Publications by authors named "David Viola"

49 Publications

Tall cell percentage alone in PTC without aggressive features should not guide patients' clinical management.

J Clin Endocrinol Metab 2021 Jun 1. Epub 2021 Jun 1.

Department of Surgical, Medical, Molecular Pathology and Critical Area, University of Pisa.

Purpose: Recent diagnostic criteria updates of the tall cell variant of papillary thyroid carcinoma (TCPTC) by the World Health Organization (WHO) have determined the inclusion of tumours with 30-49% of tall cells. However, the impact of tall cell percentage on papillary thyroid carcinoma (PTC) patients' prognosis is still debated. We aimed to evaluate whether tall cell percentage affects patients' outcome in the absence of aggressive features.

Methods: Rates of aggressive features, recurrence-free survival (RFS) and distant RFS (DRFS) (5-year median follow-up) were compared among tumours with less than 30%, 30-49% and at least 50% of tall cells. We also evaluated the impact of the new tall cell cut-off on patient management.

Results: Overall, 3092 tumours (15.7% of all PTC) were collected: 792 PTC had less than 30%, 503 had 30-49%, and 1797 had 50% or more tall cell areas. With the new definition of WHO, the number of TCPTC increased by 28%. There were no differences in recurrence rates according to tall cell percentage. The coexistence of BRAF and TERT promoter mutations predicted a worse RFS. Considering the new definition of TCPTC, the level of risk according to the American Thyroid Association increased from low to intermediate in 4.2% of cases. However, the recurrence rate within this subgroup was comparable to low-risk.

Conclusions: TCPTC and PTC with tall cell areas can be considered as a unique group with similar recurrence risk. However, whenever aggressive features are absent, tumors have a low risk of recurrence independently of tall cell percentage.
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http://dx.doi.org/10.1210/clinem/dgab388DOI Listing
June 2021

Thyroid Cancers: From Surgery to Current and Future Systemic Therapies through Their Molecular Identities.

Int J Mol Sci 2021 Mar 18;22(6). Epub 2021 Mar 18.

Endocrine Unit, Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy.

Differentiated thyroid cancers (DTC) are commonly and successfully treated with total thyroidectomy plus/minus radioiodine therapy (RAI). Medullary thyroid cancer (MTC) is only treated with surgery but only intrathyroidal tumors are cured. The worst prognosis is for anaplastic (ATC) and poorly differentiated thyroid cancer (PDTC). Whenever a local or metastatic advanced disease is present, other treatments are required, varying from local to systemic therapies. In the last decade, the efficacy of the targeted therapies and, in particular, tyrosine kinase inhibitors (TKIs) has been demonstrated. They can prolong the disease progression-free survival and represent the most important therapeutic option for the treatment of advanced and progressive thyroid cancer. Currently, lenvatinib and sorafenib are the approved drugs for the treatment of RAI-refractory DTC and PDTC while advanced MTC can be treated with either cabozantinib or vandetanib. Dabrafenib plus trametinib is the only approved treatment by FDA for mutated ATC. A new generation of TKIs, specifically for single altered oncogenes, is under evaluation in phase 2 and 3 clinical trials. The aim of this review was to provide an overview of the current and future treatments of thyroid cancer with regards to the advanced and progressive cases that require systemic therapies that are becoming more and more targeted on the molecular identity of the tumor.
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http://dx.doi.org/10.3390/ijms22063117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8003273PMC
March 2021

Role of Prophylactic Central Compartment Lymph Node Dissection on the Outcome Of Patients With Papillary Thyroid Carcinoma and Synchronous Ipsilateral Cervical Lymph Node Metastases.

Endocr Pract 2020 Aug;26(8):807-817

From the Department of Surgical, Medical, Molecular Pathology and Critical Area, Unit of Endocrine Surgery, University Hospital of Pisa, Pisa, Italy.

Objective: Prophylactic central compartment lymph node dissection (pCCND) results in a higher percentage of surgical-related complications. To date, no evidence of the impact of pCCND on the clinical outcome of papillary thyroid carcinoma (PTC) patients with synchronous ipsilateral cervical lymph node metastases has been reported.

Methods: We evaluated all consecutive patients affected by PTC and synchronous ipsilateral cervical, but without evidence of central compartment, lymph node metastases. We selected 54 consecutive patients (group A) treated by total thyroidectomy, ipsilateral cervical lymph node dissection, and pCCND and 115 patients (group B) matched for sex, age at diagnosis, number and dimension of the metastatic lateral cervical lymph nodes, without pCCND. Clinical outcome after a median of 5 years and surgical-related complications were assessed.

Results: The two groups were completely similar in terms of clinical features. Clinical outcomes showed a higher percentage of biochemical and indeterminate but not structural response in group B. Group B required significantly more radioiodine treatments, but no difference was shown in the need to repeat surgery for recurrences. Conversely, the prevalence of permanent hypoparathyroidism was significantly higher in group A (14.8%) than in group B (4.3%).

Conclusion: In PTC patients with synchronous ipsilateral cervical lymph node metastases, in absence of clinically evident lymph node metastases of the central compartment, performing pCCND does not improve the 5-year outcome in terms of structural disease, despite a greater number of I treatments. However, pCCND is severely affected by a higher percentage of permanent hypoparathyroidism, even in the hands of expert surgeons.

Abbreviations: IQR = interquartile range; pCCND = prophylactic central compartment lymph node dissection; PTC = papillary thyroid carcinoma; Tg = thyroglobulin; US = ultrasound.
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http://dx.doi.org/10.4158/EP-2019-0532DOI Listing
August 2020

Ca19.9 Positivity and Doubling Time Are Prognostic Factors of Mortality in Patients with Advanced Medullary Thyroid Cancer with No Evidence of Structural Disease Progression According to Response Evaluation Criteria in Solid Tumors.

Thyroid 2021 Jan 7. Epub 2021 Jan 7.

Endocrinology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.

Serum Ca19.9 positivity is a prognostic factor for mortality in patients with advanced medullary thyroid cancer (aMTC), independently from calcitonin doubling time (DT). However, it is unknown whether aMTC patients who become positive for Ca19.9 also have progressive disease (PD) according to response evaluation criteria in solid tumors (RECIST) and whether Ca19.9 DT has a role in the management of aMTC patients. The aims of this study were to evaluate whether in aMTC, when serum Ca19.9 becomes positive, PD develops, and to determine the role of Ca19.9 DT in predicting mortality and PD. Serum Ca19.9 was periodically measured in 107 aMTC patients, and the DTs were calculated. Restaging of the disease was radiologically performed in 104 of 107 patients and PD was evaluated according to RECIST. At the end of follow-up, 25 of 107 patients were Ca19.9 positive and PD was identified in 30 of 104 patients. No significant association was found between Ca19.9 positivity and PD, while there was a significant association between Ca19.9 positivity and mortality ( < 0.0001). Ca19.9 DTs <6 months and <1 year were not associated with PD but were associated with mortality ( < 0.0001 and  < 0.0001, respectively). In particular, 3 patients who had a Ca19.9 DT <6 months with no evidence of PD according to RECIST died of their disease after 6, 5, and 3 months, respectively. Serum Ca19.9 positivity and DTs <6 months and <1 year are prognostic factors for mortality but not for PD. Serum Ca19.9 positivity and DTs <6 months and <1 year should be considered in the decision-making process of whether to initiate systemic therapy even if there is no evidence of PD according to RECIST.
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http://dx.doi.org/10.1089/thy.2020.0060DOI Listing
January 2021

No difference in the outcome of metastatic thyroid cancer patients when using recombinant or endogenous TSH.

