Hydroa vacciniforme lymphoproliferative disorder: a retrospective study of 42 paediatric cases.

Hydroa vacciniforme lymphoproliferative disorder (HVLPD) is a rare disease related to Epstein-Barr virus (EBV), mainly in children, and is an EBV-associated cutaneous T and natural killer (NK) cell lymphoproliferative disorder. The disorder in some patients may progress to EBV-associated systemic T or NK-cell lymphoma. To summarize the characteristics of HVLPD in Chinese paediatric patients and to examine the risk factors indicating poor prognosis. We performed a retrospective analysis of patients with HVLPD from the Department of Dermatology, Beijing Children's Hospital. Based on diagnosis, medical history, examination results, and immunophenotype, we analysed HVLPD in 42 paediatric cases in order to examine the clinical features, prognoses, and risk factors. Forty-two paediatric patients were enrolled, with a median onset age of five years. All patients presented with papulovesicular lesions, and 32 systemic HVLPD (sHVLPD) patients had systemic symptoms, including fever, lymphadenopathy, hepatomegaly, splenomegaly, and liver dysfunction. Of the sHVLPD cases, 13 also had severe mosquito bite allergy (SMBA). Twenty-five cases were T-type, and nine were CD56+-dominant type. Follow-up data showed that 12 patients had complete remission, and three patients died. SMBA is a risk factor for disease progression in patients with HVLPD, and the pathological CD56+-dominant phenotype is associated with poor prognosis.

Coexpression of natural killer cell antigens by T-cell large granular lymphocytes in hydroa vacciniforme lymphoproliferative disorder and the involvement of Vδ1 + epithelial-type γδT cells.

Hydroa vacciniforme lymphoproliferative disorder (HV-LPD) is a cutaneous variant of chronic active Epstein-Barr virus disease. We examined the coexpression of T- and natural killer (NK)-cell antigens in five patients with classic HV (cHV) and five with systemic HV (sHV). T-cell receptor (TCR) repertoire analysis was performed with high­throughput sequencing. All five cHV patients had increased γδT cells (> 5%), whereas five sHV patients showed γδT- and αßT-cell dominance in two patients each, and a mixture of abnormal γδT and αßT cells in one. Circulating CD3 + T cells expressed CD16/CD56 at 7.8-42.3% and 1.1-9.7% in sHV and cHV, respectively. The percentage of CD16/CD56 + T cells was higher in the large granular lymphocyte or atypical T-cell fractions in sHV, but no TCR Vα24 invariant chain characteristic of NKT cells was detected. Considerable numbers of CD3 + cells expressing CD56 were observed in sHV skin infiltrates. Of the circulating γδT cells tested, TCR Vδ1 + cells characteristic of the epithelial type of γδT cells were dominant in two sHV cases. Thus, atypical αßT and γδT cells in HV-LPD can express NK-cell antigens, such as CD16 and CD56, and Vδ1 + epithelial-type γδT cells are a major cell type in some HV-LPD cases.

Diagnostic and disease severity determination criteria for hydroa vacciniforme lymphoproliferative disorders and severe mosquito bite allergy.

Hydroa vacciniforme lymphoproliferative disorder (HV-LPD) and severe mosquito bite allergy (SMBA) are both cutaneous forms of Epstein-Barr virus (EBV)-associated T/natural killer (NK) cell LPDs and are closely related to chronic active EBV disease (CAEBV) and EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH). HV-LPD is further divided into classic HV, a benign subtype mediated by EBV-positive γδT cells, and systemic HV, another life-threatening subtype mainly associated with EBV-positive αßT or γδT cells. The vast majority of patients with SMBA have increased numbers of EBV-infected NK cells in the blood. Clinical symptoms of HV-LPD and SMBA often overlap in the same patient and may progress to more serious disease conditions equivalent to the systemic form of CAEBV. To define the disease spectrum of HV-LPD and SMBA, we propose the diagnostic criteria and the determination criteria for disease severity. The proposed diagnostic criteria are consistent with those for CAEBV and EBV-HLH in the guidelines for the management for CAEBV and related disorders 2023.

