Calcitonin Test Research Articles

Defining the Functional Sensitivity for the Siemens Atellica Calcitonin Assay: Insight From a Single-Center Study

BackgroundDetectable, and especially rising postthyroidectomy serum calcitonin and carcinoembryonic antigen levels, as per American Thyroid Association guidelines, indicate potential disease presence, requiring frequent calcitonin measurement or imaging for early detection of persistent or recurrent medullary thyroid carcinoma. 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. MethodsA retrospective analysis was conducted using Siemens Atellica for calcitonin testing on 56 samples from 40 patients between September 27, 2022 and August 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. Carcinoembryonic antigen results were also reviewed. ResultsPrecision analysis at 2.94 and 5.24 pg/mL revealed coefficients of variation at 16.49% and 8.87%, respectively. For the evidence of post-total thyroidectomy persistent or recurrent medullary thyroid carcinoma 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. ConclusionsOur 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.

The impact of preoperative calcitonin screening on the prognosis of patients with medullary thyroid cancer: a retrospective multicenter cohort study.

There is still controversy in different guidelines regarding the necessity of routine preoperative calcitonin (Ctn) testing in medullary thyroid cancer (MTC). The level of preoperative Ctn may influence the extent of surgery. This retrospective multicenter cohort study involved 149 MTC patients from 6 centers between 2013 to 2023. Clinical characteristics, surgical procedure and clinical outcomes were compared between Ctn-screened and Non-screened group. Kaplan-Meier method was used to estimate recurrence-free survival (RFS) and overall survival (OS). In total, 127 MTC patients with preoperative Ctn screening and 22 MTC patients without screening were analyzed. MTC patients with preoperative Ctn screening underwent more radical surgical procedures including total thyroidectomy and lymph node dissection, compared to those without screening (84.3% vs. 68.2% and 91.3% vs. 72.7%, respectively). The rate of recurrence and death were lower in the Ctn-screened group (16.1% vs. 36.4%, 0.8% vs. 18.2%, respectively). The survival curve showed a significantly better overall survival in Ctn-screened group than Non-screened group (HR:17.932, 95% CI 1.888-170.294, p-value = 0.001), while no significant difference was observed of RFS between two groups (HR:1.6, 95% CI 0.645-3.966, p-value = 0.307). Preoperative Ctn screening can prompt surgeons choosing more radical initial surgical treatment for MTC patients, potentially leading to better long-term outcomes. Further evaluation of the cost-effectiveness of routine Ctn screening in thyroid nodule patients is warranted.

Ultrasonographic features of thyroid carcinoma of different sizes: comparison between medullary thyroid carcinomas and papillary thyroid carcinomas

Objective: To investigate the ultrasonographic features of medullary thyroid carcinomas (MTCs) of different sizes and supply valid information for separating MTCs from papillary thyroid carcinomas (PTCs). Methods: There were 87 patients with MTC and 220 patients with PTC detected by ultrasonography and confirmed by pathology at Tianjin Medical University Cancer Institute and Hospital from June 2018 to March 2022. Nodules were divided into the large nodule group (the maximum diameter of the tumor was＞1 cm) and the small nodule group (the maximum diameter of the tumor was ≤1 cm). There were 97 cases in the small nodule group, including 28 cases of MTC and 69 cases of PTC. There were 210 cases in the large nodule group, including 59 cases of MTC and 151 cases of PTC. After stratification by thyroid nodules, ultrasonographic features of thyroid nodules and metastatic lymph nodes, preoperative serum calcitonin (CT) and carcinoembryonic antigen (CEA) levels were compared between MTC and PTC patients. Results: In the small nodule group, the proportion of MTCs exhibiting hypoecho, smooth margins, and having blood flow signals was higher than that of PTCs, with statistically significant differences (all P＜0.05). In the large nodule group, the proportion of MTCs showing cystic solidity, hypoecho, smooth margins, blood flow, and the type Ⅳvascular distribution was higher than PTCs, and the difference of calcification type between them was also statistically significant (all P＜0.05). In contrast, the differences in the number of lesions and aspect ratio between MTCs and PTCs were not statistically significant regardless of nodule size (all P＞0.05). In the small nodule group,6 metastatic lymph nodes of medullary thyroid carcinoma (LNM-MTC) and 11 metastatic lymph nodes of papillary thyroid carcinoma (LNM-PTC) were correctly diagnosed by ultrasound, respectively. The diagnostic compliance rate of ultrasound was 78.6% (22/28) and 78.3% (54/69), respectively, with no statistically significant difference (P=0.973). In the large nodule group, 28 LNM-MTC and 11 LNM-PTC were correctly diagnosed by ultrasound, respectively. The diagnostic compliance of ultrasound was 88.1% (52/59) and 73.5% (111/151), respectively, which was statistically significant (P=0.022). Among them, 82.1% of LNM-MTC and 56.6% of LNM-PTC showed abnormal blood flow signals, with a statistically significant difference (P=0.016). There were significant differences in preoperative serum CT and CEA levels of different sizes of MTCs (all P＜0.05). Conclusions: Different sizes of MTCs require diverse demonstrative criteria. Abnormal blood flow signal is of great significance in the diagnosis of LNM-MTC. Within the absence of ultrasonic characteristics, preoperative serum CT test can provide confidence for the diagnosis of MTC.

