Testicular cancer is the most common malignancy in men in the 20–40- year age group. The germ-cell tumors (GCTs) are the most prevalent type of testicular cancer. Their incidence has risen over the past two decades, as has the most prevalent risk factor for GCT, an undescended testis (cryptorchidism), suggesting that numbers of men afflicted with testicular cancer will continue to rise for the foreseeable future.
Unlike ovarian tumors, which are likely to arise from the epithelium covering the gland, 90% of primary testicular tumors arise from intratubular germ cells. Histologically, there are six distinct types of GCT. Five of these occur in young men and one is seen exclusively in older men (Fig. 40.1). The five subtypes seen in young men include seminoma, choriocarcinoma, endodermal sinus tumor (yolk sac carcinoma), embryonal carcinoma and teratomas, both benign and malignant. Spermatocytic seminomas are typically seen in men over 50 and are quite rare. The germ cells of origin in GCT affecting young and old men are distinct and appear to be at different stages of maturation. The associated tumors therefore have distinct neoplastic behaviors.
All GCTs of young men arise from spermatogonial cells. The five tumors that develop from this single precursor cell type are quite heterogeneous and several exhibit embryonal-like differentiation. Prognosis and treatment depends upon whether GCTs are pure seminomas (SGCTs) or mixed cell tumors (nonseminomas, NSGCTs). Seminomas have a homogeneous germ-cell morphology. Nonseminomas have features of embryonal cells and can mimic the histogenesis of the very early embryo. Embryonal carcinoma is the most primitive, or pluripotent, of the NSGCTs. It can progress along extraembryonic lines as choriocarcinoma or yolk sac carcinoma, or along embryonic lines as a teratoma. Individual tumors can contain a mixture of any of the histologic subtypes.
About 80% of GCTs secrete tumor markers that can be detected in the serum. Tumors with yolk sac components typically secrete alpha fetoprotein (AFP), an embryonic protein normally produced by the yolk sac during development. Other NSGCTs can also secrete AFP but seminomas do not. Human chorionic gonadotropin (hCG) is typically secreted by choriocarcinomas; however, small amounts of hCG production have been found in SGCTs as well as NSGCTs. The distribution of these two markers by specific cell types suggests the associated tumors arise from precursors at different levels of differentiation. AFP is a very primitive marker of embryonal differentiation whereas hCG represents trophoblastic differentiation. A third marker, placental-like alkaline phosphatase (PLAP), is found in carcinoma in situ (CIS) and about 50% of seminomas. Clinical paradigms using serum levels of AFP and hCG have been developed to assist in the diagnosis and staging of GCT.
Most GCTs are diagnosed at an early tumor stage when the tumor is confined to the testis. Serum screening, physical exam and testicular ultrasounds are useful in identifying early tumors in patients at high risk for GCT, such as formerly cryptorchid men and intersex individu- als who keep their gonads. Men who present with solid testicular masses are usually treated by radical orchidectomy (removal of the testis). When GCT metastasizes, it typically spreads unilaterally to the para-aortic nodes. Distant metastases are generally found only in tumors with trophoblastic components.
Like gestational trophoblast disease in women (Chapter 45), GCT has a very high cure rate. Virtually all patients with early stage disease can expect to be cured. Initial treatment of stage I disease involves removal of the affected testes, followed by either retroperitoneal lymph node dissection, a short course of adjuvant chemotherapy or close surveillance. Even metastatic disease responds to chemotherapy with cure rates in excess of 90%.
Leydig cell tumors are a very rare form of testicular cancer (1–3%) and are associated with isosexual precocious puberty (Chapter 28). Gonadal stromal tumors (sex cord-stromal tumors) include both Sertoli–Leydig cell and granulosa-theca cell tumors. They are extraordinarily rare in boys and men and are associated with phenotypic feminization.
