Testicular Cancer

April 1, 2005

Most testicular tumors are malignant and of germ-cell origin. They constitute only 1% of cancers in males overall but are the most common malignant neoplasm in men aged 15 to 35 years. Testicular cancers frequently present at an early stage, are very sensitive to chemotherapy, and are variably sensitive to radiotherapy.

Epidemiology and EtiologyPathology and Natural HistoryDiagnosisStaging and TreatmentConclusionsReferences

Most testicular tumors are malignant and of germ-cell origin. They constitute only 1% of cancers in males overall but are the most common malignant neoplasm in men aged 15 to 35 years. Testicular cancers frequently present at an early stage, are very sensitive to chemotherapy, and are variably sensitive to radiotherapy. These tumors are highly curable, and the success in treating testicular cancer has turned the focus of many studies to reducing toxicity in selected good-prognosis patients and identifying poor-prognosis patients who require more aggressive treatment. In this section, we review the epidemiology, etiology, pathology, diagnosis, and treatment of testicular cancers.

Epidemiology and Etiology

In 1995, an estimated 7,100 new cases of testicular cancer will be diagnosed in the United States, with an associated 370 deaths. This represents an incidence of 2.1 cases per 100,000 males [1,2]. Testicular cancer is most common in white males, who have an incidence more than four times that of black males [3,4]. The risk is highest in northern Europe. For example, in Denmark, the incidence is reported to be 6.3 per 100,000 males [5].

Several conditions have been associated with testis cancer. Abnormal testicular development and descent are strongly associated with cancer; males with cryptorchidism are 10 to 40 times more likely than males with normal testes to develop testicular carcinoma [6]. The risk appears to be greater if the testis is retained in the abdomen rather than in the inguinal canal [7,8]. Surgical placement of the undescended testis into the scrotum before the age of 6 years reduces the risk but not to a normal level [9]. The higher temperature the undescended testis is exposed to in cryptorchidism was held to play a role in the development of testicular cancer, but epidemiologic studies have not supported this hypothesis [10]. In patients with unilateral cryptorchidism, 25% of testis cancers occur in the normally descended testis.

Testicular feminization syndromes have been shown to increase the risk of cancer in the gonads by 40 times, and these tumors are often bilateral. Herniorrhaphy before age 15 years, exposure to diethylstilbestrol early in gestational life, disorders of sexual differentiation, and infertility constitute other risk factors [11-14]. In addition, trauma, torsion of the testis, testicular atrophy from mumps, orchitis, radiation, and exposure to dimethylformamide during leather tanning are possible risk factors [15].

Pathology and Natural History

Testicular cancer is a general term for several distinct but related neoplasms. The most commonly used classification in the United States is a modified version of the system described by Dixon and Moore in 1952 (Table 1)[16]. Germ-cell neoplasms account for nearly 93% of all primary testicular malignancies. Testicular lymphomas represent about 4% to 5% of testicular cancers, and sex cord-stromal tumors make up nearly 3%. A few other rare tumors are occasionally seen.

Carcinoma in situ

Carcinoma in situ was originally perceived as a curiosity. Though not malignant, it is now recognized as an important precursor to testicular cancer. In one study, incidence of progression to invasive cancer was estimated to be 70% at 7 years. In this study, no cases of regression were noted [17]. In 75% to 99% of testicular cancers, carcinoma in situ is found adjacent to the tumor [18]. It is unclear whether all germ-cell tumors go through this stage, but it must be regarded as a preinvasive lesion and not ignored.

Seminoma

Pure seminoma is the most common germ-cell tumor and accounts for approximately 45% of testicular cancers [19]. The distinction between seminoma and nonseminoma is important, because the natural histories of these tumor types and their responses to treatment modalities differ, and hence so do appropriate treatment strategies.

Seminomas are believed to arise from primordial germ cells and have distinct clinical and pathologic features. The metastatic potential is low, and most patients present with early-stage disease. Overall, 75% present with stage I disease, 20% with stage II disease, and 5% with stage III or IV disease [20]. Seminoma is generally divided into two types: classic seminoma, which accounts for about 90% of cases, and spermatic seminoma, which accounts for the rest.

Classic seminoma typically presents in the fourth or fifth decade as an enlarging, painless testicular mass, and 2% of the time, bilateral disease is present. The pattern of spread is predominantly via the lymphatics to the para-aortic lymph nodes and then to the mediastinal and supraclavicular lymph nodes. Hematogenous dissemination to lung, liver, bone, and adrenals occurs, but is generally a late finding.

Low levels of beta-human chorionic gonadotropin (beta-hCG) are seen in 10% to 25% of pure seminomas, but this characteristic does not appear to influence prognosis [21]. Seminomas do not secrete alpha-fetoprotein (AFP), and an elevated AFP level should alert the clinician to the presence of nonseminomatous elements.

Anaplastic seminoma used to be regarded as a separate category because it appears more aggressive under a microscope and tends to present at a later stage. However, when compared with classic seminoma on a stage-for-stage basis, the prognosis is no worse. For this reason, it is no longer regarded as a distinct entity and is included with the classic variant.

Spermatic seminoma accounts for about 10% of seminomas. It differs from classic seminoma in that it typically appears after the age of 60 years, it is bilateral 10% of the time, and it has an extremely indolent course. Metastases are rare, and the prognosis is excellent.

Nonseminomatous Germ-Cell Tumors

Nonseminomatous germ-cell tumors are a heterogeneous group of tumors that are grouped in the same category largely because they are frequently found together. It is difficult to generalize about their collective behavior, so each will be discussed separately, but it should be remembered that several or all of the histologic types discussed below may be present in the same patient. Nonseminomatous tumors that contain elements of seminoma are also common; they behave like nonseminomas and should be treated as such.

Embryonal Carcinoma: Embryonal carcinoma is the second most common testicular malignancy and in its pure form accounts for 15% to 30% of nonseminomatous germ-cell tumors. It occurs most commonly in the second decade of life and is rare after the fifth decade. It is not found in infants or children. One third of patients present with metastases to the para-aortic lymph nodes, lungs, or liver. This tumor secretes both AFP and beta-hCG. Placental alkaline phosphatase and cytokeratin are usually elevated, but carcinoembryonic antigen (CEA) generally is not [22,23].

