C-cell Hyperplasia Research Articles

A Calcitonin-Negative Neuroendocrine Tumor Derived from Follicular Lesions of the Thyroid.

Neuroendocrine lesions of the thyroid are rare. The most common types are medullary thyroid carcinomas (MTCs) and C-cell hyperplasia. MTCs originate from thyroid parafollicular cells that secrete calcitonin which serves as a serum marker of MTCs. Here, the rare case of a calcitonin-negative neuroendocrine tumor (NET) derived from follicular lesions of the thyroid is described. A 34-year-old man presented at our hospital for the surgical management of an incidental thyroid nodule that was observed on an ultrasound sonography (USG) of the neck. Initially, USG-guided aspiration cytology was performed, and a MTC was suspected. The expressions of thyroglobulin and thyroid transcription factor-1, which are thyroid follicular cell markers, and synaptophysin and chromogranin A, which are neuroendocrine markers, was confirmed following surgical pathology. However, the staining of calcitonin, a marker of MTCs, was not observed. A nonmedullary NET of the thyroid is uncommon, and the distinction between calcitonin-negative NETs and MTCs of the thyroid may be important due to differences in their clinical courses and management.

A cut-off value of basal serum calcitonin for detecting macroscopic medullary thyroid carcinoma.

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 (≥2·9pmol/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 (119·5pmol/l) was significantly higher than those of other groups (4·0, 3·8 and 3·8pmol/l, P<0·001). When we adopted 19·0pmol/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 29·2pmol/l (100pg/ml) and 19·0pmol/l (65pg/ml) as cut-off values, 19·0pmol/l was more sensitive and accurate than 29·2pmol/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 19·0pmol/l can be a useful cut-off value for detecting macroscopic MTC, even though values below 19·0pmol/l cannot exclude the presence of MTC like small volume MTC or premalignant C-cell hyperplasia.

Is Hashimoto's thyroiditis a risk factor for medullary thyroid carcinoma? Our experience and a literature review.

The etiology of medullary thyroid carcinoma remains unknown. The aim of this study was to determine whether there is a significant association between medullary thyroid carcinoma and Hashimoto's thyroiditis in the histopathologic material of thyroidectomized patients. Retrospective cross-sectional study. In this study, we reviewed the medical records of all patients who underwent total thyroidectomy for different thyroid-related complaints between January 2000 and January 2012 at Jordan University Hospital-Amman, Jordan. To highlight relevant previously published studies addressing this topic, a literature search was conducted for English language studies reporting "medullary thyroid carcinoma" or "C-cell hyperplasia" in patients with Hashimoto's thyroiditis. Of the 863 patients with a mean age of 47.2 ± 12.3 years who underwent total thyroidectomy during the study period, 78 (9.04 %) were diagnosed with Hashimoto's thyroiditis, and 15 (1.74 %) had medullary thyroid carcinoma, 3 (20 %) of whom had coexistent Hashimoto's thyroiditis. A total of 683 (79.1 %) patients had benign thyroid disease, 67 (9.8 %) of whom had Hashimoto's thyroiditis. The difference between these rates was not statistically significant (p = 0.19). When examined by gender, 9 females had medullary thyroid carcinoma, 3 (33.3 %) of whom had coexistent Hashimoto's thyroiditis; by contrast, of 560 females with benign thyroid disease, 62 (11.1 %) had Hashimoto's thyroiditis (p = 0.04). Although this study population represents a small and single-institution experience, our results suggest that there might be an association between Hashimoto's thyroiditis and medullary thyroid carcinoma only in female patients who undergo total thyroidectomy.

Refining Calcium Test for the Diagnosis of Medullary Thyroid Cancer: Cutoffs, Procedures, and Safety

Calcitonin (CT) measurement is crucial to the early diagnosis and the follow-up of medullary thyroid cancer (MTC). If the evaluation of stimulated CT levels is required, a provocative test can be performed, being the high-dose Ca test recently reintroduced in clinical practice. Our objective was to identify gender-specific thresholds for MTC diagnosis in a large series of patients who underwent the Ca test. A total of 91 patients (49 females and 42 males) underwent the Ca test (calcium gluconate, 25 mg/kg) before thyroidectomy and both basal CT (bCT) and stimulated CT (sCT) were compared with histological results by receiver operating characteristic plot analyses. To evaluate possible side effects of Ca administration, cardiac function has been extensively studied. bCT levels were found to harbor the same accuracy as sCT in the preoperative diagnosis of MTC. The best Ca thresholds for the identification of MTC were >26 and >68 for bCT and >79 and >544 pg/mL for sCT in females and males, respectively. The high tolerability and safety of the Ca test was demonstrated and advice offered to be followed before and during the test. Gender-specific bCT and sCT cutoffs for the identification of C-cell hyperplasia and/or MTC have been defined. The bCT and sCT were found to have a similar accuracy, indicating that serum CT assays with improved functional sensitivity may likely decrease the relevance of the stimulation test in several conditions. Finally, systematic cardiac monitoring confirms the safety of the Ca test.

