Hepatocellular carcinoma

Hepatocellular carcinoma

What every physician needs to know:

Hepatocellular carcinoma (HCC) is the most common primary malignant tumor of the liver and the third most common cause of cancer-related death worldwide. The incidence of HCC appears relatively static in most endemic regions. Previously considered uncommon in the United States and Europe, its incidence and mortality have increased three-fold in the past two decades, secondary to parallel increases in chronic hepatitis C virus (HCV) and non-alcoholic steatohepatitis (NASH).

Although surgical resection and liver transplantation are potentially curative therapies, the vast majority (>80%) of patients present with advanced disease that is not amenable to curative treatment modalities. In addition to patients presenting with advanced tumors, many of these patients also have underlying liver dysfunction which can be a rate-limiting step to initiating treatment.

The diagnosis and treatment plans should be made in a multi-disciplinary fashion consisting of a team of hepatologists, oncologists, surgeons and radiologists.

Are you sure your patient has hepatocellular carcinoma? What should you expect to find?

The clinical presentation of HCC varies considerably and is often dependent on the degree of hepatic reserve. Many patients with HCC are asymptomatic at the time of diagnosis or have their tumors incidentally discovered on imaging done for unrelated reasons. Given that the vast majority of patients with HCC have concomitant cirrhosis, the first manifestation of HCC can be hepatic decompensation, such as jaundice, hepatic encephalopathy, or ascites.

In a patient with known cirrhosis, a decline in a patient’s hepatic function should heighten clinical suspicion for the development of HCC. However, a lack of known chronic liver disease at presentation does not preclude the possibility of HCC. Oftentimes, patients were exposed to one of the inciting risk factors, such as HCV, decades earlier and simply have unrecognized chronic liver disease. In our experience, nearly 40% of patients had HCC as their first presentation of cirrhosis.

The most common symptoms of HCC upon initial presentation include the following: abdominal pain, weight loss, weakness, abdominal swelling (ascites) and jaundice. An additional 1-3% of patients initially present with symptoms related to metastatic disease, including body pain to the spine or hips. The most common signs of HCC are hepatomegaly, ascites, fever, splenomegaly, muscle wasting and jaundice.

Laboratory values are non-specific and are often more related to the underlying liver disease than the HCC. Early in the disease most of these symptoms and signs are absent and are only exhibited in the late stages of disease.

Beware of other conditions that can mimic hepatocellular carcinoma:

In patients with known cirrhosis or chronic HBV infection who present with a new mass on ultrasonography or axial imaging, HCC is the diagnosis until proven otherwise. However, other primary malignant and benign tumors of the liver can mimic the radiological findings (as discussed later) of HCC and include the following: intrahepatic cholangiocarcinoma, hepatic adenoma, hepatic hemangioma and focal nodular hyperplasia of the liver.

Which individuals are most at risk for developing hepatocellular carcinoma?

Most cases of HCC are attributable to chronic liver disease resulting from chronic HCV or HBV infection alone or exacerbated by comorbid conditions such as chronic alcohol use, metabolic syndrome, and infectious diseases (including human immunodeficiency virus).

Hepatitis C virus

In the United States, Europe, and Japan, chronic HCV infection with associated cirrhosis is the major risk factor of developing HCC. Patients with chronic HCV infection and cirrhosis have a 3-5% per year incidence of developing HCC and the incidence is exacerbated by the previously listed comorbid conditions, particularly chronic alcohol use.

Treatment of patients with chronic HCV infection with interferon has been demonstrated to reduce the incidence of HCC in historically controlled studies, however a meta-analysis demonstrated that patients who were successfully treated had only a modest decrease in developing HCC. It is important to remember that patients with HCV cirrhosis have a reduced risk of HCC with successful eradication of HCV, although these patients still have some risk for HCC and deserve continued HCC surveillance (see below).

Hepatitis B virus (HBV)

In Asia (with the exception of Japan) and Africa the major risk factor is chronic HBV infection with or without cirrhosis. The HBV carrier state is usually established in early childhood by vertical transmission at the time of birth or horizontal infection in children not vaccinated adequately.

