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Purpose: Lateral neck nodal metastases are common in patients with differentiated thyroid cancer (DTC) and usually have an indolent nature. They may be detected via neck palpation or preoperative ultrasound (US) of the neck. We hypothesized that preoperative neck metastases detected with US did not affect regional recurrence or long-term survival., Methods: A retrospective analysis of patients' records treated for DTC at our institution between January 2006 and December 2016 was performed. Information about preoperative US of the neck, treatment, demographics, staging, and histopathology was obtained. The endpoints for the study were nodal recurrence and survival. Differences in survival were analyzed between three groups of patients divided by presence or lack of preoperative US and/or palpable cervical lymph nodes (PLN). Furthermore, the prognostic value of multiple variables was tested by univariate and multivariate analysis., Results: There were 1108 patients with DTC, 221 males and 887 females. The median age was 48.3 years (range 3 to 86), the median time of observation was 68 months (range 0 to 142). Eight hundred sixty-two patients without PLN or preoperative US represented group 1, 112 patients with PLN were in group 2, and 134 patients without PLN and with preoperative US were in group 3. Only five patients had a regional recurrence, one died due to distant metastases. There was no statistically significant difference in survival between the groups (p = 0.841) and neck US was not significantly associated with overall survival neither in univariate nor in multivariate analysis., Conclusion: In patients with DTC, the benefits of preoperative US of cervical lymph nodes are probably limited and "less is more" approach is advised., (© 2021. The Author(s).)

Objective: Medullary thyroid cancer (MTC) is a challenging neuroendocrine malignancy where the role of nuclear medicine imaging is currently limited. This paper investigates the potential diagnostic value of [ 18 F]Fluorocholine PET/CT in primary MTC., Methods: We prospectively enrolled 25 patients (10 male, 15 female) with suspicion for primary MTC based on fine-needle aspiration biopsy (FNAB). All patients had a baseline three phase [ 18 F]Fluorocholine PET/CT (2.5 MBq/kg): two regional head and neck and upper mediastinum studies at 5 min (first phase) and 120 min (third phase) and a whole-body PET/CT (from the skull vertex to mid-thighs) at 60 min (second phase). Any non-physiological radiotracer uptake was regarded as MTC positive. All patients referred to surgery had a preoperative neck-US. True lesion status was assessed using either histopathology, FNAB results or follow-up imaging and laboratory (calcitonin, CEA) results. Results with p < 0.05 were considered statistically significant., Results: Nineteen of 25 patients (76%) were surgically treated and histopathology reports were obtained. Patient-based sensitivity and positive predictive value for detection of any MTC lesion using [ 18 F]Fluorocholine PET/CT were both 100%. Neck-US was more specific (100% vs 70%; p = 0.002) and had a higher positive predictive value than [ 18 F]Fluorocholine PET/CT (100% vs 55%; p = 0.018) for N1a and N1b staging. [ 18 F]Fluorocholine PET/CT had a higher sensitivity (100% vs 50%; p = 0.025) and higher negative predictive value (100% vs 81%; p = 0.026) than neck-US for N1b staging. The optimal SUV max cut-off to differentiate malignant from benign neck lesions at 60 and 120 min was 2.56. Patients with M1 stage on PET/CT had higher calcitonin (median of 5,372 vs 496.6 pg/ml; p = 0.005) and CEA concentrations (median of 95.8 vs 18.65 µg/l; p = 0.034) compared to patients with M0 disease., Conclusion: [ 18 F]Fluorocholine PET/CT appears to be a promising radiotracer for primary staging of MTC by increasing diagnostic accuracy for N staging and detecting possible distant metastatic sites at initial presentation of disease.

Background: Anaplastic thyroid carcinoma (ATC) may arise de novo or from a preexistent differentiated carcinoma. It is well known that higher iodine intake in the diet causes higher frequency of papillary thyroid carcinoma, but decreases the frequency of follicular thyroid carcinoma. However, it is not known how the change in iodine intake influences the frequency of ATC. The aim of our study was to compare the incidence of ATC during the periods when the intake of potassium iodide in salt was 10 and 25 mg/kg., Methods: A total of 205 patients with ATC (140 women, 65 men; median, 69 years) were treated in the Republic of Slovenia between 1972 and 2008. In Slovenia, a country with a population of 2 million people, the salt was iodinated with 10 mg of potassium iodide/kg from 1972 to 1997. From 1998 to 2008 the degree of iodination of salt was increased to 25 mg of potassium iodide/kg. The frequency of ATC during the two periods and the characteristics of the patients during these periods were compared., Results: The mean incidences of ATC during 1972-1997 and 1998-2008 was 6.2 (range, 3-12) and 4 (range, 2-10) patients per year, respectively. During the period 1972-1997 and 1998-2008, the mean age of patients was 66.7 and 72.2 years (p = 0.02), and the mean tumor diameter was 9.6 and 8.6 cm (p = 0.21), respectively. However, the median survival of patients in both periods was 3 months., Conclusion: The incidence of ATC decreased after higher iodination of salt. The patients with ATC during the period of higher iodination of salt were older than those from the period with lower iodination of salt.

