Diagnostics and Treatment of Thyroid Carcinoma.

Revised Guidelines of Polish National Societies Prepared on the initiative of the Polish Group for Endocrine Tumours approved in their final version between November 16th and 28th, 2015 by the Scientific Committee of the V Conference "Thyroid Cancer and other malignancies of endocrine glands" organised between November 14th and 17th, 2015 in Wisla, Poland; called by the following Societies: Polish Endocrine Society, Polish Society of Oncology, Polish Thyroid Association, Polish Society of Pathologists, Society of Polish Surgeons, Polish Society of Surgical Oncology, Polish Society of Clinical Oncology, Polish Society of Radiation Oncology, Polish Society of Nuclear Medicine, Polish Society of Paediatric Endocrinology, Polish Society of Paediatric Surgeons, Polish Society of Ultrasonography Gliwice-Wisla, 2015 DECLARATION: These recommendations are created by the group of delegates of the National Societies, which declare their willingness to participate in the preparation of the revised version of the Polish Guidelines. The members of the Working Group have been chosen from the specialists involved in medical care of patients with thyroid carcinoma. Directly before the preparation of the Polish national recommendations the American Thyroid Association (ATA) published its own guidelines together with a wide comment fulfilling evidence-based medicine (EBM) criteria. ATA Guidelines are consistent with National Comprehensive Cancer Network (NCCN) Recommendation. According to the members of the Working Group, it is necessary to adapt them to both the specific Polish epidemiological situation as well as to the rules referring to the Polish health system. Therefore, the Polish recommendations constitute a consensus of the experts' group, based on ATA information. The experts analysed previous Polish Guidelines, published in 2010, and other available data, and after discussion summed up the results in the form of these guidelines. It should be added that Part II, which constitutes a pathological part, has been available at the website of the Polish Society of Pathologists for acceptance of the members of the Society, and no essential comments have been proposed. The Members of the Group decided that a subgroup elected from among them would update the Guidelines, according to EBM rules, every year. The Revised Guidelines should help physicians to make reasonable choices in their daily practice; however, the final decision concerning an individual patient should be made by the caring physician responsible for treatment, or optimally by a therapeutic tumour board together with the patient, and should take into consideration the patient's health condition. It should be emphasised that the recommendations may not constitute a strict standard of clinical management imposed on medical staff. The data from clinical trials concerning numerous clinical situations are scarce. In such moments the opinion of the management may differ from the recommendations after considering possible benefits and disadvantages for the patient.

Timing and criteria for prophylactic thyroidectomy in asymptomatic RET carriers - the role of Ct serum level.

Authors summarize in this brief review results of European discussion, held on ETA-CRN Meeting in Lisbon, 2009, on the American Thyroid Association Medullary Thyroid Cancer (MTC) Guidelines published in the same year and focus on the timing of prophylactic thyroidectomy. ATA 2009 guidelines classified RET protooncogene mutation carriers into 4 levels: A, B, C, D. ATA for prophylactic thyroidectomy were generally independent of the serum calcitonin (Ct) concentration but based on a priori risk levels. This was well accepted as the important novelty was to delineate risk level specially for RET 634 mutation (level C). In the ATA Guidelines total prophylactic thyroidectomy below age 5 years was recommended in RET 634 mutation carriers regardless of Ct status. However, some European experts favored to base the decision not only on the results of DNA testing but also on the going Ct level. The European discussion reflected divergent opinions and indicated the need of publication of European experience instead of arbitrary opinions. It was stressed that patients carrying the same RET mutation present heterogenic progression to the clinically overt medullary thyroid cancer, even in the same family. Thus, in summary, the ATA MTC guidelines constituted a positive stimulus to publish further evidence for Ct-guided pre-emptive thyroidectomy for RET gene mutation carriers and the conclusion is drawn on the basis of experience expressed in Lisbon and published later evidence that the integrated algorithm based on age - Ct - type of RET mutation should be considered in the decision of pre-emptive thyroidectomy.

The prognostic value of tumor markers doubling times in medullary thyroid carcinoma - preliminary report.

