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Author: Dr Selene Ting, Medical Registrar, Middlemore Hospital, Auckland, New Zealand. DermNet NZ Editor in Chief: Adjunct A/Prof Amanda Oakley, Dermatologist, Hamilton, New Zealand. Copy edited by Gus Mitchell. September 2019.
Epstein–Barr virus (EBV), also known as human herpesvirus 4 (HHV-4), is one of the eight known lymphotropic herpesviruses .
The pathogenesis of EBV conforms to the following process .
EBV-associated lymphoproliferative disorders are rare; the criteria for which are:
EBV-associated lymphoproliferative disorders can occur as a result of latency dysregulation with:
The classification of EBV-associated lymphoproliferative disorders is based on the lineage of the target cells, B, T, and natural killer (NK) cells .
EBV-associated B-cell lymphoproliferative disorders include :
EBV-associated T-cell and NK-cell lymphoproliferative disorders include :
EBV has been most directly implicated in the latter two types .
The cutaneous features of lymphoproliferative disorders associated with EBV mainly arise from infected T cells or NK cells. These cutaneous manifestations are seen in:
According to the current World Health Organization (WHO) classification of haematolymphoid tumours, extranodal NK/T cell lymphoma is a rare but extremely aggressive form of lymphoma . Most of the patients with this type of lymphoma present with cellulitis or a facial ulcer .
Subcategories are based on their anatomical sites of involvement :
When extranodal NK/T-cell lymphoma presents initially with skin signs, it is known as primary cutaneous extranodal NK/T-cell lymphoma. Nasal NK/T-cell lymphoma can also present with cutaneous metastases .
Nasal-type extranodal NK/T-cell lymphoma typically includes nodules, and less commonly, ulceration on the abdomen and extremities . Nasal-type NK/T-cell lymphoma is clinically less aggressive and more localised than the nasal type.
The diagnosis of extranodal NK/T-cell lymphoma depends on its staging, and involves completing the following investigations :
Histologically, extranodal NK/T-cell lymphoma is characterised by EBV-positive atypical lymphoid cytotoxic infiltrate, vascular destruction, and tissue necrosis (see DermNet NZ's page on extranodal NK/T-cell lymphoma, nasal type, pathology).
Treatment of extranodal NK/T-cell lymphoma is dependent on its staging .
EBV-MCU was added to the 2016 WHO classification and is a localised condition that does not involve the lymph nodes, bone marrow, liver, or spleen. It usually presents as a painful solitary, well-demarcated ulcer in the oropharynx, skin, or gastrointestinal tract and may be associated with weight loss .
Predisposing factors for EBV-MCU include:
The pathogenesis of EBV-MCU correlates with a diminished T-cell population in immunosuppressed patients, resulting in the proliferation of restricted clones of EBV-specific T cells in the body. This leads to a localised EBV-driven lymphoproliferation as the immune system can only keep the virus in a dormant state .
The diagnostic work-up for EBV-MCU usually involves histological evaluation with immunohistochemistry. The EBV viral load is typically negative. Histologically, the lesions are made up of infiltrates of lymphocytes, plasma cells, histiocytes, and eosinophils, with atypical large B-cell blasts resembling Hodgkin Reed–Sternberg cells. As a result of its similar histological features to other B-cell proliferative cancers, misdiagnoses of classical Hodgkin lymphoma or diffuse large B cell lymphoma have occurred .
The disease course for EBV-MCU typically waxes and wanes and is relatively benign. Patients can spontaneously remit or have a complete clinical response to a reduction in immunosuppressive therapies. However, some cases have a persistent debilitating course requiring aggressive therapy [3,11].
Treatment options include:
Lymphomatoid granulomatosis is a rare disorder where there is an overproduction of abnormal B cells infected by EBV . The cells infiltrate and accumulate within various tissues in the body.
The symptoms of lymphomatoid granulomatosis vary depending on the organs affected.
Cutaneous lymphomatoid granulomatosis may present with :
Biopsy of lymphomatoid granulomatosis tends to show an infiltrate of atypical B cells and polymorphous T cells, with inflammation and necrotic foci within the lymphoid cells . A biopsy is not always reliable as the characteristic abnormal cells may be missing.
Treatment for lymphomatoid granulomatosis depends on the number of EBV-positive B cells and the extent of necrosis . Some patients can spontaneously remit, but most will require treatment with interferon alfa-2b or combination chemotherapy with rituximab.
PBL is a rare but aggressive subtype of diffuse large B-cell lymphoma . It is frequently associated with underlying immunosuppression in patients with HIV or solid organ transplantation, but PBL can also affect immunocompetent patients . Many cases of PBL are associated with EBV, which has important therapeutic implications . Some studies have reported that EBV positivity is not predictive of outcome, while others have reported that it denotes a better prognosis .
PBL tends to be confined to the oral cavity and jaw, but it can also involve the skin, lymph nodes, bone marrow, lungs, and intestines . In the post-transplant setting, the skin and lymph nodes are the more common sites of disease distribution .
Primary cutaneous PBL is very rare. Clinical features include purple nodules, erythematous infiltrated plaques, and ulcerative or infiltrative lesions on the legs [15,17].
Treatment for PBL has not been standardised. The options for treatment include:
The prognosis of PBL is poor, with overall median survival of 8 months .
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