Calcium-stimulated calcitonin test for the diagnosis of medullary thyroid cancer: results of a multicenter study and comparison between different assays.

A basal serum calcitonin (Ct) increase >100 pg/mL in patients with a thyroid nodule is consistent with the diagnosis of medullary thyroid cancer (MTC). In cases where the CT test have a slight to moderate increase, the calcium gluconate stimulation test is helpful to increase diagnostic accuracy. However, reliable cut-offs for calcium-stimulated Ct are still lacking. The aim of this study was to evaluate the sex-specific calcium-stimulated Ct cutoffs for the diagnosis of MTC in a multicenter series. A comparison between different Ct assays has been also performed. 90 subjects undergone calcium-stimulated Ct for a suspected MTC in 5 Endocrine Units between 2010-2021 were retrospectively analyzed. Serum Ct concentrations were assessed by immunoradiometric (IRMA) or chemiluminescence (CLIA) assays. MTC was diagnosed in 37 (41.1%) and excluded in 53 (58.9%) patients. The best calcium-stimulated Ct cut-off to identify MTC was 611 pg/mL in males (AUC =0.90, 95% CI (0.76;1) and 445 pg/mL in females (AUC=0.79, 95% CI (0.66;0.91). Logistic regression analysis showed that both basal (OR 1.01, P=0.003) and peak Ct after stimulation (OR 1.07, P=0.007) were significantly associated with MTC, together with sex (OR=0.06, P<0.001). The "Ct assay" variable was also considered in the logistic regression model, but it was not significantly associated with MTC (OR=0.93, P=0.919). This study indicates that calcium test could be helpful to identify patients with early-stage MTC and those without MTC. A Ct value of 611 pg/mL in males and 445 pg/mL in females are proposed as the optimal Ct cut-offs at the stimulation test.

Calcitonin testing in patients with thyroid nodules for screening medullary thyroid carcinoma: a “gray zone”

