Testicular cancer, although an uncommon malignancy, is the most frequently occurring cancer in young men. In the year 2008, an estimated 8,090 cases of testicular cancer will be diagnosed in the United States. For unknown reasons, the incidence of this cancer has increased since the turn of the century, from 2 cases per 100,000 population in the 1930s, to 3.7 cases per 100,000 population from 1969 to 1971, to 5.4 cases per 100,000 population from 1995 to 1999. The greatest rise has been observed in Puerto Rico (1973 to 1997: 220%). This trend seems greatest for the development of seminoma.

Most testicular tumors are of germ-cell origin. These cancers are uniquely sensitive to chemotherapy and are considered the model for the treatment of solid tumors. Perhaps the most controversial area in the management of germ-cell tumors is the proper approach to early-stage disease (ie, surveillance vs primary lymphadenectomy [for nonseminoma germ-cell tumors] or radiation therapy [for seminomas]). In advanced disease, chemotherapy plays an essential role, but novel treatment regimens are currently being evaluated through multi-institution clinical trials.

Epidemiology

Age Testicular cancer can occur at any age but is most common between the ages of 15 and 35 years. There is a secondary peak in incidence after age 60. Seminoma is the most common histology in the older population but is rare in those younger than age 10. There is a slight increased prevalence of testicular cancer among fathers and brothers of testicular cancer patients.

Race Although testicular cancer is rare in African-Americans (1.6/100,000 population), these men present with higher grade disease and have significantly worse survival at 5 and 10 years. The incidence of this cancer has increased in whites during the 20th century but has remained flat in African Americans. Non-Hispanic white patients typically present with disease at early stages compared with African Americans, Native Americans, Hawaiians, and Hispanic patients.

Geography Denmark has the highest incidence of testicular cancer; the Far East has the lowest.

Primary site Germ-cell tumors present most commonly in the testes (90%) and only infrequently in extragonadal sites (10%). The most common extragonadal sites (in decreasing order of frequency) are the retroperitoneum, mediastinum, and pineal gland. Many patients presumed to have a primary retroperitoneal germ-cell tumor may have an occult germ-cell tumor of the testicle. This possibility should be evaluated with testicular ultrasonography, especially when the retroperitoneal tumor is predominantly one-sided.

Survival The 5-year survival rate for all patients with testicular cancer is ~95%. Cure rates are highest for early-stage disease, which is treated primarily with surgery or radiation therapy (early seminoma), and lower for advanced disease, for which chemotherapy is the primary therapy (Table 1).

Etiology and risk factors

The specific cause of germ-cell tumors is unknown, but various factors have been associated with an increased risk of this malignancy.

Prior testicular cancer Perhaps the strongest risk factor for germ-cell tumors is a history of testicular cancer. Approximately 1% to 2% of patients with testicular cancer will develop a second primary in the contralateral testis over time. This represents a 500-fold increase in incidence over that in the normal male population.

The risk of contralateral testicular cancer was studied in a large population-based cohort of men diagnosed with testicular cancer before the age of 55. For 29,515 cases reported from 1973 through 2001 to the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program, the 15-year cumulative risk of developing metachronous contralateral testicular cancer was 1.9%, reaffirming the practice of not performing a biopsy on the contralateral testis at initial presentation.

Cryptorchidism Patients with cryptorchidism have a four- to eight-fold increased risk of developing germ-cell tumors compared with their normal counterparts. Orchiopexy, even at an early age, appears to reduce the incidence of germ-cell tumor only slightly (if at all). For an undescended testis, the most common malignant histology is seminoma. For those undergoing early orchiopexy, the most common malignancy is non-seminoma. Of note, in ~10% of patients with cryptorchidism who develop germ-cell tumors, the cancer is found in the normally descended testis. Biopsies of nonenlarged cryptorchid testes demonstrate an increased incidence of intratubal germ-cell neoplasm, a presumed precursor lesion.

Genetics Klinefelter’s syndrome (47XXY) is associated with a higher incidence of germ-cell tumors, particularly primary mediastinal germ-cell tumors. For first-degree relatives of individuals affected with 47XXY, approximately a 6- to 10-fold increased risk for germ-cell tumors has been observed. In addition, patients with Down’s syndrome have been reported to be at increased risk for germ-cell tumors. Also thought to be at greater risk are patients with testicular feminization, true hermaphrodites, persistent müllerian syndrome, and cutaneous ichthyosis.

Family history Although familial testicular cancer has been observed, the incidence among first-degree relatives remains low. One investigator, however, reported a sixfold increased risk among male offspring of a patient with testicular cancer.

Environment Numerous industrial occupations and drug exposures have been implicated in the development of testicular cancer. Although exposure to diethylstilbestrol (DES) in utero is associated with cryptorchidism, a direct association between DES and germ-cell neoplasm is weak at best.

Reports have suggested an increased risk of testicular cancer among individuals exposed to exogenous toxins, such as Agent Orange and solvents used to clean jets. One author has suggested that based on epidemiologic evidence, ochratoxin A correlated with incidence data for testicular cancer.

Prior trauma, elevated scrotal temperature (secondary to the use of thermal underwear, jockey shorts, and electric blankets), and recurrent activities such as horseback riding and motorcycle riding, do not appear to be related to the development of testicular cancer.

No supporting findings substantiate a viral etiology.

Fertility An increased risk of infertility exists for men with unilateral testicular cancer successfully treated with orchiectomy. For example, 40% of patients have subnormal sperm counts, and by 1 year, 25% continue to have subnormal sperm counts.