Plasmablastic lymphoma

Plasmablastic lymphoma is a rare and aggressive type of cancer that affects white blood cells. It poses significant challenges in diagnosis and treatment, often occurring in people with weakened immune systems, particularly those with HIV infection.

Table of contents

• What is plasmablastic lymphoma?
• Who gets plasmablastic lymphoma?
• Causes and risk factors
• Signs and symptoms
• How is plasmablastic lymphoma diagnosed?
• Treatment approaches
• Outlook and prognosis

What is plasmablastic lymphoma?

Plasmablastic lymphoma (PBL) is an uncommon but aggressive subtype of diffuse large B-cell lymphoma, which is a cancer of the white blood cells. The disease was first described in 1997 by researcher Delecluse and colleagues in a case series of patients, most of whom had HIV infection.^[1] Since then, despite significant advances in understanding lymphomas, PBL continues to present challenges for both diagnosis and treatment.^[1]

This lymphoma develops when plasmablasts, which are cells that B-cells briefly become during their transformation into plasma cells, become cancerous.^[2] The disease is characterized by a diffuse proliferation of large cells that resemble B immunoblasts but have the characteristics of plasma cells. These cancer cells show a distinctive pattern where they typically do not express CD20, a protein usually found on B-cells, but instead express proteins associated with plasma cells.^[4]

PBL is recognized by the World Health Organization as belonging to a subgroup of lymphomas called lymphoid neoplasms with plasmablastic differentiation.^[3]

Who gets plasmablastic lymphoma?

Plasmablastic lymphoma is a rare disease that makes up about 2 percent of HIV-related lymphomas.^[2] The disease predominantly affects males, with about 73 percent of cases occurring in men.^[3] Additionally, approximately 3 out of 4 people with PBL are men.^[2]

Individuals presenting with PBL are typically middle-aged or elderly, with ages ranging from 1 to 88 years and a median age of 58 years.^[3] Although PBL can occur in people of all ages, it is rare in children.^[2] Only a few cases have been reported in pediatric patients.^[3]

In a large US study, 69 percent of PBL patients were found to be HIV positive, demonstrating a strong link between HIV infection and this disease.^[11] However, PBL can also occur in people without HIV infection, particularly those who are immunosuppressed for other reasons. About 5 percent of all individuals with PBL appear to be immunocompetent, meaning they have no apparent defect in their immune system.^[3]

Causes and risk factors

The exact cause of plasmablastic lymphoma is not fully understood. However, research strongly points to chronic viral infections and immune system dysfunction as important factors.^[11]

PBL often develops in people who have immunodeficiencies, which are disorders in which the immune system doesn’t work properly.^[2] About half of people with PBL have HIV infections.^[2] The disease is classically seen in association with HIV infection, and estimates suggest that around two-thirds of people with PBL also have HIV.^[11]

PBL has also been found in people who are not infected with HIV but have a weakened immune system for other reasons. These include individuals who have had an organ or bone marrow transplant, or those with underlying autoimmune disorders, which are conditions where the body mistakenly attacks its own healthy cells.^[11] Some elderly adults who have working immune systems also develop PBL.^[2] The development of this variant appears due, at least in part, to immunosenescence, which is the immunodeficiency occurring in old age.^[3]

Another viral infection linked with PBL is the Epstein-Barr virus (EBV), often known for causing mononucleosis. About 2 out of 3 people with PBL also have Epstein-Barr virus infections.^[2] EBV can cause gene changes that help B cells resist death and grow too quickly.^[2] More than half the cases of PBL have malignant plasmablasts infected with EBV.^[3] There’s also evidence suggesting that there could be a link between PBL and the HHV-8 virus, though this is still being studied.^[11]

Signs and symptoms

Plasmablastic lymphoma leads to tumors in various places within the body. The location of PBL cells determines which symptoms a person experiences.^[2] Patients usually present with extranodal masses, which are growths outside of the lymph nodes, involving the oral cavity or the gastrointestinal tract. Disease confined to lymph nodes without involvement of other areas is rare.^[1]

The most common tumor location, accounting for a little less than half of PBL cases and about 12 percent according to other data, is within the oral cavity (mouth).^[2][3] Oral PBL tumors usually don’t cause many symptoms. They may feel like a lump or a sore. Sometimes, they bleed.^[2]

PBL lesions occurred most commonly in lymph nodes (approximately 23 percent of cases), the gastrointestinal tract (approximately 18 percent), bone marrow (16 percent), and oral cavity (12 percent).^[3] Less frequently involved tissues include the skin, genitourinary tract, paranasal sinuses, lung, and bones.^[3][5]

• Oral cavity (mouth)
• Lymph nodes
• Gastrointestinal tract
• Bone marrow
• Skin
• Genitourinary tract
• Paranasal sinuses
• Lung
• Bones

PBL tumors in other parts of the body cause other symptoms, including lumps in the affected location. If tumors occur in the gastrointestinal (digestive) system, they may cause pain, diarrhea, or blood in the stool. PBL masses in the nose may lead to nosebleeds, a runny nose, or inflammation of the sinuses.^[2]

