Liver cancer (Hepatocellular Carcinoma)

Author: Dr Tim Davern California Pacific Medical Center 2008-10-05

Hepatocellular Carcinoma Hepatocellular carcinoma (HCC) is an increasingly recognized complication of cirrhosis. This article briefly reviews the epidemiology of HCC, its diagnosis, prognosis and treatment.

Epidemiology of HCC

Hepatocellular carcinoma (HCC), also called hepatoma, is the most frequent type of primary liver cancer and one of the leading causes of cancer death worldwide, responsible for over 600,000 deaths per year.  The vast majority of people who develop HCC have underlying liver disease, most often from chronic viral hepatitis. Males are generally affected more frequently than are females.  The incidence of HCC in much of Asia is high due to endemic infection with hepatitis B, while in the US the incidence appears to be rising primarily as a result of HCC developing in patients with cirrhosis from chronic hepatitis C (HCV) infection and, to a lesser extent, from alcoholic and non-alcoholic fatty liver disease (NAFLD).  However, in the US, HCC is still a relatively rare tumor; most Americans with malignant liver tumors have metastatic disease that has spread from a distant site (e.g., colon or breast cancer).  The prognosis for HCC is related to the size of the tumor and the severity of the underlying liver disease.  Patients diagnosed with HCC should be referred to specialized centers with multidisciplinary teams including hepatologists, surgeons, radiologists, pathologists, and oncologists dedicated to the evaluation and treatment of liver cancer.

 Screening and Diagnosis of HCC

In patients diagnosed with HCC only after symptoms develop, the prognosis is dismal; by the time symptoms, such as right upper abdominal pain, jaundice, and weight loss develop, the cancer is usually quite large and it is usually too late to offer curative therapy.  By contrast, patients diagnosed with small tumors often enjoy 5-year disease-free survival exceeding 50% when treated with resection or liver transplantation.  This, in part, provides rationale for screening for HCC – that is, performing diagnostic tests in patients who are asymptomatic but at relatively high risk for developing the cancer.  The goal of screening is to detect liver tumors while they are still relatively small and thus treatable.  Typically, screening for HCC consists of performing an abdominal imaging test, usually an ultrasound, every six months.  This interval is based on the average growth rate (doubling time) of liver cancers.  Often a serum alfa-fetoprotein is obtained at this interval as well, although the utility of this test for HCC screening has been questioned recently.  There has been considerable debate about the effect of screening for HCC and specifically whether or not it decreases mortality.  Nonetheless, most studies suggest that screening appropriate patients for HCC is cost effective when compared with other screening procedures, such as mammography for detection of breast cancer in women.

Because HCC is relatively rare, screening everyone in the general population is not appropriate.  Instead, screening programs are ideally focused on high-risk groups.  For example, most studies suggest that Asian patients with chronic hepatitis B are about 100 times more likely to develop HCC than the uninfected patients (i.e., they have a relative risk of HCC of about 100), and that screening for HCC in such patients is useful.   Additional high-risk groups that have been identified for screening include:

• Patients with cirrhosis from any cause (e.g., alcoholism, viral hepatitis B and C, genetic hemochromatosis, primary biliary cirrhosis, non-alcoholic steatohepatitis, alpha1-antitrypsin deficiency)
• Patients with chronic hepatitis B, particularly if Asian or African
• Patients infected with viral hepatitis (B or C) and human immunodeficiency virus (HIV)
• Patients with certain underlying genetic conditions, including tyrosinemia and some forms of porphyria

Two issues relevant to patients with HCV infection bear special mention.  First, HCC in chronic HCV infection occurs almost exclusively in the setting of histological cirrhosis, or at least advanced fibrosis.  Thus, patients with chronic HCV infection but minimal or no fibrosis (as determined by liver biopsy) are at very low risk for HCC and do not require screening.  On the other hand, patients with hepatitis C and cirrhosis who have undergone successful antiviral therapy with interferon and have achieved viral clearance on therapy remain at risk for developing HCC and should continue to undergo surveillance for this reason.

