Basal Calcitonin Levels Research Articles

Diagnostic capabilities of PET/CT with <sup>18</sup>F-DOPA in biochemical recurrence of medullary thyroid carcinoma: a retrospective study

INTRODUCTION: Medullary thyroid carcinoma (MTС) is a rare neuroendocrine malignant neoplasm of the thyroid gland. In most cases, sporadic MTС is diagnosed at late stages due to the absence of specific symptoms. The main method of treatment of MTС is surgical — thyroidectomy and in most cases cervical lymphodissection. Current international guidelines suggest the use of basal calcitonin levels and cancer embryonic antigen (CEA) as markers of biochemical recurrence. In biochemical recurrence of the disease, it is advisable to search for tumor foci regardless of the level of cancer markers. Positron emission tomography combined with computed tomography (PET/CT) has the highest sensitivity and specificity for searching for local recurrence and distant metastases. Anatomical imaging methods (computed tomography (CT), magnetic resonance imaging (MRI)) have suboptimal sensitivity and specificity in detection of a recurrent tumor.OBJECTIVE: To explore the diagnostic capabilities of PET/CT with 18F-DOPA in patients with biochemical recurrence of medullary thyroid carcinoma, depending on the concentration of calcitonin in blood plasma.MATERIALS AND METHODS: To evaluate the diagnostic capabilities of PET/CT with 18F-DOPA in patients with biochemical recurrence of medullary thyroid carcinoma, 81 PET/CT studies were analyzed in patients after thyroidectomy. In most cases (76/81), at the time of the study, patients had elevated basal calcitonin levels (>10 pg/ml, including in 52/81 cases >150 pg/ml), which corresponded to a biochemical recurrence of the disease. In 6 cases, the calcitonin level was <10 pg/ml. PET/CT results were processed by visual image analysis, measurement of a semi-quantitative indicator of the maximal standardized level of radiopharmaceutical accumulation normalized to lean body mass (SUVlbm max) and the total volume of PET-positive tumor tissue (metabolic tumor volume).RESULTS: In 41 studies, foci of pathological accumulation of 18F-DOPA were identified, corresponding to recurrent tumor foci. DOPA-negative results in patients with elevated calcitonin levels were regarded as false negative. The highest sensitivity of the method was achieved at calcitonin levels >150 pg/ml. A noticeable positive correlation was found between the concentration of basal serum calcitonin, the number of pathological foci of 18F-DOPA hyperaccumulation and the total metabolic volume of tumor tissue. In most cases of biochemical recurrence, the PET method was superior to the CT method in detecting recurrent tumor foci.CONCLUSION: PET/CT with 18F-DOPA is the most informative method for molecular and structural imaging in patients with biochemical recurrence of medullary thyroid carcinoma. The results of the study directly correlate with the level of basal calcitonin in the blood.

Sexual dimorphism in medullary thyroid cancer aggressiveness.

Thyroid cancer is the only nonreproductive cancer with striking female predominance, although men with thyroid cancer develop more aggressive disease. This study aimed to quantify sex-specific differences in medullary thyroid cancer (MTC) spread after controlling for primary thyroid tumor size. Included in this retrospective analysis were all patients with unilateral solitary MTC who underwent initial neck surgery at a tertiary referral center. A total of 565 patients, 255 men and 310 women, were identified, of whom 467 had sporadic and 98 hereditary MTC. When stratified by sex, and after correction for multiple testing, men had higher preoperative basal calcitonin levels (medians of 655 vs 181 pg/mL; P < 0.001), more frequent extrathyroid extension (25 vs 9%; P < 0.001) and node metastasis (53 vs 27%; P < 0.001) with more involved nodes (medians of 2 vs 0 nodes; P < 0.001) than women but achieved less often biochemical cure (53 vs 74%; P < 0.001). Although absent in patients with very small (≤5 mm) thyroid tumors, sex disparities were immediately apparent in patients with 5.1-40 mm (node metastasis and biochemical cure) and 10.1-40 mm (extrathyroid extension) large thyroid tumors but were lost in patients with thyroid tumors >40 mm as women caught up. Sex disparities were strongest for node metastasis with a 27-41% (overall 24.0%) point difference, followed by biochemical cure with a -15-35% (overall -20.3%) point difference and extrathyroid extension with a 17-24% (14.2% overall) point difference. These findings indicate that the male predominance in MTC aggressiveness is largely biologically driven, warranting further research.

New Opportunities for Preoperative Diagnosis of Medullary Thyroid Carcinoma.

