Hepatic Carcinoma, Primary
Synonyms and related keywords: hepatocellular carcinoma, HCC, hepatoma, liver cancer, primary liver cancer, liver carcinoma, primary liver carcinoma, cirrhosis, liver failure, liver dysfunction, hepatic dysfunction, liver tumor, hepatic tumor, liver disease, jaundice, hepatitis B, hepatitis C, hepatitis virus, alcoholism, alcoholic liver disease, hemochromatosis, aflatoxin, liver function test, liver function testing, LFTs, OLT, orthotopic liver transplantation, liver transplantation, liver transplant
INTRODUCTION
Frequency:
- In the US: Although HCC is uncommon, comprising only 2% of all malignancies, since the mid-1980s the incidence of HCC has been rising at an alarming rate. The age-adjusted incidence rates increased 2-fold between 1980 and 1998. Much of this increase is likely due to hepatitis C infection, a known risk factor for HCC. The current incidence is 4 cases per 100,000, with about 8,500-11,000 new cases diagnosed each year.
- Internationally: HCC is the fifth most common cancer in men and the eighth most common cancer in women worldwide. An estimated 560,000 new cases are diagnosed annually. The incidence of HCC worldwide varies according to the prevalence of hepatitis B and C infections. Areas such as Asia and sub-Saharan Africa with high rates of infectious hepatitis have incidences as high as 120 cases per 100,000.
Mortality/Morbidity:
- Cure, usually through surgery, is possible in less than 5% of all patients.
- Median survival from time of diagnosis is generally 6 months. Length of survival depends largely on the extent of cirrhosis in the liver; cirrhotic patients have shorter survival times and more limited therapeutic options; portal vein occlusion, which occurs commonly, portends an even shorter survival.
- Complications from HCC are those of hepatic failure; death occurs from cachexia, variceal bleeding, or (rarely) tumor rupture and bleeding into the peritoneum.
Race: HCC is most commonly found among Asians, due to childhood infections with hepatitis B. However, due to the implementation of childhood hepatitis B vaccination programs in many Asian countries, a decrease in the incidence of HCC among Asians is expected.
Sex:
- HCC occurs more commonly in men than in women.
- In the United States, 74% of HCC occurs in men.
- In high-risk areas (China, sub-Saharan Africa, Japan), the difference between genders is more pronounced, with male-to-female ratios as high as 8:1.
Age:
- Age at diagnosis varies widely according to geographic distribution.
- In the United States and Europe, the median age at diagnosis is 65 years. HCC is rarely diagnosed before age 40 years. However, between 1975 and 1998, the 45- to 49-year age group had the highest rate, a 3-fold increase in the incidence of HCC.
- In Africa and Asia, age at diagnosis is substantially younger, occurring in the fourth and fifth decades of life, respectively. Diagnosis at a younger age is thought to reflect the natural history of hepatitis B and C related HCC.
CLINICAL
History: Patients generally present with symptoms of advancing cirrhosis.
DIFFERENTIALS
Cholangiocarcinoma
Cirrhosis
Hepatocellular Adenoma
Other Problems to be Considered:
Dysplastic nodules in cirrhosis
Fibrous nodular hyperplasia
Metastatic disease
Primary hepatic lymphoma
WORKUP
- Obtain liver imaging using ultrasonography, CT scanning, or MRI. When performed for suspected HCC due to a rising AFP, each test has a 70-85% chance of finding a solitary lesion; sensitivity is higher with multiple tumors.
- Ultrasonography is the least expensive choice for screening, but it is highly operator-dependent. A suspicious lesion on a sonogram generally requires additional imaging studies to confirm the diagnosis and the stage of the tumor. Sensitivity of ultrasonography for detection of small nodules is low. An advantage is that Doppler imaging can be performed at the same time to determine the patency of the portal vein.
- Use the triphasic technique when performing CT scanning (ie, without contrast, then with early [arterial] and late [portal] imaging). The addition of arterial phase imaging to conventional CT scanning increases the number of tumor nodules detected. Unfortunately, in nodular cirrhotic livers, the sensitivity of CT scanning for detecting HCC is low. CT scanning has the added benefit of detecting extrahepatic disease, especially lymphadenopathy.
- MRI may detect smaller lesions and can also be used to determine flow in the portal vein. The overall sensitivity of MRI is thought to be similar to that of triphasic CT scanning. However, in patients with nodular cirrhotic livers, MRI has been shown to have better sensitivity and specificity. High cost and restricted access to MRIs makes its widespread use limited.
- Angiography shows characteristic tumor blush in HCC lesions. Less invasive imaging with CT scan and MRI has decreased the necessity for this mode of imaging. Angiography is still used for chemoembolization, one of the treatment options for HCC.