Several issues specific to patients with chronic hepatitis B should also be highlighted.  Chronic hepatitis B carriers, defined by the presence of hepatitis B surface antigen in the blood, have a dramatically increased risk of developing HCC even in the absence of cirrhosis, particularly when infection is acquired early in life as it often is in parts of Asia and Sub-Saharan Africa.  Indeed, current recommendations suggest that hepatitis B carriers from Africa should undergo regular surveillance for HCC beginning at age 20 years, while Asian patients should begin surveillance at age 40 years in men and 50 years in women.  However, HBV carriers born in the US, who typically acquire infection later in life, probably do not require HCC surveillance in the absence of cirrhosis.

Other factors can also affect the risk of developing HCC.  As suggested above, male gender appears to clearly increase the risk of developing HCC, particularly in Asians.  Also relevant to Asian hepatitis B carriers, a family history of HCC in first-degree relatives is also a very strong risk factor for development of HCC.   Active (as opposed to quiescent) hepatitis B infection increases the risk of HCC.  Finally, co-infection with human immunodeficiency virus (HIV) and either hepatitis B or C tends to follow a more aggressive course than hepatitis infection alone and the risk of developing HCC appears to be increased.    

The tests that are used to diagnose HCC include AFP serology, abdominal imaging, and biopsy.

• Alfa-fetoprotein (AFP):  The AFP blood test is now considered a poor screening test for HCC because of relatively low sensitivity and specificity.  That is, many patients that develop HCC will have normal or only minimally elevated or even normal AFP values, and conversely many patients with elevated AFP levels will ultimately be found to have no evidence of cancer.  However, while its role in screening has diminished, AFP measurements are often still useful in the diagnosis of HCC.  For example, an AFP greater than 400ng/ml in a patient with cirrhosis and a new liver mass on imaging almost certainly has HCC and should be treated as such without the need for further diagnostic testing such as liver biopsy.  Furthermore, a persistently elevated AFP in the setting of cirrhosis appears to be a risk factor for developing HCC, and massive elevation of the serum AFP (i.e., greater than 1,000 ng/ml) seems to be associated with a worse prognosis.  Several other serum markers, including des-gamma-carboxy prothrombin (DGCP) and the ratio of glycosylated AFP (L3 fraction) to total AFP, may have better performance characteristics than AFP but none have enjoyed widespread use to date.
• Abdominal Imaging:  As mentioned above, the imaging test used most often for HCC surveillance is abdominal ultrasonography.  The major problems with ultrasound as a screening tool are that it has limited sensitivity, particularly in nodular (cirrhotic) livers and in obese patients in whom ultrasound beam penetration is problematic; successful imaging is dependent on the skill and experience of the radiologist who performs the study.  Liver nodules detected on ultrasound that are < 1 cm should be followed with a repeat study about 3-6 months later.  If there has been no interval growth of the nodule over a period of 2 years (i.e., several scans), then the nodule is likely not HCC, which would be anticipated to grow over time.  Nodules larger than 1 cm on ultrasound in a patient with cirrhosis should be investigated further with a dynamic imaging study, generally either computed tomography (CT) scan or magnetic resonance imaging (MRI) with contrast.  On a multiphase contrast-enhanced CT, HCC typically shows contrast uptake, synonymous with hypervascularity, in the early (arterial) phases of the scan, and “washout” or de-enhancement in the delayed (portal venous) phases (FIGURE).  A nodule > 2 cm in a patient with cirrhosis that shows these typical features of HCC on CT, probably does not require biopsy for the diagnosis of HCC.  An elevated AFP and growth of the lesion on serial imaging studies, while not necessary for the diagnosis, are also certainly supportive of HCC.  CT is significantly more sensitive and specific than ultrasound for diagnosing HCC, and generally appears to be less operator-dependent.  However, CT does require administration of intravenous contrast and involves some radiation exposure, so it is generally not used as a primary screening test for HCC, except perhaps in patients with extremely nodular livers or in the very obese in whom ultrasound screening is problematic.
• Biopsy:  A biopsy of a suspicious liver mass in a patient with cirrhosis is only required when the results of imaging tests and serum AFP are not diagnostic.  For example, in a patient with cirrhosis from chronic hepatitis C, with a new 2.5 cm mass detected on screening ultrasound that is hypervascular with washout on contrast CT, and is associated with an elevated serum AFP, biopsy of the lesion is not required.  Liver biopsy should be used in situations where a diagnosis of HCC is in doubt, such as when nodules occur in non-cirrhotic livers or have atypical appearances on contrast CT.  This is because biopsy in this situation, which is usually performed under either ultrasound or CT-guidance, has some significant limitations and risks.  The main limitation of biopsy is low sensitivity resulting in a high false negative rate; that is, a biopsy will often yield tissue that is non-cancerous even if liver cancer is present because the nodule is missed by the biopsy needle.  So with a negative result, you are not sure if the nodule is really non-cancerous or if the biopsy is falsely negative.  In a sense, the biopsy is really only helpful if positive (i.e., reveals cancer) and, if this is true, why do the test, particularly if there is some risk involved?  The main risks of biopsy are bleeding and tracking of tumor cells along the path of the biopsy needle as it is withdrawn from the tumor through the skin.  The latter problem, although rare, is catastrophic because the tumor will recur along the needle track following what otherwise could have been a curative surgical resection or liver transplantation.  A final problem with biopsy is that distinguishing mildly abnormal, precancerous liver cells (dysplasia) from liver cancer can be challenging, even for expert pathologists.  The bottom line is that biopsy of liver nodules suspected of being HCC should be carefully considered, not a reflex action, and should be done only after carefully weighing the risks and benefits, as well as anticipating how the possible results of biopsy will influence treatment options. 

