BACKGROUND: Poorly differentiated thyroid carcinoma (PDTC) and anaplastic thyroid carcinoma (ATC) are very rare tumors with extremely aggressive behavior. Their comprehensive genetic background is still unclear. Some of the main genetic changes of differentiated thyroid carcinomas, such as mutations in BRAF and RAS genes, as well as changes in CTNNB1, PIK3CA, TP53, AXIN1, PTEN or APC genes leading to the dedifferentiation of the tumors, are described. MATERIALS AND METHODS: DNAs from fresh frozen thyroid tissues of 3 PDTCs and 5 ATCs were extracted. The next-generation sequencing (NGS) approach was used to target 94 genes involved in cancer. The samples were prepared using a TruSight Cancer panel and sequenced with a MiSeq sequencer. Analysis of variants was performed by the MiSeq Reporter and NextGENe software and stringent criteria for prioritization of the variants were used in the Illumina VariantStudio software. RESULTS: Using NGS, we identified 26 genetic changes in 18 genes, novel variants included. CONCLUSION: NGS is a useful tool for searching for new variants and genes involved in PDTC and ATC. It seems that each of these rare tumor types has its own specific genetic background. These data could be helpful for recognizing new genetic markers and targets for future personalized therapy.

• MeSH
• Thyroid Carcinoma, Anaplastic genetics   pathology   MeSH
• Cell Differentiation genetics   MeSH
• Phosphatidylinositol 3-Kinases genetics   MeSH
• PTEN Phosphohydrolase genetics   MeSH
• Humans MeSH
• Mutation MeSH
• Biomarkers, Tumor genetics   isolation & purification   MeSH
• Neoplasm Proteins genetics   MeSH
• Thyroid Neoplasms genetics   pathology   MeSH
• Proto-Oncogene Proteins B-raf genetics   MeSH
• High-Throughput Nucleotide Sequencing MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

• MeSH
• Cell Differentiation drug effects   MeSH
• Fluorescent Antibody Technique MeSH
• Reverse Transcriptase Inhibitors therapeutic use   MeSH
• Cells, Cultured MeSH
• Humans MeSH
• Tumor Cells, Cultured MeSH
• Thyroid Neoplasms metabolism   pathology   therapy   MeSH
• Nevirapine therapeutic use   MeSH
• Carcinoma, Papillary metabolism   pathology   therapy   MeSH
• Iodine Radioisotopes pharmacokinetics   therapeutic use   MeSH
• Aged MeSH
• Thyroid Gland cytology   metabolism   drug effects   MeSH
• Thyroglobulin analysis   MeSH
• Thyroidectomy MeSH
• Check Tag
• Humans MeSH
• Aged MeSH
• Female MeSH

• Keywords
• nemoci štítné žlázy, cytopatologie, biopsie, cytodiagnostika, cytologická technika,
• MeSH
• Biopsy MeSH
• Cytodiagnosis MeSH
• Thyroid Gland pathology   MeSH

Karcinomy štítné žlázy jsou nejčastější malignitou endokrinního systému a jejich incidence stále vzrůstá. Většina nádorů štítné žlázy se vyskytuje sporadicky, nicméně některé se dědí v rodinách. Podle buněk původu můžeme karcinomy rozdělit na dvě skupiny. Do první skupiny patří medulární karcinom štítné žlázy vycházející z parafolikulárních C-buněk. 20 - 25 % medulárních karcinomů štítné žlázy je dědičných v rámci syndromů mnohočetné endokrinní neoplázie typu 2. Genetickou příčinou jsou aktivující zárodečné mutace v RET proto-onkogenu, které se dědí autozomálně dominantně. V současné době je již zavedeno rutinní genetické testování a presymptomatická léčba v podobě profylaktické totální tyreoidektomie, která je načasována na základě genotypově-fenotypové korelace. Druhou skupinou karcinomů jsou karcinomy pocházející z folikulárních buněk štítné žlázy, které se dále dělí na diferencované (papilární a folikulární) a nediferencované (anaplastický a nízce diferencovaný). I zde je 5-15 % karcinomů dědičných, a to buď v rámci různých dědičných syndromů (Gardnerův, Cowdenův, Wernerův, Carneyho komplex), nebo jen jako samostatný familiární papilární karcinom štítné žlázy. Ačkoliv u dědičných rakovinných syndromů je genetická podstata již většinou známá (APC, PTEN, PRKAR1α a WRN geny), příčina nesyndromického familiárního papilárního karcinomu štítné žlázy se zatím zkoumá, nicméně již bylo objeveno několik slibných genetických lokusů.