The preoperative diagnostics of medullary thyroid carcinoma (MTC), including the measuring of the blood calcitonin level, has a number of limitations. Particular focus has recently been placed on the role of miRNAs in the development of various malignant tumors; a comparative analysis of accuracy of the existing methods for MTC diagnosis with a novel diagnosis method, evaluation of the miRNA-375 expression level, was performed in this study. The expression level of miRNA-375 in cytology samples from 555 patients with the known histological diagnosis, including 41 patients with confirmed postoperative diagnosis of MTC, was assessed. The diagnostic parameters of the basal calcitonin level, calcitonin in wash-out fluid from the FNAB needle, and miRNA-375 were compared. An assessment of the miRNA-375 expression level made it possible to detect all the MTC samples with a 100% accuracy among all the 555 cytology specimens, as well as in non-informative FNAB specimens, and specimens from the ipsilateral thyroid lobe. Parameters such as sensitivity, specificity, PPV, and NPV were 100%. The miRNA-375 level, unlike calcitonin, does not correlate with tumor volume, so it does not have the so-called "gray zone". An assessment of the miRNA-375 expression allows one to accurately distinguish MTC from other malignant and benign thyroid tumors.

A nomogram to predict lateral lymph node metastases in lateral neck in patients with medullary thyroid cancer.

BackgroundMedullary thyroid cancer (MTC) can only be cured by surgery, but the management of lateral lymph nodes is controversial, especially for patients with cN0+cN1a. To address this challenge, we developed a multivariate logistic regression model to predict lateral lymph node metastases (LNM).MethodsWe retrospectively collected clinical data from 124 consecutive MTC patients who underwent initial surgery at our institution. The data of 82 patients (from 2010 to 2018) and 42 patients (from January 2019 to November 2019) were used as the training set for building the model and as the test set for validating the model, respectively.ResultsIn the training group, the multivariate analyses indicated that male and MTC patients with higher preoperative basal calcitonin levels were more likely to have lateral LNM (P = 0.007 and 0.005, respectively). Multifocal lesions and suspected lateral LNM in preoperative ultrasound (US) were independent risk factors (P = 0.032 and 0.002, respectively). The identified risk factors were incorporated into a multivariate logistic regression model to generate the nomogram, which showed good discrimination (C-index = 0.963, 95% confidence interval [CI]: 0.9286–0.9972). Our model was validated with an excellent result in the test set and even superior to the training set (C-index = 0.964, 95% CI: 0.9121–1.000).ConclusionHigher preoperative basal calcitonin level, male sex, multifocal lesions, and lateral lymph node involvement suspicion on US are risk factors for lateral LNM. Our model and nomogram will objectively and accurately predict lateral LNM in patients with MTC.

Parathyroid hormone and calcitonin response during the calcium infusion test in patients with primary hyperparathyroidism.

While activation of the calcium (Ca) sensing receptor (CaSR) suppresses parathyroid hormone (PTH) secretion, calcitonin (CT) secretion is stimulated via CaSR. The aim of this study was to evaluate PTH and CT responses during a calcium infusion test (CIT) in patients with primary hyperparathyroidism (PHPT). This pivotal prospective study included 64 patients (44 PHPT patients vs. 20 healthy controls [HCs], median age 57 [25-79] vs. 56 [39-74] years). All PHPT patients underwent parathyroidectomy (PTX). A week before and 1month after PTX, the CIT was performed (bolus infusion of Ca gluconate 0.2ml/kg body weight), followed by plasma sampling for Ca2+, PTH, and CT at 0, 1, 2, 3, 5, 8, and 10min. PTH suppression was lower in PHPT patients compared to HCs (49.82 vs. 64.06%, p = 0.006), but after PTX suppression, it was higher (76.3%, p < 0.001). PHPT patients had attenuated CT response vs. HCs during the CIT (3.1- vs. 8.0-fold increase, p < 0.001), but after PTX, it improved (5.8-fold increase). The PTHmin > 19.3ng/l and CTmax ≤ 27.5ng/l cut-off values predict diagnosis of PHPT (sensitivity 90.9%, 97.7%, and specificity 100%, 75%, respectively). Patients with adenoma had lower basal CT levels vs. hyperplasia both before and after PTX (4.5 vs. 6.8 and 5.4 vs. 7.9ng/l, respectively, p = 0.008, p = 0.018). PTH and CT responses during the CIT in PHPT patients may be an additional diagnostic tool. The CIT could play a role in both the diagnosis of PHPT and in the differential diagnosis between adenoma and hyperplasia.