- Chest radiography may demonstrate pulmonary metastases.
- Bone scanning and head CT scanning are of low yield in the absence of specific symptoms.
- PET scan has been evaluated in the experimental setting, but, to date, its role is uncertain. Routine use of PET scan for diagnosis or staging of HCC is not recommended.
Procedures:
- Biopsy is frequently necessary in order to make the diagnosis. In general, core biopsy is favored over fine needle biopsy since larger amounts of tissue, often with normal surrounding parenchyma, can be obtained.
- Controversy exists regarding the potential risk of tumor seeding along the needle tract. Some studies report a small increase in risk (approximately 1/1000), while others show no difference. Regardless, potential risks and complications should be considered before performing a biopsy.
- Biopsy may be omitted in a clinical setting of a growing mass in a cirrhotic liver (>2 cm) noted on 2 coincident imaging techniques with at least one imaging showing contrast enhancement. Likewise, a growing mass in a cirrhotic liver on one imaging modality with an associated AFP level greater than 500-1000 ng/mL is clinically diagnostic of HCC. The need for biopsy should be carefully evaluated, especially if the risk for complications is high.
- Biopsy is generally obtained percutaneously under ultrasonographic or CT guidance. Prior to obtaining biopsy, large-volume paracentesis may be useful in patients with massive ascites; similarly, platelet transfusion may be necessary in patients with cirrhosis with severe thrombocytopenia (less than 50,000). Bleeding risk does not correlate with elevations in prothrombin time.
- Lesions that are 2-3 cm or smaller may be dysplastic nodules in a cirrhotic background. These are probably premalignant, and obtaining a biopsy is especially important to distinguish them from HCC. False-negative rates as high as 30-40% have been reported for biopsied tumors smaller than 2 cm in size.
- Using laparoscopic guidance may make obtaining a percutaneous biopsy easier. Laparoscopy allows visualization of the liver to evaluate the extent of cirrhosis if surgery is being contemplated.
- Obtaining a biopsy may be unnecessary in patients who will undergo resection regardless of diagnosis.
Staging: The tumor, node, and metastases (TNM) staging system, while widely accepted, is really only useful in patients who undergo surgical resection. This is a small minority of patients.
Since most patients are unresectable, and prognosis actually depends more upon the state of the liver rather than the size of the tumor, several staging systems have been evaluated that incorporate clinical features of the liver and the patient, such as ascites, portal vein involvement, and performance status. One such system is the CLIP (Cancer of the Liver Italian Program) scoring system, which assigns a cumulative prognostic score ranging from 0-6 based upon Child-Pugh stage, tumor morphology, alpha-fetoprotein level, and portal vein thrombosis, which can predict median survival time. Below is a summary of the TNM staging criteria and the CLIP scoring system.
- TNM staging criteria for HCC
- T1 - Solitary tumor without vascular invasion
- T2 - Solitary tumor with vascular invasion or multiple tumors none more than 5 cm
- T3 - Multiple tumors more than 5 cm or tumor involving a major branch of the portal or hepatic vein(s)
- T4 - Tumor(s) with direct invasion of adjacent organs other than the gallbladder or with perforation of visceral peritoneum
- N0 - Indicates no nodal involvement
- N1 - Indicates regional nodal involvement
- M0 - Indicates no distant metastasis
- M1 - Indicates metastasis presence beyond the liver
- Stage grouping
- Stage I = T1 + N0 + M0
- Stage II = T2 + N0 + M0
- Stage IIIA = T3 + N0 + M0
- Stage IIIB = T4 + N0 + M0
- Stage IIIC = TX + N1 + M0
- Stage IVB = TX + NX + M1
- CLIP scoring system: Score of 0-2 is assigned for each of the 4 features listed below; cumulative score ranging from 0-6 is the CLIP score.
- Child-Pugh stage
- Stage A = 0
- Stage B = 1
- Stage C = 2
- Tumor morphology
- Uninodular and extension less than 50% = 0
- Multinodular and extension less than 50% = 1
- Massive and extension greater than 50% = 2
- Alpha-fetoprotein
- Less than 400 = 0
- Greater than 400 = 1
- Portal vein thrombosis
- Absent = 0
- Present = 1
- Estimated survival based on CLIP score: Patients with a total CLIP score of 0 have an estimated survival of 31 months; those with score of 1, about 27 months; score of 2, 13 months; score of 3, 8 months; and scores 4-6, approximately 2 months.
TREATMENT
- A variety of combination chemotherapy regimens have also been studied. Recently, cisplatin-based combination regimens have shown improved response rates around 20%, but to date, no survival advantage as compared to supportive care alone has been shown. No difference seems to exist in response rates between 2 or 3-drug regimens. Moreover, some of these combination regimens cause considerable toxicity.
