Preoperative Basal Calcitonin Levels Research Articles

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.

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.

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).

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.

Large sporadic thyroid medullary carcinomas: predictive factors for lymph node involvement.

Lymph node involvement (LNI) is one of the most important prognostic factors for poor survival in medullary thyroid carcinoma (MTC). At diagnosis, LNI is found in over 50% of sporadic MTCs, and especially in large tumours. Cervical lymph node dissection is therefore mandatory during MTC surgery. However, some large tumours (responsible for high preoperative basal calcitonin levels) are found to lack LNI, and can be cured definitely. Preoperative detection of these particular tumours might spare patients from undergoing extensive cervical dissection. The objective of the present retrospective study of a series of large sporadic MTCs was to identify clinical, biological and pathological factors that were predictive of LNI. Consecutive cases of large, sporadic MTCs (measuring at least 1cm in diameter) were retrieved and reviewed. The levels of several mature microRNAs (miRs) in paraffin-embedded samples were assessed using qPCR. Of the 54 MTCs, 26 had LNI and 28 were pN0. Relative to pN0 patients, patients with LNI had a significant higher preoperative basal calcitonin level (p = 0.0074) and a greater prevalence of infiltrative margins (p < 0.0001), lymphovascular invasion (p = 0.0004), extrathyroidal extension (p < 0.0001), a higher pT stage (p = 0.0003) and more abundant desmoplastic stroma (p = 0.0006). Tumour expression levels of miR-21 (p = 0.0008) and miR-183 (p = 0.0096) were higher in the LNI group. The abundance of desmoplastic stroma (p = 0.007) and the miR-21 expression level (p = 0.0026) were independent prognostic factors for LNI. The abundance of desmoplastic stroma and high levels of miR-21 expression were strong indicators of LNI, and may thus help the surgeon to choose the extent of cervical lymph node dissection for large, sporadic MTCs with no preoperatively obvious LNI.

A Nationwide Study of Multiple Endocrine Neoplasia Type 2A in Norway: Predictive and Prognostic Factors for the Clinical Course of Medullary Thyroid Carcinoma.

Multiple endocrine neoplasia type 2A (MEN 2A) is an autosomal dominant syndrome caused by activating germline mutations in the RET (REarranged during Transfection) proto-oncogene. MEN 2A has a strong (>95%) and age-dependent (5-25 years) clinical penetrance of medullary thyroid carcinoma (MTC). Several major studies have analyzed the predictive and prognostic factors for MEN 2A to find indicators that predict the optimal timing of prophylactic thyroidectomy. The aims of this study were to describe all known RET positive MEN 2A patients diagnosed in Norway and to evaluate the clinical course of MTC, as well as its predictive and prognostic factors. This nationwide retrospective cohort study included data for 65 (14 index and 51 screening patients) out of a total of 67 MEN 2A patients with the RET gene mutation who were diagnosed in Norway since 1974. Data were collected by reviewing patient files. The variables analyzed were genotype, phenotype, preoperative basal calcitonin, age at thyroid surgery, central lymph node dissection and nodal status at primary surgery, number of surgical procedures, and biochemical cure. Of the 65 patients, 60 had undergone thyroid surgery. The median follow-up period was 9.9 years. The patients were divided into pre-RET-and RET-era, which included patients who had thyroid surgery before January 1, 1994, and after, respectively. In index and screening patients, MTC was found, respectively, in 100% and 45% of cases, central lymph node dissection at primary surgery was done for 64% and 52% of patients, and the median total number of surgical procedures was two (range 1-6) and one (range 1-4). At primary surgery, all patients (n = 13) with lymph node metastases had preoperative basal calcitonin levels ≥68 pg/mL, and all patients (n = 17) without central lymph node dissection and preoperative basal calcitonin <40 pg/mL were biochemically cured. Multivariate analysis showed that preoperative basal calcitonin was a significant predictive factor for MTC superior to age at thyroid surgery when analyzing the entire period (p = 0.009) and the RET-era separately (p = 0.021). Prognostic factors for biochemical cure were preoperative basal calcitonin, central lymph node dissection, and nodal status at primary surgery (p = 0.037, p = 0.002, and p = 0.005) when analyzing the entire period, but only nodal status at primary surgery when the RET-era was considered separately (p = 0.006). Preoperative basal calcitonin alone can serve as an indicator for optimal timing and the extent of thyroid surgery for MEN 2A patients that could be considered safe. The results are consistent with previously reported data.

