Related narrative: Non-Seminomatous Germ Cell Tumor
Over 90% of testicular tumors develop in the germ cells, which are responsible for sperm production. The other 10% are tumors of the supportive or hormone-producing tissues, testicular lymphomas, or secondary tumors. Germ cell tumors are broadly divided into seminoma types, which comprise 40% of all germ cell tumors, and nonseminoma types, comprising the other 60%. This distinction is important for treatment planning because seminomas are more sensitive to radiation therapy. For patients with seminoma (all stages combined), the cure rate exceeds 90%. For patients with low-stage disease, the cure rate approaches 100%. The majority of nonseminomas have more than one cell type, including embryonal carcinoma, teratoma, yolk sac carcinoma, choriocarcinoma, and various combinations of those. Risk of metastases is lowest for teratoma and highest for choriocarcinoma, with the other cell types being intermediate.
Epidemiology and Risk Factors
Testicular cancer accounts for 1% of all malignancies in men, causing about 5,000-8,000 new cases a year in the U.S.; it is the most common cancer among men aged 15-35. Because of multimodal treatments, testicular cancer has become one of the most curable solid neoplasms, resulting in a decrease in patient mortality from greater than 50% before 1970 to less than 10% in 1996. However, despite its overall curability, approximately 400-500 men in the U.S. die each year from germ cell tumors.
While occasionally germ cell tumors occur in children and in men over 70, by and large they are malignancies of early adulthood, with the incidence of seminoma peaking in the 25-45-year-old group; the highest incidence of nonseminoma occurs in a slightly younger group of 15-30-year-olds. Bilateral tumors occur in 2-4% of patients. While the large majority of testicular neoplasms in young men are germ cell tumors, in men over 60 years, only 25% of malignancies will be of germinal origin. Testicular malignancies in this age group are predominantly lymphomas, although metastases to the testicles from other primary tumors should be considered.
There is an ethnic variation in risk. The incidence of testicular tumors in American blacks is approximately one third that in American whites but 10 times that in African blacks. In Israel, Jews have at least an eightfold higher incidence of testis tumors in comparison with non-Jews. In Hawaii, the incidence among Filipino/Japanese sectors is approximately one tenth that of the Chinese/white/native Hawaiian populations. Evidence also supports the importance of congenital factors in the etiology of germ cell tumors. During development, the germ cell may be altered by environmental factors, resulting in disturbed differentiation. The development of the germ cell is conceivably affected by cryptorchidism, gonadal dysgenesis, hereditary predisposition, or by chemical carcinogens, trauma, or orchitis. There is growing support for the concept of transplacental damage to the fetal gonad by maternal estrogen levels as a contributing causative agent of germ cell cancer.
Clinical Manifestations and Diagnosis
The most common presentation of testicular cancer is testicular swelling (73% in one series of 450 patients). A misconception is that testicular cancers are mostly painless, and that painful masses need not be evaluated for malignancy. In fact, testicular pain is a presenting feature of 18-46% of patients with germ cell tumors. Less commonly presenting symptoms will include gynecomastia in tumors such as choriocarcinoma (10%), back or flank pain from metastatic disease (10%), and infertility in less than 5% of tumors. Most tumors are first found by the patients.
The physical examination of the testicles is performed by fully palpating all areas of the testicle between thumb and fingers. Testicular masses are firm to hard, and generally the scrotal sac is normal in appearance unless there is a large mass causing distension. The initial evaluation of a testicular mass is ultrasound. Testicular ultrasonography is a sensitive and specific test that can discriminate between a testicular neoplasm and nonmalignant processes. Transscrotal biopsy is not recommended because of the risk of local dissemination of tumor into the scrotum or spread to inguinal lymph nodes. Any patient with a testicular mass or abnormal ultrasonography, or both, should have testicular carcinoma ruled out by a unilateral radical transinguinal orchiectomy (see radical orchiectomy). Orchiectomy is the definitive procedure for both pathologic diagnosis and local control of the primary tumor and in some cases may be curative.
The differential diagnosis of a testicular mass includes testicular torsion, epididymitis, or epididymo-orchitis. Less common problems include hydrocele, hernia, hematoma, spermatocele, or syphilitic gumma. Signs and symptoms indistinguishable from acute epididymitis have been observed in up to one quarter of patients with testicular neoplasms, and lengthy delays can occur when patients are treated for presumed epididymitis. Therefore, the clinical diagnosis of epididymitis should prompt a careful physical examination as well as ultrasonographic examination of the scrotum, particularly in those patients who fail to respond to antibiotics. In any patient with a solid, firm, intratesticular mass, testicular cancer must be the considered diagnosis until proven otherwise.
