Cancer in the Organ Donor

1. Cancer in the Organ Donor Sandy Feng, M.D., Ph.D. 8th Banff Conference on Allograft Pathology Edmonton, Alberta July 19, 2005

2. The organ shortage He’s # 60,453 as of 7/19/05

3. Pieter Brueghel: The Beggars (1568)

4. Two donor situations • No known history of cancer • Organ recipient(s) develop cancer early after transplantation • Donor origin • Determined by molecular or chromosomal analysis • Strongly suggested if multiple organ recipients develop the same cancer • Known history of cancer: the primary topic of this talk!!!

5. Donors with history of “acceptable” malignancies • Low grade skin cancer • In situ cervical carcinoma

6. Expanding considerations • Primary brain tumors • Renal cell carcinoma • ? Other common cancers • Breast • Colon

7. Data sources for transmission risk • Natural history of cancer: oncology • Word of mouth • Eurotransplant Foundation database • French-Speaking Transplantation Society • Center or country experiences reported at meetings • Case reports • Registries • UNOS: voluntary / underreporting • ANZODR: voluntary / underreporting / smaller experience • IPITTR: event-driven / overreporting

8. Risk and benefit? Risk of death Next offer Decline Higher risk Same risk Lower risk Organ offer Risk of tumor transmission Accept

9. Primary Brain Tumors

10. Burden of CNS tumors • Approximately 17,000 new cases/year • 2x cases of Hodgkin’s lymphoma • Versus 145,000 cases of colon cancer • Versus 210,000 cases of breast cancer • 1,500 – 2000 occur in children • Cause of death for 13,000 annually • 100,000 deaths/year with symptomatic intracranial metastases of other cancers • Versus 56,000 for colon cancer • Versus 40,000 for breast cancer

11. U.S. organ donors with primaryCNS tumor as cause of death YEAR ALL CNS % DONORS TUMORS 1995 5,358 53 1.0 1996 5,418 50 0.9 1997 5,477 63 1.2 1998 5,801 55 1.0 1999 5,849 51 0.9 2000 5,985 61 1.0 13,000 deaths/year 2º primary CNS tumor

12. Theoretical barriers to metastasis • Impassable dura • Absence of true lymphatic channels • Unique extracellular matrix • Tough basement membrane that surrounds intracerebral blood vessels • Early occlusion of soft-walled cerebral veins easily collapse by advancing tumor • Specific metabolic requirements of CNS tumor cells

13. Extracranial metastases • RARE, but widely varying estimates • 0.5% - 5.0% • Incidence may be increasing • Improved treatment strategies • Prolonged patient survival • Metastases can occur virtually anywhere • Lungs / pleura • Lymph nodes • Bone • Liver • Heart, adrenal gland, kidney, mediastinum, pancreas, thyroid, and peritoneum

14. Risk factors for extracranial metastases of CNS tumors • Underlying pathology • Malignancy grade • Compromise of blood-brain barrier • Surgery • Chemotherapy • Radiotherapy • Shunt placement • Duration of disease

15. Tumor types • Named for primary cell type • Diagnosis based upon multiple lines of evidence • Histology / morphology • Immunocytochemistry • Molecular diagnostics • Genetic profiles • Proteomics • Chemo- or radiation therapy can render diagnosis extremely difficult

16. Brain cell types in the CNS • Neurons • Glia (glue): supportive cells • Astrocytes • Oligodendrocytes • Microglia • Meningeal cells Neuron Astrocyte Oligodendrocyte Microglia

17. Tumor grade • WHO system = 4 malignancy grades • I = least aggressive to IV = most aggressive • Some tumor types < 4 grades • Grading is based upon • Nuclear atypia • Mitoses • Microvascular proliferation • Necrosis • Grade often increases with time • Grading is based upon the most malignant portion of the tumor • Information from biopsies necessarily reflect a minimum grade

18. Histologic criteria for classification of gliomas DIFFUSE ASTROCYTOMA Increased cellularity; monomorphic cells ANAPLASTIC ASTROCYTOMA Nuclear atypia; Mitoses Gr II Gr III GLIOBLASTOMA Necrosis; pseudo-palisading cells around necrotic tissue; increased vascularity Gr IV

19. Routes of metastasis • Blood, lymph, CSF, and direct extension • Blood brain barrier: not intact within tumors • Reduced tight junction fusion between endothelial cells • Importance of hematogenous spread: lungs are the commonest site • There are lymphatic channels in the brain • Lymph node metastases frequently in cervical or retroauricular lymph nodes • Lymph nodes are 2nd commonest site

20. MRI of glioblastoma multiforme: Disrupted blood-brain barrier Blue: frank tumor Red: surrounding tissue T1-weighted Pre-operative T2-weighted Pre-operative T1-weighted Post-operative

21. Major shortcoming of available data:Incomplete data re tumor type, grade, and therapy • UNOS: 418/46,956 donors (1992–2000) • Includes benign and malignant tumors • <10% known histological tumor type • 35 GBM + 34 astrocytoma + 5 medulloblastoma • IPITTR: 36/>17,000 “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

22. Known cases of CNS tumor transmission • Histologies • Glioblastoma • Medulloblastoma • Astrocytoma grade III • Malignant meningioma • Lymphoma • “Cerebellar malignancy” • All solid organs except small bowel have been involved in transmission • Pancreas was transplanted with kidney

