Tumor Markers for Testicular Cancer

Testicular cancer is one of the few cancers associated with tumor markers.  It is not clear why testicular cancers release these markers.  Most testis cancers that secrete tumor markers are non-seminomatous germ cell tumors (NSGCT) and 85% of NSGCT will secrete at least one tumor marker.  These cancers often develop from the germ cells in the testis that have the potential to transform into a variety of cell types.  It is hypothesized that as these germ cells turn into cancer cells, they turn on genes and secrete proteins usually only released during fetal development.[1,2]

Despite the lack of understanding as to the cause of elevated tumor markers, these markers are well-established to help in the diagnosis, prognosis, treatment and monitoring of testis cancer.  However, many patients and their families are confused about where tumor markers come from, what an elevation in a level means, and how markers should change over time.  Here we review the basic regarding the three important tumor markers for testicular cancer:

• HCG (human chorionic gonadotropin)
• AFP (alpha fetoprotein)
• LDH (lactate dehydrogenase)

alpha-fetoprotein (AFP)

NORMAL RANGE <40 micrograms/L

HALF-LIFE 5-7 days

AFP is a protein secreted by the fetal yolk sac, liver and gastrointestinal tract and appears in high levels in the blood of the fetus.[3]  AFP can be secreted by NSGCT that contain embryonal carcinoma, yolk sac tumor or teratoma.  By definition, seminoma or choriocarcinoma do not secrete AFP.  Therefore any patient with an elevated AFP must have a non-seminomatous component of testis cancer.

AFP can be elevated in patients with a number of other malignancies including with hepatocellular (liver) carcinoma, cancer of the stomach, pancreas, biliary tract and lung.  In addition, AFP elevation is associated with a number of non-malignant diseases including diseases of the liver and the rare diseases ataxic telangiectasia and hereditary tyrosinemia.  

human chorionic gonadotropin (HCG)

NORMAL RANGE <5 IU/L

HALF-LIFE 24-36 hours

HCG is a glycoprotein produced by the placenta to maintain the corpus luteum during pregnancy.  HCG can be elevated in a number of other malignancies including cancers of the liver, lung, pancreas and stomach.[3]  In germ cell tumors of the testis, including both seminomas and NSGCT, cancerous cells can transform into syncytiotrophoblasts (a normal component of the placenta) and secrete HCG.  Levels greater than 5,000 IU are usually indicative of NSGCT and, in NSGCT, higher levels of HCG are associated with a worse prognosis.  However, HCG-producing seminoma (approximately 15% of seminomas) has the same prognosis as seminoma that does not produce HCG.[4]  

The HCG molecule is cross-reactive with another protein, leutenizing hormone (LH).  Hypogonadal men can have elevated LH levels and subsequently falsely elevated HCG levels - administration of exogenous testosterone can help distinguish HCG elevation from hypogonadism from HCG from testis cancer.  In addition, marijuana smoking has been associated with an elevated HCG level.

lactate dehydrogenase (LDH)

NORMAL RANGE 1.5-3.2 microkat/L

HALF-LIFE 24 hours

LDH is a cellular enzyme found in every tissue in the body.  Highest concentrations of LDH in normal tissue are found in muscle (including skeletal, cardiac and smooth muscle), liver and brain.  LDH is expressed on chromosome 12p, which is often amplified in testis cancer cells.  LDH is less specific for testis cancer than HCG or AFP.  However, elevated LDH levels are correlated to high tumor burden in seminoma and recurrence in NSGCT.[5,6]

Future blogs will address the prognostic information gained by tumor marker levels at the time of diagnosis, after orchiectomy or other treatments.

This blog was written by Phillip M. Pierorazio, MD, Director of the Division of Testis Cancer at the Brady Urological Institute at Johns Hopkins.

[1] Uriel, J. Retrodifferentiation and the fetal patterns of gene expression in cancer. Adv. Cancer Res. 29, 127–174 (1979).

[2] Abelev, G. I. Alpha-fetoprotein as a marker of embryo-specific differentiations in normal and tumor tissues. Transplant Rev. 20, 3–37 (1974).

[3] Richie, J. & Steele, G. in Campbell-Walsh Urology (eds Wein, A. J., Kavoussi, L. R., Novick, A. C., Partin, A. W. & Peters, C. A.) 893–935 (Saunders, 2006).

[4] Weissbach, L. et al. Prognostic factors in seminomas with special respect to HCG: results of a prospective multicenter study. Seminoma Study Group. Eur. Urol. 36, 601–608 (1999).

[5] Skinner, D. G. & Scardino, P. T. Relevance of biochemical tumor markers and lymphadenectomy in management of nonseminomatous testis tumors: current perspective. J. Urol. 123, 378–382 (1980).

[6] Stanton, G.  et al. Treatment of patients with advanced seminoma with cyclophosphamide, bleomycin, actinomycin D, vinblastine and cisplatin [abstract]. Proc. Am. Soc. Clin. Oncol. 2, 1 (1983).