Thyroid carcinoma is the most common malignancy of the endocrine system and its incidence is still growing. The majority of thyroid tumors occur in sporadic form, however, some are inherited in families. The carcinomas can be divided into two groups according to the types of thyroid cells. Medullary thyroid carcinoma is derived from parafollicular C-cells. 20 - 25% of medullary thyroid carcinomas are inherited in multiple endocrine neoplasia type 2 syndromes. Genetic causes are activated by germ-line mutations in the RET proto-oncogene, which are transmitted autosomal, dominantly. At present the routine genetic screening and presymptomatic treatment (i.e. prophylactic total thyreoidectomy) on the basis of genotype-phenotype correlation has already been developed. The second group consists of carcinomas derived from follicular cells of thyroid that can be divided into differentiated (papillary and follicular) and nondifferentiated (anaplastic and poorly differentiated) ones. Also in this group 5-15% of carcinomas are cases of different familial syndromes (Gardner, Cowden, Werner syndromes and Carney complex) or only simple familial papillary thyroid carcinoma. Although the genetic basis of inherited cancer syndromes are mostly known (APC, PTEN, PRKAR1α and WRN genes), the cause of nonsyndromic familial papillary thyroid carcinoma is still under investigation, several predisposition genetic loci are recognized.

• Keywords
• medulární karcinom štítné žlázy, MEN2 syndrom,
• MeSH
• Carney Complex genetics   MeSH
• DNA, Neoplasm genetics   MeSH
• Adenomatous Polyposis Coli genetics   MeSH
• Carcinoma, Papillary, Follicular * genetics   MeSH
• Gardner Syndrome genetics   MeSH
• Genetic Predisposition to Disease * MeSH
• Genetic Testing MeSH
• Humans MeSH
• Carcinoma, Medullary * drug therapy   genetics   prevention & control   MeSH
• Multiple Endocrine Neoplasia Type 2a genetics   MeSH
• Multiple Endocrine Neoplasia Type 2b genetics   MeSH
• DNA Mutational Analysis MeSH
• Biomarkers, Tumor genetics   MeSH
• Thyroid Neoplasms * drug therapy   genetics   prevention & control   MeSH
• Hamartoma Syndrome, Multiple genetics   MeSH
• Thyroidectomy MeSH
• Protein-Tyrosine Kinases antagonists & inhibitors   therapeutic use   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH

• MeSH
• Cytodiagnosis standards   MeSH
• Cytological Techniques MeSH
• Diagnostic Techniques, Endocrine MeSH
• Diagnosis, Differential MeSH
• Thyroid Diseases diagnosis   classification   pathology   MeSH
• Reference Standards MeSH
• Biopsy, Fine-Needle MeSH
• Publication type
• Atlas MeSH

• Conspectus
• Buněčná biologie. Cytologie
• NML Fields
• endokrinologie
• cytologie, klinická cytologie

BACKGROUND: Activating point mutation of the BRAF gene, the most common genetic alteration reported in papillary thyroid carcinomas (PTC), has been associated with poor prognostic characteristics. AIM: Our objective was to determine the frequency of BRAFV600E mutation in PTC tumor tissues from the period 1960-2007 and to correlate it with clinicopathological parameters. SUBJECTS AND METHODS: DNAs were extracted from 242 PTCs, 23 sporadic medullary carcinomas, one anaplastic carcinoma and 6 poorly differentiated carcinomas. The presence of BRAFV600E mutation was determined using single strand conformation polymorphism method and verified by direct sequencing. RESULTS: BRAFV600E mutation was detected in 81 of 242 PTCs (33.5%), in one of 6 poorly differentiated carcinomas (16.7%) and in anaplastic carcinoma. BRAFV600E mutation was much less frequent in the follicular variant compared to classical variant and mixed follicular- classical variant of PTCs (p=0.001). BRAFV600E mutation was significantly associated with presence of nodal metastasis (p=0.029), more advanced TNM stage (p=0.014) and recurrence of disease (p=0.008). The mutation correlated with a higher age at diagnosis (p=0.049) and with a greater tumor size (p=0.041). Multivariate analysis confirmed these findings. The prevalence of BRAFV600E mutation before 1986 was significantly lower than after it (p=0.008). CONCLUSIONS: Our data suggest that BRAFV600E mutation is associated with high-risk clinicopathological characteristics of PTC and worse prognosis of patients. The frequency of the mutation significantly varied during the observed period but rather because of the different age distribution of patients in particular periods than as a consequence of Chernobyl accident.