Introduction. The results of the calcitonin (Ctn) study in patients with thyroid nodules are included in the clinical guidelines for the treatment of differentiated thyroid cancer. However, the management of patients with moderately elevated Ctn up to 100 pg/mL is not clearly defined.Materials and methods. The study included 103 patients with thyroid nodules and a Ctn level above the reference, but not more than 100 pg/ml. The Ctn concentration was determined using the Cobas e platform (Roche, Germany) or by the immunoradiometric method (Izotop, Hungary). 45 patients were operated on. The analysis of the incidence of medullary thyroid carcinoma (MTC), other thyroid and nonthyroid pathology in patients with elevated Ctn scan was carried out. The results of additional examination are presented: the serum cancer embryonic antigen, Ctn in wash-out, stimulated Ctn, gene RET mutation testing.The study objective is to evaluate the probability MTC with Ctn level &lt;100 pg/ml, propose management tactics for patients with elevated Ctn and negative cytological results.Results. The incidence of MTC was 22 % (23/103). The maximum probability of mTC was at Ctn above 50 pg/mL (81 %, 13/16), at Ctn 31-50 pg/mL mTC was detected in 38 % (3/8). With Ctn &lt;30 pg/mL and &lt;20 pg/mL, the incidence of MTC was 9 % (7/79) and 6 % (4/64), respectively. In the majority of MTC patients (65 %), the tumor size did not exceed 1 cm. However, 22 % (5/23) had metastases to the neck lymph nodes. postoperative Ctn normalization was achieved in 96 % (22/23). In 26 % (5/19), a RET germ-line mutation was detected, most often p.val804met.Among patients without MTC, other thyroid tumors were found in 35 % (28/80), more often papillary thyroid cancer (25 %, 20/80). 13 % (10/80) had other malignant neoplasms. parathyroid adenoma was detected in 3 % (2/80). The maximum Ctn in this group was in patients with chronic kidney disease and metastatic liver disease with cholestasis and ascites.Cancer embryonic antigen was increased in 53 % of patients with MTC and in 7 % of patients without MTC. Ctn in washout was &gt;2000 pg/mL in mTC and up to 938 pg/mL in patients with histologically confirmed absence of MTC.Conclusion. If the Ctn level is &lt;100 pg/mL and there is no cytological confirmation, the issue of surgery is decided individually, taking into account many factors. After excluding other causes of hypercalcitoninemia (hyperparathyroidism, kidney disease, other tumors), measurement of serum cancer embryonic antigen and Ctn in wash-out is recommended. In some cases, testing for a RET mutation can be helpful.

Unilateral Surgery for Medullary Thyroid Carcinoma: Seeking for Clinical Practice Guidelines

Optimized preoperative diagnostic tools with calcitonin tests, ultrasound features, functional imaging modalities, and genetic testing to detect hereditary forms have led to an increased rate of earlier diagnosis and surgery for medullary thyroid cancer (MTC). This helps to adapt the primary surgery to the tumor stage and avoid surgical overtreatment for localized tumor growth, i.e., deviating from the regularly recommended thyroidectomy with bilateral central lymph node dissection in favor of a limited unilateral approach. To limit primary surgical therapy, it is crucial that the MTC is clinically unifocal, sporadic, and confined to the thyroid, and that calcitonin levels indicate biochemical recovery after surgery. The main requirement for such a limited approach is the availability of frozen section studies that reliably indicate (i) R0 resection of the MTC, (ii) absence of infiltration of the organ capsule, (iii) lack of desmoplasia (i.e., evidence of the metastatic potential of the MTC), (iiii) absence of contralateral disease or precancerous lesions. Informed consent is mandatory from the patient, who has been fully informed of the advantages, disadvantages, and potential risks of not undergoing the “classic” surgical procedure. The aim of this article is to review the guidelines for the management of early-stage MTC.

The dilemma of routine testing for calcitonin thyroid nodule’s patients to detect or exclude medullary carcinoma: one single negative test should be valuable as rule-out strategy to avoid further calcitonin measurements over time

PurposeWhile calcitonin (CT) measurement is recognized as the most accurate tool to diagnose medullary thyroid carcinoma (MTC), its routine use in patients with thyroid nodule (TN) is not universally accepted. The present study raised the question whether a TN patient with an initial normal CT can have suspicious CT levels (i.e., at least >20 pg/ml) later during his follow-up.MethodsThe historical database of our institution was searched to select TN patients undergone multiple CT tests, having an initial normal CT, and clinically followed up for years. The event of a CT above 20 pg/ml (mild-to-moderate suspicion) and 100 pg/ml (high suspicion) was searched in the follow-up of the included patients.ResultsAccording to the study design, the study sample encompassed 170 patients (131 female, 39 male) with initial CT value ≤10 pg/ml. On the first CT test, patients were 54.8 years and median CT was 2.1 pg/ml in both females and males. Over a period of 14.5 years and a median clinical follow-up of patients of 53.0 (23.9–102.5) months, MTC could be excluded by histology or cytology in 109 (64%) and clinically in the remaining ones. On the follow-up over time, no patients had CT >20 pg/ml and only two cases had CT just above 10 pg/ml.ConclusionAccording to the present results, one single CT testing with normal value could be reasonably used as a rule-out strategy in patients with TN to avoid further CT measurements.