Background and Objectives: Estimation of the risk of malignancy in a Hürthle cell (HC) neoplasm is important for optimum extent of thyroid surgical treatment. The aim of this retrospective study was to find predictive factors of carcinoma in patients with HC neoplasm., Methods: A total of 279 patients (241 females, 38 males; median age 55 years, range 15-86 years) with HC neoplasm in whom carcinoma was only suspected and who were surgically treated at our Institute in the period 1990-2007, were included in this study. Risk factors for malignancy were identified by the chi-squared test and logistic regression., Results: The histopatological diagnoses were carcinoma, benign goiter and adenoma in 71 (25%), 68 (25%) and 140 (50%) patients, respectively. Predictive factors for carcinoma, shown by chi-square test, were: age of patients, tumor diameter, thyroid volume and T(g) concentration. The independent predictors of malignancy as shown by multivariate logistic regression were age of patients and pre-operative T(g) concentration. Carcinoma was more common in the patients older than 65 years of age and with T(g) concentration over 1,000 ng/ml., Conclusions: The independent predictors of malignancy in HC neoplasm were age of patients and pre-operative T(g) concentration.

Background: No agreement has been made about the optimal extent of thyroidectomy or lymph node dissection in papillary thyroid microcarcinoma (PTMC). Our aim was to find out the factors associated with the presence of lymph node metastases in the patients with PTMC and to discuss the extent of thyroidectomy and lymphadenectomy., Methods: A total of 254 patients with PTMC (212 women, 42 men; age 14 to 85 years, median 47 years) were treated at our institute between 1975 and 2007. Lymph node metastases were confirmed in 59 patients (23%) by histopathology. The median observation time was 56 (range, 1-397) months, and the recurrence was diagnosed in seven patients. Modified radical neck dissection and central neck dissection were performed in 55 and 30 patients, respectively. The data on the clinicopathological characteristics of patients and treatment were collected., Results: An incidental PTMC was diagnosed in 107 patients postoperatively. In none of them was a lymph node metastasis or tumor recurrence detected. Preoperatively, an overt PTMC was diagnosed in 147 patients. Clinically manifest metastases were diagnosed in 59 (40%) of them: in 51 preoperatively, and in 8 during the surgical procedure. In 147 patients who had preoperative diagnosis of PTMC, the factors that correlated (P < 0.05) with the presence of lymph node metastases were sex, age, and tumor type., Conclusions: The patients with high-risk PTMC with preoperatively confirmed lymph node metastases had a higher recurrence rate than those with low-risk PTMC without preoperatively detectable lymph node metastases; therefore, careful therapeutic node dissection is necessary in high-risk patients.

Background: The aim of this retrospective study was to find predictive factors of carcinoma in patients with follicular neoplasm. The specific aim was to discover whether preoperative serum thyroglobulin (Tg) concentration in patients with thyroid neoplasm can differentiate between those with thyroid carcinoma and those with benign disease., Material/methods: A total of 327 patients (263 females, 64 males, median age: 51.5 years) with follicular neoplasm in whom carcinoma was only suspected and who were surgically treated at the authors' institute in 1988-2004 were included in the study. Patients who had distant and/or regional metastases were excluded. Risk factors for malignancy were identified by the chi-squared test and logistic regression., Results: The histopathological diagnoses were carcinoma, benign goiter, and adenoma in 119 (36%), 104 (32%), and 104 (32%) patients, respectively. The independent predictors of malignancy as shown by multivariate logistic regression were tumor diameter and preoperative Tg concentration. Thyroid carcinoma was more common in the patients with follicular neoplasm and serum Tg concentration over 300 ng/ml than in those with lower Tg concentrations., Conclusions: Predictors of malignancy were tumor diameter and preoperative Tg concentration.

