International Initiative on a Refined Staging System for Medullary Thyroid Cancer: A Multinational Multicenter Study

PURPOSE To refine the suboptimal prognostic discrimination of the American Joint Committee on Cancer (AJCC) 8th edition TNM (TNM-8) staging system for medullary thyroid carcinoma (MTC). METHODS This retrospective study enrolled patients with MTC from 43 centers across 15 countries under the framework of the International Medullary Thyroid Cancer Staging Consortium (IMTCSC). Pooled data were analyzed with disease-specific survival as the primary end point. With M1 disease fixed in stage IVC, we redefined the schema for stages I to IVB in M0 patients. Using exhaustive enumeration, all possible TN combinations were fitted into multivariable Cox models, with the lowest Akaike information criterion (AIC) defining the proposed system. Prognostic discrimination was assessed using adjusted hazard ratios (aHRs) and the concordance index (C-index). RESULTS The IMTCSC cohort included 2,573 patients with MTC (female-to-male ratio: 1.25; median age 52 years [IQR, 41-62]; median follow-up 76.3 months [IQR, 37.3-121.0]). Level VII metastasis correlated with poorer survival, supporting its upgrade to N1c. Exhaustive search of 116,284 admissible stage-grouping schemas identified the optimal model (lowest AIC) defining stages I to IVB: I (T1N0-N1a/T2N0), II (T1N1b/T2N1a/T3N0), III (T1N1c/T2N1b/T3N1a/T4aN0-N1a), IVA (T2N1c/T3N1b-N1c/T4aN1b), and IVB (T4aN1c/T4b any N). Compared with AJCC TNM-8 (stage I as reference; stage II aHR, 0.84, P = .652; stage III aHR, 1.48, P = .172; stage IV aHR, 7.95, P < .001), the proposed system showed a clearer monotonic increase in disease-specific death risk (stage II aHR 2.22; stage III aHR, 4.81; stage IV aHR 15.75; all P ≤ .001) and a higher C-index (0.892 v 0.856, P < .001), which was also evaluated in the SEER cohort (N = 1,909). CONCLUSION The proposed MTC staging system confers an improved schema for prognostic stratification compared with AJCC TNM-8.

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Journal
Journal of Clinical Oncology
Published
2026-11-04
DOI
https://doi.org/10.1200/jco-26-01146
Primary Topic
Thyroid Cancer Diagnosis and Treatment
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article
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article

International Initiative on a Refined Staging System for Medullary Thyroid Cancer: A Multinational Multicenter Study

Omar Hamdy, Amy Sheen, 关海霞, Christoph Becker et al.
Journal of Clinical Oncology
Thyroid Cancer Diagnosis and Treatment
article

International Initiative on a Refined Staging System for Medullary Thyroid Cancer: A Multinational Multicenter Study

Omar Hamdy, Amy Sheen, 关海霞, Christoph Becker, Simone De Leo, Alexander Papachristos, Antonio Matrone, Bin Xu, Carlos Eduardo Jiménez-Canizales, Minghua Ge, Qinghai Ji, Luis G. Carvajal‐Carmona, Kewei Jiang, Xiangqian Zheng, Andrea Repaci, Mohamed Amine Bani, Lori J. Wirth, Ana Patricia Estrada-Florez, Rossella Elisei, Shaoyan Liu, Zijie Niu, Anthony James Gill, Angela Y. Pan, JESUS VELIZ, Mark S. Sywak, Martin Jean Schlumberger, Yu Wang, Domenico Salvatore, Mábel Bohórquez, Mira Fink, Laura Fugazzola, Fabián Pitoia, Brian R. Untch, João Martins Gama, Dat Quoc Ngo, Changming An, Moon Young Oh, Anh Tu Thai, Berna Evranos Ogmen, Quốc Thắng Phạm, Dongmei Ji, Julien Hadoux, Ekin Yiğit Köroğlu, Ian Ganly, Nelson Wohllk G, Andreas Spörlein, Louise Davies, Ilya V. Sleptsov, Leonardo Rossi, Gabriele Materazzi, Xiao Hua SHI, Giovanni Tallini, Ronald A. Ghossein, Benjamin Houot, Cristina Luongo, Семенов Арсений Андреевич, Dapeng Li, Young Joo Park, Yihao Liu, Kehan Song, Matteo Trevisan, Stanley B. Sidhu, Cuiwei Li, Miao Mo, Yulong Wang, Hanqing Liu, BEKİR ÇAKIR, Chenyi Wang, Gabriela Sansó, Cenkai Shen, Maria João Martins, Zhihui Li, Lei Ye, Chuang Chen, Ming Gao, Wenjun Wei, Anggi Vélez-Bohórquez, Javiera Arancibia, Yijun Wu, Zhiyan Liu, Yuan Li, Yan Zhang, Zhihong Wang, Liang Guo, Yansong Lin, Cosimo Durante, Han Luo, Peng Li, Ming Song, Haipeng Xiao, Wuyang Ji, Pablo Guzman, Hao Zhang, Qiaomu Liu
article en