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.

Pheochromocytoma as the first manifestation of MEN2A with RET mutation S891A: report of a case

We report a rare case with pheochromocytoma as the first manifestation of multiple endocrine neoplasia type 2A with RET mutation S891A. Bilateral pheochromocytomas were identified in a 54-year-old woman. Screening for RET revealed a rare S891A mutation located in the intracellular tyrosine kinase domain. This mutation was previously recognized as one of the mutations only in cases manifesting solely medullary thyroid carcinomas (MTCs). Since calcitonin stimulation test indicated positive result, total thyroidectomy was performed 1 year after the bilateral adrenalectomy, and C-cell hyperplasia was diagnosed by histopathological examination. Our report suggests that cases with S891A mutation, akin to those with other RET mutations, require screening for pheochromocytoma. In addition, it is indicated that calcitonin stimulation test should be performed even in the unaffected elder cases with S891A mutation although the mutation is classified as lowest risk group on MTC in guidelines.

Patient affected by neurofibromatosis type 1 and thyroid C-cell hyperplasia harboring pathogenic germ-line mutations in both NF1 and RET genes

Neurofibromatosis type 1 (NF1) is a rare autosomal dominant disease with an estimated incidence of 1 in 3000/3500 live births. NF1 is caused by a mutation in a gene which encodes a protein known as neurofibromin. In up to 5% of cases, NF1 is associated with pheochromocytomas.RET proto-oncogene encodes a member of the receptor tyrosine kinase family involved in the normal development or the neoplastic growth of neural crest cell lineages. Germ-line RET mutations account for cases of Multiple Endocrine Neoplasia type 2 (MEN2), an autosomal dominant genetic syndrome where medullary thyroid carcinoma (MTC) is the major and more clinically severe feature, with nearly complete penetrance. C-cell hyperplasia (CCH) is described in MEN2 patients, and it has been implicated as the precursor of in situ MTC. Patients with RET mutations develop pheochromocytomas in 50% of cases.Rarely, patients with NF1 have been found to present, in addition to the NF1 clinical picture, other lesions, such as parathyroid hyperplasia/adenoma and/or medullary thyroid carcinoma. In spite of the presence of these MEN2 lesions, in none of these patients mutations of gene RET have been found so far.In this report, we describe the first case of a patient affected by a germ-line mutation in both NF1 and RET genes.

The Diagnostic Value of Calcitonin Measurement in Wash-out Fluid from Fine-Needle Aspiration of Thyroid Nodules in the Diagnosis of Medullary Thyroid Cancer

The diagnostic value of calcitonin measurement in fine-needle aspiration biopsy (FNAB) wash-out fluid (Ct-FNAB) for medullary thyroid cancer (MTC) remains to be determined. This prospective study aimed to assess the diagnostic value of Ct-FNAB in thyroid nodules in comparison with basal serum calcitonin (Ct), pentagastrin-stimulated Ct (Pg-sCt), and cytology. Among patients with goiter addressed with US-FNAB who had an initial clinical suggestion for thyroidectomy, 27 patients with thyroid nodule/s (n = 60) and normal, borderline, or increased Ct fulfilled the criteria for thyroidectomy. All 27 patients (enrolled according to exclusion/inclusion criteria) underwent ultrasonography (US), Ct, Pg-sCt, US-assisted FNAB of each patient's nodule for both cytology, and Ct-FNAB before thyroidectomy. Ct-FNAB always resulted in >1,000 pg/mL in MTC nodules at histology. For values between 36 and 1,000 pg/mL, MTCs and nodular or micronodular C-cell hyperplasia (CCH) results overlapped. Most of the nodules without MTC and/or CCH had Ct-FNAB ≤ 17 pg/mL. Ct-FNAB diagnostic power was superior to and similar to other diagnostic procedures (Ct, Pg-sCt, and cytology) in identifying both MTC and CCH, and MTC alone, respectively. The diagnostic power of Ct-FNAB is valuable compared with other routine procedures. Ct-FNAB is highly reliable for the early detection and accurate localization of MTC in thyroid nodules, but it does not differentiate between MTC and CCH. Ct-FNAB is an extremely valuable diagnostic tool, especially considering that other diagnostic procedures do not provide a definitive diagnosis, and it can be included in the clinical work-up of thyroid nodules when MTC is suspected.

