Testicular tumors are uncommon in the general population but are some of the most common and important malignant tumors in young men. Worldwide, 52,000 new cases and 9,000 deaths were estimated from this disease in 2008.¹ The vast majority are primary germ cell tumors (GCTs); the others include lymphomas and sarcomas. The incidence of GCTs has doubled in the past 30 years. Although most patients (70% to 80%) present with early-stage, highly curable disease, the continued rise in incidence of these tumors presents a major challenge. Management is based on histologic type and disease extent. Advances in chemotherapy, imaging, and multidisciplinary care have led to improvements in outcomes over the past three decades. In this chapter, we will discuss the management principles for patients with primary GCTs of the testis, malignant extragonadal GCTs, and other rare testicular tumors.

Etiology and Epidemiology

Testicular cancer accounts for only 1% to 2 % of all cancers in men in most populations across the world.² Germ cell testicular tumors are the most common solid malignant tumors in men between 20 and 35 years of age, and it was estimated that in the United States in 2010, there would be 8480 new cases and 350 deaths from testicular cancer.³ The cumulative lifetime risk of developing a GCT for a white man in the United States is 0.2%.⁴ Although the disease is rare, the observed rising incidence is a concern. Between 1973 and 2003 the incidence of GCTs rose by 61% in the United States, with the major rise occurring in seminomas rather than nonseminomas.⁵

The age distribution of testicular cancer is similar in all populations of European origin. There is a small peak in early childhood at around 2 years of age, with rates then remaining low until 15 years of age. There is a second peak in young adults at around 25 to 40 years of age, and the rate then declines, with a small peak again between 65 and 75 years of age. Testicular cancers occurring in childhood and in the young adult years are usually GCTs, whereas those occurring after age 65 years are principally non-germ cell malignant tumors, mainly lymphomas. Nonseminomatous tumors are more common in childhood and in young men between 15 and 30 years of age, whereas seminomas present on average 1 decade later (at 25 to 40 years of age).

Risk factors for testicular germ cell cancer (TGCC) include a family history of cancer, the presence of an undescended testis or gonadal dysgenesis, subfertility, and testicular microlithiasis. Men with a history of cryptorchidism have an approximately six-fold increased chance of developing testicular cancer.⁶ Orchiopexy prior to puberty appears to lower the risk of developing a subsequent tumor and may help preserve Leydig cell function and enhance fertility.^7,⁸ Although most testicular cancers in men with a history of maldescent occur on the ipsilateral side, approximately 5% to 20% develop in the contralateral testicle.⁶ The mechanism by which cryptorchidism increases the risk of developing GCTs is unknown, but the effects of maldescent on the testis (i.e., increased temperature or increased risk of trauma if the testis is in the inguinal region) have been suggested as possible factors. The increase in the incidence of tumors in the contralateral testicle, however, suggests that maldescent and testicular cancer may result from the same prenatal etiologic process. Other genitourinary abnormalities associated with testicular cancers include hydrocele and hypospadias.⁹

There is considerable geographic and ethnic variation in the incidence of testicular tumors, with the highest incidence being reported from Denmark (8.4 per 100,000 men per year) and Switzerland (6.2 to 8.8 per 100,000 men per year).⁸ The incidence of testicular cancer is lower in non-Europeans as compared with Europeans. In the United States, white men (6.36 per 100,000 per year) are five to six times more likely to develop testicular cancers than black men (1.30 per 100,000 per year); low incidence rates are seen in other ethnic groups, such as Americans of Chinese and Japanese descent.⁵ A high incidence of testicular cancer is seen in some nonwhite populations such as the Maoris in New Zealand and Native Americans.¹⁰

Prior testicular cancer is a major risk factor for the development of a contralateral malignant tumor. In a large population-based follow-up study of 29,515 patients with unilateral testicular cancer, the cumulative risk (at 15 years after diagnosis of the primary tumor) of developing a contralateral malignant tumor was 1.9%.¹¹

Heritability of Testicular Germ Cell Cancer

The racial disparities in persons who develop GCTs and the association with other urogenital abnormalities strongly suggest a genetic susceptibility to this disease. In support of this hypothesis, GCTs are among the most heritable of all cancers. Several studies estimate the risk to brothers and fathers of patients with testicular germ cell cancer (TGCC) to be 4 to 6 times increased and 8 to 10 times increased, respectively. This is far greater than the twofold elevated risk of first-degree relatives in other cancers, such as cancers of the breast or colon or melanoma. The relative risk is much greater in monozygotic and dizygotic twins. In addition, brothers and fathers of patients with bilateral tumors have a risk 3.9 and 4.7 times greater, respectively, than relatives of patients with monozygotic tumors.

Given the strong familial association of TGCC, extended pedigrees with this disease are curiously rare. Most families with TGCC have two affected members, most commonly sibling pairs. The International Testicular Germ Cell Linkage Consortium has carried out two large-scale genome scans, neither of which provided convincing or replicable evidence for susceptibility gene(s).¹² Candidate association studies have demonstrated that rare gr/gr deletions of the Y chromosome predispose to TGCC, but such deletions cannot explain more than a fraction of heritable cases of this disease.

More recently, two groups carried out association studies, based on genome-wide, single-nucleotide polymorphisms (SNPs), of patients with TGCC and controls.^13,¹⁴ Both research groups identified strong evidence for two susceptibility loci for seminoma and nonseminoma; one locus is on chromosome 12p22, within the KITLG gene, encoding the ligand for the receptor tyrosine kinase KIT, and the second locus is on chromosome 5q31.3 near the SPRY4 gene, encoding sprouty 4, an inhibitor of the MAP kinase pathway. A third locus on chromosome 6 was identified by only one of the research groups and is not associated with a known gene. The relative risk was approximately 3 for the KITLG locus and about 1.4 for the other two loci. Both the KITLG gene and the SPTY4 gene are biologically feasible candidates because their products lie in the same signal transduction pathway. Moreover, activating mutations of the KIT gene have been identified in a subset of seminomas, while paradoxically, deletions of the KIT gene predispose to germ cell cancer in the SV/129 mouse strain. Of note, cases in the association studies included patients with and patients without a family history of TGCC, but none of these loci were enriched in the familial cases and neither were they associated with other abnormalities such as an undescended testis.

As mentioned above, the SV/129 mouse strain is particularly susceptible to the development of germ cell cancer, and this system has been exploited by Nadeau and colleagues ^14a to map several genes predisposing to the disease. Curiously, none of the corresponding loci in humans appear to have any role in TGCC development.

In summary, TGCC is a highly heritable disease, and at least two loci may contribute to its risk in the general population. Despite almost two decades of studies, however, no gene has yet been identified in families with this disease, suggesting that the genetic underpinnings of TGCC may be highly heterogeneous or novel, or both.

Environmental Factors and Testicular Germ Cell Cancer

Other factors linked to the development of TGCCs include a history of testicular trauma, an increased body mass index, immunosuppression following organ transplantation, and human immunodeficiency virus (HIV) infection.^2,¹⁵^–¹⁷ There is no evidence to suggest a causal relationship between testicular trauma and the development of a tumor, and the likely explanation is that testicular trauma leads to examination of the testes. Because of the age distribution of testicular cancer, exposure must occur early in life if there is an environmental contribution to the etiology of these tumors. Prenatal factors linked to the later development of testicular cancers include threatened miscarriage, excessive maternal nausea, and birth by caesarean delivery.² To explain these associations it has been suggested that exposure of the germinal epithelium in utero to an elevated level of free unbound maternal estrogen could give rise to subsequent cryptorchidism and an elevated risk of developing a testicular tumor; the prenatal estrogen theory remains unproven, however.²

Prevention and Early Detection

The identification of carcinoma in situ (CIS) or testicular intraepithelial neoplasia (TIN) as a precursor of testicular GCTs has raised the possibility that the development of invasive testicular cancer could be prevented by treating CIS. In adults, CIS is found adjacent to GCTs in virtually 100% of cases, and it is thought that, with the exception of spermatocytes seminoma, CIS precedes the development of all invasive tumors.¹⁸ The natural history of testicular CIS is unknown, but the Danish experience suggests that all cases of adult CIS will ultimately progress to invasive cancer.¹⁸

The diagnosis of testicular CIS can only be made by testicular biopsy. Because the incidence of CIS in the general population is low (at most, 0.7%), screening biopsies are currently not recommended. They should be considered in high-risk patients, however, including those with presumed extragonadal germ cell cancer, intersex individuals, and select patients with contralateral GCT (age <40 years and testicular volumes of <12 mL).¹⁹

The management of patients with testicular CIS is controversial. Orchiectomy has been suggested for unilateral disease, and in cases diagnosed after orchiectomy for GCT, three options can be considered and discussed with the patient: orchiectomy, low-dose RT, or surveillance.¹⁹ Although both orchiectomy and RT offer definitive treatment for testicular CIS, they both destroy any residual fertility. Surveillance, with careful follow-up of the affected testis, is a reasonable option, especially given the excellent prognosis for metachronous testicular cancers.²⁰

Testicular self-examination has been advocated for the early detection of invasive tumors, but its usefulness is unproven. There is no evidence to indicate that a population-based screening program would be of benefit; however, there is a need for education about the early signs and symptoms of testicular cancer to reduce delay at diagnosis. The optimal follow-up schedule for patients with unilateral testicular GCTs and those with cryptorchidism, both of whom have a risk of approximately 2% to 5% of developing a future testicular cancer, is unclear, but a yearly testicular ultrasound examination from age 15 years would seem reasonable.

