Management of Hepatocellular Carcinoma
Management of Hepatocellular Carcinoma
Hepatocellular carcinoma (HCC) is the most common
primary neoplasm of the liver, accounting for almost half a million
deaths annually worldwide. Although the incidence of HCC is
particularly high in parts of Asia and Africa, recent studies have
documented a clear rise in the number of cases in Japan, Western
Europe, and the United States.
The rising incidence in the United States, as well as other parts of
the world, is attributed largely to the increase in hepatitis
Crelated liver disease, a known risk factor for the disease.
In the United States alone, the seroprevalence of hepatitis C virus
is estimated to be 3.9 million cases. Other risk factors for HCC
include hepatitis B viral infection, alcoholic cirrhosis, aflatoxin
exposure, and a variety of inherited metabolic disorders.
Complex management options confront clinicians treating patients with
HCC, making a multidisciplinary team comprised of hepatologists,
interventional radiologists, medical oncologists, radiation
oncologists, and surgeons necessary for optimal care. Unfortunately,
there are few randomized clinical trials comparing the multitude of
treatment options. Furthermore, many published studies lack
statistical power and fail to stratify treatment arms by known
prognostic indicators. In this report, an effort is made to provide
an overview of the current management modalities available for
patients with HCC and to describe the most appropriate clinical
contexts in which they should be employed.
Because patients with HCC most commonly manifest nonspecific symptoms
of advanced disease, including abdominal pain, weakness, and weight
loss, routine use of serum alpha-fetoprotein (AFP) levels and
transabdominal ultrasound (US) are used to screen individuals at high
risk (ie, those with chronic hepatitis and/or cirrhosis). A normal
level of AFP is less than 20 ng/mL, and a measurement above 500 ng/mL
is considered diagnostic. Intermediately elevated levels, although
indicative of HCC, can also be associated with benign conditions.
In high-incidence regions, the sensitivity of an abnormal AFP level
is 80% to 90%; however, this drops to 50% to 70% in areas of low
incidence. The specificity is 90%.
Many imaging modalities are available to help establish the diagnosis
of HCC. Their respective sensitivities for detecting lesions £
3 cm are listed in Table 1.[5-9]
Dynamic magnetic resonance imaging (MRI) and helical computed
tomography (CT) are commonly used to screen high-risk patients for
HCC because they are less invasive than other available imaging
techniques (Figure 1).
The sensitivity of most modalities significantly drops for lesions
< 1 cm. However, Lipiodol CT still has a sensitivity of about 70%
for detecting lesions of this size, making it the most sensitive
preoperative imaging technique currently available.
Lipiodol is an iodized oily agent that accumulates selectively in
vascular HCC liver nodules after intra-arterial injection. Although
used most commonly therapeutically as part of transarterial
chemoembolization, some centers employ diagnostic Lipiodol CT
routinely in cases of suspected HCC or to rule out multifocal or
The sensitivity of intraoperative ultrasound (US) for detecting HCC
tumors is 98% for lesions 1 to 3 cm in size and 86% for those < 1
cm. Therefore, exploratory laparotomy with intraoperative US
remains the gold standard for determining resectability of HCC.
Recently, encouraging results of staging of liver malignancies by
laparoscopy with laparoscopic US have been reported. In
particular, for patients with HCC, laparoscopy with laparoscopic US
may avoid unnecessary laparotomy in certain instances.
Preoperative needle biopsy is rarely necessary in resectable patients
with a clear diagnosis of HCC (ie, AFP > 500 ng/mL and a lesion
identified on imaging studies). In most cases, the diagnosis is
evident, and preoperative biopsy rarely alters management. Moreover,
needle biopsy can be associated with the potential risks of bleeding,
tumor rupture, and dissemination of malignant cells along the needle
Percutaneous biopsy is most useful if the patient has unresectable
HCC or is being considered for liver transplantation. In selected
cases in which the diagnosis is unclear or multifocal disease is
being ruled out, needle biopsy should be considered prior to major
resection. Other roles of biopsy include evaluation of cases in
which nonoperative ablation is being contemplated and determination
of the extent of cirrhosis in the nontumorous liver.
Evaluating Hepatic Function
Assessment of hepatic functional reserve is important for deciding
whether resection, liver transplantation, or other treatment
modalities should be pursued. Prognostically useful data for both
surgical and medical patients may be obtained from staging using the
functional Child-Pugh classification system (Table
Another method, the indocyanine green retention rate, may also
provide an estimate of underlying liver function. Although this
test is used in some centers, it is not employed in most cases.
