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Overview

Practice Essentials

Acquired immune deficiency syndrome (AIDS)–related lymphoma is a subset of lymphomas commonly encountered in patients infected with human immunodeficiency virus (HIV).^[1]Most are aggressive lymphomas of B-cell origin^[2] and include the following subtypes^[3]:

Non-Hodgkin lymphoma (NHL)
Hodgkin lymphoma (HL)
Primary effusion lymphoma
Primary central nervous system (CNS) lymphoma

AIDS-related NHLs include the following:

Diffuse large B-cell lymphoma (DLBCL), immunoblastic variant
Burkitt lymphoma
Plasmablastic lymphoma
Other lymphomas (eg, indolent B-cell lymphoma, T-cell and natural killer [NK]-cell lymphoma)

Pathophysiology

The pathogenesis of NHL development in the setting of HIV infection is not well elucidated. However, the following factors are thought to play an important role:

Chronic B-cell stimulation ^[4]
Cytokine dysregulation
Co-infection with oncogenic viruses (Epstein-Barr virus [EBV], human herpesvirus 8 [HHV-8], hepatitis B and C viruses) in the setting of immune dysregulation, resulting in decreased surveillance for tumor antigens ^{[5, 6]}
Genetic abnormalities (decreased BCL-2 activation and increased BCL-6 and MYC expression) ^{[7, 8]}

Different clinicopathologic categories of AIDS-related lymphomas arise from distinct B-cell subtypes, and the factors mentioned above interplay in varying proportions to give rise to different varieties of NHL.

Epidemiology

It is estimated that 25% to 40% of patients with HIV infection will develop a malignancy and approximately 10% will develop NHL.^[9] AIDS-related lymphoma is more common in males than in females.^[10]With the advent of anti-retroviral therapy (ART), the incidence rate of AIDS-defining lymphoma has substantially declined; however, it still remains substantially higher compared with the general population.^[11] A meta-analysis of over 400,000 patients showed the observed rate of lymphoma development in the HIV population to be 11.03 times that of the general population.^[12]

Up to 85% of AIDS-related lymphomas are highly aggressive and include DLBCL, immunoblastic variant; and Burkitt lymphoma. Incidences and relative risks of AIDS-related lymphomas are shown in Table 1, below.^{[13, 14, 15, 16, 17]}

Table 1: Incidence and relative risk of AIDS-related lymphoma subtypes (Open Table in a new window)

Lymphoma subtype	Incidence (% of HIV-related lymphomas)	Relative risk (compared with the general population)
DLBCL, immunoblastic variant	64	652
Burkitt lymphoma	21	260
Indolent B-cell lymphoma	< 10	15
T-cell lymphoma	3	15
Hodgkin lymphoma	< 10	15-30
Primary CNS lymphoma	2-6	1000
Plasmablastic lymphoma	3	>1000
Primary effusion lymphoma	< 1	>1000

Risk Factors

Risk factors for developing AIDS-related lymphoma include the following:^[18]

Low CD4 count - A study of 52,278 patients from the French Hospital Database found CD4 cell count to be the most predictive risk factor of AIDS-related cancer incidence: Hodgkin lymphoma was 5.4 times more likely to develop in patients with CD4 cell count < 50/μL than in those with CD4 count > 500/μL. ^[19]
High HIV viral load
EBV co-infection
Genetic factors - CCR5-32 deletion is associated with favorable prognosis, whereas CXCR-4 is associated with increased risk for NHL development ^{[20, 21]}
Other undefined risk factors that increase the risk of NHL in the general population

Prognosis

ART can significantly affect the outcomes of AIDS-related lymphoma by reducing viral replication, and its use plays a pivotal role in improving prognosis. In addition, the prognosis of patients with AIDS-related lymphoma have been associated with the following factors:^[3]

Stage (extent of disease, extranodal or CNS involvement)
Age
Severity of the underlying immunodeficiency (measured by CD4 cell count)
Performance status
Prior AIDS diagnosis (ie, history of opportunistic infection or Kaposi sarcoma)

An AIDS-related lymphoma International Prognostic Index (IPI) has been developed and employs the age adjusted-IPI in addition to CD4 count, viral load, and prior history of AIDS.^[22]This index performed better in predicting risk of death compared to the age-adjusted IPI.

Prognosis in patients with AIDS-related lymphoma varies depending on histologic subtype. A large body of evidence indicates that HIV-infected patients whose HIV disease is well controlled with ART and are treated with standard chemotherapies for DLBCL, Burkitt lymphoma, and Hodgkin lymphoma have outcomes similar to those of their uninfected counterparts.^[23] However, a diagnosis of primary effusion lymphoma or plasmablastic lymphoma generally confers a poor prognosis.^[24]

Clinical Presentation

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Media Gallery

Burkitt lymphoma under low magnification showing sheets of atypical mononuclear cells. Scattered macrophages can be seen (as demonstrated by the green arrows) giving rise to classical "starry-sky" pattern.
Burkitt lymphoma under high magnification showing sheets of atypical mononuclear cells. The cells are intermediate to large in size with scant cytoplasm, round to irregular nuclear contour, smudged chromatin and some with nucleoli. Mitosis and apoptosis are frequent with scattered macrophages giving focal "starry-sky" pattern. Green arrows = macrophages; yellow arrows = mitosis.
Diffuse large B cell lymphoma under low magnification showing diffuse proliferation of large atypical lymphoid cells in this lymph node specimen.
Diffuse large B cell lymphoma under high power showing cells that have moderate to abundant cytoplasm, round to irregular nuclear contour, vesicular nuclear chromatin and one to multiple nucleoli. Scattered small mature lymphocytes are seen. Green arrows = atypical lymphocytes; yellow arrows = small lymphocytes.