Role of Preoperative Basal Calcitonin Levels in the Timing of Prophylactic Thyroidectomy in Patients With Germline RET Mutations

The American Thyroid Association (ATA) published recommendations for the timing of prophylactic surgery for medullary thyroid carcinoma based on the specific mutation, patient age, family history, and serum calcitonin levels. The aim of this study was to assess the role of preoperative basal calcitonin (prebCt) levels in predicting the presence of medullary carcinoma of the thyroid in patients with RET mutations. We conducted a retrospective study in two endocrine surgery departments. Between 1986 and 2012, a total of 32 patients with RET mutations underwent prophylactic thyroidectomy. The patients were stratified into four ATA risk levels: A, B, C, and D. All of the patients were biologically cured. Microcarcinoma was observed in the final pathology report for four of the 20 patients with normal prebCt (25%) and for nine of the 12 patients with elevated prebCt (75%). In the level A group, four patients with normal prebCt and one patient with elevated prebCt presented with microcarcinoma. In the level C group, one patient with normal prebCt and six of the seven patients with elevated prebCt (86%) presented with microcarcinoma. PrebCt can predict the presence of microcarcinoma according to surgical pathological analysis. Patients with microcarcinoma can be biochemically and clinically cured using prophylactic thyroidectomy.

Surgical management of the lateral neck compartment for metastatic thyroid cancer

The lateral neck compartment is the second most frequent target region for metastatic papillary thyroid cancer (PTC) and medullary thyroid cancer (MTC). Lateral lymph node metastases are associated with locoregional recurrence and, when they involve either side of the neck, with mediastinal and distant metastases. For tumors originating from the upper thyroid pole, the first nodal basin is not invariably the central compartment (as for primaries arising from the inferior thyroid pole) but often the upper part of the ipsilateral lateral compartment. Lymph node dissection of the first basin may differ depending on the location of the primary tumor. Involvement of the contralateral lateral compartment is seen in PTC with extensive central compartment involvement, and in MTC with preoperative basal calcitonin levels more than 200 pg/ml (normal limit <10 pg/ml). After lateral lymph node dissection for metastatic thyroid cancer, dysfunction of lateral neck nerves is fairly common. This observation underpins the importance of striking a balance between oncological benefit and surgical risk. Lateral lymph node dissection may be warranted for an upper thyroid pole primary, for a tumor with extensive involvement of the central compartment, and for an MTC with increased basal calcitonin level of 20-200 pg/ml (ipsilateral dissection) or more than 200 pg/ml (bilateral dissection).

Constitutive RET tyrosine kinase activation in hereditary medullary thyroid cancer: clinical opportunities

The ground-breaking discovery of genotype-phenotype relationships in hereditary medullary thyroid cancer has greatly facilitated early prophylactic thyroidectomy. Its timing depends not solely on a positive gene test but, more importantly, on the type of the REarranged during Transfection (RET) mutation and its underlying mode of RET receptor tyrosine kinase activation. In the past decade, the therapeutic corridor opened by molecular information has been defined down to a remarkable level of detail. Based on mutational risk profiles, preemptive thyroidectomy is recommended at 6 months of age for carriers of highest-risk mutations, before the age of 5 years for carriers of high-risk mutations, and before the age of 5 or 10 years for carriers of least-high-risk mutations. Additional lymph node dissection may not be needed in the absence of increased preoperative basal calcitonin levels. Better comprehension of RET function should enable the design of targeted therapies for RET carriers beyond surgical cure in whom the DNA-based 'window of opportunity' has been missed.

Clinical and Oncological Features of Children and Young Adults with Multiple Endocrine Neoplasia Type 2A

