Relationship between Trace Elements and Matrix Metalloproteinases 2 and 9 and their Tissue Inhibitors in Medullary Thyroid Carcinoma.

Medullary Thyroid Carcinoma (MTC) constitutes around 5% of all thyroid cancers. Trace elements assessment has emerged as a useful strategy in the diagnostics of MTC combined with Matrix Metalloproteinases (MMPs) and Tissue Inhibitors of Matrix Metalloproteinases (TIMPs) analysis. The aim of this study was to compare the presence and content of trace elements (i.e., Copper (Cu), Zinc (Zn), Iron (Fe), and Manganese (Mn)) in MTC with respect to control samples and their potential relationship with markers of MTC in tissues. The study included 26 patients who had undergone thyroidectomy, due to the diagnosis of MTC and 17 patients as control. We combined tumour pathology and staging, immunohistochemical analysis of calcitonin, MMPs, and TIMPs, with analytical biochemistry using Inductively Coupled Plasma - Mass Spectrometry (ICP-MS) to determine the levels of trace elements. No differences by MTC type for MMPs and their TIPMs, although strong TIMP-1 and TIMP-2 immunohistochemical expression of MTC were unveiled. Additionally, Zn, Fe, and Mn tended to be decreased, and Cu to be increased in samples presenting MTC with respect to controls. Moreover, Zn was the unique trace element which seemed to be correlated with MMPs and TIMPs. Trace elements such as Zn, Fe, and Mn are decreased in tissues affected by MTC. In addition, Zn may be the trace element which saves more relationship with the proportion and intensity of MMPs, being considered altogether useful biomarkers of MTC. We therefore suggest the analysis of novel and traditional markers of MTC as a novel approach in this pathology.

Matrix Metalloproteinases 2 and 9 and Their Tissue Inhibitors in the Diagnostics of Medullary Thyroid Carcinoma.

Medullary Thyroid Carcinoma (MTC) is a tumor of the neuroendocrine system. In recent years, the need to assess the MTC diagnostic-related parameters has emerged with the aim to elucidate the mechanisms involved in this pathology. The objective of this study was to evaluate the role of Matrix Metalloproteinases (MMPs) 2 and 9, their tissue inhibitors of matrix metalloproteinases (TIMPs), S100 protein, and amyloid in the diagnostic of MTC. Thirty-two samples with MTC (72% women) were included in this cross-sectional study and divided by groups: T category 1 (T1)≤20 mm and T category 2 (T2) 20 to 40 mm of tumor size. MMPs 2 and 9, TIMPs 2 and 1, S100 protein, and calcitonin in tissues were obtained by immunohistochemical techniques. The presence of amyloid in tissue sections was detected on Thioflavin T-stained slides under fluorescent microscope. Percentage of positive cells (P) observed for MMP-2 was higher in those samples presenting T2 MTC with respect to those with T1 MTC ( P <0.05). Moreover, P-MMP-2 showed a direct correlation with higher T category of MTC (Rho=0.439, P < 0.001), whereas P-MPP-9 was directly correlated with S100 protein and the intensity of calcitonin in tissues (Rho=0.419, P =0.017; Rho=0.422, P =0.016, respectively. Therefore, MMPs were directly correlated with some traditional biomarkers of MTC. In this regard, P-MMP-2 was more expressed in type 2 MTC. Combining the analysis of traditional and other useful biomarkers of MTC as MMPs 2 and 9 could be a useful strategy in the diagnostic of MTC.

Predictive Value of Calcium Test for Preoperative Diagnosis of Medullary Thyroid Carcinoma in Patients With Moderately Elevated Basal Calcitonin.

