Hepatocellular carcinoma

I. What every physician needs to know.

Hepatocellular carcinoma (HCC), also known as hepatoma, is the most common primary malignant neoplasm of the liver arising from hepatocytes and is second leading cause of cancer death worldwide. Most HCC cases arise in the setting of cirrhosis (80-90%), particularly secondary to chronic viral hepatitis. HCC is often diagnosed late in its course as it may not affect liver function or cause clinical findings until it has grown quite large or metastasized.

Most cases of HCC occur in areas endemic for hepatitis B and C and account for over 80% of all HCC worldwide. Due to an increasing prevalence of hepatitis C, HCC has become the most rapidly increasing cause of cancer deaths in the U.S. with a 3-fold increase in the last two decades. Non-alcoholic fatty liver disease and alcohol related liver disease are other common causes of HCC in US.

To help prevent HCC, everyone with immune compromise or at risk of developing HBV infection should be immunized. Likewise, appropriate antiviral treatment for patients with HBV or HCV can reduce the risk of developing HCC. For the hospitalist to maximize detection of HCC, it is important to include it in the differential diagnosis of any patient presenting with acute decompensated liver disease.

II. Diagnostic Confirmation: Are you sure your patient has hepatocellular carcinoma?

Diagnosing HCC often requires a combination of serum markers, imaging, and histologic confirmation, though the diagnosis can be made with imaging alone.

The diagnosis of HCC generally occurs with liver imaging, either during screening or as an incidental finding on ultrasound, computed tomography (CT) or magnetic resonance imaging (MRI). Serum alpha-feto protein (AFP) is often used in conjunction with imaging when evaluating a patient for HCC.

Confirmatory diagnosis may require a tissue sample for histological evaluation. The histologic appearance of HCC ranges from well differentiated (with individual hepatocytes appearing nearly identical to normal hepatocytes) to poorly differentiated tumors consisting of large multinucleate anaplastic giant tumor cells.

A. History Part I: Pattern Recognition:

Most patients who develop HCC have cirrhosis and often have no symptoms other than those attributed to their chronic liver disease. A clinician should have increased suspicion for HCC when someone develops hepatic decompensation (ascites, encephalopathy, jaundice, variceal bleeding).

Some patients report increasing upper abdominal pain, early satiety, weight loss, or a palpable abdominal mass. Other presentations include obstructive jaundice, diarrhea, bone pain or dyspnea, intraperitoneal bleeding due to tumor rupture, fever, or other paraneoplastic syndromes. Patients with HCC can develop hypoglycemia due to the tumor’s high metabolic needs as well as erythrocytosis due to tumor secretion of erythropoietin.

HCC can also occur in patients with cirrhosis due to Wilson’s disease, hemochromatosis, alpha-1-antitrypsin deficiency, autoimmune hepatitis, some porphyrias and in other patients with chronic liver inflammation with or without cirrhosis. Heavy, prolonged cigarette smoking, older age, male gender, and Asian ethnicity have also been identified as risk factors.

B. History Part 2: Prevalence:

The incidence of HCC in the past 20 years has increased tremendously. HCC accounts for approximately 782,000 new cases and 746,000 deaths worldwide each year based on 2012 estimates. HCC and intrahepatic bile duct cancers are relatively rare as compared to other cancers in the US as per National Cancer Institute. HCC and intrahepatic bile duct cancers ranked 13 on common cancers list of US and represents about 2.2% cases of all newly diagnosed cancers in US. It is projected that cases of HCC secondary to HCV infection will continue to increase in the United States over the next 2 to 3 decades. There were about 50,734 patients living with hepatocellular carcinoma and intrahepatic bile duct cancers in US based on 2012 estimates. In 2015, it is estimated that there will be 35,660 new cases of liver and intrahepatic bile duct cancer and an estimated 24,550 people will die of this disease.

