Chordomas are rare midline axial skeletal neoplasms that typically present in adults. They are infrequent in childhood with typical localization in the spheno-occipital skull base. They are derived from remnants of the embryonic notochord. We present the case of 4 months old girl, who was born with „blueberry muffin” syndrome and was first negatively diagnosed for neuroblastoma and leukemia (two negative skin biopsies were performed) was admitted with axial laxity. In imaging testes there was a tumor of the scull base, metastases in the lungs and kidneys (that were not seen at previous assessments) and a small lesion in the heart. The third biopsy of skin lesion was performed and pathological examination revealed a neoplasm composed of cords, clusters, and chains of multivacuolated cells embedded within a myxoid matrix and separated by fibrous septa. No atypical and dedifferentiated features were present. Mitotic activity was not observed. Neoplastic cells showed the typical cytoplasmic immunostaining for EMA, S100 and cytokeratin AE1/AE3, strong nuclear brachyury expression, and retention of nuclear INI-1 expression. The diagnosis of chordoma was established. Neoplastic tissue and blood samples were obtained for molecular analysis using next generation sequencing, including germline mutations assessment (are ongoing). Chemotherapy as for soft tissue sarcomas was undertaken. Currently a patient is on treatment with improvement of neurological status.
INTRODUCTION: Diffuse pediatric-type high-grade gliomas are diffuse gliomas with histological features of malignancy, typically occurring in children, and infants. For these tumors, precise classification, identification of prognostic and predictive factors requires molecular analysis. The ROS proto-oncogene 1 (ROS1) gene encodes a receptor tyrosine kinase that is involved in chromosomal rearrangements in numerous malignancies, and may be an attractive therapeutic target, since specific inhibitors have been approved for several neoplasms. Molecular evaluation including detection of ROS1 fusions in pediatric gliomas are not included in standard diagnostic tests so far, therefore data on its significance is still limited. We present two cases of pediatric ROS1 fusion-positive brain tumors. METHODS AND RESULTS: The patient no.1 was 1 year old boy with disseminated brain lesions. Histopathological examination displayed the presence of a neoplasm, which was composed of round and spindle-shaped cells with palisading necrosis, mitotic activity, and microvascular proliferation. The patient no.2 is 9 years old girl with tumor located in left frontal lobe. Microscopically, the neoplasm revealed the presence of oligodenroglial-like component with microvascular proliferation, and high mitotic activity. Targeted gene sequencing panel - Ampliseq Childhood Cancer Panel for Illumina was used to detect diagnostic and targetable gene fusions. In both of patients ROS1:GOPC gene fusions were detect. Identified fusions allowed to established diagnosis - infant-type hemispheric glioma with ROS1 fusion (patient no 1) and - diffuse pediatric-type high grade glioma with ROS1 fusion (patient no 2). CONCLUSIONS: Our results indicate, that the presence of ROS1 fusions are not limited to the infant-type hemispheric gliomas only and may play a role in other glioma entities. It may be worth to include this biomarker in the diagnostic panel of pediatric brain tumors to establish a more precise diagnosis and a potential therapeutic target. Funded by National Science Centre, Poland (2016/23/B/NZ2/03064).
Purpose: The purpose of this study was to compare the survival of CHEK2 mutations positive and CHEK2 mutations negative patients with bladder or kidney cancer. Materials and methods: 1419 patients with bladder and 835 cases with kidney cancer and 8302 controls were genotyped for four CHEK2 variants: 1100delC, del5395, IVS2+1G>A and I157T. Predictors of survival were determined among CHEK2 carriers using the Cox proportional hazards model. The median follow-up was 17 years. Covariates included age (≤65; >66), smoking status (non-smoking; smoking), cancer family history (negative; positive) and gender (females; males). Results: Of the 1419 bladder patients enrolled in the study, 118 (8.32%) carried a CHEK2 mutation (all variants combined) (OR=1.4; 95% CI 1.17–1.78; p=0.0006), including 25 (1.76%) cases with a truncating mutation (OR=1.84; 95% CI, 1.17-2.89; p=0.01) and 93 (6.55%) patients with a missense mutation (OR=1.35; 95% CI, 1.07-1.7; p=0.01). We found no impact of CHEK2 mutations on bladder or kidney cancer survival. The 10-year survival for all CHEK2 mutation for bladder cancer carriers was 19% and for non-carriers was 13% (p=0.7). The 10-year survival for kidney cancer carriers was 6% and for non-carriers was 4% (p=0.9). Conclusion: We found no impact of CHEK2 mutations on bladder or kidney cancer survival regardless of their age, sex, cancer family history and smoking status.
In the recent 5th edition of the WHO classification of CNS tumors, ‘Astroblastoma, MN1 altered’ is recognized a distinct brain tumor type, occurring in children and young adults. Due to its rarity and novelty, little is known about clinical and molecular traits. Therefore, we initiated an international effort and collected tissue samples, clinical and molecular data from 176 patients with Astroblastoma, MN1 altered, identified by their distinct DNA methylation profiles. DNA methylation-based t-SNE clustering analyses revealed that Astroblastoma, MN1 altered tumors form one distinct main cluster (n=158) showing MN1:BEND2 and single cases with EWSR1:BEND2 fusions and a further adjacent, but distinct smaller cluster (n=18) mostly defined by MN1:CXXC5 fusions. Both fusion partner-defined groups show a median age of 12 years but distinct copy-number aberrations, characteristically a gain of chromosome 5 in one third of the CXXC5-fused group and a loss of chromosome 16q in one third of BEND2-fused cases. As previously reported, a vast majority of Astroblastoma, MN1 altered patients are female, which we confirm for the BEND2-fused group (85%). The CXXC5-fused group, however, shows 75% male patients. Interestingly, 9/10 tumors of the few male patients observed in the BEND2-fused group were all located infratentorially or in the spinal cord, whereas almost all female cases show a supratentorial location (85/87). Histologically, the BEND2-fused group was primarily reported as Astroblastoma (39%), whereas in the CXXC5-fused cases, 31% CNS-PNET and only 8% Astroblastoma histologies were originally assigned. Preliminary clinical analyses showed that the BEND2-fused group has a relatively good 5/10-year OS of 97%/89%, but a less favorable 5/10-year PFS of 48%/35%, in line with previous studies. Patients showing CXXC5-fused tumors (n=8) indicated 5/10-year OS and PFS rates of 83%/83% and 60%/60%, respectively. Additional survival and molecular analyses are being conducted to further characterize Astroblastoma, MN1 altered tumors and its molecular subgroups.
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