Search

Mutant isocitrate dehydrogenase (IDH) in chondrosarcoma produces the oncometabolite 2-hydroxyglutarate (2-HG) and contributes to malignant progression, and is therefore a potential therapeutic target for chondrosarcoma. Robust historical control data are important in clinical trials of rare cancers such as chondrosarcoma in order to show a clear benefit of new drugs. However, it remains controversial whether IDH mutation status is associated with the clinical outcome of chondrosarcoma, and this hinders the development of mutant IDH inhibitors in clinical trials.background METHODS: We investigated the relationship between IDH gene status and clinicopathological data in 38 chondrosarcoma patients from whom frozen tumor samples were obtained at the time of biopsy or surgery. Targeted next-generation sequencing was also performed to compare genetic alterations between patients with and without IDH mutations.The results revealed 15 cases (40%) of heterozygous IDH1 mutations and five cases (13%) of IDH2 mutations. IDH-mutant chondrosarcoma was associated with worse overall survival than IDH-wild-type chondrosarcoma (IDH1/2 Mut vs. IDH Wt, P = 0.006; IDH1 Mut vs. IDH Wt, P = 0.030; IDH2 Mut vs. IDH Wt, P 0.0001). IDH mutation was also a significant poor prognostic factor both in univariate (P = 0.026) and multivariate (P = 0.048) analyses. Targeted next-generation sequencing revealed that characteristic mutations in chondrosarcoma, including TP53 and COL2A1, were more common in the IDH-mutant group than in the IDH-wild-type group.results CONCLUSION: This study is the first to report in detail the characteristics and clinical courses of IDH-mutant chondrosarcoma patients in Japan. Our data suggested that IDH-mutant chondrosarcomas might have a worse prognosis than that of IDH-wild-type chondrosarcoma, possibly through the more aggressive characters after metastasis. This information will be useful for designing clinical trials of mutant IDH inhibitors for treatment of advanced chondrosarcoma.

Synovial sarcoma (SS) is an aggressive tumor that most often affects the deep soft tissues in young adults. Intrathoracic SS is rare and is associated with poor outcome, highlighting the urgent need for a novel therapeutic strategy. In the process of clinical sequencing, we identified two patients with intrathoracic SS harboring the BRAF V600E mutation. The patients were women aged 32 and 23 years, and both presented with SS18-SSX2-positive monophasic SS in the thoracic cavity. BRAF V600E mutations were detected by next generation sequencing, and validated immunohistochemically by diffuse intense positivity to BRAF V600E mutation-specific antibodies. The phosphorylated ERK (pERK) immunohistochemistry result was also positive. One patient received a combination therapy of dabrafenib and trametinib, which led to tumor shrinkage. However, the tumor growth progressed 7.5 months later with an additional NRAS Q61K mutation. Immunohistochemical screening of 67 archival SS tumor samples failed to identify additional samples with BRAF V600E mutation. However, 32% of BRAF V600E-negative cases was positive for pERK, and one of the six tumors showing the highest pERK expression harbored an FGFR2-activating mutation. This is the first report of targetable BRAF mutation in a small subset of SS. Our study suggests involvement of the mitogen-activated protein kinase pathway and the potential clinical implication of BRAF mutation screening in SS.

Background The use of nomograms for prognostication of individual cancer patients has been recommended in order to facilitate precision medicine. However, models for patients with soft tissue sarcomas (STSs) are limited because of the rarity and heterogeneity of such cancers. In addition, no model has been developed on the basis of an Asian cohort. Here, we attempted to develop and internally validate nomograms for patients with localized STSs of the trunk and extremity. Methods This study retrospectively extracted 2827 patients with primary trunk and extremity STSs after definitive surgery using the Bone and Soft Tissue Tumor Registry, which is a nationwide sarcoma database in Japan. We developed three nomograms predicting the probability of local recurrence-free survival (LRFS), distant metastasis-free survival (DMFS) and disease-specific survival (DSS) at 2 years after surgery, using the Cox multivariate model. The nomograms were internally validated for discrimination and calibration using bootstrap resampling and assessed for their clinical applicability by decision curve analysis (DCA). Results Local recurrence, distant metastasis and disease-specific death occurred in 241 patients (8.5%), 554 patients (19.6%) and 230 patients (8.1%), respectively. Histological diagnosis, grade and tumor size strongly influenced all three endpoints. The nomograms predicted accurately the probability of LRFS, DMFS and DSS (concordance index: 0.73, 0.70 and 0.75, respectively). DCA demonstrated that our nomograms had clinical applicability. Conclusion We have developed the first nomograms for STSs based on an Asian cohort. These nomograms allowed accurate prediction of LRFS, DMFS and DSS at 2 years after definitive surgery, and can be used as a guide by clinicians for appropriate follow-up and counseling of patients. Electronic supplementary material The online version of this article (10.1186/s12885-019-5875-y) contains supplementary material, which is available to authorized users.