OBJECTIVE: Medullary thyroid carcinoma (MTC) can be very aggressive, and early diagnosis is based on routine measurement of serum calcitonin (CT) and RET genetic testing for hereditary forms. Basal serum CT (bCT) concentrations are useful in the early detection of MTC, although it is still unclear whether they can also be used for the differential diagnosis between MTC and C-cell hyperplasia (CCH). Since false-positive results can be obtained with the basal measurement of CT, a provocative test to evaluate stimulated CT (sCT) is often needed. The objective of this study was to investigate the utility of a calcium gluconate test for CT in distinguishing MTC from CCH, a precancerous condition in hereditary forms of MTCs but with unclear significance in sporadic MTCs. METHODS: A total of 74 patients underwent the calcium loading test before thyroidectomy, and bCT and sCT levels were compared with histologic results by receiver operating characteristic plot analyses. RESULTS: A peak CT level of 388.4 pg/mL after stimulation with calcium gluconate was able to significantly distinguish patients with MTC from those with CCH and those without C-cell pathology, with 81.8% sensitivity and 36.5% specificity. A bCT level of 16.1 pg/mL was able to distinguish between these 2 groups of patients with a sensitivity of 90%. CONCLUSION: High-dose calcium test is an effective procedure that can be applied for differential diagnosis of MTC and CCH. Reference ranges for calcium sCT levels and CT thresholds in different groups of patients have been identified.

Case report of parathyroid carcinoma in a pediatric patient.

Parathyroid carcinoma is extremely rare in pediatric population. The authors report a case of 15-year-old girl with extremely elevated serum calcium (4.1 mmol/L) and parathyroid hormone (1170 pg/mL), with palpable neck mass. After en bloc resection, the patient remained normocalcemic within the next 2 years. To the best of our knowledge, this is the fourteenth documented case of parathyroid carcinoma in patients younger than 16 years. Even though parathyroid carcinoma is very uncommon in children with good prognosis, this diagnosis has to be considered when a child has severe hypercalcemia, elevated parathyroid hormone and palpable neck mass.

Risk Factors for Intraoperative Hypertension during Surgery for Primary Hyperparathyroidism.

OBJECTIVE: To investigate the incidence and identify risk factors for the occurrence of intraoperative hypertension (IOH) during surgery for primary hyperparathyroidism (pHPT). SUBJECTS AND METHODS: The study included 269 patients surgically treated between January 2008 and January 2012 for pHPT. IOH was defined as an increase in systolic blood pressure ≥20% compared to baseline values which lasted for 15 min. The investigated influence were demographic characteristics, surgical risk score related to physical status (based on the American Society of Anesthesiologists [ASA] classification), comorbidities, type and duration of surgery, and duration of anesthesia on IOH occurrence. The investigated factors were obtained from the patients' medical history, anesthesia charts, and the daily practice database. Logistic regression analysis was done to determine the predictors of IOH. RESULTS: Of the 269 patients, 153 (56.9%) had IOH. Based on the univariate analysis, age, body mass index, ASA status, duration of anesthesia, and preoperative hypertension were risk factors for the occurrence of IOH. Multivariate analysis showed that independent predictors of IOH were a history of hypertension (OR = 2.080, 95% CI: 1.102-3.925, p = 0.024) and age (OR = 0.569, 95% CI: 0.360-0.901, p = 0.016). CONCLUSION: In this study, a high percentage (56%) of the patients developed IOH during surgery for pHPT, which indicates that special attention should be paid to these patients, especially to the high-risk groups: older patients and those with a history of hypertension. Further, this study showed that advanced age and hypertension as a coexisting disease prior to parathyroid surgery were independent risk factors for the occurrence of IOH.

Surgical treatment of concomitant thyroid and parathyroid disorders: analysis of 4882 cases.

