Clinic Heterogeneity and Management of Pediatric Patients With Germline RET Proto-oncogene Mutation: Single-center Experience.

Inherited forms of medullary thyroid carcinoma (MTC) can cause serious problems in diagnosis and follow-up. Family screening is performed, and prophylactic thyroidectomy at an appropriate age can be life-saving. This study aimed to investigate the diagnostic, clinical, laboratory characteristics, and treatment methods of cases with rearranged during transfection ( RET) mutation in the childhood age group. Patients diagnosed with hereditary MTC and patients who were evaluated by detecting MTC and/or RET mutations in their families were included in this study. Nine cases from 6 families were included in the study. Seven patients were evaluated as a result of screening, whereas 2 patients, one of whom was MEN2B, were symptomatic. Prophylactic thyroidectomy was performed in 7 cases. Medullary microcarcinoma was found in all, and additional papillary thyroid carcinoma in one. An inoperable tumor was detected in one patient, and sorafenib treatment was applied. A very heterogeneous clinical presentation can be seen in a group of pediatric patients with RET mutation. In rare RET mutations, the genotype-phenotype relationship is still unclear, and different clinical pictures can be seen. Although prophylactic thyroidectomy is life-saving, it can cause iatrogenic hypothyroidism and hypoparathyroidism. Concomitant papillary microcarcinomas may occur in very young children with germline RET mutation.

[The trends in early precision diagnosis and treatment strategies of multiple endocrine neoplasia type 2].

Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant hereditary neuroendocrine cancer syndrome characterized by medullary thyroid carcinoma, in combination or not with pheochromocytoma, hyperparathyroidism and extra-endocrine features, and two forms subtyped as MEN2A and MEN2B. Based on the correlation between RET proto-oncogene mutation and MEN2 phenotype, MEN2 could be prevented through prenatal diagnosis and preimplantation genetic testing. Integrating the detection of RET mutation with measurement of serum calcitonin, plasma or urinary metanephrine/normetanephrine, and serum parathyroid hormone levels could accurately predict the progression of MEN2, and then facilitating implementation of personalized precision treatment. In addition, increased awareness of MEN2 is needed, which requires participation of physicians, patients/family members, and relevant organizations, supplemented by psychological support, which could promote the comprehensive management of MEN2. The "5P" strategies for MEN2 represents a paradigm of precision medicine, which could effectively avoid or reduce the clinical adverse outcomes, improve the prognosis and quality of life of MEN2 patients.

Molecular targets of tyrosine kinase inhibitors in thyroid cancer.

Thyroid cancer (TC) is the eighth most frequently diagnosed cancer worldwide with a rising incidence in the past 20 years. Surgery is the primary strategy of therapy for patients with medullary TC (MTC) and differentiated TC (DTC). In DTC patients, radioactive iodine (RAI) is administered after thyroidectomy. Neck ultrasound, basal and thyroid-stimulating hormone-stimulated thyroglobulin are generally performed every three to six months for the first year, with subsequent intervals depending on initial risk assessment, for the detection of possible persistent/recurrent disease during the follow up. Distant metastases are present at the diagnosis in ∼5 % of DTC patients; up to 15 % of patients have recurrences during the follow up, with a survival reduction (70 %-50 %) at 10-year. During tumor progression, the iodide uptake capability of DTC cancer cells can be lost, making them refractory to RAI, with a negative impact on the prognosis. Significant advances have been done recently in our understanding of the molecular pathways implicated in the progression of TCs. Several drugs have been developed, which inhibit signaling kinases or oncogenic kinases (BRAFV600E, RET/PTC), such as those associated with Platelet-Derived Growth Factor Receptor and Vascular Endothelial Growth Factor Receptor. Tyrosine kinase receptors are involved in cancer cell proliferation, angiogenesis, and lymphangiogenesis. Several tyrosine kinase inhibitors (TKIs) are emerging as new treatments for DTC, MTC and anaplastic TC (ATC), and can induce a clinical response and stabilize the disease. Lenvatinib and sorafenib reached the approval for RAI-refractory DTC, whereas cabozantinib and vandetanib for MTC. These TKIs extend median progression-free survival, but do not increase the overall survival. Severe side effects and drug resistance can develop in TC patients treated with TKIs. Additional studies are needed to identify a potential effective targeted therapy for aggressive TCs, according to their molecular characterization.

Multiple endocrine neoplasia type 2: A review.

