Testicular cancer, although an uncommon malignancy, is the most frequently occurring cancer in young men. In the year 2000, an estimated 7,400 cases of testicular cancer will be diagnosed. 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 from 1969 to 1971 to 4.1 cases per 100,000 from 1983 to 1987. 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

CT Scans are important in staging these men to look for lymph nodes in the abdomen or pelvis or spread to the lung or mediastinum. Tumor markers are also important: 

The serum tumor markers alpha-fetoprotein (AFP), lactate dehydrogenase (LDH), and human chorionic gonadotropin (hCG) are of critical importance in diagnosis, prediction of prognosis, and assessment of treatment outcome. They should be determined before, during, and after treatment as well as throughout the followup period. Alpha-fetoprotein is a serum tumor marker produced by nonseminomatous cells (embryonal carcinoma, yolk-sac tumor) and may be seen at any stage. An approximate half-life of alphafetoprotein is 5-7 days. A nonseminoma, therefore, is associated with elevated serum concentrations of AFP. An elevated serum concentration of hCG (half-life is approximately 1-3 days) may also be present with both seminomatous and nonseminomatous tumors.

Seminomas are occasionally associated with an elevated serum concentration of hCG, but not an elevated concentration of AFP. Nonseminoma is the more clinically aggressive tumor. When both a seminoma and nonseminoma elements are present, management follows that for a nonseminoma.

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 under age 10.

Race Testicular cancer is rare in African-Americans, occurring at a rate of 0.9 per 100,000 population. 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 and the Far East, 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 occult germ-cell tumors of the testicle. This possibility should be evaluated with testicular ultrasound, especially when the retroperitoneal tumor is predominantly one-sided.

Survival The 5-year survival rate for all patients with a germ-cell tumor 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.

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 previous 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 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 neoplasm¾a presumed precursor lesion.

Genetics Klinefelter’s syndrome (47XXY) is associated with a higher incidence of germ-cell tumors, particularly primary mediastinal germ-cell tumors. 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 6-fold 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 (DES) in utero is associated with cryptorchidism, a direct association between DES and germ-cell neoplasm is weak at best.

At least two 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.

Prior trauma, elevated scrotal temperature (secondary to 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.

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. Ultrasound 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 b-subunit human chorionic gonadotropin (b-HCG) and a-fetoprotein (AFP) are elevated in ~ 80%-85% of patients with extensive germ-cell tumors. Patients with pure seminoma may have elevated levels of b-HCG but not AFP (elevated AFP indicates the presence of nonseminomatous germ-cell elements). False-positive b-HCG levels can be seen in patients who have hypogonadism (cross-reactivity with luteinizing hormone) or who use marijuana, whereas AFP 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.

Trans-scrotal incisions or biopsies should not be performed, as they ultimately lead to aberrant lymphatic drainage from the tumor.

Pathology

Germ-cell tumors are classified into two broad histologic categories: seminoma and nonseminomatous germ-cell tumor. Patients with seminoma who have increased AFP or any focus of nonseminomatous germ-cell tumor components (including teratoma) are considered to have a nonseminomatous germ-cell tumor.

Seminoma

Seminoma is the most common single histology, accounting for ~ 30% of all germ-cell tumors. Up to 10% of seminomas have focal syncytiotrophoblast cells, thought to be the source of b-HCG in some cases.

Spermatocytic seminoma, a rare subset of germ-cell tumors, often grows to large size, occurs almost exclusively in men over 50 years old, and rarely metastasizes.

Nonseminoma

Embryonal carcinoma is composed of large pleomorphic cells with different architectural patterns. This tumor may be associated with an elevation of serum b-HCG and/or AFP.

Endodermal sinus tumor (yolk sac carcinoma) is the most common testicular tumor seen in infants and young children. Like embryonal carcinoma, yolk sac tumor has a variety of architectural patterns. This tumor is associated with elevated serum AFP.

Choriocarcinoma, as a pure entity, is one of the least common germ-cell tumors. These tumors have a great propensity for hematogenous spread, often skipping the retroperitoneum. Choriocarcinoma is associated with increased serum b-HCG.

Teratoma is a generally benign tumor with elements from each of the germ layers (ectoderm, mesoderm, and endoderm). Teratoma is uncommonly seen as the sole histology in primary tumors, but it is frequently associated with other histologic elements, including those mentioned above. Of patients with residual disease following chemotherapy for nonseminomatous germ-cell tumor, ~ 45% have teratoma in resected specimens.

