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Hepatocellular carcinoma overview

Published: July 05, 2009. Updated: July 29, 2009

 

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Hepatocellular carcinoma is a primary malignancy of the liver.

Incidence

Hepatocellular carcinoma is a primary malignancy of the liver. The annual is around 5 cases per 100,000 per year. Estimated new cases and deaths from liver and intrahepatic bile duct cancer in the United States in 2005:

  • New cases: 17,550.
  • Deaths: 15,420.

A study analyzing SEER (Surveillance, Epidemiology, and End Results) data has shown that the incidence of hepatocellular carcinoma is rising in both white and black populations in the United States, with a current incidence of about 3.4 cases per 100,000 in whites and 5.6 per 100,000 in blacks.

Gender

Hepatocellular carcinoma is the most common tumor in males worldwide, with a male-to-female ratio of 5:1 in Asia and 2:1 in the United States.

Age

The incidence of hepatocellular cancer increases with age. The mean age at diagnosis is 53 years in Asia and 67 years in the United States.

Race and ethnicity

The incidence of hepatocellular tumors is higher in Asian immigrants and blacks than in whites.

Geography

Tumor incidence varies significantly, depending on geographical location. In the Far East and sub- Saharan Africa, this neoplasm occurs at an incidence of 150 per 100,000 population and comprises almost 50% of all diagnosed tumors, whereas in the United States, hepatocellular carcinoma represents < 2% of all tumors.

Causes and risk factors

Hepatitis B virus

High titres of HBsAg and HBcAb are frequently found in patients with hepatocellular carcinoma. The close geographic relationship between hepatitis B incidence and hepatocellular carcinoma rates is well recognized. In endemic areas of HCC is increased 140 fold in HBsAg carriers. Anti-HBcAb was found in the serum of up to 90% of cases in the Far East.

Cirrhosis

Hepatocellular carcinoma is associated with cirrhosis in 50% to 80% of patients, alcoholism being the most common cause of hepatic cirrhosis. While 5% of cirrhotic patients eventually develop hepatocellular cancer, which is often multifocal.

Aflatoxin

Aflatoxin has also been implicated as a factor in the etiology of primary liver cancer in parts of the world where this mycotoxin occurs in high levels in ingested food.

Other factors

  • Oral contraceptive use for 8 or more years is associated with increased risk of HCC.
  • Cigarette smoking, alcohol intake, diabetes and insulin intake appear to be significant risk factors.
  • Mutations of p53 tumor suppressor gene have been reported in 50% of the cases.
  • Workers who were exposed to vinyl chloride before controls on vinyl chloride dust were instituted developed sarcomas in the liver, most commonly angiosarcomas.

Symptoms and signs

Symptoms

Patients usually present with abdominal pain and other vague symptoms, including malaise, fevers, chills, anorexia, weight loss, and jaundice. Some differences are observed in presenting signs and symptoms between high- and low-incidence areas.

  • Abdominal pain (40%). The most common symptom is abdominal pain, particularly in high-risk areas. It is usually present in South African blacks, whereas only a minority (40% to 50%) of Chinese and Japanese patients present with abdominal pain.
  • No symptom (24%).
  • Weight loss (20%). Unexplained weight loss in a patient known to have cirrhosis should suggest a diagnosis of HCC. Anorexia and abdominal fullness occur in approximately 60% of Chinese patients but only in 30% of European and African patients. All of these symptoms apply to large (more than 2 cm) HCCs.
  • Appetite loss (11%).
  • Weakness and malaise (15%). Weakness and malaise occur in approximately 70% of Asians, although only 30% of African blacks and Europeans present with this symptom. Similarly, weight loss occurs in most Asians and Europeans but in fewer than 5% of Japanese. This may be due to the fact that Japanese hepatoma is typically diagnosed at an earlier stage, due to a rigorous surveillance program.
  • Jaundice (5%). Jaundice is infrequent and, when present, is usually due to underlying liver disease. However, only 10% of patients presenting with jaundice have jaundice attributable to the HCC. This may be due to obstruction of the main intrahepatic ducts, obstruction of the common hepatic duct at the porta hepatis, infiltration into the biliary radicals, or, extremely rarely, blood in the biliary tree.
  • Cirrhosis symptoms (ankle swelling, abdominal bloating, increased girth, pruritus, encephalopathy, gastrointestinal bleeding) (18%).
  • Diarrhea (1%).
  • Tumor rupture (1%). Occasionally, central necrosis or acute hemorrhage into the peritoneal cavity leads to death. It occurs in 10% to 20% of Asians and approximately 6% of blacks but is rare among Europeans. Hemoperitoneum from bleeding HCC is also a well-recognized complication of needle biopsy of highly vascular hepatomas.
  • Hematemesis may occur due to esophageal varices from the underlying chronic liver disease with portal hypertension.
  • Respiratory symptoms may occur on presentation but are rare. They are usually due to elevated hemidiaphragm consequent to hepatomegaly or pain from rib metastases. Pleural effusions may occur, but symptomatic lung metastases are rare.

