1. UNUSUAL PRESENTATION
OF HCC
DR. RAJKUMAR, R.
III YR POST GRADUATE
DR. KALAICHELVI D.M.
H.O.D. & PROF
DEPT. OF MEDICAL ONCOLOGY
MADRAS MEDICAL COLLEGE
CHENNAI

2. MR . X 60/ M REFERRED FROM SGE I
C/O SWELLING OVER THE ANT. CHEST WALL – 6
MONTHS .
H/O PAIN FOR THE PAST- 2 WEEKS.
NON ALCOHOLIC/ BEEDI SMOKER

3. 10×7 CM MASS OVER THE ANT. CHEST WALL
FIRM IN CONSISTENCY
P/A- HEPATOMEGALY

4. INVESTIGATIONS
• CBC- NORMAL
• LFT- S. BILIRUBIN- 1.3
DIRECT- 0.9
ALK.POS- 80
T.PROT- 6.8
ALB- 3.7
• RFT- NORMAL
• HbSAG- NEGATIVE
• ANTI HCV- NEGATIVE
• HIV I & II- NEGATIVE
• ALPHA-FETO PROTEIN- 1.62 IU/ml
• USG ABDOMEN- HETEROECHOIC LESION
RIGHT LOBE OF LIVER-11.5×10.5 CM –
• IMPRESSION- HCC Rt. LOBE OF LIVER

14. HCC – METASTATIC
• UNUSAL EXTRA HEPATIC
METASTATIC SITE
• NON CIRRHOTIC BACKGROUND
• GOOD P.S. STATUS
• BCLC STAGE C
• SORAFENIB – 200 MG B.I.D.
• PALLIATIVE R.T. - STERNUM

15. LITERATURE REVIEW

18. HCC: COMMON AND
INCREASING
• 694,000 deaths from liver cancer yearly
worldwide[1]
• Age-adjusted US incidence has
increased 2-fold from 1985-1998[2]
– Expected to continue to increase until 2015-
2020[3]
• American Cancer Society statistics for
liver cancer in 2010[4]
– Estimated new cases: 24,120
– Estimated deaths: 18,910
– 5th leading cause of cancer deaths in males
1. GLOBOCAN 2008. 2. SEER stat fact sheets: liver and intrahepatic bile duct. 3.
Llovet JM. J Gastroenterol. 2005;40:225-235. 4. American Cancer Society. Cancer
facts & figures 2010.

21. M.M.C. DATA
• 2010-2011
• TOTAL NO. CASES- 88
ALCOHOLISM- 36%
HEPATITIS B – 14.7%
HEP B & ALCO -13.6%
HEP C – 1.1%
• MALE- 78.4%
• FEMALE- 21.2%
• BCLC D – 85.3%

22. HCC: RISK FACTORS
The most important risk factor is
cirrhosis from any cause:
1. Hepatitis B (integrates in DNA)
2. Hepatitis C
3. Alcohol
4. Aflatoxin
5. Other

23. HCC: Metastases
• Rest of the liver
• Portal vein
• Lymph nodes
• Lung
• Bone
• Brain

25. Natural History of Nonsurgical HCC
Study Design: Control Arm of 2
RCTs
• 102 untreated cirrhotic patients with
unresectable HCC
– Managed with symptomatic treatment
• Median survival of 17 months (range:
1-60 months)
– 1-yr survival was 54%
– 2-yr survival was 40%
– 3-yr survival was 28%
Llovet JM, et al. Hepatology. 1999;29:62-67.

28. Malignant Transformation:
Multistep
HCC[2]
Epigenetic alterations
Genetic alterations
Dysplastic nodules[1]
Liver cirrhosis
Hepatitis C
Hepatitis B Potential Targets
Ethanol Oxidative Viral Carcinogen
NASH stress and oncogenes s
inflammation
Normal liver
Growth Telomere Cancer
factors shortening stem cells
Loss of cell Antiapopto Angiogenes
cycle sis is
checkpoints
1. Tornillo L, et al. Lab Invest. 2002;82:547-553. 2. Verslype C, et al. AASLD 2007. Abstract 24.

29. Vascularity of HCC

32. CONTRAST WASHOUT IN
HCC
Arterial Phase Portal Venous Phase

33. STAGING SYSTEMS IN HCC
Staging Hepatic Function Alpha- Performance Tumor Staging
System fetoprotein Score
Okuda Ascites, albumin, and No No Tumor > or < 50% of cross-
bilirubin sectional area of liver
TNM No No No Number of nodules, tumor size,
presence of portal vein thrombosis,
and presence of metastasis
CLIP CTP < 400 or No Number of nodules, tumor > or
≥ 400 ng/mL < 50% area of liver, and portal vein
thrombosis
BCLC CTP No Yes Tumor size, number of
nodules, and portal vein
thrombosis
CUPI Bilirubin, ascites, < 500 or Presence of TNM
alkaline phosphatase ≥ 500 ng/mL symptoms
JIS CTP No No TNM
GRETCH JA, et Bilirubin, alkaline,
Marrero al. Hepatology. 2005;41:707-716.35 or
< Yes Portal vein thrombosis
phosphatase ≥ 35 µg/L