• MeSH
• Chernobyl Nuclear Accident MeSH
• DNA, Neoplasm biosynthesis   genetics   MeSH
• Adult MeSH
• Exons genetics   MeSH
• Gene Frequency MeSH
• Neoplasm Invasiveness genetics   MeSH
• Codon genetics   MeSH
• Middle Aged MeSH
• Humans MeSH
• Mutation physiology   MeSH
• Thyroid Neoplasms epidemiology   genetics   pathology   MeSH
• Carcinoma, Papillary epidemiology   genetics   pathology   MeSH
• Reverse Transcriptase Polymerase Chain Reaction MeSH
• Polymorphism, Single-Stranded Conformational genetics   MeSH
• Proto-Oncogene Proteins B-raf genetics   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Age Factors MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Geographicals
• Czech Republic MeSH

Pohled na některé léze štítné žlázy se za posledních několik desetiletí zásadně proměnil, zejména v důsledku zavedení nových jednotek; díky zahrnutí molekulárně genetických metod do diagnostiky dochází ke změnám či zpřesnění klasifikačních kritérií u některých lézí. V textu je věnována pozornost pěti oblastem, kde jsou změny zvláště markantní - problematice folikulární varianty papilokarcinomu, folikulárním nádorům s hraniční morfologií, papilárnímu mikrokarcinomu a otázce jeho biologického potenciálu, onkocytárním nádorům a málo diferencovanému karcinomu.

Current view on certain lesions of the thyroid gland has dramatically changed during last several decades, namely due to definition of some new entities and inclusion of molecular genetic methods into diagnostic process. This results in change or more precise definition of diagnostic criteria of certain entities. In the article are discussed namely the following topics: follicular variant of papillary carcinoma, tumors of uncertain malignant potential, papillary microcarcinoma, oncocytic tumors and poorly differentiated carcinoma.

• MeSH
• Research Support as Topic MeSH
• Carcinoma, Papillary, Follicular pathology   MeSH
• Humans MeSH
• Thyroid Neoplasms classification   pathology   MeSH
• Oxyphil Cells pathology   MeSH
• Neoplasm Staging methods   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Review MeSH

Nová WHO klasifikace tyroidálních a paratyroidálních novotvarů z r. 2004 vykazuje řadu formál- ních i obsahových změn oproti předchozí z r. 1988. Srovnání obou klasifikací jsme doplnili o apli- kaci nové normy v některých otázkách aktuální diagnostické praxe. Diagnostiku nediferencova- ných, málo diferencovaných a směsně diferencovaných tyreoidálních nádorů vcelku uspokojivě ře- ší imunohistochemické postupy zavedené do rutinní diagnostiky. Přetrvávají však některé problé- my zatřídění nádorů, jež nejsou tímto způsobem řešitelné. Jde zejména o vymezení FVPTC v jeho hraniční podobě, ještě více v případě onkocytární varianty. Posun nastal v klasifikaci onkocytární varianty papilárních karcinomů – je pro ně nově nutnou podmínkou přítomnost jaderných cha- rakteristik papilárního ca. Nejistoty v hodnocení TNM u multifokálních lézí jsou vyřešeny, ve spor- ných situacích poslouží rovněž odkaz na konzultační stránky. V klasifikaci jsou zařazeny i základní cytodiagnostické znaky a obrazy. V souvislosti s touto pravi- delnou diagnostickou metodou jsou uvažovány následky tenkojehlové aspirace v diagnóze mini- málně invazivního folikulárního karcinomu. Z hlediska formální logiky je kritizovatelnou položkou nové klasifikace „Synonymika“ – v odstav- ci „Synonyms“ jsou uváděna jak skutečná synonyma, tak speciální podjednotky – varianty disku- tované kategorie. Celkově však nová klasifikace i tím, že zařadila literární odkazy na někdy i va- riabilní názory a předkládá tedy zjevně spíše názorová těžiště než deklarovaně pevné pravdy, představuje úspěšný a užitečný normativní text.

