1. Liver Surgery for HCC
- Present & Future -
Masatoshi Makuuchi, MD, PhD.
Department of Surgery,
University of Tokyo.

2. HCC-incidence in the World
<2 2-5 5 - 10 10 - 20 20 <
Sweden
UK
Korea
France Poland
Germany China
USA
Spain Japan
Israel
Italy Greece Thailand
Taiwan
Hong Kong
South
Africa
Australia New
Zealand
1,000,000/year/world

3. North
HCC-incidence in Japan
40 - /100,000
30 - 39
25 - 29
- 24
30,000/year/Japan
South

4. Cancer Death in Japan
100
80
Mortality/100,000
Stomach
60
Lung
40
Liver
32/100,000
20
Colon
Pancreas
Esophagus
0
1965 1970 1975 1980 1985 1990 1995

5. Overall survival in HCC
Liver Cancer Study Group of Japan (‘88-’99)
%
100
100 92%
● Surgery (n=21,711)
80
80
●
69%
●
60
60
●
52%
●
40
40
20
20
0
0 1
1 2
2 3
3 4
4 5 Yr
5 Yr

6. Overall survival in HCC
Liver Cancer Study Group of Japan (‘88-’99)
%
100
100 92%
● Surgery (n=21,711)
PEI (n=12,876)
80
80 87%
●
TAE (n=17,821)
69%
●
60
60 73%
●
64% 52%
●
40
40
40%
38%
20
20
21%
0
0 1
1 2
2 3
3 4
4 5 Yr
5 Yr

7. Overall survival / Single, ≦2cm, LD=A
%
Liver Cancer Study Group of Japan (’88-’96)
100
Surgery (n=1,318)
80 72% PEI (n=767)
60 52%
40
20
OP vs PEI, p=0.01
0 1 2 3 4 5 6 7 8 Yr
Arii et al. Hepatology 2000; 32: 1224

8. Overall survival / Single, 2-5cm, LD=A
% Liver Cancer Study Group of Japan (’88-’96)
100
Surgery (n=2,722)
PEI (n=587)
80
60%
60
41%
40
20
OP vs PEI, p=0.001
0 1 2 3 4 5 6 7 8 Yr
Arii et al. Hepatology 2000; 32: 1224

9. Hepatic resection vs. Ethanol injection
Liver Damage
HCC A B
OP PEI p OP PEI p
<=2cm, Single 72% 52% 0.01 58% 38% 0.69
<=2cm, 2 tumors 61% 66% 0.58 48% 40% 0.67
2-5cm, Single 60% 41% 0.001 45% 28% 0.001
2-5cm, 2 tumors 42% 37% 0.59 38% 17% 0.007
Arii et al. Hepatology 2000; 32: 1224

10. Neoplastic Seeding after PEI and RFA

11. RFA for HCC
Neoplastic seeding 12%
Llovet JM. Hepatology 2001.
Mortality 0.3%
Livraghi et al. Lodi 2002.

13. Recent Advancement in Liver
Surgery
No mortality Hx has been realized.
It should be lass than
1%

14. Increased Safety of Hepatic Resection
~ ‘79 ‘80~ 84 ‘85~ 89 ~ ‘90
Operative mortality in HCC Patients
LCSGJ 15.8% 5.4% 2.6% 2.2%
NCC 1M. 10.1% 4.2% 1.0% 1.4%
6M. 31.9% 13.2% 6.2% 6.5%
Rate of blood tr. >90% 40% 25% <10%
LCSGJ: ’78~79 (44 / 279), ’80~83 (98 / 1506), ’88~89 (66 / 2570),
’90~93 (167/1758)
NCC : ’79 (7, 22 / 69), ’80~84 (7, 22 / 167), ’88~89 (4, 25 / 402),
’90~ (12, 56 / 856)