THE ROLE OF CALCITONIN IN THE PREOPERATIVE STAGE AS THE PREDICTOR OF MEDULLARY THYROID CANCER METASTASES

the aim of the stydy was to analyze the detectability of medullary thyroid metastases in patients at treatment and diagnostic stages, to investigate the applicability of serum calcitonin level as predictor of possible presence of medullary thyroid metastases. The study included data from 148 patients who underwent surgical treatment for the initial diagnosis of medullary thyroid cancer. The age of patients ranged from 12 to 83 years, the mean age was 48,2±1,9 years; the distribution by gender was as follows: men – 34 (23%), women – 114 (77%). Patients were divided into two groups depending on the pathomorphological report: 1 group (100 (67,6%) – patients without metastases), 2 group (48 (32,4%) – patients with locoregional metastases). Among 148 studied patients with medullary thyroid cancer, as a result of the histopathological conclusion, in 48 (32,4%) metastases were detected in regional lymph nodes, among which 10 (6,7%) patients had metastases only in the central collector and 38 (25, 7%) –both in the central and lateral collectors. At the preoperative stage, the level of undiagnosed metastases by ultrasound was 64,58% (31 patients). Subsequently, at the intraoperative stage, during the rapid histological biopsy, the number of undiagnosed metastases decreased to 37,5% (18 patients), and in the postoperative period, according to the results of histopathological examination, the remaining patients were diagnosed with the medullary thyroid cancer metastases. Ultrasound helped to detect metastases in 17 patients, which was 35,42% of all detected metastases. At the stage of intraoperative study, the detection of metastases increased and amounted to 30 (62,5%), and in the postoperative period as a result of histopathological examination metastases were confirmed in 48 patients (100%). Quantitative indicators of both detected and undiagnosed metastases at all stages of treatment and diagnostic search are statistically significant (p&lt;0,01). The detection of metastases in the central lymphatic collector (N1a) at the preoperative stage was 2,08%, this index has doubled (to 4,16%) after intraoperative rapid histological conclusion, and after histopathological conclusion the index has increased more than 10 times (20,84 %). This tendency to grow of metastaseses detection was followed also on lateral collectors: N1b and psilateral were observed at 15 (31,2%) patients at the preoperative stage, their number increased to 23 (47,9%) intraoperatively and to 31 (64,6%) postoperatively; N1b contralateral was observed in 1 (2,1%), 5 (10,4%) and 7 (14,6%), respectively. Such a low percentage of metastases detection at the preoperative stage by ultrasound prompted to CT level study as the predictor of possible metastases. We investigated the preoperative basal blood CT value as a marker of the medullary thyroid cancer metastases presence probability. Due to the small number of the group (n=10) with N1a, the association of CT (cut-off level 137 pg/ml) with the possible presence of metastases was not significant (AUC = 0.594), while in the group with N1b there was a more significant difference. Thus, CT cut-off levels of 358 pg/ml for N1b ipsilateral, and 498 pg/ml for N1b contralateral detection of possible metastases in collectors, with AUC: 0.877 and 0.832, respectively, which justifies the importance of the lateral neck dissection in addition to the mandatory central dissection in order to remov possible medullary thyroid cancer metastases. Thus, ultrasound is insufficiently reliable method of metastases verifying in medullary thyroid cancer (DE = 35.4% at d mts &lt;0.6 cm). In the absence of ultrasound data (or fine needle aspiration (FNA) biopsy results) on the presence of metastases to raise awareness of the disease prevalence, to clarify the prognosis of its development it’s important to use the additional criterion – the calcitonin level. Basal calcitonin level is the reliable predictor of the medullary thyroid cancer metastases. Its cut-off level of 137 pg/ml indicates the possible presence of metastases in the central group (N1a) (AUC=0,594). The CT cut-off level – 358 pg/ml (AUC=0,793) suggests the presence of the medullary thyroid cancer metastases (N1a+N1b). CT cut-off levels – 358 pg/ml for N1b ipsilateral, and 498 pg / ml for N1b contralateral (AUC: 0,877 and 0,832), respectively. The calculated values of the countersensitivity test to detect metastases for different levels of basal CT in the preoperative stage in the clinical setting will help the practitioner in deciding on treatment tactics to determine the extent of surgery in patients diagnosed (or suspected) with the medullary thyroid cancer metastases.

Calcitonin level in the postoperative period as a risk factor for persistence of medular thyroid cancer

