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(American Journal of Pathology. 2003;162:1053-1060.)
© 2003 American Society for Investigative Pathology

Short Communication

Genetic and Biological Subgroups of Low-Stage Follicular Thyroid Cancer

Christopher A. French^*, Erik K. Alexander, Edmund S. Cibas^*, Vania Nose, Julia Laguette^*, William Faquin, Jeff Garber^¶, Francis Moore, Jr^||, Jonathan A. Fletcher^*, P. Reed Larsen and Todd G. Kroll^**

From the Division of Endocrinology, Departments of Medicine, Surgery,^|| and Pathology,^* Brigham and Women’s Hospital, Boston, Massachusetts; the Department of Pathology, Children’s Hospital, Boston, Massachusetts; the Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts; and Harvard Vanguard Medical Associates,^¶ Harvard Medical School, Boston, Massachusetts; and the Departments of Pathology and Laboratory Medicine and Hematology and Oncology,^** Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia

Investigations of cancer-specific gene rearrangements have increased our understanding of human neoplasia and led to the use of the rearrangements in pathological diagnosis of blood cell and connective tissue malignancies. Here, we have investigated 3p25 rearrangements of the peroxisome proliferator-activated receptor (PPAR) gene in follicular epithelial tumors of the human thyroid gland. Eleven of 42 (26%) low-stage follicular carcinomas, 0 of 40 follicular adenomas, 1 of 30 Hurthle cell carcinomas, 1 of 90 papillary carcinomas, and 0 of 10 nodular goiters had 3p25 rearrangements by interphase fluorescence in situ hybridization. All 11 follicular carcinomas with 3p25 rearrangement exhibited strong, diffuse nuclear immunoreactivity for PPAR, consistent with expression of PPAR fusion protein. Twelve of 42 (29%) low-stage follicular carcinomas had 3p25 aneusomy without PPAR rearrangement (P = 0.01), suggesting that PPAR rearrangement and aneuploidy are independent early events in follicular cancer. Eleven of 12 follicular carcinomas with 3p25 aneusomy exhibited no PPAR immunoreactivity, supporting the existence of two independent pathways. Follicular carcinoma patients with PPAR rearrangement more frequently had vascular invasion (P = 0.01), areas of solid/nested tumor histology (P < 0.001), and previous nonthyroid cancers (P < 0.01) compared with follicular carcinoma patients without PPAR rearrangement. Our experiments identify genetic subgroups of low-stage follicular thyroid cancer and provide evidence that follicular carcinomas with PPAR rearrangement are a distinct biological entity. The findings support a model in which separate genetic alterations initiate distinct pathways of oncogenesis in thyroid carcinoma subtypes.

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