15. Hepatectomy
Authors Dx. n Ischemia Transection Mortality Morbidity Transfuse
Torzilli, Makuuchi HCC 107 Pringle + Clamp 0% 26% 9%
Arch Surg 1999; 134: 984-992.
Selective
Fan HCC 330 Pringle + Clamp + 6% 39% >36%
Ann Surg 1999; 229: 322-330. No Pringle CUSA
Fong, Blumgart HCC 154 n.d. n.d. 5% 45% n.d.
Ann Surg 1999; 229: 790-800.
Takenaka, HCC CUSA
280 Pringle + 2% 50% n.d.
Sugimachi Selective
Arch Surg 1996; 131: 71-76.
Fuster HCC 48 Pringle Clamp 4% 46% 25%
Ann Surg 1996; 223: 297-302.
Gozzetti HCC + meta 522 Pringle + n.d. 3% 26% 62%
No Pringle
Br J Surg 1995; 82: 1105-1110.
Sitzmann HCC + meta 105 Pringle CUSA 3% 33% 75%
Ann Surg 1994; 219: 31-37.

16. Hepatectomies in Tokyo University
(1994.10- 2002.5)
Hepatocellular carcinoma: 532
Other liver malignancies: 262
(Cholangiocellular carcinoma,
Metastatic liver tumors, etc)
Biliary malignancies: 57
(Hilar bile duct cancer, GB cancer)
Living donor for liver transplantation: 174
Other benign disease: 31
Total 1056

17. Demographics of 1056 hepatectomies
Operative time * : 420 (75-1495) (min)
Blood loss * : 577 (0-8200) (mL)
Red blood cell transfusion rate and amount
6.1 (0-3200 mL) (% (range))
Morbidity rate: 38 %
Surgical intervention rate: 2.5 %
Overall mortality rate
(In-hospital & <30 days): 0%
* Data are expressed as median (range).

19. For the Safety of Hx
1. Evaluation of hepatic functional reserve
2. IOUS
3. Intermittent inflow occlusion
4. Volumetric analysis & PVE

20. Makuuchi et al. Seminar in Surg Oncol 1993; 9: 298

21. To achieve no mortality Hx
Post-op. jaundice is not acceptable.
Hepatic surgeon should consider that
operative indication is not appropriate
when jaundice followed Hx.

22. Intraoperative Ultrasonography
Lane & Glazer Lancet 2: 334; 1980
Sigel et al. Radiology 137: 531; 1980
Cook & Lytton. Urol Clin North Am 8: 319; 1981
Makuuchi et al. Jpn J Clin Oncol 11: 367; 1981
Plainfosse et al. Radiology 147: 829; 1983
Angelini et al. Ital J Surg Sci 13: 203; 1983
Bismuth et al. Presse Med 13: 1819; 1984
Belghiti et al. Presse Med 13: 1839; 1984
Igawa et al. World J Surg 8: 772; 1984
Sheu JC et al. Surgery 97: 97; 1985
Makuuchi et al. Surg Gynecol Obstet 161: 346; 1985
Gozzetti et al. Surgery 99: 523; 1986
Makuuchi et al. Surg Gynecol Obstet 164: 68; 1987

23. New Operative Procedures
Due to Introduction of IOUS
Limited Resection
Kanematsu et al, Ann Surg, 1981.
Subsegmentectomy
Makuuchi et al, SGO, 1985.
IRHV Preserving Hxs
Makuuchi et al, SGO, 1987.

24. Operative Procedure of Systematic Subsegmentectomy
Staining of Marking with Tattooing of
Subsegment Electric Cautery Parenchyma
Hemihepatic Division of Raw Surface
Blood Occlusion Parenchyma after Segmentectomy
Makuuchi et al. Surg Gynecol Obstet 1985; 161: 346.

28. RHV IVC RHV IVC
A-S PV
A-S PV
P-S PV MHV MHV
P-S PV
GB
IVC IVC
RHV MHV RHV M + LHV
A-S PV A-S PV
P-S PV P-S PV
Makuuchi et al. Surg Gynecol Obstet 1987; 164: 68.