INTRODUCTION: Calcitonin (Ct) and carcinoembrional antigen (CEA) are widely used as tumor markers for the post-operative follow-up of patients with medullary thyroid carcinoma (MTC).In patients with elevated serum Ct and CEA their dynamics can be described by calculating the doubling time (DT) - the time, they need to double the serum concentration. Previous reports concluded that the Ct and CEA DT have prognostic value in MTC patients. PATIENTS AND METHODS: We retrospectively analyzed data of 70 MTC patients with elevated serum Ct or CEA. In total, doubling times were calculated and the DT of the less favorable marker was used to stratify the patients into the low- and high-risk group with the cut-off value of 2 years. The survival analysis was performed using Cox proportional hazard method. RESULTS: The doubling time < = 2 years of the less-favorable marker had significant prognostic impact for recurrence-free survival, HR = 2.61 (1.43-4.71) and overall survival, HR = 8.99 (3.51-23.04). CONCLUSIONS: The calcitonin and carcinembrional antigen doubling times of less than two years are negative prognostic factors for MTC recurrence-free and total survival in patients with persistent or recurrent disease. They may be used as predictive factors for more intensive search of disease localization in asymptomatic hypercalcitoninemia and for therapy choice in symptomatic disease.

Occurrence of BRAF mutations in a Polish cohort of PTC patients - preliminary results.

INTRODUCTION: Genetic alterations involving the mitogen-activated protein kinase (MAPK) pathway are frequently demonstrated in papillary thyroid cancer (PTC). BRAF(V600E), the most frequent mutation in adult patients, is present in approximately 50% of PTC. Most clinical studies have demonstrated an association of BRAF(V600E) mutation with aggressive clinicopathological characteristics and high tumour recurrence, although the results are controversial. In this study we present the preliminary results of BRAF mutation frequence in a group of 88 Polish patients with papillary thyroid cancer (PTC) and relate it to the outcome all DTC patients operated in 2004 and 2005. BRAF (V600E) mutation was diagnosed in 38 (43%) of cases. MATERIAL AND METHODS: The presence of BRAF mutation was evaluated in 88 PTC tumours. DNA was isolated from tissue parafin blocks, and the mutation V600E was evaluated by sequence analysis with an AbiPrism 377 and 3130 xl genetic analyzer (Life Technologies). Statistical analysis was carried out with the use of SPSS 12 software. The chi² and Kaplan-Meyer survival analysis were performed. RESULTS: From all analyzed clinico-pathological factors, only older age positively correlated with BRAF mutation frequency (p = 0.0017). Lymph node/distant metastases, multifocality, and extra-thyroid extension did not correlate with BRAF status. One cancer related death and two reccurences were observed in the BRAF+ group while one relapse was diagnosed in the BRAF- group. CONCLUSIONS: Although many studies document BRAF mutation as a prognostic factor in PTC our results underline that it is too early to consider it as a routine clinical predictive factor.

Has differentiated thyroid cancer (DTC) staging changed with in the last ten years in the Silesia region of Poland?

INTRODUCTION: The aim of the study was to compare the advancement of thyroid cancer at diagnosis in Polish patients from the Silesian district in the years 1999 and 2008. MATERIAL AND METHODS: The analyzed group consisted of Silesian district patients with thyroid cancer, who were registered by the Department of Tumour Epidemiology of the Institute of Oncology in Gliwice in the years 1999 and 2008. From a group of 186 patients who entered on record in 1999, 167 were qualified for this analysis. Similarly, from 238 patients registered in 2008, finally 226 were added. We analyzed: sex, age at diagnosis, histotype of thyroid cancer, and DTC staging according to TNM (UICC 2002). In 1999 there were 137 females (82.04 %) and 30 males (17.93%) with thyroid cancer diagnosed at ages 5-81 years. In 2008 there were 183 females (80.97%) and 43 males (19.03%) diagnosed at ages 14-80 years. In both groups, in 1999 and 2008, the median age was the same (51 years). RESULTS: In the year 1999, 119 (71%) and in 2008, 197 (87%) patients were diagnosed with papillary thyroid cancer (p = 0.0003). Relations between age and sex were similar in these years. There was some increase in frequency of patients diagnosed with papillary microcancer (pT1a), which was on the border of statistical significance (p = 0.05). A statistically significant increase of pT1 (p = 0.02) and decrease of pT4 (p = 0.001) and of pTx (p = 0.002) was observed in the year 2008 in the whole cohort of DTC patients. CONCLUSIONS: 1. In 2008 the contribution of papillary histotype to all thyroid cancer patients (87%) was significantly higher than in 1999. 2. The percentage of DTC patients diagnosed with pT1 disease was significantly higher in 2008.