Eur J Endocrinol 2020 Oct;183(4):411-417

Unit of Endocrinology, Department of Clinical and Experimental Medicine.

Objective: At present, recombinant TSH cannot be used for the treatment of metastatic differentiated thyroid cancer patients. The aim of this study was to evaluate if the type of TSH stimulation, recombinant or endogenous, had an impact on the outcome of these patients.

Design And Methods: We compared the outcome of two propensity score-matched groups of metastatic patients, stimulated by either only recombinant TSH (n = 43) or only endogenous TSH (n = 34).

Results: As expected from the matching procedure, the clinical-pathological features and the cumulative 131-I activities administered to the two groups were very similar. After 4 years of follow-up, 4% of patients were cured, 3% had biochemical disease and 93% had structural disease. However, 91% of patients obtained a clinical benefit from this therapy in terms of stabilization of the disease or complete remission or partial response. When considering the two groups separately, we did not find any difference in their outcome. When considering the response to 131-I therapy of the single type of metastases, 8% of lymph node metastases and 8% of lung metastases disappeared but none of the bone metastases. The response to 131-I therapy of the single type of metastases was similar when we looked at the two groups separately.

Conclusions: This study shows (i) an overall clinical benefit of the 131-I therapy, since the majority of patients remained affected but with a stable disease, and (ii) that the preparation with either recombinant or endogenous TSH has no impact on the 131-I therapy efficacy and the outcome of our two groups of patients.
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http://dx.doi.org/10.1530/EJE-20-0088DOI Listing
October 2020

Thyroglobulin Changes are Highly Dependent on TSH in Low-risk DTC Patients not Treated with Radioiodine.

J Clin Endocrinol Metab 2020 08;105(8)

Department of Clinical and Experimental Medicine, Unit of Endocrinology, University Hospital of Pisa, Pisa, Italy.

Introduction: Low-risk differentiated thyroid cancer (DTC) is currently rarely treated with radioiodine (131I) to ablate the postoperative remnant. Therefore, the interpretation of the serum thyroglobulin (Tg) values should be reconsidered. The aim of our study was to evaluate the changes in Tg values during follow-up with regard to the changing values in thyroid stimulating hormone (TSH).

Materials And Methods: We evaluated 271 low-risk DTC patients, treated with total thyroidectomy but not 131I. To be included, patients had to be negative for Tg antibodies and have at least 3 evaluations in our department. All patients were on levothyroxine (L-T4) therapy.

Results: After a median follow-up of 73 months, the overall Tg values were stable, while TSH values slightly increased. Therefore, we pooled data of Tg and TSH from all evaluations and a significant positive correlation was demonstrated (R = 0.2; P < 0.01), and was also demonstrated when we performed the analysis using time-weighted values (R = 0.14; P = 0.02). Moreover, when dividing patients into 3 groups according to first postoperative Tg (Group A [Tg < 0.2 ng/ml], Group B [Tg 0.2-1 ng/ml], and Group C [Tg > 1 ng/ml]) most patients showed stable values of Tg at the end of follow-up but TSH variations had a clear impact on the changes in Tg among the groups.

Conclusion: We demonstrated that in low-risk DTC not treated with 131I, serum Tg remains substantially stable over time, and the variations observed were correlated with the concomitant variations of TSH levels, mainly due to the modification of LT-4 therapy performed according to the ongoing risk stratification.
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http://dx.doi.org/10.1210/clinem/dgaa297DOI Listing
August 2020

Medullary thyroid cancer treated with vandetanib: predictors of a longer and durable response.

Endocr Relat Cancer 2020 01 20;27(2):97-110. Epub 2020 Jan 20.

Department of Clinical and Experimental Medicine, University Hospital of Pisa, Unit of Endocrinology, Pisa, Italy.

Vandetanib is an important treatment option for advanced metastatic medullary thyroid cancer. The aims of this study were to evaluate the predictors of both a longer response to vandetanib and the outcome. Medical records of 79 medullary thyroid cancer patients treated with vandetanib at our center were analysed. Twenty-five patients were treated for <12 months, 54 were treated for ≥12 months and 24 of these latter were treated for ≥48 months (short-, long- and very long-term). The median progression free survival of the long and very long-term treated patients was significantly longer than in the ZETA trial. When comparing the groups of short - and long-term treated patients the only significant difference was that these latter were less frequently previously treated with a tyrosine kinase inhibitor. However, the long-term treated patients had a younger age, both at diagnosis and enrolment, which was statistically significant in the very long-term treated patients. In the long-term treated group, younger age, enrolment for symptoms and development of adverse events were significantly correlated with a better outcome. The enrolment for symptoms remained the only statistically significant predictor of a good outcome in the very long-term treated patients. In conclusion, early treatment with vandetanib, when patients are younger, with a good ECOG performance status and symptomatic disease, not necessarily progressing for RECIST, seem to be the best predictors of a longer and durable response. Further studies are needed to confirm these results
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January 2020

BRAF V600E status may facilitate decision-making on active surveillance of low-risk papillary thyroid microcarcinoma.

Eur J Cancer 2020 01 29;124:161-169. Epub 2019 Nov 29.

Laboratory for Cellular and Molecular Thyroid Research, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. Electronic address:

Introduction: Conservative active surveillance has been proposed for low-risk papillary thyroid microcarcinoma (PTMC), defined as ≤1.0 cm and lacking clinical aggressive features, but controversy exists with accepting it as not all such PTMCs are uniformly destined for benign prognosis. This study investigated whether BRAF V600E status could further risk stratify PTMC, particularly low-risk PTMC, and can thus help with more accurate case selection for conservative management.

Methods: This international multicenter study included 743 patients treated with total thyroidectomy for PTMC (584 women and 159 men), with a median age of 49 years (interquartile range [IQR], 39-59 years) and a median follow-up time of 53 months (IQR, 25-93 months).

Results: On overall analyses of all PTMCs, tumour recurrences were 6.4% (32/502) versus 10.8% (26/241) in BRAF mutation-negative versus BRAF mutation-positive patients (P = 0.041), with a hazard ratio (HR) of 2.44 (95% CI (confidence interval), 1.15-5.20) after multivariate adjustment for confounding clinical factors. On the analyses of low-risk PTMC, recurrences were 1.3% (5/383) versus 4.3% (6/139) in BRAF mutation-negative versus BRAF mutation-positive patients, with an HR of 6.65 (95% CI, 1.80-24.65) after adjustment for confounding clinical factors. BRAF mutation was associated with a significant decline in the Kaplan-Meier recurrence-free survival curve in low-risk PTMC.

Conclusions: BRAF V600E differentiates the recurrence risk of PTMC, particularly low-risk PTMC. Given the robust negative predictive value, conservative active surveillance of BRAF mutation-negative low-risk PTMC is reasonable whereas the increased recurrence risk and other well-known adverse effects of BRAF V600E make the feasibility of long-term conservative surveillance uncertain for BRAF mutation-positive PTMC.
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http://dx.doi.org/10.1016/j.ejca.2019.10.017DOI Listing
January 2020

Active Surveillance in Papillary Thyroid Microcarcinomas is Feasible and Safe: Experience at a Single Italian Center.