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Table 1: Incidence and relative risk of AIDS-related lymphoma subtypes

Lymphoma subtype	Incidence (% of HIV-related lymphomas)	Relative risk (compared with the general population)
DLBCL, immunoblastic variant	64	652
Burkitt lymphoma	21	260
Indolent B-cell lymphoma	< 10	15
T-cell lymphoma	3	15
Hodgkin lymphoma	< 10	15-30
Primary CNS lymphoma	2-6	1000
Plasmablastic lymphoma	3	>1000
Primary effusion lymphoma	< 1	>1000

Table 2: Common chemotherapeutic options for initial treatment of AIDS-related DLBCL

Chemotherapy	Outcomes (complete remission rate %)	Indication
CHOP	63^[39]	Most patients with advanced-stage disease; addition of rituximab recommended for CD20+ disease when CD4 count over 50 /μL
Dose-adjusted EPOCH	74^[40]	Patients with a high proliferation index or plasmabatic histology; addition of rituximab recommended for CD20+ disease when CD4 count > 50 /μL
CDE	45^[41]
CDE = cyclophosphamide, doxorubicin, etoposide; CHOP = cyclophosphamide, doxorubicin, vincristine, prednisone; EPOCH = etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin (hydroxydaunorubicin)

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Author

Christina Poh, MD Clinical Assistant Professor of Medicine, Division of Medical Oncology (Lymphoma), University of Washington School of Medicine

Christina Poh, MD is a member of the following medical societies: American Association for Cancer Research, American Society of Clinical Oncology, American Society of Hematology, Hemostasis and Thrombosis Research Society

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Incyte Morphosys<br/>Received research grant from: Incyte Morphosys.

Coauthor(s)

Joseph M Tuscano, MD Associate Chief, Department of Hematology/Oncology/Internal Medicine, Veterans Administration Northern California System of Clinics; Professor, Department of Internal Medicine, Division of Hematology/Oncology, University of California, Davis, School of Medicine

Joseph M Tuscano, MD is a member of the following medical societies: American Association of Immunologists, American College of Physicians, American Society for Blood and Marrow Transplantation, American Society of Clinical Oncology, American Society of Hematology

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

Emmanuel C Besa, MD Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American Society of Clinical Oncology, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, New York Academy of Sciences

Disclosure: Nothing to disclose.

Additional Contributors

Mudassar Zia, MD Assistant Professor of Medicine, University of Missouri-Kansas City School of Medicine

Mudassar Zia, MD is a member of the following medical societies: American College of Physicians

Disclosure: Nothing to disclose.

Hesham M Taha, MD, FACP, MRCP(UK) Attending Physician, Department of Internal Medicine, Division of Hematology/Oncology, Nassau University Medical Center

Hesham M Taha, MD, FACP, MRCP(UK) is a member of the following medical societies: American College of Physicians, American Medical Association, American Society of Hematology, Royal College of Physicians, American Society of Clinical Oncology, Royal College of Physicians and Surgeons of Glasgow

Disclosure: Nothing to disclose.

Muhammad A Mir, MD, FACP Assistant Professor of Medicine (Hematology, Blood/Marrow Transplant) Milton S Hershey Medical Center, Pennsylvania State University College of Medicine

Muhammad A Mir, MD, FACP is a member of the following medical societies: American College of Physicians, American Society of Hematology, American Society for Blood and Marrow Transplantation, American Society of Clinical Oncology

Disclosure: Nothing to disclose.

Acknowledgements

Adnan A Jabbar, MD, PhD Adjunct Clinical Assistant Professor, Department of Medicine, New York College of Osteopathic Medicine of NY Institute of Technology; Fellow, Hematology and Medical Oncology, Emory University

Adnan A Jabbar, MD, PhD is a member of the following medical societies: American College of Physicians, American Medical Association, Chicago Medical Society, and Sigma Xi

Disclosure: Nothing to disclose.

Hesham M Taha, MD, FACP, MRCP(UK) Attending Physician, Department of Internal Medicine, Division of Hematology/Oncology, Nassau University Medical Center

Hesham M Taha, MD, FACP, MRCP(UK) is a member of the following medical societies: American College of Physicians, American Medical Association, American Society of Clinical Oncology, American Society of Hematology, Royal College of Physicians, and Royal College of Physicians and Surgeons of Glasgow

Disclosure: Nothing to disclose.

Acknowledgments

Medscape Reference and the previous authors would like to thank the following physicians for their valuable contributions to this article: Roshan Patel, MD, Department of Pathology, Westchester Medical Center-NYMC and Kyle Bradley, MD, Department of Pathology, Emory University School of Medicine.

AIDS-Related Lymphomas

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Epidemiology

Risk Factors

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