Medullary Thyroid Carcinoma Syndrome Research Articles

Approach to the patient with thyroid nodules: considering GLP-1 receptor agonists.

Glucagon-like peptide 1 receptor agonists (GLP1RA) have rapidly changed the landscape of diabetes and obesity treatment. Enthusiasm for their use is tempered with concerns regarding their risk for inducing C-cell tumors based on preclinical studies in rodents. A black-box warning from the United States Food and Drug Administration (USFDA) recommends against using GLP1RA in patients with a personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia syndrome type 2A or 2B (MEN2), providing clear guidance regarding this cohort of patients. However, emerging data also suggest an increased incidence of differentiated thyroid cancer (DTC) in patients treated with these agents. Other studies, though, have not confirmed an association between GLP1RA and DTC. With conflicting results concerning thyroid cancer risk, there is no clear consensus regarding the optimal approach to screening patients prior to initiating the medications and/or evaluating for thyroid cancer during GLP1RA treatment. Within the context of patient cases, this review will summarize the existing data, describe ongoing controversies, and outline future areas for research regarding thyroid cancer risk with GLP1RA use.

Sporadic and Familial Medullary Thyroid Carcinoma: A Retrospective Single Center Study on Presentation and Outcome

ABSTRACT Background Medullary Thyroid Carcinoma (MTC) is a neuroendocrine tumor that arises from the thyroid C-cells. Most cases are sporadic (sMTC) while, approximately 25%, are hereditary (hMTC) due to germline mutations of REarranged during Transfection (RET) gene mutations and manifest in the framework of multiple endocrine neoplasia (MEN) 2A or 2B, or as pure familial MTC syndrome (FMTC). Objective The aim of this study is to evaluate the clinical, histopathological, biochemical and outcome differences between sMTC and hMTC. Methods Retrospective analysis of a consecutive series of 102 patients with histologically proven MTC diagnosed in the period between 2000 and 2022. For the analysis patients with MTC diagnosed during screening through genetic test were excluded. Results Patients with hMTC had higher incidence of multifocal and bilateral MTC and younger age at diagnosis. We did not found differences on tumor stage at diagnosis between sMTC and hMTC, such as time to progression and rate of persistent and recurrent disease. At univariate analysis, factors associated with persistent and recurrent disease during follow-up in patients with sMTC were tumor size, extrathyroidal extension, presence of lymph node metastases at diagnosis, pre- and post-operative calcitonin, post-operative CEA; in patients with hMTC, features associated with persistent and recurrent disease were lymph node metastases, post-operative calcitonin and pre- and post-operative CEA values. Conclusion Patients with hMTC and sMTC had similar histopathological characteristics and clinical outcome.

Suppressed thyroid stimulating hormone levels after initiation of a subcutaneous glucagon-like peptide-1 receptor agonist in a post-thyroidectomy patient managed with levothyroxine case report

ObjectivesGlucagon-like peptide-1 receptor agonist (GLP-1 RA) therapy has demonstrated an increased risk of thyroid C-cell hyperplasia and C-cell tumors in rodents. Due to this risk, a boxed warning for this drug class exists for people with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2. There is a lack of data regarding any possible effect of GLP-1 RA therapy on serum thyroid levels. The objective of this case report is to describe a case of suppressed thyroid stimulating hormone levels after initiation of a subcutaneous semaglutide in a post-total thyroidectomy patient managed with levothyroxine in order to highlight the need for closer monitoring of these patients and further research in this area. Case SummaryThe patient described in the case underwent a total thyroidectomy in 2015 with stable thyroid hormone replacement requirements with levothyroxine for 5 years until the initiation and titration of subcutaneous semaglutide. The reduction in thyroid stimulating hormone (TSH) after starting GLP-1 RA therapy necessitated a 25 percent dose reduction of levothyroxine from her original dose. Practice implicationsThis patient experienced suppressed TSH levels following initiation and titration of subcutaneous semaglutide. The etiology of these changes may be related to the direct effects of GLP-1 RA therapy on TSH levels, changes in absorption related to delayed gastric emptying rates, secondary to GLP-1 RA-associated weight loss, or a combination of these proposed mechanisms. It may be prudent to exercise more frequent monitoring of medications that require weight-based dosing and those with a narrow therapeutic index when initiating and titrating GLP-1 RA-based therapies and is an area of potential study.