Preoperative calcitonin testing improves the diagnosis of medullary thyroid carcinoma in female and male patients.

Calcitonin (Ctn) measurement in patients with thyroid disease could potentially increase the detection rates of medullary thyroid carcinoma (MTC) but remains a controversial issue. The aim of this study was to evaluate routine preoperative Ctn measurements. All patients with thyroid surgery documented in the prospective StuDoQ|Thyroid registry between March 2017 and September 2020 were included. Cutoff levels for Ctn were determined with receiver-operating characteristic analyses to assess the preoperative diagnosis of MTC in subgroups for females and males. In 29 590 of 39 679 patients (75%) participating in the registry, routine preoperative Ctn testing was performed. In 357 patients (227 females and 130 males), histopathology confirmed MTC with a mean tumor size of 14.7 mm (±12.43). Biochemical cure was achieved in 71.4% of the patients. Ctn levels between 11 and 20 pg/mL were seen in 2.6% of the patients, and only 0.7% of the patients had Ctn levels above 21 pg/mL. Cutoff levels for the diagnosis of MTC were 7.9 pg/mL for females and 15 pg/mL for males (P < 0.001). The sensitivity and specificity for females were 95 and 98%, and 96 and 97% for males, respectively. Routine Ctn testing is a reliable predictor for MTC and provides the opportunity for earlier thyroidectomy before lymph node metastases occur, resulting in a better prognosis. Females with Ctn levels >7.9 pg/mL and males >15 pg/mL without any other extrathyroidal sources for an elevated Ctn should be monitored. Thyroid surgery should be considered if Ctn levels are increasing or ultrasound detects suspicious thyroid lesions.

Calcitonin: current concepts and differential diagnosis.

Calcitonin (CT) is most effectively produced by the parafollicular cells of the thyroid gland. It acts through the calcitonin receptor (CTR), a seven-transmembrane class II G-protein-coupled receptor linked to multiple signal transduction pathways with its main secretagogues being calcium and gastrin. It is clinically used mostly in the diagnosis and follow-up of medullary thyroid carcinoma (MTC). Hypercalcitoninemia can be attributed to primary (e.g. CT-secreting tumor) or secondary (e.g. due to hypercalcemia) overproduction, underexcretion (e.g. renal insufficiency), drug reaction (e.g. β-blockers), or false-positive results. In clinical practice, elevated basal calcitonin (bCT) is indicative, but not pathognomonic, of MTC. Current literature leans toward an age as well as gender-specific cutoff approach. bCT >100 pg/ml has up to 100% positive prognostic value (PPV) for MTC, whereas bCT between 8 and 100 pg/ml for adult males and 6 and 80 pg/ml for adult females should be possibly further investigated with stimulation calcitonin (sCT) tests. Calcium is showing similar efficacy with pentagastrin (Pg) sCT; however, the real value of these provocative tests has been disputed given the availability of new, highly sensitive CT immunoassays. Anyhow, evidence concludes that sCT <2 times bCT may not be suggestive of MTC, in which case, thyroid in addition to whole body workup based on clinical evaluation is further warranted. Moreover, measurement of basal and stimulated procalcitonin has been proposed as an emerging concept in this clinical scenario. Measuring bCT levels in patients with thyroid nodules as a screening tool for MTC remains another controversial topic. It has been well established, though, that bCT levels raise the sensitivity of FNAB (Fine Needle Aspiration Biopsy) and correlate with disease progression both pre- and postoperatively in this situation. There have been numerous reports about extrathyroidal neoplasms that express CT. Pancreatic, laryngeal, and lung neuroendocrine neoplasms (NENs) are most frequently associated with hypercalcitoninemia, but CT production has also been described in various other neoplasms such as duodenal, esophageal, cutaneous, and paranasal NENs as well as prostate, colon, breast, and lung non-NENs. This review outlines the current biosynthetic and physiology concepts about CT and presents up-to-date information regarding the differential diagnosis of its elevation in various clinical situations.

