J Neurosurg 120:1313–1320, 2014 ©AANS, 2014
Male sex as a risk factor for the clinical course of skull base chordomas Clinical article *Walter Rachinger, M.D.,1 Sabina Eigenbrod, M.D., 2 Stephan Dützmann, M.D., 3 Matthias Simon, M.D., 4 Guenther C. Feigl, M.D., 5 Natalia Kremenevskaja, M.D., 6 Hans Kretzschmar, M.D., 2 Stefan Zausinger, M.D.,1 Friedrich-Wilhelm Kreth, M.D.,1 Niklas Thon, M.D.,1 and Jörg-Christian Tonn, M.D.1 1 Department of Neurosurgery and 2Center for Neuropathology and Prion Research, Ludwig Maximilian University of Munich; 3Department of Neurosurgery, Goethe University Hospital, Frankfurt; 4Department of Neurosurgery, University of Bonn; 5Department of Neurosurgery, University of Tübingen; and 6Department of Neurosurgery, University of Erlangen, Germany
Object. Chordomas of the skull base are rare and locally invasive and have a poor prognosis. The aim of this retrospective multicenter study was to evaluate the current pattern of care and clinical course and to identify prognostic factors. Methods. A total of 47 patients (26 men; mean age 48.5 years) treated in 5 centers were included. Histology was centrally reviewed; additionally, semiquantitative N- and E-cadherin expression analysis was performed. Prognostic factors were obtained from multivariate regression models. For survival analysis the Kaplan-Meier method was used. Results. The median follow-up period was 5.2 years. Complete resection, incomplete resection, and extended biopsy were performed in 14.9%, 80.9%, and 4.3% of patients, respectively. Surgical morbidity was not associated with extent of resection. Adjuvant radiation therapy was performed in 30 (63.8%) of 47 patients. The median progression-free survival (PFS) was 7.3 years. Complete resection prolonged median overall survival (OS) (p = 0.04). Male patients presented with worse PFS (4.8 years vs 9.8 years; p = 0.04) and OS (8.3 years vs not reached; p = 0.03) even though complete resection was exclusively achieved in the male subpopulation. Multivariate analysis confirmed male sex as the most important risk factor for tumor progression (p = 0.04) and death (p = 0.02). Age, duration of symptoms, initial Karnofsky Performance Scale score, brainstem compression, involvement of the petrous bone, infiltration of the dura mater, modality and dose of radiation therapy, and the E- and N-cadherin expression patterns did not gain prognostic relevance. Conclusions. In skull base chordomas, male patients bear a higher risk of progressive disease and death. Male patients might benefit from more aggressive adjuvant therapy and/or from a closer follow-up schedule. (http://thejns.org/doi/abs/10.3171/2013.11.JNS131137)
C
Key Words • skull base • chordoma • cadherin • sex • prognostic factors
(WHO Grade I) of the skull base are rare tumors, accounting for 0.1% of all intracranial neoplasms in adults.1,2,5–7,15,16,20,31 They arise from remnants of the primitive notochord. The tumor’s biology, however, is poorly understood. Although considered as slowly growing benign lesions, the disease course is ultimately fatal as these tumors cause destruction of their anatomical environment and are difficult to treat.4,15,18 Maximum resection is considered the cornerstone of curhordomas
Abbreviations used in this paper: KPS = Karnofsky Performance Scale; OS = overall survival; PBRT = proton beam radiotherapy; PFS = progression-free survival. * Drs. Rachinger and Eigenbrod contributed equally to this work.
J Neurosurg / Volume 120 / June 2014
rent treatment concepts. However, both 5-year progression-free survival (PFS) and overall survival (OS) after initial resection have been reported to be highly variable, ranging from 15% to 80% and 61% to 100%, respectively.1,4,5,9,12,15,18,24,26,31,32 There is some evidence that complete resection improves clinical outcome.2,8,11,19,30 Tumor-free margins, however, are often difficult to achieve because of the anatomical sites of origin and the chordoma’s highly infiltrative growing behavior.8,18,19,26,27,30 Adjuvant treatment of residual tumors frequently includes proton beam radiotherapy (PBRT), fractionated stereotactic raThis article contains some figures that are displayed in color online but in black-and-white in the print edition.
1313
W. Rachinger et al. diation therapy, carbon beam radiation therapy, and radiosurgery.3,9,10,14,25,28,32 Both the absence of prospective comparative studies and the limited knowledge of the prognostic profile of these tumors explain that optimal treatment of skull base chordomas remains challenging. A recently published study has associated cadherin expression with the clinical prognosis of the disease.29 This current multicenter study was conducted to analyze the pattern of care, clinical course, and prognostic factors of patients with clival chordomas.
Methods Patient Population
Patients with either de novo or recurrent skull base chordomas (WHO Grade I)16 who were consecutively treated (between 1996 and 2008) in one of the 5 studyassociated German university hospitals (Bonn, Erlangen, Frankfurt, Munich, and Tübingen) were included. No patient had received any form of radiation therapy at the time of study inclusion. Radiation therapy was normally not performed after complete resection. In case of residual tumor after surgery, PBRT was the preferred treatment modality. Follow-up evaluation was done 3 months after surgery and then in 6-month intervals in all centers. The following parameters were analyzed: sex, age, Karnofsky Performance Scale (KPS) score, neurological deficits, duration of preoperative symptoms, de novo versus recurrent tumor status at study inclusion, tumor extension, surgical approach, extent of resection, type and dose of adjuvant therapy, and expression of cadherins.
