1. Hepatocelluar carcinoma
Young Youn Cho, M.D.
Department of Internal Medicine, Liver Research Institute,
Seoul National University College of Medicine

2. Hepatocellular carcinoma (HCC)
The 5th most common cancer worldwide
The 3rd leading cause of cancer-related deaths
Hypervascular tumor
“Two diseases” in One organ
Intrahepatic recurrence
Extrahepatic metastasis

3. 1. RADIOLOGIC DIAGNOSIS WITHOUT BIOPSY

4. Diagnosis of HCC
EASL Clinical Guidelines

5. Diagram of the mechanism underlying changes in drainage vessels (top) and histologic features (bottom) of HCC during multistep hepatocarcinogenesis
Kitao A et al. Radiology 2009;252:

6. Characteristics of HCC Hypervascularity & Washout

7. 2. INFLAMMATORY TUMOR

8. The main risk factors for HCC
Hepatitis B
Hepatitis C
Alcoholism
Cirrhosis of the liver
Non-alcoholic steatohepatitis
Type 2 diabetes (probably aided by obesity)
Aflatoxin
Iron and copper deposition
SNUBH

9. Cirrhosis is a major risk factor of HCC
HBV >> HCV, hepatic adenoma, hereditary tyrosinemia
Noncirrhotic Pathway
Chronic hepatitis LC
HCC
LC in chronic hepatitis pts
10-20% / 5 yr
HCC in LC pts
: 1-5% / yr

10. Pathophysiology of HCC in hepatitis B

11. Local intra-hepatic inflammation promote hepatocarcinogenesis
Cell Jan 22;140(2):

12. 3. HIGH RATE OF RECURRENCE AFTER CURATIVE TREATMENTS

13. HCC Recurrence rate after resection
5Yr Survival rate: 50-70%
5Yr Recurrence rate: 60-80%
H. Imamura et al. Journal of Hepatology 2003;38:

14. Bimodal recurrence after HCC resection
H. Imamura et al. Journal of Hepatology 2003;38:

15. Early recurrence; intrahepatic metastasis de novo carcinogenesis
Late recurrence;
de novo carcinogenesis
New lesion
Intrahepatic
microscopic
metastatic foci

16. Sorafenib adjuvant treatment failed
- STORM trial
Lancet Oct, p1344–1354,

17. HBV treatment reduces RFS
J Clin Oncol Oct 10;31(29):

18. CIK immunotherapy
Gastroenterology Jun;148(7): e6

19. 4. IMMUNOLOGIC TUMOR?

20. Sites of Extrahepatic HCC
No of Pt. (N=148)
No of Pt. with Other metastatic sites
at initial Presentation
Lungs
81 (55%)
23 / 81 (28%)
Lymph Nodes
78 (53%)
56 / 78 (72%)
Bone
41 (28%)
27 / 41 (66%)
Adrenal
16 (11%)
7 / 16 (44%)
Peritoneum +/- omentum
9 / 16 (56%)
Brain
3 (2%)
3 / 3 (100%)
Rectum
2 (1%)
0 / 2 (0%)
Spleen
1 / 2 (50%)
Diaphragm
2 / 2 (100%)
Duodenum
1 (1%)
1 / 1 (100%)
Esophagus
Pancreas
Seminal vesicle
Bladder
Katyal S et al. Radiology 2000;216:

21. Current guidelines : BCLC classification
EASL Clinical Guidelines

22. Mechanism of Sorafenib
Cancer Research 2004;64:

23. Sorafenib in Advanced HCC
SHARP trial
Asia-Pacific trial
Median Survival :
10.7 vs 7.9 months
Median Survival :
6.5 vs 4.2 months
Llovet JM et al., Sorafenib in Advanced HCC
NEJM 2008;359:378-90
Cheng AL et al., Asia-Pacific trial Lancet Oncol 2009;10:25-34

24. Landscape of systemic treatment in hepatocellular carcinoma

25. Targets of Regorafenib
Journal of Cancer Therapy Vol.4 No.2A(2013)

26. Mutational landscape of HCC
Note that some mutations may co-exist in the same patient. Data suggest that background etiology impact mutation rate. Most mutations affect 3 genes, TERT promoter, CTNNB1 and TP53.
TERT promoter mutations are the most prevalent genetic event both in HCC and pre-neoplastic lesions (dysplastic nodules) and correlate with aberrant TERT expression.
J Hepatol Nov;65(5):

27. Locoregional treatments induce immunologic response
Clin Cancer Res December 15; 19(24):

28. Recur after cryoablation
PLoS One. 2011;6(9):e23621.

29. HCV infection associated with T-cell exhaustion
Adaptive immune responses associated with differential outcome of acute HCV infection. A strong and maintained CD4 T cell response appears to be a critical factor for the outcome of acute HCV infection. In its presence, HCV–specific CD8 T cell populations with an initially “stunned” phenotype acquire multiple effector functions (upper panel). In the absence or loss of a strong CD4 T cell response, CD8 T cells develop exhausted phenotypes, which are attributed to chronic antigen-specific stimulation. Those CD8 T cells that target HCV escape variants remain functional with a memory phenotype in the chronic phase of infection (see text for details). Treg, regulatory T cell.
Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are associated with manifestations of immune suppression, including upregulation of programmed death-1 (PD-1) receptor,7 T-cell exhaustion, and spontaneous apoptosis of immune cells8
Immunity January 16; 40(1): 13–24.

30. Nivolumab (mAb to PD-1 receptor): interim analysis of phase I/II study
Objective responses occurred in 35 of 214 (16%) patients
Response occurred regardless of PD-L1 status
Nivolumab is a fully human IgG4 monoclonal antibody to the PD-1 receptor, blocking the interaction with PD-L1/PD-L213 and restoring T-cell–mediated antitumor activity
Objective responses occurred in 35 of 214 (16%) patients (Table 4)
•PD-L1 expression on tumor cells, as assessed by immunohistochemistry, was quantifiable in 128 patients and responses occurred regardless of PD-L1 status (ORR = 5/26 [19%] patients with PD-L1 ≥ 1% and 20/102 [20%] patients with PD-L1 < 1%). For patients without quantifiable PD-L1 expression data, the ORR was 10/86 (12%)
 In the study, responses were frequently delayed, with a complete response occurring after 24 months of treatment. When considering those with stable disease, the disease control rate was 65%. 
ASCO 2016

31. Take Home Messages
Radiologic diagnosis : hypervascularity & washout on image
Inflammatory tumor : Cirrhosis is an almost invariable precursor to HCC, except in chronic hepatitis B
Frequent intrahepatic recurrence after curative Tx
Immunologic tumor ?
Future treatment focus on immunotherapy