Different types of neuroendocrine cancer, including medullary thyroid cancer (MTC) and thyroid C-cell hyperplasia, are part of multiple endocrine neoplasia type 2 (MEN2). A proto-oncogene mutation of the rearranged during transfection (RET) gene changes the way that receptor tyrosine kinases work. Multiple endocrine neoplasia, a pathological condition, involves these kinases. When the RET protooncogene changes, it can cause endocrine adenomas and hyperplasia to happen at the same time or one after the other. Pheochromocytoma, medullary thyroid carcinoma, and hyperparathyroidism, alone or in combination, are present in MEN2A patients. Some patients may also have skin lichen amyloidosis or Hirschsprung's disease. Patients with MEN2A often present with MTC. MTC is aggressive and has the worst prognosis, as most patients exhibit lymph node metastasis. MTC is one of the important causes of death in patients with MEN2A. RET mutation analysis aids in identifying MEN2A symptoms and monitoring levels of calcium, thyroid hormones, calcitonin, normetanephrine, fractionated metanephrines, and parathyroid hormone. The earlier diagnosis of MTC significantly improves survival and prompts better management of MEN2A. In this editorial, we will discuss the significance of molecular diagnostic approaches in detecting RET oncogene mutations in MEN2A.

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.

The FNA-CT is useful for the diagnosis of MTC. The aim of this study was to evaluate the performance of FNA-CT in TNs coexisting with CCH.

This study retrospectively reviewed the records of 11 patients with TNs submitted to thyroidectomy on the basis of elevated basal and/or stimulated serum CT values, which at histology were not confirmed to be MTC. The results obtained in this group were compared with those of a previously reported group of histologically proven MTC patients submitted to an identical presurgical evaluation. All patients, negative for known mutations in the RET proto-oncogene, were preoperatively submitted to neck ultrasound, FNA-cytology, and FNA-CT.

Approximately 6 of 11 patients showed increased (>36 ng/mL, as established in previous studies not involving patients with CCH) FNA-CT. All these patients showed diffuse CCH at histology in the thyroid lobe submitted to FNA; 5 of them were benign at histology, while only one was malignant (papillary thyroid carcinoma, PTC). The remaining 5 of 11 patients had low FNA-CT (<36 ng/mL), and all of them showed only focal CCH in the lobe submitted to FNA; three of them were malignant (2 PTC, 1 follicular carcinoma), while two were benign.

Employing the currently proposed cut-off values, false-positive FNA-CT results may be observed in benign/malignant TNs with coexisting diffuse CCH. FNA-CT must therefore be cautiously used in the diagnostic approach for patients with TNs and a slightly increased basal or stimulated serum CT concentration in order to avoid unnecessary surgery.

Although calcitonin (Ctn) measurement is recognized as the most accurate diagnostic test for medullary thyroid carcinoma (MTC), its routine execution is not universally accepted for several reasons, including the lack of recommendations for managing indeterminate Ctn values (ICV); such as 10-to-100 pg/mL. This study aimed to gather data on 1) the frequency of ICV among patients undergoing Ctn test and 2) the MTC rate among patients with ICV.

This review was conducted according to the Meta-analyses Of Observational Studies in Epidemiology guidelines. PubMed and Cochrane databases were searched, with no language restrictions. The final search was completed on January 2023. Then, quality assessment and proportion meta-analyses were performed.

The online search retrieved 233 articles and 15 were included for quantitative analysis. The risk of bias was low. The number of patients undergone Ctn testing was 29,533. The pooled percentage of those with ICV was 1.7% (95% confidence interval [CI]:1.2-2.3). The pooled proportion of MTC incidence among patients with ICV was 9.6% (95% CI:5-14.1). Heterogeneity was explained by the covariates of Ctn assay sensitivity and the resection rate. The subgroup with Ctn 10-20 pg/mL showed a significantly lower MTC rate than the subgroup with Ctn 20-100 pg/mL.

The percentage of ICV among patients with thyroid nodules who underwent Ctn testing is negligible. The rate of MTC in patients with ICV cannot be overlooked. Among the ICV intervals, the risk of MTC increases significantly when Ctn is above 20 pg/mL.

