Hydroa Vacciniforme-like Epstein-Barr Virus-associated Lymphoproliferative Disease in a Child
A case of hydroa vacciniforme-like Epstein-Barr virus-associated lymphoproliferative disease (LPD) in a 9-year-old boy is reported in this paper. The patient had recurrent fever for 3 months accompanied by skin lesions. Immunohistochemistry of a skin biopsy revealed that the lymphocytes were positive for T cell markers. Flow cytometric analysis of peripheral blood showed a significantly increased percentage of natural killer cells and 91% CD158i monoclonal expression. The conclusion of the skin histopathology was EBV-positive cutaneous LPD. Laboratory tests on peripheral blood and immunohistochemistry of the skin biopsy confirmed that the child was infected with Epstein-Barr virus. Note: CD158i (Official Full Name: killer cell immunoglobulin-like receptor, two domains, short cytoplasmic tail, 4)
Keyword : Epstein-Barr virus; Lymphoproliferative disease; T/natural killer cell
Hydroa vacciniforme (HV) is a chronic photosensitivity disorder induced by ultraviolet (UV) radiation, and is characterised by recurrent vacciniform vesicles, necrotic ulcers, and healing by atrophic scarring on sun-exposed areas in childhood. In atypical HV induced by latent Epstein-Barr virus (EBV) infection, patients with severe HV-like eruptions usually have high fever, liver dysfunction, hepatomegaly or splenomegaly, and oedematous swelling of the cheeks, eyelids, ears, and lips.1 We report a case of CD158i monoclonal expression in HV-like EBV-associated lymphoproliferative disease (LPD).
A 9-year-old boy presented to our paediatric department with a 3-month history of recurrent fever accompanied by skin lesions. Three months ago, the boy had a fever (38°C-40°C) and developed blisters involving his scalp, face, and extremities. The boy received multiple antibiotics and different kinds of antihistamine drugs in local hospitals, but the skin lesions increased in severity, along with swelling on his face and eyelids. The skin lesions exhibited a slowly progressive relapsing course, changing from oedema, to blistering, ulceration, and final scarring. The boy had a history of hypersensitivity to mosquito bites, but not to sun-exposure.
On examination, swelling of the face and eyelids was present. The skin lesions were polymorphic presenting with vesicles, bulla, necrosis, atrophic scars, and ulceration, which involved the scalp, lower left limb, and both forearms(Figure 1). The liver was enlarged and palpable at two centimetres below the costal margin. The enlarged lymph nodes of the right armpit and groin were about one centimetre in diameter.
A punch biopsy was performed on a vesicle lesion of the left lower limb. Histopathological examination showed presence of lymphocytes, eosinophils, and neutrophils in the bulla. Acute and chronic inflammatory cells infiltrated the dermis and subcutaneous tissue. Acute inflammatory cells were in the majority. Vasculitis and focal necrosis were seen in the corium layer. Lymphoid cells had no obvious nuclear polymorphism or atypia. Immunohistochemical staining showed that the lymphocytes were positive for CD4 (Figure 2a), CD5, CD7, CD20, TIA-1, and Ki67 at 60%; strongly positive for CD3 (Figure 2b) and CD8 (Figure 2c); and negative for CD30, CD79a, and Granzyme B. T lymphocytes showed EBER positivity in the skin biopsy. The conclusion of the skin histopathology was EBV-positive cutaneous LPD.
A trephine biopsy was performed on the posterior superior iliac spine. The results showed that bone marrow granulocyte series were inactive, granulocytes were reduced at all stages, with no obvious abnormality in morphology. Erythrocyte series hyperplasia was active, intermediate and late erythroblast hyperplasia was dominant, and no obvious abnormality was found in morphology. There were three megakaryocytes in all sections. However, CD56 was not tested in the bone marrow.
On laboratory examination, the patient had mild anaemia (haemoglobin 96 g/L), leukopenia (3.56x109/L), neutrophils 45.1%, lymphocytes 40.5%, and a normal platelet count. No atypical lymphocyte was found on the peripheral blood smear. Blood biochemical analysis was unremarkable except increased aspartate aminotransferase(AST 104 U/L, normal 5-50 U/L), alanine aminotransferase (ALT 199 U/L, normal 5-55 U/L). The percentage of CD3+ T, CD4+ T, CD8+ T, CD20+ B, and CD56+ natural killer (NK) cells from the patient was 30.36%, 18.1%, 5.67%, 2.20%, and 36.29%, respectively, as determined by flow cytometric analysis in peripheral blood. NK cells mostly expressed 91% CD158i, which was monoclonal expression. Serum IgE (3550, normal 0-100 IU/ml) was elevated, but IgG, IgA, IgM, C3, and C4 was normal. Ultrasonic scan showed slight enlargement of the liver. Other results were negative, including antinuclear antibody spectrum, bone marrow aspiration, computed tomography scan of the abdomen, chest X-ray, and electrocardiogram.
