Midterm Prognosis and Surgical Implication of Clival Chordoma after an Extended Transsphenoidal Tumor Removal and Gamma Knife Radiosurgery


 Background: Treatment for chordoma by surgery alone is often ineffective, so surgery and irradiation is often performed with a reported 5-year survival rate of 60-75%. The clinical course varies; however, disease rarity has prevented large number clinical investigations. Methods: Nineteen patients suffering from clival chordomas were retrospectively investigated. They were initially treated with maximal tumor removals by extended transsphenoidal approach. When total removal was achieved prophylactic irradiation was not performed. If tumor remnants or recurrence was confirmed, gamma knife (GK) was performed. Follow-up periods ranged from 9 to 224 months (mean 85.4 months). Results: Total removal was achieved in 10 patients; however, 4 patients suffered recurrence and required GK. Overall progression free intervals were 9 to 151 months (mean 59.9 mzonths). GK was applied for 11 patients with a 50 % isodose of 13 to 18 Gy (mean 15.4 Gy). Eight patients remained progression free, but 3 patients suffered repeated local recurrence and died from tumor related complications. Overall survival was 9 to 224 months (mean 90.9 months). Eighteen patients survived more than 5 years with the exception of one male patient, who died of lung cancer 36 months after the initial treatment (5-year survival rate 94.7 %). The results indicated that sex (males), those given more than 15 Gy of a 50% isodose by GK, and prophylactic brain scanning were significant favorable prognostic factors. Conclusions: The favorable outcomes in this investigation may indicate value for early detection and early treatment. The role of surgery may be adequate conditioning for enough dose of GK.


Background
Chordomas arise from the prenatal remnants of the notochord and are frequently located at the midline of the skull base, cervical vertebrae and sacrum [3]. The frequency of occurrence is only 0.5% among all the intracranial tumors, and 1-4% among skeletal tumors [1,16,[20][21]. This disease rarity has prevented large number clinical investigations and the results lead to a great discrepancy between the indolent pathological features and the malignant clinical course [5,[7][8][9][10][12][13][14][15], with a reported 5-year survival is 60-75%. Although the tumor doubling time is rather long for chordomas, repeated local recurrence and dissemination are not unusual due to invasive growth along bone marrow [2,5]. Tumor control by surgery alone is thought to be di cult, and therefore, the majority of the patients are treated by combined therapy with irradiation [6-9, 14, 17]. Because this tumor usually resists against conventional radiation therapy and evidence for effective chemotherapy has not yet been established, ion beam therapy including proton or heavy ion beam therapy has been expected to provide good tumor control [6,8,17]. However once again disease rarity has prevented large number clinical experiences and insurance is barely but partially adapted in Japan for ion beam therapy.
We present a single-center experience of maximal tumor removal of clival chordomas by the extended transsphenoidal approach following gamma knife radiosurgery for visualized remnants or tumor recurrence. The role and the implications of surgery are also discussed.

Methods
In this report 14 males and 5 females aged from 41 to 85 years (mean age 60.4 years) suffering from clival chordomas were included with histological con rmation at the Department of Neurosurgery, Kohnan Hospital between March 2006 and July 2019. The most common initial symptom was diplopia in 6 patients owing to cranial nerve palsy, but 2 patients owing to optic nerve dysfunction and 1 patient owing to spontaneous cerebrospinal uid leakage (clival erosion with no visible tumor). Overall 8 patients were asymptomatic and the tumors were detected by prophylactic brain scans at each checkup. Initial treatments were applied for 17 patients; however, the remaining 2 patients had suffered from re-growth after pleural tumor removal and radiation therapy ( Table 1). All of the tumors extended along the clivus; 8 patients experienced extra-arachnoidal localization, and the remaining 11 experienced tumor extension into the subarachnoid spaces. The patients were initially treated with maximal tumor removal by the extended transsphenoidal approach with simultaneous removal of the surrounding bone cortex and bone marrow as far as possible within the technical range of skull base repair. When gross total removal was achieved prophylactic irradiation was not performed, and patients were simply observed at 6-months intervals. If tumor remnants were visualized, the gamma knife was stood by until the skull base regeneration was accomplished (3 months after the operation) and applied. When tumor recurrence was con rmed, gamma knife surgery was subsequently applied to the visualized tumor bulk; this occurred in all patients except for one female patient (case 16), who was treated with postoperative fractionated irradiation because of her older age (85 years old). All the patients were followed up though out their clinical course with 9 to 224 months of follow up (mean 85.4 months). The surgical specimens were immediately xed for histological and immunohistochemical examinations with 10% buffered formalin, then embedded in para n, and serial sections were cut to 3-µm thickness.
Hematoxylin and eosin, and periodic acid-Schiff staining were performed in all cases. The avidin-biotinperoxidase complex method was applied for immunohistochemical staining and cell proliferation was assessed for Ki-67 (MIB-1, Dako, 1:100). Immunohistochemical positive cells were counted within at least 1000 background cells in three high power visual elds including the hot spot and other elds, and then indicated as a percentage. Positive controls used normal lymph nodes for Ki-67. Statistical comparisons were made using Statmate 5 software (ATMS Co., Ltd., Tokyo, Japan), and P values of less than 0.05 were regarded as signi cant.
The patients were informed preoperatively of the salvage treatment protocol and the study design was approved by the Ethical Committee of Kohnan Hospital 2020.

