Transcript UCSF Abdominal Transplant Surgery Fellowship

Cancer in the
Organ Donor
Sandy Feng, M.D., Ph.D.
8th 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


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!!!
Donors with history of
“acceptable” malignancies
 Low
 In
grade skin cancer
situ cervical carcinoma
Expanding considerations
 Primary
 Renal
?
brain tumors
cell carcinoma
Other common cancers

Breast

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?
Decline
Organ
offer
Accept
Risk of death
Next offer
Higher
risk
Risk of tumor
transmission
Same
risk
Lower
risk
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
DONORS
CNS
TUMORS
%
1995
1996
1997
1998
1999
2000
5,358
5,418
5,477
5,801
5,849
5,985
53
50
63
55
51
61
1.0
0.9
1.2
1.0
0.9
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


Incidence may be increasing



0.5% - 5.0%
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
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
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




Neuron
Astrocytes
Oligodendrocytes
Microglia
Meningeal cells
Astrocyte
Oligodendrocyte
Microglia
Tumor grade

WHO system = 4 malignancy grades



Grading is based upon






I = least aggressive to IV = most aggressive
Some tumor types < 4 grades
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
DIFFUSE ASTROCYTOMA
Increased cellularity;
monomorphic cells
ANAPLASTIC ASTROCYTOMA
Nuclear atypia; Mitoses
Gr II
Gr III
GLIOBLASTOMA
Gr IV
Necrosis; 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
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
Major shortcoming of available data:
Incomplete data re tumor type, grade, and therapy

UNOS: 418/46,956 donors (1992–2000)




IPITTR: 36/>17,000 “cases” (1970-2002)



Includes benign and malignant tumors
<10% known histological tumor type
35 GBM + 34 astrocytoma + 5 medulloblastoma
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
Medulloblastoma
Glioblastoma
Astrocytoma
Buell JF et al., Transplantation 2003
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
Donors
Transmissions
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
A cautionary note:
secondary brain tumors


Metastatic tumors are much more common than
primary tumors
IPITTR: misdiagnoses involving 29 donors







23%
19%
12%
10%
17%
22%
=
=
=
=
=
=
melanoma
renal cell carcinoma
choriocarcinoma
sarcoma
Kaposi’s sarcoma
variable
Poor outcomes


64% metastatic disease
32% 5 year survival
 59% with explantation/immunosuppression cessation
 0% without explantation
Buell et al., Trans Proc, 2005
Strategies adopted by DSAs for donors
with known history of CNS tumor

Obtain history from family



Obtain old records




Diagnosis and timing
Center and general course of treatment
Operative note
Histopathology
Radiology
Formal neurosurgical consult
Strategies adopted by DSAs for donors
with undiagnosed CNS tumor

Obtain history from family





Full body CT scan
Neurosurgical consultation and biopsy



Elicit symptoms including headache, visual
disturbances
Contact family MD
Obtain any available evaluation
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
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
•Combined
activation of Ras
and Akt leads to
GBM development in mice.
•mTOR is a
critical downstream component of the
Akt pathway.
Parsa and Holland, Trends in
Molecular Medicine, 2004
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





3 patients: in vivo excision after transplantation




14 patients
Tumor size:
2.1 cms (0.5-4.0 cm)
Fuhrman grade: I–II/IV
No recurrences
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/IV
2mm margins
J. 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
Stage
5-yr
survival
Donor/Tumor
Factors
Safe diseasefree interval
99-100%
None
Safe / 0 yrs
>95%
Caucasian male
>1 yrs
90-95%
Female
> 5 yrs
<90%
AA male
None
99-100%
Comedo, grade,
extensive*
Safe / 0 yrs
COLON
0
T1/T2
T1/T2
T1/T2
BREAST
0
T1a/b
91% 10yr
10yrs
T1c
78% 10yr
None
*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



Melanoma



93% transmission
64% (69%) death
74% transmission
58% (78%) death
Lung cancer


43% transmission
32% (75%) death
J. Buell, ASTS Winter Symposium 2003
Living Donor
Transplantation
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
Donation after
Cardiac Death
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
Detry O et al; Liver Transplantation 2005
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
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.