Cancer in the Organ Donor

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Cancer in the Organ Donor. Sandy Feng, M.D., Ph.D. 8 th Banff Conference on Allograft Pathology Edmonton, Alberta July 19, 2005. The organ shortage. He’s # 60,453 as of 7/19/05. Pieter Brueghel: The Beggars (1568). Two donor situations. No known history of cancer - PowerPoint PPT Presentation

Text of Cancer in the Organ Donor

  • Cancer in the Organ Donor Sandy Feng, M.D., Ph.D.

    8th Banff Conference on Allograft Pathology

    Edmonton, AlbertaJuly 19, 2005

  • Hes # 60,453 as of 7/19/05The organ shortage

  • Pieter Brueghel: The Beggars (1568)

  • Two donor situationsNo known history of cancerOrgan recipient(s) develop cancer early after transplantation Donor origin Determined by molecular or chromosomal analysisStrongly suggested if multiple organ recipients develop the same cancer

    Known history of cancer: the primary topic of this talk!!!

  • Donors with history of acceptable malignanciesLow grade skin cancer

    In situ cervical carcinoma

  • Expanding considerationsPrimary brain tumorsRenal cell carcinoma? Other common cancersBreastColon

  • Data sources for transmission riskNatural history of cancer: oncology

    Word of mouthEurotransplant Foundation databaseFrench-Speaking Transplantation SocietyCenter or country experiences reported at meetings

    Case reports

    RegistriesUNOS:voluntary / underreportingANZODR:voluntary / underreporting / smaller experienceIPITTR:event-driven / overreporting

  • Risk and benefit?Risk of tumor transmissionRisk of deathAcceptNext offerDeclineOrganofferHigherriskSameriskLowerrisk

  • PrimaryBrain Tumors

  • Burden of CNS tumorsApproximately 17,000 new cases/year2x cases of Hodgkins lymphomaVersus 145,000 cases of colon cancerVersus 210,000 cases of breast cancer1,500 2000 occur in children

    Cause of death for 13,000 annually100,000 deaths/year with symptomatic intracranial metastases of other cancersVersus 56,000 for colon cancerVersus 40,000 for breast cancer

  • U.S. organ donors with primary CNS tumor as cause of deathYEAR ALL CNS %DONORSTUMORS

    1995 5,358 531.01996 5,418 500.91997 5,477 631.21998 5,801 551.01999 5,849 510.92000 5,985 611.013,000 deaths/year 2 primary CNS tumor

  • Theoretical barriers to metastasisImpassable duraAbsence of true lymphatic channelsUnique extracellular matrixTough basement membrane that surrounds intracerebral blood vesselsEarly occlusion of soft-walled cerebral veins easily collapse by advancing tumorSpecific metabolic requirements of CNS tumor cells

  • Extracranial metastasesRARE, but widely varying estimates0.5% - 5.0%

    Incidence may be increasingImproved treatment strategiesProlonged patient survival

    Metastases can occur virtually anywhereLungs / pleuraLymph nodesBoneLiverHeart, adrenal gland, kidney, mediastinum, pancreas, thyroid, and peritoneum

  • Risk factors for extracranial metastases of CNS tumorsUnderlying pathologyMalignancy gradeCompromise of blood-brain barrierSurgeryChemotherapyRadiotherapyShunt placementDuration of disease

  • Tumor typesNamed for primary cell type

    Diagnosis based upon multiple lines of evidenceHistology / morphologyImmunocytochemistryMolecular diagnostics Genetic profilesProteomics

    Chemo- or radiation therapy can render diagnosis extremely difficult

  • Brain cell types in the CNSNeuronsGlia (glue): supportive cellsAstrocytesOligodendrocytes MicrogliaMeningeal cellsNeuronAstrocyteMicrogliaOligodendrocyte

  • Tumor gradeWHO system = 4 malignancy grades I = least aggressive to IV = most aggressiveSome tumor types < 4 grades

    Grading is based upon Nuclear atypiaMitosesMicrovascular proliferationNecrosis

    Grade often increases with time

    Grading is based upon the most malignant portion of the tumorInformation from biopsies necessarily reflect a minimum grade

  • Histologic criteria for classification of gliomasGr IIGr IVGr IIIDIFFUSE ASTROCYTOMAIncreased cellularity;monomorphic cellsANAPLASTIC ASTROCYTOMANuclear atypia; MitosesGLIOBLASTOMANecrosis; pseudo-palisading cells around necrotic tissue; increased vascularity

  • Routes of metastasisBlood, lymph, CSF, and direct extension

    Blood brain barrier: not intact within tumorsReduced tight junction fusion between endothelial cellsImportance of hematogenous spread: lungs are the commonest site

    There are lymphatic channels in the brainLymph node metastases frequently in cervical or retroauricular lymph nodesLymph nodes are 2nd commonest site

  • Blue:frank tumorRed:surrounding tissueT1-weightedPre-operativeT2-weightedPre-operativeT1-weightedPost-operativeMRI of glioblastoma multiforme:Disrupted blood-brain barrier

  • Major shortcoming of available data:Incomplete data re tumor type, grade, and therapyUNOS: 418/46,956 donors (19922000)Includes benign and malignant tumors17,000 cases (1970-2002)16 donors with astrocytoma, some with high grade histology (grade III IV)?15 organs from donors with gliomas or glioblastoma ?

