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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

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          Abstract

          Medullary thyroid carcinoma (MTC) is a rare non-follicular cell-derived tumor. A robust grading system may help better stratify patients at risk for recurrence and death from disease. One hundred forty-four MTC between 1988 and 2018 were subjected to a detailed histopathologic evaluation. Clinical and pathologic data were correlated with disease specific survival (DSS), local recurrence free survival (LRFS) and distant metastasis free survival (DMFS). Median age was 53 years (range: 3–88). Median tumor size was 1.8 cm (range: 0.2–11). Lymph node metastases were present in 84 (58%) cases while distant metastases at presentation were found in 9 (6%) patients. Seven (5%) had ≥5 mitoses/10 HPFs. Tumor necrosis was present in 30 cases (20%) while lymphovascular invasion occurred in 41 (28%) of tumors. Extra-thyroidal extension was found in 44 (31%) and positive margins were seen in 19 (14%). There was a strong correlation between increasing tumor size and tumor necrosis (p<0.001). Median follow up was 39 months. In univariate analysis, male gender, higher AJCC stage group, larger tumor size, tumor necrosis, high mitotic index (≥5/10 HPF), nodal status, size of largest nodal metastasis, and elevated post-operative serum calcitonin predicted worse DSS, LRFS and DMFS (p<0.05). Extra-thyroidal extension correlated with DSS and DMFS while positive margins and distant metastasis at presentation imparted worse DSS (p<0.05). In multivariate analysis, tumor necrosis and mitotic activity (5 mitosis/10 HPFs as the cutoff) were the only independent predictors for DSS (p=0.008 and 0.026 respectively). Tumor necrosis was the sole independent prognostic factor for LRFS and DMFS (p=0.001 and 0.003 respectively). The presence of tumor necrosis and high mitotic rate are powerful independent prognostic factors in MTC and outperform serum calcitonin and stage. We propose a grading system based on tumor necrosis and mitotic activity to better stratify MTC patients for counseling, post resection surveillance and therapy.

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          Most cited references 46

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          Prognostic significance of somatic RET oncogene mutations in sporadic medullary thyroid cancer: a 10-year follow-up study.

          Medullary thyroid carcinoma (MTC) is a well-differentiated thyroid tumor that maintains the typical features of C cells. An advanced stage and the presence of lymph node metastases at diagnosis have been demonstrated to be the most important bad prognostic factors. Somatic RET mutations have been found in 40-50% of MTCs. Although a relationship between somatic mutations and bad prognosis has been described, data are controversial and have been performed in small series with short-term follow ups. The aim of this study was to verify the prognostic value of somatic RET mutations in a large series of MTCs with a long follow up. We studied 100 sporadic MTC patients with a 10.2 yr mean follow-up. RET gene exons 10-11 and 13-16 were analyzed. The correlation between the presence/absence of a somatic RET mutation, clinical/pathological features, and outcome of MTC patients was evaluated. A somatic RET mutation was found in 43 of 100 (43%) sporadic MTCs. The most frequent mutation (34 of 43, 79%) was M918T. RET mutation occurrence was more frequent in larger tumors (P=0.03), and in MTC with node and distant metastases (P<0.0001 and P=0.02, respectively), thus, a significant correlation was found with a more advanced stage at diagnosis (P=0.004). A worse outcome was also significantly correlated with the presence of a somatic RET mutation (P=0.002). Among all prognostic factors found to be correlated with a worse outcome, at multivariate analysis only the advanced stage at diagnosis and the presence of a RET mutation showed an independent correlation (P<0.0001 and P=0.01, respectively). Finally, the survival curves of MTC patients showed a significantly lower percentage of surviving patients in the group with RET mutations (P=0.006). We demonstrated that the presence of a somatic RET mutation correlates with a worse outcome of MTC patients, not only for the highest probability to have persistence of the disease, but also for a lower survival rate in a long-term follow up. More interestingly, the presence of a somatic RET mutation correlates with the presence of lymph node metastases at diagnosis, which is a known bad prognostic factor for the definitive cure of MTC patients.
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            Medullary thyroid carcinoma: clinical characteristics, treatment, prognostic factors, and a comparison of staging systems.