Prognosis of HCC

As mentioned above, patients who present with symptoms from HCC, including abdominal pain, jaundice, and unexplained weight loss, generally have advanced HCC and a very poor prognosis.  In addition, a poorly marginated, infiltrative pattern on CT, and a very elevated serum AFP level are also associated with more aggressive tumor biology and a worse prognosis.  However, similar to other solid tumors, prognosis with HCC is largely dependent on the stage of the cancer, which in turn reflects the size and number of tumors, and the presence or absence of vascular invasion and metastasis.  However, the situation is more complex with HCC because prognosis is also dependent on the severity of the underlying liver disease.  Patient with decompensated liver disease and small tumors may, however, have a good prognosis with liver transplant. 

Treatment of HCC

With few exceptions, treatment of HCC has not been guided by large, randomized, placebo-controlled studies.  Treatment options are guided by medical center experience and expertise. In general, HCC patients should be evaluated and treated at academic liver transplant centers with a multidisciplinary team of hepatologists, surgeons, diagnostic and interventional radiologists, pathologists, and oncologists.

Surgical Resection and Liver Transplantation

Although no large study to date has directly compared resection with liver transplantation, most experts at this time believe that the treatment of choice for HCC in non-cirrhotic patients is resection.  Patients with cirrhosis, particularly if advanced, on the contrary, usually do not survive major liver resections because the cirrhotic liver remaining after resection does not regenerate well.  The advantage of resection over transplant is that it does not depend on donor livers, which are in short supply, and does not involve postoperative, life-long immunosuppression, which is almost universally required following liver transplantation. Nonetheless, with liver resection, even if the entire primary tumor is removed, the remaining non-tumorous liver remains a “fertile field” for new liver tumors to form in the future.  As a result, the recurrence rate of HCC following resection is quite high, well over 50% at 5 years postoperative in most studies.

On the other hand, by removing the entire liver, liver transplantation should be curative as long as the entire tumor burden is removed and no tumor cells have left the liver prior to the transplant procedure.

At many transplant centers, liver surgeons will attempt to surgically resect all HCC patients who are resectable (i.e., either without cirrhosis or with very early cirrhosis), acknowledging that the recurrence rate will be relatively high but with a plan of offering liver transplantation as “salvage” therapy to appropriate candidates who recur.  Unfortunately, this plan is somewhat risky in that many tumors that recur after surgical resection will do so in a multi-focal, biologically aggressive fashion, with relatively rapid growth, early vascular invasion and metastasis.  Patients with such recurrences are seldom liver transplant candidates for the reasons outlined above.