Yolk-Sac Carcinoma (Endodermal Sinus Tumor): Yolk-sac carcinoma is the most common testicular neoplasm in children, accounting for 75% of testicular tumors in this population. It is associated with an excellent prognosis [24]. It is rare in its pure form in adults but is frequently seen next to other germ-cell elements. When it does appear as pure yolk-sac carcinoma in adults, it is a virulent neoplasm. It typically spreads via the lymphatics but frequently has hematogenous dissemination. It has particular affinity for metastasis to the liver. AFP levels are generally elevated, whereas beta-hCG levels are not [24].

Choriocarcinoma: Choriocarcinoma is extremely rare in its pure form, accounting for fewer than 1% of all testicular tumors, but is commonly found as a component of other testis tumors [22]. This is the most aggressive variant in adults, with early hematogenous and lymphatic spread. The poor prognosis of these patients is probably related to the typically larger volume of disease at presentation rather than an intrinsic resistance to treatment. This tumor secretes high levels of beta-hCG but normal levels of AFP.

Teratoma: Teratoma is a common component of mixed germ-cell tumors but in its pure form only represents 2% to 3% of all testicular malignancies. It has been referred to as benign in the past because, technically, no malignant tissue exists in these terminally differentiated tumors. Degeneration to a malignant form, however, is observed, and patients have died of associated metastases. Younger patients tend to have more mature tumors and older patients more immature forms. These tumors do not respond to chemotherapy and can manifest as an enlarging mass during chemotherapy in a serologically responding tumor. Surgery is the only effective therapy. Teratomas can secrete both beta-hCG and, more typically AFP, although usually neither is elevated.

Mature Teratoma: All three germ-cell elements (endoderm, mesoderm, and ectoderm) are presenting mature forms of teratoma, and elements such as skin, bone, teeth, and hair can sometimes be seen histologically.

Immature Teratoma: Immature tumors contain tissues that cannot be recognized as normal elements. The immaturity of the teratoma has not been shown to be an indicator of biologic aggressiveness. This behavior appears to be more related to the age of the patient, with aggressive disease more common in older patients [25].

Teratoma With Malignant Transformation: A variant of teratoma containing malignant non-germ-cell elements, presumably derived from somatic tissue within the teratoma, has recently been described [26]. The presence of malignant non-germ-cell elements at diagnosis or after induction chemotherapy implies a poor prognosis [27]. Teratomas have been demonstrated to degenerate into a variety of poor-prognosis malignancies, including sarcomas, adenocarcinomas, and neuroepitheliomas [28,29]. AML also occurs in patients with a history of teratomas [30-32].

Patients with one of these tumors who have had a germ-cell malignancy in the past should be evaluated for a duplication on the short arm of chromosome 12p, or i(12p). This duplication is a good indicator that the tumor is of germ-cell origin. Limited success has been reported using platinum based chemotherapy [26].

Sex Cord-Stromal Tumors

Leydig (Interstitial)-Cell Tumors: Leydig-cell tumors account for 1% to 3% of all testicular neoplasms [33]. They can appear at any age, but the median age at which they develop is 60 years. Leydig cells secrete both androgens and estrogens, and the clinical symptoms are usually related to endocrine abnormalities. Testicular swelling, gynecomastia, and decreased libido are common in patients with these tumors. Only 7% to 10% metastasize.

Sertoli-Cell Tumors: Fewer than 1% of testicular neoplasms are Sertoli-cell tumors. They can occur at any age, but 30% appear in the first decade of life. Patients generally present with a scrotal mass and sometimes have gynecomastia. Only about 10% of these tumors are malignant and, as with Leydig-cell tumors, the primary treatment is surgical.

Granulosa-Cell Tumor: Granulosa-cell tumors have two distinct types: juvenile and adult. The juvenile variety is the most frequently seen non-germ-cell testicular tumor in infants, and no malignant behavior has been reported in this type. The adult form is the least common of the sex cord-stromal tumors.

Gonadoblastomas: Gonadoblastoma is a mixed germ-cell and sex cord tumor that generally occurs in dysgenetic gonads or undescended testes during the teenage years. It is bilateral about 30% of the time. These tumors are clinically benign, but pathologic analysis reveals that they are accompanied by foci of malignant germ-cell tumors in 10% to 50% of cases. The prognosis varies and appears to depend on the other germ-cell components present and their extent of invasion. For patients with pure gonadoblastoma, the outcome is excellent [34].

Lymphomas and Leukemias

Primary malignant lymphomas of the testis are uncommon, accounting for only 5% of all testicular neoplasms. Lymphoma involves the testis more commonly as a late manifestation of disseminated disease. This occurs in about 20% of all cases of lymphoma. It is important to note that the frequency of primary testicular lymphoma increases with age, and in patients over 60 years old it is the most common malignant tumor of the testis.

Leukemic infiltration of the testis usually occurs when the disease is disseminated; it can be detected in autopsy in up to 5% of patients with acute leukemia and 30% of patients with chronic leukemia. Testicular involvement is especially common among children with acute lymphoblastic leukemia who have had relapses after therapy [35].

Rhabdomyosarcomas

Rhabdomyosarcoma is the most common sarcoma in children and can originate in the testis. Ninety-five percent of these patients present with a scrotal mass. The testicular parenchyma is rarely involved, but the tumor is common in the spermatic cord and paratesticular tissue. After surgery, local recurrences are frequent, and the pelvic lymph nodes are a common site of metastases.

Metastatic Neoplasms

Testicular metastases occur in 2.5% of men with malignant tumors. The most common primary sites are the prostate, lung, skin (melanoma), colon, and kidney [36].

Extragonadal Germ-Cell Tumors

Extragonadal germ-cell tumors account for about 2% to 4% of all germ-cell tumors [37]. They can be seminomas or nonseminomas and generally occur in midline structures in the retroperitoneum, mediastinum, or pineal gland. Historically, it was felt that extragonadal nonseminomas had a worse prognosis than tumors arising in the testis. This is certainly true for those arising in the mediastinum. However, recent data indicate that nonseminomas arising in the retroperitoneum behave similarly to comparably sized stage II nonseminomas in the testis [37-40].