Aim — to evaluate the possibility of using basal calcitonin levels in the postoperative period to assess the effectiveness of surgical treatment of medullary thyroid cancer and the likelihood of its persistence (recurrence). Materials and methods. A single-site retrospective study was conducted to assess results of surgical treatment of 194 patients (74.2 % women and 25.8 % men), from them148 (76.3 %) patients had primary forms of the disease (group 1) and 46 (23.8 %) the recurrent form (group 2). Primary surgery included thyroidectomy, supplemented with thecentral and lateral dissection of the neck. Patients in group 1 were divided into two subgroups depending on the postoperative calcitoninlevels: group 1A with normal calcitonin levels (≤ 18 pg/ml)and group 1B with hypercalcitoninemia (&gt; 18 pg/ml). The quantitative­determination of blood serum calcitonin levels was performed using automatic immunochemiluminescent analyzer «MAGLUMI» («Snibe Diagnostic», China) in 1 week and 1 year after surgery. Accumulation and primary data processing were performed in MS Excel 2013, statistical processing was performed using StatPlus programs with descriptive statistics, parametric and nonparametric methods for testing statistical hypotheses (Student’s criteria, Mann-Whitney, Fisher angular transformation), analysis of conjugation tables, ROC-analysis. The results were considered statistically significantat p &lt; 0.05. Results. The average duration of follow-up was 67.5 months. The results of surgery were analyzed in terms of absence or presence of clinical recurrence, calcitoninlevels in the early postoperative period (5 days) were used as a predictor. After 2 years of follow-up,normocalcitoninemiawas accompanied by recurrence in almost 2 % of cases, while hyper­calcitoninemia — in 61 % to 74 %, depending on the stage and frequency of the disease. The correlationsbetween postoperative calcitonin levels and presence of recurrence (persistence) of medullary thyroid cancer has been established: AUC = 0.928 (0.867; 0.989, Juden index (J) = 0.429, threshold (cut-off point) ≥ 28.1 pg/ml, sensitivity = 0.938 (0.854; 1,000), specificity = 0.855 (0.789; 0.920), predictive value of positive result(PPV) = 0.699, predictive value of negative resultPNV = 0.991. Moreover, countersensitivity scores and incidence of negative test results in patients with relapse depending on the level of postoperative calcitonin were calculated. Conclusions. Postoperative calcitonin levels in 5 days after surgery can be used for assessment of efficacy of the surgical treatment (AUC — 0,928 (0,867; 0,989), Juden index — 0,429)). The prognosis of recurrence-free disease does not depend on the disease stage. At calcitonin levels &lt; 18 pg/ml, clinical signs of the disease persistence (recurrence) were detected in 1.5 % of cases (PNV = 0.991). The reliability of predicting the disease recurrence depended on the stage and frequency of surgery: PRV = 0.612 in primary forms without metasta­­ses, PRV = 0.825 in recurrent forms. Calcitonin values &lt; 28.1 pg/ml can be considered a relatively «safe» level.

Presence or severity of Hashimoto's thyroiditis does not influence basal calcitonin levels: observations from CROHT biobank.

The influence of Hashimoto's thyroiditis (HT) on calcitonin (Ct) production is unresolved question. The aim of this study was to explore if basal Ct levels are influenced by the presence/severity of HT or correlated with clinical phenotypes of HT patients. We included 467 HT patients and 184 control participants, from Croatian Biobank of HT patients (CROHT), in this retrospective study. Calcitonin levels between HT patients and controls were compared using Mann-Whitney test. Ct levels between two subgroups of HT patients, divided by intake of levothyroxine (LT4) therapy, were additionally tested to take into account the illness severity. Spearman rank correlation test was used to analyze correlations between Ct levels and 14 relevant phenotypes. We have not detected significant differences in median Ct levels between HT patients and controls (2.2 vs 2.35pg/mL, respectively, P = 0.717) nor in-between two subgroups of HT patients (P = 0.347). We have not detected statistically significant correlations between Ct levels and clinical phenotypes, although we identified three weak nominal correlations: negative correlation of Ct with TgAb in all HT patients (r = - 0.1, P = 0.04); negative correlation of Ct with age in subgroup of HT patients without LT4 therapy (r = - 0.13, P = 0.04); positive correlation of Ct with BSA in subgroup of HT patients on LT4 therapy (r = 0.16, P = 0.042). Our results suggest that HT patients of all disease stages preserve Ct production as healthy individuals and there is no need for Ct measurements in the absence of a nodule. Additional confirmation and clarification of observed nominal correlations are needed due to potential clinical relevance of TgAb and age-dependent Ct decrease in HT women.

1749P A multivariate logistic regression model to predict lateral lymph node metastases of medullary thyroid cancer

Surgery is the only way to cure medullary thyroid cancer (MTC), but the management of lateral lymph nodes is controversial especially for patients with cN0+cN1a. Based on preoperative basal calcitonin (Ctn) levels, ultrasound (US) results and baseline characteristics of patients, we created a multivariate logistic regression model to predict lateral lymph nodes metastases (LNM).

Mildly Elevated Basal Calcitonin Level in Patients With Thyroid Goiter: Using the Calcitonin Measurement in Fine-Needle Aspirate Washout Fluid of the Healthy Lobe to Define Medullary Thyroid Cancer and Reactive C-Cell Hyperplasia

