Forms Of Medullary Thyroid Cancer Research Articles

Complexities in diagnosis and treatment of medullary thyroid cancer. Clinical observation

This article discusses the etiology of sporadic and hereditary forms of medullary thyroid cancer (MTC), diagnostic criteria that allow the most accurate and accurate diagnosis and differentiate it from similar symptoms, morphological changes in MTC, which is one of the least studied due to the peculiarities of its histogenetic genesis and low frequency of treatment of the population with this a problem. MTC is often diagnosed at the time of planned hospitalization of patients for problems in a related area, but not directly related to thyroid cancer. In this article, clinical manifestations presented in a specific clinical case are investigated, markers of immunohistochemical studies are determined. This case is interesting and unusual for the duration of the patient's treatment, as well as successful surgical interventions that were aimed at removing multiple metastases. To date, the number of referrals from patients with minimal structural and functional changes in the thyroid gland is small, which indicates that the disease is often diagnosed at a later date. In the minds of a certain percentage of the population, the idea of a possible self-healing of the body is firmly fixed, which is often decisive with the progression of the disease (especially with a sharp jump in progress, for example, after a general somatic decrease in the immune response after infectious diseases, hypothermia, radiation exposure). This article is indicative in this matter – it clearly demonstrates the need for timely vigilance and care for the body, timely medical examination of the population and attentive attitude in particular to the thyroid gland.

RATIONALE FOR THE APPLICATION OF CALCITONIN LEVEL IN THE EARLY POSTOPERATIVE PERIOD TO EVALUATE THE EFFECTIVENESS OF SURGICAL TREATMENT OF MEDULLARY THYROID CANCER.

To determine the effectiveness of the basal calcitonin (CTb) determination in the early postoperative period to predict the possible recurrence (persistence) of medullary thyroid cancer (MTC). A retrospective study of the treatment results in 194 patients with MTC (148 (76.3%) primary - group 1 and 46 (23.8%) recurrent - group 2) according to the levels of CTb in the first week after surgery and one year later. All groups were analyzed by staging, the level of preoperative and postoperative basal calcitonin 5 days and 1 year after the primary surgery. Among all patients, women prevailed - 144 (74.2%), the average age was (48.7±15.2), the average follow-up period was 67.5 months. Basal calcitonin was studied in patients of all groups in the preoperative and serially in the postoperative periods: 5 days and 1 year after the most radical surgical volumes. To test the hypothesis about the possibility of using CTb indicators in the early postoperative period, the degree of compliance with normal calcitonin indicators (≤18 pg/mL) was assessed by observation groups 5 days and 1 year after surgery. 1. The CTb value 5 days after surgery is no less a reliable marker of the result of surgical treatment of MTC than the currently recommended CTb measurement 2-3 months after surgery. 2. The technique is applicable for both primary and reoperations used for recurrent forms of medullary thyroid cancer.

Clinical case of familial medullary thyroid carcinoma

Medullary thyroid cancer (MTC) accounts for 5—10 % of all thyroid cancers. Most cases are sporadic (75 %), but the proportion of patients with MTC and familial medullary thyroid carcinoma (FMTC) is the highest among any hereditary cancer syndromes (appro­ximately 25 %), and this risk should be considered when evaluating a patient with MTC. In this clinical case study, case of FMTC has been elucidated. Diagnostic criteria of the disease, molecular-genetic aspects, treatment tactics and post-operative observation findings have been presented. The case study illustrates, the efficacy of genomic profiling for the identification of molecular genetic drivers of the disease and its role in ensuring proper and timely diagnosis and treatment of familial form of MTC. When planning prophylactic thyroidectomy, it is recommended to focus on the stratification of the level of RET gene mutation and the timing of prophylactic thyroidectomy as proposed by the American Thyroid Association. The use of molecular genetic investigations in clinical practice for diagnosing MTC makes it possible to objectify the genetic line of the disease in a particular biological family. The patient was found to have a pathogenic germline missense mutation c.2304 G> T (p.E768D, CM020961) in a heterozygous state, which refers to moderate risk of aggressiveness of MTC. In addition, molecular genetic test was performed for the patient's biological child, a 4-year-old girl. Pathogenic mutation was found in the CHEK2 gene, c.47OT> C (p.Ile 157 Thr) in a heterozygous state. These mutations increase the risk of developing breast cancer by 2-3 times, and by 4-5 times in the presence of family history of cancer. The presence of this mutation increases the risk of developing other types of cancers such as stomach, breast, intestinal, prostate and thyroid cancers. Timely diagnosis of FMTC allows to formulate adequate treatment strategy at the preclinical stage of the disease and can significantly improve the quality and duration of life.

