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Alpha Fetoprotein Tumor Marker

Alpha fetoprotein (AFP) is a 69,000 kD single chain polypeptide which is similar in size and structure to human serum albumin. In human embryos, AFP is first made in the yolk sac and later in the fetal liver. As the fetal liver matures, it gradually switches to albumin synthesis. In the fetus, AFP synthesis gradually declines to the normal adult range by 6 to 12 months after birth. During pregnancy, AFP levels in maternal serum rise steadily to a peak of approximately 500 ng/mL at about 32 weeks of gestation. Thereafter, they decline until term.

As a tumor marker, AFP is useful in detecting germ cell tumors of the ovary and testis, primary hepatocellular carcinoma in adults, and hepatoblastoma in children. AFP is not specific for these cancers. In addition to the elevations seen during pregnancy, serum values can be high in patients with a variety of liver diseases. Modest elevations of AFP occur in about 20% of patients with hepatitis, cirrhosis, biliary tract obstruction, or alcoholic liver disease. The highest values are seen in acute viral hepatitis, which may reach 500 ng/mL. AFP levels begin to rise, when transaminases are beginning to decline, suggesting that AFP synthesis is related to hepatocellular regeneration. Chronic elevations in patients with cirrhosis may also reflect ongoing necrosis and regeneration.

AFP levels are useful in screening for liver cancer in areas of high incidence, such as Southeast Asia, South Africa, China, and Alaska. The sensitivity of AFP for hepatoma is 60 to 80%. AFP levels greater than 300 ng/mL are found in asymptomatic individuals with small, surgically resectable tumors. The most common cause of false positive AFP elevations is pregnancy. General population screening in countries, such as the U.S., where the incidence of hepatoma is much lower, is not as effective. However, selective screening of high risk groups, such as patients with cirrhosis, chronic active hepatitis, and hemochromatosis is probably warranted.

AFP levels are useful in distinguishing hepatocellular carcinoma from benign hepatic disorders in symptomatic patients. The magnitude of AFP elevation is helpful in assessing the likelihood of cancer. Serum AFP concentrations above 500 ng/mL are essentially diagnostic of an AFP producing cancer. One half of the cases of hepatoma have AFP levels >1000 ng/mL at diagnosis. A tumor must be >3 cm in diameter to produce an AFP level of this magnitude. Serial measurements are useful since elevations secondary to nonmalignant diseases are usually temporary, while increases secondary to malignancies continue to increase. In benign liver disease, AFP levels are usually elevated only transiently, tend to rise only during the regenerative phase after peak elevation of liver enzymes, and rarely exceed 500 ng/mL.

Pretreatment AFP levels in hepatoma patients do not significantly correlate with response to therapy or survival time. Posttreatment AFP levels correlate well with response to therapy. Failure of AFP levels to return to normal after surgery indicates incomplete resection or the presence of metastases. The half-life of serum AFP is approximately 5 days. The failure of AFP levels to decline at this rate suggests residual cancer. AFP levels also correlate with response to chemotherapy. Serial measurements of AFP can be used to detect relapses before they become clinically apparent.

The seminiferous tubules contain two cell populations: supporting (Sertoli) cells and spermatogenic cells (spermatogonia). Clusters of Leydig cells, which secrete androgens, are embedded in the interstitial stroma. Ninety five percent of all primary testicular tumors arise from germinal cells and 5% arise from Sertoli and Leydig cells.Germinal neoplasms are divided into seminoma and nonseminomatous germ cell tumors. Seminoma is the most common germinal cancer, accounting for 40%; embryonal carcinoma, 20-25%; teratocarcinoma, 25-30%; teratoma 5-10%; and pure choriocarcinoma, 1%.Germ cell tumors are best diagnosed using a combination of AFP and beta hCG, since these tumors may be comprised of mixtures of seminoma, yolk sac, and embryonal carcinoma cells.AFP is produced by embryonal carcinoma, teratocarcinoma, yolk sac tumor, or compbined tumors. It is usually not produced by pure seminomas.hCG is produced by choriocarcinomas, 60% of embryonal carcinomas, and 5 to 10% of pure seminomas.Seminomas that secrete hCG usually produce serum levels less than 100 U/mL.

% Patients with Elevated hCG or AFP

 

The sensitivity of AFP for non-seminomatous germ cell testicular tumors is 50 to 60%, the sensitivity of hCG is 30 to 60%, and the sensitivity of both exceeds 60%. Therefore, the combined use of AFP and hCG is more effective than either marker alone. Serum levels may reach very high values; AFP may reach 80,000 ng/mL and hcG may reach one million U/mL. The pattern of tumor marker positivity may also aid in the differential diagnosis of germ cell tumors. Elevation of AFP in any tumor considered a pure seminoma by biopsy, should be reevaluated for germ cell elements, since this may influence therapeutic decisions. Elevation of hCG in a patient with seminoma may suggest previously undetected choriocarcinoma.

Pretreatment elevations of AFP and hCG correlate with clinical stage. Tumor markers are elevated in approximately 20% of patients with stage I testicular cancer, 60% of stage II cancers, and 90% of stage III cancers. Measurement of these markers after orchiectomy, but before definitive therapy, allows more accurate determination of the clinical stage and prognosis. Patients whose levels remain elevated are at high risk of recurrence, while those patients whose levels return to normal have little chance of recurrent disease.

The best documented clinical application for the two markers in testicular cancer is monitoring tumor activity during definitive therapy. Serial measurement of both markers can accurately assess response to therapy. Increasing concentrations of one or both markers are associated with tumor growth. Typically, germ cell tumors are of mixed cellularity and recurrent or metastatic disease may not produce the same markers seen with the primary tumor.

Since AFP's half life is 3.5 to 6 days and hCG's half life is about 16 hours, the markers should be measured once or twice a week during the time of expected greatest therapeutic response. If marker levels after orchiectomy, or other ablative therapy, fall at a slower than expected rate, residual tumor is likely. A rise in tumor marker levels within 5 days after initiation of chemotherapy is usually related to tumor lysis, and does not signify tumor recurrence. AFP and hCG can detect cancer up to 14 months earlier than other clinical modalities.

Approximately 30% of patients with disease confined to the testes develop metatastatic disease while under surveillance despite having negative tumor markers immediately after orchiectomy. About 40% of patients with documented retroperitoneal involvement have negative tumor markers.

Tumor markers are also useful in diagnosis and monitoring of ovarian germ cell tumors. Germ cell tumors comprise less than 5% of all ovarian cancers and usually occur between childhood and 30 years of age. Dysgerminoma, endodermal sinus tumor, and embryonal carcinoma are most often encountered. It is important to measure both AFP and hCG since some germ cell tumors produce only one marker. AFP is useful in following patients with endodermal sinus tumor, while HCG and AFP are useful in following patients with embryonal carcinoma.

Adult reference range is 0 - 8 ng/mL and includes 99% of healthy individuals. A difference of more than 20% between two measurements is considered to be medically significant.

Specimen requirement is one SST of blood.