Impact of ultrasonographic features, cytomorphology and mutational testing on malignant and indeterminate thyroid nodules on diagnostic accuracy of fine needle cytology samples: A prospective analysis of 141 patients.

OBJECTIVE: Fine needle cytology (FNC) is the first-line diagnostic method to determine the benign or malignant nature of thyroid nodules. The gray zone of cytological classifications remains, however, a crucial and challenging area for cytopathologists. DESIGN, PATIENTS AND MEASUREMENTS: In the present study, 141 thyroid cytological samples, with ultrasonographic suspicious features, have been prospectively analysed. Molecular analyses were performed by an innovative technology using two multiplex PCRs for the amplification of BRAF, N-H-K-RAS and RET exon genes. RNA samples were studied for RET/PTC1 and RET/PTC3 rearrangements by PCR amplification, and the conditions were set-up to study, with a single experiment, both wild-type PAX8 and PAX8/PPARÉ£ rearrangements. In total, 111 samples were examined for BRAF, N-H-KRAS and RET genes. An ultrasonographic, cytological and molecular correlation was also carried out in an attempt to suggest a possible way to manage the patients with thyroid nodules. Cyto-histological correlation was available in 115 cases, and it was used to verify the global diagnostic accuracy of this combined approach. RESULTS: According to the histopathological diagnosis, FNC accuracy was 100% for TIR5 and metastases; 89% for TIR4; 84% for TIR3A and 58% for TIR3B. About 11% of the studied samples showed either RET-PTC1 or RET/PTC3 chromosomal rearrangements, and only one sample simultaneously presented RET/PTC1 and RET/PTC3 rearrangements. PAX8/PPARÉ£ rearrangement was found in 6% of the samples. CONCLUSIONS: A multidisciplinary approach to the thyroid is therefore necessary to develop innovative methods suitable for an improved diagnostic and prognostic definition of thyroid cancer.

Thyroid cancer management: from a suspicious nodule to targeted therapy.

Thyroid nodules are very common, and their frequency is four to five times higher in women than in men. Most of them are benign, with only a very little percentage revealing a malignant neoplasm. About 50% of thyroid nodules are detected by self-palpation of neck, whereas the other 50% are diagnosed by neck ultrasonography and following fine-needle aspiration. Management of thyroid nodules is very difficult, because benign nodules are prevalent, whereas thyroid carcinoma is uncommon, representing only 1% of all malignancies. A standard diagnostic approach is represented by 'first-level' exams, consisting in neck ultrasonography and serum thyroid-stimulating hormone measurement, followed, only for nodules that are suspicious of malignancy, by 'second-level' exams, consisting of fine-needle aspiration and mutational test, which does detect particular DNA mutations present only in malignant cells. In this review, we will analyze the genetics of thyroid cancer and its heterogeneity, and we will briefly describe the current available diagnostic and therapeutic approaches.

Follicular thyroid carcinoma with skull metastases.

Thyroid carcinoma with distant metastases at initial presentation, is uncommon. Skull metastases occur very rarely, with a reported incidence of 2.5-5.8%. Here we report two cases of follicular thyroid cancer with skull involvement, and describe the diagnostic and therapeutic approach to metastatic thyroid cancer. We present the cases of a 70-year-old female and a 74-year-old female who presented with painless, large slow-growing masses of the skull. The patients underwent surgical excision of the skull masses, which were histologically diagnosed as metastatic follicular thyroid cancer, and total thyroidectomy, which confirmed the diagnosis of follicular thyroid carcinoma. They were treated with radioiodine and suppressive levothyroxine, which achieved local control of the disease. Management of metastatic thyroid cancer, requires a multidisciplinary approach and multimodality treatment. Distant metastases should be surgically removed whenever possible. Initial aggressive treatment is crucial in the management of metastatic thyroid carcinoma, providing the best chance to prolong patient survival.

Survival predictors of radioiodine-refractory differentiated thyroid cancer treated with lenvatinib in the real-life.