Biologic Characteristics and Molecular Biology

GCTs have a distinctive capacity for totipotential differentiation as demonstrated by the frequent finding of combinations of choriocarcinoma, embryonal carcinoma, and seminoma in a single tumor. They also can retain their ability to differentiate as displayed by the not infrequent identification of mature teratoma in residual post-treatment retroperitoneal masses. Cytogenetic analysis of GCTs has shown that chromosome numbers are more homogenous in seminomas than in nonseminomas.²¹^–²³ Triploid and tetraploid chromosomal patterns are common in seminomas, and hyperdiploid to hypertriploid counts are common in nonseminomas. A characteristic chromosome anomaly in GCTs of all histologic types is the presence of an isochromosome of the short arm of chromosome 12.²⁴ This isochromosome, first reported by Atkin and Baker in 1982,²¹ consists essentially of two chromosome 12 short arms. It is present in more than 80% of cases, and GCTs without a 12p isochromosome have extra copies of 12p segments incorporated into other chromosomes. The 12p isochromosome is also found in testicular CIS.²⁴ Isochromosome copies tend to be more numerous in nonseminomas than in seminomas.

It is not known how these chromosomal changes contribute to the development of the neoplastic phenotype. The frequent finding of the 12p isochromosome in both CIS and invasive tumors, however, indicates that this chromosome plays an important role in the biology of these tumors. The possibility of amplification of normal or modified genes, such as the DDX1 gene on the 12p isochromosome, is currently being investigated.²⁵ Proto-oncogenes present on the short arm of chromosome 12 could be activated by point mutations, deletions, or translocations to become oncogenes, which could then act in a dominant manner.²⁶ The KRAS gene is located on the short arm of chromosome 12, and amplification or enhanced expression of this gene has been reported to occur in testicular tumors and derived cell lines. Other candidate genes being studied include the c-KIT oncogene and its ligand KITGL or SCF, the c-MOS oncogene, and the CCND2 gene. In addition to chromosome 12, 17q is overrepresented in 50% of cases of GCT; this area contains a number of genes of interest, including the GRB7 gene and the plakoglobin gene.²²

The study of the genetics and molecular biology of GCTs has enhanced our understanding of these tumors. To date, however, cytogenetics has had little impact in the clinic, with the possible exception of the use of various markers for the identification of non-TGCCs located elsewhere in the body.²⁷^–²⁹

Pathology and Pathways of Spread

Pathology

Testicular cancers can arise from intratesticular and paratesticular cells (Table 53-1). The vast majority are of germ cell origin, and three major classification schemes have been in use worldwide³⁰^–³² (Table 53-2). The Dixon and Moore classification as modified by Mostofi has been adopted by the World Health Organization (WHO) and is the classification scheme most widely used in North America.³³

TABLE 53-1 Histologic Classification of Testicular Neoplasms

TABLE 53-2 Three Classifications of Germ Cell Tumors

Dixon and Moore, 1953³⁰	WHO Classification³³	Pugh, 1976³²
Group I Seminoma Spermatocytic seminoma Group II Embryonal carcinoma Group III Teratoma, pure Group IV Teratoma with carcinoma or sarcoma Group V Teratoma with embryonal carcinoma or choriocarcinoma

Seminoma

Spermatocytic seminoma

Embryonal carcinoma, adult-type

Teratoma

Mature

Immature

Teratoma with malignant areas other than seminoma, embryonal carcinoma, or choriocarcinoma

Embryonal carcinoma and teratoma (teratocarcinoma)

Infantile embryonal carcinoma

Polyembryoma

Seminoma

Spermatocytic seminoma

Malignant teratoma, undifferentiated

Teratoma, differentiated

Malignant teratoma, intermediate

Yolk sac tumor; orchioblastoma

For clinical purposes, GCTs are classified into two major groups: seminomas and nonseminomas (NSGCTs). It should be noted that patients with pure seminoma may have recurrence with pure NSGCT, and vice versa. Approximately 60% of GCTs are pure seminomas, 30% are NSGCTs, and 10% are mixed tumors (both seminomatous and NSGCT elements are present).³⁴ Patients with mixed tumors are clinically considered to have NSGCT, the only exception being tumors with syncytiotrophoblastic cells in cases of seminoma.

Carcinoma in Situ

Intratubular germ cell neoplasia, or CIS, is felt to precede the development of all cases of seminoma and NSGCT in adults (with the exception of spermatocytic seminoma).³⁵ On light microscopy, CIS cells closely resemble seminoma cells and in most cases are found within the seminiferous tubules. Cytologically, there is no difference between the CIS cells that develop into seminomas and those that develop into NSGCTs. In the general population, the incidence of CIS is very low (0.2%), but it is somewhat higher in men with impaired fertility (0.5%) and in those with cryptorchid testes (2% to 4%).¹⁸

Seminomas

Seminoma, the most common type of testicular GCT, is most often seen in the fourth decade of life. On gross examination, the tumors are usually well demarcated from the residual testicular tissue and rarely have foci of necrosis or hemorrhage. On microscopic examination, the classical or typical seminoma type is made up of large cells with abundant cytoplasm divided by connective tissue septae into sheets or cords.³⁶ These cells typically have round, hyperchromatic or vesicular nuclei with prominent nucleoli. Frequently, there is a lymphocytic infiltrate, and macrophages, plasma cells, and multinucleated giant cells are often present. Syncytiotrophoblasts are present in 15% to 20% of cases, and their presence does not appear to alter the prognosis.

On immunohistochemical testing, virtually all seminomas express placental leukocyte alkaline phosphatase (PLAP) and do not express low-molecular-weight keratins, blood group antigens, or vimentin. Several histologic variants of seminoma have been identified, including anaplastic seminoma and spermatocytic seminoma. Anaplastic seminoma is diagnosed when there are three or more mitoses seen per high-power field.³⁶ Spermatocytic seminoma is a rare subtype mainly seen in older men and is not associated with CIS or bilateral disease.³⁵ Also, these tumors do not stain for PLAP on immunohistochemical testing and rarely, if ever, metastasize. An atypical variant of seminoma with some features similar to those of NSGCT on immunohistochemical examination has been reported, although its morphologic appearance is similar to that of classical seminoma.³⁷ Usually, there is little or no lymphocytic infiltrate and the tumor cells have less cytoplasm than classical seminoma cells. In terms of prognosis, this atypical variant appears to have the same prognosis as classical seminoma.

Nonseminomatous Germ Cell Tumors

Nonseminomatous tumors make up 40% of TGCCs and occur most commonly in the third decade of life. In the WHO classification system, NSGCTs include embryonal carcinoma, teratoma (mature, immature, or with malignant differentiation), choriocarcinoma, yolk sac tumor, and mixed GCTs. Most tumors are mixed, with two or more cell types present. Although some tumors have a component of seminoma, the association of seminoma within a histologically confirmed NSGCT has no major impact on the clinical outcome.³⁸ Patients with combined tumors present at an age (median, 33 years) intermediate between those with seminoma (median, 36 years) and those with nonseminoma (median, 27 years).³⁸ On gross examination, there is usually a soft irregular mass poorly demarcated from the surrounding testicular tissue, and a considerable amount of necrosis and hemorrhage is often present. Immunohistochemical studies usually demonstrate cytoplasmic expression of low-molecular-weight keratins in embryonal carcinomas, and yolk sac elements, low-molecular-weight keratin, and/or vimentin expression in mature teratomas.

Teratomas are tumors composed of cells derived from two or more of the germ cell layers (ectoderm, mesoderm, or endoderm). When one of the component tissues in any of the types of teratoma exhibits the histologic appearance of another malignant tumor, such as sarcoma or carcinoma, the term teratoma with malignant transformation is used.

Choriocarcinomas are tumors composed of both multinucleated syncytiotrophoblasts and mononuclear cytotrophoblast cells. Pure choriocarcinoma is very rare and is usually associated with widespread metastases, very high levels of β-human chorionic gonadotropin (β-HCG), and a poor prognosis. Elements of choriocarcinoma are found in up to 10% of NSGCTs and do not appear to affect the prognosis.

Yolk sac tumor, also known as endodermal sinus tumor, is composed of cells that usually produce α-fetoprotein (AFP) and resemble those seen in the yolk sac in an embryo. Pure yolk sac tumors are rare but are the most common variant of childhood GCT. Elements of yolk sac tumor are found in up to 50% of NSGCTs.

Pathways of Spread

Direct extension of tumor into the epididymis, through the tunica vaginalis, into the spermatic cord (T3), and rarely into the scrotum (T4) may occur. Locally extensive tumors are rare, however.

Lymphatic spread is the most common route of metastatic spread. The lymphatic drainage of the testis is directly to the para-aortic lymph nodes. There are differences in the distribution of metastases from left or right testicular tumors. The left testicular vein drains to the left renal vein, and the lymphatic drainage is primarily to the lymph nodes in the para-aortic area, directly below the left renal hilum. On the right side, the testicular vein drains directly to the inferior vena cava below the level of the renal vein, and, therefore, paracaval and interaortocaval nodes are the first ones to be involved in right-sided tumors. Figure 53-1 shows the distribution of retroperitoneal lymph node metastases in NSGCT.³⁹ Contralateral nodal involvement occurs in approximately 15% of cases and is rarely found in the absence of ipsilateral involvement. Supradiaphragmatic spread can occur through the thoracic duct, and although left supraclavicular nodal disease is infrequent at presentation, it is often seen at the time of relapse.

Figure 53-1 Distribution of retroperitoneal lymph node metastases in early-stage nonseminoma germ cell tumor. A, Right testis primary tumor. B, Left testis primary tumor.