A subset of patients with immature teratoma that contains non-germ-cell histologies (eg, sarcoma, adenocarcinoma) has been reported. In contrast to most teratomas, these tumors may grow locally and can be lethal. In addition, late recurrences of both teratoma and carcinoma have been reported in patients with teratoma. Serum markers are normal in patients with pure teratoma.

Treatment

surgical treatment of stage I or II disease

Initial intervention for testicular cancer is radical inguinal orchiectomy. Orchiectomy may be deferred temporarily in patients with advanced-stage disease in whom the diagnosis of nonseminomatous germ-cell tumor can be made on clinical grounds (elevated markers). In such patients, an orchiectomy must be performed later, as there is incomplete penetration of chemotherapy into the testes.

Further therapy hinges on the pathologic diagnosis. In general, pure seminomas (normal AFP with or without elevated b-HCG) are treated with radiotherapy and/or chemotherapy, whereas most nonseminomas are treated with surgery and/or chemotherapy.

Radiation therapy for Stage I or II seminomas

Seminomas of the testes are exquisitely sensitive to radiation. This characteristic, combined with their predictable lymphatic spread, make these cancers amenable to radiotherapy. Since low radiation doses are used, acute and late side effects are few.

Stage I disease

Prophylactic radiotherapy vs chemotherapy vs surveillance Primary lymphatic drainage of the testis is to the para-aortic lymph nodes from the level of the renal vessels to the bifurcation of the aorta. While ipsilateral pelvic nodal failures and, to a much lesser extent, inguinal failures have been reported following tumor resection by inguinal orchiectomy in patients with stage I disease, these sites have a much lower risk of failure than do the para-aortic lymph nodes. Based on surveillance data, the overall incidence of disease failure without radiotherapy is 15%-27% (median, 20%), whereas only 2%-5% (median, 3%) of patients who are treated with radiotherapy relapse.

Although surveillance would appear to be a reasonable approach for patients with stage I disease, since 80% of these patients will be treated unnecessarily, follow-up is problematic because progression usually is not associated with symptoms until the tumor burden is large. Surveillance requires frequent abdominopelvic CT scans and chest x-rays for 4-5 years. Despite excellent salvage rates reported in patients who relapse while undergoing surveillance (initial salvage rates of approximately 90%, with ultimate salvage rates after relapse of approximately 95%), most groups have discontinued surveillance protocols in lieu of prophylactic radiotherapy to the draining lymphatics or chemotherapy. Those patients who do develop a recurrence usually receive 4 cycles of etoposide plus Platinol (EP).

Several phase II trials have evaluated 1-2 cycles of carboplatin (Paraplatin) for prophylactic treatment of stage I seminona. The preliminary results are comparable to radiotherapy in terms of recurrence rates. Late toxicity data are lacking, and prophylactic carboplatin therapy is not considered to be a standard approach in this country.

Radiation fields and doses The radiotherapy portals typically include the para-aortic lymph nodes from T10-L5 and the ipsilateral hemipelvis, including the inguinal scar. However, recent studies that reduced the size of para-aortic fields and omitted hemipelvis radiation in selected patients (eg, those with no prior orchiopexy or other pelvic, inguinal, or scrotal surgery) are encouraging. Pelvic and/or inguinal failures occurred in < 5% of these patients. The smaller treatment volume reduces the dose to the remaining testicle and probably the risk of second malignancy.

The hemiscrotum is usually treated if the tumor penetrated the tunica albuginea, a trans-scrotal incision was performed, or orchiopexy was done for cryptorchidism. Although treatment of the hemiscrotum for these reasons remains a standard practice, it has been questioned since the incidence of scrotal failure is low even in the presence of these risk factors. In fact, some surgeons advocate trans-scrotal exploration to rule out benign lesions.

The sites listed above are treated with 25-30 Gy over 3-3.5 weeks, although some data suggest that 20 Gy is sufficient. The 5-year actuarial rate of disease freedom using such techniques is 97% and the rate of overall survival is nearly 100% since the availability of platinum-based chemotherapy for salvage. The few failures observed following radiotherapy most often occur in the next echelon of lymph node drainage sites, such as the mediastinum or left supraclavicular fossa.

