Epstein–Barr virus-associated lymphoproliferative disorders

What is Epstein–Barr virus?

Epstein–Barr virus (EBV), also known as human herpesvirus 4 (HHV-4), is one of the eight known lymphotropic herpesviruses [1].

• EBV most commonly causes infectious mononucleosis, also known as glandular fever, which is characterised by fever, sore throat, and lymphadenopathy [2].
• Most individuals are exposed to EBV during the first few decades of life and are asymptomatic [2,3]. After the primary infection, the EBV virus remains latent in memory B-cells, and for most people, does not have any major health consequences [4].
• In some cases, EBV can potentiate (increase the effectiveness of) B-cell transformation and cause a lymphoproliferative disorder.

What is the pathogenesis of Epstein–Barr virus infection?

The EBV virus firstly infects the epithelium of the oropharynx (back of the throat) and salivary glands and is shed from these cells [2].

• The virus then infects nearby B-cells either directly in the tonsillar crypts or after contact with the epithelial cells.
• The circulating infected B-cells then spread through the bloodstream.
• The proliferation of the EBV-infected B-cells leads to enlargement of lymphoid tissues, including the lymph glands.
• The B-cells infect any reactive T-cells that it contacts in turn.
• The virus is passed from person to person by oral secretions.

What are Epstein–Barr virus-associated lymphoproliferative disorders?

EBV-associated lymphoproliferative disorders are rare; the criteria for which are:

• One or more types of lymphoid cell are infected with EBV
• The infected lymphoid cells can divide excessively and lead to the development of a benign disorder or a malignancy [5]
• EBV-associated malignancies include B-cell lymphoma, T-cell lymphoma, and the non-lymphoproliferative cancers, nasopharyngeal and gastric carcinoma [2]
• EBV-associated lymphoproliferative disorders as a result of latency dysregulation can occur with:
• Human immunodeficiency virus infection and acquired immune deficiency syndrome (HIV/AIDS)
• Other forms of immunodeficiency 
• Immunosuppressive therapy after solid organ transplantation
• Age-related immunosenescence [4,6].

How are Epstein–Barr virus-lymphoproliferative disorders classified?

The classification of EBV-associated lymphoproliferative disorders is based on the lineage of the target cells: B, T and natural killer (NK) cells [7].

EBV-associated B-cell lymphoproliferative disorders include:

• Burkitt lymphoma
• Classical Hodgkin lymphoma
• Post-transplant lymphoproliferative disorder
• HIV-associated lymphoproliferative disorders
• Other histotypes [7].

EBV-associated T-cell and NK-cell lymphoproliferative disorders include:

• Peripheral T-cell lymphoma
• Chronic active EBV infection of T-cell and NK-cell type (with cutaneous and systemic forms)
• Angioimmunoblastic T-cell lymphoma
• Extranodal nasal NK/T-cell lymphoma [7].

EBV has been most directly implicated in the latter two types.

What are the cutaneous manifestations of Epstein–Barr virus-associated lymphoproliferative disorders?

The cutaneous features of lymphoproliferative disorders associated with EBV mainly arise from infected T-cell or NK-cells. They are seen in:

• Extranodal NK/T-cell lymphoma [1]
• EBV-positive mucocutaneous ulcer [5]
• Lymphomatoid granulomatosis
• Plasmablastic lymphoma [8].

Extranodal NK/T-cell lymphoma

According to the current World Health Organisation (WHO) classification of haematolymphoid tumours, extranodal NK/T cell lymphoma is a rare but extremely aggressive form of lymphoma [7]. Most of the patients with this type of lymphoma present with cellulitis or a facial ulcer [8].

Subcategories based on their anatomical sites of involvement:

• ‘Nasal’ NK/T-cell lymphoma usually involves the upper digestive tract
• ‘Nasal-type’ NK/T-cell lymphoma involves the skin, soft tissue, gastrointestinal tract and testis [8].

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 [9].

Nasal-type extranodal NK/T-cell lymphoma typically includes nodules, and less commonly, ulceration on the abdomen and extremities [10]. Nasal-type NK/T-cell lymphoma is clinically less aggressive and more localised than the nasal type.