The thyroid gland disease incidence in hyperparathyroidism (HPT) is higher than the incidence of thyroid disease in general population. Likewise, HPT is more frequent in patients primary admitted due to thyroid disease, than in general population. The aim of this study was to determine the incidence and clinical characteristics of concomitant HPT and thyroid disease, based on a single center experience. From 2009 to 2014, a total of 4882 patients underwent thyroidectomy and/or parathyroidectomy at the Center for Endocrine Surgery, Belgrade. We reviewed the database to find out indications for surgery, clinical characteristics, operative and histopathological findings. Out of 4033 patients, who underwent thyroidectomy, in 114 cases (2.8 %) parathyroidectomy was simultaneously performed. Out of these 114 patients, 42 patients (37 %) had normocalcemic HPT. Among 849 patients primary operated due to HPT, thyroid gland disease that required surgery was found in 224 (26.4 %). In patients primary seen for HPT, thyroid cancer was found in 22 (9.8 %), Hashimoto's thyroiditis in 41 (18.3 %) and micropapillary carcinoma in 36 cases (16.1 %). Due to residual or recidivant HPT, 16 patients (15 who primary underwent parathyroidectomy and 1 primary seen for thyroid disease) needed a reoperation. There are a considerable number of patients with concomitant thyroid and parathyroid disease; this justifies the routine analyses of calcemia and PTH level in patients preparing for thyroidectomy, and sets up the ground for the thyroid investigations in HPT.

Papillary Thyroid Carcinoma: A Malignant Tumor with Increased Antioxidant Defense Capacity.

Papillary thyroid carcinoma (PTC) is the commonest thyroid malignancy worldwide for which the radiation exposure is the most influential risk factor. The levels of oxidative stress in PTC are not well characterized on the tissue level. The objective of this study was to evaluate total oxidant status (TOS) and total antioxidant status (TAS) in PTC and benign goiter (BG) tissues and to examine their association with clinicopathological characteristics. Tumor and normal thyroid tissue samples were collected from 59 PTC patients, and goiter tissues were collected from 50 BG patients. TOS and TAS were quantified in the tissue homogenates by spectrophotometric assays. TOS values in tumor tissues did not differ significantly from normal and goiter tissues; however, PTC tissues have significantly higher TAS values than normal and goiter tissues. TOS values correlated with retrosternal growth in BG patients. The significant correlations were found between TOS and TAS values and thyroid function parameters. In 17 PTC patients with multiple tumor foci (multicentric phenotype), TAS values were significantly lower, compared to 42 patients with unicentric PTC. TAS and TOS are the most useful predictors of thyroid capsular invasion by PTC. The age, sex, body mass index, smoking, familial history of thyroid disease and nodule size did not influence TOS and TAS in PTC or BG patients. In conclusion, we show the profiles of TOS and TAS in PTC and BG tissues. Importantly, PTC tissues possess increased antioxidant capacity. The redox status influences the parameters of the thyroid function and tumor's biological behavior.

Quality of life improvement in patients with Hashimoto thyroiditis and other goiters after surgery: A prospective cohort study.

INTRODUCTION: Hashimoto thyroiditis (HT) and other benign goiters (BG) might influence patients' quality of life (QoL). The objective of this study was to analyze influence of surgery on these patients' QoL. METHODS: A prospective cohort study was conducted. The ThyPRO questionnaire was used in the QoL assessment. RESULTS: The HT patients experienced significantly worse hypothyroid symptoms and sex life than the BG patients. The improvement in QoL in the BG patients was significant after surgery in all ThyPRO domains. In the HT patients, the improvement was significant in all but two domains, eye symptoms and cognitive impairment. The best improvement in both groups was in overall QoL. None of the patients developed permanent consequences. CONCLUSIONS: The QoL of HT and BG patients is impaired and improves significantly after surgical treatment. Thyroidectomy should be considered as a treatment option in the HT patients more often as in the BG patients.

Changes in the expression pattern of apoptotic molecules (galectin-3, Bcl-2, Bax, survivin) during progression of thyroid malignancy and their clinical significance.