Pelvic and inguinal lymph node involvement is rare (<3%). Factors predisposing to inguinal lymph node involvement include prior scrotal or inguinal surgery, scrotal orchiectomy with incision of the tunica albuginea, tumor invasion of the tunica vaginalis or lower third of the epididymis, and cryptorchid testis.^40,⁴¹ Disruption of lymphatic vessels in the spermatic cord during inguinal surgery has been shown to induce anastomoses between the testicular lymphatic vessels and the regional lymphatics destined for inguinal or pelvic lymph nodes. In an occasional patient, a connection with the contralateral inguinal lymph nodes may be established, but this is very uncommon. In a small proportion of patients with inguinal relapse, no predisposing factors may be apparent.⁴⁰

In patients with NSGCTs, hematogenous spread occurs early in the course of the disease. The lung parenchyma is the commonest site of hematogenous spread, but liver, bone, brain, kidney, and gastrointestinal metastases are also seen. In a review of over 5000 patients with metastatic GCT, pulmonary metastases were present in 44% of cases and liver metastases in 6% of cases, with all other areas of hematogenous spread present in 1% or less of cases.⁴² Mediastinal and neck node involvement was present in 11% to 12% of cases.

Clinical Manifestations, Patient Evaluation, and Staging

Clinical Manifestations

Patients with testicular tumors most commonly present with a painless testicular mass. Up to 45% of patients may have testicular pain, with signs and symptoms suggestive of acute epididymitis in up to 25% of patients. Much less common presenting features include those related to the presence of metastases, for example, back pain, dyspnea, and gynecomastia (from malignant tumors that produce HCG). Up to 3.5% of patients—those with very high HCG levels—may develop hyperthyroidism because the alpha subunit of HCG is identical to that of thyroid-stimulating hormone (TSH) and may therefore stimulate the thyroid.⁴³ The differential diagnosis of a testicular mass (in addition to tumor) includes torsion, hydrocele, varicocele, spermatocele, and epididymitis. A small percentage of tumors are associated with a hydrocele, so the presence of transillumination on examination does not rule out a diagnosis of malignancy.

Patient Evaluation

In patients who present with no obvious evidence of metastasis, a diagnostic and therapeutic radical orchiectomy is usually performed after a solid mass is detected on physical examination or by ultrasonography. Serum tumor markers, including α-fetoprotein (AFP), β-human chorionic gonadotropin (β-HCG), and lactate dehydrogenase (LDH) should be measured preoperatively to allow monitoring of decay with treatment. Staging investigations are performed after the histologic diagnosis is confirmed, with the exception of patients with a poor performance status and metastatic disease, for whom systemic therapy may be instituted based on a clinical diagnosis supported by unequivocal elevation of AFP and β-HCG. In these cases, the histologic diagnosis can often be obtained via needle biopsy.

Routine staging investigations include chest x-ray, CT scanning of the abdomen and pelvis, CT scanning of the thorax, and tumor markers. CT scanning of the thorax does not add value in patients with seminoma with no evidence of retroperitoneal lymph node involvement. There is no role for bipedal lymphography in staging patients; however, magnetic resonance imaging (MRI) with lymphotrophic nanoparticles has shown promise in a number of studies but needs further evaluation before it can be adopted into clinical practice.⁴⁴ In stage II and III seminomas, especially in patients with bulky retroperitoneal disease, a bone scan should also be performed. Abnormal serum marker levels should be monitored to document postorchiectomy decay according to their respective half-lives. Patients with extensive metastatic disease, nonpulmonary visceral metastases (NPVMs), or very high tumor marker levels are at risk for brain metastases, and CT or MRI of the brain should be performed.⁴⁵ Baseline pulmonary and renal functions are assessed in patients who require chemotherapy.

Tumor Markers

Measurements of AFP, β-HCG, and LDH are essential in the diagnosis and management of patients with GCTs.⁴⁶ HCG is a glycoprotein with a molecular weight of 45,000 daltons, composed of two subunits, of which the α-subunit is identical to that of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and thyroid-stimulating hormone (TSH), and a distinct β-subunit. HCG is normally produced by the placenta. About 15% of patients with seminoma have elevated β-HCG levels. Low levels of β-HCG may be found in other neoplasms, including prostate, bladder, and renal tumors. The use of marijuana derivatives also may lead to elevated levels. Some cross-reactivity with LH does occur, and in cases where an elevated HCG level is thought to be due to this cross-reactivity, consideration should be given to having levels remeasured after treatment with testosterone.⁴⁷ The half-life of β-HCG in blood is approximately 22 hours. In the subset of GCT patients with very high levels of HCG, a plateau of this tumor marker is often reached after the fourth cycle of chemotherapy that is considerably greater than normal. Such patients often remain in remission with slowly falling levels of HCG, possibly resulting from tissue binding of this tumor marker. Such persistent elevation of HCG levels following chemotherapy is not in itself an indication for salvage therapy.⁴⁸

AFP is the major serum protein of fetal life. It is a glycoprotein of molecular weight 70,000 daltons. In addition to being elevated in nonseminomatous GCTs, it is elevated in hepatocellular carcinoma, cirrhosis, and hepatitis and during pregnancy. The half-life of AFP is approximately 5 days. AFP is not found in pure seminoma; its elevation in this setting implies the presence of nonseminomatous tumor elements. Liver disease should be considered in the differential diagnosis in patients whose disease appears to be responding and in whom the AFP level fails to fall appropriately or is found to be increasing.

One or both of these markers are elevated in 85% of patients with nonseminomatous GCTs. Experience with surveillance of patients with early-stage disease has shown that normal markers do not exclude the presence of occult disease.⁴⁹

LDH is another important marker in patients with GCTs. It is elevated in up to 60% of patients with nonseminomas and also in a high proportion of patients with advanced seminomas.42,50

Both AFP and β-HCG levels are useful in the diagnosis of malignancy when they are measured before orchiectomy. The rate of decline after orchiectomy indicates the likelihood of residual tumor. Determination of tumor marker levels is used to assess response to treatment, to predict the likelihood of achieving complete remission, and in regular follow-up to indicate relapse, often in the absence of symptoms, physical findings, or abnormal imaging studies.

PLAP is an isoenzyme of alkaline phosphatase and is normally expressed by placental syncytiotrophoblasts. It is also expressed by testicular tissue and has been investigated as a tumor marker in seminoma. Although PLAP levels are often elevated in patients with seminoma, this factor has proven to be of little value in clinical management.⁵¹

Staging

The 2009 American Joint Committee on Cancer/International Union Against Cancer (AJCC/UICC) TNM classification (Table 53-3) is the recommended staging system. In stage I disease, one of the most important determinants of outcome is the presence of vascular invasion in the primary tumor, and this differentiates a pT1 tumor from a pT2 tumor.⁵² Tumors with invasion of the spermatic cord are staged as pT3 cancers, and the rare tumors with scrotal invasion are classified as pT4 lesions.

TABLE 53-3 Staging of Testis Tumors by the American Joint Committee on Cancer (AJCC)

In stage II disease, the extent of retroperitoneal adenopathy and serum tumor marker level determines treatment and outcome. Patients with retroperitoneal lymph nodes less than 5 cm in diameter (N1/N2 disease) are often successfully treated with regional therapy, either retroperitoneal lymph node dissection (RPLND) in NSGCTs or external beam RT (EBRT) in seminomas; however, those with nodal disease greater than 5 cm in diameter have a high risk of distant failure following regional therapy and are usually treated with systemic chemotherapy.

With the current use of cisplatin-based chemotherapy, the survival rate of patients with metastatic testicular tumors is excellent. A minority of patients still succumb to testicular cancer in spite of treatment, however.

The International Germ Cell Cancer Collaborative Group (IGCCCG) analyzed data from 5168 patients with advanced disease.⁴² Independent prognostic variables identified by the IGCCCG were included: histologic type (nonseminoma vs. seminoma), site of the primary tumor (testis, retroperitoneal site, or other), presence or absence of NPVMs (brain, bone, or liver), and degree of marker elevation (AFP, β-HCG, and LDH). Based on the results of multivariate analysis, the IGCCCG recommended three prognostic groups for nonseminomatous tumors and two prognostic groups for seminomatous tumors. For nonseminomatous cancers, the 5-year overall survival (OS) for the good-prognosis group was 92%, for the intermediate-prognosis group, 80%, and for the poor-prognosis group, 48%. For seminoma, only two prognostic groups were identified: a good-prognosis group without NPVMs with a 5-year OS of 86% and an intermediate-prognosis group with NPVMs with a 5-year OS of 72%. This classification system has been validated by van Dijk and associates⁵⁰ using Cox regression analysis and recursive partitioning in a cohort of 3048 NSGCT patients.

Primary Therapy

The initial management involves a radical inguinal orchiectomy in almost all cases. Postorchiectomy management is based on the histologic type and extent of disease. The management policies for both seminomatous and nonseminomatous tumors have evolved separately but currently are quite similar, with the exception of the use of EBRT in early-stage seminoma. Sperm testing and banking should be considered before treatment with chemotherapy, RPLND, and EBRT because of potential effects on fertility.

Surgery

Surgery involves a radical inguinal orchiectomy to allow high division of the spermatic cord. Orchiectomy is both diagnostic and therapeutic by providing adequate tissue to ascertain the diagnosis and offering cure in a high proportion (60% to 90%) of patients with stage I disease.^19,⁵³ Although not recommended, an accidental scrotal approach does not appear to compromise the outcome, and no additional therapy is required following scrotal violation, provided that the scrotal cavity has not been grossly contaminated by tumor. In patients with life-threatening metastatic disease and a clear-cut diagnosis of germ cell malignancy, initial management should be with chemotherapy and surgery should be postponed until completion of systemic treatment.^19,⁵³ The role of partial orchiectomy in patients with metachronous or synchronous bilateral tumors will be discussed later.