Clinicoprognostic Study of Hydroa Vacciniforme-like Lymphoproliferative Diseases: A Systematic Review.

BACKGROUND: Limited clinicopathological and prognostic data are available on hydroa vacciniforme (HV)-like lymphoproliferative diseases (HVLPD). METHODS: This systematic review searched HVLPD reports in Medline via PubMed, Embase, Cochrane, and CINAHL databases in October 2020. RESULTS: A total of 393 patients (65 classic HV, 328 severe HV/HV-like T-cell lymphoma [HVLL]) were analyzed. Among severe HV/HVLL cases, 56.0% were Asians, whereas 3.1% were Caucasians. Facial edema, hypersensitivity to mosquito bites, the onset of skin lesion, and percentage of severe HV/HVLL differed significantly by race. Progression to systemic lymphoma was confirmed in 9.4% of HVLPD patients. Death occurred in 39.7% patients with severe HV/HVLL. Facial edema was the only risk factor associated with progression and overall survival. Mortality risk was higher in Latin Americans than in Asians and Caucasians. CD4/CD8 double-negativity was significantly associated with the worst prognosis and increased mortality. CONCLUSION: HVLPD is a heterogeneous entity with variable clinicopathological features associated with genetic predispositions.

[Delayed diagnosis of hydroa vacciniforme-like lymphoproliferative disorder in a patient with skin rashes].

Chronic active Epstein-Barr virus (CAEBV) infection is characterized by persistent EBV infection and can lead to fatal conditions such as hemophagocytic syndrome and malignant lymphoma through the clonal expansion of EBV-infected T or natural killer (NK) cells. Hydroa vacciniforme lymphoproliferative disorder (HV) and hypersensitivity to mosquito bites (HMB) have been identified as skin diseases in EBV-associated T- or NK-cell lymphoproliferative diseases. We present the case of a 33-year-old man. The patient had frequent episodes of a facial rash for three years before he visited our hospital, he visited several dermatologists but did not receive a diagnosis of HV. He was referred to the hematology department of our hospital for assessment of atypical lymphocytes in peripheral blood. Based on routine blood and bone marrow test we were unable to diagnose HV. However, when the patient's liver function deteriorated six months later, we considered the possibility of HV after reevaluating the skin rash. After performing EBV-related tests, we were able to definitively diagnose CAEBV with HV. It is crucial to be able to connect clinical observations to EBV-related tests when diagnosing CAEBV. Hematologists must be knowledgeable of the EBV-associated skin conditions of HV and HMB.

Clinical and Pathological Features of Hydroa Vacciniforme-Like Lymphoproliferative Disorder Along with Risk Factors Indicating Poor Prognosis.

Purpose: To examine the clinical and pathological features, laboratory markers, therapeutic options and risk factors indicating poor prognosis of hydroa vacciniforme-like lymphoproliferative disorder (HVLPD). Patients and Methods: Seven patients with HVLPD had their clinical and pathological data collected. Immunohistochemical staining, Epstein-Barr virus-encoded RNA (EBER) in situ hybridization experiments, T-cell receptor (TCR) gene rearrangement, RT-PCR tests and the Elisa assay were carried out. Results: The main clinical manifestations were papulovesicular lesions and ulcers on the face, neck, or trunk. Five cases had systemic symptoms. Three of the deceased patients had significant facial edema, deep body necrosis, and ulceration. The pathological results demonstrated that lymphocytes infiltrated blood vessels and sweat glands in addition to the dermis and subcutaneous tissues. All patients tested positive for CD3 and EBER. Six cases tested positive for TCRßF1, but none tested positive for TCRδ. TCRγ monoclonal rearrangement, strongly positive expression of TIA-1 and a Ki67 proliferation index of 40% occurred in 3 fatal cases. When compared to the survival group, the plasma EBV DNA in the deceased group was considerably higher (P<0.05). IFN-γ and TNF-α cytokine levels in patients were higher than in the control group, particularly in the deceased group (P<0.05). The skin lesions on all patients recovered quickly underwent conservative care. Nonetheless, 3 patients passed away as the disease progressed in its latter stages. Conclusion: In our cases, the main infiltrating cells were T cells and the dominant lymphocyte subclass was αßT cells. A significant increase in lgE level, plasma EBV DNA, IFN-γ, and TNF-α cytokine levels, decreased hemoglobin level, strongly positive expression of TIA-1, high Ki67 proliferation index, and positive TCR gene rearrangement are all indicators of a poor prognosis.