Eighty-five percent of cases are in developing countries, the highest incidence rate reported in areas where hepatitis B virus (HBV) is endemic. HCC rarely occurs in patients younger than 40 years old. The peak incidence is approximately 70 years old. HCC related to chronic Hepatitis C virus (HCV) infection has become the fastest rising cause of cancer death in the United States. The 5-year cumulative risk of developing HCC in patients with cirrhosis ranges from 5-30%.

The major risk factors for development of HCC are infection with HCV or HBV, alcoholic liver disease, and non-alcoholic fatty liver disease. HBV infection accounts for approximately 50% of all cases of HCC and nearly all childhood cases.

The risk of HCC among patients with chronic HBV infection is increased if they are male or elderly, have been infected for a longer time, have a family history of HCC, have been exposed to the mycotoxin aflatoxin, are co-infected with HCV or hepatitis delta virus, have high levels of HBV hepatocellular replication or are infected with HBV genotype C. Among patients with HCV infection, risk factors for the development of HCC include coinfection with HIV or HBV, diabetes mellitus and obesity.

C. History Part 3: Competing diagnoses that can mimic hepatocellular carcinoma.

The differential diagnosis for a liver lesion includes hemangioma, metastatic disease from another primary neoplasm, focal nodular hyperplasia, hepatic adenoma, liver abscess, cholangiocarcinoma and HCC. These are distinguished by size, rate of growth, vascular appearance on imaging (particularly CT and MRI) and histologic appearance if a biopsy is indicated.

D. Physical Examination Findings.

Physical exam findings usually reflect the patient’s underlying liver disease. The clinician may note hepatomegaly, splenomegaly, ascites, jaundice, or other signs of decompensated liver disease. A liver bruit may be auscultated.

Cutaneous manifestations of HCC include dermatomyositis, pemphigus foliaceus, the sign of Leser-Trelat (sudden appearance of multiple seborrheic keratoses in association with skin tags and acanthosis nigracans), pityriasis rotunda, and porphyria cutanea tarda.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Routine liver function tests, coagulation parameters, complete blood count, and serum chemistries should be ordered for any patient with decompensated liver disease and suspicion of HCC. Common lab abnormalities include: thrombocytopenia, hypoalbuminemia, hyperbilirubinemia, and an elevated serum INR. Mild anemia is often noted as are electrolyte abnormalities. Conversely, erythrocytosis may be present in HCC due to tumor production of erythropoietin. Liver function tests are usually elevated in a non-specific pattern.

Serum Alpha-Fetoprotein (AFP):

Serum alpha-fetoprotein (AFP) is produced by the fetal liver and yolk cell as well as regenerating hepatocytes. It is the most commonly used marker for HCC, though AFP can be elevated in many other conditions such as pregnancy, various neoplasms including germ cell tumors, gastric tumors, viral hepatitis and following liver resection or toxic injury. Furthermore, AFP can be normal in small HCC tumors and as elevations have low specificity, the positive predictive value of an abnormal test is poor. AFP does not correlate well with size, stage or prognosis of HCC.

AFP is only 40-64% sensitive as many tumors do not produce AFP or do so only at advance stages. When elevated, AFP is 74-91% specific. Values >400 ng/dl are considered diagnostic of HCC in proper clinical scenario with supporting imaging. Given these values, experts state that serum AFP alone is of limited utility in detecting HCC.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Ultrasonography:

Most patients with underlying liver disease who present with acute decompensation of their disease should have a liver Doppler ultrasound to evaluate for hepatic masses and hepatic blood flow. Meta-analysis suggested that ultrasonography could be only 60% sensitive. Ultra-sonographic identification could be difficult in background of regenerative nodules in cirrhosis. Doppler analysis could be helpful as HCC will have more arterial blood supply and neovascularization as compared to regenerative nodules. In patients with cirrhosis and a liver mass less than 1 cm, repeat imaging every 3-6 months should be performed to monitor for any changes in the lesion as per AASLD guidelines.

