Introduction

Although testicular cancer accounts for only 1% of all male malignancies, the understanding and study of this disease are important for a variety of reasons. The evolution of therapy for germ cell tumors (GCTs) has been deliberate and thoughtful, and has resulted in cures of 85%. GCT therapy serves as a model for the treatment of curable cancers, and is particularly notable because GCT occurs in young men who are entering their most productive years. Nonetheless, challenges in the management of GCTs remain. Because of their young age, patients who have been cured are at risk of long-term, treatment-induced toxicity. Furthermore, an 85% cure rate also implies that 15% of patients with GCTs will not be cured, and will ultimately succumb to their disease. An understanding of staging and risk assessment is crucial if (1) patients with good risk features are not to be overtreated and exposed to undue toxic risks and (2) patients with poor risk features are to receive adequate (curative) therapy.

GCTs account for 1% of all male malignancies, and it is estimated that 8590 new cases were diagnosed in the United States in the year 2011.¹ Despite its overall curability, approximately 360 men in the United States died in the year 2011 as a consequence of germ cell tumors. Although GCT is an uncommon malignancy, it is the most common malignancy among men aged 15 to 35. Seminoma accounts for half of all germ cell tumors, whereas nonseminoma germ cell tumors (NSGCTs) account for the remaining half. Although occasionally GCT occurs in children (generally yolk sac tumors), and in men over 70 (generally spermatocytic seminoma), by and large it is a malignancy of early adulthood, with the incidence of seminoma peaking in the 25- to 45-year-old group; the highest incidence of nonseminoma occurs in a slightly younger group of men (15- to 30-year-old group).² Although the incidence of germ cell neoplasms in African American men is one fourth that of white men, African Americans have a higher disease stage at diagnosis than white men.³ Bilateral tumors occur in 2% to 4% of patients.⁴

Molecular Biology

The cytogenetic and molecular biology of GCT has only recently begun to be understood. Most interest has focused on changes involving chromosome 12. The isochromosome of the short arm of chromosome 12, i(12p), has been reported in up to 90% of GCT patients,12,13 and cases in which the isochromosome is not seen, excess genetic material is typically found on the p arm of chromosome 12.¹⁴ Although it is occasionally found in gastric cancer, i(12p) is nearly a pathognomic feature of GCT of all histologic types, whether of gonadal or extragonadal origin. This cytogenetic abnormality has been reported in carcinoma in situ tissue, suggesting it is an early marker, if not a cause, of germ cell tumorigenesis.¹⁵ In patients with mediastinal GCT, in whom there is an increased incidence of hematologic malignancies, often acute myeloid leukemia i(12p) can be found in both the mediastinal GCT tissue and in the leukemic cells,¹⁶ suggesting a common clonal origin for both. Similarly, i(12p) is found in malignant tissue of diverse histologies that has developed from the malignant transformation of teratoma, which is a component of nonseminomatous germ cell cancers. The presence of i(12p) has been utilized diagnostically in patients with midline carcinomas of unknown origin,¹⁷ allowing, in one series, a definitive diagnosis of GCT in 28% of patients and also serving as a marker of chemotherapy sensitivity (within the group of patients with midline malignancies of uncertain histogenesis).¹⁸ The presence of three or more copies of i(12p) has been correlated with poor prognosis GCT.¹⁹ Other changes in chromosome 12 are seen in GCT. Deletions of the terminal portion of 12q have been observed in up to 44% of patients with GCT, as well as in several GCT cell lines, suggesting the possibility of a tumor suppressor gene in this area.²⁰