CONTEXT: Lenvatinib is approved for the treatment of radioiodine-refractory differentiated thyroid cancer (RR-DTC). The definition of predictive factors of survival is incomplete. OBJECTIVE: To identify pre- and post- treatment survival predictors in a real-life cohort of RR-DTC treated with lenvatinib. DESIGN: Multicenter, retrospective, cohort study. SETTING: Three Italian thyroid cancer referral centers. PARTECIPANTS: 55 RR-DTC treated with lenvatinib. MAIN OUTCOME MEASURES: Progression-free survival (PFS) and overall survival (OS). RESULTS: Lenvatinib was the first-line kinase-inhibitor in 96.4% of subjects. Median follow-up was 48 months. Median PFS and OS were 26 (95% CI 19.06-32.93) and 70 months (95% CI 36-111.99), respectively. Pre-treatment setting: Eastern Cooperative Oncology Group (ECOG) performance status was independently related to PFS (p < 0.001; HR 18.82; 95% CI 3.65-97.08: score 0-1 as reference) and OS (p = 0.001; HR 6.20; 95% CI 2.11-18.20; score 0-1 as reference); radioactive iodine (RAI)-avidity was independently related to PFS (p = 0.047; HR 3.74; 95% CI 1.01-13.76; avid disease as reference). Patients with good ECOG status (0-1) and RAI-avid disease obtained objective response in 100% of cases and achieved a median PFS of 45 months without any death upon a median follow-up of 81 months. Post-treatment setting: best radiological response independently predicted PFS (p = 0.001; HR 4.6; 95% CI 1.89-11.18; partial/complete response as reference) and OS (p = 0.013; HR 2.94; 95% CI 1.25-6.89; partial/complete response as reference). CONCLUSIONS: RR-DTC with good performance status and RAI-avid disease obtain the highest clinical benefit from lenvatinib. After treatment initiation, objective response was the only independent survival predictor.

Aberrant expression of posterior HOX genes in well differentiated histotypes of thyroid cancers.

Molecular etiology of thyroid cancers has been widely studied, and several molecular alterations have been identified mainly associated with follicular and papillary histotypes. However, the molecular bases of the complex pathogenesis of thyroid carcinomas remain poorly understood. HOX genes regulate normal embryonic development, cell differentiation and other critical processes in eukaryotic cell life. Several studies have shown that HOX genes play a role in neoplastic transformation of several human tissues. In particular, the genes belonging to HOX paralogous group 13 seem to hold a relevant role in both tumor development and progression. We have identified a significant prognostic role of HOX D13 in pancreatic cancer and we have recently showed the strong and progressive over-expression of HOX C13 in melanoma metastases and deregulation of HOX B13 expression in bladder cancers. In this study we have investigated, by immunohistochemisty and quantitative Real Time PCR, the HOX paralogous group 13 genes/proteins expression in thyroid cancer evolution and progression, also evaluating its ability to discriminate between main histotypes. Our results showed an aberrant expression, both at gene and protein level, of all members belonging to paralogous group 13 (HOX A13, HOX B13, HOX C13 and HOX D13) in adenoma, papillary and follicular thyroid cancers samples. The data suggest a potential role of HOX paralogous group 13 genes in pathogenesis and differential diagnosis of thyroid cancers.

Exposure to Bisphenol A increases malignancy risk of thyroid nodules in overweight/obese patients.

