Clinical features and surgical outcomes of patients with skull base chordoma: a retrospective analysis of 238 patients.

Skull base chordoma is relatively rare, and a limited number of reports have been published regarding its clinical features. Moreover, the factors associated with extent of resection, as well as the value of marginal resection for long-term survival, are still in question for this disease. The objective of this study was to investigate these factors by evaluating their clinical features and surgical outcomes.  A retrospective analysis of 238 patients with skull base chordomas, who met the inclusion criteria, was performed. This study summarized the clinical features, selection of approaches, degree of resection, and postoperative complications by statistical description analyses; proposed modified classifications of tumor location and bone invasion; studied the contributions of the clinical and radiological factors to the extent of resection by Pearson χ2, ANOVA, rank test, and binary logistic regression analysis; and estimated the differences in overall survival and progression-free survival rates with respect to therapeutic history, classification of tumor location, extent of bone invasion, and extent of tumor resection by the Kaplan-Meier method. A p value < 0.05 was considered statistically significant.  The study included 140 male and 98 female patients with a mean age of 38.1 years. Headache and neck pain (33.2%) and diplopia (29%) were the most common initial symptoms. Sphenoclival type accounted for the largest proportion of tumor location (59.2%); endophytic chordoma was the more common type of bone invasion (81.5%). Lateral open approaches were performed in two-thirds of the study population (78.6%). The rate of marginal resection was 66%, composed of gross-total resection (11.8%) and near-total resection (54.2%). Meningitis (8%) and CSF leakage (3.8%) were the most frequent complications. The mean follow-up period was 43.7 months. The overall survival and progression-free survival rates at 5 years were 76% and 45%, respectively. Recurrent tumor and larger tumor volume (≥ 40 cm3) were identified as risk factors of marginal resection. Patients who presented with recurrent tumor and underwent intralesional resection had a worse long-term outcome.  The classifications of both tumor location and bone invasion demonstrated clinical value. Marginal resection was more likely to be achieved for primary lesions with smaller volumes (< 40 cm3). The rate of CSF leakage declined due to improved dura mater repair with free fat grafts. Marginal resection, or gross-total resection when possible, should be performed in patients with primary chordomas to achieve better long-term survival.

Related papers:

title: The endoscope-assisted ventral approach compared with open microscope-assisted surgery for clival chordomas.
abstract: The current management paradigm for clival chordomas includes cytoreductive surgery with adjuvant radiotherapy. Surgical approaches have traditionally utilized the microscope to remove these lesions through approaches that require extensive bone drilling, brain retraction, and mobilization of normal anatomy to create a suitably large corridor. The endoscopic ventral approaches provide a direct route to the tumor using natural orifices. Little data exist comparing these 2 surgical strategies. We conducted a systematic review of case series and case reports in hope of furthering our understanding of the role of endoscopy in the management of these difficult cranial base lesions.



We performed a MEDLINE (1950 to 2010) search to identify relevant studies. Statistical analyses of categorical variables such as extent of resection, morbidity, and visual outcome were carried out using chi-square and Fisher exact tests.



Thirty-seven studies, involving 766 patients, were included. Compared with the open surgery cohort, the endoscopic cohort had a significantly higher percentage of gross total resection (61.0% vs. 48.1%; P = 0.010), fewer cranial nerve deficits (1.3% vs. 24.2%, P < 0.001), fewer incidences of meningitis (0.9% vs. 5.9%, P = 0.029), less mortality (4.7% vs. 21.6%, P < 0.001), and fewer local recurrences (16.9% vs. 40.0%, P = 0.0001). There was no significant difference in the incidence of postoperative cerebrospinal fluid leak (P = 0.084). Follow-up was longer in the open compared with the endoscopic cohort (59.7 vs. 18.5 months, P < 0.001).



Our systematic analysis supports the endoscopic ventral approaches as a safe and effective alternative for the treatment of certain clival chordomas. Although the overall literature supports this technique in carefully selected patients, longer follow-up is needed to more definitively address therapeutic efficacy. Careful patient selection and meticulous multilayer closure are critical to obtaining maximal resection and acceptably low cerebrospinal fluid leak rates.

title: Skull base chordoma and chondrosarcoma: influence of clinical and demographic factors on prognosis: a SEER analysis.
abstract: Chordomas and chondrosarcomas are rare skull base tumors, with similar radiographic and clinical presentations. We investigated factors influencing long-term survival in these 2 tumors using the Surveillance Epidemiology and End Results (SEER) database.



Patients with chordoma (n = 416) and chondrosarcoma (n = 269) within the skull base from 1983 to 2009 were identified within the SEER database. Kaplan-Meier curves and Cox proportional hazards models were used to test associations with survival. t tests and χ(2) tests were used to compare groups.



