1. Lymphoma & other HIV-related malignancies
AM report 9/30/2009
Darrell Laudate

2. Non-AIDS defining malignancies & HIV
As patients have survived longer with AIDS, the frequency of non-AIDS-defining malignancies has increased compared to the non-HIV-infected population, and cancer deaths have accounted for an increasing fraction of the deaths in HIV-infected individuals.
probably reflects a true increased prevalence, combined with greater screening, more frequent detection of incidental lesions, better reporting, and longer survival in the HIV-infected population 1
The usual suspects: Lung, Breast, , Prostate, Testicular, Bladder, Renal, Colorectal
Also , HCC, Skin (BCC, SCC, Melanomas), Head & Neck SCC, Conjunctival Ca, Hematologic Malignancies (Hodgkins, Plasma Cell disorder, AML)

3. AIDS defining Malignancies
Kaposi's Sarcoma
Invasive Cervical Cancer (as well as malignancies of the anogenital tract, including the anus, vulva, penis, and perianal skin)
NHL 
Primary CNS Lymphoma

4. Role of HIV in Malignancy
not generally considered oncogenic, a direct pathogenic role for HIV infection has been suggested by the following observations:
Components of the HIV viral genome have been incorporated into the fur gene complex on chromosome 15 in some cases of HIV-associated non-B cell malignant lymphomas.2   
The HIV tat gene protein product appears to be a growth factor for KS. 
Other viruses including EBV, HPV, HHV-8, HBV, & HCV

5. Role of HAART
HAART causes both an immunologic response (manifested by a sustained elevations in CD4 lymphocyte counts) and a virologic response (nearly complete suppression of HIV viral replication).  
Both of these responses are important in achieving at least partial immune restoration, and thus decreasing the incidence of opportunistic infections, reducing the risk of developing NHL or KS, and prolonging survival. 
Since the widespread introduction of HAART, the incidence of KS and NHL has declined in HIV-infected patients, and is inversely proportional to the CD4 lymphocyte count.3

6. NHL Overview

7. WHO/REAL Classification of Lymphoid Neoplasms
B-Cell Neoplasms
Precursor B-cell neoplasm
Precursor B-lymphoblastic leukemia/lymphoma
(precursor B-acute lymphoblastic leukemia)
Mature (peripheral) B-neoplasms
B-cell chronic lymphocytic leukemia / small lymphocytic lymphoma
B-cell prolymphocytic leukemia
Lymphoplasmacytic lymphoma‡
Splenic marginal zone B-cell lymphoma
(+ villous lymphocytes)*
Hairy cell leukemia
Plasma cell myeloma/plasmacytoma
Extranodal marginal zone B-cell lymphoma of MALT type
Nodal marginal zone B-cell lymphoma
(+ monocytoid B cells)*
Follicular lymphoma
Mantle cell lymphoma
Diffuse large B-cell lymphoma
Mediastinal large B-cell lymphoma
Primary effusion lymphoma†
Burkitt’s lymphoma/Burkitt cell leukemia§
T and NK-Cell Neoplasms
Precursor T-cell neoplasm
Precursor T-lymphoblastic leukemia/lymphoma
(precursor T-acute lymphoblastic leukemia
‡ Formerly known as lymphoplasmacytoid lymphoma or immunocytoma
II Entities formally grouped under the heading large granular lymphocyte
leukemia of T- and NK-cell types
* Provisional entities in the REAL classification
Mature (peripheral) T neoplasms
T-cell chronic lymphocytic leukemia / small
lymphocytic lymphoma
T-cell prolymphocytic leukemia
T-cell granular lymphocytic leukemiaII
Aggressive NK leukemia
Adult T-cell lymphoma/leukemia (HTLV-1+)
Extranodal NK/T-cell lymphoma, nasal type#
Enteropathy-like T-cell lymphoma**
Hepatosplenic γδ T-cell lymphoma*
Subcutaneous panniculitis-like T-cell lymphoma*
Mycosis fungoides/Sézary syndrome
Anaplastic large cell lymphoma, T/null cell,
primary cutaneous type
Peripheral T-cell lymphoma, not otherwise characterized
Angioimmunoblastic T-cell lymphoma
primary systemic type
Hodgkin’s Lymphoma (Hodgkin’s Disease)
Nodular lymphocyte predominance Hodgkin’s lymphoma
Classic Hodgkin’s lymphoma
Nodular sclerosis Hodgkin’s lymphoma (grades 1 and 2)
Lymphocyte-rich classic Hodgkin’s lymphoma
Mixed cellularity Hodgkin’s lymphoma
Lymphocyte depletion Hodgkin’s lymphoma
† Not described in REAL classification
§ Includes the so-called Burkitt-like lymphomas
** Formerly known as intestinal T-cell lymphoma
# Formerly know as angiocentric lymphoma