If the lesion is stable after 18-24 months of surveillance, routine surveillance every 6-12 months with hepatic ultrasonography and measurement of serum AFP (as is recommended for all patients with hepatic cirrhosis secondary to viral hepatitis) should be resumed. If the lesion is enlarging, further evaluation and treatment is indicated according to the lesion’s size.

CT scan:

CT scan of abdomen is often performed to evaluate an abnormality detected on ultrasound or screening of HCC. New CT techniques like helical multi detector CT scan using contrast has increased accuracy as compared to traditional scanning. The sensitivity of helical CT scan in detecting HCC may be as high as 90%. Typical CT findings of HCC are hypervascular pattern with arterial enhancement and rapid washout during portal venous phase. Some tumors may not change much during both arterial and portal phase imaging and may be missed.

Magnetic Resonance Imaging (MRI):

MRI has similar sensitivity as helical CT scan in detecting HCC and thus has advantage of avoiding nephrotoxic contrast and ionization radiation. On MRI, HCC exhibit variety of features depending upon tumor architecture, grade, and fat and glycogen content of tumor cells. Typically, well differentiated tumors are hyper intense on T1 images and isointense on T2 images. Poorly differentiated tumors are hyper intense on T2 images and isointense on T1 images.

Other imaging modalities being studies in the setting of HCC include endoscopic ultrasound, CT hepatic arteriography, arterial portography and PET scanning.

AASLD has updated recommendation for detection of HCC in 2010. EASL guidelines from 2012 are similar; though differ with regard to interval obtaining follow up ultrasounds.

– Nodules on ultrasound surveillance <1 cm should be followed with ultrasound at every 3-6 months. If there has been no growth over a period of up to 2 years, revert back to routine screening.

– Lesions > 1 cm should be evaluated by either Multi detector CT scan using contrast or dynamic MRI. If appearance is typical of HCC no further investigation is needed. If appearance is not typical (and not suggestive of hemangioma) either get a second study (CT or MRI, whichever is not performed) or a biopsy. If second study is also not suggestive of HCC (and not suggestive of hemangioma), then lesion should be biopsied.

– If biopsy is negative for HCC, lesion should be followed by imaging every 3-6 months until it disappears, enlarges or displays characteristics of HCC. If lesion enlarges and remains atypical repeat biopsy is indicated.

III. Management.

Treatment options for a patient with HCC depend on tumor size, liver functional reserves, underlying comorbidities and treatment center resources.

Surgical Resection:

For patients with a solitary HCC lesion without vascular invasion and good liver function, surgical resection is preferred and is associated with a 5-year survival rate of 90%. Assessment of liver functional reserves is most important before resection as mortality is almost twice in patients with cirrhosis as compared to patients without cirrhosis. In patients with cirrhosis, surgical resection can be performed in patients with Child Pugh class A disease who have normal bilirubin, and well preserved liver functions. Resection in patients with Child Pugh B cirrhosis is controversial. The 5-year risk of HCC recurrence after resection is approximately 70%, mostly because the underlying liver disease continues to put patients at risk of re-developing HCC.

For patients with larger lesions, vascular invasion, or contraindications to surgery, treatment options include radiofrequency ablation (RFA), transarterial chemoembolization (TACE) and orthotopic liver transplantation (OLT). These are prioritized on a case by case basis with attention paid to the extent of disease, the patient’s hepatic function, and other comorbidities.

Orthotopic Liver Transplantation (OLT):

In patients with HCC and underlying cirrhosis, orthotopic liver transplantation is the treatment option with the lowest risk of tumor recurrence. Patients with HCC who meet criteria for orthotopic liver transplantation (a solitary nodule measuring less than 5cm in diameter or 3 nodules each measuring less than 3 cm that have not metastasized) have an expected 4-year survival rate of 85% and a recurrence-free survival rate of 92%.

