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Medullary thyroid cancer (MTC) is rare but aggressive. It can be cured only if intrathyroid at diagnosis. MTC can be sporadic (75%) or familial (25%) and the 2 forms are distinguished by RET mutations analysis. Calcitonin is the specific serum marker; its doubling time is the most important prognostic factor for survival and progression; 30% of MTC patients have distant metastases at diagnosis and, when progressing, systemic therapy with vandetanib or cabozantinib should be considered. Before starting this treatment, the possibility of using a local treatment should be evaluated to delay systemic therapy. A multidisciplinary team should care for these patients., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Medullary thyroid carcinoma (MTC) is a calcitonin (CT)-producing C-cell tumor. In hereditary cases, a germline RET mutation is found in 98% of families. Because MTC is cured only if intrathyroidal, prophylactic thyroidectomy is recommended in the gene carrier (GC)., Aims: The aim was to determine whether thyroidectomy performed when stimulated CT becomes detectable is as safe as prophylactic thyroidectomy and to identify the serum CT cutoff able to distinguish intrathyroidal from extrathyroidal MTC., Patients: Eighty-four GC were prospectively enrolled; 53 of the 84 underwent total thyroidectomy, one refused surgery, and 30 with normal basal and stimulated CT were under surveillance. The follow-up ranged from 2 to 18 yr., Results: GC operated on for elevated stimulated CT included 27 GC with a positive peak CT at the screening and four cases who became positive after 4 yr. All of them had intrathyroidal MTC and no node metastases; all were cured after a mean follow-up of 7.5 yr. Among those operated on for detectable basal CT, intrathyroidal tumors were found when CT was below 60 pg/ml, whereas either node metastases or larger tumors were observed when CT was above 60 pg/ml. No correlation among serum CT, age, and type of RET mutation was observed. Thirty GC were still biochemically negative at the annual control., Conclusions: The time of thyroidectomy in GC with negative CT could be personalized and safely planned when stimulated CT becomes positive, independent of the type of RET mutation and patient's age. In this series, a basal CT below 60 pg/ml was always associated to an intrathyroidal localization of MTC.

Calcitonin (CT) is secreted mainly by parafollicular C cells. In normal subjects, serum CT (sCT) levels are low and barely detectable by commonly used assays. Increased sCT levels are highly suggestive of medullary thyroid carcinoma (MTC). Since the clinical manifestation of MTC is a thyroid nodule, either single or in the context of a multinodular goitre, the routine measurement of sCT in the evaluation of thyroid nodule(s) facilitates the diagnosis of MTC. sCT measurement is indeed more sensitive than cytology in finding MTC. There are two major benefits from this clinical practice: (a) the surgeon is alerted to the need to perform total thyroidectomy and central compartment lymphadenectomy, which is the minimal surgical treatment for MTC; and (b) the outcome of MTC is favourably affected because it is usually identified at a less advanced stage. However, other non-MTC causes of hypercalcitoninaemia and false sCT positivity do exist and must be recognized. The differential diagnosis is possible using previously validated assays against possible sources of interference, and performing stimulation tests with pentagastrin or, eventually, calcium infusion.

The survival rate of patients with medullary thyroid carcinoma (MTC) is significantly better in patients diagnosed and treated when the tumor is limited to the thyroid. In a pioneer study carried out in 1991, we demonstrated that routine measurement of serum calcitonin (CT) in nodular thyroid disease allowed the preoperative diagnosis of unsuspected sporadic MTC with better accuracy than routine fine needle aspiration cytology (FNAC). This finding has been confirmed in subsequent studies. In the present study we report the results of CT screening in 10,864 patients with thyroid nodular disease seen in the years 1991-1998 (group 1). We analyzed the prevalence of MTC and compared their outcomes with those of a historical group of patients (group 2) diagnosed before the introduction of CT screening (1970-1990). The prevalence of MTC found by CT screening in group 1 was 0.40% (44 patients). A positive CT test had a higher diagnostic sensitivity and specificity compared with FNAC. CT screening allowed the diagnosis of MTC at an earlier stage compared with group 2 (P = 0.004). Normalization of serum CT levels (undetectable) after surgery was more frequently observed in group 1. At the end of follow-up, complete remission was observed in 59% of group 1 and in 2.7% of group 2 (P = 0.0001). Our study confirms that MTC is not an infrequent finding among patients with thyroid nodules (nearly 1 in 250 patients). In addition, screening thyroid nodules with serum CT measurement allows the diagnosis and treatment of MTC at an earlier stage, resulting in a better outcome compared with MTC not detected by serum CT measurement. One of the reasons for this finding is that increasing the preoperative diagnostic accuracy of MTC prompts the surgeon to perform a more radical and possibly curative treatment. On this basis, routine measurement of basal serum CT levels should be considered an integral part of the diagnostic evaluation of thyroid nodules.

