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Abstract Background Tenosynovial giant cell tumor (TSGCT) is a benign fibrohistiocytic tumor that affects the synovium of joints, bursa, and tendon sheaths and is categorized into localized TSGCT (LTSGCT) and diffuse TSGCT (DTSGCT). LTSGCT and DTSGCT are characterized by recurrent fusions involving the colony-stimulating factor 1 (CSF1) gene and its translocation partner collagen type VI alpha 3 chain. The fusion gene induces intratumoral overexpression of CSF1 mRNA and CSF1 protein. CSF1 expression is a characteristic finding of TSGCT and detection of CSF1 mRNA and CSF1 protein may be useful for the pathological diagnosis. Although there have been no effective anti-CSF1 antibodies to date, in situ hybridization (ISH) for CSF1 mRNA has been performed to detect CSF1 expression in TSGCT. We performed CSF1 immunohistochemistry (IHC) using anti-CSF1 antibody (clone 2D10) in cases of TSGCT, giant cell-rich tumor (GCRT), and GCRT-like lesion and verified its utility for the pathological diagnosis of TSGCT. Methods We performed CSF1 IHC in 110 cases including 44 LTSGCTs, 20 DTSGCTs, 1 malignant TSGCT (MTSGCT), 10 giant cell tumors of bone, 2 giant cell reparative granulomas, 3 aneurysmal bone cysts, 10 undifferentiated pleomorphic sarcomas, 10 leiomyosarcomas, and 10 myxofibrosarcomas. We performed fluorescence ISH (FISH) for CSF1 rearrangement to confirm CSF1 expression on IHC in TSGCTs. We considered the specimens to have CSF1 rearrangement if a split signal was observed in greater than 2% of the tumor cells. Results Overall, 50 of 65 TSGCT cases, including 35 of the 44 LTSGCTs and 15 of the 20 DTSGCTs, showed distinct scattered expression of CSF1 in the majority of mononuclear tumor cells. MTSGCT showed no CSF1 expression. Non-TSGCT cases were negative for CSF1. FISH revealed CSF1 rearrangement in 6 of 7 CSF1-positive cases on IHC. On the other hand, FISH detected no CSF1 rearrangement in all CSF1-negative cases on IHC. Thus, the results of IHC corresponded to those of FISH. Conclusion We revealed characteristic CSF1 expression on IHC in cases of TSGCT, whereas the cases of non-TSGCT exhibited no CSF1 expression. CSF1 IHC may be useful for differentiating TSGCTs from histologically mimicking GCRTs and GCRT-like lesions.

Abstract It is important to determine the activation status of Rac and Cdc42 in cancer tissues for the prediction of metastasis and patient prognosis. However, it has been impossible to detect their spatial activation on formalin-fixed paraffin embedded (FFPE) surgical specimens thus far. Here, we established a novel detection technique for activated Rac/Cdc42 in human colon cancer FFPE tissues by using a p21-activated kinase (PAK)-Rac binding domain (RBD) detection probe fused with glutathione S-transferase (GST), designated GST-PAK-RBD, and novel rapid-immunohistochemistry (R-IHC) systems using noncontact alterating-current electric field mixing, although there is a technical limitation in that it may not distinguish between Rac members and Cdc42. In 50 cases of colon cancer, various activation patterns of Rac/Cdc42 were observed, which were designated plasma membrane, cytoplasm, mixed pattern, and polarized distribution. The activity was striking in the invasive fronts of tumors and significantly correlated with tumor invasion properties evaluated by TNM classification. Of note, in tissue microarray (TMA) samples, 29 of 33 cases demonstrated higher Rac1/Cdc42 activity in the tumor area than the corresponding normal mucosa. In addition, positive correlations were detected between Rac/Cdc42 activity and clinicopathological factors such as venous and lymphatic vessel invasion. These results suggest that understanding Rac and Cdc42 activations in cancer tissues would be valuable as an option for molecular therapy as personalized medicine.

Abstract Background Predicting the prognosis of patients with solitary fibrous tumor (SFT) is often difficult. The prognostic risk models developed by Demicco et al. are now the standard for evaluating the risk of SFT metastasis in the current World Health Organization classification of soft tissue and bone tumors. Methods In this study, we examined the prognostic usefulness of a modified version of the Demicco risk models that replaces the mitotic count with the Ki-67 labeling index. We compared the three-variable and four-variable Demicco risk models with our modified risk models using Kaplan–Meier curves based on data for 43 patients with SFT. Results We found a significant difference in metastasis-free survival when patients were classified into low-risk and intermediate/high-risk groups using the three-variable (P = 0.022) and four-variable (P = 0.046) Demicco models. There was also a significant difference in metastasis-free survival between the low-risk and intermediate/high-risk groups when the modified three-variable (P = 0.006) and four-variable (P = 0.022) models were used. Conclusion Modified risk models that include the Ki-67 labeling index are effective for prediction of the prognosis in patients with SFT.

Abstract Background A definitive diagnosis of malignant peripheral nerve sheath tumor (MPNST) is challenging, especially in cases without neurofibromatosis 1 (NF1), because MPNST lacks specific markers on immunohistochemistry (IHC). Methods We performed IHC for histone 3 trimethylated on lysine 27 (H3K27me3) and evaluated the percentage of cells with H3K27me3 loss using measured values at 10% intervals, categorized as complete loss (100% of tumor cells lost staining), partial loss (10% to 90% of tumor cells lost staining), and intact (no tumor cells lost staining). We conducted fluorescence in situ hybridization (FISH) for NF1 and p16 deletions comparing 55 MPNSTs and 35 non-MPNSTs, consisting of 9 synovial sarcomas (SSs), 8 leiomyosarcomas (LMSs), 10 myxofibrosarcomas (MFSs), and 8 undifferentiated pleomorphic sarcomas (UPSs). We assessed the percentage of cells with homozygous and heterozygous deletions and defined “deletion” if the percentage of either the NF1 or p16 deletion signals was greater than 50% of tumor cells. Results Among the 55 MPNSTs, 23 (42%) showed complete H3K27me3 loss and 32 (58%) exhibited partial loss or intact. One each of the 9 SSs (11%), 8 LMSs (12%), and 8 UPSs (12%) showed complete H3K27me3 loss and many non-MPNSTs exhibited intact or partial H3K27me3 loss. Among the 55 MPNSTs, 33 (60%) and 44 (80%) showed NF1 or p16 deletion, respectively. Co-deletion of NF1 and p16 was observed in 29 (53%) MPNSTs. Among the 23 MPNTSs showing H3K27me3 complete loss, 18 (78%) and 20 (87%) exhibited NF1 or p16 deletion, respectively. Among the 32 MPNSTs with H3K27me3 partial loss or intact, 15 (47%) and 24 (75%) exhibited NF1 or p16 deletion, respectively. The frequency of NF1 and/or p16 deletion tended to be lower in non-MPNSTs than in MPNSTs. Approximately 90% of MPNSTs included cases with H3K27me3 complete loss and cases showing H3K27me3 partial loss or intact with NF1 and/or p16 deletion. Approximately 50% of MPNSTs showed co-deletion of NF1 and p16 regardless of H3K27me3 loss. Conclusions FISH for NF1 and p16 deletions, frequently observed in high-grade MPNSTs, might be a useful ancillary diagnostic tool for differentiating MPNST from other mimicking spindle cell and pleomorphic sarcomas.