34. Barcelona Clinic Liver Cancer
Staging Classification
Stage 0 Stage A-C Stage D
PST 0, Child-Pugh A Okuda 1-2, PST 0-2, Child-Pugh A-B Okuda 3, PST > 2,
Child-Pugh C
Very early stage (0) Early stage (A) Intermediate stage (B) Advanced stage (C) Terminal
Single < 2 cm Single or 3 nodules Multinodular, PST 0 Portal invasion, stage (D)
Carcinoma in situ < 3 cm, PST 0 N1, M1, PST 1-2
Single 3 nodules ≤ 3 cm
Portal pressure/bilirubin
Increased Associated
diseases
Normal No Yes
Liver transplantation Systemic
Resection PEI/RFA Chemoembolism
(CLT/LDLT) treatment
Curative treatments Randomized controlled trials Symptomatic
50% to 75% at 5 yrs 40% to 50% at 3 yrs vs 10% at 3 yrs treatment
Llovet JM et al. Lancet. 2003;362:1907-1917.

35. COMPARISON OF HCC STAGING
SYSTEMS
• BCLC system uses key independent
predictors of survival
– Performance score, portal vein thrombosis,
tumor diameter
• Compared with other staging systems in
cohort study
– BCLC had best stratification of survival
across all stages
– BCLC was only system to have independent
predictive value on survival
• BCLC is the only staging system that
stratifies patients into treatment groups
Marrero JA, et al. Hepatology. 2005;41:707-716.

36. LIVER TRANSPLANTATION FOR HCC:
MILAN CRITERIA (STAGE 1 AND 2)
Single tumor, not > 5 cm Up to 3tumors, none>3Cm
+
Absence of macroscopic vascular invasion,
absence of extrahepatic spread
• 5-yr survival with transplantation: ~ 70%
• 5-yr recurrent rates: < 15%
Mazzaferro V, et al. N Engl J Med. 1996;334:693-699.
Llovet JM. J Gastroenterol Hepatol. 2002;17(suppl 3):S428-S433.

37. Candidates for RFA/PEI
• Includes individuals who are not
candidates for surgery
• Radiofrequency ablation generally
preferred over percutaneous ethanol
injection
– Necrotic effect more predictable across
tumor sizes
– Meta-analyses suggest survival benefit
with radiofrequency ablation vs
percutaneous ethanol injection
Bruix J, et al. AASLD HCC guidelines. July
2010.

38. CHEMOEMBOLIZATION
Image courtesy of www.hopkinscoloncancercenter.org.

39. Contraindications to TACE
• Extrahepatic tumor spread
• Lack of portal blood flow
– Portal vein thrombosis, portosystemic
anastomoses or hepatofugal flow
• Advanced liver disease (Child-Pugh
Class B or C)
• Clinical symptoms of end-stage
cancer
Bruix J, et al. AASLD HCC guidelines. July 2010.

40. Molecular Signaling Pathways
in HCC
Tumor Blood
Vessels
Sorafenib
Growth
and
survival Autocrine loop
factors EGF/HGF
(eg, VEGF, Apoptosis
PDGF)
RAS
RAF
MEK Mitochondria
HIF-2
ERK EGF/HGF
PDGF Tumor Cell
VEGF
Nucleus
Proliferation
Survival
Wilhelm S, et al. Cancer Res. 2004;64:7099-7109.

41. Phase III SHARP Study: Sorafenib
vs Placebo in Advanced HCC
Sorafenib
400 mg PO BID, continuous dosing
(n = 299)
Patients with advanced
Stratified by macroscopic
hepatocellular vascular invasion and/or
carcinoma, extrahepatic spread; ECOG PS;
ECOG PS ≤ 2, no geographical region
previous systemic
treatment Placebo
(N = 602) 2 tablets PO BID, continuous dosing
(n = 303)
Primary endpoints: OS, time to symptomatic progression
Secondary endpoint: TTP (independent review)
Llovet JM, et al. N Engl J Med. 2008;359:378-390.

42. Sorafenib in Advanced HCC
(SHARP): Survival
Sorafenib median OS:
1.00
46.3 wks (10.7 mos)
(95% CI: 40.9-57.9)
Placebo median OS:
0.75 34.4 wks (7.9 mos)
Survival Probability
(95% CI: 29.4-39.4)
0.50
0.25
HR (S/P): 0.69 (95% CI: 0.55-0.87; P < .001)
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Mos Since Randomization
Llovet JM, et al. ASCO 2007. Abstract LBA1. Llovet JM, et al. N Engl J Med.
2008;359:378-390.

43. Multidisciplinary HCC
Management
• HCC is the intersection of 2 diseases
– Liver disease and cancer
• Skilled pathologists needed for diagnosis
• Specialists required to deliver treatment
options
– Surgeons for resection or transplantation
– Radiologists for ablation and
chemoembolization
• Hepatologists and oncologists follow
treatment strategy and labs
• Midlevel providers bring
support, particularly for oral therapy

44. Conclusions
• HCC occurs in cirrhotic patients and
complicates diagnosis and treatment
• The Barcelona Clinic Liver Cancer
staging system accounts for key
prognostic factors: hepatic function,
performance score, and tumor burden
• Chemoembolization is the best option in
nonresectable patients without vascular
involvement
• Sorafenib is the best option for advanced
tumors
• Novel therapies are needed