Seminoma

Most patients present with stage I disease (70% to 80%); stage II disease is found in 15% to 20% of cases; and stage III disease in 5% of cases. Of the predicted 5000 cases of seminoma in the United States in 2010, 4000 were expected to present as stage I disease.

In stage I seminoma, postorchiectomy management options include surveillance, RT, or adjuvant chemotherapy. In the past, the standard management of patients with stage I seminoma has been adjuvant retroperitoneal RT. Although RT provided excellent long-term results, with local control in the abdomen and pelvis in virtually all patients, it is now known that over 85% of patients are cured with orchiectomy alone and that RT has been associated with an increased risk of late gonadal toxicity, development of secondary malignant tumors, and, in some cases, an increased risk of cardiovascular disease.⁵⁴^–⁵⁸ Various approaches have been tried to reduce radiation morbidity, including a reduced radiation dose and treatment volume. In addition, such alternative management strategies as surveillance (including risk-adapted surveillance) and adjuvant chemotherapy have been investigated.⁵⁹^–⁶³ Although adjuvant retroperitoneal RT constituted the standard of care for the past 50 to 60 years, surveillance is now the standard approach, minimizing the burden of treatment while maintaining the cure rate at 100%.^64,65,66

For stage II disease, retroperitoneal irradiation is very effective and is recommended for patients with nonbulky tumor (stage IIA to IIB), whereas chemotherapy is the treatment of choice for patients with more advanced disease. In certain rare instances, RPLND can be considered.

In stage III disease, chemotherapy is the treatment of choice.^19,⁵³

Management of Stage I Seminoma

Surveillance

The data on seminoma surveillance are now mature, and relapse rates of 15% to 24% have been reported * (Table 53-4). The two largest reported series are from Copenhagen and Toronto.^60,⁶⁶ In the Copenhagen series of 394 patients, with a median follow-up of 60 months, the crude relapse rate was 17.5%. In the Princess Margaret Hospital, Toronto, series of 421 patients, with a median follow-up of 8.1 years, the actuarial 5-year relapse-free survival (RFS) was 85.5%. The other studies with adequate follow-up (>36 months) have reported similar relapse rates. The predominant site of relapse in all studies was the para-aortic lymph nodes (82% in the Danish Testicular Cancer Study Group (DATECA) study and 89% in the Princess Margaret Hospital series.^60,⁶⁶ The median time to relapse ranged from 12 to 18 months, but occasional late relapses (>4 years) have also been reported.⁷⁰

TABLE 53-4 Results of Surveillance in Stage I Seminoma

Prognostic factors for relapse have been studied in a number of the surveillance studies, and age, tumor size, and small vessel invasion have been reported as predictive of relapse. To more accurately determine prognostic factors for relapse in patients with stage I testicular seminoma managed by surveillance, a pooled analysis of four large surveillance series was performed using individual patient data.⁷¹ In 638 patients, tumor size and rete testis invasion predicted for relapse on multivariable analysis. The effect of tumor size on the relapse rate is shown in Figure 53-2, and the hazard ratio for relapse with a tumor size of more than 4 cm was 2 (95% CI, 1.3 to 3.2) relative to baseline (tumor size <4 cm and no rete testis invasion). This model has not been validated in an independent dataset and does not have sufficient discrimination to be clinically useful, because patients in the high-risk group have only a 35% risk of relapse during surveillance. For these reasons, these prognostic factors should not dictate treatment strategy.

Figure 53-2 Relapse-free rate based on primary tumor size.

From Warde P, Specht L, Horwich A, et al: Prognostic factors for relapse in stage I seminoma managed by surveillance. A pooled analysis. J Clin Oncol 20:4448-4452, 2002. Copyright © American Society of Clinical Oncology.

At relapse, most patients have been treated with retroperitoneal RT. The incidence of second relapse after irradiation is approximately 10%. The likelihood of detecting early progression in the retroperitoneal lymph nodes (nodes <5 cm) and, therefore, suitability of the patient for RT depends on the frequency of follow-up CT scans of the abdomen and pelvis. The current Princess Margaret Hospital follow-up policy is shown in Table 53-5. One of the concerns regarding the routine use of surveillance was the potential for an increased need for chemotherapy. In the Toronto experience, a similar percentage of patients managed with surveillance (4.6%) and adjuvant RT (3.9%) required chemotherapy as part of their management. Therefore, surveillance does not lead to an increased use of chemotherapy, with its ensuing toxicity.

TABLE 53-5 Follow-up Protocol for Stage I Seminoma

Another concern regarding surveillance relates to the increased use of imaging studies. There are no prospective data available that quantitate the risk of radiation-induced cancer from CT scanning. A recent paper used long-term follow-up data from survivors of the Hiroshima and Nagasaki atomic bombings to estimate the risk of low-level exposure approximating that of one or more CT scans. This approach has been criticized for methodologic reasons. Nonetheless, the seminoma surveillance population is likely at some risk of induced cancer, given the young age of many patients and the use of repeated CT scans of the abdomen. It seems reasonable to attempt to decrease the frequency of imaging as much as possible until more data on the risk of such scans are available. In addition, the use of low-dose CT protocols is currently under study, and these may be used in standard surveillance protocols in the future.⁷²

Radiation Therapy

Overall survival (OS) ranges between 92% and 99% at 5 to 10 years, with the cause-specific survival (CSS) approaching 100%. Most deaths are due to intercurrent illness, but concern exists that premature deaths may be occurring from radiation-induced cancers or cardiac disease.^54,⁵⁸ With modern-era RT, the relapse rate has varied from 0.5% to 5%^66,⁷³^–⁷⁷ (Table 53-6). In-field relapse is rare, and when it is suspected, biopsy should be performed to rule out a nonseminomatous tumor or another malignant tumor. The commonest sites of relapse following adjuvant RT are the mediastinum, lungs, and left supraclavicular fossa. A small proportion of patients, usually with predisposing factors, develop relapse in the inguinal nodes. Uncommon sites of isolated metastases such as the brain and tonsils have been noted.^45,⁷⁷ For supradiaphragmatic relapse, chemotherapy is the treatment of choice and results in a cure rate of nearly 100%. Inguinal relapse can often be treated successfully with RT to the involved area.⁷⁸

TABLE 53-6 Results of Retroperitoneal Radiation Therapy in Stage I Seminoma

Most relapses occur within 2 years of RT. In the Princess Margaret Hospital series of 282 patients treated between 1981 and 1999, the median time to relapse was 18 months, with the latest relapse occurring at 6 years. Follow-up efforts should therefore concentrate on the 2 years after RT. This is similar to the policy used for patients during surveillance, except that a CT scan of the abdomen and pelvis is also obtained at all visits.

With such excellent results, the prognostic factors for relapse are difficult to identify. One of the potential adverse factors examined was the presence of anaplastic histologic findings. In the Princess Margaret Hospital experience, 8 of 55 patients with anaplastic seminoma relapsed compared with 2 of 116 patients with classical seminoma (14.5% vs. 1.7%).⁷⁸ The WHO criteria for the diagnosis of anaplastic seminoma (three or more mitoses per high-power field) are not uniformly used, and other series indicate that the prognosis for patients with anaplastic seminoma is similar to that for patients with classical seminoma.⁷⁹ Other factors associated with a higher risk of relapse include tumor invasion of the tunica albuginea, lymphovascular invasion, invasion of the epididymis, raised preoperative HCG levels, and spermatic cord involvement.^73,⁷⁸

Various strategies have been investigated to reduce the long-term complications of adjuvant RT in stage I seminoma. They include reducing the radiation dose and/or treatment volume (see the section on Techniques and Dose of Irradiation), deciding to use surveillance for more patients and reserve RT for patients who relapse, and using adjuvant chemotherapy rather than RT.

Adjuvant Chemotherapy

Because chemotherapy is very effective in seminoma, adjuvant carboplatin has been investigated as an alternative strategy to RT or surveillance in stage I disease. The use of one to two courses of carboplatin after orchiectomy was initially pioneered by Oliver,⁸⁰ who treated 78 patients (53 patients with two courses and 25 patients with one course). With a median follow-up of 44 months, only one patient had relapsed. Subsequent phase II studies have reported relapse rates of between 0% and 8.6%; the variability in results noted may be related to the dosing formula used in the various reports.⁸¹

The Medical Research Council in the United Kingdom (MRC UK) has conducted a randomized phase III study comparing adjuvant RT and a single course of carboplatin in 1447 patients.⁸² The 2008 report showed similar relapse rates at 3 years in both arms of the study (4% RT vs. 5% carboplatin), with most of the relapses in the carboplatin arm occurring in the retroperitoneal lymph nodes.⁸³ One possible benefit of adjuvant carboplatin noted in this study was a reduction in the incidence of second primary testicular germ cell tumors, although this observation has recently been questioned by Powles.⁶³ In addition, this study reported that patients who received higher doses of carboplatin (using the area under the curve [AUC] formula) had lower relapse rates.

Data from other single-institution series indicate that if adjuvant carboplatin is given in this setting, then two courses of treatment are necessary.^59,⁸⁴ Even with two courses of carboplatin, a small but significant percentage of patients develop relapse in the retroperitoneum, and the usefulness of this approach is therefore questionable.^59,⁸⁴ The relapse pattern mandates that continued surveillance of the retroperitoneal lymph nodes is required (similar to the surveillance policy), and the reduction in relapse rates is only 10% (15% with surveillance and 5% with adjuvant chemotherapy). Eighty-five percent of patients receive unnecessary treatment, and the potential long-term toxicity of this strategy is unknown.

