Lymph node metastases of seminoma.

Testicular cancers are uncommon. In 2007, the estimated number of testicular cancers was 7,920 cases (1). Approximately 90% of testicular cancers are germ cell tumors, and these tumors are very responsive to therapy. As a result, the estimated number of deaths attributable to testicular cancer in 2006 was low—only 380 (1).

Seminoma is the most common germ cell tumor of the testis, representing approximately 50% of all germ cell tumors in its pure form (2). Seminoma also may be associated with other types of germ cell tumor, including embryonal carcinoma, teratoma, and choriocarcinoma, representing an additional 10% of all germ cell tumors (2). Two types of seminoma are recognized, typical and spermatocytic. The latter is uncommon, represents less than 10% of all seminomas, and almost never metastasizes and, therefore, is not discussed further. In contrast with other types of testicular germ cell tumors, typical seminoma has the greatest propensity to involve lymph nodes and histologically can most closely resemble lymphomas, in particular, lymphomas with numerous clear cells. For these reasons, seminoma is the focus of the remainder of this chapter.

Seminomas originate from primordial, pluripotential germ cells that are likely to be derived from the inner cell mass of the blastocyst (2). This hypothesis is suggested by the ultrastructural resemblance of the two types of cells (3), the high content of alkaline phosphatase and glycogen in both seminoma and germ cells (4), and the occurrence of seminoma in situ within the seminiferous tubules, also known as intratubular germ cell neoplasia (5). More recently, gene expression profiling analysis has shown a similar expression profile for germ cells and germ cell tumors (6).

The highest frequency of seminoma occurs in whites of Northern European heritage, with a low frequency in African Americans and Asians (2). A number of conditions predispose males to testicular tumors, particularly seminomas. Perhaps the best-known factor is cryptorchidism, associated with 4% to 12% of testicular germ cell tumors (7). The risk for malignancy in undescended testes is estimated to be 14 to 40 times greater than that in descended testes (8,9). Other factors that have been reported to predispose to testicular germ cell tumors include viral infections, trauma, inguinal hernia, and infertility (2,9,10,11). The fact that androgen levels are highest in patients at the same time the frequency of testicular germ cell tumors is also highest suggests that hormonal factors may be involved (12). Certain occupations have been associated with an increased risk of testicular germ cell tumors, particularly those involving exposure to pesticides and organic solvents (13). The incidence of testicular germ cell tumors, and seminomas in particular, is also increased in patients with immunodeficiency syndromes such as human immunodeficiency virus infection (14).

Genetic factors are also involved in the pathogenesis of testicular germ cell tumors. An increased incidence in some families is associated with defects in urologic development (15). A susceptibility gene at chromosome locus Xq27 has been identified (16). Patients with Klinefelter syndrome (47 XXY) or Down syndrome (trisomy 21) are associated with an increased risk of developing germ cell tumors (17,18), and studies of monozygotic twins have shown that the twin of an affected individual also has an increased risk of developing a testicular germ cell tumor (19).

The average age of patients with seminoma is 40 years, which is 5 to 10 years older than the average age of patients with nonseminomatous tumors (20). Seminoma is almost never seen in children younger than 10 years of age (21). The right testis is more often involved than the left in a ratio of 5:4 (9). Typically, patients present with a large and hard testis that is usually painless, but can be painful in 10% to 20% of patients (2). The testis can be as much as 10 times normal size, and this increase in volume may be diffuse or associated with palpable nodules (9). In 5% to 10% of cases, the first symptoms are caused by metastases (9,22). Seminomas are highly responsive to therapy, either radiotherapy (for localized disease) or chemotherapy, even at time of relapse, and long-term survival is very high (2).

Metastases of seminomas are relatively common and may be present in as many as 10% of patients at the time of initial diagnosis (9). Metastases follow the lymphatic vessels to the common iliac and paraaortic lymph nodes (23). In 80% to 85% of cases, metastases remain restricted to the ipsilateral lymph nodes (9). From the retroperitoneal lymph nodes, metastases spread to the thoracic and left supraclavicular lymph nodes. Involvement of the epididymis allows tumor spread through the epididymal lymphatics into the inguinal lymph nodes. Similarly, involvement of scrotal skin permits tumor spread to inguinal lymph nodes. Hematogenous dissemination also occurs, with metastases to internal organs. Autopsy studies show that the paraaortic and iliac lymph nodes are involved in 71%, the liver in 54%, and the lungs in 37% of cases of seminoma. The left kidney and adrenal gland more commonly are the sites of metastases, compared with their right-sided counterparts (9).

Seminomas have been reported to occur in the retroperitoneum and mediastinum in the absence of a testicular tumor (24). This occurrence is much less frequent than was reported initially, as detailed examination in many patients has disclosed unsuspected microscopic foci of seminoma in grossly normal or atrophic testes. Thus, most seminomas in the retroperitoneum and mediastinum are, in fact, metastatic tumors with origins in occult primary testicular tumors, represented in some cases by microscopic foci of seminoma (9,22) and in others by seminomas that spontaneously regressed (25,26). Supradiaphragmatic lymph nodes can be involved when seminoma involves the retroperitoneum or mediastinum, and these metastases can be asymptomatic (2).

Although testicular germ cell tumors secrete markers into the serum that can be used for diagnosis and management, this is much less true for seminomas than nonseminomatous tumors. Serum human chorionic gonadotropin (hCG) is mildly elevated in approximately 10% of patients with seminoma.
This is usually associated with the presence of small foci syncytiotrophoblast in the tumor (27). Serum lactate dehydrogenase (LDH) levels can be elevated. α-Fetoprotein is not elevated in patients with seminoma (2).