BACKGROUND: Papillary carcinoma of the thyroid (PTC) is generally a slow growing tumor with favorable prognosis, while anaplastic thyroid carcinoma (ATC) is highly aggressive malignancy. Genetic defects in apoptotic pathways may contribute to differences in their biological behavior. METHODS: In this study, we analyzed immunohistochemically the expression of apoptosis-related molecules: galectin-3, Bcl-2, survivin (antiapoptotic), and Bax (pro-apoptotic), in archival tissue sections of PTC (n = 69) and ATC (n = 30) and correlated the results with clinicopathological parameters of these tumors. RESULTS: Galectin-3 and Bcl-2 showed a similar trend of down-regulation from high levels of both in PTC to low levels in ATC (p < 0.05). Bax was expressed at high levels in both type of thyroid carcinoma. Expression of survivin increased from PTC to ATC (p < 0.05), which may, at least in part, further facilitate the ability of malignant thyroid cell of ATC to escape programmed cell death despite high Bax expression. Only survivin, but not galectin-3, Bcl-2, or Bax, correlated significantly with lymph node metastasis presence and advanced stages of malignancy. CONCLUSIONS: In conclusion, this study documented down-regulation of galectin-3 and Bcl-2 (antiapoptotic molecules) and stepwise increase of survivin (inhibitor of apoptosis), during thyroid tumor progression from PTC to ATC. Correlation of high survivin expression with aggressive behavior implies its role in progression of thyroid tumor malignancy and suggests that survivin could be a useful tool in the prediction of aggressiveness of a subset of papillary carcinomas and a possible target for molecular therapy for ATC patients.

Copper as ancillary diagnostic tool in preoperative evaluation of possible papillary thyroid carcinoma in patients with benign thyroid disease.

Preoperative diagnosis of papillary thyroid carcinoma (PTC) comprises numerous diagnostic procedures which are mostly applicable in tertiary institutions. Normal thyroid function depends on the presence of many trace elements and copper (Cu) and zinc (Zn) are some of those. The study is based on retrospective review of 118 patients with preoperatively diagnosed benign thyroid disease (BTD) and 12 with PTC, who underwent thyroid surgery at the Center for Endocrine Surgery Clinical Center of Serbia, Belgrade, between 2010 and 2012. The objective was to evaluate concentrations of Cu and Zn in serum as possible prediction markers for PTC in patients who underwent surgery for preoperatively diagnosed BTD. Concentrations of Cu and Zn ions in serum were measured using atomic absorption spectrophotometer. Data were analyzed using methods of descriptive statistics, Anova and t-test (p < 0.05 was considered statistically significant). Definitive pathohistological findings revealed PTC in 23 (19.5%) and papillary microcarcinoma-mPTC in 13 (11.0%) of BTD patients. The concentrations of Cu ions in serum of PTC patients as well as in serum of patients with mPTC were significantly higher than in serum of BTD patients (p < 0.05). The concentrations of Zn ions and Cu/Zn ratio in serum of PTC and mPTC patients were not significantly higher than in serum of BTD patients. The concentration of Cu ions in serum of patients before thyroid surgery can be useful, easy available, and a low-cost tool in prediction of preoperatively undiagnosed PTC in patients with BTD.

Improvement of quality of life in patients with benign goiter after surgical treatment.

PURPOSE: A quality of life (QoL) assessment is considered an important outcome measure in the treatment of benign thyroid diseases. The aims of this study were to analyze the impact of different surgical treatments on QoL in patients with benign thyroid diseases and to evaluate factors correlating with the QoL outcomes. METHODS: A prospective longitudinal study was conducted. One hundred thirty-two patients met the inclusion/exclusion criteria and completed the disease-specific questionnaire, thyroid patient-reported outcome (ThyPRO), before surgery and after 6 months. Preoperative and postoperative QoL outcomes were compared and correlating factors were analyzed. RESULTS: Indication for surgery was euthyroid goiter, toxic goiter, and suspicious malignant thyroid disease in 58.3, 29.5, and 12.1 % of the patients, respectively. None of the patients had overtly toxic goiter. There were 65.2 % of the patients who underwent total thyroidectomy, while 34.8 % underwent hemithyroidectomy. The total postoperative complication rate was 5.3 %. QoL improved significantly after surgical treatment, independent of the extent of performed surgery. The most affected domain, pre- and postoperative, was for tiredness. QoL improvement was significant for women in all domains, while for men, it was significant in only three domains (goiter symptoms, emotional susceptibility, and cosmetic complaints) and in overall QoL. Younger patients had significantly better cognitive functioning and daily life, while elderly patients had significantly less cosmetic complaints. The factors that significantly correlated with improvement of QoL in different domains were lower education level, duration of disease, and microcarcinoma at final histology. CONCLUSION: QoL in patients with benign thyroid diseases improves significantly after operative treatment, independent of the extent of the operation.

