Incidence and Epidemiology

Testicular cancer accounted for some 8090 new cases and 380 estimated deaths in 2008.² Although it represents only 1% of cancers in men it is the most common malignancy among men aged 20 to 30 years. Bilateral involvement is seen in 2% to 4% of patients. These tumors are highly curable even in advanced stage. The peak age incidence for seminoma is slightly older compared to NSGCT, with the histologic variant spermatocytic seminoma occurring in men older than age 60.³ Interestingly the worldwide incidence of testicular cancers has doubled in the past 40 years.² Although germ cell tumors can rarely occur in extragonadal sites, their management follows that of testicular germ cell tumors.

Cryptorchidism, or an undescended testis, is the most studied risk factor for developing testis cancer. The relative risk of developing testicular cancer is 3.7 to 7.5.⁴^,⁵ Orchiopexy before puberty decreases this risk.⁶ HIV as a risk factor is controversial. Although many reports show an increase in incidence,⁷ population-based studies have failed to confirm this.⁸^,⁹ Chromosomal abnormalities most commonly involve chromosome 1 and 12. Deletions are seen in both arms of chromosome 1. The most frequent, and sometimes used diagnostically, is the isochrome of the short arm of chromosome 12, denoted as i(12p), and has been reported in up to 90% of germ cell tumors.¹⁰ Testicular cancers are observed 5 times more frequently among White men than among Black men. An association with the dysplastic nevus syndrome and Klinefelter’s syndrome has also been noted.

Anatomy

The adult testicle typically measures 4 to 5 cm in length and 2.5 cm in diameter. The testicle is covered by a parietal and visceral layer of the tunica vaginalis (Fig. 46-1). When this potential space accumulates fluid, a hydrocele forms. The testicle is encased by a hard outer capsule, the tunica albuginea. On the posterior-lateral aspect of the testicle, the tunica albuginea projects inwards, creating the mediastinum testis, the point of entry of blood vessels and ducts transporting sperm. Within the testicle, approximately 300 lobules exist, containing one or more seminiferous tubules: the site of spermatogenesis as well as site of origin for germ cell tumors. Each lobule of seminiferous tubules has short straight tubes that enter the mediastinum testis which then coalesce, forming the “rete testis” which, in turn, become fewer in number and wider in caliber, forming “efferent ductules.” These exit the testis and enter the head of the epididymis and subsequently the body and tail, where they become the vas deferens. Leydig cells reside in the interstitial tissue between seminiferous tubules and are responsible for testosterone production.

FIGURE 46-1 • Diagram the anatomy of the testis. A, Testis and epididymis. B, Cross section of the testis.

(From Tanagho EA: Anatomy of the lower urinary tract. In Walsh PC, et al, eds: Campbell’s urology, ed 6, Philadelphia, 1992, WB Saunders.)

Pathology

The majority of testicular tumors are of germ cell origin. From a therapeutic perspective, these histologies are divided into two types: seminoma and NSGCTs. The histologies are listed in Table 46-1. The frequency of germ cell tumor histologies encountered is given in parentheses.

Table 46-1 Histologies of Testicular Tumors

Germ Cell Tumors (95%)

Pure seminoma (40%)

Classic Seminoma

Anaplastic Seminoma

Spermatocytic Seminoma

Nonseminoma germ cell tumors (60%)

Non–Germ Cell Tumors (5%)

Stromal

Lymphoma

Seminoma (35%)

Three histologic subtypes of pure seminoma have been described. However, stage for stage, there is no prognostic significance to any of these subtypes. Classic seminoma accounts for 85% of all seminomas and is most common in the fourth decade of life. Grossly, coalescing gray nodules are observed (Fig. 46-2). Microscopically, monotonous sheets of large cells with clear cytoplasm and densely staining nuclei are seen (Fig. 46-3). It is noteworthy that syncytiotrophoblastic elements are seen in approximately 10% to 15% of cases, an incidence that corresponds approximately to the incidence of human chorionic gonadotropin (hCG) production in seminomas.

FIGURE 46-2 • Gross pathologic specimen of a testicular seminoma.

FIGURE 46-3 • Histology of classic seminoma.

Anaplastic seminoma accounts for 5% to 10% of all seminomas. Diagnosis requires the presence of three or more mitoses per high-power field, and the cells demonstrate a higher degree of nuclear pleomorphism than the classic types. Anaplastic seminoma tends to present at a higher stage than the classic variety. When stage is taken into consideration, however, this subtype does not convey a worse prognosis.

