Response to therapy of papillary thyroid cancer of known BRAF status.

OBJECTIVE: A dynamic risk stratification with modified initial estimated risk based on response to therapy and disease course is one of the crucial changes adopted recently by the American Thyroid Association (ATA). This approach focuses on an individualized risk-adapted approach to the management of differentiated thyroid cancer. The BRAF V600E mutation is the most common genetic alteration in papillary thyroid cancer (PTC). However, the prognostic value of this mutation remains unclear. The aim of this study was to examine the relation between the BRAF V600E status in PTC and all ATA response-to-therapy categories, as well as the recurrence and persistence of both biochemical disease and structural disease. PATIENTS: Unselected PTC cases with known BRAF status diagnosed from 2000 to 2013 and actively monitored at one institution (n=723) were reviewed retrospectively. The association between the BRAF V600E mutation and clinicopathological characteristics, ATA 2015 response-to-therapy category, recurrence after a period of no evidence of disease (NED) and persistent biochemical or structural disease, was analysed. RESULTS: BRAF V600E was found in 65.7% (475/723) of PTC cases. Although BRAF mutation status correlated significantly with certain clinicopathological prognostic factors, there was no correlation with any of the response-to-therapy categories. Recurrences and persistent biochemical or structural disease were not associated with BRAF status. CONCLUSIONS: Our data are consistent with those of other studies reporting a positive relation between BRAF V600E mutation and poor prognostic factors in PTC; however, the BRAF status did not significantly correlate with a response to therapy.

A Significance of Concomitant BRAFV600E and TERT Mutations in Polish Patients with Papillary Thyroid Microcarcinoma: A Retrospective Cohort Study Based on 430 Cases.

Background: The incidence of papillary thyroid cancer is increasing worldwide due to more frequent pathological detection of papillary thyroid microcarcinomas (PTMC), which are cancers measuring 1 cm or less in diameter. In rare cases, the course of PTMC can be aggressive, with an increased risk of recurrence/persistent disease. The aim of this study of Polish patients diagnosed with PTMC was to assess the impact of concomitant B-type Raf kinas-activating mutation in codon 600 of exon 15 (BRAFV600E) and telomerase reverse transcriptase (TERT) hotspot mutations on clinicopathological features, response to treatment, potential recurrence, and the final outcome. Methods: A retrospective analysis of the 430 PTMC cases diagnosed during 2001-2020 at a single center was performed. All PTMC cases were assessed histopathologically, and analyses of BRAFV600E and TERT promoter were performed based on DNA isolated from tumor blocks. Results: There were 29/430 (6.7% [confidence interval: 4.6-9.5]) patients in whom the TERTC228T and/or TERTC250T mutations coexisted with the BRAFV600E mutation. A statistical comparison between PTMC cases with concomitant BRAFV600E and TERT hotspot mutations and those without any of those mutations revealed no significant differences between the two groups with respect to risk stratification, response to primary treatment, clinical course, or final disease status. Conclusion: Regardless of the molecular background of PTMC, the overall response to therapy is excellent, and long-term disease-free survival rates can be achieved by most patients.

Incidence of the CHEK2 Germline Mutation and Its Impact on Clinicopathological Features, Treatment Responses, and Disease Course in Patients with Papillary Thyroid Carcinoma.

The CHEK2 gene is involved in the repair of damaged DNA. CHEK2 germline mutations impair this repair mechanism, causing genomic instability and increasing the risk of various cancers, including papillary thyroid carcinoma (PTC). Here, we asked whether CHEK2 germline mutations predict a worse clinical course for PTC. The study included 1547 unselected PTC patients (1358 women and 189 men) treated at a single center. The relationship between mutation status and clinicopathological characteristics, treatment responses, and disease outcome was assessed. CHEK2 mutations were found in 240 (15.5%) of patients. A CHEK2 I157T missense mutation was found in 12.3%, and CHEK2 truncating mutations (IVS2 + 1G > A, del5395, 1100delC) were found in 2.8%. The truncating mutations were more common in women (p = 0.038), and were associated with vascular invasion (OR, 6.91; p < 0.0001) and intermediate or high initial risk (OR, 1.92; p = 0.0481) in multivariate analysis. No significant differences in these parameters were observed in patients with the I157T missense mutation. In conclusion, the CHEK2 truncating mutations were associated with vascular invasion and with intermediate and high initial risk of recurrence/persistence. Neither the truncating nor the missense mutations were associated with worse primary treatment response and outcome of the disease.

Is Male Sex A Prognostic Factor in Papillary Thyroid Cancer?

Identifying risk factors is crucial for predicting papillary thyroid cancer (PTC) with severe course, which causes a clinical problem. The purpose of this study was to assess whether male sex can be such a predictive factor and to verify whether including it as a predictive factor of high initial risk of recurrence/persistence would help to enhance the value of the American Thyroid Association initial risk stratification system (ATA). We retrospectively analyzed 1547 PTC patients (1358 females and 189 males), treated from 1986 to 2018. The relationship between sex and clinicopathological features, response to therapy, and disease status was assessed. Men with PTC showed some adverse clinicopathological features more often than women, including angioinvasion, lymph node metastases, and tumor size > 40 mm. There were sex-related disparities with respect to response to initial therapy and final follow-up. Male sex is associated with some unfavorable clinicopathological features of PTC, which may affect response to initial therapy or final disease status. In our study, modification of the ATA system by including male sex as a risk factor does not enhance its value. Thus, further studies are needed to assess whether males require treatment modalities or oncological follow-up protocols that are different from those of females.

Does the presence of regional lymph node metastases have any impact on the complete remission rate in patients with distant metastases of papillary thyroid carcinoma (PTC), treated by radioiodine therapy?

INTRODUCTION: The presence of regional nodal and/or distant metastases has an influence on the results of treatment in patients with differentiated thyroid carcinoma (DTC). The aim of the study was to evaluate the frequency of complete remission in patients with DTC depending on the presence of lymph nodes and/or distant metastases. MATERIAL AND METHODS: A total of 102 patients (82 females, 20 males) aged 20-86 with N1 or M1 (according to TNM staging) after thyroidectomy and 131I therapy were chosen from among the 625 patients with DTC who were treated in our Department. The patients were divided in 3 groups: group I - TxN1M0, group II - TxN0M1, and group III - TxN1M1. The documentation was analyzed by classifying the complete remission patients as being those without the presence of radioiodine uptake in the neck or pathological lesions in the whole body 131I scintigraphy scan after six months of ablation therapy, with negative serum thyroglobulin in the absence of anti-thyroglobulin antibodies, and with normal ultrasound image of the neck. We compared the frequency of complete remission in three groups of patients. RESULTS: We recognized complete remission in 57 patients (82.6%) in group I (TxN1M0), 4 patients (28.6%) in group II (TxN0M1) and 6 patients (31.6%) in group III (TxN1M1). CONCLUSIONS: 1. The highest percentage of complete remission was observed in patients with lymph nodes but without distant metastases (group I). 2. In the case of the presence of distant metastases there was no statistically significant difference in the percentage of complete remission between patients with or without the presence of metastases in lymph nodes.

Telomeres and telomerase in oncogenesis.

Telomeres are located at the ends of chromosomes and protect them from degradation. Suppressing the activity of telomerase, a telomere-synthesizing enzyme, and maintaining short telomeres is a protective mechanism against cancer in humans. In most human somatic cells, the expression of telomerase reverse transcriptase (TERT) is repressed and telomerase activity is inhibited. This leads to the progressive shortening of telomeres and inhibition of cell growth in a process called replicative senescence. Most types of primary cancer exhibit telomerase activation, which allows uncontrolled cell proliferation. Previous research indicates that TERT activation also affects cancer development through activities other than the canonical function of mediating telomere elongation. Recent studies have improved the understanding of the structure and function of telomeres and telomerase as well as key mechanisms underlying the activation of TERT and its role in oncogenesis. These advances led to a search for drugs that inhibit telomerase as a target for cancer therapy. The present review article summarizes the organization and function of telomeres, their role in carcinogenesis, and advances in telomerase-targeted therapy.

Does the TT Variant of the rs966423 Polymorphism in DIRC3 Affect the Stage and Clinical Course of Papillary Thyroid Cancer?

Thyroid cancer (TC) is the most common cancer of the endocrine system. Most new diagnoses are of low-grade papillary thyroid cancer (PTC), suggesting that PTC may be over-diagnosed. However, the incidence of advanced-stage PTC has increased in recent years. It is therefore very important to identify prognostic factors for advanced PTC. Somatic mutation of the BRAF gene at V600E, or the coexistence of the BRAF V600E mutation and mutations in the TERT promoter are associated with more aggressive disease. It would also be valuable to identify genetic risk factors affecting PTC prognosis. We therefore evaluated the impact of the rs966423 polymorphism in the DIRC3 gene, including its relationship with unfavorable histopathological and clinical features and mortality, in differentiated thyroid cancer (DTC). The study included 1466 patients diagnosed with DTC from one center. There was no significant association between the DIRC3 genotype at rs966423 (CC, CT, or TT) and any histopathological or clinic factor examined, including initial response to therapy, response at follow-up, or overall mortality, in DTC patients.

Coexisting Germline CHEK2 and Somatic BRAFV600E Mutations in Papillary Thyroid Cancer and Their Association with Clinicopathological Features and Disease Course.

BRAFV600E is the most common somatic mutation in papillary thyroid carcinoma (PTC) and the majority of evidence indicates that it is associated with an aggressive clinical course. Germline mutations of the CHEK2 gene impair the DNA damage repair process and increase the risk of PTC. Coexistence of both mutations is expected to be associated with poorer clinical course. We evaluated the prevalence of concomitant CHEK2 and BRAFV600E mutations and their associations with clinicopathological features, treatment response, and disease course in PTC patients. The study included 427 unselected PTC patients (377 women and 50 men) from one center. Relationships among clinicopathological features, mutation status, treatment response, and disease outcomes were assessed. Mean follow-up was 10 years. CHEK2 mutations were detected in 15.2% and BRAFV600E mutations in 64.2% patients. Neither mutation was present in 31.4% cases and both BRAFV600E and CHEK2 mutations coexisted in 10.8% patients. No significant differences in clinicopathological features, initial risk, treatment response, or disease outcome were detected among these patient groups. CHEK2 mutations were significantly associated with older age, while BRAFV600E was significantly associated with older age and extrathyroidal extension. The coexistence of both mutations was not associated with more aggressive clinicopathological features of PTC, poorer treatment response, or disease outcome.

Impact of BRAF V600E and TERT Promoter Mutations on Response to Therapy in Papillary Thyroid Cancer.

In this study, we examined the relationship between coexisting BRAF V600E and TERT promoter mutations in papillary thyroid cancer (PTC) and response to therapy. PTC cases (n = 568) with known BRAF and TERT status, diagnosed from 2000 to 2012 and actively monitored at one institution, were reviewed retrospectively. Associations between BRAF V600E and TERT promoter mutations and clinicopathological features, Tumor-Node-Metastasis stage, initial risk, response to therapy, follow-up, and final disease outcome were assessed according to American Thyroid Association 2015 criteria and the American Joint Committee on Cancer/Tumor-Node-Metastasis (8th edition) staging system. Median follow-up was 120 months. TERT promoter mutations (any type) were detected in 13.5% (77/568) of PTC cases with known BRAF status. The C228T and C250T TERT hotspot mutations were found in 54 (9.5%) and 23 (4%) patients, respectively, and 22 other TERT promoter alterations were identified. Coexisting BRAF V600E and TERT hotspot promoter mutations were detected in 9.5% (54/568) of patients, and significantly associated with older patient age (P = 0.001), gross extrathyroidal extension (P = 0.003), tumor stage pT3-4 (P = 0.005), stage II to IV (P = 0.019), intermediate or high initial risk (P = 0.003), worse than excellent response to primary therapy (P = 0.045), recurrence (P = 0.015), and final outcome of no remission (P = 0.014). We conclude that coexisting BRAF V600E and TERT mutations in patients with PTC are associated with poor initial prognostic factors and clinical course and may be useful for predicting a worse response to therapy, recurrence, and poorer outcome than in patients without the above mutations.

The impact of BMI on clinical progress, response to treatment, and disease course in patients with differentiated thyroid cancer.

INTRODUCTION: Obesity is a serious health problem worldwide, particularly in developed countries. It is a risk factor for many diseases, including thyroid cancer. The relationship between obesity and prognostic factors of thyroid cancer is unclear. AIMS: We sought to ascertain the relationship between body mass index (BMI) and clinicopathological features increasing the risk of poor clinical course, treatment response, and clinical outcome in patients with differentiated thyroid cancer (DTC). SUBJECTS & METHODS: The study included 1181 patients with DTC (88% women and 12% men) treated at a single center from 2000 to 2016. BMI before surgery and aggressive clinicopathological features, according to the American Thyroid Initial Risk stratification system, were analyzed. The relationship between BMI and initial risk, treatment response, and final status of the disease was evaluated, incorporating the revised 2015 American Thyroid Association guidelines and the 8th edition of the American Joint Committee on Cancer/Tumor-Node-Metastasis (AJCC/TNM) staging system. Patients were stratified according to the World Health Organization classification of BMI. Statistical analysis was performed using univariate and multivariate logistic regression analysis. RESULTS: Median follow-up was 7.7 years (1-16 years). There were no significant associations between BMI and extrathyroidal extension (microscopic and gross), cervical lymph node metastasis, or distant metastasis in univariate and multivariate analyses. BMI did not affect initial risk, treatment response or disease outcome. Obesity was more prevalent in men (p = 0.035) and in patients ≥55 years old (p = 0.001). There was no statistically significant relationship between BMI and more advanced TNM stage in patients ≤55 years old (stage I vs. stage II) (p = 0.266) or in patients >55 years old (stage I-II vs. III-IV) (p = 0.877). CONCLUSIONS: Obesity is not associated with more aggressive clinicopathological features of thyroid cancer. Obesity is not a risk factor for progression to more advanced stages of disease, nor is it a prognostic factor for poorer treatment response and clinical outcome.

Increase in Papillary Thyroid Cancer Incidence Is Accompanied by Changes in the Frequency of the BRAF V600E Mutation: A Single-Institution Study.

BACKGROUND: Thyroid cancer (TC) has one of the fastest increasing incidences worldwide and primarily involves papillary thyroid cancer (PTC). The BRAF(V600E) mutation is the most common genetic alteration identified in PTC. There are few data concerning an association between the rising incidence of PTC and the increasing prevalence of BRAF-positive cases. Environmental factors such as iodine intake may be responsible for the changing molecular features of PTC. The aim of this study was to evaluate probable variations in the frequency of the BRAF(V600E) mutation in PTC that were diagnosed at a single institution over 14 years in Poland, a country with a demonstrated improvement in iodine supplementation in the early 21st century. METHODS: Time-dependent trends in the prevalence of the BRAF(V600E) mutation during three time periods (2000-2004, 2005-2009, and 2010-2013) were analyzed. The BRAF mutation was genotyped using direct sequencing, allele-specific polymerase chain reaction (PCR), and real-time PCR in 723 unselected cases of PTC that were diagnosed in 2000-2013. Trends in the clinicopathologic characteristics of all PTCs and BRAF(V600E)-positive PTCs were also analyzed. RESULTS: The proportion of PTCs with mutations significantly increased over the study period (54.8% vs. 70.6%; p = 0.001). The median tumor size of all and BRAF-positive tumors decreased (p = 0.008 and p = 0.001, respectively) and correlated with an increase in the proportion of all and mutated microcarcinomas (p = 0.003 and p = 0.003, respectively). A decrease in all and mutated tumors between 2 and 4 cm was also observed (p = 0.002 and p = 0.006, respectively). A significant decrease in tumors ≥ 4 cm in size was only observed in BRAF-positive cases (p = 0.017). The proportion of classic PTC with BRAF(V600E) mutation was observed to increase (57.6% vs. 74.4%; p = 0.001) and was stable for the follicular variant of PTC (p = 0.336). CONCLUSIONS: The prevalence of the BRAF(V600E)mutation increased significantly in PTCs diagnosed in the authors' institution. Improved detection and several causative factors, most likely environmental and changes in iodine intake, may contribute to the increasing occurrence of TC.

The Delayed Risk Stratification System in the Risk of Differentiated Thyroid Cancer Recurrence.

CONTEXT: There has been a marked increase in the detection of differentiated thyroid carcinoma (DTC) over the past few years, which has improved the prognosis. However, it is necessary to adjust treatment and monitoring strategies relative to the risk of an unfavourable disease course. MATERIALS AND METHODS: This retrospective study examined data from 916 patients with DTC who received treatment at a single centre between 2000 and 2013. The utility of the American Thyroid Association (ATA) and the European Thyroid Association (ETA) recommended systems for early assessment of the risk of recurrent/persistent disease was compared with that of the recently recommended delayed risk stratification (DRS) system. RESULTS: The PPV and NPV for the ATA (24.59% and 95.42%, respectively) and ETA (24.28% and 95.68%, respectively) were significantly lower than those for the DRS (56.76% and 98.5%, respectively) (p<0.0001). The proportion of variance for predicting the final outcome was 15.8% for ATA, 16.1% for ETA and 56.7% for the DRS. Recurrent disease was rare (1% of patients), and was nearly always identified in patients at intermediate/high risk according to the initial stratification (9/10 cases). CONCLUSIONS: The DRS showed a better correlation with the risk of persistent disease than the early stratification systems and allows personalisation of follow-up. If clinicians plan to alter the intensity of surveillance, patients at intermediate/high risk according to the early stratification systems should remain within the specialized centers; however, low risk patients can be referred to endocrinologists or other appropriate practitioners for long-term follow-up, as these patients remained at low risk after risk re-stratification.

The Cut-Off Level of Recombinant Human TSH-Stimulated Thyroglobulin in the Follow-Up of Patients with Differentiated Thyroid Cancer.

BACKGROUND: The treatment of differentiated thyroid cancer (DTC) ends in full recovery in 80% of cases. However, in 20% of cases local recurrences or distant metastases are observed, for this reason DTC patients are under life-long follow-up. The most sensitive marker for recurrence is stimulated thyroglobulin (Tg) which, together with neck ultrasound (US), enables correct diagnosis in nearly all cases of the active disease. For many years the only known stimulation was a 4-5 week withdrawal from the L-T4 therapy (THW). For the last couple of years stimulation with the use of recombinant human TSH (rhTSH) has been available. This method of stimulation may have a significant influence in obtaining the Tg level. However, it is important to determine the cut-off level for rhTSH-stimulated Tg (rhTSH/Tg). MATERIALS AND METHODS: This is a retrospective analysis of consecutive patients from one facility who have qualified over a period of two years for repeated radioiodine therapy (RIA). In our facility the ablation effectiveness evaluation is always carried out with the use of rhTSH, with the repeated therapy following THW. Such a procedure enables two Tg measurements in the same patient after both types of stimulation within 4-5 weeks. The obtained values were compared, cut-off levels in THW conditions were used (2.0 ng/ml for patients in remission and 10.0 ng/ml for patients with an active disease). In order to determine the cut-off level for rhTSH/Tg, regression analysis and ROC curves were used. RESULTS: In 63 patients the Tg measurement of both methods of stimulation were obtained. It was observed that there was a high correlation between rhTSH/Tg and THW/Tg. However, the rhTSH/Tg level was significantly lower than THW/ Tg. The rhTSH/ Tg cut-off levels which corresponded to the 2.0 ng/ml and 10.0 ng/ml limits for THW/Tg were calculated and the values were 0.6 ng/ml and 2.3 ng/ml respectively. CONCLUSIONS: The method of stimulation has a significant impact on the obtained Tg concentrations. The assumed THW/Tg cut off levels must not be transferred to rhTSH/Tg.

The role of 18F-Fluorodeoxyglucose Positron Emission Tomography in patients with suspected recurrence or metastatic differentiated thyroid carcinoma with elevated serum thyroglobulin and negative I-131 whole body scan.

BACKGROUND: The aim of this study is to evaluate the role of ¹8F-FDG PET/CT in the detection of recurrence or distant metastasis in patients with differentiated thyroid carcinoma (DTC) with elevated serum thyroglobulin (Tg) and negative ¹³¹I whole-body scan. MATERIAL AND METHODS: The study included 19 patients (13 female, 6 male, average age 64 years) with DTC after total thyroidectomy and ¹³¹I ablation therapy that had elevated stimulated Tg and negative whole-body radioiodine scan. In all patients, standard imaging methods showed no suspicious changes. ¹8F-FDG PET/CT was performed after TSH stimulation with rhTSH or withdrawal of thyroid hormone. An evaluation of the dependence of the result of ¹8F-FDG PET/CT on the stimulated Tg levels was made accordingly. The statistical analysis was performed using Kruskal-Wallis test and ROC curves. RESULTS: Based on the results of the study ¹8F-FDG PET/CT in 6 patients, the suspicion of metastasis involved: the cervical lymph nodes (3 patients, ~16%) and lungs (3 patients, ~16%). The patients underwent surgery. The histopathology confirmed metastatic thyroid cancer in all cases. High levels of TSH-stimulated Tg (Tg from 32 to >300 ng/ml, median of 59.7 ng/ml) in patients were reported. The group of remaining 13 patients (~68%) with negative 18F-FDG PET/CT had low levels of TSH-stimulated Tg (Tg of from 1.76 to 10.2 ng/ml, median of 4.0 ng/ml). A particular correlation was observed between ¹8F-FDG PET positivity and stimulated Tg levels. The receiver operating characteristic curve (ROC) analysis demonstrated a stimulated Tg cut-off of 28.5 ng/ml with 100% sensitivity and specificity. Stimulated Tg has a large and statistically significant (p<0.0001) accuracy in the detection of recurrence/metastasis. CONCLUSION: 1. ¹8F-FDG PET/CT is useful in the diagnosis of radioiodine-negative DTC in patients with high levels of stimulated Tg. 2. The sensitivity of ¹8F-FDG PET/CT increases with stimulated Tg levels. At stimulated Tg > 28.5 ng/ml, the sensitivity of the study reaches 100%.