International Medullary Thyroid Carcinoma Grading System: A Validated Grading System for Medullary Thyroid Carcinoma

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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Grading of medullary thyroid carcinoma on the basis of tumor necrosis and high mitotic rate is an independent predictor of poor outcome

Modern Pathology ◽

10.1038/s41379-020-0532-1 ◽

2020 ◽

Vol 33 (9) ◽

pp. 1690-1701 ◽

Cited By ~ 1

Author(s):

Bayan Alzumaili ◽

Bin Xu ◽

Philip M. Spanheimer ◽

R. Michael Tuttle ◽

Eric Sherman ◽

...

Keyword(s):

Thyroid Carcinoma ◽

Medullary Thyroid Carcinoma ◽

Tumor Necrosis ◽

Independent Predictor ◽

Mitotic Rate ◽

Medullary Thyroid ◽

Poor Outcome

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Screening for Medullary Thyroid Carcinoma with Serum Calcitonin Measurements in Patients with Thyroid Nodules in the United States and Canada

Thyroid ◽

10.1089/thy.2010.0297 ◽

2011 ◽

Vol 21 (11) ◽

pp. 1199-1207 ◽

Cited By ~ 40

Author(s):

Gilbert H. Daniels

Keyword(s):

United States ◽

Thyroid Carcinoma ◽

Medullary Thyroid Carcinoma ◽

Thyroid Nodules ◽

The United States ◽

Serum Calcitonin ◽

Medullary Thyroid

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Replication of newly proposed TNM staging system for medullary thyroid carcinoma: a nationwide study

Endocrine Connections ◽

10.1530/ec-18-0494 ◽

2019 ◽

Vol 8 (1) ◽

pp. 1-7 ◽

Cited By ~ 1

Author(s):

Jes Sloth Mathiesen ◽

Jens Peter Kroustrup ◽

Peter Vestergaard ◽

Per Løgstrup Poulsen ◽

Åse Krogh Rasmussen ◽

...

Keyword(s):

United States ◽

Thyroid Carcinoma ◽

Medullary Thyroid Carcinoma ◽

Stage Iv ◽

Staging System ◽

The United States ◽

Population Based ◽

Tnm Staging ◽

Medullary Thyroid ◽

Tnm Staging System

A recent study proposed new TNM groupings for better survival discrimination among stage groups for medullary thyroid carcinoma (MTC) and validated these groupings in a population-based cohort in the United States. However, it is unknown how well the groupings perform in populations outside the United States. Consequently, we conducted the first population-based study aiming to evaluate if the recently proposed TNM groupings provide better survival discrimination than the current American Joint Committee on Cancer (AJCC) TNM staging system (seventh and eighth edition) in a nationwide MTC cohort outside the United States. This retrospective cohort study included 191 patients identified from the nationwide Danish MTC cohort between 1997 and 2014. In multivariate analysis, hazard ratios for overall survival under the current AJCC TNM staging system vs the proposed TNM groupings with stage I as reference were 1.32 (95% CI: 0.38–4.57) vs 3.04 (95% CI: 1.38–6.67) for stage II, 2.06 (95% CI: 0.45–9.39) vs 3.59 (95% CI: 1.61–8.03) for stage III and 5.87 (95% CI: 2.02–17.01) vs 59.26 (20.53–171.02) for stage IV. The newly proposed TNM groupings appear to provide better survival discrimination in the nationwide Danish MTC cohort than the current AJCC TNM staging. Adaption of the proposed TNM groupings by the current AJCC TNM staging system may potentially improve accurateness in survival discrimination. However, before such an adaption further population-based studies securing external validity are needed.

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Expression of Prox1 in Medullary Thyroid Carcinoma Is Associated with Chromogranin A and Calcitonin Expression and with Ki67 Proliferative Index, but Not with Prognosis

Endocrine Pathology ◽

10.1007/s12022-019-9576-5 ◽

2019 ◽

Vol 30 (2) ◽

pp. 138-145 ◽

Cited By ~ 1

Author(s):

Chiara Saglietti ◽

Stefano La Rosa ◽

Gerasimos P. Sykiotis ◽

Igor Letovanec ◽

Jean-Luc Bulliard ◽

...

