CP1081584-1
CP1081584-1
Incidence of CholangiocarcinomaIncidence of CholangiocarcinomaC
um
ula
tive
inci
den
ce o
fch
ola
ng
ioca
rcin
om
a (%
)C
um
ula
tive
inci
den
ce o
fch
ola
ng
ioca
rcin
om
a (%
)
Years since PSC diagnosisYears since PSC diagnosisCP1042831-1
0.0
2.5
5.0
7.5
10.0
0 2 4 6
Relationship Between the Natural History of a Disease and Effective Screening
Relationship Between the Natural History of a Disease and Effective Screening
CP1164484-1CP1164484-1
BiologicBiologiconsetonset
BiologicBiologiconsetonset
EarlyEarlyclinicalclinical
diagnosisdiagnosis
EarlyEarlyclinicalclinical
diagnosisdiagnosis
UsualUsualclinicalclinical
diagnosisdiagnosis
UsualUsualclinicalclinical
diagnosisdiagnosis
IneffectiveIneffectivetherapytherapy
IneffectiveIneffectivetherapytherapy
EffectiveEffectivetherapytherapy
EffectiveEffectivetherapytherapy
CP1081584-2
ROC for CA 19-9 in Identifying Cholangiocarcinoma in PSC
ROC for CA 19-9 in Identifying Cholangiocarcinoma in PSC
SensitivitySensitivity
0.0
0.2
0.4
0.6
0.8
1.0
0.0 0.2 0.4 0.6 0.8 1.0
1-specificity1-specificity
CA 19-9>100CA 19-9>100SensitivitySensitivity 75%75%SpecificitySpecificity 80%80%
CP925977-1
Chalasani et al:Chalasani et al:Hepatology 31:7-11, 2000Hepatology 31:7-11, 2000
200200
180180
128128 100100
4141
Performance for Routine Cytology Interpretation
Performance for Routine Cytology Interpretation
0%
20%
40%
60%
80%
100%
Sensitivity Specificity Accuracy Equivocal
Initial
Path.#1Path.#2
0%
20%
40%
60%
80%
100%
Sensitivity Specificity Accuracy Equivocal
Initial
Path.#1Path.#2
Harewood et al Am J Gastro, 2004Harewood et al Am J Gastro, 2004
CP901472- 8
Advances in Diagnostic ModalitiesAdvances in Diagnostic Modalities
Digital Image Analysis Improves the Diagnostic Yield of Brush CytologyDigital Image Analysis Improves the Diagnostic Yield of Brush Cytology
• Feulgen dye to stain DNA• Employs computer-assisted
technology to assess DNA content of cells
• Quantitates ploidy at the single cell level
• Aneuploidy = malignancy
• Feulgen dye to stain DNA• Employs computer-assisted
technology to assess DNA content of cells
• Quantitates ploidy at the single cell level
• Aneuploidy = malignancy
Fluorescent In Situ Hybridization (FISH)Fluorescent In Situ Hybridization (FISH)
• Fluorescent hybridization oligonucleotides
chromosome 3chromosome 17chromosome 7locus 9p21
• Fluorescent hybridization oligonucleotides
chromosome 3chromosome 17chromosome 7locus 9p21
Prospective Study of DIA vsBrush Cytology
Prospective Study of DIA vsBrush Cytology
CP1037610-6
• Consecutive patients with bile duct strictures (n=97)
• Classification of benign vs malignant
Surgical specimens
Follow-up
• Consecutive patients with bile duct strictures (n=97)
• Classification of benign vs malignant
Surgical specimens
Follow-up
0
25
50
75
100sensitivity
specificity
CytologyCytology DIADIA FISHFISH
Per
cen
tP
erce
nt
N=130, 69 malignant and 61 benign
Sensitivity and Specific of Cytology, DIA, and FISHSensitivity and Specific of Cytology, DIA, and FISH for Malignant Biliary Stricturesfor Malignant Biliary Strictures
FISH
• Polysomy of 2 or more chromosomes = cholangiocarcinoma• Trisomy of chromosome 7 can be
observed without cholangiocarcinoma - 50% no cancer
- ? Early marker of neoplasia
CEP7/EGFR ProbeCEP7/EGFR Probe
CEP7=GreenEGFR=Red
PROBES
HypothesisHypothesis
CP1164484-3CP1164484-3
Trisomy 7Trisomy 7 EGFR amplificationEGFR amplification
GrowthadvanceGrowthadvance
CancerCancer
EGFRinhibition
EGFRinhibition
PSC Screening?PSC Screening?