Prognostic value of lymph node metastases of differentiated thyroid cancer (DTC) according to the local advancement and range of surgical excision.

UNLABELLED: : In differentiated thyroid carcinoma (DTC) with primary tumor smaller than 1 cm, the routine central lymph node (LN) dissection is questioned, due to increased risk of post-surgery complications and lack of confirmed benefit. AIM: The analysis of prognostic significance of LN metastases, in DTC patients to verify the potential role of central neck lymphadenectomy on disease staging. MATERIALS AND METHODS: The group of 195 DTC patients, primarily operated between 2004 and 2005, was retrospectively analyzed. 184 patients after radical operation, with no distant metastases diagnosed before surgery, were included into analysis. LN metastases were observed in 55 of cases (28%). In 124 cases only dissection of central LN compartment was performed, in 36 patients also uni- or bilateral modified cervical lymphadectomy was carried out. In 24 patients with tumor limited to the thyroid gland without suspicious lymph nodes, the routine central lymph node dissection was not done. RESULTS: Median follow-up was 4 years. The 5-year overall and disease free survival standardized ratio were 100% and 95% respectively. The risk of LN metastases increased with the more locally advanced cancer. In the group of 124 patients, in whom only central LN dissection was performed, LN metastases were diagnosed in 15 cases (12%). No significant relation between multifocality and frequency of central and/or lateral LN metastases was noticed. Significant correlation between N feature and extrathyroidal invasion was observed (p = 0,0003). The presence of LN metastases was related to worsening of disease free survival from 99 to 90%. During the follow-up recurrence occurred in 6 (3%) cases. In 24 patients in whom only total thyroidectomy was done, no local or distant recurrence was observed. The assessment of early postoperative complications (hypoparathyroidism, paresis of vocal cords) indicated that the frequency of early calcium balance disturbances was significantly lower in patients in whom central LN dissection was not performed (p = 0,04) CONCLUSIONS: Our result indicate that in the early diagnosis of thyroid cancer, the occurrence of LN DTC metastases is rarer and was observed only in 12% of elective dissections of central LN node compartment, if no lateral dissection was indicated due to the lack of clinical suspicion. In DTC patients with tumor diameter <1 cm and no sonographical or inraoperative suspicion on LN involvement, routine central lymphadenectomy may be not obligatory.

Pheochromocytoma in rats with multiple endocrine neoplasia (MENX) shares gene expression patterns with human pheochromocytoma.

Pheochromocytomas are rare neoplasias of neural crest origin arising from chromaffin cells of the adrenal medulla and sympathetic ganglia (extra-adrenal pheochromocytoma). Pheochromocytoma that develop in rats homozygous for a loss-of-function mutation in p27Kip1 (MENX syndrome) show a clear progression from hyperplasia to tumor, offering the possibility to gain insight into tumor pathobiology. We compared the gene-expression signatures of both adrenomedullary hyperplasia and pheochromocytoma with normal rat adrenal medulla. Hyperplasia and tumor show very similar transcriptome profiles, indicating early determination of the tumorigenic signature. Overrepresentation of developmentally regulated neural genes was a feature of the rat lesions. Quantitative RT-PCR validated the up-regulation of 11 genes, including some involved in neural development: Cdkn2a, Cdkn2c, Neurod1, Gal, Bmp7, and Phox2a. Overexpression of these genes precedes histological changes in affected adrenal glands. Their presence at early stages of tumorigenesis indicates they are not acquired during progression and may be a result of the lack of functional p27Kip1. Adrenal and extra-adrenal pheochromocytoma development clearly follows diverged molecular pathways in MENX rats. To correlate these findings to human pheochromocytoma, we studied nine genes overexpressed in the rat lesions in 46 sporadic and familial human pheochromocytomas. The expression of GAL, DGKH, BMP7, PHOX2A, L1CAM, TCTE1, EBF3, SOX4, and HASH1 was up-regulated, although with different frequencies. Immunohistochemical staining detected high L1CAM expression selectively in 27 human pheochromocytomas but not in 140 nonchromaffin neuroendocrine tumors. These studies reveal clues to the molecular pathways involved in rat and human pheochromocytoma and identify previously unexplored biomarkers for clinical use.