Retroperitoneal Lymph Node Dissection

Retroperitoneal lymph node dissection (RPLND) is an often forgotten treatment option in seminoma. It is an alternative approach available for patients unwilling to comply with surveillance or unable to be treated with RT, such as those with inflammatory bowel disease or those previously treated with retroperitoneal irradiation. RPLND may also be appropriate in patients with a concurrent or previous malignant tumor for whom histologic examination of the lymph nodes is essential to plan treatment.

Overview of Management of Stage I Seminoma

Almost 100% of patients with stage I testicular seminoma are cured regardless of the choice of postorchiectomy management. The most attractive feature of surveillance is the ability to limit treatment to orchiectomy alone. Surveillance does not compromise the survival rate, and only one disease-related death was observed in the two largest surveillance series.^60,⁶⁶ Surveillance requires a commitment to close and prolonged follow-up from both patients and clinicians. Although isolated occurrences of second no testicular tumors following treatment of seminoma with irradiation have been reported for decades, there is now convincing data from long-term studies indicating that patients with seminoma treated with irradiation have an increased risk of developing cardiac disease and second malignant tumors, and these factors must be considered when deciding on postorchiectomy management.^19,^54,⁵⁶^–⁵⁸

Although physicians may view one management approach as preferable, surveillance should be offered to all patients with stage I seminoma and individual patients’ preferences must be considered.⁸⁵ These preferences may be based on many socioeconomic factors as well as the side effects associated with both approaches. Also, the identification of prognostic factors for occult disease may allow patients and clinicians to choose management based on a more accurate assessment of an individual patient’s risk of relapse.

Management of Stage II Seminoma

Approximately 15% to 20% of patients have radiologically involved para-aortic lymph nodes and are classified as having stage II disease. Patients are divided into three groups depending on the transverse diameter of the largest retroperitoneal lymph node mass (≤2 cm, stage IIA; 2.1 to 5 cm, stage IIB; and >5 cm, stage IIC). Approximately 70% of stage II patients have small-bulk retroperitoneal disease at presentation with lymph nodes that are 5 cm or less. The number of patients with stage II disease is too small to mount phase III studies of management, and treatment decisions must be based on data from single institutions where patients have been treated in a uniform fashion.

The most important prognostic factor in stage II seminoma is the bulk of retroperitoneal disease, usually defined by the transverse diameter of the largest lymph node mass visible on CT scanning. This was the only prognostic factor for relapse in a consecutive series of 95 patients with stage II seminoma treated with RT at the Princess Margaret Hospital between 1981 and 1999.⁸⁶ The 5-year relapse-free rate in 79 patients with stage IIA or IIB disease was 91%, compared with 44% in 16 patients with stage IIC disease. Relapse occurred most commonly in mediastinal or supraclavicular lymph nodes, lung, or bone. These results are similar to other series in the literature (Table 53-7) and support the continued use of primary RT in stage IIA or IIB patients. In stage IIC disease, chemotherapy is recommended.

TABLE 53-7 Results of Retroperitoneal Radiation Therapy in Stage IIA or IIB Seminoma

Substage of disease, however, should not be the only parameter used to decide on treatment of retroperitoneal disease in patients with stage II seminoma; overall tumor bulk, location of disease relative to normal tissue, and anatomic variants must also be considered. Patients with nodal disease extending 10 cm from L1 to L5 in the retroperitoneum with a maximum transverse diameter of 4 cm are classified as having IIB disease, and these patients with bulky disease should be treated with chemotherapy. Lymph node masses that are situated laterally may necessitate irradiating a large volume of one or both kidneys or the liver in order to adequately encompass the tumor. The same situation may arise in patients with abnormal anatomic findings such as a horseshoe, or pelvic, kidney. These patients are better treated with chemotherapy because of an unacceptably high risk of radiation toxicity. Patients in whom RT and chemotherapy are contraindicated or the diagnosis is uncertain should be considered for RPLND.

The use of carboplatin with RT in stage IIA or IIB seminoma has been suggested by Gilbert.⁸⁷ In a series of 59 patients treated with one course of carboplatin 4 to 6 weeks prior to RT, the 5-year RFS was 98.3% versus 80.7% for patients treated in the 1980s with RT alone. This approach cannot be accepted as routine practice without further data, because stage migration could explain the better results in the modern cohort of patients.

The commonest sites of relapse following RT in stage II patients are mediastinal or supraclavicular nodes, lung, and bone. Most relapsing patients are cured with chemotherapy, which emphasizes the importance of regular follow-up with clinical examination and chest x-ray after RT. CT imaging of the abdomen and pelvis is not necessary after complete resolution of abdominal disease.

The technique of irradiation in stage II seminoma is similar to that used in stage I disease. This is discussed in the section on Techniques and Dose of Irradiation.

Residual Retroperitoneal Mass

Following treatment, patients with stage II disease require follow-up imaging of the abdomen until complete regression of disease is observed. A stable persistent mass usually represents fibrosis or necrosis, and only the minority contain an active tumor. The possibility of a nonseminomatous component to explain the residual mass needs to be kept in mind, however, even in patients whose primary tumors show pure seminoma. In addition, surgical extirpation of retroperitoneal nodes in the setting of seminoma is technically challenging and is associated with considerable morbidity.⁸⁸

Therapeutic options for patients with residual masses after treatment include observation, surgical removal, or, after chemotherapy, irradiation. The role of positron emission tomography (PET) imaging to detect residual tumor is controversial, and the decision to treat the residual mass should not be based exclusively on a positive PET image, because false-positive results occur.⁸⁹^–⁹¹

A number of centers have reviewed their experience with surgery for residual masses in the setting of seminoma. The Memorial Sloan-Kettering Cancer Center (MSKCC) group published their data on 55 of 104 patients who demonstrated residual masses following chemotherapy.⁹² Of these 55 patients, 32 (58%) had a formal RPLND and 23 (42%) had multiple intraoperative biopsies performed because the residual mass was deemed unresectable. Among patients with a mass of more than 3 cm (27 patients), 8 (30%) had residual viable tumor. Interestingly, two of the eight patients had teratoma and six had seminoma. No patients with tumors of less than 3 cm had a viable tumor when the final pathologic findings were obtained. Among the eight patients with preoperative tumor masses of more than 3 cm and positive pathologic findings, six remained relapse-free at 47 months of follow-up. Two patients died of disease; both had poorly defined masses on CT scanning. Given this high proportion of persistent malignant disease, MSKCC investigators have recommended resection or biopsy of masses of 3 cm or larger. In contrast, Culine and Droz from the Centre Léon-Bérard⁹³ have suggested that as long as the retroperitoneal mass continues to decrease in size after treatment, continued observation is a reasonable strategy.

The use of RT in patients with masses following chemotherapy is often mentioned as a therapeutic option. Horwich and colleagues ⁹⁴ published their experience with both observation and RT for these masses and found that the relapse rate was similar whether RT or observation was performed. The MRC Testicular Tumor Working Party published a retrospective pooled analysis assessing the role of RT for postchemotherapy residual masses among men with seminoma.⁹⁵ In 123 patients with a residual abdominal mass, 56% received consolidative RT. There was no significant difference in outcome among patients who did or did not receive RT. Given these data it was concluded that routine RT is not indicated for a postchemotherapy residual mass.

It is now widely accepted that patients with a residual mass of 3 cm or less can safely be observed. For patients with larger masses, surgery or observation should be considered.

Management of Stage III Seminoma

This is an uncommon presentation seen in less than 5% of patients. Seminoma is exceptionally chemosensitive, and the use of cisplatin-based regimens results in high cure rates. Patients with stage III seminoma should be classified according to the IGCCCG system into either the good prognostic group or intermediate prognostic group based on the presence or absence of NPVMs.⁴² For patients in the good-prognosis group, three courses of 5-day BEP chemotherapy (bleomycin, etoposide, cisplatin) should be considered the standard of care.^53,⁹⁶ In patients unsuitable for bleomycin, four courses of etoposide-cisplatin (EP) can be given.⁵³ For patients with intermediate-prognosis disease, four courses of 5-day BEP should be administered.^53,⁹⁶

Nonseminoma

Since the 1970s, when cisplatin, bleomycin, etoposide, and vinblastine were introduced, nonseminoma has become one of the most curable adult cancers. Before these drugs were available, nonseminomatous tumors were treated with a wide range of chemotherapeutic agents and there were occasional reports of long-term remissions with the use of single-agent mithramycin and actinomycin D.⁹⁷ The modern era in treating advanced disease began at the M.D. Anderson Hospital with the use of continuous infusions of bleomycin and vinblastine; at MSKCC with the vincristine plus actinomycin D plus bleomycin (VAB) regimens; and, later, at Indiana University, with the cisplatin plus vinblastine plus bleomycin (PVB) regimen.⁹⁸^–¹⁰⁰ With these regimens, complete responses to treatment became frequent and cures were seen in patients with metastatic disease. The current BEP protocol (bleomycin, etoposide, cisplatin) emerged in the 1990s and is now the standard for first-line chemotherapeutic treatment of metastatic seminoma and nonseminoma.

