BACKGROUND: Detectable, and especially rising post-thyroidectomy serum calcitonin and Carcinoembryonic Antigen (CEA) levels, as per American Thyroid Association (ATA) guidelines, indicate potential disease presence, requiring frequent calcitonin measurement or imaging for early detection of persistent or recurrent Medullary Thyroid Carcinoma (MTC). Thus, defining the clinical cutoff value of detection of calcitonin assays relative to imaging and clinical status is crucial for patient care. This study aimed to evaluate postoperative calcitonin levels using the new Siemens Atellica assay system to determine the most appropriate levels for clinical decision-making.
METHODS: A retrospective analysis was conducted using Siemens Atellica for calcitonin testing on 56 samples from 40 patients between 09/27/2022 and 08/11/2023. Only calcitonin results performed at least 3 months post-total thyroidectomy were included. Imaging studies, within 6 months of the calcitonin report, were assessed. CEA results were also reviewed.
RESULTS: Precision analysis at 2.94 and 5.24 pg/mL revealed coefficients of variation (CVs) at 16.49% and 8.87%, respectively. For the evidence of post-total thyroidectomy persistent or recurrent MTC confirmed by imaging, using a 1.89 pg/mL cutoff for calcitonin yielded 43% sensitivity and 67% specificity. Using a 5.00 pg/mL cutoff resulted in 0% sensitivity and 100% specificity.
CONCLUSIONS: Our findings indicate the potential suitability of a 5 pg/mL calcitonin cutoff on the Siemens Atellica platform for evaluating tumor persistence or recurrence in post-thyroidectomy patients in our institution. However, individual laboratories should establish their own clinical cutoff value when evaluating calcitonin levels for monitoring tumor recurrence post-thyroidectomy.

UNASSIGNED: Lateral lymph node metastasis (LLNM) is very common in medullary thyroid carcinoma (MTC), but there is still controversy about how to manage cervical lateral lymph nodes, especially for clinically negative MTC. The aim of this study is to develop and validate a nomogram for predicting LLNM risk in MTC.
UNASSIGNED: A total of 234 patients from two hospitals were retrospectively enrolled in this study and divided into LLNM positive group and LLNM negative group based on the pathology. The correlation between LLNM and preoperative clinical and ultrasound variables were evaluated by univariable and multivariable logistic regression analysis. A nomogram was generated to predict the risk of the LLNM of MTC patients, validated by external dataset, and evaluated in terms of discrimination, calibration, and clinical usefulness.
UNASSIGNED: The training, internal, and external validation datasets included 152, 51, and 31 MTC patients, respectively. According to the multivariable logistic regression analysis, gender (male), relationship to thyroid capsule and serum calcitonin were independently associated with LLNM in the training dataset. The predictive nomogram model developed with the aforementioned variables showed favorable performance in estimating risk of LLNM, with the area under the ROC curve (AUC) of 0.826 in the training dataset, 0.816 in the internal validation dataset, and 0.846 in the external validation dataset.
UNASSIGNED: We developed and validated a model named MTC nomogram, utilizing available preoperative variables to predict the probability of LLNM in patients with MTC. This nomogram will be of great value for guiding the clinical diagnosis and treatment process of MTC patients.

Few studies have investigated the impact of primary tumor resection (PTR) on patients with distant metastasis medullary thyroid carcinoma (DMMTC). This population-based study aims to assess the application of PTR in DMMTC patients, ascertain its benefits, and identify optimal surgical indications. DMMTC Patients diagnosed between 2010 and 2020 were included through the Surveillance, Epidemiology, and End Results (SEER) program. Logistic regression analysis identified driving factors of surgical decision-making. Propensity score matching (PSM), Kaplan-Meier method, and Cox regression were utilized to compare overall survival (OS) and disease-specific survival (DSS) between surgical and non-surgical groups. Subgroup analyses were performed to determine optimal surgical indications. Of 238 DMMTC patients included, 122 (51.3%) patients underwent PTR. Extrathyroidal extension and N1 stage emerged as independent factors promoting the surgical decision. PSM-adjusted survival analyses revealed significant advantages in both OS and DSS for the surgical group. Moreover, subgroup analyses indicated that except for patients aged ≥ 65 years, tumors ≤ 20 mm, or with multiple metastasized sites (> 1), the others significantly benefit from PTR. PTR significantly improves prognosis in selected DMMTC patients. The decision to undergo PTR in other patients should be based on a comprehensive assessment of the disease, surgeon\'s experience, and family discussions for potential survival benefits.

