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Spermatocytic seminomas are solid tumors found solely in the testis of predominantly elderly individuals. We investigated these tumors using a genome-wide analysis for structural and numerical chromosomal changes through conventional karyotyping, spectral karyotyping, and array comparative genomic hybridization using a 32 K genomic tiling-path resolution BAC platform (confirmed by in situ hybridization). Our panel of five spermatocytic seminomas showed a specific pattern of chromosomal imbalances, mainly numerical in nature (range, 3-24 per tumor). Gain of chromosome 9 was the only consistent anomaly, which in one case also involved amplification of the 9p21.3-pter region. Parallel chromosome level expression profiling as well as microarray expression analyses (Affymetrix U133 plus 2.0) was also done. Unsupervised cluster analysis showed that a profile containing transcriptional data on 373 genes (difference of z3.0-fold) is suitable for distinguishing these tumors from seminomas/ dysgerminomas. The diagnostic markers SSX2-4 and POU5F1 (OCT3/OCT4), previously identified by us, were among the top discriminatory genes, thereby validating the experimental set-up. In addition, novel discriminatory markers suitable for diagnostic purposes were identified, including Deleted in Azospermia (DAZ). Although the seminomas/dysgerminomas were characterized by expression of stem cell-specific genes (e.g., POU5F1, PROM1/CD133, and ZFP42), spermatocytic seminomas expressed multiple cancer testis antigens, including TSP50 and CTCFL (BORIS), as well as genes known to be expressed specifically during prophase meiosis I (TCFL5, CLGN, and LDHc). This is consistent with different cells of origin, the primordial germ cell and primary spermatocyte, respectively. Based on the region of amplification defined on 9p and the associated expression plus confirmatory immunohistochemistry, DMRT1 (a male-specific transcriptional regulator) was identified as a likely candidate gene for involvement in the development of spermatocytic seminomas.

Testicular germ cell tumors of adolescents and adults (TGCTs) can be classified into seminomatous and nonseminomatous tumors. Various nonseminomatous cell lines, predominantly embryonal carcinoma, have been established and proven to be valuable for pathobiological and clinical studies. So far, no cell lines have been derived from seminoma which constitutes more than 50% of invasive TGCTs. Such a cell line is essential for experimental investigation of biological characteristics of the cell of origin of TGCTs, i.e., carcinoma in situ of the testis, which shows characteristics of a seminoma cell. Before a cell line can be used as model, it must be verified regarding its origin and characteristics. Therefore, a multidisciplinary approach was undertaken on TCam-2 cells, supposedly the first seminoma cell line. Fluorescence in situ hybridization, array comparative genomic hybridization, and spectral karyotyping demonstrated an aneuploid DNA content, with gain of 12p, characteristic for TGCTs. Genome wide mRNA and microRNA expression profiling supported the seminoma origin, in line with the biallelic expression of imprinted genes IGF2/H19 and associated demethylation of the imprinting control region. Moreover, the presence of specific markers, demonstrated by immunohistochemistry, including (wild type) KIT, stem cell factor, placental alkaline phosphatase, OCT3/4 (also demonstrated by a specific Q-PCR) and NANOG, and the absence of CD30, SSX2-4, and SOX2, confirms that TCam-2 is a seminoma cell line. Although mutations in oncogenes and tumor suppressor genes are rather rare in TGCTs, TCam-2 had a mutated BRAF gene (V600E), which likely explains the fact that these cells could be propagated in vitro. In conclusion, TCam-2 is the first well-characterized seminoma-derived cell line, with an exceptional mutation, rarely found in TGCTs.

We describe three unrelated girls who had an immunodeficiency disease with granulomas in the skin, mucous membranes, and internal organs. All three girls had severe complications after viral infections, including B-cell lymphoma associated with Epstein-Barr virus (EBV). Other findings were hypogammaglobulinemia, a diminished number of T and B cells, and sparse thymic tissue on ultrasonography. Molecular analysis revealed that the patients were compound heterozygotes for mutations in recombination activating gene 1 or 2 (RAG1 or RAG2). In each case, both parents were heterozygous carriers of a RAG mutation. The mutations were associated with reduced function of RAG in vitro (3 to 30% of normal activity). The parents and one sibling in the three families were healthy.

Two separate groups of GCTs with distinct clinical features relevant for differential diagnosis and the diagnostic assessment can be distinguished. This observation correlates with genetic studies that reveal different genetic changes in childhood and adolescence GCTs. Further studies are needed to elucidate the molecular mechanisms of germ cell and GCT development that account for the age- and sex-dependent clinical manifestation.

In mature and immature teratoma the treatment is surgical. The risk of recurrence can be estimated from the parameters primary site (with the coccygeal tumors being most at risk), histological grade of immaturity and completeness of the primary resection including the adjacent organ of origin (coccyx, ovary, testis etc.). In case of a microscopically complete tumor resection there is no role for adjuvant chemo- or radiotherapy irrespective of the histological grade of immaturity. Malignant germ-cell tumors (GCT) account for 2.9% of all malignant tumors of children younger than 15 years of age. More than half of the tumors occur at extragonadal sites such as the ovaries (26%), the coccygeal region (24%), the testes (18%) and the brain (18%) represent then primary sites. In patients with extensive tumor growth, metastatic disease or secreting intracranial tumors a delayed tumor resection after preoperative chemotherapy is preferable. In these patients malignant non-seminomatous GCT may be diagnosed clinically due to the increased serum or cerebrospinal fluid levels of the tumor markers AFP and/or beta-HCG. Current risk adapted treatment protocols containing cisplatinum allow long-term remissions in about 80% including patients with bulky or metastatic tumors. In the cisplatinum era the prognostic factors like histology, primary site of the tumor and initial tumor stage have partly lost their former impressive significance in infants and children. On the other hand the completeness of the primary tumor resection according to oncological standards has been established as the most powerful prognostic parameter superior to tumor marker levels or primary site of the tumor.

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BACKGROUND. Mesenchymal chondrosarcoma (MCS) is a rare tumor with a strong tendency toward late recurrences leading to reported 10‐year survival rates below 50%. The recommended treatment is resection with wide margins; the effectiveness of chemo‐ and radiotherapy remain poorly defined. As reports about MCS in young patients are scarce, treatment and outcomes of children/adolescents/young adults in the CWS and COSS studies were investigated. METHODS. Since 1977, 15 of >7000 CWS and COSS patients ≤25 years had a confirmed diagnosis of MCS. RESULTS. The median age was 16.6 (range, 1–25) and median follow‐up 9.6 years (range, 1–22). Four MCS were osseous and 11 extraosseous. All but 1 patient had nonmetastatic disease. Tumor sites were head/neck (n = 6), paravertebral (n = 3), pelvis (n = 3), limbs (n = 2), and kidney (n = 1). All tumors were resected, but only 8 completely. Thirteen individuals received chemotherapy, 6 were irradiated. Actuarial 10‐year event‐free and overall survival rates were 53% and 67%, respectively. Four recurrences occurred, all within 4 years from diagnosis (3 local, 1 combined; 2 of these in irradiated patients). One of these patients survived after surgery and radiation for local recurrence. Seven of 8 patients whose tumors were completely resected during primary treatment, but only 4 of 7 patients with incomplete surgery survived disease‐free. CONCLUSIONS. This series of 15 MCS differs from others: the median age was young, most tumors were extraosseous, most patients received chemotherapy, and the outcome was better than published. Despite long‐term follow‐up, characteristic late metastatic recurrences were not observed. Treating MCS according to standard multimodal soft tissue/bone sarcoma regimens is proposed. Cancer 2008. © 2008 American Cancer Society.