Background and Objectives: Within the group of patients with papillary thyroid microcarcinoma (PTMC), the prognostic factors have not been well defined and the optimal treatment has not been proved. The aim of this study was to find out the factors associated with the tumor recurrence in the patients with PTMC., Methods: A total of 228 patients with PTMC (189 females, 39 males; age 14-85 years, median 46 years) were treated at our Institute between 1975 and 2006. The data on patients' gender, age, extent of disease, pathomorphological characteristics, therapy, locoregional control, disease-free survival and disease-specific survival were collected. Statistical correlation between possible prognostic factors and the duration of disease-free interval was analyzed by univariate and Cox's multivariate survival analysis., Results: The tumor diameter ranged from 0.1 to 10 mm (mean 6.1 mm). The median length of observation was 84 months (range 1-385). During the follow-up period, the recurrence was diagnosed in 7 patients (6 locoregional and 1 distant). Multivariate analysis showed that tumor size and lymph node metastases were independent prognostic factors for disease-free interval., Conclusions: Longer disease-free interval was found in the patients with a tumor diameter < or =6 mm and without lymph-node metastases., (2007 Wiley-Liss, Inc)

Background: Medullary thyroid cancer (MTC) is a rare endocrine tumor that may be sporadic or inherited in settings of MEN2A, MEN2B and FMTC. Germline point mutations in the RET proto-oncogene are responsible for tumor occurrence, inheritance and great clinical variability. The aim of this study was to correlate the genotype and phenotype of patients with hereditary MTC (age at diagnosis, sex, TNM classification and clinical features)., Patients: Between 1997 and 2003 genetic testing was performed in 69 out of 98 patients with "sporadic" MTC. Carriage of mutation was found in 14 (20.2%) patients (index patients) and in 16 out of 31 (51.6%) of their relatives. One patient with MEN2B and codon 918 mutation was excluded from further analysis., Methods: Genomic DNA was isolated from peripheral blood leukocytes. Exons 10, 11, 13, 14, 15 and 16 of the RET proto-oncogene were amplified in polymerase chain reactions. Point mutations of the RET gene were detected with single-strand conformation analysis and DNA sequencing. Detected mutations were confirmed with restriction enzyme analysis., Results: Codon 634 mutations were detected in 15 patients (50%; aged 18-76 years; 6 families), codon 618 in nine patients (30%; aged 12-65 years; 4 families) and codon 790 in five patients (16.6%; aged 16-74 years; 3 families). The median age at diagnosis was 31 +/- 17.3, 33 +/- 15.9 and 36 +/- 23.8 years for patients with codon 618, 634 and 790 mutations. Selected by sex, females with codon mutations 618 and 634 versus 790 had median age at diagnosis of 34.5 +/- 15.6 years and 43.5 +/- 22.9 years, whereas the inverse result was observed in males (26.5 +/- 18.0 versus 16 years). The male/female ratio was 1:2 for patients with codon 618 and 634 mutations and 1:4 for patients with codon 790 mutations. Some of the data suggested correlation between specific genotypes, tumor size, stage of MTC and age at diagnosis. Pheochromocytoma (12 out of 15 patients) and primary hyperparathyroidism (6 out of 15 patients) were diagnosed solely in patients with codon 634 mutations. One patient with FMTC and Hirschprung disease was found in a family with codon 618 mutations., Conclusion: Correlation between tumor size, stage of MTC at diagnosis in view of patient's age, and specific genotype were indicated in our limited series and were more evident in female patients with codon 790 mutations. Later onset and a probably less aggressive course of MTC in these patients than in patients with other mutations should be considered in planning prophylactic thyroid surgery. MEN2A syndrome was related solely to codon 634 mutations.

Hürthle cell papillary thyroid carcinoma (HCPTC) has been studied separately from other types of thyroid carcinoma in relatively few studies. The aim of our study was to determine the factors associated with the survival of patients with HCPTC in Slovenia, an iodine-deficient region. A total of 1552 patients with thyroid carcinoma were seen at our institute during the period of 1976-2003; of them, 42 patients (33 females, 9 males; age 10-85 years, median 56.5 years) had histopathologically verified HCPTC. The data on the patients' gender, age, disease history, extent of disease, morphologic characteristics, therapy, locoregional control, disease-free interval, and survival were collected. The statistical correlation between possible prognostic factors and the disease-free interval and survival was analyzed by chi2 test and log rank analysis. The tumor diameter ranged from 1 to 9 cm (median, 3 cm). Extrathyroid tumor growth was found in 19 patients, lymph node metastases in 13 patients, and distant metastases in 2 patients. Primary treatment consisted of total or near-total thyroidectomy (39 patients), lobectomy (2 patients), radioiodine ablation of the thyroid remnant (37 patients), external irradiation (14 patients), and chemotherapy (3 patients). Locoregional recurrence was diagnosed in four patients, and dissemination in 1 patient during the follow-up period of 0.75-20 years (median, 5.5 years). Three patients died of thyroid carcinoma during the follow-up period. The 5-year and 10-year survivals were 94% and 87%, respectively. The 5-year and 10-year disease-free intervals were 93% and 81%, respectively. The factors correlated with the survival were: age, extrathyroid tumor growth, primary tumor stage, and regional and distant metastases. Although extrathyroidal tumor growth was found in 45% of the patients with HCPTC, our patients had a favorable prognosis. Long-term survival and locoregional control of disease are likely after the radical tumor resection, radioiodine ablation of the thyroid remnant, and external irradiation.

