Torsten Strohmeyer

Expression of the c-kit Proto-Oncogene and Its Ligand Stem Cell Factor (SCF) in Normal and Malignant Human Testicular Tissue

Recent findings suggest an important role of the proto-oncogene c-kit, a surface membrane receptor of the tyrosine kinase family, and its ligand stem cell factor (SCF) in normal spermatogenesis and possibly in the pathogenesis of certain testicular germ cell tumors. To further investigate this potential role, the expression of c-kit and SCF was studied in normal and malignant human testicular tissue specimens at the mRNA and protein level by Northern blot analysis and immunohistochemistry, respectively. The detection of the c-kit receptor in normal human germ cells and its natural ligand SCF in Sertoli cells suggests the presence of a local trophic regulatory system that may be active in human spermatogenesis. Additionally, c-kit expression was detected in the seminoma but not in the nonseminoma subtype of human testicular germ cell tumors (GCT). Stem cell factor was not expressed at the mRNA level in tissue from either subtype of GCT as determined by Northern blot analysis; however, the protein was detected immunohistochemically in the cytoplasm of rare tumor cells.

Classic and modern prognostic indicators in renal cell carcinoma. Review of the literature.

The value of classic and modern prognostic factors in renal cell carcinoma as reported in the literature is determined in a review. Tumor stage is the most important single independent prognostic factor. The presence or absence of distant metastases is highly prognostic and presence of lymph node metastases is of higher prognostic value than the presence of renal vein invasion. For each given tumor stage tumor grade (especially nuclear grade) is the most reliable additional independent prognostic factor predicting patient survival. The significance of DNA cytometry as an independent prognostic factor is less clear, though it might be useful in combination with nuclear grading. Patient-related potential prognostic factors such as age, sex and serologic parameters are of lesser, if any, importance. In the future, data from molecular analysis on oncogenes and suppressor genes are likely to provide additional prognostic information.

Analysis of the DCC tumor suppressor gene in testicular germ cell tumors: mutations and loss of expression.

Inactivation of the DCC (Deleted in Colon Carcinoma) tumor suppressor gene by allelic loss and/or reduced expression is associated with the development of colon cancer, gliomas, gastric and prostatic malignancies. In a total cohort of 51 testicular germ cell tumors (GCT) of different histologies we analyzed restriction fragment length polymorphism (RFLP) for DCC at two specific DNA sites in 37 GCT and DCC mRNA expression compared to that of the adjacent normal testicular tissue in 41 GCT, one Leydig cell tumor and one testicular metastasis of a non-small cell lung cancer (NSCLC). Two of 17 tumors (11.7%) informative for the Msp I polymorphic site of the DCC gene and 6/25 tumors (24.0%) informative for variable number of tandem repeat (VNTR) showed loss of heterozygosity (LOH). DCC expression was analyzed by semi-quantitative polymerase chain reaction after initial reverse transcription (RT-PCR). Thirty of 41 GCT (73.1%) and both, the Leydig cell tumor and the testicular metastasis of NSCLC, had a nearly complete or total loss of DCC mRNA expression. Six of 11 (54.5%) seminomas and 24/30 (80.0%) nonseminomas had this loss of expression. Twelve of 17 (70.5%) localized tumors, 9/13 (69.2%) tumors with lymph node involvement and 9/11 (82.2%) tumors with distant metastases showed decreased or absent DCC expression. This data suggests that inactivation of the DCC gene, especially the loss of DCC expression, is associated with the development and progression of human GCT.

ALTERATIONS OF THE METASTASIS SUPPRESSOR GENE nm23 AND THE PROTO-ONCOGENE c-myc IN HUMAN TESTICULAR GERM CELL TUMORS

The putative metastasis suppressor genes nm23-H1, nm23-H2 and the c-myc proto-oncogene were investigated in testicular germ cell tumors (GCTs) using Southern and Northern blotting as well as semiquantitative reverse transcription polymerase chain reaction (RT-PCR) and single strand conformation polymorphism (SSCP) analysis. When studying Bgl II RFLPs, allelic losses of the nm23 gene were found in 3/12 (25%) informative tumors, and all 3 had lymph node and/or distant metastases. A 2 to 7 fold nm23 mRNA overexpression was found in 22/34 (64.7%) tumors examined. RT-PCR revealed that this phenomenon is mainly a consequence of nm23-H2 overexpression. Overexpression of both the H1 and the H2 gene was predominantly found in the seminoma subtype and was not associated with tumor stage. Only 1/25 tumors, a seminoma with distant metastases, had a point mutation in the coding region of the nm23-H2 gene as demonstrated by SSCP analysis. None of the 8 seminomas and only 1/13 non-seminomas had c-myc overexpression. No abnormalities of the c-myc gene could be detected on the DNA level. Despite the fact that in previous investigations nm23-H2 was demonstrated to be a putative transcription factor for c-myc, no coexpression of c-myc and nm23-H2 was found by quantitative RT-PCR in this study.

Late metastases in seminoma: incidence, localization, and therapeutic implications.

Late metastases of seminoma testis were found in 2 patients thirty and nine years after orchiectomy and radiotherapy. Metastases involved retroperitoneal lymph nodes and lung in 1 case and obstruction of the sigmoid colon and left ureter in the other. Cases of late, atypically localized metastases of seminoma described in the literature are reviewed. Therapy includes surgical removal of the metastases, radiation therapy, and systemic chemotherapy. Therapeutic considerations must include toxicity of preceding radiotherapy.

Value of Computed Tomography in the Staging of Testicular Tumors

To analyze the value of computed tomography (CT) for the exact staging of testicular tumors, 2 groups of 28 patients each were examined. All patients underwent retroperitoneal lymph node dissection in the course of their treatment. Pretherapeutic stages as determined by CT were compared to the histologically verified definite tumor stages. In 68% of the patients, the stage found by CT was correct but 3 (5%) false-positive and 13 false-negative results were obtained. Thus, almost 40% (13/33) of the patients with clinical stage I disease presumably would have had a progression if managed by a surveillance strategy. It can be concluded that this strategy should be restricted to certain centers with guaranteed long-term standardized patient observation and extremely high patient compliance.