It is common for HCC to be discovered on routine physical examination findings, elevated results on liver function tests (24%). Routine workup of anemia or other diseases (12%). Routine screening of known cirrhosis (17%). Routine screening of known hepatitis (13%).

Physical findings

Common physical signs include hepatomegaly, hepatic bruit, ascites, splenomegaly, jaundice, wasting, and fever.

  • Abdominal mass and hepatomegaly is the most frequent physical sign, occurring in 50% of patients. The size of the liver may be massive, particularly in endemic areas. An abdominal mass or swelling may be noticed by patients and is often associated with pain. Abdominal swelling may occur as a consequence of ascites due to the underlying chronic liver disease or may be due to a rapidly expanding tumor.
  • Ascites occurs in 30% to 60% of patients. It is usually due to the underlying liver disease, although occasionally may be caused by hemoperitoneum.
  • Splenomegaly occurs commonly, mainly due to the associated portal hypertension from the underlying liver disease. Acute splenomegaly may be due to portal vein occlusion by the tumor.
  • Abdominal bruits arising from the HCC, presumably from the associated vascularity, have a variable incidence, ranging from 6% to 25%.
  • Weight loss and muscle wasting are common, particularly with rapidly growing or large tumors.
  • Fever is found in 10% to 50% of patients with HCC. The cause is not clear, although tumor necrosis has been invoked as an explanation. The signs of chronic liver disease may often be present, including jaundice, dilated abdominal veins, palmar erythema, gynecomastia, testicular atrophy, and peripheral edema.
  • Budd-Chiari syndrome has been reported in several series due to HCC invasion of the hepatic veins. This causes tense ascites and a large, tender liver.

Less common findings include abdominal tenderness and spider nevi.

Paraneoplastic Syndromes

A variety of paraneoplastic syndromes have been described. Most of these are biochemical abnormalities without associated clinical consequences.

The most important ones include

  • Hypoglycemia (also caused by end-stage liver failure). Hypoglycemia occurs in two settings. Relatively mild hypoglycemia occurs in rapidly growing HCC among the Chinese as part of a terminal illness. In the other setting, the HCC is more slowly growing, but the hypoglycemia may be profound. Its pathogenesis is unclear.
  • Erythrocytosis (5%).
  • Hypercalcemia
  • Hypercholesterolemia (20%): This has been shown to be due to an absence of normal feedback control in hepatoma cells and is due to a deletion in -hydroxy-methylglutaryl-coenzyme A reductase.
  • Dysfibrinogenemia
  • Carcinoid syndrome
  • Increased thyroxin-binding globulin levels
  • Sexual changes (gynecomastia, testicular atrophy, and precocious puberty)
  • Porphyria cutanea tarda.

Metastasis

Metastases appear to obtain access to the systemic circulation, usually by hematogenous spread through either the portal vein or the hepatic artery. The lymphatics of the liver course between lobules and drain primarily through vessels surrounding the portal veins directly into the liver hilum and cisterna chyli. The remaining 20% of the liver is drained by vessels ascending along the vena cava.