Background: Multivariate studies concerning the prognosis of patients with anaplastic carcinoma of the thyroid gland are scarce. The aim of our study was to determine the prognostic factors associated with survival of patients with anaplastic carcinoma in Slovenia, an iodine-deficient region., Methods: This retrospective study was carried out on a group of 188 patients (130 female, 58 male; median age 68 years) with anaplastic carcinoma of the thyroid who had been treated at a tertiary care centre from 1972 to 2003. For each patient, data on gender, age, disease history, extent of disease, morphological characteristics, mode of therapy, and survival were collected. Statistical correlation between possible prognostic factors and survival was analysed by univariate and Cox's multivariate analysis. Treatment modality was not included in the analysis to avoid selection bias., Results: The median survival of all the patients was 3 (+/-0.36) months. Overall 1-year survival of our patients was 13%, and 2-year survival was 6%. Multivariate analysis showed that the patients' age, performance status, tumour growth, tumour extension and distant metastases were independent prognostic factors for the survival., Conclusion: Patients younger than 71 years, with a good performance status and slowly growing tumours confined to the thyroid, and without distant metastases, had the best prognosis.

The knowledge of prognostic factors is essential for an optimal treatment of patients. The aim of our study was to find out if age is an independent prognostic factor for patients with follicular or Hürthle cell carcinoma. This retrospective study was carried out in 261 patients (median age, 62 years) with follicular or Hürthle cell thyroid carcinoma treated at our institute from 1972-2002. For all patients the follow-up was performed at our institute at least once per year. The data on gender and age of the patients, disease history, extent of disease, morphologic characteristics, mode of therapy, outcome, and survival were collected. Statistical correlation between possible prognostic factors and cause-specific survival was analyzed by univariate and Cox's multivariate survival analysis. The 10-year and 20-year survival of all 261 patients were 70% and 42%, respectively. Even 10 of 49 (20%) of our patients who were under 45 years of age (i.e., in stage II of the tumor, node, metastases [TNM] classification system) died of disease. Multivariate analysis showed that primary tumor size and distant metastases were independent prognostic factors for survival. Lymph node metastases as well as the age of patients were not found to be independent prognostic factors. Therefore, the patients with distant metastases or tumor stage T4 who are under 45 years of age cannot be considered to have favorable prognosis.

The crucial step in cellular immortalisation seems to be the activation of telomerase, the enzyme that synthesizes telomere repeat ending sequences. Since the telomerase activity has been detected in almost all types of cancer tissue it has been proposed as new reliable tumor marker. This study was conducted to evaluate the significance of appearance of circulating RNA for telomerase subunits hTR and hTERT in the plasma of cancer patients. Seven healthy volunteers, 25 primary breast cancer patients (stage I-III), 29 patients with advanced malignant melanoma (stage III-IV), and 4 patients with advanced thyroid cancer (stage III-IV) were included in the study. The total RNA was extracted from plasma samples, reverse transcribed to cDNAs, and specific cDNAs for hTR and hTERT were amplified by semi-nested PCR. In healthy volunteers, the control GAPDH was positive in all, hTR was positive in 3 cases, and hTERT was negative in all 7 tested cases. Among 25 breast cancer patients, hTR was positive in 23, and hTERT in 12 patients. Two cases, that were hTR and hTERT negative, were at the same time negative also for GAPDH. Of the 29 patients with malignant melanoma, 24 were positive for hTR, and 17 for hTERT. Again, the 5 patients that were negative for hTR and hTERT, were negative also for the control GAPDH. In all plasma samples from thyroid cancer patients, hTR and hTERT were positive. In conclusion, the RT-PCR followed by semi-nested PCR is a highly sensitive method for detection of circulating RNA in the plasma. Among the telomerase subunits, only hTERT could serve as an unspecific tumor marker in the plasma of cancer patients.