The new (2004) WHO Classification of Tumours of the Thyroid and Parathyroid Gland exhibits both formal and contentual changes compared to the previous one from the year 1988. Comparing both texts we have tried to apply the new norm to some recent diagnostic tasks. The classification of poorly differentiated and undifferentiated neoplasms has been successfully solved by employing the immunohistochemical procedures into the daily routine. Nevertheless, some diagnostic problems persist and can not be solved this way. This is true especially for the borderline neoplasm in the FVPTC category and even more for its oncocytic variant. There appeared shift in the criteria for the diagnosis of oncocytic variant of papillary carcinoma. Newly, the obligatory presence of the nuclei with the characteristics of the conventional papillary neoplasms is required. Thorough elaboration of the TNM system has solved the problem of multifocal lesion staging. Moreover, a web consultation source is recommended. The new Classification includes descriptions of the basic cytodiagnostic features. The post aspiration capsular damage consideration in relation to the diagnosis of the minimally invasive follicular carcinoma is one practical profit thereof. In terms of formal logic a criticisable feature of the new classification is the introduction of the so called „Synonyms“. These listings include in fact partly real synonyms by definition, but together in one table quite often also subunits or variants of the nosologic units described. In general, the new Classification represents a successful consensus reached. As there are newly also references with varying opinions included, it is presented more like a point of gravity in this field than an undoubted truth. This also makes it a valuable and useful normative text.

• MeSH
• Cytodiagnosis MeSH
• Immunohistochemistry MeSH
• Carcinoma diagnosis   classification   MeSH
• Parathyroid Neoplasms diagnosis   classification   MeSH
• Thyroid Neoplasms diagnosis   classification   MeSH
• World Health Organization MeSH
• Terminology as Topic MeSH

The WHO Classification of Tumours of Endocrine Organs is the tenth volume in the 4th Edition of the WHO series on histological and genetic typing of human tumours. This authoritative, concise reference book provides an international standard for oncologists and pathologists and will serve as an indispensable guide for use in the design of studies evaluating response to therapy and clinical outcome. Diagnostic criteria, pathological features, and associated genetic alterations are described in a disease-oriented manner. Sections on all recognized neoplasms and their variants include new ICD-O codes, epidemiology, clinical features, pathology, genetics, prognosis and predictive factors. The book, prepared by 166 authors from 25 countries, contains more than 700 colour images and tables, and more than 3100 references.

• MeSH
• Neoplastic Syndromes, Hereditary MeSH
• International Classification of Diseases MeSH
• Endocrine Gland Neoplasms genetics   pathology   MeSH
• Pituitary Neoplasms MeSH
• Adrenal Gland Neoplasms MeSH
• Parathyroid Neoplasms MeSH
• Pancreatic Neoplasms MeSH
• Thyroid Neoplasms MeSH
• Neuroendocrine Tumors MeSH
• World Health Organization MeSH
• Publication type
• Handbook MeSH

• Conspectus
• Patologie. Klinická medicína
• NML Fields
• endokrinologie
• onkologie
• NML Publication type
• publikace WHO

Chromosomal rearrangements of NTRK genes are oncogenic driver mutations in thyroid cancer (TC). This study aimed to identify NTRK fusion-positive thyroid tumors and to correlate them with clinical and pathological data and determine their prognostic significance. The cohort consisted of 989 different TC samples. Based on the detected mutation, samples were triaged, and those that were positive for a BRAF, HRAS, KRAS, NRAS, RET, RET/PTC or PAX8/PPARγ mutation were excluded from further analyses. NTRK fusion gene testing was performed in 259 cases, including 126 cases using next-generation sequencing. NTRK fusion genes were detected in 57 of 846 (6.7%) papillary thyroid carcinomas and in 2 of 10 (20.0%) poorly differentiated thyroid carcinomas. A total of eight types of NTRK fusions were found, including ETV6/NTRK3, EML4/NTRK3, RBPMS/NTRK3, SQSTM1/NTRK3, TPM3/NTRK1, IRF2BP2/NTRK1, SQSTM1/NTRK1 and TPR/NTRK1.NTRK fusion-positive carcinomas were associated with the follicular growth pattern, chronic lymphocytic thyroiditis and lymph node metastases. NTRK1-rearranged carcinomas showed a higher frequency of multifocality and aggressivity than NTRK3-rearranged carcinomas. Tumor size, presence of metastases, positivity for the NTRK3 or NTRK1 fusion gene and a late mutation event (TERT or TP53 mutation) were determined as factors affecting patient prognosis. NTRK fusion genes are valuable diagnostic and prognostic markers.

• Publication type
• Journal Article MeSH