Tabulation of all extrahepatic metastatic sites showed the most common to be in the:

  • Lung in (55%)
  • Abdominal lymph nodes in (41%)
  • Bone in (28%)

Virchow-Trosier nodes occur in the supraclavicular region but are rarely observed. Cutaneous metastases have also been reported as red-blue nodules.

Diagnosis

Imaging

Ultrasound

The initial diagnostic test in the symptomatic patient may be ultrasonography, as it is noninvasive and can detect lesions as small as 1 cm. Ultrasound findings should be followed up with more specific imaging. Ultrasound guided biopsies may be used to establish the diagnosis.

CT and MRI

Triple-phase, high-resolution CT and contrast-enhanced MRI are the primary imaging modalities used to diagnose and stage hepatocellular carcinoma. CT scan predicts resectability in only 40%-50% of cases and does not accurately determine the functional extent of cirrhosis. Major difficulties arise when the liver parenchyma is not homogeneous and the lesions are smaller than 1 cm.

Grossly, metastatic tumors are often peripheral and multiple and cause umbilication of the surface of the liver, whereas primary liver tumors are more often central and can be solitary, but are usually hypervascular on the arterial phase of a helical CT scan.

Invasion of the portal vein and to a lesser extent the hepatic vein is typically seen on dynamic CT as an obstruction of portal flow with venous expansion, which thus distinguishes malignant from benign thrombosis. Malignant thrombi are often hypervascular on the arterial phase of the CT, whereas bland thrombi are not hypervascular.

Biopsy

Some authors believe that percutaneous liver biopsy carries a high risk and has little diagnostic value. Nevertheless, a biopsy is imperative to establish the diagnosis either by percutaneous technique or by surgery.

Laparoscopy

Laparoscopy is useful for the evaluation of small tumors, the extent of cirrhosis, peritoneal seeding, and the volume of noninvolved liver and therefore may be used prior to open laparotomy for resection. Laparoscopic or intraoperative ultrasonography should be used to confirm preoperative imaging tests. The laparoscopic results may change surgical management in up to one third of selected patients.

Labs

α-Fetoprotein is produced by 70% of hepatocellular carcinomas. The normal range for this serum marker is 0-20 ng/mL, and a level > 200 ng/mL is essentially diagnostic for hepatocellular cancer in the absence of chronic, active hepatitis B infection. In the presence of active hepatitis B infection, the diagnostic cutoff is considered to be at least 1,000 ng/mL. In the setting of hepatitis C infection, the cutoff for diagnosis of hepatocellular carcinoma has not been well studied. False-positive results may be due to acute or chronic hepatitis, germ-cell tumors, or pregnancy.

Pathology

Malignant tumors of the liver can be classified by the tissue of origin (mesenchymal tumors or the more common epithelial neoplasms).

Malignant epithelial neoplasms constitute 85% to 95% of all tumors of the liver (whether benign or malignant). Six percent to 12% are benign and again are largely of epithelial origin.

Malignant epithelial tumors of the liver are primarily adenocarcinomas, with 2 major cell types: hepatocellular and cholangiocarcinoma. Mixed HCC and cholangiocarcinoma can also be found (2% of cases).

  • Hepatocellular carcinoma (liver cell carcinoma).
  • Hepatocellular carcinoma (fibrolamellar variant).
  • Cholangiocarcinoma (intrahepatic bile duct carcinoma).
  • Mixed hepatocellular cholangiocarcinoma.
  • Undifferentiated.
Primary Malignant Epithelial Tumors (90%)
1. Hepatocellular carcinoma variants: childhood, fibrolamellar, combined, spindle cell, clear cell, giant cell, carcinosarcoma, sclerosing hepatoblastoma
2. Cholangiocarcinoma and cholangiocellular carcinoma
3. Hepatic cystadenocarcinoma, squamous cell carcinoma
Primary Malignant Mesenchymal Tumors (3%)
Angiosarcoma, hemangioendothelioma, leiomyosarcoma, malignant schwannoma, fibrosarcoma, malignant fibrous, histiocytoma, lymphoma, osteosarcoma, rhabdomyosarcoma, mesenchymal sarcoma

Immunohistochemistry

Specialized immunohistochemical staining can be used to distinguish primary tumors of the liver from metastatic deposits. Specifically, positive staining for AFP, polyclonal but not monoclonal carcinoembryonic antigen, and loss of reticulin staining are very useful.

