To the Editor: We read with great interest the article by Brito da Silva et al.1 on the preoperative sekhar grading system for cranial chordomas. The authors developed a new chordoma grading system based on several clinical parameters (specifically including tumor size, location, vascular involvement, intradural invasion, and tumor regrowth after prior treatment) and attempted to identify different prognostic groups using this model. They found that a low score according to this system was significantly associated with increased risk of disease recurrence and also showed a trend toward reduced overall survival of the patients. We commend the authors for performing this interesting study; however, we noted that the authors did not include the chordoma pathologic type for prognostic stratification in their system, which may compromise the accuracy and reliability of the grading model as this variable has been widely reported to be correlated with clinical outcomes in patients with skull base chordoma (SBC).2 Another issue of this study is that the authors did not incorporate the molecular biology of chordoma into their preoperative grading system. At present, many biomarkers have been shown to contribute to SBC prognosis.3-7 Among them, brachyury is currently considered as a promising candidate marker in predicting SBC progression and patient survival, which has been suggested as a potentially effective target for chordoma therapy.8,9 For example, a recent study showed that brachyury-YAP (Yes-associated protein) pathway could regulate chordoma stemness and aggressiveness, highlighting brachyury as a new therapeutic target for this tumor entity.10 In vitro, knockdown of Brachyury was demonstrated to have the ability to suppress the growth of SBC cells.5 Additionally, it has been reported that brachyury expression in SBC is significantly associated with poor patient outcome.5,11 Recently, researchers also found that through partially promoting degradation of Brachyury, Afatinib displayed potent antiproliferative activity against clival chordoma cell line.12 These data strongly suggest that brachyury is closely correlated with SBC development and progression. Considering this, we believe that adding the immunohistochemical evaluation of brachyury expression to SBC grading system may be more helpful for prognostic risk stratification. Clinically, large variations in survival outcomes can exist even among a very homogeneous subgroup of chordoma patients. This finding indicates that the tumor heterogeneity across chordoma cells should be considered in attempt to establish a reliable prognostic grading system. Previous studies have suggested that evaluation of the composition of the immunological microenvironment is less affected by tumor heterogeneity.13 Therefore, measuring the immune parameters within the chordoma microenvironment may likely provide more accurate and meaningful information on prognosis. Published data have offered a growing body of evidence supporting the use of the immune parameters as powerful prognostic tool in cancers,14,15 which even outperform the traditional staging system in predicting clinical outcomes.16 Similarly, in chordoma, researchers found a frequent microenvironmental immune cells infiltration and their significant association with prognosis.17-19 Taken together, these findings suggest that inclusion of the pathological immunity analysis within the microenvironment in chordoma prognostic grading system is necessary in order to improve outcome prediction and guide therapeutic optimization. Disclosures The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article. REFERENCES 1. Brito da Silva H, Straus D, Barber JK, Rostomily RC, Ferreira M Jr, Sekhar LN. Cranial chordoma: a new preoperative grading system. Neurosurgery . 2017. doi:10.1093/neuros/nyx423 [published online ahead of print]. 