Medullary Thyroid Carcinoma Research Articles

Molecular Mechanisms of Melatonin for Treating Medullary Thyroid Cancer Using in silico Analysis

Molecular Mechanisms of Melatonin for Treating Medullary Thyroid Cancer Using in silico Analysis

MO4-5 Efficacy of selpercatinib as tyrosine kinase inhibitor in RET-mutant medullary thyroid cancer: a systematic review

MO4-5 Efficacy of selpercatinib as tyrosine kinase inhibitor in RET-mutant medullary thyroid cancer: a systematic review

Second-look ultrasound with positron emission tomography (PET) for evaluating recurrent lesions of medullary thyroid cancer: a case description.

Second-look ultrasound with positron emission tomography (PET) for evaluating recurrent lesions of medullary thyroid cancer: a case description.

Translating the desmoplastic microenvironment of medullary thyroid cancer into surgical practice.

The tumor microenvironment often induces a scarring process known as tumor fibrosis or desmoplasia, which plays an important role in the initiation, progression, and clinical outcome of many types of cancer. This report aimed to highlight recent progress made in the field of de-escalation surgery for sporadic medullary thyroid cancer (MTC), building a bridge from basic science to current and emerging medical practice. This narrative review entails a holistic description and interpretation of the English-language literature on MTC desmoplasia. Absence of primary tumor desmoplasia on intraoperative frozen section and definitive histopathology goes hand in hand with absence of node metastases in up to one-third of patients with sporadic MTC. Patients with desmoplasia-negative MTC require no more than hemithyroidectomy for cure. Thyroid desmoplasia is a powerful predictive tissue biomarker for the intraoperative management of patients with sporadic MTC, outpacing conventional tumor classification systems that depend on definitive histopathology.

Tight Junctions and Cancer: Targeting Claudin-1 and Claudin-4 in Thyroid Pathologies.

Purpose: Claudins are tight junction proteins partaking in epithelial-mesenchymal transition and cancer progression. In this study, we investigated the expression patterns of claudin-1 and claudin-4 in thyroid pathologies, discussed their links with the pathogenesis of thyroid cancers, and reviewed the therapeutic potential of targeting claudins in cancers. Methods: The research group 162 cores of thyroid samples from patients (70 female and 11 male) diagnosed with thyroid adenoma, goiter, papillary, medullary, and anaplastic thyroid cancers. All samples were stained for the expression of claudin-1 and claudin-4, and the analysis of IHC was performed. Results: Goiter samples showed negative claudin-1 and mostly positive expression of claudin-4. Papillary thyroid cancer and thyroid adenoma showed positive expression of claudin-1, while claudin-4 was positive in papillary thyroid cancers, goiters, and adenomas. In The Cancer Genome Atlas cohort, claudin-1 and claudin-4 were overexpressed in papillary thyroid cancer compared to normal thyroid tissues. Patients with high claudin-1 expression had significantly lower 5-year overall survival than patients with low claudin-1 levels (86.75% vs. 98.65, respectively). In multivariate analysis, high claudin-1 expression (HR 7.91, CI 95% 1.79-35, p = 0.006) and advanced clinical stage remained statistically significant prognostic factors of poor prognosis in papillary thyroid cancer. Conclusions: The pattern of claudin-1 staining was pathology-specific and changed between cancers of different histology. This phenomenon may be associated with the different pathogenesis of thyroid cancers and early metastasis. The loss of claudin-1 and claudin-4 characterized more aggressive cancers. Several studies have shown the benefits of targeting claudins in cancers, but their implementation into clinical practice requires further trials.

Lymph Node ACTH Washout: New Assistant Method for Localizing the Source of Ectopic ACTH Secretion in a Case of Metastatic Medullary Thyroid Carcinoma

Lymph Node ACTH Washout: New Assistant Method for Localizing the Source of Ectopic ACTH Secretion in a Case of Metastatic Medullary Thyroid Carcinoma

The Value of Pretherapeutic Basal Calcitonin Cut-Offs for the Therapeutic Strategy and Prediction of Long-Term Outcome of Patients with Medullary Thyroid Cancer—A 30-Year Single-Center Experience