Keyword(s):

Thyroid Carcinoma ◽

Medullary Thyroid Carcinoma ◽

Chromogranin A ◽

Proliferative Index ◽

Medullary Thyroid

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What Lies Beneath? - Medullary Thyroid Cancer in Nodular Graves’ Disease

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.1845 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A904-A904

Author(s):

Rongzhi Wang ◽

Shirisha R Vallepu ◽

Herbert Chen ◽

Rajasree Nambron

Keyword(s):

Thyroid Carcinoma ◽

Total Thyroidectomy ◽

Medullary Thyroid Carcinoma ◽

The United States ◽

Endocrine Surgery ◽

Graves Disease ◽

Hormone Production ◽

Thyroid Cancers ◽

Medullary Thyroid ◽

Central Lymph Node Dissection

Abstract Background: Medullary thyroid carcinoma (MTC) accounts for 1%-2% of thyroid cancers in the United States (US). MTC originates from thyroid parafollicular C-cells, occurring either sporadically or hereditarily as part of type 2 multiple endocrine neoplasia (MEN) or familial MTC (FMTC). Hyperthyroidism is prevalent in approximately 1.2%, and Graves’ Disease (GD) is the most common cause of hyperthyroidism in the US. GD is an autoimmune disorder that results in increased thyroid hormone production due to the stimulation of TSH receptor by thyrotropin receptor antibodies (TRAb). Thyroid carcinoma in general is uncommon in GD patients, while MTC is extraordinarily rare. We report a case of sporadic MTC in GD, which is extremely rare. A recent publication stated that there were only 15 reported cases of MTC coexisting in GD until 2019. Clinical Case: A 62-year-old male with hypertension, diabetes and obesity presented to the endocrine surgery clinic with symptoms of diaphoresis, chest pain and fullness, shortness of breath, and palpitations. The patient had a brother with a pancreatic mass of unknown pathology and multiple family members with thyroid disease. On physical exam, there was a palpable non-tender left-sided nodule with no lymphadenopathy. His FT4 was 8.5 (0.76-1.46 ng/dL), TSH was <0.006 (0.36-3.74 μIU/dL) and thyroid-stimulating antibody was 1.25 (<0.10 IU/L). Ultrasound showed a multinodular goitre with a dominant nodule in the left lower pole measuring 2.3x1.9x1.5 cm. He was diagnosed with GD, treated with methimazole, and his symptoms improved. Subsequent nuclear medicine uptake scan showed diffusely increased uptake and a cold nodule in the left thyroid lobe. Repeat labs showed low TSH (<0.01μIU/dL) and elevated FT4, CEA, calcitonin, PTH, metanephrine, and normetanephrine (1.04 ng/dl, 5.2 (3-5 ng/ml), 796 (<18 pg/ml), 58.10 (18.40-88.00 pg/mL), 90 (< OR = 57 pg/ml) and 222 (< OR = 148 pg/ml), respectively). A thyroid fine-needle aspiration (FNA) was suggestive of MTC (Bethesda Category VI). Total thyroidectomy with left central lymph node dissection revealed a 2.5cm MTC confined in the left lobe with focal lymphovascular invasion. His postoperative course was uneventful, and CEA and calcitonin levels trended down (1.1 ng/ml and <2 pg/mL, respectively). Conclusion: The coexistence of medullary thyroid carcinoma and Graves’ Disease is rare, incidental, with five-year survival rates lower than other thyroid cancers. A delayed diagnosis of MTC would be detrimental. Patients with thyroid nodules and GD are five times more likely to be diagnosed with thyroid carcinoma. Radiation, chemotherapy and thyroidectomy are standard treatment options for MTC, with total thyroidectomy being the preferred option. It is necessary to evaluate patients with GD for possible thyroid cancers, especially in the presence of nodules.

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