29. Inflow Occlusion Technique (1)
Pringle
Total inflow occlusion (Pringle’s maneuver)
Ann Surg 1908.
Heaney et al.
Inflow and outflow occlusion (TVE).
Ann Surg 1966.
Makuuchi et al.
Intermittent selective vascular occlusion
J Jpn Surg Soc 1985 (in Japanese)
Makuuchi et al.
Intermittent inflow occlusion.
SGO 1987.

30. Inflow Occlusion Technique (2)
Isozaki et al.
Superiority of intermittent to continuous
occlusion in rats. Br J Surg 1992.
Belghiti et al.
Superiority of Pringle’s maneuver to TVE.
Ann Surg 1996.
Belghiti et al.
Superiority of intermittent to continuous
occlusion in human. Ann Surg 1999.

31. Ischemic Preconditioning (1)
Murry et al. Dog myocardium.
Circulation 1986.
Peralta et al. Rat liver (warm ischemia).
BBRC 1996.
Hardy et al. Rat liver (warm ischemia).
Aust NZ J Surg 1996.
Yin, Sankary et al. Rat liver transplantation
(cold ischemia).
Transplantation 1998.

32. Ischemic Preconditioning (2)
Clavien et al.
Human liver resection (warm ischemia).
Ann Surg 2000.
Imamura, Makuuchi et al.
Human liver transplantation
(living donor). Lancet 2002

33. Late Ichio Honjo
(1913 ～ 1987)
PV branch ligation
Professor of Kyoto University
He did right hepatectomy in March, 1949.
Honjo : Shujutu 9: 345, 1950 (in Japanese).
Honjo and Araki : J Int Surgeons 18: 23, 1955.
Foster and Berman’s “Solid Liver Tumors”

34. History of PVE
Makuuchi et al. NCCH June 1982
Okuda et al. Kurume Univ. Jan. 1983
Inoue et al. Osaka City Univ. Nov. 1983
Makuuchi et al. : Nichi Rin Ge Shi 45: 1558, 1984.
(in Japanese)
Makuuchi et al. : Surgery 107: 521, 1990.

36. Indication Criteria of PVE
1. Amount of liver resection exceeds
60% of the whole normal liver.
2. Amount of liver resection between 40 and 60%
of the liver with ICG retention rate at 15’
between 10 and 20%
Kubota et al. Hepatology 1997;26:1176.

38. Recent Challenges
In Surgical Resection for HCC
1. Tumor thrombus in HCC.
2. Multiple HCC.
3. Repeated resections.
4. Caudate lobe resection.

39. Tumor Thrombus in HCC
Dismal Prognosis against any kinds
of treatment modalities.
We have to find some selection
criteria for surgical resection.

40. Overall survival in HCC /PVTT*
Liver Cancer Study Group of Japan (’88-’99)
%
100 91%
Vp0
74% Vp1
80 Vp2
Vp3
57%
60
41%
40 49%
29%
20 23%
17% 13% 12%
0
1 2 3 4 5 6 7 8 9 10 Yr
PVTT*: tumor thrombosis in portal venous branch

41. Purpose of Preoperative TAE for PVTT
1. Interruption of rapid growth of TT.
2. Estimation of the other side of the liver.
3. Enhance the atrophy-hypertrophy process.

42. Minagawa et al. Ann Surg 2001; 233: 379.

43. Relative risk of mortality with Cox’s proportional hazard mode
Univariate 95% confidence limits Multivariate 95% confidence limits
Variable
RR# Lower Upper p-value RR# Lower Upper p-value
Therapy <0.0001 <0.0001
Hepatectomy 1 1
Non-Hepatectomy 13.3 4.4 40.2 10.9 3.2 37
ICG-R15 0.0086 N.S.
<20 1
>/=20 2.7 1.3 5.5
Number of Primary Nodules 0.0013 N.S.
1 or 2 1
>/=3 3.3 1.6 7
Distribution* -
1 or 2 Sectors
>/=3 Section 1.9 1 3.8 N.S.
PVTT 0.0012 N.S.
Portal occlusion (-)
Portal occlusion (+) 3.3 1.7 7.9
# Relative Risk * distribution of primary and daughter nodules