Multiple endocrine neoplasias are rare hereditary syndromes some of them with malignant potential. Multiple endocrine neoplasia type 2 (MEN 2) is an autosomal dominant hereditary cancer syndrome due to germline variants in the REarranged during Transfection (RET) proto-oncogene. There are two distinct clinical entities: MEN 2A and MEN 2B. MEN 2A is associated with medullary thyroid carcinoma (MTC), phaeochromocytoma, primary hyperparathyroidism, cutaneous lichen amyloidosis and Hirschprung's disease and MEN 2B with MTC, phaeochromocytoma, ganglioneuromatosis of the aerodigestive tract, musculoskeletal and ophthalmologic abnormalities. Germline RET variants causing MEN 2 result in gain-of-function; since the discovery of the genetic variants a thorough search for genotype-phenotype associations began in order to understand the high variability both between families and within family members. These studies have successfully led to improved risk classification of prognosis in relation to the genotype, thus improving the management of the patients by thorough genetic counseling. The present review summarizes the recent developments in the knowledge of these hereditary syndromes as well as the impact on clinical management, including genetic counseling, of both individual patients and families. It furthermore points to future directions of research for better clarification of timing of treatments of the various manifestations of the syndromes in order to improve survival and morbidity in these patients.

5P Strategies for Management of Multiple Endocrine Neoplasia Type 2: A Paradigm of Precision Medicine.

Multiple endocrine neoplasia type 2 (MEN2) is a neuroendocrine cancer syndrome characterized by medullary thyroid carcinoma, in combination or not with pheochromocytoma, hyperparathyroidism, and extra-endocrine features. MEN2 syndrome includes two clinically distinct forms subtyped as MEN2A and MEN2B. Nearly all MEN2 cases are caused by germline mutations of the RET proto-oncogene. In this review, we propose "5P" strategies for management of MEN2: prevention, prediction, personalization, psychological support, and participation, which could effectively improve clinical outcomes of patients. Based on RET mutations, MEN2 could be prevented through prenatal diagnosis or preimplantation genetic testing. Identification of pathogenic mutations in RET can enable early diagnosis of MEN2. Combining RET mutation testing with measurement of serum calcitonin, plasma or urinary metanephrine/normetanephrine, and serum parathyroid hormone levels could allow risk stratification and accurately prediction of MEN2 progression, thus facilitating implementation of personalized precision treatments to increase disease-free survival and overall survival. Furthermore, increased awareness of MEN2 is needed, which requires participation of physicians, patients, family members, and related organizations. Psychological support is also important for patients with MEN2 to promote comprehensive management of MEN2 symptoms. The "5P" strategies for management of MEN2 represent a typical clinical example of precision medicine. These strategies could effectively improve the health of MEN2 patient, and avoid adverse outcomes, including death and major morbidity, from MEN2.

Biochemistry may be misleading in metachronous MEN2A-associated phaeochromocytoma following unilateral total adrenalectomy.

A 63-year-old woman with multiple endocrine neoplasia type 2A (MEN2A) presented with recurrent spells of headaches, sweats and palpitations decades after right adrenalectomy for phaeochromocytoma, and total thyroidectomy for medullary thyroid cancer. She was hypertensive and in sinus rhythm. DOTA-TATE positron-emission tomography (PET) demonstrated a 12mm enhancing left adrenal incidentaloma. 24 hours urine catecholamines, and multiple plasma metanephrine and normetanephrine measurements were all within normal reference ranges. Based on her symptoms and imaging findings, left adrenalectomy was performed and found a 40 mm phaeochromocytoma. Her symptoms have since completely resolved and plasma metanephrine is now undetectable MEN2-associated phaeochromocytomas are often bilateral and may be metachronous. Patients at high risk of phaeochromocytoma who develop symptoms of catecholamine excess should be carefully evaluated even if plasma or urinary metanephrines are within the normal reference range. Biochemical reference ranges for metanephrines need to be adjusted accordingly in patients who have had prior unilateral total adrenalectomy.

Anti-PD-1 Immunotherapy-Induced Flare of a Known Underlying Relapsing Vasculitis Mimicking Recurrent Cancer.