Bisphenol A (BPA) is a widespread thyroid disruptor, but evidence about an association with thyroid cancer is weak. Excess body weight is a risk factor for thyroid cancer and affects activity of endocrine disruptors. Aim of the study was to investigate the association between BPA exposure and thyroid cancer, verifying the effect modification related to body weight. We performed a multicentre, cross-sectional study including consecutive patients referring for nodular goiter. The quantitative determination of BPA in serum samples was performed through high performance liquid chromatography system, coupled in tandem with ultraviolet and fluorescence detection. Ninety-six patients were included: 55 benign nodules, 41 thyroid cancers, 28 normal weight, and 68 overweight/obese. BPA was detected in 79 subjects. In the overall study population and in the group with BMI<25 kg/m2 BPA exposure was not significantly correlated to thyroid cancer (p = 0.08 and 0.759, respectively). In the group with BMI≥25 kg/m2, BPA-exposed subjects showed significantly higher risk of malignancy (OR: 5.3, p = 0.028). At multivariate analysis, such association was independent of smoking, alcohol consumption, occupational exposure, and phthalates exposure (p = 0.021 and 0.016, respectively), but was lost after adjustment for the presence of metabolic syndrome (p = 0.089). In overweight/obese subjects, BPA exposure was significantly associated with higher thyroid stimulating hormone levels. Our study suggests that BPA exposure is a risk factor for thyroid cancer in overweight/obese subjects.

Circulating cell-free DNA (cfDNA) in patients with medullary thyroid carcinoma is characterized by specific fragmentation and methylation changes with diagnostic value.

Medullary Thyroid Carcinoma (MTC) is a rare neuroendocrine tumour whose diagnosis includes evaluating calcitonin serum levels, which can present fluctuations unrelated to MTC. Here, we investigated circulating DNA fragmentation and methylation changes as potential biomarkers using ddPCR on cell-free DNA (cfDNA) isolated from the plasma of MTC patients. For cfDNA fragmentation analysis, we investigated the fragment size distribution of a gene family and calculated short fragment fraction (SFF). Methylation analyses evaluated the methylation levels of CG_16698623, a CG dinucleotide in the MGMT gene that we found hypermethylated in MTC tissues by analyzing public databases. The SFF ratio and methylation of CG_16698623 were significantly increased in plasma from MTC patients at diagnosis, and patients with clinical remission or stable disease at follow-up showed no significant SFF difference compared with healthy subjects. Our data support the diagnostic value of cfDNA traits that could enable better management of MTC patients.

A Data-Driven Approach to Refine Predictions of Differentiated Thyroid Cancer Outcomes: A Prospective Multicenter Study.

CONTEXT: The risk stratification of patients with differentiated thyroid cancer (DTC) is crucial in clinical decision making. The most widely accepted method to assess risk of recurrent/persistent disease is described in the 2015 American Thyroid Association (ATA) guidelines. However, recent research has focused on the inclusion of novel features or questioned the relevance of currently included features. OBJECTIVE: To develop a comprehensive data-driven model to predict persistent/recurrent disease that can capture all available features and determine the weight of predictors. METHODS: In a prospective cohort study, using the Italian Thyroid Cancer Observatory (ITCO) database (NCT04031339), we selected consecutive cases with DTC and at least early follow-up data (n = 4773; median follow-up 26 months; interquartile range, 12-46 months) at 40 Italian clinical centers. A decision tree was built to assign a risk index to each patient. The model allowed us to investigate the impact of different variables in risk prediction. RESULTS: By ATA risk estimation, 2492 patients (52.2%) were classified as low, 1873 (39.2%) as intermediate, and 408 as high risk. The decision tree model outperformed the ATA risk stratification system: the sensitivity of high-risk classification for structural disease increased from 37% to 49%, and the negative predictive value for low-risk patients increased by 3%. Feature importance was estimated. Several variables not included in the ATA system significantly impacted the prediction of disease persistence/recurrence: age, body mass index, tumor size, sex, family history of thyroid cancer, surgical approach, presurgical cytology, and circumstances of the diagnosis. CONCLUSION: Current risk stratification systems may be complemented by the inclusion of other variables in order to improve the prediction of treatment response. A complete dataset allows for more precise patient clustering.

A Prospective Multicenter Study Examining the Relationship Between Thyroid Cancer Treatment Outcomes and the Presence of Autoimmune Thyroiditis.

