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Hepatocellular carcinoma
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%).

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Physical findings

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

1. 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.
2. Ascites occurs in 30% to 60% of patients. It is usually due to the underlying liver disease, although occasionally may be caused by hemoperitoneum.
3. 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.
4. Abdominal bruits arising from the HCC, presumably from the associated vascularity, have a variable incidence, ranging from 6% to 25%.
5. Weight loss and muscle wasting are common, particularly with rapidly growing or large tumors.
6. 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.
7. 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.

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