Lymphomas Associated with HIV Infection

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Primary Author(s)*

Patricia V. Hernandez, M.D., Washington University School of Medicine

Cancer Category/Type

Immunodeficiency-Associated Lymphoproliferative Disorders

Cancer Sub-Classification / Subtype

Lymphomas Associated with HIV Infection

Definition / Description of Disease

Lymphomas associated with HIV infection are a heterogeneous group of aggressive B-cell non-Hodgkin lymphomas that arise in individuals with active HIV infection. They are not currently assigned a separate International Classification of Diseases for Oncology Code, instead they are grouped with other morphologically or phenotypically similar hematological malignancies in the WHO guidelines. [1] These diseases include, but are not limited to, lymphoproliferative disorders associated with Epstein-Barr virus (EBV) infected tumor cells such as plasmablastic lymphoma and primary effusion lymphoma. [1] Diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma, and primary central nervous system (CNS) lymphoma are stage 3 (i.e. acquired immunodeficiency syndrome (AIDS))-defining illnesses, in the context of preexisting HIV infection. [2] Hodgkin lymphoma is not an AIDS-defining illness, but the incidence of Hodgkin lymphoma is significantly increased in the context of HIV infection. Lymphomas associated with HIV infection can be categorized into the following groups:

Synonyms / Terminology

  • HIV-related lymphomas
  • AIDS-related lymphomas
  • HIV-associated cancers

Epidemiology / Prevalence

In a study involving 448,258 people living with HIV from 1996 to 2012 in the United States, 3,687 individuals presented with lymphomas associated with HIV infection, representing 17.3% of all cancers (21,294 cases) in HIV-infected population. [3] The most common type of HIV-related lymphoma observed was DLBCL, accounting for 48% of cases, followed by Burkitt lymphoma (18%). [4] The incidence of Hodgkin lymphoma is 5-20 times higher in HIV-positive patients than in HIV-negative control groups. [5] The severity of functional immunodeficiency of patients living with HIV infection, mainly assessed via the measurement of declining CD4 cell counts, is closely linked to the pathogenesis of HIV-related lymphomas. [5] HIV infection may contribute to the development of malignancy via multiple mechanisms, including downregulation of cellular and viral immunosurveillance, chronic inflammatory activation, and direct genetic damage by HIV. [4][6]

Clinical Features

Lymphoproliferative disorders may be the initial presentation of an HIV infection, particularly in the case of aggressive B-cell lymphomas or Hodgkin lymphomas. [1] The severity of CD4 count reductions correlates with the types of lymphoma most likely to develop, as shown in the below table.

Lymphoma type Signs and Symptoms CD4 count
DLBCL Extranodal and disseminated disease at presentation are more common in HIV-associated DLBCL. The central nervous and gastrointestinal systems are the most commonly involved extra-nodal sites. [7] CD4 < 200/μL [5]
Burkitt lymphoma The initial presentation is often due to symptoms associated with tumor expansion at sites of extra-nodal involvement (e.g. GI symptoms and cytopenias), although B symptoms (i.e. fever, night sweats, and weight loss) are also common. [8] CD4 > 200/μL[8][5]
AIDS-related primary CNS lymphoma Focal neurologic deficits, an altered level of consciousness, behavioral changes, seizures, and other symptoms related to intracranial mass effect are the main presentations. Imaging usually demonstrates enhanced single ring-enhancing CNS lesions. [9] CD4 < 100/μL [1]
Primary effusion lymphoma Originally described as an isolated malignant effusion of serous cavities (pleural, pericardial and/or peritoneal), however nodal and extra-nodal manifestations may occur. [1] Commonly seen with another HHV-8 related disease, such as Kaposi's sarcoma, KSHV-associated multicentric Castleman disease, or both. [1][5] Decreased [10][11]
Plasmablastic lymphoma Involvement of oral cavity and mandibular lesions are common. However, both nodal and extra-nodal manifestations may occur. [1] CD4 < 200/μL [5]
KSHV-associated multicentric Castleman disease Fever, cachexia, sweats, lymphadenopathy, hepatosplenomegaly and hypoalbuminemia. [1][12] Can coexist with plasma cell dyscrasias and in association with POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes). [5][12] No correlation with CD4 count [5]
Hodgkin lymphoma Associated with advanced age. B symptoms are more common than in HIV-negative patients. [1] Additionally, unusual presentations with extranodal symptoms may occur. [1] CD4 > 200/μL [5]

Sites of Involvement

Extra-nodal involvement is common [5][6][13]:

  • CNS
  • GI
  • Serous body cavities
  • Bone marrow
  • Oral cavity/pharynx

Morphologic Features

Morphologic features are heterogeneous and will depend on lymphoma type:

Lymphoma type Morphologic features
DLBCL B-cell neoplasm that is classified into:

- Germinal B-cell (mainly centroblastic variant): accounts for 25% of HIV-related DLBCL, being characterized by a diffuse proliferation of neoplastic cells with moderately abundant cytoplasm and round regular nuclei containing with two or more prominent nucleoli. [14]

- Non-germinal B-cell (mainly represented by activated/immunoblastic and plasmablastic variant): large blastic cells with a small basophilic cytoplasm and large nuclei. It presents Ki67-index higher than 80%. [14]

Burkitt lymphoma Similar to endemic and sporadic Burkitt lymphoma; classical starry-sky appearance, with small cells with abundant basophilic cytoplasm, round nuclei with two to four nucleoli. Tumors display high mitotic activity, with Ki67-index of 95% or higher. Can display plasmacytoid differentiation. [4][8][14]
AIDS-related primary CNS lymphoma Primary CNS lymphomas are DLBCL in the vast majority of cases (non-germinal center B-cell subtype). Rarely, they can display a more Burkitt-like morphology. [9]
Primary effusion lymphoma Monoclonal B-cell population, with mixed characteristics of anaplastic large-cell and plasmablastic lymphomas. [15] Cytoplasm is abundant and basophilic, with a large nucleus and prominent nucleoli. [16]
Plasmablastic lymphoma Features similar to activated B-cell DLBCL, a starry-sky pattern and/or high mitotic activity with Ki67-index > 80% may be seen. Malignant cells may be distinctive large plasmablasts with abundant basophilic cytoplasm and large nuclei. [4][16]
KSHV-associated multicentric Castleman disease Significant vascular proliferation and hyalinization is seen in lymph nodes, with germinal centers surrounded by lymphocytes arranged in onion-skin appearance. [12]
Hodgkin lymphoma Histologic features vary depending on CD4 count. In more severely immunocompromised individuals, there is a predominance of unfavorable histologic features (mixed cellularity and lymphocyte depletion), with unusually large proportions of Reed-Sternberg cells generally seen with EBV-coinfection. [1][17] Nodular sclerosis subtype is mostly seen in patients with higher CD4 count. [17]

Immunophenotype

Immunophenotype of lymphomas associated with HIV infection is displayed below:

Lymphoma type Marker
DLBCL CD10+ [18], CD20+ [1], CD45+ [6], CD30+, EBV+ [6], LMP1+ [6], BCL2+ [6], BCL6+/- [6], MUM1/IRF4+/- [6], CD138+/- [6]
Burkitt lymphoma CD20+ [1], CD10+ [1], BCL6+ [8], EBV+/- [8], BCL2- [8], CD30- [6]
AIDS-related primary CNS lymphoma CD10+ [9], CD20+ [1], BCL6+ [9], MUM-1+ [9], EBV+ [1]
Primary effusion lymphoma CD45+ [16], CD30+ [16], CD38+ [16], CD138+ [6], IL-2 R beta [16], EMA+ [16], EBV+ [1], HHV-8 [1], CD19- [16], CD20- [1], CD79a- [16], BCL6- [6]
Plasmablastic lymphoma EBV+ [1], CD38+ [5], CD138+ [5], MUM/IRF41+ [5], EMA+,CD20- [1], CD79a- [16], PAX5- [6], CD45 - [16]
KSHV-associated multicentric Castleman disease HHV-8+ [1], OCT2+ [12], BLIMP1+ [12], IRF4/MUM1+ [12][19], BCL6-[19], CD138+/- [19], CD79a- [19], EBV-, PAX- [12], BCL-6[12]
Hodgkin lymphoma CD138+, LMP1+ [17], MUM1 IRF4+ [17], BCL6- [17], EBV+ [1][17]

Chromosomal Rearrangements (Gene Fusions)

Chromosomal Rearrangement Genes in Fusion (5’ or 3’ Segments) Pathogenic Derivative Prevalence Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown)
t(8;14)(q24;q32) [1][8]

3'IGH::5'MYC [20]

der(14) [20] 79.1% of overall HIV-related non-Hodgkin lymphomas [21] Unknown Unknown in lymphomas associated with HIV infection Unknown
t(14;18)(q32;q21) [22] 5'BCL2::3'IGH [20] der(14) [20] 30% of HIV-associated DLBCL [23] Unknown Poor prognosis in the setting of DLBCL and HIV infection [22] Unknown

Individual Region Genomic Gain/Loss/LOH

None of the lymphomas associated with HIV infection display specific individual region genomic gains, losses or regions of loss of heterozygosity.