Simultaneous papillary and medullary thyroid carcinoma, primary hyperparathyroidism and ACTH-independent Cushing syndrome- an intriguing puzzle of endocrine disorders

Simultaneous papillary and medullary thyroid carcinoma, primary hyperparathyroidism and ACTH-independent Cushing syndrome- an intriguing puzzle of endocrine disorders

Never Forget the Family History: MEN2A Syndrome Presenting as Metastatic Medullary Thyroid Cancer and Bilateral Pheochromocytoma

Abstract Introduction: MEN 2A is an autosomal dominant hereditary syndrome considered part of the medullary thyroid carcinoma (MTC) syndromes. This is characterized by MTC, pheochromocytoma, and parathyroid hyperplasia or adenomas causing primary hyperparathyroidism (PHPT). Clinical Case: A 34 year old female was referred to our clinic for multi-nodular goiter diagnosed during routine gynecologic evaluation. A thyroid ultrasound revealed a heterogeneous right thyroid lobe with a hypoechoic 2.5 cm nodule, associated macro calcifications and increased vascularity; and a left nodule measuring 2.3 cm with the same characteristics. Bilateral thyroid nodule biopsies were performed, resulting in MTC confirmed by positive calcitonin staining. Pre-operative studies revealed serum calcitonin and carcinoembryonic antigen (CEA), both of which are considered serologic markers of MTC activity, at 4,340 pg/ml (n <= 5) and 276.2 ng/mL (n <= 2.5 in non-smokers) respectively. The patient reported father with history of unspecified thyroid cancer, and paternal uncle with history of pheochromocytoma with a p.Cys634Trp mutation in RET proto-oncogene. Due to her family history, pre-operative screening for primary hyperparathyroidism (PHPT) resulted in a calcium 10 mg/dL (n 8.6-10.2), PTH 34 pg/mL (n 14-64). Additionally, screening for pheocromocytoma revealed an elevated 24 hour urine metanephrines of 2,276 (n <= 49-290) ug/24h, plasma metanephrines, including fractionated metanephrine (MN) at 163 (n <= 57) pg/ml, fractionated nor-metanephrine (NMN) at 182 (n <= 148) pg/ml, and total, Free (MN+NMN) metanephrines at 345 (n <= 205) pg/ml. CT abdomen revealed bilateral adrenal nodules, right measuring 1.4 x 3.3 cm and left 2.4 x 3.3 cm. The patient underwent posterior retroperitoneoscopic adrenalectomy with cortex sparing prior to thyroidectomy. Adrenal pathology resulted in bilateral pheochromocytoma with peri-adrenal adipose tissue microscopic involvement, and positive synaptophysin and S-100 stain. Subsequently, she underwent total thyroidectomy with extensive cervical lymph node resection, with pathology resulting in MTC with lymph node metastasis, involving 5/18 cervical lymph nodes. Post-operative labs revealed serum calcitonin <= 2 pg/ml, CEA 26.8 ng/mL, MN < 25 pg/ml, NMN 102 pg/ml, and MN+NMN of 102 pg/ml, which suggested initial surgical success. Post-operative genetic test evaluation revealed abnormal RET oncogene testing compatible with MEN 2A, variant 1: c.1902C>G (p.Cys634Trp). Conclusion: This case illustrates that patients presenting with MTC and reporting family history of thyroid cancer should be screened for familial MTC syndrome. Patients with RET mutation should be screened for pheochromocytoma prior to surgery for MTC to prevent life-threatening hypertensive crisis.

Hereditary medullary thyroid carcinoma syndromes: experience from western India.