J Clin Endocrinol Metab 2020 03;105(3)

Unit of Endocrinology, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Pisa, Italy.

Context: The dramatic rise in the incidence of thyroid cancer over the last 30 years is largely attributable to the increasing diagnosis of papillary microcarcinomas (mPTCs). Current guidelines endorse an observational management approach in properly selected cases.

Objective: To evaluate the feasibility of active surveillance in mPTC in Italy, its impact on real life, and to identify risk factors of progression.

Design And Setting: In 2014 we started a prospective-observational study of active surveillance in mPTC patients.

Patients: Included patients demonstrated a single Thy4 or Thy5 thyroid nodule, with largest diameter ≤1.3 cm, and no suspicious laterocervical lymph nodes by neck ultrasonography. Of 185 eligible subjects, 50.3% (93/185) enrolled in the observational management protocol while the others opted for surgery and were excluded from this analysis.

Intervention: Enrolled patients were followed with neck ultrasound at 6- to 12-month intervals. Disease progression was defined as the appearance of abnormal lymph nodes or nodule enlargement during follow-up. In these cases, patients were directed to surgery.

Results: Three patients (3/93, 3%) showed clinical progression and required surgery. Another 19 patients (19/93, 20%) decided to transition to surgical intervention even though there was no evidence of disease progression. All operated patients had excellent response to initial treatment despite the delayed surgery.

Conclusions: Within an Italian medical context, active surveillance appears to be a feasible and safe alternative to immediate surgery in healthy mPTC patients. Only 3% of mPTC demonstrated disease progression during a median follow-up of 19 months (range 6-54) and importantly demonstrated excellent outcomes after surgical intervention in a short-term follow-up.
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http://dx.doi.org/10.1210/clinem/dgz113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105780PMC
March 2020

Lenvatinib Administered via Nasogastric Tube in Poorly Differentiated Thyroid Cancer.

Case Rep Endocrinol 2019 18;2019:6831237. Epub 2019 Sep 18.

Unit of Endocrinology, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Pisa 56124, Italy.

Background: The tyrosine kinase inhibitors (TKIs) are indicated for the treatment of locally advanced or metastatic progressive thyroid carcinoma (CDT), refractory to radioactive iodine. The following report describes the efficacy of lenvatinib administered through a nose-gastric tube (SNG) in a patient affected with a poorly differentiated thyroid carcinoma (PDTC) which determined a stenosis of the esophagus.

Material And Methods: A patient was followed up for papillary thyroid carcinoma follicular variant (T3NxMx), subjected to total thyroidectomy and treated with iodine-131 radio metabolic therapy. Two years after surgery, following the onset of dysphonia and dysphagia, patient was submitted to a computed tomography (CT) scan of the neck that showed the presence of a lesion of 6 × 2.5 × 3.5 cm, which determined trachea deviation and cervical esophagus compression. The biopsy indicated the presence of PDTC, triggering tracheal lumen reduction and sub-stenosis of the cervical esophagus for an ab-extrinsic compression. A nose-gastric tube (SNG) was placed and lenvatinib was started at a dose of 20 mg/day, administered via this probe after opening the capsules and diluting the drug in 10 ml of saline solution.

Results: One month later, CT showed a significant cervical lesion reduction. Bronchoscopy confirmed tracheal infiltration, but the residual caliber was improved from 50% to 75%. At the esophagogastroduodenoscopy (EGDS), the sub stenosis of the cervical esophagus was no longer appreciated; however, a double perforation of the esophagus was found, without fistula.

Conclusion: Lenvatinib therapy is effective also when administered via SNG. Our result is of particular relevance in the management of thyroid cancer patients, especially in the presence of subjects unable to swallow. Further studies are needed to validate the administration of lenvatinib by SNG, in order to extend the indications to this alternative administration way, beside the oral one.
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http://dx.doi.org/10.1155/2019/6831237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6766666PMC
September 2019

Genetic Landscape of Somatic Mutations in a Large Cohort of Sporadic Medullary Thyroid Carcinomas Studied by Next-Generation Targeted Sequencing.

iScience 2019 Oct 26;20:324-336. Epub 2019 Sep 26.

Unit of Endocrinology, Department of Clinical and Experimental Medicine, University-Hospital of Pisa, Pisa 56124 Italy.

Sporadic Medullary Thyroid Carcinoma (sMTC) is a rare but aggressive thyroid tumor. RET and RAS genes are present in about 50%-80% of cases, but most of the remaining cases are still orphan of a genetic driver. We studied the largest series of sMTC by deep sequencing to define the mutational landscape. With this methodology we greatly reduced the number of RET- or RAS-negative cases and we confirmed the central role of RET and RAS mutations. Moreover, we highlighted the bad prognostic role of RET mutations in sMTC and consolidated the favorable prognostic role of RAS mutations. For the first time, we showed that the variant allele frequency represents an additional prognostic marker inside the group of RET-mutated sMTC.
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http://dx.doi.org/10.1016/j.isci.2019.09.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6817656PMC
October 2019

DELAYED 131-I FIRST TREATMENT AFTER SURGERY HAS NO IMPACT ON THE MEDIAN TERM OUTCOME OF PATIENTS WITH INTERMEDIATE RISK DIFFERENTIATED THYROID CANCER.

Endocr Pract 2020 Jan 26;26(1):58-71. Epub 2019 Sep 26.

In intermediate risk (IR) differentiated thyroid cancer (DTC) patients, selective use of radioiodine (131-I) for remnant ablation and/or as adjuvant therapy (RRA) is advocated. The recently suggested postoperative evaluation could delay the use of RRA. The aim of this study was to evaluate if a delayed RRA can worsen the clinical outcome of IR-DTC patients. Four hundred and fourteen consecutive IR-DTC patients were divided according to the time elapsed from surgery to RRA, <6 months (group A, 186/414 [44.9%]), or ≥6 months (group B, 228/414 [55.1%]). Clinical and biochemical data were collected, and clinical outcome was analyzed at the first evaluation (EV) after RRA (first-EV) and after a median of 6 years of follow-up (last-EV). No difference in the clinical outcome of group A and B was found. Since a different activity of 131-I could have an impact on the outcome, we separately analyzed the groups according to the 131-I activity (low-activity group: 1,110 MBq/30 mCi [n = 320], and high-activity group: 3,700 MBq/100 mCi [n = 94]), further subdivided according to the time elapsed from surgery to RRA. No major differences were found in both the low- and high-activity groups when comparing the features of their subgroups A and B, as far as in their clinical outcome. The time elapsed between surgery and the first 131-I treatment does not influence the clinical outcome of IR-DTC patients. This finding allows a more relaxed attitude in the decision making process whether to perform the RRA in IR-DTC cases in which a selective use of 131-I is recommended. = American Thyroid Association; = differentiated thyroid cancer; = evaluation; = high risk; = radioiodine; = intermediate risk; = low risk; = recombinant human thyroid-stimulating hormone; = radioiodine for remnant ablation; = thyroglobulin; = thyroglobulin autoantibody; = ultrasound.
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http://dx.doi.org/10.4158/EP-2019-0182DOI Listing
January 2020

Twenty-Five Years Experience on RET Genetic Screening on Hereditary MTC: An Update on The Prevalence of Germline RET Mutations.