Hydroa vacciniforme-like lymphoproliferative disorder in Ecuadorian children: A case series.

We report the clinical and histopathological features of hydroa vacciniforme-like lymphoproliferative disorder in five indigenous and Mestizo children. All the children resided at higher altitudes, experiencing maximal solar exposure. All cases presented with prurigo along with Epstein-Barr virus infection. Histopathologic examination showed an atypical, CD30 + lymphocytic infiltrate with angiocentricity in all, while three cases demonstrated panniculitis-like infiltrate.

An update on viral-induced cutaneous lymphoproliferative disorders. CME Part I.

Viral-induced cutaneous T-cell lymphomas are an uncommon group of lymphoproliferative disorders characterized by a viral infection of T and natural killer (NK) cells. This group of cutaneous T-cell lymphomas is more commonly encountered in Asians and Native Americans from Central and South America compared with Western populations. Viral-associated lymphoproliferative disorders include a spectrum of entities that range from nonneoplastic lesions, such as chronic active Epstein-Barr virus infection and infective dermatitis to malignant diseases, such as extranodal NK/T-cell lymphoma, hydroa vacciniforme-like T-cell lymphoma, and adult T-cell leukemia/lymphoma. This review article will focus on hydroa vacciniforme-like lymphoproliferative disorder, extranodal NK/T-cell lymphoma, adult T-cell leukemia/lymphoma, lymphomatoid granulomatosis, and Epstein-Barr virus-positive mucocutaneous ulcers. We will review the pathogenesis of these conditions and the challenges of making a timely diagnosis in early-stage disease and discuss the common clinicopathologic manifestations, mutational landscape, and approaches to treat these highly aggressive and frequently lethal types of lymphoma.

The Immunogenetics of Photodermatoses.

Photodermatosis is an abnormal skin inflammatory reaction to light. The major classifications of photodermatoses are idiopathic photodermatoses, photodermatoses due to exogenous or endogenous agents, photo-exacerbated dermatoses, and photosensitive genodermatoses. In this chapter, we focus on idiopathic photodermatoses and drug-related photodermatoses and emphasize on the epidemiology and immunogenetic backgrounds. Idiopathic photodermatoses, a spectrum of diseases with abnormal responses to ultraviolet radiation (UVR), include polymorphous light eruption, actinic prurigo, hydroa vacciniforme, chronic actinic dermatitis, and solar urticaria. Young people are more susceptible to most idiopathic photodermatoses except for chronic actinic dermatitis. Interestingly, idiopathic photodermatoses exhibit different characteristics between Caucasians and Asians. For example, the average age of Asian actinic prurigo patients is older than that of Caucasians in which genetic backgrounds or Fitzpatrick skin type might play a role. Drug-induced photodermatoses can be classified into phototoxic and photoallergic drug reactions. Certain drug-induced photodermatoses may mimic other dermatoses. For instance, drug-induced lupus erythematosus (LE) should be considered if an old man is diagnosed with LE but had a poor response to standard treatments.

Hydroa vacciniforme-like lymphoproliferative disorder: A retrospective study on clinicopathological characteristics of 32 cases.

The clinicopathological features of 32 patients (17 females and 15 males) with a median age of 8 years (range, 1.5-21 years) from Southwestern China diagnosed with hydroa vacciniforme-like lymphoproliferative disorder (HVLPD) were reviewed. At presentation, 6 patients showed only skin lesions, while 26 patients showed both skin lesions and systemic symptoms, including fever, lymphadenopathy and hepatosplenomegaly. As the disease progressed, systemic symptoms occurred in all patients. Follow-up data of 29 patients showed that 14 patients were still alive with disease with a median follow-up time of 22 months (range 3.6-71 months), and 15 patients died within a median follow-up of 6 months (range 0-60 months).

Ocular Involvement Preceded the Onset of Cutaneous Lesions in Hydroa Vacciniforme-Like Lymphoproliferative Disorder: A Case Report.