Chordoma and chondrosarcoma patients were similar demographically. Survival at 5 years was 65% for chordomas and 81.8% (P < 0.0001) for chondrosarcomas and at 10 years was 32.3% and 49.5% (P = 0.004). Multivariate analysis demonstrated chordomas had a worse prognosis even when we controlled for age and tumor size (hazard ratio 3.0, 95% confidence interval 1.9-4.7, P < 0.0001). For chordomas, multivariate analysis demonstrated increasing age and tumor size were significantly associated with reduced survival. For chondrosarcomas, multivariate analysis demonstrated older age, earlier decade of diagnosis, and mesenchymal subtype were significantly associated with reduced survival. Postoperative radiation was given to 42% and 41% of patients with chordomas and chondrosarcomas, respectively. The addition of radiation did not improve survival.



Consistent with previous case series, skull base chordomas have significantly worse prognosis than chondrosarcomas. Patients in the SEER database had worse survival overall compared with existing case series for both chordomas and chondrosarcomas, suggesting selection bias in the existing literature.

title: Current Comprehensive Management of Cranial Base Chordomas: 10-year Meta-Analysis of Observational Studies
abstract: Object The role of surgery and adjuvant radiation therapy for cranial base chordomas is not well established. This meta-analysis measures the relationship of complete resection and type of adjuvant radiation therapy to 5-year progression-free survival (PFS) and overall survival (OS) of cranial base chordomas.  A systematic MEDLINE search (1999–present) yielded 23 observational studies and 807 patients who fit inclusion criteria. The following analyses were performed: 1) Kaplan-Meier 5-year PFS and OS compared based on the extent of resection and type of adjuvant radiation therapy using the log-rank method; 2) a random-effects model comparing 5-year PFS with complete or incomplete resection; and 3) paired z-test comparisons of weighted average 5-year OS and PFS grouped by type of adjuvant radiation therapy.  The weighted average follow-up was 53.6 months. The weighted average 5-year PFS and OS were 50.8% and 78.4%, respectively. Complete resection conferred a higher 5-year PFS than incomplete...

title: Outcomes and patterns of care in adult skull base chordomas from the Surveillance, Epidemiology, and End Results (SEER) database
abstract: This study aims to demonstrate survival rates and treatment patterns among patients with chordomas of the skull base using a large population database. Patients with cranial chordomas between 1973 and 2009 were identified from the USA Surveillance, Epidemiology, and End Results (SEER) public use database. Kaplan-Meier analysis was used to examine the effect of surgery and radiation on overall survival. We identified 394 patients with histologically-confirmed cranial chordomas. Median survival was 151 months. Most patients (89.09%) underwent surgery. Less than half (44.92%) received radiation after diagnosis. Patients who underwent surgical resection survived significantly longer than those who did not undergo resection, regardless of other treatments (151 versus 81 months, p<0.001). Ten year survival was lower among patients receiving radiation (44.8% versus 61.4%, p=0.66). Surgery predicted better overall survival by univariate analysis (hazard ratio [HR] 0.603, p=0.0293); younger age at diagnosis (HR 1.028, p<0.001), and later year of diagnosis (HR 0.971, p=0.0027) were prognostic of improved survival in a multivariate model. In subgroup analysis of patients with documented tumor size, smaller tumor size (HR 1.021, p=0.0067), younger age (HR 1.031, p=0.001), and treatment within a higher volume registry (HR 0.490, p=0.0129) predicted improved survival. Surgical intervention offers survival benefit for cranial chordomas. Findings of decreased survival in patients receiving radiation may be associated with selection. Studies examining surgical extent of resection data and radiation details are needed to determine the impact of radiotherapy.

title: Prognostic factors for long-term outcome of patients with surgical resection of skull base chordomas—106 cases review in one institution
abstract: Skull base chordoma are still challenging. Between May 1993 and June 2005, 106 consecutive patients with skull base chordoma underwent surgical removal at Skull Base Division of Neurosurgery, Beijing Tiantan Hospital, China. Retrospective analysis included medical charts and images. The age of the patients ranged from 7 to 65 years old, with an average age of 35.6 years. Sixty patients were male; the other 46 were female (1.3:1). Follow up data were available in 79 cases ranging from 10 to 158 months (average 63.9 months) after operation. The prognostic factors for recurrence and survival were analyzed with Kaplan‐Meier, Cox regression and t‐test. Overall, 1, 3, 5 and 10 years survival rates were 87.2%, 79.4%, 67.6%and 59.5% respectively. One, 3, 5 and 10 year recurrent rates were 19.1%, 34.7%, 52.9% and 88.3%, respectively. The long term outcome of the skull base chordomas is poor. The previous radiotherapy or surgery, dedifferentiated pathology, and less tumor resection are risk factors for longterm survival and recurrence (p < 0.05). Although there is no statistic significant role of tumor adherent to vital structure for outcome (p = 0.051), it can not exclude its importance for favorable outcome. Gender, age, tumor size and staging are not independent risk factors for outcome. Surgical technique leading to radical tumor resection with less morbidity is advocatory and beneficial for patients with skull base chordoma with long term outcome, if the tumor could be exposed and resected completely, the recurrence rate was very low for most benign chordomas.