PurposeCabozantinib, a tyrosine kinase inhibitor (TKI) of hepatocyte growth factor receptor (MET), vascular endothelial growth factor receptor 2, and rearranged during transfection (RET), demonstrated clinical activity in patients with medullary thyroid cancer (MTC) in phase I.Patients and methodsWe conducted a double-blind, phase III trial comparing cabozantinib with placebo in 330 patients with documented radiographic progression of metastatic MTC. Patients were randomly assigned (2:1) to cabozantinib (140 mg per day) or placebo. The primary end point was progression-free survival (PFS). Additional outcome measures included tumor response rate, overall survival, and safety.ResultsThe estimated median PFS was 11.2 months for cabozantinib versus 4.0 months for placebo (hazard ratio, 0.28; 95% CI, 0.19 to 0.40; P < .001). Prolonged PFS with cabozantinib was observed across all subgroups including by age, prior TKI treatment, and RET mutation status (hereditary or sporadic). Response rate was 28% for cabozantinib and 0% for placebo; responses were seen regardless of RET mutation status. Kaplan-Meier estimates of patients alive and progression-free at 1 year are 47.3% for cabozantinib and 7.2% for placebo. Common cabozantinib-associated adverse events included diarrhea, palmar-plantar erythrodysesthesia, decreased weight and appetite, nausea, and fatigue and resulted in dose reductions in 79% and holds in 65% of patients. Adverse events led to treatment discontinuation in 16% of cabozantinib-treated patients and in 8% of placebo-treated patients.ConclusionCabozantinib (140 mg per day) achieved a statistically significant improvement of PFS in patients with progressive metastatic MTC and represents an important new treatment option for patients with this rare disease. This dose of cabozantinib was associated with significant but manageable toxicity.

Context: The clinical response after surgery is a determinant in the management of patients with medullary thyroid carcinoma (MTC). In case of excellent or structural incomplete response, the follow-up strategies are well designed. Conversely, in case of biochemical incomplete response (BiR) the management is not clearly defined. Objective: This work aimed to evaluate the overall and per-site prevalence of structural disease detection in sporadic MTC patients with BiR and to assess the predictive value of various clinical, biochemical, and genetic features. Methods: We evaluated data of 599 consecutive patients surgically treated for sporadic MTC (2000-2018) and followed-up at the endocrine unit of the University Hospital of Pisa. Results: After a median of 5 months from surgery, 145 of 599 (24.2%) patients were classified as BiR. Structural disease was detected in 64 of 145 (44.1%), after a median time of 3.3 years. In 73.6%, structural disease was detected at a single site, prevalently cervical lymph nodes. Among several others, at the time of first evaluation after surgery, only basal calcitonin (bCTN) and stage IVa/b were independent predictive factors. Also, structural disease was more frequent in patients with shorter CTN doubling time and somatic RET mutation. Conclusion: In sporadic MTC patients with BiR, the risk of detection of structural disease was about 50% at 10 years. Higher bCTN levels and staging predicted the risk of detecting structural disease. According to these findings, stricter follow-up should be reserved for MTC with BiR and elevated values of bCTN and to those with an advanced stage. Long follow-up should be considered for all BiR patients since 50% of them develop structural disease within 10 years. [ABSTRACT FROM AUTHOR]

