Kaibing Tian

Clinical and Pathological Features of Intradural Retroclival Chordoma

OBJECTIVE To investigate the clinical and pathologic characteristics of primary intradural retroclival chordoma and improve the understanding of this rare disease. METHODS 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. RESULTS 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. CONCLUSIONS 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.

Factors for tumor progression in patients with skull base chordoma.

Skull base chordoma is a rare and fatal disease, recurrence of which is inevitable, albeit variable. We aimed to investigate the clinicopathologic features of disease progression, identify prognostic factors, and construct a nomogram for predicting progression in individual patients. Data of 229 patients with skull base chordoma treated by one institution between 2005 and 2014 were retrieved and grouped as primary and recurrent. Kaplan–Meier survival of progression was estimated, taking competing risks into account. Multivariable Cox regression was used to investigate survival predictors. The primary group consisted by 183 cases, gained more benefits on 5‐year progression‐free survival (PFS) (51%) and mean PFS time (66.9 months) than the recurrent group (46 cases), in which 5‐year postrecurrent PFS was 14%, and mean postrecurrent PFS time was 29.5 months. In the primary group, visual deficits, pathological subtypes, extent of bone invasion, preoperative Karnofsky performance scale (KPS) score, and variation in perioperative KPS were identified as independent predictors of PFS. A nomogram to predict 3‐year and 5‐year PFS consisted of these factors, was well calibrated and had good discriminative ability (adjusted Harrell C statistic, 0.68). In the recurrent group, marginal resection (P = 0.018) and adjuvant radiotherapy (P = 0.043) were verified as protective factors associated with postrecurrent PFS. Factors for tumor progression demonstrated some differences between primary and recurrent cases. The nomogram appears useful for risk stratification of tumor progression in primary cases. Further studies will be necessary to identify the rapid‐growth histopathological subtype as an independent predictor of rapid progression.

The Brachyury Gly177Asp SNP Is not Associated with a Risk of Skull Base Chordoma in the Chinese Population

A recent chordoma cancer genotyping study reveals that the rs2305089, a single nucleotide polymorphism (SNP) located in brachyury gene and a key gene in the development of notochord, is significantly associated with chordoma risk. The brachyury gene is believed to be one of the key genes involved in the pathogenesis of chordoma, a rare primary bone tumor originating along the spinal column or at the base of the skull. The association between the brachyury Gly177Asp single nucleotide polymorphism (SNP) and the risk of skull base chordoma in Chinese populations is currently unknown. We investigated the genotype distribution of this SNP in 65 skull-base chordoma cases and 120 healthy subjects. Comparisons of the genotype distributions and allele frequencies did not reveal any significant difference between the groups. Our data suggest that the brachyury Gly177Asp SNP is not involved in the risks of skull-base chordoma, at least in the Chinese population.

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

OBJECTIVE 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.

Brachyury: A sensitive marker, but not a prognostic factor, for skull base chordomas

Patients with skull base chordomas have a poor prognosis, and the role of the protein expression of brachyury in chordomas remains to be fully elucidated. The present study used immunohistochemistry to analyze 57 cases of skull base chordoma, and analyzed the clinical data of the patients. The results demonstrated that the protein expression of brachyury was negative in 8.8% (5/57) of the cases. The weak/positive, positive and strong/positive rates were 5.3% (3/5 7), 21.1% (12/57) and 64.9% (37/57), respectively. The association between the expression of brachyury and recurrence was not statistically significant. Kaplan-Meier analysis revealed that the degree of surgery, rather than the expression of brachyury, was associated with tumor recurrence (P=0.001). In conclusion, the results of the present study demonstrated that the expression of Brachyury offers a sensitive marker, but not a risk factor, for skull base chordomas, and radical surgery is recommended.

Bone invasiveness is associated with prognosis in clivus chordomas

Clivus chordomas present a great challenge for neurosurgeons, and the prognosis is poor. To investigate bone invasiveness characteristics in regard to the prognosis of clivus chordomas, a retrospective study of 19 patients with primary clivus chordoma was performed. Clinical data, MRI, CT scans and follow-up data were examined, and the bone invasiveness of the chordoma was classified into two growth patterns (endophytic and exophytic) which were analyzed with regard to prognosis. The overall survival rate was 78.9% with radical surgery and adjuvant radiation, with a mean follow-up of 44.5months. There were 12 patients in the endophytic group and seven in the exophytic group, and the exophytic group exhibited a higher recurrence rate than the endophytic group (p=0.006). Chordomas with an exophytic growth pattern were more likely to recur than those with an endophytic growth pattern, and the surgical approach can be tailored according to each growth pattern.