Total thyroidectomy and adjuvant radioiodine treatment independently decrease locoregional recurrence risk in childhood and adolescent differentiated thyroid cancer.

UNLABELLED: We sought to assess whether extensive surgical treatment, postsurgical radioiodine therapy, or both decrease the risk of locoregional recurrence (LR) after curative primary treatment in children and adolescents diagnosed with differentiated thyroid cancer (DTC) at age

[Expression of DPP4 gene in papillary thyroid carcinoma]. / Ekspresja genu DPP4 w raku brodawkowatym tarczycy.

INTRODUCTION: DPP4 gene (dipeptidyl peptidase IV) is expressed in epithelial cells of many organs and cells of immune system. There is no expression of DPP4 in normal healthy thyroid, while it is highly expressed in papillary thyroid carcinoma (PTC), as shown by gene expression profiling. In this study we validated expression of DPP4 in papillary thyroid cancer and normal thyroid tissue and evaluated its usefulness for diagnostic purposes. MATERIAL AND METHODS: The analysis was carried out on total RNA extracted from 102 PTCs and 77 normal thyroid fragments with use of Q-PCR reaction. Beta-glucuronidase was the reference gene. RESULTS: We confirmed the distinct increase of DPP4 expression in papillary thyroid carcinoma. However, the ROC (relative operating characteristic) analysis revealed that the diagnostic efficiency of DPP4 estimation is limited. CONCLUSIONS: DPP4 is increased in papillary thyroid cancer, however, its diagnostic usefulness as a single PTC marker is doubtful.

[Completion total thyroidectomy in children with differentiated thyroid cancer]. / Radykalizacja leczenia operacyjnego zrósnicowanego raka tarczycy u dzieci.

INTRODUCTION: The optimal surgical treatment of children with differentiated thyroid cancer remains an important point of discussion. Especially the need for completion operation is questioned in young patients. Our objective was to examine the rate of residual neoplastic disease after non radical initial operation. MATERIAL AND METHODS: From the 235 children diagnosed with differentiated thyroid cancer, 131 (56%) needed completion operation due to incomplete primary surgery. Completion operation involved thyroid bed, lymph nodes or both respectively in 91 (39%), 13 (6%) and 27 (11%) cases. Risk factors responsible for residual disease were evaluated by means of logistic regression analysis. RESULTS: Residual disease was detected in 46 (35%) of reoperated children (25% in thyroid bed and 85% in lymph node of lateral neck compartment). Sex and age did not influence the risk of residual disease in thyroid bed or lymph nodes. Papillary type of cancer and multifocality increased risk of residual disease in thyroid bed respectively by the factor of 15 (95% CI: 2-125) and 2.3 (95% CI: 1.2-4.4). Infiltration of thyroid capsule did not correlate with the risk of residual disease. Lymph node metastases in primary operation increased risk of residual disease by the factor of 16 (95% CI: 1.2-245). Histopathology, multifocality of primary tumour or infiltration of lymph node capsule did not influence the risk of residual disease in lymph nodes of lateral neck compartment. CONCLUSIONS: In children with differentiated thyroid cancer residual disease is diagnosed in about 1/3 of non radically operated cases. This high incidence justifies completion operations. The risk of residual disease is significantly increased in papillary thyroid cancer, multifocal tumours and cases with lymph node metastases.

[Evaluation of the therapeutic benefits in relation to the extent of surgery in patients with differentiated thyroid carcinoma]. / Ocena korzysci terapeutycznych z zastosowania okreslonego zakresu operacji u chorych na zrósnicowane raki tarczycy.

