Epstein-Barr virus-associated lymphoproliferative disorders

What is the Epstein-Barr virus?

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

• EBV most commonly causes infectious mononucleosis, also known as glandular fever, characterized by fever, sore throat and lymphadenopathy [2].
• Most people are exposed to EBV during the first decades of life and are asymptomatic [2,3]. After the primary infection, the EBV virus remains latent in B-cell memory, and for most people, it has no major health consequences [4].
• In some cases, EBV can enhance (increase the effectiveness of) B cell transformation and cause a lymphoproliferative disorder.

Which is the Pathogenesis from Epstein-Barr virus infection?

EBV virus infects first 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.
• Circulating infected B cells spread through the bloodstream.
• the proliferation of EBV-infected B cells leads to enlargement of lymphoid tissues, including lymphatic glands.
• B cells infect reactive T cells which they contact in turn.
• The virus is transmitted from person to person through oral secretions.

What are Epstein-Barr virus associated lymphoproliferative disorders?

Lymphoproliferative disorders associated with EBV are rare; The criteria for which are:

• One or more types of lymphoid cells are infected with EBV
• Infected lymphoid cells can divide excessively and lead to the development of a benign disorder or a malignancy [5]
• EBV-associated malignancies include B cells lymphoma, T cell lymphoma and non-lymphoproliferative cancers, nasopharyngeal and gastric carcinoma [2]
• Lymphoproliferative disorders associated with EBV as a result of latency deregulation can occur with:

  • Human immunodeficiency virus infection and acquired immune deficiency syndrome (HIV/AIDS)

  • Other forms of immunodeficiency

  • Immunosuppressive therapy after solid Organ transplant

  • 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
• Classic Hodgkin lymphoma
• Send-transplant lymphoproliferative disorder

• Lymphoproliferative disorders associated with HIV.

• Other histotypes [7].

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

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

The VEB has been more directly implicated in the last two types.

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

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

• Extranodal NK / T cell lymphoma [1]

• Positive EBV mucocutaneous ulcer [5]

• Lymphomatoid granulomatosis

• Plasmoblastic lymphoma [8].

Extranodal NK / T cell lymphoma

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

Subcategories based on their anatomical sites of participation:

• "Nasal" NK / T cell lymphoma usually affects the upper digestive tract
• NK / T cell lymphoma of the "nasal" type affects the skin, Soft fabric, gastrointestinal tract and testis [8].

When extranodal NK / T cell lymphoma initially presents with cutaneous signs, it is known as primary extranodal cutaneous NK / T cell lymphoma. Nasal NK / T cell lymphoma can also present with metastasis [9].

Nasal type extranodal NK / T-cell lymphoma typically includes nodulesand less often ulceration in the abdomen and extremities [10]. Nasal NK / T cell lymphoma is clinically less aggressive and more located than the nasal type.

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

• Flexible nasal breadendoscopy with biopsies assess nasal involvement
• Bone marrow biopsy
• Connecticut examination of the chest, abdomen and pelvis

• Skin biopsy of any suspicious skin. injury.

Histologically, extranodal NK / T-cell lymphoma characterized by positive EBV 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 it is dependent in its staging [9].

• Systemic chemotherapy It is usually offered.
• Radiotherapy it is beneficial in patients with stage I or II disease limited to the nasal cavity.
• Antiviral The therapy is used for patients with a high EBV burden.
• Allogeneic hematopoietic stem cell transplantation may be considered.
• Monoclonal antibodies are being investigated

Epstein-Barr virus positive mucocutaneous ulcer

EBV-positive mucocutaneous ulcer (EBVMCU) was added to the 2016 WHO classification and is a localized condition that does not involve lymph nodes, bone marrow, liver or spleen. Usually comes across as a painful loner, 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
  • Tumor necrosis factor alpha (anti-TNF alpha) inhibitors
  • Current steroids [11]
• Age-related immunosenescence
• Primary immunodeficiencies [3].

The pathogenesis of EBVMCU is correlated with a decrease in the T cell population in immunosuppressed patients, resulting in the proliferation of restricted clones of EBV-specific T cells in the body. This leads to localized EBV-driven lymphoproliferation as the immune system can only maintain the virus in a latent state [11].

Making EBVMCU generally involves histological evaluation with immunohistochemistry. The EBV viral load is typically negative. Histologically, the lesions are formed by infiltrators of lymphocytes, plasma cells, histiocytes and eosinophils with atypical large B-cell blasts that resemble Hodgkin Reed-Sternberg (HRS) cells. As a result of histological characteristics similar to other B cells proliferative cancers, classic Hodgkin lymphoma misdiagnosis, or diffuse big Cell B lymphoma (DLBCL) has occurred [6].

The disease course for EBVMCU generally waxes and wanes and is relatively benign. Patients may 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 directed by CD30 antibody therapy
• Local radiotherapy
• Local surgical excision
• Systemic chemotherapy
• Combination therapy

Lymphomatoid granulomatosis

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

Symptoms of lymphomatoid granulomatosis vary depending on the organs affected.

• 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 discomfort, fever and weight loss.

Cutaneous lymphomatoid granulomatosis can present with:

• Macules or patches
• Papules or plates
• Subcutaneous or dermal nodules
• Ulceration

The biopsy shows an infiltrate of atypical B cells and polymorphous T cells with inflammation and necrotic foci within 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 degree of necrosis [12]. Some patients may remit spontaneously, but most will require treatment with interferon alfa-2b or chemotherapy combined with rituximab.

Plasmoblastic lymphoma

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

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

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

Treatment for PbL has not been standardized. Treatment options include:

• Chemotherapy
• Surgical excision
• Combined treatment
• Highly active antiretroviral therapy (HAART) in HIV-related plasmablastic lymphoma.

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