First reported case in Ireland of MEN2A due to a rare mutation in exon 8 of the RET oncogene

SummaryWe present the case of a 30-year-old female who was diagnosed with hereditary phaeochromocytoma secondary to a rare gene mutation in exon 8 of the RET oncogene. This genetic mutation was picked up as part of an extended genetic screen using a method known as next generation sequencing. Detection of this genetic mutation prompted further screening for the manifestation of multiple endocrine neoplasia type 2A (MEN2A). The patient subsequently underwent a thyroidectomy with histology confirming C-cell hyperplasia.Learning points Genetic analysis is an important step in the diagnostic work up of phaeochromocytoma.Extended genetic analysis is important when there is a strong suspicion of hereditary phaeochromocytoma.Mutations in exon 8 of the RET gene are associated with phaeochromocytoma as part of MEN2A syndrome.

Incidental medullary thyroid microcarcinoma revealed by mild increase of preoperative serum calcitonin levels: therapeutic implications

To investigate whether further, diagnostic procedures should be recommended in patients with slight increase of preoperative serum basal calcitonin (bCT) levels in whom surgical treatment can be recommendable. Fourteen consecutive patients with nodular thyroid disease underwent thyroidectomy in our center for suspected medullary thyroid microcarcinoma (MTC) because their serum bCT levels were slightly higher than the upper limit of normal range. Serum bCT was measured by radioimmunoassay, normality range = 0-20 ng/L. Surgical specimens were examined by the same pathologist using histologic and immunohistochemistry techniques. An extensive search for parafollicular C-cell hyperplasia (CCH) and/or microscopic MTC foci was performed. At preoperative ultrasound, a single thyroid nodule was depicted in three patients while a multinodular goiter in 11. The bCT values ranged between 24.4 and 94.6 ng/L, median 42.2 ng/L while the pentagastrin-stimulated CT (sCT) values by pentagastrin test ranged between 61.5 and 1,262 ng/L, median 245.0 ng/L. Total thyroidectomy was performed in 13 patients, and lobectomy in the other one; central node dissection was also performed in eight cases. At histology, MTC was diagnosed in nine patients (64.3 %), showing a median maximum diameter of 6.1 mm (range, 1.5-17 mm); CCH was diagnosed in the other five patients (35.7 %). The pentagastrin stimulation test was obtained in all patients. It is worth noting that a very high increase of sCT >100 ng/mL was observed in 5/9 patients with MTC and in 2/4 patients with HCC, therefore suggesting the absence of a relationship between the entity of response to pentagastrin test with a specific pathology (MTC vs. HCC). In six patients, the MTC was the nodule on which preoperative FNAC had been performed, while in other three patients preoperative FNAC had been performed on a different nodule from the MTC. Based on our experience, in case of the pentagastrin stimulation test with sCT <100 ng/L and a single nodule, the CT assay on FNAC may be useful, subsequently lobectomy with definitive histological diagnosis is recommended. In case of the Pg test with sCT <100 ng/L and bilateral goiter, total thyroidectomy with histological diagnosis is recommended. In this way, as for the surgical procedure, total thyroidectomy is recommended in cases of bilateral goiter, while lobectomy can be offered for cases with single nodes with serum dosage of bCT in the strict follow up. In case of the pentagastrin stimulating test with sCT <100 ng/L and bilateral goiter, total thyroidectomy with histological diagnosis is recommended.