Background: There is some controversy on the potential relationship between autoimmune processes and clinicopathologic features as well as prognosis of differentiated thyroid cancer (DTC), and the evidence is limited by its largely retrospective nature. We examined the relationship between the presence of autoimmune thyroiditis (AT) and 1-year thyroid cancer treatment outcomes in a large multicenter study using prospectively collected data. Methods: We included data from consecutive DTC patients enrolled in the Italian Thyroid Cancer Observatory (ITCO) database (NCT04031339). We divided the groups according to the presence (AT) or absence (no autoimmune thyroiditis [noAT]) of associated AT. We used propensity score matching to compare the clinical features and outcomes between the two groups at 1-year follow-up. Results: We included data from 4233 DTC patients, including 3172 (75%) females. The American Thyroid Association (ATA) risk levels were as follows: 51% (2160/4233) low risk, 41.3% (1750/4233) intermediate risk, and 7.6% (323/4233) high risk. There were 1552 patients (36.7%) who had AT. Before propensity score matching, AT patients were significantly younger and had a smaller and bilateral tumor (p < 0.0001). Patients with AT more frequently fell into the low- and intermediate-risk categories, while the ATA high risk was more frequent among noAT patients (p = 0.004). After propensity score matching, patients with AT more frequently showed evidence of disease (structural/biochemical incomplete response) versus excellent/indeterminate response, compared with patients without AT (7.3% vs. 4.5%, p = 0.001), with an odds ratio of 1.86 ([confidence interval: 1.3-2.6], p = 0.0001). However, when considering only structural persistence as the outcome, no statistically significant differences were observed between patients with or without AT (3.4% vs. 2.7%, p = 0.35). The elevated risk associated with the ATA intermediate and high risk at diagnosis remained consistently statistically significant. Conclusions: In this large prospective series, biochemical persistence was more frequent, at 1-year follow-up, in AT patients. However, there was no significant association between the presence of AT and structural persistence of disease. These findings may be explained by the presence of a residual thyroid tissue.

Axillary node metastasis from differentiated thyroid carcinoma with Hürthle and signet ring cell differentiation. A case of disseminated thyroid cancer with peculiar histologic findings.

BACKGROUND: Differentiated thyroid cancer is usually associated with an excellent prognosis and indolent course. Distant metastases are rare events at the onset of thyroid cancer. Among these presentations, metastasis to the axillary lymph nodes is even more unusual: only few cases were previously reported in the literature; there has been no report of axillary lymph node metastasis from follicular thyroid carcinoma. Axillary lymph node metastasis generally arises in the context of disseminated disease and carries an ominous prognosis. CASE PRESENTATION: Here we present a case of axillary lymph node metastasis in the context of disseminated differentiated thyroid cancer. The patient underwent near total thyroidectomy and neck and axillary lymph node dissection. A histopathological diagnosis of poorly differentiated follicular carcinoma with "signet ring cells" and Hürthle cell features was established. The patient received radioactive iodine therapy and TSH suppression therapy. Subsequently his serum thyroglobulin level decreased to 44.000 ng/ml from over 100.000 ng/ml. DISCUSSION AND CONCLUSION: Currently there are only few reported cases of axillary node metastases from thyroid cancer, and to our knowledge, this is the first report on axillary lymph node metastasis from follicular thyroid carcinoma. "Signet ring cell" is a morphologic feature shared by both benign and, more rarely, malignant follicular thyroid neoplasm, and it generally correlates with an arrest in folliculogenesis. Our case is one of the rare "signet ring cells" carcinomas so far described.

Kinase-inhibitors for iodine-refractory differentiated thyroid cancer: still far from a structured therapeutic algorithm.