OBJECTIVE: Despite several factors that may have been associated with poor disease-free survival (DFS) in patients with medullary thyroid carcinoma (MTC), only a few studies have evaluated the prognostic factors affecting DFS in MTC patients. Therefore, this study evaluated the prognostic factors affecting DFS, in a large number of patients with MTC.
METHODS: Patients treated for MTC were retrospectively analyzed. Patients were stratified as having persistent/recurrent disease and no evidence of disease (NOD) at the last follow-up. The factors affecting DFS after the initial therapy and during the follow-up period were investigated.
RESULTS: This study comprised 257 patients [females 160 (62.3%), hereditary disease 48 (18.7%), with a mean follow-up time of 66.8 ± 48.5 months]. Persistent/recurrent disease and NOD were observed in 131 (51%) and 126 (49%) patients, respectively. In multivariate analysis, age > 55 (HR: 1.65, p = 0.033), distant metastasis (HR: 2.41, p = 0.035), CTN doubling time (HR: 2.7, p = 0.031), and stage III vs. stage II disease (HR 3.02, p = 0.048) were independent predictors of persistent/recurrent disease. Although 9 (8%) patients with an excellent response after the initial therapy experienced a structural recurrence, the absence of an excellent response was the strongest predictor of persistent/recurrent disease (HR: 5.74, p < 0.001).
CONCLUSIONS: The absence of an excellent response after initial therapy is the strongest predictor of a worse DFS. However, a significant proportion of patients who achieve an excellent response could experience a structural recurrence. Therefore, careful follow-up of patients, including those achieving an excellent response is essential.

The incidence rate of medullary thyroid carcinoma (MTC) continues to grow, along with its mortality rate in the USA. However, the subgroup trends in MTC have not yet been established. This population-based retrospective cohort study was based on the Surveillance, Epidemiology, and End Results (SEER) 17/12 registry database. Subgroup analysis was performed through clinicopathological and treatment-related characteristics. Annual average percentage change (AAPC) was calculated using joinpoint regression analysis. A total of 3833 MTC patients and 536 death cases were diagnosed in the SEER database. Between 2000 and 2019, the incidence (AAPC = 1.64) and mortality (AAPC = 3.46) rates of MTC continued to rise. Subgroup analysis showed the proportion of elderly patients (65-84 years) gradually increased in incidence between 2000 and 2020. Patients with early-stage tumors, such as tumors ≤20 mm, showed the same trends. Aspects of treatment, the implementation rate of total thyroidectomy (AAPC = 0.38) and lymph node dissection (AAPC = 1.06) also increased persistently in almost all of the age subgroups. The incidence and mortality of MTC consistently increased from 2000 to 2019. Subgroup analysis indicated a significant increase in elderly patients and early-stage patients, and more attention should be paid to the management of these increased subgroups.

