Objective: Think about concepts you don’t think about in your every day evidence based approach to the practice of medicine without falling asleep
What are the AIDS Defining Malignancies? AIDS Associated Malignancies?
AIDS Defining Malignancies Kaposi’s sarcoma Non Hodgkin’s lymphoma Squamous cell carcinoma of the cervix/anus* * AIDS associated malignancy
Variations on a Theme • Oncogenic viral infection • KS • Lymphoma • SCCa cervix/anus • Proliferation of a benign cell • KS • Lymphoma • SCCa cervix/anus • Immune dysregulation • Up regulation • Down regulation • Direct role of HIV
Variations on a Theme • Oncogenic viral infection • KS = KSHV • Lymphoma = EBV and KSHV • SCCa cervix/anus = HPV • Proliferation of a benign cell • KS = lymphatic endothelial cell • Lymphoma = B lymphocyte • SCCa cervix/anus = squamous epithelium • Immune dysregulation • Increased production of inflammatory cytokines • Loss of cell mediated immunity to control viral infections • Any direct role of HIV: Tat up regulation of virus gene expression
How do viruses cause cancer? What about cytokines How does being CD4 T lymphopenic make you susceptible to cancer?
Case 1 • A 28 year old man with early stage HIV presented anxious and upset over the development of disfiguring skin lesions.
Don’t treat without meat…... This is bacillary angiomatosis, an infection due to Bartonella sp. It is treated with erythromycin
Kaposi’s Sarcoma • Was among the initial features of AIDS • Three epidemiologic subsets • Endemic - seen in sub Saharan Africa • Epidemic - associated with HIV infection • Sporadic - aging men of Mediterranean descent • Strong relationship with immune deficiency • Transplant patients • Recipients of immunosuppressive agents • Aged individuals • Long thought to have an infectious etiology • HHV-8 or KSHV was discovered in 1994 by Moore and Chang
Kaposi Sarcoma Herpes VirusHuman Herpes Virus - 8 How prevalent is KSHV in the US population? How prevalent is KSHV in HIV infected persons? What is the primary route of transmission of KSHV Does everyone with KSHV infection get KS?
Kaposi Sarcoma Herpes VirusHuman Herpes Virus - 8 • Prevalence of KSHV infection is 5% in USA. • Prevalence of KSHV infections is 26% to 40% in HIV infected persons. • Shed in the SALIVA, the primary route of transmission • KS develops in a minority of immune competent persons, but 50% of HIV infected persons. • Present in ALL KS lesions from ALL types of KS
Two types of KSHV (HHV-8) Infection • Latent seen in Kaposi’s sarcoma • No virus replication • Limited expression of virus genes • Lytic seen primary effusion lymphoma • Production of virus progeny • Expression of many viral genes
Many of the KSHV genes operate to create the perfect environment for malignancy • Inhibition of cell cycle regulation • Prevent apoptosis • Modulate the immune system • Promote angiogenesis • Latent infection can be converted to lytic infection under conditions of hypoxia.
Pathogenesis • KSHV has tropism for lymphatic endothelial cells, B cells, macrophages, and epithelial cells. • In KS latent infection is more prevalent than lytic. • Latent state KSHV genes codes for proteins that support KS oncogenesis • LANA-1 inhibits p53 • vCyclin (homolog of cyclin D2) that is resistant to CDK inhibitors • vFLIP (homolog of FLIP) that inhibits apoptosis
Role of cytokines in pathogenesis • Cytokines • From HIV-infected macrophages and activated T cells • IL-1, IL-2, PF4, IFN-g, TNF- a • Cause proliferation of lymphatic endothelial cells • Permissive environment for KSHV infection
Treatment • First Line: protease inhibitor containing regimen • 20% to 60% of patients may respond with HAART alone. • Best responses: drug naïve, skin only, and CD4 increase >150 • CR is not necessarily protective against recurrence. • Advanced KS in late stage AIDS often requires more Rx • Enhanced immunity against KSHV is not enough • VEGF inhibitors, liposomal adriamycin, conventional cytotoxic Rx • Goal of treatment is palliation
Where has all the KS gone? • There has been a dramatic decline in incidence with HAART • Adjusted incidence pre HAART: 15.2/1000 person years • Adjusted incidence post HAART: 4.9/1000 person years • Immune reconstitution and better control of KSHV • Anti angiogenesis effects of protease inhibitors
AIDS associated Lymphomas Peripheral lymphomas ? ?
AIDS associated Lymphomas Peripheral lymphomas Primary effusion lymphomas Primary CNS
Epidemiology • Rates may be under estimated 2° to hierarchy of reporting. • Incidence in AIDS is estimated from 4 to 16%. • Risk of NHL in HIV is 100-200X risk of HIV neg. • 80% of HIV lymphomas are high grade, 15% are low grade. • Just the opposite for HIV negative persons
What viruses contribute to lymphomagenesis? EBV KSHV HIV
Lymphomagenesis: virus • HIV - not directly involved in malignant transformation. • EBV - causes polyclonal B cell proliferation leading to genetic instability increasing the chance of a transforming mutation, such as myc translocation. • Implicated in CNS and Primary Effusion Lymphomas • KSHV - how could this virus possibly cause lymphoma? • Implicated in primary effusion lymphoma and multicentric Castleman’s disease
Lymphomagenesis • Cytokines • IL-6 and IL-10 • Loss of immune surveillance • Loss of CD4 clones that control EBV infected B cells • Loss of CD8 function (due to loss of CD4 help) • Permits proliferation of EBV infected B lymphoblasts • EBV infected lymphs can evade immune detection
Prognosis • Most prognostic data comes from pre-HAART era • CD4< 200 median survival = 4 months • CD4 >200 median survival = 11 to 18 months • Overall median survival in HAART era 24 months • NCI AIDS Malignancy Branch peripheral lymphoma patients receiving EPOCH ± R - at 53 months follow up overall survival is 60%. • Median survival for PEL 3 to 6 months. • Median survival for primary CNS lymphoma • Radiation alone - 4 months • Chemotherapy 10 to 18 months
Antiviral therapy and Epidemiology • Modern antiretroviral therapy does not prevent lymphoma, but rather maintains CD4 counts at levels that prevents development of the poor prognosis lymphomas (immunoblastic and primary CNS lymphoma).