Background: The clinical relevance of clearly defined pretherapeutic basal calcitonin (bCt) cut-offs for predicting lymph node metastases (LNMs) and long-term outcomes (LOs) has so far not been tested in a large cohort of patients with medullary thyroid cancer included in a Ct screening program during the initial diagnostic workup of thyroid nodules. Material and Methods: Female (f) patients with a bCt level of ≤23 pg/mL and male (m) patients with a level of ≤43 pg/mL were assigned to Group 1 (minimal oncologic risk), patients with a bCt between 24 and 84 pg/mL (f) and 44–99 pg/mL (m) to Group 2 (low oncologic risk), and those with a bCt of ≥85 pg/mL (f) and ≥100 pg/mL (m) to Group 3 (high oncologic risk). All patients underwent surgery applying a uniform surgical protocol. The median follow-up was 100 months. Results: The study included 306 patients. In 3/115 (2.6%) patients in Group 1 and in 3/50 (6.0%) in Group 2, LNM in the central but not lateral neck and no distant metastases (DMet) were documented. In both groups, the biochemical long-term cure rate was 95.7% and the disease-specific-survival (DSS) rate was 100% at 10, 15 and 20 years. Lateral LNM and DMet were diagnosed only in Group 3. The bCt levels of N0 and N1 patients showed broadly overlapping ranges, thus impeding the differentiation between those patients through bCt. Both the cure rate and DSS were significantly worse in Group 3. The overall biochemical long-term cure rate was 78.2%. Conclusions: Within a Ct screening program, grouping patients upon pretherapeutic bCt provides a simple risk classification system for indicating surgery, predicting LN involvement, and LOs.

Clinical observation of a patient with multiple endocrine neoplasia syndrome type 2a

The article is devoted to the clinical observation of a patient with multiple endocrine neoplasia syndrome 2A, characterized by a combination of pheochromocytoma, medullary thyroid cancer and hyperplasia of the parathyroid glands. The features of diagnostics of this disease, preoperative preparation, as well as principles of observation for several years after surgical treatment are described. In addition, data on the features of diagnostic search and tactics of management of family members with this syndrome are provided.

Detection of SEZ6, a therapeutic target, in medullary thyroid carcinoma.

Seizure-related 6 homolog (SEZ6) is a cDNA that strongly associated with neuroendocrine differentiation. Recently, SEZ6 expression was found in a subset of small cell lung carcinoma (SCLC). Furthermore, ABBV-011, a novel antibody drug conjugate targeting SEZ6 has been developed and is currently in clinical trial in treating SCLC and neuroendocrine neoplasms, including medullary thyroid carcinoma (MTC). We herein presented the first evidence that SEZ6 was highly expressed in MTC. SEZ6 immunoexpression was studied in 78 MTCs and correlated with clinicopathologic characteristics, outcome, and molecular profile. SEZ6 was highly expressed in primary tumors, regional recurrence, and distant metastasis. Using two different SEZ6 antibody clones SC17.14 and 14E5, SEZ6 immunopositivity was seen in 91% to 93% of primary MTCs, 100% of regional recurrence, and 75% to 83% of distant metastasis. High level of SEZ6 immunoexpression determined using H score was associated with male sex, advance stage, and extrathyroidal thyroidal extension. There was no correlation between SEZ6 expression and outcome or RET/RAS mutation status in MTC. The frequency of SEZ6 positivity in MTC without RET/RAS mutations were 83%. SEZ6 may serve as a novel biomarker for MTCs. Although SEZ6 lacks any prognostic values in MTC, its positivity in 91% to 93% of MTCs, including MTCs without RET and RAS mutations, renders SEZ6-targetted antibody-drug conjugate therapy a promising targeted therapy for MTCs.

Development and validation of a prognostic nomogram for predicting liver metastasis in thyroid cancer: a study based on the surveillance, epidemiology, and end results database

This study aimed to create a prognostic nomogram to predict the risk of liver metastasis (LM) in thyroid cancer (TC) patients and assess survival outcomes for those with LM. Data were collected from the SEER database, covering TC patients from 2010 to 2020, totaling 110,039 individuals, including 142 with LM. Logistic regression and stepwise regression based on the Akaike information criterion (AIC) identified significant factors influencing LM occurrence: age, histological type, tumor size, bone metastasis, lung metastasis, and T stage (p < 0.05). A nomogram was constructed using these factors, achieving a Cindex of 0.977, with ROC curve analysis showing an area under the curve (AUC) of 0.977. For patients with TCLM, follicular TC, medullary TC, papillary TC, and examined regional nodes were associated with better prognosis (p < 0.001, HR < 1), while concurrent brain metastasis indicated poorer outcomes (HR = 2.747, p = 0.037). In conclusion, this nomogram effectively predicts LM risk and evaluates prognosis for TCLM patients, aiding clinicians in personalized treatment decisions