The time lag between infection with HBV and development of HCC is often decades and patients will typically present in the fourth and fifth decade of life. Patients with chronic HBV infection without cirrhosis have a 0.3-0.6% per year incidence of HCC. Patients with concomitant cirrhosis have a 3-8% per year incidence of HCC.

Multiple studies, including a randomized controlled trial and a meta-analysis, have demonstrated a decreased incidence of HCC following HBV treatment but patients with treated HBV are still at risk for developing HCC.

Other risk factors

Cirrhosis from any cause of liver disease, including alcoholic liver disease, non-alcoholic steatohepatitis (NASH), hereditary hemochromatosis, alpha 1-antitrypsin deficiency, Wilson’s disease, exposure to aflatoxin B1, type 1 and type 2 glycogen storage disease and type 1 hereditary tyrosinemia also predisposes to HCC.

The majority of patients that develop HCC (95% in the United States, Europe and Japan, 60% in Asian and African countries) will develop the disease in the background of cirrhosis. The annual incidence of HCC in cirrhosis not caused by viral hepatitis is not accurately known.

Although chronic alcohol-related cirrhosis is a well-established risk factor for HCC, the exact annual incidence is unclear due to a large percentage of concomitant viral hepatitis. More recently, NASH-related cirrhosis has also been deemed a risk factor for HCC, but the incidence is unclear as most published studies involve a paucity of patients and the definition of NASH by non-invasive measures does not have a universal consensus.

Which at-risk patients should be screened for hepatocellular carcinoma?

The goal of any surveillance program for cancer should be to diagnose the disease at an early stage when curative treatment modalities exist and can increase overall survival. The decision to enter a patient into a surveillance program for HCC is based on identifying which patients are at sufficiently high risk of developing HCC.

Currently there is no level of evidence to indicate what annual incidence level should trigger entry into a surveillance program. Based on cost-effectiveness data, surveillance should likely be offered to patients who have greater than 1.5% risk per year of developing HCC.

The American Association for the Study of Liver Disease (AASLD) currently recommends that the following groups of patients be entered into a surveillance program:

• Asian male hepatitis B carriers over age 40.

• Asian female hepatitis B carriers over age 50.

• African hepatitis B carriers over age 20.

• Hepatitis B carriers with a family history of HCC.

• Hepatitis B carriers with cirrhosis.

• Hepatitis C with cirrhosis.

• Alcoholic cirrhosis.

• Non-alcoholic steatohepatitis.

• Stage 4 primary biliary cirrhosis.

• Hemachromatosis with cirrhosis.

• Alpha 1-antitryspin deficiency with cirrhosis.

• Patients with any other cause of cirrhosis.

The AASLD recommends that risk patients should be screened with an abdominal ultrasound every 6-12 months. Currently, less than 30% of patients with cirrhosis in the United States are appropriately receiving HCC surveillance on an annual basis.

Historically, the diagnosis of HCC was based on alpha-fetoprotein (AFP) level, radiological imaging, and/or histology. In the past, an AFP level greater than 200 ng/mL and a mass on cross-sectional imaging was sufficient for the diagnosis of HCC. However, recent data has demonstrated AFP lacks sufficient specificity to be used as a diagnostic test for HCC.

AFP can be elevated in patients with intrahepatic cholangiocarcinoma and/or hepatic metastases from other malignancies such as gastric cancer. Therefore, the AASLD has removed AFP from the HCC diagnostic algorithm in its more recent guidelines.

What laboratory and imaging studies should you order to characterize this patient's tumor (i.e., stage, grade, CT/MRI vs PET/CT, cellular and molecular markers, immunophenotyping, etc.) How should you interpret the results and use them to establish prognosis and plan initial therapy?

Imaging

HCC can be diagnosed in most cases without the need for a biopsy, provided characteristic radiological features are present in the appropriately completed imaging studies. A four-phase imaging study, either dynamic contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI), consisting of unenhanced (Figure 1), arterial (Figure 2), venous (Figure 3) and delayed (Figure 4) phase images are necessary to accurately assess for HCC.

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Since HCC tumors typically only contain arterial vascular supply (via branches of the hepatic artery), HCC lesions should enhance compared to the remaining liver on the arterial images. On venous images, the lesion should display “washout” as the surrounding liver will have a greater portal venous blood flow than the HCC.