Case 2 • A 37 year old man with long standing HIV infection presents with mid epigastric pain, hemoccult positive stools, and a microcytic hypochromic anemia. • Upper endoscopy revealed:
Peripheral Lymphoma Histology • Burkitt’s and Burkitt’s-like • Occurs in state of relative immune preservation • Bone marrow and nodal sites predominate • EBV is absent esp in sporadic Burkitt's • Diffuse Large B cell Lymphoma; centroblastic • Occurs in state of relative immune preservation • GI and CNS sites predominate • Good prognosis • Diffuse Large B cell Lymphoma; immunoblastic • Occurs in later stage HIV infection • GI and CNS sites predominate • Poor prognosis
Peripheral Lymphomas • Extranodal involvement is common. • CNS (leptomeninges) - 20 to 40% at presentation • GI - 30% at presentation • Orbit, skin, salivary glands, heart, lung, muscle, bones, adrenals, rectum, gonads, placenta • Stage • Most present with stage III, IV or IE bulky disease
Treatment • Induction of remission requires chemotherapy. • All patients receive CNS prophylaxis • Controversial Issues • Dose intensity and regimen • Infusional (EPOCH) vs. bolus (CHOP) therapy • Concurrent use of HAART • Use of rituximabWHY?
Case 3 • A 39 year old man, known to be HIV positive presents with new onset ascites. • Further examination and evaluation reveal bilateral pleural effusions and pericardial effusion. • A pericardiocentesis reveals:
Primary Effusion Lymphoma • Usually occurs in young, homosexual men with advanced HIV • Epidemiology similar to that of KS • Disease usually restricted to pericardium, pleura, peritoneal cavity without contiguous tumor mass. • Poor outcome (survival <5 mos). • Tumor cell is B cell lineage: • Kappa and lambda light chain mRNA • Ig heavy chain with k light chain mRNA • Uniformly express KSHV; frequently EBV
PEL Treatment • Refractory to conventional chemotherapy • Some short remissions with EPOCH • Experimental therapies exploit KSHV pathophysiology • KSHV codes for several kinases • These kinases phosphorylate (activate) AZT and ganciclovir • Theoretically, the drugs will be activated primarily in KSHV infected B cells, killing primarily those cells.
Thymidine AZT Guanosine Ganciclovir
AZT and GCV are phosphorylated and then incorporated into a growing chain of DNA. What do you think happens next?
AZT AZT GCV GCV AZT AZT ACTGACTGACTGACTGACT GCV GCV AZT TGACTGACTGACTGACTGA AZT GCV AZT cKINASE B lymphoctye from person treated with AZT, GCV
AZT AZT GCV GCV AZT AZT ACTGACTGACTGACTGACT GCV GCV TGACTGACTGACTGACTGA AZT AZT GCV - (PO4)3 - (PO4)3 AZT cKINASE Kinases triphosphorylate both AZT, GCV
AZT AZT KSHV GCV GCV AZT AZT ACTGACTGACTGACTGACT GCV GCV TGACTGACTGACTGACTGA AZT AZT GCV - (PO4)3 - (PO4)3 AZT cKINASE v KINASE KSHV infected B cell has additional kinase activity
AZT AZT KSHV - (PO4)3 - (PO4)3 - (PO4)3 GCV GCV AZT AZT ACTGACTGACTGACTGACT - (PO4)3 GCV GCV TGACTGACTGACTGACTGA AZT AZT GCV - (PO4)3 - (PO4)3 AZT KINASE v KINASE What do you think happens to this cell?
Theoretically, there is more cell kill in the KSHV infected B cells because there is more phosphorylation of the drugs. Yes this therapy is toxic, but it targets virus infected cells. ACTGACTGACTGACTGACT ACTGACTGACTGACTGACT
Case 4 • A 45 year old man with long standing HIV infection presents with focal neurologic deficits. • Imaging reveals:
Primary CNS • Occurs in setting of severe immune suppression • 20X decrease incidence with modern antivirals • Multifocal (few large 3 to 5 cm lesions), developing at perivascular cuffs • Primarily immunoblastic histology • Monoclonal B cell population, EBV+ ALWAYS • PET +, thallium +, EBV PCR of CSF for dx vs. brain bx • Nuc med scan + and PCR + has neg predictive value of 100%
Primary CNS Treatment • Optimize antiretrovirals to restore or enhance EBV immunity. • Radiation, 4000cGy, is standard approach • Considerable morbidity associated with WB XRT • Rubinstein (ASCO 2006): high dose methotrexate with leucovorin rescue, temozolomide, and rituximab for induction, then high dose ARA-C with etoposide infusion for consolidation. • 52% complete remission rate • Median progression free survival is 11.5 months • Median overall survival has not been reached with 27.5 months follow up. • Median survival pre HAART 4 months; HAART era 15 mos.
Case 5 • 48 year old man presents for follow up of rectal bleeding, a sensation of rectal fullness, and some pain with defecation. • On exam he is found to have a numerous anal condylomata and a firm 4cm mass just inside the anal verge which is tender to palpation and slightly ulcerated.