Jun-Ichi Hata

Outcome of pediatric renal tumor treated using the Japan Wilms Tumor Study-1 (JWiTS-1) protocol: a report from the JWiTS Group

PurposeIn 1996, the Japan Wilms Tumor Study (JWiTS) group was founded to elucidate the efficacy and safety of the regimen established by the National Wilms Tumor Study (NWTS) group in the USA, and a multicenter cooperative study (JWiTS-1) was started in Japan. This report reviews the results of JWiTS-1.MethodsA total of 307 patients with malignant renal tumor were enrolled in the JWiTS-1 study between 1996 and 2005. Central pathological diagnosis and follow-up data were available in 210 cases. The protocol regimens were similar to the NWTS-5 regimens. Clinical stage was classified according to the Japanese Staging System.ResultsFive-year overall survival (OS) rate was 91.1% for nephroblastoma, 72.9% for clear cell sarcoma of the kidney (CCSK), and 22.2% for rhabdoid tumor of the kidney (RTK). In the nephroblastoma patients, 5-year OS was 90.5% for stage I disease, 92.2% for stage II, 90.9% for stage III, 86.7% for stage IV, and 78.7% for stage V.ConclusionsThe OS of patients in the JWiTS-1 study were comparable with the results of other multicenter studies in the USA and Europe. The outcome for patients with nephroblastoma and CCSK was fair. In contrast, the cure rate for those with RTK was not satisfactory. New treatment strategies are needed for patients with RTK.

DNA Methylation Profile Distinguishes Clear Cell Sarcoma of the Kidney from Other Pediatric Renal Tumors

A number of specific, distinct neoplastic entities occur in the pediatric kidney, including Wilms’ tumor, clear cell sarcoma of the kidney (CCSK), congenital mesoblastic nephroma (CMN), rhabdoid tumor of the kidney (RTK), and the Ewing’s sarcoma family of tumors (ESFT). By employing DNA methylation profiling using Illumina Infinium HumanMethylation27, we analyzed the epigenetic characteristics of the sarcomas including CCSK, RTK, and ESFT in comparison with those of the non-neoplastic kidney (NK), and these tumors exhibited distinct DNA methylation profiles in a tumor-type-specific manner. CCSK is the most frequently hypermethylated, but least frequently hypomethylated, at CpG sites among these sarcomas, and exhibited 490 hypermethylated and 46 hypomethylated CpG sites in compared with NK. We further validated the results by MassARRAY, and revealed that a combination of four genes was sufficient for the DNA methylation profile-based differentiation of these tumors by clustering analysis. Furthermore, THBS1 CpG sites were found to be specifically hypermethylated in CCSK and, thus, the DNA methylation status of these THBS1 sites alone was sufficient for the distinction of CCSK from other pediatric renal tumors, including Wilms’ tumor and CMN. Moreover, combined bisulfite restriction analysis could be applied for the detection of hypermethylation of a THBS1 CpG site. Besides the biological significance in the pathogenesis, the DNA methylation profile should be useful for the differential diagnosis of pediatric renal tumors.

Immunological Properties of Hematopoietic Malignancies in Childhood

Childhood non-Hodgkin’s lymphomas were immunohistochemically analyzed utilizing monoclonal antibodies. Eighty-two cases were studied and 98% cases were histologically subtyped into lymphoblastic (LB,39%), Burkitt’s lymphoma (BL,31%), and large cell (LA,28%) types. BLs were all positive for pan B markers (immunoglobulins and CD 19/20/22), as well as the activated B-cell antigens, CD 10 and B5. However, BLs were phenotypically heterogenous with the combination of L30 and L29, which detect resting and activated B cells, respectively. With L30 and L29, BLs were subgrouped into three phenotypes (L30+L29−, L30+L29+, and L30−L29+). Study on the distribution of these antigens on normal B cells, as well as on in vitro activation, revealed that the heterogenous antigen expression of BLs corresponds to the dynamic phenotypic change during early activation of mature B cells. Therefore, it is likely that BLs are tumors of early activated B cells. In LAs, 14 anaplastic large cell lymphomas (Ki-1 lymphoma) were included. Phenotypically, Ki-1(CD30), epithelial membrane antigen (EMA), HLA-DR, and the IL-2 receptor were frequently identified. The tumor cells expressed no specific T— cell (CD3/5/8) or B-cell (CD19/20) markers, but coexpression of CD4 and alpha-1-antitrypsin was frequently seen. The results indicate that Ki-1 lymphoma is a heterogenous group of tumors including those of non-lymphoid cell origin.