Staging and prognostic factors

Staging techniques -
Local extent

Ultrasound

The initial diagnostic test in the symptomatic patient may be ultrasonography, as it is noninvasive and can detect lesions as small as 1 cm. Ultrasound findings should be followed up with more specific imaging. Ultrasound guided biopsies may be used to establish the diagnosis.

CT and MRI

Triple-phase, high-resolution CT and contrast-enhanced MRI are the primary imaging modalities used to diagnose and stage hepatocellular carcinoma. CT scan predicts resectability in only 40%-50% of cases and does not accurately determine the functional extent of cirrhosis. Major difficulties arise when the liver parenchyma is not homogeneous and the lesions are smaller than 1 cm.

Lung metastasis (50%)

1. Chest x-ray

A chest radiograph in two planes is indicated on a regular basis to screen for metastatic disease in the follow-up of patients with primary tumors that preferentially spread to the lungs.

Benefits

  • Sensitivity and specificity for chest radiography were 50 and 90%, respectively for nodules >5mm.
  • It more accurately detects a 1-cm nodules 1cm or greater.

2. Chest CT

When metastatic nodules are identified, helical computed tomography (CT) of the chest should be performed to assess their number and characteristics.

Benefits

  • A high-resolution CT scan can identify nodules 3 mm in diameter.
  • CT has an overall sensitivity 62% in detecting pulmonary nodules (all sizes). However it underestimated the extent of the disease in 25%, and overestimated the extent of the disease in 14%.
  • Sensitivity is increased to 95% for intrapulmonary nodules more than or equal to 6 mm and 100% for intrapulmonary nodules > 10 mm.

The limitations of CT scan in this study were mainly associated with pleural-based nodules and intrapulmonary nodules < 6 mm.

Staging of hepatocellular carcinoma

  • See staging system for hepatocellular carcinoma

Prognostic factors

1. Alpha-fetoprotein

AFP levels have been shown to be prognostically important, with the median survival of AFP-negative patients significantly longer than that of AFP-positive patients.

2. Performance status

3. Liver functions

4. Cirrhosis

The presence or absence of cirrhosis and its severity in relation to the Child-Pugh classification.

Other distinctions made clinically and reflected in the staging system include:

  • The size of the tumor, with those smaller than 2 cm often representing tumors with the very best prognosis.
  • Tumors having a well-defined rim on computed tomography (CT) scan or on subsequent pathologic examination have a better prognosis.
  • Tumors arising in patients from the West may even be less aggressive than those arising in individuals from Asian countries.
  • A characteristic of HCC is invasion of the portal vein and to a lesser extent the hepatic vein. Such invasion is unquestionably the most important negative prognostic factor for resection and for liver transplantation, after positive margins and lymph nodes.
  • It is important to tap the ascites of any HCC patient and send it for cytologic examination, because positive ascitic cytology results have a major adverse impact on prognosis.

Treatment

Treatment options and prognosis are dependent on many factors but especially on tumor size and staging.

Localized resectable cases

1. Partial hepatectomy

Solitary tumor and no major vascular invasion are the main criteria for respectability in a non cirrhotic liver or patients with adequate liver reserve. Partial hepatectomy in early stage disease carries a significant likelihood chance for cure.

Contraindications

  • Patients Inadequate liver reserve and/or Modified Child-Pugh classification B or C
  • Main portal vein involvement
  • Extrahepatic metastatic disease
  • Comorbidities that would preclude surgery of any kind

Rationale

  • Partial hepatectomy has resulted in a 5-year survival exceeding 50%.

2. Transplantation

Owing to the risk of hepatic failure following resection in cirrhotic patients, transplantation has become a potentially curative option for patients with hepatocellular cancer who are cirrhotic and/or with inadequate liver reserve . Patients with cirrhosis and single tumors < 5 cm or multiple tumors (up to 3 with none > 3 cm) are thebest candidates for transplantation with 4 year survival of 85%.

