Bin Xu1, Talia L Fuchs2,3, Sara Ahmadi4, Mohammed Alghamdi1, Bayan Alzumaili1, Mohamed-Amine Bani5, Eric Baudin6, Angela Chou2,3, Antonio De Leo7, James A Fagin8, Ian Ganly9, Anthony Glover3,10, Dana Hartl11, Christina Kanaan5, Pierre Khneisser5, Fedaa Najdawi12, Aradhya Nigam9, Alex Papachristos3,10, Andrea Repaci13, Philip M Spanheimer9, Erica Solaroli14, Brian R Untch9, Justine A Barletta12, Giovanni Tallini7, Abir Al Ghuzlan5, Anthony J Gill2,3, Ronald A Ghossein1. 1. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY. 2. NSW Health Pathology, Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards, NSW, Australia. 3. University of Sydney, Sydney, NSW, Australia. 4. Department of Medicine, Division of Endocrinology and Metabolism, Brigham and Women's Hospital, Boston, Harvard Medical School, MA. 5. Medical Pathology and Biology Department, Gustave Roussy Campus Cancer, Villejuif, France. 6. Department of Endocrine Oncology and Nuclear Medicine, Gustave Roussy Cancer Campus Grand Paris, Villejuif, France. 7. Pathology Unit-Azienda USL di Bologna, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy. 8. Division of Subspecialty Medicine, Memorial Sloan Kettering Cancer Center, New York, NY. 9. Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY. 10. Endocrine Surgical Unit, Royal North Shore Hospital, St Leonards, NSW, Australia. 11. Department of Surgery, Gustave Roussy Cancer Campus Grand Paris, Villejuif, France. 12. Department of Pathology, Brigham and Women's Hospital, Boston, MA. 13. Endocrinology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy. 14. Endocrinology Unit-Azienda USL di Bologna, Bologna, Italy.
Abstract
PURPOSE: Medullary thyroid carcinoma (MTC) is an aggressive neuroendocrine tumor (NET) arising from the calcitonin-producing C cells. Unlike other NETs, there is no widely accepted pathologic grading scheme. In 2020, two groups separately developed slightly different schemes (the Memorial Sloan Kettering Cancer Center and Sydney grade) on the basis of proliferative activity (mitotic index and/or Ki67 proliferative index) and tumor necrosis. Building on this work, we sought to unify and validate an internationally accepted grading scheme for MTC. PATIENTS AND METHODS: Tumor tissue from 327 patients with MTC from five centers across the United States, Europe, and Australia were reviewed for mitotic activity, Ki67 proliferative index, and necrosis using uniform criteria and blinded to other clinicopathologic features. After reviewing different cutoffs, a two-tiered consensus grading system was developed. High-grade MTCs were defined as tumors with at least one of the following features: mitotic index ≥ 5 per 2 mm2, Ki67 proliferative index ≥ 5%, or tumor necrosis. RESULTS: Eighty-one (24.8%) MTCs were high-grade using this scheme. In multivariate analysis, these patients demonstrated decreased overall (hazard ratio [HR] = 11.490; 95% CI, 3.118 to 32.333; P < .001), disease-specific (HR = 8.491; 95% CI, 1.461 to 49.327; P = .017), distant metastasis-free (HR = 2.489; 95% CI, 1.178 to 5.261; P = .017), and locoregional recurrence-free (HR = 2.114; 95% CI, 1.065 to 4.193; P = .032) survivals. This prognostic power was maintained in subgroup analyses of cohorts from each of the five centers. CONCLUSION: This simple two-tiered international grading system is a powerful predictor of adverse outcomes in MTC. As it is based solely on morphologic assessment in conjunction with Ki67 immunohistochemistry, it brings the grading of MTCs in line with other NETs and can be readily applied in routine practice. We therefore recommend grading of MTCs on the basis of mitotic count, Ki67 proliferative index, and tumor necrosis.
PURPOSE: Medullary thyroid carcinoma (MTC) is an aggressive neuroendocrine tumor (NET) arising from the calcitonin-producing C cells. Unlike other NETs, there is no widely accepted pathologic grading scheme. In 2020, two groups separately developed slightly different schemes (the Memorial Sloan Kettering Cancer Center and Sydney grade) on the basis of proliferative activity (mitotic index and/or Ki67 proliferative index) and tumor necrosis. Building on this work, we sought to unify and validate an internationally accepted grading scheme for MTC. PATIENTS AND METHODS: Tumor tissue from 327 patients with MTC from five centers across the United States, Europe, and Australia were reviewed for mitotic activity, Ki67 proliferative index, and necrosis using uniform criteria and blinded to other clinicopathologic features. After reviewing different cutoffs, a two-tiered consensus grading system was developed. High-grade MTCs were defined as tumors with at least one of the following features: mitotic index ≥ 5 per 2 mm2, Ki67 proliferative index ≥ 5%, or tumor necrosis. RESULTS: Eighty-one (24.8%) MTCs were high-grade using this scheme. In multivariate analysis, these patients demonstrated decreased overall (hazard ratio [HR] = 11.490; 95% CI, 3.118 to 32.333; P < .001), disease-specific (HR = 8.491; 95% CI, 1.461 to 49.327; P = .017), distant metastasis-free (HR = 2.489; 95% CI, 1.178 to 5.261; P = .017), and locoregional recurrence-free (HR = 2.114; 95% CI, 1.065 to 4.193; P = .032) survivals. This prognostic power was maintained in subgroup analyses of cohorts from each of the five centers. CONCLUSION: This simple two-tiered international grading system is a powerful predictor of adverse outcomes in MTC. As it is based solely on morphologic assessment in conjunction with Ki67 immunohistochemistry, it brings the grading of MTCs in line with other NETs and can be readily applied in routine practice. We therefore recommend grading of MTCs on the basis of mitotic count, Ki67 proliferative index, and tumor necrosis.
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