Genes (Basel) 2019 09 10;10(9). Epub 2019 Sep 10.

Department of Clinical and Experimental Medicine, Unit of Endocrinology University of Pisa, 56124 Pisa, Italy.

Background: Pathogenic germline mutations affecting the proto-oncogene underlie the development of hereditary medullary thyroid carcinoma (MTC). The aims of this study were to evaluate the prevalence of germline mutations in a large series of MTC, collected over the last 25 years, and to reappraise their clinical significance.

Methods: We performed genetic screening in 2031 Italian subjects: patients who presented with sporadic (n = 1264) or hereditary (n = 117) MTC, plus 650 relatives.

Results: A germline mutation was found in 115/117 (98.3%) hereditary and in 78/1264 (6.2%) apparently sporadic cases: in total, 42 distinct germline variants were found. The V804M mutation was the most prevalent in our cohort, especially in cases that presented as sporadic, while mutations affecting cysteine residues were the most frequent in the group of clinically hereditary cases. All M918T mutations were "de novo" and exclusively associated with MEN2B. Several variants of unknown significance (VUS) were also found.

Conclusions: a) genetic screening is informative in both hereditary and sporadic MTC; b) the prevalence of different mutations varies with V804M being the most frequent; c) the association genotype-phenotype is confirmed; d) by screening, some VUS can be found but their pathogenic role must be demonstrated before screening the family.
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http://dx.doi.org/10.3390/genes10090698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6771015PMC
September 2019

Less than 2% of the Low- and Intermediate-Risk Differentiated Thyroid Cancers Show Distant Metastases at Post-Ablation Whole-Body Scan.

Eur Thyroid J 2019 Apr 13;8(2):90-95. Epub 2018 Dec 13.

Endocrinology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.

Background: Recently, there has been a trend to reduce the use of radioiodine remnant ablation (RRA) in patients with low-risk (LR) and intermediate-risk (IR) differentiated thyroid cancer (DTC).

Objectives: The aim of this paper was to evaluate the diagnostic role of whole-body scan (ptWBS) performed after RRA in LR and IR DTC patients.

Methods: We analyzed 545 DTC patients treated with total thyroidectomy and RRA in hypothyroidism followed by a ptWBS. Neck ultrasound (US) and serum thyroglobulin measurement were performed. According to the American Thyroid Association guidelines, patients were classified as LR ( = 345) and IR ( = 200).

Results: In addition to the thyroid remnant, the ptWBS showed the presence of further areas of I uptake in 16/545 (2.9%) cases. ptWBS showed laterocervical lymph node metastases in 11/16 patients (10/11 were also detected by US), mediastinal uptake in 1/16, lung metastases in 3/16, and bone metastases in 1/16. Only 6/545 (1.1%) metastases were detected by ptWBS alone. After 7.8 years, 8/16 patients were free of disease, and 8 had persistent disease: 4 "biochemical" and 4 "structural." Remission was achieved in 3 cases after one single I course, in 1 case after surgery, and in the last 4 cases after several I courses.

Conclusions: The ptWBS diagnostic role was clinically relevant for the therapeutic strategies of our patients only in 1.1% of the cases. The cost-effectiveness of performing RRA and ptWBS in all LR and IR patients to find 1-2% of the cases with distant metastases remains controversial.
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http://dx.doi.org/10.1159/000494290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6514496PMC
April 2019

Risk of incident circulatory disease in patients treated for differentiated thyroid carcinoma with no history of cardiovascular disease.

Clin Endocrinol (Oxf) 2019 08 17;91(2):323-330. Epub 2019 May 17.

Institute of Applied Health Research, University of Birmingham, Birmingham, UK.

Context: The incidence of differentiated thyroid cancer (DTC) is increasing, yet the prognosis is favourable and long-term survival is expected. Exogenous TSH suppression has been used for many years to prevent DTC recurrence and may be associated with increased risks of circulatory diseases.

Design: Risks of circulatory disease in patients treated for DTC were compared to randomly matched patients without DTC (controls) up to a 1:5 ratio using age, sex, body mass index (BMI) and smoking as the matching parameters in a population-based, open cohort study using The Health Improvement Network.

Patients: A total of 3009 patients treated for DTC with no pre-existing cardiovascular disease were identified and matched to 11 303 controls, followed up to median of 5 years.

Results: A total of 1259 incident circulatory events were recorded during the observation period. No difference in the risk of ischaemic heart disease (IHD) (adjusted hazards ratio [aHR]: 1.04, 95% CI: 0.80-1.36) or heart failure (HF) (aHR: 1.27, 95% CI: 0.89-1.81) was detected. The risk of atrial fibrillation (AF) and stroke was significantly higher in patients with DTC (aHR: 1.71, 95% CI: 1.36-2.15 and aHR: 1.34, 95% CI: 1.05-1.72, respectively). In a sensitivity analysis limited to newly diagnosed patients with DTC, only the risk of AF was consistently elevated (aHR: 1.86, 95% CI: 1.33-2.60).

Conclusions: The increased risk of AF in patients who have undergone treatment for DTC but without pre-existing CVD may warrant periodic screening for this arrhythmia. Whereas no evidence of increased risk of IHD or HF was observed, the increased risk of stroke/TIA warrants further investigation.
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http://dx.doi.org/10.1111/cen.13990DOI Listing
August 2019

Management of Medullary Thyroid Cancer.

Endocrinol Metab Clin North Am 2019 03 26;48(1):285-301. Epub 2018 Dec 26.

Endocrine Unit, Department of Clinical and Experimental Medicine, University of Pisa, Via Paradisa 2, Pisa 56124, Italy. Electronic address:

Medullary thyroid cancer (MTC) is rare but aggressive. It can be cured only if intrathyroid at diagnosis. MTC can be sporadic (75%) or familial (25%) and the 2 forms are distinguished by RET mutations analysis. Calcitonin is the specific serum marker; its doubling time is the most important prognostic factor for survival and progression; 30% of MTC patients have distant metastases at diagnosis and, when progressing, systemic therapy with vandetanib or cabozantinib should be considered. Before starting this treatment, the possibility of using a local treatment should be evaluated to delay systemic therapy. A multidisciplinary team should care for these patients.
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http://dx.doi.org/10.1016/j.ecl.2018.11.006DOI Listing
March 2019

Fifty Years After the First Description, MEN 2B Syndrome Diagnosis Is Still Late: Descriptions of Two Recent Cases.

J Clin Endocrinol Metab 2019 07;104(7):2520-2526

Unit of Endocrinology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.

Background: Multiple endocrine neoplasia type 2B (MEN 2B) is a very rare syndrome characterized by a very peculiar phenotype with mucosal neuromas, marfanoid habitus, and bumpy lips associated with medullary thyroid cancer (MTC) and pheochromocytoma (PHEO). Although the syndrome was first described 50 years ago, it is still diagnosed too late, when the MTC is metastatic and frequently when the PHEO has already developed.

