HIV Associated Malignancies

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HIV Associated Malignancies

• Amanda Peppercorn, M.D.
• Assistant Professor of Medicine
• Division of Infectious Diseases

2
Overview

• HIV associated malignancies
• Indicator condition in AIDS
• Interplay with oncogenic viruses
• Epidemiology
• Diagnosis
• Therapy

3
Case 1

• HPI 73 yo CM, Yale professor, no significant
  pmhx
• Jan 2003- complained of fatigue to PCP, routine
  labs showed new anemia with Hct 32 and platelets
  110K
• Extensive evaluation by Heme/onc over next
  several months including bone marrow bx
  unrevealing except for abd u/s showed
  splenomegaly and he was diagnosed after extensive
  GI eval with cryptogenic cirrhosis even though
  no evidence of liver pathology, portal HTN or
  liver synthetic dysfunction
• November 2003- episode of left thoracic zoster,
  self resolves

4

• May 2004- develops new left facial palsy, treated
  for HSV and Lyme cranial neuritis (despite
  negative Lyme antibody) with steroids, valtrex
  and doxycycline with improvement in sx
• July 2004- facial palsy returns and over 1-2
  weeks is noted by son to be confused
• August 2004- develops lethargy?obtundation and is
  admitted to OSH where Brain MRI shows new
  peri-ventricular rim enhancing lesion with mass
  effect
• HIV antibody finally sent and is positive
• LP done after administration of steroids
• EBV PCR, atypical lymphocytes c/w Primary CNS
  Lymphoma
• CD4 70, Viral load 75K

5

• Patient treated with Combivir and Sustiva with
  good virologic response
• Required neupogen and erythropoitin throughout
  cancer treatment course
• Lymphoma treated with IT methotrexate, steroids
  and whole brain XRT with regression
• Complicated by febrile neutropenia
• Complicated by severe perianal HSV outbreak
• Patients neurologic status completely improved

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Historical Time-line

• March 1981 First report of 8 cases of Kaposis
  sarcoma among MSM in SF and NY
• June 1981 MMWR reports 5 cases PCP in previously
  healthy young MSM in LA, 2 died
• 1982 phrase AIDS coined, first 4 cases NHL
  reported
• 1983 Primary CNS lymphoma (PCNSL) described
• 1984 viruses LAV (lymphadenopathy associated
  virus) and HTLV-III isolated
• 1985 Non-Hodgkins Lymphoma added to KS and PCNSL
  by CDC as AIDS-defining condition
• 1986 LAV/HTLV-III?HIV
• 1993 Cervical carcinoma added as ADC

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AIDS Defining Malignancies (ADMs)

• KS
• Lymphoma PCNSL, Immunoblastic, Burkitts,
  Primary Effusion
• Cervical carcinoma
• Up to 40 of HIV pts had an ADM in the pre-HAART
  era
• After PCP, malignancy was most frequent OI

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HAART Era

• Decline in KS, NHL, proportional to CD4 count
• Non-ADMs gt ADMs in overall morbidity/mortality
• Cancer accounts for approx 30 deaths in HIV
  currently
• Traditional RFs smoking, etoh, viral
  co-infections

• Non-ADMs with greater frequency in
  HIV(SIRstandardized incidence ratio)
• Anal (HPV), SIR 19.6
• Lung (tobacco), SIR 2.6
• Hodgkins disease (EBV), SIR 13.6
• Liver (HBV, HCV, etoh), SIR 3.3
• Head/neck (tobacco, etoh, HPV), 2.2
• Melanoma, other skin cancers (SCC, merkel cell,
  BCC)
• MM, SIR 2.2
• Leukemia, SIR 2.2
• Brain CA, gastric, renal, testicular (seminoma)

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Oncogenic Virus Association
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Pathogenesis

• Similar risk as seen in transplant recipients who
  experience 100-fold increased risk of cancer
  (renal, SCC, NLH, KS, uterine, cervic, vulva,
  sarcoma)
• Loss of immune surveillance of tumor cells
• ?Role of HIV genes in oncogenesis (esp as growth
  factors)

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KS

• Low grade soft tissue sarcoma, vascular
• Low CD4
• HHV-8 (KSHV)
• Skin (predominant)
• Visceral bronchus/lung, GI tract, liver, oral
• Treatment HAART, XRT, anthracyclines,
  paclitaxel, pegylated interferon, laser or
  cryotherapy
• IRIS

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KS on heel of immunocompromised patient
Images courtesy of Dr. Stephen Tabet.Nicodemus M
et al. HEPP News (Brown Medical School),
August/September 2001.
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TIS Staging Classification
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NHL

• 70-90 High grade B cell lymphomas (large B cell,
  immunoblastic, Burkttsc-myc translocation)
• PCNSL15
• Primary Effusion Lymphoma (Body Cavity
  Lymphoma)rare

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NHL

• Present at more advanced stage, extranodal
  disease (GI tract common), bone marrow, liver and
  lung, CNS, 80 Stage 4 disease at presentation
• More often with B sxnight sweats, fever,
  weight loss
• Incidence inversely related to CD4 count but can
  occur at any CD4
• Diagnosis same as in non-HIV pt but higher rate
  of asymptomatic CNS involvement
• FNA usually not adequate, need excisional BX

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NHL Treatment

• Optimal therapy not defined
• Standard first line therapies (CHOP) not as
  effective or durable in HIV population (increased
  expression of MDR-1 gene)
• IT methotrexate or ara-C
• HAART definitely improves survival
• 50-60 response rate
• High rate of OI complications
• Alternative regimens EPOCH, M-BACOD
• No good second line regimens, BMT not an option
  currently