Medullary thyroid cancer is a rare, neuroendocrine, tumor. It arises from parafollicular or C-cells with the ability to produce and secrete different bioactive substances like calcitonin (TC) and CEA (1-5) TC is ideal tumor marker in early diagnosis, in patents' follow up and in evaluation of their treatment. TC determinations after ca/pentagastrine stimulation test give us even more accurate results and the procedure is used for biochemical family screening. MTC occurs as a sporadic tumor or in hereditary settings MEN 2A, MEN 2B and FMCT. Germ/line point mutations in RET proto/onkogene are responsible for tumor arise and inheritance of settings. Genetic screening provides information of these RET mutations in family members even before pathologic changes occur. These individuals with MEN 2A, 2B and FMCT characteristic RET mutations are almost certain to acquire MTC (95% penetrance) in their lives and are candidates for preventive total thyroidectomy (TT), with or without central neck dissection (CND). Surgery is still the treatment of choice for MTC and only C-cell hyperplasia and early stage of MTC can be cured. Prophylactic thyroid surgery eliminates the possibility of MTC but doesn't influence appearance of other diseases (PHEO, HPTH) of MEN 2 syndromes.

Aims: There is no reliable diagnostic test for pre-operative differentiation between benign and malignant follicular and Hurthle cell neoplasms. Measurements of serum thyroglobulin (Tg) are currently only used post-operatively as a marker of recurrent disease or distant metastases in the follow-up of patient with differentiated thyroid cancer. In this study pre-operative serum Tg measurements were performed with the aim of investigating whether Tg levels differ in benign and malignant follicular and Hurthle cell neoplasms., Methods: In 516 patients who underwent thyroid surgery at the Institute of Oncology in Ljubljana, Slovenia, from 1990 to 1996, serum Tg concentration was measured in addition to the standard pre-operative tests (fine-needle aspiration biopsy, ultrasonography, 99mTc scanning and hormonal profile). After the operation, patients were divided into 11 groups based on their histological diagnosis (papillary cancer--classic, papillary cancer--follicular variant, papillary cancer oncocytic variant, occult papillary cancer, follicular adenoma, follicular cancer, Hurthle cell adenoma, Hurthle cell cancer, anaplastic cancer, medullary cancer, nodular goiter) and the serum Tg values of the different groups were compared., Results: In groups of patients with follicular and Hurthle cell cancer, median Tg values were higher (2895 and 638.5 ng/ml) and, statistically, differed significantly from the serum Tg values in all other groups (P<0.01). Sensitivities and specificities of the tests were 71.8% and 80.4% for follicular cancer and 55.6% and 83.8% for Hurthle cell cancer, while positive and negative predictive values were 75.6% and 77.1% for follicular cancer and 75% and 68.4% for Hurthle cell cancer., Conclusions: These results indicate that pre-operative serum Tg measurements might be an important additional diagnostic tool in the pre-operative work-up of patients with thyroid tumours.

Thyroglobulin (Tg) is a glycoprotein produced exclusively by the thyroid. It can be found in the serum of healthy people as well as of those with various thyroid disorders. Elimination of Tg from the body occurs through the liver. The data on Tg serum half-life in the literature are scarce, and the reported values vary from 6-96 h. The aim of our study was to determine the Tg half-life after surgical removal of the thyroid gland. Knowing the exact half-life of Tg would enable rational timing of sampling serum for determination of Tg after thyroid surgery or chemotherapy and/or irradiation for evaluation of treatment in patients with differentiated thyroid cancer (DTC). In 11 patients (10 females and one male, aged 27-85 years) serum samples were taken 24, 48, 72 and 168 h after a near-total or total thyroidectomy. Serum Tg levels were determined and Tg half-life calculated by the use of a one-compartment kinetic model. Mean Tg half-life was 65.2 h (SEM = 4.3), and Tg levels decrease below 5-10 ng/ml approximately only 25 days after thyroidectomy (7-10 x t1/2). Therefore, earlier determination of Tg cannot be used either for reliable detection of distant metastases or for evaluation of the effect of chemotherapy and/or irradiation.

Marginal vacuoles (MV) found in Giemsa-stained fine-needle aspirates of the thyroid gland have been observed in toxic and also in non-toxic goiters. The aim of our retrospective study was to disclose the incidence and diagnostic significance of MV in 46 smears from 43 patients with primary and/or metastatic follicular thyroid carcinoma (FTC). Typical MV, MV-like structures, or both were found in 14 of 36 specimens (39%) of the primary tumor and in four of seven specimens (57%) obtained from metastases of FTC. No association between the appearance of MV/MV-like structures and degree of tumor differentiation was demonstrated. On the other hand, MV or/and MV-like structures were more frequently (69%) documented in hyperthyroid patients (P < 0.05). Accordingly, our study demonstrated relatively frequent appearance of MV or MV-like structures in FTC independent of tumor differentiation. Their appearance, however, seems to be associated with hyperthyroidism.