Medullary Thyroid Cancer in Patients Older than 45-Epidemiologic Trends and Predictors of Survival.

Simple SummarySporadic medullary thyroid cancer can occur anytime in life although they tend to present at a later age (≥45 years old) when the tumors are more easily discernible or become symptomatic. We present, in this study, a group of patients diagnosed with medullary thyroid cancer at or after 45 years of age when they are more likely to develop sporadic forms of medullary thyroid cancer with regard to their natural history and prognosis. In this study, we evaluated factors affecting survival in such patients. We found that the incidence of medullary thyroid cancer in patients ≥45 years of age is increasing. Our findings suggest that patients should be offered surgical resection at an early stage to improve their outcomes.Sporadic medullary thyroid cancer (MTC) can occur anytime in life although they tend to present at a later age (≥45 years old) when the tumors are more easily discernible or become symptomatic. We aimed to identify the factors affecting the survival in patients ≥45 years of age diagnosed with MTC. We analyzed the Surveillance, Epidemiology, and End Results (SEER) registry from 1973–2016 focusing on patients ≥45 years of age with MTC as an isolated primary. A total of 2533 patients aged ≥45 years with MTC were identified. There has been a statistically significant increase of 1.19% per year in the incidence of MTC for this group of patients. The disease was more common in females and the Caucasian population. Most patients had localized disease on presentation (47.6%). Increasing age and advanced stage of presentation were associated with worse survival with HR 1.05 (p < 0.001) and HR 3.68 (p < 0.001), respectively. Female sex and surgical resection were associated with improved survival with HR 0.74 (p < 0.001) and 0.36 (p < 0.001), respectively. In conclusion, the incidence of MTC in patients ≥45 years of age is increasing. Patients should be offered surgical resection at an early stage to improve their outcomes.

CURRENT CAPABILITIES AND PROSPECTS OF CHEMORADIOTHERAPY FOR MEDULLARY THYROID CANCER (A LITERATURE REVIEW)

Medullary thyroid cancer (MTC) is characterized by the most aggressive course among differentiated thyroid carcinomas and is accompanied by early and extensive metastasis. Up to 60 % of patients with MTC already have disseminated forms of the disease (stage III– IV) by the moment of diagnosis. Overall five-year and ten-year survival of patients with MTC is 85–89 and 73–75 %, respectively, whereas five-year survival rate in patients with stage III–IV MTC is significantly lower and does not exceed 5–10 %. Therefore, treatment of disseminated forms of MTC is an extremely important problem in clinical oncology. The article gives an overview of Russian and foreign publications on the effectiveness of radiation and drug therapy for generalized MTC. Particular attention is paid to modern promising treatment strategies used for this category of patients, such as radionuclide therapy of bone metastases and targeted therapy with tyrosine kinase inhibitors.

Erratum to: PI3K/Akt/mTOR signaling in medullary thyroid cancer: a promising molecular target for cancer therapy.

The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is a central hub for the regulation of cell proliferation, apoptosis, cell cycle, metabolism, and angiogenesis. Several studies have recently suggested that the PI3K/Akt/mTOR signaling pathway is implicated in the pathogenesis and progression of neuroendocrine tumors. Medullary thyroid cancer (MTC) is a neuroendocrine tumor developing from the C cells of the thyroid. Mutations in the RET proto-oncogene are involved in the pathogenesis of several forms of MTC. The deregulation of the PI3K/Akt/mTOR pathway seems to contribute to the tumorigenic activity of RET proto-oncogene mutations. Targeting this pathway through specific inhibitors at simple or multiple sites may represent an attractive potential therapeutic approach for patients with advanced MTCs. The aim of this review is to examine the role of the PI3K/Akt/mTOR pathway in the development and progression of MTC and the new therapeutic options that target this signaling pathway.

