Testicular Cancer — Discoveries and Updates

Copyright © 2014 Massachusetts Medical Society. There have been substantial advances in the treatment of testicular cancer. Fifty years ago, a diagnosis of metastatic testicular cancer meant a 90% chance of death within 1 year. Today, a cure is expected in 95% of all patients who have received a diagnosis of testicular cancer and in 80% of patients with metastatic disease. This review highlights recent discoveries, updates in care, and existing controversies in the treatment of patients with testicular cancer. In the United States, the incidence of testicular cancer, which is highest among whites and lowest among blacks, has increased steadily over the past 20 years.1 In some parts of northern Europe, the incidence has doubled, and in Denmark and Norway, 1% of men will receive a diagnosis of testicular cancer during their lifetime.2,3 Genetic and environmental factors appear to play a role in this increase in incidence. The risk of testicular cancer is 8 to 10 times as high in a brother of a person with testicular cancer and 4 to 6 times as high in a son of a person with testicular cancer as in a brother or son of an unaffected family member.4 Genetic disorders, including Down’s syndrome and the testicular dysgenesis syndrome, are also associated with increased risks of testicular cancer.3 Cryptorchidism, which occurs in 2 to 5% of boys born at term, is the most wellcharacterized risk factor for testicular cancer.5,6 The timing of orchiopexy influences the future risk of testicular cancer. In a study involving 16,983 men with cryptorchidism, the relative risk of testicular cancer was 2.2 among those who underwent orchiopexy before 13 years of age, as compared with 5.4 among those who underwent orchiopexy at 13 years of age or older, suggesting that hormonal changes at puberty are a factor in the risk of testicular cancer among boys.5 However, 90% of persons with testicular cancer do not have a history of cryptorchidism. Recent investigations have shed light on the malignant transformation of normal gonocytes into germ-cell tumors (Fig. 1). Germ-cell tumors appear to develop as a result of a tumorigenic event in utero that leads to a precursor lesion classified as intratubular germ-cell neoplasia.7,8 Approximately 90% of germ-cell tumors are associated with adjacent intratubular germ-cell neoplasia, which carries a 50% risk of testicular cancer within 5 years. Intratubular germ-cell neoplasia is derived from gonocytes that maintain their ability to develop into germinal and somatic tissues; although these gonocytes may be regarded as pluripotent, they have failed to differentiate into spermatogonia.8 The invasive potential of intratubular germ-cell neoplasia is not attained until after hormonal changes occur during puberty. Seminomas consist of transformed germ cells that resemble the gonocyte but are blocked in their differentiation. Embryonal carcinoma cells resemble undifferentiated stem cells, and their patterns of gene expression are similar to those of stem cells and intratubular germ-cell neoplasms9,10; choriocarcinomas and yolk-sac tumors have extraembryonic differentiation, and teratomas have somatic differentiation. Studies have identified several genetic loci that confer a predisposition to testicular cancer.11-13 The variant with the highest effect size was detected at 12q21, Dan L. Longo, M.D., Editor