INTRODUCTION: Evaluation of the therapeutic benefits in relation to the stage of thyroid cancer and to the extent of surgery and the risk of postoperative complications. MATERIAL AND METHODS: Retrospective analysis of differentiated thyroid carcinoma (DTC) patients staged T1M0 versus T2-T4M0 was performed. All of them were treated or diagnosed in Institute of Oncology in Gliwice between 1986-1998. Previously they were operated in various surgical centers all-over Poland. The risk of death, local relapse and postoperative complications were analyzed using the decisiontree model to evaluate the therapeutic benefits. RESULTS: The recurrent laryngeal nerve injury (transient or permanent) was observed in retrospective analysis in 21% of patients, while postoperative hyperparathyroidism in 15.8%. The analysis of the therapeutic benefit index showed no advantage of total thyroidectomy in the T1M0 group (0.96 vs. 0.98 in patients treated by less than total thyroidectomy). The advantage of radical surgery was confirmed in T2-T4M0 group. The therapeutic benefit index was 0.92 in patients treated by total thyroidectomy and 0.69 in those who received less extensive operation. CONCLUSIONS: The analysis of therapeutic benefits confirmed the limit of 1 cm tumor diameter between less extensive surgery and total thyroidectomy. It showed that total thyroidectomy brings a significant therapeutic benefits in patients in > T1M0 stage. The improvement of overall survival and decrease of local relapse far outweigh the disadvantages related to postoperative complications.

[The impact of the extent and time of operation on the survival in patients with differentiated thyroid carcinoma (DTC)]. / Znaczenie zakresu i czasu leczenia operacyjnego u chorych na zróznicowane raki tarczycy.

INTRODUCTION: To analyze the impact of time and extent of operation on overall and disease-free survival in patients with differentiated thyroid carcinoma (DTC). MATERIAL AND METHODS: Retrospective analysis of 1235 DTC patients, a representative probe of patients diagnosed or treated between 1986 to 1998 was performed. 277 patients were staged T1M0 and 958 ones staged > T1M0. 10-year outcomes were analyzed by Kaplan-Meier survival curves and Cox proportional-hazard model. RESULTS: The T1M0 patients were characterized by the best overall and disease-free survival independently of the time and the extent of operation (98% and 96% respectively); in > T1M0 group the survival was better in patients who were treated by total thyroidectomy (94% and 68% respectively) than in patients treated by non-total thyroidectomy (78% and 47% respectively). In patients treated by completion of total thyroidectomy delayed more than 1 year post cancer diagnosis the incidence of carcinoma in postoperative pathological material was twice as high in comparison to the group in whom total thyroidectomy was performed within the first year of therapy (p = 0.000). CONCLUSIONS: 1. In differentiated thyroid carcinoma the prognosis is related to the extent of operation only in patients staged more than T1M0. 2. A delay > 12 months in completion surgery in patients with differentiated thyroid cancer (tumors > 1 cm of diameter) significantly increases the risk of progression of multifocal disease in thyroid remnants.

[Indications for surgery of thyroid cancer based on bioptate molecular examination]. / Wskazania do leczenia operacyjnego raka tarczycy na podstawie badania molekularnego bioptatu.

INTRODUCTION: In differentiated thyroid cancer (DTC) the differentiation between reactive and metastatic lymph nodes is difficult at the early stages of metastasis. The aim of the study was to assess the results of fine needle aspiration (FNA) samples examination by the use of RT-PCR for Tg mRNA. The special attention was directed to the evaluation of specificity of TgRNA estimation. MATERIAL AND METHODS: The group consisted of 193 DTC patients with suspicion of lymph node recurrence and at least one positive RT-PCR result. Thyroglobulin RT-PCR was conducted in residual material left after preparation of cytological smears from FNA specimens. Primer spanning exons 3-5 were used with 39 cycles of PCR. RNA isolation control and cDNA amplification were carried out using GAPDH starters. 308 lymph node biopsies were included. RESULTS: 246 positive results for Tg RNA were observed in the analyzed group, 71.1% confirmed by FNA. Among other 71 results, in which cytological examination did not correspond unequivocally to molecular findings, in 34 metastases were confirmed both by cytological and clinical examination. There were 11 patients operated due to the positive serial molecular examination only. In 10 (91%) of them DTC metastases were confirmed. So, the positive predictive value of the molecular result ranged between 75-89% and the negative one was 100%. CONCLUSIONS: In DTC patients RT-PCR Tg mRNA is helpful in qualification of suspicious lymph nodes to surgery in DTC patients. At the negative cytological finding, the positive molecular result constitutes an indication for early surgery.

