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Colorectal neuroendocrine neoplasm (CRNEN), especially rectal tumours, are diagnosed with increased frequency due to the widespread use of colonoscopy, including screening examinations. It is important to constantly update and promote the principles of optimal diagnostics and treatment of these neoplasms. Based on the latest literature and arrangements made at the working meeting of the Polish Network of Neuroendocrine Tumours (June 2021), this paper includes updated and supplemented data and guidelines for the management of CRNEN originally published in Endokrynologia Polska 2017; 68: 250-260.

Updated Polish recommendations for the management of patients with neuroendocrine neoplasms (NENs) of the small intestine (SINENs) and of the appendix (ANENs) are presented here. The small intestine, and especially the ileum, is one of the most common locations for these neoplasms. Most of them are well-differentiated and slow-growing tumours; uncommonly - neuroendocrine carcinomas. Their symptoms may be untypical and their diagnosis may be delayed or accidental. Najczęściej pierwszą manifestacją ANEN jest jego ostre zapalenie. Typical symptoms of carcinoid syndrome occur in approximately 20-30% of SINENs patients with distant metastases. In laboratory diagnostics the assessment of 5-hydroxyindoleacetic acid concentration is helpful in the diagnosis of carcinoid syndrome. The most commonly used imaging methods are ultrasound examination, computed tomography, magnetic resonance imaging, colonoscopy and somatostatin receptor imaging. Histopathological examination is crucial for the proper diagnosis and treatment of patients with SINENs and ANENs. The treatment of choice is a surgical procedure, either radical or palliative. Long-acting somatostatin analogues (SSAs) are essential in the medical treatment of functional and non-functional SINENs. In patients with SINENs, at the stage dissemination with progression during SSAs treatment, with high expression of somatostatin receptors, radioisotope therapy should be considered first followed by targeted therapies - everolimus. After the exhaustion of the above available therapies, chemotherapy may be considered in selected cases. Recommendations for patient monitoring are also presented.

After another meeting of experts of the Polish Network of Neuroendocrine Tumours, updated recommendations for the management of patients with gastric and duodenal neuroendocrine neoplasms, including gastrinoma, have been issued. As before, the epidemiology, pathogenesis and clinical symptoms of these neoplasms have been discussed, as well as the principles of diagnostic procedures, including biochemical and histopathological diagnostics and tumour localisation, highlighting the changes introduced in the recommendations. Updated principles of therapeutic management have also been presented, including endoscopic and surgical treatment, and the options of pharmacological and radioisotope treatment. The importance of monitoring patients with gastric and duodenal NENs, including gastrinoma, has also been emphasised.

In this paper, we present the current guidelines for the diagnostics and management of pancreatic neuroendocrine neoplasms (PanNENs) developed by Polish experts providing care for these patients in everyday clinical practice. In oncological diagnostics, in addition to biochemical tests, molecular identification with the use of NETest liquid biopsy and circulating microRNAs is gaining importance. Both anatomical and functional examinations (including new radiopharmaceuticals) are used in imaging diagnostics. Histopathological diagnosis along with immunohistochemical examination still constitute the basis for therapeutic decisions. Whenever possible, surgical procedure is the treatment of choice. Pharmacological management including biotherapy, radioisotope therapy, targeted molecular therapy and chemotherapy are important methods of systemic therapy. Treatment of PanNENs requires a multidisciplinary team of specialists in the field of neuroendocrine neoplasms.

