General Information About Testicular Cancer
Incidence and Mortality
Estimated new cases and deaths from testicular cancer in the United States in 2015:
- New cases: 8,430.
- Deaths: 380.
Testicular cancer is a highly treatable, usually curable, cancer that most often develops in young and middle-aged men. Most testicular cancers are germ cell tumors. For treatment planning, germ cell tumors are broadly divided into seminomas and nonseminomas because they have different prognostic and treatment algorithms. For patients with seminoma (all stages combined), the cure rate exceeds 90%. For patients with low-stage seminoma or nonseminoma, the cure rate approaches 100%.[2-6]
Risk factors for testicular cancer include the following:
- An undescended testis (cryptorchidism).
- A family history of testis cancer (particularly in a father or brother).
- A personal history of testis cancer.
Surgical correction of an undescended testis (orchiopexy) before puberty appears to lower the risk of testis cancer, but this isn't certain.
Types of testicular germ cell tumors: Seminomas versus nonseminomas
The five histopathological subtypes of testicular germ cell tumors include:
- Embryonal carcinomas.
- Yolk sac tumors.
Tumors that are 100% seminoma are considered seminomas. All other tumors, including those that have a mixture of seminoma and nonseminoma components, are considered and should be managed as nonseminomas. Most nonseminomas consist of a mixture of the different germ-cell tumor subtypes. Tumors that appear to have a seminoma histology but are accompanied by an elevated serum level of alpha-fetoprotein (AFP) should be treated as nonseminomas because seminomas do not produce AFP.
Prognosis and Staging
Serum tumor markers and testis cancer: AFP, beta-hCG, and LDH
Alpha-fetoprotein (AFP), beta-human chorionic gonadotropin (beta-hCG), and lactase dehydrogenase (LDH) play an important role as serum tumor markers in the staging and monitoring of germ cell tumors and should be measured prior to removing the involved testicle. For patients with nonseminomas, the degree of tumor-marker elevation after the cancerous testicular has been removed is one of the most significant predictors of prognosis. Serum tumor markers are also very useful for monitoring all stages of nonseminomas and for monitoring metastatic seminomas because elevated marker levels are often the earliest sign of relapse.
AFP: Elevation of serum AFP is seen in 40% to 60% of men with nonseminomas. Seminomas do not produce AFP. Men who have an elevated serum AFP should be considered to have a mixed germ cell tumor (i.e., nonseminomatous germ cell tumors [NSGCT]) even if the pathology shows a pure seminoma, unless there is a more persuasive explanation for the elevated AFP, such as liver disease.
Beta-hCG: Elevation of the beta subunit of hCG is found in approximately 14% of the patients with stage I pure seminoma prior to orchiectomy and in about half of patients with metastatic seminoma.[11-13] Approximately 40% to 60% of men with nonseminomas have an elevated serum beta-hCG.
Significant and unambiguously rising levels of AFP and/or hCG are an indication of relapsed germ cell tumor in most cases and are an indication for treatment even in the absence of radiological evidence of metastatic disease. Nonetheless, tumor-marker elevations do need to be interpreted with caution. For example, false-positive hCG levels can result from cross reactivity of the assay with luteinizing hormone, in which case an intramuscular injection of testosterone should result in normalization of hCG values. There are also clinical reports of marijuana use resulting in elevations of serum hCG and some experts recommend querying patients about drug use and retesting hCG levels after a period of abstinence from marijuana use. Similarly, AFP is chronically mildly elevated in some individuals for unclear reasons and can be substantially elevated by liver disease.
LDH: Seminomas and nonseminomas alike may result in elevated lactate dehydrogenase (LDH) but such values are of less clear prognostic significance because LDH may be elevated in many different conditions unrelated to cancer. A study of the utility of LDH in 499 patients with testicular germ cell tumor undergoing surveillance after orchiectomy or after treatment of stage II or III disease reported that 7.7% of patient visits had elevations in LDH unrelated to cancer, whereas only 1.4% of visits had cancer-related increases in LDH. Of 15 relapses, LDH was elevated in six and was the first sign of relapse in one. Over 9% of the men had a persistent false-positive increase in LDH. The positive predictive value for an elevated LDH was 12.8%.
