Testicular cancer, although an uncommon malignancy, is the most frequently occurring cancer in young men. In the year 2005, an estimated 8,010 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 1995-1999. 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 germcell 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 multiinstitution 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. Race Testicular cancer is rare in African-Americans, occurring at a rate of 1.4 per 100,000 population. The incidence of this cancer has increased in whites during the 20th century but has remained flat in African-Americans. 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 testis (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%-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. Cryptorchidism Patients with cryptorchidism have a 20- to 40-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). 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, individuals with persistent müllerian syndrome, and persons with 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 testicular cancer patient. Environment Numerous industrial occupations and drug exposures have been implicated in the development of testicular cancer. Although exposure to diethylstilbestrol(Drug information on 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. Signs and symptoms Local disease
Scrotal mass The most common complaint of patients on presentation is a painless scrotal mass, which, on physical examination, cannot be separated from the testis. This finding distinguishes the mass from epididymitis. Not infrequently, the mass may be painful and thus may mimic epididymitis or testicular torsion. Hydrocele Approximately 20% of patients with germ-cell tumors have an associated hydrocele. Inguinal adenopathy Patients generally do not have inguinal adenopathy in the absence of prior scrotal violation. Other symptoms include low back pain (from retroperitoneal adenopathy) and gynecomastia (usually bilateral). In cases of massive retroperitoneal lymphadenopathy, abdominal pain, nausea, vomiting, and constipation may be reported. Disseminated disease
Patients with disseminated germ-cell tumors usually present with symptoms from lymphatic or hematogenous dissemination. Mediastinal adenopathy may be associated with chest pain or cough. Supraclavicular lymphadenopathy may also be present. The cumulative 10-year risk of developing metachronous testicular cancer for patients with extragonadal germ-cell tumors is 10.3%. Patients with extragonadal tumors of the retroperitoneum and nonseminomatous cell type have a 14.3% 10-year risk for the development of metachronous testicular cancer. Hematogenous spread to the lungs may be associated with dyspnea, cough, or hemoptysis. Infrequently, patients with extensive disease may present with signs and symptoms of CNS metastases or bone pain from osseous metastases (most common in patients with seminoma). Metastases to the liver are not uncommon and may manifest as fullness in the upper abdomen or vague abdominal discomfort. More likely, they will be identified on CT scan in an otherwise asymptomatic patient. Primary mediastinal germ-cell tumors
Primary mediastinal germ-cell tumors are associated with several unique syndromes, including Klinefelter's syndrome and acute megakaryocytic leukemia. In addition, mediastinal tumors have a great propensity for the development of non-germ-cell malignant histology as a major component of the tumor (eg, embryonal rhabdomyosarcoma, adenocarcinoma, and peripheral neuroectodermal tumor). Screening and diagnosis Screening
Self-examination Testicular self-examination is both simple to learn and safe to perform. The rarity of this disease, however, calls into question the value of routine aggressive screening procedures. Testicular biopsy Testicular biopsy of a suspicious lesion is not recommended. Approximately 95% of patients with a mass within the testicle have a malignancy. Orchiectomy is the preferred treatment for patients with a testicular mass. Carcinoma in situ (CIS) appears to be the precursor lesion for most testicular germ-cell tumors, except spermatocytic seminoma. Most patients harboring CIS can be expected to develop testicular cancer but with a latency period of a decade or more. The incidence of CIS in infertile men is about 0.6%. In patients with prior testicular cancer, biopsy will reveal CIS in the contralateral testis at a rate of ~5%-6%. Men with a history of cryptorchidism and presumed extragonadal germ-cell tumor are at greater risk for CIS. Some investigators suggest routine biopsy of the contralateral testis in men with CIS. Diagnosis
Ultrasonography can reliably identify masses within the testis. In virtually all patients, ultrasonography can distinguish a testicular from an extratesticular mass and may detect lesions that are not palpable on physical examination. Ultrasonographic findings cannot consistently differentiate benign from malignant tumors of the testis (95% of such masses are malignant). Most patients with testicular cancer, especially seminoma, have hypoechoic lesions compared to adjacent tissue. Nonseminomatous tumors, however, may have mixed signals, including hyperechoic masses, which are commonly seen with teratoma. Serum markers Serum levels of β-subunit human chorionic gonadotropin (β-hCG) and α-fetoprotein (AFP) are elevated in ~80%-85% of patients with extensive germ-cell tumors. Patients with pure seminoma may have elevated levels of β-hCG but not AFP (a significantly elevated AFP level usually indicates the presence of nonseminomatous germ-cell elements). False-positive β-hCG levels can be seen in patients who have hypogonadism (cross-reactivity with luteinizing hormone) or who pursue the use of marijuana; AFP levels may be elevated in patients with liver dysfunction or hepatitis. Inguinal orchiectomy When a testicular mass is discovered, the patient should undergo an orchiectomy through an inguinal incision. Inguinal orchiectomy When a testicular mass is discovered, the patient should undergo an orchiectomy through an inguinal incision. Trans-scrotal incisions or biopsies should not be performed, as they ultimately lead to aberrant lymphatic drainage from the tumor. Staging evaluation The principal objective of the staging evaluation is to ascertain whether the patient has early-stage disease (which is amenable to local therapy, such as retroperitoneal lymphadenectomy [for nonseminoma] or radiation therapy [for seminoma]) or disseminated disease (which requires chemotherapy). Chest radiograph A chest x-ray can determine whether or not a patient has gross supradiaphragmatic metastases, which would mandate initial chemotherapy. Chest CT In patients with a normal chest x-ray, chest CT is recommended in both patients with seminoma and those with nonseminoma when abdominal adenopathy is found, to rule out occult metastases within the lungs or mediastinum. If such metastases are present, the patient should be treated with primary chemotherapy. Abdominopelvic CT provides important information about the retroperitoneal lymph nodes. Usually, periaortic adenopathy is noted on the ipsilateral side of the primary tumor. Patients with primary retroperitoneal germ-cell tumors often show an enlarged retroperitoneal mass in the midline. Although hepatic metastases are infrequent, at present CT is the most viable method of determining these metastatic lesions. PET ¹⁸Fluorodeoxyglucose (FDG)-PET is emerging as a significant adjunct in staging and follow-up. Seminomas are FDG-avid. Nodal and extranodal metastases not appreciated on CT scans may be noted with PET-FDG in some cases. The optimal usage of PET-FDG is in patients with residual masses following systemic therapy for pure seminoma. In such cases, the scans should be performed at least 3-4 weeks beyond the last course of chemotherapy. Other scans In the absence of symptoms or signs, a CT scan (or MRI) of the head and radionuclide bone scan are unnecessary. A lymphangiogram is rarely used today to identify microscopic nodal involvement in patients with stage I disease who choose to undergo surveillance. PET scans may be useful in patients with residual disease following chemotherapy for seminoma.