NTRK fusions in malignant tumors are therapeutic targets of tyrosine kinase inhibitors. Because they occur only in a small subset of mesenchymal tumors, knowledge regarding the corresponding histology is important to effectively identify patients who could benefit from targeted therapy. In this study, using RNA sequencing, we identified novel NTRK3 fusions involving related partner genes in 2 adult bone and soft tissue tumors that met the current histologic criteria of fibrosarcoma. Case 1 involved the left radius of a 38-year-old woman, whereas in case 2, the right thigh of a 26-year-old man was affected. Histologically, both tumors consisted of the long fascicular growth of long spindle cells. The tumor in case 1 additionally showed focal myxoid changes. Tumor cells had nonpleomorphic, atypical nuclei, and lacked evidence of a specific line of differentiation. Both tumors showed widespread CD34 immunoreactivity and very limited expression of actin. RNA sequencing detected in-frame fusion transcripts of STRN (exon 3)-NTRK3 (exon 14) in case 1 and STRN3 (exon 3)-NTRK3 (exon 14) in case 2, which were confirmed by reverse transcription polymerase chain reaction and Sanger sequencing. Pan-TRK immunostaining was diffusely positive in both cases. Fluorescence in situ hybridization showed signal patterns compatible with NTRK3 rearrangements in both cases, with case 2 additionally harboring a CDKN2A homozygous deletion. This study expands the clinicopathologic and genetic spectrum of sarcomas associated with NTRK fusions, and suggests that CD34-positive fibrosarcoma of bone and soft tissue could be a good candidate for NTRK testing.

Granular cell tumors (GCTs) are rare mesenchymal tumors that exhibit a characteristic morphology and a finely granular cytoplasm. The genetic alterations responsible for GCT tumorigenesis had been unknown until recently, when loss-of-function mutations of ATP6AP1 and ATP6AP2 were described. Thus, we performed whole-exome sequencing, RNA sequencing, and targeted sequencing of 51 GCT samples. From these genomic analyses, we identified mutations in genes encoding vacuolar H+ -ATPase (V-ATPase) components, including ATP6AP1 and ATP6AP2, in 33 (65%) GCTs. ATP6AP1 and ATP6AP2 mutations were found in 23 (45%) and 2 (4%) samples, respectively, and all were truncating or splice site mutations. In addition, seven other genes encoding V-ATPase components were also mutated, and three mutations in ATP6V0C occurred on the same amino acid (isoleucine 136). These V-ATPase component gene mutations were mutually exclusive, with one exception. These results suggest that V-ATPase function is impaired in GCTs not only by loss-of-function mutations of ATP6AP1 and ATP6AP2 but also through mutations of other subunits. Our findings provide additional support for the hypothesis that V-ATPase dysfunction promotes GCT tumorigenesis.

OBJECTIVEThe purpose of this study was to compare the clinical results of revision interbody fusion surgery between lateral lumbar interbody fusion (LLIF) and posterior lumbar interbody fusion (PLIF) or transforaminal lumbar interbody fusion (TLIF) with propensity score (PS) adjustments and to investigate the efficacy of indirect decompression with LLIF in previously decompressed segments on the basis of radiological assessment.METHODSA retrospective study of patients who underwent revision surgery for recurrence of neurological symptoms after posterior decompression surgery was performed. Postoperative complications and operative factors were evaluated and compared between LLIF and PLIF/TLIF. Moreover, postoperative improvement in cross-sectional areas (CSAs) in the spinal canal and intervertebral foramen was evaluated in LLIF cases.RESULTSA total of 56 patients (21 and 35 cases of LLIF and PLIF/TLIF, respectively) were included. In the univariate analysis, the LLIF group had significantly more endplate injuries (p = 0.03) and neurological deficits (p = 0.042), whereas the PLIF/TLIF group demonstrated significantly more dural tears (p < 0.001), surgical site infections (SSIs) (p = 0.02), and estimated blood loss (EBL) (p < 0.001). After PS adjustments, the LLIF group still showed significantly more endplate injuries (p = 0.03), and the PLIF/TLIF group demonstrated significantly more dural tears (p < 0.001), EBL (p < 0.001), and operating time (p = 0.04). The PLIF/TLIF group showed a trend toward a higher incidence of SSI (p = 0.10). There was no statistically significant difference regarding improvement in the Japanese Orthopaedic Association scores between the 2 surgical procedures (p = 0.77). The CSAs in the spinal canal and foramen were both significantly improved (p < 0.001).CONCLUSIONSLLIF is a safe, effective, and less invasive procedure with acceptable complication rates for revision surgery for previously decompressed segments. Therefore, LLIF can be an alternative to PLIF/TLIF for restenosis after posterior decompression surgery.