Case Presentations: We report on two cases of MEN 2B that were diagnosed too late, preventing a cure. The cases involve two females who were 25 and 12 years old. Both were previously treated for congenital skeletal abnormalities; however, despite their bumpy lips and mucosal neuromas, MEN 2B syndrome was not recognized. When they arrived at our center for both the presence of thyroid nodules and elevated serum calcitonin values, the MTC was already metastatic, and the older patient had already developed a bilateral PHEO. After 3 years and 1 year of follow-up, the two patients are still alive but with persistent structural and biochemical disease.

Discussion: These two cases show that knowledge of this syndrome is still insufficient and that the lack of knowledge impairs the ability to obtain an early diagnosis and cure. Because most patients with MEN 2B have no familial history, the only way to ensure a timely diagnosis is to recognize the MEN 2B phenotype on a clinical basis.
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http://dx.doi.org/10.1210/jc.2018-02102DOI Listing
July 2019

Lung Recurrence of Papillary Thyroid Cancer Diagnosed With Antithyroglobulin Antibodies After 10 Years From Initial Treatment.

Front Endocrinol (Lausanne) 2018 9;9:590. Epub 2018 Oct 9.

Unit of Endocrinology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.

Papillary thyroid cancer (PTC) is the most common endocrine malignancy. More than 98% of patients achieve an excellent response with no evidence of clinical, biochemical, or structural disease after initial treatment. In these patients structural recurrence is rare, more frequently diagnosed in the first 5 years from initial treatment and almost invariably localized in neck lymph nodes. We report the case of a woman affected by PTC who presented with rapidly rising anti-thyroglobulin antibodies (TgAb) level after 10 years from clinical, morphological and biochemical remission. In 2003, a 56 year old patient was treated with total thyroidectomy and radioiodine remnant ablation (RRA) for a PTC (2 cm) with minimal extrathyroidal extension (T3N1aM0 according to the 6th AJCC TNM staging system) associated with diffuse lymphocytic thyroiditis. In 2004 the patient was free of disease defined as undetectable Tg after recombinant human TSH administration in the absence of TgAb and structural disease. Since February 2012 the appearance and progressive increase of TgAb titer was observed and in 2014 a FDG-PET scan documented three hypermetabolic lesions suggestive of lung micrometastases. The lung lesions were cytologically confirmed as PTC metastases. Both the primary tissue and the lung metastasis were positive for BRAF mutation. The patient was treated with 131-radioiodine that showed radioiodine avid lung lesions that lose the ability to take up iodine at the following treatment. The patient is still alive and the lung lesions are growing slowly. Structural recurrence in patients that demonstrated an excellent response after initial treatment for PTC is extremely rare, and distant metastases exceptional but possible. This case is peculiar because recurrence was early identified after 10 years from initial treatment for the presence of detectable TgAb in a patient that had an histological diagnosis of lymphocytic thyroiditis but with an atypical clinical presentation (normal thyroid at neck ultrasound and undetectable TgAb and anti-thyroid peroxidase antibodies). For this reason TgAb should be tested with Tg in patients with a history of lymphocytic thyroiditis, either histological or humoral, also when TgAb is in the normal range and not suggestive of autoimmune thyroiditis.
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http://dx.doi.org/10.3389/fendo.2018.00590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6190843PMC
October 2018

BRAF V600E Confers Male Sex Disease-Specific Mortality Risk in Patients With Papillary Thyroid Cancer.

J Clin Oncol 2018 09 2;36(27):2787-2795. Epub 2018 Aug 2.

Fei Wang, Shihua Zhao, and Yangang Wang, The Affiliated Hospital of Qingdao University, Qingdao, People's Republic of China; Fei Wang, Xiaopei Shen, Guangwu Zhu, Rengyun Liu, and Mingzhao Xing, Johns Hopkins University School of Medicine, Baltimore, MD; David Viola and Rossella Elisei, University of Pisa, Pisa; Efisio Puxeddu, University of Perugia, Perugia; Laura Fugazzola and Carla Colombo, Istituto Auxologico Italiano, Istituto di Recovero e Cura a Carattere Scientifico (IRCCS), and University of Milan, Milan; Caterina Mian, University of Padua; Federica Vianello, Veneto Institute of Oncology, IRCCS, Padua, Italy; Barbara Jarzab and Agnieszka Czarniecka, Maria Sklodowska-Curie Institute Oncology Center, Gliwice, Poland; Alfred K. Lam, Griffith University, Gold Coast, Queensland; Christine J. O'Neill, Mark S. Sywak, and Roderick Clifton-Bligh, University of Sydney, Sydney, New South Wales, Australia; Linwah Yip, University of Pittsburgh, Pittsburgh, PA; Garcilaso Riesco-Eizaguirre, Hospital Universitario La Paz and Hospital Universitario de Móstoles; Garcilaso Riesco-Eizaguirre and Pilar Santisteban, Biomedical Research Institute "Alberto Sols" and Health Institute Carlos III, Madrid, Spain; and Bela Bendlova and Vlasta Sýkorová, Institute of Endocrinology, Prague, Czech Republic.

Purpose To test whether the prognostic risk of male sex in papillary thyroid cancer (PTC) is determined by BRAF V600E and can thus be stratified by BRAF status. Patients and Methods We retrospectively investigated the relationship between male sex and clinicopathologic outcomes in PTC, particularly mortality, with respect to BRAF status in 2,638 patients (male, n = 623; female, n = 2,015) from 11 centers in six countries, with median age of 46 years (interquartile range, 35-58 years) at diagnosis and median follow-up time of 58 months (interquartile range, 26-107 months). Results Distant metastasis rates in men and women were not different in wild-type BRAF PTC but were different in BRAF V600E PTC: 8.9% (24 of 270) and 3.7% (30 of 817; P = .001), respectively. In wild-type BRAF PTC, mortality rates were 1.4% (five of 349) versus 0.9% (11 of 1175) in men versus women ( P = .384), with a hazard ratio (HR) of 1.59 (95% CI, 0.55 to 4.57), which remained insignificant at 0.70 (95% CI, 0.23 to 2.09) after clinicopathologic multivariable adjustment. In BRAF V600E PTC, mortality rates were 6.6% (18 of 272) versus 2.9% (24 of 822) in men versus women ( P = .006), with an HR of 2.43 (95% CI, 1.30 to 4.53), which remained significant at 2.74 (95% CI, 1.38 to 5.43) after multivariable adjustment. In conventional-variant PTC, male sex similarly had no effect in wild-type BRAF patients; mortality rates in BRAF V600E patients were 7.2% (16 of 221) versus 2.9% (19 of 662) in men versus women ( P = .004), with an HR of 2.86 (95% CI, 1.45 to 5.67), which remained significant at 3.51 (95% CI, 1.62 to 7.63) after multivariable adjustment. Conclusion Male sex is a robust independent risk factor for PTC-specific mortality in BRAF V600E patients but not in wild-type BRAF patients. The prognostic risk of male sex in PTC can thus be stratified by BRAF status in clinical application.
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http://dx.doi.org/10.1200/JCO.2018.78.5097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6145834PMC
September 2018

Clinical, pathological and genetic features of anaplastic and poorly differentiated thyroid cancer: A single institute experience.

Oncol Lett 2018 Jun 12;15(6):9174-9182. Epub 2018 Apr 12.

Endocrine Unit, Department of Clinical and Experimental Medicine, University Hospital of Pisa, I-56124 Pisa, Italy.