Spermatocytic seminoma accounts for 5% to 10% of all seminomas. Microscopically, cells vary in size and are characterized by densely staining cytoplasm and round nuclei that contain condensed chromatin (Fig. 46-4). More than half the patients with spermatocytic seminoma are over the age of 50. The important clinical aspect of spermatocytic seminoma is that they do not metastasize, thus, orchiectomy is curative and no additional therapy is needed.

FIGURE 46-4 • Histology of spermatocytic seminoma.

Embryonal Cell Carcinoma (20%)

Two variants of embryonal cell carcinoma are common: the adult type and the infantile type, or yolk sac tumor (also called endodermal sinus tumor). Extensive hemorrhage and necrosis may be observed grossly. The infantile variant, or yolk sac tumor, is the most common testicular tumor of infants and children. When seen in adults, it usually occurs in mixed histologic types and possibly is responsible for α-feto protein (AFP) production in these tumors.

Teratoma (5%)

Teratomas may be seen in both children and adults. They contain more than one germ cell layer in various stages of maturation and differentiation. Grossly, the tumor appears lobulated and contains variable-sized cysts filled with gelatinous or mucinous material. Mature teratoma may have elements resembling benign structures derived from ectoderm, mesoderm, and endoderm, whereas immature teratoma consists of undifferentiated primitive tissue. In contrast to its ovarian counterpart, the mature teratoma of the testis does not attain the same degree of differentiation as teratoma of the ovary.

Choriocarcinoma (<1%)

Pure choriocarcinoma is rare. Lesions tend to be small within the testis and usually demonstrate central hemorrhage on gross inspection. Microscopically, syncytio- and cytotrophoblasts must be visualized. Clinically, choriocarcinomas behave in an aggressive fashion characterized by early hematogenous spread. Paradoxically, small intratesticular lesions can be associated with widespread metastatic disease.

Mixed Cell Type (40%)

Within the category of mixed cell types, most (up to 25% of all testicular tumors) are teratocarcinomas, which are a combination of teratoma and embryonal cell carcinoma. Up to 6% of all testicular tumors are of the mixed cell type, with seminoma being one of the components. Treatment for these mixtures of seminoma and NSGCT is similar to that of NSGCT alone.

Carcinoma in situ

A series of 250 patients with unilateral testicular cancer ¹¹ demonstrated the presence of carcinoma in situ (CIS) in 13 (5.2%) of the contralateral testes. This is approximately twice the overall incidence of bilateral testicular cancer. The presence of contralateral atrophy or ultrasonographic microlithiasis in patients with testicular tumors warrants contralateral biopsy. If diagnosed, CIS (also called testicular intraepithelial neoplasia, TIN) is usually treated by external beam radiotherapy to the involved testis with doses in the range of 18 to 20 Gy.¹²^,¹³

Clinical Presentation

The classic presentation is that of a painless mass in the testes. Among the differential diagnoses are epididymitis, orchitis, and hydrocele. Trauma may lead to the discovery of an existing tumor but is not thought to be causative. Pain, though not common can be associated with presentation 40% of the time. Delay in diagnosis of greater than 3 to 6 months have been associated with worse prognosis.¹⁴ Evaluation of infertility occasionally leads to the diagnosis.¹⁵^,¹⁶ Analysis of 38,000 men from the Surveillance, Epidemiology and End Results (SEER) database revealed that infertile men with abnormal semen analyses have a 20-fold greater incidence of testicular cancer compared to the general population.¹⁵ Gynecomastia and breast tenderness may be seen in 5% of patients¹⁷ owing to the production of estradiol in response to elevated levels of hCG. Patients with metastases to lymph nodes in the retroperitoneum most commonly present with low back pain and may or may not have hydronephrosis with secondary ureteral obstruction.

Serum Tumor Markers

Germ cell tumors frequently produce proteins that can serve as tumor markers for disease burden as well as diagnosis (Table 46-2). The two most important of these are AFP and the β subunit of human chorionic gonadotropin (β-hCG). Lactate dehydrogenase (LDH) level is also used as a marker for disease burden. It should be kept in mind, however, that these proteins are not specific to germ cell tumors. The serum half-life of these tumor markers is of clinical relevance and is 4 to 6 days for AFP; for β-hCG, 1 to 2 days. After 5 half-lives a previously elevated serum marker should return to within normal levels if all tumor cells have been eradicated. In pure seminoma elevated β-hCG is present about 10% of the time, yet if present tends to be modest in magnitude (usually <100). AFP, by contrast, is never present with pure seminoma.

Table 46-2 Frequency of Serum Marker Elevation in Testicular Tumors