DR. MOHAMMED EL SEBAYEL

1. Role of Surgery in HCC
March 2014
Dubai-UAE
Mohammed Al Sebayel MD,FRCS,MPH
Professor and Chairman
Dept. of Liver Transplantation & Hepatobiliary-Pancreatic Surgery
King Faisal Specialist Hospital &RC, Riyadh, SAUDI ARABIA

2. Themes ……..Themes ……..
• Introduction
• Anatomy and technical aspects.
• Diagnosis and Staging.
• Where does resection and OLTx stands with
other modalities.
• Selection aspects.
• Outcome.
• Neo-adjuvant and Down staging
• Future direction

3. Themes ……..Themes ……..
• Introduction
• Anatomy and technical aspects.
• Diagnosis and Staging.
• Where does resection and OLTx stands with
other modalities.
• Selection aspects.
• Outcome.
• Neo-adjuvant and Down staging
• Future direction

4. HEPATOCELLULAR CARCINOMA
• Most common Liver Tumor in adult.
• Account for as many as 1 million death
per year.
• The 5th
most common cancer in the world.
• The 3rd
most common cause of cancer-
related death in the world.
• Incidence as high as 50/100,000/year

5. Liver Cancer: Sixth Most Common
Cancer Worldwide1
196,298
226,787
230,555
200,774
314,256
330,963
529,283
559,094
711,128
782,647
1,066,543
1,167,020
1,301,867
1,549,121
0 200,000 400,000 600,000 800,000 1,000,000 1,200,000 1,400,000 1,600,000 1,800,000
Non-Hodgkin's Lymphoma
Corpus Uteri
Ovary
Oral Cavity
Bladder
Leukemia
Esophagus
Cervix Uteri
Liver
Prostate
Stomach
Colon/Rectal
Breast
Lung
• Liver cancer is the third most common cause of cancer-related death2
• HCC is the most common primary liver malignancy in adults2
• HCC is the most common primary liver malignancy in adults2
1. Garcia M, et al. American Cancer Society, 2007. www.cancer.org. Accessed March 20, 2008.
2. http://www.who.int/mediacentre/factsheets/fs297/en/index.html. Accessed June, 2008.
3. Perz JF, et al. J Hepatol. 2006;45:529-538.

6. China
Middle Africa
Japan
Eastern Africa
Southeastern Africa
Melanesia
Western Africa
Southern Europe
Micro/Polynesia
Caribbean
Southern Africa
Western Europe
Eastern Europe
Northern America
Central America
Western Asia
Northern Africa
Australia/New Zealand
South America
Northern Europe
0 10 20 30 40 501020304050
Liver Cancer: Global Incidence
Age Standardized Incidence per 100,000
Parkin D, et al. CA Cancer J Clin. 2005;55;74-108.

7. Worldwide HCC IncidenceWorldwide HCC Incidence
Incidence per 100,000
Worldwide
- 100 million cases
- 1.2 million case/yr
-1 million deaths/yr
-3rd
leading cause of cancer-
related death

9. Hepatocellular Carcinoma
Liver Cirrhosis (HBV – HCV)

10. Themes ……..Themes ……..
• Introduction
• Anatomy and technical aspects.
• Diagnosis and Staging.
• Where does resection and OLTx stands with
other modalities.
• Selection aspects.
• Outcome.
• Neo-adjuvant and Down staging
• Future direction

11. Extent of Resection

12. Incision

13. Liver Mobilization
Hilar Dissection
Blumgart, 2000

16. Blumgart, 2000

17. Mobilization of R. lobe
Blumgart, 2000

18. Transection of R. Hepatic Vein

19. Parenchyma
l
Transection
Blumgart, 2000

20. Technique of Parenchymal
Transection
• Finger fracture.
• Ultrasonic transection
• Water Jet.
• Control of Bleeding:
– Diathermy.
– Suture ligature and clips.
– Ligature
– RFA……..etc

23. SVIII HV
MHV
SIVb HVRHV

24. Mortality and Morbidity for Benign
and Malignant liver lesions
• Benign lesions and colo-rectal tumors.
• Mortality was 0.
• Morbidity 31% (16% were major)
• Multivariate analysis/
– Prolonged surgical procedure.
– Co-morbid conditions
– Surgical irradicality
Erdagon et al Liver International (2009); 175-180

25. Themes ……..Themes ……..
• Introduction
• Anatomy and technical aspects.
• Diagnosis and Staging.
• Where does resection and OLTx stands with
other modalities.
• Selection aspects.
• Outcome.
• Neo-adjuvant and Down staging
• Future direction