The gene or genes on i(12p) that may be involved in carcinogenesis have not been identified, although the oncogene KRAS, which is located on i(12p), has been implicated in GCT cell lines.²¹ Cyclin D2, encoded by the gene CCND2, has received much attention in normal testicular development as well as in the pathogenesis of GCT. It has an important role in cellular proliferation and its expression is tightly regulated throughout the cell cycle. It facilitates passage of cells though the G1 cell-cycle checkpoint. The gene is located on the short arm of chromosome 12 and it is overexpressed in nearly all GCTs. CCND2 is therefore a candidate GCT oncogene.²⁰ Activated mutations in the protooncogene KIT have also been isolated from seminoma specimens.²² KIT encodes a transmembrane receptor tyrosine kinase that appears to have a role in normal spermatogenesis, and it is expressed in early fetal germ cells up to 12 weeks of gestation, but not beyond. In addition, it has also been detected in carcinoma in situ and seminoma cells reflecting a possible role in GCT oncogenesis.^22,23 Epidermal growth factor receptor (EGFR) has also been found to be overexpressed in approximately 25% of the β-human chorionic gonadotropin (β-hCG)–expressing component of mixed GCTs.²⁴ EGFR is a membrane protein that after binding to its ligand activates protein tyrosine kinase activity. This leads to activation of a cascade of biochemical and physiological responses that are involved in the mitogenic signal transduction of normal as well as malignant cells.

Most primary testicular cancers are of germinal origin and are felt by some to be the malignant counterparts of normal embryonic development. In this model, the normal embryonic development counterpart of seminoma is the spermatocyte, whereas pluripotential early cleavage stage tissues are the counterpart of embryonal cell carcinoma. More differentiated malignancies find their normal tissue counterparts in tissues derived from the developing embryo, such as the embryo itself (teratoma), the yolk sac (yolk sac tumors), and the placenta (choriocarcinoma).

A commonly used histologic classification of testicular neoplasms is derived from the Armed Forces Institute of Pathology classification schema of Dixon and Moore,²⁵ which recognizes pure seminoma, as well as four other categories, each of which may occur with or without seminoma elements: (1) embryonal carcinoma, (2) teratoma, (3) teratoma with foci of embryonal carcinoma and choriocarcinoma (also termed teratocarcinoma), and (4) choriocarcinoma with and without embryonal elements.

The World Health Organization (WHO) international classification divides tumors into those of single histologic type (seminoma, spermatocytic seminoma, embryonal carcinoma, choriocarcinoma, teratoma, and yolk sac tumors) and those of more than one type, in which the listing and estimation of relative proportion of each type is required.²⁶ The major important differences between these two schemas are the recognition by the WHO schema of yolk sac tumors (endodermal sinus tumors) and spermatocytic seminoma as distinct categories (Table 86-1). Representative photomicrographs of various germ cell tumors can be seen in Figure 86-1.

Testicular cancers that are of nongerminal origin include specialized gonadal stromal neoplasms as well as sarcomas. These, in addition to adenocarcinoma (of the rete testis) and secondary (nonprimary) malignancies such as acute leukemia, lymphoma, carcinoma, and melanoma, comprise less than 5% of testicular neoplasms. The frequency and natural history of specific histologic subtypes are discussed below and summarized in Table 86-2.

Overview of Natural History

The natural history of GCT is largely defined by lymphatic spread to the retroperitoneal lymph nodes early in the disease, with hematogenous dissemination developing later. Thus virtually all GCTs with pulmonary or visceral metastases will have concomitant retroperitoneal lymph node involvement. Pure choriocarcinoma is an exception, characterized by early hematogenous dissemination to lungs, brain, and viscera. The more aggressive biology of nonseminomatous GCT is evidenced by the approximately 60% to 70% of patients with nonseminomatous GCT who will have nodal or other metastatic involvement at presentation, compared with 25% in patients with pure seminoma. These figures are somewhat biased, because patients with clinical stage I seminoma (confined to testis) do not routinely undergo pathological staging with a retroperitoneal lymph node dissection (RPLND), whereas pathological staging is often undertaken in similar nonseminomatous patients.

Seminoma usually spreads to first-station paraaortic nodes, although (as with nonseminomatous GCT) pelvic nodes may be involved if the scrotal sac has been violated, either by the primary tumor or in the case of transscrotal exploration by inguinal surgery. Although nodal involvement is less common in seminoma than in NSGCT, ureteral obstruction seems to occur more commonly than in nonseminomas, because of either bulky disease or more diffuse sheetlike spreading. It is extremely unusual for seminomas to present with hepatic or pulmonary metastases; when they do, it is virtually always in the setting of retroperitoneal nodal involvement. The presence of nonpulmonary visceral metastasis (e.g., bone or liver) portends an adverse prognosis.

