Tumors of the Testis
Malignant tumors of the testis are rare, with approximately 9 new cases per 100,000 males reported in the United States each year. Of all primary testicular tumors, 90–95% are germ cell tumors (seminoma and nonseminoma), while the remainders are nongerminal neoplasms (Leydig cell, Sertoli cell, gonadoblastoma). The lifetime probability of developing testicular cancer is 0.2% for a white male in the United States. Survival of patients with testicular cancer has improved dramatically in recent years, reflecting the development and refinement of effective combination chemotherapy. Of the 8480 new cases of testicular cancer in the United States in 2010, only 350 deaths are expected.
The incidence of testicular cancer shows marked variation among different countries, races, and socioeconomic classes. Scandinavian countries report up to 6.7 new cases per 100,000 males annually; Japan reports 0.8 per 100,000 males. In the United States, the incidence of testicular cancer in blacks is approximately one-fourth that in whites. Within a given race, individuals in the higher socioeconomic classes have approximately twice the incidence of those in the lower classes.
Testicular cancer is slightly more common on the right side than on the left, which parallels the increased incidence of cryptorchidism on the right side. Of primary testicular tumors, 1–2% are bilateral, and about 50% of these tumors occur in men with a history of unilateral or bilateral cryptorchidism. Primary bilateral tumors of the testis may happen synchronously or asynchronously but tend to be of the same histologic type. Seminoma is the most common germ cell tumor in bilateral primary testicular tumors, while malignant lymphoma is the most common bilateral tumor of the testis.
Although the cause of testicular cancer is unknown, both congenital and acquired factors have been associated with tumor development. The strongest association has been with the cryptorchid testis. Approximately 7–10% of testicular tumors develop in patients who have a history of cryptorchidism; seminoma is the most common form of tumor these patients have. However, 5–10% of testicular tumors occur in the contralateral, normally descended testis. The relative risk of malignancy is highest for the intra-abdominal testis (1 in 20) and is significantly lower for the inguinal testis (1 in 80). Placement of the cryptorchid testis into the scrotum (orchiopexy) lowers the risk of malignancy if it is performed prior to the age of 13 (Pettersson et al, 2007).
Exogenous estrogen administration to the mother during pregnancy has been associated with an increased relative risk for testicular tumors in the fetus, ranging from 2.8 to 5.3 over the expected incidence. Other acquired factors such as trauma and infection-related testicular atrophy have been associated with testicular tumors; however, a causal relationship has not been established.
Numerous classification systems have been proposed for germ cell tumors of the testis. Classification by histologic type proves to be the most useful with respect to treatment. The two major divisions are seminoma and nonseminomatous germ cell tumors (NSGCTs), which include embryonal, teratoma, choriocarcinoma, and mixed tumors.
During embryonal development, the totipotential germ cells can travel down normal differentiation pathways and become spermatocytes. However, if these totipotential germ cells travel down abnormal developmental pathways, seminoma or embryonal carcinomas (totipotential tumor cells) develop. If the embryonal cells undergo further differentiation along intraembryonic pathways, teratoma will result. If the embryonal cells undergo further differentiation along extraembryonic pathways, either choriocarcinoma or yolk sac tumors are formed (Figure 24–1). This model helps to explain why specific histologic patterns of testicular tumors produce certain tumor markers. Note that yolk sac tumors produce alpha-fetoprotein (AFP) just as the yolk sac produces AFP in normal development. Likewise, choriocarcinoma produces human chorionic gonadotropin (hCG) just as the normal placenta produces hCG.
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. Microscopically, monotonous sheets of large cells with clear cytoplasm and densely staining nuclei are seen. It is noteworthy that syncytiotrophoblastic elements are seen in approximately 10–15% of cases, an incidence that corresponds approximately to the incidence of hCG production in seminomas.
Anaplastic seminoma accounts for 5–10% 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 5–10% of all seminomas. Microscopically, cells vary in size and are characterized by densely staining cytoplasm and round nuclei that contain condensed chromatin. More than half of the patients with spermatocytic seminoma are older than 50 years.
Two variants of embryonal cell carcinoma are common: the adult type and the infantile type or yolk sac tumor (also called endodermal sinus tumor). Histologic structure of the adult variant demonstrates marked pleomorphism and indistinct cellular borders. Mitotic figures and giant cells are common. Cells may be arranged in sheets, cords, glands, or papillary structures. 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 AFP production in these tumors. Microscopically, cells demonstrate vacuolated cytoplasm secondary to fat and glycogen deposition and are arranged in a loose network with large intervening cystic spaces. Embryoid bodies are commonly seen and resemble 1- to 2-week-old embryos consisting of a cavity surrounded by syncytio- and cytotrophoblasts.