The diagnosis of extranodal NKTL depends on its staging, which is completed by the following investigations [9]:

• Flexible nasal pan-endoscopy with biopsies evaluating nasal involvement
• Bone marrow biopsy
• CT scan of the chest, abdomen, and pelvis
• Skin biopsy of any suspicious cutaneous lesion.

Histologically, extranodal NK/T-cell lymphoma is characterized by EBV-positive atypical lymphoid cytotoxic infiltrate, vascular destruction, and tissue necrosis. See extranodal NK/T cell lymphoma, nasal type, pathology.

Treatment of extranodal NK/T-cell lymphoma is dependent on its staging [9].

• Systemic chemotherapy is usually offered.
• Radiotherapy is beneficial in patients with stage I or II disease limited to the nasal cavity.
• Antiviral therapy is used for patients with high EBV load.
• Allogeneic haematopoietic stem cell transplantation may be considered.
• Monoclonal antibodies are undergoing investigation.

Epstein–Barr virus-positive mucocutaneous ulcer

EBV-positive mucocutaneous ulcer (EBVMCU) 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 [5].

Predisposing factors include:

• Immunosuppressants
• Methotrexate
• Azathioprine
• Tacrolimus
• Mycophenolate
• Tumour necrosis factor-alpha inhibitors (anti-TNF α)
  
• Topical steroids [11]
• Age-related immunosenescence
• Primary immunodeficiencies [3].

The pathogenesis of EBVMCU 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 [11].

Work up of EBVMCU 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 (HRS) cells. As a result of similar histological features to other B-cell proliferative cancers, misdiagnoses of classical Hodgkin lymphoma or diffuse large B cell lymphoma (DLBCL) have occurred [6].

The disease course for EBVMCU 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:

• Monoclonal antibodies such as CD20- (eg, rituximab) or CD30-directed antibody therapy
• Local radiation therapy
• Local surgical excision
• Systemic chemotherapy
• Combination therapy.

Lymphomatoid granulomatosis

Lymphomatoid granulomatosis is a rare disorder where there is an overproduction of abnormal B-cells infected by EBV [12]. The cells infiltrate and accumulate within various tissues in the body.

The symptoms of lymphomatoid granulomatosis vary depending on the affected organs.

• Lymphomatoid granulomatosis of the lungs causes shortness of breath, cough and chest pain.
• Other sites are the central nervous system, kidneys, liver, and skin.
• Systemic symptoms may occur, such as malaise, fever, and weight loss.

Cutaneous lymphomatoid granulomatosis may present with:

• Macules or patches
• Papules or plaques
• Subcutaneous or dermal nodules
• Ulceration.

Biopsy shows an infiltrate of atypical B-cells and polymorphous T-cells with inflammation and necrotic foci within the lymphoid cells [13]. 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 [12]. Some patients can spontaneously remit, but most will require treatment with interferon alfa-2b or combination chemotherapy with rituximab.

Plasmablastic lymphoma

Plasmablastic lymphoma (PbL) is a rare but aggressive subtype of diffuse large B-cell lymphoma (DLBCL) [14]. It is frequently associated with underlying immunosuppression in patients with HIV or solid organ transplantation, but can also affect immunocompetent patients [15]. Many cases of PbL are associated with EBV, which has important therapeutic implications [14]. Some studies have reported that EBV positivity is not predictive of outcome, whilst others have reported that it denotes a better prognosis [16].

Plasmablastic lymphoma tends to be confined to the oral cavity and jaw, but can also involve the skin, lymph nodes, bone marrow, lungs, and intestines [17]. In the post-transplant setting, skin and lymph nodes are the more common sites of disease distribution [18].

Primary cutaneous plasmablastic lymphoma is very rare. Clinical features include purple nodules, erythematous infiltrated plaques, and ulcerative or infiltrative lesion on the legs [15,17].

Treatment for PbL has not been standardised. The options for treatment include:

• Chemotherapy
• Surgical excision
• Combination treatment
• Highly active antiretroviral therapy (HAART) in the case of HIV-related plasmablastic lymphoma.

The prognosis of PbL is poor, with an overall survival median of 8 months [16].