The data from the Indian subcontinent on Medullary thyroid carcinoma (MTC) and associated endocrinopathies in hereditary MTC (HMTC) syndromes are limited. Hence, we analyzed clinical and biochemical characteristics, management, and outcomes of HMTC and other associated endocrinopathies [Pheochromocytoma (PCC) and Primary hyperparathyroidism (PHPT)] and compared with apparently sporadic MTC. The records of 97 (51 sporadic and 46 hereditary) consecutive MTC patients were retrospectively analyzed. RET mutation was available in 38 HMTC patients. HMTC group was subclassified into Multiple endocrine neoplasia (MEN) 2A index (n = 25), MEN2B index (n = 8), and MEN2A detected by familial screening (n = 12). Patients with HMTC and MEN2B index were younger at presentation than sporadic MTC. MEN2A patients detected by familial screening, but not MEN2A index and MEN2B index patients, had significantly lower serum calcitonin, smaller thyroid nodule size, more frequent early stage presentation (AJCC Stage ≤ II), and higher cure rate than sporadic MTC, which emphasizes the need for early diagnosis. RET (REarranged during Transfection) 634 mutations were the most common cause of HMTC and more frequently associated with PCC (overall 54% and 100% in those aged ≥ 35years). Patients in ATA-Highest (HST) group had a universal presentation in stage IV with no cure. In contrast, the cure rate and postoperative disease progression (calcitonin doubling time) were similar between ATA-High (H) and ATA- Moderate (MOD) groups, suggesting the need for similar follow-up strategies for the latter two groups. Increased awareness of endocrine (PCC/PHPT) and non endocrine components may facilitate early diagnosis and management.

Abstract 4783: Selective antitumor activity of NSC311152 toward medullary thyroid cancer by downregulating the transcription of RET oncogene

Abstract The RET (REarranged during Transfection) proto-oncogene encodes a tyrosine-kinase receptor specifically expressed in tissues originated from neuroectodermal tissues. Dominant-activating mutations in this RET proto-oncogene is often associated with Multiple Endocrine Neoplasia type 2A and 2B and Familial Medullary Thyroid Carcinoma syndromes, characterized by the occurrence of medullary thyroid carcinomas. Human medullary thyroid carcinoma cell line TT cell line harbours a MEN2A-type mutation, so this cell line could be a useful cell system to investigate the antitumor activity of new agents interfering with the function of RET oncogene in medually thyroid cancer. Recently, ellipticine and its derivatives were identified as excellent RET G-quadruplex stabilizing agents. Furthermore, these compounds also interfered with the transcriptional mechanism of the RET gene in TT cells, subsequently decreasing the endogenous RET protein expression. In present study, we demonstrated the specificity of NSC311152 by using papillary thyroid carcinoma (PTC) cells, the K1, which carry BRAF and PIK3CA mutations but lacks the dominant-activating mutations in this RET proto-oncogene. NSC311152 selectively suppresses cell proliferation by inhibiting the intracellular Raf/MEK/ERK and PI3K/Akt/mTOR signaling pathways in the TT cells. The systemic administration of NSC311152 in a mouse MTC xenograft model significantly inhibited the tumor growth through RET downregulation, whereas NSC31152 only showed a moderate antitumor activity against K1 xenograft tumors. Citation Format: Daekyu Sun, Vishnu Muthuraj Kumarasamy, Tariq Alqahtani. Selective antitumor activity of NSC311152 toward medullary thyroid cancer by downregulating the transcription of RET oncogene [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4783.

Functional diagnostics in endocrinology

When investigating many endocrinological diseases, basal laboratory parameters are not sufficient to distinguish between physiological and pathological hormone secretion. Functional diagnostics plays a decisive role in this context. Stimulation and suppression tests are used depending on whether under- or over-function needs to be diagnosed. This review article discusses selected functional tests, each of which plays an important role in current guidelines. Indications and test principles, including their performance, reliability, and limitations, are discussed. Topics covered include the ACTH stimulation test for the diagnosis of adrenal cortex insufficiency and the dexamethasone inhibition test for suspected Cushing's syndrome, as well as functional tests for the diagnosis of primary hyperaldosteronism, pheochromocytoma, acromegaly, growth hormone deficiency, thyroid nodules and suspicion of medullary thyroid carcinoma, insulinoma, and Zollinger-Ellison syndrome. Functional tests that are explicitly not recommended are also addressed.

