Association of EWS-FLI1 Type 1 Fusion with Lower Proliferative Rate in Ewing’s Sarcoma

The Ewing's sarcoma (ES) family of tumors, including peripheral neuroectodermal tumor (PNET), is defined genetically by specific chromosomal translocations resulting in fusion of the EWS gene with a member of the ETS family of transcription factors, either FLI1 (90-95%) or ERG (5-10%). A second level of molecular genetic heterogeneity stems from the variation in the location of the translocation breakpoints, resulting in the inclusion of different combinations of exons from EWS and FLI1 (or ERG) in the fusion products. The most common type of EWS-FLI1 fusion transcript, type 1, is associated with a favorable prognosis and appears to encode a functionally weaker transactivator, compared to other fusion types. We sought to determine whether the observed covariation of structure, function, and clinical course correlates with tumor cell kinetic parameters such as proliferative rate and apoptosis, and with expression of the receptor for insulin-like growth factor I (IGF-1R). In a group of 86 ES/PNET with defined EWS-ETS fusions (45 EWS-FLI1 type 1, 27 EWS-FLI1 non-type 1, 14 EWS-ERG), we assessed proliferation rate by immunostaining for Ki-67 using MIB1 antibody (n = 85), apoptosis by TUNEL assay (n = 66), and IGF-1R expression by immunostaining with antibody 1H7 (n = 78). Ki-67 proliferative index was lower in tumors with EWS-FLI1 type 1 than those with non-type 1 EWS-FLI1, whether analyzed as a continuous (P = 0.049) or categorical (P = 0.047) variable. Logistic regression analysis suggests that this association was secondary to the association of type 1 EWS-FLI1 and lower IGF-1R expression (P = 0.04). Comparing EWS-FLI1 to EWS-ERG cases, Ki-67 proliferative index was higher in the latter (P = 0.01, Mann-Whitney test; P = 0.02, Fisher's exact test), but there was no significant difference in IGF-1R. TUNEL results showed no significant differences between groups. Our results suggest that clinical and functional differences between alternative forms of EWS-FLI1 are paralleled by differences in proliferative rate, possibly mediated by differential regulation of the IGF-1R pathway

Osteoblastoma: varied histological presentations but with a benign clinical course: an analysis of 55 cases.

The presence of epithelioid osteoblasts, lace- or sheet-like osteoid production, and a permeative pattern of tumor growth in osteoblastomas is thought to be associated with an aggressive clinical behaviour. This study assessed the prognostic significance of these and other histologic parameters by analyzing a large group of cases. Histologic material obtained from 55 patients who had osteoblastoma diagnosed and treated at Memorial Sloan-Kettering Cancer Center was analyzed. Additionally, the radiographic images were studied and the lesions were radiologically staged as stage 1 (quiescent), stage 2 (active), or stage 3 (aggressive). Epithelioid osteoblasts were detected in 14% of the cases without any mitotic activity. Lace- or sheet-like osteoid was present in 36% of the cases studied. A permeative pattern of tumor growth was present in 15% of lesions in all but one arising in the short tubular or large flat bones. Thirty-four percent of the lesion were in stage 1, 48% in stage 2, and 17% in stage 3. All stage 1 tumors involved long tubular bones, whereas all stage 3 tumors arose in the short tubular or flat bones. Local recurrence was noted in 16% of patients, all of whom had stage 2 lesions. One patient with a vertebral tumor eventually died with persistent disease. No association between the histologic features and disease outcome was demonstrated. The clinically aggressive behavior of osteoblastoma is not related to particular histologic features, but rather to the skeletal location. Mitotic activity is not present in osteoblasts in the osteoblastoma

Treatment algorithm for locally recurrent osteosarcoma based on local disease-free interval and the presence of lung metastasis

10.1002/cncr.22197Cancer10771607-1616CANC

Elevated physiologic tumor pressure promotes proliferation and chemosensitivity in human osteosarcoma

10.1158/1078-0432.CCR-04-2048Clinical Cancer Research1162389-239

Tumour interstitial fluid pressure may regulate angiogenic factors in osteosarcoma

Annals of the Academy of Medicine Singapore38121041-104