3. HIV ASSOCIATED
MALIGNANCIES
AIDS DEFINING MALIGNANCIES(ADMs)
1. Kaposi Sarcoma
2. CERTAIN NHL
1. Burkitts
2. DLBCL
3. Immunoblastic
4. Primary DLBCL of CNS
3. Ca cervix
5. Epidemiology-incidence
Pre-ART vs post-ART
Malignancy accounted for <10% of mortality in
pre-ART period.
But increased to 28% in post-ART period(after
1996).
Decrease in incidence of ADMs.
3 fold increase in incidence of NADMs.
6.
7. AIDS-defining malignancies
Accounted for 88% in the pre-ART period,
47% in the early ART period and 33% in the
late ART period.
Normalization of CD4 count and suppression
of HIV replication.
KS and NHL.
Incidence of cervical cancer remain
unchanged.
8. Non-AIDS defining malignancies
Increasing incidence in post –ART era .
Factors responsible-
Increase incidence of HIV patients
Increase survival
Tobacco and alcohol
Oncogenic viruses
9. Pathogenesis
Direct effects of HIV-
activation of protooncogenes, inhibition of tumor
suppressor genes, or other genetic instability
Immunosuppression(NHL,KS)-related to CD4
count
Increased susceptibility to carcinogens
Oncoviruses(HHV-8,HPV,EBV,HBC,HCV)
Smoking in lung cancer
10. AIDS-Defining Virus
Kaposi’s Sarcoma HHV-8
Non-Hodgkin’s Lymphoma EBV, HHV-8
(systemic and CNS)
Invasive Cervical Carcinoma HPV
Non-AIDS Defining
Anal Cancer HPV
Hodgkin’s Disease EBV
Head and neck HPV
Liver HBV,HCV
Merkel cell ca Merkel cell polyoma virus
14. KSHV infected spindle cells
Expression of KSHV encoded mimics
of human genes,viral microRNA and
activation of cellular genes
ORF74,v-MIP, v-IL 6
Overproduction of human cytokines
and growth factors like VEGF and
PDGF
Hyperproliferation of spindle cells
Angiogenesis
15.
16. KS-Staging and prognosis
Multifocal tumor without clonal expansion and
dissemination.
Standard oncologic staging and response
criteria not applicable.
AIDS Clinical Trials Group oncology
committee TIS staging system.
17. KS staging – AIDS clinical trial
Group staging Classification
Good risk (0)(ALL) Poor risk (1)(ANY ONE)
Tumor (T) • skin
• LN
• Non nodular oral, confined to
palate
• Edema/ ulcer
• Extensive oral KS
• GIT
• In other non-nodal
viscera
I (not if HIV
sensitive to ART)
CD4 >150 CD4<150
Systemic
illness(S)
• No opportunistic infectn
• No B symptoms.
• No other HIV related illness
+
+
PS<70
18. Treatment
t/t Indication
c ART HIV related KS
Stop/ dec
immunosuppressants
Transplant related KS
Anti KS chemotherapy • T1 KS
• Not responding to above t/t
• Need rapid t/t – pulmonary KS , extensive
cutaneous, symptomatic, visceral, life
threatening
19. Chemotherapy for KS
1. Liposomal Doxorubicin – 20 mg/m2 every 3 wk
2. Paclitaxel
3. Oral Etoposide
4. IFN alpha – for limited disease with preserved CD4
5. Thalidomide
6. Targeted therapies like Bevacizumab and Imatinib.
Till response plateau/ remission
Partial response = 50% dec in no., area, flattening
Complete = resolutn of all, inc pigmentatn
Restart if progression
20. Local therapies for KS
Limited utility
Symptomatic disease in highly restricted areas.
Topical 9-cis-retinoic acid
Intralesional inj. Low dose vinblastine or 3%
sodium tetra dodecyl sulphate.
Laser therapy, cryotherapy and radiotherapy.
S/E-painful, unsatisfactory cosmesis and
progression.
