as systemic EBV+ T/NK-cell lymphoma [2, 3].

However, it is not always possible to distinguish between HV-LPD and systemic EBV+ T/NK-cell lymphoma, because these disorders often have overlapping clinical and pathological features at the time of presentation and/or during disease progression [10, 11]. Moreover, patients with HV-LPD exhibit variable clinical courses, but often have fatal outcomes. There are no guidelines or consensus opinions to guide clinicians in making a HV-LPD diagnosis, evaluating disease progression, or selecting treatment. Therefore, we retrospectively reviewed 19 cases of HV-LPD, first to characterize further the clinicopathological and molecular features, and second, to propose clinicopathological prognostic factors and potentially effective treatment.

HV-LPD is extremely rare in Western countries. Most studies described recurrent skin lesions with T-cell or NK-cell phenotypes in children and adolescents from Asian and Latin American countries [11, 16, 17]. South China has a high-incidence of EBV-associated nasopharyngeal carcinoma and extranodal NK/T-cell lymphoma, nasal type [13]. In our previous study, HV-LPD comprised 8.1% of peripheral T/NK-cell neoplasms in children and adolescents [18], indicating the prevalence of specific EBV strains and genetic background or genetic predisposition, a hypothesis that requires further study for confirmation.

In our study, all cases of HV-LPD had undergone an initial smoldering stage that lasted from 1 to 10 years. The early stage clinical features fit the criteria for hydroa vacciniforme. All patients had self-limited vesiculopapular eruptions on exposed areas, including the face, dorsal surfaces of the hands, and lower limbs, with no manifestation or only mild fever. As the disease progressed, most patients exhibited severe, extensive skin lesions with systemic manifestations, including fever, hepatosplenomegaly, and lymphadenopathy, consistent with other reports [2, 19, 20]. The term HV-LPD changed from hydroa vacciniforme-like lymphoma to lymphoproliferative disorder by the 4th revised edition of WHO classifications would be a more appropriate classification and a more descriptive term [1, 21, 22].

The histopathology of biopsies from 11 patients showed that atypical lymphocytes had infiltrated, and subcutaneous tissues were involved. Nine patients died of systemic T/NK lymphoma. All had elevated LDH levels (range: 318 to 1202 IU/L) and higher EBV DNA blood loads. Our study confirmed previous results that indicated that HV-LPD and HVLL groups comprised a spectrum of cutaneous CAEBV forms. HV-LPD is an EBV-associated lymphoproliferative disorder of T or NK-cell phenotype with risk for progression to HVLL.

There is no method in the literature for distinguishing between HV-LPD and progression to systemic NK/T cell lymphoma. This lack of distinction often confuses pathologists and chemotherapy physicians. The challenge remains to identify morphological or clinical markers for predicting which patients are at high risk of progressing to systemic lymphoma. We found that the presence of a TCR gene rearrangement was not useful for making a diagnosis of lymphoma, because, in our study, case 14 and 18 had monoclonalities in the early stage. Four patients developed systemic lymphoma and died of the disease progression during chemotherapy treatment. As shown in Table 1, all those patients displayed atypical, medium- to large-sized cells with deep skin ulcers, highly elevated LDH, long-lasting high EBV DNA loads (typically > 1 × 10⁵ copies), severe systemic manifestations, diffuse effacement of normal nodal architecture by atypical cell infiltration, and bone marrow involvement. Older patients tended to develop lymphoma, which was probably associated with an irreversible process [23].

HV-LPD was originally thought to be derived from skin-homing cytotoxic T-cells or NK cells. The majority of studies on HV-LPD reported a T-cell phenotype with divergent immunoexpression of either CD4 or CD8 [24, 25]. However, EBV-infected cells might be CD4+ T cells, CD8+ T cells, or NK cells. EBV-infected cellular lineages have varied in different studies and populations. Doeden et al. described patients with a NK-cell phenotype [6]. Interestingly, our cases exhibited the CD4+ phenotype (7/19), the CD8+ phenotype (5/19), and the NK-cell phenotype (7/19). The clinical course of the CD56 phenotype was not more aggressive than that of the T-cell phenotype; only two cases died of systemic NK lymphoma. The other two patients with the CD56 phenotype had longer clinical courses, and were alive with disease after 3 or 7 years of follow up. This finding was consistent with findings in previous reports [5]. Doeden et al. described two boys with the CD56 phenotype that exhibited an indolent disease course. In the present study, T-cell or NK-cell lineages were not identified as independent adverse prognostic factors. However, the sample size was quite small; in future, a larger sample is needed to analyze the association between phenotype and disease course or outcome.

Currently, there is no standard therapy for patients with HV-LPD. Several treatments for HV-LPD have been suggested, including antiviral agents, anti-inflammatory agents, radiotherapy, chemotherapy, EBV-specific cytotoxic T-cell regimen, bone marrow or allogeneic hematopoietic stem cell transplantation, and immunomodulative therapies, such as interferon-a or interleukin-2 [5, 26‐28]. Chemotherapy and/or immunomodulative therapies have been used to treat many patients in progressing stages, but they provided only temporary remission or limited benefit.

In this study, the main regimens of chemotherapy were BFM-90/95, for pediatric non-Hodgkin lymphoma (NHL), and gemcitabine, for adult extranodal NK/T-cell lymphoma, nasal type. The effects were typically transient, and they did not result in persistent remission. These treatments killed the EBV-infected cells, but they could not prevent patients from EBV re-infection. Only one patient (No. 11) received allogeneic hematopoietic stem cell transplantation and EBV-CTL treatment after chemotherapy, and that patient was the only one alive without disease at the latest follow up. Thus, allogeneic HSCT appeared to be the only curative treatment for HV-LPD. This result was consistent with those from previous reports [29, 30].

In summary, we demonstrated that HVL-LPD had specific features that could be classified into different clinicopathological categories; this finding might potentially impact future clinical treatments and outcomes. We established the diagnosis of systemic EBV+ T/NK cell lymphoma as a result of HV-LPD progression, based on the clinical, histopathological, and immunohistochemical features, in addition to EBV detection. We showed that EBV-DNA loads, LDH, cytopenia, and multiorgan destructive involvement were poor independent prognostic factors, distinct from findings in previous studies. The monoclonality of TCR gene rearrangements could be a referential index for evaluating HV-LPD progression. Future studies on genetic abnormalities might contribute to our understanding of the biological behavior of HVL-LPD and to establishing a therapeutic strategy for patients.