Management of Stage I Nonseminoma

Current treatment options include surveillance, a modified bilateral retroperitoneal lymph node dissection (RPLND), and adjuvant chemotherapy. The presence of vascular invasion or embryonal carcinoma, the absence of yolk sac elements, and the immunohistochemical proliferation rates, as assessed by the MIB-1 score in the primary tumor, are associated with a high risk of occult nodal disease.¹⁰¹^–¹⁰⁴ Vascular invasion is the most important factor predicting relapse, and the presence or absence of this factor has been used to divide patients into those with high-risk disease (a third of cases), who have an approximately 50% risk of relapse, and those with low-risk disease, who have an approximately 15% to 20% risk of relapse.⁵²

In studies of surveillance in 1768 patients with a follow-up range of 19.5 months to 76 months, the overall relapse rate was 21.4% (378 cases), with 14 deaths (0.79%) from testicular cancer and/or treatment.¹⁰⁵ Up to 95% of patients who progress do so within 12 months of diagnosis; progression after 24 months from diagnosis is rare. Approximately 60% of patients progress in the retroperitoneal lymph nodes, with or without other evidence of disease. The other common presentations of disease progression are lung metastases or tumor marker elevation alone. At the time of progression, patients are usually treated with chemotherapy, although RPLND may be successfully used in selected cases with small retroperitoneal lymph nodes. Most patients are cured, and CSS in most series is greater than 98%* (Table 53-8).

TABLE 53-8 Prospective Trials of Surveillance in Stage I Nonseminoma

The optimal follow-up protocol for nonseminoma surveillance has not been defined. In most centers, clinical examination, tumor marker measurements, chest radiographs, and physical examination are performed every 2 months, with CT scanning of the abdomen and pelvis every 4 months for 2 years and less frequent follow-up thereafter. It has been suggested that the number of CT scans could be reduced to two, at 3 and 12 months after diagnosis, but this approach has not been widely accepted.¹¹⁴ Given the concern that CT scanning may increase the risk of second malignant tumors, this approach should be explored further.

RPLND is a recognized alternative to surveillance in clinical stage I disease. A modified unilateral infrahilar RPLND is performed, with nerve-sparing techniques to preserve ejaculation. For right-sided tumors, the interaortocaval nodes and paracaval nodes are removed, with preservation of the left sympathetic chain, and for left-sided tumors, the para-aortic and interaortocaval nodes are removed and the right autonomic chain is preserved. If significant lymphadenopathy is revealed at surgery, a more extensive surgical resection is performed. The relapse rate following surgery is approximately 10% for patients with pathologic stage I disease.¹¹⁵ Most patients who relapse after RPLND are cured with subsequent chemotherapy.¹¹⁶

In some centers, patients with clinical stage I NSGCT at high risk of relapse on surveillance are offered adjuvant chemotherapy.¹¹⁷ In a recent meta-analysis of one randomized and seven nonrandomized studies of adjuvant chemotherapy, with a total of 873 evaluable patients, 23 relapses (2.6%) were observed.¹⁰⁵ To reduce treatment-related toxicity, a number of studies have tested a single cycle of adjuvant BEP. In a recent randomized clinical trial comparing one course of BEP versus RPLND alone, the relapse rate was only 1% (2 of 191 patients) with BEP, and this has sparked renewed interest in this approach.¹¹⁸

The OS rate in stage I nonseminoma approaches 100% in most series irrespective of the treatment strategy used.¹⁰⁵ A risk-adapted approach with surveillance for low-risk disease and treatment (either adjuvant chemotherapy or RPLND for patients at a moderate to high risk of occult metastatic disease) has been advocated by some. A surveillance policy, however, is associated with excellent outcomes, and overall, 75% of patients avoid any treatment after orchidectomy.^105,¹¹⁹ International consensus statements have concluded that all three approaches should be discussed with the patient.^19,^53,⁹⁶

Management of Clinical Stage II Nonseminoma

The cure rate for stage II nonseminoma is approximately 98%. Patients with stage IIA disease with marker elevations (AFP, β-HCG, or LDH) or stage IIB disease regardless of marker status should be treated with chemotherapy according to the algorithms for patients with advanced disease.^53,⁹⁶ Patients with stage IIA disease with no marker have several options. The moderately enlarged nodes may be benign or they may contain teratoma, pure embryonal carcinoma, or mixed tumor elements. If the primary tumor histologic type is pure embryonal carcinoma, either short-term observation to see if the nodes regress or immediate treatment with chemotherapy is a reasonable option. If the primary tumor is of a mixed histologic type or a teratoma, either short-term observation or immediate RPLND is the preferred option. After RPLND, surveillance or adjuvant chemotherapy may be employed. For patients with pathologic stage IIA or IIB disease, the risk of relapse with no adjuvant treatment after surgery is 30% to 50%.^96,¹²⁰ Relapses occur almost exclusively outside the retroperitoneum. Adjuvant chemotherapy with two cycles of BEP in all pathologic stage IIA or IIB patients after RPLND reduces this risk of relapse to 0% to 7%.¹²¹ However, adjuvant chemotherapy represents overtreatment in 50% to 70% of pathologic stage IIA or IIB patients, with resulting treatment-related toxicity and possible late sequelae.

Management of Stage III Disease

Patients with advanced GCTs should always be considered potentially curable. Survival outcomes appear to be better in specialized centers, and this may be related to experience, case selection, volume, or organization of multidisciplinary care. Referral of all patients with advanced GCTs for consultation to a specialized center is strongly recommended.

Chemotherapy with or without Retroperitoneal Lymph Node Dissection

The standard first-line chemotherapy for all patients is bleomycin, etoposide, and cisplatin (BEP) using a 5-day schedule.^53,⁹⁶ Modifications in BEP, such as substitution of cisplatin with carboplatin to reduce toxicity or improve convenience, should be avoided because they may reduce efficacy.⁵³ In patients with IGCCCG good-prognosis disease, three cycles of BEP should be given, and if there is a contraindication to bleomycin, four cycles of etoposide and cisplatin (EP) can be given. This strategy, however, has been associated with a nonstatistically significant but higher death rate in one randomized clinical trial, possibly because of cisplatin toxicity.¹²²

In patients with IGCCCG intermediate- or poor-prognosis disease, four cycles of BEP should be considered the standard therapy.^53,⁹⁶ The VIP regimen (etoposide, ifosfamide, and cisplatin) has been compared with BEP in this patient population and shows similar outcomes but with more toxicity. The VIP regimen represents an alternative to BEP for patients with a contraindication to bleomycin or who develop pulmonary compromise while receiving BEP.¹²³ For intermediate- or poor-prognosis patients, there is no evidence to date that the use of high-dose chemotherapy with autologous stem cell transplantation is superior to the standard four cycles of BEP.^124,¹²⁵ Chemotherapy should be given, preferably without dose reductions, even in the setting of a critically ill patient, at 21-day intervals with no delays between cycles. In patients with life-threatening disease, orchiectomy should not delay the initiation of curative therapy and can be performed at the end of therapy.⁵³ If possible, these patients should be treated in centers with expertise in the management of germ cell tumors.

During chemotherapy, assessment of tumor markers prior to each treatment cycle is essential; if there is no tumor marker elevation prior to treatment, repeat imaging should be performed after two cycles. As long as tumor markers are declining, a full course of chemotherapy should be completed. If there is a slow tumor marker decline or stable tumor markers, earlier radiologic restaging can be considered.

If metastases can be seen growing on radiologic examination as tumor marker levels are declining, a diagnosis of growing teratoma syndrome should be considered. In most cases, the full course of chemotherapy should be completed and resection of the residual masses should be done following chemotherapy.

Postchemotherapy radiologic restaging should be performed in all patients 4 to 6 weeks following the final cycle of chemotherapy. If tumor marker decline is seen, as expected, all residual masses should be managed appropriately (see the following section). Only in the case of unequivocal tumor marker rise should salvage chemotherapy be initiated.

Residual Retroperitoneal Mass

In many patients who complete chemotherapy and have normalized tumor markers, residual masses are seen on imaging. If technically feasible, these masses should be resected 4 to 6 weeks after chemotherapy. On histologic testing. approximately 50% will show necrosis, 35% mature teratoma, and 15% malignant disease.⁵³ In some centers, RPLND is performed in all cases, even in patients with no residual retroperitoneal disease on imaging. However, there is increasing evidence that observation in patients with complete response after chemotherapy, reserving surgery for those who relapse, gives excellent results and spares many patients unnecessary surgery.¹²⁶

Treatment Complications

Radiation Therapy Complications

With the low-dose RT used in seminoma, most patients tolerate treatment well.¹²⁷ Although mild nausea and vomiting occur, only a small proportion of patients require regular antiemetics and are unable to complete daily tasks. Diarrhea develops in a minority of patients. Severe late radiation complications are not expected, unless the patient has an underlying medical problem or a technical error occurs.