Anaplastic (ATC) and poorly differentiated thyroid cancer (PDTC) are very aggressive cancers whose histological diagnosis is not always straightforward. Clinical, pathological and genetic features may be useful to improve the identification of these rare histotypes. In the present study the clinical, pathological and genetic features of two groups of ATC (n=21) and PDTC (n=21) patients were analyzed. Clinical data were retrieved from a computerized database. The oncogenic profiles were studied using the Sanger sequencing method of a selected series of oncogenes and/or tumor suppressor genes known to be altered in these tumors. The presence of macrophages in both series of tissues was evaluated by immunohistochemistry. Patients with ATC were older and affected by a more advanced disease at diagnosis than those with PDTC. The median survival was significantly shorter in ATC compared with PDTC patients (P=0.0014). ATC showed a higher prevalence of and mutations (10/21, 47.6% and 9/21, 42.8%, respectively) while and mutations were the most prevalent in the PDTC group (7/21, 33.3% and 4/23, 19% respectively). Genetic heterogeneity (i.e., >2 mutations) was more frequent in ATC (10/21, 28.6%) compared with in PDTC (3/21, 4.7%) (P=0.03). Macrophages were more frequently present in ATC, particularly in those cases with mutations. In conclusion, these data indicate that ATC and PDTC may be characterized by different clinical, pathological and genetic profiles. In particular ATC, but not PDTC, were positive for and alterations. Complex mutations were also found in ATC but not in PDTC. Moreover, genetic heterogeneity was more frequent in ATC than PDTC. Finally, mutation and the accumulation of several mutations correlated with a shorter survival time.
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http://dx.doi.org/10.3892/ol.2018.8470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5958691PMC
June 2018

Patient Age-Associated Mortality Risk Is Differentiated by BRAF V600E Status in Papillary Thyroid Cancer.

J Clin Oncol 2018 02 14;36(5):438-445. Epub 2017 Dec 14.

Xiaopei Shen, Guangwu Zhu, Rengyun Liu, and Mingzhao Xing, Johns Hopkins University School of Medicine, Baltimore, MD; David Viola and Rossella Elisei, University of Pisa, Pisa; Efisio Puxeddu, University of Perugia, Perugia; Laura Fugazzola and Carla Colombo, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Istituto Auxologico Italiano and University of Milan, Milan; Caterina Mian, University of Padua; Federica Vianello, Veneto Institute of Oncology, IRCCS, Padua, Italy; Barbara Jarzab and Agnieszka Czarniecka, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice, Poland; Alfred K. Lam, Menzies Health Institute Queensland, Griffith University, Gold Coast, Queensland; Christine J. O'Neill, Mark S. Sywak, and Roderick Clifton-Bligh, The University of Sydney, Sydney, New South Wales, Australia; Linwah Yip, University of Pittsburgh School of Medicine, Pittsburgh, PA; Garcilaso Riesco-Eizaguirre, Hospital Universitario La Paz and Hospital Universitario de Móstoles; Garcilaso Riesco-Eizaguirre and Pilar Santisteban, Biomedical Research Institute "Alberto Sols," Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid; Garcilaso Riesco-Eizaguirre and Pilar Santisteban, Ciberonc, Health Institute Carlos III, Madrid, Spain; and Bela Bendlova and Vlasta Sýkorová, Institute of Endocrinology, Prague, Czech Republic.

Purpose For the past 65 years, patient age at diagnosis has been widely used as a major mortality risk factor in the risk stratification of papillary thyroid cancer (PTC), but whether this is generally applicable, particularly in patients with different BRAF genetic backgrounds, is unclear. The current study was designed to test whether patient age at diagnosis is a major mortality risk factor. Patients and Methods We conducted a comparative study of the relationship between patient age at diagnosis and PTC-specific mortality with respect to BRAF status in 2,638 patients (623 men and 2,015 women) with a median age of 46 years (interquartile range, 35 to 58 years) at diagnosis and a median follow-up time of 58 months (interquartile range, 26 to 107 months). Eleven medical centers from six countries participated in this study. Results There was a linear association between patient age and mortality in patients with BRAF V600E mutation, but not in patients with wild-type BRAF, in whom the mortality rate remained low and flat with increasing age. Kaplan-Meier survival curves rapidly declined with increasing age in patients with BRAF V600E mutation but did not decline in patients with wild-type BRAF, even beyond age 75 years. The association between mortality and age in patients with BRAF V600E was independent of clinicopathologic risk factors. Similar results were observed when only patients with the conventional variant of PTC were analyzed. Conclusion The long-observed age-associated mortality risk in PTC is dependent on BRAF status; age is a strong, continuous, and independent mortality risk factor in patients with BRAF V600E mutation but not in patients with wild-type BRAF. These results question the conventional general use of patient age as a high-risk factor in PTC and call for differentiation between patients with BRAF V600E and wild-type BRAF when applying age to risk stratification and management of PTC.
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http://dx.doi.org/10.1200/JCO.2017.74.5497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5807010PMC
February 2018

BRAF V600E Mutation-Assisted Risk Stratification of Solitary Intrathyroidal Papillary Thyroid Cancer for Precision Treatment.

J Natl Cancer Inst 2018 04;110(4):362-370

Laboratory for Cellular and Molecular Thyroid Research, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.

Background: Precise risk stratification-based treatment of solitary intrathyroidal papillary thyroid cancer (SI-PTC) that is larger than 1.0 cm and 4.0 cm or less is undefined.

Methods: A genetic-clinical risk study was performed on BRAF V600E in 955 patients (768 women and 187 men) with SI-PTC, with median age of 46 years and median clinical follow-up time of 64 months at 11 medical centers in six countries. The chi-square test or, for analyses with small numbers, Fisher's exact test was performed to compare recurrence rates. Recurrence-free probability was estimated by Kaplan-Meier (KM) analysis, and the independent effect of BRAF mutation on the recurrence was analyzed by Cox regression and Cox proportional hazard analyses. All statistical tests were two-sided.

Results: Recurrence of SI-PTC larger than 1.0 cm and 4.0 cm or less was 9.5% (21/221) vs 3.4% (11/319) in BRAF mutation vs wild-type BRAF patients, with a hazard ratio (HR) of 3.03 (95% confidence interval [CI] = 1.46 to 6.30) and a patient age- and sex-adjusted hazard ratio of 3.10 (95% CI = 1.49 to 6.45, P = .002). Recurrence rates of SI-PTC larger than 2.0 cm and 4.0 cm or less were 16.5% (13/79) vs 3.6% (5/139) in mutation vs wild-type patients (HR = 5.44, 95% CI = 1.93 to 15.34; and adjusted HR = 5.58, 95% CI = 1.96 to 15.85, P = .001). Recurrence rates of SI-PTC larger than 3.0 cm and 4 cm or less were 30.0% (6/20) vs 1.9% (1/54) in mutation vs wild-type patients (HR = 18.40, 95% CI = 2.21 to 152.98; and adjusted HR = 14.73, 95% CI = 1.74 to 124.80, P = .01). Recurrences of mutation-positive SI-PTC were comparable with those of counterpart invasive solitary PTC, around 20% to 30%, in tumors larger than 2.0 cm to 3.0 cm. BRAF mutation was associated with a statistically significant decrease in recurrence-free patient survival on KM analysis, particularly in SI-PTC larger than 2.0 cm and 4.0 cm or less. Similar results were obtained in conventional SI-PTC. The negative predictive values of BRAF mutation for recurrence were 97.8% (95% CI = 96.3% to 98.8%) for general SI-PTC and 98.2% (95% CI = 96.3% to 99.3%) for conventional SI-PTC.