title: INTRADURAL CLIVAL CHORDOMA AND ECCHORDOSIS PHYSALIPHORA: A CHALLENGING DIFFERENTIAL DIAGNOSIS CASE REPORT
abstract: OBJECTIVEPurely intradural clival chordomas are rare neoplasms, and only a few cases have been reported. The reported cases present features similar to ecchordosis physaliphora, which is a notochordal remnant. We describe these 2 entities and their differential diagnoses, clinical courses, and management. This is the first reported case to be treated using a neuroendoscopic technique. CLINICAL PRESENTATIONA 60-year-old man presenting with memory loss underwent magnetic resonance imaging, which revealed an intradural retroclival mass without bone involvement. INTERVENTIONThe patient underwent an endoscopic transsphenoidal-transclival procedure with subtotal removal of the tumor. Histological findings confirmed the diagnosis of a chordoma. CONCLUSIONEven if some parameters exist for a differential diagnosis, ecchordosis physaliphora and intradural chordoma may represent different aspects of the spectrum of the same pathology. Intradural clival chordomas have a better prognosis with respect to classic chordomas. Therefore, in subtotal removal such as that performed in our case, postoperative radiation therapy should be performed only if a regrowth of the remnant is seen during neuroradiological follow-up.

title: Experimental Study on Differences in Clivus Chordoma Bone Invasion: An iTRAQ-Based Quantitative Proteomic Analysis
abstract: Although a bone tumor, significant differences in the extent of bone invasion exist in skull base chordoma, which directly affect the extent of surgical resection, and have an impact on its prognosis. However, the underlying mechanism of the phenomenon is not clearly understood. Therefore, we used an iTRAQ-based quantitative proteomics strategy to identify potential molecular signatures, and to find predictive markers of discrepancy in bone invasion of clivus chordoma. According to bone invasive classification criteria, 35 specimens of clivus chordoma were calssified to be either endophytic type (Type I) or exophytic type (Type II). An initial screening of six specimens of endophytic type and six of exophytic was performed, and 250 differentially expressed proteins were identified. Through the GO and IPA analysis, we found evidence that the expression of inflammatory activity-associated proteins up-regulated in endophytic type, whereas the expression of cell motility-associated proteins up-regulated in exophytic ones. Moreover, TGFβ1 and mTOR signal pathway seemed to be related with bone invasion. Thus, TGFβ1, PI3K, Akt, mTOR, and PTEN were validated in the following 23 samples by immune histochemistry and Western blot. The expression levels of TGFβ1 and PTEN were significantly lower in the endophytic type than in the exophytic ones. It was found that TGFβ1 may play an important role in its bone invasion. The mechanisms may be related with conducting an increased inflammatory cell response and a decline in cytoskeletal protein expression. PTEN is confirmed to be associated with the degree of bone invasion. The PI3K/AKT/mTOR signaling pathway might be associated with the bone invasion, but still needs a larger sample size to be verified These results, for the first time, not only demonstrate the biological changes that occur in different growth patterns from the perspective of proteomics, but also provide novel markers that may help to reveal the mechanisms behind clivus chordomas.

title: Intraosseous Benign Notochord Cell Tumors (BNCT): Further Evidence Supporting a Relationship to Chordoma
abstract: BackgroundPrevious studies have documented the existence of intraosseous benign notochordal cell tumors (BNCTs) within the axial skeleton. Evidence suggests that they may be associated with the development of chordomas. To further investigate the relationship between BNCT and classic chordoma, we reviewed a large series of resected sacral/coccygeal chordomas in an attempt to identify the presence of coexisting BNCTs. DesignEighty-two sacrectomy/coccygectomy specimens performed for chordoma were identified. Available hematoxylin and eosin slides were reviewed to identify BNCTs and assess their relationship with the coexisting chordoma. BNCTs were defined, in accordance with prior descriptions, as cohesive aggregates of large cells that appeared adipocytelike because of their vacuolated cytoplasm. The cells exhibited only minimal nuclear atypia and lacked lobulation and myxoid stroma. ResultsWe identified 6 BNCTs, each was adjacent to but separate from the sacral chordoma. There were 5 females and 1 male, and the mean age was 58 years. Five lesions arose in the sacrum. One lesion arose in the coccyx, and involved 2 contiguous vertebral levels. The BNCTs ranged in size from 1 to 20 mm with a mean size of 6.1 mm. The lesions were exclusively composed of adipocytelike nuclei without significant nuclear atypia or myxoid stroma. Three lesions contained sclerotic bony trabeculae and intralesional hematopoietic elements were identified in 1 case. In all cases the chordoma was of the conventional type and were morphologically different from the BNCT. ConclusionsBNCTs were identified in 7.3% of sacral/coccygeal resections performed for primary chordoma. We speculate that this finding provides further evidence that BNCT is the precursor lesion for chordoma. Additional investigations are needed to further understand this relationship.

title: Clinical and pathological features of intradural retroclival chordoma.
abstract: To investigate the clinical and pathologic characteristics of primary intradural retroclival chordoma and improve the understanding of this rare disease.



A retrospective study was conducted on six cases patients withof an intradural chordoma in the retroclival region who underwent surgery and were confirmed by pathology and imaging. Expression of brachyury, galectin-3, and Ki-67 in paraffin-embedded sections of the specimens was detected by streptavidin-peroxidase immunohistochemistry.