22. Lymphoma in HIV
Also in
immunocompetent
More sp in HIV + Also in other
immunodeficiency
BL Primary effusion
lymphoma
Polymorphic B cell L
(PTLD like)
DLBCL - germinal
center, activated Bcell
subtype
Large B cell L in
KS ass MCD
Extranodal marginal
zone B cell L of MALT
Plasmablastic L
cHL Primary DLBCL
of CNS
23. More common Rare
DLBCL, BL, cHL PCNSL, immunoblastic
DLBCL, PEL, plasmablastic L,
KSHV – MCD
Immunocompetent Dec immunity
Curable Challenging t/t
24. Pathogenesis
Degree of immune suppression
Uncontrolled HIV viremia
Immune activation of EBV infected and EBV-uninfected
B cells
Translocation and
Aberrant somatic hypermutation
27. TREATMENT
DECISION ACC. TO
1. Type
2. Immune status
3. AIDS related comorbidities
CNS PROPHYLAXIS
- Intraventricular/ intrathecal
Methotrexate
- Till 2wks after –ve cytometry
in CSF
Wklyx6-8wks -> mnthlyx6m
SUPPORTIVE CARE
- Prophylaxis for infn if CD4<
100
- PCP – trimethoprim+
sulfameth
Atypical mycobacterium –
Azithro
HSV - vanciclovir
Concurrent cART and
Chemotherapy
Avoid cART if CD4 > 100
Start after chemo
28. DLBCL
IHC, FISH,GEF, PCR is reqd for subtyping.
GC phenotype=Good prognosis
ABC phenotype=Bad prognosis
Rituximab-good results as CD 20+.
Standard therapy=R based chemotherapy +/-cART.
R based chemotherapy regimens
Dose adjusted EPOCH-R
Short course EPOCH-R
R-CHOP
Excellent response of SC-EPOCH-RR in GC-DLBCL.
29. BURKITTS LYMPHOMA
Relatively preserved immune status
17% of all HIV related lymphomas.
Poor outcome with CHOP regimen in HIV
associated BL.
Excellent 90% long term survival with SC-EPOCH-
R with full dose cyclophos and intrathecal
methotrexate.
c ART may be deferred until after treatment.
30.
31. Primary DLBCL of CNS
CD 4 count < 50
D/D – Toxoplasmosis
Diagnosis
1. Stereotactic biopsy
2. High EBV viral load in CSF
3. Ring enhancing brain mass on MRI
4. Positive 201 Tl- SPECT or FDG-PET scan
32. Primary DLBCL of CNS:
Treatment
No standard therapy.
Poor outcome.
Initiation of c ART
Whole brain irradiation-64% OS at 3yrs but
significant late neurotoxicity.
Best therapeutic approach
c ART + Rituximab based chemotherapy
34. HODGKIN LYMPHOMA
Non AIDS-defining malignancy.
Intact CD 4 count(>200).
Develops in first year of c ART therapy.
Due to immune reconstitution syndrome(IRIS).
EBV assoc mixed cellularity is most common.
Higher stage disease and older patients.
Mediastinal LN – less
Extranodal, B symptoms, BM invasion – more
35. t/t and outcome same as non HIV.
Concurrent c ART
Early stage disease---ABVD regimen
Advanced stage---BEACOPP regimen.
Avoid protease inhibitors with vinblastine.
Brentuximab(Anti CD 30) based
chemotherapy regime are under trial.
36. HPV ASSOC. CANCERS in HIV
CERVIX, ANAL,PENIS, VULVA and OROPHARYNX.
Pathogenesis- 3 factors
1. Increased HPV exposure due to immunosuppression
2. Increased premalignant conditions in HIV
patients(CIN/AIN)
3. Smoking
37. Cervical cancer
5-fold increased risk in HIV patients.
Screening(CDC&US preventive task force)
Initial PAP smear when HIV is diagnosed
Repeat in 3m if severe inflammation.
Repeat Pap smear + HPV-DNA after 6mth.
Every 6monthly if high risk HPV, else yearly.
Same as non HIV if on effective cART,
preserved CD4, no HPV, PAP normal.
38. CIN/ ASCUS
Colposcopy and biopsy
CIN1 – observe
CIN 2/3 – cART + ablation/ loop excision/
conization/ cryotherapy
Carcinoma
Extensive LN may be due to HIV
Treatment same
39. Anal cancer
Increased risk in women and MSM
Role of screening
1. Routine cytological examination of anal mucosa
in high risk individuals.
