Hepatocellular Carcinoma: Targeted Therapy and Multidisciplinary P12 pot

7 Evidence-Based Guidelines for Treatment of Hepatocellular Carcinoma in Japan 95
Revisions of the Guidelines Based on the Latest Knowledge
There have been remarkable advances in the management of HCC recently, and
the content of parts of the 2005 version of the guidelines, which was based on the
literature as of 2002, has become outdated. The work of adding new knowledge and
evidence discovered in the period 2003–2007 and revising them is currently under
way at present.
The widespread adoption of RFA would seem to be the greatest change that
can contribute to the treatment algorithm since 2003. RFA enables reliable treat-
ment of a larger area via a single puncture and was introduced in Japan around
1999. Since then it has been widely adopted and becoming covered by Japanese
national health insurance in April 2004 provided an added boost, so that now it
can be said to have replaced PEI. Moreover, the results of RCTs comparing RFA
and PEI have been published [14, 15], and the superiority of RFA over PEI appears
to have been established as evidence level Ib. Accordingly, not only the answers
to the research question group related to percutaneous ablation treatment cited in
the 2005 version but the research questions themselves may become the targets of
revision.
Evaluation of the efficacy of treatment by liver resection and percutaneous abla-
tion treatment has also had an impact on the widespread adoption of RFA. The
2005 version of the treatment algorithm is based on the results of treatment by
liver resection and PEI, but now that the superiority of RFA over PEI has been
established, a comparison between liver resection and percutaneous ablation treat-
ment should be performed based on the results of RFA. The results of two RCTs in
2005–2006 have been reported [16, 17], and both of them concluded that the results
of liver resection and percutaneous ablation treatment were equivalent. However,
there were major problems with both of them, including in their design, and neither
of them could be regarded as providing adequate evidence [18]. A paper compar-
ing the outcome of liver resection, RFA, and PEI based on a nationwide follow-up
survey by the Liver Cancer Study Group of Japan has recently been published [19].
Although the results showed that liver resection was significantly better in cases

of recurrence, the differences in survival were not significant; however, the short
follow-up period was a problem. The conduct of a high-quality RCT that is able
to rigorously evaluate the outcome of RFA and liver resection is awaited in the
future.
The recommendations of the Japanese guideline about liver transplantation are
based on the results of deceased liver transplantation outside Japan. There is a rapid
increase in the number of living-donor liver transplantations for HCC in Japan since
1999 [20]. Thus, the recommendations should be amended in an algorithm that
reflects their results.
Moreover, the results of an RCT that showed the efficacy of a multikinase
inhibitor (Sorafenib) against advanced HCC were reported in 2008 [21]. Since there
has never been a drug whose efficacy against HCC was demonstrated by a statis-
tically significant difference in as sufficient a number of cases as in this study, it
generated considerable interest.
96 K. Hasegawa and N. Kokudo
Conclusion
Because many effective methods are available to treat HCC and the balance between
tumor status and liver function status must be taken into consideration, the judgment
of skilled specialists is required to make the choice of treatment. On the other hand,
the principle of treatment selection based on the hopes and preferences of patients,
socioeconomic circumstances, etc., is also important. The treatment algorithm of
the Japanese guideline extracts evidence at and above a certain level and reflects it,
and it is useful for explaining the complex decision-making process to patients in
a way that is easy to comprehend, and for obtaining their understanding in clinical
settings, where time is limited.
References
1. Makuuchi M, Kokudo N (2006) Clinical practice guidelines for hepatocellular carcinoma: the
first evidence based guidelines from Japan. World J Gastroenterol 12:828–829
2. Makuuchi M, Kokudo N, Arii S et al (2008) Development of evidence-based clinical guide-
lines for the diagnosis and treatment of hepatocellular carcinoma in Japan. Hepatol Res