Lesions were located in the subdural prepontine cistern. Computed tomography scan showed that the bone of the skull base was not destroyed, and findings on magnetic resonance imaging varied, resulting in a misdiagnosis of 50% of the cases in the preoperative imaging. All six cases were classified by their pathology into the classical subtype. They presented a strong positive staining for brachyury and galectin-3, and the Ki-67 labeling index was between 2.5% and 8.2%. Three cases presented no signs of recurrence or regrowth, whereas in the other three patients recurrence or regrowth occurred at 7 ∼ 14 months after initial surgery. Two patients died of this disease.



Our study suggests that a positive staining for brachyury, galectin-3, and Ki-67 would be helpful for differential diagnosis, discriminating intradural retroclival chordoma from ecchordosis physaliphora and chordoid meningioma. Our study also shows that within intradural retroclival chordoma, there are significant prognostic differences. Tumors with an abundant blood supply, flake-like cellular arrangement, and a Ki-67 labeling index greater than 5% belong to a rapid-growth type and are prone to short-term recurrence and poorer prognosis.

title: Surgical resection of upper-middle clivus chordomas via a modified anterior transpetrous approach
abstract: Skull base chordomas are challenging and have a high rate of recurrence.



A modified anterior transpetrous approach (ATPA) was performed in 17 upper clivus chordomas, and clinical data were retrospectively studied.



All 17 cases were radically treated via the modified ATPA, and the total removal and subtotal removal rates were 23.5% and 76.5%, respectively. The primary complaints were headaches and visual disturbances. The short-term postoperative complications were diplopia (12 cases, 70.6%) and facial numbness (7 cases, 41.2%). With a mean follow up of 44.5 months, 5 cases (29.4%) presented with tumor recurrence, and most cases had relatively good outcomes except for 2 patients who died because of rapid recurrence. The long-term complications were facial numbness (35.3%).



The upper skull base chordomas could be radically removed via the modified ATPA under selected conditions, with limited complications and improved outcomes. The radical surgery treatment strategy was recommended for skull base chordomas. However, the present series included limited cases; therefore, post-operative follow-up, long-term outcomes and a larger number of cases of clivus chordomas should be observed to evaluate the effectiveness of the modified ATPA approach.

title: Chordomas of the craniocervical junction: follow-up review and prognostic factors.
abstract: OBJECT
Chordomas are rare tumors that arise from the remnants of the notochord. Because of their deep location, local infiltrative nature, and involvement of surrounding bone, treatment of chordomas is a challenge. In this study the authors analyze the data and prognostic factors obtained during the follow-up period (range 1-150 months, median 38 months) in 53 patients with craniocervical junction chordomas and 10 patients with chondrosarcomas.



Several surgical approaches were used, and some tumor excisions required staged procedures. Survival was calculated according the Kaplan-Meier method. Statistical analysis was performed using Fisher exact, log rank and Kruskal-Wallis tests. Radical/subtotal resection was achieved in 77.8% of the patients. The mortality rate during the follow-up period was 14.3%. In patients harboring chondrosarcoma better 5-year recurrence-free survival (RFS) rates were demonstrated than in those with chordoma (100% and 50.7%. respectively). Histological patterns (typical or chondroid chordomas) and patient age at onset of symptoms had no effect on the RFS rates. Radical/subtotal resections were associated with better RFS rates than partial resection. Adjuvant proton-beam therapy was shown to increase the RFS rates compared with conventional radiotherapy (90.9% and 19.4%, respectively, at 4 years posttreatment). Karyotypically abnormal tumors were associated with the worst RFS rates compared with karyotypically normal lesions (44.5% and 90.3%, respectively, at 3 years). Cases of cranial nerve palsy followed by those with cerebrospinal fluid leakages were the most frequent postoperative complications. Permanent postoperative neurological deficit was observed in 28.6% of the patients.



A better prognosis was observed in patients with chondrosarcoma compared with those harboring chordoma. Histological pattern and patient age at symptom onset were not factors that influenced prognosis in cases of chordoma. Extensive resection and possibly adjuvant proton-beam therapy provided better prognoses for these patients.

title: Male sex as a risk factor for the clinical course of skull base chordomas.
abstract: 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.



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.



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.



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.

title: Clival chordomas: clinical management, results, and complications in 71 patients.
abstract: OBJECT
Chordomas are rare malignant neoplasms arising predominantly at the sacrum and skull base. They are uniformly lethal unless treated with aggressive resection and proton beam irradiation. The authors present results of the surgical management of a large number of patients with clivus chordomas. Factors that influence the surgeon's ability to achieve radical tumor resection are also evaluated.



Between 1991 and 2005, 71 patients with clivus chordomas underwent surgery. The average follow-up was 66 months (median 60 months, range 3-189 months). Sixty-five patients had complete records that were analyzed in the present report. Thirty-five percent of them had undergone surgery before being treated by the authors. They were evaluated with MR imaging and CT scanning and underwent surgery utilizing a variety of skull base techniques aimed at achieving radical excision. Many also underwent postoperative radiation, usually in the form of proton beam therapy. The patients were followed up with serial imaging at regular intervals as well as with neurological evaluation.