Risk factors for sporadic medullary thyroid carcinoma.

Medullary thyroid cancer is a rare tumour that appears in two distinct forms. The rarer familial form is genetically determined. The sporadic form is more common, but its aetiology has not been defined clearly so far. The aim of this study was to examine the risk factors for development of sporadic medullary thyroid cancer (sMTC). A case-control study was carried out during the period 2000-2009. The case group included 98 consecutive patients with sMTC. The control group comprised twice as many cases (196), who were neighbours of the patients from the case group. Patients were individually matched by sex, age and place of residence. Conditional univariate and multivariate logistic regression methods were applied in data analyses. According to the univariate logistic regression method, sMTC was significantly related to smoking status, duration of smoking, number of cigarettes smoked per day, personal history of goitre or thyroid nodules, personal history of nonthyroid cancer, menarche after 14 years of age, first full-term pregnancy before 20 years of age and usage of oral contraceptives. According to the multivariate logistic regression method, sMTC was independently related to smoking status [odds ratio (OR)=0.46, 95% confidence interval (CI)=0.20-0.90], personal history of goitre or thyroid nodules (OR=11.29, 95% CI=1.16-73.45) and menarche after 14 years of age (OR=2.77, 95% CI=1.33-6.28). Risk factors for sMTC were goitre or thyroid nodules and late menarche; cigarette smoking appeared to be a protective factor.

Case-control study of anaplastic thyroid cancer: goiter patients as controls.

Anaplastic thyroid cancer is very serious disease with bad prognosis and unknown etiology. The aim of the study was to test some hypotheses about other factors in addition to goiter related to anaplastic thyroid cancer occurrence. A case-control study was performed during the period 1993-2005. The case group comprised 126 patients with newly diagnosed anaplastic thyroid cancer. The control group comprised 252 patients who had for the first time goiter operation, and had no malignancy of thyroid gland. Cases and controls were individually matched by age, sex and place of residence (urban/rural). According to conditional multivariate logistic regression analysis, anaplastic thyroid cancer was significantly related to lower education (odds ratio=1.85, 95% confidence interval=1.21-2.82), other malignant tumors in personal history (odds ratio=4.37, 95% confidence interval=1.11-17.31), blood group B (odds ratio=3.69, 95% confidence interval=1.10-12.49), menarche at >or=15 years of age (odds ratio=2.63, 95% confidence interval=1.15-5.88), and first full-term pregnancy before 19 years of age (odds ratio=2.96, 95% confidence interval=1.26-6.96). On the basis of the results obtained, risk factors for anaplastic thyroid cancer are similar to risk factors for differentiated thyroid cancers.

Galectin-3 expression in papillary thyroid carcinoma: relation to histomorphologic growth pattern, lymph node metastasis, extrathyroid invasion, and tumor size.

BACKGROUND: Galectin-3 has been recently recognized as a promising presurgical marker of thyroid malignancy. METHODS: Galectin-3 expression was examined immunohistochemically in 202 specimens of papillary thyroid carcinoma (PTC) in relation to histomorphologic subtypes and clinicopathologic data. RESULTS.: The sensitivity of galectin-3 immunostaining versus conventional histology was 98% (100 of 102) for classical PTC, 85.2% (46 of 54) for follicular variant, and 50% (23 of 46) for follicular/solid variant of PTC. All cases (n = 36) involving lymph node metastases and 42 of 45 cases with extrathyroid invasion expressed galectin-3. However, among the galectin-3-positive cases (n = 169), 133 were without lymph node metastases, and 127 were without extrathyroid invasion. Galectin-3 expression was not related to the size of intrathyroid PTC. CONCLUSIONS: Galectin-3 immunohistochemical expression itself is not an indicator of local metastatic spread or extrathyroid invasion of PTC, thus being irrelevant clinically from this aspect. Galectin-3 is an excellent marker for classical PTC but must be used with caution in diagnosing unconventional variants of PTC because of the possibility of false-negative results.