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Abstract We have recently witnessed a rapid increase in the incidence of differentiated thyroid carcinoma (DTC), particularly low and very low-risk papillary thyroid carcinoma. Simultaneously, the number of cancer-related deaths has remained stable for more than 30 years. Such an indolent nature and long-term survival prompted researchers and experts to an ongoing discussion on the adequacy of DTC management to avoid, on the one hand, the overtreatment of low-risk cases and, on the other hand, the undertreatment of highly aggressive ones. The most recent guidelines of the American Thyroid Association (ATA GL) moved primary thyroid surgery in DTC towards a less aggressive approach by making lobectomy an option for patients with intrathyroidal low-risk DTC tumors up to 4 cm in diameter without evidence of extrathyroidal extension or lymph node metastases. It was one of the key changes in DTC management proposed by the ATA in 2015. Following the introduction of the 2015 ATA GL, the role of thyroid lobectomy in DTC management has slowly become increasingly important. The data coming from analyses of the large databases and retrospective studies prove that a less extensive surgical approach, even if in some reports it was related to a slight increase of the risk of recurrence, did not show a negative impact on disease-specific and overall survival in T1T2N0M0 low-risk DTC. There is no doubt that making thyroid lobectomy an option for low-risk papillary and follicular carcinomas was an essential step toward the de-escalation of treatment in thyroid carcinoma. This review summarizes the current recommendations and evidence-based data supporting the necessity of de-escalation of primary thyroid surgery in low-risk DTC. It also discusses the controversies raised by introducing new ATA guidelines and tries to resolve some open questions.

Multiple endocrine neoplasia 2B (MEN2B) is a rare syndrome with prevalence estimated at approximately 0.2 per 100,000; it is caused by mutation of the RET proto-oncogene. MEN2B is characterized by early-onset medullary thyroid carcinoma (MTC), ganglioneuromatosis of the aerodigestive tract, marfanoid habitus, ophthalmologic abnormalities, and pheochromocytoma in adulthood. Mutations in the RyR1 gene manifest clinically in congenital myopathies and/or malignant hyperthermia susceptibility. We present a case of a 4-year-old boy with an accidentally detected RET and RyR1 mutations in the course of diagnostic approach of short stature and delayed motor development. Due to a poor and blurred clinical picture of MEN2B syndrome, accompanied by RyR1 mutation symptoms, the diagnostic path was extended. Our patient had no family history of MTC. In the imaging studies of the thyroid gland, no abnormalities were found, whereas the serum level of calcitonin was elevated to 34 pg/mL (N < 5.0). The patient qualified for total thyroidectomy, and the histopathological examination confirmed the diagnosis of MTC. The postoperative serum calcitonin level dropped to normal ranges. This case shows how new genetic diagnostic procedures could be crucial in accidentally diagnosing rare endocrine disease with atypical symptoms, giving an opportunity for relatively early intervention.

Abstract The role of radiotherapy in advanced medullary thyroid carcinoma (MTC) is confined to patients in whom surgical treatment or the administration of tyrosine kinase inhibitors are not possible or contraindicated. High fractionated radiation doses during radiosurgery or fractionated stereotactic radiotherapy are applied to reduce cancer-related symptoms and stabilize irradiated lesions. This study aimed to retrospectively evaluate the therapeutic effect of stereotactic radiotherapy in MTC patients. Material and methods The study group involved 11 MTC patients, treated due to 16 cancer lesions, mainly bone metastases (10 lesions), lymph node (2 lesions) metastases, or liver metastases (2 lesions), one primary thyroid tumor, and one MTC recurrence in the thyroid bed. The fractionated and total radiation doses ranged between 5 and 12 Gy and 8–44 Gy, respectively. Six lesions were treated with a single radiation fraction, three lesions with 2 fractions, another 6 lesions with 3 fractions, whereas the remaining one metastatic lesion with 9 fractions of stereotactic radiosurgery. Results The beneficial effect of stereotactic radiosurgery was obtained in all treated lesions. None of treated lesions progressed in the further disease course. Fourteen lesions were stable (87.5 %), including eight lesions showing progression before radiosurgery (good response). Disease control was obtained in all soft-tissue metastases. Regarding bone metastases, partial regression was achieved in 20 % lesions, whereas in 30 % lesions progressive before radiotherapy, the treatment led to disease stabilization. Conclusions Our data pointed to the effectiveness of high-dose fractionated radiotherapy in MTC. However, an observation of a larger group of patients is required to confirm it.

