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Identification of borderline thyroid tumors by gene expression array analysis
Cancer, 08/13/09

Arora N et al. - In a study to examine the identification of borderline thyroid tumors by gene expression array analysis, it appears that gene expression profiling supports the finding that encapsulated thyroid follicular lesions with partial nuclear features of papillary thyroid carcinoma (PTC) are biologically borderline tumors that are distinct molecularly from benign and malignant tumors.

Methods

Gene expression profiling and advanced significance analyses were performed on 50 histologically unequivocal benign and malignant tumors, and a list of 61 differentially expressed genes was generated.
By using this 61-gene list, unsupervised hierarchical and K-means cluster analyses were performed on 40 additional tumors, including 15 histologically borderline tumors, 11 benign tumors, and 14 PTCs.

Results

Analysis revealed 3 distinct tumor groups - benign, malignant, and intermediate.
Tumors in the intermediate group (n=15) were mostly histologic borderline tumors and had an expression profile overlapping with the benign and malignant groups.
27 genes were expressed differentially between the benign and intermediate groups, including the cyclic AMP response element-binding protein/p300-interactivator with glutamic acid/aspartic acid-rich carboxy-terminal domain 1 or CITED1 gene and fibroblast growth factor receptor 2 or FGFR2 gene.
14 genes were expressed differentially between the intermediate group and malignant tumors, notably overexpression of the met proto-oncogene and the high-mobility group adenine/thymine-hook 2 or HMGA2 gene in malignancies.
Mutations of the v-raf murine sarcoma viral oncogene homolog B1 or BRAF gene were identified in 4 of 14 malignant tumors but not in benign or intermediate tumors.
Pts who had either histologically or molecularly borderline tumors did not have metastasis or recurrences.

Exclusive Author Commentary
Nimmi Arora, Thomas J. Fahey III, 08/23/09

We have used gene profiling to confirm a suspicion that an intermediate or borderline group of thyroid tumors exists that is neither distinctly benign nor malignant. Several individual studies have also described thyroid tumors that do not fit into standard categories of benign or malignant based on histopathology, immunohistochemistry, or mutational analysis. We believe that our study will provide a basis for which a new classification of these borderline tumors may emerge. Future investigations using the molecular signature provided can guide selection of tumors to be studied. Long-term follow-up will be needed to characterize the clinical behavior of this unique group of tumors so that a uniform consensus can be formed by clinicians, pathologists, and other investigators.

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