Late Gonadal Toxicity

Testicular germinal epithelium is exquisitely sensitive to ionizing radiation. Although the contralateral testis is not located directly in the radiation field, a scatter radiation dose may cause profound depression of spermatogenesis and compromise fertility. In a series of 451 consecutive patients treated for testicular cancer, RT had a significantly greater deleterious effect on fertility than chemotherapy.¹²⁸ A radiation dose between 20 and 50 cGy may produce temporary aspermia, and doses greater than 50 cGy may preclude recovery of spermatogenesis.¹²⁹ The use of scrotal shielding reduces the scattered radiation dose to the testis but cannot ensure protection of spermatogenesis in all patients. In men who recover spermatogenesis after RT for seminoma, there is no evidence of an increased incidence of genetic abnormalities among offspring.¹³⁰ Limiting the target volume to the para-aortic and common iliac area does not eliminate concerns regarding irradiation-induced fertility. In the MRC randomized trial of para-aortic RT alone versus para-aortic and pelvic RT, the median time to a normal post-treatment sperm count was 13 months in patients treated to the para-aortic lymph nodes alone.⁶¹ This was significantly better than the time for patients treated to the para-aortic and pelvic lymph nodes (20 months). However, at 3 years of follow-up, there was no significant difference in sperm counts between the two groups. Testicular shielding should be used in all patients who wish to retain fertility after treatment.¹³¹

Cardiovascular Toxicity

Since mediastinal RT has been abandoned, the risk of cardiovascular disease in long-term survivors has decreased. Data from the M.D. Anderson Cancer Center and the Royal Marsden Hospital, however, suggest that long-term survivors of testicular seminoma treated with RT following orchiectomy are at significant excess risk of death as a result of cardiac disease.^54,⁵⁸ The etiology of this effect is currently unclear. Although the relevance of these data to the modern practice of RT has been questioned by some, patients should be informed of this increased risk of cardiac disease when deciding whether to undergo RT in the adjuvant setting.¹³²

Second Malignant Tumor

In discussing second malignant tumors after treatment of testicular cancer, a distinction must be made between second germ cell tumors of the testis, which reflect a common risk factor for this disease, and unrelated malignant tumors, which may be treatment induced. An increased risk of second cancers has been documented in a number of studies, and because this increased risk is expressed more than 10 to 15 years following RT, it is often not apparent in series with shorter follow-up times.¹³³ The largest study of second cancers in long-term survivors of testicular cancer was conducted by Travis and co-workers⁵⁶ at the National Cancer Institute. This report combined 14 population-based registries including 10,534 patients with seminoma treated with RT. The overall relative risk of a second nontesticular malignant tumor was 2 (95% CI, 1.8 to 2.2). For a 35-year-old patient with seminoma, the cumulative 40-year risk of a second malignant tumor was 36%, compared with 23% in the normal population. The increased risk of second malignant tumors after treatment with RT was also shown in a Dutch population-based study of more than 2700 long-term survivors where the risk of a second malignant tumor with subdiaphragmatic RT was 2.6-fold increased as compared with surgery alone.⁵⁷ The increased risk associated with irradiation was similar to the increased cancer risk seen with smoking. Limitation of the RT field to the infradiaphragmatic region results in a lower risk of second malignant tumors than more extensive fields.

Psychological Toxicity

Testicular cancer survivors have a higher level of anxiety and a higher prevalence of anxiety disorders than the normal population, and screening using a simple tool such as the Hospital Anxiety and Depression Scale (HADS) should be part of routine follow-up care.^127,¹³⁴ Appropriate social support should be offered to patients with testicular tumors. Although highly curable, testicular cancer is still a life-threatening condition in young patients with a concomitant threat of infertility and impaired sexual function as a result of the disease or its treatment.¹³⁵

Chemotherapy Complications

The complications of chemotherapy in testicular GCTs are related to the drugs employed.¹²⁷ Nausea and vomiting occur with all the drugs used but are controlled effectively in most patients with 5-hydroxytryptamine receptor-3 (5-HT3) antagonists and steroids. Myelosuppression is frequent. Febrile neutropenia is seen in about 10% to 15% of patients receiving EP, and such patients may benefit from hematopoietic growth factors. Nephrotoxicity, primarily a reduction in the glomerular filtration rate, occurs with the use of cisplatin and ifosfamide. Renal tubule function is normal in most patients, but hypomagnesemia is seen in patients after repeated use of cisplatin. Raynaud phenomenon has been reported in 23% to 49% of patients, although resolution of symptoms is common.¹³⁶ Chronic peripheral neuropathy (often asymptomatic) is well recognized after treatment with cisplatin, vinblastine, and etoposide. This symptom may require up to 12 to 18 months to resolve or may be permanent. Cisplatin-induced hearing loss is common, particularly at higher frequencies. Many patients report a loss of discrimination (cocktail party effect); tinnitus is another common complaint. Risk factors for hearing loss include a family history of deafness and exposure to other ototoxic drugs. Pulmonary toxicity is seen with the use of bleomycin and can be fatal in a small number of cases.¹³⁷ Impaired fertility, which may precede the use of chemotherapy, may also continue after its use. Although chemotherapy also produces infertility, recovery of sperm counts at least to levels compatible with fertility has been observed in the majority of patients.¹³⁸ Approximately 75% of patients who attempt paternity after chemotherapy are successful.¹³⁹

Non–Germ Cell Testicular Tumors

Leydig Cell Tumors

Leydig cell, or interstitial cell, tumors account for less than 2% of testicular tumors.¹⁴⁰ Twenty-five percent occur in children and can present with signs of prepubertal virilization. Seventy-five percent are in patients presenting between the age of 20 and 50 years, usually with a painless testicular mass. Most Leydig cell tumors are benign, and there are no definite histologic criteria for malignancy.¹⁴⁰ The regional lymph nodes are the commonest site of metastatic disease, but lung, bone, and liver metastases have also been reported. The initial management is similar to that for GCTs, with a radical inguinal orchiectomy followed by staging assessment with a chest radiograph and CT scanning of the abdomen and pelvis.¹⁴¹ Testis-sparing surgery can be considered in experienced hands. Urinary and serum steroids should also be assessed. RPLND can be considered in selected cases. There is no role for adjunctive or definitive irradiation or chemotherapy.

Sertoli Cell Tumors

Sertoli cell tumors account for less than 1% of all testicular tumors.¹⁴⁰ They have been classified into three subtypes: classic, large cell calcifying, and sclerosing.¹⁴² Most present with a painless testicular mass, and initial management is with a radical inguinal orchiectomy. Both precocious puberty and feminization have been reported to be associated with Sertoli cell tumors in children. Most Sertoli cell tumors are benign, and orchiectomy is nearly always curative.

Extragonadal Germ Cell Tumors

Extragonadal germ cell tumors (EGCTs) have histologic findings similar to those of testicular GCTs but are found in other parts of the body, in the absence of a testicular mass. They account for 1% to 5% of all GCTs and like testicular GCTs tend to occur in young men, although the median age of presentation is 5 to 10 years older than with testicular GCTs.¹⁴³ Ten percent of adult EGCTs occur in women, usually as ovarian dysgerminomas, and these will be discussed elsewhere (see Ovarian Cancer, Chapter 59). In infants, EGCTs are more common than testicular primary tumors (usually, sacrococcygeal teratomas).¹⁴³

Overall, patients with EGCTs (especially NSGCTs) have a worse prognosis than patients with testicular primary tumors.¹⁴⁴ An increased incidence of EGCTs is seen in Klinefelter syndrome. A number of patients present with poorly differentiated carcinomas (predominantly in midline locations), with a cytogenetic pattern similar to those with typical EGCTs, and do respond to cisplatin-based chemotherapy regimens.¹⁴⁵

EGCTs most commonly arise in three midline sites in the mediastinum, the pineal and suprasellar regions, and the sacrococcyx (usually in infants). There have been rare case reports of tumors arising in the orbit, prostate, vagina, and liver. Tumors arising in the retroperitoneum are usually thought to be associated with an occult testicular primary lesion. Mediastinal GCTs usually occur in the anterior superior region of the mediastinum adjacent to the thymus. Patients may present with cough, dyspnea, and chest pain, and tumor marker levels are frequently abnormal. Local invasion or metastatic disease to the lungs, liver, or bone is common. Biopsy should always be performed because treatment is dependent on the histologic subtype. For mature teratomatous tumors surgery is advised, whereas for NSGCTs or seminomas the preferred approach is cisplatin-based chemotherapy. Surgical resection is recommended for residual mass after chemotherapy. However, the precise role of locoregional therapy after primary chemotherapy is unclear.

The results of an international analysis of 635 consecutive patients with EGCT treated in 11 European and U.S. centers have shown that patients with pure seminomatous histologic typing had a long-term cure rate of 89%, irrespective of the primary site (retroperitoneum or mediastinum).¹⁴⁴ In patients with nonseminomatous tumors, however, a mediastinal primary site was an adverse feature, with only 45% of these patients alive at 5 years as compared with 63% of patients with retroperitoneal presentations.¹⁴⁴ Prognostic variables for response and outcome have been identified, and four prognostic risk groups have been identified based on histologic findings, the presence of liver, lung or CNS metastases, elevation of β-HCG levels, and number of metastatic sites involved with disease.¹⁴⁶ The best prognostic group has an 89% 5-year survival rate and encompasses all patients with seminoma. The other groups all have nonseminomatous histologic findings and 5-year survival rates of 69%, 55%, and 17%, respectively. The excellent treatment results with chemotherapy alone of mediastinal seminomatous tumors would suggest that there is no routine role for RT in their management. Platinum-based chemotherapy regimens are recommended. Although a 5-year survival rate of 73% has been reported with the use of cisplatin, vincristine, methotrexate, bleomycin, actinomycin D, cyclophosphamide, and etoposide (POMB/ACE), there is no evidence that this regimen is superior to BEP.¹⁴⁷ In contrast, POMB/ACE is considerably more toxic, and its routine use cannot be recommended.