A second study reported that among 494 patients with stage I germ cell tumors who subsequently relapsed, 125 had an elevated LDH at the time of relapse. Of these 125, all had other evidence of relapse: 112 had a concurrent rise in AFP and/or hCG, one had CT evidence of relapse prior to the elevation in LDH, one had palpable disease on examination and one complained of back pain that led to imaging that revealed retroperitoneal relapse. Measuring LDH thus appears to have little value during surveillance of germ cell tumors for relapse. On the other hand, for patients with metastatic NSGCT, large studies of prognostic models have found the LDH level to be a significant independent predictor of survival on multivariate analysis.[10,16]
Staging and risk stratification
There are two major prognostication models for testicular cancer: staging, and for risk-stratification of men with distant and/or bulky retroperitoneal metastases, the International Germ Cell Cancer Consensus Group classification. The prognosis of testicular germ cell tumors is determined by the following factors:
- Histology (seminoma vs. nonseminoma).
- The extent to which the tumor has spread (testis only vs. retroperitoneal lymph node involvement vs. pulmonary or distant nodal metastasis vs. nonpulmonary visceral metastasis).
- For nonseminomas, the degree to which serum tumor markers are elevated.
Thus, for men with disseminated seminomas, the main adverse prognostic variable is the presence of metastases to organs other than the lungs (e.g., bone, liver, or brain). For men with disseminated nonseminomas, the following variables are independently associated with poor prognosis:
- Metastases to organs other than the lungs.
- Highly elevated serum tumor markers.
- Tumor that originated in the mediastinum rather than the testis.
Nonetheless, even patients with widespread metastases at presentation, including those with brain metastases, may have curable disease and should be treated with this intent.
Radical inguinal orchiectomy with initial high ligation of the spermatic cord is the procedure of choice in diagnosing and treating a malignant testicular mass. As noted above, serum AFP, LDH, and hCG should be measured prior to orchiectomy. Transscrotal biopsy is not considered appropriate because of the risk of local dissemination of tumor into the scrotum or its spread to inguinal lymph nodes. A retrospective analysis of reported series in which transscrotal approaches had been used showed a small but statistically significant increase in local recurrence rates compared with the recurrence rates when the inguinal approach was used (2.9% vs. 0.4%).[Level of evidence: 3iiiDii] Distant recurrence and survival rates, however, were indistinguishable in the two approaches.
Evaluation of the retroperitoneal lymph nodes, usually by CT scanning, is an important aspect of staging and treatment planning in adults with testicular cancer.[21,22] Patients with a negative result have a substantial chance of having microscopic involvement of the lymph nodes. Nearly 20% of seminoma patients and 30% of nonseminoma patients with normal CT scans and serum tumor markers will subsequently relapse if not given additional treatment after orchiectomy.[23-25] For nonseminoma patients, retroperitoneal lymph node dissection (RPLND) increases the accuracy of staging but as many as 10% of men with normal imaging, normal tumor markers, and benign pathology at RPLND will still go on to relapse. About 25% of patients with clinical stage I nonseminomatous testicular cancer will be upstaged to pathologic stage II with RPLND, and about 25% of clinical stage II patients will be downstaged to pathologic stage I with RPLND.[26-28] In prepubertal children, the use of serial measurements of AFP has proven sufficient for monitoring response after initial orchiectomy. Lymphangiography and para-aortic lymph node dissection do not appear to be useful or necessary in the proper staging and management of testicular cancer in prepubertal boys. (Refer to the Genital/Urinary Tumors section in the PDQ summary on Unusual Cancers of Childhood for more information.)