Prophylactic thyroidectomy results among RET germline mutation bearers in families with hereditary forms of medullary thyroid cancer

Genetically caused medullary thyroid cancer (MTC) is associated with unfavorable survival prognosis, so it makes necessary to develop new diagnostic techniques to reveal pre-clinical stage of disease as well as to introduce into clinical practice the effective method of tumor prevention. The article represents first in Russia summary clinical experience of prophylactic thyroidectomy have been executed in the period 1998 – 2015 yeas among ten bearers of RET gene germlinemutation in families with hereditary disease including syndrome MEN2A and familial MTC. Aim : to evaluate the results of surgical treatment of asymptomatic carriers of germinal mutations in the RET gene. Materials and methods . In the period from 1998 to 2015, in two centers: N.N. Blokhin Russian Cancer Research Center, Moscow and A. Tsyb Medical Radiological Research Centre – branch of the National Medical Research Radiological Centre, Obninsk was conducted prophylactic surgical treatment in 10 patients – asymptomatic carriers of germinal mutations in RET. Age of patients – from 2 to 23 years old. 9 patients – from families with the syndrome of multiple endocrineneoplasia type 2A (MEN2A), one – with the family of MTC. According to genealogy in 9 families of patients there have been cases of death from MTC or pheochromocytoma (PC). In all cases, surgical treatment was performed in a volume of TE, two patients additionally performed lymph node dissection VI level. The observation period after surgery ranged from 6 months to 16 years. Results . DNA diagnostics in 8 patients identified a mutation in exon 11, in one case – in exon 10 and one patient had revealed two mutations in exons 13 and 14. The age of patients ranged from 2 to 23 years. Basal calcitonin level was elevated in 7 of 10 patients. Such prophylactic TE in 2 patients was supplemented by selective lymph node dissection. Histological examination of the removal of the thyroid gland (TG) revealed foci of medullary cancer in 6 of 10. At 2 patients revealed a C-cell hyperplasia and at 2 patients were found signs of the well expressed and weakly expressed sclerosis in thyroid tissue. The earliest age to identify MTC was a child 3 years old, mutations in codon 634, from a family where relatives observed for aggressive MTC. In the course of follow-recurrence was detected in one patient, a child of 15 years, a similar mutation carrier. Conclusion . In view of the risk of MTC developing identifying a mutation in RET gene and preventive TE should be carried out as soon as possible. The high risk of MTC developing in RET-gene positive subjects was confirmed in this study (6 cases of cancer from 10 patients).

PI3K/Akt/mTOR signaling in medullary thyroid cancer: a promising molecular target for cancer therapy.

The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is a central hub for the regulation of cell proliferation, apoptosis, cell cycle, metabolism, and angiogenesis. Several studies have recently suggested that the PI3K/Akt/mTOR signaling pathway is implicated in the pathogenesis and progression of neuroendocrine tumors. Medullary thyroid cancer (MTC) is a neuroendocrine tumor developing from the C cells of the thyroid. Mutations in the RET proto-oncogene are involved in the pathogenesis of several forms of MTC. The deregulation of the PI3K/Akt/mTOR pathway seems to contribute to the tumorigenic activity of RET proto-oncogene mutations. Targeting this pathway through specific inhibitors at simple or multiple sites may represent an attractive potential therapeutic approach for patients with advanced MTCs. The aim of this review is to examine the role of the PI3K/Akt/mTOR pathway in the development and progression of MTC and the new therapeutic options that target this signaling pathway.

RET Gene Abnormalities and Thyroid Disease: Who Should be Screened and When

Mutations in the RET proto-oncogene have been implicated in the pathogenesis of several forms of medullary thyroid cancer (MTC). Multiple endocrine neoplasia type 2 (MEN-2) is an autosomal dominant syndrome caused by germline activating mutations of the RET proto-oncogene and has been categorized into three distinct clinical forms. MEN-2A is associated with MTC, bilateral pheochromocytoma, and primary hyperparathyroidism. MEN-2B is associated with MTC, bilateral pheochromocytoma, and mucosal neuromas. The rarest clinical form of MEN-2 is familial MTC (FMTC), which is also associated with MTC, but other endocrinopathies are characteristically not present. Each clinical form of MEN-2 results from a specific RET gene mutation, with a strong correlation of phenotype expression with regard to the onset and course of MTC and the presence of other endocrine tumors and a corresponding genotype. Recommendations for screening of RET mutations are necessary as their presence or absence will influence interventional strategies such as the timing of a prophylactic thyroidectomy and extent of surgery. Timing of screenings and development of interventional strategies are extremely important in caring for patients with certain RET mutations as evidence of metastatic MTC has been documented as early as 6 years of age. Interventional strategies should consider the risks of complications of these interventions based on certain characteristics of each individual case such as age of the patient, course of disease in affected family members, and the invasiveness of any proposed surgical procedure. Conflict of interest:None declared.