23. IPITTR: Incidence of donor transmitted CNS malignancy Medulloblastoma Glioblastoma Astrocytoma Buell JF et al., Transplantation 2003

24. IPITTR: Survival after organ transplantation from donors with CNS malignancy Astrocytoma Glioblastoma Medulloblastoma Buell JF et al., Transplantation 2003

25. Risk factors for donor CNS tumor transmission: same as for metastasis! • Histology • Grade • Therapeutic interventions • “Extensive” craniotomy • Effect of newer techniques such as gamma knife surgery or stereotactic biopsy is unknown. • Ventricular shunting • Radiation or chemotherapy • ?Duration of disease • Absence of risk factors does not exclude possibility of metastases

26. Impact of risk factors on transmission Risk factors: high grade tumors, ventricular shunts, or surgery Donors Caveat: “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. . . . Trans- missions Buell JF et al., Transplantation 2003

27. A cautionary note:secondary brain tumors • Metastatic tumors are much more common than primary tumors • IPITTR: misdiagnoses involving 29 donors • 23% = melanoma • 19% = renal cell carcinoma • 12% = choriocarcinoma • 10% = sarcoma • 17% = Kaposi’s sarcoma • 22% = variable • Poor outcomes • 64% metastatic disease • 32% 5 year survival • 59% with explantation/immunosuppression cessation • 0% without explantation Buell et al., Trans Proc, 2005

28. Strategies adopted by DSAs for donors with known history of CNS tumor • Obtain history from family • Diagnosis and timing • Center and general course of treatment • Obtain old records • Operative note • Histopathology • Radiology • Formal neurosurgical consult

29. Strategies adopted by DSAs for donors with undiagnosed CNS tumor • Obtain history from family • Elicit symptoms including headache, visual disturbances • Contact family MD • Obtain any available evaluation • Full body CT scan • Neurosurgical consultation and biopsy • Frozen section reading at local hospital • If any question of malignancy: transfer biopsy to pre-designated center with expertise • Alternative: place and procure organs; perform brain biopsy immediately following

30. Additional considerations during procurement • Meticulous dissection during procurement • Immediate frozen section diagnosis • Consider use of intra-operative ultrasound • Request post-mortem examination

31. Genetic insights into glioblastoma • Combined activation of Ras and Akt leads to GBM develop-ment in mice. • mTOR is a critical down-stream com-ponent of the Akt pathway. Parsa and Holland, Trends in Molecular Medicine, 2004

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

33. mTOR inhibition in human trials • Low efficacy • Not all human GBMs have increased Akt activity • Human GBMs may harbor additional genetic alterations • These alterations may render tumor independent of mTOR • Weekly CCl-779 administration ineffective • May however sensitize tumors to other therapies such as chemotherapy • Has been observed in Akt-driven lymphomas

34. Renal Cell Carcinoma

35. New trends in RCC • Smaller tumors: incidentalomas • Nephron sparing surgery is widely practiced in the general population • Smaller excision margins acceptable • Historically: 2cm • Currently: 1mm – 5mm • Laparoscopic approaches

36. Transplantation of kidneys with RCC:IPITTR data • 70 patients at risk • 14 patients: ex vivo excision before transplantation • 14 patients • Tumor size: 2.1 cms (0.5-4.0 cm) • Fuhrman grade: I–II/IV • No recurrences • 3 patients: in vivo excision after transplantation • 3 patients at 3, 4, and 12 months • Tumor size: 2-5 cms • No recurrences • 28 transmissions with unresectable lesions • 10 deaths (14% of total; 32% after transmission)

37. Resection of renal cell carcinoma prior to transplantation 2cm Fuhrman II/IV 2mm margins J. Buell, ASTS Winter Symposium 2003

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

39. Breast and Colon Cancer

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

41. Other Cancers

42. Scant information • Prostate cancer • One donor with local tumor spread transmitted cancer • Thyroid, cervical, testicular, leukemia/ lymphoma, and hepatobiliary • 1-8 recipients at risk • No tumor transmission

43. Non CNS cancer types widely accepted as “unacceptable”: IPITTR data • Choriocarcinoma • 93% transmission • 64% (69%) death • Melanoma • 74% transmission • 58% (78%) death • Lung cancer • 43% transmission • 32% (75%) death J. Buell, ASTS Winter Symposium 2003

44. Living Donor Transplantation

45. Donor tumor transmission reported to IPITTR after living donor transplantation LU 11% n=32 LR 1% n=4 Deceased 88% n=251 J. Buell ASTS Winter Symposium 2003

46. Donation after Cardiac Death

47. First report of tumor transmission from a DCD donor • 60 yo F without history of cancer • 53 yo M liver recipient presented with cholestasis 13 months after tx • Kidney 1 = PNF excised 10 days post- tx • Kidney 2 = excised 12 months post-tx for malignant tumor = spindle cell sarcoma CT scan Spindle Cell Sarcoma FISH Detry O et al; Liver Transplantation 2005

48. Conclusions (1) • The increasing severity of organ shortage has motivated serious reconsideration of donors with (a history of) malignancy • Risk - benefit analysis • There are certain tumor types which are strongly ill-advised. • Glioblastoma and medulloblastoma • Choriocarcinoma, melanoma, and lung cancer

49. Conclusions (2) • Available data regarding transmission risk of cancer from donors with (a history of) malignancy is flawed. • Oncologic data regarding survival and metastases rates for specific tumor histology, grade, and stage may ultimately provide the best guidance.