• Linwah Yip, Marina N Nikiforova, Jenny Y Yoo, Kelly L McCoy, Michael T Stang, Michaele J Armstrong, Kristina J Nicholson, N Paul Ohori, Christopher Coyne, Steven P Hodak, Robert L Ferris, Shane O LeBeau, Yuri E Nikiforov, and Sally E Carty.
• *Department of Surgery, Division of Endocrine Surgery, University of Pittsburgh, Pittsburgh, PA †Department of Pathology, University of Pittsburgh, Pittsburgh, PA ‡Department of Medicine, Division of Endocrinology, University of Pittsburgh, Pittsburgh, PA §Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA.
• Ann. Surg. 2015 Sep 1; 262 (3): 519-25; discussion 524-5.

ObjectivesTo correlate thyroid cancer genotype with histology and outcomes.BackgroundThe prognostic significance of molecular signature in thyroid cancer (TC) is undefined but can potentially change surgical management.MethodsWe reviewed a consecutive series of 1510 patients who had initial thyroidectomy for TC with routine testing for BRAF, RAS, RET/PTC, and PAX8/PPARG alterations. Histologic metastatic or recurrent TC was tracked for 6 or more months after oncologic thyroidectomy.ResultsPapillary thyroid cancer (PTC) was diagnosed in 97% of patients and poorly differentiated/anaplastic TC in 1.1%. Genetic alterations were detected in 1039 (70%); the most common mutations were BRAFV600E (644/1039, 62%), and RAS isoforms (323/1039, 31%). BRAFV600E-positive PTC was often conventional or tall cell variant (58%), with frequent extrathyroidal extension (51%) and lymph node metastasis (46%). Conversely, RAS-positive PTC was commonly follicular variant (87%), with infrequent extrathyroidal extension (4.6%) and lymph node metastasis (5.6%). BRAFV600E and RET/PTC-positive PTCs were histologically similar. Analogously, RAS and PAX8/PPARG-positive PTCs were histologically similar. Compared with RAS or PAX8/PPARG-positive TCs, BRAFV600E or RET/PTC-positive TCs were more often associated with stage III/IV disease (40% vs 15%, P < 0.001) and recurrence (10% vs 0.7%, P < 0.001; mean follow-up 33 ± 21 mo). Distant metastasis was highest in patients with RET/PTC-positive TC (10.8%, P = 0.02).ConclusionsIn this large study of prospective mutation testing in unselected patients with TC, molecular signature was associated with distinctive phenotypes including cancers, with higher risks of both distant metastasis and early recurrence. Preoperative genotype provides valuable prognostic data to appropriately inform surgery.

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