Over-Expression of c-MET Is Associated with Increased Recurrence in Childhood Thyroid Cancer

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Abstract 557 Poster Session I, Saturday, 5/1 (poster 304)

The cMet receptor is thought to be important in the induction of metastasis for many diverse cancers. Previous studies have shown that cMET is expressed in adult papillary thyroid cancer (PTC), however, only one study of 120 adults has explored the relationship between cMet expression in PTC and distant metastasis. In contrast to most other cancers, cMET expression did not predict distant metastasis. Several observations suggest PTC in children may be different than in adults: children rarely develop anaplastic thyroid cancer, die of disease, or have mutations in Gsα. Because of these differences, we hypothesized that cMET expression might be different in childhood PTC. We designed this study to examine cMET expression in childhood PTC and to correlate cMET expression with clinical outcome. Our group maintains a clinical data base which includes normals, benign thyroid diseases, and over 150 children and adolescents with PTC. Original tissue blocks were available for analysis of 4 normals, 17 benign thyroid diseases (6 adenomatoid nodules, 3 Graves, 1 Hashimoto's thyroiditis, 3 multinodular goiter, 3 follicular adenoma, 1 Hurthle Cell adenoma), and 32 PTC. The PTC group included 23 girls and 9 boys with a median age of 17 yr (range 6 - 21) and a median follow-up of 62 months (range 0 - 246). At diagnosis, 16 patients had disease confined to the thyroid gland (Class I), 11 had regional lymph node involvement (Class II), 4 had either direct extension or incomplete resection (Class III), and 1 had distant metastasis (Class IV). During follow up, 6 patients (19%) developed recurrence. Archival tissue blocks were sectioned and stained for cMET using an immunohistochemical method. Sections were incubated with rabbit polyclonal anti-cMET (human), followed by biotinylated secondary antibody, streptavidin- biotinylated horseradish peroxidase, and diaminobenzidine chromogen. The intensity of staining was graded by two independent, blinded examiners and quantified as grade 0 (absent) through grade 4 (uniformly & intensely stained). Of the patients with PTC, 16% were cMET grade 0, 16% grade 1, 19% grade 2, 34% grade 3, and 15% grade 4. cMET was overexpressed in PTC (mean intensity = 2.2) compared to both normal thyroid tissue (mean = 0.2, p=0.01) and benign thyroid disease (mean =0.6, p<0.0005, Mann-Whitney). In addition, more intense cMET expression was directly correlated with disease recurrence (p=0.05, Kaplan-Meyer, log rank comparison). There was no correlation between cMET expression and either disease class or metastasis at diagnosis. We conclude that cMET expression is increased in childhood PTC and that those PTC with the most intense cMET staining have the greatest risk of recurrence.

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Ramirez, R., Fenton, C., Patel, A. et al. Over-Expression of c-MET Is Associated with Increased Recurrence in Childhood Thyroid Cancer. Pediatr Res 45, 96 (1999) doi:10.1203/00006450-199904020-00574

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