Extragonadal seminomas, regardless of their origin, do no worse than testicular seminomas of similar stage [41]. Many, if not most, germ-cell tumors arising in the retroperitoneum originate in the testis, so patients with retroperitoneal tumors should all be evaluated for an occult testicular malignancy. At least 40% will have an occult testis tumor or carcinoma in situ. This is not the case for germ-cell tumors arising in the mediastinum; testicular biopsies for individuals with such tumors are not indicated [42,43].

Diagnosis

Testicular cancer is the most common malignancy in young males and frequently occurs during a crucial developmental period of their lives. For a variety of psychological, social, and educational reasons, the average delay in diagnosis after symptoms appear is 4 to 6 months [44]. There are no early symptoms. About 65% of patients present with painless swelling or a nodule in one gonad. In another 20%, the testicular enlargement is painful because of bleeding or infarction in the tumor, and acute pain in a patient with a cryptorchid testis suggests torsion of a hidden mass. About 10% of patients present with symptoms from metastases, such as lumbar back pain, gastrointestinal disturbance, respiratory symptoms, or a neck mass. Gynecomastia is seen in about 5% of patients and occasionally infertility is the initial complaint. Exophthalmos and skin metastases can be the first manifestations of choriocarcinoma.

The physical examination should include bimanual examination of the testes. The normal testis has an even consistency, is freely movable, and is separable from the epididymis. Any nodule or firm fixed area or mass is suggestive of disease, and testicular cancer must be considered until this possibility is disproved.

The differential diagnosis includes testicular torsion, epididymitis, epididymal orchitis, hydrocele, hernia, hematoma, or spermatocele. High-resolution ultrasonography is a rapid, reliable tool for excluding the possibility of hydrocele or epididymitis when a tumor is suspected. It can also demonstrate whether the mass is intratesticular or extratesticular. If it is extratesticular and does not involve the tunica albuginea, then conservative treatment can be elected [44].

A suspected testicular tumor should be surgically explored and biopsied through an inguinal incision. Careful histologic examination will establish the diagnosis. Trans-scrotal biopsy is contraindicated because it alters the lymphatic drainage, and if a malignancy is found, a more extensive surgical procedure is required to remove the primary tumor [45]. After the diagnosis is made, clinical tests to stage the patient are performed. These include a computed tomography (CT) scan of the abdomen and pelvis, chest x-ray and beta-hCG, AFP, lactate dehydrogenase (LDH), and sometimes placental alkaline phosphatase. If clinically indicated, a magnetic resonance imaging (MRI) or CT scan of the brain and a bone scan may be done.

The diagnosis and staging evaluations for extragonadal germ-cell tumors are similar to those for testicular tumors. Those with a retroperitoneal presentation should be explored for an occult testicular primary, which is frequently present. Again, with a mediastinal tumor, this is not indicated [42,43].

Tumor Markers and Cytogenetic Abnormalities

Our ability to accurately diagnoses, stage tumors, monitor response to treatment, and assess patients for early relapse has been greatly facilitated with the identification of tumor markers. These markers can be divided into three categories: (1) serum proteins, such as beta-hCG, AFP, placental alkaline phosphatase, and LDH, (2) cytogenetic or chromosomal markers, such as i(12p), and (3) molecular markers, including oncogenes and tumor suppressor genes. Serum protein markers are the best studied and the most clinically relevant to date.

Beta-hCG, first detected in 1930 in the urine of patients with advanced choriocarcinoma, was the first tumor marker associated with testis cancer [46]. Subsequent refinements in our ability to measure CG have taken us from detecting it only occasionally in advanced disease to precisely measuring it in patients who have no observable tumor. The CG protein is composed of 2 subunits, alpha and beta, and modern assays measure only the beta portion. Beta-hCG is elevated in 40% to 50% of patients with testis cancer, including all patients with choriocarcinoma, approximately 80% of patients with embryonal carcinoma, and 10% to 25% of patients with pure seminoma [47,48]. The degree of elevation has some correlation with the volume of disease, and recurrent elevation is an excellent marker of early relapse [49,50]. Beta-hCG has a half-life of 24 to 36 hours, and, after surgery, levels should fall in accordance with this half-life. If they do not, residual disease is likely present.

When using beta-hCG to monitor response to chemotherapy, a 90% decrease every 21 days should be seen. Less steep declines are associated with the emergence of drug resistance and a poorer outcome [51]. It is important to note that some beta-hCG assays cross-react with luteinizing hormone (LH) [52]. When the treatment has resulted in testicular atrophy, the LH can be substantially elevated. If a falsely elevated beta-hCG level is suspected, a single 200-mg injection of testosterone cypionate can be given and the beta-hCG level rechecked after 2 weeks [53]. Beta-hCG can also be increased in patients who use tobacco or marijuana, and this possibility should be looked into if a minor elevation persists.

Alpha-Fetoprotein (AFP) was detected in adult germ-cell tumors in 1974 [54]. It is an abundant serum-binding protein in the fetus, but only minimal amounts of AFP are normally detectable in individuals more than 1 year old. Fifty to seventy percent of patients with testis cancer have elevations of AFP, which are most often seen in patients who have elements of embryonal or yolk-sac carcinoma [47,49] and occasionally seen in patients with teratoma, but not seen in patients with pure choriocarcinoma or pure seminoma [55]. Seminoma with an elevated AFP behaves like nonseminoma and should be treated as such.

High levels of AFP correlate with bulky disease, and after treatment, rising levels are a good marker for early recurrence. Because of AFP's long half-life (5 to 7 days), its occasional production by teratomas, its frequent sequestration inside cysts, and the variety of benign liver conditions that can cause it to be elevated, caution should be used when monitoring its rate of decline to assess response to therapy.

LDH: Levels of LDH and, in particular, its isoenzyme 1 are elevated in approximately 80% of patients with advanced testis cancer. Though not as specific as beta-hCG or AFP, in some patients LDH is the only elevated marker, so it can have clinical utility. High levels correlate with tumor burden, risk for relapse, and a poorer survival [51].