The genomic characteristics of dedifferentiated liposarcoma (DDLPS) that are associated with clinical features remain to be identified. Here, we conduct integrated whole exome and RNA sequencing analysis in 115 DDLPS tumors and perform comparative genomic analysis of well-differentiated and dedifferentiated components from eight DDLPS samples. Several somatic copy-number alterations (SCNAs), including the gain of 12q15, are identified as frequent genomic alterations. CTDSP1/2-DNM3OS fusion genes are identified in a subset of DDLPS tumors. Based on the association of SCNAs with clinical features, the DDLPS tumors are clustered into three groups. This clustering can predict the clinical outcome independently. The comparative analysis between well-differentiated and dedifferentiated components identify two categories of genomic alterations: shared alterations, associated with tumorigenesis, and dedifferentiated-specific alterations, associated with malignant transformation. This large-scale genomic analysis reveals the mechanisms underlying the development and progression of DDLPS and provides insights that could contribute to the refinement of DDLPS management., Understanding the genomic features of dedifferentiated liposarcoma (DDLPS) is likely to uncover new options for management. Here, the authors reveal three prognostic groups, and highlight molecular markers associated with malignant transformation.

Aims Ewing sarcoma is a small round cell tumour that affects bone and soft tissues. Although the detection of the specific fusion gene is a robust method of its diagnosis, immunohistochemistry may serve as a practical surrogate. Recent tissue microarray studies suggested that PAX7 is a novel marker, because it was expressed consistently in Ewing sarcoma, in addition to rhabdomyosarcoma and synovial sarcoma. Here, we evaluated the utility of PAX7 immunohistochemistry in whole-tissue sections of an expanded array of round cell malignancies with adequate molecular characterisation. Methods and results We stained 30 molecularly confirmed Ewing sarcomas, one EWSR1-NFATC2 sarcoma and 141 non-Ewing round cell tumours by a monoclonal antibody against PAX7. Staining was considered positive if at least 5% of tumour cells were stained. PAX7 was expressed in 27 of 30 Ewing sarcomas (90%), mainly in a diffuse and strong manner. Although NKX2-2 showed similar sensitivity, PAX7 showed more extensive and strong reactivity. One EWSR1-NFATC2 sarcoma co-expressed PAX7 and NKX2-2. PAX7 was also expressed in 24 of 141 non-Ewing tumours, including alveolar rhabdomyosarcomas (seven of 10), poorly differentiated synovial sarcomas (seven of 10), BCOR-CCNB3 sarcomas (eight of 10), small-cell osteosarcoma (one of five) and desmoplastic small round cell tumour (one of 10), one-third of which showed diffuse strong reactivity. Conclusions Although we confirmed that PAX7 is a sensitive marker for Ewing sarcoma, anti-PAX7 antibody also stained several Ewing sarcoma mimics, whose spectrum was distinct from NKX2-2-positive non-Ewing entities. Further studies are required to determine how PAX7 could be integrated into practice to classify small round cell tumours efficiently.

Aims Extraskeletal osteosarcoma (ESOS) is a sarcoma in the non-skeletal tissue that directly produces neoplastic osteoid or bone. De-differentiated liposarcoma (DDLPS) and malignant peripheral nerve sheath tumour (MPNST) are the two most common types of sarcoma that can harbour heterologous osteosarcomatous differentiation. We aimed to determine the potential relationship of ESOS to DDLPS and MPNST. Methods and results We investigated MDM2 and H3K27me3 status in 19 cases of ESOS, two of which contained a low-grade component. The ESOS affected deep soft tissues (n = 10), superficial soft tissues (n = 3) and organs (n = 6). Among 10 deep soft-tissue ESOS, six showed MDM2 amplification, four of which also harboured CDK4 co-amplification. Both ESOS with a low-grade component showed co-amplification for MDM2 and CDK4. Among the six organ-based ESOS three giant cell-rich ESOS showed an H3K27me3 deficiency (one in primary and two in metastatic sites). Using targeted next generation sequencing, an H3K27me3-deficient ESOS showed EED homozygous deletion, while none of the three showed alterations in NF1, CDKN2A or SUZ12 genes. During median follow-up of 20 months, all six patients with MDM2-amplified ESOS lived for 3-103 months, while two of the three patients with H3K27me3-deficient ESOS died from this disease in 4 and 20 months, respectively. Conclusion We demonstrate that ESOS may include at least two small subsets: an MDM2-amplified deep soft-tissue ESOS (which may be related to DDLPS) and an H3K27me3-deficient organ-based ESOS (which is probably unrelated to MPNST). Larger studies are required to validate the present observations and investigate the clinical implications of such subcategorisation.

