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Transforming Growth Factor Receptors and p27^kip in Thyroid Carcinoma

Carlos A. Muro-Cacho, MD, PhD; Teresita Muñoz-Antonia, PhD; Sandra Livingston; Douglas Klotch, MD

Arch Otolaryngol Head Neck Surg. 1999;125:76-81.

Objective  To investigate the role of cell cycle regulators in the pathogenesis of papillary carcinoma of the thyroid.

Design  Resistance to transforming growth factor –mediated inhibition is a well-known pathogenic mechanism in epithelial neoplasias. In a retrospective study, the expression of transforming growth factor receptors types I and II, cyclin D1, and the cyclin-dependent inhibitor p27^kip, was analyzed by immunohistochemistry. Results were interpreted in the context of clinicopathological data. Patient follow-up ranged from 1 to 18 years, with a mean of 4 years.

Materials  Twenty conventional primary papillary carcinomas and their metastases were selected according to current pathologic criteria. Nonconventional papillary carcinomas (eg, tall-cell, columnar) were excluded from the analysis.

Results  Cyclin D1 was expressed more intensely in the tumor than in adjacent nonneoplastic parenchyma. Within a given tumor, however, there was significant heterogeneity in expression intensity and percentage of positive cells, particularly in metastases. Type I receptors were strongly expressed in 90% of tumors, while 80% of the tumors revealed low to no expression of type II receptors. In 10% of tumors, type I receptors were absent and type II receptors expressed. Simultaneous absence of both receptors was not observed. While p27^kip was strongly expressed in nonneoplastic thyroid, it was not detected in any of the primary tumors or their metastases.

Conclusions  The results strongly suggest that functional abnormalities in type II receptors result in increased levels of cyclin D1 and down-regulation of p27^kip. This would maintain cells in a proliferative state and would promote tumor progression.

From the Departments of Pathology (Dr Muro-Cacho and Ms Livingston) and Biochemistry and Molecular Biology (Dr Muñoz-Antonia), and Division of Otolaryngology (Dr Klotch), H. Lee Moffitt Cancer Center and Research Institute and University of South Florida College of Medicine, Tampa.