Epidemiology of GCT
The single largest risk factor for GCT is cryptorchidism (Chapter 26). It is estimated that 2–3% of cryptorchid men will develop GCT, a rela- tive risk 5–10 times that of the general population. GCT disproportionately affects white men of European descent and is uncommon in African and Asian men, independent of where they currently reside. Familial cases are also common. Pedigree analyses suggest that a single dominant gene with low penetrance is involved in these cases. The strong developmental association of cryptorchidism with hormonal abnormalities suggests that fetal or neonatal endocrine imbal- ances may be involved in the initiation of GCT. The higher incidence of testicular cancer, cryptorchidism and hypospadias seen among the sons of women who were treated with the synthetic estrogen diethylstilbestrol (DES) may provide mechanistic insights. Overexposure to estrogens during fetal development may provide activation (Fig. 40.1). Increased levels of maternal estrogen can suppress the fetal pituitary production of follicle-stimulating hormone (FSH) through negative feedback. Less FSH leads to reduced Sertoli cell multiplication and lower levels of Müllerian-inhibiting substance (MIS). Increased estro- gens may also impair Leydig cell function, thus decreasing local androgen production and inhibiting testicular descent. MIS has been implicated as necessary for both normal descent of the testes and normal differentiation of fetal gonocytes into early spermatogonia. Over the past 20 years, maternal estrogen ingestion in the form of phytoestrogens (soya) and chemical pollutants with estrogenic activity has increased, as has the incidence of both cryptorchidism and GCT.
Exposure of the cryptorchid testis to high temperatures may also have a role in the development of GCT, as the maturation of gonocytes to early spermatogonia is significantly inhibited in abdominal testes. Still, maldescended testes that have been restored to the scrotum in infancy or childhood do retain an increased lifetime risk of GCT, as does the contralateral testis in cases of unilateral cryptorchidism. Heat exposure cannot be solely responsible.
Molecular biology of GCT
Because all GCTs have a sex chromosome constitution of XY, all tumors must originate in germ cells prior to the first meiotic division. These tumors are often aneuploid. Most common is a near triploid autosome content. Almost all GCTs exhibit multiple copies of chromosome 12p, either as one or more copies of i(12p) or as tandemly duplicated segments of 12p on marker chromosomes. These findings have led to the following model of tumorigenesis in GCT.
The precursor cell for GCT is the pachytene spermatocyte. These are the final premeiotic spermatogonial cells and therefore contain a 4n DNA content (Chapters 4 and 8). The homologous autosomes within these cells are paired as bivalents and the sex chromosomes are aligned. These chromosomes will cross-over and segregate as they progress to metaphase 1. The process of crossing-over requires activation of specific genes to repair the resulting open chromosomal ends. If the repair mechanisms fail, the affected spermatocyte degenerates. A meiosis stage cell with a defective repair mechanism is rescued from death only by the initiation of a new program for mitotic division. Such a proliferation is neoplastic. In the spermatocyte, the aberrant chromatid exchange event that initiates the new cell cycle must involve a locus on p12, given that it is almost uniformly abnormal in GCT. Aberrations in the p12 gene product appear to rescue the cell from death. Initiation of another round of DNA replication in the improperly repaired cell will lead to a tetraploid cell with an i(p12) or amplified p12. Because the initial repair defect remains, the cell is genetically unstable and more susceptible to additional chromosomal changes, such as nondisjunction, mutation and microdeletion.
It is not clear whether all GCTs derive from a single cell that has undergone malignant transformation (clonal expansion) or whether tumorigenesis can be multifocal. An alternative, but related, theory for GCT development hypothesizes that a subset of gonocytes experiences “activation 1,” during which the gonocytes become binucleated or multinucleated spermatogonia (Fig. 40.2). Nuclear fusion occurs in some of these abnormal spermatogonia and they become tetraploid cells. These aneuploid cells then receive a “second hit” or “activation 2.” As a result, they lose specific genes or chromosomes that are important for tumor suppression. The clonality or multifocality of a given tumor might then depend on the nature of specific activating factors.
Regardless of how these cells undergo malignant transformation, it is clear that tumorigenesis can occur in infancy or even prenatally, perhaps as early as during testicular differentiation. Testicular CIS has been found in both fetal and neonatal testes. It is a polyploid nonin- vasive precursor to GCT that shares its aneuploidy and 12p amplifications. As the peak incidence of frankly invasive carcinoma occurs 2–3 decades after precursor lesions, GCT appears to have a very long latency, which supports the second hit or activation theory for the development of GCT. Early hormonal imbalances, particularly androgen exposure at puberty, may also have a role in the development of GCT, perhaps through the “activation 2” step.
In contrast to GCT in young men, the spermatocytic seminomas seen in older men are more indolent and slow growing. Spermatocytic seminomas appear to arise from mature spermatogonia and not from spermatogonial stem cells, which may explain their less aggressive behavior. The molecular basis for such different biological behaviors may rely on imprinting (discussed further in Chapter 45).