Magnetic Resonance Imaging
Neuroradiological assessment was retrospectively performed in a blinded fashion at each of the academic centers. Standard MRI included axial T2-weighted sequence with a slice thickness of 2–3 mm, and T1-weighted sequences (with and without contrast enhancement) with a slice thickness of 1–2 mm. Tumor size was assessed by a 3D volume calculation using the largest diameter in the axial, coronal, and sagittal planes. Additionally, involvement of petrosal bone, condyles, or clivus; infiltration of dura; and compression of brainstem was noted. In selected cases CT was available to assess involvement of bone structures. Neuroradiological assessments at study inclusion and at first clinical follow-up 3 months after surgery were available for all patients and were used for comparative analysis. Complete resection was considered to have been achieved if no residual tumor was seen. Tumor removal of more than 50% was classified as a partial resection. Tumor removal below this threshold was categorized as extended biopsy. Tumor progression was determined by follow-up MRI and was suspected if a new lesion was seen.
Histopathology and Semiquantitative Analysis of Cadherin Expression
Central review of histopathology according to the classification of tumors of soft tissue and bone16 was done at the Center for Neuropathology and Prion Research,
1314
Ludwig Maximilian University of Munich, and confirmed the diagnosis of chordoma Grade I in all patients. Semiquantitative analysis of N-cadherin and E-cadherin expression was also centrally done at this center. Tumor samples were fixed with 4% buffered formalin (Fisher Scientific GmbH), paraffin embedded, and subjected to routine staining on a benchmark staining machine with a standard 3,3ʹ-diaminobenzidine (DAB) detection system according to the manufacturer’s instructions (Ventana Medical Systems). Tumor morphology in 2-mm paraffin sections was visualized using H & E staining as well as mouse monoclonal anti–human cytokeratin antibody (clone LU-5, Dianova). Expression of cadherins was analyzed using anti–N-cadherin mouse monoclonal antibody (clone 13A9, Calbiochem) and mouse monoclonal anti– human E-cadherin antibody (clone 36B5, Novocastra), respectively. Semiquantitative analysis of protein expression was performed in an independent and blinded fashion by 2 experienced neuropathologists (S.E. and H.K.) and was classified according to a 3-scaled staining score as follows:29 immunostaining < 10%, 10%–50%, and > 50% of the respective total chordoma tissue under investigation refer to a staining score of 1 (weak), 2 (moderate), and 3 (strong), respectively. In case of discordant findings, a conference for reevaluation was initiated to achieve a consensus concerning the expression score. Statistical Analysis
The reference point of the study was the date of first surgery. Last follow-up was performed in June 2012. Primary and secondary end points were tumor progression and death. Progression-free survival and OS were analyzed using the Kaplan-Meier method. Prognostic factors were obtained from the proportional hazards model. Parameters tested in univariate models are presented in Table 1. Only those being significant were subsequently included in multivariate proportional hazards models. For comparison of continuously scaled patient- and tumor-related parameters, the Wilcoxon test was used. Categorical variables were analyzed using the chi-square test or the Fisher’s exact test, if necessary. Statistical significance was assigned to p < TABLE 1: Results of univariate analysis for PFS and OS p Value Parameter
PFS
OS
age sex E-cadherin initial KPS score tumor size dura infiltration extent of resection radiotherapy type of radiotherapy radiation dose petrous bone brainstem compression
0.41 0.04 0.92 0.86 0.27 0.89 0.72 0.74 0.49 0.40 0.39 0.34
0.49 0.03 0.23 0.08 0.35 0.18 0.04 0.09 0.94 0.34 0.86 0.80
J Neurosurg / Volume 120 / June 2014
Influence of sex on skull base chordomas 0.05. All calculations were performed using the statistical analysis software SAS version 9.2.
Patient Characteristics
Results
The study cohort comprised 47 patients (26 men and 21 women). Basic characteristics of the study population are presented in Table 2. Men and women did not differ in any of the addressed patient- and tumor-related parameters (Table 2). Ten patients (21%) had undergone prior resection at another institution, and 37 patients (78.7%) suffered from de novo tumors. The groups did not differ in any of the patient- or tumor-related parameters. Magnetic resonance imaging revealed brainstem compression in 20 patients (42.6%), the condyles were involved in 8 patients (17%), petrosal bone was affected in 17 patients (36.2%), and dural infiltration was seen in 8 patients (17%) (a typical example of a clival chordoma is given in Fig. 1).
Pattern of Care and Clinical Course
The preferred operative approaches are summarized in Table 3. Complete resection and partial resections were achieved in 7 patients (14.9%) and 38 patients (80.9%), respectively. Two patients (4.3%) underwent extended biopsy only. All patients with complete resection were men (7 of 26 vs 0 of 21 women, p = 0.036). Surgical morbidity was documented for 8 patients (17.0%) and included 6 patients with postoperative worsening of preexisting cranial
Fig. 1. Left: Sagittal T2-weighted MR image depicting a chordoma in a 20-year-old woman, which caused displacement of the brainstem. Right: Axial T1-weighted MR image obtained in the same patient after Gd administration.