Hereditary and familial thyroid tumours.

The worldwide incidence of thyroid malignancies has been increasing rapidly. Sensitive imaging modalities and early detection of thyroid lesions have made thyroid cancers the most rapidly increasing cancers in the USA in 2017 (SEER Cancer Facts, 2017). Clinical awareness of potential risk factors, such as inherited thyroid cancers, has allowed earlier recognition of more vulnerable population clusters. Hereditary thyroid neoplasms arising from calcitonin-producing C cells are known as familial medullary thyroid carcinomas (FMTCs), and include well-documented syndromes such as multiple endocrine neoplasia IIA or IIB, and pure familial medullary thyroid carcinoma syndrome. Familial thyroid cancers arising from follicular cells are referred to as familial non-medullary thyroid carcinoma (FNMTC), or familial follicular cell-derived carcinoma. Clinicopathological correlations have resulted in the further subclassification of FNMTCs into two groups. Among the first group are found syndromes characterised by a predominance of non-thyroidal tumours, including familial adenomatous polyposis, Cowden syndrome, Werner syndrome, Carney complex, and Pendred syndrome. The second group encompasses a spectrum of familial syndromes characterised by a predominance of non-medullary thyroid tumours, such as pure familial papillary thyroid carcinoma with or without oxyphilia, familial papillary thyroid carcinoma with papillary renal cell carcinoma, and familial papillary carcinoma with multinodular goitre. Most familial thyroid cancers have been described as being more aggressive than sporadic thyroid cancers, with a predisposition for lymph node metastasis, extrathyroidal invasion, and a younger age of onset. The distinct thyroid pathology in some of these syndromes should alert the pathologist to a possible familial cancer syndrome.

Analysis of Newly Identified and Rare Synonymous Genetic Variants in the RET Gene in Patients with Medullary Thyroid Carcinoma in Polish Population

Gain-of-function germline mutations of the RET proto-oncogene are responsible for initiation of carcinogenesis within the thyroid gland and development of hereditary form of medullary thyroid carcinoma and MEN2 syndrome. Genotype-phenotype correlations are established for most RET mutations, but the importance of the synonymous changes in this gene remains debatable. We aimed to analyze RET gene variants in Polish population. Genetic testing for the RET gene variants was performed with standard methods in 585 people aged 1–85, including 448 patients with medullary thyroid carcinoma and 131 of their first- and second-degree relatives, as well as six patients suspected of MTC/MEN2. Besides the most frequent synonymous changes, p.Leu769Leu, p.Ser836Ser, and p.Ser904Ser, four rare changes—c.1827C>T (p.Cys609Cys), c.2364C>T (p.Ile788Ile), c.2418C>T (p.Tyr806Tyr), and c.2673G>A (p.Ser891Ser)—were found in the RET gene, in the Polish population. Two of the rare changes, p.Cys609Cys and p.Ile788Ile, had not been previously described. The frequency of molecular synonymous variants in the general population was evaluated by testing 400 anonymous blood samples of neonates. Our findings may contribute to a better understanding of the genetic diversity of the RET gene and the involvement of synonymous variants in this diversity.

Complete Resolution of Hypercortisolism with Sorafenib in a Patient with Advanced Medullary Thyroid Carcinoma and Ectopic ACTH (Adrenocorticotropic Hormone) Syndrome