Multiple TKIs approved in recent months

Evolution of TKIs Patients with CML and ALL Imatinib (Gleevec—Novartis) was approved more than a decade ago as a targeted leukemia therapy (i.e., Bcr-Abl TKI). Since that time, researchers have uncovered much information regarding its resistance mechanisms and potential ways to overcome resistance. Imatinib resistance reportedly occurs in approximately 33% of patients and can be subclassifi ed as Bcr-Abl–dependent or Bcr-Abl–independent. The BcrAbl–dependent mechanisms involve Bcr-Abl mutation and amplifi cation, resulting in an alteration of imatinib’s binding affi nity to the Bcr-Abl tyrosine kinase. One of the most frequently identifi ed mutations is T315l. Second-generation TKIs such as dasatinib (Sprycel—Bristol-Myers Squibb) and nilotinib (Tasigna—Novartis) are more potent than imatinib and can be used as fi rst-line agents for the management of chronic-phase CML as well as for imatinib-resistant or -intolerant patients. The new agent bosutinib is also classifi ed as a second-generation TKI. It targets the Bcr-Abl kinase and inhibits Scr-family kinases including Src, Lyn, and HcK. Pharmacologic data have shown that bosutinib inhibits 16 of 18 imatinib-resistant forms of Bcr-Abl kinases expressed in experiential cell lines. This agent, however, has no effect on T315I mutant cells. Ponatinib is classifi ed as a thirdgeneration TKI. The agent is unique in that it targets cells with a T315I mutation, which makes these cells resistant to all other currently approved TKIs. Medullary thyroid cancer Cabozantinib has a different indication and, therefore, targets another set of tyrosine kinases. It has been shown to inhibit proinvasive receptor tyrosine kinases implicated in tumor growth, metastasis, and angiogenesis, including RET, MET, and VEGFR-1, -2, and -3. Activating mutations in RET have been shown to play a central role in tumorigenesis in both inherited and sporadic forms of medullary thyroid cancer. MET and VEGF have also been implicated in the pathogenesis of this rare thyroid disease.

Medullary thyroid carcinoma: surgical treatment advances

In recent years new technologies have been proposed and applied in thyroid surgery, among these molecular diagnosis and endoscopic procedures. The authors review relevant medical literature published on the influence of these new techniques in the treatment of medullary thyroid cancer. Searches were last updated in October 2007. Mutations of the RET proto-oncogene have been demonstrated to be causative of the familial form of medullary thyroid cancer. The number and type of recognized RET genetic mutations have grown over the last years, especially after the introduction of genetic screening in the work-up of all patients with medullary thyroid cancer. Prophylactic surgery for patients carrying a positive RET proto-oncogene is highly effective. Cervical endoscopic procedures have been recently described and applied for positive RET carriers: a video-assisted thyroidectomy with central compartment dissection (level 6) has proved feasible, safe and effective for these patients. There have been some important papers in the recent literature that apply to many aspects of new technologies for medullary thyroid cancer treatment. This article discusses some of these articles, emphasizing where this literature makes new contributions and supports established recommendations.

Medullary thyroid carcinoma: surgical treatment advances

Since medullary thyroid cancer (MTC) was first recognized as a distinct tumor in 1959, it became clear that MTC is more difficult to cure than papillary thyroid cancer and has higher rates of recurrence and mortality. MTC represents 5–8% of thyroid cancers. It derives from parafollicular cells of the ultimobranchial body derived from the neural crest. MTC secretes calcitonin and other hormonal peptides and is considered part of the amine precursor uptake and decarboxilation system. MTC may occur either as a hereditary or nonhereditary entity. Hereditary MTC can occur either alone as the familial MTC or as the thyroid manifestation of multiple endocrine neoplasia (MEN) type 2 syndromes (MEN 2A MEN 2B). Activating point mutations of the RET proto-oncogene have demonstrated to be causative of the familial form of medullary thyroid cancer, both isolated familial MTC and associated with MEN 2A and 2B. In the last 10 years, major improvements and new technologies have been proposed and applied in thyroid surgery; among these are molecular diagnosis with genetic screening and mini-invasive video-assisted thyroidectomy. The history of thyroid surgery starts with Billroth, Kocher and Halsted, who developed the technique for thyroidectomy between 1873 and 1910. Prophylactic surgery for patients carrying a positive RET proto-oncogene has proven to be highly effective in curing those likely to experience the development of MTC. Video-assisted procedures with central compartment dissection have proved feasible for patients carrying a positive RET proto-oncogene. This paper reviews relevant medical literature published in the English language on surgery of MTC in well-controlled trials. We discuss the particular ethical and legal issues that thyroid prophylactic surgery raises. Searches were last updated in February 2007.

