To the Editor: We appreciate the interest of Zou et al.1 The comments are directed towards our recent article in Neurosurgery titled “Cranial Chordoma: A New Preoperative Grading System.”2 The proposed classification was designed by the senior author with the following objectives: to predict the difficulty of a case, to help the surgeon in advance regarding areas of anatomic difficulty, and to help decision making of further therapy. As was detailed in the original manuscript, it incorporates anatomic, radiological, and clinical features.2 Previous recent publications led by the senior author showed the importance of complete resection on progression-free survival3 and that aggressive surgical resection could be performed with the preservation of functional status.4 These publications are the basis for the development of the preoperative grading system. SUMMARY OF THE OBJECTIONS IN THE LETTER TO THE EDITOR In the letter1 sent to Neurosurgery by Zou et al regarding our grading system, the main criticisms are the following: the absence of a pathological subtype characterization of the skull base chordomas and the absence of biomarkers such as brachyury-YAP. Finally, the commentator1 cites some recent studies in the molecular biology of chordomas that, in the words of the commentators, constitute “a growing body of evidence supporting the use of the immune [sic] parameters as powerful prognostic tool in cancers.” This refers again to a biomarker for chordomas. OUR RESPONSE The main purpose of a grading system is to help neurosurgeons to make surgical decisions prior to the procedure itself. With that in mind, the criteria of the Sekhar Grading System for Cranial Chordomas (SGSCC) are as follows: tumor size, site, vascular involvement, intradural invasion, and tumor regrowth after prior treatment.2 These criteria are the type of information that is readily available to any neurosurgeon before planning a surgical procedure. The criterion prior treatment is an interaction between biological aggressiveness of the chordoma and incomplete resection due to an inadequate choice of the surgical approach, if that is the case for a particular patient. Therefore, the SGSCC purposely did not include any advanced molecular or pathological markers because these are not currently available prior to the surgical intervention itself. Still, at the end of our original publication,2 we specifically addressed that future developments in the genetic knowledge of chordomas could lead to reappraisal of the classification. There are some important points to be addressed regarding the use of molecular biology markers. It is well known that stereotactic-guided biopsy cannot provide an accurate diagnosis,5 that all the molecular markers are tissue dependent, and that there is a great heterogeneity in any tumor sample sent to pathological analysis. Therefore, surgical resection is necessary for a full tumor characterization and for any immune-histochemical analysis, or other types of molecular profiling. An ideal tumor prognostic marker would be one that could be obtained preoperatively and would have a high specificity and sensitivity. Currently that is not the case, although through advanced biophysical methods such as Raman spectroscopy6,7 this might be possible in the future. PROGNOSTIC FACTORS As mentioned above, the ideal molecular prognostic factor would be one that in addition to high sensitivity and high specificity could be obtained easily preoperatively. The experience with meningiomas provides a good template for the evolution of molecular markers and the current problems faced by neurosurgeons when confronted with a case. The original Simpson classification for meningiomas was published in 1957;8 over the years, many authors have published on molecular markers for meningiomas. Perry et al9 included a preoperative radiological criterion and a postoperative histological marker when looking into the survival of patients diagnosed with meningiomas. Later, in 2004, Perry, Gutman, and Reifenberg10 stated: “A better understanding of the molecular mechanisms involved in meningioma pathogenesis may not only lead to the identification of novel diagnostic and prognostic marker but will also facilitate the development of new pathogenesis-based therapeutic strategies”.10 Following that, innumerable studies have been published on molecular markers for meningiomas. However, Nanda et al11 recently showed that the degree of surgical resection of the meningiomas still represented the most important factor for recurrence free survival and that the Simpson classification was still relevant. Chordomas are rare tumors, but efforts are being made to understand their pathogenesis. Thus, in addition to brachyury-YAP and the other studies cited by Zou et al,1 we would like to mention some other recent developments regarding molecular markers for chordomas. Regarding brachyury (transcription factor T), Pillay et al12 confirmed that a single nucleotide variant of gene T (chromosome 6q27) is implicated in the pathogenesis of chordomas and the duplication of the T gene is associated with familial risk. Other possible markers for chordomas include loss of heterozygosity at the phosphatase and tensin homolog,13 cathepsin K,14 which is associated with chordoma invasion and reduced progression-free survival, and SMARCB1/INI1.15 Recently