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
Hes 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 Hodgkins 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 primary CNS 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

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Brain cell types in the CNS

• Neurons
• Glia (glue) supportive cells
• Astrocytes
• Oligodendrocytes
• Microglia
• Meningeal cells

Neuron
Astrocyte
Microglia
Oligodendrocyte
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Tumor grade

• WHO system 4 malignancy grades
• I least aggressive to IV most aggressive
• Some tumor types
• 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

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Histologic criteria for classification of gliomas
DIFFUSE ASTROCYTOMA Increased cellularity monomor
phic cells
ANAPLASTIC ASTROCYTOMA Nuclear atypia Mitoses
Gr II
Gr III
GLIOBLASTOMA Necrosis pseudo-palisading cells
around necrotic tissue increased vascularity
Gr IV
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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
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Major shortcoming of available dataIncomplete
data re tumor type, grade, and therapy

• UNOS 418/46,956 donors (19922000)
• Includes benign and malignant tumors
• 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

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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 notesecondary 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 Kaposis 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 RCCIPITTR 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 III/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
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Breast and Colon Cancer
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Stage, risk factors, and disease free intervals
for breast and colon cancer
Increases nodal disease risk to ?2
Reid Adams, ASTS Winter 2003
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Other Cancers
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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 n32
LR 1 n4
Deceased 88 n251
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.