26. HCC
CT FINDINGS

27. HCC
MRI

28. Prognosis-Staging Systems for HCC
System
Tumor
Features
Vasc.
Invasion
Histol.
Grade
Liver Function
Met. AFP
Cancer
Symptoms
TNM1
   
Okuda2
  
JIS3
 
CLIP4
   
BCLC5
    
CUPI6
        
GRETCH7
    
Vasc. = vascular; Histol. = histologic; AP = alkaline phosphatase; Met. = metastases;
Child-
Pugh Bilirubin AP Ascites
1. AJCC Cancer Staging Manual. 6th ed. 2002; 2. Schafer DF, et al. Lancet. 1999;353:1253-1257; 3. Liver Cancer Study Group of Japan. 4th edn. Tokyo:
Kanehara, 2000. 4. CLIP. Hepatology. 1998;28:751-755; 5. Llovet JM, et al. Semin Liver Dis. 1999;19:329-338; 6. Leung T, et al. Cancer. 2002;94:1760-69;
7. Chevret S, et al. J Hepatol. 1999;31:133-141.

29. Child-Pugh Scoring System
Points
1 2 3
Encephalopathy (grade) None 1-2 3-4
Ascites None Slight Moderate
Albumin (g/dL) >3.5 2.8-3.5 <2.8
Prothrombin time prolonged (sec) 1-4 4-6 >6
Bilirubin (mg/dL) 1-2 2-3 >3
For primary biliary cirrhosis 1-4 4-10 >10
Class A = 5-6 points; Class B = 7-9 points; Class C = 10-15 points.
Pugh RN, et al. Br J Surg. 1973;60:646-649.

30. HCC Staging is Multifaceted
ECOG
PS
TNMChild-
Pugh
Liver Tumor
BCLC4
GRETCH5
Okuda6
CUPI7
CLIP8
JIS9
Patient Staging is used for prognosis
and to guide treatment1
 Staging HCC1
– Most patients have underlying liver
disease
– Key prognostic indicators are not
clearly defined
– Prognostic indicators vary during the
course of disease
 Factors affecting staging
systems2,3
– Tumor stage
– Liver function
– Health status
– Impact of treatment

31. Barcelona Clinic Liver Cancer staging
and treatment strategy
Stage A–C
Okuda 1–2; Child–Pugh A–B; PST 0–2
Stage D
Okuda 3; Child–Pugh C; PST >2
Liver transplantation Chemoembolisation SorafenibResection PEI/RF
Symptomatic treatment (30%)
1-year survival: 10%
Curative treatments (30%)
5-years survival: 50–70%
Randomised controlled trials (30%)
3-years survival: 20–40%
Extrahepatic disease
YesNo
Associated diseases
YesNo
3 nodules ≤3cm
Increased
Normal
Portal pressure/
bilirubin
HCC
Very early
stage (0)
Single HCC <2cm
Carcinoma in situ
Early Stage (A)
Single HCC or
3 nodules <3cm
PST 0
Intermediate
stage (B)
Multinodular; PST 0
Advanced stage (C)
Portal invasion N1, M1,
PST 1–2
Terminal
stage (D)
Stage 0
Child–Pugh A; PST 0
Single HCC
Llovet JM, et al, Lancet 2003;362:1907–17PST=Performance status

32. Themes ……..Themes ……..
• Introduction
• Anatomy and technical aspects.
• Diagnosis and Staging.
• Where does resection and OLTx stands with
other modalities.
• Selection aspects.
• Outcome.
• Neo-adjuvant and Down staging
• Future direction

33. Surgery
Remains the
Gold Standard
Liver Resection

34. Resection in cirrhotics
• Best in a single lesion
• Asymptomatic
• Preserved liver function
– Absent clinically relevant portal hypertension ( hepatic
venous pressure gradient less than 10, platelets less
than 100,000 and no varices or splenomegally)
– Normal bilirubin
• 70% survival at 5 years
• Only 5-10% meet these criteria
Llovet et al, Resection Vs Tx, hepatology 1999

35. OUTCOMES OF HCC PATIENTS TREATED WITH CURATIVE INTENTION
SURGICAL RESECTION
TREATMENT &
SELECTION CRITERIA
N ACTUAL SURVIVAL
1 year 5 years
Fong et al, Ann Surg 1999
Child A-B, median 6 cm
100 77% 37%
Llovet et al,Hepatology 1999
Single, no portal HT, normal bilirubin
Portal HT, normal bilirubin
Portal HT, abnormal bilirubin
35
15
27
91%
93%
74%
74%
50%
25%
Arii et al, Hepatology 2000
Stage I:
HCC < 2 cm
HCC 2-5 cm
Stage II:
HCC < 2 cm
HCC 2-5 cm
1318
2722
502
1548
96%
95%
92%
95%
72%
58%
55%
58%
Yamamoto et al, Hepatology 2001
</= 3 cm, Child A-B
58 96% 61%
Sakamoto et al, Jpn J Clin Oncol
Single HCC < 2 cm early tumors
53 100% 89%