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HAART with Chemotherapy

• Burkitts Retrospective study of Hyper-CVAD /-
  HAART Cortes, Cancer 2002
• 6/7 on HAART CR, 4/4 no HAART died
• Large B cell Lymphoma Retrospective study of
  CHOP-HAART (24 pts) versus CHOP (/- AZT mono, 80
  pts)Vaccher, Cancer 2001
• OI 18 v 52
• Survival long term survival versus medium 7
  months

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HAART and Chemotherapy

• PI v NNRTI based regimen equivalent
• Some anti-neoplastic effect of AZT and PIs
• Need to implement OI prophylaxis with low CD4
  counts in setting of bone marrow suppression
• Mucositis, chemo related n/v can inhibit oral
  intake of ARVs
• IL-6 inhibitors under investigation
• Role of rituximab unclear marked increased death
  rate due to infection Kaplan, Blood 2005

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Primary Effusion Lymphoma

• Rare
• HHV-8
• Serous effusions (pleural, peritoneal,
  pericardial, joint effusions) with malignant
  lymphocytes
• No mass lesions
• CHOP HAART
• Very poor prognosis

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PCNSL

• EBV
• 100-1000x higher than general population
• CD4lt100, usually lt50
• Dx LP EBV, MRI with homogeneous, sometimes ring
  enhancing lesions, often peri-ventricular, often
  mass effect, Thallium SPECT with early uptake
• Tx whole brain XRT steroids /- IT
  methotrexate
• Prognosis poor in pre-HAART era, overall still
  very poor

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Hodgkins Lymphoma and HIV

• Usually advanced stage at time of diagnosis
  (stage 3,4)
• More extra-nodal involvementbone marrow, liver
• Worse prognostic cell typemixed cellularity
  histologic subtype (nodular schlerosis most
  common in non-HIV)
• Worse overall prognosis
• Better outcomes in era of HAART

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Cervical Cancer

• Co-infection with HPV
• Earlier age with advanced disease
• Paps recommended twice a year at time of HIV dx
  if normal, can screen every year
• Dx, Management same as in non-HIV population
• No relation to CD4 count

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Global HIV epidemic, 1990?2005
HIV prevalence, adult (15?49)
Number of people living with HIV (millions)

• 38.6 million living with HIV 33 to 46
  million
• 24.5 million in SS Africa
• 21.6 to 27.4 million
• 4.1 million new infections 3.4 to 6.2
  million
• 2.8 million deaths 2.4 to 3.3 million

50
5.0
40
4.0
30
3.0
20
2.0
10
1.0
0
0.0
1990
1995
2000
2005
Number of people living with HIV
Bar indicates the range around the estimate
Source UNAIDS 2006
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Children

• Leiomyosarcoma (?EBV)
• NHL
• Cervical, thyroid/ lung
• KS
• Burkitts

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ADMs in Developing Nations

• KS in Africa (men and women)
• NHL (less than developed nations)
• Cervical cancer (unclear how HIV has impacted)
• SCC of the conjunctiva (?HPV)
• Related to sun exposure
• Risen over past 30 years in Ss Africa
• 10 fold higher in HIV

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Case 2

• 60 yo woman w longstanding HIV c/bHIVAN on HD,
  remote PCP, remote GB
• HAART regimen abacavir, efavirenz, atazanavir,
  ritonavir with excellent CD4 and virologic
  suppression
• Routine mammogram 8 cm left breast mass with
  enlarged left axillary mass

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• Work up T2N2M0 disease locally advanced due to
  LN
• Well differentiated, ER, PR-, Her-2-
• Treated with dose-reduced neoadjuvant Taxol
  alone due to co-morbidities
• Taxol tolerated well except for diarrhea and
  alopecia
• Followed by radical modified mastectomy which
  showed poor response to chemo with 3 cm residual
  disease
• CD4 drop from 800 to 150, dapsone initiated

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• Oncologist starts pt on Tamoxifen
• Seen in HIV clinic
• Tamoxifen metabolism made completely
  unpredictable by ritonavir
• Recommendation made to oncology to use Arimidex
  instead of Tamoxifen for more reliable anti-tumor
  effect
• Seen recently in clinic for CA-MRSA gluteal
  abscess and bacteremia

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Lessons

• Screen PSA, mammogram, cervical (anal) pap,
  colonoscopy, yearly CXR in smokers, AFP/liver
  imaging in HBV and ESLD/cirrhosis/HCV
• ADVOCATE!
• Check HAART drug interactions with chemotherapy
  and make necessary modifications
• Try to maintain full chemo and full HAART
• Monitor carefully for infectious complications,
  need to implement OI prophylaxis
• Emerging data that HAART high CD4 count renders
  pt outcomes to general cancer treatment
  equivalent to non-HIV population

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EuroSIDA Reduction in the incidence of AIDS and
death since the introduction of HAART
Morbidity and mortality across Europe, Israel and
Argentina 10,000 patients
100
100
patients on HAART Combined rate of AIDS and
death
80
60
Combined AIDS and death rates
Patients
10
40
20
1
0
Sept 1999March 2000
Sept 2000March 2001
Sept 1994
Sept 1998March 1999
March 1998Sept 1998
March 1995Sept 1995
Sept 1995March 1996
March 1996 Sept 1996
Sept 1996March 1997
Sept 1997March 1998
March 1997Sept 1997
Mltarch 1995
March 2000Sept 2000
Sept 2001onwards
March 1999 Sept 1999
March 2001 Sept 2001
Mocroft A. et al, Lancet 2003 362 2229