nerve dysfunction as well as 2 patients with new deficits. Perioperative complications were not associated with any of the patient-, tumor-, or surgery-related covariates. Thirty patients (63.8%), mainly those with residual tumors after initial surgery (28 of 40 with residual tumors vs 2 of 7 without residual tumors, p = 0.035), received adjuvant treatment; PBRT was applied in 22 patients (mean maximal dose 59.3 Gy, range 40–66 Gy), conventionally fractionated radiotherapy in 3 patients (mean maximal dose 65 Gy, range 60–70 Gy), and radiosurgery in 5 patients (mean maximal dose 24 Gy, range 17–36 Gy). The applied adjuvant treatment regimens were similar for men
TABLE 2: Clinical data in 47 patients stratified for sex* Value Characteristic
Total (n = 47)
Male (n = 26)
Female (n = 21)
p Value (M/F)
median age (yrs) median KPS score median duration of symptoms (mos) median tumor vol (cm3) de novo tumor E-cadherin expression† 50% N-cadherin expression† 50% extent of resection total resection partial resection extended biopsy radiotherapy recurrence death
49.2 80 4.3 28.6 37 (78.7)
48.9 80 4.2 28.2 20 (76.9)
48.0 80 4.5 29.4 17 (81.0)
NS NS NS NS NS NS
26 (56.5) 8 (17.4) 12 (26.1)
17 (65.4) 5 (19.2) 4 (15.4)
9 (45.0) 3 (15.0) 8 (40.0)
1 (2.2) 4 (8.7) 41 (89.1)
1 (3.8) 2 (7.7) 23 (88.5)
0 (0) 2 (10.0) 18 (90.0)
7 (14.9) 38 (80.9) 2 (4.3) 30 (63.8) 26 (55.3) 8 (17.0)
7 (27.0) 18 (69.2) 1 (3.8) 14 (53.8) 14 (53.8) 7 (26.9)
0 (0) 20 (95.2) 1 (4.8) 16 (76.2) 12 (57.1) 1 (4.8)
NS
0.036
NS NS 50%) expression (Cases 1–3). Immunohistochemical assessment of E-cadherin (E-Cad) showed a more heterogeneous staining, with some cases displaying no or minimal (< 10%, Case 1), moderate (10%–50%, Case 2), or extensive (> 50%, Case 3) expression. Arrowheads indicate small groups of E-cadherin positive tumor cells in Case 2 scored as “moderate.” Bars in lower magnification images (columns 1, 3, and 5) = 500 mm; bars in higher magnification images (columns 2, 4, and 6) = 50 mm.
Fig. 4. Kaplan-Meier plot showing PFS after stratification for E-cadherin. Plots indicate censored patients.
1318
J Neurosurg / Volume 120 / June 2014
Influence of sex on skull base chordomas diation therapy should be stringently applied in patients with skull base chordomas independent of the extent of resection. In accordance with the literature, PBRT was the preferred modality in this series (22 of 30 patients) as it has been suggested to provide longer survival rates at lower risk for the patients than conventional megavoltage radiotherapy. However, the current literature does not provide enough evidence yet to support superiority of protons over photons in skull base chordomas. The role of Gamma Knife or linear accelerator (LINAC) radiosurgery is also poorly defined.9,11,22 We are aware that extended time intervals and collections from multiple centers are necessary to include a high number of patients with skull base chordomas for evaluation of prognosis and outcome.11 Given the fact that treatment protocols are continuously modified or improved, the exact elucidation of treatment effects is notoriously difficult.
Conclusions
Sex appears to be an independent prognostic factor for PFS and OS in skull base chordomas. Complete resection might be associated with favorable OS. N-cadherin or E-cadherin expression did not gain prognostic relevance. The male subpopulation might require more aggressive initial treatment even in cases of complete tumor resection. Further prospective studies are needed to elucidate the potential mechanism of sex disparity with regard to tumor progression and prognosis. Acknowledgment We thank the Department of Medical Informatics, Biometry, and Epidemiology, LMU Munich, Germany, for support of statistical analysis. Disclosure The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper. Author contributions to the study and manuscript preparation include the following. Conception and design: Rachinger, Thon, Tonn. Acquisition of data: Rachinger, Eigenbrod, Dützmann, Simon, Feigl, Kremenevskaja, Kretzschmar. Analysis and interpretation of data: Rachinger, Eigenbrod, Kretzschmar, Zausinger, Kreth, Thon, Tonn. Drafting the article: Rachinger, Zausinger, Thon, Tonn, Kreth. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Rachinger. Statistical analysis: Kreth. References 1. al-Mefty O, Borba LA: Skull base chordomas: a management challenge. J Neurosurg 86:182–189, 1997 2. Almefty K, Pravdenkova S, Colli BO, Al-Mefty O, Gokden M: Chordoma and chondrosarcoma: similar, but quite different, skull base tumors. Cancer 110:2457–2467, 2007 3. Amichetti M, Cianchetti M, Amelio D, Enrici RM, Minniti G: Proton therapy in chordoma of the base of the skull: a systematic review. Neurosurg Rev 32:403–416, 2009
J Neurosurg / Volume 120 / June 2014
