eMedicine Specialties > Oncology > Carcinomas of the Genitourinary Tract

Germ Cell Tumors

Author: Mansoor Javeed, MD, FACP, Clinical Assistant Professor of Medicine, University of California Davis; Consultant, Sierra Hematology-Oncology Medical Center, Folsom, California
Coauthor(s): Charles J Ryan, MD, Assistant Clinical Professor, Department of Medicine, Division of Hematology and Oncology, University of California at San Francisco; Issam Makhoul, MD, Associate Professor, Department of Medicine, Division of Hematology/Oncology, University of Arkansas for Medical Sciences; Kush Sachdeva, MD, Private Practice, Southern Oncology and Hematology Associates, South Jersey Hospital System, Fox Chase Cancer Center; Brendan Curti, MD, Director, Genitourinary Oncology Research, Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Portland Medical Center
Contributor Information and Disclosures

Updated: Jul 27, 2006

Introduction

Background

Germ cell tumors (GCTs) are a morphologically distinct group of neoplasms with varied clinical presentation. Ninety-five percent of tumors arising in the testes are GCTs, indicating that they originate from the primordial germ cells. More than 90% of patients with GCT diagnosed early are cured. A delay in diagnosis correlates with a higher stage at presentation and, consequently, a lower cure rate. The success in treating GCTs in the past 2 decades is attributed largely to the effectiveness of cisplatin-containing combination chemotherapy in curing advanced disease.

Pathophysiology

Biology

Recent studies of GCTs have suggested that cyclin D2 is overexpressed in malignant germ cells and is oncogenic.

GCT differentiation may be influenced by several interacting pathways, such as regulators of germ-cell totipotentiality, embryonic development, and genomic imprinting. Sensitivity and resistance to chemotherapy may be based in part on a p53 -dependent apoptotic pathway.

Mechanism of germ cell transformation

Almost 100% of tumors show increased copy numbers of 12p (i12p). This chromosomal marker has been noted in carcinoma in situ (CIS), suggesting that it is one of the early changes associated with the origin of GCT. CIS is considered to be a precursor of all GCTs. Two models have been proposed to explain the origin of CIS cells, as follows:

Model 1: Fetal gonocytes that escape normal development into spermatogonia undergo abnormal cell division and proliferation. These gonocytes are prone to invasive growth, mediated by postnatal and pubertal gonadotrophin stimulation.

Model 2: Increased 12p copy number, cyclin D2 expression, consistent near triploid-tetraploid chromosome numbers, and increased expression of wild-type p53 result in tumorigenesis. Abnormal chromatid exchanges during meiotic crossing over leads to increased 12p copy number and cyclin D2 overexpression. In cells containing unrepaired DNA strand breaks, cyclin D2 can block p53 -dependent apoptosis and leads to re-initiation of cell cycle and genomic instability.

Recently, models involving other cyclins and inhibitory molecules have also been proposed.

Frequency

United States

More than 9000 cases of GCTs are diagnosed each year.

International

For unknown reasons, worldwide incidence has more than doubled in the past 40 years. The incidence of GCT varies by geographic area. The highest incidence is in Scandinavia, Germany, and New Zealand. It is lower in the United States and lowest in Asia and Africa.

Mortality/Morbidity

For all patients with GCT, the 5-year survival rate is about 95%. Cure rates are highest for early stage disease and lower for advanced disease.

Race

GCTs are seen predominantly in whites and rarely in African Americans. The incidence ratio of whites to African Americans is approximately 5:1.

Despite this, a sharp increase in the incidence of germ cell tumors in men of African descent has occurred. In the United States, the incidence increased by 100% from 1988 to 2001. Diagnoses of seminomas increased 124% in that time period and nonseminomas increased by 64%. No significant increase occurred in the incidence of early-stage disease in proportion to all diagnoses in this population, indicating that the significant increase was not due to an increased prevalence of screening or earlier detection.

Age

GCT is the most common solid tumor in men aged 15-35 years. However, the disease has 3 modal peaks: infancy, ages 25-40 years, and age 60 years.