Introduction The aim of this prospective study was to evaluate long-term outcomes in differentiated thyroid cancer (DTC) patients postoperatively treated with distinct RAI activities of 30 mCi, 60 mCi, and 100 mCi. Material and methods The analysis involved 277 low-risk and 46 intermediate-risk patients, who underwent radioiodine (RAI) ablation with 30 mCi, 60 mCi or 100 mCi under prospective, randomized clinical trials. Seventy-eight patients from the low-risk group received 30 mCi, whereas 125 and 74 patients received 60 mCi and 100 mCi, respectively. Regarding the intermediate-risk group, 20 patients were given 60 mCi, and 26 subjects were given 100 mCi. The mean time of follow-up was 11 years. Results An excellent treatment response was obtained in 88%, 89% and 90% of low-risk patients treated with 30 mCi, 60 mCi, and 100 mCi, respectively, and in 85% of intermediate-risk patients, who were administered 60 or 100 mCi. An indeterminate response was achieved in 9.4% and 6.5%, whereas an incomplete structural response was obtained in 1.4% and 6.5% of low-risk and intermediate-risk patients, respectively. An incomplete biochemical response was observed only in 2.2% of intermediate-risk patients. The differences in treatment response regarding RAI activity were not significant. Conclusions RAI activity of 30 mCi demonstrates a comparable efficacy as 60 mCi and 100 mCi in low-risk DTC. RAI activity of 60 mCi seems to be effective in intermediate-risk DTC.

The value of postoperative radiotherapy in the treatment of medullary thyroid carcinoma (MTC) has not been unequivocally demonstrated. Therefore our study aimed to answer the question of whether adjuvant radiotherapy showed any impact on the risk of local recurrence and whether there were any differences in respo nse to radiotherapy between hereditary and sporadic MTC. Methods: A retrospective analysis involved 254 MTC patients, among them 73 patients with a hereditary disease. Two hundred and twenty-four patients, including 43 persons at a high risk of local relapse, underwent only initial surgery; 18 other patients were operated due to MTC recurrences, whereas the remaining 12 patients had cytoreductive procedure or were not amenable for surgery. Radiotherapy was carried out in 132 patients. One hundred and twenty patients underwent adjuvant radiotherapy, among them 102 patients after initial surgery. The median follow-up was 10 years (range 0.5–29 years). Results: Local recurrence occurred in 107/254 patients, among them in 63 subjects after prior radiotherapy. The frequency of relapse showed significantl y increasing trend toward higher MTC stages (P

Optimal therapeutic strategy in low advanced papillary thyroid carcinoma (PTC) is still a matter of debate. The management differs depending on the country.A prospective non-randomized study was performed to evaluate whether less extensive surgery could be a safe, acceptable, and sufficient therapeutic option in PTC cT1N0M0 patients. The present paper summarizes the results of over a 5-year follow-upMaterialOur prospective group (PG) treated between 2011 and 2015 consisted of 139 patients with cT1aN0M0 PTC who underwent lobectomy (LT) as initial surgical treatment (PGcT1aN0M0 group) and 102 cT1bN0M0 patients in whom total thyroidectomy (TT) with unilateral central neck dissection (CND) was performed (PGcT1bN0M0). PG was compared with the retrospective group (RG) of patients who underwent TT with bilateral CND between 2004 and 2006: 103 cT1aN0M0 patients (RGcT1aN0M0) and 91cT1bN0M0 (RGcT1bN0M0). The risks of reoperation, cancer relapse and postoperative complications were analyzed.ResultsOnly 12 cT1aN0M0 patients (7.6%) withdrew from the trial and underwent TT with bilateral CND. Over 90% of patients accepted less extensive surgery. In 4 cT1aN0M0 cases, TT with CND was performed due to lymph node metastases found intraoperatively. The initial clinical stage according to the TNM/AJCC 7th edition was confirmed histologically in 77% of cases in PGT1aN0M0 and in 72% in PGT1bN0M0, respectively. 24 PGcT1aN0M0 patients were reoperated on. In this group, cancer lesions in the postoperative histological specimens were found in 8 cases (32%). Five-year disease-free survival (DFS) was excellent. However, no statistically significant differences were found between PG and RG groups (99.3% in PGcT1aN0M0 and 99.0%, in RGcT1aN0M0; p = 0.41 and 98%, in PGcT1bN0M0 and 94.4% in RGcT1bN0M0; p=0.19). No significant differences were observed in the incidence of early paresis of the recurrent laryngeal nerves between PG and RG. However, as predicted, LT completely eliminated the risk of postoperative hypoparathyroidism.SummaryThe results of the prospective clinical trial confirm that less extensive surgery in adequately selected low-advanced PTC patients is both safe and sufficient.