Placental Alkaline Phosphatase: Placental alkaline phosphatase is the fetal isoenzyme of adult alkaline phosphatase. It is detectable in 30% to 50% of patients with stage I seminoma and in nearly 100% of patients with advanced seminoma but is less commonly elevated in nonseminomatous tumors [56-58]. Clinical experience with this marker is more limited than with beta-hCG, AFP, or LDH, but when it is elevated, it can be useful in following the course of seminoma. Smoking can cause false elevations of this marker; thus, in patients who smoke, placental alkaline phosphatase monitoring is less reliable [51].

Cytogenetics and Molecular Markers: Cytogenetic abnormalities in testicular tumors are beginning to be explored. Detailed karyotypic analysis has revealed nonrandom changes in chromosomes 1, 5, 6, 7, 9, 11, 12, 16, 17, 21, 22, and X [59]. Of these, a duplication on the short arm of chromosome 12p, or i(12p), is the best studied and the most characteristic. This marker was present in one or more copies in approximately 89% of seminomas and 81% of nonseminomas studied [58]. Most of the remaining patients had other abnormalities involving the 12p chromosome [60]. The i(12p) marker is also observed in extragonadal germ-cell tumors and occasionally in ovarian dysgerminomas but is rare in other tumors. It is a highly specific marker for germ-cell tumors and a useful diagnostic tool in cancers of unknown origin [61].

How i(12p) participates in the development of testis cancer is unknown. The oncogene c-ki-ras 2 resides on the short arm of chromosome 12 [62], but amplification of this gene as a transforming event has been difficult to show. Other oncogenes and their products have been investigated, but as yet their significance and roles in the pathogenesis of testis cancer remain to be demonstrated.

In summary, beta-hCG, AFP, LDH, and placental alkaline phosphatase have been shown to be of value in diagnosis by identifying patients who have histologic types other that those reported, in staging by identifying patients with high tumor volume that is not readily radiographically apparent, in monitoring response to treatment, and in detecting relapse early, when it is most curable. The presence of i(12p) is useful in identifying tumors of unknown origin. Molecular markers are at present still research tools but ultimately are expected to yield improved diagnostic and therapeutic strategies as well as provide a much better understanding of these diseases.

Staging and Treatment

Carcinoma in situ

Carcinoma in situ (CIS) is known to be a preinvasive lesion, and detecting and treating it early in patients at risk for testicular carcinoma could potentially prevent cancer development. The only reliable way to diagnose CIS is with a surgical biopsy after puberty.

The likelihood of eventually developing a testicular tumor where CIS is present is extremely high, so screening is useful in groups at high risk of developing CIS [42]. Estimates of individuals with increased risk show that men with a unilateral testicular tumor have a 6% incidence of CIS in the other testis [63], and men with a history of cryptorchidism have a 2% to 3% incidence of CIS [64]. In patients with extragonadal germ-cell tumors of the retroperitoneum, the incidence is greater than 40% [43], and in intersex patients as well as individuals with gonadal dysgenesis, a greater than 25% incidence has been reported [65].

Orchiectomy is the treatment of choice in patients in whom one testis is normal and the other contains CIS. In men who have had a previous unilateral orchiectomy and now have CIS in the remaining testis, 20 Gy of radiation given in 10 doses of 2 Gy is sufficient to eradicate the CIS and still maintain adequate endogenous testosterone [42]. Fertility does not appear to be compromised by this degree of radiation, but men with a history of testicular cancer in one testis and CIS in the other frequently have impaired spermatogenesis prior to any therapy.

Screening is only recommended for patients with a history of unilateral testis cancer, extragonadal germ-cell tumors of retroperitoneal origin, or gonadal dysgenesis and for intersex patients. In patients with a history of cryptorchidism, a testicular biopsy can be considered. Newer methods that involve examining the semen are being developed that may expand the designation of reasonable candidates for screening.

Seminoma

The treatment of seminoma is gratifying to the oncologist because the disease is quite curable. The expected overall survival is approximately 97% [66]. This tumor is quite radiosensitive as well as very chemosensitive.

Seminoma is relatively indolent and follows a predictable pattern of progression. It starts in the testis and spreads via the para-aortic lymph nodes to the mediastinal nodes and then the supraclavicular nodes. It rarely metastasizes to distant organs such as the lungs or bones without first being seen at nodal sites. Overall, 75% of patients present with stage I disease (confined to the testis), 20% with stage II disease, and fewer than 5% with stage III or IV disease [66]. Several similar staging systems for seminomas have been devised (Table 2). The main differences are in the definition of stage II and in the way bulky and nonbulky retroperitoneal disease are divided.

Royal Marsden HospitalM.D. Anderson Cancer CenterMemorial Sloan-Kettering Cancer CenterAmerican Joint Committee on CancerBoden-Gibb Commission on Cancer
I: confined to testisI: confined to testisA: confined to testisI: confined to testisA: confined to testis
IIa: RPLN < 2 cmIIa: RPLN < 5 cm
IIN1: microscopic disease in RPLNB: RPLN involved
IIb: RPLN = 2 cm or more and < 5 cmIIb: RPLN = 5 cm or more and = 10 cm or lessB1: RPLN < 5 cmIIN2: 5 LNs or less involved, all < 2 cm
IIc: RPLN = 5 cm or more and < 10 cmIIc: RPLN > 10 cmB2: RPLN = 5 cm or more and < 10 cmIIN3: > 5 LNs involved or LN > 2 cm
B3: RPLN = 10 cm or moreIIN4: unresectable LN
III: LN above diaphragm involvedIII: LN above diaphragm or visceral organs involvedC: LN above diaphragm or visceral organs involved

The initial considerations when planning treatment are to confirm that the tumor is truly a pure seminoma and to determine its stage. Careful review of the histologic and pathologic features is mandatory. The AFP level must be normal for the tumor to be considered a pure seminoma; beta-hCG and LDH levels should be tested and potentially will be elevated. The initial staging evaluation should include a chest x-ray, CT of the abdomen and pelvis, bone scan if symptoms indicate, and CT or MRI of the brain if neurologic symptoms are present.