Conclusions: BRAF V600E identifies a subgroup of SI-PTC larger than 1.0 cm and 4.0 cm or less, particularly tumors larger than 2.0 cm and 4.0 cm or less, that has high risk for recurrence comparable with that of invasive solitary PTC, making more aggressive treatment reasonable.
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http://dx.doi.org/10.1093/jnci/djx227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6658860PMC
April 2018

Protein kinase inhibitors for the treatment of advanced and progressive radiorefractory thyroid tumors: From the clinical trials to the real life.

Best Pract Res Clin Endocrinol Metab 2017 06 15;31(3):319-334. Epub 2017 Jun 15.

Unit of Endocrinology, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Via Paradisa 2, 56124 Pisa, Italy. Electronic address:

The last ten years have been characterized by the introduction in the clinical practice of new drugs named tyrosine kinase inhibitors for the treatment of several human tumors. After the positive conclusion of two international multicentric, randomized phase III clinical trials, two of these drugs, sorafenib and lenvatinib, have been recently approved and they are now available for the treatment of advanced and progressive radioiodine refractory thyroid tumors. We have been involved in most clinical trials performed with different tyrosine kinase inhibitors in different histotypes of thyroid cancer thus acquiring a lot of experience in the management of both drugs and their adverse events. Aim of this review is to give an overview of both the rationale for the use of these inhibitors in thyroid cancer and the major results of the clinical trials. Some suggestions for the management of treated patients in the real life are also provided.
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http://dx.doi.org/10.1016/j.beem.2017.06.001DOI Listing
June 2017

KIF5B/RET Rearrangement in a Carcinoma of the Thyroid Gland: A Case Report of a Fatal Disease.

J Clin Endocrinol Metab 2017 09;102(9):3091-3096

Endocrine Unit, Department of Clinical and Experimental Medicine, University Hospital of Pisa, 56124 Pisa, Italy.

Background: The diffuse sclerosing variant of papillary thyroid cancer (DSV-PTC) is a rare variant of papillary thyroid cancer (PTC) with different clinicopathological features compared with conventional PTC.

Case: An advanced DSV-PTC was diagnosed in a 39-year-old man. The radioiodine posttherapeutic whole-body-scan showed only an uptake in the central neck, whereas the computerized tomography showed multiple latero-cervical and mediastinum lymph node metastases, a single and spiculated lung lesion and multiple bilateral cerebellum metastases. The patient died after 6 months from the initial diagnosis. The histological revision of the thyroid tumor confirmed the diagnosis of DSV-PTC, and its molecular analysis revealed a KIF5B/RET rearrangement that, until now, was described only in a minority of lung adenocarcinoma. Other 18 cases of DSV-PTC were then studied for the presence of KIF5B/RET rearrangement, but all of them were negative.

Conclusions: This was a case of DSV-PTC positive for KIF5B/RET rearrangement, but considering that this alteration has been described only in lung adenocarcinoma and that the clinical course was more typical of lung carcinoma, we cannot completely rule out the possibility that this was a metastatic lesion from a lung tumor mimicking a DSV-PTC. As an alternative, we can also hypothesize that this was a case of fusion of two tumoral tissues deriving from a DSV-PTC and a metastasis of a KIF5B/RET positive lung adenocarcinoma. The question of whether the molecular findings, particularly when specifically reported only in some subtypes of human tumors, can overcome the morphological diagnosis is a matter of discussion.
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http://dx.doi.org/10.1210/jc.2017-00304DOI Listing
September 2017

The Prognostic Value of Tumor Multifocality in Clinical Outcomes of Papillary Thyroid Cancer.

J Clin Endocrinol Metab 2017 09;102(9):3241-3250

Laboratory for Cellular and Molecular Thyroid Research, Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287.

Context: Multifocality is often treated as a risk factor for papillary thyroid cancer (PTC), prompting aggressive treatments, but its prognostic value remains unestablished.

Objective: To investigate the role of tumor multifocality in clinical outcomes of PTC.

Methods: Multicenter study of the relationship between multifocality and clinical outcomes of PTC in 2638 patients (623 men and 2015 women) with median [interquartile range (IQR)] age of 46 (35 to 58) years and median (IQR) follow-up time of 58 (26 to 107) months at 11 medical centers in six countries. Surveillance, Epidemiology and End Results (SEER) data were used for validation.

Results: Disease recurrence in multifocal and unifocal PTC was 198 of 1000 (19.8%) and 221 of 1624 (13.6%) (P < 0.001), with a hazard ratio of 1.55 [95% confidence interval (CI), 1.28 to 1.88], which became insignificant at 1.13 (95% CI, 0.93 to 1.37) on multivariate adjustment. Similar results were obtained in PTC variants: conventional PTC, follicular-variant PTC, tall-cell PTC, and papillary thyroid microcarcinoma. There was no association between multifocality and mortality in any of these PTC settings, whereas there was a strong association between classic risk factors and cancer recurrence or mortality, which remained significant after multivariate adjustment. In 1423 patients with intrathyroidal PTC, disease recurrence was 20 of 455 (4.4%) and 41 of 967 (4.2%) (P = 0.892) and mortality was 0 of 455 (0.0%) and 3 of 967 (0.3%) (P = 0.556) in multifocal and unifocal PTC, respectively. The results were reproduced in 89,680 patients with PTC in the SEER database.

Conclusions: Tumor multifocality has no independent risk prognostic value in clinical outcomes of PTC; its indiscriminate use as an independent risk factor, prompting overtreatments of patients, should be avoided.
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http://dx.doi.org/10.1210/jc.2017-00277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5587077PMC
September 2017

Postoperative Thyroglobulin and Neck Ultrasound in the Risk Restratification and Decision to Perform 131I Ablation.

J Clin Endocrinol Metab 2017 03;102(3):893-902

Departments of Clinical and Experimental Medicine, Unit of Endocrinology, and.

Context: There is much debate surrounding the choice of which patient should be submitted to postsurgical remnant radioiodine remnant ablation (RRA), particularly in low-risk (LR) and intermediate-risk (IR) differentiated thyroid cancer (DTC).

Objective: The aim of this study was to evaluate the role of postoperative high-sensitive thyroglobulin (Tg) on L-thyroxine (LT4-HSTg) and postoperative neck ultrasound (US) in risk restratification and decision to perform RRA.

Patients: We evaluated 505 patients with LR or IR DTC 3 to 4 months after total thyroidectomy (TTx). All patients underwent RRA and a posttherapeutic whole body scan (ptWBS).

Results: After TTx, 29.7% DTC patients had LT4-HSTg <0.1 ng/mL (Group A) and could be restratified as cured: 1 of 150 had lymph node metastases (LN mets) detected by neck US but negative at ptWBS. 56.8% DTC patients had LT4-HSTg between 0.1 and ≤1 ng/mL (Group B) and could be restratified either as cured or not cured. In this group, 15 of 287 (5.2%) had metastases but only 7 were detected by ptWBS; 13.5% DTC patients had LT4-HSTg >1 ng/mL (Group C) and could not be considered as cured by definition. LN mets were present in 11 of 68(16.2%) cases, all detected by neck US. No correlation was found with the presence of metastases and serum LT4-HSTg values or with the level of risk.

