Expression of c-MET, low-molecular-weight cytokeratin, matrix metalloproteinases-1 and -2 in spinal chordoma.

AIMS: In skull base chordoma, c-MET expression has been reported to correlate with younger patient age and favourable prognosis; however, it also contributes to tumour invasiveness, especially in recurrent lesions, suggesting variable roles for c-MET according to clinical status. The aim of this study was to investigate the significance of c-MET expression in spinal chordoma, which affects patients who are 10-20 years older than those with skull base chordoma. METHODS AND RESULTS: Using immunohistochemical techniques, the expression of c-MET and its ligand, hepatocyte growth factor (HGF) was investigated in 34 primary spinal chordomas and compared with other clinicopathological parameters. Expression of c-MET and HGF was observed in 85.3 and 21.7% of lesions, respectively. c-MET expression correlated with the expression of an epithelial marker, low-molecular-weight cytokeratin (CAM5.2). Lesions with higher c-MET expression showed significantly stronger expression of proteinases, including matrix metalloproteinase (MMP)-1 and MMP-2. However, c-MET expression was not associated with patient age, proliferative ability estimated by MIB-1 labelling index, or prognosis. CONCLUSIONS: c-MET expression was observed in most spinal chordomas and correlated with the expression of CAM5.2, suggesting a relationship to an epithelial phenotype.

Clivus chordoma in continuity with a large pontine cyst.

Chordomas are tumors commonly of extradural origin associated with bone destruction; their central nervous system invasion has rarely been reported. The authors describe a rare case of a 37-year-old man presenting with a clivial chordoma invading the brainstem with a large pontine cyst. A median suboccipital approach was selected to remove the tumor.

Expression of matrix metalloproteinases-1, -2, and -9; tissue inhibitors of matrix metalloproteinases-1 and -2; cathepsin B; urokinase plasminogen activator; and plasminogen activator inhibitor, type I in skull base chordoma.

Little is known about proteinase expression in skull base chordoma, a rare bone tumor exhibiting local invasiveness. Using immunohistochemical techniques, we investigated the expression of matrix metalloproteinases (MMPs)-1, -2, and -9; tissue inhibitors of matrix metalloproteinases (TIMPs)-1 and -2; cathepsin B (CatB); urokinase plasminogen activator (uPA); and plasminogen activator inhibitor, type I (PAI1), in 45 patients with skull base chordoma (45 primary and 25 autologous recurrent lesions). We compared these data with clinicopathologic parameters and the expression of cell differentiation markers. MMP-1, MMP-2, TIMP-1, CatB, uPA, and PAI1 were frequently expressed, and there was a significant correlation in the expression of some proteinases. Immunoreactivity for MMP-1, MMP-2, CatB, and uPA was significantly higher in lesions exhibiting tumor infiltration of host bone than in those without such components. Expression of MMP-1, TIMP-1, CatB, and uPA was associated with that of low-molecular-weight cytokeratin (CAM5.2). There were no differences in proteinase expression in 25 pairs of primary and their recurrent lesions, and proteinase expression did not predict local recurrences. However, patients with higher expression of both MMP-1 and uPA showed worse prognosis compared with the others. In conclusion, expression of some proteinases correlated with CAM5.2 expression and seemed to play an important role in a synergistic manner in the invasion process in skull base chordoma. The authors believe that elevated expression of MMP-1 and uPA can be used to identify patients with a worse prognosis in skull base chordoma.

Chordomas of the skull base: surgical management and outcome.

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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Extra-Articular Tenosynovial Chondromatosis of the Finger: A Case Series Study of Three Cases, One Including Excessive Osseous Invasion.

BACKGROUND: Synovial chondromatosis is characterized by cartilaginous metaplasia in synovial tissues. Extra-articular tenosynovial chondromatosis is considered to be an anatomical counterpart of articular synovial chondromatosis. Extra-articular tenosynovial chondromatosis occurs preferentially in the hand, although its frequency is low. RESULTS: We report three cases of extra-articular tenosynovial chondromatosis. A 65-year-old female presented with a history of symptoms over 40 years related to the dorsum of her index finger (Case 1), A 46-year-old female presented with a 6-month history of symptoms at the volar surface of her middle finger (Case 2), and a 66-year-old male presented with a 3-month history of symptoms in a dorsal ring finger. Case 2 had evidence of ossification, which could be classified as osteochondromatosis. Interestingly, the index finger lesions (Case 1) were accompanied by excessive bone involvement. The signal intensity of T2-weighted magnetic resonance imaging varies from low to high, possibly reflecting histological variations, such as ossification and fatty tissue changes. All lesions were resected without complications. CONCLUSION: Variations in anatomical sites suggest that overuse or mechanical overloading was not causative. Extensive involvement of the nearby tendon and joint capsule, as well as the bone, would require attention during the resection. Preoperative analysis of images is important, not only for the diagnosis, but also to assess the extent of the lesion, particularly given the complex anatomy of the finger.