Imaging techniques may shed light on the extent of cirrhosis in some
cases. For example, a CT scan or MRI can identify the loss of liver
volume or hepatic contour changes indicative of more extensive
cirrhosis. Visualization of portal vein collaterals, splenomegaly, or
ascites can indicate more advanced disease.
Overall, there is no consensus on specific guidelines for evaluating
hepatic function prior to treatment of HCC.
Once diagnosed, the clinical staging of HCC is based on tumor size
and number, whether there is vascular invasion, and the presence of
regional lymph node or distant metastases (Table
3). A shortcoming of the TNM staging system is the absence
of liver functional status, which is an important prognostic
indicator for HCC. Collectively, performance status,
comorbidities, liver function, and extent of disease greatly
influence the range of treatment options available to a patient with HCC.
For patients without cirrhosis, surgical resection with partial
hepatectomy is clearly the treatment of choice. However, no more than
30% of patients with HCC present with resectable disease, and up to
90% of patients have cirrhosis on presentation.[20,21] Extrahepatic
disease, lack of sufficient hepatic functional reserve, multifocal
disease within the liver, tumors in locations not amenable to
resection, and main portal vein involvement, as well as comorbid
disease, are all contraindications to resection.
In patients with well-compensated, mild cirrhosis (Child-Pugh class
A-B) (Table 2), partial hepatectomy
should be considered. Overall, the presence of cirrhosis is
associated with worse long-term survival following
resection.[19,22,23] In addition to cirrhosis, poor prognostic
factors include large tumor size, multifocality, presence of vascular
invasion, and poorly differentiated grade.[19,21,23,24] Following
partial hepatectomy, overall 5-year survival rates range between 35%
and 50% (Table 4).[25,19,26-31]
In recent years, improvements in operative mortality can be
attributed to advances in preoperative imaging, better patient
selection, development of new operative techniques and equipment, and
advances in operative and postoperative anesthesia and critical
care. Although earlier reports demonstrated substantially
increased operative mortality (up to 20%) following resection in
patients with cirrhosis, more current studies from both western and
eastern investigators showed similar postoperative mortality (<
5%) for patients with and without cirrhosis.[19,24,28-30] Centers in
which a higher volume of liver resections are performed have a lower
Even among patients in whom resection is performed with curative
intent, intrahepatic recurrence is seen in up to 70% of cases. It
is thought that some intrahepatic recurrences may actually be de novo
multifocal disease or metachronous new tumors within the liver. These
distinctions can be difficult to make. Nevertheless, with aggressive
management of recurrences, long-term survival can also be achieved in
Orthotopic Liver Transplantation
In light of the high concomitant incidence of cirrhosis and HCC and
the potential for multifocal malignancy, the prospect of removing the
entire liver containing the tumor and replacing it with a healthy one
is attractive. However, limited donor availability with attendant
long waiting lists, high cost, significant morbidity, and the
potential cytostimulatory effect of systemic immunosuppression remain
formidable obstacles to transplantation.
Stage for stage, liver transplantation can achieve 5-year survival
rates comparable or superior to those of partial hepatic resection in
selected cases (Table 5).[13,25,34-39]
Transplantation has a more favorable prognosis in patients with a
solitary tumor < 5 cm or those with no more than three nodules,
each £ 3 cm (the so-called 3-3 rule).
More extensive disease should be considered an absolute
contraindication to transplantation. Importantly, in patients with
cirrhosis, a 4-year survival rate of 75% is achievable following
total hepatectomy and transplantation for unresectable tumors < 5
cm or no more than three nodules, each £
3 cm. Bilobar disease, by itself, is not considered a
contraindication to transplantation.
Contraindications to liver transplantation include the presence of
extrahepatic disease and comorbid factors precluding transplantation
for benign indications. Other relative contraindications include the
presence of vascular invasion or a poorly differentiated grade.
Due to the long wait times for cadaveric donor organs (often more
than 1 year), various alternatives to standard organ availability
have been considered. These include increasing the priority status of
patients with HCC for transplantation, utilizing split liver
techniques, or considering marginal donor organ quality for patients
with a malignancy. In addition, the increasing use of adult
living donor transplantation may improve transplant availability for
the cancer patient.
Attempts have been made to restrain HCC growth while patients await
transplantation. Many institutions have published small series
employing preoperative chemotherapy, radiotherapy, and/or
transarterial chemoembolization administered prior to
transplantation; these studies have had mixed results.[41-44]
Similarly, the role of postoperative adjuvant chemotherapy is undefined.
At present, conclusions cannot be made, and definitive
recommendations for the use of preoperative or adjuvant therapy await
the results of ongoing, multicenter, randomized clinical trials.
Currently, only selected patients with small tumors and moderate to
severe cirrhosis should undergo liver transplantation.