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Cancer in the Organ Donor
Sandy Feng, M.D., Ph.D.
8th Banff Conference on Allograft Pathology
Edmonton, AlbertaJuly 19, 2005
He’s # 60,453 as of 7/19/05
The organ shortage
Pieter Brueghel: The Beggars (1568)
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!!!
Two donor situations
Donors with history of “acceptable” malignancies
Low grade skin cancer
In situ cervical carcinoma
Expanding considerations
Primary brain tumors
Renal cell carcinoma
? Other common cancersBreast
Colon
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
Risk and benefit?
Risk of tumor transmission
Risk of death
Accept
Next offerDecline
Organoffer
Higherrisk
Samerisk
Lowerrisk
Primary
Brain Tumors
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
U.S. organ donors with primary CNS tumor as cause of death
YEAR ALL CNS %DONORS TUMORS
1995 5,358 53 1.01996 5,418 50 0.91997 5,477 63 1.21998 5,801 55 1.01999 5,849 51 0.92000 5,985 61 1.0
13,000 deaths/year 2º primary CNS tumor
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
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
Underlying pathology Malignancy grade Compromise of blood-brain barrier
Surgery Chemotherapy Radiotherapy
Shunt placement Duration of disease
Risk factors for extracranial metastases of CNS tumors
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
Brain cell types in the CNS
Neurons Glia (glue): supportive cells
Astrocytes Oligodendrocytes Microglia
Meningeal cells
Neuron Astrocyte MicrogliaOligodendrocyte
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
Histologic criteria for classification of gliomas
Gr II
Gr IV
Gr III
DIFFUSE ASTROCYTOMAIncreased cellularity;monomorphic cells
ANAPLASTIC ASTROCYTOMANuclear atypia; Mitoses
GLIOBLASTOMANecrosis; pseudo-palisading cells around necrotic tissue; increased vascularity
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
Blue:frank tumorRed: surrounding tissue
T1-weightedPre-operative
T2-weightedPre-operative
T1-weightedPost-operative
MRI of glioblastoma multiforme:Disrupted blood-brain barrier
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
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
IPITTR: Incidence of donor transmitted CNS malignancy
Buell JF et al., Transplantation 2003
Astrocytoma
Glioblastoma
Medulloblastoma
IPITTR: Survival after organ transplantation from donors with CNS malignancy
Astrocytoma
Glioblastoma
Medulloblastoma
Buell JF et al., Transplantation 2003
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
Impact of risk factors on transmission
Risk factors: high grade tumors, ventricular shunts, or surgery
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. . . .
Buell JF et al., Transplantation 2003
Donors
Trans- missions
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
A cautionary note:secondary brain tumors
Buell et al., Trans Proc, 2005
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
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
Strategies adopted by DSAs for donors with undiagnosed CNS tumor
Additional considerations during procurement
Meticulous dissection during procurement Immediate frozen section diagnosis
Consider use of intra-operative ultrasound
Request post-mortem examination
Genetic insights into glioblastoma
Parsa and Holland, Trends in Molecular Medicine, 2004
•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.
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
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
Renal Cell
Carcinoma
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
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)
Resection of renal cell carcinoma prior to transplantation
2cm Fuhrman II/IV2mm margins
J. Buell, ASTS Winter Symposium 2003
RCC: New frontiers in prognostication and staging; emerging molecular markers
Breast and
Colon Cancer
Stage5-yr
survivalDonor/Tumor
FactorsSafe disease-free interval
COLON
0 99-100% None Safe / 0 yrs
T1/T2 >95% Caucasian male >1 yrs
T1/T2 90-95% Female > 5 yrs
T1/T2 <90% AA male None
BREAST
0 99-100%Comedo, grade,
extensive*Safe / 0 yrs
T1a/b 91% 10yr 10yrs
T1c 78% 10yr None
Stage, risk factors, and disease free intervals for breast and colon cancer
*Increases nodal disease risk to 2%
Reid Adams, ASTS Winter 2003
Other Cancers
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
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
Living Donor
Transplantation
Deceased88%
n=251
LU11%n=32
LR1%n=4
Donor tumor transmission reported to IPITTR after living donor transplantation
J. Buell ASTS Winter Symposium 2003
Donation after
Cardiac Death
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
First report of tumor transmission from a DCD donor
Detry O et al; Liver Transplantation 2005
CT scan Spindle Cell Sarcoma FISH
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
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.
Conclusions (2)