44. Repeated resections and challenge to multiple
tumor resection in both sides of the liver are
future problems both in HCC and Met.
10 nodules
HCC
4 times
58 nodules
Meta
5 times
HBP Surgery, University of Tokyo

45. Rate of Repeat Hx. For Recurrent HCC
Years at 1st Hx. N Hepatic Rec. 2nd Hx. Rate
Oct. 94~Sep. 96 91 58 18 31%
Oct 96~Sep. 98 109 48 16 33%
Oct. 98~Dec. 99 82 11 5 45%
HBP Surgery, University of Tokyo

47. Isolated Subtotal Caudate Lobe Resection
Takayama T J Am Coll Surg 1994;179:72-75
High Dorsal Resection
Kosuge T Arch Surg 1994;129:280-284
Anterior Transhepatic Approach

49. Transplantation for HCC
- Selection Criteria -
Authors N Single Multiple Vas. Inv. Rec.(5Y) Survival(5Y)
Bismuth 1993 < 3cm <3, <3cm absent 17% (3Y) 83% (3Y)
Mazzaferro 1996 48 < 5cm - 3, <3cm absent 8% 75% (4Y)
Bismuth 1999 45 < 3cm <3, <3cm absent 11% 74%
Llovet 1999 79 < 5cm Solitary absent 4% 74%
Iwatsuki 2000 344 any any 282 absent 31% 49%
62 macro(+)
Jonas 2001 120 < 5cm -3, <3cm absent 16% 71%
Yao 2001 70 <=6.5cm -3, <=4.5cm absent 75%
<=8cm total

50. LDLT for HCC
Decreases drop-out rate during waiting time
Tumor growth
Liver Failure
Enables to challenge for extended indication
(i.e. advanced HCC without distant metastases)

51. In 1993, Shinshu group successfully performed
adult LDLT firstly in the world.

52. Which side of the liver should be use as a graft?
pros and cons
Jaundice, Ascites? Donors Completely safe
Low rate of cholestasis Higher mortality rate
Higher chance of survival Recipients

53. To obtain sufficient graft
with complete safety of donor
Donor side Recipient side
Remnant liver >30% Demanding >40%
SLV graft
(Rt. Liver > 70%
L+C < RLS (80%))

54. To obtain a sufficient graft
with maximum safety of donor
1. Left Liver Graft with Caudate Lobe
Miyagawa Transplantation 1998
Takayama J Am Coll Surg 1999
2. Right Lateral Sector Graft
Sugawara Transplantation 2001
3. Right Liver Graft without MHV
+ Reconstruction of MHV Tributaries
Lee SG Transplantation 2001
Sugawara Ann Surg 2003

55. Left Liver Graft with Caudate Lobe
Merit of -10% graft weight gain
L 38+-6%
L+C 41+-6%
Graft volume gain = 8+-2 %
Risk of cholestasis*
L 7/14 (50%) P=0.1
L+C 5/35 (14%)
* Serum total bilirubin levels over 10 mg/dl at the 21 POD
Sugawara et al. Surgery 2002; 132: 904

56. Right Lateral Sector Graft
Donor hepatectomy
RHV
R
P
A
P A
Sugawara et al. Transplantation 2002; 73: 111

57. Venous congestion

59. Indication for Reconstruction of the Hepatic Veins
1. No regurgitating blood flow in occluded hepatic
veins can be seen in the peripheral tributaries.
2. Blood flow of the relevant portal venous branches are
regurgitating.
3. Under occlusion of the hepatic artery discolored area
appears, and when the volume of the area deducts
from the remnant liver, the remaining liver volume
is smaller than the safe limit of the metabolic
demand.
Sano et al. Ann Surg 2002; 236: 241.

60. Maema et al. Transplantation 2002; 73: 765-769

61. Tape Switching Technique
RHV
V8 MHV
V5

63. Conclusion
1. Last 25 years developments in Hx for HCC.
2. PVE, TACE+Hx, Repeated Hx may
improve survival.
3. Isolated subtotal caudate Hx is established.
4. New variation of donor Hx enables
challenging LDLT for advanced HCC.