PURPOSE: To report a case of ocular involvement associated with hydroa vacciniforme-like lymphoproliferative disorder (HVLPD). CASE REPORT: A 10-year-old HVLPD boy suffered conjunctivitis, interstitial keratitis, and anterior uveitis sequentially during the whole course. Interestingly, this case manifested initially only with ocular findings, which preceded 1 year earlier than the onset of cutaneous lesions. And his later ocular findings occurred simultaneously with cutaneous lesions. The patient was treated with oral prednisone, ganciclovir, and light protection. Topical corticosteroid drops used to control ocular inflammation. Since then, he has not had any flares of ocular inflammation, and the cutaneous lesions improved. Although corneal nebula had been formed, the vision was still good. CONCLUSION: Our case was supportive of ocular involvement in HVLPD. Ophthalmologists should be aware of ocular involvement in HVLPD could be preceded the onset of cutaneous lesions, and prudently perform a careful ophthalmic examination at regular intervals to limit long-term sequelae.

Refractory Hydroa Vacciniforme-like Lymphoma: Biological Insights from Morphoproteomic Analysis.

T-cell/natural killer cell lymphoproliferative disorders are rare, associated with poor overall survival, and have limited treatment options. We report a case of a patient who developed hydroa vacciniforme-like lymphoma (HVLL, an EBV-peripheral T-cell lymphoma), refractory to multiple lines of systemic therapy including methotrexate, mycophenolate mofetil, dapsone, thalidomide, prednisone, and romidepsin. We conducted morphoproteomic analysis of the patient's tumor which provided important biological insights. Histopathology showed primarily lymphohistiocytic infiltrates strongly positive EBV expression with a Ki-67 of >50% in the pretreatment biopsy and approximately 90% in the post-treatment biopsy, strong expression of Enhancer of Zester Homolog 2 (EZH2), a constitutively active mTOR pathway, 50% cytoplasmic BCL-2 expression; largely negative PD-1 positive CD8 T-cells. Based on this morphoproteomic analysis and published literature, we postulated that novel agents, including venetoclax, tazemetostat, and other agents may provide a targeted approach for treating HVLL. This case illustrates the use of morphoproteomic analysis to better understand the biology of tumors.

Hydroa vacciniforme-like lymphoproliferative disorder with eye involvement.

Hydroa vacciniforme-like lymphoproliferative disorder (HVLPD) is characterized by vesiculopapular eruptions on sun-exposed and sometimes unexposed skin. Though ocular involvement in HVLPD is rare, it may present with conjunctivitis, corneal opacities, uveitis, and interstitial keratitis. We report a case of a 7-year-old boy with HVLPD, whose ophthalmic symptoms were neglected for over 2 years, who developed anterior uveitis and corneal nebulae without vision impairment. Awareness of eye involvement in patients with HVLPD may help to prevent severe complications.

Oral manifestations of Hydroa vacciniforme-like lymphoproliferative disorder: a clinicopathological study of a Peruvian population.

BACKGROUND: Hydroa vacciniforme-like lymphoproliferative disorder (HVLPD) is a chronic Epstein-Barr virus (EBV)-positive lymphoproliferative disease which may either present as an indolent condition or progress to a systemic T-cell lymphoma. METHODS: All HVLPD diagnosed over a 10-year period were retrieved, and clinical data regarding sex, age, oral and systemic manifestations, and clinical follow-up were obtained. Immunohistochemistry was done in order to characterize the lymphoid cells, and in situ hybridization was used to demonstrate the presence of EBV. RESULTS: Eleven cases were included, with a male predominance and a mean age of 25.1 years. Buccal mucosa and the lips were the most affected oral sites, appearing as painful ulcers. All patients exhibited facial oedema, usually affecting the lips, nose and periorbital region. The clinical course was gradual but progressive, with four patients having fever and 3 showing lymphadenopathies. All cases showed a moderate to severe lymphocytic infiltrate with angiotropism, angiocentricity and epidermotropism. Two cases affecting the lip skin exhibited a periappendageal lymphocytic infiltrate. Few large pleomorphic cells were found, surrounded by smaller and medium-sized lymphoid cells, as well as reactive plasma cells, macrophages, neutrophils and eosinophils. All lesions exhibited a cytotoxic T-cell (CD8+) phenotype with a variable proliferative index. All cases were associated with EBV, and all patients died due to complications of the disease. CONCLUSIONS: HVLPD is a rare disease that may show oral involvement with a cytotoxic T-cell phenotype, and is strongly associated with EBV. As shown in this series, HVLPD may show aggressive clinical behaviour.

