Yueye Huang1,2, Shen Qu2, Guangwu Zhu1, Fei Wang1, Rengyun Liu1, Xiaopei Shen1, David Viola3, Rossella Elisei3, Efisio Puxeddu4, Laura Fugazzola5, Carla Colombo5, Barbara Jarzab6, Agnieszka Czarniecka6, Alfred K Lam7, Caterina Mian8, Federica Vianello9, Linwah Yip10, Garcilaso Riesco-Eizaguirre11,12,13, Pilar Santisteban12,13, Christine J O'Neill14, Mark S Sywak14, Roderick Clifton-Bligh14, Bela Bendlova15, Vlasta Sýkorová15, Mingzhao Xing1. 1. Laboratory for Cellular and Molecular Thyroid Research, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD. 2. Department of Endocrinology and Metabolism and the Shanghai Research Center of Thyroid Diseases, The Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China. 3. Endocrine Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy. 4. Department of Internal Medicine, University of Perugia, Perugia, Italy. 5. Division of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, and Department of Pathophysiology and Transplantation, University of Milan, Milan Italy. 6. Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice, Poland. 7. Cancer Molecular Pathology of School of Medicine and Menzies Health Institute Queensland, Griffith University, Gold Coast, Australia. 8. Department of Medicine, Endocrinology Unit, University of Padua, Padua, Italy. 9. Veneto Institute of Oncology, IRCCS, Padua, Italy. 10. University of Pittsburgh School of Medicine, Pittsburgh, PA. 11. Department of Endocrinology and Nutrition Hospital Universitario La Paz and Hospital, Universitario de Mostoles, 28029 Madrid, Spain. 12. Biomedical Research Institute "Alberto Sols," Consejo Superior de Investigaciones Cientificas and Universidad Autonoma de Madrid, 28029 Madrid, Spain. 13. Ciberonc, Health Institute Carlos III, 28029 Madrid, Spain. 14. Endocrine Surgical Unit, The University of Sydney, Sydney, Australia. 15. Department of Molecular Endocrinology Institute of Endocrinology, Prague, Czech Republic.
Abstract
Background: Precise risk stratification-based treatment of solitary intrathyroidal papillary thyroid cancer (SI-PTC) that is larger than 1.0 cm and 4.0 cm or less is undefined. Methods: A genetic-clinical risk study was performed on BRAF V600E in 955 patients (768 women and 187 men) with SI-PTC, with median age of 46 years and median clinical follow-up time of 64 months at 11 medical centers in six countries. The chi-square test or, for analyses with small numbers, Fisher's exact test was performed to compare recurrence rates. Recurrence-free probability was estimated by Kaplan-Meier (KM) analysis, and the independent effect of BRAF mutation on the recurrence was analyzed by Cox regression and Cox proportional hazard analyses. All statistical tests were two-sided. Results: Recurrence of SI-PTC larger than 1.0 cm and 4.0 cm or less was 9.5% (21/221) vs 3.4% (11/319) in BRAF mutation vs wild-type BRAF patients, with a hazard ratio (HR) of 3.03 (95% confidence interval [CI] = 1.46 to 6.30) and a patient age- and sex-adjusted hazard ratio of 3.10 (95% CI = 1.49 to 6.45, P = .002). Recurrence rates of SI-PTC larger than 2.0 cm and 4.0 cm or less were 16.5% (13/79) vs 3.6% (5/139) in mutation vs wild-type patients (HR = 5.44, 95% CI = 1.93 to 15.34; and adjusted HR = 5.58, 95% CI = 1.96 to 15.85, P = .001). Recurrence rates of SI-PTC larger than 3.0 cm and 4 cm or less were 30.0% (6/20) vs 1.9% (1/54) in mutation vs wild-type patients (HR = 18.40, 95% CI = 2.21 to 152.98; and adjusted HR = 14.73, 95% CI = 1.74 to 124.80, P = .01). Recurrences of mutation-positive SI-PTC were comparable with those of counterpart invasive solitary PTC, around 20% to 30%, in tumors larger than 2.0 cm to 3.0 cm. BRAF mutation was associated with a statistically significant decrease in recurrence-free patient survival on KM analysis, particularly in SI-PTC larger than 2.0 cm and 4.0 cm or less. Similar results were obtained in conventional SI-PTC. The negative predictive values of BRAF mutation for recurrence were 97.8% (95% CI = 96.3% to 98.8%) for general SI-PTC and 98.2% (95% CI = 96.3% to 99.3%) for conventional SI-PTC. Conclusions: BRAF V600E identifies a subgroup of SI-PTC larger than 1.0 cm and 4.0 cm or less, particularly tumors larger than 2.0 cm and 4.0 cm or less, that has high risk for recurrence comparable with that of invasive solitary PTC, making more aggressive treatment reasonable.
