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)