Safe use of immune checkpoint blockade in patients with cancer and autoimmune disorders requires a better understanding of the pathophysiology of immunologic activation. We describe the immune correlates of reactivation of granulomatosis with polyangiitis (GPA)-an antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis-in a patient with metastatic urothelial carcinoma treated with pembrolizumab. After PD-1 blockade, an inflammatory pulmonary nodule demonstrated a granulomatous, CD4+ T-cell infiltrate, correlating with increased CD4+ and CD8+ naïve memory cells in the peripheral blood without changes in other immune checkpoint receptors. Placed within the context of the existing literature on GPA and disease control, our findings suggest a key role for PD-1 in GPA self-tolerance and that selective strategies for immunotherapy may be needed in patients with certain autoimmune disorders. We further summarize the current literature regarding reactivation of autoimmune disorders in patients undergoing immune checkpoint blockade, as well as potential immunosuppressive strategies to minimize the risks of further vasculitic reactivation upon rechallenge with anti-PD-1 blockade. KEY POINTS: Nonspecific imaging findings in patients with cancer and rheumatological disorders may require biopsy to distinguish underlying pathology.Patients with rheumatologic disorders have increased risk of reactivation with PD-(L)1 immune checkpoint blockade, requiring assessment of disease status before starting treatment.Further study is needed to evaluate the efficacy of treatment regimens in preventing and controlling disease reactivation.

Clinico-pathologic and dynamic prognostic factors in sporadic and familial medullary thyroid carcinoma: an Israeli multi-center study.

OBJECTIVE: Multiple clinical, pathological and biochemical variables, including the response to initial treatment, are associated with medullary thyroid carcinoma (MTC) prognosis. Studies that include separate analyses of familial and sporadic MTC patients followed for long period are scarce. This study evaluated the association between baseline clinico-pathologic variables and response to initial treatment and short- and long-term disease outcomes in sporadic and familial MTC. METHODS: Patients treated for MTC at four tertiary medical centers were retrospectively analyzed. Clinical and pathological data were collected. The outcomes measured included disease persistence 1 year after diagnosis, disease persistence at last follow-up, disease-related mortality (DRM) and all-cause mortality. RESULTS: The study enrolled 193 patients (mean age: 48.9 ± 18.7, 44.7% males), of whom 18.1% were familial cases. The mean follow-up period was 10.1 ± 9.4 years (8.5 ± 8.1 in sporadic and 16.9 ± 11.6 in familial MTC). Disease persistence 1-year after diagnosis and at last follow-up was detected in 56.1 and 60.4% patients, respectively. All-cause and DRM were 28.5 and 12.6%, respectively. Extra-thyroidal extension (ETE) and distant metastases (DM) were associated with disease persistence at last follow-up. ETE and DM were also significantly associated with DRM. Complete remission 1 year after diagnosis had high correlation with no evidence of disease at last follow-up (Cramer's V measure of association 0.884, P < 0.001) and with 100% disease-specific survival (Cramer's V measure of association 0.38, P < 0.001). CONCLUSIONS: Apart from clinico-pathologic parameters, close correlation was found between 1-year status and long-term prognosis. These results underscore the importance of combining classical and dynamic factors for both sporadic and familial MTC prognostication and treatment decision making.

Survival and Long-Term Biochemical Cure in Medullary Thyroid Carcinoma in Denmark 1997-2014: A Nationwide Study.

BACKGROUND: Survival of medullary thyroid carcinoma (MTC) subgroups in relation to the general population is poorly described. Data on the factors predicting long-term biochemical cure in MTC patients are nonexistent at a population level. A nationwide retrospective cohort study of MTC in Denmark from 1997 to 2014 was conducted, aiming to detect subgroups with survival similar to that of the general population and to identify prognostic factors for disease-specific survival and long-term biochemical cure. METHODS: The study included 220 patients identified from the nationwide Danish MTC cohort between 1997 and 2014. As a representative sample of the general population, a reference population matched 50:1 to the MTC cohort was used. RESULTS: Patients diagnosed with hereditary MTC by screening (hazard ratio [HR] = 1.5 [confidence interval (CI) 0.5-4.3]), patients without regional metastases (HR = 1.4 [CI 0.9-2.3]), and patients with stage I (HR = 1.3 [CI 0.6-3.1]), stage II (HR = 1.1 [CI 0.6-2.3]), and III (HR = 1.3 [CI 0.4-4.2]) disease had an overall survival similar to the reference population. On multivariate analysis, the presence of distant metastases (HR = 12.3 [CI 6.0-25.0]) predicted worse disease-specific survival, while the absence of regional lymph node metastases (odds ratio = 40.1 [CI 12.0-133.7]) was the only independent prognostic factor for long-term biochemical cure. CONCLUSIONS: Patients with hereditary MTC diagnosed by screening, patients without regional metastases, and patients with stages I, II, and III disease may have similar survival as the general population. The presence of distant metastases predicted worse disease-specific survival, while the absence of regional metastases predicted long-term biochemical cure.