The distribution of retroperitoneal lymph node metastases in nonseminomatous GCT has been described by Ray et al.²⁷ and Donohue et al.,²⁸ and they provide the basis for the specific surgical and therapeutic approaches described below. Figure 86-2 diagrams the anatomy and distribution of retroperitoneal lymph node involvement in GCT. A right-sided testicular primary is most frequently found to have interaortocaval nodal metastases, followed (in order of decreasing frequency) by the precaval and preaortic nodes. Contralateral nodal involvement occurs in 15% of patients, but in virtually every case with contralateral involvement, ipsilateral nodes were also involved. Left testis tumors most frequently have nodal spread to the left paraaortic, preaortic, and interaortocaval nodes, in that order. Suprahilar nodal involvement does not occur in patients with microscopic or low burden infrahilar disease (stage B1; see below), whereas 25% of patients with gross infrahilar disease have been found to have positive suprahilar nodes.²⁷ Other nodal metastases are rare, but can occur in the external iliac and obturator nodes if the primary tumor invades the epididymis or extends up the spermatic cord, or in inguinal lymph nodes if the tumor extends through the tunica vaginalis to involve the scrotum, or if transscrotal exploration has been used.²⁹

Seminoma

Seminomas account for 40% of all GCTs. The three distinct histologic patterns that have historically been described are classic seminoma, anaplastic seminoma, and spermatocytic seminoma. However, a clinical distinction can only be made between classic seminoma and spermatocytic seminoma, and the histologic definition of anaplastic seminoma (more than five mitotic figures per high-power field, cellular anaplasia, and tissue disruption) is of historic interest only, as neither response to therapy nor survival are adversely affected by the presence of anaplastic features.³⁰

Classic seminoma usually manifests in the fourth or fifth decade. It is localized to the testes (stage I) in approximately 70% of patients and is metastatic to lymph nodes (generally stage II) in 25%.³¹ Metastases to lymph nodes occur in an orderly sequential fashion along draining lymph node chains. Visceral metastases are present at presentation in less than 5% of patients, and in general occur late in the course of the disease. Seminomas tend to appear homogeneous, with little necrosis or hemorrhage on gross inspection. Microscopically, they consist of sheets of uniform cells with large central hyperchromatic nuclei and clear or granular cytoplasm, which are divided by thin fibrous septations. Although lymphocytic infiltration and occasional giant cells may be seen, neoplasms in which any teratomatous or embryonal elements are seen are by definition not considered to be pure seminomas.²⁵ Spermatocytic seminoma represents approximately 5% of all seminomas, and warrants special consideration. It generally occurs in the sixth decade. Although it is more likely to be bilateral than typical seminoma (6% vs. 2%), it is nonetheless a fairly indolent malignancy in which metastatic events are distinctly uncommon.³² Spermatocytic seminoma can be histologically distinguished from classic seminoma by the relative lack of compartmentalization of sheets of cells by fibrous septae, by the marked variation in cell size, and by the absence of lymphocytic infiltration.

Teratoma and Teratocarcinoma

Mature teratoma has elements of one or more of the three germinal layers that are fully differentiated. Pure teratoma is uncommon and comprises less than 5% of GCT in adults. More than 75% of nonseminomas have been reported to have variable amounts of teratomatous elements, so that “pure” teratomas must be sampled carefully to exclude undifferentiated foci. The term teratocarcinoma refers to teratomas in combination with other elements, although some pathologists reserve the term for the combination of teratoma and embryonal carcinoma. When a teratoma has cellular and active stroma with mitotic figures, it is referred to as immature teratoma. Teratomas and teratocarcinomas are composed of solid and cystic spaces on cut surface, with areas of hemorrhage and necrosis. A histologic mix of fully differentiated cartilage, muscle, or epithelial tissue and malignant embryonal elements is seen. Predominant teratomatous features account for one-third of teratocarcinomas, whereas approximately two-thirds are mostly composed of nonteratomatous elements.²⁵ Mature teratoma is the least aggressive of the nonseminoma GCTs, although up to 30% of adult patients with clinical stage I teratoma treated with orchiectomy alone will subsequently relapse, suggesting that pure teratomas should not be exempted from the usual clinical and pathological staging of GCT or from the usual subsequent therapeutic interventions.³⁴ The natural history of teratocarcinomas lies somewhere between that of mature teratoma and embryonal carcinoma, but for practical (diagnostic and therapeutic) purposes, teratocarcinomas can be grouped with embryonal cell carcinomas. The likelihood that residual or recurrent masses after treatment are composed of mature teratoma is increased in patients with more extensive teratomatous elements at presentation and is discussed below.