Abstract Background: Mildly elevated basal calcitonin level (bCT), that suggests a bCT increase up to 100 pg/ml, may testify either medullary thyroid carcinoma (MTC) or reactive thyroid C-cell hyperplasia (CCH). The latter is observed under many conditions such as hypercalcemia, hypergastrinemia, thyroiditis, neuroendocrine tumors (NET), renal end-stage kidney disease, obesity, and smoking. The research is aimed at analyzing the clinical significance of the calcitonin measurement in the fine needle aspiration washout fluid sample (FNA-CT) for screening certain patients with nodular thyroidopathy and elevated bCT. Patients and Methods: 70 patients with mildly elevated bCT (for women 6-100 pg/ml, for men 19-100 pg/ml) underwent ultrasound-guided FNA-CT measurement of the thyroid nodules and healthy lobe tissue. After obtaining a FNA-CT specimen, the needle was washed with 0.5 ml of saline solution. The calcitonin (CT) was measured by ECLIA (LIAISON XL). Results: There were 51 females and 19 males, with a mean age of 46.8 ± 14.4 years (range 16-81). The mean value of bCT was 23.3 ± 19 pg/ml (range: 7-86.5). According to ultrasound, 66 patients (95%) presented with thyroid nodules, in 4 cases previously identified nodes were not confirmed. The mean lesion size was 10.8 ± 4.9 mm (range: 4-26). Thyroid nodules were evaluated by FNA biopsy which revealed according to the Bethesda system category I in 6 cases, II - 44, III - 2, IV - 4, V - 6, and VI - 1. Analyzing FNA-CT results we identified 13 cases (18%) with MTC with low CT level of healthy lobe tissue (1-89.6 pg/ml) and high CT level of the lesion (&amp;gt;2000 pg/ml), which was confirmed by final histological examination. Low CT level from both healthy lobe and the nodule (&amp;lt;20 pg/ml) was observed in 10 cases, we carried out the measurement of stimulated CT to exclude the extrathyroidal CT production, which was confirmed in 1 case. All 4 patients with no nodules possessed significantly higher T-rates (1650-2000 pg/ml). The remaining 43 cases (61%) had an increased CT-level of healthy tissue (&amp;gt;2000 pg/ml) with a lower level from the lesion. Among these patients, the probable predisposing CCH factors were obesity - 8 cases, thyroiditis - 12, NET - 3, hypercalcemia - 3, renal kidney disease - 1, and smoking - 3. These 54 patients were kept under dynamic control. The observation period for patients - 1 year. 4 patients underwent surgical treatment, subsequently, histological examination revealed papillary thyroid cancer, follicular adenoma, colloid goiter against CCH, and CT-producing NET. Conclusion: The measurement of FNA-CT of the healthy lobe tissue may be useful to differentiate MTC and CCH, but requires new data in a major cohort of patients. The disadvantage of this study is the impossibility of CCH histological verification in the follow-up group.

Basal and pentagastrin-stimulated calcitonin cut-off values in diagnosis of preoperative medullary thyroid cancer

Background/aimMedullary thyroid cancer (MTC) originates from parafollicular cells (C cell) and produces calcitonin (CT). Basal serum CT was used in the diagnosis and treatment of MTC. If basal CT level is 100 pg/mL or higher, it is likely to have MTC, but if basal CT level is below 10 pg/mL, the probability of developing thyroid disease is low. In cases with basal CT level between 10–100 pg/mL, pentagastrin-stimulated (PS) CT level is studied to evaluate MTC and C cell hyperplasia (CHH). This study aimed to determine cut-off value for basal and PS peak CT level for diagnosis of MTC. Materials and methodsWe retrospectively reviewed files of patients presented to endocrine outpatient clinic of Ege University, Medicine School, between 2010 and 2019; 176 patients with basal CT level of 10–100 pg/mL and patients with PS test were included to the study. ResultsThe receiver operating characteristic curve (ROC) analysis was used to determine cut-off value for basal CT that can discriminate cases with MTC and those with nodular goiter. Cut-off value for basal CT was calculated as 46.5 pg/mL (specificity; 100 %, sensitivity; 74 %). In the ROC analysis for peak PS CT, cut-off value was calculated as 285 pg/mL (specificity:100 %; sensitivity:82 %). When peak CT level was > 290 pg/mL in PS test, both specificity and sensitivity for MTC were determined as 100 %. The PS peak CT level > 285 pg/mL was significant for MTC diagnosis while range of 117–274 pg/mL was significant for CHH. ConclusionIn this study, cut-off value was calculated as 46.5 pg/mL for basal CT, whereas 285 pg/mL for PS peak CT in the diagnosis of preoperative MTC.

Elevated basal serum levels of calcitonin and simultaneous surgery of MEN2A-specific tumors.

Multiple endocrine neoplasia type 2A (MEN2A) is a rare syndrome caused almost by germline RET mutation, and characterized by medullary thyroid carcinoma (MTC), in combination or not with pheochromocytoma (PHEO), hyperparathyroidism (HPTH), cutaneous lichen amyloidosis (CLA), and Hirschsprung's disease (HD). The basal serum calcitonin (Ctn)/carcinoembryonic antigen (CEA) levels are significantly correlated with the MTC stage. Metachronous surgery of MEN2A-specific tumors is a routine procedure. We aimed to explore the clinical significance of pro-gastrin-releasing peptide (proGRP) in MTC with elevated Ctn and simultaneous surgery of MEN2A-specific tumors. We retrospectively investigated 8 RET mutation carriers of 2 Chinese pedigrees with MEN2A. Clinical profiles, imaging examinations, preoperative and postoperative biochemical data, surgical procedures, and follow-up records were evaluated. Three patients showed levels of elevated Ctn but normal proGRP. Among them, one patient (FAIII-6) in Family A (one for RET C634R mutation), diagnosed with bilateral MTC, left PHEO, bilateral HPTH, and CLA, classified as MEN2A-related CLA subtype, underwent successfully simultaneous adrenal-sparing surgery (ASS), total thyroidectomy (TT), and parathyroidectomy, while TT of the other two patients (FBII-3 and FBIII-7) diagnosed with bilateral MTC in Family B (all for RET C618R mutation) were performed. Unexpectedly, the absence of neck lymph node MTC metastasis was indicated by histopathological examination. Postoperatively, all had consistently "undetectable" or normal levels of Ctn/CEA during follow-up. Patients with normal proGRP, despite high levels of Ctn, might have no regional lymph node MTC metastasis, and neck dissection should be avoided. Moreover, simultaneous surgery for coexistent PHEO and either MTC or HPTH is an approach of choice to use as an alternative treatment pattern. Recognition of MEN2A-related CLA and subsequently early screening of RET mutation may be favorable for timely management of MEN2A-specific tumors.