Follow-up and Survivorship
Patients who have been cured of testicular cancer have approximately a 2% cumulative risk of developing a cancer in the opposite testicle during the 15 years after initial diagnosis.[30,31] Within this range, men with nonseminomatous primary tumors appear to have a lower risk of subsequent contralateral testis tumors than men with seminomas.
HIV-infected men are reported to be at increased risk for developing testicular seminomas. Depending on comorbid conditions such as active infection, these men are generally managed similarly to non-HIV-infected patients.
Because the majority of testis cancer patients who receive adjuvant chemotherapy or radiation therapy are curable, it is necessary to be aware of possible long-term effects of the various treatment modalities, such as the following:
- Fertility: Many patients have oligospermia or sperm abnormalities prior to therapy, but semen analysis results generally become more normal after treatment. The impact of standard chemotherapy on fertility in testis cancer patients is not well defined, although it is well documented that most men can father children after treatment, often without the use of cryopreserved semen. In two, large studies, roughly 70% of patients actually fathered children after treatment for testicular cancer.[33,34] The likelihood of recovering fertility is related to the type of treatment received. The children do not appear to have an increased risk of congenital malformations, but the existing data are not adequate to properly investigate this issue.[35,36] It is recommended that men wait at least 3 months after completing chemotherapy before conceiving a child (unless using cryopreserved sperm collected before chemotherapy was administered).
Radiation therapy, used to treat pure seminomatous testicular cancers, can cause fertility problems because of radiation scatter to the remaining testicle during radiation therapy to retroperitoneal lymph nodes (as evidenced in the SWOG-8711 trial, for example). (Refer to the PDQ summary on Sexuality and Reproductive Issues for more information on fertility.) Depending on scatter dose, sperm counts fall after radiation therapy but may recover over the course of 1 to 2 years. Shielding techniques can be used to decrease the radiation scatter to the remaining normal testicle. Because chemotherapy, retroperitoneal lymph node dissection, and radiation therapy can each result in infertility, men should be offered the opportunity to bank sperm before undergoing any treatment for testis cancer other than orchiectomy.
- Secondary leukemias: Several reports of elevated risk of secondary acute leukemia, primarily nonlymphocytic, have appeared.[38,39] An increased risk of leukemia has been associated with platinum-based chemotherapy and radiation therapy. Etoposide-containing regimens are also associated with a risk of secondary acute leukemias, usually in the myeloid lineage, and with a characteristic 11q23 translocation.[40,41] Etoposide-associated leukemias typically occur sooner after therapy than alkylating agent-associated leukemias and often show balanced chromosomal translocations on the long arm of chromosome 11. Standard etoposide dosages (<2 g/m2 cumulative dose) are associated with a relative risk of 15 to 25, but this translates into a cumulative incidence of leukemia of less than 0.5% at 5 years. Preliminary data suggest that cumulative doses of more than 2 g/m2 of etoposide may confer higher risk.
- Renal function: Minor decreases in creatinine clearance occur (about a 15% decrease, on average) during platinum-based therapy, but these appear to remain stable in the long term and without significant deterioration.
- Hearing: Bilateral hearing deficits occur with cisplatin-based chemotherapy, but the deficits generally occur at sound frequencies of 4 kHz to 8 kHz, which is outside the range of conversational tones; therefore, hearing aids are rarely required if standard doses of cisplatin are administered.
- Lung function: A study of pulmonary function tests in 1,049 long-term survivors of testis cancer reported a cisplatin-dose-dependent increase in the incidence of restrictive lung disease. Whereas men receiving up to 850 mg of cisplatin had a normal risk of restrictive lung disease, men who received over 850 mg of cisplatin had a three-fold increased risk. In absolute terms, patients who received no chemotherapy had an incidence of restrictive lung disease of less than 8%, whereas the incidence of restrictive lung disease among those receiving over 850 mg of cisplatin was nearly 18%. However, only 9.5% of those with pulmonary function testing indicative of restrictive lung disease reported dyspnea. Although cisplatin was more strongly associated with decreased lung function in this study, cumulative bleomycin dose was also associated with a decline in forced vital capacity and the 1-second forced expiratory volume (FEV1) but not with restrictive lung disease.