For lesions greater than 1cm in maximum diameter, the presence of arterial enhancement and delayed washout on one imaging study is sufficiently specific for HCC and no further imaging or biopsy is necessary.

For lesions greater than 1cm without arterial enhancement and delayed washout, a second cross-sectional imaging study (CT or MRI) should be performed to further characterize the lesion. If the second imaging modality still does not characterize the lesion by the presence of arterial enhancement and delayed washout, or there is a discrepancy in imaging findings, we would then proceed to percutaneously biopsy of the lesion (only then).

The abandonment of routine biopsy for all lesions concerning for HCC is driven by increasing specificity for newer generation imaging modalities as well as the difficulty in discerning between histological diagnosis between a well differentiated HCC and a high-grade dyplastic nodule on histology in a small tumor in a cirrhotic liver.

If a biopsy is done, it should be interpreted by an experienced pathologist using with the aid of markers staining for:

• MOC-31

• Hep Par 1

• glypican-3 (GPC-3)

• polyclonal carcinoembryonic antigen (CEA).

• A combination of Hep Par 1 and MOC-31 will distinguish HCC from metastatic adenocarcinoma in most cases.

Liver tumors staining negative for MOC-31, an antibody consistently expressed in metastatic adenocarcinoma, and positive for Hep Par 1 in the appropriate clinical and morphologic setting confirms the diagnosis of HCC. Concerns over tumor seeding the biopsy tract or bleeding from a biopsy appear to be unfounded.

Lesions smaller than 1cm are typically thought to have a higher likelihood of being dysplastic nodules than HCC and we generally will simply repeat imaging in 3-6 months to assess for growth or change in character.

There is currently no role for PET imaging to either aid in the diagnosis or staging of HCC.

If there are concerns for metastatic disease, we will obtain a bone scan, chest CT, and/or MRI of the head as indicated.

Laboratory Tests

For the initial evaluation of a patient with HCC we order the following:

• CBC

• liver chemistries

• basic metabolic panel

• coagulation panel

• viral hepatitis serologies (if unknown)

• AFP

Despite its suboptimal sensitivity and specificity, we still recommend obtaining an AFP at baseline as it can serve as a prognostic marker and may have potential in assessing response to treatment. This approach will allow for both an assessment of the tumor burden as well as underlying liver function to implement a treatment regimen.

Staging

Therapy for HCC patients should be based on the patient’s prognosis, which in turn is based on the patient’s tumor stage, underlying liver function and overall performance status. Unfortunately there is a lack of consensus about which of the available systems most accurately stages patients with HCC.

Traditionally the American Joint Committee on Cancer/Union internationale contre le cancer (AJCC/UIC) TNM staging system is used to stage most cancers. Although this system adequately stratifies patients into prognostic groups, it is only applicable for patients that have undergone surgical resection or orthotopic liver transplantation as it fails to take into consideration the patients underlying liver function or overall performance status.

The Okuda, Cancer of the Liver Italian Program (CLIP), Japan Integrated Scoring System (JIS) and Barcelona Clinic Liver Cancer (BCLC) classification systems attempt to overcome the shortcomings of TNM staging by combining both tumor-related parameters with underlying liver function and patient performance status with tumor-related parameters.

Although all 5 of these staging systems have been externally validated with varying degrees of success, we prefer to use the BCLC system (Figure 5) to initially stage patients diagnosed with HCC. The BCLC system not only combines underlying tumor characteristics including metastases, portal venous thrombus and size with patient performance status and underlying liver function as demonstrated by the Child-Pugh score (Table I), but also is the only staging system that has been directly linked to appropriate treatment options.

Figure 5.

Table I.

The use of a universal staging system upon presentation is vital when comparing results between studies of different treatment modalities. In our clinical practice we use the BCLC system when first evaluating a patient with HCC to help determine the optimal treatment plan; we then use the AJCC/UIC TNM system in those patients who undergo either surgical resection or orthotopic liver transplantation for pathological staging. (Table II)

What therapies should you initiate immediately i.e., emergently?