Analytical Performance Evaluation of a New Calcitonin Assay.

The use of efficient laboratory calcitonin (CT) testing is required for optimal management of medullary thyroid carcinoma. Several pitfalls are related to the calcitonin laboratory assays and a careful evaluation is needed. We report the analytical performances of the new Siemens ADVIA-Centaur-CALCT (CT-XPT) assay and its comparison with our standard method DiaSorin-Calcitonin-II-Gen (CT-LIA) assay. Analytical performance of the CT-XPT-assay, limit of blank (LOB), limit of detection (LOD), and limit of quantification (LOQ), were determined. We also evaluated the in vitro stability of the sample, together with the linearity and percentage recovery. The CT-XPT-assay showed a better detection limit than the CT-LIA assay, with lower values of LOB (0.86 pg/mL vs 1.00 pg/mL) and LOQ (1.65 pg/mL vs 3.00 pg/mL). Both values were in agreement with those reported by the manufacturer. Within- and between-run precision demonstrated a good concordance of results. Regarding the in vitro stability of CT, the low CT concentration sera showed a much greater decrease in CT levels compared to the high concentration sera. Correlation studies showed a good correlation between the two methods (Kappa Cohen coefficent, KC: 0.68, agreement % for male: 89.58%; KC: 0.63; agreement % for female: 88.33%). Our findings showed a good correlation between the CT-LIA and CT-XPT methods. Moreover, we demonstrated that the analytical performance of the CT-XPT assay, together with its technical specifications, could represent major features of the CT-XPT method. Collectively, the technical evaluation and the analytical results described in the presented paper highlight that the novel CT-XPT is a valid method for CT testing in a clinical diagnostic setting.

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.

Clinical significance and cost-benefit analysis of serum calcitonin assay in diagnosis and treatment of medullary thyroid carcinoma

Objective: To study the clinical significance of serum calcitonin in the diagnosis and treatment of medullary thyroid carcinoma and to analyze its cost-benefit. Methods: One hundred and forty one patients with medullary thyroid carcinoma who undertook calcitonin test and frozen pathological examination were enrolled in this study from Oct 2012 to Mar 2018. Using the method of χ(2) test, the positive rate of calcitonin test and frozen pathological examination in diagnosis of medullary thyroid carcinoma(MTC) were compared. Firstly, we compared the correct checkout cost of calcitonin test and that of frozen pathological examination (total number of patients×cost of examination/the correctly detected number of patients) . Secondly, we calculated whether calcitonin test help patients save money(average cost of treatment in hospital for MTC×number of patients who were evaluated to be candidate for surgery-cost of calcitonin test×total number of patients)/total number of patients. Results: 139 patients were positive in calcitonin test among 141 patients, and the positive rate was 98.58%. 91 patients were positive in frozen pathological examination, and the positive rate was 64.54% (χ(2)=97.821, P<0.000 1) . Cost-benefit analysis showed that the correct checkout cost of calcitonin test and frozen pathological examination were 71.01 yuan and 426.10 yuan, also,1 371 938.64 yuan could be saved totally and 9 730.06 yuan could be saved per patient because of calcitonin test. Conclusion: Serum calcitonin test had a significant effect on the diagnosis and treatment of medullary thyroid carcinoma and was economical and practical.

Blockade of SDF-1/CXCR4 reduces adhesion-mediated chemoresistance of multiple myeloma cells via interacting with interleukin-6.