36. LIVER TRANSPLANTATION
TREATMENT &
SELECTION CRITERIA
N ACTUAL SURVIVAL
1 year 5 years
Mazzaferro et al, N Engl J Med 1996
Single </= 5 cm, 3 nodules </= 3 cm
48 84% 74%
Llovet et al,Hepatology 1998 [28]
Single </=5 cm
58 84% 74%
Bismuth et al, Semin Liver Dis 1999
3 nodules </= 3 cm
45 82% 74%
Llovet et al, Hepatology 1999
Single </= 5 cm
Intention-to-treat analysis
79
87
86%
84%
75%
69%
Jonas et al, Hepatology 2001
Well-differentiated HCC
Moderately-differentiated HCC
Poorly-differentiated HCC
40
60
20
90%
90%
75%
84%
73%
41%

37. PERCUTANEOUS THERAPIES
TREATMENT &
SELECTION CRITERIA
N ACTUAL SURVIVAL
1 year 5 years
Livraghi et al, Radiology 1995 [35]
Child A, HCC </= 5 cm
Child B, HCC </= 5 cm
293
149
98%
93%
47%
29%
Arii et al, Hepatology 2000 [18]
Stage I:
HCC < 2 cm
HCC 2-5 cm
Stage II:
HCC < 2 cm
HCC 2-5 cm
767
587
426
483
96%
95%
92%
87%
54%
38%
33%
28%
Rossi et al, Am J Roentgenol 1996 [36]
HCC </= 3 cm 39 94% 40%

38. • Curative Strategies in one third of all
patients
• Resection…….compensated
• Ablation……non surgical candidate ???
Curative
• Liver Transplantation……….Best Survival
with up to 70% at 5 years
No comparative studies in compensated
patients

39. Themes ……..Themes ……..
• Introduction
• Anatomy and technical aspects.
• Diagnosis and Staging.
• Where does resection and OLTx stands with
other modalities.
• Selection aspects.
• Outcome.
• Neo-adjuvant and Down staging
• Future direction

40. Surgery for Hepatocellular
Carcinoma
• Resection
• Limitations are:
• Anatomy
• Cirrhosis
• Resection Vs Transplantation
• Donor Issue

41. Criteria for Selection
• Anatomical:
– Imaging
– Simulation
• Functional:
– Clinical.
– Biochemical.
– Functional test: ICG

42. How Much Can be Resected?
• Child Classification:
A Formal Resection
B 25%
C Never or 15%
• Tumor is non functioning, Look for
Hypertrophy

43. MELD as a predictor of
Mortality/Morbidity after Resection
MELD below 9 MELD 9-10 Meld Above 10
Na above 140
Major resection
Up to 4 segments
Segmentectmy or
limited resection
Risk of
irreversible liver
failure more
than 15% in all
type of resection
Na below 140
Segmentectmy or
bisegmentectomy
Cecon et al: ARCH SURG/VOL 144 (NO. 1), JAN 2009

44. 5 years Survival after
Resection
Function Single Multiple
PHT** No PHT PHT No PHT
Child-Pugh A 68% 71% 58% 56%
Child-Pugh B Over all 5 year survival 19%
Resection
after
recurrence*
79% 81% 73% 73%
*3 year survival
**PHT defined as varices and or platelets less than 100000
Ishizawa T, Gastroenterology. 2008;134:1908–16.

45. Best candidate and second to
best candidate
• Portal hypertension
• Functional capacity
• Multiple tumors
• Vascular invasion
• Comorbid conditions

46. Themes ……..Themes ……..
• Introduction
• Anatomy and technical aspects.
• Diagnosis and Staging.
• Where does resection and OLTx stands with
other modalities.
• Selection aspects.
• Outcome.
• Neo-adjuvant and Down staging
• Future direction

47. Safety, Accuracy and outcome
– Surgical techniques
– Perioperative care.
– Patient selection

48. Outcome
• offers a 5-year overall survival rate of more than
50%.
• operative mortality as low as 0.8% in Japan.
• Operative mortality of 0–6.4% at major
hepatobiliary centers in other countries.
Ikai et al: Hepatol Res. 2007;37:676–91.
Fan ST et al: Ann Surg. 1999;229:322–30.
Fong Y et al. Ann Surg.1999;229:790–9.

