Early and accurate diagnosis of hepatocellular carcinoma (HCC), the most common type of liver cancer, is crucial for effective treatment and improved patient outcomes. Several screening tests are utilized to detect HCC, particularly in high-risk individuals such as those with cirrhosis or chronic hepatitis. This article delves into the common screening methods, including serum markers and imaging techniques, evaluating their strengths and limitations in the diagnosis of HCC.
Alpha-fetoprotein (AFP) in HCC Diagnosis
Alpha-fetoprotein (AFP) has been a recognized marker for HCC for over four decades. AFP is a glycoprotein present at high levels in fetal development, with levels declining significantly after birth. Elevated serum AFP levels in adults can indicate underlying pathologies, including malignancies. While AFP elevations can be associated with cancers of the stomach, pancreas, and biliary tree, as well as pregnancy and nonseminomatous germ-cell tumors, it is notably used in the context of HCC diagnosis. It’s important to note that chronic hepatitis and cirrhosis can also cause AFP level increases, often fluctuating with inflammatory activity.
In HCC, AFP levels can vary widely, from normal to extremely high (>100,000 ng/ml). A significant portion of HCC patients, around 30%, may present with normal AFP levels at diagnosis, and these levels may remain low even in advanced stages. While AFP levels exceeding 400–500 ng/ml are highly suggestive of HCC, fewer than half of patients exhibit such elevated levels. At these high thresholds, AFP demonstrates high specificity, approaching 100%, but its sensitivity is compromised, falling below 45%. Lowering the cut-off point to 20 ng/ml increases sensitivity to approximately 79%, but reduces specificity to around 78%. The positive predictive value (PPV) of AFP remains low, ranging from 9% to 32%, indicating that a positive AFP test has a relatively low probability of truly indicating HCC. Despite some studies suggesting survival benefits with AFP surveillance in high-risk groups like chronic hepatitis B patients, its limited accuracy has led to it not being universally adopted as a standalone screening tool.
Advancements in AFP Isoform Analysis
Efforts to enhance the diagnostic accuracy of AFP have focused on analyzing AFP isoforms, which may offer greater specificity for HCC. Human AFP is a complex glycoprotein with variations in its sugar side chains, resulting in up to 11 different isoforms. Microheterogeneity in these isoforms can be identified using lectin electrophoresis. Lectins, proteins that bind to specific sugars, have been used to identify AFP isoforms specific to HCC, such as AFP-L3, concanavalin A, and erythroagglutinating phytohemagglutinin (E-PHA). AFP-L3, for example, has shown promise in detecting small HCC tumors (<2 cm), potentially appearing in serum up to nine months before imaging detection. Isoelectric focusing, another technique, separates AFP into four bands (I-IV), with bands III and IV showing specificity for HCC and aiding in differentiation from AFP elevations due to cirrhosis or pregnancy. Studies have indicated improved PPV for HCC detection using AFP band II compared to conventional AFP. However, the routine clinical application of these advanced isoform techniques is limited by their high cost and complex assay procedures.
Des-gamma-carboxy Prothrombin (DCP) or PIVKA II
Des-gamma-carboxy prothrombin (DCP), also known as protein induced by vitamin K absence-II (PIVKA II), is another tumor marker widely used, particularly in Japan, for HCC diagnosis. DCP is an abnormal form of prothrombin and has been reported to be highly specific for HCC. While prospective surveillance studies are lacking, some studies in Western populations have reported high specificity for DCP, around 95%. However, other studies have indicated limitations in sensitivity, especially for smaller tumors. Recent research suggests that DCP levels may have prognostic value in HCC patients.
Imaging Techniques for HCC Diagnosis
Imaging modalities play a crucial role in HCC diagnosis, often used in conjunction with or as an alternative to AFP.
Ultrasound (US)
Ultrasound is a commonly employed imaging technique for liver tumor detection. However, its effectiveness is influenced by operator skill and can be limited in patients who are obese or have cirrhosis. In cirrhotic individuals, ultrasound sensitivity and PPV can be as low as 35% and 15%, respectively. Typically, HCC lesions under 3 cm appear hypoechoic on ultrasound compared to surrounding liver tissue. Larger lesions often present as hyperechoic with an infiltrative or mosaic pattern, possibly with a thin hypoechoic fibrous capsule. The sonographic appearance can vary due to factors such as fat, calcium deposits, and necrosis within the tumor.
Computed Tomography (CT)
Computed Tomography (CT) scans are not primarily used for routine HCC surveillance but are more commonly employed for further diagnostic evaluation. A study in hepatitis C cirrhotic patients demonstrated that CT scans had higher sensitivity for HCC detection compared to ultrasound or AFP alone. Despite this higher sensitivity, the limited availability and higher cost of CT scans restrict their use as a widespread surveillance tool. However, a significant proportion of hepatologists in the United States do utilize CT scans for high-risk patients.
Magnetic Resonance Imaging (MRI)
Data on the use of Magnetic Resonance Imaging (MRI) as a surveillance tool for HCC is currently limited. Further research is needed to establish its role in routine HCC screening programs.
Conclusion
Diagnosing hepatocellular carcinoma effectively relies on a combination of screening tests and diagnostic approaches. While AFP and its isoforms, along with DCP, offer potential as serum biomarkers, their limitations in sensitivity and PPV necessitate a multi-faceted diagnostic strategy. Imaging techniques, particularly ultrasound and CT scans, are essential components of HCC diagnosis, each with its own strengths and weaknesses. Continued research and advancements in both biomarker analysis and imaging technologies are vital to improve the accuracy and early detection of hepatocellular carcinoma, ultimately leading to better patient outcomes.
