Introduction
Background
The study of testicular germ cell tumors (GCTs) is a unique area of urologic oncology, as treatment algorithms have benefited from numerous randomized prospective clinical trials (unlike prostate cancer) and because metastatic disease is highly responsive to multimodal treatment (unlike renal cell carcinoma). Seminoma is a histologic subtype of GCTs, which are discussed separately as nonseminomas in Germ Cell Tumors.
The interest in GCTs is disproportional to its incidence because of its fascinating pathologic subtypes, success of multimodal therapy (even for metastatic disease), and almost universal incidence in otherwise healthy males aged 15-35 years. Testicular GCTs have various pathologic subtypes, including seminoma, embryonal, yolk sac, teratoma, and choriocarcinoma. The most important clinical distinction is between seminoma and nonseminoma, two broad categories with different treatment algorithms: (1) Seminoma as a classification refers to pure seminoma upon histopathologic review, and (2) any nonseminomatous elements (even if seminoma is prevalent) change the classification to nonseminoma.
Pathophysiology
Testicular seminoma is a pathologic diagnosis in which only seminomatous elements are observed upon histopathologic review after a radical orchiectomy and in which serum alpha-fetoprotein (AFP) is within the reference range. Any elevation of AFP levels or nonseminomatous elements in the testis specimen mandates diagnosis of nonseminomatous GCT (NSGCT) and an appropriate treatment change.
GCTs have the following subtypes and frequencies: seminoma (40%), embryonal (25%), teratocarcinoma (25%), teratoma (5%), and choriocarcinoma (pure; 1%). Seminomas can be further subdivided into one of three categories based on histology: classic, anaplastic, and spermatocytic (see Histologic Findings).1
Germ cell carcinoma in situ (CIS) is a premalignant condition with a natural history of progression to seminoma or embryonal cancer. Patients with infertility, intersex disorders, cryptorchidism, prior contralateral GCTs, or atrophic testes more commonly have CIS. Histologically, it demonstrates intratubular atypical germ cells within seminiferous tubules. Most patients with seminomas (except spermatocytic seminoma) and NSGCTs have CIS or severe atypia associated with the primary tumor.2 In patients with GCTs, 5% of those with contralateral testes harbor CIS.3
Testicular microcalcifications observed on scrotal sonograms were long held to be implicated in the development of testicular carcinoma. However, a recent analysis of 83 patients with asymptomatic microcalcifications observed for 5 years demonstrated only one with testicular carcinoma development over the interim. This represented an odds ratio for the study population of 317 (95% CI, 36-2756), with over 98% of men with asymptomatic microcalcifications having a benign course. A recommendation of continued monthly self-examination without further intervention was given for management of this indolent finding.4
Frequency
United States
Testicular GCTs are rare, representing only 1%-2% of all male malignancies and occurring in 1 of 250 men by age 65 years; however, GCT is the most common malignancy in men aged 15-35 years. Incidence rates are 3.7 and 0.9 cases per 100,000 persons per year for whites and blacks, respectively.5
International
The incidence of testis cancer has increased from the early 1960s to the mid 1980s. Nonwhite populations have a lower incidence than white populations. The highest rates of testis cancer are in Denmark (11.5 cases per 100,000 persons per year), Norway (9 cases per 100,000 persons per year), and Switzerland (11 cases per 100,000 persons per year). Rates vary across Europe.6
A review by Bray and colleagues (2006) of 41 cancer registries in 14 countries found the seminoma rates to be highest in Denmark and Switzerland (9 cases per 100,000 persons per year) and the lowest rates in Japan, Israel, and Finland (1-3 cases per 100,000 persons per year).7
Race
Established data sets have consistently demonstrated a higher incidence of GCTs in whites than in African Americans—as high as a 5:1 ratio. McGlynn et al (2005) published an analysis of 9 registries of the Surveillance, Epidemiology, and End Results (SEER) database from 1973-2001. They found an increasing incidence among African Americans starting in the 1990s. The increased incidence was 100% for GCTs overall—124% for seminoma and 64% for nonseminoma. The reasons for this increase are unclear, and the author's review of the data suggests environmental or nonperinatal factors (occupation, physical activity, diet) rather than early screening as the predominant cause.8
Age
Testicular GCTs represent the most common malignancy in men aged 15-35 years. Seminoma accounts for one third of these diagnoses.9
Clinical
History
- Common presentation
- Typically, a male aged 15-35 years presents with a painless testicular lump that has been noticeable for several days to months.