Identification of a Novel Point Mutation in the RET Gene (Ala883Thr), Which Is Associated with Medullary Thyroid Carcinoma Phenotype Only in Homozygous Condition

The RET protooncogene mutations responsible for multiple endocrine neoplasia type 2 are inherited as autosomic dominant traits. We describe here a novel germline homozygous mutation in exon 15 of the RET gene that determines an amino acid substitution (Ala->Thr) at codon 883. The index case was a 51-yr-old patient with an apparently sporadic form of medullary thyroid cancer (MTC). RET gene mutations screening was performed in exons 10, 11, 13, 14, 15, and 16 by automatic sequence analysis. An unexpected homozygous GCT->ACT point mutation was found at codon 883 in exon 15 and confirmed by restriction analysis (Alu I). The presence of the two chromosomes 10 was confirmed by fluorescence in situ hybridization analysis on lymphocytes. As expected on the basis of the homozygosity of the index case, the parents were consanguineous (second-degree cousins). Eight relatives were further investigated: the mother, two sisters, and the son were positive for heterozygous RET mutation. The mother (82 yr old) showed a nodular goiter but was negative both for basal and pentagastrin stimulated calcitonin. The young son (15 yr old) and the two sisters (63 and 58 yr old) did not show any clinical and/or biochemical sign of MTC. One brother (59 yr old) was negative both for RET mutation and clinical/biochemical examination. The other brother, 56 yr of age, was positive for both homozygous RET mutation and serum calcitonin. When operated, the histological examination of the thyroid showed the presence of MTC and C cell hyperplasia. In conclusion, we identified a new germline RET gene mutation during a routine RET gene screening of an apparently sporadic MTC case. This mutation showed a very low transforming activity as demonstrated by the absence of MTC phenotype in heterozygous subjects. The possibility that the homozygous gene carriers were indeed carrying a germline loss of heterozygosity was excluded by fluorescence in situ hybridization analysis for RET gene performed on lymphocytes derived from one homozygous patient. The analysis of several RET polymorphisms also confirmed the presence of two mutated alleles in MTC affected patients and both mutated and wild-type allele in heterozygous subjects.

Video assisted prophylactic thyroidectomy and central compartment nodes clearance in two RET gene mutation adult carriers

Activating point mutations of RET gene have been demonstrated to be causative of the familial form of medullary thyroid cancer (MTC), both isolated (FMTC) and associated to other endocrine neoplasia [multiple endocrine neoplasia (MEN) 2A and 2B]. In RET gene mutation carriers, who are prone to developing MTC, prophylactic thyroidectomy is recommended to obtain their definitive cure. The simultaneous excision of the central node compartment is mandatory when the stimulation pentagastrin test for serum calcitonin is positive. Although the minimally invasive video assisted thyroidectomy (MIVAT) is nowadays currently adopted in many centers, it has never been employed for the prophylactic thyroidectomy of RET gene mutation carriers. The fear of obtaining an incomplete lymphadenectomy of the central compartment was the main reason for this reluctance. Since RET gene mutation carriers have often normal thyroid volume and, if involved, small lymph nodes, they indeed represent the best candidates to this approach especially when considering that they are usually young and concerned about the cosmetic results and the period of hospitalization. The excellent results obtained by MIVAT in the last few years induced us to propose this procedure together with a central compartment lymphadenectomy to 2 RET gene mutation carriers recently found by genetic screening. As assessed by a negative pentagastrin stimulation test performed after 6 months from the MIVAT, they were definitively cured without any surgical complication with the exception of a transient hypoparathyroidism. They showed a great satisfaction for both the cosmetic results and the very short period of hospitalization, thus supporting the idea that MIVAT can be used in association with the central node dissection for the prophylactic treatment of RET mutation gene carriers whose thyroid volume is still normal.