Radical tumor resection was achieved in 58% of the group. The overall 5-year survival rate was 75%. Radical resection had a positive impact on survival. The ability to achieve radical resection was dependent on the preoperative tumor volume and the number of anatomical areas involved by the tumor. Cranial nerve impairment and CSF leakage were the most frequent postoperative complications.



Radical excision is the ideal surgical goal in the treatment of clival chordomas and can be achieved with reasonable risks. Several different surgical approaches may be necessary to accomplish this.

title: Patient Outcome at Long-term Follow-up after Aggressive Microsurgical Resection of Cranial Base Chordomas
abstract: In this study, we evaluated patients' clinical outcome and recurrence rates at long-term follow-up after aggressive microsurgical resection of cranial base chordomas. Seventy-four patients with chordomas underwent operations during a 16-year period from 1988 to 2004. The philosophy was to perform complete resection whenever possible and to provide adjuvant radiotherapy for remnants. Staged operations were performed for extensive tumors or if a sizable tumor remnant was noted after the first resection. Patients included primary (previously untreated) and previously operated or irradiated cases. Information was prospectively gathered concerning the patients' neurological condition, Karnofsky Performance Scale score, and tumor status on magnetic resonance imaging scans. There were 47 primarily operated patients (63.5%) and 27 patients (36.5%) who had previously undergone surgery or radiotherapy. A total of 121 procedures were performed in 74 patients. The mean follow-up period was 96 months, with a range of 1 to 198 months. A single stage removal was performed in 41 (55.4%) of the patients and multiple stage removal was performed in 33 (44.5%) of the patients. Gross total removal was accomplished in 53 (71.6%) of the patients, and subtotal resection was accomplished in 21 (28.4%) of the patients. During the follow-up period, 24 (32%) of the patients had no evidence of disease, 37 (50%) of the patients were alive with evidence of disease, 11 (14.8%) of the patients died of disease, and two (2.7%) of the patients died of complications. Recurrence-free survival at 10 years was 31% for the whole group, 42% for the primarily operated patients, and 26% for the reoperation cases (P = 0.0001). The average Karnofsky Performance Scale score was 80 ± 11.7 preoperatively, 84 ± 8.9 at the 1-year follow-up, and 86 ± 12.8 at the last follow-up in surviving patients. No conclusion could be drawn regarding the value of radiotherapy because of the treatment philosophy and the small number of patients. Aggressive microsurgical resection of chordomas can be followed by long-term, tumor-free survival with good functional outcome. A more conservative strategy is recommended in reoperation cases, especially after previous radiotherapy, to reduce postoperative complications.

title: Skull base chordomas: a management challenge.
abstract: Because of their critical location, invasive nature, and aggressive recurrence, skull base chordomas are challenging and, at times, frustrating tumors to treat. Both radical surgical removal and high-dose radiation therapy, particularly proton beam therapy, reportedly are effective in tumor control and improve survival rates. The authors posit that these tumors are best treated with radical surgery and proton-photon beam therapy. During the last 5 years, they treated 25 patients (15 females and 10 males) who harbored pathologically diagnosed skull base chordomas. The mean age of the patients was 38.4 years (range 8-61 years). Previous surgery or radiation therapy was performed at other institutions in seven and two patients, respectively. The authors performed 33 surgical procedures on 23 patients. Radical removal (defined as absence of residual tumor on operative inspection and postoperative imaging) was achieved in 10 patients; subtotal resection (defined as resection of > 90% of the tumor) was achieved in 11 patients; and partial resection (defined as resection of < 90% of the tumor) was achieved in two patients. Radical surgical removal included not only the excision of soft-tumor tissue, but also extensive drilling of the adjacent bone. Adjuvant therapy consisted of postoperative combined proton-photon beam therapy (given to 17 patients and planned for one patient) and conventional radiation therapy (two patients); three patients received no adjunct therapy. To date, four patients have died. One patient who had undergone previous surgery and sacrifice of the internal carotid artery died postoperatively from a massive stroke; one patient died from adenocarcinoma of the pancreas without evidence of recurrence; and two patients died at 25 and 39 months of recurrent tumor. Permanent neurological complications included third cranial nerve palsy (one patient) and hemianopsia (one patient); radiation necrosis occurred in three patients. Of the 21 patients followed for more than 3 months after surgery, 16 have had no evidence of recurrence and five (including the two mortalities noted above) have had recurrent tumors (four diagnosed clinically and one radiologically). The mean disease-free interval was 14.4 months. A longer follow-up period will, hopefully, support the early indication that radical surgical removal and postoperative proton-photon beam therapy is an efficacious treatment. The use of skull base approaches based on the tumor classification introduced in this paper is associated with low mortality and morbidity rates.