49. Result of resection with bad
prognostic factors
• With clinically relevant portal hypertension,
5 year survival is 50%
• With CRPH and Jaundice survival at 5
years is only 25%

50. Recurrence after resection
• Micro vascular invasion
• Differentiation
• Satellite nodules
High recurrence rate with more than 70% at
5 years

51. RESECTION in Non Cirrhotics
Applies to only 5% of patients

52. Philosophy of Liver Resection in
Compensated Cirrhotics
“Why Not Transplantation?”
• Immunosuppressive therapy may
accelerate the growth rate of recurrent
HCC
• Mean tumour doubling times (TDT)
 after transplantation is 40 days
 after resection is 275 days
(Yokoyama et al, 1991)
• Sever organ shortage
• Doubtful Diagnosis (regenerating nodules)

53. Liver Transplantation
• The most effective treatment in cirrhotics
• Classical selection criteria leads to 70%
survival at 5 years and recurrence rate of
15%
• Drop out rate while waiting 20-50% if
waiting is more than 1 year
• MELD score and adjuvant therapy
• LDLT

54. Liver Transplantation for HCC
“Patient Selection”
Milan’s Criteria (Mazzaferro et al, 1994)
Single tumorSingle tumor ≤ 5≤ 5 cmcm or ≤≤ 3 lesions, each lesion3 lesions, each lesion ≤ 3≤ 3 cmcm
NoNo Macro-Vascular Invasion andMacro-Vascular Invasion and NoNo Extra-hepatic SpreadExtra-hepatic Spread

55. Management While on the Waiting List
24 12 39 6 (Months)
5 mm 10
15
20
30
40
Tumor Doubling Time (TDT)
(From J Fung with permission)
2 yrs
9 months

56. LT for HCC at KFSH&RC: Patients Selection
HCC
Within
Milan
Outside
Milan
Multiple
≥2 cm
RejectDDLT +/-
Neo-adjuvant
Accept
LDLT
Solitary ≤2
cm
Within
UCSF
Outside
UCSF
RFA
Down Staging

57. Themes ……..Themes ……..
• Introduction
• Anatomy and technical aspects.
• Diagnosis and Staging.
• Where does resection and OLTx stands with
other modalities.
• Selection aspects.
• Outcome.
• Neo-adjuvant and Down staging.
• Future direction

58. Neo-adjuvant and Down-staging
prior to resection
• Not recommend if tumor is resectable:
– Delay (tumor progression or liver failure in 10%).
– Technically more difficult.
– May be associated with more morbidity.
• Not resectable for anatomical reasons ….6-28%
become respectable.
– Recurrence: 40-85%
– Survival: 5 years…..25 to 60%
• These strategies are well established and accepted
for resection.

59. Neo-adjuvant and Down-staging
prior to Transplantation
• More complex than in resection.
• Is the patient within transplant criteria?
Neo-adjuvant Vs down-staging
• Waiting list priority.
• Living Vs. Cadaveric
• Community Vs. Individual.

60. Neo-adjuvant for transplant
candidate within the criteria
 Currently one third to half receive neo-adjvant while
on the waiting list. (TACE followed by RFA).
 It decreases drop out from waiting list.
 Better post transplant survival (UNOS data).
 Full response to TACE better survival than partial.
 Best palliation for patients who eventually will drop
out.
 Recommendation: Neo-adjuvant if this does not
delay transplant
 LDLT Vs Cadaveric

61. Down-Staging
 Which tumors to be down-staged? Inclusion
criteria.
 What to use?
 What are the criteria of success?
 When to do the transplant?
 What kind of survival outcome is accepted?
 What is the price we pay?
• Community Vs individual……
• Living donor……..

62. Inclusion Criteria
• Entry Criteria:
– Size and number or total volume.
– Biological, molecular or pathological
characteristics.
• Definition success of down staging:
– Size (radiological)
– Necrosis (radiological)
– AFP (biological)
• Defining the time between down staging and
listing

63. Down staging to Resection, RFA and Bridge to
transplantation;
• 90Y for 35 patients with T3 unresectable HCC.
• Down-Staging in 19 (56%) to T2.
• 8 patient were transplanted.
• Survival 84 and 27% at one and 3 years
Kulik et al (2006) Journal of surgical oncology; 94:572-586
• 90Y for 21 patient with T3 Unresectable HCC.
• Down staging in 21.
• 2 transplanted, 3 resected and one RF and resection
• Median survival 44 month Vs 22 months.
Inarrairaegui, 2012 EJSO 38, 594-601

64. King Faisal Specialist Hospital Liver Transplant
Program

65. Down-staging and bridging: KFSH
Experience
• 9 patients: 5 female and 4 males
• Their current age range is 40-72 years with a mean of
53.8± 9.5 years.
• Follow up following liver transplantation ranged between
3.7 -60.1 months (mean of 15.8 ±17.7 moths).
• TheraSphere and liver transplantation ranged between
14-707 days (mean of 194±226.2 days).
• All living with excellent graft function and no disease
recurrence.