ERCP with cytology for FISH (1-2 years)
Trisomy 7
? Chemoprevention
EGFR Inhibitor
Position Emission Tomography(PET)
• ? Cholangiocarcinoma
Utility of PET scanning in cholangiocarcinoma (n=21)Utility of PET scanning in
cholangiocarcinoma (n=21)
• Primary tumorsensitivity 92%specificity 93%
• Metastases sensitivity 15%
• Primary tumorsensitivity 92%specificity 93%
• Metastases sensitivity 15%
Kluge, et al, Hepatololgy, 2001Kluge, et al, Hepatololgy, 2001
Initial Diagnosis of Symptomatic PSCInitial Diagnosis of Symptomatic PSC
CP1037610-3
Brushings/biopsies• DIA• FISH
Brushings/biopsies• DIA• FISH
PET scanPET scan
Serum CA 19-9Serum CA 19-9
PSCPSC
??
Evaluation of Indeterminate StrictureEvaluation of Indeterminate Stricture
CP1037610-4
Pathology (DIA, FISH)Pathology (DIA, FISH)
PostivePostive NegativeNegative
CA 19-9CA 19-9
>100 U/mLTreat as malignant
>100 U/mLTreat as malignant
<100 U/mL<100 U/mL
MRI + feredexMRI + feredex
SuspiciousSuspicious NegativeNegative
PETPET
CholangiocarcinomaCholangiocarcinoma
• Incidence• Risk factors• Diagnosis• Staging• Treatment
• Incidence• Risk factors• Diagnosis• Staging• Treatment
Staging CholangiocarcinomaPeriductal ExtensionStaging CholangiocarcinomaPeriductal Extension
CP1041236-2
Submucosal tumor
Submucosal tumor
Staging of CholangiocarcinomaStaging of Cholangiocarcinoma
CP1037610-1
MR studies
• Cholangiogram
• Feredex
• Angiogram
EUS
• FNA of lymph nodes
MR studies
• Cholangiogram
• Feredex
• Angiogram
EUS
• FNA of lymph nodes
Feredex MRFeredex MR
CP1037610-5
Feredex
•Fe based
•Kupffer cells
signal on MR
Allows visualizaton of bile duct tumors
Feredex
•Fe based
•Kupffer cells
signal on MR
Allows visualizaton of bile duct tumors
Endoscope
CP1041236-1
EUS and Staging CholangiocarcinomaEUS and Staging Cholangiocarcinoma
Lymph node metastasis
Lymph Node
Utility of EUS in the Staging of Cholangiocarcinoma
Utility of EUS in the Staging of Cholangiocarcinoma
CP1037610-2
30 patients
• Operative candidates
• Negative CT scans for nodal metastases
EUS with FNA
• Positive in 17%
30 patients
• Operative candidates
• Negative CT scans for nodal metastases
EUS with FNA
• Positive in 17%
CholangiocarcinomaCholangiocarcinoma
• Incidence• Risk factors• Diagnosis• Staging• Treatment
• Incidence• Risk factors• Diagnosis• Staging• Treatment
Surgical Resction for Cholangiocarcinoma
0
20
40
60
80
100
0 1 2 3 4 5 6 7
Survival Following Resection for Perihilar Cholangiocarcinoma
Survival Following Resection for Perihilar Cholangiocarcinoma
CP1156855-2CP1156855-2
Survival rate (%)Survival rate (%)
Time (yr)Time (yr)Rea et al: Archives of Surgery 139:54, 2004Rea et al: Archives of Surgery 139:54, 2004
Liver Transplantation for Cholangiocarcinoma
0.0
0.2
0.4
0.6
0.8
1.0
0 1 2 3 4 5 6 7 8 9 10 11 12 13
Liver Transplantation for Hepatobiliary Malignancy in PSC
Liver Transplantation for Hepatobiliary Malignancy in PSC
CP1156855-1CP1156855-1
Survivalprobability
Survivalprobability
Years post-transplantationYears post-transplantation
No HB-malignancyNo HB-malignancy
HCCHCC
GBCGBC
CCACCA
n=192n=192
n=9n=9
n=4n=4
n=17n=17
Brandsaeter et al: J Hept 40:815, 2004Brandsaeter et al: J Hept 40:815, 2004