Exploring Multiple Endocrine Neoplasia Type 2B: Key Findings from a Case Report

Multiple endocrine neoplasia type 2B (MEN 2B) is an autosomal dominant syndrome primarily caused by the germline M918T RET mutation. It is characterized by medullary thyroid carcinoma (MTC), pheochromocytoma (PC), and non-endocrine features. Symptoms depend on the glandular elements present. The initial diagnosis of MEN 2B is relatively late, and the diagnosis by non-endocrine components is extremely weak. The initial management consists of a total thyroidectomy with dissection of the lymph nodes. If PC is present, its treatment is surgical removal, which should be performed before thyroidectomy for MTC. The prognosis of MTC in MEN 2B depends on the stage at diagnosis, and only early diagnosis and intervention offer a chance of cure. It is necessary to underline the need to treat the extra-endocrine signs in these patients. We present below a case of MEN 2B who consulted late for a cervical tumor and morphological abnormalities of the lips and tongue.

A rare case of chronic diarrhoea: medullary carcinoma of the thyroid

A rare case of chronic diarrhoea: medullary carcinoma of the thyroid

Dihydroartemisinin Inhibits Epithelial-Mesenchymal Transition Progression in Medullary Thyroid Carcinoma Through the Hippo Signaling Pathway Regulated by Interleukin-6.

Dihydroartemisinin (DHA), an artemisinin derivative, can influence certain malignancies' inflammatory response and growth. This study used Cell Counting Kit-8 and Transwell assays to show that DHA suppressed the growth, migration, and invasion of medullary thyroid cancer cells. Furthermore, the authors used enzyme-linked immunosorbent assay, Western blotting, and immunofluorescence to confirm the expression of the transcriptional coactivators Yes-associated protein (YAP)/transcriptional coactivator with a PDZ-binding domain (TAZ) downstream of the Hippo pathway and changes in the expression of the epithelial-mesenchymal transition (EMT) process markers E-cadherin and N-cadherin. These results demonstrate that DHA effectively reduced the expression of interleukin (IL)-6 in medullary thyroid carcinoma (MTC) cells and hindered the EMT process by regulating the Hippo pathway. This regulation was achieved by promoting YAP phosphorylation and inhibiting YAP/TAZ protein expression. Additional activation of the Hippo pathway by GA-017 alleviated the inhibitory effect of DHA on IL-6. Hippo pathway activation led to an increase in the expression of E-cadherin, a marker of EMT. In conclusion, DHA was demonstrated to regulate the Hippo pathway by inhibiting IL-6 secretion, leading to the inhibition of EMT in MTC. These findings provide a theoretical foundation for further exploration of the anticancer mechanisms of DHA and offer valuable insights into its potential clinical application as a combinatorial drug.

Targeting the p90RSK/MDM2/p53 Pathway Is Effective in Blocking Tumors with Oncogenic Up-Regulation of the MAPK Pathway Such as Melanoma and Lung Cancer

In most human tumors, the MAPK pathway is constitutively activated. Since p90RSK is downstream of MAPK, it is often hyperactive and capable of phosphorylating oncogenic substrates. We have previously shown that p90RSK phosphorylates MDM2 at S166, promoting p53 degradation in follicular thyroid carcinomas. Thus, the inhibition of p90RSK restores p53 expression, which in turn inhibits cell proliferation and promotes apoptosis. In the present study, we demonstrated that the p90RSK/MDM2/p53 pathway proved to be an excellent target in the therapy of tumors with MAPK hyperactivation. For this purpose, we selected p53wt melanoma, lung and medullary thyroid carcinoma cell lines with high activation of p90RSK. In these cell lines, we demonstrated that the p90RSK/MDM2/p53 pathway is implicated in the regulation of the cell cycle and apoptosis through p53-dependent transcriptional control of p21 and Bcl-2. Furthermore, with an immunohistochemical evaluation of primary melanomas and lung tumors, which exhibit highly activated p90RSK compared to corresponding normal tissue, we demonstrated that MDM2 stabilization was associated with p90RSK phosphorylation. The results indicate that p90RSK is able to control the proliferative rate and induction of apoptosis through the regulation of p53wt levels by stabilizing MDM2 in selected tumors with constitutively activated MAPKs, making p90RSK a new attractive target for anticancer therapy.