Resistance to chemotherapy represents a major cause for treatment failure in multiple myeloma (MM). Herein, this study was conducted to explore the effect of SDF-1/CXCR4 and interleukin-6 (IL-6) in MM cell adhesion-mediated chemoresistance. Enzyme-linked immunosorbent assay was applied to detect expressions of SDF-1α and IL-6 in MM patients and healthy controls. RPMI-8226 cells and isolated bone marrow stromal cells (BMSCs) were stimulated using recombinant SDF-1α and IL-6. Effect of cocultured BMSCs and RPMI-8226 cells on chemosensitivity and apoptosis of RPMI-8226 cells was analyzed. Effect of doxorubicin on the adhesion rate of RPMl-8226 cells to BMSCs was analyzed by calcitonin test. Effect of SDF-1α-induced upregulation of IL-6 on chemotherapeutic resistance and apoptosis of RPMI-8226 cells in adhesion state was analyzed. Cell adhesion model was treated with recombinant protein SDF-1α and phosphoinositide 3-kinase (P13K) inhibitor Wortmarmin. The levels of P13K and protein kinase B (AKT) and its phosphorylation as well as the expression of IL-6 were analyzed. SDF-1α was positively correlated with IL-6. Recombinant human SDF-1α increased IL-6 expression and induced IL-6 secretion in a time- and dose-dependent manner in BMSCs, which was inhibited by IL-6 and SDF-1α neutralizing antibodies. Coculture of MM cells with BMSCs increased the drug resistance and inhibited the apoptosis on MM cells. SDF-1α-induced IL-6 upregulation mediates chemoresistance and apoptosis of RPMI-8226 cells in adhesion state. SDF-1α may up-regulate the expression of IL-6 by activating the P13K/AKT signaling pathway. SDF-1/CXCR4 may up-regulate the expression of IL-6 through the activation of the P13K/AKT signaling pathway, thereby affecting the chemoresistance mediated by adhesion in MM cells.

NOVEL MARKERS FOR EARLY DIAGNOSIS AND PROGNOSTIC CLASSIFICATION IN MEDULLARY THYROID CARCINOMA.

Medullary thyroid carcinoma is a neuroendocrine tumour of the parafollicular C cells of the thyroid gland. It is an aggressive tumor that can be cured only by complete resection of the thyroid tumour and any local and regional metastases. Thus, the discovery of novel diagnostic and prognostic markers is very important for early diagnosis and correct management, in order for the survival rates to rise. New research has emphasized the potential role of various genes, serum and immunohistochemical markers, as well as potential targets for therapeutic agents. The calcium stimulated calcitonin test has been recently reintroduced in clinical practice, and current medullary thyroid carcinoma guidelines encourage laboratories to set their own criteria defining reference ranges for elevated serum basal and stimulated calcitonin levels.

My, How Things Have Changed in Multiple Endocrine Neoplasia Type 2A!