A seminal study in the early 1990s by Mazzafero and colleagues from Milan, Italy demonstrated that patients with a solitary HCC tumor < 5cm or with up to 3 nodules, all smaller than 3 cm, enjoyed excellent results with liver transplant with a 5-year survival of  > 70%.  (Of note, one inch is 2.54 cm, so a 5 cm tumor is just under 2 inches in size.  To put this in perspective, a typical children’s marble is about half an inch or 1.25 cm across.)  Patients exceeding these Milan criteria (1 lesion < 5 cm or 2 to 3 lesions each < 3 cm) did less well, with a higher cancer recurrence rate, and patients with evidence of vascular invasion (i.e., malignant portal vein invasion) did very poorly. 

Currently, liver transplant candidates with HCC that do not exceed the Milan criteria are given extra priority on the transplant list, so that they may be transplanted before their liver cancer progresses and they “dropout” from the list as a result.  Priority on the liver transplant waiting list in the US is determined by the MELD (“Model for End-stage Liver Disease”) score, a numerical scoring system ranging from 6 (lowest) to 40 (highest).  The MELD score is derived from a calculation using the patient’s laboratory blood tests, including the INR (the “international ratio,” a standardized form of the prothrombin time, a measure of liver function), the albumin (another measure of liver function), and the creatinine (a measure of kidney function).  As the score rises, the chances that the patient will die from liver disease increases, and the patient’s priority on the liver transplant list thus rises, with the goal of transplanting the patient before he dies.  However, patients with HCC may have relatively well-compensated cirrhosis, with normal laboratory values and a low MELD score; their MELD score may only rise when the tumor has progressed and replaced much of the liver, and at that point the size of the HCC would likely be far in excess of Milan criteria.  To prevent this situation, patients listed for liver transplant with HCC within Milan criteria are given a MELD dispensation and are artificially elevated on the liver transplant list.  The degree of dispensation for HCC has evolved over the last 5 years because with the original scheme it was realized that too high a priority was given to HCC patients and that this was unfair to patients on the transplant without cancer.  At the current time, patients meeting United Network for Organ Sharing (UNOS) criteria (1 lesion 2-5 cm or 2 to 3 lesions £ 3 cm) are eligible for priority listing and are given 22 MELD points with a 10% point increase given for every 3 months on the waiting list.  In some regions of the country, such as Northern California, a MELD score of approximately 30 is required to have sufficient priority for liver transplant, so HCC patients in these regions may wait a year or more for liver transplant.  Such patients may want to consider non-conventional routes to liver transplant using either living (as opposed to conventional cadaveric/”brain dead”) donors or so-called extended criteria (colloquially termed “marginal”) cadaveric donors in order to shorten their waiting time and decrease the chances of “dropout” from the waiting list (see Liver Transplant Knol).

Rationale for liver transplant size criteria – The Mickey Mantle Story

The Yankees Baseball great, Mickey Mantle, received a liver transplant at Baylor University Medical Center in Dallas, on June 8, 1995, after his liver had been ravaged by years of chronic alcoholism and hepatitis C.  In addition to other complications of cirrhosis, Mantle had developed hepatocellular carcinoma.  Although details regarding the stage of his HCC based on pre-transplant imaging tests are sketchy, he had a high pretransplant AFP (~2,400), and the final pathology report on the diseased liver removed from Mr. Mantle showed the cancer was about 6.5 cm in diameter, with a second smaller tumor close by.  Both had an aggressive histology called poorly differentiated hepatocellular carcinoma.  There was also microscopic evidence that the cancer had begun to invade blood vessels.  Although Mantle initially did well, he developed evidence of pulmonary metastasis within a month and intraabdominal spread of tumor soon thereafter despite treatment with chemotherapy, including Adriamycin and cisplatin.  Tragically, Mickey Mantle died on August 13, 1995, only 9 weeks after his liver transplant.  Although liver transplantation may have represented Mickey Mantle’s only chance of long-term survival, if the extent of his HCC, which was relatively advanced, was fully appreciated prior to liver transplantation, the procedure should not have been performed, as it was probably not in his best interest.  This is because with advanced HCC, the likelihood of tumor spread outside the liver is quite high, although this spread may be microscopic and not appreciated on even state-of-the art imaging.  After liver transplant, these microscopic deposits (metastasis) remain behind, usually in the patient’s lungs or bone, when the diseased liver is removed, and they often grow much faster in the environment of immunosuppression that must be administered following transplant, to prevent rejection of the new liver.  Thus, we believe that in certain patients with advanced HCC, liver transplantation may actually shorten life by changing the natural history of the tumor remaining after transplant and making a bad situation worse.  Furthermore, because of the nationwide shortage of donor organs, liver transplantation must be limited to patients with good anticipated outcomes.