The kinase-inhibitors (KIs) sorafenib and lenvatinib demonstrated efficacy in iodine-refractory DTC upon phase III studies. However, evidence allowing a punctual balance of benefits and risks is poor. Furthermore, the lack of a direct comparison hampers to establish the proper sequence of administration. However, some insights may provided: a) indirect comparison between phase III trials showed milder toxicity for sorafenib, which should be preferred in case of cardiovascular comorbidities; b) prospective evidence of efficacy in KIs pre-treated patients is available only for lenvatinib, which should be used as second-line. Promising activity was found for the majority of other tested KIs, but no placebo-controlled trials are available. Emerging, but still early, frontiers include the restoration of iodine-sensitivity and the selective activity on pathogenic mutations. In conclusion, the use of KIs in iodine-refractory DTC is far from a structured therapeutic algorithm.

Minimal Extrathyroidal Extension in Predicting 1-Year Outcomes: A Longitudinal Multicenter Study of Low-to-Intermediate-Risk Papillary Thyroid Carcinoma (ITCO#4).

Background: The role of minimal extrathyroidal extension (mETE) as a risk factor for persistent papillary thyroid carcinoma (PTC) is still debated. The aims of this study were to assess the clinical impact of mETE as a predictor of worse initial treatment response in PTC patients and to verify the impact of radioiodine therapy after surgery in patients with mETE. Methods: We reviewed all records in the Italian Thyroid Cancer Observatory database and selected 2237 consecutive patients with PTC who satisfied the inclusion criteria (PTC with no lymph node metastases and at least 1 year of follow-up). For each case, we considered initial surgery, histological variant of PTC, tumor diameter, recurrence risk class according to the American Thyroid Association (ATA) risk stratification system, use of radioiodine therapy, and initial therapy response, as suggested by ATA guidelines. Results: At 1-year follow-up, 1831 patients (81.8%) had an excellent response, 296 (13.2%) had an indeterminate response, 55 (2.5%) had a biochemical incomplete response, and 55 (2.5%) had a structural incomplete response. Statistical analysis suggested that mETE (odds ratio [OR] 1.16, p = 0.65), tumor size >2 cm (OR 1.45, p = 0.34), aggressive PTC histology (OR 0.55, p = 0.15), and age at diagnosis (OR 0.90, p = 0.32) were not significant risk factors for a worse initial therapy response. When evaluating the combination of mETE, tumor size, and aggressive PTC histology, the presence of mETE with a >2 cm tumor was significantly associated with a worse outcome (OR 5.27 [95% confidence interval], p = 0.014). The role of radioiodine ablation in patients with mETE was also evaluated. When considering radioiodine treatment, propensity score-based matching was performed, and no significant differences were found between treated and nontreated patients (p = 0.24). Conclusions: This study failed to show the prognostic value of mETE in predicting initial therapy response in a large cohort of PTC patients without lymph node metastases. The study suggests that the combination of tumor diameter and mETE can be used as a reliable prognostic factor for persistence and could be easily applied in clinical practice to manage PTC patients with low-to-intermediate risk of recurrent/persistent disease.

Real-World Performance of the American Thyroid Association Risk Estimates in Predicting 1-Year Differentiated Thyroid Cancer Outcomes: A Prospective Multicenter Study of 2000 Patients.