38:37–51
3. Liver Cancer Study Group of Japan (1997) Classification of primary liver cancer. Kanehara &
Co., Ltd., Tokyo p. 21
4. Makuuchi M, Kosuge T, Takayama T et al (1993) Surgery for small liver cancers. Semin Surg
Oncol 9:298–304
5. Llovet JM, Brú C, Bruix J (1999) Prognosis of hepatocellular carcinoma: the BCLC staging
classification. Semin Liver Dis 19:329–338
6. Bruix J, Sherman M (2005) Management of hepatocellular carcinoma. Hepatology 42:
1208–1236
7. Ishizawa T, Hasegawa K, Aoki T et al (2008) Multiple tumors and concomitant portal hyper-
tension are not operative contraindications for hepatocellular carcinoma. Gastroenterology
134:1908–1916
8. Vauthey JN, Lauwers GY, Esnaola NF et al (2002) Simplified staging for hepatocellular
carcinoma. J Clin Oncol 20:1527–1536
9. Arii S, Yamaoka Y, Futagawa S et al (2000) Results of surgical and nonsurgical treatment
for small-sized hepatocellular carcinomas: a retrospective and nationwide survey in Japan.
Hepatology 32:1224–1229
10. Llovet JM, Real MI, Montaña X et al (2002) Arterial embolisation or chemoembolisa-
tion versus symptomatic treatment in patients with unresectable hepatocellular carcinoma:
a randomized controlled trial. Lancet 359:1734–1739
11. Minagawa M, Makuuchi M, Takayama T et al (2001) Selection criteria for hepatectomy
in patients with hepatocellular carcinoma and portal vein tumor thrombus. Ann Surg 233:
379–384
12. Eddy DM (1990) Clinical decision making: from theory to practice. Designing a practice
policy. Standards, guidelines, and options. JAMA 263:3077, 3081, 3084
13. Kokudo N, Sasaki Y, Nakayama T et al (2007) Dissemination of evidence-based clinical prac-
tice guidelines for hepatocellular carcinoma among Japanese hepatologists, liver surgeons,
and primary care physicians. Gut 56:1020–1021
14. Lencioni RA, Allgaier HP, Cioni D et al (2003) Small hepatocellular carcinoma in cirrho-
sis: randomized comparison of radio-frequency thermal ablation versus percutaneous ethanol

injection. Radiology 228:235–240
7 Evidence-Based Guidelines for Treatment of Hepatocellular Carcinoma in Japan 97
15. Shiina S, Teratani T, Obi S et al (2005) A randomized controlled trial of radiofrequency abla-
tion with ethanol injection for small hepatocellular carcinoma. Gastroenterology 129:122–130
16. Huang GT, Lee PH, Tsang YM et al (2005) Percutaneous ethanol injection versus surgical
resection for the treatment of small hepatocellular carcinoma: a prospective study. Ann Surg
242:36–42
17. Chen MS, Li JQ, Zheng Y et al (2006) A prospective randomized trial comparing percuta-
neous local ablative therapy and partial hepatectomy for hepatocellular carcinoma. Ann Surg
243:321–328
18. Hasegawa K, Kokudo N, Makuuchi M (2008) Surgery or ablation for hepatocellular carci-
noma? Ann Surg 247:557–558
19. Hasegawa K, Makuuchi M, Takayama T, et al. for the Liver Cancer Study Group of
Japan (2008) Surgical resection vs. percutaneous ablation for hepatocellular carcinoma: a
preliminary report of the Japanese nationwide survey. J Hepatol 49:589–594
20. Todo S, Furukawa H, Tada M; Japanese Liver Transplantation Study Group (2007) Extending
indication: role of living donor liver transplantation for hepatocellular carcinoma. Liver
Transpl 13(11 Suppl 2): S48–S54
21. Llovet JM, Ricci S, Mazzaferro V, et al. for SHARP Investigators Study Group (2008)
Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359:378–390