Prophylactic thyroidectomy for MEN 2-related medullary thyroid carcinoma based on predictive testing for RET proto-oncogene mutation and basal serum calcitonin in China

Early and normative surgery is the only curative method for multiple endocrine neoplasia type 2 (MEN 2)-related medullary thyroid carcinoma (MTC). To study the timing of prophylactic total thyroidectomy (TT) for MEN 2-related MTC with different RET mutations in a Chinese population, and to compare the sensitivity and accuracy of fully-automated chemiluminescence immunoassay (FACLIA) and radioimmunoassay (RIA) for serum calcitonin (Ct). We collected 24 asymptomatic individuals from 8 unrelated Chinese families with MEN 2, and analyzed RET mutation and Ct levels. Then we performed TT on 17 of the 24 individuals, including TT (2/17), TT with bilateral level VI lymph-node dissection (B-LND(VI); 12/17) and TT with B-LND(VI)+modified unilateral/bilateral/local neck dissection (3/17). Histopathology revealed bilateral/unilateral MTC in 15/17 (88.2%; median diameter, 1.0cm) and bilateral C-cell hyperplasia in 2/17 (11.8%; p.V292M/R67H/R982C and p.C618Y). Lymph-node metastasis/fibro-adipose tissue invasion (p.C634R) or solely fibro-adipose tissue invasion (p.C634Y) were found in 2/17 (11.8%). Elevated pre-surgical Ct (pre-Ct) was identified by FACLIA in 17/17 (median age, 24.0), while pre-Ct by RIA was found in only 6/15 (P<0.001). The median follow-up was 22.0 months, during which 16/17 had no abnormality (one p.C634R individual had elevated Ct), and another 7 carriers still had consistently undetectable Ct by FACLIA. Our study highlights the importance and feasibility of individualized prophylactic TT for MEN 2-related MTC, based on predictive integrated screening of RET and pre-Ct levels. Besides, we recommend FACLIA to measure Ct for earlier diagnosis, treatment and follow-up monitoring of MTC.

Simultaneous medullary carcinoma, papillary carcinoma and granulomatous inflammation of the thyroid

Thyroid tumours with both papillary and medullary carcinoma features are rare and represent less than 1% of all thyroid malignancies. These tumours have a different clinical presentation and biological behaviour from tumours that have only papillary or medullary carcinoma features. The phenomenon of mixed thyroid tumours can be observed in two settings--a mixed tumour showing dual differentiation, or a collision tumour. For a precise diagnosis of this rare mixed thyroid carcinoma, fine needle aspiration cytology results should be correlated with serum calcitonin and thyroglobulin levels. The diagnosis should also be confirmed using immunocytochemistry. Surgery is the treatment of choice, and the role of postoperative radioiodine is controversial. We herein report the case of a 35-year-old man with a mixed medullary-papillary carcinoma of the thyroid, which presented with C-cell hyperplasia, granulomatous inflammation and metastasis to the cervical lymph nodes. The patient was treated with total thyroidectomy and nodal clearance. This case highlights the need for awareness of coexistent entities as they warrant separate treatments.

A ten‐year clinical update of a large RET p.Gly533Cys kindred with medullary thyroid carcinoma emphasizes the need for an individualized assessment of affected relatives

Reviewing the clinical outcomes of a large kindred with a RET p.Gly533Cys mutation, 10 years after the first description of this kindred, has provided an important set of clinical data for healthcare decision-making. We identified 728 RET533 Brazilian relatives, spread out over 7 generations. We performed clinical examination, biochemical and imaging analyses in the proband and in 103 carriers. The proband has been followed without evidence of structural disease in the last 10 years but with elevated calcitonin. The clinical and surgical features of 60 thyroidectomized RET533 relatives were also described. Forty-six patients had MTC (21-72 years), and 11 patients had C-cell hyperplasia (CCH) (5-42 years). Twelve MTC patients with lymph node metastases had a tumour size of 0·7-2·8 cm. Calcitonin level and CEA were correlated with disease stage, and none of the patients presented with an altered PTH or metanephrine. A 63-year-old woman developed pheochromocytoma and breast cancer. Two other RET533 relatives developed lung squamous cell carcinoma and melanoma. A vast clinical variability in RET533 presentation was observed, ranging from only an elevated calcitonin level (3%) to local metastatic disease (25%). Many individuals were cured (42%) and the majority had controlled chronic disease (56%), reinforcing the need for individualized ongoing risk stratification assessment. The importance of this update relies on the fact that it allows us to delineate the natural history of RET 533 MEN2A 10 years after its first description.