The treatment of advanced medullary thyroid carcinoma (MTC) has evolved significantly over the past decade. The discovery of genetic abnormalities in MTC has led to the development of targeted therapies such as vandetanib and cabozantinib. Other kinase inhibitors (KI), such as sorafenib, have been investigated in this setting and are an alternative therapeutic option. The lack of specificity of these KIs to a single target may result in additional, unexpected effects. In this report, we describe a patient with metastatic MTC and Ectopic ACTH (adrenocorticotropic hormone) Syndrome in whom treatment with sorafenib resulted in complete resolution of hypercortisolism. A 45-year-old male with progressive metastatic MTC presented with clinical manifestations suspicious for Cushing's syndrome. Investigation revealed ACTH-dependent hypercortisolism suggestive of Ectopic ACTH Syndrome. Treatment with sorafenib 400 mg twice a day was initiated resulting in a rapid and significant reduction of cortisol and ACTH levels associated with dramatic clinical improvement. The rapid and effective control of hypercortisolism in the absence of a significant tumor reduction raises the question of whether sorafenib may have a direct effect on ACTH or cortisol hypersecretion. This report suggests a previously unknown potential effect of sorafenib on the pituitary-adrenal axis. Further studies will be necessary to investigate the role of sorafenib in other cases of ACTH excess and to understand the mechanisms by which it alters steroid synthesis, action, or secretion.

Management of medullary thyroid carcinoma and MEN2 syndromes in childhood

Medullary thyroid carcinoma (MTC) and the multiple endocrine neoplasia (MEN) type 2 syndromes are rare but important endocrine diseases that are increasingly managed by pediatric providers. MTC is generally associated with a favorable prognosis when diagnosed during childhood, where it frequently occurs secondary to activating mutations in the RET proto-oncogene and arises from pre-existing C-cell hyperplasia. MEN2A accounts for 90-95% of childhood MTC cases and is most commonly due to mutations in codon 634 of RET. MEN2B is associated with the most aggressive clinical presentation of MTC and is almost always due to the Met918Thr mutation of RET. Surgery is the primary treatment and only chance of cure, although the advent of targeted therapies seems to be improving progression-free survival in advanced cases. Since the discovery of the role of RET in MEN2A, considerable advances in the management of this syndrome have occurred, and most of the children with MEN2A who have undergone early thyroidectomy will now lead full, productive lives. Strong genotype-phenotype correlations have facilitated the development of guidelines for interventions. Contemporary approaches for deciding the appropriate age at which surgery should take place incorporate data from ultrasonography and calcitonin measurements in addition to the results of genotyping. To optimize care and to facilitate ongoing research, children with MTC and the MEN2 syndromes are optimally treated at tertiary centers with multidisciplinary expertise.

Familial Follicular Cell Tumors: Classification and Morphological Characteristics

Familial follicular cell-derived well-differentiated thyroid cancer, papillary (PTC), and follicular thyroid carcinomas (FTC), accounts for 95% of thyroid malignancies. The majority of are sporadic, and at least 5% of these patients will have familial disease. Familial thyroid syndromes are classified into familial medullary thyroid carcinoma (FMTC), derived from calcitonin-producing C cells, and familial follicular cell tumors or non-medullary thyroid carcinoma (FNMTC), derived from follicular cells. Twenty-five percent of patients with medullary thyroid cancer (MTC) have a familial form; however, this accounts for only 1% of all patients with thyroid cancer. The familial follicular cell-derived lesions or familial non-medullary thyroid cancer can be divided into two clinical-pathological groups. The first group includes familial syndromes characterized by a predominance of non-thyroidal tumors, such as familial adenomatous polyposis (FAP), PTEN-hamartoma tumor syndrome (Cowden disease; PHTS), Carney complex, Werner syndrome, and Pendred syndrome. The second group includes familial syndromes characterized by predominance of papillary thyroid carcinoma (PTC), such as pure fPTC, fPTC associated with papillary renal cell carcinoma, and fPTC with multinodular goiter. Most of the progress in the genetics of familial thyroid cancer has been in patients with MTC. This is usually a component of multiple endocrine neoplasias IIA or IIB, or as pure familial medullary thyroid carcinoma syndrome. The genetic events in the familial C-cell-derived tumors are known and genotype-phenotype correlations are well established. The mutations in patients with isolated NMFTC have not been as well defined as in MTC. In many cases, patients have a known familial syndrome that has defined risk for thyroid cancer. The clinician must be knowledgeable in recognizing the possibility of an underlying familial syndrome when a patient presents with thyroid cancer. Some characteristic thyroid morphologic findings should alert the pathologist of a possible familial cancer syndrome, which may lead to further molecular genetics evaluation.