    ANZODR: 46/1,781 donors (1989-1996)28 malignant tumors 4 glioma + 10 astrocytoma + 4 glioblastoma + 5 medulloblastoma + 1 malignant meningioma + 4 unspecified

  • Known cases of CNS tumor transmissionHistologiesGlioblastomaMedulloblastomaAstrocytoma grade IIIMalignant meningiomaLymphomaCerebellar malignancy

    All solid organs except small bowel have been involved in transmissionPancreas was transplanted with kidney

  • IPITTR: Incidence of donor transmitted CNS malignancyBuell JF et al., Transplantation 2003AstrocytomaGlioblastomaMedulloblastoma

  • IPITTR: Survival after organ transplantation from donors with CNS malignancyAstrocytomaGlioblastomaMedulloblastomaBuell JF et al., Transplantation 2003

  • Risk factors for donor CNS tumor transmission: same as for metastasis!HistologyGradeTherapeutic interventionsExtensive craniotomyEffect of newer techniques such as gamma knife surgery or stereotactic biopsy is unknown.Ventricular shuntingRadiation or chemotherapy?Duration of diseaseAbsence of risk factors does not exclude possibility of metastases

  • Impact of risk factors on transmissionRisk factors: high grade tumors, ventricular shunts, or surgeryCaveat: a donor with low-grade CNS malignancy (astrocytoma, glioblastoma, or medulloblastoma) in the absence of any known risk factor carries a 7% risk of tumor transmission. . . .Buell JF et al., Transplantation 2003 Donors Trans- missions

  • A cautionary note:secondary brain tumorsMetastatic tumors are much more common than primary tumorsIPITTR: misdiagnoses involving 29 donors23% = melanoma19% = renal cell carcinoma12% = choriocarcinoma10% = sarcoma17% = Kaposis sarcoma22% = variable Poor outcomes64% metastatic disease32% 5 year survival59% with explantation/immunosuppression cessation0% without explantationBuell et al., Trans Proc, 2005

  • Strategies adopted by DSAs for donors with known history of CNS tumorObtain history from familyDiagnosis and timingCenter and general course of treatment

    Obtain old recordsOperative noteHistopathologyRadiology

    Formal neurosurgical consult

  • Strategies adopted by DSAs for donors with undiagnosed CNS tumorObtain history from familyElicit symptoms including headache, visual disturbancesContact family MDObtain any available evaluationFull body CT scanNeurosurgical consultation and biopsyFrozen section reading at local hospitalIf any question of malignancy: transfer biopsy to pre-designated center with expertiseAlternative: place and procure organs; perform brain biopsy immediately following

  • Additional considerations during procurementMeticulous dissection during procurementImmediate frozen section diagnosis

    Consider use of intra-operative ultrasound

    Request post-mortem examination

  • Genetic insights into glioblastomaParsa and Holland, Trends in Molecular Medicine, 2004Combined activation of Ras and Akt leads to GBM develop-ment in mice.

    mTOR is a critical down-stream com-ponent of the Akt pathway.

  • m-TOR inhibition: a therapy for gliomas?Loss of enhancement after 7 days of treatmentTUNEL staining shows treatment leads to apoptosis cell deathHu et al., Neoplasia 2005

  • mTOR inhibition in human trialsLow efficacyNot all human GBMs have increased Akt activityHuman GBMs may harbor additional genetic alterationsThese alterations may render tumor independent of mTORWeekly CCl-779 administration ineffective

    May however sensitize tumors to other therapies such as chemotherapyHas been observed in Akt-driven lymphomas

  • Renal CellCarcinoma

  • New trends in RCCSmaller tumors: incidentalomas

    Nephron sparing surgery is widely practiced in the general populationSmaller excision margins acceptableHistorically: 2cmCurrently: 1mm 5mmLaparoscopic approaches

  • Transplantation of kidneys with RCC:IPITTR data70 patients at risk14 patients: ex vivo excision before transplantation14 patientsTumor size: 2.1 cms (0.5-4.0 cm)Fuhrman grade:III/IVNo recurrences

    3 patients: in vivo excision after transplantation3 patients at 3, 4, and 12 monthsTumor size: 2-5 cmsNo recurrences28 transmissions with unresectable lesions10 deaths (14% of total; 32% after transmission)

  • Resection of renal cell carcinoma prior to transplantation2cm Fuhrman II/IV2mm marginsJ. Buell, ASTS Winter Symposium 2003

  • RCC: New frontiers in prognostication and staging; emerging molecular markers

  • Breast and Colon Cancer

  • Stage, risk factors, and disease free intervals for breast and colon cancer*Increases nodal disease risk to 2%Reid Adams, ASTS Winter 2003

    Stage5-yr survivalDonor/Tumor FactorsSafe disease-free intervalCOLON 099-100%NoneSafe / 0 yrs T1/T2>95%Caucasian male>1 yrsT1/T290-95%Female> 5 yrs T1/T2

  • Other Cancers

  • Scant informationProstate cancer One donor with local tumor spread transmitted cancer

    Thyroid, cervical, testicular, leukemia/