Surgical resection of upper-middle clivus chordomas via a modified anterior transpetrous approach

BACKGROUND Skull base chordomas are challenging and have a high rate of recurrence. METHODS A modified anterior transpetrous approach (ATPA) was performed in 17 upper clivus chordomas, and clinical data were retrospectively studied. RESULTS 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%). CONCLUSIONS 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.

Experimental study on differences in clivus chordoma bone invasion: an iTRAQ-based quantitative proteomic analysis.

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.

T gene isoform expression pattern is significantly different between chordomas and notochords.

The T gene plays a key role in chordoma pathology. To investigate the role of T gene isoforms in chordoma, 22 skull base chordomas, three chordoma cell lines and 9 infant notochords, which were used as normal controls, were collected. We first conducted droplet digital PCR to quantify the absolute expression levels of the long and short isoforms of the T gene (T-long and T-short, respectively) and revealed that T-long was dominantly expressed in all chordomas and chordoma cell lines, but not in the notochords. The T-long/T-short ratio was significantly different between the chordomas and the notochords. Next, we validated the isoform expression pattern at protein expression level using Western blot in 9 chordomas. Furthermore, the T gene single nucleotide polymorphism site rs2305089, which is the only marker reported to be associated with chordomas, was sequenced in all of the chordoma samples. Association between rs2305089 and T-long/T-short ratio was not significant, indicating it was not involved in T gene alternative splicing. In conclusion, two T gene isoforms were investigated in skull base chordomas and chordoma cell lines, and the longer isoform was dominantly expressed. The distinct expression patterns of these T gene isoforms may contribute to the pathogenesis of skull base chordomas. However, further studies on the function of these isoforms are needed.

Clinical course of untreated thalamic cavernous malformations: hemorrhage risk and neurological outcomes

OBJECTIVE The natural history of cerebral cavernous malformations (CMs) has been widely studied, but the clinical course of untreated thalamic CMs is largely unknown. Hemorrhage of these lesions can be devastating. The authors undertook this study to obtain a prospective hemorrhage rate and provide a better understanding of the prognosis of untreated thalamic CMs. METHODS This longitudinal cohort study included patients with thalamic CMs who were diagnosed between 2000 and 2015. Clinical data were recorded, radiological studies were extensively reviewed, and follow-up evaluations were performed. RESULTS A total of 121 patients were included in the study (56.2% female), with a mean follow-up duration of 3.6 years. The overall annual hemorrhage rate (subsequent to the initial presentation) was calculated to be 9.7% based on the occurrence of 42 hemorrhages over 433.1 patient-years. This rate was highest in patients (n = 87) who initially presented with hemorrhage and focal neurological deficits (FNDs) (14.1%) (χ2 = 15.358, p < 0.001), followed by patients (n = 19) with hemorrhage but without FND (4.5%) and patients (n = 15) without hemorrhage regardless of symptoms (1.2%). The initial patient presentations of hemorrhage with FND (hazard ratio [HR] 2.767, 95% CI 1.336-5.731, p = 0.006) and associated developmental venous anomaly (DVA) (HR 2.510, 95% CI 1.275-4.942, p = 0.008) were identified as independent hemorrhage risk factors. The annual hemorrhage rate was significantly higher in patients with hemorrhagic pres entation at diagnosis (11.7%, p = 0.004) or DVA (15.7%, p = 0.002). Compared with the modified Rankin Scale (mRS) score at diagnosis (mean 2.2), the final mRS score (mean 2.0) was improved in 37 patients (30.6%), stable in 59 patients (48.8%), and worse in 25 patients (20.7%). Lesion size (odds ratio [OR] per 0.1 cm increase 3.410, 95% CI 1.272-9.146, p = 0.015) and mRS score at diagnosis (OR per 1 point increase 3.548, 95% CI 1.815-6.937, p < 0.001) were independent adverse risk factors for poor neurological outcome (mRS score ≥ 2). Patients experiencing hemorrhage after the initial ictus (OR per 1 ictus increase 6.923, 95% CI 3.023-15.855, p < 0.001) had a greater chance of worsened neurological status. CONCLUSIONS This study verified the adverse predictors for hemorrhage and functional outcomes of thalamic CMs and demonstrated an overall annual symptomatic hemorrhage rate of 9.7% after the initial presentation. These findings and the mode of initial presentation are useful for clinicians and patients when selecting an appropriate treatment, although the tertiary referral bias of the series should be taken into account.