2. Zou MX, Lv GH, Zhang QS, Wang SF, Li J, Wang XB. Prognostic factors in skull base chordoma: a systematic literature review and meta-analysis. World Neurosurg . 2018; 109: 307- 327. Google Scholar CrossRef Search ADS PubMed 3. Luo P, Wang X, Zhou J, Li L, Jing Z. C-Cbl and Cbl-b expression in skull base chordomas is associated with tumor progression and poor prognosis. Hum Pathol . 2018. doi:10.1016/j.humpath.2017.12.019. 4. Li M, Zhai Y, Bai J et al. SNF5 as a prognostic factor in skull base chordoma. J Neurooncol . 2018; 137( 1): 139- 146. Google Scholar CrossRef Search ADS PubMed 5. Otani R, Mukasa A, Shin M et al. Brachyury gene copy number gain and activation of the PI3K/Akt pathway: association with upregulation of oncogenic Brachyury expression in skull base chordoma. J Neurosurg . 2017. doi:10.3171/2016.12.JNS161444. 6. Zhai Y, Bai J, Wang S et al. Analysis of clinical factors and PDGFR-β in predicting prognosis of patients with clival chordoma. J Neurosurg . 2018. doi:10.3171/2017.6.JNS17562. 7. Zou MX, Lv GH, Wang XB, Li J. Letter: factors predicting recurrence after resection of clival chordoma using variable surgical approaches and radiation modalities. Neurosurgery . 2017; 81( 2): E28- E31. Google Scholar CrossRef Search ADS PubMed 8. Colia V, Stacchiotti S. Medical treatment of advanced chordomas. Eur J Cancer . 2017; 83: 220- 228. Google Scholar CrossRef Search ADS PubMed 9. Whelan JS, Davis LE. Osteosarcoma, chondrosarcoma, and chordoma. J Clin Oncol . 2018; 36( 2): 188- 193. Google Scholar CrossRef Search ADS PubMed 10. Shah SR, David JM, Tippens ND et al. Brachyury-YAP regulatory axis drives stemness and growth in cancer. Cell Rep . 2017; 21( 2): 495- 507. Google Scholar CrossRef Search ADS PubMed 11. Kitamura Y, Sasaki H, Kimura T et al. Molecular and clinical risk factors for recurrence of skull base chordomas. J Neuropathol Exp Neurol . 2013; 72( 9): 816- 823. Google Scholar CrossRef Search ADS PubMed 12. Magnaghi P, Salom B, Cozzi L et al. Afatinib is a new therapeutic approach in chordoma with a unique ability to target EGFR and Brachyury. Mol Cancer Ther . 2017. doi: 10.1158/1535-7163.MCT-17-0324. 13. Fritzsching B, Fellenberg J, Moskovszky L et al. CD8+/FOXP3+-ratio in osteosarcoma microenvironment separates survivors from non-survivors: a multicenter validated retrospective study. Oncoimmunology . 2015; 4( 3): e990800. Google Scholar CrossRef Search ADS PubMed 14. Becht E, Giraldo NA, Germain C et al. Immune contexture, immunoscore, and malignant cell molecular subgroups for prognostic and theranostic classifications of cancers. Adv Immunol . 2016; 130: 95- 190. Google Scholar CrossRef Search ADS PubMed 15. Fridman WH, Pages F, Sautes-Fridman C, Galon J. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer . 2012; 12( 4): 298- 306. Google Scholar CrossRef Search ADS PubMed 16. Galon J, Pages F, Marincola FM et al. Cancer classification using the Immunoscore: a worldwide task force. J Transl Med . 2012; 10( 1): 205. Google Scholar CrossRef Search ADS PubMed 17. Zou MX, Lv GH, Li J, She XL, Jiang Y. Upregulated human telomerase reverse transcriptase (hTERT) expression is associated with spinal chordoma growth, invasion and poor prognosis. Am J Transl Res . 2016; 8( 2): 516- 529. Google Scholar PubMed 18. Zou MX, Guo KM, Lv GH et al. Clinicopathologic implications of CD8+/Foxp3+ ratio and miR-574-3p/PD-L1 axis in spinal chordoma patients. Cancer Immunol Immunother . 2018; 67( 2): 209- 224. Google Scholar CrossRef Search ADS PubMed 19. Feng Y, Shen J, Gao Y et al. Expression of programmed cell death ligand 1 (PD-L1) and prevalence of tumor-infiltrating lymphocytes (TILs) in chordoma. Oncotarget . 2015; 6( 13): 11139- 11149. Google Scholar CrossRef Search ADS PubMed Copyright © 2018 by the Congress of Neurological Surgeons
Neurosurgery – Oxford University Press
Published: Apr 17, 2018
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