Endometrial stromal sarcoma (ESS) is a rare mesenchymal neoplasm. Herein, we report a low-grade ESS with a novel MEAF6-SUZ12 fusion gene. A 40-year-old woman presented with a 9.0-cm abdominal wall mass juxtaposed to the postoperative scar of surgeries for uterine “leiomyomas” and cesarean section. Histologically, mostly hypocellular and myxoid nodules were comprised of uniform spindle cells and exhibited tongue-like infiltration. Immunohistochemically, the tumor cells were positive for CD10, estrogen receptor, and CD34 (focal). There were occasional h-caldesmon-positive cohesive nests. RNA sequencing along with reverse transcriptase-polymerase chain reaction and Sanger sequencing identified an in-frame fusion of MEAF6 (exon 4) and SUZ12 (exon 2). Upon review of the previous “leiomyomas,” we revised their diagnoses as low-grade ESS. The patient is alive without disease 2 years after the surgery. In addition to expanding the molecular landscape of low-grade ESS, this case highlights the challenge of diagnosing low-grade ESS in an uncommon clinicopathological setting.

Granular cell tumors (GCTs) are rare mesenchymal tumors that exhibit a characteristic morphology and a finely granular cytoplasm. The genetic alterations responsible for GCT tumorigenesis had been unknown until recently, when loss-of-function mutations of ATP6AP1 and ATP6AP2 were described. Thus, we performed whole-exome sequencing, RNA sequencing, and targeted sequencing of 51 GCT samples. From these genomic analyses, we identified mutations in genes encoding vacuolar H

Dedifferentiated chondrosarcoma is a rare bone sarcoma, whose genetic background remains incompletely understood. Mutations in SUZ12 or EED, which encode polycomb repressive complex 2 (PRC2) components, and resulting deficiency in H3K27me3 are characteristic features of the majority of malignant peripheral nerve sheath tumors. Here, we investigated H3K27me3 and PRC2 status in dedifferentiated chondrosarcoma. Among 19 evaluable dedifferentiated chondrosarcoma cases, six (32%) showed immunohistochemical loss of H3K27me3 only in the dedifferentiated component, whereas the well-differentiated component retained H3K27me3. H3K27me3-deficient dedifferentiated chondrosarcoma occurred in two men and four women with a median age of 66. All of these tumors affected bones of the upper half of the body, with the ribs being preferentially involved, which represented a significantly different distribution compared to that in the 13 H3K27me3-intact dedifferentiated chondrosarcomas. H3K27me3-deficient dedifferentiated chondrosarcomas were histologically different from H3K27me3-intact dedifferentiated chondrosarcomas, as the former invariably demonstrated dedifferentiated histology with a striking similarity to classic malignant peripheral nerve sheath tumor, comprising sweeping to swirling fascicles of relatively uniform spindle cells. Heterologous rhabdomyoblastic differentiation, the focal presence of grade 3 chondrosarcoma histology, and a cartilaginous component in the metastatic sites were exclusively seen in some cases of H3K27me3-deficient dedifferentiated chondrosarcoma. In all three H3K27me3-deficient dedifferentiated chondrosarcomas that contained focal grade 3 histology, dedifferentiated components did not juxtapose to the grade 3 areas but transitioned abruptly from the grade 1-2 components. Targeted next generation sequencing, which was successfully performed on four H3K27me3-deficient dedifferentiated chondrosarcomas, identified an IDH2 mutation in one case and COL2A1 truncations in three cases. The dedifferentiated areas of three cases harbored SUZ12 or EED alterations, which were absent in the well-differentiated component, suggesting a role for PRC2 aberrations in dedifferentiation. H3K27me3 deficiency defines a novel subset of dedifferentiated chondrosarcoma that requires recognition because of its diagnostic and potential clinical implications.