Clinical Manifestations

The most common presentation of testicular cancer is testicular swelling (73% in one series of 450 patients).³⁵ A commonly held misconception is that testicular cancers are by and large painless and that painful testicular masses need not be evaluated for malignancy. In fact, testicular pain is a manifesting feature of 18% to 46% of patients with GCT.³⁵ Acute pain may be associated with torsion of the neoplasm, infarction or bleeding in the tumor, as well as with epididymitis. Signs and symptoms indistinguishable from acute epididymitis have been observed in up to one-fourth of patients with testicular neoplasms. Less commonly presenting symptoms will include gynecomastia in hCG-producing tumors such as choriocarcinoma (10%), back or flank pain from metastatic disease (10%), and infertility in less than 5% of tumors. Approximately 25% of patients with advanced disease have symptoms referable to their metastases, such as back pain.⁴⁰ This is frequently the manifesting symptom in patients with primary retroperitoneal GCT. Pulmonary symptoms including shortness of breath, chest pain, and hemoptysis are rare but can occur in patients with advanced pulmonary disease or primary mediastinal GCT.

The physical examination of the testicles is performed by fully palpating all areas of the testicle between thumb and fingers. Testicular masses are firm to hard, and generally the scrotal sac is normal in appearance unless there is a large mass causing distention. The patient with a testicular mass must of course have a careful and complete physical examination, including examination for lymphadenopathy, intraabdominal masses, hepatomegaly, bone tenderness, and pulmonary abnormalities. A thorough neurological history and neurological examination is essential if there is concern for brain metastases, particularly in patients with any component of choriocarcinoma.

The constellation of elicited symptoms and physical examination findings can offer a clue to the histology of a testicular mass. For example, it has been reported that pain more commonly occurred in patients who had embryonal carcinoma elements in their tumors than in those without that histologic feature (56% vs. 37%; P < 0.02). The same study reported a significantly higher incidence of testicular swelling when the primary tumors contained teratoma or yolk sac tumor elements.³⁵ Primary tumors from patients with seminoma tend to be larger and more homogeneous, with diffuse involvement of the testicle, whereas embryonal and teratomatous elements tend to from smaller, discrete masses. Rapidly growing tumors, particularly those with extranodal dissemination, should raise the possibility of choriocarcinoma. These observations are of course no substitute for the appropriate clinical staging and histopathological evaluation.

In addition to malignancy, the differential diagnosis of a testicular mass includes testicular torsion, hydrocele, varicocele, spermatocele, and epididymitis. Benign hydroceles tend to extend along the spermatic cord, and can be transilluminated. However, it is prudent to recall that a small percentage of testicular cancers are associated with hydroceles. Varicoceles occur in the venous pampiniform plexus of the spermatic cord and result in what has been classically described as a “bag of worms” on palpation. Spermatoceles are found in the posterior, superior portion of the scrotum and also transilluminate. As noted above, testicular cancer is perhaps most often mistaken for epididymitis, which is marked by a swollen, extremely tender testicle with occasional fever and pyuria. Delays in treatment of testicular cancer of up to 9 months have been observed as patients are treated for presumed epididymitis. Thus the clinical diagnosis of epididymitis should prompt a careful physical examination as well as ultrasonographic examination of the scrotum, particularly in those patients who fail to respond to a 10-day course of antibiotics.