At a Glance

When a patient discovers a usually painless testicular mass, either unintentionally or by self-examination, or when a testicular mass is discovered by routine physical examination, testicular cancer should be suspected.

Testicular cancer risk factors include:

Males with cryptorchidism have 3-17 times the average risk, and approximately 7-10% of patients with testicular tumors have a history of cryptorchidism.

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A history of testicular cancer is associated with a higher risk of a contralateral tumor.

Testicular cancer is the most common malignancy in men 15-35 years of age. It accounts for approximately 1% of all cancers in men. About 95% of testicular tumors are malignant and derived from germ cells, whereas the remaining 5% are nongerm cell or stromal tumors derived from Leydig and Sertoli cells of the gonadal stroma. Malignant tumors include five basic cell types: seminoma (60%), embryonal carcinoma, yolk sac tumor, choriocarcinoma, and teratoma.

Advances in treatment have transformed testicular cancer from the most common cause of cancer death among 15-35 year old men into one of the most curable cancers. Although screening would be very unlikely to decrease mortality substantially because therapy is so effective even for advanced stages of disease, earlier diagnosis, at the stage of localized disease, should decrease the amount and extent of treatment required and lower morbidity.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

The following three serum tests should be performed if testicular cancer is suspected: human chorionic gonadotropin (hCG), alpha-fetoprotein (AFP), and lactate dehydrogenase (LDH). These tests assist with diagnosis, staging and risk assessment, evaluation of response to therapy, and early detection of relapse.

AFP is normally secreted during gestation and declines to low levels at 1 year of age. Elevated levels in serum are found in the majority of patients with embryonal and teratocarcinomas of the testis and ovary, as well as in patients with extragonadal germ cell tumors. Pure seminomas do not secrete AFP. Therefore, the presence in serum indicates a tumor or metatases with nonseminomatous elements.

hCG is a two chain (alpha and beta) glycoprotein hormone normally secreted by the trophoblastic epithelium of the placenta. Although the beta subunit is normally present in maternal serum during pregnancy, high levels in males and nonpregnant females is indicative of cancer. hCG is secreted by virtually all choriocarcinomas, one-third of embryonal cell carcinomas, and teratomas, and, rarely, pure seminomas.

Despite its lack of specificity, LDH is a useful marker, especially for staging seminoma and nonseminomatous germ cell tumor (NSGCT).

In a patient with testicular cancer, the levels of AFP, hCG, and LDH all have prognostic implications and their monitoring is useful to evaluate the effectiveness of therapy. A rise in titer indicates disease progression, and it might precede the clinical evidence of the disease by weeks or months.(Table 1)

Table 1.
Human chorionic gonadotropin (hCG) Alpha-fetoprotein (AFP) Lactate dehydrogenase (LDH)
Positive in almost all choriocarcinomas, one-third of embryonal cell carcinomas, and teratomas. Positive in embryonal cell cancers. Useful for staging seminoma and nonseminomatous germ cell tumor (NSGCT).
Rarely positive in pure seminomas. Pure seminomas do not secrete AFP.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

Elevated serum AFP levels are not specific for testicular cancer, and increases can be seen in patients with hepatocellular carcinoma, gastrointestinal cancers, benign liver disease, particularly hepatitis, and chemotherapy induced liver damage. These conditions can also result in rising AFP levels, making it more difficult to interpret the results. However, moderately elevated values that remain stable do not usually indicate relapse.

Two types of hCG assays are available: total hCG to denote an assay providing the measurement of the intact alpha-beta heterodimer and hCG-beta to denote an assay providing measurement of the beta chain. Since seminomas may produce only hCG-beta and not intact heterodimer, it is essential to measure both total hCG and hCG-beta when monitoring testicular cancers. In addition, the beta subunit displays various degrees of homology. For example, the homology between hCG-beta and LH-beta is about 80%, and a specific hCG-beta assay should be performed to distinguish hCG-beta from cross reacting LH-beta.

Chemotherapy often causes gonadal suppression, which can be spontaneous, that increases hCG levels. Therefore, hCG levels increasing from 2 to 8 U/L during chemotherapy are often iatrogenic and do not indicate relapse.

Interferences in hCG and AFP assays, similar to all immunoassays, can be seen because of heterophilic antibodies (i.e., anti-human antibodies) and the so-called “hook effect.” These interferences can be avoided by carefully selecting the method used in clinical practice. However, if interference is suspected, results should be repeated on diluted specimens or with an alternative method.

LDH is expressed in many tissues, and elevated levels may be found in several diseases, so the results should be interpreted in the clinical context. In addition, hemolysis may cause falsely elevated LDH values and testing hemolyzed specimens should be avoided.

Additional Issues of Clinical Importance

During chemotherapy, a persistent elevation in markers of testicular cancer (e.g., AFP, hCG) indicates residual disease. The rate of marker decline also reflects the response to therapy. In the absence of residual disease after orchidectomy, the half-life of hCG is about 1.5 days, whereas that of AFP is about 5 days. However, chemotherapy might induce a transient increase in tumor markers during the first week of treatment, and the half-lives of both markers might be increased. In most cases, during chemotherapy, half-lives longer than 3.5 days for hCG and 7 days for AFP are suggestive of cancer recurrence.

Errors in Test Selection and Interpretation

If a testicular cancer is suspected, all three tumor markers (AFP, hCG, and LDH) should be requested. In fact, according to the histological type, one or more tumor markers should be increased in serum. In the case of suspected seminoma and in the absence of clear histological evidence or equivocal findings, an increase of serum AFP shifts the diagnosis and treatment toward NSGCT.

Errors can occur, as can for any other laboratory test, by wrong procedures and mistakes in all phases (pre-, intra- and post-analytical) of the testing process. The primary mistake a clinician can make is to conclude that testicular cancer is absent if tumor marker levels fall within the reference range. For example, analytical interferences, as with any immunoassay, can produce falsely low results. In addition, the presence of anti-heterophilic antibodies may significantly interfere with some immunoassays, providing misleading results. If interference is suspected, the measurement should be repeated by using diluted specimens and/or by an alternative method.