[Medullary thyroid carcinoma: the comparison of the hereditary and sporadic types of cancer]. / Rak rdzeniasty tarczycy: porównanie postaci dziedzicznej i sporadycznej.

INTRODUCTION: The assessment of frequency and type of mutation and differences in prognosis between sporadic and hereditary type of medullary thyroid carcinoma (MTC), based on own DNA analysis, was performed. MATERIAL AND METHODS: The group of 190 persons with hereditary MTC or asymptomatic mutation carriers was analyzed. Patients with sporadic MTC without RET gene mutation were included into control group (708 persons). The recognition of MTC type was based on assessment of family history, physical examination and genetic analysis. The family history consisted of information about MTC, pheochromocytoma and other neoplasms and hyperparathyroidism in relatives. RESULTS: The mutations located in codon 634 of exon 11 were the most often (43% of all mutations and 49% of mutations in syndrome MEN 2A/FMTC). The age of diagnosis was ranged between 7 and 71 years (mean age: 39 +/- 15.2 years, median age: 41 years). In hereditary MTC the mean age of diagnosis was 27 +/- 13.9 years and was significantly lower than in sporadic one, where it was 45.7 +/- 14.3 years. The relationship between diagnosis, age and subtypes of hereditary MTC was assessed--no significant differences in examined subgroups were observed. The mean age of diagnosis in MEN 2A/FMTC and MEN 2A syndrome was 28-29 years, in MEN 2B - 21 years. The overall survival in sporadic MTC after 5 years was 97%, in hereditary MTC - 79%. Analysis performed after excluding suprarenal causes of death revealed no statistically significant differences in overall survival between both subtypes of MTC. CONCLUSIONS: 1. Hereditary MTC is still diagnosed too late, besides of DNA analysis. 2. In hereditary and sporadic MTC the prognosis is comparable.

[Gene expression profile of medullary thyroid carcinoma--preliminary results]. / Profil eksresji genów w raku rdzeniastym tarczycy--doniesienie wstepne.

INTRODUCTION: Medullary thyroid carcinoma occurs both as a sporadic and a familial disease. Inherited MTC (iMTC) patients usually exhibit better prognosis than patients with sporadic form of MTC (sMTC), however, in both subtypes the outcome is unpredictable. No molecular markers contributing to the prognosis or predicting the type of therapy have been introduced to clinical practice until now. The aim of this study was to analyze gene expression pattern of MTC by high density oligonucleotide microarray. MATERIAL AND METHODS: 24 samples were studied: 12 MTC and 12 corresponding normal tissues, (Affymetrix HG-U 133A). Among MTC patients there were half inherited cases and half sporadic ones. RESULTS: First, the differences between MTC and thyroid tissue were analyzed by Singular Value Decomposition (SVD) which indicated three main modes determining the variability of gene expression profile: the first two were related to the tumor/normal tissue difference and the third one was related to the immune response. The characteristic expression pattern, beside of numerous changes within cancer- related genes, included many up-regulated genes specific for thyroid C cells. Further analysis of the second component revealed two subgroups of MTC, but the subdivision was not related to the iMTC/sMTC difference. Recursive Feature Replacement (RFR) confirmed the very similar expression profile in both forms of MTC. With subsequent ANOVA analysis some genes with differential expression could be specified, among them monoamine oxidase B (MAOB) and gamma-aminobutyric acid receptor (GABRR1) which were consistently up-regulated in sMTC. In contrary, some genes involved in regulation of cell proliferation: opioid growth factor receptor(OGFR) and synaptotagmin V (SYT 5) were up-regulated in iMTC. CONCLUSIONS: The obtained data indicate a very similar gene expression pattern in inherited and sporadic MTC. Minor differences in their molecular profile require further analysis.

Molecular analysis of the RET and NTRK1 gene rearrangements in papillary thyroid carcinoma in the Polish population.

