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Background: The impact of extranodal extension (ENE) of metastatic papillary thyroid carcinoma (PTC) on short- and long-term clinical outcomes, including biochemical testing, has not been reported. Methods: This single-institution National Cancer Institute-designated Comprehensive Cancer Center cohort study included patients with macroscopic metastases and excluded patients with gross residual disease after surgery, distant disease, or poorly differentiated papillary carcinoma. A suppressed or stimulated thyroglobulin (Tg) <1 ng/mL, without suspicious imaging or anti-thyroglobulin antibodies, after radioactive iodine (RAI) treatment was termed an excellent or 'complete biochemical response' (CR). Results: Of 89 subjects included, 60 previously untreated patients underwent total thyroidectomy and therapeutic neck dissection; 29 additional patients underwent a neck dissection for persistence or recurrence after prior surgery and RAI administration. ENE, identified in 29 patients (33%), was associated with T4 classification ( p=0.02) and involvement of a greater number of nodes (median 11 vs. 5, p=0.03). ENE was associated with a 20% increased risk of nodal persistence necessitating additional surgery ( p=0.02). In a multivariable analysis, ENE, T4 classification, and recurrence/persistence proved to be independent predictors of systemic disease progression (ENE: hazard ratio [HR] 4.3 [95% confidence interval (CI) 1.2-15], p=0.02; T4 classification: HR 4.2 [CI 1.3-14], p=0.01; recurrent/persistent status: HR 3.6 [CI 1.1-12], p=0.035). Nodal or systemic disease progression was rare after a biochemical CR; in contrast, in previously untreated patients, stimulated Tg levels (sTg) >50 ng/mL prior to initial RAI administration, heralded the progression of nodal disease, and also predicted the eventual development of systemic disease ( p=0.0001). Of those with a sTg >50 ng/mL, over 70% underwent surgery for nodal persistence within five years. The presence of ENE diminished the odds of a biochemical CR (odds ratio 3.5% [CI 1.3-10], p=0.02), and increased the probability that the sTg levels after surgery will exceed 50 ng/mL (odds ratio 5 [CI 1.2-21], p=0.03). Following surgery for tumor persistence, 25% of those with ENE were rendered biochemically free of disease. Conclusions: ENE diminishes the probability of a biochemical CR after treatment for regional metastatic PTC, and increases the probability of tumor persistence after initial resection, likely from abundant metastasis. ENE and nodal persistence independently predict eventual systemic disease progression. [ABSTRACT FROM AUTHOR]