Data have recently emerged from several transplant programs suggesting that good post-transplant survival can be achieved after modest expansion of tumor size limits for liver transplant.  Using the various loco-regional therapies described below to “down-stage” larger tumors to meet current UNOS criteria for transplant is another strategy that is being actively studied at some transplant centers. 

Loco-regional Therapy

Because the waiting for liver transplant is considerable for most patients with HCC, most liver transplant programs now routinely perform some form of loco-regional ablative therapy in an effort to reduce the tumor burden and slow tumor progression, thereby preventing “dropout” from the tumor list.  There are several different options for such ablative therapy that may be employed for this purpose, including:

• Transarterial chemoembolization (TACE) (see Figure below): During the TACE procedure, which is performed by a specialist in interventional radiology (IR), a catheter is threaded into an artery feeding the liver under x-ray guidance, usually starting in the groin, similar to a cardiac (heart) catheterization.  The liver tumor is identified by injecting radiocontrast dye that typically results in a “tumor blush” due to abnormal vessels within the tumor.  Once the HCC is localized in this fashion, the artery feeding the mass is injected with a cocktail of chemotherapy agents, usually mixed with an oil (such as Lipiodol) to promote tumor retention of the chemotherapy.  In addition, the artery feeding the HCC, which represents its major blood supply, is also clotted, most often using gelfoam.  Thus, the tumor is both poisoned and its blood supply is strangled during TACE. Patients are usually monitored overnight in the hospital after the procedure. Common complications of the procedure include right upper quadrant pain, nausea, mild vomiting, and fever, the latter presumably reflecting necrosis of the tumor.  These symptoms usually resolve in a few days after the procedure.  More seriously, TACE can also compromise liver function and lead to liver failure, particularly in patients with advanced, decompensated cirrhosis.  However, in carefully selected patients, and when performed by an experienced IR team, TACE is generally effective and safe.

 

• Radiofrequency ablation (RFA):  During this procedure, which may be done through the skin by an IR physician or via a laparoscope by a surgeon, a special multi-tip electrode is inserted into the tumor under ultrasound guidance and the tips are heated to induce a wide region of tumor necrosis.  Potential complications include bleeding, thermal injury of adjacent structures (e.g., bile ducts, gall bladder, diaphragm), liver decompensation, and peritoneal seeding of tumor cells, especially in tumors close to the capsule of the liver.  Tumors larger than 5-6 cm are difficult to completely ablate with RFA. In addition, large vessels in close proximity to the tumor make RFA difficult, as they can act as a heat sink, diverting heat from the target tumor and lessening the effectiveness of the treatment.  Nonetheless, RFA often results in excellent tumor ablation and may be used as definitive therapy is some patients in lieu of resection or liver transplantation.
• Percutaneous ethanol injection (PEI): Injection of ethanol (alcohol) into tissue, including tumor tissue, causes extensive necrosis.  Like RFA, PEI is usually performed by an IR physician using ultrasound to guide the needle into the tumor.  PEI is highly effective for small (< 2-3 cm) tumors, is generally well tolerated, and is relatively inexpensive.  However, PEI does not result in adequate necrosis of tumors larger than 3 cm, limiting its utility to patients with small tumors.  PEI may also rarely result in tumor seeding along the needle track, similar to diagnostic biopsy.   
• Other ablative therapies:  Tumor necrosis can be accomplished by injection of chemicals other than ethanol (e.g., acetic acid), by heating (e.g., microwave), or cooling (i.e., cryotherapy).  Although generalized irradiation of the liver is poorly tolerated, selective radiation through intrarterial injection of radiopharmaceuticals (e.g., lipiodol-I-131, Ytrium-90 labelled microspheres) has some anti-tumor activity and is generally well tolerated.