Stage I Treatment: Treatment of stage I seminoma is somewhat controversial. The para-aortic lymph nodes are involved in approximately 15% of clinical stage I cases, and standard treatment has been orchiectomy plus radiotherapy to the para-aortic nodes, as well as the ipsilateral common iliac and external iliac nodes. If there has been a previous inguinal surgery or if an advanced local primary has invaded the scrotal skin, there is an increased risk of pelvic node spread, and the radiotherapy field is extended to include the ipsilateral inguinofemoral node region [67].

The standard dose of radiation, 25 to 40 Gy, results in a disease-free survival of 98% to 99%. A dose of 40 Gy has not been shown to be more effective than 25 Gy, so the lower dose should be used [68-71]. Side effects of radiation include dyspepsia in 6% of patients and frank peptic ulceration in 3% [4]. The effects on fertility are unclear, but most patients experience a decrease in sperm count that usually resolves in 3 years [72,73]. The relative risk of developing a second cancer within the irradiated field seems to be increased, but this effect does not become evident until 15 years after treatment [74-76].

Because salvage treatment in seminoma is so successful and most patients with stage I seminoma patients are cured with their initial surgery, close surveillance after orchiectomy is being reported as a viable option to radiation to reduce short- and long-term toxicity. The advantage of this approach is that it avoids radiation in the 85% of patients who are cured with orchiectomy. The disadvantage is that those who relapse will have an increased tumor volume and may be more difficult to cure.

The results in 583 patients treated with orchiectomy alone and followed by investigators from the Princess Margaret Hospital, the Royal Marsden Hospital, and the Danish National Study are encouraging [65]. At 3 years, the rate of relapse was 15.5%, with a median time to relapse of 12 to 15 months. The relapses were treated with salvage radiation or chemotherapy. Only 2 of the original 583 patients (0.3%) died with disease, producing a 99.7% disease-free survival [66].

It must be remembered that the lack of a sensitive and reliable marker in addition to the slow natural history of a seminoma make the surveillance approach challenging. The follow-up schedule in Table 3 is recommended. It is imperative that the patient be dependable and available for frequent follow-up for an extended period of time.

Test*BaselineYears 1 and 2Years 3 and 4Year 5
Every 3 monthsEvery 4 monthsEvery 4 monthsEvery 6 months6 monthsYearly
Histology/pathologyXX
beta-hCG, AFP, LDHXX
Chest x-rayXXX
CT abdomen/pelvisX

Stage II Treatment: The treatment strategy for stage II disease differs with the size of the involved abdominal lymph nodes. Historically, radiotherapy was used for all stage II patients, and it is still the treatment of choice for early stage II disease (abdominal masses less than 5 cm).

The usual dose is 36 Gy, which yields a disease-free survival of about 95% [68,70,77-81]. Mason and Kearsley, in a review of the literature, found that the risk of relapse in stage II disease was directly related to tumor bulk. Abdominal masses between 5 and 10 cm had a risk of relapse of 8%, and for masses greater than 10 cm, the risk of relapse increased to 35% [82]. Prophylactic irradiation to the mediastinum for abdominal masses smaller than 10 cm should be avoided, because this strategy does not appear to improve survival but does cause an excess of cardiac, pulmonary, and marrow toxic effects [83].

There is no consensus on the optimal treatment for abdominal masses between 5 and 10 cm in diameter. The kidneys generally tolerate only 15 to 20 Gy of fractionated radiotherapy, and with tumors greater than 5 cm, there is frequently a significant amount of tumor overlying the kidneys. For this reason, some centers now recommend chemotherapy for all tumors greater then 5 cm [74]. If, however, the tumor is less than 10 cm and the kidneys are not in the field of radiation, then radiotherapy is still a good choice. Stage II disease with an abdominal mass larger than 10 cm is treated with chemotherapy similar to that used for stage III disease.

Stage III Treatment: The development of effective chemotherapy for advanced seminoma has lagged behind that for nonseminoma, in part because advanced seminoma is so uncommon. In the era before platinum drugs, responses to chemotherapy were common but cures were not. Platinum-based therapy has dramatically improved our ability to cure advanced-stage seminoma.

In 1974, the activity of cisplatin (Platinol) in germ-cell tumors was first reported [84], and this agent quickly became the backbone of testicular chemotherapy regimens. Improved results with the PVB (cisplatin, vinblastine, and bleomycin [Blenoxane]) regimen were first reported in 1981 [85] and subsequently confirmed in a larger multicenter trial [86]. The most common variations on this regimen are the BEP (bleomycin, etoposide [VePesid], and cisplatin) regimen, in which etoposide is substituted for vinblastine [87,88], and the VIP (vinblastine, ifosfamide [Ifex], cisplatin) regimen in which ifosfamide is used in place of bleomycin [89]. These have yielded comparable disease-free survivals, ranging from 75% to 85% [74].

Recently, the combination of cisplatin and etoposide has been shown to be at least as effective as other standard regimens with less toxicity, and it is now the standard in some institutions. The role of bleomycin in the treatment of seminoma is uncertain. The drug appears to add little benefit, and the high frequency of fatal pulmonary side effects among patients with pure seminoma suggests that this population may have a unique sensitivity to bleomycin [90].

A somewhat different approach employs the use of sequential weekly cisplatin and cyclophosphamide (Cytoxan, Neosar). In one study, this combination resulted in a 92% long-term continuous disease-free survival [91]. In another group of patients, cisplatin alone and carboplatin (Paraplatin) alone were less successful, but a high proportion of these patients did respond to cisplatin-based salvage regimens. In 1992, a cure rate of 97% was reported with the combination of carboplatin, ifosfamide, and selective consolidation with alternating non-cross-resistant chemotherapy agents [92].

Residual Mass: A residual mass can be detected after chemotherapy for bulky metastatic seminoma in one half to two thirds of cases. Attempts to resect these masses have often revealed only densely fibrotic tissue that is adherent to major blood vessels, and severe operative and postoperative complications have been reported [97,92]. The relationship between the size of a residual mass and whether it contains viable tumor is unclear, with some studies showing that a mass greater than 3 cm correlates with residual disease [93,94] and other studies not demonstrating this relationship [95,96]. A practical policy is to monitor these masses closely and administer radiotherapy to those that do not continue to shrink [97].