People with PBL who have had organ transplants are more likely to have PBL in the skin. Skin masses look like a lump or growth underneath the top skin layer.^[2] Plasmablastic lymphoma lesions are most commonly rapidly growing, soft tissue masses that may be ulcerating, bleeding, and/or painful.^[3]

Most types of lymphoma lead to enlarged lymph nodes, but this symptom is less common in people with HIV-positive PBL. However, about 1 out of 3 people who develop PBL after an organ transplant have swollen lymph nodes.^[2]

Some cases of PBL lead to B symptoms, which include drenching night sweats, fever, and unexpected weight loss. These symptoms are more common in people with HIV infections than in those without.^[2] Most individuals present with a widespread stage III or IV disease which in approximately 40 percent of cases is accompanied by B symptoms.^[3]

How is plasmablastic lymphoma diagnosed?

PBL is diagnosed primarily through histologic evaluation, which is a process where doctors closely examine the patient’s cells under a microscope. This may be done with or without genetics and immunophenotyping, which is a process of studying the proteins in and on cells.^[1][11] The first step in diagnosing PBL is often a physical exam. Doctors may ask about certain symptoms or look for lymphoma signs.^[2]

However, diagnosing PBL is difficult due to overlapping features with plasmablastic myeloma and other high-grade lymphomas with plasmablastic morphology.^[1] Each of the lymphomas in the subgroup of lymphoid neoplasms with plasmablastic differentiation have distinctive clinical, morphological, and abnormal gene features. However, key features of these lymphomas sometimes overlap with other lymphomas. In consequence, correctly diagnosing these lymphomas has been challenging.^[3]

This histology can be determined by positive histology (including peripheral blood) with or without genetics and/or immunophenotyping.^[5] The tumor cells showed large cells similar to immunoblastic B cells but expressed plasma cell associated antigens.^[4]

Genetic testing may reveal clonal IgH light chain rearrangement and MYC translocation (more common in EBV-positive cases).^[5] Gene expression analysis identified unique molecular features in PBL, including frequent c-MYC rearrangement and downregulation of BCR signaling pathway.^[4]

Immunophenotyping reveals distinctive patterns. The cells typically show CD20 weakly positive or negative, CD38 expression positive, CD138 expression positive, and expression of cytoplasmic immunoglobulins, most frequently IgG and either kappa or lambda light chain. EBV is positive in many cases. Other markers include CD79a positive, EMA positive, and IRF4/MUM1 expression. Ki67 proliferation index is usually very high. PAX5 is weakly positive or negative, and CD45 is weakly positive or negative.^[5]

Treatment approaches

Chemotherapy remains the cornerstone of the management of PBL and requires a multidisciplinary approach incorporating medical oncology and infectious disease experts.^[1] However, optimal treatment strategies remain unclear partly because of the relative rarity of this disease.^[1]

Several factors could impact the result, including achieving complete remission, performance status, clinical stage, MYC status, and the International Prognostic Index (IPI).^[8] Physically fit patients might benefit from a more intensive treatment protocol, such as DA-EPOCH, instead of the conventional CHOP regimen. Combinations with Bortezomib, Daratumumab, or Lenalidomide may be considered.^[8]

Patients who achieve complete remission following the initial treatment may be eligible for additional intensification through autologous bone marrow transplantation, which uses the patient’s own stem cells.^[8] PBL has an aggressive and relapsing course, which results in poor outcomes despite the institution of multi-drug intensive chemotherapy regimens and autologous stem cell transplantation.^[1]

The effectiveness of rituximab is reduced since tumor cells do not have CD20 expression, although it may be employed in certain rare CD20-positive cases.^[8] CNS prophylaxis can be considered on a case-by-case basis.^[8]

It is highly recommended that patients who are HIV-positive and receiving chemotherapy utilize combination antiretroviral treatment (cART). Healthcare providers should consider the possibility of simultaneous toxicity.^[8]

Individuals with persistent or recurring illnesses that do not respond to treatment should consider palliative care.^[8] Consolidation and palliative care applications can benefit from radiation therapy as an effective approach.^[8]

New drugs like Bortezomib, Daratumumab, Lenalidomide, Brentuximab vedotin, PD1/PDL1 blocking agents, and Selinexor can be used to treat cases that have relapsed or are not responding to treatment.^[8]

Outlook and prognosis

Plasmablastic lymphomas are aggressive and rare malignancies that usually respond poorly to chemotherapy and carry a very poor prognosis.^[3] Despite recent advances in the treatment of PBL, the prognosis of PBL patients remains dismal.^[4]

The range of median progression-free survival is between 6 and 11 months, whereas the most recent reported median overall survival is from 14 to 57 months.^[8] Individuals with limited stages of the disease, especially among pediatric populations, have achieved long-term survival.^[8]

Multivariate analysis showed that EBER (Epstein-Barr virus encoded RNA) remained the only independent factor affecting overall survival.^[10]

PBL

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