Calcitonin testing for detection of medullary thyroid cancer in people with thyroid nodules.

Thyroid nodules are very common in general medical practice, but rarely turn out to be a medullary thyroid carcinoma (MTC). Calcitonin is a sensitive tumour marker for the detection of MTC (basal calcitonin). Sometimes a stimulation test is used to improve specificity (stimulated calcitonin). Although the European Thyroid Association's guideline advocates calcitonin determination in people with thyroid nodules, the role of routine calcitonin testing in individuals with thyroid nodules is still questionable. The objective of this review was to determine the diagnostic accuracy of basal and/or stimulated calcitonin as a triage or add-on test for detection of MTC in people with thyroid nodules. We searched CENTRAL, MEDLINE, Embase and Web of Science from inception to June 2018. We included all retrospective and prospective cohort studies in which all participants with thyroid nodules had undergone determination of basal calcitonin levels (and stimulated calcitonin, if performed). Two review authors independently scanned all retrieved records. We extracted data using a standard data extraction form. We assessed risk of bias and applicability using the QUADAS-2 tool. Using the hierarchical summary receiver operating characteristic (HSROC) model, we estimated summary curves across different thresholds and also obtained summary estimates of sensitivity and specificity at a common threshold when possible. In 16 studies, we identified 72,368 participants with nodular thyroid disease in whom routinely calcitonin testing was performed. All included studies performed the calcitonin test as a triage test. Median prevalence of MTC was 0.32%. Sensitivity in these studies ranged between 83% and 100% and specificity ranged between 94% and 100%. An important limitation in 15 of the 16 studies (94%) was the absence of adequate reference standards and follow-up in calcitonin-negative participants. This resulted in a high risk of bias with regard to flow and timing in the methodological quality assessment. At the median specificity of 96.6% from the included studies, the estimated sensitivity (95% confidence interval (CI)) from the summary curve was 99.7% ( 68.8% to 100%). For the median prevalence of MTC of 0.23%, the positive predictive value (PPV) for basal calcitonin testing at a threshold of 10 pg/mL was 7.7% (4.9% to 12.1%). Summary estimates of sensitivity and specificity for the threshold of 10 pg/mL of basal calcitonin testing was 100% (95% CI 99.7 to 100) and 97.2% (95% CI 95.9 to 98.6), respectively. For combined basal and stimulated calcitonin testing, sensitivity ranged between 82% and 100% with specificity between 99% and 100%. The median specificity was 99.8% with an estimated sensitivity of 98.8% (95% CI 65.8 to 100) . Both basal and combined basal and stimulated calcitonin testing have a high sensitivity and specificity. However, this may be an overestimation due to high risk of bias in the use and choice of reference standard The value of routine testing in patients with thyroid nodules remains questionable, due to the low prevalence, which results in a low PPV of basal calcitonin testing. Whether routine calcitonin testing improves prognosis in MTC patients remains unclear.

Prediction of lateral neck lymph node metastasis according to preoperative calcitonin level and tumor size for medullary thyroid carcinoma.

Medullary thyroid carcinoma (MTC) accounts up to 10% of all thyroid cancers, but is responsible for a disproportionate number of deaths. While surgery is the only curative treatment for MTC, indications for lateral neck lymph node (LLN) dissection are controversial. We performed a retrospective review to describe clinical outcomes in 93 MTC patients from July 1995 to March 2015. We analyzed their clinicopathologic factors, and cut-off values of tumor size and calcitonin levels were calculated using a receiver operating characteristic curve. Using the instances of lymph node metastases, the tumor size cut-off value was 0.95 cm (area under curve, AUC = 0.697) in patients with ipsilateral central lymph node (CLN) metastases, 2.25 cm (AUC = 0.793) in contralateral CLN metastases, and 1.75 cm (AUC = 0.753) in ipsilateral LLN metastases. The cut-off values of preoperative calcitonin levels were 226.6 pg/mL (AUC = 0.746) in ipsilateral CLN, 755.0 pg/mL (AUC = 0.840) in contralateral CLN metastases, and 237.0 pg/mL (AUC = 0.775) in ipsilateral LLN metastases. This study supports the notion that ipsilateral LLN metastases occur before contralateral CLN metastases. Therefore, ipsilateral LLN dissection should be considered in patients with contralateral CLN metastases. The extent of surgery should be based on the status of LN metastases, preoperative basal calcitonin level, and tumor size to help individualize the extent of surgery.

