John D. Hainsworth, MD; F. Anthony Greco, MD
Malignant mediastinal germ cell tumors of various histologies were first described as a clinical entity approximately 50 years ago. Mediastinal and other extragonadal germ cell tumors were initially thought to represent isolated metastases from an inapparent gonadal primary site. However, there is now abundant clinical evidence to substantiate the extragonadal origin of these tumors. Extragonadal germ cell tumors, particularly those arising in mediastinal and pineal sites, represent a malignant transformation of germinal elements distributed to these sites and can occur in the absence of a primary focus in the gonad. Some investigators suggest that this distribution arises as a consequence of abnormal migration of germ cells during embryogenesis. Others hypothesize a widespread distribution of germ cells to multiple sites during normal embryogenesis, with these cells conveying genetic information or providing regulatory functions at somatic sites.
Malignant germ cell tumors of the mediastinum are uncommon, representing only 3 to 10% of tumors originating in the mediastinum. They are much less common than germinal tumors arising in the testes, and account for only 1 to 5% of all germ cell neoplasms. These figures, most of which are derived from retrospective series reported between 1950 and 1975, may underestimate the true occurance of mediastinal germ cell tumors. The histology of these tumors may be similar to that of other malignant mediastinal tumors, including malignant thymoma and high-grade non-Hodgkin's lymphoma. Some patients with "poorly differentiated neoplasm" or "poorly differentiated carcinoma" of the mediastinum have the i(12p) chromosomal abnormality diagnostic of germ cell tumor. Other patients with "poorly differentiated carcinoma" of the mediastinum have clinical characteristics and treatment responses typical of patients with extragonadal germ cell tumors. Although there is no doubt that mediastinal germ cell tumors are uncommon, increasing familiarity with the tumors by both clinicians and pathologists will probably result in their increased recognition.
The great majority of mediastinal malignant germ cell tumors occur in patients between 20 and 35 years of age. For unknown reasons, most are found in males. In the rare occurrences reported in females, mediastinal malignant germ cell tumors have appeared histologically and biologically identical to those occurring in males. The relative rarity of extragonadal germ cell tumors in women parallels the lower incidence of female gonadal germ cell tumors as compared with their incidence in males. Although the incidence of primary testis tumors is low amongst racial minorities in the United States, the occurrence of extragonadal germ cell tumors is somewhat more common (7% versus 16% of cases, respectively).
In general, mediastinal germ cell tumors appear histologically identical to germ cell tumors arising in the testis, and all histologic subtypes seen in gonadal germ cell neoplasms have also been recognized in the mediastinum. In a recent review of 229 malignant mediastinal germ cell tumors seen between 1960 and 1994 at the Armed Forces Institute of Pathology, pure seminoma was the most common histology, accounting for 52% of cases. Nonseminomatous histologies included teratocarcinoma (20%), yolk-sac tumor (17%), choriocarcinoma (3.4%), embryonal carcinoma (2.6%), and mixed nonseminomatous tumors (5.2%).
Unlike benign germ cell tumors of the mediastinum, malignant mediastinal tumors are usually symptomatic at the time of diagnosis. Most mediastinal malignant tumors are large and cause symptoms by compressing or invading adjacent structures, including the lungs, pleura, pericardium, and chest wall. Pure seminomas are somewhat slower growing and have less potential for early metastasis than do tumors with nonseminomatous elements; their initial presentation, therefore, varies somewhat. Pure seminomas and tumors with nonseminomatous elements are discussed separately, although a great deal of overlap exists in their clinical characteristics.
Seminoma Seminomas grow relatively slowly and can become very large before causing symptoms. Tumors 20 to 30 cm in diameter can exist with minimal symptomatology. Approximately 20 to 30% of seminomas are detected by routine chest radiography while still asymptomatic. The most common initial symptom is a sensation of pressure or dull retrosternal chest pain. Additional symptoms include exertional dyspnea, cough, dysphagia, and hoarseness. Superior vena caval syndrome develops in approximately 10% of patients. Systemic symptoms related to metastatic lesions are uncommon.
At the time of diagnosis, only 30 to 40% of patients with mediastinal seminoma have localized disease; the remainder have one or more sites of distant metastases. The lungs and other intrathoracic structures are the most common metastatic sites. The skeletal system is the most frequently involved extrathoracic metastatic site; the propensity of advanced testicular seminoma to metastasize to bone has also been recognized. The retroperitoneum is an uncommon site of metastasis in patients with mediastinal seminoma.
Pure seminoma appears radiographically as a large, noncalcified anterior mediastinal mass, which can compress or deviate the trachea or bronchi if of sufficient size. A computed tomography (CT) scan of the chest typically shows a large homogeneous anterior mediastinal mass that obliterates the fat planes surrounding mediastinal vascular structures. The radiographic findings are not specific enough to allow the distinction of mediastinal seminoma from other mediastinal tumors.
Elevated serum levels of HCG are detected in approximately 10% of mediastinal seminomas. This incidence is similar to that reported in advanced testicular seminoma. Levels of HCG exceeding 100 ng/mL are unusual, and suggest the presence of nonseminomatous elements. The serum α-fetoprotein level is always normal in pure mediastinal seminoma, and any elevation of this tumor marker indicates the presence of nonseminomatous elements. Serum lactic dehydrogenase is also elevated in the majority of patients with mediastinal seminoma.
Nonseminomatous Germ Cell Tumor Very few patients with these rapidly growing neoplasms are asymptomatic at diagnosis. Symptoms caused by compression or invasion of local mediastinal structures are identical to those seen in patients with mediastinal seminoma. However, presenting symptoms caused by metastatic lesions are much more common, because 85 to 95% of these patients have at least one metastatic site at the time of diagnosis. Common metastatic sites include the lungs, pleura, lymph nodes (particularly supraclavicular and retroperitoneal), and liver. Less frequent sites of involvement include the bone, brain, and kidney. High levels of HCG sometimes are associated with gynecomastia. Neoplasms with elements of choriocarcinoma have a marked hemorrhagic tendency; these patients may have catastrophic events related to uncontrolled hemorrhage at a metastatic site (eg, massive hemoptysis, intracranial hemorrhage). Constitutional symptoms, including weight loss, weakness, and fever, are more common in these patients than in those with pure seminoma.
Chest radiographic features of mediastinal nonseminomatous germ cell tumors are similar to those seen in mediastinal seminomas. The CT scan frequently shows an inhomogeneous mass, with multiple areas of hemorrhage and necrosis, differing from the usually homogeneous appearance of mediastinal seminoma.
The serum tumor markers HCG and α-fetoprotein are usually abnormal in patients with mediastinal nonseminomatous germ cell tumors. α-Fetoprotein is most frequently abnormal and is elevated either alone or in conjunction with HCG in approximately 80% of patients, whereas elevation of HCG occurs in only 30 to 35% of patients. This pattern of marker elevation differs slightly from that seen in testicular cancer, where elevations of HCG and α-fetoprotein occur with nearly equal frequency and are seen in 50 to 70% of patients with metastatic tumor. As in mediastinal seminoma, elevation of serum lactic dehydrogenase is frequent, occurring in 80 to 90% of patients.