Survival in medullary thyroid carcinoma patients who fail to achieve a biochemical cure: implications of postoperative 1-month calcitonin levels and targeted therapy

PurposeThe survival rate of patients with medullary thyroid carcinoma (MTC) who fail to achieve a biochemical cure after surgery is reduced. This study aimed to investigate the prognostic factors affecting the survival of MTC patients who do not achieve a biochemical cure after surgery.MethodsCox univariate and multivariate proportional hazard models were used to determine the influence of different variables on overall survival (OS). Pearson’s chi-square test was used for categorical variables, and paired t-test was used for continuous variables.ResultsIn our study of 277 MTC patients treated between 2012 and 2022, there were 96 with raised postoperative 1-month calcitonin (Ct) levels (0–9.52 pg/ml). The overall survival (OS) rates of patients with high postoperative 1-month Ct values at 1, 3, and 5 years were 97.9%, 94.6%, and 86.8%, respectively. The univariate analysis revealed that patients with a postoperative 1-month Ct > 441.9 pg/ml had a greater risk of mortality than patients with postoperative 1-month Ct values ranging from 9.52 to 73.4 pg/ml (p = 0.043). Subsequent analyses revealed that receiving targeted therapy did not improve the OS of patients with distant metastasis among those with high postoperative 1-month Ct values (p = 0.527).ConclusionThis study confirmed that MTC patients who did not achieve biochemical remission after surgery had an increased risk of death when the Ct level was > 441.9 pg/ml 1 month after surgery. Additionally, for MTC patients who have not achieved biochemical remission and have experienced disease progression or distant metastasis after surgery, the use of targeted therapy does not prolong survival.

Thyroid Malignancy and Cutaneous Lichen Amyloidosis: Key Points Amid RET Pathogenic Variants in Medullary Thyroid Cancer/Multiple Endocrine Neoplasia Type 2 (MEN2).

We aimed to provide an updated narrative review with respect to the RET pathogenic variants and their implications at the clinical and molecular level in the diagnosis of medullary thyroid cancer (MTC)/multiple endocrine neoplasia (MEN) type 2, particularly with respect to the presence of cutaneous lichen amyloidosis (CLA). We searched English-language, in extenso original articles with no timeline nor study design restriction that were published on PubMed. A traditional interplay stands for CLA and MTC in MEN2 (not MEN3) confirmation. While the connection has been reported for more than three decades, there is still a large gap in understanding and addressing it. The majority of patients with MEN2A-CLA have RET pathogenic variants at codon 634; hence, it suggests an involvement of this specific cysteine residue in both disorders (most data agree that one-third of C634-positive subjects have CLA, but the ranges are between 9% and 50%). Females seem more prone to MEN2-CLA than males. Non-C634 germline RET pathogenic variants included (at a low level of statistical evidence) the following: RET V804M mutation in exon 14 for MTC-CLA (CLA at upper back); RET S891A mutation in exon 15 binding OSMR variant G513D (familial MTC and CLA comprising the lower legs to thighs, upper back, shoulders, arms, and forearms); and C611Y (CLA at interscapular region), respectively. Typically, CLA is detected at an early age (from childhood until young adulthood) before the actual MTC identification unless RET screening protocols are already applied. The time frame between CLA diagnosis and the identification of RET pathogenic variants was between 5 and 60 years according to one study. The same RET mutation in one family is not necessarily associated with the same CLA presentation. In MTC/MEN2 subjects, the most affected CLA area was the scapular region of the upper back. Alternatively, another hypothesis highlighted the fact that CLA is secondary to long-term prurit/notalgia paresthetica (NP) in MTC/MEN2. OSMR p. G513D may play a role in modifying the evolutionary processes of CLA in subjects co-harboring RET mutations (further studies are necessary to sustain this aspect). Awareness in CLA-positive patients is essential, including the decision of RET testing in selected cases.