We provide an update on calcitonin (Ctn) screening for the early detection of medullary thyroid carcinoma (MTC) and present the results of a large single-center analysis evaluating sex-specific cut-off-levels and long-term courses.

A total of 12,984 consecutive adult patients (20.1% male and 79.9% female) with thyroid nodules who had undergone routine Ctn measurement were retrospectively analyzed. Patients with confirmed suspicious Ctn values were referred for surgery.

Ctn measurements were elevated in 207 (1.6%) patients, with values below twice the sex-specific reference limit in 82% of these cases. Further clarification was possible in 124/207 cases, of which MTC could be ruled out in 108 cases. Histopathological assessment confirmed MTC in 16/12,984 patients.

Our extrapolated MTC prevalence of 0.14% is significantly lower than that described in early international screening studies. The stimulation test can usually be dispensable when using a decision-making concept based on sex-specific basal Ctn cut-off values. Ctn screening is recommended even in patients with very small thyroid nodules. High quality standards in pre-analytics, laboratory measurements, and the interpretation of data must be ensured, as well as close interdisciplinary cooperation between medical disciplines.

The usefulness of routine calcitonin measurement for early detection of medullary thyroid carcinoma (MTC) in patients with nodular thyroid disease (NTD) has been investigated in various studies. Recently, a Cochrane review has been published on this issue, but a meta-analysis is lacking yet. Therefore, we performed this meta-analysis.

We performed an electronic search using PubMed/Medline, Embase and the Cochrane Library. Studies assessing the diagnostic accuracy of routine calcitonin measurement for detecting MTC in patients with NDT were selected. Statistics were performed by using Stata software, risk of bias was assessed using Review Manager version 5.3.

Seventeen studies, involving 74,407 patients were included in the study. Meta-analysis, using the bivariate random effects model and the hierarchical summary receiver operating characteristic (HSROC) curve revealed the following pooled estimates: sensitivity 0.99 (95% CI, 0.81-1.00), specificity 0.99 (95% CI, 0.97-0.99), positive likelihood ratio (L+) 72.4 (95% CI, 32.3-162.1), and negative likelihood ratio (L-) 0.01 (95% CI, 0.00-0.23). Meta-regression analysis showed that the threshold of basal calcitonin is an independent factor, but in particular performing stimulation test is not an independent factor.

We showed that routine basal serum calcitonin measurement in the management of patients with thyroid nodules is valuable for the detection of MTC. However, the published cut-off values should be considered and, if applicable, the patients monitored in a wait-and-see strategy by experienced physicians to avoid overtreatment.

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.

Calcitonin-secreting neuroendocrine tumors are rare and have been reported in literature as case reports or case series in various organs including lung, pancreas, larynx, bladder, and ovary. These tumors have similar cytologic features and immunohistochemical profile to medullary thyroid carcinoma and thus it is difficult to distinguish them, especially when calcitonin-secreting neuroendocrine tumors are intermediate or higher grade and there is a mass lesion in the thyroid gland. Here, we report a rare case of calcitonin secreting atypical carcinoid tumor of the lung in a patient with thyroid nodule. However, after extensive ancillary studies on the thyroid gland, no tumor was detected and subsequent resection specimen revealed a pulmonary atypical carcinoid tumor with metastasis to level 11 lymph node. Being aware of this entity has significant clinical, diagnostic, and therapeutic implications and can prevent unnecessary thyroidectomies with subsequent possible morbidities.

To evaluate the diagnostic accuracy of routine calcitonin measurement in patients with nodular thyroid disease.

Consecutive patients with nodular thyroid disease (n = 640) were studied. Serum calcitonin levels were measured under basal conditions, and when basal values were between 10-100 pg/mL, testing was repeated after pentagastrin (PG) stimulation. Patients with previously diagnosed or familial medullary thyroid cancer (MTC) were excluded. Patients were operated on when basal or stimulated calcitonin >100 pg/mL or when other surgical indications were present.