Hasselblatt et al16 reported that chordomas with SMARCB1/INI1 loss are a distinct molecular entity with dismal prognosis. Similar to other types of cancer, in chordoma cell lines, it seems that there is a role of long noncoding RNA LOC554202 for chordoma cell proliferation and invasion.17 Additionally, MicroRNA possibly will play a very important role in the understanding of the molecular pathways of chordomas.18 Therefore, the biology of chordomas is complex, many groups were able to find markers that will eventually translate in a better understanding prognosis in a similar fashion to oligodendrogliomas. CONCLUSION The ideal prognostic grading system would factor clinical and molecular features prior to surgery for any type of tumor, currently that is not possible. However, the SGSCC incorporates all the relevant anatomic, radiological, and clinical features.2 Now any neurosurgeon around the world can easily predict the difficulty of the case and know which areas of the skull base will need attention and further therapy. The grading system was planned as such that new developments in the technology for molecular markers can be easily incorporated into it. Disclosure The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article. REFERENCES 1. Zou M , Liu F , Lv G , Wang X , Li J . Letter: cranial chordoma: a new preoperative grading system . Neurosurgery . 2018 . 83 ( 1 ): E44 - E45 . 2. Brito da Silva H , Straus D , Barber JK , Rostomily RC , Ferreira M Jr. , Sekhar LN . Cranial chordoma: a new preoperative grading system . Neurosurgery . 2017 . published online ahead of print: November 3, 2017 (doi: 10.1093/neuros/nyx423) . 3. Di Maio S , Temkin N , Ramanathan D , Sekhar LN . Current comprehensive management of cranial base chordomas: 10-year meta-analysis of observational studies . J Neurosurg . 2011 ; 115 ( 6 ): 76 - 83 . Google Scholar CrossRef Search ADS 4. Di Maio S , Rostomily R , Sekhar LN . Current surgical outcomes for cranial base chordomas: cohort study of 95 patients . Neurosurgery . 2012 ; 70 ( 6 ): 1355 - 1360 ; discussion 1360 . Google Scholar CrossRef Search ADS PubMed 5. Jackson RJ , Fuller GN , Abi-Said D et al. Limitations of stereotactic biopsy in the initial management of gliomas . Neuro-Oncol . 2001 ; 3 ( 3 ): 193 - 200 . Google Scholar CrossRef Search ADS PubMed 6. Barroso EM , Ten Hove I , Bakker Schut TC et al. Raman spectroscopy for assessment of bone resection margins in mandibulectomy for oral cavity squamous cell carcinoma . Eur J Cancer . 2018 ; 92 ( 3 ): 77 - 87 . Google Scholar CrossRef Search ADS PubMed 7. Haifler M , Pence I , Sun Y et al. Discrimination of malignant and normal kidney tissue with short wave infra-red dispersive Raman spectroscopy . J Biophotonics . 2018 . doi: 10.1002/jbio.201700188. [Epub ahead of print] 8. Simpson D . The recurrence of intracranial meningiomas after surgical treatment . J Neurol Neurosurg Psychiatry . 1957 ; 20 ( 1 ): 22 - 39 . Google Scholar CrossRef Search ADS PubMed 9. Perry A , Scheithauer BW , Stafford SL , Lohse CM , Wollan PC . “Malignancy” in meningiomas: a clinicopathologic study of 116 patients, with grading implications . Cancer . 1999 ; 85 ( 9 ): 2046 - 2056 . Google Scholar PubMed 10. Perry A , Gutmann DH , Reifenberger G . Molecular pathogenesis of meningiomas . J Neuro-oncol . 2004 ; 70 ( 2 ): 183 - 202 . Google Scholar CrossRef Search ADS 11. Nanda A , Bir SC , Maiti TK , Konar SK , Missios S , Guthikonda B . Relevance of Simpson grading system and recurrence-free survival after surgery for World Health Organization Grade I meningioma . J Neurosurg . 2017 ; 126 ( 1 ): 201 - 211 . Google Scholar CrossRef Search ADS PubMed 12. Pillay N , Plagnol V , Tarpey PS et al. A common single-nucleotide variant in T is strongly associated with chordoma . Nat Genet . 2012 ; 44 ( 11 ): 1185 - 1187 . Google Scholar CrossRef Search ADS PubMed 13. Lee DH , Zhang Y , Kassam AB et al. Combined PDGFR and HDAC inhibition overcomes PTEN disruption in chordoma . PLoS One . 2015 ; 10 ( 8 ): e0134426 . Google Scholar CrossRef Search ADS PubMed 14. Tian K , Ma J , Wang L et al. Expression of cathepsin K in skull base chordoma . World Neurosurg . 2017 ; 101 ( 3 ): 396 - 404 . Google Scholar CrossRef Search ADS PubMed 15. Antonelli M , Raso A , Mascelli S et al. SMARCB1/INI1 involvement in pediatric chordoma: a mutational and immunohistochemical analysis . Am J Surg Pathol . 2017 ; 41 ( 1 ): 56 - 61 . Google Scholar CrossRef Search ADS PubMed 16. Hasselblatt M , Thomas C , Hovestadt V et al. Poorly differentiated chordoma with SMARCB1/INI1 loss: a distinct molecular entity with dismal prognosis . Acta Neuropathol . 2016 ; 132 ( 1 ): 149 - 151 . Google Scholar CrossRef Search ADS PubMed 17. Ma X , Qi S , Duan Z et al. Long non-coding RNA LOC554202 modulates chordoma cell proliferation and invasion by recruiting EZH2 and regulating miR-31 expression . Cell Prolif . 2017 ; 50 ( 6 ). doi: 10.1111/cpr.12388. Epub 2017 Sep 30. 18. Gulluoglu S , Tuysuz EC , Kuskucu A et al. The potential function of microRNA in chordomas . Gene . 2016 ; 585 ( 1 ): 76 - 83 . Google Scholar CrossRef Search ADS PubMed Copyright © 2018 by the Congress of Neurological Surgeons This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)
Neurosurgery – Oxford University Press
Published: Apr 17, 2018
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