- Chemoimmunotherapy uses a combination of chemotherapy and immunomodulatory agents, such as interferon-alpha, to try to achieve better tumor response rates. Immunotherapy has had encouraging results in patients with certain types of cancers such as renal cell carcinoma and melanoma. PIAF is a combination of cisplatin, interferon-alpha, doxorubicin, and infusional 5-fluorouracil that is associated with a response rate of 26%, which is higher than the response rates with single chemotherapy agents. Although overall median survival is longer with PIAF than single-agent doxorubicin, treatment-related toxicity is significant. The best candidates for this therapy are young patients without liver cirrhosis and normal bilirubin levels.
- Chemoembolization is the delivery of high concentrations of chemotherapeutic agents directly to the HCC tumor via the hepatic artery, which provides the tumor with most of its blood supply. The remainder of the liver may be spared because it can rely on the portal vein for its blood supply.
- Embolizing agents such as cellulose, microspheres, lipoidal, and gelatin foam particles are used to deliver intra-arterial chemotherapy (mitomycin, doxorubicin, cisplatin) to the tumor via the hepatic artery.
- Morbidity from this procedure is greatly dependent on the extent of cirrhosis. In general, patients with portal vein thrombosis, encephalopathy, or biliary obstruction are not candidates for chemoembolization.
- Response rates of 60-80% are seen. In addition, 2 recent clinical trials from Spain and Hong Kong showed a modest survival benefit with the use of doxorubicin (Adriamycin) or cisplatin with embolization as compared to supportive care only in patients with unresectable tumors.
- In the United States, resection is possible in only 5% of patients. In general, solitary HCC lesions confined to the liver without vascular invasion with well-preserved hepatic function have the best outcomes. Although there are no strict criteria in terms of tumor size, many surgeons use less than 5 cm as their cutoff.
- Five-year survival rates for resectable lesions vary widely from 40% to as high as 90% for very early stage HCC lesions. Fibrolamellar HCC may have a better prognosis for survival after surgical resection because of a more favorable size, predominantly left lobe location, and the absence of cirrhosis in the unaffected portion of the liver.
- Appropriate evaluation of patients prior to resection is crucial since intraoperative mortality is doubled in cirrhotic versus noncirrhotic patients. Preoperative laparoscopic inspection aids in diagnosing both the tumor and extent of cirrhosis.
- Orthotopic liver transplantation can be considered for patients who meet the Milan criteria—one tumor less than 5 cm or up to 3 tumors all less than 3 cm. These highly selected patients have excellent survival rates, similar to those of patients who undergo liver transplantation for end-stage liver disease without HCC.
- Although availability of donor organs is still limited, the Organ Procurement and Transplantation Network (OPTN) and the United Network for Organ Sharing (UNOS) have recognized the urgency of proceeding to transplantation in patients with limited stage HCC. Over the past 5 years, revision of the UNOS policy has established medical criteria by which a patient with early/small HCC can be assigned additional priority for liver allocation so as to increase the likelihood of a favorable transplant outcome. This has resulted in shorter wait times to transplantation and better overall outcomes. Bridging therapy with local therapies, such as chemoembolization or radiofrequency ablation (RFA), is sometimes considered for patients on the transplant waiting list.
- Radiofrequency ablation (RFA) is the delivery of radiofrequency thermal energy to the HCC lesion causing necrosis of the tumor. During RFA, a high frequency alternating current is delivered from the tip of an electrode into the surrounding tissue. The ions within the tissue attempt to follow the direction of the alternating current resulting in friction and eventual heating of the tissue. As tissue temperature elevates above 60°C, tumor cells begin to die resulting in an area of tumor necrosis. The needle electrode is advanced into the HCC lesion usually via a percutaneous route with the guidance of ultrasonography. The procedure can also be performed surgically via laparoscopy or laparotomy.
- RFA is usually used for treatment of tumors less than 4 cm in size. For small tumors, studies show good initial local tumor control with an average local recurrence rate of 5-6% within the first 20 months. The treatment of larger tumors results in much higher rates of local recurrence. Unfortunately, a significant proportion of patients eventually develop clinically detectable hepatic or extrahepatic disease from their preexisting micrometastatic lesions. RFA is usually well-tolerated, but complications including fever, pain, bleeding, pleural effusion, hematoma, and intermittent transaminitis among others have been reported.
FOLLOW-UP
- For excellent patient education resources, visit eMedicine's Hepatitis Center and Liver, Gallbladder, and Pancreas Center. Also, see eMedicine's patient education articles, Cirrhosis, Hepatitis B, Hepatitis C, and Liver Transplant.
MISCELLANEOUS
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