Pediatric Clival Chordoma: A Case Series and Rationale for Next-Generation Sequencing

Background Clival chordoma is very rare in the pediatric population. Current standard treatment includes gross total resection with adjuvant radiotherapy, and current systemic therapies have shown limited clinical efficacy. Our group previously sequenced several adult chordoma tumors, finding aberrations implicating the PI3K/PTEN/AKT and STAT-3 pathways in pathogenesis. To this effect, we aim to study the pediatric chordoma population to discover both clinical and genetic differences in this population.

Case Series We present three unique cases of pediatric clival chordoma:

Case 1 is a 9-year-old girl with history of opsoclonus/myoclonus/ataxia syndrome and ganglioneuroblastoma, who presented with an intradural anaplastic clival chordoma. She was treated via transsphenoidal resection followed by adjuvant proton radiotherapy. Immunohistochemistry (IHC) shows INI-1(−), brachyury(+). She has stable imaging at 27 months of follow-up.

Case 2 is a 13-year-old female who presented with transdural prepontine clival chordoma with brainstem compression. She was treated via a combined endonasal and transoral resection with anterior spinal fusion. Complicated postoperative course resulted in delayed adjuvant proton radiotherapy. This patient notably has a positive family history of uncle with clival chordoma. IHC shows INI-1(+), brachyury(+). She has a progressively recovering abducens palsy and stable imaging at 9 months of follow-up.

Case 3 is a 16-year-old male who presented with massive retropharyngeal and intradural clival chordoma, preoperative bilateral hypoglossal palsy, and abducens palsy. He was treated via staged endonasal and transoral resections and left transcervical resection for lateral tumor extension. He underwent further expanded endonasal re-resection for rapid recurrence. He completed adjuvant radiation therapy and is receiving pembrolizumab on clinical trial. IHC shows brachyury(+), INI-1(+), and PD-L1(+). This tumor cell line is growing in vitro and will be submitted as a candidate for the first pediatric chordoma cell line.

Discussion Pediatric clival chordoma poses unique challenges related to anatomy, longer anticipated follow-up, and in some cases, highly aggressive behavior. The described cases notably exhibit anaplastic pathology, positive family history, and massive size with PD-L1 positivity and propensity for cell line growth in vitro, respectively. Extent and location near the brainstem precluded complete negative margins as is frequent in chordoma, highlighting a role for improved adjuvant therapies. Chordoma growth in vitro is challenging, and successful pediatric cell line development may have far reaching implications. There are currently few genetic studies of pediatric skull base tumors, particularly clival chordoma. Potential identification of targetable gene alterations is a rationale for next-generation sequencing (NGS) in this group. Pending IRB approval for NGS of pediatric skull base patients, we will compare findings to our existing adult sequencing data (collaboration with Chordoma Foundation), validated chordoma cell lines with full exome sequencing data, and existing published datasets of primarily adult patients.

Conclusion Pediatric clival chordoma is a rare disease entity which may present and act differently from tumors diagnosed in adulthood. A multidisciplinary approach to care at an experienced cranial base center is recommended for these highly complex cases. NGS identification of genetic biomarkers within this population may lead to more effective targeted therapies.