8. When to suspect Lymphoma
Suspicious PMH
Positive family history
Radiation, chemotherapy, immunosuppressive agents
Infectious agents
HIV, HTLV-1, EBV, HCV, HBV
Connective tissue diseases
SLE, RA, Sjogren’s
Immunodeficiency's
Cryoglobulinemia
IBD treated with Azathioprine
Unexplained “B” symptoms
Lymphadenopathy

9. HIV and NHL
AIDS-related lymphoma is generally divided into three type:
Systemic non-Hodgkin lymphoma (most common)
Primary CNS lymphoma
Primary effusion ("body cavity") lymphomas
HIV immunosuppression and coinfection with EBV seem to drive B cell clonal expansion
70% of lymphomas in HIV have mutations resulting in deregulation of BCL-6 proto-oncogene
Diffuse lymph node involvement is considered much less common
Marrow involvement 30% of time
thus consider marrow biopsy if no other sites
80% present with Stage IV disease

10. Clinical Presentation
“B” symptoms
more common in patients with aggressive and highly aggressive histologies (47%), especially in those with hepatic and extranodal involvement.
In contrast, less than 25% of patients with indolent lymphomas have B symptoms
Systemic complaints of fatigue, malaise, and pruritus occur less frequently in fewer than 10%
Bone pain or gastrointestinal symptoms may indicate extranodal involvement in these areas  
> 2/3 of patients with NHL present with peripheral LAD
CNS involvement
lethargy, focal neurologic symptoms, seizures, or paralysis
Rare - spinal cord compression, meningitis

11. Physical Exam Lymph Nodes HEENT Chest Abd/pelvis GU CNS
Waldeyer’s Ring involvement in NHL>HL
CNS Lymphomas can affect cranial nerves
Chest
SVC Syndrome, pleural effusions
Abd/pelvis
Retroperitoneal, mesenteric, pelvic nodes in NHL>HL
If large enough, leads to nausea, early satiety, anorexia GU
Testicular masses (men >60yo NHL is #1 malignancy of testes)
CNS

12. Labs/Imaging
CBC w/ differential and smear for evaluation Unexplained anemia, thrombocytopenia, or leukopenia due to extensive bone marrow infiltration or hypersplenism from splenic involvement
Renal and hepatic function, including LDH
Hypercalcemia (present in 15% but not usually symptomatic)
Hyperuricemia causing symptoms of gout or nephrolithiasis are unusual at presentation
certainly a concern following treatment of a rapidly proliferative NHL
Testing for HIV, HBV, and HCV (in select patients)
CXR
Mediastinal involvement, SVC compression, effusions
Intrathoracic involvement HL>NHL, but parenchymal involvement NHL>HL
CT Abd/Pelvis
Particularly for Staging
BM Biopsy often considered especially when biopsy would be otherwise difficult to obtain
Lumbar puncture (if CNS involvement suspected)

13. Ann Arbor Staging I. 1 nodal group
II. 2 nodal groups on the same side of the diaphragm
III. Disease above and below the diaphragm
IV. (Extranodal) Disease in other organs

14. Tissue is the Issue Neg Positive Tenderness Generalized Pruritus
When to biopsy a Lymph Node? 4
Neg Positive
Tenderness Generalized Pruritus
Size < 1cm Supraclavicular
Hard
Courtesy of Lee Berkowitz

15. FNA vs Excisional Biopsy
Accurate histopathologic evaluation of sufficient neoplastic tissue, preferably an intact lymph node, is critical. Although a tissue diagnosis can be suggested by fine needle aspiration (FNA), an excisional biopsy is often required in order to confirm the FNA findings of “lymphoma”5
Only an excisional biopsy of an intact node consistently allows sufficient tissue for histologic, immunologic, molecular biologic assessment, and classification
If no peripheral lymph nodes accessible for biopsy, consider CT guided biopsy vs laproscopic evaluation

16. References
Pantanowitz et al. Evolving spectrum and incidence of non-AIDS-defining malignancies. Curr Opin HIV AIDS 2008; 4:27.
Shiramizu et al. Identification of a common clonal human immunodeficiency virus integration site in human immunodeficiency virus- associated lymphomas.; Cancer Res 1994 Apr 15;54(8):
Biggar et al. AIDS-related cancer and severity of immunosuppression in persons with AIDS. J Natl Cancer Inst Jun 20;99(12): Epub Jun 12
Vasilakopoulos et al. Application of a Prediction Rule to Select which Patients Presenting with Lymphadenopathy Should Undergo a Lymph Node Biopsy. Medicine 79(5) 2000:338 – 47.
Hehn et al. Utility of fine-needle aspiration as a diagnostic technique in lymphoma. J Clin Oncol 2004 Aug 1;22(15):
Berkowitz. Lymphoma for the Internist ppt witz.ppt. Oct 2007