A Perspective from Pediatric Endocrinology on the Hereditary Medullary Thyroid Carcinoma Syndromes

ThyroidVol. 19, No. 6 Editorials and CommentaryA Perspective from Pediatric Endocrinology on the Hereditary Medullary Thyroid Carcinoma SyndromesSteven G. WaguespackSteven G. WaguespackSearch for more papers by this authorPublished Online:5 Jun 2009https://doi.org/10.1089/thy.2009.0127AboutSectionsPDF/EPUB ToolsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail FiguresReferencesRelatedDetailsCited byLong-term outcome of prophylactic thyroidectomy in children carrying RET germline mutations17 January 2018 | British Journal of Surgery, Vol. 105, No. 2Impact of central node dissection on postoperative morbidity in pediatric patients with suspected or proven thyroid cancerSurgery, Vol. 160, No. 2Inherited Medullary Thyroid Carcinoma: Indications and Technique of Early Thyroidectomy21 July 2016Timing and extent of thyroid surgery for gene carriers of hereditary C cell disease—a consensus statement of the European Society of Endocrine Surgeons (ESES)3 December 2013 | Langenbeck's Archives of Surgery, Vol. 399, No. 2Pheochromocytoma and multiple endocrine neoplasia syndromesManagement of medullary thyroid carcinoma and MEN2 syndromes in childhood23 August 2011 | Nature Reviews Endocrinology, Vol. 7, No. 10Do the recent American Thyroid Association (ATA) Guidelines accurately guide the timing of prophylactic thyroidectomy in MEN2A?Surgery, Vol. 148, No. 6Multiple Endocrine Neoplasia24 March 2010 Volume 19Issue 6Jun 2009 InformationCopyright 2009, Mary Ann Liebert, Inc.To cite this article:Steven G. Waguespack.A Perspective from Pediatric Endocrinology on the Hereditary Medullary Thyroid Carcinoma Syndromes.Thyroid.Jun 2009.543-546.http://doi.org/10.1089/thy.2009.0127Published in Volume: 19 Issue 6: June 5, 2009PDF download

Familial Thyroid Carcinoma

Thyroid carcinomas derived from follicular cells are the most common endocrine malignancies, and papillary thyroid carcinoma (PTC) is the most common type. Although, the majority of papillary and follicular thyroid carcinomas (FTCs) are sporadic, familial forms have been described in recent years. Familial syndromes are classified into familial medullary thyroid carcinoma and familial nonmedullary thyroid carcinoma. Multifocal papillary carcinoma is the most frequent presentation of familial nonmedullary thyroid carcinoma, and based on clinico-pathologic findings it is divided into 2 groups. The first includes familial syndromes characterized by a predominance of nonthyroidal tumors, such as familial adenomatous polyposis, PTEN-hamartoma tumor syndrome, Carney complex type 1, and Werner syndrome. The second group includes familial syndromes characterized by a predominance of NMTC, such as pure familial (f) PTC with or without oxyphilia, fPTC with papillary renal cell carcinoma, and fPTC with multinodular goiter. Medullary thyroid carcinoma is derived from calcitonin-producing C cells. The familial form accounts for 20% to 25% of cases, and is usually a component of multiple endocrine neoplasia (MEN) IIA or IIB, or presents as pure familial medullary thyroid carcinoma syndrome. C-cell hyperplasia is the precursor lesion of these heritable syndromes. Some characteristic morphologic findings should alert the pathologist of a possible familial cancer syndrome, which may lead to further molecular genetic evaluation.