Special Treatment Situations

Germ Cell Tumors in Patients with Horseshoe Kidney

Horseshoe kidney (pelvic kidney) occurs in approximately 1 in 400 persons in the general population.¹⁴⁸ There are two main problems in the management of GCTs associated with horseshoe kidney. The first is related to the technical problem of delivery of RT in patients with seminoma. In a number of cases of horseshoe kidney, a large part of the renal parenchyma directly overlies the regional lymph nodes and lies within the standard radiation volume. The delivery of a standard radiation dose would be associated with an unacceptable risk of radiation nephritis. The second problem is related to the possible abnormalities in lymphatic drainage of the testis and, therefore, the possibility of relapse when the standard radiation fields are used. Unusual patterns of relapse have been observed in patients managed by surveillance, confirming concerns regarding abnormal lymphatic pathways.¹⁴⁹ For these reasons, in patients with seminoma and NSGCTs, postorchiectomy surveillance in stage I and chemotherapy in stage II have usually been recommended. However, an RPLND is another option for patients unwilling to follow the surveillance program. Reports in the literature suggest that RPLND was both safe and effective in the selected cases where it was performed.¹⁴⁹

Testicular Tumors Developing in Immunosuppressed Patients

It is well established that the risks of developing Kaposi’s sarcoma and non-Hodgkin lymphoma are markedly increased in patients with human immunodeficiency virus (HIV) infection.¹⁵⁰ Initial data suggested that HIV-infected men have an increased incidence of testicular cancer, but more recent studies have indicated that this may not be true.^17,¹⁵⁰ Organ transplant patients may also have an increased incidence of testicular tumors.¹⁵¹ The clinical course of immunosuppressed patients with testicular tumors is similar to that of nonimmunosuppressed patients, and these patients should be offered standard oncologic therapy. Both chemotherapy and RT reduce the CD4 count even when antiretroviral therapy is used; therefore, wherever possible, surveillance should be used in patients with stage I disease.¹⁷ Caution must be exercised because benign retroperitoneal adenopathy related to acquired immunodeficiency syndrome (AIDS) may be mistaken for metastasis from a testicular primary tumor. For those receiving chemotherapy, consideration should be given to concomitant prophylaxis for opportunistic infection. Most patients can be cured of their tumors, and the outcome of patients with HIV-related GCTs is similar to that of non-HIV patients.

Bilateral Testicular Germ Cell Tumors or Tumors Arising in a Single Testicle

Patients with cancer in one testicle are significantly more likely to develop a testicular tumor in the contralateral testicle, with rates of metachronous or synchronous development of second testis cancers of 1% to 5% reported.¹⁵² Bilateral orchiectomy is recommended as standard management, with resulting infertility, lifelong dependence on androgen substitution, and psychological morbidity due to castration at a young age.¹⁵³

To preserve endogenous hormonal function, organ-sparing surgery followed by low-dose RT (16 to 20 Gy in 2-Gy daily fractions using a direct field with electrons) to the remaining testis to eradicate residual CIS is a viable therapeutic option with a high likelihood of cure in a highly select group of patients.^19,¹⁵⁴ Adjuvant irradiation after surgery may be postponed if fertility is an issue provided that follow-up is rigorous.¹⁵⁴ Patients with large tumors (>30% of the testis volume) or clinical evidence of metastatic disease should not be considered for this approach.¹⁵⁴ The recent European Consensus on the diagnosis and treatment of testis cancer has emphasized the need for organ-sparing approaches to be offered only in centers with experience in this area.¹⁹

Central Nervous System Metastases

Approximately 2% to 3 % of patients with metastatic GCT will present with brain metastases, and up to 40% of patients who die of progressive disease will have brain metastases at autopsy. Patients who present at the time of diagnosis with brain metastases can achieve approximately 50% 5-year CSS with aggressive treatment.⁵³ The optimal sequence of chemotherapy, RT, and surgery has not yet been fully established. Systemic chemotherapy is required in all cases, and in one study the addition of cranial RT improved OS.¹⁵⁵ It is unclear, however, if RT is necessary if a complete response is obtained with chemotherapy. Surgery can also be considered in resectable disease. If RT is given, a dose of 40 to 45 Gy should be given to gross disease, preferably using a stereotactic approach. The role of total brain irradiation is unclear, but if this treatment is given, the dose should not exceed 40 Gy. Patients presenting with late relapse with central nervous system (CNS) metastases should be treated aggressively because long-term disease-free survival times are possible.¹⁵⁶ Patients who develop brain metastases during chemotherapy have a very poor prognosis.¹⁵⁶

Spermatocytic Seminoma

Spermatocytic seminoma is a rare testicular tumor accounting for only 1% to 2% of all seminomas.¹⁵⁷ It usually occurs at age 50 to 60 years but is seen in younger patients.¹⁵⁷ It is distinct in its histologic characteristics, usually having three different cell sizes, spherical nuclei, a lack of cytoplasmic glycogen, and sparse or absent lymphocytic infiltrate when compared with classical seminoma.¹⁵⁸ Unlike classical seminoma, it does not appear to arise from CIS and it occurs solely in the testis and has no ovarian equivalent. All patients present with stage I disease, and subsequent metastatic disease is extremely rare. In the past, the treatment approach was similar to seminoma with adjuvant RT. Current recommendations call for surveillance in all patients.¹⁵⁹

Irradiation Techniques and Dose

Stage I Seminoma

Various strategies have been investigated to reduce the long-term complications of adjuvant RT in stage I seminoma, including reduction in the treatment volume and dose of RT and reduction in the number of patients receiving RT with the use of either surveillance or adjuvant chemotherapy.

Radiation Target Volume

The traditional management of stage I seminoma patients has consisted of irradiation to the para-aortic and pelvic (retroperitoneal) lymph nodes. The most frequently used field arrangement is parallel opposed anteroposterior fields, and patients are treated with 10- to 18-MeV linear accelerator photons. The clinical target volume included the para-aortic lymph nodes and ipsilateral pelvic lymph nodes, and with left-sided tumors, the left renal hilum is included in the field by shaping the left lateral border of the RT portal. This classical plan was called the “hockey-stick” field in North America and the “dogleg” field in the United Kingdom and Europe. Usually, the radiation fields extended from the top of the T11 vertebral body to the inguinal ligament. With this technique, the penis was moved out of the field and, in addition, the contralateral testis was placed in a scrotal shield to protect fertility and hormonal function. Verification, simulator, and port fields were routine. In general, scrotal irradiation was avoided even in patients with scrotal violation. The only instance where scrotal irradiation may be recommended is in patients with very extensive local disease, incomplete surgery, and gross scrotal contamination prior to surgery.

Reduction in Radiation Treatment Volume

The low incidence of pelvic lymph node involvement in stage I seminoma and a desire to reduce radiation-induced morbidity led to the investigation of RT directed to the para-aortic lymph nodes alone. The advantages of such an approach include decreased scatter to the contralateral testicle and a reduction in the integral irradiation dose with a presumed decrease in the risk of second malignant tumors. Reports from phase II trials and institutional experiences have shown excellent results with few pelvic failures.79,86a In the MRC Testicular Study Group randomized study of 478 patients comparing para-aortic plus pelvic RT and para-aortic RT alone, patients treated with para-aortic RT alone had a 4% relapse rate as compared with a 3.4% relapse rate with para-aortic and pelvic irradiation.¹⁵⁵ All patients who received para-aortic and pelvic RT relapsed in supradiaphragmatic sites, but four patients (1.6%) treated to the para-aortic lymph nodes alone failed in the pelvis. This trial demonstrated that a small risk of pelvic failure is present if para-aortic RT alone is given. It highlighted that regular imaging with CT of the pelvic lymph nodes must be performed to detect pelvic relapse. If no routine evaluation of the pelvis is carried out after para-aortic RT alone, patients fail with bulky disease (median, 5 cm). Recent data from the German Testicular Cancer Study Group indicate that follow-up imaging may be confined to the first 3 years after irradiation.¹⁶⁰ The advantages of para-aortic RT alone are not clear, when surveillance is an excellent option.

A compromise between traditional irradiation fields and para-aortic irradiation alone is to treat the para-aortic and ipsilateral common iliac lymph nodes by positioning the inferior border of the radiation fields at midpelvis ¹⁶¹ (Fig. 53-3). This encompasses the lymph nodes that are typically removed at lymphadenectomy in patients with nonseminomatous tumors and also covers the vast majority of pelvic nodal relapses in patients treated with para-aortic irradiation alone.^86a

Figure 53-3 Radiation fields, stage I.

Radiation Dose

The minimum dose of radiation required to control occult seminomatous tumor has not been clearly defined; however, there are ample data to suggest that a dose of 20 to 25 Gy is sufficient. At Princess Margaret Hospital in Toronto, a dose of 25 Gy prescribed at midline and delivered in 20 daily fractions of 1.25 Gy has been used for over 25 years and no in-field recurrences have been observed.⁶⁶ In the MRC TE18 trial, 625 patients were randomized to 30 Gy in 15 fractions over 3 weeks and 20 Gy in 10 fractions over 2 weeks.⁶² The median follow-up was 61 months. A total of 10 and 11 relapses, respectively, occurred in the 30-Gy and 20-Gy groups (hazard ratio [HR], 1.11; 90% CI, 0.54 to 2.28). The 5-year relapse rates were 3% and 3.6%, respectively, for the 30-Gy and 20-Gy groups. This trial was updated at the 2008 American Society of Clinical Oncology (ASCO) meeting, and the original findings were confirmed with longer follow-up.⁸³

Stage II Seminoma

The RT technique in stage II seminoma is similar to that used in stage I disease. The penis is always positioned out of the field, and the contralateral testis is placed in a scrotal shield. The treatment volume includes the gross tumor as well as the para-aortic and ipsilateral common and external iliac lymph nodes (Fig. 53-4A). The radiation dose is typically 25 Gy in 20 daily fractions plus a boost of a further 10 Gy to the gross lymphadenopathy (see Fig. 53-4B). At Princess Margaret Hospital, this boost is given concurrently with the large-field treatment. The contralateral iliac lymph nodes may also be treated in cases where lymphadenopathy in the low para-aortic area is deemed to increase the risk of these nodes being involved by tumor. This is probably of most concern, however, in patients with bulky retroperitoneal lymphadenopathy who are better treated with primary chemotherapy as discussed previously. Adjuvant RT of the supraclavicular lymph nodes in patients with stage II disease has been suggested by some, although it is not justified on a routine basis in view of the low risk of isolated supraclavicular relapse (2 of 79 patients with stage IIA or IIB disease in the Princess Margaret Hospital series).^86c ^,162