Characteristic Chromosomal Patterns

No lymphomas associated with HIV infection display characteristic chromosomal-level changes.

Gene Mutations (SNV/INDEL)

Gene; Genetic Alteration Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other) Prevalence (COSMIC / TCGA / Other) Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown)
TP53 [8][16]; SNV leading to missense or nonsense mutations TSG 37% of HIV-related lymphomas [21] Unknown Unknown in lymphomas associated with HIV infection Unknown
BCL-6; SNV in the 5' noncoding region of BCL-2 [24] Oncogene 58% of HIV-related lymphomas [24] Unknown Unknown in lymphomas associated with HIV infection Unknown
PAX5, RHO/TTF, PIM1: mutation occurs in 5' untranslated region overlapping with coding sequences [14] Oncogene 50% of HIV-related lymphomas [14] Unknown Unknown in lymphomas associated with HIV infection Unknown
Ras family; activation of Ras family proto-oncogenesis by SNVs at codons 12,13, and 61 [21] Oncogene Infrequent [21] Unknown Unknown in lymphomas associated with HIV infection Unknown
ID3, TCF3, CCND1: [8] SNV leading to missense, nonsense, splice-site mutations Oncogene 67% of HIV-associated Burkitt lymphoma [8] Unknown Unknown in lymphomas associated with HIV infection Unknown


Epigenomic Alterations

None of the lymphomas associated with HIV infection display characteristic epigenomic alterations.

Genes and Main Pathways Involved

The main pathways involved in HIV-driven lymphomagenesis are described below:

Pathway Pathophysiologic Outcome
NF-κB signaling In HIV-infected lymphoid cells, co-infection with EBV activates the NF-κB pathway via LMP-1, resulting in increased cell growth and decreased p53-induced apoptosis. In parallel apoptosis is also abrogated by enhanced expression of anti-apoptic proteins BCL2 and A20. [25]
pRb2/p130 signaling HIV-1 TaT binds to pRb2/p130, resulting in inactivation of its oncosuppressive features. This ultimately leads to the induction of oncogenes needed to proceed through the cell cycle including p107, cyclin A, and cyclin B. [23][26][27]
DNA polymerase β HIV-1 TaT protein interacts with cellular transcription factors to increase the steady-state levels of DNA polymerase β in B-cells, resulting in increased and potentially oncogenic DNA recombination, leading to the development of lymphoma. [23][28]
PI3K/Akt signaling activation The presence of HIV-1 matrix protein variant p17 has been demonstrated to activate the PI3K/Akt signaling pathway, resulting in increased B-cell proliferation. [29] S75X variants also upregulated LMP-1 expression, contributing to EBV-induced cell proliferation. [30]
bFGF and VEGF-A; Activating mutations HIV1-TaT enhances the angiogenic activities of bFGF and VEGF-A, also activates the VEGF receptor 2 in HIV-related cancers, and results in development of HHV-8-related malignancies in the setting of HIV infection. Furthermore, viral IL-6, encoded by HHV-8, stimulates B cell growth and angiogenesis via VEGF-A in primary effusion lymphoma and KSHV-associated multicentric Castleman disease. [31]
VCAM-1, E-selectin, ICAM-1 induction HIV-1 TaT can induce cell surface expression of vascular cell adhesion molecule-1 (VCAM-1) and E-selectin and concurrently increase the expression of ICAM-1. This results in increased lymphoma cells migration and adhesion to endothelial cells in the context of Burkitt and primary effusion lymphomas. [32]
LMP-1 induction via IL-10 overexpression with suppression of T-cells and macrophages HIV-1 TaT can induce IL-10 gene expression, which contributes to oncogenicity of EBV by inducing LMP-1, in addition to causing immunosuppression of T-cells and macrophages. [33][34]

Genetic Diagnostic Testing Methods

  • Fluorescence in situ hybridization (FISH)
  • Chromosome analysis
  • NGS

Familial Forms

N/A

Additional Information

N/A

Links

Diffuse Large B-cell Lymphoma, Not Otherwise Specified

Burkitt Lymphoma

Plasmablastic Lymphoma

Hodgkin Lymphomas

Primary Diffuse Large B-Cell Lymphoma of the CNS

References

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