66. Patient #
Number
of
lesions
Size of lesion
(in cms)
Unilobar
disease
AFP
(UI/mL)
Tumor
volume
BCLC
Relation to the main
transplantation criteria
V=(a*b2
)/2 Stage
1st 2nd 3rd UNOS Milan UCSF
1 2 6.2*4.7 1.7*1.3 - YES 217
69.9
(68.5+1.4)
B T3 Beyond Within
2 1 3.7*3 - - YES 3 16.6 B T2 Within Within
3 2 4.7*4.6 2*2 - YES 7 53.7 (49.7+4) B T3/T4 Beyond Within*
4 1 7.3*6.3 - - YES 5 144.8 B T3 Beyond Beyond
5 1 3.5*2.4 - - YES 499 10.1 B T2 Within Within
6 1 5*4.4 - - YES 10 48.4 B T2 Within Within
7 1 8.7*7.6 - - YES 5 251.3 B T3 Beyond Beyond
8 1 2.1*1.3 - - YES 13 1.8 A T2 Within Within
9 3 1*1 2*1.2 1*1 YES 125
2.4
(0.5+1.4+0.5)
A T2 Within Within

67. Patient
#
Therasphere
Other
locoregional
modalities
Child Pugh
score in
relation to
Therasphere
Complications
Interval to
transplant Type of
transplant
Indication Type Dose
Following
Theraspher
e
Before After
(days)
1 Bridging Selective 140 None 5 6 None 32 DDLT
2 Bridging Superselective 146 None 6 6 None 14 DDLT
3
Down
staging*
Selective 156 None 6 7 None 40 DDLT
4
Down
staging
Selective 153 None 5 6 None 86 DDLT
5 Bridging Superselective 146 None 6 6 None 116 LDLT
6 Bridging Superselective 221 None 5 6 None 231 LDLT
7
Down
staging
Selective 146 None 5 6 None 394 LDLT
8 Bridging Superselective 148 None 6 6 None 126 LDLT
9 Bridging Selective 147 RFA/Alcohol 6 6 None 707 LDLT

68. Down staging and Bridging for advanced HCC
Patient Transplant date Relation to transplant criteria
UNOS Milan UCSF
1 June 2008 T3 Beyond Within
2 Oct. 2008 T2 Within Within
3 Oct. 2010 T3/T4 Beyond Within*
4 Feb. 2012 T3 Beyond Beyond
5 March 2012 T2 Within Within
6 March 2012 T2 Within Within

69. Case No: 4

70. Tumor Necrosis- Gross appearance

71. Normal
Hepatocytes
Hepatocellular
Carcinoma

72. Tumor Necrosis 1

73. Tumor Necrosis 2
Microsphere

74. Themes ……..Themes ……..
• Introduction
• Anatomy and technical aspects.
• Diagnosis and Staging.
• Where does resection and OLTx stands with
other modalities.
• Selection aspects.
• Outcome.
• Neo-adjuvant and Down staging
• Future direction

75. Future Direction
• More technological advances in functional
imaging.
• Better technology to facilitate resection.
• Determination of where resection stay
within other options.
• Down staging.
• Diagnostics, genomics and Microarray.
• Molecular targeted therapy.
• Individualized treatment.

76. Preoperative Simulation of liver Resection
using three dimensional
computed tomography
• Accurate assessment of the segmental liver
volume
• vascular anatomy that is required to
complete the anatomic resection.
• Estimation of venous occlusion.
• Determination of the need for venous
reconstruction.
– Remaining volume (non congested less than 40%)
– ICG

77. Hepatectomy Simulation: Based
on liver circulation
Saito S, Hepatology. 2005;41:1297–304.

78. Conclusion
• Surgical management of HCC is evolving.
• Potential for cure is increasing.
• Multidisciplinary Approach.
• Technology.
• Better techniques and perioperative care
• Molecular biology.
• Personalized medicine.

79. King Faisal Specialist Hospital
& Research Center
Riyadh, KSA
Thank You