Spontaneous Rupture

The major life-threatening complication of HCC is the spontaneous rupture of the tumor with peritoneal hemorrhage. The incidence is 3%-15% in patients with HCC, with a decreasing incidence over the last decade due to earlier diagnosis of the tumor. However, the mortality rate remains high (25-75%) presumably due to a combination of uncontrolled hemorrhage and acute decompensation of liver function.

Presentation

Prior to the onset of appropriate treatment the diagnosis of a ruptured HCC must be achieved. This can oftentimes be quite difficult due to the lack of history of known HCC or cirrhosis. Typically, patients present with acute abdominal pain and hemodynamic instability. Confirmation of diagnosis is usually made with a contrast enhanced axial imaging modality (CT or MRI) that demonstrates hemoperitoneum and presence of tumor (Figure 6).

Figure 6.

Treatment

The tenets of treatment are based on the degree of hemodynamic instability and local expertise. In a hemodynamically stable patient, close monitoring for further signs of bleeding as an inpatient is usually the first step, followed by a staged partial hepatectomy in the future in an elective fashion, or other appropriate therapy depending on the extent of tumor burden and underlying liver function. In a hemodynamically unstable patient resuscitation of the patient with blood products and coagulation factors followed by a procedure aimed at hemostasis is the first step.

Depending on local expertise, the least invasive and preferred hemostasis procedure is transarterial embolization (TAE). TAE is both diagnostic and therapeutic as the bleeding vessel, typically an arterial source, is identified via celiac trunk angiography and then treated using a variety of embolic materials including gel foam, polyvinyl alcohol or stainless steel coils.

During the angiography, flow through the portal vein can be assessed and complete occlusion of the portal vein is a contraindication to TAE. TAE is successful as a hemostatic procedure in 53%-100% of cases of ruptured HCC. The main complication of TAE is post-embolization syndrome (discussed in the following section).

Following TAE and stabilization, definitive treatment of the patient proceeds according to tumor burden and underlying liver function. If TAE is not available or fails to control bleeding, open surgical exploration is the next step of the algorithm. Surgical options include:

• Perihepatic packing of the liver to allow tamponade of the bleeding liver and correction of coagulopathy. The packs are typically left in place for 24-48 hours and are removed once the patient becomes more hemodynamically stable.

• Ligation of the hepatic artery.

• Partial hepatectomy.

• Suture plication of the bleeding area.

• Injection of absolute alcohol into the bleeding area.

If the patient becomes hemodynamically stable, a plan for definitive treatment should be implemented.

What should the initial definitive therapy for hepatocellular carcinoma be?

The initial therapy for HCC is based on tumor characteristics, underlying liver function and the overall performance status of the patient. In our clinic we utilize the BCLC algorithm (Figure 5) to aid in the decision making process.

Surgical Resection

Patients with a single focus of HCC, preserved liver function (Child-Pugh A), and a good overall performance status will undergo a surgical resection of their lesion consisting of a partial hepatectomy.

Prior to surgical resection it is important to pre-operatively assess the patient’s liver function adequately to avoid post-operative liver failure and subsequent mortality. Although the Child-Pugh score provides a rough estimation of liver function into A, B and C scores, where B and C scores are not considered for resection, it does not adequately stratify operative risk among Child-Pugh A patients.

Prior to consideration of a major hepatectomy consisting of more than 3 segments of the liver (Figure 8), especially in a patient with a background of cirrhosis, volumetric analysis of the future remnant liver (FLR) is suggested.

Figure 8.

In a cirrhotic liver generally post-operative liver failure does not occur if the FLR is above 40%. The use of portal vein embolization (PVE) has been employed to increase the FLR and reduce post-operative complications in patients with a small FLR. This technique occludes the portal vein branches on the side of the liver to be resected, producing a contralateral hypertrophy of the remaining liver.

PVE also serves as a litmus test, as patients who do not undergo hypertrophy following PVE are not considered for surgical resection and are offered alternative therapies.

From a technique standpoint, resection for HCC is generally done in an anatomical fashion, provided that there is adequate hepatic reserve due to the propensity of HCC to spread intravascularly. A randomized controlled trial looking at wide (>2cm) and narrow (1cm) surgical margins demonstrated early local recurrence rates and decreased overall survival in the narrow margin group.