Side effects The acute side effects of radiotherapy are limited to nausea, vomiting, and diarrhea, all of which usually can be readily controlled with medication. Late toxicities are rare, although peptic ulcers (~ 5%) and marginally higher rates of second malignancies have been reported.

Permanent infertility from scattered radiation to the contralateral testis is uncommon, whereas prolonged aspermia for over 1 year may occur, especially with irradiation of the hemiscrotum. Nevertheless, sperm banking is recommended for those concerned about childbearing.

Stage II disease

The majority of patients with infradiaphragmatic para-aortic and/or pelvic adenopathy < 5 cm are treated with radiotherapy alone, while those with larger lymph node metastases are treated with platinum-based chemotherapy. Some advocate a 10-cm adenopathy cut-off point for deciding whether to use radiotherapy or chemotherapy. Among patients who are candidates for radiotherapy, it is essential that renal function be preserved in case chemotherapy is necessary for salvage treatment.

Radiation fields The radiotherapy fields are similar to those used for stage I disease except that the fields are widened to include any para-aortic or pelvic adenopathy with a 2- to 3-cm margin. In the past, mediastinal and supraclavicular treatment was standard in patients with stage II disease. However, data from several series revealed only a 3% rate of mediastinal/supraclavicular relapse. In addition, late cardiac toxicity has been reported. Although treatment to these sites has largely been abandoned in these cases, one report indicates that the rate of failures in the left supraclavicular fossa is greater than was previously believed.

The actuarial rate of freedom from disease at 5 years for patients with para-aortic adenopathy < 5 cm is ~ 90%, vs 85% for those with adenopathy > 5 cm and < 10 cm. Most of the data on the latter group of patients are from older studies in which patients often received prophylactic mediastinal and supraclavicular irradiation, and outcome may be poorer without such treatment. However, this approach has been abandoned today in view of the excellent salvage rates with chemotherapy.

Radiation doses The involved areas are treated with 30-35 Gy and the uninvolved areas, with 25-30 Gy. There is no evidence of a dose-response effect above 25 Gy for uninvolved areas and above 30 Gy for involved areas. Failures within the irradiated volume are anecdotal.

Medical Treatment of Stage II nonseminomas

Over the past several years, the threshold for primary surgery in patients with stage II disease on CT scans has changed. At present, masses > 3 cm in greatest cross-sectional diameter are generally handled primarily with chemotherapy. For patients with tumor sizes £ 3 cm, primary RLND is considered the standard approach. It should be noted that up to 25% of patients with enlarged lymph nodes on CT scans will be found to have pathologic stage I (false-positives) disease by RLND.

Adjuvant chemotherapy for nonseminomas

The risk of systemic recurrence is 5%-10% in patients with pathologic stage I nonseminoma, 15%-30% in those with completely resected stage IIa (N2a) disease, and 30%-50% in those with stage IIb (N2b) disease. Recurrence usually occurs in the lungs within the first 24 months after surgery. The risk of retroperitoneal recurrence in patients with stage I, IIa, or IIb disease is < 1% after a properly performed RLND.

Following RLND, patients with complete resection of stage II disease can be considered candidates for adjuvant chemotherapy.

The decision of whether or not to prescribe adjuvant therapy following lymph node dissection is somewhat arbitrary, and often depends on the patient’s social circumstances and likelihood of adhering to close follow-up. A patient with completely resected carcinoma who undergoes an RLND has a 70% chance for cure; thus, the majority of patients will never need chemotherapy. However, these patients must be monitored carefully with chest x-rays and serum marker determinations every month for 1 year, every 2 months for an additional year, and then every 6 months for the next 3 years. (CT scanning is not performed routinely unless clinically indicated.) The 30% of patients followed in such a manner who do develop a recurrence will present with a tumor of low volume (eg, small pulmonary metastases or elevated serum markers); nearly 100% of these patients should be cured with appropriate systemic therapy.

However, some patients with resected stage II disease elect to receive adjuvant chemotherapy to minimize the risk of cancer recurrence. For such therapy, 2 cycles of BEP (bleomycin, 30 IU/wk ×8; etoposide, 100 mg/m² on days 1-5 and 29-34; and Platinol, 20 mg/m²on days 1-5 and 29-34) are recommended.

It should be emphasized that in a patient who agrees to close follow-up, the chance of dying of cancer should be negligible in either scenario. For patients who have persistently elevated or increasing serum markers following RLND or who have undergone an incomplete lymph node dissection, 3 cycles of BEP are indicated.