The history of medullary thyroid carcinoma (MTC) has been characterized by several distinct phases. The initial descriptive phase originated with the 1961 report from John Sipple describing the association of thyroid carcinoma and pheochromocytoma (1). Subsequent investigators correctly identified the thyroid malignancy as MTC, showed that the tumor produced the newly discovered hormone calcitonin, and further categorized this syndrome into its two major subtypes—multiple endocrine neoplasia (MEN) types 2A and 2B (2–4). The second phase began in the late 1960s with the use of serum calcitonin measurements to identify MTC and successful treatment of the malignancy by total thyroidectomy and lymph node dissection. In the 1970s and 1980s, investigators questioned whether MTC could be identified in children at risk for inheriting the disease through the use of provocative calcitonin testing and treatment by early thyroidectomy (5, 6). These studies identified well-defined kindreds with MEN2, an essential resource for the genetic linkage analysis to map the causative gene. The third phase began in 1993 with the identification of RET proto-oncogenemutations inMEN2and theuseof this information to identify affected children (7, 8). The fourth phase began in 2002 with the recognition that small organic molecules that inhibit phosphorylation of RET (and other kinase receptors) have therapeutic efficacy for treatment of metastatic MTC (9), leading to recent Food and Drug Administration approval of two agents for this purpose (10, 11). Machens and Dralle (12), in their insightful report published in this issue, summarize their substantial lifetime contributions to this field and, through their experience, chronicle the changes that have occurred over the past 50 years. Perhaps the most significant observation made by the authors in their report has been the impact of early thyroidectomy on the presence of disease and identifiable metastasis, assessed by histological evaluation of the thyroid gland and lymph nodes removed for treatment of MTC. For those non-index patients with American Thyroid Association (ATA)-labeled level C (high-risk) mutations (13), the percentage with MTC found in the thyroid gland at thyroidectomy has fallen from 100% in the 1985–1989 period to 19% in the 2010–2014 period. This dramatic decrease was caused initially by provocative testing that lowered the age of thyroidectomy to an average of 13 years, with a drop from 100% MTC to approximately 50% in the series of cases that encompassed the period from 1971–1988 (6). The decline was further accelerated by the rapid adoption of genetic testing and the acceptance of the recommendation that children with level C mutations undergo thyroidectomy by age 5 or 6 years. Interestingly, there has not been a comparable decline in the MTC or node positivity in the level A or B mutations, a point to which we will return later. Another important observation, highlighted by their data, is the shift in frequency of specific mutations over the past 20 years. In the classic report by Eng et al (14) in 1996, approximately 80% of mutations identified in MEN2 occurred at codon 634 of the RET proto-oncogene (Figure 1). Sipple’s syndrome, or classic MEN2A, the association of MTC, pheochromocytoma, and hyperparathyroidism caused most commonly by a codon 634 RET mutation, came to attention in 1961 (1) because it is a “noisy” syndrome with as many patients initially identified based on the presence of hypercalcemia or pheochromocytoma as MTC, facilitating its identification in the pregenetic era. Subsequent reports by Yip et al (15) in 2003 and Frank-

Occult medullary carcinoma of thyroid - an unusual clinical and pathologic presentation

Background: Medullary thyroid cancer is a neuroendocrine tumor originating from the parafollicular C cells of the thyroid which secrete calcitonin. MTC accounts for approximately 4% of all clinically detected thyroid malignancies. The prevalence of occult MTC in the general population is not well established. Case Presentation: We describe a rare patient with occult sporadic MTC who presented with cervical lymphadenopathy and an asymptomatic mediastinal mass and elevation of calcitonin and carcinoembryonic antigen levels. Conclusion: Our practice is to recommend basal calcitonin testing for thyroid nodule patients with increased risk of MTC, including those with a family history of MTC, with a diagnosis of hyperparathyroidism or pheochromocytoma, or symptoms of flushing or diarrhea.

Hypercalcitoninemia and thyroid nodules

Medullary thyroid carcinoma (MTC) can assume various cytomorphological and architectural forms, mimicking other thyroid and extra-thyroid tumors and rendering the cytological and histological diagnosis challenging. Consequently, measurement of calcitonin (CT) levels is generally considered to be more accurate than cytology in diagnosing MTC. Here, we report on a patient with a multinodular goiter and significantly elevated basal CT levels; based on cytology examination and CT immunocytostains, neither MTC nor C-cell hyperplasia was detected upon final histopathological examination. CT testing has a high false-positive rate and low positive predictive value for detecting clinically relevant MTC. Judicious integration of cytological examination with immunocytochemical stains (when needed) may be useful for selecting the most appropriate therapy and avoiding overtreatment (i.e., central neck lymph node dissection in the present case). This case demonstrates that cytological examination with ancillary techniques is still valuable in patients with thyroid nodules and suspicious MTC.

