Gastrolearning II modulo/8a lezione Il colangiocarcinoma: Presentazione Clinica, Diagnosi e Trattamento Prof. D. Alvaro - Università di Roma La Sapienza

1. Univ. Sapienza, Rome, Italy.Domenico ALVARO, Univ.“Sapienza” Rome,
Italy
Neo Gr.E.Ca.S., Cosenza, 6 Dicembre 2013.
IL COLANGIOCARCINOMA
Presentazione Clinica, Diagnosi e Trattamento

2. Distal
INTRAHEPATIC
CHOLANGIOCARCINOMA (CCA): a heterogeneus cancer !
Hilar
UICC classification
WHO classification
Klatskin t.
second-order bile ducts

3. INTRAHEPATIC CCA (IH-CCA)
Macroscopic pattern of growth !
Mass-forming
Periductal-
infiltrating
Intraductal growing
(LSCGJ)
Mixed type
(AJCC/UICC )

4. Mass-forming = 89 %
Single mass = 67%
HBV or HCV+ = 21%
Cirrhosis = 10%
Obstructive cholestasis = 10%

5. Anatomical location of IH-CCA
24/52 segment IV)
IH-CCA, N= 116.
Mass-forming = 94 %
Single mass = 78.4%
HBV or HCV+ = 30.2%
Cirrhosis = 13.8%
Obstructive cholestasis = 10%
50%

6. IH-CCA : PRESENTING SYMPTOMS (%)
4% Pruritus
4.4 % Other

7. IH-CCA: Algorithm for the diagnosis.
Intrahepatic mass
Esclude extrahepatic
malignancy !
4-phase MDCT, dynamic
contrast-enhanced MRI
contrast arterial enhancement
and prompt venous washout
HCC
Cirrhosis
> 1 cm
The impact of imaging procedures in
discriminating
HCC vs mixed-CCA or combined HCC-
CCA
scarcely investigated !

8. N= 31 nodules, N 9 < 2 cm.

9. -Progressive homogeneous contrast
uptake during the three vascular phase (42%)
N. 40 IH-CCA nodules on cirrhosis (N= 11 < 2 cm):
all nodules lacked the radiologic hallmark of HCC !
-Arterial periphereal-rim enhancement (50%);

10. N. 28 IH-CCA nodules on cirrhosis:
< 3 cm: 5/8 washout pattern similar to HCC !
> 3 cm: 20/20 no washout, 9/20 arterial periphereal-rim enhanc.!

11. Biopsy
IH-CCA: Algorithm for the diagnosis.
Intrahepatic mass
Esclude extrahepatic
malignancy !
4-phase MDCT, dynamic
contrast-enhanced MRI
contrast arterial enhancement
and prompt venous washout
HCC
Atypical
appearance
cirrhosisnon-cirrhotic liver

12. No marker specific for CCA!
Immunohistochemistry (IHC) marker panel
CK7 (+), CK20(-/+), CDX-2(-),
TTF-1 (-), PR (-), BRST-2 (-) , PSA (-)
Histology/IHC cannot differentiate
CCA from metastatic gallbladder cancer,
pancreas, or upper gastrointestinal tract
Histological diagnosis of IH-CCA:
a diagnosis of exclusion !
(HCC ?, metastasis ? )
MembranousN-cadherin +: sensitivity 67%; specificity 88%
Membranous N-cadherin +/CK7+:sensitivity 67% ; specificity 98%
Sempoux C. et al.
Seminar in liver disease
Vol. 31, 2011. .

13. CHOLANGIOCARCINOMA: Diagnosis
Novel target genes and a valid biomarker panel
identified for CCA. Andresen K. et al. Epigenetics 2012; 7 (11).
CDO1, DCLK1, SFRP1 and ZSCAN18, high methylation
frequencies in CCA ….unmethylated in controls.
At least one of these four biomarkers was positive in 87%
of the tumor samples, with a specificity of 100% !

14. Nodular
Nodular
Periductal-
infiltrating
Intraductal
growing
(LSCGJ)
Exophyti
c
EXTRAHEPATIC CCA (EH-CCA)
Classification based on Macroscopic pattern of
growth !