4. Ammirati M, Bernardo A: Management of skull base chordoma. Crit Rev Neurosurg 9:63–69, 1999 5. Catton C, O’Sullivan B, Bell R, Laperriere N, Cummings B, Fornasier V, et al: Chordoma: long-term follow-up after radical photon irradiation. Radiother Oncol 41:67–72, 1996 6. Chambers PW, Schwinn CP: Chordoma. A clinicopathologic study of metastasis. Am J Clin Pathol 72:765–776, 1979 7. Chugh R, Tawbi H, Lucas DR, Biermann JS, Schuetze SM, Baker LH: Chordoma: the nonsarcoma primary bone tumor. Oncologist 12:1344–1350, 2007 8. Colli B, Al-Mefty O: Chordomas of the craniocervical junction: follow-up review and prognostic factors. J Neurosurg 95:933–943, 2001 9. Dassoulas K, Schlesinger D, Yen CP, Sheehan J: The role of Gamma Knife surgery in the treatment of skull base chordomas. J Neurooncol 94:243–248, 2009 10. Debus J, Schulz-Ertner D, Schad L, Essig M, Rhein B, Thillmann CO, et al: Stereotactic fractionated radiotherapy for chordomas and chondrosarcomas of the skull base. Int J Radiat Oncol Biol Phys 47:591–596, 2000 11. Di Maio S, Temkin N, Ramanathan D, Sekhar LN: Current comprehensive management of cranial base chordomas: 10year meta-analysis of observational studies. Clinical article. J Neurosurg 115:1094–1105, 2011 12. Eid AS, Chang UK, Lee SY, Jeon DG: The treatment outcome depending on the extent of resection in skull base and spinal chordomas. Acta Neurochir (Wien) 153:509–516, 2011 13. Fajkovic H, Halpern JA, Cha EK, Bahadori A, Chromecki TF, Karakiewicz PI, et al: Impact of gender on bladder cancer incidence, staging, and prognosis. World J Urol 29:457–463, 2011 14. Feigl GC, Bundschuh O, Gharabaghi A, Safavi-Abassi S, El Shawarby A, Samii M, et al: Evaluation of a new concept for the management of skull base chordomas and chondrosarcomas. J Neurosurg 102 Suppl:165–170, 2005 15. Ferraresi V, Nuzzo C, Zoccali C, Marandino F, Vidiri A, Salducca N, et al: Chordoma: clinical characteristics, management and prognosis of a case series of 25 patients. BMC Cancer 10:22, 2010 16. Fletcher CDM, Unni KK, Mertens F: World Health Organization Classification of Tumours. Pathology and Genetics: Tumours of Soft Tissue and Bone. Lyon: IARC Press, 2002 17. Gasinska A, Richter P, Darasz Z, Niemiec J, Bucki K, Malecki K, et al: Gender-related differences in repopulation and early tumor response to preoperative radiotherapy in rectal cancer patients. J Gastrointest Surg 15:1568–1576, 2011 18. Ito E, Saito K, Okada T, Nagatani T, Nagasaka T: Long-term control of clival chordoma with initial aggressive surgical resection and gamma knife radiosurgery for recurrence. Acta Neurochir (Wien) 152:57–67, 2010 19. Jawad MU, Scully SP: Surgery significantly improves survival in patients with chordoma. Spine (Phila Pa 1976) 35:117–123, 2010 20. McMaster ML, Goldstein AM, Bromley CM, Ishibe N, Parry DM: Chordoma: incidence and survival patterns in the United States, 1973-1995. Cancer Causes Control 12:1–11, 2001 21. Molife R, Lorigan P, MacNeil S: Gender and survival in malignant tumours. Cancer Treat Rev 27:201–209, 2001 22. Muthukumar N, Kondziolka D, Lunsford LD, Flickinger JC: Stereotactic radiosurgery for chordoma and chondrosarcoma: further experiences. Int J Radiat Oncol Biol Phys 41:387– 392, 1998 23. Nakamura H, Ando K, Shinmyo T, Morita K, Mochizuki A, Kurimoto N, et al: Female gender is an independent prognostic factor in non-small-cell lung cancer: a meta-analysis. Ann Thorac Cardiovasc Surg 17:469–480, 2011 24. Pallini R, Maira G, Pierconti F, Falchetti ML, Alvino E, Cimino-Reale G, et al: Chordoma of the skull base: predictors of tumor recurrence. J Neurosurg 98:812–822, 2003
1319
W. Rachinger et al. 25. Pamir MN, Ozduman K: Tumor-biology and current treatment of skull-base chordomas. Adv Tech Stand Neurosurg 33:35–129, 2008 26. Samii A, Gerganov VM, Herold C, Hayashi N, Naka T, Mirzayan MJ, et al: Chordomas of the skull base: surgical management and outcome. J Neurosurg 107:319–324, 2007 27. Stüer C, Schramm J, Schaller C: Skull base chordomas: management and results. Neurol Med Chir (Tokyo) 46:118–125, 2006 28. Takahashi S, Kawase T, Yoshida K, Hasegawa A, Mizoe JE: Skull base chordomas: efficacy of surgery followed by carbon ion radiotherapy. Acta Neurochir (Wien) 151:759–769, 2009 29. Triana A, Sen C, Wolfe D, Hazan R: Cadherins and catenins in clival chordomas: correlation of expression with tumor aggressiveness. Am J Surg Pathol 29:1422–1434, 2005 30. Tzortzidis F, Elahi F, Wright D, Natarajan SK, Sekhar LN: Patient outcome at long-term follow-up after aggressive microsurgical resection of cranial base chordomas. Neurosurgery 59:230–237, 2006
1320
31. Watkins L, Khudados ES, Kaleoglu M, Revesz T, Sacares P, Crockard HA: Skull base chordomas: a review of 38 patients, 1958-88. Br J Neurosurg 7:241–248, 1993 32. Yoneoka Y, Tsumanuma I, Fukuda M, Tamura T, Morii K, Tanaka R, et al: Cranial base chordoma—long term outcome and review of the literature. Acta Neurochir (Wien) 150:773– 778, 2008
Manuscript submitted May 31, 2013. Accepted November 21, 2013. Please include this information when citing this paper: published online January 3, 2014; DOI: 10.3171/2013.11.JNS131137. Address correspondence to: Walter Rachinger, M.D., Department of Neurosurgery, Klinikum Großhadern, Marchioninistr. 15, Munich 81377, Germany. email: [email protected].