Provided that patients with HCC are selected as described above, surgical resection can be done safely with less than a 5% peri-operative mortality and 15%-25% morbidity. Surgical complications include post-operative ascites that can usually be managed with the initiation of a diurectic regimen:

• Spironolactone started at 150mg PO daily (may be increased up to 400mg PO daily), and/or

• furosemide started at 20mg PO daily.

For the well selected patient with a single HCC nodule, five-year overall survival rates range from 38%-68%, with five-year disease free rates ranging from 19%-46%.

Liver Transplantation

Candidates for liver transplant include patients with:

• Multi-focal disease consisting of 3 or fewer lesions smaller than 3 cm in size, or

• a solitary lesion smaller than 5 cm.

A seminal study by Mazzaferro et al established the “Milan criteria” where carefully selected patients had four-year survival rates approaching 75% following liver transplantation. This was a drastic change to previous reports where patient selection was not stringent and survival rates were only 15%-40%.

Many centers have started to expand the Milan criteria by selecting patients with solitary tumors less than 6.5cm, or 3 or less tumors smaller than 4.5 cm in size with a total tumor diameter less than 8 cm. This University of California, San Francisco (UCSF) expanded criteria has achieved survival rates comparable with the Milan criteria in published reports.

Within the United States, patients with HCC are listed in priority for liver transplantation based on their Model for End-Stage Liver Disease (MELD) score, which is a mathematical formula taking into consideration total bilirubin, INR and creatinine.

Currently United Network for Organ Sharing (UNOS) allocates 22 MELD points for patients with HCC within the Milan, or expanded (depending on geographical UNOS area), criteria with an increase of 10% for every 3 months on the waiting list. Waiting times are dependent on the geographical location and in some regions can exceed 12-18 months.

While the patient is on a waiting list, our center will typically bridge to liver transplantation with a locoregional treatment such as transarterial chemoembolization (TACE) to prevent tumor growth. If whilst on the waiting list, the tumor grows outside the specified criteria, the patient is no longer eligible for transplantation.

Percutaneous ablation techniques

Patients with either a single focus of HCC or 3 or fewer nodules anatomically eligible for liver transplantation, but with comorbidities excluding them for surgical resection or transplantation, are generally treated with percutaneous ablation with either percutaneous ethanol injection(PEI) or radiofrequency ablation (RFA). Both procedures are performed under ultrasound guidance typically by interventional radiology.

Percutaneous Ethanol Injection (PEI)

PEI generally involves repeated injections of 100% absolute alcohol into the center of the tumor. In tumors less than 2cm, PEI achieves a necrosis rate approaching 100%, but the rate of necrosis is only 70% in tumors between 2 and 3cm in size, and 50% in tumors greater than 3cm. The main complications of PEI are temporary pain and a feeling of alcohol intoxication.

Radiofrequency Ablation (RFA)

RFA, the more commonly used ablative technique in the United States and Europe, has demonstrated similar necrosis rates as PEI in tumors under 2cm, with less number of treatments but with a slightly higher complication rate, including pleural effusions and peritoneal bleeding. In tumors greater than 2cm, RFA appears to be better than PEI at controlling local disease.

It is our practice to offer RFA to patients with early stage HCC who are not candidates for either surgical resection or transplantation. The use of RFA over surgical resection even in small (< 2cm) tumors in patients who are surgical candidates is very controversial and its use as a first-line therapy cannot be recommended at this time.

The one randomized controlled trial demonstrating RFA was equivalent with surgical resection had several biases including comparing patients of different stages. Thus, until this trial is confirmed by other authors, it is our practice to use surgical resection over RFA in the appropriately selected patients.

Locoregional therapies

Patients with multifocal HCC outside of transplantation criteria, and relatively preserved liver function (either Child-Pugh A or B), are treated with locoregional therapies including transarterial embolization (TAE) or transarterial chemoembolization (TACE).

