Klinefelter Syndrome Klinefelter syndrome is a relatively common chromosomal abnormality characterized by hypogonadism, azoospermia, and elevated gonadotropin levels in association with a 47,XXY karyotype. A slightly increased incidence of breast cancer has been described in these men, but a general predisposition to other cancers has not been observed. The association of Klinefelter syndrome and mediastinal nonseminomatous germ cell tumors is now well recognized. Four of 22 consecutive patients (18%) treated at Indiana University for primary mediastinal germ cell tumors had karyotypic confirmation of Klinefelter syndrome, and an additional patient had clinical features. The average age of patients with Klinefelter syndrome who develop extragonadal germ cell tumors is approximately 18 years, 10 years younger than the median age of those developing this tumor in the absence of Klinefelter syndrome. Testicular germ cell neoplasms have rarely been reported in association with Klinefelter syndrome; therefore, the association with mediastinal germ cell tumor seems specific.
The explanation for this association is unknown, but it seems reasonable to assume that the chromosomal abnormality plays some role. Increasing evidence indicates that many individuals who develop germ cell tumors have underlying germ cell defects. Many patients with extragonadal germ cell tumors have histories of infertility, and testicular biopsy in these patients shows various abnormalities, including decreased spermatogenesis, peritubular fibrosis, and interstitial edema.
In addition, patients who are successfully treated for extragonadal germ cell tumors have a markedly increased risk of developing a subsequent testicular germ cell tumor. These data suggest that either a congenital or an acquired germ cell defect contributes not only to defective spermatogenesis but also to the development of extragonadal germ cell tumors.
Hematologic Neoplasia A unique association between mediastinal nonseminomatous germ cell tumors and a variety of hematologic neoplasms is now well described. Hematologic neoplasms have included acute myeloid leukemia, acute nonlymphocytic leukemia, acute lymphocytic leukemia, erythroleukemia, acute megakaryocytic leukemia, myelodysplastic syndrome, and malignant histiocytosis. In a series of 635 patients with extragonadal germ cell tumors, 17 patients developed hematologic malignancies at a median of 6 months after the extragonadal germ cell tumor was diagnosed. All hematologic neoplasms developed in the 287 patients with mediastinal nonseminomatous germ cell tumors, for a 2% incidence in this group. Median survival was only 5 months after the hematologic disorder was diagnosed, and no patient survived for more than 2 years.
Recent evidence indicates that the hematologic neoplasms in this setting are not treatment related, but rather arise from clones of malignant lymphoblasts or myeloblasts contained within the mediastinal germ cell tumor. Foci of malignant lymphoblasts have been recognized histologically in several mediastinal germ cell tumors. More importantly, several patients have had an identical chromosomal abnormality (an isochromosome of the short arm of chromosome 12) in the neoplastic cells from the mediastinal germ cell tumor and the hematologic neoplasm, providing strong evidence for a common origin. However, the specific association of leukemias and other hematologic neoplasms with mediastinal nonseminomatous germ cell tumors, rather than with all germ cell tumors, remains unexplained.
In addition to hematologic neoplasia, several cases of idiopathic thrombocytopenia in association with mediastinal nonseminomatous germ cell tumors have been reported. These patients had normal numbers of megakaryocytes in the bone marrow; however, immune destruction of platelets could not be demonstrated. Prednisone and splenectomy were unsuccessful in increasing the platelet count; persistent thrombocytopenia caused significant morbidity in all patients and made treatment extremely difficult. At present, the cause of this syndrome is unknown.
The diagnosis of a mediastinal germ cell tumor should be considered in all young males with a mediastinal mass. In addition to physical examination and routine laboratory studies, initial evaluation should include CT of the chest and abdomen, and determination of serum levels of HCG and α-fetoprotein. Any symptoms suggestive of distant metastases should be appropriately evaluated with radiologic studies.
If distant metastasis or obviously unresectable intrathoracic tumor is present, a histologic diagnosis should be made using the least-invasive approach, because surgical therapy does not play a role in the initial treatment of these patients and rapid initiation of definitive systemic therapy is essential. In patients with tumors that seem localized to the mediastinum, exploration via thoracotomy or median sternotomy, with an attempt at tumor resection, is sometimes appropriate. Such an approach should not be used in patients with tumors that are obviously unresectable because of invasion of mediastinal structures or intrathoracic spread outside the anterior mediastinum. Surgical resection should also not be contemplated in patients with high levels of HCG or with any elevation of serum α-fetoprotein, because these patients have nonseminomatous tumors and should proceed immediately to definitive systemic therapy.
Revision date: June 14, 2011
Last revised: by Sebastian Scheller, MD, ScD