What is Alpha-Fetoprotein (AFP) and what are its sensitivity and specificity for cancer diagnosis?

Alpha-Fetoprotein (AFP): Characteristics, Sensitivity, and Specificity in Cancer Diagnosis

Alpha-fetoprotein (AFP) has suboptimal performance as a cancer biomarker with low sensitivity (40-60%) and variable specificity, making it inadequate as a standalone diagnostic test for hepatocellular carcinoma (HCC) or other cancers.

What is Alpha-Fetoprotein?

• AFP is an oncofetal glycoprotein that was one of the first protein tumor markers discovered and has been widely used in clinical practice 1
• It is normally produced during fetal development by the yolk sac and fetal liver, with levels declining rapidly after birth 2
• AFP is a heterogeneous molecule with different glycoforms that can be separated and characterized by their affinity for lectins such as Concanavalin A and Lens culinaris agglutinin 3
• It was first identified as a cancer biomarker by Russian scientist Yuri Semenovich Tatarinov in 1963 4

AFP in Cancer Diagnosis

Sensitivity and Specificity for HCC

• AFP has poor sensitivity ranging from 39% to 65% for HCC diagnosis 5
• Specificity ranges from 76% to 97%, depending on the cut-off values used 5
• At the commonly used cut-off of 20 ng/ml, AFP shows good sensitivity but low specificity 5
• At higher cut-offs of 200 ng/ml, sensitivity drops significantly to only 22%, though specificity improves 5
• AFP is only elevated in 40-60% of HCC cases, particularly showing poor sensitivity in early-stage disease 5

Limitations as a Diagnostic Tool

• AFP has been shown to be relatively insensitive as it is only elevated in 40-60% of HCC cases 5
• Many HCC patients exhibit normal AFP serum levels, particularly during early-stage disease 5
• AFP levels can be elevated in non-HCC patients, including those with non-cancerous chronic liver diseases, intrahepatic cholangiocarcinoma, and metastatic colon cancer 5
• Fluctuating levels of AFP in patients with cirrhosis might reflect flares of HBV or HCV infection, exacerbation of underlying liver disease, or HCC development 5
• Only a small proportion of tumors at an early stage (10-20%) present with abnormal AFP serum levels 5

Clinical Applications and Guidelines

Current Guideline Recommendations

• Current clinical practice guidelines do not recommend AFP (or any other biomarker) as a standalone test for the diagnosis of HCC 5
• European Association for the Study of the Liver (EASL) and American Association for the Study of Liver Disease (AASLD) no longer recommend AFP for HCC screening due to concerns about sensitivity and specificity 5
• When used in combination with ultrasound for surveillance, AFP levels only provide additional detection in 6-8% of cases not previously identified by ultrasound 5
• The National Comprehensive Cancer Network (NCCN) states that AFP may have utility for enhancing detection of HCC when used in combination with ultrasound in screening high-risk individuals 5

AFP Isoforms and Emerging Applications

• Different AFP isoforms have been identified with potential disease-specific associations 6
• HCC-associated isoforms (Band +II) represent glycoproteins characterized by being mono-sialylated, whereas those associated with benign liver disease and non-seminomatous germ cell tumors are di- and a-sialo species, respectively 6
• AFP-L3 (lens culinaris agglutinin-reactive fraction of AFP) has been proposed as a more specific marker for HCC 3
• Combination of AFP with novel biomarkers such as AFP-L3, Golgi specific membrane protein (GP73), and des-gamma-carboxyprothrombin has shown improved accuracy in detecting HCC 2

Practical Considerations in AFP Testing

• At values over 200 IU/ml, AFP is more reliable as a tumor marker, but the percentage of patients with such high levels is very small 5
• AFP testing can be useful in conjunction with other test results to guide management when HCC is suspected 5
• An elevated AFP level in conjunction with imaging results showing a growing liver mass has high positive predictive value for HCC 5
• AFP has been used beyond diagnosis to guide therapeutic choices in HCC and monitor treatment response 1
• The diagnostic accuracy of absolute AFP cutoff values has not been validated, and values may vary by institution and patient population 5

In conclusion, while AFP has historical significance as one of the first tumor markers discovered, its clinical utility is limited by suboptimal sensitivity and specificity. Current guidelines recommend using AFP only as an adjunct to imaging studies rather than as a primary diagnostic tool for cancer detection.