To study the clinicopathological characteristics of patients with synchronous medullary and papillary thyroid carcinomas.
The clinical data of patients with medullary thyroid carcinoma (MTC) operated in our hospital (Department of Thyroid Surgery, China-Japan Union Hospital, Jilin University) from February 2009 to February 2023 were evaluated using an analytical review approach. They were divided into an observation group (patients with synchronous MTC and papillary thyroid carcinoma PTC) and a control group (simple MTC) according to whether the clinical data were associated with MTC, in order to compare the clinical features, pathological types, stage characteristics and molecular biology characteristics of the two groups and to investigate the follow-up of the two groups.
The study included 122 MTC, 30 with synchronous MTC/PTC and 92 simple MTC. When the data were compared, the sex ratio, preoperative calcitonin level, preoperative CEA level, presence of calcifications in the MTC lesions, surgical methods, number of MTC lesions, presence of nodular goitre and presence of thyroiditis were higher in the observation group than in the control group. There was a significant difference between the groups when the MTC lesion diameter was ≤1cm in terms of preoperative CEA value (P<0.05); when the MTC lesion diameter was >1cm, there was a statistical difference between the two groups in terms of preoperative Ctn value (P<0.05). Type III was significantly different from the simple group, while type IV was more similar to the simple group. The preoperative serum Ctn value was positively correlated with maximum tumour diameter in both groups, although the correlation was stronger in the easy group. Preoperative CEA was positively correlated with maximum tumour diameter in both groups, with a stronger correlation in the combination group. Preoperative Ctn and CEA were positively correlated with lymph node metastasis in the simple group, whereas there was no apparent correlation with lymph node metastasis in the combination group. The cut-off value of preoperative serum Ctn for cervical lymph node metastases in the simple group was 39.2pg/ml and for lateral cervical lymph node metastases 195.5pg/ml. The cut-off value of preoperative serum Ctn for cervical lymph node metastases in the combination group was 60.79pg/ml and for lateral cervical lymph node metastases 152.6pg/ml. In the simple group, prognosis was significantly worse in the progression group (P<0.001), with no statistical difference between the remission and stable groups. In the combination group, the prognosis of the progression and stable groups was significantly worse than that of the remission group (P<0.001), with no statistical difference between the progression and stable groups.
In patients with synchronous medullary and papillary thyroid carcinomas, preoperative Ctn and CEA levels, calcifications, solitary lesions, combined goitre or thyroiditis differ significantly from simple MTC. Therefore, clinical management should pay attention to the above factors and early risk screening should be performed to improve prognosis as much as possible.

OBJECTIVE: Medullary thyroid carcinoma has a high rate of recurrence and distant metastasis. The aim of this study was to investigate the risk factors for distant metastasis in patients with primary medullary thyroid carcinoma.
METHODS: Patients diagnosed with primary medullary thyroid cancer between 2010 and 2015 were enrolled using the Surveillance, Epidemiology, and End Results (SEER) database. Patient demographics and tumor clinicopathological features were evaluated to identify potential risk factors for distant metastasis in patients with primary medullary thyroid cancer. Univariate and multivariate logistic regression analyses were used to determine independent risk factors for distant metastasis in patients with primary medullary thyroid carcinoma. All statistical analyses were performed using SPSS statistical software (version 27.0). A two-tailed P < 0.05 was considered statistically significant.
RESULTS: We collected 685 patients with primary medullary thyroid carcinoma, 40 of whom (5.84%) developed distant metastases. Univariate logistic regression analysis showed that except marital status, age, sex, race, pT stage, N stage, multifocal and capsular infiltration were significantly correlated with distant metastasis of medullary thyroid carcinoma. Multivariate logistic regression analysis showed that patients aged ≤ 18 years or > 55 years, Black race, higher pT stage and N stage were independent risk factors for distant metastasis of medullary thyroid carcinoma.
CONCLUSIONS: This study found that ≤ 18 years or > 55 years, black race, higher pT stage and N stage were significantly associated with distant metastasis of medullary thyroid cancer. This is important for clinicians to identify patients at high risk of distant metastasis in a timely manner.