Background: Precise risk stratification-based treatment of solitary intrathyroidal papillary thyroid cancer (SI-PTC) that is larger than 1.0 cm and 4.0 cm or less is undefined. Methods: A genetic-clinical risk study was performed on BRAFV600E in 955 patients (768 women and 187 men) with SI-PTC, with median age of 46 years and median clinical follow-up time of 64 months at 11 medical centers in six countries. The chi-square test or, for analyses with small numbers, Fisher's exact test was performed to compare recurrence rates. Recurrence-free probability was estimated by Kaplan-Meier (KM) analysis, and the independent effect of BRAF mutation on the recurrence was analyzed by Cox regression and Cox proportional hazard analyses. All statistical tests were two-sided. Results: Recurrence of SI-PTC larger than 1.0 cm and 4.0 cm or less was 9.5% (21/221) vs 3.4% (11/319) in BRAF mutation vs wild-type BRAFpatients, with a hazard ratio (HR) of 3.03 (95% confidence interval [CI] = 1.46 to 6.30) and a patient age- and sex-adjusted hazard ratio of 3.10 (95% CI = 1.49 to 6.45, P = .002). Recurrence rates of SI-PTC larger than 2.0 cm and 4.0 cm or less were 16.5% (13/79) vs 3.6% (5/139) in mutation vs wild-type patients (HR = 5.44, 95% CI = 1.93 to 15.34; and adjusted HR = 5.58, 95% CI = 1.96 to 15.85, P = .001). Recurrence rates of SI-PTC larger than 3.0 cm and 4 cm or less were 30.0% (6/20) vs 1.9% (1/54) in mutation vs wild-type patients (HR = 18.40, 95% CI = 2.21 to 152.98; and adjusted HR = 14.73, 95% CI = 1.74 to 124.80, P = .01). Recurrences of mutation-positive SI-PTC were comparable with those of counterpart invasive solitary PTC, around 20% to 30%, in tumors larger than 2.0 cm to 3.0 cm. BRAF mutation was associated with a statistically significant decrease in recurrence-free patient survival on KM analysis, particularly in SI-PTC larger than 2.0 cm and 4.0 cm or less. Similar results were obtained in conventional SI-PTC. The negative predictive values of BRAF mutation for recurrence were 97.8% (95% CI = 96.3% to 98.8%) for general SI-PTC and 98.2% (95% CI = 96.3% to 99.3%) for conventional SI-PTC. Conclusions: BRAFV600E identifies a subgroup of SI-PTC larger than 1.0 cm and 4.0 cm or less, particularly tumors larger than 2.0 cm and 4.0 cm or less, that has high risk for recurrence comparable with that of invasive solitary PTC, making more aggressive treatment reasonable.
Authors: Paula Soares; Antónia Afonso Póvoa; Miguel Melo; João Vinagre; Valdemar Máximo; Catarina Eloy; José Manuel Cameselle-Teijeiro; Manuel Sobrinho-Simões Journal: Endocr Pathol Date: 2021-03-02 Impact factor: 3.943
Authors: Mourad Zerfaoui; Koji Tsumagari; Eman Toraih; Youssef Errami; Emmanuelle Ruiz; Mohammed Sohail M Elaasar; Moroz Krzysztof; Andrew B Sholl; Sameh Magdeldin; Mohamed Soudy; Zakaria Y Abd Elmageed; A Hamid Boulares; Emad Kandil Journal: Am J Cancer Res Date: 2022-07-15 Impact factor: 5.942