title: Outcome of 132 Operations in 97 Patients With Chordomas of the Craniocervical Junction and Upper Cervical Spine
abstract: OBJECTIVETo study the outcomes of surgery for chordomas of the craniocervical junction and upper cervical spine as well as complication rates, survival, and associated adverse factors. METHODSRetrospective review of patients (1982–2007) at 2 European centers who underwent transoral, transfacial, transmandibular, and anterior cervical approaches for excision of chordomas of the craniocervical junction and cervical spine. The χ2 test and Fisher exact test were used to determine significant adverse factors (P < .05), and log-rank survival analysis was used to compare outcome in different groups. RESULTSOne hundred thirty-two operations were performed in 97 patients. The most common operations were transoral surgeries and maxillotomies. After surgery, neck pain was the same or better in 98.1% of patients. Of the 18.6% of patients who presented with myelopathy, 27.8% improved, 44.4% remained unchanged, and 27.8% deteriorated. Major complication rates were velopharyngeal incompetence, 3.1%; vertebral artery stroke, 1%; wound infection, 3.1%; dysphagia, 3.1%; failure of fixation, 2.1%; sepsis, 3.1%; meningitis, 3.1%; and cerebrospinal fluid leakage, 6.2%. Five- and 10-year overall survivals were 55% and 36%, respectively. Patients who presented to our units for revision surgery, after prior attempts at resection elsewhere, were associated with a worse survival than patients who underwent de novo surgery. CONCLUSIONWe present, to our knowledge, the largest published series of chordomas at the craniocervical junction. Complication rates for these major operations can be minimized at specialist centers, with careful patient selection and counseling. As complete or as radical an operation as possible should be performed at first presentation; the best chance for the patient is the first chance.

title: Factors predicting recurrence after resection of clival chordoma using variable surgical approaches and radiation modalities.
abstract: Clival chordomas frequently recur because of their location and invasiveness.



To investigate clinical, operative, and anatomic factors associated with clival chordoma recurrence.



Retrospective review of clival chordomas treated at our center from 1993 to 2013.



Fifty patients (56% male) with median age of 59 years (range, 8-76) were newly diagnosed with clival chordoma of mean diameter 3.3 cm (range, 1.5-6.7). Symptoms included headaches (38%), diplopia (36%), and dysphagia (14%). Procedures included transsphenoidal (n=34), transoral (n=4), craniotomy (n=5), and staged approaches (n=7). Gross total resection (GTR) rate was 52%, with 83% mean volumetric reduction, values that improved over time. While the lower third of the clivus was the least likely superoinferior zone to contain tumor (upper third=72%/middle third=82%/lower third=42%), it most frequently contained residual tumor (upper third=33%/middle third=38%/lower third=63%; P<.05). Symptom improvement rates were 61% (diplopia) and 53% (headache). Postoperative radiation included proton beam (n=19), cyberknife (n=7), intensity-modulated radiation therapy (n=6), external beam (n=10), and none (n=4). At last follow-up of 47 patients, 23 (49%) remain disease-free or have stable residual tumor. Lower third of clivus progressed most after GTR (upper/mid/lower third=32%/41%/75%). In a multivariate Cox proportional hazards model, male gender (hazard ratio [HR]=1.2/P=.03), subtotal resection (HR=5.0/P=.02), and the preoperative presence of tumor in the middle third (HR=1.2/P=.02) and lower third (HR=1.8/P=.02) of the clivus increased further growth or regrowth, while radiation modality did not.



Our findings underscore long-standing support for GTR as reducing chordoma recurrence. The lower third of the clivus frequently harbored residual or recurrent tumor, despite staged approaches providing mediolateral (transcranial+endonasal) or superoinferior (endonasal+transoral) breadth. There was no benefit of proton-based over photon-based radiation, contradicting conventional presumptions.

title: Chordomas of the skull base: surgical management and outcome.
abstract: OBJECT
The goal of this study was to report on the surgical management of skull base chordomas and to evaluate both the short- and long-term treatment outcomes.



The authors retrospectively studied data from 49 patients who had undergone consecutive surgeries at a single institution. They also analyzed patterns of chordoma extension. Complications and surgery-related morbidity were recorded. A Kaplan-Meier analysis was performed to determine survival rates in patients 5 and 10 years after their first surgery. Operative approaches were selected on the basis of the predominant tumor extension.



The approach used most frequently was the transethmoidal in 36.3%, followed by the pterional in 23.4% and the retrosigmoid in 23.4%. The tumor was totally removed in 49.4% and subtotally in 50.6%. The rate of total removal was highest at initial surgery (78%) and progressively declined thereafter. In 11.8% of cases a new neurological deficit developed, while the preoperative deficit remained unchanged. In 20% of cases the preoperative deficits improved, but new deficits also appeared. The 5- and 10-year survival rates are 65 and 39%, respectively.



