Clinical significance of molecular expression profiles of Hürthle cell tumors of the thyroid gland analyzed via tissue microarrays Journal Article


Authors: Hoos, A.; Stojadinovic, A.; Singh, B.; Dudas, M. E.; Leung, D. H. Y.; Shaha, A. R.; Shah, J. P.; Brennan, M. F.; Cordon-Cardo, C.; Ghossein, R.
Article Title: Clinical significance of molecular expression profiles of Hürthle cell tumors of the thyroid gland analyzed via tissue microarrays
Abstract: Hürthle cell tumors are rare thyroid neoplasms for which disease biology is poorly understood and diagnosis of carcinoma can be challenging. The aim of the study was to characterize molecular expression profiles of Hürthle cell tumors and to determine the clinical significance of identified phenotypes. Paraffin-embedded tissue cores of normal thyroid (n = 18), and histopathologically well-defined Hürthle cell adenomas (n = 27), Hürthle cell tumors of unknown malignant behavior (n = 7), and minimally (n = 14) and widely (n = 21) invasive Hürthle cell carcinomas were arrayed in triplicate on tissue microarrays. Expression profiles of p53, mdm-2, p21, Bcl-2, cyclin D1, and Ki-67 were detected by immunohistochemistry and correlated with clinicopathological data and patient outcome using standard statistical methodology. Median follow-up time was 8 years. High Ki-67 proliferative index was evident only in the clinically aggressive widely invasive Hürthle cell carcinomas and was associated with significantly reduced relapsefree (P = 0.001) and disease-specific (P < 0.001) survival. The molecular phenotype of Hürthle cell tumors, independent of histopathological subtype diagnosis, was characterized by p53(-), mdm-2(+), p21(±), cyclin D1(-), and Bcl-2(±). Normal thyroid tissue demonstrated a p53(-), mdm-2(-), p21(-), cyclin D1(-), and Bcl-2(+) phenotype. The Bcl-2(+) phenotype was associated with improved relapse-free survival (P = 0.04) and disease-specific survival (P = 0.01) in widely invasive carcinomas and the Ki-67(+)/ Bcl-2(-) phenotype was associated with the diagnosis of widely invasive Hürthle cell carcinoma (P < 0.001). This study demonstrates that tissue microarray-based profiling allows identification of molecular markers that are associated with patient prognosis. High Ki-67 proliferative index was associated with adverse outcome in Hürthle cell neoplasms. Together with down-regulation of Bcl-2, high Ki-67 proliferative index may be useful for diagnosing widely invasive Hürthle cell carcinomas. Molecular alterations in the p53 pathway play a role in Hürthle cell tumorigenesis, but other unidentified molecular changes seem to be required to induce the malignant phenotype.
Keywords: immunohistochemistry; adolescent; adult; cancer survival; child; clinical article; controlled study; human tissue; protein expression; child, preschool; histopathology; ki 67 antigen; biological markers; phenotype; cell cycle proteins; cell division; protein bcl 2; gene expression profiling; protein p53; oncocytoma; adenoma, oxyphilic; carcinogenesis; oligonucleotide array sequence analysis; neoplasm invasiveness; thyroid carcinoma; thyroid neoplasms; dna microarray; cyclin d1; protein p21; proto-oncogene proteins c-bcl-2; thyroid tumor; protein mdm2; humans; prognosis; human; male; female; priority journal; article
Journal Title: American Journal of Pathology
Volume: 160
Issue: 1
ISSN: 0002-9440
Publisher: Elsevier Science, Inc.  
Date Published: 2002-01-01
Start Page: 175
End Page: 183
Language: English
PUBMED: 11786411
PROVIDER: scopus
PMCID: PMC1867123
DOI: 10.1016/S0002-9440(10)64361-1
DOI/URL:
Notes: Export Date: 14 November 2014 -- Source: Scopus
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MSK Authors
  1. Murray F Brennan
    1053 Brennan
  2. Ronald A Ghossein
    449 Ghossein
  3. Ashok R Shaha
    671 Shaha
  4. Bhuvanesh Singh
    236 Singh
  5. Denis Heng Yan Leung
    114 Leung
  6. Axel Hoos
    28 Hoos
  7. Jatin P Shah
    701 Shah
  8. Maria E Dudas
    53 Dudas