            The clinical courses of patients with medullary thyroid carcinoma (MTC) vary, and a number of prognostic factors have been studied, but the significance of some of these factors remains controversial. The study group consisted of 104 patients with MTC or C-cell hyperplasia managed at the hospitals of the University of California, San Francisco, between January 1960 and December 1998. Patients were classified as having sporadic MTC, familial non-multiple endocrine neoplasia (MEN) MTC, MEN 2A, or MEN 2B. The TNM, European Organization for Research and Treatment of Cancer (EORTC), National Thyroid Cancer Treatment Cooperative Study (NTCTCS), and Surveillance, Epidemiology, and End Results (SEER) extent-of-disease stages were determined for each patient. The predictive values of these staging or prognostic scoring systems were compared by calculating the proportion of variance explained (PVE) for each system. Fifty-six percent of the patients had sporadic MTC, 22% had familial MTC, 15% had MEN 2A, and 7% had MEN 2B. The overall average age at diagnosis was 38 years, and patients with sporadic MTC presented at an older age (P < 0.05). Thirty-two percent of the patients with hereditary MTC were diagnosed by screening (genetic and/or biochemical). These patients had a lower incidence of cervical lymph node metastasis (P < 0.05) and 94.7% were cured at last follow-up (P < 0.0001) compared with patients not screened. Patients with sporadic MTC who had systemic symptoms (diarrhea, bone pain, or flushing) had widely metastatic MTC and 33.3% of those patients died within 5 years. Overall, 49.4% of the patients were cured, 12.3% had recurrent MTC, and 38.3% had persistent MTC. The mean follow-up time was 8.6 years (median, 5.0 years) with 10.7% (n=11) and 13.5% (n=14) cause specific mortality at 5 and 10 years, respectively. Patients with persistent or recurrent MTC who died of MTC lived for an average of 3.6 years (ranging from 1 month to 23.7 years). Patients who had total or subtotal thyroidectomy were less likely to have persistent or recurrent MTC (P < 0.05), and patients who had total thyroidectomy with cervical lymph node clearance required fewer reoperations for persistent or recurrent MTC (P < 0.05) than patients who underwent lesser procedures. In univariate analysis, age, gender, clinical presentation, TNM stage, sporadic/hereditary MTC, distant metastasis, and extent of thyroidectomy were significant prognostic factors. Only age and stage, however, remained independent prognostic factors in multivariate analysis. The TNM, EORTC, NTCTCS, and SEER staging systems were all accurate predictors of survival, but the EORTC prognostic scoring system had the highest PVE in this cohort. Screening for MTC and early treatment (total thyroidectomy with central neck lymph node clearance) had nearly a 100% cure rate. Patients with postoperative hypercalcitoninemia without clinical or radiologic evidence of residual tumor after apparently curative surgery may enjoy long term survival but have occult MTC. Only patient age at presentation and TNM stage were independent predictors of survival. The EORTC criteria, which included the greatest number of significant prognostic factors in our cohort, had the highest predictive value. Copyright 2000 American Cancer Society.
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              Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma.

              The American Thyroid Association appointed a Task Force of experts to revise the original Medullary Thyroid Carcinoma: Management Guidelines of the American Thyroid Association.
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                Author and article information

                Journal
                8806605
                6644
                Mod Pathol
                Mod. Pathol.
                Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc
                0893-3952
                1530-0285
                20 March 2020
                20 April 2020
                September 2020
                20 October 2020
                : 33
                : 9
                : 1690-1701
                Affiliations
                [1 ]Department of Pathology, Mount Sinai Hospital, New York, New York.
                [2 ]Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY
                [3 ]Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
                [4 ]Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
                [5 ]Department of Medical oncology, Memorial Sloan Kettering Cancer Center, New York, NY
                Author notes
                [*]

                BA and BX contributed equally.

                [#]

                Co-senior authorship

                Correspondence: Ronald A. Ghossein MD, Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, ghosseir@ 123456mskcc.org , Brian R. Untch MD, Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, untchb@ 123456mskcc.org
                Article
                NIHMS1577738
                10.1038/s41379-020-0532-1
                7483270
                32313184

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                Categories
                Article

                Pathology

                ret, medullary thyroid carcinoma, grading, necrosis, mitosis

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