Caratteristiche clinico molecolari dei carcinomi tiroidei differenziati ad alto rischio

Background: Differentiated thyroid carcinoma (DTC) is the most common endocrine malignancy, and its incidence is rapidly increasing. Its prognosis is usually excellent, but some patients exhibit an aggressive tumor with poor clinical outcome. The clinical-molecular features that confer an aggressive phenotype in DTC are object of various studies, being the clinical significance of some of them still uncertain. A greater knowledge of clinical, pathological and molecular features of DTC might improve the diagnostic frame and lead to an individualized therapy. The objectives of the study: 1) clinical characterization of high-risk DTC cases; 2) molecular characterization with reference on the study of BRAF, RAS, TP53, PTEN and PIK3CA genes and TERT promoter; 3) correlation between clinical and molecular features; 4) comparison of clinical-molecular profile between high- and low risk DTC. Materials and methods: We studied 119 high-risk patients (max dimension >40mm and/or metastatic) who underwent surgery for diagnosis of DTC between 2007 and 2016. Clinical-molecular features of these patients were compared with those of 144 adult patients, consecutive for molecular study, who underwent surgery for diagnosis of DTC between 2007 and 2010. Results: subjects with metastatic tumor or both metastatic and tumor size larger than 40mm had worse outcome than subjects with tumor larger than 40mm: during the follow-up they had a persistent disease or were dead in 62% and 79% of cases respect to 13% of the latter (p<0,01), they were also more likely to undergo a second treatment (67% and 86% respect to 8%, p<0,01) and had a reduced Disease-Free Survival (DFS) (p<0,01). Among patients with high-risk tumors, we detected BRAF mutations in 26% of cases, RAS mutations in 10% of cases, TERT promoter mutations in 18% of cases, TP53 mutations in 1% of cases, PTEN mutations in 2% of cases, PIK3CA in 3% of cases. No link was found between these mutations and outcome, except for TERT promoter mutations that were linked to a more severe disease. Metastatic subjects had a higher prealence of TERT promoter mutations than subjects with larger size tumors (27% vs 11%, p<0,01). Patients with high-risk cancer had worse clinical-pathological features than low-risk patients, except for the rate of multifocal disease. Regarding the outcome, high-risk patients had poorer clinical outcome, were more likely to have second treatment and had reduced DFS. BRAF gene mutations were more often found in low-risk carcinomas respect to the high-risk ones (61% vs 26%, p40mm, so that TERT mutations (18% vs 3%, p<0,01), particularly among metastatic subjects. Globally, TERT promoter mutations, even in association with other molecular events, are related to older age (67 years vs 47 years, p<0,01), larger tumor size (43mm vs 17mm, p<0,01), tumor extension (T4: 11% vs 4%, p<0,01), distant metastases (56% vs 18%, p<0,01), advanced stage (stage IV: 41% vs 11%, p<0,01), need for a second treatment (27% vs 17%, p<0,01) and worse outcome (persistence/death 69% vs 18%, p<0,01). With the multivariate analysis, TERT mutations, lymph node involvement and distant metastatis resulted independent risk factors for predicting a persistent disease. Conclusions: patients with high-risk tumors, particularly metastatic ones, had a worse outcome. The prognostic value of sex, age, tumor size, multifocality, T, N, M and stage was confirmed; TERT mutations, lymph node involvement and distant metastases were found to be independent risk factors for predicting a persistent disease. Patients carrying TERT promoter mutations were found to have a poorer prognosis: they have aggressive carcinomas and worse clinical outcome. No link was found between BRAF, RAS, TP53, PTEN and PIK3CA gene mutations and the clinical-pathological features analyzed

Prognostic Impact of miR-224 and RAS Mutations in Medullary Thyroid Carcinoma

Little is known about the function of microRNA-224 (miR-224) in medullary thyroid cancer (MTC). This study investigated the role of miR-224 expression in MTC and correlated it with mutation status in sporadic MTCs. A consecutive series of 134 MTCs were considered. Patients had a sporadic form in 80% of cases (107/134). In this group, REarranged during transfection (RET) and rat sarcoma (RAS) mutation status were assessed by direct sequencing in the tumor tissues. Quantitative real-time polymerase chain reaction was used to quantify mature hsa-miR-224 in tumor tissue. RAS (10/107 cases, 9%) and RET (39/107 cases, 36%) mutations were mutually exclusive in sporadic cases. miR-224 expression was significantly downregulated in patients with the following: high calcitonin levels at diagnosis (p=0.03, r=−0.3); advanced stage (p=0.001); persistent disease (p=0.001); progressive disease (p=0.002); and disease-related death (p=0.0001). We found a significant positive correlation between miR-224 expression and somatic RAS mutations (p=0.007). Patients whose MTCs had a low miR-224 expression tended to have a shorter overall survival (log-rank test p=0.005). On multivariate analysis, miR-224 represented an independent prognostic marker. Our data indicate that miR-224 is upregulated in RAS-mutated MTCs and in patients with a better prognosis and could represent an independent prognostic marker in MTC patients