With an individually tailored surgical approach, total tumor removal in 78% of the cases was achieved at the initial surgery. Radical surgery appears to increase slightly the surgical morbidity, but at the same time prolongs the recurrence-free interval. Chordomas cannot be regarded as surgically curable tumors given the 5- and 10-year survival rates in patients harboring such lesions.

title: Building a global consensus approach to chordoma: a position paper from the medical and patient community.
abstract: Chordomas are very rare bone malignant tumours that have had a shortage of effective treatments for a long time. New treatments are now available for both the local and the metastatic phase of the disease, but the degree of uncertainty in selecting the most appropriate treatment remains high and their adoption remains inconsistent across the world, resulting in suboptimum outcomes for many patients. In December, 2013, the European Society for Medical Oncology (ESMO) convened a consensus meeting to update its clinical practice guidelines on sarcomas. ESMO also hosted a parallel consensus meeting on chordoma that included more than 40 chordoma experts from several disciplines and from both sides of the Atlantic, with the contribution and sponsorship of the Chordoma Foundation, a global patient advocacy group. The consensus reached at that meeting is shown in this position paper.

title: Chordoma: current concepts, management, and future directions.
abstract: Chordoma is a rare bone cancer that is aggressive, locally invasive, and has a poor prognosis. Chordomas are thought to arise from transformed remnants of notochord and have a predilection for the axial skeleton, with the most common sites being the sacrum, skull base, and spine. The gold standard treatment for chordomas of the mobile spine and sacrum is en-bloc excision with wide margins and postoperative external-beam radiation therapy. Treatment of clival chordomas is unique from other locations with an enhanced emphasis on preservation of neurological function, typified by a general paradigm of maximally safe cytoreductive surgery and advanced radiation delivery techniques. In this Review, we highlight current standards in diagnosis, clinical management, and molecular characterisation of chordomas, and discuss current research.

title: Predictors of recurrence following resection of intracranial chordomas
abstract: Management of intracranial chordomas remains challenging, despite improvements in microsurgical techniques and radiotherapy. Here, we analyzed the prognostic factors associated with improved rates of tumor control in patients with intracranial chordomas, who received either gross (GTR) or subtotal resections (STR). A retrospective review was performed to identify all patients who were undergoing resection of their intracranial chordomas at the Ronald Reagan University of California Los Angeles Medical Center from 1990 to 2011. In total, 57 patients undergoing 81 resections were included. There were 24 females and 33 males with a mean age of 44.6 years, and the mean tumor diameter was 3.36 cm. The extent of resection was not associated with recurrence. For all 81 operations, the 1 and 5 year progression free survival (PFS) was 87.5 and 40.4%, and 88.0 and 33.6% for STR and GTR, respectively (p=0.90). Adjuvant radiotherapy was associated with improved rates of PFS (hazard ratio [HR] 0.20; p=0.009). Additionally, age >45 years (HR 5.88; p=0.01) and the presence of visual deficits (HR 7.59; p=0.03) were associated with worse rates of tumor control. Tumor size, sex, tumor histology, and recurrent tumors were not predictors of recurrence. Younger age, lack of visual symptoms on presentation and adjuvant radiotherapy were associated with improved rates of tumor control following surgery. However, GTR and STR produced comparable rates of tumor control. The surgical management of intracranial chordomas should take a conservative approach, with the aim of maximal but safe cytoreductive resection with adjuvant radiation therapy, and a major focus on quality of life.

title: Intracranial chordomas: a clinicopathological and prognostic study of 51 cases.
abstract: Fifty-one patients with intracranial chordomas who were surgically treated between 1960 and 1984 were studied. Median patient age was 46 years, and 73% presented with diplopia or headache. Nineteen tumors were classified as the "chondroid" type. The extent of surgical removal was a biopsy in 11 patients and subtotal removal or greater in 40. Thirty-nine patients received postoperative radiation therapy. At the time of analysis, 17 patients were alive, and the estimated 5- and 10-year survival rates were 51% and 35%, respectively, for the group of 51 patients. Univariate analysis showed that: 1) patients undergoing resection lived longer (the 5-year survival rate was 36% for the 11 biopsy patients compared with 55% for the 40 patients who had resection; 2) patients who underwent postoperative radiotherapy tended to have longer disease-free survival times; and 3) overall and disease-free survival data were the same for patients with chondroid tumors and those with typical chordomas. Multivariate analysis showed that: 1) age was the factor most strongly associated with longer overall and disease-free survival; 2) diplopia was associated with longer survival; and 3) tumoral mitotic activity tended to be associated with shorter disease-free survival. One tumor metastasized to the cervical cord, and two tumors underwent anaplastic transformation. These data suggest that the prognosis in patients with chordomas is unfavorable, young age is the single factor most strongly associated with longer survival, surgical resection is beneficial, and postoperative radiotherapy may prolong disease-free survival.

title: Chordoma of the skull base: predictors of tumor recurrence.
abstract: OBJECT
Chordomas of the skull base are generally regarded as slow-growing tumors; however, approximately 20% of these lesions have been shown to recur as early as 1 year postsurgery. The classic pathological paradigms are poor predictors of outcome, and additional markers are needed to identify patients at risk for early tumor recurrence. In this study the authors describe such a marker.