Familial Non-Medullary Thyroid Carcinoma: An Update

Familial thyroid cancer can arise from follicular cells (familial non-medullary thyroid carcinoma (FNMTC)) or from the calcitonin-producing C-cell (familial medullary thyroid carcinoma). This is usually a component of multiple endocrine neoplasias (MEN) IIA or IIB, or as pure familial medullary thyroid carcinoma syndrome. The genetic events in the familial C-cell-derived tumors are known and genotype-phenotype correlations are well established. In contrast, the case for a familial predisposition of non-medullary thyroid carcinoma is only now beginning to emerge. Although the majority of papillary (PTC) and follicular thyroid carcinomas (FTC) are sporadic, familial tumors account for over 5% of cases. The presence of multifocal papillary carcinoma is a common feature of FNMTC. The familial follicular cell-derived tumors or non-medullary thyroid carcinomas encompass a heterogeneous group of diseases, including diverse syndromic-associated tumors and non-syndromic tumors. Based on clinico-pathologic findings, FNMTC is divided into two groups. The first includes familial syndromes characterized by a predominance of non-thyroidal tumors, such as familial adenomatous polyposis (FAP), PTEN hamartoma tumor syndrome (PHTS), Carney complex type 1, and Werner syndrome. The second group includes familial syndromes characterized by a predominance of NMTC, such as pure familial (f) PTC with or without oxyphilia, fPTC with papillary renal cell carcinoma, and fPTC with multinodular goiter. Some characteristic morphologic findings should alert the pathologist of a possible familial cancer syndrome, which may lead to further molecular genetic evaluation.

Self-association of the transmembrane domain of RET underlies oncogenic activation by MEN2A mutations

In patients with medullary thyroid carcinoma (MTC) and type 2A multiple endocrine neoplasia (MEN2A), mutations of cysteine residues in the extracellular juxtamembrane region of the RET receptor tyrosine kinase cause the formation of covalent receptor dimers linked by intermolecular disulfide bonds between unpaired cysteines, followed by oncogenic activation of the RET kinase. The close proximity to the plasma membrane of the affected cysteine residues prompted us to investigate the possible role of the transmembrane (TM) domain of RET (RET-TM) in receptor-receptor interactions underlying dimer formation. Strong self-association of the RET-TM was observed in a biological membrane. Mutagenesis studies indicated the involvement of the evolutionary conserved residues Ser-649 and Ser-653 in RET-TM oligomerization. Unexpectedly, RET-TM interactions were also abrogated in the A639G/A641R double mutant, first identified in a sporadic case of MTC. In agreement with this, no transforming activity could be detected in full-length RET carrying the A639G and A641R mutations, which remained fully responsive to glial cell-line-derived neurotrophic factor (GDNF) stimulation. When introduced in the context of C634R - a cysteine replacement that is prevalent in MEN2A cases - the A639G/A641R mutations significantly reduced dimer formation and transforming activity in this otherwise highly oncogenic RET variant. These data suggest that a strong propensity to self-association in the RET-TM underlies - and may be required for - dimer formation and oncogenic activation of juxtamembrane cysteine mutants of RET, and explains the close proximity to the plasma membrane of cysteine residues implicated in MEN2A and MTC syndromes.

Association of mitochondrial DNA transversion mutations with familial medullary thyroid carcinoma/multiple endocrine neoplasia type 2 syndrome

