Se ha denunciado esta presentación.
Utilizamos tu perfil de LinkedIn y tus datos de actividad para personalizar los anuncios y mostrarte publicidad más relevante. Puedes cambiar tus preferencias de publicidad en cualquier momento.

Immunosupp related malig

HIV related and transplant related malignancies

  • Sé el primero en comentar

Immunosupp related malig

  1. 1. IMMUNOSUPPRESSION RELATED MALIGNANCIES DR RAJIV PAUL
  2. 2. HIV associated malignancies Transplantation related malignancies
  3. 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
  4. 4.  NON-AIDS DEFINING MALIGNANCIES(NADMs)- 1. Hodgkin lymphoma 2. Oral cavity 3. Anus 4. Lung 5. Vagina and vulva 6. Seminoma 7. Penis 8. RCC 9. Liver 10. Myeloma 11. Breast 12. Colon 13. Prostate.
  5. 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. 6. 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.
  7. 7. Non-AIDS defining malignancies  Increasing incidence in post –ART era .  Factors responsible-  Increase incidence of HIV patients  Increase survival  Tobacco and alcohol  Oncogenic viruses
  8. 8. 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
  9. 9. 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
  10. 10. Kaposi Sarcoma  Multifocal angioproliferative disorder  KSHV  Purplish lesion  Proliferative spindle cells, KSHV infected = hallmark  Markers of lymphatic endothelial cells  Leaky vascular slits  Inflammatory infiltrate  Site = skin(mc), lung, lymphatic, gIT  Polyclonal, monoclonal if advanced
  11. 11. KS – epidemiologic classification Classical –Elderly mediterranean male, indolent Endemic – Africa,both sexes,younger Iatrogenic – Immunosuppressed populations(transplant recipients) Epidemic – in HIV +
  12. 12. KS - Pathogenesis KSHV infected spindle cell proliferation Decreased immunity (decreased CD4 count) HIV – Tat protein -> KSHV coinfection
  13. 13. 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
  14. 14. 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.
  15. 15. 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
  16. 16. 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
  17. 17. 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
  18. 18. 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.
  19. 19. KSHV associated multicentric Castleman`s disease  Plasmablastic variant of MCD.  Polyclonal B cell hyperproliferative disorder.  Intermittent flare of inflammatory symptoms + lymphadenopathy + splenomegaly  GI, pulm, neuro, rheumatic  Diagnosis – LN biopsy  t/t – Rituximab + Doxorubicin  Zidovudine+ Ganciclovir  High relapse rate.
  20. 20. 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
  21. 21. More common Rare DLBCL, BL, cHL PCNSL, immunoblastic DLBCL, PEL, plasmablastic L, KSHV – MCD Immunocompetent Dec immunity Curable Challenging t/t
  22. 22. Pathogenesis  Degree of immune suppression  Uncontrolled HIV viremia  Immune activation of EBV infected and EBV-uninfected B cells  Translocation and  Aberrant somatic hypermutation
  23. 23. Diagnosis  Rapidly growing mass/ B symptoms  Biopsy/IHC/FISH  GEP for phenotype  Staging  CT chest, Abdomen, pelvis  PET CT  LDH, CBC  BM biopsy  CSF cytology  MRI brain  Baseline HIV viral load,CD4 count.
  24. 24. 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
  25. 25. 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.
  26. 26. 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.
  27. 27. 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
  28. 28. 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
  29. 29. PRIMARY EFFUSION LYMPHOMA  AGGRESSIVE MATURE B CELL lymphoma  Present as 1. Lymphomatous effusion – pleural, pericardial, peritoneal, leptomeningeal 2. LN, cutaneous, GIT, S/S 3. Inflammatory syndrome  Diagnosis – KSHV (100%)+, EBV coinfection(>80%) , CD 30, 38, 71,138+  Poor outcome  OS < 6mnths
  30. 30. 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
  31. 31.  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.
  32. 32. 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
  33. 33. 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.
  34. 34.  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
  35. 35. 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
  36. 36. 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.
  37. 37. TRANSPLANTATION RELATED MALIGNANCIES
  38. 38. 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
  39. 39. HCT - > Subsequent Malignant Neoplasm (SMN)  Classification of SMNs 1. Myelodysplasia and AML ( tMDS-AML) 2. Lymphoproliferative disorders 3. Solid tumors
  40. 40. 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
  41. 41. 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
  42. 42. 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
  43. 43. 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
  44. 44. 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
  45. 45. 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
  46. 46. 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
  47. 47. 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)
  48. 48. 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
  49. 49. Pathogenesis  Radiation(TBI) at young age  Oncogenic viruses – HPV  Chronic tissue stress, GVHD  Genetic predisposition
  50. 50. Management of solid tumors  Standard t/t unless evidence that they will not tolerate
  51. 51. Thank You

×