Context: Measurement of driver mutations in circulating tumoral DNA (ctDNA) obtained by liquid biopsy has been shown to be a sensitive biomarker in several human tumors. Objective: The aim of this study was to evaluate the clinical relevance of pre- and post-operative ctDNA in sporadic medullary thyroid cancer (sMTC). Methods: We studied pre- and post-operative ctDNA in 26 and 23 sMTC patients, respectively. ctDNA results were correlated to serum calcitonin (Ct), carcinoembryonic antigen (CEA), and other clinical/pathological features. Results: Twenty-six of 29 (89.7%) sMTCs were mutated either for RET or RAS and 3/29 (10.3%) were negative. Four of 26 (15.4%) cases showed positive pre-operative ctDNA with a significantly higher presence of RET M918T mutation (P = 0.0468). Patients with positive preoperative ctDNA showed a higher variation allele frequency value of the somatic driver mutation (P = 0.0434) and a higher frequency of persistent disease (P = 0.0221). Post-operative ctDNA was positive only in 3/23 (13%) sMTCs and no one was positive for pre-operative ctDNA. Higher values of both Ct (P = 0.0307) and CEA (P = 0.0013) were found in positive ctDNA cases. Finally, the 7 cases harboring either pre- or post-operative positive ctDNA had a persistent disease (P = 0.0005) showing a higher post-operative serum Ct when compared with cases with negative ctDNA (P = 0.0092). Conclusions: Pre-operative ctDNA in medullary thyroid cancer is not useful for diagnostic purposes, but it can be useful for predicting the outcome of the disease. In our series, post-operative ctDNA showed a potential for monitoring the response to therapies, but further studies are required to confirm our results. [ABSTRACT FROM AUTHOR]

Medullary thyroid carcinoma (MTC) is a neuroendocrine malignant tumor originating from parafollicular C-cells producing calcitonin. Most of cases (75%) are sporadic while the remaining (25%) are hereditary. In these latter cases medullary thyroid carcinoma can be associated (multiple endocrine neoplasia type IIA and IIB) or not (familial medullary thyroid carcinoma), with other endocrine diseases such as pheochromocytoma and/or hyperparathyroidism. RET gene point mutation is the main molecular alteration involved in MTC tumorigenesis, both in sporadic and in hereditary cases. Total thyroidectomy with prophylactic/therapeutic central compartment lymph nodes dissection is the initial treatment of choice. Further treatments are needed according to tumor burden and rate of progression. Surgical treatments and local therapies are advocated in the case of single or few local or distant metastasis and slow rate of progression. Conversely, systemic treatments should be initiated in cases with large metastatic and rapidly progressive disease. In this review, we discuss the details of systemic treatments in advanced and metastatic sporadic MTC, focusing on multikinase inhibitors, both those already used in clinical practice and under investigation, and on emerging treatments such as highly selective RET inhibitors and radionuclide therapy. [ABSTRACT FROM AUTHOR]

One of the most discussed and controversial issue in the management of thyroid nodules is the need to perform a routine measurement of serum Calcitonin (Ct) in all cases. The American Thyroid Association guidelines do not recommend in favor or against this procedure since they retain that there are not enough evidences that it can determine an advantage to the health outcomes of these patients. This is not the view of many European experts who met in Lisbon in 2009 at the European Thyroid Association-Cancer Research Network meeting to discuss all the still open controversial issues on the management of medullary thyroid cancer patients. This paper is focused on the routine measurement of serum Ct in all patients with thyroid nodule(s): the evidences, the rational and the benefits of this procedure are deeply analysed following the discussion that was done in Lisbon. The conclusions reached at that time are reported in detail. [ABSTRACT FROM AUTHOR]

The long-term survival of patients with thyroid cancer and the possibility of tumour recurrence up to 30-40 years after the achievement of a disease-free status illustrate the importance of lifelong follow-up in these individuals. This Review discusses the most innovative aspects of follow-up protocols for patients with differentiated thyroid cancer, that is, of papillary or follicular hystotype, and those with medullary thyroid cancer. Particular focus is placed on the relevance of new ultrasensitive assays for thyroglobulin measurement and the option of using recombinant human TSH to stimulate thyroglobulin secretion. Methods to compensate for the loss of diagnostic significance of serum thyroglobulin levels in patients with differentiated thyroid cancer and circulating anti-thyroglobulin antibodies are highlighted, as well as the role of the postoperative calcitonin stimulation test and the clinical relevance of determining the doubling time of calcitonin and carcinoembryonic antigen in patients with medullary thyroid cancer. Moreover, this Review gives some insights into the role of molecular thyroid cancer testing, both for prognostic and for therapeutic purposes. Finally, a general overview of traditional imaging procedures, such as neck ultrasonography, CT, MRI and bone scintigraphy, is provided alongside a comparison with new nuclear imaging tests such as PET. [ABSTRACT FROM AUTHOR]