In a series of 26 patients with chordomas of the skull base, the authors investigated the relationship between the biological behavior of the tumor, which was determined according to the interval for its recurrence and volume doubling time, and several pathological and molecular features, which included the histological variant, proliferative activity, mutation of p53 protein, expression of human telomerase reverse transcriptase (hTERT) messenger (m)RNA, loss of heterozygosity (LOH), and microsatellite instability. The major finding in this study was that hTERT mRNA expression in chordoma cells identifies those tumors that exhibit unusually fast rates of growth. The expression of hTERT mRNA was frequently associated with mutation of p53 protein, indicating that telomerase dysfunction combines with abnormal p53 function to initiate the unrestrained clonal expansion of the tumor cells. In cases in which the tumor was partially removed, mutation of p53 protein and expression of hTERT mRNA predicted increased doubling time for residual tumor as well as the probability of tumor recurrence. Cell proliferation, as investigated using the Ki-67 method, was significantly related to the tumor doubling time; however, the authors found that the pattern of cell proliferation was not homogeneous throughout the chordoma tissue, and that the proliferative index might change by a factor as high as 8 among different regions of the same tumor. The LOH and microsatellite instability do not seem to affect the prognosis of skull base chordomas.



Reactivation of telomerase in chordomas is a reliable predictor of outcome. The ability to predict the biological behavior of chordomas might have immediate implications in the management of this disease in patients who undergo surgery.

title: Endoscopic endonasal transclival resection of chordomas: operative technique, clinical outcome, and review of the literature.
abstract: OBJECT
Transcranial approaches to clival chordomas provide a circuitous route to the site of origin of the tumor often involving extensive bone drilling and brain retraction, which places critical neurovascular structures between the surgeon and pathology. For certain chordomas, the endonasal endoscopic transclival approach is a novel minimal access, but it is an equally aggressive alternative providing the most direct route to the tumor epicenter.



The authors present a consecutive series of patients undergoing endonasal endoscopic resection of clival chordomas. Extent of resection was determined by postoperative volumetric MR imaging and divided into > 95% and < 95%.



Seven patients underwent 10 operations. Preoperative cranial neuropathies were present in 4. The mean patient age was 52.0 years. The mean tumor volume was 34.9 cm3. Intraoperative lumbar drainage was used in 1 patient, and the tumors extended intradurally in 3. One patient underwent 2 intentionally palliative procedures for subtotal debulking. Greater than 95% resection was achieved in 7 of 8 operations in which radical resection was the goal (87%). All tumors with volumes < 50 cm3 had > 95% resection (p = 0.05). The overall mean follow-up was 18.0 months. Cranial neuropathies resolved in all 3 patients with cranial nerve VI palsies. One patient with recurrent nasopharyngeal chordoma died of disease progression; another experienced 2 recurrences before receiving radiation therapy. All surviving patients remain progression free. There were no intraoperative complications; however, 1 patient developed a pulmonary embolus postoperatively. There were no postoperative CSF leaks.



The endonasal endoscopic transclival approach represents a less invasive and more direct approach than a transcranial approach to treat certain moderate-sized midline skull base chordomas. Longer follow-up is necessary to determine comparability to transcranial approaches for long-term control. Large tumors with significant extension lateral to the carotid artery may not be suitable for this approach.

title: Chordoma of the Mobile Spine: Fifty Years of Experience
abstract: A consecutive series of 52 chordomas of the mobile spine observed over a 50-year period includes a retrospective review of 15 cases treated prior to 1991 and a prospective group of 37 cases treated from 1991 to 2002.  This series reviews epidemiologic issues as well as clinical patterns of spinal chordomas. We attempt to correlate tumor extent, treatment, and outcomes over time.  Chordoma is the most frequent primary tumor of the mobile spine. Due to slow growth, both initial symptoms and recurrences after treatment arise later, making it difficult to evaluate the effectiveness of treatment protocols.  A prospective series of 37 cases is compared with a retrospective group of 15 patients observed between 1954 and 1991. In the prospective study, all patients had imaging studies, and oncologic and surgical staging. When en bloc resection was not feasible, intralesional extracapsular excision was combined with radiation therapy. The prospective patients were clinically evaluated and imaged. Patients in the retrospective group were evaluated by chart and available images; of these, only one en bloc resection (intralesional margin) was performed. Survivors were all evaluated clinically and had radiographic studies.  Forty-eight patients were available for long-term follow-up. Four died due to post-operative complications, and six due to disease less than 2 years after treatment. Forty-two patients were followed over 2 years; 26 patients had over 5 years follow-up. All patients having radiation alone, intralesional excision, or a combination had recurrences in less than 2 years, and died in some cases after a long survival with symptomatic disease. Intralesional extracapsular excision with radiation had a high rate of recurrence (12 of 16 at average 30 months), but 3 patients are continuously disease-free (CDF) at mean 52 months and 5 are alive with disease at average 69 months (ranging 24 to 146). Twelve of 18 patients having en bloc resection are CDF at average 8 years (48 to 155 months). The remaining 6 recurred and of these 1 died. All of these (6) had been previously treated and/or had en bloc resections with contaminated margins.  The only treatment protocol associated with CDF at follow-up longer than 5 years is margin-free en bloc resection.