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, while 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. Microscopically, ectoderm may be represented by squamous epithelium or neural tissue; endoderm may be represented by intestinal, pancreatic, or respiratory tissue; and mesoderm may be represented by smooth or skeletal muscle, cartilage, or bone.
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. The syncytial elements are typically large, multinucleated cells with vacuolated, eosinophilic cytoplasm; the nuclei are large, hyperchromatic, and irregular. Cytotrophoblasts are uniform cells with distinct cell borders, clear cytoplasm, and a single nucleus.
Clinically, choriocarcinomas behave in an aggressive fashion characterized by early hematogenous spread. Paradoxically, small intratesticular lesions can be associated with widespread metastatic disease.
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 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.
In a series of 250 patients with unilateral testicular cancer, Berthelsen et al (1982) 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 is usually treated by external beam radiation therapy.
With the exception of choriocarcinoma, which demonstrates early hematogenous spread, germ cell tumors of the testis typically spread in a stepwise lymphatic fashion. Lymph nodes of the testis extend from T1 to L4 but are concentrated at the level of the renal hilum because of their common embryologic origin with the kidney. The primary landing site for the right testis is the interaortocaval area at the level of the right renal hilum. Stepwise spread, in order, is to the precaval, preaortic, paracaval, right common iliac, and right external iliac lymph nodes. The primary landing site for the left testis is the para-aortic area at the level of the left renal hilum. Stepwise spread, in order, is to the preaortic, left common iliac, and left external iliac lymph nodes. In the absence of disease on the left side, no crossover metastases to the right side have ever been identified. However, right-to-left crossover metastases are common. These observations have resulted in modified surgical dissections to preserve ejaculation in selected patients (see Section “Treatment”).
Certain factors may alter the primary drainage of a testis neoplasm. Invasion of the epididymis or spermatic cord may allow spread to the distal external iliac and obturator lymph nodes. Scrotal violation or invasion of the tunica albuginea may result in inguinal metastases. Although the retroperitoneum is the most commonly involved site in metastatic disease, visceral metastases may be seen in advanced disease. The sites involved in decreasing frequency include lung, liver, brain, bone, kidney, adrenal, gastrointestinal tract, and spleen. As mentioned previously, choriocarcinoma is the exception to the rule and is characterized by early hematogenous spread, especially to the lung. Choriocarcinoma has also a predilection for unusual sites of metastasis such as the spleen.
Many clinical staging systems have been proposed for testicular cancer. However, most are variations of the original system proposed by Boden and Gibb (1951). In this system, a stage A lesion was confined to the testis, stage B demonstrated regional lymph node spread, and stage C was spread beyond retroperitoneal lymph nodes. Numerous clinical staging systems have also been suggested for seminoma. A stage I lesion is confined to the testis. Stage II has retroperitoneal nodal involvement (IIA is <2 cm, IIB is >2 cm). Stage III has supradiaphragmatic nodal involvement or visceral involvement. The TNM classification of American Joint Committee (2010) has attempted to standardize clinical stages as in Table 24–1.
T—Primary tumor | |
TX: T0: Tis: T1: T2: T3: T4: | Cannot be assessed No evidence of primary tumor Intratubular cancer (CIS) Limited to testis and epididymis, no vascular invasion Invades beyond tunica albuginea and into tunica vaginalis or has vascular invasion Invades spermatic cord Invades scrotum |
N—Regional lymph nodes | |
NX: N0: N1: N2: N3: | Cannot be assessed No regional lymph node metastasis Lymph node metastasis ≤2 cm, or multiple nodes, none >2 cm and <6 nodes positive Nodal mass >2 cm and ≤5 cm or ≥6 nodes positive Nodal mass >5 cm |
M—Distant metastasis | |
MX: M0: M1a: M1b: | Cannot be assessed No distant metastasis Distant metastasis present in nonregional lymph nodes or lungs Nonpulmonary visceral metastases |
S—Serum tumor markers | |
SX: S0: S1: S2: S3: | Markers not available Marker levels within normal limits Lactic acid dehydrogenase (LDH) <1.5 × normal and hCG <5000 mIU/mL and AFP <1000 ng/mL LDH 1.5–10 × normal or hCG 5000–50,000 mIU/mL or AFP 1000–10,000 ng/mL LDH >10 × normal or hCG >50,000 mIU/mL or AFP >10,000 ng/mL |
The most common symptom of testicular cancer is a painless enlargement of the testis. Enlargement is usually gradual, and a sensation of testicular heaviness is not unusual. The typical delay in treatment from initial recognition of the lesion by the patient to definitive therapy (orchiectomy) ranges from 3 to 6 months. The length of delay correlates with the incidence of metastases. The importance of patient awareness and self-examination is apparent. Acute testicular pain is seen in approximately 10% of cases and may be the result of intratesticular hemorrhage or infarction.