Corrigendum: Medullary thyroid cancer. Returning to the need to determine the preoperative basal calcitonin level in patients with thyroid nodular pathology (Endocrine surgery. 2018;12(4). doi: 10.14341/serg10044)

A corrigendum on «Medullary thyroid cancer. Returning to the need to determine the preoperative basal calcitonin level in patients with thyroid nodular pathology»&#x0D; by Elena E. Stanyakina, Ilia S. Romanov, Tatiana T. Kondratieva, Alexander S. Krylov, Alexey D. Ryzhkov, Sergey V. Shiryaev (2018). Endocrine Surgery. 12(4). doi: 10.14341/serg10044&#x0D; There is an error on the page 189: "Blood test for hormones: thyroid stimulating hormone (TSH) — 52.6 mIU/l (reference values 0.25–4.0), adrenocorticotropic hormone (ACTH) &lt;20 IU/ml (0–30), thyreoglobulin (TG) &lt;0.2 ng/ml (0–30)". Instead of "antibodies to thyroglobulin (ATTG)" was published "adrenocorticotropic hormone (ACTH)".&#x0D; The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way.&#x0D; The original article has been updated.

Reactive C cell hyperplasia as an incidental finding after thyroidectomy for papillary carcinoma.

The biologic and clinical significance of reactive C cell hyperplasia (CCH), adjacent to differentiated thyroid cancers, remains unknown. Our aim was to investigate the presence of CCH in thyroidectomy specimens with papillary thyroid carcinomas (PTC) and discuss its epidemiology and histology. In total, 413 patients were prospectively included in the study (189 benign goiters, 224 PTC). Reactive CCH was observed in 9.8% of PTC cases (32% males, 68% females, mean age 48.3 ± 16.4years) and usually ipsilateral to the primary tumor (91%). Histologically, CCH was either focal (91%) or diffuse (9%) and almost always (92%) found in the middle or upper thirds of the thyroid lobes. Patients with PTC/CCH were generally younger than patients with benign goiters (0.027). On the other hand, patients with PTC and with PTC/CCH did not differ in terms of age, gender, basal calcitonin levels, primary tumor size, multifocality, extrathyroidal invasion, or lymph node metastasis. Thyroiditis, however, was more frequent in cases with PTC/CCH compared to PTC alone. Reactive CCH is considered a physiological response of the C cells to various stimuli, differentiated thyroid cancer among others. It bears no malignant potential and requires no additional treatment, following thyroidectomy.

Possibilities of single photon emission tomography in the diagnosis of bone metastases in patients with disseminated medullary thyroid carcinoma (case report)

The study objective : using a clinical example to demonstrate possibilities of single photon emission computerized tomography (SPECT) in combination with computed tomography (CT) in identifying latent bone metastases, taking into account the dynamics growth of serum basal calcitonin. Materials and methods . Patient S., 60 years old, visited N.N. Blokhin National Medical Research Center of Oncology for consultation on multiple lung metastases of cancer of unknown primary. Results. Taking into account basal calcitonin level, immunohistochemistry, ultrasound investigation andfine-needle aspiration biopsy of the node in the right thyroid lobe a diagnose of medullary thyroid cancer was made. CT revealed multiple metastases in both lungs. Specialist erformed thyroidectomy with central lymphadenectomy and facial neck dissection on both sides. During next four months basal calcitonin level increased twice. Control contrast CT lung screening showed the growth of previously identified metastases and the appearance of multiple new ones. Bone scan showed focuses of increased radio-pharmaceutical accumulation in the area of 7 h left rib, left iliac wing, in the left bones of cranial vault, in C 7 , Th 6 , Th 9 , Th I2 vertebrae and right foot bones. Additional examination using SPECT/CT (from the skull base to the hip joints) revealed metastases in corpuses of Th 9 , Th I2 vertebrae and the left iliac wing, and suspicion for metastasis in 7 h left rib. Magnetic resonance imaging (MRI) confirmed metastasis in Th 9 , Th I2 , L 3 vertebral bodies and in the left iliac wing. Conclusion. Conclusion . In this clinical example, SPECT/CT allowed to correctly detect metastases in both Th 9 and Th I2 vertebrae while bone scan was questionable, and MRI showed an additional damage of L 3 vertebra. Changes in the 7 h left rib could not be verified using CT, although this changes may be an emerging metastasis. Obviously, extensive use of radiation methods does not guarantee complete identification of all pathological focuses, it therefore allows assessing the prevalence of the pathological process. It is crucially important to control calcitonin level in these patients, since its rapid growth allowed suspecting additional distant metastases.

