A key change in the recently published 5th edition of the WHO Classification of Endocrine and Neuroendocrine Tumors was the subdivision of thyroid tumors into new categories that more clearly reflect their cell of origin, molecular classification, cytopathological and histopathological features, and biological behaviors.

With regards to medullary thyroid carcinoma (MTC), “the most important update . . . is the introduction of a grading scheme,” Baloch and colleagues wrote in a summary of changes related to the thyroid gland in the 5th edition. Their summary appeared in Endocrine Pathology.

Since MTC was defined histologically in the 1950s, there has never been a recognized grading system for this cancer. But in 2020, 2 groups of researchers independently developed grading systems for MTC. Let us take a look at their work. 

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Categorizing MTC by Necrosis and Mitotic Rate 

Alzumaili and colleagues performed a detailed histopathological review of 144 MTC samples and studied the clinical outcome of the patients from whom these samples were taken. In Modern Pathology, they proposed the grading of MTC based on mitotic rate and tumor necrosis.

For the histopathological examination, the researchers used the largest tumor nodule of each MTC sample and assessed the mitotic rate and the presence of tumor necrosis. Mitotic counts were performed in areas that demonstrated higher proliferative activity. Tumor necrosis was defined by a pattern of degenerating cytoplasm and punctuate, karyorrhectic nuclear debris.

Read more about MTC etiology 

Follow-up data of the patients was obtained through medical records. The researchers recorded the following information: age at thyroidectomy, type of thyroid surgery, sex of the patient, germline RET status, postoperative serum calcitonin and carcinoembryonic antigen (CEA) levels, and distant metastatic status at presentation and on follow-up.

Results demonstrated that a higher mitotic rate and the presence of tumor necrosis were both independent predictors of poor clinical outcomes. They thus proposed a 2-tiered grading system of MTC based on those factors:  

  • Low-grade if the MTC contained <5 mitosis/10 HPF and no tumor necrosis
  • High-grade if the MTC had ≥5 mitosis/10 HPF and/or tumor necrosis.

The research team expressed hope that the grading system “will enable the treating clinician to better counsel the patient, design the optimal follow up and better select those individuals who may benefit from systemic therapy.” 

A Proposed 3-Tier Grading Scheme

In The American Journal of Surgical Pathology, Fuchs and colleagues proposed a grading system of MTC based on the prognostic value of histological parameters. A total of 76 MTC samples from patients who underwent primary tumor resection were collected. Data on the patients and the tumor were recorded.

“In addition to the clinical features of age and the diagnosis of MEN2, the only histologic features that significantly predicted reduced overall survival were Ki-67 proliferative index, mitotic count, and the presence of coagulative necrosis,” Fuchs and colleagues wrote. 

Read more about MTC patient education 

They hence proposed a 3-tier grading system based only on necrosis and proliferative activity (Ki-67 proliferative index and mitotic count): 

  • Low-grade MTC has low proliferative activity, defined as a Ki-67 index of less than 3% and less than 3 mitoses/2 mm2. There must be no presence of coagulative necrosis. 
  • Intermediate-grade MTC has an intermediate proliferative index, defined as a Ki-67 index of 3% to 20%, as well as 3 to 20 mitoses/2 mm2. There must be no presence of coagulative necrosis. 
  • High-grade MTC either has an intermediate proliferative index (with the same definition used above) and coagulative necrosis, or a high proliferative index, defined as a Ki-67 index of more than 20% and more than 20 mitoses/2 mm2, with or without coagulative necrosis. 

This 3-tier grading system was found to be prognostically significant after controlling for MEN2 status and age.

“If our findings are confirmed in other multi-institutional cohorts, a strong argument could be made to include this simple and inexpensive grading system in routine clinical practice,” Fuchs et al wrote.

Making MTC Treatment More Precise 

It is notable that both research teams essentially used the same factors for their proposed systems—proliferative activity and tumor necrosis). In 2021, the WHO adopted a 2-tiered grading system in which high-grade tumors were defined as having at least one of the following features: 

  • Tumor necrosis
  • Mitotic count of 5 per 2 mm2 or more
  • Ki67 proliferation index of 5% or more. 

The movement to adopt a grading system for MTC is the result of years of research and is intended to make the care of patients with MTC more precise. “This novel histologic grade may benefit high-grade patients leading to closer follow-up, low thresholds for cross-sectional imaging, and careful monitoring for distant metastasis,” Baloch and colleagues wrote. 


Baloch ZW, Asa SL, Barletta JA, et al. Overview of the 2022 WHO classification of thyroid neoplasmsEndocr Pathol. 2022;10.1007/s12022-022-09707-3. doi:10.1007/s12022-022-09707-3

Alzumaili B, Xu B, Spanheimer PM, et al. Grading of medullary thyroid carcinoma on the basis of tumor necrosis and high mitotic rate is an independent predictor of poor outcomeMod Pathol. 2020;33(9):1690-1701. doi:10.1038/s41379-020-0532-1

Fuchs TL, Nassour AJ, Glover A, et al. A proposed grading scheme for medullary thyroid carcinoma based on proliferative activity (Ki-67 and mitotic count) and coagulative necrosisAm J Surg Pathol. 2020;44(10):1419-1428. doi:10.1097/PAS.0000000000001505