Nonseminomatous Germ-Cell Tumors

The natural history of nonseminomatous germ-cell tumors tends to be less indolent and less predictable than that of seminomas. Nonseminomas have a greater likelihood of dissemination via the blood to distant sites, sometimes while bypassing the retroperitoneal lymphatics. Although nonseminomas (except for teratomas) are probably equally as chemosensitive as seminomas, they are less radiosensitive. As a result of these differences, the staging, treatment, and follow-up recommendations for nonseminoma are somewhat different from those for seminoma.

Several staging systems for nonseminomas have been proposed, but most of them are similar. Table 4 lists some of the more common systems in use. The main distinctions are in how the stages are labeled rather than in the actual stages themselves.

DescriptionStage
MSKCCWRTNM
Confined to testisAIN0
Microscopic nodal involvement only, 5 or less nodes involved, and all nodes < 2 cmB1IIAN1 or N2A
Grossly positive nodes, or 6 or more nodes involvedB2IIBN2B
Bulky retroperitoneal invovlement, unresectableB3IICN3
Metastases above the diaphragm or spread to solid visceral organsCIIIM1

The full tumor-node-metastasis (TNM) staging system is shown in Table 5.

Tumor statusªRegional lymph-node statusMetastasis status
T2: Confined to body or testisN0: No nodes involvedM1: Supradiaphragmatic or extralymphatic involvement
T2: Extending through the tunica albicaN1: Microscopic only
T3: Involving the rete testis or epididymis, 6 or more involved nodesN2A: Largest node = 2 cm or less, and
T4: Involving the scrotal wallN3: Nodal extension into adjacent structures

Stage I Treatment: Clinical stage I tumors represent approximately 50% of all nonseminomatous germ-cell tumors. About 30% of these patients will relapse with occult metastatic disease if not given some form of adjuvant therapy. Numerous treatment approaches for stage I nonseminoma have been tried, but there is no consensus on which is best. These approaches have included (1) retroperitoneal lymph-node dissection (RPLND) after orchiectomy, (2) close surveillance after orchiectomy (no adjuvant therapy), (3) adjuvant chemotherapy for all patients or for selected individuals with adverse prognostic features, (4) RPLND and adjuvant chemotherapy for pathologic stage II patients, and (5) adjuvant radiotherapy.

Most of these approaches have their advocates, but adjuvant radiotherapy has fallen out of favor. Nonseminomas are less radiosensitive than seminomas, and side effects from the increased doses of radiation required to treat nonseminomas are prohibitive. Also, nonseminoma is more likely than seminoma to relapse outside the radiation ports [98].

Proponents of RPLND for all stage I nonseminomas list the following advantages: This technique provides more accurate staging, it may be curative in 60% to 75% of cases with early evidence of nodal metastases, and it can provide an indication for immediate adjuvant chemotherapy in cases with more extensive nodal disease [99]. The disadvantages of the procedure include the following: Retrograde ejaculation occurs in most patients who undergo traditional RPLND and in 10% to 15% of patients who have a nerve-sparing RPLND, even when performed by experienced urologists [99]; a major surgery is performed in the 70% of patients who were already cured by orchiectomy alone; and the rate of relapse in patients who undergo RPLND is only decreased from 30% to about 12%. Most of these relapses, however, occur in the lungs and are generally easily managed with chemotherapy.

Another approach, surveillance after orchiectomy was introduced at the Royal Marsden Hospital in 1979 and is currently the recommended treatment for most clinical stage I patients in Europe and some centers in the United States. In 1993, Sternberg [100] reported on 1,337 patients culled from published studies who were not given RPLND or other adjuvant therapy. The median follow-up was 40 months, and the relapse rate was 28% with a median time to relapse of 5 to 6 months. The rate of complete remission with chemotherapy after recurrence and the overall survival were 99%. If surveillance is chosen, the follow-up is similar to that for surveillance for stage I seminoma (Table 3).

Adjuvant chemotherapy after orchiectomy with two cycles of chemotherapy, either for all patients or for selected high-risk patients, is another choice. This option is only beginning to be studied, so there are few data on it. The extremely high rate of cure with observation and chemotherapy at recurrence makes it difficult to justify giving adjuvant chemotherapy to all patients. However, if a group with a sufficient risk of developing metastatic disease could be identified and if these patients could be cured with less chemotherapy and less associated toxicity, then it would be a reasonable option.

The Medical Research Council recently reported on a group of 259 patients, of which 61 were felt to have a greater than 50% chance of relapse [101-103]. This assessment was based on the presence of three or all of the following four factors: tumor invasion of the testicular veins, tumor invasion of the testicular lymphatics, the presence of undifferentiated cells, or the absence of yolk-sac elements. These high-risk patients were given two cycles of adjuvant BEP chemotherapy, and after a median follow-up of 18 months, no relapses have been seen.

In summary, none of the above treatment options have been conclusively shown to be superior, and the best choice for a given patient will likely depend on the resources and experience of the treating institution as well as the preferences and reliability of the individual.

Stage II Treatment: The optimal management of stage II nonseminomas is no more settled than for stage I disease, but fortunately, several good options exist. Stage IIC (unresectable) should be treated with chemotherapy similar to that recommended for good-prognosis stage III patients. However, for stage IIA and IIB, the decision of whether to treat initially with chemotherapy or with RPLND with or without adjuvant chemotherapy is unsettled. In Europe and in a few centers in the United States, primary chemotherapy for stage II patients is becoming the standard. However, most large cancer centers in the United States still recommend that patients with resectable stage II disease be treated with RPLND first.

Drawing conclusions from the literature is challenging because comparative trials are not available, and it is likely that neither option is superior in every situation. The expected cure rate with either treatment is greater than 95%, and aggressive therapy is not likely to affect this rate significantly. Thus, the goal is to maintain this cure rate while minimizing morbidity. Opinions vary as to whether chemotherapy or RPLND is more toxic, but it is obvious that surgery and full-course chemotherapy together are associated with greater morbidity than either approach alone. The goal, therefore, is to select the therapy that is most likely to be curative by itself.

