Adult Chordoma Research Articles

Pediatric Chordoma: A Tale of Two Genomes.

Little is known about the genomic alterations in chordoma, with the exception of loss of SMARCB1, a core member of the SWI/SNF complex, in poorly differentiated chordomas. A TBXT duplication and rs2305089 polymorphism, located at 6q27, are known genetic susceptibility loci. A comprehensive genomic analysis of the nuclear and mitochondrial genomes in pediatric chordoma has not yet been reported. In this study, we performed WES and mtDNA genome sequencing on 29 chordomas from 23 pediatric patients. Findings were compared with that from whole-genome sequencing datasets of 80 adult patients with skull base chordoma. In the pediatric chordoma cohort, 81% of the somatic mtDNA mutations were observed in NADH complex genes, which is significantly enriched compared with the rest of the mtDNA genes (P = 0.001). In adult chordomas, mtDNA mutations were also enriched in the NADH complex genes (P < 0.0001). Furthermore, a progressive increase in heteroplasmy of nonsynonymous mtDNA mutations was noted in patients with multiple tumors (P = 0.0007). In the nuclear genome, rare likely germline in-frame indels in ARID1B, a member of the SWI/SNF complex located at 6q25.3, were observed in five pediatric patients (22%) and four patients in the adult cohort (5%). The frequency of rare ARID1B indels in the pediatric cohort is significantly higher than that in the adult cohort (P = 0.0236, Fisher's exact test), but they were both significantly higher than that in the ethnicity-matched populations (P < 5.9e-07 and P < 0.0001174, respectively). Implications: germline ARID1B indels and mtDNA aberrations seem important for chordoma genesis, especially in pediatric chordoma.

Sacral Chordoma in A Pediatric Patient: A Case Report

Chordomas are rare malignant tumours arising from primitive notochordal remnants and comprises of 0.2 % of primary brain tumours and less than 5 % of primary bone tumours [1]. Only 5 % of them occur in the first two decades. Only 300 paediatric cases have been reported so far in the literature [2-5]. The average age at diagnosis in children is 10 years with a male-to-female ratio being close to 1. Adult chordomas are primarily found in the sacro-coccygeal region whereas the majority of paediatric chordomas are intracranial. Metastatic spread seems to be more common in children under 5-year-old with more frequent in case of sacro-coccygeal locations and undifferentiated histology. The tumour location majorly determines the clinical presentation. Sacrococcygeal forms may present with an ulcerated subcutaneous mass, radicular pain, bladder and bowel dysfunctions. Diagnosis is suspected on computerised tomography showing the bone destruction and with typically lobulated appearance, hyperintense on T2-weighted magnetic resonance imaging. Management of these tumours is based on possible complete primary resection followed by local irradiation, ideally proton beam therapy. A major prognostic factor identified in chordomas was age of onset and it is notable that the worst progression occurs in very young children, under the age of 5 years. Prognosis is better in children than in adults except for the aggressive form of chordomas occurring in children under 5 years of age. The brachyury growth factor (growth factor T) is a specific marker of chordomas, implicated in notochordal development. Its locus 6q27 is frequently amplified within chordoma cells and its inactivation can block growth of chordoma tumour cell lines (U-CH1) in vitro

The NIH pediatric/young adult chordoma clinic and natural history study: Making advances in a very rare tumor.

Chordomas are rare tumors arising from the skull base and spine, with approximately 20 pediatric chordoma cases in the Unitedn States per year. The natural history and optimal treatment of pediatric chordomas, especially poorly differentiated and dedifferentiated subtypes, is incompletely understood. Herein, we present findings from our first National Cancer Institute (NCI) chordoma clinic and a retrospective analysis of published cases of pediatric poorly differentiated chordomas (PDC) and dedifferentiated chordomas (DC). Patients less than 40years old with chordoma were enrolled on the NCI Natural History and Biospecimens Acquisitions Study for Children and Adults with Rare Solid Tumors protocol (NCT03739827). Chordoma experts reviewed patient records, evaluated patients, and provided treatment recommendations. Patient-reported outcomes, biospecimens, and volumetric tumor analyses were collected. A literature review for pediatric PDC and DC was conducted. Twelve patients (median age: 14years) attended the clinic, including four patients with active disease and three patients with PDC responsive to systemic therapy. Consensus treatment, management, and recommendations were provided to patients. Literature review returned 45 pediatric cases of PDC or DC with variable treatments and outcomes. A multidisciplinary expert clinic was feasible and successful in improving understanding of pediatric chordoma. While multimodal approaches have all been employed, treatment for PDC has been inconsistent and a recommended standardized treatment approach has not been defined. Centralized efforts, inclusive of specialized chordoma-focused clinics, natural history studies, and prospective analyses will help in the standardization of care for this challenging disease.