TREATMENT OF Stage III Disease

Seminomas

Chemotherapy is the treatment of choice for patients with stage III seminomas. The management of patients with bulky disease after chemotherapy (residual mass > 3 cm) is somewhat controversial. Investigators at Memorial Sloan-Kettering suggest that such patients require consolidation with radiotherapy or surgical removal of radiographically evident disease. More recent data from the Royal Marsden Hospital report a relapse rate of 10%-15% in patients with residual masses with or without post-chemotherapy surgery or radiotherapy, supporting the practice of observation in patients with residual disease following chemotherapy.

Nonseminomas

As mentioned above, patients with nonseminomas being treated with chemotherapy can be classified as having good- or poor-risk disease.

Good-risk nonseminomas In patients with good-risk nonseminomas, 3 cycles of BEP (bleomycin, 30 IU/wk, and etoposide, 100 mg/m², both on days 1-5, plus Platinol, 20 mg/m² on days 1-5) given every 3 weeks or, alternatively, 4 cycles of etoposide plus Platinol without bleomycin (EP; at the same dosages) appear to yield equivalent results. Over 90% of good-risk patients should be cured with these therapies.

Post-chemotherapy resection If a patient has persistent radiographic disease with normal serum markers 4-6 weeks following chemotherapy for a nonseminomatous germ-cell tumor, surgical resection should be performed when possible.

Post-resection chemotherapy Histologic examination of residual disease will reveal necrotic fibrous tissue in ~ 45% of such cases, benign teratoma in ~ 45%, and persistent carcinoma in ~ 10%-15%. If persistent carcinoma is detected in the resected specimen, 2 additional cycles of cisplatin plus etoposide should be administered. For patients with complete resection of mature and immature teratoma or necrosis, no additional therapy is needed.

Poor-risk nonseminomas A cohort of patients with disseminated germ-cell tumors present with very advanced or poor-risk disease. “Poor risk” has been variously defined  but represents a patient population with a cure rate of £ 50% with standard cisplatin-based combination chemotherapy.

Prior to the use of cisplatin-based chemotherapy, radiation had been used in the treatment of minimal residual nonseminoma following surgical dissection. The doses required for local control were 40-50 Gy. Such treatment has been supplanted by chemotherapy. Radiation is useful in the treatment of metastatic nonseminoma to the brain.

Chemotherapy During the last several years, several trials have evaluated a variety of combination regimens in patients with poor-risk disease. These include the use of high-dose cisplatin (40 mg/m² on days 1-5) or VIP (VePesid, ifosfamide, and Platinol). However, to date, none of these regimens has demonstrated superiority over 4 cycles of BEP.

An ongoing intergroup trial is currently comparing the role of high-dose chemotherapy with autologous bone marrow transplantation (BMT) as part of induction chemotherapy vs standard BEP in patients with poor-risk disease.

Post-chemotherapy resection The ultimate goal of combination chemotherapy in these patients is resolution of all radiographically visible disease and normalization of tumor markers. If residual radiographic abnormalities persist in the lungs and/or abdomen, surgical resection of residual disease is indicated.

A post-chemotherapy retroperitoneal lymph node resection must clear the region of residual disease. In general, post-chemotherapy resections are extremely difficult and incomplete resections are unacceptable. After the retroperitoneum is cleared of persistent radiographic disease, persistent pulmonary lesions are resected. In cases with residual disease in the retroperitoneum and thorax, the RPLND should be performed first. If necrosis is found, the disease within the chest can be observed. If teratoma or cancer is noted, the supradiaphragmatic disease should be resected.

Complicating factors associated with post-chemotherapy resections include the risk of oxygen toxicity secondary to bleomycin, as well as intense fibrosis and adherence of residual disease to the aorta and other vital retroperitoneal organs. Inspired oxygen levels must remain below 35% to prevent bleomycin-related acute respiratory distress syndrome, which has a fatality rate ³ 50%.

After successful resection, the only visible structures remaining should include the back muscles, nerves, anterior spinous ligament, aorta, IVC, renal vessels, kidneys, and ureters. Up to 20% of patients with advanced abdominal disease may require resection of a kidney or even the IVC. Operative mortality in centers with experience performing resections of these advanced-stage tumors should be < 2%.

Post-resection chemotherapy As mentioned, 2 additional cycles of chemotherapy are indicated for patients with persistent viable carcinoma in the resected specimen.