Chapter 8
Hepatocellular Carcinoma Arising
in the Non-viral, Non-alcoholic Liver
Charles E. Woodall, Robert C.G. Martin, Kelly M. McMasters,
and Charles R. Scoggins
Keywords HCC risk factors · HCC in the non-fibrotic liver · Non-cirrhotic
hepatoma · Fibrolamellar carcinoma (FLC) · Hereditary hemochromatosis
(HH) · Non-alcoholic fatty liver disease (NAFLD)
Hepatocellular carcinoma is one of the five most common cancers worldwide and

is one of the top three in regard to annual mortality. Greater than 80% occur in
either sub-Saharan Africa or East Asia, and most of these cases are attributed to
viral hepatitis. Increased public awareness and educational campaigns have led to
decreasing incidences in these endemic areas. However, the rate of HCC in a number
of areas with traditionally low rates of viral hepatitis, including Australia, the United
States, Canada, and the United Kingdom, has increased significantly. This rising
incidence cannot be easily explained by changes in immigration, hepatitis C virus,
or ethanol.
Risk Factors for Hepatocellular Carcinoma
It is widely known that chronic hepatitis B and C virus infection remains the most
dominant risk factor in HCC incidence. Other well-known hepatocellular carci-
noma risk factors include alcoholic cirrhosis and carcinogen exposure. The universal
belief has always been that cirrhosis precedes the development of HCC, even in the
United States where continued reports state that approximately 95% of HCC arises
in the background of cirrhosis [1]. Indeed, most cases of HCC occur in the setting
of cirrhosis, thus impacting the treatment modalities available.
However, some cases of HCC arise in a normal liver in patients with no history
of alcoholism and negative viral serologies. A certain proportion of these cases are
R.C.G. Martin (B)
Division of Surgical Oncology, Department of Surgery, University of Louisville School of
Medicine, Louisville, KY, USA
99
K.M. McMasters, J N. Vauthey (eds.), Hepatocellular Carcinoma,
DOI 10.1007/978-1-60327-522-4_8,
C

Springer Science+Business Media, LLC 2011
100 C.E. Woodall et al.
associated with rare etiologies such as non-alcoholic fatty liver disease, hemochro-
matosis, aflatoxin exposure, or variant subtypes of hepatoma not associated with

cirrhosis. Recently, epidemiologic research has generated data demonstrating the
emergence of HCC in the absence of underlying liver disease. These data may par-
tially explain why there has been a two-fold increase in the age-adjusted incident
rate of HCC in the United States between 1985 and 2002 [2]. This incidence has
caused an increase of 1.3 per 100,000 during 1978–1980 to 3.3 per 100,000 during
1999–2001 [3]. Interestingly, the largest increase during this period has occurred
in Caucasians (including Hispanics) while the lowest increase has been within the
Asian population. More recent reports have demonstrated that as many as 40% of the
HCC diagnosed in the United States is of unknown cause (i.e., no alcohol, hepatitis,
or cirrhosis) [3] (Fig. 8.1).
Aflatoxin
Alcohol
Chronic HBV
Genetic disease
e.g.
hemochromatosis
HCV
Cirrhosis (Genetic
Alterations)
Unknown Environmental Exposure
Genetic Polymorphisms
Unknown Viral Exposure
HCC
Age and Gender
Fig. 8.1 Potential causes of non-cirrhotic hepatocellular cancer
8 Hepatocellular Carcinoma Arising in the Non-viral, Non-alcoholic Liver 101
HCC in the Non-fibrotic Liver
The etiology of HCC in patients without chronic hepatitis infection or chronic cir-
rhosis from other causes remains unclear. To date, because of the overwhelming data
demonstrating that most cases of HCC arise in the cirrhotic liver (either associated

with viral hepatitis or alcohol-related damage), there has been little attention on the
increasing incidence of HCC in patients who lack fibrosis. Recent data from centers
in the central United States have shed some light onto the rising incidence of HCC
in the absence of fibrosis. It is quite possible that national increase in the incidence
of HCC reflects similar increases in HCC among patients without hepatitis or cir-
rhosis in other regions [4]. Why some patients with apparently normal liver tissue
would develop HCC is poorly understood.
One reason for the increased incidence of HCC may be related to changes in the
diagnostic criteria used in epidemiologic databases. In the 1970s and early 1980s,
the SEER database only recorded histologically confirmed cases of HCC. While
this is highly specific, it may underestimate the true incidence of HCC. The average
yearly age-adjusted incidence rates of all HCC captured by the SEER database irre-
spective of the method of diagnosis have increased approximately 30%. Because the
diagnosis of HCC now can occur without histologic confirmation, based on the pres-
ence of underlying cirrhosis, nodular mass seen CT or MRI, and an elevated AFP
level, the corresponding increased incidence in the SEER database may be partially
related to these changes in diagnostic criteria.
Similarly, with the rapid rise in hepatic resections now being performed at all
age groups, some patients who were initially diagnosed and treated for cancer of
unknown primary are now being appropriately being diagnosed as having HCC.
Perhaps the true incidence of HCC is not rising as quickly as previously described;
instead, there might be some shift in the diagnosis, with the incidence of carci-
noma of unknown primary decreasing as our ability to appropriately diagnose these
patients as having either HCC or intrahepatic cholangiocarcinoma improves. A more
liberal policy of resection in appropriate patients who were initially diagnosed as
unknown primary cancers has led to more precise diagnoses, some of which are
HCC. This type of policy may also contribute to the higher regional incidence of the
non-cirrhotic hepatoma [4].
Other potential etiologies for the increasing incidence of the non-cirrhotic hep-
atoma may include the ever-increasing age of the US population. The elderly