Use of Dexmedetomidine in a Parturient With Multiple Endocrine Neoplasia Type 2A Undergoing Adrenalectomy and Thyroidectomy: A Case Report.

Dexmedetomidine is a selective α2-agonist, frequently used in perioperative medicine as anesthesia adjunct. The medication carries a Food and Drug Administration pregnancy category C designation and is therefore rarely used for parturients undergoing nonobstetric surgery. We are reporting the use of dexmedetomidine in the anesthetic management of a parturient undergoing minimally invasive unilateral adrenalectomy for pheochromocytoma during the second trimester of pregnancy. Additionally, because of the multiple endocrine neoplasia type 2A constellation with diagnosis of medullary thyroid cancer, the patient underwent a total thyroidectomy 1 week after the adrenalectomy.

Different outcomes in sporadic versus familial medullary thyroid cancer.

BACKGROUND: Medullary thyroid carcinoma (MTC) has varying clinical course with familial cases (fMTC) diagnosed earlier than sporadic MTC (spMTC). METHODS: A total of 273 MTCs (familial: n = 110 [40.3%], males: 38.5%) were followed for 1-35 years (median 5.0 years). Fifty one of the familial cases were operated because of positive findings at genetic screening. Disease extent at diagnosis and follow-up was recorded. RESULTS: Mean age at diagnosis was: fMTC = 33.85 ± 16.5 years (range 4-74) and spMTC = 52.6 ± 14.0 years (range 16-81, P < .001). This difference remained when genetic screening cases were excluded. fMTCs had more frequently multifocality, smaller size, and more favorable stage at diagnosis (stages I and II: 60.9% vs 47.9%, stage III: 30.0% vs 23.9%, stage IV: 9.1% vs 28.9%, P = .01). fMTC had lower preoperative and postoperative calcitonin, more frequently remission (59.1% vs 47.2%) and less frequently progressive disease (8.2% vs 35.0%, P < .001). After excluding genetic screening cases, no difference in stage at diagnosis was observed. Outcome was more favorable in fMTC compared to sporadic (P = .002); the 10-year probability of lack of progression of disease differed significantly between fMTCs and spMTCs (86.4% vs 65.0%, P < .001). CONCLUSION: After excluding genetic screening cases, although stage at diagnosis is similar, disease outcome remains worse in sporadic compared to fMTCs.

Update on multiple endocrine neoplasia Type 1 and 2.

Multiple endocrine neoplasia type 1 is a rare genetic syndrome, characterized by the co-occurrence, in the same individual or in related individuals of the same family, of hyperparathyroidism, duodenopancraetic neuroendocrine tumors, pituitary adenomas, adrenocortical tumors, and neuroendocrine tumors (carcinoids) in the thymus, the bronchi, or the stomach. Multiple endocrine neoplastic type 2 is a rare genetic syndrome, characterized by the familial occurrence of medullary thyroid carcinoma either isolated or associated with pheochromocytoma, primary hyperparathyroidism, or typical features (Marfanoid habitus, mucosal neuromas). Subjects with clinical MEN1 and those who carry a mutation in the MEN1 gene should be offered biochemical and imaging screening in order to detect tumors and evaluate their progression over time. Children with mutation in the RET gene should have prophylactic total thyroidectomy according to the category of aggressiveness of the detected mutation whereas those with clinical MEN2 should be operated on upon diagnosis. In MEN1 patients, special attention should be paid to evaluate the progression duodenopancraetic neuroendocrine tumors because of their malignant potential. Also, thymic neuroendocrine tumors should be detected as soon as possible because they represent the most lethal tumor. In MEN2, calcitonin and carcinoembryonic antigen (CEA) serve as excellent tumor markers for medullary thyroid carcinoma. Their preoperative levels are correlated with tumor size and predict postoperative cure. Moreover, calcitonin or CEA doubling time has important prognostic value. In both MEN syndromes, multidisciplinary approaches are very important in the care of affected patients. Moreover, those patients should be comprehensively informed and enabled to participate in the decision-making procedure. In addition to multidisciplinary approaches, every effort should be made to follow the recommendations and guidelines issued by national (the French Group of Endocrine Tumors) and international groups.

Patient quality of life and prognosis in multiple endocrine neoplasia type 2.