Clinical

History

Most patients present with a complaint of a painless testicular mass. Less common presenting symptoms, such as back pain, cough, and hemoptysis, arise from metastatic disease.

• Approximately 95% of GCTs occur in the gonads, and the rest occur in extragonadal tissues (see Extragonadal Germ Cell Tumors).
• A painless testicular mass is the most common presentation in patients with testicular cancer. However, about 20-40% of patients with primary testicular cancer present with pain, swelling, hardness, or a combination of these symptoms. Treating patients who have no palpable mass using a trial of antibiotics is reasonable, as infectious epididymitis or orchitis is more common than tumor. A testicular ultrasound examination is indicated if symptoms and signs are not controlled or do not revert in 2 weeks. Tumor-bearing testicles may be more susceptible to bleeding and hematoma development; therefore, patients who experience a hematoma with minor trauma should undergo evaluation for an underlying tumor.
• Testicular pain may be associated with epididymitis, torsion of the testes, tumor, or bleeding or infarction in the tumor. Flank pain, back pain, or abdominal pain can occur from metastatic disease.
• Gynecomastia may occur in patients with tumors that produce human chorionic gonadotropin (HCG), such as choriocarcinoma.
• Pulmonary symptoms such as shortness of breath, chest pain, and hemoptysis, although rare, can occur in patients with advanced pulmonary disease or primary mediastinal GCT.
• Symptoms due to central nervous system metastasis or to bone metastases are rare.

Physical

• Physical examination of the testicles is performed by fully palpating all areas of the testicle between thumb and fingers. Testicular mass with or without pain is a finding that requires immediate attention.
• Other areas of emphasis include examination for the following:
  • Left supraclavicular lymphadenopathy
  • Hepatomegaly
  • Bone tenderness
  • Gynecomastia
  • Abdominal mass
  • GCTs should be distinguished by seminoma versus nonseminoma subtypes because they are treated differently.
• Seminoma, a GCT subtype, has the following clinical features:
  • This usually presents in the fourth decade of life. Seminoma is confined to the testes in about 70% of cases and metastasizes to the lymph nodes in about 25% of cases. Metastatic disease is present in 5% of cases at presentation. These testicular primary tumors are usually homogenous and large.
  • Spermatocytic seminoma occurs in the sixth decade of life. It presents bilaterally more often than seminoma and is an indolent tumor that rarely metastasizes. Spermatocytic seminoma is not associated with CIS.
• Nonseminomatous germ cell tumor (NSGCT) is often composed of several histologic forms (mixed) and may contain any of the following forms:
  • Embryonal carcinoma is characterized by rapid and bulky growth and by spread via lymphatic and hematogenous routes to distant viscera (eg, lungs, liver). More than 60% of patients have metastases at the time of presentation. Pain is a common feature in these patients.
  • Teratoma is found commonly in residual or recurrent masses. It is the least aggressive form, but approximately 30% of patients with clinical stage 1 disease have relapse after orchiectomy.
  • Choriocarcinoma is the most aggressive of the NSGCTs. It disseminates hematogenously to lungs, liver, brain, and other viscera very early in the disease process. Bleeding is common in patients with metastatic choriocarcinoma and may present as hemoptysis, gastrointestinal bleeding, or, rarely, intracerebral hemorrhage.
  • Yolk sac tumors typically present as a large primary tumor.

Causes

No environmental exposures have been proven to lead to GCTs. However, a few congenital developmental defects are related to the development of GCTs.

• Cryptorchidism: Risk of developing GCT in the cryptorchid testis is 10- to- 40-fold higher than in the normally descended testis. About 5-20% of patients with a history of cryptorchid testis develop tumors in the normally descended testis. The risk of developing GCT when a cryptorchid testis is intraabdominal is about 5%. The risk falls to 1% if the testis is retained in the inguinal canal and decreases further if the undescended testis is surgically placed in the scrotum when the patient is younger than 6 years.
• Diethylstilbestrol: No clear association is seen between diethylstilbestrol and development of GCT.
• Klinefelter syndrome: Patients with Klinefelter syndrome have an increased incidence of mediastinal GCT.

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