- Delay in diagnosis is common because of (1) a patient's failure to perform self-examinations, (2) a patient's failure to alert the physician about the mass, or (3) a physician's delay while treating the patient for presumed epididymoorchitis or testicular trauma.
- Patients commonly have abnormal findings on semen analysis at presentation, and they may be subfertile.10
- Patients may present with a hydrocele, and scrotal ultrasonography may identify a nonpalpable testis tumor. The presence of a hydrocele complicates manual examination and identification of a testicular lump, nodule, or mass.
- Overall, in approximately 75% of patients, the seminomas are localized (stage I) at diagnosis. However, 15% have metastatic disease to the regional lymph nodes, and 5-10% have involvement of juxtaregional nodes or visceral metastases.
- Uncommon presentation
- Testicular pain, possibly with an acute onset, especially when associated with a hydrocele, prevents adequate physical examination.
- A testis tumor may become metastatic and may manifest as large retroperitoneal and/or chest lesions, while the primary tumor is nonpalpable. Scrotal ultrasonography may locate the primary tumor. Histopathology of the primary testis often shows a focus of tumor surrounded by fibrous scar, termed burned-out testis cancer.
- In 1996, Miller and associates reported on a series of patients with previously nonpalpable testes that were explored and incorrectly diagnosed as vanished testes. A subsequent seminoma was diagnosed intra-abdominally.11
Causes
- Patients with history of cryptorchidism have a 10- to 40-times increased risk of testis cancer; 10% of patients with GCTs have a history of cryptorchidism (see Image 1).11
Testicular seminoma. A 57-year-old man presents with abdominal pain of slow onset. CT scanning shows a large 25-cm retroperitoneal lesion encompassing the aorta and renal vasculature and displacing the right kidney laterally. The patient had a history of cryptorchidism repaired at age 8 years. Testes were normal and descended; however, ultrasonography showed a small 5-mm lesion on the right testis, which proved to be pure seminoma at orchiectomy. The beta-human chorionic gonadotropin level was 70 mIU/mL (reference range, <5 mIU/mL), and the alpha-fetoprotein level was within the reference range; no metastatic lesions were observed above the diaphragm, indicating stage IIb (bulky), T1N3M0. The patient was referred for 4 cycles of cisplatin-based chemotherapy.
- Risk is greater for the abdominal versus inguinal location of undescended testis.
- An abdominal testis is more likely to be seminoma, while a testis surgically brought to the scrotum by orchiopexy is more likely to be NSGCT.
- Orchiopexy allows for earlier detection by physical examination but does not alter the risk of GCT.
- Genetic changes in the form of amplifications and deletions are observed mainly in the 12p11.2-p12.1 chromosomal regions.12
- A gain of 12p sequences is associated with invasive growth of both seminomas and NSGCTs.
- In contrast, spermatocytic seminoma shows a gain of chromosome 9, while most infantile yolk sac tumors and teratomas show no chromosomal changes.
- Somatic mutations of the KIT gene occur in approximately 5% of all testicular GCTs. Of these, Coffey and colleagues (2008) demonstrated that only seminomas contain activating mutations of the KIT gene.13
- Other risks include trauma, mumps, and maternal estrogen exposure.
- Hemminki and colleagues (2004) demonstrated a familial risk for testicular cancer, with a 4-fold increased risk in a male with a father who had a GCT and a 9-fold increased risk if a brother was affected.14
More on Testicular Seminoma |
 Overview: Testicular Seminoma |
| Differential Diagnoses & Workup: Testicular Seminoma |
| Treatment & Medication: Testicular Seminoma |
| Follow-up: Testicular Seminoma |
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| References |
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Keywords
testicular seminoma, testis cancer, cancer of the testes, testis germ cell carcinoma, testicular cancer, seminoma, germ cell tumor, GCT, radical orchiectomy, germ cell carcinoma in situ, germ cell CIS, classic seminoma, anaplastic seminoma, spermatocytic seminoma