15. Nodular+PI = 94%
Obstructive jaundice = 79 % (299/376)
Biliary drainage = 74.3%
BSG guidelines

16. EH-CCA, N= 102
Nodular-PI = 82 %
HBV or HCV+ = 18.6 %
Cirrhosis = 4.3%
Obstructive cholestasis = 70%

17. EH-CCA : PRESENTING SYMPTOMS (%)
6.8%
Pruritus
3,9 %
abdominal pain
5.9 %
No symptoms
9.9 % others

18. ObservationCCA
EH-CCA: Algorithm for the diagnosis
Suspicion of CCA
(Clinical + US)
MRI+MRCP
ERCP (citology, brushing, FISH, biopsy)
Under evaluation: Endoscopic Ultrasound (EUS), Intraductal Ultrasound
(IDUS), Choledochoscopy, cholangioscopy (chromoendoscopy, confocal
endoscopy, narrow band imaging)
Neg. citology, brushing, FISH
No dominant stricture
CCA
Biopsy
(tumor spread !!)
Positive biopsy, citology,
brushing or polysomy(Fish)
Vascular enhancement
Mass-like
appearance
Biliary stricture
Dominant stricture in PSC
PET (?)
Hot spot?
yes NO
Definite diagnosis
Perihilar mass with associated
biliary stricture + hypertrophy–
atrophy complex + vascular
encasement
microscopic confirmation is
needed to confirm the diagnosis
Presence and level of stricture
sensitivity, specificity = 98%
Malignancy detection
sensitivity 88%, specificity = 95%
(Ann. Int. Med 2003)

19. CHOLANGIOCARCINOMA
Diagnosis
(Gut 2012)

20. CHOLANGIOCARCINOMA
Diagnosis
(Gut 2012)

21. CHOLANGIOCARCINOMA
Diagnosis

22. CHOLANGIOCARCINOMA
Diagnosis

23. Definitive diagnosis before surgery: 61%
No evidence of cancer on resected tissues 10 %
*Polisomy on bile citology or brushing
*IGF1 on bile samples (ERCP)
Never reached routine clinical use !

24. *Surgery is the only curative treatment for CCA !
5-year survival rates: IH-CCA 22-44 %
distal EH-CCA 27-37 %
hilar EH-CCA 11-41 %
*Survival depends: R0 or R1 status, vascular invasion and
lymphonode metastases.
CHOLANGIOCARCINOMA
TREATMENT !

25. Open surgery 57% IH- vs 42% EH-CCA
Curative 45% IH- vs 29% EH-CCA

26. CHOLANGIOCARCINOMA
Adjuvant therapy ?
* No evidence support postoperative adjuvant therapy !
*A phase III RCT with Mito+5FU…. no advantage (only GBC)
* UK NCRI-BILCAP study with CAPECITABINE is ongoing
(final report 2014)
*France-NCT: GEMOX (final report 2015)
BSG guidelines

27. April 2010
*The efficacy of CisGem regimen confirmed (Furuse J. 2011)
* CisGem cost-effective vs Gem alone (Roth JA 2012)
BSG guidelines

28. Metanalysis of Survival, Complications, and Imaging Response
following Chemotherapy-based Transarterial Therapy in
Patients with Unresectable Intrahepatic Cholangiocarcinoma.
Ray CE, J Vasc Int. Radiol. 2013
MESSAGE:
transarterial chemotherapy-based treatments for CCA
appears to confer a survival benefit of 2-7 months compared
with systemic therapies !

29. Yttrium-90 Radioembolization for IH-CCA . Mouli S. et al.
J Vasc Int. Radiol. 2013
46 pts IH-CCA unresectable.
25% partial response
73% stable disease
5 pts converted to resectable status !

30. A phase II trial of sorafenib (SOR) in patients (pts) with
advanced cholangiocarcinoma (CCA). C. Dealis ASCO 2008.
CONCLUSIONS:
Sorafenib as a single agent has a low
activity in cholangiocarcinoma !

31. Targeted agents in development for CCA
Cholangiocarcinoma: registered trials
Sorafenib + Gem.+ cisplatin phase II
Cediranib + Folfox phase II
Panitumumab + Gem.+ Irinotecan phase II
Vandenatinib + Gem. phase II
Sunitinib phase II
Pazopanib + GSK1120212 phase II
Erlotinib phase II