Frequency and significance of Ras, Tert promoter, and Braf mutations in cytologically indeterminate thyroid nodules: A monocentric case series at a tertiary-level Endocrinology unit

PurposeThe management of thyroid nodules of indeterminate cytology is controversial. Our study aimed to establish the frequency and significance of H-,K-,N-RAS, TERT promoter, and BRAF gene mutations in thyroid nodes of indeterminate cytology and to assess their potential usefulness in clinical practice.MethodsH-,K-,N-RAS, TERT promoter and BRAF gene mutations were examined in a series of 199 consecutive nodes of indeterminate cytology referred for surgical excision.Results69/199 (35%) were malignant on histopathological review. RAS mutations were detected in 36/199 (18%), and 19/36 cases (53%) were malignant on histological diagnosis. TERT promoter mutations were detected in 7/199 (4%) nodules, which were all malignant lesions. BRAF mutations were detected in 15/199 (8%), and a BRAF K601E mutation was identified in 2 follicular adenomas and 1 noninvasive follicular thyroid neoplasm with papillary-like nuclear features. Altogether, this panel was able to identify 48% of the malignant lesions, achieving a specificity, positive predictive value, and negative predictive value for malignancy of 85, 62, and 75%, respectively.ConclusionThe residual malignancy risk in mutation-negative nodes is 25%. These nodes still need to be resected, but mutation analysis could help to orient the appropriate surgical strategy

A constitutive active MAPK/ERK pathway due to BRAFV600E positively regulates AHR pathway in PTC

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor mediating the toxicity and tumor-promoting properties of dioxin. AHR has been reported to be overexpressed and constitutively active in a variety of solid tumors, but few data are currently available concerning its role in thyroid cancer. In this study we quantitatively explored a series of 51 paired-normal and papillary thyroid carcinoma (PTC) tissues for AHR-related genes. We identified an increased AHR expression/activity in PTC, independently from its nuclear dimerization partner and repressor but strictly related to a constitutive active MAPK/ERK pathway. The AHR up-regulation followed by an increased expression of AHR target genes was confirmed by a meta-analysis of published microarray data, suggesting a ligand-independent active AHR pathway in PTC. In-vitro studies using a PTC-derived cell line (BCPAP) and HEK293 cells showed that BRAF(V600E) may directly modulate AHR localization, induce AHR expression and activity in an exogenous ligand-independent manner. The AHR pathway might represent a potential novel therapeutic target for PTC in the clinical practice

PROGNOSTIC SIGNIFICANCE OF TERT PROMOTER AND BRAF MUTATIONS IN TIR-4 AND TIR-5 THYROID CYTOLOGY

Objective: Follicular-derived thyroid cancers generally have a good prognosis, but in a minority of cases, they have an aggressive behavior and develop distant metastases, with an increase in the associated mortality. None of the prognostic markers currently available prior to surgery can identify such cases. Methods: TERT promoter and BRAF gene mutations were examined in a series of 436 consecutive TIR-4 and TIR-5 nodes referred for surgery. Follow-up (median: 59 months, range: 7-293 months) was available for 384/423 patients with malignant nodes. Results: TERT promoter and BRAF mutations were detected in 20/436 (4.6%) and 257/434 thyroid nodules (59.2%), respectively. At the end of the follow-up, 318/384 patients (82.8%) had an excellent outcome, 48/384 (12.5%) had indeterminate response or biochemical persistence, 18/384 (4.7%) had a structural persistence or died from thyroid cancer. TERT promoter mutations correlated with older age (P < 0.0001), larger tumor size (P = 0.0002), oxyntic and aggressive PTC variants (P = 0.01), higher tumor stages (P < 0.0001), distant metastases (<0.0001) and disease outcome (P < 0.0001). At multivariate analysis, TERT promoter mutation was not an independent predictor of disease outcome. TERT promoter mutation- (OR: 40.58; 95% CI: 3.06-539.04), and N1b lymph node metastases (OR: 40.16, 95% CI: 3.48-463.04) were independent predictors of distant metastases. BRAF mutation did not predict the outcome, and it correlated with a lower incidence of distant metastases (P = 0.0201). Conclusions: TERT promoter mutation proved an independent predictor of distant metastases, giving clinicians the chance to identify many of the patients who warranted more aggressive initial treatment and closer follow-up

Caratteristiche clinico molecolari dei carcinomi tiroidei differenziati ad alto rischio