2. Anoscopy and biopsy if abnormal cytology
3. Topical imiquimod/ cidofovir for high grade AIN
4. Laser/ cautery/ infrared
5. But , it does not prevent CA and resection is
difficult
40. Treatment of anal cancer in HIV
patients
Concurrent c ART
Chemoradiation in stageI-III.
Increased toxicity if CD 4<200 in pre-ART era.
Toxicities decreased with c ART+ IMRT
Similar outcome that of general population.
42. Introduction
8-10 fold increased risk of SMN after
hematopoietic Cell Transplantation (HCT)
Risk factors
1. Age at HCT
2. Exposure to CT/RT prior to HCT
3. Total body irraradiation, high dose chemo for
myeloablation
4. EBV, HBV, HCV
5. Autologous vs allogeneic
6. Immunosuppressive drugs used for GVHD
43. HCT - > Subsequent Malignant
Neoplasm (SMN)
Classification of SMNs
1. Myelodysplasia and AML ( tMDS-AML)
2. Lymphoproliferative disorders
3. Solid tumors
44. tMDS-AML
9% after autologous
HCT
Median latency = 12-
24 mnths
Diagnosis
Significant marrow
dysplasia in > 2 cell lines
Peripheral cytopenia
without explanation
Blasts in marrow(FAB) or
cytogenetic abnormality
45. Clinicopathological syndromes:
Alkylating agent/RT
related t-MDS/AML
Topoisomerase II
inhibitor related AML
Overt leukemia
6mth-5yrs
Translocations
4-7 yrs after exposure.
2/3rd MDS and 1/3rd AML
without MDS.
Cytopenia
5q and 7q deletion
46. Risk factors of tMDS- AML
Old age at HCT
Alkylating agents/ topoisomerase II
inhibitors/RT pretransplantation
PBSC
Conditioning with TBI
Low CD34+ cells infused
Multiple transplants
47. Pathogenesis of tMDS-AML
Therapy induced genetic abnormalities – 5q del, 7q del, translocation of AML1 gene,
altered MLL function, NRAS mutation
Genetic susceptibility – genes for drug metabolism and DNA repair
Telomeric shortening following autologous HCT and therapy before that, older
age at HCT
Hematopoetic abnormality – pretransplant chemo induced damage of primitive
progenitor cells + defective microenvmnt ->t MDS-AML
Altered gene expression profile before disease onset
48. t-MDS- AML - outcomes
Poor outcome if
Age >35
Poor risk cytogenetics(del 7q)
t-AML not in remission or advanced t-MDS
Unmatched donor
Chemo – lower response
Allogeneic HCT –successful outcome.
Prompt t/t – most important, so follow pts closely
49. PREDICTION OF RISK OF t-
MDS/AML
Technique -
1. Cytogenetics, FISH
2. PCR for point mutation
3. Gene expression profiling – 38 gene signature
Risk reduction
1. Minimize pretreatment cytotoxic exposure.
2. Allogenic rather than autologous, non
transplant in high risk patients
50. Post transplantation lymphoproliferative
disorders(PTLD)
Most common SMN in the 1st yr after
allogeneic T cell depleted HCT.
EBV + decreased immunity
Risk
1. T cell depletion of donor marrow
2. Antithymocyte globulin use
3. Unrelated/ HLA mismatched grafts
4. Ac or chr GVHD
5. Older age
6. Multiple Transplants
51. Treatment of PTLD
No role of chemotherapy or antiviral agents.
Preemptive therapy
Close monitoring of viral load.
EBV genome in blood > 1000/ 105 peripheral blood
mononuclear cells
Rituximab and EBV-cytotoxic T lymphocyte
significantly reduces the risk of death due to EBVPTLD in
HCT recipients with survival rates of ~90%.
For established PTLD –
~60% (rituximab) to ~80% (cytotoxic T lymphocytes)
52. SOLID TUMORS AFTER
TRANSPLANT
Eight fold risk who survive>10yrs after HCT.
1. Melanoma, BCC, SCC of skin
2. Oral cavity Ca
3. Salivary gland
4. Brain
5. Liver uterine,cervix
6. Thyroid, bone, breast, connective tissue