Intralesional fibrous septum in chordoma: a clinicopathologic and immunohistochemical study of 122 lesions.

Intralesional fibrous septum (IFS) generally is considered a reactive tissue in chordoma; however, little is known about its significance. We studied 122 chordomas for IFS using immunohistochemical techniques and compared IFS and lobular growth patterns (LGPs) formed by IFS with clinicopathologic parameters. Seventy-nine tumors (64.8%) revealed IFS. However, IFS frequently was infiltrated and interrupted by tumor cells with increased expression of proteases; only 33 (42%) of 79 tumors had LGP. In non-skull base chordomas, IFS and LGP were associated with nuclear pleomorphism, a previously described prognostic indicator, mitosis, and the MIB-1 labeling index, indicating a role of IFS and LGP in tumor growth or progression. Paradoxically, patients without LGP tended to have a worse prognosis than those with LGP. We believe that IFS exerts diverse influences on chordoma; however, invasion of IFS leading to loss of the LGP indicates advanced stages of tumor development, possibly predicting an unfavorable prognosis in chordoma.

Histogenesis of intralesional fibrous septum in chordoma.

Intralesional fibrous septum (IFS), a histologic architecture that is typical of chordoma, consists of proliferating spindle-shaped, fibroblast-like cells with an abundance of collagen fibers. However, the histogenesis of IFS is still controversial. In a series of 122 chordomas, special emphasis was placed on the morphology of host tissues involved in IFS and on a transition between IFS and neighboring tissues. In 23 lesions, IFS was also characterized both histochemically and immunohistochemically. IFS was observed in 79 (64.8%) lesions. Occasionally, IFS contained bone fragments and hyalinized matrix with no lining of osteoblastic cells, suggesting degenerated rather than metaplastic bone tissue. Moreover, IFS occasionally showed a direct transition to host bone trabeculae. Histochemically and immunohistochemically, IFS included calcium deposits positive for Alizarin red S staining and expressed both type I and type III collagen. In extraosseous lesions extending to the adjacent soft tissues, IFS frequently involved muscle fibers or peripheral nerve fibers and displayed a smooth transition to neighboring soft tissues. We believe that IFS is induced by a tumor-host interaction that is based on the host bone trabeculae in intraosseous lesions or on soft tissues in extraosseous lesions.

Expression of matrix metalloproteinase (MMP)-1, MMP-2, MMP-9, cathepsin B, and urokinase plasminogen activator in non-skull base chordoma.

We analyzed the expression of proteases and the clinicopathologic significance in non-skull base chordoma (NSBC). By using immunohistochemical techniques, we studied the expression of matrix metalloproteinase (MMP)-1, MMP-2, MMP-9, cathepsin B (CatB), and urokinase plasminogen activator (uPA) in 29 NSBCs and compared these data with clinicopathologic parameters and the expression of cell differentiation markers. Expression of MMP-1 (P = .092), MMP-2 (P = .041), and CatB (P = .058) was associated with nuclear pleomorphism, a previously described adverse prognostic indicator. Expression of cytokeratin 8 correlated with that of MMP-1 (P = .005), MMP-2 (P = .002), and uPA (P = .032). Patients with higher MMP-2 expression had a poorer prognosis than those with lower MMP-2 expression (P = .013). We believe that NSBCs with nuclear pleomorphism or stronger epithelial character have a higher invasive ability than those without. In addition, high MMP-2 expression was an indicator of an unfavorable clinical outcome in NSBC.

Expression of hepatocyte growth factor and c-MET in skull base chordoma.