Results
Gross total removal was achieved in 10 patients and 9 patients had tumor remnants with a removal rate that ranged from 73 to 100 (mean 92.8%). Four of 10 patients with gross total removal developed tumor recurrence and required gamma knife treatment thereafter. The remaining 6 patients were observed only and all of them were asymptomatic preoperatively. Overall progression free intervals were 9 to 151 months (mean 59.9 months), and overall survival was 9 to 224 months (mean 90.9 months), with the exception of one male patient, who died of lung cancer 36 months after the initial treatment (case 12). The other 18 patients survived more than 5 years (5-year survival rate 94.7%).
Preoperative tumor volume ranged from 0.17 to 68.4 ml (mean 16.2 ml) and the maximum tumor diameter ranged from 8 to 63 mm (mean 32.2 mm). Postoperative residual tumor volume ranged from 0 to 6.17 ml (mean 1.61 ml). Gamma knife surgery was applied for 11 patients with a 50% isodose of 13 to 18 Gy (mean 15.4 Gy). Eight of 11 patients remained progression free, but 3 patients suffered repeated local recurrence and died of tumor related complications. Ki-67 labeling index ranged from less than 1 to 25.1% (mean 8.91%). The clinical data are shown in Table 2. The results showed that male patients (p < 0.01), those who received more than 15 Gy of a 50% isodose at the time of gamma knife radiosurgery (p < 0.05), and those who received regular brain scans (p < 0.05) had a signi cantly favorable prognosis. Gross total removal and tumor volume less than 1 ml before gamma knife surgery did not appear to have a signi cant effect on prognosis. Age older than 60, a tumor volume more than 10 ml or a tumor maximum diameter more than 30 mm was not adverse prognostic factors. A comparison of patients with a Ki-67 labeling index between more or less than 10% did not show statistical signi cance in the present investigation (Table 3).

Discussion
According to one meta-analysis for chordomas, the 5-year survival of patients was reported to be 60 to 75% and thus far, treatment results have shown little improvement even with modern surgical procedures [12]. Although the 5-year survival in this investigation was 95% and therefore a little higher than previously reported with no postoperative acquired neurological de cits, total removal had not become prognostic factor. So adjuvant irradiation to this tumor is con rmed to be essential once again. On the contrary preoperative tumor volume, maximum tumor diameter and residual tumor volume before irradiation were not identi ed as signi cant prognostic factors, but delivering a dose higher than 15 Gy of a 50% isodose had a signi cant effect as previous report had suggested [11]. Although objective surgical goals are varied between the reports and the ideal relationship between surgery and postoperative gamma knife irradiation is unclear [7,9,13,23], the results in this investigation may suggest an importance of reducing maximal tumor volume, provide an adequate condition for su cient irradiation, of which maximal reduction of tumor volume and to secure a distance from the optic pathway. Along this principal we tried to remove the tumor bulk together with the surrounding bone cortex and bone marrow as far as possible within the technical range of skull base repair. This expansion of removal could contribute dose escalation of irradiation and/or localization of the radiation eld.
Performing regular prophylactic brain scans was also identi ed as another prognostic factor, which was applied as prophylactic medicine mainly targeted to un-ruptured cerebral aneurysm or asymptomatic arterial stenosis. Because e cacy for larger population and the necessary social expense are greatly varied between the nations this system has not become popular in many countries except for Japan.
However, the favorable outcomes in this investigation may indicate some value for early detection and early treatment of this malignant disease. If the tumor is detected, a wait and see approach should not be adopted, and instead, early surgery should be implemented even for asymptomatic lesions. The extended transsphenoidal approach is thought to be less invasive and therefore a better approach for treatment.
Pathophysiological investigations revealed a possible in uence of Ki-67 labeling index, overexpression of p53 and receptor tyrosine kinase expression [4,19,22]. Another report presumed the prognostic difference between chondroid chordoma and chordoma [18]. Although no signi cant difference was found between these parameters in this investigation (data not shown), study volume and/or the difference in treatment protocols may inadvertently cover up that signi cance.
The limitation of this investigation was the low patient number, which is consistent with previous reports. These reports have been compared the prognosis by conducting meta-analyses of different treatment protocols and different disease backgrounds. To establish classi ed treatment guideline, larger multiinstitutional investigation is strongly encouraged.

Ethics approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Consent to participates
The surgical policy was explained preoperatively to the patients and written informed consents were obtained.

Consent for publication
This is a retrospective investigation, and overall study design was approved by the Ethical Committee of Kohnan Hospital 2020.