Simple Summary: MEN2 has a very high penetrance for the development of medullary thyroid cancer. However, intra- and inter-familial variabilities have been described. Accordingly, in this precision medicine era, a personalized approach should be adopted in subjects harboring RET mutations. In these subjects, we showed that thyroid surgery could be safely timed according to basal and stimulated calcitonin, especially in children who can reach adulthood, avoiding the risks of thyroid surgery and decreasing the period of a long-life hypothyroidism treatment. Multiple Endocrine Neoplasia 2 (MEN2) is a hereditary cancer syndrome for developing medullary thyroid cancer (MTC) due to germline mutations of RET gene. Subjects harboring a germline RET mutation without any clinical signs of MTC are defined as gene carriers (GCs), for whom guidelines propose a prophylactic thyroid surgery. We evaluate if active surveillance of GCs, pursuing early thyroid surgery, can be safely proposed and if it allows safely delaying thyroid surgery in children until adolescence/adulthood. We prospectively followed 189 GCs with moderate or high risk germline RET mutation. Surgery was planned in case of: elevated basal calcitonin (bCT) and/or stimulated CT (sCT); surgery preference of subjects (or parents, if subject less than 18 years old); other reasons for thyroid surgery. Accordingly, at RET screening, we sub-grouped GCs in subjects who promptly were submitted to thyroid surgery (Group A, n = 67) and who were not (Group B, n = 122). Group B was further sub-grouped in subjects who were submitted to surgery during their active surveillance (Group B1, n = 22) and who are still in follow-up (Group B2, n = 100). Group A subjects presented significantly more advanced age, bCT and sCT compared to Group B. Mutation RETV804M was the most common variant in both groups but it was significantly less frequent in Group A than B. Analyzing age, bCT, sCT and genetic landscape, Group B1 subjects differed from Group B2 only for sCT at last evaluation. Group A subjects presented more frequently MTC foci than Group B1. Moreover, Group A MTCs presented more aggressive features (size, T and N) than Group B1. Accordingly, at the end of follow-up, all Group B1 subjects presented clinical remission, while 6 and 12 Group A MTC patients had structural and biochemical persistent disease, respectively. Thank to active surveillance, only 13/63 subjects younger than 18 years at RET screening have been operated on during childhood and/or adolescence. In Group B1, three patients, while actively surveilled, had the possibility to reach the age of 18 (or older) and two patients the age of 15, before being submitted to thyroid surgery. In Group B2, 12 patients become older than 18 years and 17 older than 15 years. In conclusion, we demonstrated that an active surveillance pursuing an early thyroid surgery could be safely recommended in GCs. This patient-centered approach permits postponing thyroid surgery in children until their adolescence/adulthood. At the same time, we confirmed that genetic screening allows finding hidden MTC cases that otherwise would be diagnosed much later. [ABSTRACT FROM AUTHOR]

Abstract: Medullary thyroid carcinoma (MTC) is an uncommon malignant tumor arising from the calcitonin-producing parafollicular cells (C cells) of thyroid. It accounts for 5–10% of all thyroid cancers, and it mostly occurs as a sporadic entity (sMTC), but a familial pattern (fMTC) is also possible. RET proto-oncogene germline mutations are crucial for the onset and the progression of fMTC, and the occurrence of single nucleotide polymorphisms could predispose to the sporadic form. In order to clarify the role of this gene in MTC, we carefully reviewed the PubMed database using appropriate terms. First, we summarized current knowledge of the germline RET mutations, mutation spectrum, and prevalence. We then performed a meta-analysis on the available case-control association studies for sMTC. Finally, we carried out in silico predictions of the best associated variants in the attempt to better define their role in the disease. To date, a total of 39 different RET germline mutations have been identified in fMTC families. The most affected codons are 609, 611, 618, 620 (exon 10) and 634 (exon 11), encoding for the extracellular cysteine-rich domain, and codons 768 (exon 13) and 804 (exon 14) of the intracellular tyrosine kinase domain. Six polymorphisms with at least three studies were included in the meta-analysis (A45A [rs1800858], G691S [rs1799939], L769L [rs1800861], S836S [rs1800862], S904S [rs1800863], and IVS1-126G>T [rs2565206]). The meta-analysis demonstrated a modest association of sMTC susceptibility with S836S and a strong association with the IVS1-126G>T polymorphism. Besides RET polymorphisms, we also investigated the role of a few other low-penetrance alleles of genes involved in the RET pathway or in xenobiotic metabolism, but none of these were confirmed. Thus, despite the well-known molecular basis of fMTC, the genetic variants of the sporadic form are still poorly understood, and functional analyses are needed to better understand the consequence of such RET variants and to improve our knowledge on the disease. [Copyright &y& Elsevier]