The guidelines Thyroid Cancer 2022 are prepared based on previous Polish recommendations updated in 2018. They consider international guidelines - American Thyroid Association (ATA) 2015 and National Comprehensive Cancer Network (NCCN); however, they are adapted according to the ADAPTE process. The strength of the recommendations and the quality of the scientific evidence are assessed according to the GRADE system and the ATA 2015 and NCCN recommendations. The core of the changes made in the Polish recommendations is the inclusion of international guidelines and the results of those scientific studies that have already proven themselves prospectively. These extensions allow de-escalation of the therapeutic management in low-risk thyroid carcinoma, i.e., enabling active surveillance in papillary microcarcinoma to be chosen alternatively to minimally invasive techniques after agreeing on such management with the patient. Further extensions allow the use of thyroid lobectomy with the isthmus (hemithyroidectomy) in low-risk cancer up to 2 cm in diameter, modification of the indications for postoperative radioiodine treatment toward personalized approach, and clarification of the criteria used during postoperative L-thyroxine treatment. At the same time, the criteria for the preoperative differential diagnosis of nodular goiter in terms of ultrasonography and fine-needle aspiration biopsy have been clarified, and the rules for the histopathological examination of postoperative thyroid material have been updated. New, updated rules for monitoring patients after treatment are also presented. The updated recommendations focus on ensuring the best possible quality of life after thyroid cancer treatment while maintaining the good efficacy of this treatment.

Nuclear medicine staff are constantly exposed to low doses of ionizing radiation. This study investigated the level of genotoxic effects in hospital employees exposed to routinely used

Continuous progress in the diagnostics and treatment of neuroendocrine neoplasms (NENs), the emerging results of new clinical trials, and the new guidelines issued by medical societies have prompted experts from the Polish Network of Neuroendocrine Tumours to update the 2017 recommendations regarding the management of neuroendocrine neoplasms. This article presents the general recommendations for the management of NENs, resulting from the findings of the experts participating in the Fourth Round Table Conference, entitled "Polish Guidelines for the Diagnostics and Treatment of Neuroendocrine Neoplasms of the gastrointestinal tract, Żelechów, June 2021". Drawing from the extensive experience of centres treating these cancers, we hope that we have managed to formulate the optimal method of treating patients with NENs, applying the latest reports and achievements in the field of medicine, which can be effectively implemented in our country. The respective parts of this work present the approach to the management of: NENs of the stomach and duodenum (including gastrinoma), pancreas, small intestine, and appendix, as well as large intestine.

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.

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.

Simple Summary The aim of our study was to evaluate whether the CHEK2 mutation was a predictor of poorer clinical course in patients with papillary thyroid cancer. The study included 1547 patients from a single center in Poland, in whom the presence and variant of the CHEK2 mutation were determined. Two hundred and forty patients were found to carry this mutation. We found significant association of the CHEK2 truncating variant with vascular invasion and intermediate or high initial risk of recurrence/persistence, whereas this relationship was not found in case of the missense CHEK2 variant. Neither the truncating nor the missense mutations were associated with worse primary treatment response and outcome of the disease. Abstract 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.

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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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.

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.

This paper presents results of 131I air activity measurements performed within nuclear medical hospitals as a tool for internal dose assessment. The study was conducted at a place of preparation and administration of 131I (“hot room”) and at a nurse station. 131I activity measurements were performed for 5 and 4 consecutive working days, at the “hot room” and nurse station, respectively. Iodine from the air was collected by a mobile HVS-30 aerosol sampler combined with a gas sampler. Both the gaseous and aerosol fractions were measurement. The activities in the gaseous fraction ranged from (28 ± 1 Bq m−3) to (492 ± 4) Bq m−3. At both sampling sites, the activity of the gaseous iodine fraction trapped on activated charcoal was significantly higher than that of the aerosol fraction captured on Petrianov filter cloth. Based on these results, an attempt has been made to estimate annual inhalation effective doses, which were found to range from 0.47 mSv (nurse female) to 1.3 mSv (technician male). The highest annual inhalation equivalent doses have been found for thyroid as 32, 27, 13, and 11 mSv, respectively, for technician male, technical female, nurse male, and nurse female. The method presented here allows to fill the gaps in internal doses measurements. Moreover, because method has been successful used for many years in radioactive contamination monitoring of air in cases of serious nuclear accidents, it should also be used in nuclear medicine.

// 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: 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.

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 Wisła in November 2015 [1].