(defined as people aged 65 years or older) will account for over 61% of all new
cancer cases and 70% of all annual cancer deaths [5]. It has been recently estimated
that the elderly patient population has 11 times the cancer risk of people under the
age of 65 years. It has also been estimated that in 2030 approximately 20% of the
US population will be older than 65 years of age [6]. These changes alone coupled
with environmental exposure and potential genetic effects along with other potential
causes are the reason for these rising incidence rates.
This reasoning is further solidified by the significant differences in the clini-
cal, radiologic, and pathologic features of the patients with non-cirrhotic hepatoma
(Table 8.1) when compared to the common cirrhotic patient with HCC (Fig. 8.2).
102 C.E. Woodall et al.
Table 8.1 Features of the
non-cirrhotic hepatoma
Patient – Advanced age
– Higher incidence of women
– Non-alcohol related
– Generally tolerate major hepatectomy well
Liver – No fibrosis
– Large, solitary tumor
Serum – Low to normal AFP level
– Absence of evidence for viral hepatitis
– Preserved hepatic synthetic function
AFP, alpha fetoprotein
Fig. 8.2 Radiologic presentation of a cirrhotic HCC (left) with shrunken liver, ascites, and invasive
lesion and non-cirrhotic HCC (right) with normal size liver, sharp liver borders, and non-evidence
of nodularity
The non-cirrhotic hepatoma patients are significantly older, more commonly female,
less often smokers, have a greater incidence of a normal alpha-fetoprotein level,
larger sized tumors, and a smaller number of tumors (most commonly a single liver
tumor). These more favorable features have led to an ability to be more surgically

aggressive in these patients because of their underlying normal hepatic parenchyma.
This variant histology responds well to aggressive surgical resection with a lower
risk for hepatic failure postoperatively [4].
In a review of Kentucky’s patients with HCC, we have seen a fourfold increase i n
age-specific HCC diagnosis, with the most rapid increase seen in the 60- to 69-year-
old age group. We also have frequently observed the phenomenon in older patients,
without hepatitis or cirrhosis, who have large solitary tumors and normal AFP levels.
We have described these as “Kentucky hepatomas” because of the unique disease
presentation that differs from most other regions with a greater endemic hepatitis
population. In the University of Louisville database of hepatobiliary cancer, 60%
of HCC patients were without hepatitis or cirrhosis (Fig. 8.3). These non-cirrhotic,
hepatitis-free patients were found to be significantly older (70 vs. 55 years; P =
0.001), to be more often female (40.3 vs. 24.4%; P = 0.01), to have a larger tumor
size (6.5 vs. 3.9 cm; P = 0.004), to have fewer liver lesions (median 1 vs. 3; P
= 0.22), and to more frequently undergo surgical therapy (75.6 vs. 53.8%; P =
0.01) than the patients with cirrhosis or hepatitis. Furthermore, the non-cirrhotic,
8 Hepatocellular Carcinoma Arising in the Non-viral, Non-alcoholic Liver 103
Fig. 8.3 Age-specific increase in incidence of HCC in t he state of Kentucky. Y-axis is percent of
patients in each of the age groups specified
non-hepatitis patients had a median AFP level of 16 vs. 320 in the group with hep-
atitis or cirrhosis (P = 0.02). We found that there was a similar increase in HCC
incidence across all 5 regions of Kentucky. Whether this phenomenon is specific to
Kentucky (and other regions of the Midwest) is not known; however, others have
seen a similar rise in HCC without cirrhosis.
In a comparison of other studies that have presented the incidence of this variant
non-cirrhotic HCC, the data from the University of Louisville demonstrate the single
largest incidence rate. A recent report from Reichman demonstrated an incidence of
26%; however, it also noted a worse overall survival when compared to the cirrhotic
population [7]. Similar high incidence (31%) was reported from Fong et al., with-
out a difference in overall survival [8]. Both of these reports were from the United