Background: Differentiated thyroid carcinoma (DTC) is the most common endocrine malignancy, and its incidence is rapidly increasing. Its prognosis is usually excellent, but some patients exhibit an aggressive tumor with poor clinical outcome. The clinical-molecular features that confer an aggressive phenotype in DTC are object of various studies, being the clinical significance of some of them still uncertain. A greater knowledge of clinical, pathological and molecular features of DTC might improve the diagnostic frame and lead to an individualized therapy. The objectives of the study: 1) clinical characterization of high-risk DTC cases; 2) molecular characterization with reference on the study of BRAF, RAS, TP53, PTEN and PIK3CA genes and TERT promoter; 3) correlation between clinical and molecular features; 4) comparison of clinical-molecular profile between high- and low risk DTC. Materials and methods: We studied 119 high-risk patients (max dimension >40mm and/or metastatic) who underwent surgery for diagnosis of DTC between 2007 and 2016. Clinical-molecular features of these patients were compared with those of 144 adult patients, consecutive for molecular study, who underwent surgery for diagnosis of DTC between 2007 and 2010. Results: subjects with metastatic tumor or both metastatic and tumor size larger than 40mm had worse outcome than subjects with tumor larger than 40mm: during the follow-up they had a persistent disease or were dead in 62% and 79% of cases respect to 13% of the latter (p<0,01), they were also more likely to undergo a second treatment (67% and 86% respect to 8%, p<0,01) and had a reduced Disease-Free Survival (DFS) (p<0,01). Among patients with high-risk tumors, we detected BRAF mutations in 26% of cases, RAS mutations in 10% of cases, TERT promoter mutations in 18% of cases, TP53 mutations in 1% of cases, PTEN mutations in 2% of cases, PIK3CA in 3% of cases. No link was found between these mutations and outcome, except for TERT promoter mutations that were linked to a more severe disease. Metastatic subjects had a higher prealence of TERT promoter mutations than subjects with larger size tumors (27% vs 11%, p<0,01). Patients with high-risk cancer had worse clinical-pathological features than low-risk patients, except for the rate of multifocal disease. Regarding the outcome, high-risk patients had poorer clinical outcome, were more likely to have second treatment and had reduced DFS. BRAF gene mutations were more often found in low-risk carcinomas respect to the high-risk ones (61% vs 26%, p40mm, so that TERT mutations (18% vs 3%, p<0,01), particularly among metastatic subjects. Globally, TERT promoter mutations, even in association with other molecular events, are related to older age (67 years vs 47 years, p<0,01), larger tumor size (43mm vs 17mm, p<0,01), tumor extension (T4: 11% vs 4%, p<0,01), distant metastases (56% vs 18%, p<0,01), advanced stage (stage IV: 41% vs 11%, p<0,01), need for a second treatment (27% vs 17%, p<0,01) and worse outcome (persistence/death 69% vs 18%, p<0,01). With the multivariate analysis, TERT mutations, lymph node involvement and distant metastatis resulted independent risk factors for predicting a persistent disease. Conclusions: patients with high-risk tumors, particularly metastatic ones, had a worse outcome. The prognostic value of sex, age, tumor size, multifocality, T, N, M and stage was confirmed; TERT mutations, lymph node involvement and distant metastases were found to be independent risk factors for predicting a persistent disease. Patients carrying TERT promoter mutations were found to have a poorer prognosis: they have aggressive carcinomas and worse clinical outcome. No link was found between BRAF, RAS, TP53, PTEN and PIK3CA gene mutations and the clinical-pathological features analyzed.Presupposti dello studio: Alcuni pazienti affetti da carcinoma differenziato tiroideo (DTC) esitano in persistenza o decesso. Una maggiore definizione delle caratteristiche clinico-molecolari potrebbe consentire un miglior inquadramento diagnostico e l’esecuzione di una terapia individualizzata. Scopo dello studio: 1) caratterizzazione clinica dei casi dei DTC ad alto rischio dell’adulto; 2) caratterizzazione molecolare (BRAF, RAS, TP53, PTEN, PIK3CA e di TERT promotore) nei DTC ad alto rischio dell’adulto; 3) correlazione tra gli aspetti clinico/molecolari; 4) confronto tra il profilo clinico/molecolare dei DTC ad alto rischio con quelli a basso rischio. Materiali e metodi: Abbiamo studiato 119 pazienti con tumore ad alto rischio (dimensione maggiore >40mm e/o metastasi a distanza), sottoposti a intervento chirurgico per DTC tra il 2007 e il 2016. Le caratteristiche clinico/molecolari dei pazienti sono state confrontate con quelle di 144 pazienti adulti consecutivi per studio molecolare. Risultati: I soggetti con tumore metastatico e metastatico di grosse dimensioni presentavano outcome peggiore dei soggetti con tumore>40mm: risultavano più frequentemente persistenti/deceduti (62% e 79% vs 13%, p40mm (27% vs 11%, p<0,01). I pazienti ad alto rischio differivano dai pazienti a basso rischio per tutte le caratteristiche clinico/patologiche analizzate, eccetto la frequenza di multifocalità, risultavano più spesso persistenti/deceduti, presentavano più frequentemente necessità di secondo trattamento e mostravano ridotta DFS. Le mutazioni di BRAF sono risultate più frequenti nel gruppo di carcinomi a basso rischio (61% vs 26%, p40mm, e di TERT promotore (18% vs 3%, p<0,01), in particolare nei soggetti metastatici. Globalmente la mutazione di TERT promotore, anche in associazione con altri eventi molecolari, era correlata ad età avanzata (64aa vs 47aa, p<0,01), dimensione maggiore (43mm vs 17mm, p<0,01), estensione del tumore (T4 11% vs 4%, p<0,01), metastasi a distanza (56% vs 18%, p<0,01), stadio avanzato (stadio IV 41% vs 11%, p<0,01), necessità di secondo trattamento (57% vs 17%, p<0,01) ed outcome peggiore (persistenza/decesso 69% vs 18%, p<0,01). All’analisi multivariata sono risultati fattori indipendenti di outcome negativo la presenza di mutazioni a carico di TERT, il coinvolgimento linfonodale e la presenza di metastasi a distanza (p<0,05). Conclusioni: i pazienti con tumore ad alto rischio, in particolare i metastatici, presentano un outcome peggiore. L’impatto prognostico di tutte le caratteristiche cliniche analizzate (sesso, età, dimensioni, multifocalità, T, N, M, stadio) è stato confermato, sebbene siano risultati fattori indipendenti per recidiva o persistenza di malattia la presenza di mutazioni di TERT promotore, il coinvolgimento linfonodale e le metastasi a distanza. La mutazione di TERT è associata ad una prognosi peggiore: i soggetti mutati presentano malattia più aggressiva e un outcome peggiore. Non sono state rilevate differenze di prognosi nei pazienti che presentavano mutazioni puntiformi negli altri geni indagati