Purpose: The prognostic importance of RET and RAS mutations and their relationship to clinicopathologic parameters and outcomes in medullary thyroid carcinoma (MTC) need to be clarified. Experimental Design: A multicenter retrospective cohort study was performed utilizing data from 290 patients with MTC. The molecular profile was determined and associations were examined with clinicopathologic data and outcomes. Results: RET germ line mutations were detected in 40 patients (16.3%). Somatic RET and RAS mutations occurred in 135 (46.9%) and 57 (19.8%) patients, respectively. RETM918T was the most common somatic RET mutation (n = 75). RET somatic mutations were associated with male sex, larger tumor size, advanced American Joint Committee Cancer (AJCC) stage, vascular invasion, and high International Medullary Thyroid Carcinoma Grading System (IMTCGS) grade. When compared with other RET somatic mutations, RETM918T was associated with younger age, AJCC (eighth edition) IV, vascular invasion, extrathyroidal extension, and positive margins. RET somatic or germ line mutations were significantly associated with reduced distant metastasis-free survival on univariate analysis, but there were no significant independent associations on multivariable analysis, after adjusting for tumor grade and stage. There were no significant differences in outcomes between RET somatic and RET germ line mutations, or between RETM918T and other RET mutations. Other recurrent molecular alterations included TP53 (4.2%), ARID2 (2.9%), SETD2 (2.9%), KMT2A (2.9%), and KMT2C (2.9%). Among them, TP53 mutations were associated with decreased overall survival (OS) and disease-specific survival (DSS), independently of tumor grade and AJCC stage. Conclusions: RET somatic mutations were associated with high-grade, aggressive primary tumor characteristics, and decreased distant metastatic-free survival but this relationship was not significant after accounting for tumor grade and disease stage. RETM918T was associated with aggressive primary tumors but was not independently associated with clinical outcomes. TP53 mutation may represent an adverse molecular event associated with decreased OS and DSS in MTC, but its prognostic value needs to be confirmed in future studies.

OBJECTIVE: The c.1998delinsTTCT variant in the RET gene (codon 666) is linked to medullary thyroid carcinoma in Belgium. We aimed to study the clinical phenotype and the age-dependent penetrance in predictive variant carriers.
METHODS: Retrospective study of index patients and predictive variant carriers, identified through familial cascade testing between 2001 and 2020.
RESULTS: The total cohort comprised 119 patients: 15 index patients, 102 heterozygous, and 2 homozygous predictive variant carriers. Among heterozygous carriers, high suspicion of clinical disease was present in 25 patients at initial evaluation and in 3 patients during follow-up. No high suspicion of clinical disease was observed during surveillance in 56 patients, and 18 patients did not proceed to screening for clinical disease. Compared to index patients, surgically treated heterozygous predictive variant carriers had a lower presurgical basal calcitonin, a lower disease stage, less need for adjuvant therapy, and higher chances of remission. In heterozygous carriers, median age at developing high suspicion of disease is 52 years (range 7-75), with a predicted penetrance of 62% (9% SE) at the age of 70 years. Two patients were identified with pheochromocytoma and 1 patient with primary hyperparathyroidism. The 2 homozygous predictive variant carriers presented with higher disease severity at first clinical evaluation.
CONCLUSIONS: The c.1998delinsTTCT variant in the RET gene is pathogenic and associated with a moderate risk for medullary thyroid carcinoma and rarely with other multiple endocrine neoplasia type 2A (MEN2A) manifestations. Active surveillance is a possible option in heterozygous gene carriers with a negative first clinical evaluation.

OBJECTIVE: The International Medullary Thyroid Carcinoma Grading System, introduced in 2022, mandates evaluation of the Ki67 proliferation index to assign a histological grade for medullary thyroid carcinoma. However, manual counting remains a tedious and time-consuming task.
RESULTS: We aimed to evaluate the performance of three other counting techniques for the Ki67 index, eyeballing by a trained experienced investigator, a machine learning-based deep learning algorithm (DeepLIIF) and an image analysis software with internal thresholding compared to the gold standard manual counting in a large cohort of 260 primarily resected medullary thyroid carcinoma. The Ki67 proliferation index generated by all three methods correlate near-perfectly with the manual Ki67 index, with kappa values ranging from 0.884 to 0.979 and interclass correlation coefficients ranging from 0.969 to 0.983. Discrepant Ki67 results were only observed in cases with borderline manual Ki67 readings, ranging from 3 to 7%. Medullary thyroid carcinomas with a high Ki67 index (≥ 5%) determined using any of the four methods were associated with significantly decreased disease-specific survival and distant metastasis-free survival.
CONCLUSIONS: We herein validate a machine learning-based deep-learning platform and an image analysis software with internal thresholding to generate accurate automatic Ki67 proliferation indices in medullary thyroid carcinoma. Manual Ki67 count remains useful when facing a tumour with a borderline Ki67 proliferation index of 3-7%. In daily practice, validation of alternative evaluation methods for the Ki67 index in MTC is required prior to implementation.