J Neurosurg / Volume 120 / June 2014
Male sex as a risk factor for the clinical course of skull base chordomas Clinical article *Walter Rachinger, M.D.,1 Sabina Eigenbrod, M.D., 2 Stephan Dützmann, M.D., 3 Matthias Simon, M.D., 4 Guenther C. Feigl, M.D., 5 Natalia Kremenevskaja, M.D., 6 Hans Kretzschmar, M.D., 2 Stefan Zausinger, M.D.,1 Friedrich-Wilhelm Kreth, M.D.,1 Niklas Thon, M.D.,1 and Jörg-Christian Tonn, M.D.1 1 Department of Neurosurgery and 2Center for Neuropathology and Prion Research, Ludwig Maximilian University of Munich; 3Department of Neurosurgery, Goethe University Hospital, Frankfurt; 4Department of Neurosurgery, University of Bonn; 5Department of Neurosurgery, University of Tübingen; and 6Department of Neurosurgery, University of Erlangen, Germany
Object. Chordomas of the skull base are rare and locally invasive and have a poor prognosis. The aim of this retrospective multicenter study was to evaluate the current pattern of care and clinical course and to identify prognostic factors. Methods. A total of 47 patients (26 men; mean age 48.5 years) treated in 5 centers were included. Histology was centrally reviewed; additionally, semiquantitative N- and E-cadherin expression analysis was performed. Prognostic factors were obtained from multivariate regression models. For survival analysis the Kaplan-Meier method was used. Results. The median follow-up period was 5.2 years. Complete resection, incomplete resection, and extended biopsy were performed in 14.9%, 80.9%, and 4.3% of patients, respectively. Surgical morbidity was not associated with extent of resection. Adjuvant radiation therapy was performed in 30 (63.8%) of 47 patients. The median progression-free survival (PFS) was 7.3 years. Complete resection prolonged median overall survival (OS) (p = 0.04). Male patients presented with worse PFS (4.8 years vs 9.8 years; p = 0.04) and OS (8.3 years vs not reached; p = 0.03) even though complete resection was exclusively achieved in the male subpopulation. Multivariate analysis confirmed male sex as the most important risk factor for tumor progression (p = 0.04) and death (p = 0.02). Age, duration of symptoms, initial Karnofsky Performance Scale score, brainstem compression, involvement of the petrous bone, infiltration of the dura mater, modality and dose of radiation therapy, and the E- and N-cadherin expression patterns did not gain prognostic relevance. Conclusions. In skull base chordomas, male patients bear a higher risk of progressive disease and death. Male patients might benefit from more aggressive adjuvant therapy and/or from a closer follow-up schedule. (http://thejns.org/doi/abs/10.3171/2013.11.JNS131137)
C
Key Words • skull base • chordoma • cadherin • sex • prognostic factors
(WHO Grade I) of the skull base are rare tumors, accounting for 0.1% of all intracranial neoplasms in adults.1,2,5–7,15,16,20,31 They arise from remnants of the primitive notochord. The tumor’s biology, however, is poorly understood. Although considered as slowly growing benign lesions, the disease course is ultimately fatal as these tumors cause destruction of their anatomical environment and are difficult to treat.4,15,18 Maximum resection is considered the cornerstone of curhordomas
Abbreviations used in this paper: KPS = Karnofsky Performance Scale; OS = overall survival; PBRT = proton beam radiotherapy; PFS = progression-free survival. * Drs. Rachinger and Eigenbrod contributed equally to this work.
J Neurosurg / Volume 120 / June 2014
rent treatment concepts. However, both 5-year progression-free survival (PFS) and overall survival (OS) after initial resection have been reported to be highly variable, ranging from 15% to 80% and 61% to 100%, respectively.1,4,5,9,12,15,18,24,26,31,32 There is some evidence that complete resection improves clinical outcome.2,8,11,19,30 Tumor-free margins, however, are often difficult to achieve because of the anatomical sites of origin and the chordoma’s highly infiltrative growing behavior.8,18,19,26,27,30 Adjuvant treatment of residual tumors frequently includes proton beam radiotherapy (PBRT), fractionated stereotactic raThis article contains some figures that are displayed in color online but in black-and-white in the print edition.
1313
W. Rachinger et al. diation therapy, carbon beam radiation therapy, and radiosurgery.3,9,10,14,25,28,32 Both the absence of prospective comparative studies and the limited knowledge of the prognostic profile of these tumors explain that optimal treatment of skull base chordomas remains challenging. A recently published study has associated cadherin expression with the clinical prognosis of the disease.29 This current multicenter study was conducted to analyze the pattern of care, clinical course, and prognostic factors of patients with clival chordomas.
Methods Patient Population
Patients with either de novo or recurrent skull base chordomas (WHO Grade I)16 who were consecutively treated (between 1996 and 2008) in one of the 5 studyassociated German university hospitals (Bonn, Erlangen, Frankfurt, Munich, and Tübingen) were included. No patient had received any form of radiation therapy at the time of study inclusion. Radiation therapy was normally not performed after complete resection. In case of residual tumor after surgery, PBRT was the preferred treatment modality. Follow-up evaluation was done 3 months after surgery and then in 6-month intervals in all centers. The following parameters were analyzed: sex, age, Karnofsky Performance Scale (KPS) score, neurological deficits, duration of preoperative symptoms, de novo versus recurrent tumor status at study inclusion, tumor extension, surgical approach, extent of resection, type and dose of adjuvant therapy, and expression of cadherins.