Clinical spectrum of MEN2A in a large family caused by the infrequent RET mutation Cys609Phe

Mutations in RET proto-oncogene cause multiple endocrine neoplasia 2A (MEN2A). Mutations in codons 609 and 611 are not frequent. We identified two MEN2A families with the Cys609Phe RET mutation, which turned out to be the same family. This mutation has been described a couple of times with no clinical details. We have characterized the clinical phenotype of this large kindred. A 54-year-old woman, with a medullary thyroid carcinoma (MTC), and a 33-year-old woman, who was operated on for an adrenal pheochromocytoma, were the index cases. 35 relatives were studied. Sixteen turned out to be carriers and 12 of them have been operated on. This family showed eight patients with C-cell hyperplasia, six patients affected by MTC and two showing pheochromocytoma. A papillary thyroid carcinoma was also found, together with the MTC, in one of the carriers. The phenotype in this large kindred is clearly of MEN2A. In carriers presenting the Cys609Phe mutation, the timing of the presentation of the syndrome is highly unpredictable. Therefore, a strict follow up of MTC must be carried out because of risk, and pheochromocytoma should not be ignored. These results reinforce the scarce data observed on this particular mutation.

Precursor lesions of endocrine system neoplasms

The concept of precursor lesions of endocrine neoplasms is a new and interesting topic in endocrine pathology. A variety of clinicopathological conditions are associated with a sequence of cellular changes from hyperplasia to neoplasia; dysplasia is, in contrast, quite rare. The majority of precursor lesions is associated with familial genetic syndromes. These include C-cell hyperplasia in thyroid that is associated with familial medullary thyroid carcinoma, adrenal medullary hyperplasia as a precursor of phaeochromocytomas in MEN2 syndrome, rare pituitary adenohypophyseal cell hyperplasia in familial syndromes associated with pituitary adenomas, MEN1-related precursor gastric enterochromaffin-like cell (ECL) hyperplasia, and duodenal gastrin producing (G) and/or somatostatin producing (D) cell hyperplasia that give rise to type II gastric neuroendocrine tumours (NETs) and duodenal NETs, respectively, and MEN1- or VHL-related islet hyperplasia, islet dysplasia and ductulo-insular complexes that are associated with pancreatic NETs. Other hyperplasias are not thought to be associated with genetic predisposition. Some are attributed to inflammation; autoimmune chronic atrophic gastritis-related ECL hyperplasia can progress to type I gastric NETs, and EC (enterochromaffin) cell or L cell hyperplasia associated with inflammatory bowel diseases can progress to colorectal NETs. In the lung, diffuse idiopathic pulmonary neuroendocrine cell hyperplasia can give rise to peripherally-located low grade pulmonary NETs and tumourlets (neuroendocrine microtumours <5 mm). Rarely, secondary hyperplasias develop into autonomous neoplasms, as in tertiary hyperparathyroidism or pituitary thyrotroph adenomas in primary hypothyroidism. While some precursor lesions, such as thyroid C cell hyperplasia, represent frankly premalignant conditions, others may represent a sequence of proliferative changes from hyperplasia to benign neoplasia that may also progress to malignancy.

Effect of GLP1R agonists taspoglutide and liraglutide on primary thyroid C-cells from rodent and man

Glucagon-like peptide 1 (GLP1) analogs have been associated with an increased incidence of thyroid C-cell hyperplasia and tumors in rodents. This effect may be due to a GLP1 receptor (GLP1R)-dependent mechanism. As the expression of GLP1R is much lower in primates than in rodents, the described C-cell proliferative lesions may not be relevant to man. Here, we aimed to establish primary thyroid cell cultures of rat and human to evaluate the expression and function of GLP1R in C-cells. In our experiments, GLP1R expression was observed in primary rat C-cells (in situ hybridization) but was not detected in primary human C-cells (mRNA and protein levels). The functional response of the cultures to the stimulation with GLP1R agonists is an indirect measure of the presence of functional receptor. Liraglutide and taspoglutide elicited a modest increase in calcitonin release and in calcitonin expression in rat primary thyroid cultures. Contrarily, no functional response to GLP1R agonists was observed in human thyroid cultures, despite the presence of few calcitonin-positive C-cells. Thus, the lack of functional response of the human cultures adds to the weight of evidence indicating that healthy human C-cells have very low levels or completely lack GLP1R. In summary, our results support the hypothesis that the GLP1R agonist-induced C-cell responses in rodents may not be relevant to primates. In addition, the established cell culture method represents a useful tool to study the physiological and/or pathological roles of GLP1 and GLP1R agonists on normal, non-transformed primary C-cells from rats and man.