Medullary thyroid carcinoma (MTC) is a malignant tumour of the calcitonin-secreting parafollicular C cells of the thyroid, and occurs sporadically or as a component of the multiple endocrine neoplasia (MEN) type 2/familial medullary thyroid carcinoma (FMTC) syndromes. In the present study, we investigated the frequency of mtDNA mutations in 26 MTC tumour specimens (13 sporadic and 13 familial MTC) and their matched normal tissues by sequencing the entire coding regions of mitochondrial genome. Nonsynonymous mutations were detected in 20 MTC samples (76.9%): nine out of 13 sporadic MTC (69.2%) and 11 out of 13 (84.6%) familial MTC/MEN2. Both transition and transversion types of mutations were found in the samples. Interestingly, 76.2% (16/21) of transversion mutations were found in FMTC/MEN2 patients, whereas 66.7% (12/18) of transition mutations were in sporadic MTC. Synonymous mutations were found in 12 MTC samples. In total, we identified 27 transversion mutations (21 nonsynonymous and six synonymous) in MTC. Of them, 22 (81.5%) were from FMTC/MEN2, and five (18.5%) were from sporadic MTC. The association of transversion mutation with familial MTC/MEN2 was statistically significant (P = 0.0015, binomial test). Majority of the mutations were involved in the genes located in the complex I of the mitochondrial genome, and were often resulting in a change of a moderately or highly conserved amino acid of their corresponding protein. Mitochondrial respiratory function was also compromised in a TT cell line, which carries mtDNA mutation at nt 4917 and 11,720, and in peripheral lymphocytes of MTC patients with mtDNA mutations. These data suggest that mtDNA mutation may be involved in MTC tumourigenesis and progression. Given that mtDNA mutation spectra are different between sporadic and familial MTC, different mechanisms of oxidative DNA damage may occur in the disease process.

Diarrea crónica de causa infrecuente

Chronic diarrhea is a common syndrome. An etiological diagnosis is often reached through clinical history, physical examination and simple tests. In some cases, when the etiology is not found, the syndrome is called functional diarrhea, even though established criteria are often not fulfilled. We present the case of a patient with diarrhea for several months. The most common causes were ruled out through clinical history, physical examination, radiographic studies and laboratory tests, and the patient was diagnosed with functional diarrhea. Three months later, the patient presented a neck mass, and biopsy revealed medullary carcinoma of the thyroid. A review of recommendations for the systematic evaluation of chronic diarrhea is presented. A general approach should include careful history taking characteristics of diarrhea (onset, associated symptoms, epidemiological factors, iatrogenic causes such as laxative ingestion), a thorough physical examination with special attention to the anorectal region, and routine laboratory tests (complete blood count and serum chemistry). In addition, stool analysis including electrolytes (fecal osmotic gap), leukocytes, fecal occult blood, excess stool fat and laxative screening can yield important objective information to classify the diarrhea as: osmotic (osmotic gaps > 125 mOsm/Kg), secretory (osmotic gaps < 50 mOsm/Kg), inflammatory or steatorrheic. At this point in the evaluation, a specific diagnosis may be made. However, if diagnosis is not reached further specific examinations should be performed for each of the 4 types of diarrhea described above. A systematic approach to the evaluation of chronic diarrhea is warranted. Medullary thyroid carcinoma and other endocrine syndromes causing chronic diarrhea are very rare. Measurement of serum peptide concentrations should only be performed when clinical presentation and findings in stool or radiographic studies suggest this etiology.

Genome-wide copy number imbalances identified in familial and sporadic medullary thyroid carcinoma.

Medullary thyroid carcinoma (MTC) is a malignant tumor of the calcitonin-secreting parafollicular C cells of the thyroid occurring sporadically and as a component of the multiple endocrine neoplasia type 2/familial medullary thyroid carcinoma syndrome. The primary genetic cause of multiple endocrine neoplasia type 2 is germline mutation of the RET protooncogene. Somatic point mutations in RET also occur in sporadic MTC. Although RET mutation is likely sufficient to cause C-cell hyperplasia, the precursor lesion to MTC, tumor progression is thought to be due to clonal expansion caused by the accumulation of somatic events. Using the genome-scanning technique comparative genomic hybridization, we identified chromosomal imbalances that occur in MTC including deletions of chromosomes 1p, 3q26.3-q27, 4, 9q13-q22, 13q, and 22q and amplifications of chromosome 19. These regions house known tumor suppressor genes as well as genes encoding subunits of the multicomponent complex of glycosylphosphatidylinositol-linked proteins (glial cell line-derived neurotrophic factor family receptors alpha-2-4) and their ligands glial cell line-derived neurotrophic factor, neurturin, persephin, and artemin that facilitate RET dimerization and downstream signaling. Chromosomal imbalances in the MTC cell line TT were largely identical to those identified in primary MTC tumors, consolidating its use as a model for studying MTC.