Magnetic Resonance Imaging
Neuroradiological assessment was retrospectively performed in a blinded fashion at each of the academic centers. Standard MRI included axial T2-weighted sequence with a slice thickness of 2–3 mm, and T1-weighted sequences (with and without contrast enhancement) with a slice thickness of 1–2 mm. Tumor size was assessed by a 3D volume calculation using the largest diameter in the axial, coronal, and sagittal planes. Additionally, involvement of petrosal bone, condyles, or clivus; infiltration of dura; and compression of brainstem was noted. In selected cases CT was available to assess involvement of bone structures. Neuroradiological assessments at study inclusion and at first clinical follow-up 3 months after surgery were available for all patients and were used for comparative analysis. Complete resection was considered to have been achieved if no residual tumor was seen. Tumor removal of more than 50% was classified as a partial resection. Tumor removal below this threshold was categorized as extended biopsy. Tumor progression was determined by follow-up MRI and was suspected if a new lesion was seen.
Histopathology and Semiquantitative Analysis of Cadherin Expression
Central review of histopathology according to the classification of tumors of soft tissue and bone16 was done at the Center for Neuropathology and Prion Research,
1314
Ludwig Maximilian University of Munich, and confirmed the diagnosis of chordoma Grade I in all patients. Semiquantitative analysis of N-cadherin and E-cadherin expression was also centrally done at this center. Tumor samples were fixed with 4% buffered formalin (Fisher Scientific GmbH), paraffin embedded, and subjected to routine staining on a benchmark staining machine with a standard 3,3ʹ-diaminobenzidine (DAB) detection system according to the manufacturer’s instructions (Ventana Medical Systems). Tumor morphology in 2-mm paraffin sections was visualized using H & E staining as well as mouse monoclonal anti–human cytokeratin antibody (clone LU-5, Dianova). Expression of cadherins was analyzed using anti–N-cadherin mouse monoclonal antibody (clone 13A9, Calbiochem) and mouse monoclonal anti– human E-cadherin antibody (clone 36B5, Novocastra), respectively. Semiquantitative analysis of protein expression was performed in an independent and blinded fashion by 2 experienced neuropathologists (S.E. and H.K.) and was classified according to a 3-scaled staining score as follows:29 immunostaining < 10%, 10%–50%, and > 50% of the respective total chordoma tissue under investigation refer to a staining score of 1 (weak), 2 (moderate), and 3 (strong), respectively. In case of discordant findings, a conference for reevaluation was initiated to achieve a consensus concerning the expression score. Statistical Analysis
The reference point of the study was the date of first surgery. Last follow-up was performed in June 2012. Primary and secondary end points were tumor progression and death. Progression-free survival and OS were analyzed using the Kaplan-Meier method. Prognostic factors were obtained from the proportional hazards model. Parameters tested in univariate models are presented in Table 1. Only those being significant were subsequently included in multivariate proportional hazards models. For comparison of continuously scaled patient- and tumor-related parameters, the Wilcoxon test was used. Categorical variables were analyzed using the chi-square test or the Fisher’s exact test, if necessary. Statistical significance was assigned to p < TABLE 1: Results of univariate analysis for PFS and OS p Value Parameter
PFS
OS
age sex E-cadherin initial KPS score tumor size dura infiltration extent of resection radiotherapy type of radiotherapy radiation dose petrous bone brainstem compression
0.41 0.04 0.92 0.86 0.27 0.89 0.72 0.74 0.49 0.40 0.39 0.34
0.49 0.03 0.23 0.08 0.35 0.18 0.04 0.09 0.94 0.34 0.86 0.80
J Neurosurg / Volume 120 / June 2014
Influence of sex on skull base chordomas 0.05. All calculations were performed using the statistical analysis software SAS version 9.2.
Patient Characteristics
Results
The study cohort comprised 47 patients (26 men and 21 women). Basic characteristics of the study population are presented in Table 2. Men and women did not differ in any of the addressed patient- and tumor-related parameters (Table 2). Ten patients (21%) had undergone prior resection at another institution, and 37 patients (78.7%) suffered from de novo tumors. The groups did not differ in any of the patient- or tumor-related parameters. Magnetic resonance imaging revealed brainstem compression in 20 patients (42.6%), the condyles were involved in 8 patients (17%), petrosal bone was affected in 17 patients (36.2%), and dural infiltration was seen in 8 patients (17%) (a typical example of a clival chordoma is given in Fig. 1).
Pattern of Care and Clinical Course
The preferred operative approaches are summarized in Table 3. Complete resection and partial resections were achieved in 7 patients (14.9%) and 38 patients (80.9%), respectively. Two patients (4.3%) underwent extended biopsy only. All patients with complete resection were men (7 of 26 vs 0 of 21 women, p = 0.036). Surgical morbidity was documented for 8 patients (17.0%) and included 6 patients with postoperative worsening of preexisting cranial
Fig. 1. Left: Sagittal T2-weighted MR image depicting a chordoma in a 20-year-old woman, which caused displacement of the brainstem. Right: Axial T1-weighted MR image obtained in the same patient after Gd administration.