Background: One of the most widely used risk stratification systems for estimating individual patients' risk of persistent or recurrent differentiated thyroid cancer (DTC) is the American Thyroid Association (ATA) guidelines. The 2015 ATA version, which has increased the number of patients considered at low or intermediate risk, has been validated in several retrospective, single-center studies. The aims of this study were to evaluate the real-world performance of the 2015 ATA risk stratification system in predicting the response to treatment 12 months after the initial treatment and to determine the extent to which this performance is affected by the treatment center in which it is used. Methods: A prospective cohort of DTC patients collected by the Italian Thyroid Cancer Observatory web-based database was analyzed. We reviewed all records present in the database and selected consecutive cases that satisfied inclusion criteria: (i) histological diagnosis of DTC, with the exclusion of noninvasive follicular thyroid neoplasm with papillary-like nuclear features; (ii) complete data of the initial treatment and pathological features; and (iii) results of 1-year follow-up visit (6-18 months after the initial treatment), including all data needed to classify the estimated response to treatment. Results: The final cohort was composed of 2071 patients from 40 centers. The ATA risk of persistent/recurrent disease was classified as low in 1109 patients (53.6%), intermediate in 796 (38.4%), and high in 166 (8.0%). Structural incomplete responses were documented in only 86 (4.2%) patients: 1.5% in the low-risk, 5.7% in the intermediate-risk, and 14.5% in the high-risk group. The baseline ATA risk class proved to be a significant predictor of structural persistent disease, both for intermediate-risk (odds ratio [OR] 4.67; 95% confidence interval [CI] 2.59-8.43) and high-risk groups (OR 16.48; CI 7.87-34.5). Individual center did not significantly influence the prediction of the 1-year disease status. Conclusions: The ATA risk stratification system is a reliable predictor of short-term outcomes in patients with DTC in real-world clinical settings characterized by center heterogeneity in terms of size, location, level of care, local management strategies, and resource availability.

Fathoming the link between anthropogenic chemical contamination and thyroid cancer.

Incidence and mortality of thyroid cancer are increasing, thus making mandatory to improve the knowledge of disease etiology. The hypothesis of a role for anthropogenic chemicals is raising wide consideration. A series of occupational studies revealed that job exposures with high risk of chemical contamination were usually more prone to thyroid cancer development. These include shoe manufacture, preserving industry, building activities, pulp/papermaker industry and the wood processing, agricultural activities, and other work categories characterized by contact with chemicals, such as chemists and pharmacists. However, such epidemiological analyses cannot define a causal relationship. Thyroid-disrupting activity has emerged for a broad set of anthropogenic chemicals, with the best evidence being gained for polychlorinated biphenyls, polybrominated diphenyl ethers, dioxins, bisphenols, phthalates, pesticides, and heavy metals. A series of case-control studies, assessing exposure to thyroid-disrupting agents, as measured on biological matrices, have been recently performed providing the following insights: a) positive relationship with thyroid cancer was found for phthalates, bisphenols, the heavy metals cadmium, copper, and lead; b) polybrominated diphenyl ethers exposure showed no relationship with thyroid cancer c) controversial results were reported for polychlorinated biphenyls and pesticides. However, such studies cannot demonstrate the causal link with disease occurrence, as exposure is assessed after tumour development. Studies with different methodological approach are therefore required for defining the role of anthropogenic environmental chemicals in thyroid carcinogenesis.

Evaluation of BRAF, RAS, RET/PTC, and PAX8/PPARg alterations in different Bethesda diagnostic categories: A multicentric prospective study on the validity of the 7-gene panel test in 1172 thyroid FNAs deriving from different hospitals in South Italy.

BACKGROUND: Thyroid fine-needle aspiration (FNA) is a reliable and cost-effective diagnostic tool for establishing the nature of thyroid nodules, although up to 30% of FNAs are still classified as "indeterminate." Molecular testing of FNAs could improve preoperative diagnosis, thereby reducing unnecessary surgery. In this multicenter prospective study the authors investigated, using a 7-gene assay, the distribution and diagnostic impact of BRAF, RAS, RET/PTC, and PAX8/PPARg, the most frequent genomic alterations occurring during thyroid oncogenesis. METHODS: In total, of 1172 routine FNAs from 7 centers in southern Italy were classified according to the Bethesda System for Reporting Thyroid Cytopathology. Each specimen was tested, and molecular data were compared with available histology or cytologic follow-up. RESULTS: In particular, for atypia of undetermined significance/follicular lesion of undetermined significance cases, the 7-gene test confirmed the high positive predictive value of BRAFV600E and BRAF-like mutations (80%) and the moderate positive predictive value of RAS-like alterations (32.4%), suggesting different surgical management, depending on the type of mutation. The rate of mutation-positive FNAs was strictly related to the risk of malignancy of each diagnostic class, supporting the identification of prognostically relevant diagnostic categories. CONCLUSIONS: The 7-gene panel test improves the preoperative risk stratification of indeterminate thyroid FNAs, especially when considering the biologic significance of the different types of mutations. Moreover, the rate of mutation-positive FNAs is related to the risk of malignancy of each diagnostic class.