A Novel Thyroid Hormone Receptor Beta Mutation (G357R) in a Family with Resistance to Thyroid Hormone Beta: Extending the Borders of the "Hot" Region in the THRB Gene

Resistance to thyroid hormone beta (RTHβ) is a syndrome characterized by high serum levels of thyroid hormone and unsuppressed serum thyrotropin concentrations. RTHβ is caused by mutations in the thyroid hormone receptor beta (THRB) gene, which are mostly clustered in three "hot" regions along the gene. Here, a report is given on a family with RTHβ caused by a novel mutation in the THRB gene (c.1069 G>C, p.G357R) occurring outside the historically known "hot" regions

Amiodarone-induced thyrotoxicosis: Differential diagnosis using 99mTc-SestaMIBI and Target-to-Background Ratio (TBR)

PURPOSE OF THE REPORT: Distinguishing between amiodarone-induced thyrotoxicosis (AIT) caused by excessive hormone synthesis (AIT-1) or by a destructive process (AIT-2) has important therapeutic implications, but is still difficult and debated. Tc-sestaMIBI thyroid scintigraphy (99m-STS) has been proposed as a tool for classifying the two forms. MATERIAL AND METHODS: 30 AIT patients (11 females and 19 males) who underwent 99m-STS were retrospectively assessed for the present study. For each patient, a target-to-background ratio (TBR) was obtained on planar images. The TBR was then correlated with the qualitative assessment of the scans and the final clinical diagnosis. RESULTS: Considering clinical response to treatment as the gold standard for differential diagnosis, 14 cases of AIT-1, 12 of AIT-2, and 4 mixed forms were identified. 99m-STS was able to qualitatively identify all the mixed forms, while 1/14 AIT-1 and 6/12 AIT-2 cases were misdiagnosed as mixed forms. When the quantitative index (the TBR) was compared with the final clinical diagnosis, ROC curve analysis enabled us to identify an IBR of 0.482 during 99m-STS as a cut-off capable of discriminating between AIT-1 and AIT-2, with 100% specificity and 91.7% sensitivity (P < 0.0001, area under the curve: 0.982). CONCLUSIONS: Taking the TBR into consideration, 99m-STS proved a very useful tool for distinguishing AIT-1 from AIT-2, and thus offering patients appropriate treatment as of their diagnosis. This approach can avoid pointless and potentially dangerous combined overtreatments, and may speed up the return to normal thyroid function, which is crucial in AIT patients suffering from heart disease

von Hippel-Lindau disease integrated care pathway: Centralizing, expanding specialists' theatre, and measuring improvement

[no abstract available