Medullary thyroid cancer (MTC) is a rare thyroid malignancy, which arises from parafollicular C-cells. It occurs in the hereditary or sporadic form. Hereditary type is a consequence of activation of the RET proto-oncogene by germline mutations, whereas about 80% of sporadic MTC tumors harbor somatic, mainly RET or rarely RAS mutations. According to the current ATA guidelines, a postoperative MTC ri sk stratification and long-term follow-up are mainly based on histopathological data, including tumor stage, the presence of lymph node and/or distant metastases (TNM class ification), and serum concentration of two biomarkers: calcitonin (Ctn) and carcinoembryonic antigen (CEA). The type of RET germline mutation also correlates with MTC clinical characteristics. The most common and the best known RET mutation in sporadic MTC, localized at codon 918, is related to a more aggressive MTC course and poorer survival. However, even if histopathological or clinical features allow to predict a long-term prognosis, they are not sufficient to select the patients showing aggressive MTC courses requiring immediate treatment or those, who are refractory to different therapeutic methods. Besides the RET gene mutations, there are currently no other reliable molecular prognostic markers. This review summarizes the present data of genomic investigation on molecular prognostic factors in medullary thyroid cancer.

We are witnessing a rapid worldwide increase in the incidence of papillary thyroid carcinoma (PTC) in the last thirty years. Extensive implementation of cancer screening and wide availability of neck ultrasound or other imaging studies is the main reason responsible for this phenomenon. It resulted in a detection of a growing number of clinically asymptomatic PTCs, mainly low-risk tumors, without any beneficial impact on survival. An indolent nature of low-risk PTC, particularly papillary thyroid microcarcinoma (PTMC), and the excellent outcomes raise an ongoing discussion regarding the adequacy of treatment applied. The question of whether PTMC is overtreated or not is currently completed by another, whether PTMC requires any treatment. Current ATA guidelines propose less extensive preoperative diagnostics and, if differentiated thyroid cancer is diagnosed, less aggressive surgical approach and limit indications for postoperative radioiodine therapy. However, in intrathyroidal PTMCs in the absence of lymph node or distant metastases, active surveillance may constitute alternative management with a low progression rate of 1%–5% and without any increase in the risk of poorer outcomes related to delayed surgery in patients, in whom it was necessary. This review summarizes the current knowledge and future perspectives of active surveillance in low-risk PTC.

Published studies on the risk of radiation-induced second primary malignancy (SPM) after radioiodine treatment (RAI) of differentiated thyroid cancer (DTC) refer mainly to patients treated as middle-aged or older adults and are not easily generalizable to those treated at a younger age. Here we review available literature on the risk of breast cancer as an SPM after RAI of DTC with a focus on females undergoing such treatment in childhood, adolescence, or young adulthood. Additionally, we report the results of a preliminary international survey of patient registries from academic tertiary referral centers specializing in pediatric DTC. The survey sought to evaluate the availability of sufficient patient data for a potential international multicenter observational case–control study of females with DTC given RAI at an early age. Our literature review identified a bi-directional association of DTC and breast cancer. The general breast cancer risk in adult DTC survivors is low, ~2%, slightly higher in females than in males, but presumably lower, not higher, in those diagnosed as children or adolescents than in those diagnosed at older ages. RAI presumably does not substantially influence breast cancer risk after DTC. However, data from patients given RAI at young ages are sparse and insufficient to make definitive conclusions regarding age dependence of the risk of breast cancer as a SPM after RAI of DTC. The preliminary analysis of data from 10 thyroid cancer registries worldwide, including altogether 6,449 patients given RAI for DTC and 1,116 controls, i.e., patients not given RAI, did not show a significant increase of breast cancer incidence after RAI. However, the numbers of cases and controls were insufficient to draw statistically reliable conclusions, and the proportion of those receiving RAI at the earliest ages was too low.In conclusion, a potential international multicenter study of female patients undergoing RAI of DTC as children, adolescents, or young adults, with a sufficient sample size, is feasible. However, breast cancer screening of a larger cohort of DTC patients is not unproblematic for ethical reasons, due to the likely, at most slightly, increased risk of breast cancer post-RAI and the expected ~10% false-positivity rate which potentially produced substantial “misdiagnosis.”

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a large and very diverse group of neoplasms. Clinical presentation of NETs depends on the site of the primary tumor and whether the tumor is functioning (i.e., secreting peptides or neuroamines that produce symptoms). The diagnosis of GEP-NET is further complicated by symptomatic differences that occur depending on the type of secreted peptide or neuroamine. Due to their heterogeneity and unique characteristics, early diagnosis of GEP-NETs is difficult, which increases the likelihood of metastatic disease and reduces the scope of therapeutic possibilities. Thus, a multidisciplinary approach for the treatment of GEP-NETs is necessary. This review is the result of presentations that were delivered during an expert meeting on the treatment of GEP-NETs supported by Ipsen. We summarize the current knowledge on the epidemiology, incidence, diagnosis, and treatment of GEP-NETs. We examined the role of the somatostatin analog (SSA) lanreotide and the impact of the data from the recently published, randomized, double-blind, placebo -controlled CLARINET study (Controlled study of Lanreotide Antiproliferative Response In Neuroendocrine Tumors) on disease management. We also review the recent treatment options and recommendations for GEP-NETs.

Background: Telomerase reverse transcriptase promoter (TERTp) mutations are related to a worse prognosis in various malignancies, including papillary thyroid carcinoma (PTC). Since mechanisms responsible for the poorer outcome of TERTp(+) patients are still unknown, searching for molecular consequences of TERTp mutations in PTC was the aim of our study. Methods: The studied cohort consisted of 54 PTCs, among them 24 cases with distant metastases. BRAF V600E, RAS, and TERTp mutational status was evaluated in all cases. Differences in gene expression profile between TERTp(+) and TERTp(−) PTCs were examined using microarrays. The evaluation of signaling pathways and gene ontology was based on the Gene Set Enrichment Analysis. Results: Fifty-nine percent (32/54) of analyzed PTCs were positive for at least one mutation: 27 were BRAF(+), among them eight were TERTp(+), and 1 NRAS(+), whereas five other samples harbored RAS mutations. Expression of four genes significantly differed in BRAF(+)TERTp(+) and BRAF(+)TERTp(−) PTCs. Deregulation of pathways involved in key cell processes was observed. Conclusions: TERTp mutations are related to higher PTC aggressiveness. CRABP2 gene was validated as associated with TERTp mutations. However, its potential use in diagnostics or risk stratification in PTC patients needs further studies.

Molecular mechanisms of distant metastases (M1) in papillary thyroid cancer (PTC) are poorly understood. We attempted to analyze the gene expression profile in PTC primary tumors to seek the genes associated with M1 status and characterize their molecular function. One hundred and twenty-three patients, including 36 M1 cases, were subjected to transcriptome oligonucleotide microarray analyses: (set A—U133, set B—HG 1.0 ST) at transcript and gene group level (limma, gene set enrichment analysis (GSEA)). An additional independent set of 63 PTCs, including 9 M1 cases, was used to validate results by qPCR. The analysis on dataset A detected eleven transcripts showing significant differences in expression between metastatic and non-metastatic PTC. These genes were validated on microarray dataset B. The differential expression was positively confirmed for only two genes: IGFBP3, (most significant) and ECM1. However, when analyzed on an independent dataset by qPCR, the IGFBP3 gene showed no differences in expression. Gene group analysis showed differences mainly among immune-related transcripts, indicating the potential influence of tumor immune infiltration or signal within the primary tumor. The differences in gene expression profile between metastatic and non-metastatic PTC, if they exist, are subtle and potentially detectable only in large datasets.

The relationships between thyroid cancer and obesity are not fully understood. Adipokines, proinflammatory cytokines, and vitamin D may mediate these associations. In this study, we estimated serum concentrations of leptin, adiponectin, chemerin, interleukin-6 (IL-6), and vitamin D in patients with papillary thyroid cancer (PTC). We searched for associations between the adipokines, IL-6, vitamin D, anthropometric parameters, and TNM AJCC/UICC 2017 classification in 177 patients diagnosed with PTC (151 women and 26 men). Normal weight patients were predominantly classified as clinical stage I. The prevalence of stages higher than I was significantly higher in PTC patients with BMI ≥ 25 or with metabolic syndrome. Using logistic regression waist circumference ≥ 88 cm in women and ≥102 cm in men, upper tertiles of IL-6 and leptin were associated with a higher clinical stage. There were no differences in the prevalence of microcarcinomas in analyzed groups (BMI ≥ 25 versus BMI

BACKGROUND:Graves' disease (GD) is a complex disease in which genetic predisposition is modified by environmental factors. Each gene exerts limited effects on the development of autoimmune disease (OR = 1.2-1.5). An epidemiological study revealed that nearly 70% of the risk of developing inherited autoimmunological thyroid diseases (AITD) is the result of gene interactions. In the present study, we analyzed the effects of the interactions of multiple loci on the genetic predisposition to GD. The aim of our analyses was to identify pairs of genes that exhibit a multiplicative interaction effect. MATERIAL AND METHODS:A total of 709 patients with GD were included in the study. The patients were stratified into more homogeneous groups depending on the age at time of GD onset: younger patients less than 30 years of age and older patients greater than 30 years of age. Association analyses were performed for genes that influence the development of GD: HLADRB1, PTPN22, CTLA4 and TSHR. The interactions among polymorphisms were analyzed using the multiple logistic regression and multifactor dimensionality reduction (MDR) methods. RESULTS:GD patients stratified by the age of onset differed in the allele frequencies of the HLADRB1*03 and 1858T polymorphisms of the PTPN22 gene (OR = 1.7, p = 0.003; OR = 1.49, p = 0.01, respectively). We evaluated the genetic interactions of four SNPs in a pairwise fashion with regard to disease risk. The coexistence of HLADRB1 with CTLA4 or HLADRB1 with PTPN22 exhibited interactions on more than additive levels (OR = 3.64, p = 0.002; OR = 4.20, p < 0.001, respectively). These results suggest that interactions between these pairs of genes contribute to the development of GD. MDR analysis confirmed these interactions. CONCLUSION:In contrast to a single gene effect, we observed that interactions between the HLADRB1/PTPN22 and HLADRB1/CTLA4 genes more closely predicted the risk of GD onset in young patients.

TERT promoter (TERTp) mutations are important factors in papillary thyroid carcinomas (PTCs). They are associated with tumor aggressiveness, recurrence, and disease-specific mortality and their use in risk stratification of PTC patients has been proposed. In this study we investigated the prevalence of TERTp mutations in a cohort of Polish patients with PTCs and the association of these mutations with histopathological factors, particularly in coexistence with the BRAF V600E mutation. A total of 189 consecutive PTC specimens with known BRAF mutational status were evaluated. TERTp mutations were detected in 8.5% of cases (16/189) with the C228T mutation being the most frequent. In six of the PTC specimens (3.2%), four additional TERTp alterations were found, which included one known polymorphism (rs2735943) and three previously unreported alterations. The association analysis revealed that the TERTp hotspot mutations were highly correlated with the presence of the BRAF V600E mutation and their coexistence was significantly associated with gender, advanced patient age, advanced disease stage, presence of lymph node metastases, larger tumor size, and tumor-capsule infiltration. While correlations were identified, the possibility of TERTp mutations being key molecular modulators responsible for PTC aggressiveness requires further studies.

INTRODUCTION:The risk of over-treatment in low-advanced PTC stages has prompted clinicians to search for new reliable prognostic factors. The presence of BRAF mutation, the most frequent molecular event in PTC, seems to be a good candidate. However, there is still lack of randomised trials and its significance has been proved by retrospective analyses, involving a large group of patients. The question arises whether this factor is useful in smaller populations, characterised for specialised centres. Thus, the aim of the study was to evaluate the use of BRAF mutation as a potential predictive marker in PTC patients. MATERIAL:233 PTC subjects treated between 2004-2006, were retrospectively analysed. Stage pT1 was diagnosed in 64.8% patients and lymph node metastases in 30.9%. Median follow-up was 7.5 years. BRAFV600E mutation was assessed postoperatively in all cases. RESULTS:BRAF V600E mutation was found in 54.5%. It was more frequent in patients > 45 years (p=0.0001), and associated with larger tumour size (p=0.004). Patients with tumours

BACKGROUND:The molecular mechanisms driving the papillary thyroid carcinoma (PTC) are still poorly understood. The most frequent genetic alteration in PTC is the BRAFV600E mutation--its impact may extend even beyond PTC genomic profile and influence the tumor characteristics and even clinical behavior. METHODS:In order to identify BRAF-dependent signature of early carcinogenesis in PTC, a transgenic mouse model with BRAFV600E-induced PTC was developed. Mice thyroid samples were used in microarray analysis and the data were referred to a human thyroid dataset. RESULTS:Most of BRAF(+) mice developed malignant lesions. Nevertheless, 16% of BRAF(+) mice displayed only benign hyperplastic lesions or apparently asymptomatic thyroids. After comparison of non-malignant BRAF(+) thyroids to BRAF(-) ones, we selected 862 significantly deregulated genes. When the mouse BRAF-dependent signature was transposed to the human HG-U133A microarray, we identified 532 genes, potentially indicating the BRAF signature (representing early changes, not related to developed malignant tumor). Comparing BRAF(+) PTCs to healthy human thyroids, PTCs without BRAF and RET alterations and RET(+), RAS(+) PTCs, 18 of these 532 genes displayed significantly deregulated expression in all subgroups. All 18 genes, among them 7 novel and previously not reported, were validated as BRAFV600E-specific in the dataset of independent PTC samples, made available by The Cancer Genome Atlas Project. CONCLUSION:The study identified 7 BRAF-induced genes that are specific for BRAF V600E-driven PTC and not previously reported as related to BRAF mutation or thyroid carcinoma: MMD, ITPR3, AACS, LAD1, PVRL3, ALDH3B1, and RASA1. The full signature of BRAF-related 532 genes may encompass other BRAF-related important transcripts and require further study.

A rising incidence of thyroid cancers (TCs) mainly small tumors, observed during recent years, lead to many controversies regarding treatment strategies. TCs represent a distinct molecular background and clinical outcome. Although in most cases TCs are characterized by a good prognosis, there are some aggressive forms, which do not respond to standard treatment. There are still some questions, which have to be resolved to avoid dangerous simplifications in the clinical management. In this article, we focused on the current advantages in preoperative molecular diagnostic tests and histopathological examination including noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). We discussed the controversies regarding the extent of thyroid surgery and adjuvant radioiodine therapy, as well as new treatment modalities for radioiodine-refractory differentiated thyroid cancer (RR-DTC). Considering medullary thyroid cancer (MTC), we analyzed a clinical management based on histopathology and RET (ret proto-oncogene) mutation genotype, disease follow-up with a special attention to serum calcitonin doubling time as an important prognostic marker, and targeted therapy applied in advanced MTC. In addition, we provided some data regarding anaplastic thyroid cancer (ATC), a highly lethal neoplasm, which lead to death in nearly 100% of patients due to the lack of effective treatment options.