Hydroa Vacciniforme-Like Lymphoproliferative Disorder in Korea: Prognostic Implication of Clinical Signs and Whole Blood Epstein-Barr Virus DNA.

BACKGROUND: Hydroa vacciniforme-like lymphoproliferative disorder (HVLPD) is rare Epstein-Barr virus (EBV)-associated disease. The classic form of HVLPD is a self-resolving disease, whereas the systemic form can progress to malignant lymphoma, resulting in fatal outcomes. However, the prognostic factors remain unclear. OBJECTIVE: This study aimed to evaluate the clinical characteristics of HVLPD and the association between whole blood EBV DNA and clinical outcomes. METHODS: We retrospectively reviewed our 25-year experience involving 11 patients with HVLPD from a single tertiary center in South Korea and evaluated the clinical characteristics of HVLPD and the correlation between whole blood EBV DNA and clinical outcomes. RESULTS: Of the total 11 patients, 54.5% (6/11) manifested classic HVLPD that resolved with conservative treatment, while 45.5% (5/11) patients had systemic HVLPD, four of whom died of progressive disease or hemophagocytic syndrome. Five patients with systemic HVLPD manifested severe skin lesions such as prominent facial edema, deep ulcers and necrotic skin lesions involving sun-protected areas. Median EBV DNA levels at initial diagnosis were higher in three dead patients than in those alive (2,290 vs. 186.62 copies/µl). CONCLUSION: When EBV DNA levels were high, patients showed severe skin lesions and when EBV DNA levels were low, skin lesions tended to improve. Thus, patients with high EBV DNA levels showed an increased risk of severe skin lesions and disease progression.

Gamma/Delta Phenotype in Primary Cutaneous T-cell Lymphomas and Lymphoid Proliferations: Challenges for Diagnosis and Classification.

Primary cutaneous T-cell lymphomas pose a diagnostic challenge for dermatopathologists, hematopathologists, and general surgical pathologists. Recognition of gamma/delta phenotype in cutaneous T proliferations has been enhanced by the availability of antibodies against TCRgamma and delta for immunohistochemistry. Thus, reporting gamma/delta phenotype in a cutaneous T-cell lymphoid proliferation may indicate a significant change in therapy and a challenge for dermatologists and oncologists who treat these patients. Herein, we discuss primary cutaneous gamma/delta T-cell lymphoma, its differential diagnosis, and other skin lymphoid proliferations that may show gamma/delta phenotype. Awareness of the occurrence of gamma/delta phenotype in both T-cell lymphomas and benign lymphoid proliferations involving skin is crucial for a better interpretation of histopathologic findings. Integration of clinical presentation, morphology, immunoprofile, and molecular findings is key for a correct diagnosis and appropriate therapy of lesions displaying gamma/delta T-cell phenotype.

Hydroa vacciniforme-like lymphoproliferative disorder: A clinicopathological, immunohistochemical, and prognostic study of 24 cases in China.