AXL Is a Novel Predictive Factor and Therapeutic Target for Radioactive Iodine Refractory Thyroid Cancer.

Papillary thyroid carcinomas (PTCs) have an excellent prognosis, but a fraction of them show aggressive behavior, becoming radioiodine (RAI)-resistant and/or metastatic. AXL (Anexelekto) is a tyrosine kinase receptor regulating viability, invasiveness and chemoresistance in various human cancers, including PTCs. Here, we analyze the role of AXL in PTC prognosis and as a marker of RAI refractoriness. Immunohistochemistry was used to assess AXL positivity in a cohort of human PTC samples. Normal and cancerous thyroid cell lines were used in vitro for signaling, survival and RAI uptake evaluations. 38.2% of human PTCs displayed high expression of AXL that positively correlated with RAI-refractoriness and disease persistence or recurrence, especially when combined with v-raf murine sarcoma viral oncogene homolog B(BRAF) V600E mutation. In human PTC samples, AXL expression correlated with V-akt murine thymoma viral oncogene homolog 1 (AKT1) and p65 nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) activation levels. Consistently, AXL stimulation with its ligand growth arrest-specific gene 6 (GAS6) increased AKT1- and p65 NF-kB-phosphorylation and promoted survival of thyroid cancer cell lines in culture. Enforced expression or activation of AXL in normal rat thyroid cells significantly reduced the expression of the sodium/iodide symporter (NIS) and the radioiodine uptake. These data indicate that AXL expression levels could be used as predictor of RAI refractoriness and as a possible novel therapeutic target of RAI resistant PTCs.

HMGA2 mRNA expression correlates with the malignant phenotype in human thyroid neoplasias.

We have analysed the expression of the HMGA2 gene in a panel of normal and neoplastic thyroid tissues by immunohistochemistry and quantitative RT-PCR. HMGA2 protein was detectable in four out of 21 follicular carcinomas, 30 out of 45 papillary carcinomas, and 11 out of 12 undifferentiated carcinomas. As far as follicular thyroid adenomas are concerned, only three cases of the 31 analysed showed HMGA2 protein expression, whereas it was absent in seven normal thyroid tissues and in 12 hyperplastic nodules. Quantitative RT-PCR showed that almost all the papillary thyroid carcinomas and 13 out of 16 follicular thyroid carcinomas express much higher HMGA2 specific mRNA levels in comparison to normal thyroids and adenomas. Therefore, our data support the quantitative RT-PCR analysis of HMGA2 expression, rather than immunohistochemistry, as a powerful tool for the diagnosis of thyroid neoplasias.

Surgical treatment of intrathyroid metastases: preliminary results of a multicentric study.

BACKGROUND: Intrathyroid metastases (ITM) are rare and usually have a dismal prognosis. The aim of this study was to detect which neoplasms metastasize most often to the thyroid gland, their clinical features and treatment options. MATERIALS AND METHODS: Retrospective analysis of clinical files of 17,122 patients submitted to surgery for thyroid disease between 1995 and 2005. Twenty-five patients (median age 61 years) were affected by ITM. RESULTS: The site of the primary tumor was: kidney (15), lung (4), colon (3), breast (1), melanoma (1), and unknown in 1 patient. Ten patients (40%) complained of preoperative symptoms, in the others, thyroid involvement was incidentally discovered during the follow-up for the primary cancer. Twenty patients (80%) underwent total thyroidectomy, 3 received thyroid lobectomy and 2 palliative procedures. Morbidity was 16%, mortality was nil. The median follow-up was 24 months. CONCLUSION: ITM should always be suspected in any patient with a previous history of malignancy. Fine-needle agobiopsy (FNAB) with immunohistochemical stains may help in preoperative workup. A long delay between the primary tumor and the recurrence warrants surgery and total thyroidectomy seems to be the treatment of choice because of the multifocality of metastasis to the thyroid gland.