Multiple endocrine neoplasia type 2 (MEN2) refers to the autosomal-dominant neuroendocrine tumour syndromes, MEN type 2A (MEN2A) and MEN type 2B (MEN2B). They are typified by the development of medullary thyroid cancer (MTC), phaeochromocytoma and parathyroid hyperplasia in MEN2A and MTC, phaeochromocytomas, ganglioneuromatosis and skeletal abnormalities in MEN2B. The aggressiveness of MTC is variable according to genotype, and although it is still the major cause of mortality in both conditions, prognosis has improved dramatically in those diagnosed and treated at a young age thanks to predictive genetic testing. Nevertheless, metastatic MTC, ganglioneuromatosis and a variety of other negative clinical and psychosocial impacts on quality of life and/or prognosis in MEN2 persist. In the absence, at the time of writing, of any large-scale research into quality of life specifically in MEN2, this review includes data from patient surveys and anonymised patient anecdotes from the records of the Association for Multiple Endocrine Neoplasia Disorders (AMEND), for whom the authors work. We recommend that these patients are cared for only in centres of expertise able to provide expert diagnosis, treatment and continuity of care, including psychological and transition support. Only in this way can the clinical advances of the last two and half decades be built upon further to ensure that the care of these complex, lifelong patients can be considered truly holistic.

Advances in the management of MEN2: from improved surgical and medical treatment to novel kinase inhibitors.

Medullary thyroid carcinoma (MTC), a tumor derived from the neural crest, occurs either sporadically or as the dominant component of the type 2 multiple endocrine neoplasia (MEN) syndromes, MEN2A and MEN2B. The discovery that mutations in the RET protooncogene cause hereditary MTC was of great importance, since it led to the development of novel methods of diagnosis and treatment. For example, the detection of a mutated RET allele in family members at risk for inheriting MEN2A or MEN2B signaled that they would develop MTC, and possibly other components of the syndromes. Furthermore, the detection of a mutated allele created the opportunity, especially in young children, to remove the thyroid before MTC developed, or while it was confined to the gland. The discovery also led to the development of molecular targeted therapeutics (MTTs), mainly tyrosine kinase inhibitors, which were effective in the treatment of patients with locally advanced or metastatic MTC. While responses to MTTs are often dramatic, they are highly variable, and almost always transient, because the tumor cells become resistant to the drugs. Clinical investigators and the pharmaceutical industry are focusing on the development of the next generation of MTTs, which have minimal toxicity and greater specificity for mutated RET.

Looking beyond the thyroid: advances in the understanding of pheochromocytoma and hyperparathyroidism phenotypes in MEN2 and of non-MEN2 familial forms.

Over the last years, the knowledge of MEN2 and non-MEN2 familial forms of pheochromocytoma (PHEO) has increased. In MEN2, PHEO is the second most frequent disease: the penetrance and age at diagnosis depend on the mutation of RET Given the prevalence of bilateral PHEO (50% by age 50), adrenal sparing surgery, aimed at sparing a part of the adrenal cortex to avoid adrenal insufficiency, should be systematically considered in patients with bilateral PHEO. Non-MEN2 familial forms of PHEO now include more than 20 genes: however, only small phenotypic series have been reported, suggesting that phenotypic features of isolated hereditary PHEO must be better explored, and follow-up series are needed to better understand the outcome of patients carrying mutations of these genes. The first part of this review will mainly focus on these points. In the second part, a focus will be given on MEN2 and non-MEN2 familial forms of hyperparathyroidism (HPTH). Again, the management of MEN2 HPTH should be aimed at curing the disease while preserving an optimal quality of life by a tailored parathyroidectomy. The phenotypes and outcome of MEN1-, MEN4- and HRPT2-related HPTH are briefly described, with a focus on the most recent literature data and is compared with familial hypocalciuric hypercalcemia.

RET-mediated modulation of tumor microenvironment and immune response in multiple endocrine neoplasia type 2 (MEN2).

Medullary thyroid carcinomas (MTC) arise from thyroid parafollicular, calcitonin-producing C-cells and can occur either as sporadic or as hereditary diseases in the context of familial syndromes, including multiple endocrine neoplasia 2A (MEN2A), multiple endocrine neoplasia 2B (MEN2B) and familial MTC (FMTC). In a large fraction of sporadic cases, and virtually in all inherited cases of MTC, activating point mutations of the RET proto-oncogene are found. RET encodes for a receptor tyrosine kinase protein endowed with transforming potential on thyroid parafollicular cells. As in other cancer types, microenvironmental factors play a critical role in MTC. Tumor-associated extracellular matrix, stromal cells and immune cells interact and influence the behavior of cancer cells both in a tumor-promoting and in a tumor-suppressing manner. Several studies have shown that, besides the neoplastic transformation of thyroid C-cells, a profound modification of tumor microenvironment has been associated to the RET FMTC/MEN2-associated oncoproteins. They influence the surrounding stroma, activating cancer-associated fibroblasts (CAFs), promoting cancer-associated inflammation and suppressing anti-cancer immune response. These mechanisms might be exploited to develop innovative anti-cancer therapies and novel prognostic tools in the context of familial, RET-associated MTC.