nerve dysfunction as well as 2 patients with new deficits. Perioperative complications were not associated with any of the patient-, tumor-, or surgery-related covariates. Thirty patients (63.8%), mainly those with residual tumors after initial surgery (28 of 40 with residual tumors vs 2 of 7 without residual tumors, p = 0.035), received adjuvant treatment; PBRT was applied in 22 patients (mean maximal dose 59.3 Gy, range 40–66 Gy), conventionally fractionated radiotherapy in 3 patients (mean maximal dose 65 Gy, range 60–70 Gy), and radiosurgery in 5 patients (mean maximal dose 24 Gy, range 17–36 Gy). The applied adjuvant treatment regimens were similar for men
TABLE 2: Clinical data in 47 patients stratified for sex* Value Characteristic
Total (n = 47)
Male (n = 26)
Female (n = 21)
p Value (M/F)
median age (yrs) median KPS score median duration of symptoms (mos) median tumor vol (cm3) de novo tumor E-cadherin expression† 50% N-cadherin expression† 50% extent of resection total resection partial resection extended biopsy radiotherapy recurrence death
49.2 80 4.3 28.6 37 (78.7)
48.9 80 4.2 28.2 20 (76.9)
48.0 80 4.5 29.4 17 (81.0)
NS NS NS NS NS NS
26 (56.5) 8 (17.4) 12 (26.1)
17 (65.4) 5 (19.2) 4 (15.4)
9 (45.0) 3 (15.0) 8 (40.0)
1 (2.2) 4 (8.7) 41 (89.1)
1 (3.8) 2 (7.7) 23 (88.5)
0 (0) 2 (10.0) 18 (90.0)
7 (14.9) 38 (80.9) 2 (4.3) 30 (63.8) 26 (55.3) 8 (17.0)
7 (27.0) 18 (69.2) 1 (3.8) 14 (53.8) 14 (53.8) 7 (26.9)
0 (0) 20 (95.2) 1 (4.8) 16 (76.2) 12 (57.1) 1 (4.8)
NS
0.036
NS NS 50%) expression (Cases 1–3). Immunohistochemical assessment of E-cadherin (E-Cad) showed a more heterogeneous staining, with some cases displaying no or minimal (< 10%, Case 1), moderate (10%–50%, Case 2), or extensive (> 50%, Case 3) expression. Arrowheads indicate small groups of E-cadherin positive tumor cells in Case 2 scored as “moderate.” Bars in lower magnification images (columns 1, 3, and 5) = 500 mm; bars in higher magnification images (columns 2, 4, and 6) = 50 mm.
Fig. 4. Kaplan-Meier plot showing PFS after stratification for E-cadherin. Plots indicate censored patients.
1318
J Neurosurg / Volume 120 / June 2014
Influence of sex on skull base chordomas diation therapy should be stringently applied in patients with skull base chordomas independent of the extent of resection. In accordance with the literature, PBRT was the preferred modality in this series (22 of 30 patients) as it has been suggested to provide longer survival rates at lower risk for the patients than conventional megavoltage radiotherapy. However, the current literature does not provide enough evidence yet to support superiority of protons over photons in skull base chordomas. The role of Gamma Knife or linear accelerator (LINAC) radiosurgery is also poorly defined.9,11,22 We are aware that extended time intervals and collections from multiple centers are necessary to include a high number of patients with skull base chordomas for evaluation of prognosis and outcome.11 Given the fact that treatment protocols are continuously modified or improved, the exact elucidation of treatment effects is notoriously difficult.
Conclusions
Sex appears to be an independent prognostic factor for PFS and OS in skull base chordomas. Complete resection might be associated with favorable OS. N-cadherin or E-cadherin expression did not gain prognostic relevance. The male subpopulation might require more aggressive initial treatment even in cases of complete tumor resection. Further prospective studies are needed to elucidate the potential mechanism of sex disparity with regard to tumor progression and prognosis. Acknowledgment We thank the Department of Medical Informatics, Biometry, and Epidemiology, LMU Munich, Germany, for support of statistical analysis. Disclosure The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper. Author contributions to the study and manuscript preparation include the following. Conception and design: Rachinger, Thon, Tonn. Acquisition of data: Rachinger, Eigenbrod, Dützmann, Simon, Feigl, Kremenevskaja, Kretzschmar. Analysis and interpretation of data: Rachinger, Eigenbrod, Kretzschmar, Zausinger, Kreth, Thon, Tonn. Drafting the article: Rachinger, Zausinger, Thon, Tonn, Kreth. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Rachinger. Statistical analysis: Kreth. References 1. al-Mefty O, Borba LA: Skull base chordomas: a management challenge. J Neurosurg 86:182–189, 1997 2. Almefty K, Pravdenkova S, Colli BO, Al-Mefty O, Gokden M: Chordoma and chondrosarcoma: similar, but quite different, skull base tumors. Cancer 110:2457–2467, 2007 3. Amichetti M, Cianchetti M, Amelio D, Enrici RM, Minniti G: Proton therapy in chordoma of the base of the skull: a systematic review. Neurosurg Rev 32:403–416, 2009
J Neurosurg / Volume 120 / June 2014