The antiproliferative effect of pasireotide LAR alone and in combination with everolimus in patients with medullary thyroid cancer: a single-center, open-label, phase II, proof-of-concept study.

PURPOSE: Medullary thyroid cancer (MTC) is a neuroendocrine tumour of the thyroid C cells. Pasireotide, a multi-receptor targeted somatostatin analogue, and everolimus, an inhibitor of mTOR, showed antitumour properties in neuroendocrine tumours. Aim of this study was to evaluate pasireotide alone and in combination with everolimus in patients with MTC. METHODS: Patients with progressive metastatic or persistent postoperative MTC received pasireotide LAR 60 mg/m for at least 6 months. Patients exhibiting progressive disease received everolimus 10 mg/d as combination therapy. Primary endpoint was progression free survival (PFS). Secondary endpoints included, overall survival, objective response rates, change in circulating markers, safety. Study registration no. NCT01625520. RESULTS: Nineteen consecutive patients were enrolled. Median follow-up was 31 months. Median PFS with pasireotide was 36 months (95% CI: 19.5-52.5). Nine patients (47%) had tumour progression: seven of them started everolimus in combination with pasireotide, achieving a median PFS of 9.0 months (95% CI: 0-21.83). Five of them (71%) had further tumour progression, one objective response (14.3%), one stopped treatment because of pulmonary embolism. Pasireotide alone and with everolimus was safe and required withdrawal only in one case. Diarrhoea and hyperglycaemia were the most frequent adverse events with pasireotide (grade 3 in 5.3% each). Hyperglycaemia was the most frequent grade 3 toxicity with the combination therapy (28.6%). CONCLUSIONS: Pasireotide therapy shows antiproliferative effects in persistent postoperative MTC suggesting further investigation on larger series of patients. In progressive MTC lesions, the combination pasireotide plus everolimus may be of benefit. Both schemes were safe and well tolerated.

Predictivity of clinical, laboratory and imaging findings in diagnostic definition of palpable thyroid nodules. A multicenter prospective study.

PURPOSE: To assess the role of clinical, biochemical, and morphological parameters, as added to cytology, for improving pre-surgical diagnosis of palpable thyroid nodules. METHODS: Patients with a palpable thyroid nodule were eligible if surgical intervention was indicated after a positive or suspicious for malignancy FNAC (TIR 4-5 according to the 2007 Italian SIAPEC-IAP classification), or two inconclusive FNAC at a ≥3 months interval, or a negative FNAC associated with one or more risk factor. Reference standard was histological malignancy diagnosis. Likelihood ratios of malignancy, sensitivity, specificity, negative (NPV), and positive predictive value (PPV) were described. Multiple correspondence analysis (MCA) and logistic regression were applied. RESULTS: Cancer was found in 433/902 (48%) patients. Considering TIR4-5 only as positive cytology, specificity, and PPV were high (94 and 91%) but sensitivity and NPV were low (61 and 72%); conversely, including TIR3 among positive, sensitivity and NPV were higher (88 and 82%) while specificity and PPV decreased (52 and 63%). Ultrasonographic size ≥3 cm was independently associated with benignity among TIR2 cases (OR of malignancy 0.37, 95% CI 0.18-0.78). In TIR3 cases the hard consistency of small nodules was associated with malignity (OR: 3.51, 95% CI 1.84-6.70, p < 0.001), while size alone, irrespective of consistency, was not diagnostically informative. No other significant association was found in TIR2 and TIR3. CONCLUSIONS: The combination of cytology with clinical and ultrasonographic parameters may improve diagnostic definition of palpable thyroid nodules. However, the need for innovative diagnostic tools is still high.