RET genotype analysis allows identification of asymptomatic carriers at risk of developing medullary thyroid carcinoma (MTC). However, there is still controversy regarding the ideal timing and extent of prophylactic thyroidectomy due to the wide spectrum of clinical presentation. Surveillance of a large number of young patients is crucial to advance our understanding of the natural course of the disease. This study aimed to describe the clinical presentation, oncological features, and treatment outcome of children and young adults harboring RET mutations followed at our institution from 1997 to 2007. Forty-one individuals aged < or =25 years from 17 independent multiple endocrine neoplasia type 2A kindred were studied. Twenty-one individuals presented with thyroid nodules at diagnosis, and 20 were disease free at physical examination. Preoperative basal calcitonin levels were elevated in 85.7% of patients with clinical disease and in 54.5% of asymptomatic carriers. Thyroid ultrasonography (US) showed one or more nodules in 69.0% of the patients. A positive correlation between age at surgery and tumor-node-metastasis (TNM) stages was observed (p < 0.001). None of the patients under 15 years of age presented lymph node or distant metastasis. After a follow-up of 4.4 +/- 1.4 years all asymptomatic patients were disease free based on physical examination, cervical US, and undetectable serum calcitonin levels. In the group of patients with clinical disease, 47.6% have persistent disease (follow-up of 12.0 +/- 5.9 years). Indeed, palpable thyroid nodule at diagnosis was significantly associated with persistent disease (p < 0.001, odds ratio [OR] 1.9, 95% confidence interval [CI 95%] 1.27-2.87). Of note, none of the patients who presented lymph node metastasis at diagnosis were cured by surgical intervention (p < 0.001, OR 5.0, CI 95% 1.45-17.0). Our data show a time-dependent MTC progression. The presence of a palpable thyroid nodule and lymph node metastasis at diagnosis was associated with persistent or recurrent disease after surgical procedure.

Difference in development of medullary thyroid carcinoma among carriers of RET mutations in codons 790 and 791*

Hereditary medullary thyroid carcinoma (MTC) is caused by germ-line mutations in the RET proto-oncogene. Our study addresses the difference in development of MTC between rare mutations in RET codons 790, 791 and 804. We evaluated tumour stage, calcitonin levels, biochemical cure rates and associated endocrinopathies in 153 German/Austrian patients with RET 790 (n = 47), 791 (n = 56) and 804 mutations (n = 50), divided into index- and screening groups. Age at diagnosis in index-patients did not differ significantly among the three codon groups (medians of 57, 61 and 53 years). Tumour stage at diagnosis was significantly less advanced with codon 791 (n = 22) than 790 (n = 16) and 804 (n = 16) mutations (P = 0.001). In screening patients, age at diagnosis did not differ significantly among the three groups (medians 19, 24 and 32 years). Tumour stage at diagnosis was also significantly less advanced with codon 791 (n = 34) than 790 (n = 31) and 804 (n = 34) (P = 0.032). Preoperative basal calcitonin levels were significantly lower in codon 791 carriers compared to codon 790 carriers, and cure rates were significantly higher in both index (75%vs. 31%; P = 0.03) and screening patients (100%vs. 75%; P = 0.015). Additional endocrinopathies were observed only with codon 791 carriers (four pheochromocytomas and two hyperparathyroidism). There is a significant difference in MTC development with less extensive C-cell disease, higher cure rate and more frequent additional endocrinopathies in carriers of RET codon 791 mutations compared with carriers of codons 790 and 804 mutations. This information should be considered when age of prophylactic thyroidectomy is discussed.

Prospects of Remission in Medullary Thyroid Carcinoma According to Basal Calcitonin Level

Prediction of remission in medullary thyroid carcinoma (MTC) depends on histopathological information often unavailable before surgery. Simply requiring a venous blood sample, preoperative basal calcitonin levels may be a better indicator of remission. In this institutional series of 224 consecutive patients with MTC and elevated preoperative basal calcitonin levels, postoperative calcitonin levels normalized in 28 (62%) of 45 patients with node-negative MTC and in 18 (10%) of 177 patients with node-positive MTC. On multivariate analysis, preoperative basal calcitonin levels greater than 500 pg/ml best predicted the failure to achieve biochemical remission, followed by nodal metastasis and reoperative status. Cumulative rates of biochemical remission fell continuously with rising serum basal calcitonin in node-negative patients. Node-positive patients did not achieve biochemical remission when their preoperative basal calcitonin levels exceeded 3000 pg/ml. Nodal metastasis started emerging at basal calcitonin levels of 10-40 pg/ml (normal range, <10 pg/ml). Distant metastasis and extrathyroidal growth began appearing in patients with node-positive MTC at basal calcitonin levels of 150-400 pg/ml. There were no differences between patients with sporadic and hereditary MTC after adjusting for multiple testing. Preoperative basal calcitonin levels may thus help individualize the extent of surgery and postoperative follow-up intervals for MTC.