Although acute bleomycin pulmonary toxic effects may occur, they are rarely fatal at total cumulative doses of less than 400 units. Because life-threatening pulmonary toxic effects can occur, the drug should be discontinued if early signs of pulmonary toxic effects develop. Although decreases in pulmonary function are frequent, they are rarely symptomatic and are reversible after the completion of chemotherapy. Survivors of testis cancer who were treated with chemotherapy have been reported to be at increased risk of death from respiratory diseases, but it is unknown whether this finding is related to bleomycin exposure.
Radiation therapy, often used in the management of pure seminomatous germ cell cancers, has been linked to the development of secondary cancers, especially solid tumors in the radiation portal, usually after a latency period of a decade or more.[45,46] These include melanoma and cancers of the stomach, bladder, colon, rectum, pancreas, lung, pleura, prostate, kidney, connective tissue, and thyroid. Chemotherapy has also been associated with an elevated risk of secondary cancers.
Other risk factors
Cardiovascular disease in testicular cancer survivors
More recently, men with testis cancer who have been treated with radiation therapy and/or chemotherapy have been reported to be at increased risk of cardiovascular events.[47-49] Other studies have reported that chemotherapy for testis cancer is associated with an increased risk of developing metabolic syndrome and hypogonadism.[50,51] Moreover, an international population-based study reported that men treated with either radiation or chemotherapy were at increased risk of death from circulatory diseases.
In a retrospective series of 992 patients treated for testicular cancer at the Royal Marsden Hospital between 1982 and 1992, cardiac events were increased approximately 2.5-fold in patients treated with radiation therapy and/or chemotherapy compared with those who underwent surveillance after a median of 10.2 years. The actuarial risks of cardiac events were 7.2% for patients who received radiation therapy (92% of whom did not receive mediastinal radiation therapy), 3.4% for patients who received chemotherapy (primarily platinum-based), 4.1% for patients who received combined therapy, and 1.4% for patients who underwent surveillance management after 10 years of follow-up.
A population-based, retrospective study of 2,339 testicular cancer survivors in the Netherlands, treated between 1965 and 1995 and followed for a median of 18.4 years, found that the overall incidence of coronary heart disease (i.e., myocardial infarction and/or angina pectoris) was increased 1.17 times (95% confidence interval [CI], 1.04–1.31) compared with the general population. Patients who received radiation therapy to the mediastinum had a 2.5-fold (95% CI, 1.8–3.4) increased risk of coronary heart disease, and those who also received chemotherapy had an almost 3-fold (95% CI, 1.7–4.8) increased risk. Patients who were treated with infradiaphragmatic radiation therapy alone had no significantly increased risk of coronary heart disease. In multivariate Cox regression analyses, the older chemotherapy regimen of cisplatin, vinblastine, and bleomycin (PVB), used until the mid-1980s, was associated with a significant 1.9-fold (95% CI, 1.2–2.9) increased risk of cardiovascular disease (i.e., myocardial infarction, angina pectoris, and heart failure combined). The newer regimen of bleomycin, etoposide, and cisplatin (BEP) was associated with a borderline significant 1.5-fold (95% CI, 1.0–2.2) increased risk of cardiovascular disease. Similarly, an international pooled analysis of population-based databases reported that the risk of death from circulatory disease was increased in men treated with chemotherapy (standardized mortality ratio 1.58) or radiation therapy (SMR = 1.70).[Level of evidence: 3iiiDii]
Although testicular cancer is highly curable, all newly diagnosed patients are appropriately considered candidates for clinical trials designed to decrease morbidity of treatment while further improving cure rates.
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