Management of familial hyperparathyroidism syndromes: MEN1, MEN2, MEN4, HPT-Jaw tumour, Familial isolated hyperparathyroidism, FHH, and neonatal severe hyperparathyroidism.

While primary hyperparathyroidism (PHPT) generally represents a common endocrine disorder, being the more frequent cause of hypercalcemia in outpatients, familial forms of PHPT (FPHPT) account for no more than 2-5% of the overall PHPT. In the last decades, many technical progresses in both molecular and biochemical-radiological evaluation have been made, and substantial advancements in understanding these disorders have been reached. Differences both in the pathogenesis and clinical presentation exist among the various hyperparathyroid syndromic forms, and, since FPHPT is frequently associated to other endocrine, proliferative and/or functional disorders, as also non-endocrine tumours, with varying clinical spectrum of occurrence in each syndrome, its early clinically detection for appropriately preventing complications (i.e. kidney and bone disorders) is strictly advised. In this review, the clinical-biochemical features and diagnostic procedures of each FPHPT form will be summarized and a general overview on surgical and pharmacological approaches to FPHPT has been also considered.

A rare missense variant in RET exon 8 in a Portuguese family with atypical multiple endocrine neoplasia type 2A.

BACKGROUND AND OBJECTIVE: Multiple Endocrine Neoplasia type 2 (MEN2) is a rare genetic disorder characterized by medullary thyroid carcinoma (MTC), pheochromocytoma and primary hyperparathyroidism. MEN2 is an autosomal dominant syndrome caused by mutations in the RET proto-oncogene. In the vast majority of patients, the mutations are localized in exons 10, 11 and 13-15 of the RET gene. Rare variants located in exon 8 were recently identified but their clinical significance remains unclear. DESIGN AND METHODS: We studied two sisters presenting with pheochromocytoma as the first tumor. One of the sisters was diagnosed with a right pheochromocytoma at the age of 44 and at age 53 she developed an invasive left pheochromocytoma with no other endocrine neoplasia. The other sister was diagnosed with a left pheochromocytoma at age 50 and at age 64 she had a right phemochromocytoma and MTC. Neither of the two sisters presented evidence of primary hyperparathyroidism. Mutations of the RET proto-oncogene were investigated by DNA sequencing. RESULTS: We detected a germline missense variant in RET exon 8 (p.Cys531Arg) in both sisters. The p.Cys531Arg variant was not present in a third 50-year-old sister who has remained to date clinically unaffected. CONCLUSION: This is the first case showing the p.Cys531Arg variant in RET exon 8 co-segregating with family members affected by a syndrome reminiscent of MEN2A. Our results suggest that this variant has a specific genotype-phenotype correlation as it is associated with the development of pheochromocytoma before the onset of MTC.

Epidemiology and Clinical Presentation of Medullary Thyroid Carcinoma.

Medullary thyroid carcinoma (MTC) is a rare neuroendocrine tumor originating from the thyroid C cells producing mainly calcitonin (CTN) used as tumor marker. MTC occurs either sporadic (75%) or in a hereditary form (multiple endocrine neoplasia type 2, MEN2), due to germline mutations in the RET proto-oncogene. The discovery of an MTC in a patient has several diagnostic implications involving a specific strategy: preoperative evaluation of the tumor marker CTN and the extent of the disease, classification of MTC as sporadic or hereditary by DNA testing, and screening for associated endocrinopathies in hereditary MTC. Elevated CTN is a highly sensitive and specific tumor marker for diagnosis and follow-up of MTC. CTN is directly related to the tumor mass. In patients with nodular thyroid disease, diagnosis of MTC could be made by CTN determination as an indicator of tumor burden in conjunction with fine-needle aspiration. Patients with confirmed sporadic or hereditary MTC should have a total thyroidectomy and depending on the preoperative CTN value and the extent of disease additional dissection of the lymph nodes in the central and lateral neck compartment. In MEN 2 patients diagnosed by screening, the time of prophylactic thyroidectomy depends on RET mutation and CTN level.