Among different genetic factors involved in the pathogenesis of the papillary thyroid carcinoma (PTC), rearrangements of RET protooncogene (RET/PTC), as well as rearrangements of NTRK1 protooncogene are best known. The resulting hybrid oncogenes are found in PTCs with variable frequency, depending on the examined population. The relationship between these chromosomal aberrations and clinical outcome of PTCs remains still controversial. The study aimed at estimating the frequency of rearrangements of RET and/or NTRK1 protooncogenes in PTC in the Polish population, and at evaluating the possible relationships between the presence of RET and/or NTRK1 oncogenes and such parameters, as patient's age, gender, histopathological variant of tumor and clinical staging. Expression analysis of RET and NTRK1 was performed by duplex reverse transcription-polymerase chain reaction (duplex RT-PCR) and OneStep RT-PCR, respectively, in tumor tissues obtained from 33 patients with PTC. Rearrangements of the RET protooncogene (RET/PTC1, RET/PTC2 and RET/PTC3) were detected in 7 out of 33 PTC (21%), and rearrangements of NTRK1 [Trk-T1 and Trk(TPM3)] were detected in 4 out of 33 examined samples (12%). In none of the examined cases, did the RET and NTRK1 rearrangements occur in the same sample. No correlations were found between RET/PTC or Trk oncogenic sequences and patient's age, gender, the histopathological variant of PTC and the assignment to particular stage in clinical staging systems (TNM Staging, the University of Chicago clinical class, and Ohio State University Staging). Our study is the first one in which the frequency of NTRK1 rearrangements in PTC was reported for the Polish population. On the other hand, the frequency of RET rearrangements in PTC, as found by us, was similar to the previously reported results for the Polish population. Our results do not confirm the relationship between the structural aberrations in question and the clinical outcome of PTC.

[Medullary thyroid carcinoma: from molecular studies to clinical decision]. / Rak rdzeniasty tarczycy: od badan molekularnych do kliniki.

The paper is focused on guidelines of practice in inherited medullary thyroid cancer, diagnosed on the basis of DNA analysis. Identification of RET mutation implies further steps of diagnostic procedure, some of them - USG, FNAB and calcitonin level tests - are common for all types of mutation, other are related to ascertained type of mutation. In asymptomatic RET mutation carriers, prophylactic thyroidectomy is indicated. In MEN2B inherited cancer reveals its symptoms quickly and shows dynamic progress. In MEN2A/FMTC the clinical picture is diversified - in some patients the course of disease is mild, however in some other cases the progression of disease and even death occur regardless of the proper treatment. Unfortunately, there are no molecular prognostic markers in medullary thyroid carcinoma. Recent papers and also our own unpublished results show that gene expression profile, is similar in MEN2A and sporadic cancer. This group differs from MEN2B by its expression profile. In conclusion it is to be emphasized that although inherited medullary thyroid carcinoma is a rare disease, the diagnostic algorithm is well established and maximizes the chance for early diagnosis. Moreover, it needs to be stressed that DNA analysis results inform us not only about the necessity of further therapy, but also suggest different ways of proceeding in particular type of mutation.

Loss of heterozygosity in 73 human thyroid tumors.

OBJECTIVES: The aim of the study was to establish the LOH frequency of selected polymorphic markers in different histological types of thyroid tumors: 18 colloid goiters (CG), five follicular adenomas (FA), nine follicular carcinomas (FTC), 40 papillary carcinomas (PTC), and one anaplastic carcinoma (ATC). For PTC, tumors negative for RET/PTC rearrangements were preferred. METHODS: LOH studies were performed using 14 highly polymorphic markers previously described as frequently lost in thyroid tumors. RESULTS: In 20 cases (27%) the loss of at least one marker was found. No difference between the frequency of the LOH in FTC and PTC tumors was revealed (33% v. 33%). No differences between histopathological subtypes of PTC in LOH were found. Papillary thyroid carcinomas showed a tendency to higher LOH frequency from patients older than 45 years of age compared to younger ones (9/23 v. 4/17) although it was not statistically significant. CONCLUSIONS: We conclude that papillary thyroid cancers, particularly those diagnosed in patients older than 45 years of age, do exhibit LOH at least with the same frequency as follicular cancers. This increased number of LOH events may contribute to the clinical aggressiveness of cancer in older patients.