4. Ammirati M, Bernardo A: Management of skull base chordoma. Crit Rev Neurosurg 9:63–69, 1999 5. Catton C, O’Sullivan B, Bell R, Laperriere N, Cummings B, Fornasier V, et al: Chordoma: long-term follow-up after radical photon irradiation. Radiother Oncol 41:67–72, 1996 6. Chambers PW, Schwinn CP: Chordoma. A clinicopathologic study of metastasis. Am J Clin Pathol 72:765–776, 1979 7. Chugh R, Tawbi H, Lucas DR, Biermann JS, Schuetze SM, Baker LH: Chordoma: the nonsarcoma primary bone tumor. Oncologist 12:1344–1350, 2007 8. Colli B, Al-Mefty O: Chordomas of the craniocervical junction: follow-up review and prognostic factors. J Neurosurg 95:933–943, 2001 9. Dassoulas K, Schlesinger D, Yen CP, Sheehan J: The role of Gamma Knife surgery in the treatment of skull base chordomas. J Neurooncol 94:243–248, 2009 10. Debus J, Schulz-Ertner D, Schad L, Essig M, Rhein B, Thillmann CO, et al: Stereotactic fractionated radiotherapy for chordomas and chondrosarcomas of the skull base. Int J Radiat Oncol Biol Phys 47:591–596, 2000 11. Di Maio S, Temkin N, Ramanathan D, Sekhar LN: Current comprehensive management of cranial base chordomas: 10year meta-analysis of observational studies. Clinical article. J Neurosurg 115:1094–1105, 2011 12. Eid AS, Chang UK, Lee SY, Jeon DG: The treatment outcome depending on the extent of resection in skull base and spinal chordomas. Acta Neurochir (Wien) 153:509–516, 2011 13. Fajkovic H, Halpern JA, Cha EK, Bahadori A, Chromecki TF, Karakiewicz PI, et al: Impact of gender on bladder cancer incidence, staging, and prognosis. World J Urol 29:457–463, 2011 14. Feigl GC, Bundschuh O, Gharabaghi A, Safavi-Abassi S, El Shawarby A, Samii M, et al: Evaluation of a new concept for the management of skull base chordomas and chondrosarcomas. J Neurosurg 102 Suppl:165–170, 2005 15. Ferraresi V, Nuzzo C, Zoccali C, Marandino F, Vidiri A, Salducca N, et al: Chordoma: clinical characteristics, management and prognosis of a case series of 25 patients. BMC Cancer 10:22, 2010 16. Fletcher CDM, Unni KK, Mertens F: World Health Organization Classification of Tumours. Pathology and Genetics: Tumours of Soft Tissue and Bone. Lyon: IARC Press, 2002 17. Gasinska A, Richter P, Darasz Z, Niemiec J, Bucki K, Malecki K, et al: Gender-related differences in repopulation and early tumor response to preoperative radiotherapy in rectal cancer patients. J Gastrointest Surg 15:1568–1576, 2011 18. Ito E, Saito K, Okada T, Nagatani T, Nagasaka T: Long-term control of clival chordoma with initial aggressive surgical resection and gamma knife radiosurgery for recurrence. Acta Neurochir (Wien) 152:57–67, 2010 19. Jawad MU, Scully SP: Surgery significantly improves survival in patients with chordoma. Spine (Phila Pa 1976) 35:117–123, 2010 20. McMaster ML, Goldstein AM, Bromley CM, Ishibe N, Parry DM: Chordoma: incidence and survival patterns in the United States, 1973-1995. Cancer Causes Control 12:1–11, 2001 21. Molife R, Lorigan P, MacNeil S: Gender and survival in malignant tumours. Cancer Treat Rev 27:201–209, 2001 22. Muthukumar N, Kondziolka D, Lunsford LD, Flickinger JC: Stereotactic radiosurgery for chordoma and chondrosarcoma: further experiences. Int J Radiat Oncol Biol Phys 41:387– 392, 1998 23. Nakamura H, Ando K, Shinmyo T, Morita K, Mochizuki A, Kurimoto N, et al: Female gender is an independent prognostic factor in non-small-cell lung cancer: a meta-analysis. Ann Thorac Cardiovasc Surg 17:469–480, 2011 24. Pallini R, Maira G, Pierconti F, Falchetti ML, Alvino E, Cimino-Reale G, et al: Chordoma of the skull base: predictors of tumor recurrence. J Neurosurg 98:812–822, 2003
1319
W. Rachinger et al. 25. Pamir MN, Ozduman K: Tumor-biology and current treatment of skull-base chordomas. Adv Tech Stand Neurosurg 33:35–129, 2008 26. Samii A, Gerganov VM, Herold C, Hayashi N, Naka T, Mirzayan MJ, et al: Chordomas of the skull base: surgical management and outcome. J Neurosurg 107:319–324, 2007 27. Stüer C, Schramm J, Schaller C: Skull base chordomas: management and results. Neurol Med Chir (Tokyo) 46:118–125, 2006 28. Takahashi S, Kawase T, Yoshida K, Hasegawa A, Mizoe JE: Skull base chordomas: efficacy of surgery followed by carbon ion radiotherapy. Acta Neurochir (Wien) 151:759–769, 2009 29. Triana A, Sen C, Wolfe D, Hazan R: Cadherins and catenins in clival chordomas: correlation of expression with tumor aggressiveness. Am J Surg Pathol 29:1422–1434, 2005 30. Tzortzidis F, Elahi F, Wright D, Natarajan SK, Sekhar LN: Patient outcome at long-term follow-up after aggressive microsurgical resection of cranial base chordomas. Neurosurgery 59:230–237, 2006
1320
31. Watkins L, Khudados ES, Kaleoglu M, Revesz T, Sacares P, Crockard HA: Skull base chordomas: a review of 38 patients, 1958-88. Br J Neurosurg 7:241–248, 1993 32. Yoneoka Y, Tsumanuma I, Fukuda M, Tamura T, Morii K, Tanaka R, et al: Cranial base chordoma—long term outcome and review of the literature. Acta Neurochir (Wien) 150:773– 778, 2008
Manuscript submitted May 31, 2013. Accepted November 21, 2013. Please include this information when citing this paper: published online January 3, 2014; DOI: 10.3171/2013.11.JNS131137. Address correspondence to: Walter Rachinger, M.D., Department of Neurosurgery, Klinikum Großhadern, Marchioninistr. 15, Munich 81377, Germany. email: [email protected].
J Neurosurg / Volume 120 / June 2014