NTRK Fusion as an Acquired Mechanism of Resistance to Selpercatinib in RET Positive Thyroid Cancer

Background: Rearrangement during Transfection (RET) proto-oncogene is involved in the pathogenesis of various thyroid cancer subtypes and drugs that block the RET tyrosine kinase pathways are used in the management of locally advanced and metastatic Medullary Thyroid Cancer (MTC). Acquired resistance to RET inhibitors likely occurs via two different mechanisms: (1) On-target mutations that prevent drug binding and (2) Activated alternative mechanisms which bypass the targeted kinase. We present a unique mechanism of selpercatinib resistance via secondary NTRK fusion mutation in a case of RET altered medullary thyroid cancer. Case Presentation: The patient is a 72-year-old female with stage III metastatic MTC who developed recurrence with newly found RET mutation 7 years after complete surgical resection. Despite initial stable response with selpercatinib for 2 years she rapidly progressed with widespread disease. Cell-free DNA (cfDNA) testing done at the time of progression revealed an NTRK1 fusion. Unfortunately, the patient succumbed to the disease despite starting targeted therapy with larotrectinib. Conclusion: This case highlights the importance of further investigation into mechanisms of resistance to RET inhibitors and drug studies directed towards overcoming them

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.

Real-world data analysis of next-generation sequencing and corresponding clinical characteristics in thyroid tumor.

Next-generation sequencing (NGS) is of great benefit to clinical practice in terms of identifying genetic alterations. This study aims to clarify the gene background and its influence on thyroid tumors in the Chinese population. NGS data and corresponding clinicopathological features (sex, age, tumor size, extrathyroidal invasion, metastasis, multifocality, and TNM stage) were collected and analyzed retrospectively from 2844 individual thyroid tumor samples from July 2021 to August 2022. Among the cohort, 2337 (82%) cases possess genetic alterations, including BRAF (71%), RAS (4%), RET/PTC (4%), TERT (3%), RET (2.2%), and TP53 (1.4%). Diagnostic sensitivity before surgery can be significantly increased from 0.76 to 0.91 when cytology is supplemented by NGS. Our results show that BRAF-positive papillary thyroid cancer (PTC) patients tend to have older age, smaller tumor size, less vascular invasion, more frequent tumor multifocality, and a significantly higher cervical lymph node metastatic rate. Mutation at RET gene codons 918 and 634 is strongly correlated with medullary thyroid cancer. However, it did not display more invasive clinical characteristics. TERT-positive patients are more likely to have older age, and have larger tumor size, more tumor invasiveness, and more advanced TNM stage, indicating a poor prognosis. Patients with TERT, RET/PTC1, and CHEK2 mutations are more susceptible to lateral lymph node metastasis. In conclusion, NGS can be a useful tool that provides practical gene evidence in the process of diagnosis and treatment in thyroid tumors.

Les cancers thyroïdiens : diagnostic et suivi

AbstractThyroid cancers are often diagnosed during the exploration of a thyroid nodule. They are developed at the expense of follicular cells mainly differentiated of papillary or vesicular types and associated with a good prognosis, more rarely of oncocytic type and exceptionally of anaplastic type, associated with a poor prognosis. Medullary thyroid carcinomas are developed at the expense of C cells and are part of a MEN 2, associated with a proto-oncogene RET mutation in 25% of cases. Thyroid function is generally conserved. Diagnosis is based on ultrasound, which will characterize the thyroid nodule(s) and the cervical adenopathies to be punctured. The cyto-histological examination establishes the definitive diagnosis and the classification of the tumor determining the management and follow-up. A total or partial thyroidectomy is performed, possibly associated with lymph node removal. Hypothyroidism is quasi-systematic after surgery requiring a supplementation by L-thyroxine. In thyroid differentiated carcinomas, a high L-thyroxine dosage to suppress TSH and an adjuvant iratherapy (1131) are recommended in the forms with high risk of recurrence. Biological follow-up relies on serum thyroglobulin, indetectable in the absence of relapse. In the case of medullary carcinoma, biological follow-up relies on serum calcitonin, indetectable in the absence of persistence or recurrence and carcinoembryonic antigen (CEA). The search for a RET mutation is always recommended.