RARE-32. PEDIATRIC METASTATIC SKULL BASE CHORDOMA WITH TP53 MUTATION – A CASE REPORT AND REVIEW OF THE LITERATURE

Chordoma is an uncommon bone tumor arising from notochordal remnant, which accounts for 1–4% of all bone malignancies. It commonly occurs along the cranial-spinal axis, and skull base is one of most frequent sites, representing 35–49% of all chordoma cases. Surgical resection is widely accepted as the first choice of treatment. There are only limited number of reports about pediatric chordoma cases, and its biological behavior including genetic backgrounds were largely unknown. Here, we present a 5 year-old girl with a large aggressive skull base chordoma of 6 cm in maximum diameter, which eventually had multiple systemic metastasis. We initially tried chemotherapy based on the protocol for the osteosarcoma, but in vain. Because the tumor was highly vascularized on angiography, after embolization of the feeding arteries and bilateral internal maxillary arteries, endoscopic endonasal surgery was performed. The tumor was sufficiently removed, achieving effective mass reduction, and the residual tumors involving the lower cranial nerves and craniocervial junction were additionally treated with Gamma Knife radiosurgery. However, one month later, it showed systemic metastasis to bilateral cervical lymph nodes and lung. We tried chemotherapy with nivolmab and imatinib for this patient, whereas they showed the partial effect. The genetic analysis revealed somatic TP53 c.569C>T, (p.P190L) mutation in chordoma specimen. In the past literature, we found only one study of the adult chordoma cases, in which majority of the patients had somatic TP53 mutation (p.P72R). Further investigation with large number of the cases is essential to clarify the molecular biology of pediatric chordomas.

Erratum to: Symptom burden and life challenges reported by adult chordoma patients and their caregivers.

Erratum to: Symptom burden and life challenges reported by adult chordoma patients and their caregivers.

Symptom burden and life challenges reported by adult chordoma patients and their caregivers

PurposeThis study aims to characterize the symptom burden and life challenges that chordoma patients and their caregivers experience.MethodsIn this cross-sectional study, we analyzed data from the Chordoma Foundation online community survey conducted in 2014. Frequency counts and percentages were calculated to determine the prevalence of self-reported symptoms and life challenges in the sample. We used Fisher’s exact test to compare self-reported symptoms among subgroups with different disease status, tumor locations, and treatments received.ResultsAmong the survey participants, 358 identified themselves as chordoma patients and 202 as caregivers. The majority of the patients were over 45 years (72%), male (56%), educated beyond high school degree (87%), and from North America (77%). Skull base was the most prevalent tumor location (40%). Chronic pain (35%) was the most commonly reported symptom followed by depression or severe anxiety (32%) and chronic fatigue (31%). Among patients, the most commonly reported challenges included delayed care (37%), long-term disability (33%), and confusion or unanswered questions about chordoma (28%). For caregivers, grief (55%), delayed diagnosis (47%), and difficulty helping the patient cope with his or her disease (45%) were most common.ConclusionsOur study findings suggest a high symptom burden and life challenges among chordoma patients and their caregivers. This study provides preliminary, limited estimates of the prevalence of a wide range of self-reported symptoms and challenges that will inform the assessment of patient-reported outcomes in future clinical trials and help clinicians better manage chordoma patients’ symptoms.

Symptom burden and life challenges reported by adult chordoma patients and their caregivers

Symptom burden and life challenges reported by adult chordoma patients and their caregivers

Prognostic value of MIB-1, p53, epidermal growth factor receptor, and INI1 in childhood chordomas

Chordomas are slow-growing tumors and most commonly involve the sacrum and clivus. Multiple recurrences are frequent. Childhood chordomas are rare and often show exceptionally aggressive behavior, resulting in short survival and a high incidence of metastatic spread. This study examined the histologic features and immunohistochemical profile of pediatric chordomas and compared them with their adult counterparts. Nine pediatric and 13 adult cases were included in the study. Childhood chordomas were classified into conventional, atypical, and poorly differentiated types. Immunohistochemistry was performed for cytokeratin, epithelial membrane antigen, vimentin, S100, brachyury, p53, INI1, epidermal growth factor receptor (EGFR), and CD117. Cytogenetic analyses were performed in a subset of tumors for SMARCB1/INI1 locus on 22q chromosome by fluorescent in situ hybridization (FISH) and analysis of the SMARCB1/INI1 gene sequence. All tumors showed expression of cytokeratin, epithelial membrane antigen, S100, vimentin, brachyury, and EGFR. Atypical morphology, p53 expression, higher MIB-1 labelling index (LI), and INI1 loss were more frequently seen in pediatric chordomas as compared with adults. None of the tumors showed CD117 expression. No point mutation in the SMARCB1/INI1 gene was noted in the tumors examined; however, 4 pediatric and 1 adult chordoma showed loss of this locus on FISH analysis. A subset of pediatric chordomas with atypical histomorphologic features needs to be identified, as they behave in an aggressive manner and require adjuvant therapy. Pediatric chordomas more frequently show p53 expression, INI1 loss, and higher MIB-1 LI as compared with adults, whereas EGFR expression is common to both.

Clinical and Histopathologic Features of Chordomas in Children and Young Adults

Chordoma is a tumor of the axial skeleton that is distinctly uncommon in children and adolescents. Previous observations have suggested that chordomas in pediatric patients differ from adult chordomas in presentation, morphology, and behavior. This study examines the clinical and histologic features of chordomas in young patients (< or =25 years old). All cases from the Mayo Clinic files were graphed according to age and a bimodal distribution was observed. The 35 cases representing the youngest population were selected for review. Histopathology ranged from low cellularity tumors with lobulated architecture and abundant myxoid matrix (conventional chordoma), to those with varying amounts of chondroid matrix (chondroid chordoma), to more cellular tumors (atypical chordoma), and finally to neoplasms with high-grade spindle-cell differentiation (dedifferentiated chordoma). Over an average follow-up period of 129 months (range 1 to 501 months), there were 13 deaths (37%) and 3 patients with metastasis. This survival rate was slightly better than the reported mortality rate for adults with chordoma, but there was a subset of young patients (those with atypical chordoma) that had a significantly worse survival rate, suggesting that histologic subtyping may be predictive of prognosis.