Potential Absence of Prognostic Implications of Severe Preoperative Hypercalcitoninemia in Medullary Thyroid Carcinoma

To evaluate preoperative hypercalcitonine-mia further as a marker of prognosis in patients with medullary thyroid carcinoma (MTC). We reviewed the clinical and laboratory data in six patients (four men and two women, 39 to 76 years old)--three with sporadic MTC, one with familial MTC, and two with multiple endocrine neoplasia type 2A--who had preoperative basal serum calcitonin levels of 400 to 16,000 pg/mL (normal, 0 to 19). Pentagastrin stimulation was performed in patients who had preoperative basal calcitonin levels less than 1,000 pg/mL, and responses ranged from 2,600 to 8,500 pg/mL. Thyroidectomy revealed intrathyroidal MTC in four patients; MTC and nodal metastatic lesions were present in two. The tumor cells were immunoreactive with anti-calcitonin immunoperoxidase staining. Serum calcitonin and carcinoembryonic antigen levels were normal postoperatively. In serial postoperative evaluation during a follow-up period of 2 to 9 years, stimulated peak plasma calcitonin levels after pentagastrin or calcium infusion were normal (in five patients) or near normal (in one patient), without clinical evidence of recurrent disease. The two patients with nodal metastatic disease have had normal calcitonin levels during a mean duration of follow-up of approximately 3 years. Pronounced preoperative hypercalci-toninemia does not necessarily preclude a favorable short-term outcome in patients with MTC.

Calcitonin kinetics in the early postoperative period of medullary thyroid carcinoma

Calcitonin is a sensitive marker for medullary thyroid carcinoma. Normalisation of calcitonin levels following resection of medullary thyroid carcinoma has been described after a few hours; however, it may be observed more than 4 weeks after surgery. The aim of this study was to correlate the postoperative calcitonin kinetics with preoperative calcitonin levels and tumour stage. Furthermore, we wanted to test the prognostic impact of the calcitonin kinetics. Therefore, only patients with postoperative normalisation of calcitonin levels (biochemical cure) were included in this study. Fourteen biochemically cured patients were analysed, including measurement of postoperative basal and pentagastrin-stimulated calcitonin concentration. With respect to the time of postoperative basal calcitonin normalisation, patients were classified into two groups: (A) patients with normalisation of basal calcitonin levels within 24 h and (B) patients with normalisation of basal calcitonin levels later than 24 h postoperatively. Eight patients were found to have normalisation of basal calcitonin levels within 24 h (group A). In the remaining six patients (group B), the period to normalisation of basal calcitonin levels varied from 6 days to 14 days and longer. There were no differences between the two groups with regard to tumour size, number and pattern of lymph node metastases and tumour stage. However, preoperative basal calcitonin levels were significantly different (258 ng/ml vs 955 ng/ml, P<0.01). In the group with slow-decreasing calcitonin levels, no strong correlation between the preoperative level and the postoperative time to normalisation of basal calcitonin levels could be established, which may be due to the small number of patients. After a median follow-up of 21 months, no patient developed tumour recurrence. However, an increased basal calcitonin level was observed in one patient from group B. All other patients had normal basal and peak calcitonin levels. Using a highly sensitive calcitonin assay, we demonstrated that normalisation of basal calcitonin levels may be delayed in patients suffering from medullary thyroid carcinoma. The lack of correlation of preoperative levels and the time to normalisation of the basal calcitonin levels, as well as the positive pentagastrin test in some of the patients, argues that this phenomenon is not simply due to prolonged biochemical calcitonin elimination. Nevertheless, a prognostic influence could not be shown in this study due to the short follow up-period. Further investigations and a longer follow-up are necessary to determine the nature and the prognostic impact of delayed normalisation of calcitonin levels.

Relation of doubling time of plasma calcitonin levels to prognosis and recurrence of medullary thyroid carcinoma.

Plasma calcitonin (CT) levels were measured serially in 54 patients surgically treated for medullary thyroid carcinoma. Patients with postoperative basal CT levels higher than 1 ng/ml measured within 1 month after surgery had a higher recurrence rate than those with lower CT levels (p less than 0.002). Patients with postoperative basal CT levels higher than 2 ng/ml had a lower survival rate than those with lower CT levels (p less than 0.01). However, preoperative basal CT levels had no significant correlation with life expectancy or recurrence during the present observation period. Serial measurements in 23 patients with elevated postoperative CT levels showed exponential increases in basal CT levels in 19 patients (p less than 0.05 in nine patients, 0.05 less than p less than 0.1 in four patients) and slight decreases in four (p less than 0.05 in one patient). Doubling time of CT levels calculated from the regression line in each patient showed the highest correlation with 3-year survival, recurrence within 5 years, and time interval between surgery and clinical recurrence of the tumor, allowing quantitative prediction of the prognosis.