Abstract

PURPOSE To refine the suboptimal prognostic discrimination of the American Joint Committee on Cancer (AJCC) 8th edition TNM (TNM-8) staging system for medullary thyroid carcinoma (MTC). METHODS This retrospective study enrolled patients with MTC from 43 centers across 15 countries under the framework of the International Medullary Thyroid Cancer Staging Consortium (IMTCSC). Pooled data were analyzed with disease-specific survival as the primary end point. With M1 disease fixed in stage IVC, we redefined the schema for stages I to IVB in M0 patients. Using exhaustive enumeration, all possible TN combinations were fitted into multivariable Cox models, with the lowest Akaike information criterion (AIC) defining the proposed system. Prognostic discrimination was assessed using adjusted hazard ratios (aHRs) and the concordance index (C-index). RESULTS The IMTCSC cohort included 2,573 patients with MTC (female-to-male ratio: 1.25; median age 52 years [IQR, 41-62]; median follow-up 76.3 months [IQR, 37.3-121.0]). Level VII metastasis correlated with poorer survival, supporting its upgrade to N1c. Exhaustive search of 116,284 admissible stage-grouping schemas identified the optimal model (lowest AIC) defining stages I to IVB: I (T1N0-N1a/T2N0), II (T1N1b/T2N1a/T3N0), III (T1N1c/T2N1b/T3N1a/T4aN0-N1a), IVA (T2N1c/T3N1b-N1c/T4aN1b), and IVB (T4aN1c/T4b any N). Compared with AJCC TNM-8 (stage I as reference; stage II aHR, 0.84, P = .652; stage III aHR, 1.48, P = .172; stage IV aHR, 7.95, P < .001), the proposed system showed a clearer monotonic increase in disease-specific death risk (stage II aHR 2.22; stage III aHR, 4.81; stage IV aHR 15.75; all P ≤ .001) and a higher C-index (0.892 v 0.856, P < .001), which was also evaluated in the SEER cohort (N = 1,909). CONCLUSION The proposed MTC staging system confers an improved schema for prognostic stratification compared with AJCC TNM-8.

Journal of Clinical Oncology
University of Pisa (IT), The University of Sydney (AU), Memorial Sloan Kettering Cancer Center (US), Shanghai Medical College of Fudan University (CN), Harvard University (US), Seoul National University (KR), Sun Yat-sen University (CN), Mansoura University (EG), University of Freiburg (DE), St Petersburg University (RU), Shanghai Jiao Tong University (CN), University of Milan (IT), Universidad de Buenos Aires (AR), Fudan University (CN), Université Paris-Saclay (FR), Royal North Shore Hospital (AU), China-Japan Friendship Hospital (CN), University Medical Center Freiburg (DE), Institut Gustave Roussy (FR), Hospitais da Universidade de Coimbra (PT), University of Medicine and Pharmacy at Ho Chi Minh City (VN), Tianjin Medical University Cancer Institute and Hospital (CN), Seoul National University Hospital (KR), Universidad del Tolima (CO), Fudan University Shanghai Cancer Center (CN), IRCCS Azienda Ospedliero-Universitaria di Bologna Policlinico di Sant'Orsola (IT), Hospital del Salvador (CL), Hospital de Clínicas "José de San Martín" (AR), Peking University People's Hospital (CN), The First Affiliated Hospital, Sun Yat-sen University (CN), First Hospital of China Medical University (CN), Shanghai Sixth People's Hospital (CN), Ankara Yıldırım Beyazıt University (TR), Tongji Hospital (CN), First Affiliated Hospital Zhejiang University (CN), Azienda Socio Sanitaria Territoriale Santi Paolo e Carlo (IT), Huazhong University of Science and Technology (CN), Mass General Brigham (US), University of Chile (CL), University of Naples Federico II (IT), Zhejiang University (CN), University of California, Davis (US), University of Bologna (IT)
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Thyroid Cancer Diagnosis and Treatment
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