Chordoma of the skull base: predictors of tumor recurrence

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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.

Methods. 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.

Conclusions. 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.

Article Information

Address reprint requests to: Roberto Pallini, M.D., Department of Neurosurgery, Catholic University School of Medicine, Largo A. Gemelli 8, 00168 Rome, Italy. e-mail: pallini@rm.unicatt.it.

© AANS, except where prohibited by US copyright law.

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Figures

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    Graph showing the intervals to tumor recurrence in 14 patients with recurrent chordoma and chondrosarcoma of the skull base.

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    Case 6, tumor sample a. Photomicrograph showing a typical chordoma that was characterized by indolent growth, with tumor recurrence 80 months after subtotal resection. Original magnification × 250. A: Several vacuolated cells with indistinct borders are seen in a mucoid matrix. H & E. B: Section treated with anti-MIB-1 antibody, which stains only rare nuclei of proliferating cells. ABC-peroxidase. C: Section treated with anti-p53 antibody, which does not stain any neoplastic cells. ABC-peroxidase. D: Section prepared using ISH for hTERT mRNA demonstrating that the tumor cells do not stain.

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    Case 15, tumor sample c. Photomicrographs showing a typical chordoma that recurred quickly after surgery. Original magnification × 250. A: Physaliphorous cells are seen in a mucoid matrix. H & E. B: Section treated with anti—MIB-1 antibody, which stains only rare nuclei of proliferating cells. ABC-peroxidase method. C: Section treated with anti-p53 antibody, which stains the nuclei of several tumor cells. D: Section prepared using ISH for hTERT mRNA revealing that the tumor cells exhibit moderate to intense cytoplasmic staining.

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    Case 22, tumor sample d. Photomicrographs showing a chordoma with malignant degeneration. Original magnification × 250. A: Marked cellular pleomorphism and nuclear hyperchromatism are seen. B: Section treated with anti—MIB-1 antibody, which stains several nuclei of neoplastic cells. ABC-peroxidase method. C: Section treated with anti-p53 antibody, which stains several nuclei. D: Section prepared using ISH for hTERT mRNA revealing that the tumor cells exhibit strongly stained cytoplasm.

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    Graphs showing the relationship between the tumor volume doubling time and Ki-67 PI in recurrent cases of typical chordoma. Upper: The two variables followed an exponential curve. Lower: In a semilogarithmic diagram, the variables were significantly related, with a 95% confidence interval (p = 0.032, Pearson linear correlation coefficient).

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    Graph showing the recurrence-free probability curves in 13 typical chordomas that exhibited different hTERT mRNA expression. There is a significant difference between the curve for chordomas that expressed hTERT mRNA and that for chordomas that had no hTERT mRNA expression (p < 0.00002, log rank test).

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    Analysis of microsatellite instability and LOH in the DNA of chordoma. Electrophoretic patterns of paired lymphocyte (N) and tumor (T) DNA are shown at the loci indicated. Upper: Microsatellite instability was detected as an alteration of electrophoretic mobility in PCR products (arrows) in a glioblastoma (lane 1) and a melanoma (lane 4), which were used as positive controls, but not in chordoma (lanes 2, 3, 5, and 6). Lower: The LOH corresponds to allele loss (arrows) in a glioblastoma (lane 1) and a melanoma (lane 4). Chordoma specimens show normal alleles (lanes 2, 3, 5, and 6).

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