Measurement of Calcitonin and Calcitonin Gene–Related Peptide mRNA Refines the Management of Patients with Medullary Thyroid Cancer and May Replace Calcitonin-Stimulation Tests

Serum calcitonin (sCT) is the main tumor marker for medullary thyroid cancer (MTC), but it has certain limitations. Various sCT assays may have important intra-assay or interassay variation and may yield different and sometimes conflicting results. A pentagastrin- or calcium-stimulation calcitonin (CT) test may be desirable in some situations. Alternatively, or in the absence of the stimulation test, mRNA detection offers the advantages of being more comfortable and less invasive; it only requires blood collection and has no side effects. The objective of this study was to investigate the applicability of measuring calcitonin-related polypeptide alpha (CALCA) gene transcripts (CT-CALCA and calcitonin gene-related peptide [CGRP]-CALCA) in patients with MTC and in relatives diagnosed with a RET mutation and to test mRNA as an alternative diagnostic tool for the calcitonin-stimulation test. Twenty-three healthy controls and 26 individuals evaluated for MTC were selected, including patients with sporadic or hereditary MTC and RET mutation-carrying relatives. For molecular analysis, RNA was extracted from peripheral blood, followed by cDNA synthesis using 3.5 μg of total RNA. Quantitative real-time polymerase chain reaction (RT-qPCR) was performed with SYBR Green and 200 nM of each primer for the two specific mRNA targets (CT-CALCA or CGRP-CALCA) and normalized with the ribosomal protein S8 as the reference gene. We detected CALCA transcripts in the blood samples and observed a positive correlation between them (r=0.946, p<0.0001). Both mRNAs also correlated with sCT (CT-CALCA, r=0.713, p<0.0001; CGRP-CALCA, r=0.714, p<0.0001). The relative expression of CT-CALCA and CGRP-CALCA presented higher clinical sensitivity (86.67 and 100, respectively), specificity (97.06 and 97.06), positive predictive value (92.86 and 93.75), and negative predictive value (94.29 and 100), than did sCT (73.33, 82.35, 64.71, and 87.50, respectively). In addition, the CALCA transcript measurement mirrored the response to the pentagastrin test. We demonstrate that the measurement of CALCA gene transcripts in the bloodstream is feasible and may refine the management of patients with MTC and RET mutation-carrying relatives. We propose considering the application of this diagnostic tool as an alternative to the calcitonin-stimulation test.

Calcium Stimulated Calcitonin Measurement: A Procedural Proposal

Human calcitonin (hCT) is a tumor marker essential to the diagnosis and follow-up of medullary thyroid cancer (MTC). Current consensus recommends hCT measurement when initially evaluating thyroid nodules; if slightly elevated, a confirmatory stimulated calcitonin test is commonly performed, usually using pentagastrin. In recent years the supply of pentagastrin was not guaranteed with long periods of unavailability; the outlook for future availability is unknown. Therefore it is desirable for many institutions to establish a procedure for calcitonin stimulation using a stimulant with a secure supply; stimulation of calcitonin using calcium represents the easiest alternative.Several schemes and dosages have been used in the past for calcium stimulated calcitonin measurement. In this paper we propose a procedure for calcium stimulated calcitonin measurement based on our experiences. Furthermore we will briefly point out the limitations of this method with regard to available data in literature.

Twenty Years of Experience with the Preoperative Diagnosis of Medullary Cancer in a Moderately Iodine-Deficient Region

Background. There is a current debate in the medical literature about plasma calcitonin screening in patients with nodular goiter (NG). We decided on analyzing our 20-year experience with patients in an iodine-deficient region (ID). Patients and Methods. 22,857 consecutive patients with NG underwent ultrasonography and aspiration cytology (FNAC). If FNAC raised suspicion of medullary cancer (MTC), the serum calcitonin was measured. Results. 4,601 patients underwent surgery; there were 23 patients among them who had MTC (0.1% prevalence). Significantly more MTC cases were diagnosed cytologically in the second decade than in the first: 11/12 and 6/11, respectively. The frozen section was of help in 2 cases out of 3. Two patients suffered from a 3-year delay in proper therapy, and reoperation was necessary in 1 case. FNAC raised the suspicion of MTC in 20 cases that were later histologically verified and did not present MTC. The diagnostic accuracy of FNAC in diagnosing MTC was 99.2%. Two false-positive serum calcitonin tests (one of them in a hemodialyzed patient) and one false-negative serum calcitonin test occurred in 40 cases. Conclusion. Regarding the low prevalence of MTC in ID regions, calcitonin screening of all NG patients does not only appear superfluously but may have more disadvantages than advantages.