Four cases of MTC were identified. MTC was diagnosed in 75% of patients with basal calcitonin >100 pg/mL. One out of 11 patients with basal calcitonin between 10-100 pg/mL was diagnosed with MTC. PG stimulation resulted in elevation in 4 cases, where 1 case was diagnosed with MTC. Positive predictive value for basal calcitonin levels in the preoperative diagnosis of MTC was 5% for values between 10-100 pg/mL and 100% for values >100 pg/mL. Possible reasons for false positivity were papillary thyroid cancer in 17%, renal insufficiency in 8.3%, Hashimoto thyroiditis in 17% and β-blocker use in 33%. Positive predictive value for the PG test (>100 pg/mL) was 25% in the entire series. The cost of adding calcitonin measurement (±PG stimulation) to the preoperative work-up, resulted in €912.68 per MTC patient to detect the disease.

Basal calcitonin measurement together with PG stimulation in cases of basal calcitonin >10 pg/mL detects MTC in 0.62% of patients with nodular thyroid disease.

Serum calcitonin (CT) level is used to detect medullary thyroid carcinoma (MTC), but the cut-off level is unclear. We aimed at identifying the optimal cut-off value of basal serum CT levels for detecting MTC.

We retrospectively enrolled patients with hypercalcitoninemia (≥2·9 pmol/l) who had undergone thyroid ultrasonography (US) and subsequent work-up between 2001 and 2013 at Asan Medical Center. We divided patients into four groups: proven MTC (group 1, n = 93), pathologically proven non-MTC after surgery (group 2, n = 57), benign single nodule by cytology (group 3, n = 68) and patients without nodules on US (group 4, n = 24).

Basal serum CT levels were evaluated.

The median CT level of group 1 (119·5 pmol/l) was significantly higher than those of other groups (4·0, 3·8 and 3·8 pmol/l, P < 0·001). When we adopted 19·0 pmol/l of CT level as a cut-off value, the sensitivity, specificity, and positive and negative predictive values were 77·4%, 98·7%, 97·3% and 87·8%, respectively. When we compared 29·2 pmol/l (100 pg/ml) and 19·0 pmol/l (65 pg/ml) as cut-off values, 19·0 pmol/l was more sensitive and accurate than 29·2 pmol/l. Factors associated with hypercalcitoninemia in non-MTC groups were autoimmune thyroiditis, chronic kidney disease, proton pump inhibitors and other malignancies. Serum CT levels tended to decrease spontaneously in non-MTC groups.

Basal serum CT levels higher than 19·0 pmol/l can be a useful cut-off value for detecting macroscopic MTC, even though values below 19·0 pmol/l cannot exclude the presence of MTC like small volume MTC or premalignant C-cell hyperplasia.

To evaluate the usefulness of preoperative serum calcitonin (sCT) in patients with nodular disease without suspicion of medullary thyroid carcinoma (MTC) in history or cytology.

sCT was measured before thyroidectomy in 494 patients with nodular disease who had no family history of MTC or multiple endocrine neoplasia type 2, and no cytological suspicion of MTC.

Basal sCT was < 10 ng/mL in 482 patients and none of them had MTC. One patient with basal sCT > 100 pg/mL had MTC. Among the 11 patients with basal sCT between 10 and 100 pg/mL, MTC was diagnosed in only one. The two patients with MTC were submitted to total thyroidectomy, combined with elective lymph node dissection indicated exclusively based on hypercalcitoninemia, and sCT was undetectable after six months.

Preoperative sCT is useful for the detection of sporadic MTC in patients with nodular disease, even in the absence of suspicious history or cytology.

Serum calcitonin (sCt) is measured in many patients with nodular thyroid disease, and the possibility of a false-positive result is a matter of concern, particularly in the case of mild hypercalcitoninemia. Among the conditions reported to cause sCt elevation, Hashimoto's thyroiditis (HT) and papillary thyroid carcinoma (PTC) are relevant. In view of the high frequency of these conditions in patients with nodular disease and the controversy regarding the extent to which they contribute to hypercalcitoninemia, the objective of this study was to determine the influence of the presence of HT and PTC on sCt levels.

Three groups of patients >12 years of age were studied. The first group (group A, n=492) consisted of patients with nodular disease evaluated before thyroidectomy and without medullary thyroid carcinoma (MTC) upon histology. The second group (group B, n=583) consisted of subjects without nodules on ultrasound. The third group (group C, n=62) consisted of patients with PTC and distant metastases after total thyroidectomy. The levels of sCt and frequency of elevated sCt were compared in patients with versus without HT (groups A and B) and those with PTC>1 cm versus without PTC (group A).