Hydroa vacciniforme-like lymphoproliferative disorder (HV-LPD) is a rare cutaneous disease associated with Epstein-Barr virus infection. We retrospectively analyzed the clinical presentation, histopathological characteristics, and prognostic study of HV-LPD in 24 Chinese patients. All patients presented with recurrent papulovesicular and necrotic eruptions on the face, neck, and extremities, with 11 showing systemic symptoms. Twenty patients were diagnosed with HV-LPD in childhood (age < 18 years) and four in adulthood (age ≥ 18 years). The median age at diagnosis was 8.5 years old (range, 2-50). Histopathology revealed variably dense lymphocyte infiltration throughout the dermis. All cases were strongly positive for CD3 and Epstein-Barr encoding region based on in situ hybridization. Of 18 cases with a T-cell phenotype, 15 harbored monoclonal rearrangements in T-cell receptor (TCR) genes. Four cases with a natural killer cell phenotype carried polyclonal rearrangements in TCR genes. Among 24 patients, eight (33.3%) received chemotherapy, two (8.3%) allogeneic hematopoietic stem cell transplantation, and both are currently alive without disease. The median follow-up period was 24 months (range, 7-120) and 23 patients were available: 15 (62.5%) were alive, and eight (33.3%) had died. Fourteen cases had a relapse of disease and three developed lymphoma within 24 months of diagnosis. The mean survival time of childhood-onset patients was longer than that of adult-onset patients (36.4 vs. 20.8 months). In summary, the wide clinical course and representative presentation of cases in our center reflect the pedigree characteristics of HV-LPD. Allogeneic hematopoietic stem cell transplantation should be a preferred choice for relapse and refractory patients due to the poor effect of chemotherapy. Adult-onset and high serum EBV DNA loads may indicate an increased risk of aggressive disease in patients with HV-LPD.

Hydroa Vacciniforme-like Lymphoproliferative disorder in an adult invades the liver and bone marrow with clear pathological evidence: a case report and literature review.

BACKGROUND: Hydroa Vacciniforme-like Lymphoproliferative Disorder (HV-LPD) is the name given to a group of Epstein-Barr virus (EBV)-associated diseases. It resembles hydroa vacciniforme (HV), the rarest form of photosensitivity, and is a T-cell disorder associated with an Epstein-Barr virus infection. The majority of diagnosed cases occur in East Asia and South America. It is rare in the United States and Europe. Multiple studies have revealed the clinical manifestation of an enlarged liver, but no gold standard such as pathology has yet supported this as a clinical sign of HV-LPD. CASE PRESENTATION: Here, we report a case of a 34-year-old Asian female with definite liver invasion. The patient had complained of a recurring facial rash for many years. The patient was admitted to the hospital because of an enlarged liver. After hospitalization, she was given an EB virus nucleic acid test. The EB virus nucleic acid test was positive, and pathological examination suggested that HV-LPD had invaded the skin, bone marrow, and liver. After being given antiviral treatment, the patient's symptoms were mitigated. CONCLUSIONS: Our case confirms the liver damage was caused by HV-LPD and the effectiveness of antiviral treatment.

Hydroa Vacciniforme and Hydroa Vacciniforme-Like Lymphoproliferative Disorder: A Spectrum of Disease Phenotypes Associated with Ultraviolet Irradiation and Chronic Epstein-Barr Virus Infection.

Hydroa vacciniforme (HV) is a rare form of photosensitivity disorder in children and is frequently associated with Epstein-Barr virus (EBV) infection, whereas HV-like lymphoproliferative disorders (HVLPD) describe a spectrum of EBV-associated T-cell or natural killer (NK)-cell lymphoproliferations with HV-like cutaneous manifestations, including EBV-positive HV, atypical HV, and HV-like lymphoma. Classic HV occurs in childhood with papulovesicules on sun-exposed areas, which is usually induced by sunlight and ultraviolet irradiation, and mostly resolves by early adult life. Unlike classic HV, atypical or severe HV manifests itself as recurrent papulovesicular eruptions in sun-exposed and sun-protected areas associated occasionally with facial edema, fever, lymphadenopathy, oculomucosal lesions, gastrointestinal involvement, and hepatosplenomegaly. Notably, atypical or severe HV may progress to EBV-associated systemic T-cell or natural killer (NK)-cell lymphoma after a chronic course. Although rare in the United States and Europe, atypical or severe HV and HV-like lymphoma are predominantly reported in children from Asia and Latin America with high EBV DNA levels, low numbers of NK cells, and T cell clones in the blood. In comparison with the conservative treatment used for patients with classic HV, systemic therapy such as immunomodulatory agents is recommended as the first-line therapy for patients with atypical or severe HV. This review aims to provide an integrated overview of current evidence and knowledge of HV and HVLPD to elucidate the pathophysiology, practical issues, environmental factors, and the impact of EBV infection.