Serum markers may detect a germ cell tumor that is too small to be detected on physical examination or x-rays and therefore have become a fundamental component of diagnosis, offering diagnostic, staging, and prognostic information, as well as measuring disease progression and response to therapy. Thus, along with the usual laboratory studies obtained on patients with suspected germ cell tumor, preorchiectomy levels of lactate dehydrogenase (LDH), beta-human chorionic gonadotropin (betaHCG), and alpha-fetoprotein (AFP) are mandatory. Measurements of AFP and betaHCG offer an excellent tool for monitoring disease progression and response to therapy. While the vast majority of seminomas are marker-negative, in general their phenotype is less malignant, and their responsiveness to therapy is extremely high, making the usual absence of biochemical markers of disease less troublesome. Routine post-orchiectomy radiographic studies can detect evidence of spread to the retroperitoneum and lungs. Therefore, patients with germ cell tumors should undergo CT of the chest, abdomen, and pelvis; however, the major limitation of CT imaging is that while gross nodal disease can usually be detected, microscopic metastases are not.
Staging of Testicular Germ Cell Tumors
Stage I: Tumors confined to the testis, with no evidence of nodal or pulmonary parenchymal involvement. In nonseminomous tumors, stage I represents about 40% of all diagnoses.
Stage II: Denotes tumors with retroperitoneal lymph node metastases.
Stage IIA implies minimal but definite nodal involvement, generally of a microscopic nature.
Stage III: Refers to disease that has spread beyond the retroperitoneum, usually to supradiaphragmatic lymph nodes, pulmonary parenchyma, or other sites including liver, bone, or brain. Some staging schemas, particularly those for seminoma, distinguish between stage III (supradiaphragmatic lymph nodes) and stage IV (any extranodal metastases, including pulmonary parenchyma, bone, and brain).
Treatment and Prognosis
Most men with testicular cancer can be cured with surgery, radiation therapy, and/or chemotherapy. Germ cell tumors are broadly divided into seminoma and nonseminoma for treatment planning because seminomatous types of testicular cancer are more sensitive to radiation therapy. Tumors that have a mixture of seminoma and nonseminoma components should be managed as nonseminoma.
A histologic diagnosis of pure seminoma implies an excellent prognosis. For seminomas, localized disease is curable with orchiectomy and low-dose adjuvant radiotherapy to lymph nodes in 98%; stage II is curable with orchiectomy and radiotherapy to involved areas in 85-95% of patients with minimal to moderately bulky disease; and stage III or bulky locally advanced disease is curable in 90% with combination chemotherapy. Controversy over the optimal management of clinical stage I nonseminomatous germ cell cancer has prompted a search for prognostic factors that can be used to predict the risk of occult nodal involvement.
Histologic subtype, local tumor extension, and vascular or lymphatic invasion have all been shown to correlate with occult nodal metastases or a high risk of relapse. A number of prognostic classification schema are in use, and most incorporate some or all of the following factors for nonseminomatous tumors, which may independently predict worse prognosis: 1) presence of liver, bone, or brain metastases; 2) very high serum markers; 3) primary mediastinal nonseminoma; and 4) large number of lung metastases. It is important to note that even patients with widespread metastases at presentation, including those with brain metastases, may still be curable and should be treated with this intent.
Prior to the advent of cis-platinum-based chemotherapy, radical retroperitoneal lymph node dissection offered the potential of cure, even to nonseminoma patients with nodal metastases. The overall survival rates resulting from radiation therapy alone in clinical stage I nonseminomatous germ cell tumors have been reported from 70 to 90%; however, highly effective chemotherapy has largely precluded radiation therapy in the treatment of clinical stage I nonseminomatous germ cell tumors. Today, stage I nonseminoma is highly curable (>95%).
If preservation of fertility is an important consideration, a surgical technique for sparing sympathetic ganglia and chains should be used for retroperitoneal lymph node dissection (generally standard for Stage I nonseminomas in adults). This technique is associated with postoperative fertility in most patients and appears to be as effective as non-nerve-sparing procedures in preventing retroperitoneal relapse. For nonseminoma, clinically localized disease is curable with orchiectomy alone in 60-80% of patients, and the risk of relapse is decreased with retroperitoneal lymphadenectomy. Radical retroperitoneal lymph node dissection in low-stage nonsemiomatous tumors has both diagnostic and therapeutic utility. The diagnostic use of retroperitoneal lymph node dissection lies in its ability to detect occult nodal metastases, which occur in 20-40% of all clinical stage I tumors. Additionally surgical cures with retroperitoneal lymph node dissection alone can be achieved in stage I patients.
Stage II disease is cured with surgery alone in 40-60% of patients, though moderate to bulky nodal disease requires combination chemotherapy. Stage III or bulky locally advanced disease is curable in 80% with combination chemotherapy, and postchemotherapy retroperitoneal lymphadenectomy can prevent subsequent relapse in selected patients.
In all testicular cancers, the salvage rate for chemotherapy is about 80% for patients who have failed surgical or radiation therapeutic treatments, while for those who have failed prior chemotherapy, second-line chemotherapy cures about 20%. Subsequent high-dose therapy with autologous bone marrow transplant/peripheral stem cell transplant is possibly curative in 15-20% of those who have failed second-line therapy.
Men who have had testicular cancer are at an increased risk of developing cancer in the other testicle. Serum markers plus chest x-rays are important parts of the monthly checkups for patients after definitive therapy of testicular cancer as well as periodic abdominal CT scans for 2-3 years. While the majority of tumor recurrences appear within two years, late relapse has been reported, and lifelong marker, radiologic, and physical examination is recommended.
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