No difference in sCt levels or in the frequency of elevated sCt was observed between patients with and without HT, irrespective of sex. Moreover, the presence of PTC>1 cm did not influence sCt levels or the frequency of hypercalcitoninemia. In fact, none of the 1075 patients in groups A and B had sCt>40 pg/mL, regardless of the presence of HT and PTC. Serum calcitonin was undetectable in any patient of group C.

The finding of hypercalcitoninemia in patients with nodular disease should be interpreted as a suspicion of MTC, even in the presence of associated HT or cytology suggestive of PTC.

Over the past years, the incidence of thyroid cancer has surged not only in Germany but also in other countries of the Western hemisphere. This surge was first and foremost due to an increase of prognostically favorable ("low risk") papillary thyroid microcarcinomas, for which limited surgical procedures are often sufficient without loss of oncological benefit. These developments called for an update of the previous practice guideline to detail the surgical treatment options that are available for the various disease entities and tumor stages.

The present German Association of Endocrine Surgeons practice guideline was developed on the basis of clinical evidence considering current national and international treatment recommendations through a formal expert consensus process in collaboration with the German Societies of General and Visceral Surgery, Endocrinology, Nuclear Medicine, Pathology, Radiooncology, Oncological Hematology, and a German thyroid cancer patient support organization.

The practice guideline for the surgical management of malignant thyroid tumors includes recommendations regarding preoperative workup; classification of locoregional nodes and terminology of surgical procedures; frequency, clinical, and histopathological features of occult and clinically apparent papillary, follicular, poorly differentiated, undifferentiated, and sporadic and hereditary medullary thyroid cancers, thyroid lymphoma and thyroid metastases from primaries outside the thyroid gland; extent of thyroidectomy; extent of lymph node dissection; aerodigestive tract resection; postoperative follow-up and surgery for recurrence and distant metastases.

These evidence-based recommendations for surgical therapy reflect various "treatment corridors" that are best discussed within multidisciplinary teams and the patient considering tumor type, stage, progression, and inherent surgical risk.

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.

The positive predictive value (PPV) of a slightly elevated basal calcitonin (CT) for the diagnosis of medullary thyroid cancer (MTC) is still under debate.

A total of 11270 patients with thyroid nodules underwent calcitonin screening. Patients with known elevation of CT, renal insufficiency, bacterial infection, alcohol abuse, proton-pump inhibitor therapy or autoimmune thyroid disease were excluded from further analysis. Serum CT was determined by the solid-phase, enzyme-labeled, two-site chemiluminescent immunoassay Immulite 2000. If possible, a pentagastrin test was done to differentiate cases of hypercalcitoninaemia.

Hypercalcitoninsemia was found in 32 patients. 20 patients underwent surgery. In 10 patients a MTC was found. The PPV of hypercalcitoninaemia for MTC was 31%. The PPV increased to 50% for those patients who underwent surgery (10/20). A subgroup of 26 patients presented with basal CT between 13 and 50 pg/ml, 14 of them underwent surgery, in 4 cases evidence of MTC was revealed. This resulted in a PPV of 15% (4/26), although the value increased to 28% when only surgically treated patients were considered (4/14).

Taking all clinical data into account, calcitonin screening has an acceptable PPV for medullary thyroid cancer in patients with thyroid nodules. Therefore, we recommend calcitonin screening in centers for thyroid disorders.

Medullary thyroid carcinoma (MTC) is a rare thyroid malignancy with the potential for aggressive behavior. Measurement of serum calcitonin (Ct) in the thyroid nodule population is the most sensitive way to detect occult MTC. An important and controversial question is whether all patients with thyroid nodules should undergo Ct measurements to detect occult MTC.

The prevalence of MTC detected by performing surgery on unselected individuals with thyroid nodules with elevated serum Ct is 0.4%. The central role of pentagastrin (PG) stimulation for triaging patients with minimally elevated serum Ct to prevent unnecessary surgery is reviewed. Data concerning a large reservoir of medullary thyroid microcarcinomas are discussed.

Given the unavailability of PG in the United States and Canada, the available data argue against routine Ct measurements in all individuals with thyroid nodules in these countries because of the potential for unnecessary surgery and the uncertain benefit in diagnosing medullary microcarcinoma.