Approximately 10% of patients present with symptoms related to metastatic disease. Back pain (retroperitoneal metastases involving nerve roots) is the most common symptom. Other symptoms include cough or dyspnea (pulmonary metastases); anorexia, nausea, or vomiting (retroduodenal metastases); bone pain (skeletal metastases); and lower extremity swelling (vena caval obstruction).
Approximately 10% of patients are asymptomatic at presentation, and the tumor may be detected incidentally following trauma, or it may be detected by the patient’s sexual partner.
A testicular mass or diffuse enlargement is found in most cases. The mass is typically firm and nontender and the epididymis should be easily separable from it. A hydrocele may accompany the testicular tumor and help to camouflage it. Transillumination of the scrotum can help to distinguish between these entities.
Palpation of the abdomen may reveal bulky retroperitoneal disease; assessment of supraclavicular, scalene, and inguinal nodes should be performed. Gynecomastia is present in 5% of all germ cell tumors but may be present in 30–50% of Sertoli and Leydig cell tumors. Its cause seems to be related to multiple complex hormonal interactions involving testosterone, estrone, estradiol, prolactin, and hCG. Hemoptysis may be seen in advanced pulmonary disease.
Anemia may be detected in advanced disease. Liver function tests may be elevated in the presence of hepatic metastases. Renal function may be diminished (elevated serum creatinine) if ureteral obstruction secondary to bulky retroperitoneal disease is present. The assessment of renal function (creatinine clearance) is mandatory in patients with advanced disease who require chemotherapy.
Several biochemical markers are of importance in the diagnosis and management of testicular carcinoma, including AFP, hCG, and lactic acid dehydrogenase (LDH). AFP is a glycoprotein with a molecular mass of 70,000 daltons and a half-life of 4–6 days. Although present in fetal serum in high levels, beyond the age of 1 year, it is present only in trace amounts. While present to varying degrees in many NSGCTs (Table 24–2), it is never found in seminomas.
hCG is a glycoprotein with a molecular mass of 38,000 daltons and a half-life of 24 hours. It is composed of two subunits: alpha and beta. The alpha subunit is similar to the alpha subunits of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and thyroid-stimulating hormone (TSH). The beta subunit conveys the activity to each of these hormones and allows for a highly sensitive and specific radioimmunoassay in the determination of hCG levels. A normal man should not have significant levels of beta-hCG. While more commonly elevated in NSGCTs, hCG levels may be elevated in up to 7% of seminomas.
LDH is a cellular enzyme with a molecular mass of 134,000 daltons that has five isoenzymes; it is normally found in muscle (smooth, cardiac, skeletal), liver, kidney, and brain. Elevation of total serum LDH and in particular isoenzyme-I was shown to correlate with tumor burden in NSGCTs. LDH may also be elevated in seminoma.
Other markers have been described for testis cancer, including placental alkaline phosphatase (PLAP) and gamma-glutamyl transpeptidase (GGT). These markers, however, have not contributed as much to the management of patients as those mentioned previously.
The primary testicular tumor can be rapidly and accurately assessed by scrotal ultrasonography. This technique can determine whether the mass is truly intratesticular, can be used to distinguish the tumor from epididymal pathology, and may also facilitate testicular examination in the presence of a hydrocele.
Once the diagnosis of testicular cancer has been established by inguinal orchiectomy, careful clinical staging of disease is mandatory. Chest radiographs (posteroanterior and lateral) and computed tomography (CT scan) of the abdomen and pelvis are used to assess the two most common sites of metastatic spread, namely, the lungs and retroperitoneum. The role of CT scanning of the chest remains controversial because of its decreased specificity. Of note is the fact that routine chest x-rays (CXR) detect 85–90% of pulmonary metastases. Pedal lymphangiography (LAG) is rarely used owing to its invasiveness as well as low specificity, although it may be warranted in patients undergoing a surveillance protocol (see Section “Treatment”).
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