CP1041236-3
Criteria for LTx
•Unresectable, perihilar
•Mass if present <3 cm
• If PSC, any ductal tumor <3 cm
Diagnosis of CholangiocarcinomaDiagnosis of Cholangiocarcinoma
• Cytology - routine cytology, positive DIA, or positive FISH
• Malignant appearing stricture with CA-19 > 100 U/L in the absence of cholangitis
• Cytology - routine cytology, positive DIA, or positive FISH
• Malignant appearing stricture with CA-19 > 100 U/L in the absence of cholangitis
CP1084287-3CP1084287-3
Treatment ProtocolTreatment Protocol
External beam radiation therapy
Brachytherapy
Capecitabine
Abdominal exploration for staging
Liver transplantation
External beam radiation therapy
Brachytherapy
Capecitabine
Abdominal exploration for staging
Liver transplantation
CP1084287-6CP1084287-6CP1084287-6CP1084287-6
RESULTS 1993 - 2004RESULTS 1993 - 2004RESULTS 1993 - 2004RESULTS 1993 - 200471 patients71 patients71 patients71 patients
4 deaths4 deaths4 deaths4 deaths4 disease progression4 disease progression4 disease progression4 disease progression
5 awaiting transplantation5 awaiting transplantation5 awaiting transplantation5 awaiting transplantation
57 staging 57 staging operationoperation57 staging 57 staging operationoperation 14 positive14 positive14 positive14 positive
38 liver 38 liver transplantationtransplantation
38 liver 38 liver transplantationtransplantation
Irradiation Irradiation + 5-FU+ 5-FU
Irradiation Irradiation + 5-FU+ 5-FU
7 deaths 7 deaths 7 deaths 7 deaths
6 waiting for lap 6 waiting for lap 6 waiting for lap 6 waiting for lap
31 Alive31 Alive 31 Alive31 Alive
Patient Demographics at Enrollment into Protocol
Characteristic Transplanted(n=38)
(+) staging lap.(n=14)
Age 45 45
Male: Female 28:10 8:6
PSC 29 (76%) 11 (78%)
IBD 10 (26%) 7 (50%)
Cirrhosis 12 (31%) 6 (43%)
CA 19-9 100 13 (34%) 6 (43%)
CA 19-9 >100 3 (8%) 4 (14%)
PATIENT SURVIVAL AFTER TRANSPLANTATION
PATIENT SURVIVAL AFTER TRANSPLANTATION
0
20
40
60
80
100
0 1 2 3 4 5 6 7
Year
Percent Survival
CCA
0
20
40
60
80
100
0 1 2 3 4 5 6 7
Year
Percent Survival
CCA
CP1084287-7CP1084287-7
Patient SurvivalPatient Survival
Survival(%)
Survival(%)
YearsYears
OLTOLT
No OLTNo OLT0
20
40
60
80
100
0 2 4 6 8 10
CP1084287-8CP1084287-8
Cause of DeathCause of Death
Recurrent CCA 4
Sudden death 1
Complications following LDLT 2
HAT, retransplant, bile leak, sepsis, MOF
Bile leak, sepsis
Recurrent CCA 4
Sudden death 1
Complications following LDLT 2
HAT, retransplant, bile leak, sepsis, MOF
Bile leak, sepsis
Rationale for Screening PSC Patients for Cholangiocarcinoma
Rationale for Screening PSC Patients for Cholangiocarcinoma
CP1164484-2CP1164484-2
BiologicBiologiconsetonset
BiologicBiologiconsetonset
Early Dx:Early Dx:ERCP +ERCP +
RC/FISH/DIARC/FISH/DIA
Early Dx:Early Dx:ERCP +ERCP +
RC/FISH/DIARC/FISH/DIA
UsualUsualclinicalclinical
diagnosisdiagnosis
UsualUsualclinicalclinical
diagnosisdiagnosis
IneffectiveIneffectivetherapytherapy
IneffectiveIneffectivetherapytherapy
? EGFR? EGFRinhibitioninhibitionLiver TxLiver Tx
? EGFR? EGFRinhibitioninhibitionLiver TxLiver Tx
CP1081584-4
North Dakota Beer CoolerNorth Dakota Beer Cooler