With all of the above ablative procedures, efficacy is assessed by obtaining a multi-phase contrast CT approximately 1 month after treatment.  The absence of contrast uptake by the treated tumor on such a study is considered to reflect tumor necrosis and successful treatment, while the persistence of contrast uptake indicates viable tumor and treatment failure. The recurrence rate after ablation is as high as for resection.  Despite apparently successful therapy, the tumor recurrence rate after most types of local ablative therapy is significant and further sessions of treatment may be required.

Systemic Therapy

Although local ablative therapy (e.g., TACE) is sometimes offered to HCC patients with metastatic disease in an effort to forestall progression of the primary tumor remaining in the liver, systemic therapy is needed in this situation to treat tumor outside the liver.  A variety of conventional chemotherapeutic agents, including doxorubicin, cisplatin, fluorouracil, interferon, epirubicin, and Taxol, as single agents or in combination, have been used in clinical trials for HCC but none has demonstrated a consistent survival benefit and all are associated with significant toxicity.

Sorafenib (Nexavar, Onyx Pharmaceuticals):  Sorafenib was recently approved by the US Food and Drug Administration (FDA) for the treatment of patients with unresectable hepatocellular carcinoma following a pivotal phase-III study showing significant improvement in survival in treated patients.  Sorafenib is a multikinase inhibitor that blocks a number of signaling pathways (Raf kinase, vascular endothelial growth factor receptor 1 (VEGFR-1), VEGFR-2, VEGFR-3, platelet-derived growth factor receptor, beta (PDGFR-B), kinase tyrosine (KIT), FLT-3, and RET kinases) that are potentially important in cancer cell growth and metastasis.  The phase-III placebo-controlled Sorafenib HCC Assessment Randomized Protocol (SHARP) trial demonstrated that sorafenib improved overall survival by 44% in patients with hepatocellular carcinoma, compared with placebo.  Patients entered in the trial had advanced liver cancer, but generally well-compensated liver disease.  The drug, which is typically prescribed as 400 mg by mouth twice a day, was reasonably well tolerated in study patients.  The most common adverse effects with sorafenib are diarrhea, fatigue, weight loss, anorexia, nausea, and a characteristic hand-foot skin syndrome that occasionally can be severe and require dose adjustment or even discontinuation of the medication.  In addition, hypertension may occur early in the course of therapy, and it is recommended that treated patients have their blood pressure monitored weekly during the first 6 months of therapy.

Interestingly, patients treated with sorafenib in general do not appear to have significant shrinkage of their tumors but, when it is effective, the drug does appear to stabilize and prevent HCC growth.  There are currently no data supporting the use of sorafenib in combination with local ablative therapy as a "bridge" therapy to liver transplant.  However, given the impressive beneficial results in the SHARP trial and the fact that the drug is generally well tolerated in patients with liver disease, the author believes that such multi-modality therapy may become standard of care in the future to prevent "dropout" from patients from the liver transplant waiting list secondary to progression of HCC.


References:

AASLD practice guideline for HCC:
https://www.aasld.org/eweb/DynamicPage.aspx?Site=AASLD3&WebKey=413f06c6-89fe-405d-b669-139fd394d24c

El Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med 1999; 340(10):745-750.

Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M, Porta C, Zeuzem S, Bolondi L, Greten TF, Galle PR, Seitz JF, Borbath I, Häussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D, Bruix J; SHARP Investigators Study Group.   Sorafenib in advanced hepatocellular carcinoma.  N Engl J Med. 2008 Jul 24;359(4):378-90.

 www.Nexavar.com
Company-sponsored website with useful information about Nexavar (sorafenib) for advanced HCC.

http://www2.niddk.nih.gov/AboutNIDDK/ResearchAndPlanning/Liver_Disease/Action_Plan_For_Liver_Disease_Intro.htm
See chapter 14 on Liver Cancer.