The traditional approach for stage IIA and IIB disease has been RPLND. The rationale is that it is effective therapy and the most accurate method of staging. In a large prospective trial reported by the Testicular Cancer Intergroup Study, the risk of recurrence after RPLND without adjuvant chemotherapy was 40% for patients with N1 disease using TNM staging (Table 5), 55% for patients with N2A disease, and 60% for patients with stage N2B disease [99]. These results agree with those of other retrospective series in that about 50% of patients with pathologic stage II disease relapse after RPLND [104,105]. The risk of recurrence after RPLND correlates with the degree of nodal involvement. When lymph nodes are larger than 3 cm, the risk of relapse rises to greater than 70%, and the need for adjuvant chemotherapy should be considered [106].

Patients who are treated initially with RPLND can either receive two cycles of adjuvant chemotherapy or be observed closely and, if relapse occurs, receive three to four cycles of chemotherapy and possibly a second surgery. The advantage of observation is that it avoids any chemotherapy in the 50% of patients who are cured with their surgery alone. The disadvantage is that more chemotherapy is required if a relapse occurs, and a second surgery could be indicated should a residual mass remain after this treatment. Because the toxicity of bleomycin and cisplatin is cumulative, two cycles of chemotherapy are significantly less toxic than three or four.

In the Testicular Cancer Intergroup Study, greater chemotherapy-related toxicity was seen in the group assigned to observation with chemotherapy at relapse than in the group treated initially with adjuvant chemotherapy. However, fewer patients in the observation arm required chemotherapy [107]. Which therapy is selected should be based on the patient's risk factors for recurrence. Individuals with risk factors such as vascular or lymphatic invasion in the primary or abdominal lymph nodes larger than 3 cm should probably receive two cycles of adjuvant chemotherapy. If these factors are not present, then close observation is a reasonable option.

A more recent approach to the management of stage IIA and stage IIB disease is to treat with three to four cycles of chemotherapy initially and to reserve RPLND for radiographically persistent retroperitoneal disease. Several studies have shown the feasibility of this approach [108-113]. Although most of these studies included patients with stage IIC disease, the complete remission rates were between 95% and 100%. However, to achieve a complete remission, 15% to 30% of the patients required an RPLND because of a residual mass. In studies of this approach with sufficient follow-up, the overall survival is comparable to that obtained with primary RPLND.

The advantages of primary chemotherapy vs RPLND alone are that a major surgery is avoided in 70% to 85% of the patients and that less compliance in returning for follow-up is required from the patient because the incidence of relapse is much less. Also, nerve-sparing RPLND cannot generally be done in this setting, and as a result, absent or retrograde ejaculation occurs in 70% to 80% of the patients undergoing RPLND [114]. The disadvantages are that every patient receives three to four cycles of chemotherapy, rather than only the 50% of patients who eventually relapse after surgery, and that 15% to 30% of the patients who receive primary chemotherapy will still require RPLND for a residual mass.

In choosing appropriate therapy, the importance of histologic type in the primary tumor site is becoming more clear [115]. If embryonal carcinoma without teratoma predominates, then initial treatment with chemotherapy is appropriate, because (1) residual abdominal masses are uncommon, and (2) this tumor frequently recurs in the lungs, making patients treated with RPLND alone at high risk of recurrence. If teratoma is present, then there is a high likelihood that a residual mass will remain in patients treated with primary chemotherapy and a RPLND will be needed anyway. Such patients would probably benefit most from initial treatment with a RPLND. At RPLND, if only minimal disease is found, then surgery alone is likely sufficient and observation is appropriate [116]. If lymph nodes larger than 3 cm are found or if the primary had, in addition to teratoma, a predominant embryonal component, then adjuvant chemotherapy is indicated [106].

Stage III Treatment: Significant progress in chemotherapy for patients with advanced nonseminomatous germ-cell tumors has been made in the past 20 years. Presently, with multimodality therapy, the majority of these individuals are cured. The development of chemotherapy for stage III (disseminated) nonseminoma has been fascinating and serves as an important model for the treatment of solid tumors in general. This evolution is reviewed in numerous publications and oncology textbooks and will not be discussed in detail here.

Patients with disseminated nonseminomatous germ-cell tumors differ widely in the volume of disease at presentation. Their prognoses and need for aggressive treatment vary and largely depend on tumor bulk at diagnosis.

Most studies divide patients into good- and poor-prognosis categories. The goal is to improve cure rates by identifying patients at increased risk of relapse and treating them more aggressively, while sparing patients with high probabilities of cure the side effects of intensive therapy when a milder approach would be as effective. Several groups have come up with different criteria for making this division, including the National Cancer Institute [116], the European Organization for Research and Treatment of Cancer [117], M. D. Anderson Cancer Center [118], Memorial Sloan-Kettering Cancer Center [119], the Southeastern Cancer Study Group [119], the Danish Testicular Cancer Study group [120], and the Medical Research Council [121]. There is no consensus on which system is best and whatever the treating physician is most familiar with is probably acceptable.

In the Medical Research Council System (Table 6) four adverse criteria were identified. Sixty-seven percent of patients studied had none of these features and were placed in the good-prognosis group. Their 3-year survival was 93%. The remaining 33% of patients had one or more adverse features and had a 3-year survival of 68% [121].

AFP > 1,000 kU/L

Beta-hCG > 1,000 IU/L

Mediastinal mass > 5 cm

Liver, osseous, or central nervous system metastasis

Chemotherapy for Stage III Good-Prognosis Disease: Regardless of the tumor classification used, a complete remission rate of greater than 90% should be achieved with appropriate treatment. The prognoses of stage IIC and good-risk stage III patients are similar and the two groups are generally treated in the same way. PVB was initially shown to have excellent activity in this group of patients [122]. Subsequent studies have shown the BEP regimen to give comparable results with less toxicity [123-125]. A randomized study that compared three vs four cycles of BEP chemotherapy did not show any benefit for four cycles in this group but did show increased toxicity, so three courses have been recommended.