Radiofrequency Ablation (RFA):

RFA is the most frequently used form of local ablation therapy. It is the best treatment for patients with early-stage HCC who are not eligible for either surgical resection or orthotopic liver transplantation. Overall survival rates are 100% and 98% at 1 and 2 years, respectively. Longer-term outcomes, however, reveal a 5-year recurrence rate of up to 70%. Randomized controlled trials comparing RFA to surgical resection show no significant differences in overall or recurrence-free survival. Compared to surgical resection, RFA is associated with lower rates of complications and hospitalizations. RFA is also used for “bridging therapy” for patients awaiting transplant, to reduce dropout rates due to disease progression.

Transarterial chemoembolization (TACE):

As most HCCs get their blood supply from hepatic artery, TACE permits direct application of chemotherapeutic agent into tumor through hepatic artery. Simultaneous or sequential occlusion of hepatic artery, feeding tumor by adding pro-coagulant along with chemotherapeutic agent may result in greater benefit than chemotherapeutic agent alone. TACE is usually used for large tumors that are not suitable for resection or RFA.

TACE improves survival in patients with preserved liver function, no extrahepatic metastases, no vascular invasion, and no prominent cancer related symptoms. A meta-analysis of randomized controlled trials showed that these procedures were associated with an improved 2-year survival rate compared to more conservative treatment.

TACE can also be used to downstage a patient’s condition in anticipation of orthotopic liver transplantation. ‘Post-embolization syndrome’, or fever and abdominal pain caused by tissue ischemia, is seen in up to 50% of patients following TACE.

Molecular Targeted Therapy, Sorafenib:

Recent randomized controlled trials have shown that sorafenib, an orally administered small-molecule multikinase inhibitor that has antiproliferative and antiangiogenic properties, is associated with a 37% increase in survival compared to placebo.

Tips to Guide Management:

Patients with HCC that are awaiting treatment are at higher risk of decompensated liver disease, biliary obstruction, and other paraneoplastic syndromes. All such patients should be monitored closely for bleeding (petechiae, ecchymoses, pallor), biliary obstruction (jaundice, increasing abdominal tenderness), and worsening encephalopathy (asterixis, apraxia).

In a patient who has undergone surgical resection of HCC or orthotopic liver transplantation, a clinician should monitor the incision site for signs of infection, perform regular abdominal exams with particular attention to increasing pain in the right upper quadrant which may be indicative of abscess formation, monitor for asterixis which may indicate developing hepatic encephalopathy.

After radiofrequency ablation, particular attention should be paid to worsening pain with palpation in the right upper quadrant.

After TACE procedure, increasing right upper quadrant pain and fevers are to be expected, but severe pain may indicate intraabdominal bleeding and should be emergently evaluated with CT imaging.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

Patients at high risk of developing HCC should have a screening hepatic ultrasound performed every 6 months. In a patient with a liver mass smaller than 1cm, serial ultrasound every 3-6 months should be performed to monitor for enlargement. If there has been no enlargement after 18-24 months of monitoring, routine ultrasound every 6 months can be resumed.

After local treatment for HCC, hepatic imaging every 3-6 months for 2 years, then annually is recommended to evaluate for tumor recurrence. Serum AFP, if initially elevated, should be checked every 3 months for 2 years, then every 6 months.

D. Long-term management.

Long-term management of patients with HCC includes deciding upon a treatment method (surgical resection, RFA, TACE, or orthotopic liver transplant). After treatment of HCC, repeat hepatic imaging at regular intervals should be performed. The exact timing of this repeat imaging varies by institution.

E. Common Pitfalls and Side-Effects of Management

It can be difficult to detect HCC since if often presents as only worsening liver disease. For this reason, any patient with acutely decompensated liver disease, increasing abdominal pain, or other new symptoms should have imaging of their liver to evaluate for masses, typically with Liver Doppler Ultrasound. Also, caution should be used when interpreting serum AFP values given the limited sensitivity and specificity as described above.

The risks of surgical resection treatment of HCC include bleeding, infection of the surgical site, or hepatic infection. Treatments such as TACE are less invasive, however still carry risks of intraabdominal bleeding and infection.