The EBV viral capsid antigen (VCA) IgG, EBV nuclear antigen IgG, and anti-EBV early antigen IgG were positive, but EBV VCA IgM andanti-EBV early antigen IgM were negative. The viral load of EBV DNA was 812.5 IU/ml of whole blood. EBV-encoded small nuclear RNA (EBER)-positive cells were detected in the dermis using in situ hybridisation (Figure 2d).
In our case based on a long history of recurrent fever accompanied by skin lesions, hepatomegaly, and skin biopsy investigations indicating detection of EBER, a diagnosis of HV-like EBV-associated LPD was confirmed. According to the therapeutic approaches for EBV-associated LPD proposed by previous reports,2,3 this patient was treated intravenously with ganciclovir (5 mg/kg/12 hours) for two weeks, methylprednisolone (2 mg/kg/day) for two days, immunoglobulin (1 g/kg) for three days, and orally with prednisolone (0.67 mg/kg/day) for six days, and cyclosporin A (4 mg/kg/day) for six days. The patient was treated with systemically for twenty days, the fever and skin lesions were relieved. We advised him to avoid mosquito bites and sun exposure in open air, as skin lesions could be triggered or aggravated by sun exposure.1 The patient has been followed up for 4 years since diagnosis. He relapsed after one month of leaving hospital. On follow-up (before stem cell transplantation), fever and skin lesions were recurrent, lymphadenopathy was not getting more prominent, hepatomegaly and liver function did not worsen, but EBV DNA was persistently positive in blood. He underwent successful stem cell transplantation at the age of 10 years and is now 13 years old with no evidence of recurrence.
Hydroa vacciniforme-like EBV associated LPD is a rare EBV-associated lymphoma that mainly occurs in children in Asia and Latin America, more in males than in females. It was initially designated under the 2008 World Health Organization (WHO) classification as a distinct entity in tumours of haematopoietic and lymphoid tissues, but in 2016, WHO designated it as Hydroa vacciniforme-like LPD (HVLPD).4 EBV-T/NK-LPD are closely related to latent EBV infection or chronic active Epstein-Barr virus (CAEBV) infection. Though CAEBV was described as a persistent EBV infection targeting B cells, the syndrome has now been primarily associated with EBV infection of T cells and less often NK cells.5
EBV-T/NK-LPD shows various clinical patterns according to the EBV-infected cell type, clonality, and morphology of infiltrated lymphocytes. Chronic active EBV infection behaves differently depending on the involvement of T cells or NK cells. The T-cell type has a poor prognosis and is characterised by fever, hepatomegaly, and high titres of EBV-related antibodies. The NK-cell type frequently includes hypersensitivity to mosquito bites, large granular lymphocytosis, and a high IgE titre accompanied with a better prognosis.6 Most infiltrating lymphoid cells in skin biopsy specimens from HV, HV-like LPD, and HV-like lymphoma express TIA-1, CD45RO, CD3, CD4, and CD8 but lack CD20 and CD56.7 The lymphoid cells had obvious nuclear polymorphism or atypia in HV-like lymphoma. At present, the diagnosis of EBV-T/NK-LPD depends on clinical characteristics and pathology. T-cell receptor gene rearrangement is useful for diagnosing T-cell LPD, and the positive rate is about 73.3%; so, even negative could not be ruled out.8 Flow cytometry of peripheral blood showed a significantly increased percentage of NK cells and 91% CD158i monoclonal expression. Large granular lymphocytosis and high IgE titres were consistent with NK-cell type LPD. In our case, HVLPD could be diagnosed based on clinical features, laboratory examination, and pathological biopsy.
Our case illustrates HV as a manifestation of chronic active EBV infection with lymphocyte proliferation. Some experts suggest that HV, HV-like LPD, and HV-like lymphoma represent variants along the same disease spectrum of EBV-associated LPD. EBV-associated LPD is a risk factor for developing systemic lymphoma.3 There are several effective treatments for EBV-T/NK-LPD, including antiviral agents, IFN-γ, thalidomide, systemic corticosteroids, cyclosporine A, and allogenic haematopoietic stem cell transplantation.2,3,9 Currently, there are no guidelines for the standard treatment of patients with HVLPD, and so, an individualised treatment approach for each patient should be considered. In a previous study, the average survival time after diagnosis of HVLPD was 20.8 months in the adult group and 56.3 months in the children group. The 5-year survival rates were 50% and 85.7% in adults and children.10
In summary, although many cases of HVLPD have been reported, misdiagnosis or mistreatment is common. HVLPD usually takes several months or years to be diagnosed due to lack of experience. If a patient has recurrent fever with skin lesions for more than one month, with EBV DNA or EBV antibody positivity in blood, HVLPD should be considered. Clinical features including presentations and evidence of CAEBV infection are helpful in HVLPD diagnosis. Skin biopsy is essential for final diagnosis.
This work was supported by Fund (LGF19H100002) from Zhejiang basic public welfare research project.
Conflict of Interest
There are no conflicts of interest to declare. This work was supported by Fund.
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