On-target Effects of GLP-1 Receptor Agonists on Thyroid C-cells in Rats and Mice

Glucagon-like peptide-1 is an incretin hormone from the gastrointestinal tract, which enhances insulin secretion, slows gastric emptying, and reduces food intake. GLP-1 receptor agonists are being developed for Type 2 diabetes mellitus. GLP-1 is rapidly degraded by serum dipeptidyl peptidase IV, so analogues with a prolonged serum half-life are used clinically. Exenatide was the first GLP-1 agonist approved and is a synthetic version of exendin-4 derived from the Gila monster. Liraglutide was approved for clinical use in 2010. GLP-1 receptor agonists have been shown to increase calcitonin secretion and stimulate C-cell hyperplasia and neoplasia in rats and mice of both sexes. Rat C-cells are more sensitive to the effects of GLP-1 agonists than mice. The effects of GLP-1 agonists on C-cell proliferation or neoplasia have not been documented in nonhuman primates or humans. The proliferative C-cell effects may be rodent-specific. GLP-1 receptors have been demonstrated on normal rodent C-cells, but are either not present or occur in low numbers on C-cells of nonhuman primates and humans. Hyperplasia and neoplasia of C-cells in rodents treated with GLP-1 agonists represent a unique example of an on-target species-specific effect that may not have relevance to humans.

Serum calcitonin estimation in medullary thyroid cancer: basal or stimulated levels?

Calcitonin (Ct) is a tumour marker essential for the diagnosis and follow-up of medullary thyroid cancer (MTC). Accurate and consistent measurements of serum Ct are of critical importance. Ct measurements by different methods can differ, leading to difficulties in the interpretation of results. Second generation assays for Ct have been developed and are now available in clinical laboratories. However, the lack of standardization for Ct assays remains a common problem with Ct assays. The reference interval and reliability should be carefully defined.The role of stimulated Ct for the diagnosis and follow-up of MTC should also be pointed out as the pentagastrin test is no more available in all countries. However, the stimulated test remains very useful to exclude MTC if the basal Ct serum level is in the grey zone (15-20 ng/L), after surgery to confirm the complete cure. A residual response after surgery could indicate a need for aggressive surgery or - in case of metastatic disease - could suggest the prognosis.High-dose Ca test (2.5mg/kg) seems to be a reliable and effective test for the diagnosis and follow-up of MTC. It seems more potent than pentagastrin with fewer side effects. The threshold able to discriminate healthy subjects from C-cell hyperplasia (CCH) cases for the stimulated Ct concentration is 184 ng/L for women and 1620 ng/L for men.As stimulated Ca test will eventually replace the pentagastrin test, there is a need to confirm or to modify the threshold identified for each assay individually.

C-Cell Hyperplasia and Papillary Thyroid Carcinoma

C-Cell Hyperplasia and Papillary Thyroid Carcinoma

Effect of exendin (exenatide)—GLP 1 receptor agonist on the thyroid and parathyroid gland in a rat model

Exenatide or Exendin-4 is a 39-amino acid agonist of the glucagon like peptide (GLP-1) receptor approved for the adjunctive treatment for type 2 diabetes. Recent reports suggest that GLP-1 agonists may also have distant effects including C-cell thyroid hyperplasia. The aim of this study was to evaluate the effect of exendin-4 on the thyroid and parathyroid cells in a rat model.Rat thyroids were stained for calcitonin, H&E and for carcinoembryonic antigen (CEA). Thyroid C-cell hyperplasia was graded on H&E stained slides using cell size and secretory granule numbers, morphological features of the parathyroid glands and the serum calcium concentrations of the rats were also evaluated. Counts of stained cells/high power field and intensity of staining were recorded by two pathologists. Data were analyzed by ANOVA/post-tests.C cell hypertrophy was elevated in exenatide-treated vs. untreated animals (22.5±8.7 vs. 10.5±2.7cells/HPF). CEA staining failed to show effects by exendin. Calcitonin staining was significantly elevated in exenatide treated controls (P<0.001). Parathyroid glands were histologically normal in both groups, and serum calcium levels were within normal range in all animals. In summary, exenatide was associated with C cell hyperplasia and increased calcitonin staining of thyroids, but was unrelated to CEA levels. These data raise important concerns about the effects of exenatide which, given its wide clinical use, should be clarified with urgency.