Rationale

Patients with liver cirrhosis have significantly better survival if treated with liver transplant rather than partial hepatectomy. While in noncirrhotic patients survival rates were not different in comparable TNM stage for patients treated with surgery or transplant.

Localized unresectable cases

1. Local regional therapy (embolization and ablation)

Chemoembolization, cryosurgery, percutaneous ethanol injection, or radiofrequency ablation for cancers smaller than 5 cm are all valid options. Survivals equivalent to resection have been reported.

1.a. Hepatic artery embolization (TAE) and chemoembolization (TACE)

Patients with unresectable/inoperable not candidates for ablation therapy and with no portal vein thrombosis nor extrahepatic metastases and adequate hepatic functional reserve are candidates for embolization. Normal hepatocytes receive most of their blood supply from the portal vein, whereas tumors create new blood vessels from branches of the hepatic arterial system. This target is exploited by embolization of the hepatic artery with different materials. Embolization is accomplished by advancing a catheter within the tumor-feeding branch of the hepatic artery. Materials injected have included Gelfoam powder, polyvinyl alcohol, iodized oil (Lipiodol), collagen, and autologous blood clot. Chemoembolization should be reserved as a sole therapy for symptomatic tumors, to reduce tumor size for resection or ablation, or as a bridge while awaiting transplant.

Rationale:

  • Radiographic response are evident in about 50% of patients.
  • Six randomized trials have shown mixed results with two randomised trialsproved survival advantage as well as their metanalysis.

1.b. Ablation

Intratumoral ethanol injection

Intralesional injection of 95% ethanol results in cellular dehydration and coagulation necrosis. Percutaneous ethanol injection (PEI)is done under ultrasonographic guidance. PEI give better results in patients with few lesions (with less than 3-4 tumor nodules), each < 5 cm, although larger lesions may be injected using multiplecessions.

Cryotherapy and radiofrequency ablation

Cryotherapy and radiofrequency ablation (RFA) techniques are treatment options for localized disease. Cryotherapy is done intraoperatively to ablate small solitary tumors outside a planned resection (ie, in patients with bilobar disease). Cryotherapy must be performed using laparotomy, which limits its use in the palliative setting.

RFA can be performed either via laparotomy or percutaneously. Radiofrequency ablation gives best results with tumors less than or equal to3 cm, its efficacy being clearly superior to PEI in larger tumors. Tumors between 3-5 cm may be treated with combination of embolization and RFA. RFA is proved to be superior to PEI in different studies.

Rationale:

  • Data on ablative therapy suggest a possible 5 year survival of 50% especially in patients with Good response and successful necrosis post therapy.

Conformal or stereotactic radiotherapy

A palliative treatment option in patients with unresectable tumorsand are not candidates for local therapy or transplantation.

Rationale:

  • Objective response rates of 40%-50% have been reported.

Advanced disease

Systemic chemotherapy

Systemic chemotherapy has been associated with low response rates e.g. anthracyclines were reported to provide a 10% response rate like wise cisplatin and 5FU, non gave survivial advanatage compared to supportive care. Combination regimen like PIAF regimen (cisplatin, interferonalpha, doxorubicin and infusional 5FU) was associated with significant toxicity.

Hormone therapy

A 1 year survival benefit was reported for patients treated withmedroxyprogesterone acetate but in a small study that was not confirmed later. Similarly a significant improvement in median survival from 7 to 18 months when megestrol acetate was reported in one trial with no validation in other trials..

Targeted therapy

The molecular pathogenesis of HCC is very complex. Tyrosine kinase inhibitors (TKIs) can suppress tumor cell proliferation and vascularisation. Sorafenib is a multikinase inhibitor tested in phase III studies in HCC and resulted in significant improvement in median survival compared to best supportive care. Sorafenib is approved by the FDA based as first line therapy in patients with Child Pugh A and selected B liver function with the following criteria:

  • unresectable extensive disease not fit for liver transplant;
  • local disease but inoperable due to comorbidity or poor general condition
  • in metastatic disease.


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