TAE is completed by the interventional radiologist selectively cannulating the arterial tumor supply and injecting embolic materials, including gelfoam, polyvinyl alcohol or metallic coils. TACE is similar to TAE except that chemotherapy, typically cisplatin, doxorubicin and/or mitomycin, is emulsified in lipiodol and injected typically into either the right or left hepatic artery, depending on the tumor location.

The lipiodol is taken up by the tumor increasing exposure to chemotherapy. TAE or TACE usually requires multiple treatment sessions over a period of a couple of months.

Although TAE and TACE have never been directly compared with regards to treatment efficacy, it is our practice to employ TACE as TAE requires selective cannulation of subsegmental tumor vascularature that can oftentimes require special expertise and long procedure times. Two RCTs have demonstrated that the use of TACE compared to best supportive care produces a significant increase in overall survival.

The most feared complication of these interventions is post-procedural hepatic failure leading to death. Post-embolization syndrome (fever, pain and nausea) is seen in nearly 50% of patients following TACE. Treatment of this is conservative and symptom-based as the syndrome is generally self-limited lasting less than 2 days. Unless prior biliary-enteric anastomosis are present, peri-procedural antibiotics are not usually given. As mentioned previously TACE is often used as a bridging therapy for liver transplantation.

Systemic chemotherapy

Patients who have advanced staged HCC as demonstrated by nodal or extra-hepatic disease, or portal venous obstruction with a good performance score (ECOG 0-2) and preserved liver function (Child-Pugh A or B) are treated with systemic chemotherapy. The only FDA approved systemic chemotherapy for HCC is sorafenib (Nexavar), a multikinase inhibitor blocking VEGFR, B-raf and MEK pathways.

In a landmark RCT, sorafenib improved overall survival and time to progression compared to placebo by nearly 3 months. Typical of other targeted therapies sorafenib does not produce a radiological response with only a 0-2% response rate by traditional RECIST criteria. Sorafenib is generally administered as follows:

• Sorafenib 400mg orally twice daily until disease progression or intolerable toxicity.

Unfortunately a large percentage of patients initially present with end stage HCC where no treatment options are feasible. Supportive care, including pain management and input from a dedicated palliative care service, is appropriate in these cases.

What other therapies are helpful for reducing adverse events following initiation of sorafenib therapy?

The SHARP clinical trial demonstrated that patients with advanced HCC have a significant overall survival benefit of nearly 3 months following initiation of sorafenib therapy compared to placebo. However, 45% of patients receiving sorafenib in this trial had either grade 3 or 4 adverse events, with nearly one-third of patients discontinuing treatment due to adverse events.

The three most common adverse events of sorafenib are:

• fatigue

• diarrhea

• hand-foot syndrome (HFS)

We encourage the patients to make sure that they maintain oral intake with nutritional supplements and stay hydrated with liquids to combat fatigue. Issues with diarrhea can usually be handled with adding an anti-diarrheal regimen to their medications. The most serious adverse event is HFS. Typically this will occur within the first few weeks of treatment. We advocate the use of urea based creamsapplied to the hands and feet at the onset of treatment, as well as avoidance of hot water, excessive friction and constrictive footwear.

If the patient develops a grade 2 HFS, consisting of painful feet and/or hands interfering with daily activities, we will dose reduce sorafenib by 50% to 200mg twice a day for one week to let the symptoms resolve. If the symptoms resolve we will gradually increase the dose back to a target dose.

For grade 3 HFS, consisting of pain or erythema preventing performance of daily activities, we will interrupt therapy until improvement back to baseline and then restart sorafenib at a lower dose. We have found that with patient education, early recognition of adverse events and dose modifications, most patients can continue receiving sorafenib therapy.

What should you tell the patient and the family about prognosis?

There are two important and sometimes conflicting processes that impact survival: the stage of cancer upon presentation, and the level of underlying liver dysfunction. Both factors shape treatment decisions, and ultimately, outcome. For instance, in a Child-Pugh C cirrhotic patient with a small amount of tumor burden but yet outside of transplant criteria, the outcome is quite dismal no matter the therapy. Less than 35% of these patients will be alive at 2 years as the degree of liver dysfunction is the driving force for outcome and not the tumor burden.

Table III below can be used as a guide for prognosis based disease stage by the BCLC classification and treatment modality: