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In 2016, Nikiforov et al. (JAMA Oncol 2:1023-1029, 2016) proposed replacing the term "non-invasive encapsulated follicular variant of papillary thyroid carcinoma" (FVPTC) with the term "non-invasive follicular thyroid neoplasm with papillary-like nuclear features" (NIFTP). In 2018, to avoid the misdiagnosis of papillary thyroid cancer as NIFTP, the authors proposed changes to the criteria for NIFTP classification. Some previous studies evaluated the impact of NIFTP on the risk of malignancy (ROM) in the fine-needle aspiration cytology (FNAC) diagnostic categories according to the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC). However, little is known about the influence of an NIFTP diagnosis on ROM on the basis of the revised criteria. The aim of this study was to assess the influence of NIFTP on ROM using the revised diagnostic criteria. The present study included 998 thyroid nodules that were diagnosed and resected at the same medical center. All specimens with a diagnosis of cancer were reviewed to identify NIFTP according to the revised 2018 criteria. Additionally, molecular diagnostics were performed to detect the BRAF p.V600E mutation and TERT promoter mutations in all the NIFTP cases. The number of cases that met the revised criteria was determined, and the ROM was calculated in each of the FNAC diagnostic categories. Only five cases (2.3% of all papillary thyroid carcinoma diagnoses) were considered NIFTP, according to the 2018 criteria. With respect to the FNAC category, one case was a follicular neoplasm or suspicious for a follicular neoplasm (FN/SFN), three cases were suspicious for malignancy (SM), and one case was malignant (M). The ROM decreased in each of the Bethesda categories (0.7% in FN/SFN, 4.3% in SM, and 0.5% in M) when a diagnosis of NIFTP was taken into account. These reductions were not statistically significant. These data indicate that the NIFTP entity has very little impact on ROM for the diagnostic categories of the Bethesda system.

Aim of the study: To assess the occurrence of cardiac arrhythmias caused by high doses of levothyroxine in patients with thyroid cancer with subclinical hyperthyroidism. Materials and Methods: This prospective study included 98 women divided into three groups according to plasma thyroid stimulating hormone (TSH) concentration

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.

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 &gt, 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.

In 2016, encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC) was reclassified as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). In 2018 the criteria for NIFTP were widened by the inclusion of the complete lack of papillae. Secondary criteria, which include molecular examination, are helpful but not required for NIFTP diagnose. The aim of this study was to assess the molecular background of NIFTP and to answer the question if the aplication of revised criteria for NIFTP diagnosis is associated with the lack of oncogenic mutation. Repeat histopathological assessment of 1117 cases of papillary thyroid carcinoma (PTC) from 2000-2016 was conducted. Using initial (2016) and revised (2018) diagnostic criteria, NIFTP was diagnosed in 23 and 13 patients respectively. 50 tumor genes hotspots mutation analysis was conducted. BRAF V600E mutations were detected in patients who fulfilled only initial NIFTP criteria. Other high-risk mutations (TP53) were found in both groups of patients. The application of restrictive, revised diagnostic criteria for NIFTP negates the need for BRAF V600E examination, but these tumors still can harbor other high-risk oncogenic mutations nonetheless. Thus, molecular examination should be considered as a necessary step in NIFTP diagnostic process.

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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.

High intensity focused ultrasound (HIFU) is a new thermoablation technique used to treat benign thyroid nodules. In this method, the ultrasound beam passes through the patient's skin and focuses very precisely on the target lesion at a distance far from the source of ultrasound generation, making HIFU the only truly non-invasive method of thermoablation developed to date. HIFU is therefore an attractive alternative to surgery and other thermoablative techniques. This review describes the principles of HIFU treatment, the selection of patients suitable for HIFU, the course and effects of treatment, and future perspectives.

Significant advances have been made in thyroid can-cer research in recent years, therefore relevant clinical guidelines need to be updated. The current Polish guidelines "Diagnostics and Treatment of Thyroid Carcinoma" have been formulated at the "Thyroid Cancer and Other Malignancies of Endocrine Glands" conference held in Wisla in November 2015 [1].

Medullary thyroid cancer (MTC) is a rare malignancy that arises from calcitonin-producing C-cells. Curative treatment for patients with metastatic MTC is challenging. Identifying the mechanisms by which cancer cells inhibit the activity of immune cells provides an opportunity to develop new therapies that restore anticancer activity. Little is known about the immunological phenomena underlying MTC. Here, we examined the expression profile of 395 genes associated with MTC. The study included 51 patients diagnosed with MTC at a single center. Bioinformatical analysis revealed that CD276 expression in MTC cells was at least three-fold higher than that in normal tissue. The expression of CD276 showed a weak but statistically significant positive correlation with tumor diameter, but we did not find a significant association between CD276 expression and other histopathological clinical factors, or the response to initial therapy. A search of published data identified the monoclonal antibody (inhibitor) enoblituzumab as a potential drug for patients diagnosed with MTC overexpressing CD276.

Background: Multiple endocrine neoplasia type 2A (MEN2A) is a rare, hereditary syndrome resulting from a germline mutation in the RET proto-oncogene and characterized primarily by medullary thyroid cancer (MTC), pheochromocytoma (PHEO), and hyperparathyroidism. Types of RET mutation have been associated with age at onset, clinical outcomes of MTC, and the penetrance of other components. Patients classified as ‘high-risk’ by the American Thyroid Association (ATA), based on the aggressiveness of MTC and the penetrance of other components, are recommended to undergo early prophylactic thyroidectomy at age ≤ 5 years and to be screened for PHEO at age ≥ 11 years. Patients with RET codon C634R mutations have been classified as high-risk. Case presentation: The present study describes a 71-year-old woman newly diagnosed with hereditary MTC related to a RET C634R germline mutation. Her basal serum calcitonin level was high, but there was no evidence of distant metastases. Surgery revealed bilateral MTC with two metastatic lymph nodes. Because microscopic resection was incomplete and extranodal extension was observed, the patient underwent adjuvant external beam radiotherapy. Response to therapy was excellent. Follow-up after 1.5 years showed no evidence of disease or other manifestations of MEN2A. Conclusion: Despite RET C634R carriers being classified as high-risk by the ATA, this patient did not present with either distant MTC or PHEO until her seventies. To our knowledge, only one other patient has shown a similar late identification of a RET C634R mutation, but MTC could not be diagnosed because the patient was lost to follow-up. Further research is required to develop optimal protocols that could allow patients requiring prophylactic thyroidectomy to be differentiated from those who can be monitored closely without early surgery.

Purpose Delayed risk stratification (DRS) system by Momesso and coworkers was accepted by the American Thyroid Association as a diagnostic tool for the risk stratification of unfavorable clinical outcomes and to monitor the clinical outcomes of differentiated thyroid cancer (DTC) patients treated without radioactive iodine (RAI). The aim of this study was to evaluate the DRS system in patients with pT1aN0/Nx stage. Methods The study included 304 low-risk patients after thyroidectomy (n = 202) or lobectomy (n = 102) without RAI and were treated at a single center. The median age was 50.5 years, 91.1% were women and the median follow-up was 4 years. DRS of the treatment response was performed based on medical records and according to the criteria of Momesso and coworkers. Disease course (recurrence, death) and status (remission, persistent disease) on December 31, 2016 were evaluated. The relationship between unfavorable outcomes and the DRS system was evaluated. Results Response to initial therapy was excellent in 272 patients (89.5%), indeterminate in 31 (10.2%) and biochemical incomplete (increased TgAb levels) in one (0.3%). Two patients in the excellent response group experienced recurrence at 6 and 7 years of follow-up (after lobectomy). None of the patients with indeterminate and biochemical incomplete response developed structural disease, and none of the patients died during the follow-up. Conclusions The DRS system was not useful for predicting the risk of unfavorable clinical outcomes and cannot be used to personalize the monitoring method of the disease in patients at pT1aN0/Nx stage who are not treated with RAI.

// Monika Szymonek 1 , Artur Kowalik 2 , Janusz Kopczynski 3 , Danuta Gąsior-Perczak 1 , Iwona Palyga 1 , Agnieszka Walczyk 1 , Klaudia Gadawska-Juszczyk 1 , Agnieszka Plusa 3 , Ryszard Mezyk 4 , Magdalena Chrapek 5 , Stanislaw Goźdź 6, 7 and Aldona Kowalska 1, 7 1 Endocrinology Clinic, Holycross Cancer Center, Kielce, Poland 2 Department of Molecular Diagnostics, Holycross Cancer Center, Kielce, Poland 3 Department of Surgical Pathology, Holycross Cancer Center, Kielce, Poland 4 Cancer Epidemiology, Holycross Cancer Center, Kielce, Poland 5 Department of Probability Theory and Statistics Institute of Mathematics, Faculty of Mathematics and Natural Science, Jan Kochanowski University, Kielce, Poland 6 Oncology Clinic, Holycross Cancer Center, Kielce, Poland 7 The Faculty of Health Sciences, Jan Kochanowski University in Kielce, Poland Correspondence to: Monika Szymonek, email: christ76@interia.pl Keywords: BRAF V600E, papillary thyroid cancer, immunohistochemistry, Sanger sequencing, qPCR Received: May 17, 2017 Accepted: July 25, 2017 Published: August 24, 2017 ABSTRACT Introduction : The BRAF V600E mutation is the most common genetic event occurring in papillary thyroid cancer (PTC). Recently, the possibility of using immunohistochemistry (IHC) to detect the BRAF V600E mutation has been reported. Materials and methods : In 140 patients with classical PTC, the status of the BRAF V600E mutation was determined by IHC (using two alternative staining protocols, IHC-1 and IHC-2) and molecular biology methods: Sanger sequencing (SEQ) and real-time PCR (qPCR). Results : The BRAF V600E mutation was detected in 57.1% (80/140) patients by IHC-1 and 62.9% (88/140) patients by IHC-2. The highest correlation in detecting the BRAF V600E mutation was found between IHC-2 and qPCR (94.2%), and between IHC-1 and qPCR (83.9%). Correlations between IHC-1 and SEQ and between IHC-2 and SEQ were 71.5% and 76.2%, respectively. The IHC-2 protocol had higher sensitivity, PPV, and NPV, and Cohen’s kappa than IHC- 1. The presence of BRAF V600E mutation in IHC-2 statistically correlated with age at diagnosis, histopathological stage, and extrathyroidal extension. Conclusions : The results obtained in this study indicate a lack of concordance between BRAF V600E detection by IHC and molecular methods. The IHC method cannot replace molecular methods for the detection of the BRAF V600E mutation.

Context 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. Objective 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 and structural disease. Participants Unselected PTC cases with known BRAF status diagnosed from 2000–2013 and actively monitored at one institution (n=723) were reviewed retrospectively. Main Outcome Measures 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 were analyzed. 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. This article is protected by copyright. All rights reserved.

This paper presents the updated Polish Neuroendocrine Tumour Network expert panel recommendations on the management of neuroendocrine neoplasms (NENs) of the stomach and duodenum, including gastrinoma. The recommendations discuss the epidemiology, pathogenesis, and clinical presentation of these tumours as well as their diagnosis, including biochemical, histopathological, and localisation diagnoses. The principles of treatment are discussed, including endoscopic, surgical, pharmacological, and radionuclide treatments. Finally, there are also recommendations on patient monitoring.

This study presents the revised Polish guidelines regarding the management of patients suffering from neuroendocrine neoplasms (NENs) of the small intestine and appendix. The small intestine, especially the ileum, is the most common location for these neoplasms. Most are well differentiated and slow growing. Their symptoms may be atypical, which can result in delayed or accidental diagnosis. Appendicitis is usually the first manifestation of NEN in this location. Typical symptoms of carcinoid syndrome occur in approximately 20-30% of patients suffering from small intestinal NENs with distant metastases. The main cause of death in patients with carcinoid syndrome is carcinoid heart disease. The most useful laboratory test is the determination of chromogranin A, while concentration of 5-hydroxyindoleacetic acid is helpful in the diagnostics of carcinoid syndrome. For visualisation, ultrasound, computed tomography, magnetic resonance imaging, colonoscopy, video capsule endoscopy, double-balloon enteroscopy, and somatostatin receptor scintigraphy may be used. A detailed his-tological report is crucial for the proper diagnostics and therapy of NENs of the small intestine and appendix. The treatment of choice is surgical management, either radical or palliative. The pharmacological treatment of the hormonally active and non-active small intestinal NENs as well as NENs of the appendix is based on long-acting somatostatin analogues. In patients with generalised NENs of the small intestine in progress during the SSA treatment, with good expression of somatostatin receptors, the first-line treatment should be radio-isotope therapy, while targeted therapies, such as everolimus, should be considered afterwards. When the above therapies are exhausted, in certain cases chemotherapy may be considered.

Neuroendocrine neoplasms/tumours (NENs/NETs) of the large intestine are detected increasingly often, especially rectal tumours, which is probably associated with the widespread use of screening colonoscopy. There is a growing body of evidence supporting the thesis that the NENs of the rectum and the NENs of the colon are two different diseases. Rectal NENs are usually small lesions, of low to moderate histological malignancy, associated with good prognosis, and most may be treated endoscopically. NENs of the colon, however, are often aggressive, poorly differentiated, associated with a poor or uncer-tain prognosis, and require surgical treatment. The management guidelines regarding these groups of patients are constantly changing. On the basis of the recent literature data and conclusions reached by the working meeting of the Polish Network of Neuroendocrine Tumours (December 2016), this study completes and updates the data and management guidelines regarding colorectal NENs published in Endokrynologia Polska 2013; 64: 358-368.

// Artur Kowalik 1, 2 , Danuta Gąsior-Perczak 3 , Martyna Gromek 1 , Monika Siolek 4 , Agnieszka Walczyk 3 , Iwona Palyga 3 , Malgorzata Chlopek 1 , Janusz Kopczynski 5 , Ryszard Mezyk 6 , Aldona Kowalska 3 and Stanislaw Goźdź 7, 8 1 Department of Molecular Diagnostics, Holycross Cancer Centre, Kielce, Poland 2 Department of Surgery and Surgical Nursing with The Scientific Research Laboratory, The Faculty of Health Sciences of The Jan Kochanowski University, Kielce, Poland 3 Endocrinology Clinic, Holycross Cancer Centre, Kielce, Poland 4 Genetic Clinic, Holycross Cancer Centre, Kielce, Poland 5 Department of Surgical Pathology, Holycross Cancer Centre, Kielce, Poland 6 Cancer Epidemiology, Holycross Cancer Centre, Kielce, Poland 7 Oncology Clinic, Holycross Cancer Centre, Kielce, Poland 8 The Faculty of Health Sciences, Jan Kochanowski University, Kielce, Poland Correspondence to: Artur Kowalik, email: arturko@onkol.kielce.pl Keywords: p.G534E, sporadic papillary thyroid carcinoma, HABP2, thyroid cancer, non-medullary thyroid cancer Received: October 20, 2016 Accepted: March 09, 2017 Published: April 06, 2017 ABSTRACT Thyroid cancer is one of the most frequently diagnosed cancers of the endocrine system. There are no known genetic risk factors for non-medullary thyroid cancer, other than a small number of hereditary syndromes; however, approximately 5% of non-medullary thyroid cancer, designated familial non-medullary thyroid cancer, exhibits heritability. The p.G534E (c.1601G>A) variant of HABP2 was recently reported as a risk factor for familial non-medullary thyroid cancer, including papillary thyroid carcinoma. We analyzed the incidence of the c.1601G>A variant of HABP2 in a Polish population consisting of 326 cases of papillary thyroid carcinoma and 400 control individuals by DNA genotyping, performed by Sanger sequencing. The c.1601G>A variant was detected in 3.7% of sporadic papillary thyroid carcinoma cases and 4.7% of healthy controls, and we did not detect an association between this variant and sporadic papillary thyroid carcinoma risk (OR = 0.71, 95% CI: 0.33–1.51; p = 0.3758). Additionally, no significant associations were identified between clinical and pathological disease features, response to primary treatment, and clinical status at the end of the observation, and HABP2 c.1601G>A genotype. In conclusion, the p.G534E variant of HABP2 is not associated with sporadic papillary thyroid carcinoma risk in the Polish population.

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.

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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.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.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).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.

Aim of the study: Fine-needle aspiration biopsy (FNAB) is the most accurate and cost-effective method to evaluate the risk of malignancy of thyroid nodules, but approximately 1–24% of FNABs generate a nondiagnostic result (ND-FNAB). The aim of this study was to determine the predictive factors of a repeated nondiagnostic result of FNAB. Material and methods : A total of 4018 FNABs performed in a territorial referral centre were analysed, of which 288 (7.17%) were nondiagnostic. Medical records were available for 245 biopsies performed in 228 patients. The retrospective analysis of factors that may influence a repeat ND-FNAB, including demographic, clinical and ultrasound characteristics, was performed. Results : A repeat FNAB was performed in 159 nodules giving a diagnostic result in 79.2% of cases. The time between the biopsies ranged from 1 to 611 days (mean 154.4, median 119). The timing of a repeat FNAB did not significantly alter the diagnostic output (p = 0.29). In the univariate analysis, significant predictors of a repeat ND-FNAB were older patient age (p = 0.02), L-thyroxine supplementation (p = 0.05), and a history of 131 I therapy (p < 0.0001). In the multivariate analysis, only a history of 131 I therapy was a statistically significant risk factor for a repeat ND-FNAB (p = 0.002). Conclusions : Patients with a history of 131 I therapy and ND-FNAB should undergo periodic ultrasonographic assessment rather than a repeat biopsy. The interval between repeated FNABs recommended by guidelines does not affect the diagnostic output.

Background Poorly differentiated thyroid cancer (PDTC) is a rare but aggressive type of thyroid cancer (TC) and the main cause of death from non-anaplastic follicular cell-derived TC. Although the Turin criteria are well defined, the pathological features that could serve as diagnostic and prognostic factors remain controversial. Materials and methods Forty-nine consecutive PDTC cases were identified in a single cancer center between 2000 and 2018. We analyzed the impact of routine histopathological and immunohistochemical features and several parameters that are not routinely included in pathology reports such as the presence of atypical mitoses, the amount of necrosis, or insulin-like growth factor-II mRNA-binding protein 3 immunostaining on the survival of patients with PDTC. Overall survival (OS) and disease-specific survival (DSS) were calculated using the Kaplan-Meier method. Results Of the 49 PDTC 34 (69.4%) showed the insular pattern of growth. The median of poorly differentiated area was 95% (range, 1-100), and 30 (61.2%) patients had a predominant (>50%) insular area. The 5-year OS and DSS rates at a median follow-up of 57 months were 60.6% and 64.3%, respectively. Univariate analysis showed that tumor size >4 cm, presence of atypical mitoses, Ki-67 >5%, and thyroglobulin (Tg)-negative immunostaining were associated with a higher risk of PDTC-related death. Atypical mitoses and Tg negativity were independent factors of worse DSS in multivariate analysis. Patients with insular and predominant insular areas showed a 3- and 6-fold higher risk of PDTC death when they displayed atypical mitoses. Conclusions In PDTC, the presence of atypical mitoses may be helpful in identifying patients with poorer outcome and worth including in pathology reports, particularly in tumors with a dominant insular pattern of growth. Additionally, the inclusion of Tg immunostaining may be considered in a prognostic context, and not only as a diagnostic feature.

Introduction: Struma ovarii accounts for 2% of mature teratomas. Struma ovarii is diagnosed when thyroid tissue accounts for >50% of the teratoma. Malignant transformation is rare, occurring in 300 ng/mL, which decreased to 38.2 ng/mL after gynecological surgery with undetectable anti-Tg antibodies. The patient underwent total thyroidectomy with no cancer detected on histopathological examination. The patient was treated with I-131 and showed no recurrence 4 years after the diagnosis. Conclusions: Malignant struma ovarii is diagnosed by surgery. Because papillary carcinoma in struma ovarii is rare and there are no guidelines regarding the management of this type of cancer, therapeutic decisions should be made individually based on clinical and pathological data.

Objective Poorly differentiated thyroid cancer (PDTC) is a rare, but aggressive thyroid cancer (TC) and a main cause of death from non-anaplastic follicular cell-derived TC. Assessing the risk of PDTC-related death and the risk of recurrence is important for clinicians. The recent American Thyroid Association (ATA) 2015 guidelines and the updated 8th edition of the American Joint Committee on Cancer/Tumor-Node-Metastasis (AJCC/TNM) staging system should support clinicians in the management approach to PDTC patients. Patients Forty-six consecutive PDTC patients treated in a single oncologic centre, 2000-2017. Measurements Retrospective analysis of TNM stage, initial risk, response-to-therapy categories, follow-up and final disease status incorporating the ATA 2015 criteria and the 8th AJCC/TNM staging system. Disease-specific survival (DSS) using the Kaplan-Meier method. Results Of the 46 PDTC 21 (45.6%) were ATA high risk (HR), 22 (47.8%), 17 (37%) and seven (15.2%) were TNM stages I, II, and III-IV, respectively. During a median follow-up of 55.5 months, two (4.3%) patients were recurrent, 18 (39.1%) died of PDTC. The 5-/10-year DSS were 65/57%, respectively. According to the AJCC/TNM, the 5-/10-year DSS of I, II, and III-IV stage were 83/83%; 77/55%, and 0/0%, respectively. According to the 2015 ATA initial risk, the 5-/10-year DSS were 91/72% for ATA intermediate risk and 38/38% for ATA HR patients. Conclusions In PDTC patients, the updated AJCC/TNM staging system accurately predicts a high risk of death in stage III-IV, whereas it seems to be inadequate for predicting a very low or low risk of death expected for differentiated TC in stage I-II. The ATA initial HR may be also used to predict a high risk of PDTC-related death.

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.

Introduction: Post-operative thyroglobulin (TgPO) is a recognised prognostic factor in patients following thyroidectomy due to differentiated thyroid cancer (DTC). However, its concentration is affected by thyroid remnants, which may diminish the prognostic value of TgPO. The aim of this paper is to assess the usefulness of stimulated post-ablative thyroglobulin (TgPA) measurements 6–9 months after 131I therapy, as a prognostic factor, and its possible advantage over TgPO determination. Material and methods: The study involved 577 DTC patients treated in the Holycross Cancer Centre in the years 2000–2013. Exclusion criteria were: patients with no recommendation for 131I adjuvant therapy, positive thyroglobulin antibody titre, and initial distant metastases. On the basis of a ROC curve analysis, values of TgPO and TgPA concentrations were determined, which enable the most accurate identification of good prognosis. Calculating area under the curves (AUCs) allowed for comparison of the data. Results: TgPO concentration ≤ 6.99 ng/mL, with 75.7% sensitivity and 94.7% specificity enables anticipation of remission of the disease. TgPA concentration ≤ 1.16 ng/mL under endogenous TSH stimulation with sensitivity of 91.1% and specificity of 94.7% allows anticipation of remission of the disease. TgPA concentration ≤ 1.24 ng/mL under rh TSH stimulation with sensitivity of 95.4% and specificity of 95.0% enables anticipation of remission of the disease. Conclusions: No differences in clinical usefulness of the assessment of TgPO and stimulated TgPA concentrations as indicators of good prognosis were found. However, TgPA allows anticipation of remission of the disease with higher sensitivity. It also appears that TgPA may be of particular prognostic importance in baseline high-risk patients (pT3-T4/N1). A sufficiently low TgPA concentration, demonstrating good response to 131I adjuvant therapy in these groups, is an indicator of improved prognosis. (Endokrynol Pol 2015; 66 (6): 486–494)

Mutations in the cell cycle checkpoint kinase 2 (CHEK2) tumor suppressor gene are associated with multi-organ cancer susceptibility including cancers of the breast and prostate. A genetic association between thyroid and breast cancer has been suggested, however little is known about the determinants of this association. To characterize the association of CHEK2 mutations with thyroid cancer, we genotyped 468 unselected patients with papillary thyroid cancer and 468 (matched) cancer-free controls for four founder mutations of CHEK2 (1100delC, IVS2 + 1G>A, del5395 and I157T). We compared the family histories reported by patients with a CHEK2 mutation to those of non-carriers. A CHEK2 mutation was seen in 73 of 468 (15.6%) unselected patients with papillary thyroid cancer, compared to 28 of 460 (6.0%) age- and sex-matched controls (OR 3.3; p A, 1100delC or del5395) was associated with a higher risk of thyroid cancer (OR = 5.7; p = 0.006), than was the missense mutation I157T (OR = 2.8; p = 0.0001). CHEK2 mutation carriers reported a family history of breast cancer 2.2 times more commonly than non-carriers (16.4% vs.8.1%; p = 0.05). A CHEK2 mutation was found in seven of 11 women (63%) with multiple primary cancers of the breast and thyroid (OR = 10; p = 0.0004). These results suggest that CHEK2 mutations predispose to thyroid cancer, familial aggregations of breast and thyroid cancer and to double primary cancers of the breast and thyroid.

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.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.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 to300 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 (p0.0001) accuracy in the detection of recurrence/metastasis.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 Tg28.5 ng/ml, the sensitivity of the study reaches 100%.

SummaryContext An activating mutation in the gene BRAF has been correlated with poorer prognosis and more aggressive clinical course in papillary thyroid carcinoma (PTC). We therefore hypothesized that the good prognosis, high 5-year disease-free rate and high survival rate of patients with less aggressive papillary thyroid microcarcinoma (pT1aNo-x) would be associated with a lower incidence of the BRAFV600E mutation. Objectives To evaluate the frequency of the activating mutation BRAFV600E in low-risk papillary thyroid microcarcinoma (pT1aNo-x at the moment of diagnosis) and the association of the mutation with the clinical outcome in a retrospective analysis. Study Design BRAFV600E was characterized in 113 PTC patients diagnosed with pT1aNo-x (one PTC focus with a diameter

Progress in the diagnostics and therapy of gastro-entero-pancreatic (GEP) neuroendocrine neoplasms (NEN), the published results of new randomised clinical trials, and the new guidelines issued by the European Neuroendocrine Tumour Society (ENETS) have led the Polish Network of Neuroendocrine Tumours to update the 2013 guidelines regarding management of these neoplasms. We present the general recommendations for the management of NENs, developed by experts during the Third Round Table Conference - Diagnostics and therapy of gastro-entero-pancreatic neuroendocrine neoplasms: Polish recommendations in view of current European recommenda-tions, which took place in December 2016 in Żelechow near Warsaw. Drawing from the extensive experience of centres dealing with this type of neoplasms, we hope that we have managed to develop the optimal management system, applying the most recent achievements in the field of medicine, for these patients, and that it can be implemented effectively in Poland. These management guidelines have been arranged in the following order: gastric and duodenal NENs (including gastrinoma); pancreatic NENs; NENs of the small intestine and appendix, and colorectal NENs.

Aim of the study To examine characteristics and treatment patterns of symptomatic neuroendocrine tumors (NETs) patients who received lanreotide Autogel 120 mg (ATG120) administered as part of routine clinical practice. Material and methods Lanro-NET is a national, multicenter, non-interventional, observational study in the population of adult patients with symptomatic NETs treated with ATG120 for at least three months before inclusion. Data on demographic and clinical characteristics of the population, dosing interval regimen and aspects of administration were collected prospectively during 12 months. Costs were calculated from the perspective of public payer for the year 2014. Results Fifty-two patients were enrolled in the study. Primary tumors were located predominantly in gastrointestinal tract (51.2%), all tumors were metastatic. The most commonly reported disease symptoms were flushing and diarrhea (55.8% of patients). 86% of patients had undergone surgery, chemotherapy and radioisotope therapy were used in 11.6% and 46.5% of patients, respectively. During the 12-months observation 12 (28%) patients received ATG120 at an extended dosing interval (> 4 weeks), the mean number of days between injections was 31.75 (SD 6.74). The cost of ATG12 was estimated at 4273.17 PLN patient/month. In all patients ATG120 was administered by nurse, 51.6% of injections in out-patient setting, 48.4% – in hospital. Conclusions This study presents the current use of ATG120 in the population of Polish NETs patients in a realistic clinical settings. Finding that 28% of patients could be treated with extended dose intervals supports the potential for ATG120 of reducing treatment burden.

The thyroid is the most common site of endocrine cancer. One type of thyroid cancer, non-medullary thyroid cancer (NMTC), develops from follicular cells and represents approximately 90% of all thyroid cancers. Approximately 5%−15% of NMTC cases are thought to be of familial origin (FNMTC), which is defined as the occurrence of the disease in three or more first-degree relatives of the patient. It is often divided into two groups: Syndrome-associated and non-syndromic. The associated syndromes include Cowden syndrome, familial adenomatous polyposis, Gardner syndrome, Carney complex and Werner syndrome. The hereditary factors contributing to the unfavorable course of FNMTC remain poorly understood; therefore, considerable effort is being expended to identify contributing loci. Research carried out to date identifies fourteen genes (DICER1, FOXE1, PTCSC2, MYH9, SRGAP1, HABP2, BRCA1, CHEK2, ATM, RASAL1, SRRM2, XRCC1, TITF-1/NKX2.1, PTCSC3) associated with vulnerability to FNMTC that are not related to hereditary syndromes. In this review, we summarize FNMTC studies to date, and provide information on genes involved in the development of non-syndromic familial non-medullary thyroid cancers, and the significance of mutations in these genes as risk factors. Moreover, we discuss whether the genetic polymorphism rs966423 in DIRC3 has any potential as a prognostic factor of papillary thyroid cancer.

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

Introduction The aim of this study was to assess the utility of [Lys40(Ahx-HYNIC-99mTc/EDDA)NH2]-exendin-4 scintigraphy in the management of patients with hypoglycemia, particularly in the detection of occult insulinoma. Materials and Methods Forty patients with hypoglycemia and increased/confusing results of serum insulin and C-peptide concentration and negative/inconclusive results of other imaging examinations were enrolled in the study. In all patients GLP-1 receptor imaging was performed to localise potential pancreatic lesions. Results Positive results of GLP-1 scintigraphy were observed in 28 patients. In 18 patients postsurgical histopathological examination confirmed diagnosis of insulinoma. Two patients had contraindications to the surgery, one patient did not want to be operated. One patient, who presented with postprandial hypoglycemia, with positive result of GLP-1 imaging was not qualified for surgery and is in the observational group. Eight patients were lost for follow up, among them 6 patients with positive GLP-1 scintigraphy result. One patient with negative scintigraphy was diagnosed with malignant insulinoma. In two patients with negative scintigraphy Munchausen syndrome was diagnosed (patients were taking insulin). Other seven patients with negative results of 99mTcGLP-1 scintigraphy and postprandial hypoglycemia with C-peptide and insulin levels within the limits of normal ranges are in the observational group. We would like to mention that 99mTc-GLP1-SPECT/CT was also performed in 3 pts with nesidioblastosis (revealing diffuse tracer uptake in two and a focal lesion in one case) and in two patients with malignant insulinoma (with the a focal uptake in the localization of a removed pancreatic headin one case and negative GLP-1 1 scintigraphy in the other patient). Conclusions 99mTc-GLP1-SPECT/CT could be helpful examination in the management of patients with hypoglycemia enabling proper localization of the pancreatic lesion and effective surgical treatment. This imaging technique may eliminate the need to perform invasive procedures in case of occult insulinoma.

The aim of the study was to assess the usefulness of circulating chemokines CXCL9 and CXCL10 measurements as surrogate markers of GO activity and as a guideline in therapeutic decision-making. Forty-two individuals were divided into 4 groups: 1. 15 euthyroid patients with clinical symptoms of orbitopathy (GO) who underwent corticosteroid therapy consisting of intravenous infusions of methylprednisolone (MP) and teleradiotherapy (TR); 2. 10 patients with hyperthyroid GD (Gtx); 3. 10 patients with GD in euthyreosis (Geu); and 4. 7 healthy volunteers age and sex-matched to groups 1-3. The serum samples were collected 24 h before MP, 24 h after first dose of MP, before TR and at the end of therapy. Serum CXCL9 and CXCL10 were determined by ELISA and TSH-Rab by RIA. There were significant reductions in CXCL9 and CXCL10 serum concentrations during CS and TR treatment as compared both to control group and to basal values in GO patients. Moreover, CXCL9 concentration was significantly diminished in comparison to controls in GO patients who were identified later as corticosteroid-respondent (p0.001). In this latter group of patients, CXCL9 was also found to be significantly reduced 24 h after first dose of MP as compared to non-respondents (p0.02). The high-degree positive correlation between CXCL9 and CXCL10 was found (R=0.8; p0.001). Our results suggest that the increased concentrations of CXCL9 (and CXCL10), at least in part, reflect the activity of orbital inflammation and therefore these chemokines could serve as a guideline in therapeutic decision-making in patients with Graves' orbitopathy.

Macroprolactin may cause elevation of prolactin (PRL) concentrations measured by standard assays. In our study, we assessed the prevalence of pituitary lesions in women with macroprolactinaemia and either oligomenorrhoea or secondary amenorrhoea. Pituitary MRI scans were performed in 61 women aged 31.0 ± 6.7 years (mean ± SD), with raised PRL concentrations due to macroprolactinaemia, detected by 25% polyethylene glycol (PEG) precipitation method (PRL recovery40%). After PEG precipitation of macroprolactin, free PRL concentrations were still raised in 36 (59%) women. Microadenomas were detected in 10 patients out of 61 (16.4%), with raised free PRL in 9 of these cases, while macroadenomas were detected in 4 out of 61 (6.6%) women, all of whom also had raised free PRL. In case of coexistence of macroprolactinaemia and raised free PRL after PEG precipitation of macroprolactin, the chance of finding of either a micro- or a macroadenoma was 36% (13 cases out of 36). We conclude that hyperprolactinaemia and macroprolactinaemia may coexist in the same patient. Furthermore, if free PRL is raised after PEG precipitation of macroprolactin, then the chance of finding either a pituitary micro- or macroadenoma in women with oligo-/amenorrhoea is over 30%. Therefore pituitary magnetic resonance imaging is mandatory in all such cases.

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.

Differentiated papillary thyroid cancer (PTC) is the most common cancer of the endocrine system. PTC has a very good prognosis and a high 5 year survival rate; however, some patients are unresponsive to treatment, and their diagnosis eventually results in death. Recent efforts have focused on searching for prognostic and predictive factors that may enable treatment personalization and monitoring across the course of the disease. The presence of the BRAF mutation is considered to contribute to the risk of poor clinical course, according to American Thyroid Association (ATA) recommendations. The method used for genotyping can impact the predicted mutation frequency; however, ATA recommendations do not address this issue. We evaluated the molecular diagnostic (BRAF p.V600E mutation) results of 410 patients treated for PTC. We thoroughly analyzed the impact of three different BRAF mutation detection methods, Sanger Sequencing (Seq), allele-specific amplification PCR (ASA-PCR), and quantitative PCR (qPCR), on the frequency of mutation detection in 399 patients. Using Seq, we detected the BRAF mutation in 37% of patients; however, we were able to detect BRAF mutations in 57% and 60% of patients using the more sensitive ASA-PCR and qPCR technologies, respectively. Differences between methods were particularly marked in the thyroid papillary microcarcinoma group; BRAF p.V600E mutations were found in 37% of patients using Seq and 63% and 66% of patients using ASA-PCR and qPCR, respectively. We also evaluated how these different diagnostic methods were impacted by DNA quality. Applying methods with different sensitivities to the detection of BRAF p.V600E mutations may result in different results for the same patient; such data can influence stratification of patients into different risk groups, leading to alteration of treatment and follow-up schemes.