BACKGROUND: Hepatocyte growth factor (HGF) is a multipotent cytokine that is mediated by its receptor, c-MET. HGF/c-MET contributes to tumor progression in many human malignancies; however, HGF/c-MET is inversely correlated with aggressive biologic behavior in other cancers. Conversely, to the authors' knowledge, little is known regarding the significance of HGF/c-MET expression in skull base chordoma. METHODS: Using immunohistochemical techniques, the authors investigated HGF/c-MET expression in 46 primary and 25 recurrent lesions, and compared it with the expression of proteinases and cell differentiation markers, proliferative ability, and other clinicopathologic parameters. RESULTS: c-MET was found to be expressed in 70.0% of primary and 88.0% of recurrent lesions. HGF expression was scarcely detected. Higher c-MET expression was found to be correlated with younger patient age. Lesions with a higher expression of low molecular weight cytokeratin (CAM5.2) demonstrated significantly higher c-MET scores in both primary and recurrent lesions compared with those with lower CAM5.2 expression. In recurrent lesions, higher c-MET expression was found to be associated with the scores of matrix metalloproteinase (MMP)-1, MMP-2, tissue inhibitor of matrix metalloproteinase-1, and urokinase plasminogen activator (uPA); however, only uPA was found to be correlated with higher c-MET expression in primary lesions. c-MET expression did not appear to be correlated with MIB-1 labeling index. Patients with higher c-MET expression were found to have longer survival. CONCLUSIONS: In the current study, c-MET expression was a common event, and was found to be correlated with CAM5.2 expression, younger patient age, and a favorable prognosis in patients with skull base chordoma. However, HGF/c-MET paracrine signaling also may contribute to its invasive ability, especially in recurrent lesions.

Alterations of G1-S checkpoint in chordoma: the prognostic impact of p53 overexpression.

BACKGROUND: To the authors' knowledge, little is known regarding the alterations of G(1)-S checkpoint and their significance in chordoma, a rare bone tumor. The authors investigated the clinicopathologic relevance of cell cycle abnormalities in chordoma. METHODS: The expression levels of p53, murine double minute 2 (MDM2), retinoblastoma protein (pRb), cyclin D1, p16(INK4a), and p27(Kip1) were investigated using immunohistochemical techniques; p53 mutations were studied by polymerase chain reaction (PCR)-single-strand conformation polymorphism, and mdm2 amplification was analyzed using real-time quantitative PCR. The results were compared with clinicopathologic parameters in 101 lesions. RESULTS: Approximately 10-45% of primary tumors presented alterations of p53, MDM2, cyclin D1, and pRb proteins; most tumors lacked expression of p16(INK4a) and p27(Kip1). Alterations of p53, MDM2, cyclin D1, and pRb proteins were found to have cooperative effects on both higher proliferative ability (MIB-1 labeling index [LI]) and increased nuclear pleomorphism, a previously described prognostic indicator for patients with chordoma. Multivariate analyses revealed that, among these alterations, p53 overexpression was the only independent factor for higher MIB-1 LI. At the genetic level, mdm2 gene amplification was detected in 15.4% of the lesions but did not correlate with MDM2 overexpression or other clinicopathologic parameters. No p53 mutations were detected in the current series. Survival analysis revealed that p53 overexpression, but no other cell cycle alterations, was associated with a reduced overall survival. CONCLUSIONS: Accumulation of cell cycle alterations led to an increased MIB-1 LI and nuclear pleomorphism, a previously described prognostic indicator in chordoma. The authors believe that p53 overexpression in particular is associated with an unfavorable prognosis in patients with chordoma.

Skull base and nonskull base chordomas: clinicopathologic and immunohistochemical study with special reference to nuclear pleomorphism and proliferative ability.

BACKGROUND: To the authors' knowledge, little is known regarding the relation between the proliferative ability and clinicopathologic parameters in skull base chordomas (SBCs) and nonskull base chordomas (NSBCs). METHODS: The authors investigated 122 conventional chordomas for their clinicopathologic parameters, proliferative ability (MIB-1 labeling index [LI]) and clinical outcome. RESULTS: Primary NSBCs were found to affect more elderly patients and demonstrated a higher MIB-1 LI compared with primary SBCs. Mitosis was more commonly noted in recurrent NSBCs compared with primary NSBCs. Apoptosis was more frequent in elderly patients than in younger patients with regard to both SBCs and NSBCs. Apoptosis also was found to be correlated with necrosis in SBCs, suggesting a common factor for the two different types of cell death. Mucoid matrix was reported to be more abundant in NSBCs than in SBCs, and appeared to occur more often in elder NSBC patients compared with younger NSBC patients. This indicates that it is produced in the later stages of tumorigenesis. In SBCs, several clinicopathologic parameters were found to be correlated with MIB-1 LI. Among them, increased age, recurrence, and nuclear pleomorphism were the only independent factors found to indicate a higher MIB-1 LI. No such parameters were found in NSBCs. However, in these lesions, prognosis was significantly poorer in those cases with nuclear pleomorphism compared with those without. CONCLUSIONS: The results of the current study suggest that nuclear pleomorphism is a prognostic indicator in NSBCs. The proliferative ability of SBCs appears to be closely associated with patient age, clinical status (recurrence), and nuclear pleomorphism.