Medullary thyroid cancer. Returning to the need to determine the preoperative basal calcitonin level in patients with thyroid nodular pathology

There are International and Russian guidelines for the diagnosis and treatment of medullary thyroid carcinoma. There is a recommendation to determine the basal level of calcitonin for all patients with nodular thyroid disease at the all of these documents. However, this test is not performed for this category of patients routinely even in large clinics for a number of reasons, the main one, which seems to be an economic issue. Six months ago a patient addressed to our clinic who underwent surgical treatment for a papillary carcinoma (follicular variant) of the thyroid gland in the volume of thyroidectomy with pre-tracheal lymphodissection and subsequent course of radioiodine therapy at the place of residence. A relapse of the disease was suspected on the control examination at the place of residence and the patient was sent for consultation to the polyclinic of the N.N. Blokhin National Medical Research Center of Oncology. In our clinic, diagnostic studies were carried out, including a revision of the finished cytological and histological preparations and a conclusion was obtained – medullary carcinoma of the thyroid. Determination of basal level of calcitonin in serum showed a value of 1292 pg/ml. The level of basal calcitonin significantly decreased after repeated surgical treatment. This case shows that in order to avoid such mistake, which is described in our clinical case, it seems necessary to follow the national recommendations, international standards to determine the level of basal calcitonin for all patients with thyroid nodal pathology who consulted and treated in medical institutions.

Serum calcitonin nadirs to undetectable levels within 1 month of curative surgery in medullary thyroid cancer.

Because serum calcitonin (CT) is a reliable marker of the presence, volume, and extent of disease in medullary thyroid cancer (MTC), both the ATA and NCCN guidelines use the 2-3 month post-operative CT value as the primary response to therapy variable that determines the type and intensity of follow up evaluations. We hypothesized that the calcitonin would nadir to undetectable levels within 1 month of a curative surgical procedure. This retrospective review identified 105 patients with hereditary and sporadic MTC who had at least two serial basal CT measurements done in the first three months after primary surgery. When evaluated one year after initial surgery, 42 patients (42/105, 40%) achieved an undetectable basal calcitonin level without additional therapies and 56 patients (56/84, 67%) demonstrated a CEA within the normal reference range. In patients destined to have an undetectable CT as the best response to initial therapy, the calcitonin was undetectable by 1 month after surgery in 97% (41/42 patients). Similarly, in patients destined to have a normalize their CEA, the CEA was within the reference range by 1 month post-operatively in 63% and by 6 months in 98%. By 6 months after curative initial surgery, 100% of patients had achieved a nadir undetectable calcitonin, 98% had reached the CEA nadir, and 97% had achieved normalization of both the calcitonin and CEA. The 1 month CT value is a reliable marker of response to therapy that allows earlier risk stratification than the currently recommended 2-3 month CT measurement.

Medullary Thyroid Carcinoma: Do Ultrasonography and F-DOPA-PET-CT Influence the Initial Surgical Strategy?

BackgroundAt the time of diagnosis, one-third of medullary thyroid carcinoma (MTC) patients show lymph node (LN) or distant metastasis. A metastasized MTC requires different surgical strategies.ObjectiveThis study aimed to determine the value of ultrasound and [18F]fluoro-dihydroxyphenylalanine positron emission tomography with computed tomography (F-DOPA-PET-CT) in localizing MTC, as well as LN and distant metastasis.MethodsThe study included 50 patients (24 males/26 females) with preoperative ultrasound, F-DOPA-PET-CT, and histologically proven MTC. Imaging results were correlated with both preoperative basal calcitonin (bCt) levels and final histology.ResultsTumors were classified as pT1a:17 (diameter, mean ± standard deviation: 5.8 ± 3.0 mm), pT1b:15 (15.0 ± 3.2 mm), pT2:9 (27.3 ± 7.0 mm), and pT3:9 (38.3 ± 24.2 mm). The median bCt level was 202 pg/mL (lower/upper quartile: 82/1074 pg/mL). Ultrasound was positive for tumor in 45/50 (92%) patients (20.0 ± 16.0 mm) and negative in 5 patients (3.2 ± 2.2 mm). Overall, 43/50 (86%) patients had positive F-DOPA local scans (20.0 ± 16.4 mm), while 7 (14%) patients were negative (7.7 ± 8.1 mm). Lastly, 21/50 (42%) patients had LN metastasis; 8/21 (38%) patients had positive LNs suspected with ultrasound, and 12/21 (57%) patients had positive LNs suspected with F-DOPA. Tumor and LN sensitivity of ultrasound was 92% and 43%, respectively, and 86% and 57% of F-DOPA-PET-CT, respectively. In 3/50 (6%) patients and 3/50 (6%) patients, mediastinal LN metastasis and distant metastasis, respectively, were diagnosed only by F-DOPA-PET-CT.ConclusionUltrasound and F-DOPA-PET-CT are sensitive for the localization of MTC but not for the presence and location of LN metastasis (limitations: size/number). Only F-DOPA ensures the diagnosis of distant metastasis and influences the extent of LN surgery. Surgical strategy cannot be predicted based on neither ultrasound nor F-DOPA-PET-CT.