Other options include the CISCA/VB (cisplatin, cyclophosphamide, daunorubicin [Cerubidine] or vinblastine, and bleomycin) regimen [115] or the POMB/ACE (cisplatin, vincristine [Oncovin], methotrexate, bleomycin or dactinomycin [Cosmegen], cyclophosphamide, etoposide) program [123,125]. These strategies use a variable number of cycles that is determined by the patient's response to therapy. Two cycles are given beyond the maximum response. Excellent results have been reported with all of these regimens, and none has been conclusively shown to be superior in randomized trials. Much of the focus of recent research has been on reducing treatment toxicity while maintaining current cure rates. Trials are currently underway to look at less toxic regimens.

Chemotherapy for Stage III Poor-Prognosis Patients: The treatment of poor-prognosis stage III disease has been less gratifying. The same regimens used for good-prognosis patients have been tried in poor-prognosis patients but with considerably less success. Long-term survival rates vary drastically from study to study, largely because of differences in how risk groups are defined, but the cure rate has generally been reported to be between 35% and 65%.

When three vs four cycles of BEP were compared in this population, three cycles were clearly inferior and are therefore not recommended. Attempts however, to escalate doses of cisplatin beyond 100 mg/m² have only increased toxicity and have not improved survival [126]. Except in clinical trials, standard doses of cisplatin should be employed. Regimens such as POMB/ACE and CISCA/VB that employ a variable number of cycles have shown promising results in poor-prognosis patients in nonrandomized trials, but appropriate randomized trials have not been done to confirm their superiority [115,127].

Newer approaches using ifosfamide [128] and autologous bone marrow transplantation (ABMT) are currently being studied [129,130], but their efficacy is unproven as yet. The only randomized trial comparing standard chemotherapy vs two cycles of chemotherapy followed by high-dose chemotherapy and ABMT failed to show any benefit for the ABMT arm. Thus, this approach cannot be recommended [130]. Other strategies using multiple courses of non-cross-resistant regimens such as BOP (bleomycin, vincristine, cisplatin), CISCA, and POMB/ACE with growth factors to decrease the time intervals between treatments are showing early promising results [118].

RPLNDP After Chemotherapy: The recommendations on whether to perform surgery after chemotherapy vary. Some investigators recommend observation for all patients irrespective of any residual radiographic abnormality [131], and others prefer surgical exploration in all patients [132,133]. The only commonly accepted contraindication to surgery is the presence of an elevated AFP or beta-hCG level, which would imply viable germ-cell tumor; these patients are better served with salvage chemotherapy [134].

A review of the literature on patients with advanced germ-cell tumors suggests that, at surgery, about 45% of patients are found to have necrosis only, 35% have teratoma, and 20% have viable tumor [135,136]. Surgery in patients with a residual mass requires that a full RPLND be done because a nerve-sparing procedure gives an unacceptably high rate of relapse [135].

Attempts have been made to identify patients in whom a RPLND can be avoided based on the following: normal levels of serum markers after chemotherapy, absence of teratoma in the primary, greater than 90% tumor shrinkage, and a residual mass smaller than 2 cm. Using these criteria, approximately 20% of patients will not require surgery, but of these, about 20% will still have residual teratoma or viable germ-cell tumor [137,138]. Surgery for any residual mass is probably the safest option because of the poor results with other treatments for these patients, but if surgery is not chosen, close follow-up is mandatory.

When necrosis or mature teratoma only is found at surgery, no further therapy is indicated. However, studies consistently show that the majority of patients in whom viable tumor is found will relapse. Overall survival is better if adjuvant chemotherapy is given initially rather than waiting and treating with salvage therapy at relapse [137,138]. The current recommendation is to give two additional cycles of alternate chemotherapy [138].

Salvage Chemotherapy

Germ-cell tumors are unusual among solid tumors because cure is still possible after relapse or even after failure to achieve a complete remission with initial therapy. Approximately 5% of good-prognosis and 35% of poor-prognosis stage III patients require salvage chemotherapy. Both standard salvage chemotherapy and high-dose chemotherapy with bone marrow support are toxic, and the majority of patients who undergo these treatments will not achieve a durable complete remission and will die from their cancer. The best predictor of who will relapse is the response to initial therapy as manifested by the rate of fall of AFP and beta-hCG [139,140].

Standard salvage chemotherapy uses new agents in combination with cisplatin to treat patients at conventional or moderately increased doses [141]. More aggressive treatment involves either increasing the frequency and number of cycles of chemotherapy [142,143] or administering very high doses of chemotherapy with bone marrow rescue [143].

The conventional approach for patients with a first relapse is to use salvage chemotherapy. Approximately 25% to 30% of patients treated in this manner will achieve a durable complete remission [142]. The prognosis is much worse for those who fail to achieve a complete remission at initial therapy. Only about 7% of these will be cured with standard salvage treatment [142]. The most common salvage regimens used are PVbI (cisplatin, vinblastine, ifosfamide) for patients who relapse after BEP, and PEI (cisplatin, etoposide, ifosfamide) for patients who relapse after PVB [144,145].

For patients who do not respond to standard salvage therapy and possibly for those who do not achieve a complete remission with initial therapy, high-dose chemotherapy with bone marrow support is another approach. A review of the literature indicates that between 8% and 20% of these patients can still achieve a durable complete remission. In some of these studies, however, follow-up was short and a selection bias was likely present [146-149]. This remission rate is far from ideal, but in this setting it is the best evaluated option so far.

New strategies are being developed that involve novel chemotherapeutic agents, alternation of non-cross-resistant courses utilizing growth factors to shorten the interval of chemotherapy based on patient hematologic and nonhematologic recovery, induction with two or more courses of standard salvage chemotherapy followed by high-dose chemotherapy with bone marrow support, and two or more courses of high-dose chemotherapy with bone marrow rescue.

Conclusions

The treatment of testicular neoplasms is both rewarding and challenging-rewarding because of its high cure rate, and challenging because knowing which therapies to select and how to use them requires a thorough understanding of the literature and the disease. It is also challenging, because patients with testis cancers frequently require aggressive treatment to provide the best opportunity for cure, yet expert management to avoid unnecessary morbidity and mortality. There are still many improvements to be made in finding ways to reduce both short-term and long-term toxicity, as well as in the area of salvage treatment.

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