States, i n New Jersey and New York, which has a higher incidence of Asian immi-
grants and thus probable higher incidence of hepatitis. Other reports have detailed
the incidence of this variant HCC in Europe and Asia [9–11] to be much lower, most
likely due to etiologic influences.
Fibrolamellar Carcinoma
Fibrolamellar carcinoma (FLC) was first described by Edmonson in 1956 [12]. It is
a rare hepatic malignancy, comprising less than 1% of primary liver malignancies
in a US population-based study [13]. The histologic appearance of FLC is distinc-
tive, consisting of deeply eosinophilic malignant hepatocytes surrounded by thick
fibrous bands arranged in a lamellar-like fashion [14]. Radiographically, the tumors
are hyper-vascular and tend to be large, be calcified, and have a central scar [15], all
distinct differences from conventional HCC (Table 8.2). Many consider it a variant
of HCC, though the epidemiology, clinicopathologic factors, and prognosis differ
widely from HCC.
FLC is largely tumors of youth and young adulthood. The median age of patients
with FLC is on the order of 25 years [16–18], far younger than conventional HCC.
104 C.E. Woodall et al.
Table 8.2 Differences between fibrolamellar carcinoma and traditional HCC
Fibrolamellar Traditional HCC
Patient related Young age
Lack fibrosis
Better survival
Patient related Older age
Cirrhotic
Worse survival
Tumor related Central scar
Typically solitary
Higher resection rate
Tumor related No scar
Often multifocal

Lower resection rate
FLC is not associated with an underlying history of cirrhosis [19–21], and this fact
may account for the differences in age distribution, given that a background of
fibrosis is not common in younger populations. There also does not appear to be
any connection with viral hepatitis, ethanol, or estrogen use, all factors commonly
considered in association with conventional HCC [19].
There are conflicting data comparing the survival of patients with FLC with
traditional HCC. Some authors have reported no survival benefit for FLC patients
who have undergone resection (when compared to traditional HCC), although the
number of cases was too small to draw firm conclusions [22]. These data are sim-
ilar to that published by others, although the rate of resectability for patients with
FLC might be higher [23]. In contrast to these data are reports demonstrating an
improved survival for patients with FLC, including one report of a 56% 5-year sur-
vival for resected patients [24]. Further data suggesting a more favorable biologic
behavior for FLC include high resectability rates and improved survival following
resection [17, 19, 20, 23].
Like traditional HCC, FLC is prone to recurrence following resection. The most
common site for recurrence appears to be in the liver remnant. Unlike traditional
HCC, however, recurrent FLC might fare better following recurrence. Data demon-
strate that patients with recurrent FLC survive longer than those patients with
recurrent traditional HCC [25, 26]. Furthermore, patients with recurrent FLC might
be amenable to re-resection, with data demonstrating a survival advantage to this
aggressive approach [27]. FLC might have a higher risk for nodal metastasis upon
presentation, and the rate of metastatic lymph nodes has been reported to be as high
as 30% [28]. This raises the question of the role of routine portal lymphadenectomy
at the time of initial hepatectomy.
Hereditary Hemochromatosis
Hereditary hemochromatosis (HH) is an autosomal recessive syndrome of iron
overload. It is characterized by increased absorption of iron in the intestines with
deposition in organs such as the heart, skin, pancreas, pituitary, and liver [29]. It is

an under-recognized congenital condition caused by missense mutations at the HFE
gene; some authors report HH is 10 times more common than cystic fibrosis [30],