Conclusions: LT4-HSTg measured 3 to 4 months after TTx is important in the risk restratification of DTC patients but is less relevant than neck US in the decision to perform RRA.
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http://dx.doi.org/10.1210/jc.2016-2860DOI Listing
March 2017

Papillary thyroid microcarcinoma and active surveillance.

Authors:
David Viola

Lancet Diabetes Endocrinol 2016 12;4(12):975

Clinical and Experimental Medicine, University of Pisa, Pisa 56100, Italy. Electronic address:

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http://dx.doi.org/10.1016/S2213-8587(16)30330-8DOI Listing
December 2016

Papillary Thyroid Carcinoma With Rare Exon 15 BRAF Mutation Has Indolent Behavior: A Single-Institution Experience.

J Clin Endocrinol Metab 2016 11 29;101(11):4413-4420. Epub 2016 Aug 29.

Unit of Surgical Pathology (L.T., E.S., M.G., F.B.), Department of Surgical, Medical, and Molecular Pathology and Critical Care Medicine; Endocrine Section (D.V., P.P., C.R., R.E.), Department of Clinical and Experimental Medicine, World Health Organization Collaborating Center for the Study and Treatment of Thyroid Diseases and Other Endocrine and Metabolic Disorders; and Endocrine Surgery Unit (G.M., P.M.), Department of Surgical, Medical, and Molecular Pathology and Critical Care Medicine, University of Pisa, 56126 Pisa, Italy.

Context: Approximately 40% of papillary thyroid carcinomas (PTCs) harbor the BRAF V600E mutation, which is significantly associated with the advanced clinicopathological features of PTC at diagnosis, a higher recurrence rate, and disease-related mortality. BRAF alterations other than V600E are less common in PTC, and their clinical significance remains to be established.

Objective: The aim of the study was to describe a large cohort of rare exon 15 BRAF alterations (r-BRAF) and the clinicopathological features of PTC harboring these alterations and to clarify their clinical significance.

Methods: A total of 2961 PTCs were collected from 2006 to 2013 and screened for exon 15 BRAF alterations.

Results: Exon 15 BRAF alterations were found in 1186 of 2961 PTC cases (40.0%). In particular, we found the BRAF V600E mutation in 95.3% (1131 of 1186) and r-BRAF in 4.7% (55 of 1186) of the cases. r-BRAF were found in 18 microcarcinomas, 33 follicular variants, one classic variant, and one trabecular/solid variant. The most frequent r-BRAF was BRAF K601E (35 of 55; 63.6%), followed by BRAF V600_K601delinsE (seven of 55; 12.7%) and BRAF T599I-V600_R603del (two of 55; 3.6%). The remaining 11 alterations were found in one case only. The large majority of these tumors were unifocal (34 of 55; 61.8%), completely encapsulated (46 of 55; 83.6%), and intrathyroidal (53 of 55; 96.4%) with a low prevalence of lymph node metastases (one of 55; 1.8%) and a less advanced tumor stage at diagnosis (American Joint Commission on Cancer stage I/II, 51 of 55; 92.7%).

Conclusions: r-BRAF are very uncommon in PTC and are found almost exclusively in PTC with low-risk clinicopathological features.
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http://dx.doi.org/10.1210/jc.2016-1775DOI Listing
November 2016

Role of YAP-1 in Thyroid Tumor Progression and Outcome.

Appl Immunohistochem Mol Morphol 2017 09;25(8):581-585

*Department of Medical Area, Azienda Ospedaliero-Universitaria Pisana, S. Chiara Hospital Departments of †Surgical, Medical, Molecular Pathology and Critical Area ‡Translational Research and of Medical and Surgical New Technologies §Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.

Context: Yes-associated protein-1 (YAP-1) is a player of the Hippo pathway and is involved in regulating cell proliferation. YAP-1 is overexpressed in papillary and anaplastic thyroid cancers. However, a correlation between YAP-1 expression and outcome in thyroid carcinoma has not been conclusively demonstrated.

Objective: This study was designed to clarify whether YAP-1 may be considered a marker of worse prognosis and outcome in thyroid cancer.

Design: A large series of cases of thyroid cancer with a long follow-up were investigated for YAP-1 expression.

Setting: The study was carried out in the Pathology section of a referral Italian center for Endocrine Surgery and Endocrinology.

Patients Or Other Participants: The study included a consecutive series of 105 patients who underwent thyroidectomy from 1985 to 1992. The mean follow-up was 15 years. For all patients, clinicopathologic features were considered. All patients completed the study.The study also included a consecutive series of 52 patients who underwent thyroidectomy from 2012 to 2013 in order to analyze more deeply the correlation of YAP-1expression with BRAF mutation.

Intervention: The 105 thyroid tumors were immunohistochemically investigated for YAP-1 expression.

Outcome Measures: We expected a correlation between YAP-1 expression and worse prognosis.

Results: Among 105 tumors, 77 scored positive for YAP-1 expression, of which 68 papillary thyroid carcinomas and 9 anaplastic thyroid carcinomas were YAP-1 positive. The correlation of YAP-1 expression with clinicopathologic characteristics was significant for the absence of a tumoral capsule, gender, and extrathyroid invasion.Interestingly, significant correlations were found between YAP-1 and both persistence of disease and death from carcinoma.

Conclusions: The data show an association of YAP-1 expression with worse clinicopathologic features of thyroid tumors that seem to have a specific impact on outcome.
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http://dx.doi.org/10.1097/PAI.0000000000000344DOI Listing
September 2017

New insights in the molecular signature of advanced medullary thyroid cancer: evidence of a bad outcome of cases with double mutations.

J Med Genet 2016 Nov 28;53(11):729-734. Epub 2016 Jul 28.

Endocrine Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.

Background: The proto-oncogene is responsible for the pathogenesis of hereditary (98%) and sporadic (40%) medullary thyroid carcinoma (MTC). In sporadic MTC, somatic mutations are associated with a poor prognosis.

Objectives: We looked at the genetic profile of patients with advanced and metastatic MTC. The correlation between these mutations and outcome was also investigated.

Methods: 70 patients with advanced and metastatic sporadic MTC were studied. Exons 10-11 and 13-16 of were analysed by direct sequencing. All cases were studied for and the majority also for mutations. -negative cases were analysed for other oncogene mutations.

Results: 64/70 cases (91.4%) showed a somatic mutation, while 6 (8.6%) were negative. Among the mutated cases, mutations, mainly M918T, were the most prevalent (93.8%). or mutations were present in 6.2% of cases and were mutually exclusive with No other mutations were found. Four tumours showed two somatic mutations. We found a complex somatic alteration in 6/60 (10%) -positive sporadic MTC cases. A positive correlation between a poor prognosis and the multiple number of mutations was found.

Conclusions: This study showed a high prevalence of somatic mutations in advanced and metastatic MTCs. mutations were present in a small percentage of cases and mutually exclusive with mutations. In a small number of cases, more than one mutation was present in the same tissue. double mutations and, to a lesser extent, also complex mutations showed a worse outcome.
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http://dx.doi.org/10.1136/jmedgenet-2016-103833DOI Listing
November 2016