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Thyroid nodules are a common, benign condition with a higher prevalence in women, individuals with iodine deficiency, and radiation exposure. Treatment options for benign thyroid nodules include pharmaceutical therapy, thyroidectomy, and thermal ablation (TA). TA, including laser ablation (LA), radiofrequency ablation (RFA), and microwave ablation (MWA), is a procedure that uses heat to cause tissue necrosis. It is commonly used for large, firm, benign, non-functioning thyroid nodules that cause severe symptoms or pain when surgery is not recommended or desired. When thyroid nodules do not respond to TA, they undergo surgery to resolve the symptoms and clarify the diagnosis. This study aims to analyze the histological alterations found in surgically excised TA-treated thyroid nodules and to evaluate the morphological criteria of differential diagnosis between benign and malignant nodules, establishing whether the alterations observed on the histological sample are a consequence of TA or indicative of neoplastic disease. For this purpose, the adoption of ancillary methods, such as immunohistochemistry, is fundamental to distinguish the artifacts induced by TA from the typical morphological characteristics of malignant neoplasms.

Aims: Several papers have shown that programmed death-ligand 1 (PD-L1) expression is a relevant predictive biomarker in anti-PD-L1 cancer immunotherapy. While its role in several human cancers is correlated with poor prognosis and resistance to anticancer therapies, in thyroid cancers the role of PD-L1 remains questionable. Few articles have studied PD-L1 in thyroid fine-needle aspiration cytology (FNAC), demonstrating a possible correlation with papillary thyroid carcinoma. However, its role in oncocytic thyroid lesions remains controversial. We accordingly examine the performance of PD-L1 immunostaining in liquid based cytology (LBC) from oncocytic lesions., Methods: From January 2019 to March 2021, 114 thyroid lesions diagnosed by FNAC from lesions with a predominant oncocytic component, were enrolled for evaluation by PD-L1 immunostaining on both LBC and corresponding histology samples., Results: The FNAC cohort included 51 benign (B, negative controls), 4 atypia of undetermined significance/follicular lesions of undetermined significance (AUS/FLUS), 57 follicular lesions (follicular neoplasm/suspicious for FN, FN/SFN) and 2 suspicious for malignancy (SFM) cases. Fifty-four cases (11B, 2 AUS/FLUS, 39 FN/SFN and 2 SFM) had histological follow-up including: 1B case resulted as a hyperplastic oxyphilic nodule in Hashimoto thyroiditis (HT), 10B as goitre, 2 AUS/FLUS cases as oncocytic adenomas (OAs); 39 FN/SFN included 27 OAs, 4 FA and 8 oncocytic follicular carcinoma (OFC). The two SFM cases were diagnosed on histopathology as OAs. Increased plasma membrane and cytoplasmic PD-L1 expression were found in 47 cases of the LBC cases (41.2%). Among the histological series, 67.3% of OAs and 75% of OFC had PD-L1 expression, while negative PD-L1 was found in hyperplastic oncocytic cells in HT. A positivity in more than 30% of the neoplastic cells was found in 72.9% of the cases including six OFC., Conclusions: These data suggest that PD-L1 expression is expressed in oncocytic thyroid lesions. While weak PD-L1 expression failed to discriminate benign from malignant lesions, OFC demonstrated more intense cytoplasmic and membranous expression., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: TP53 gene plays a major role in the negative control of cell proliferation and in the regulation of signaling cascades. TP53 mutation may have a relevant role in the malignant transformation of thyroid cells as well as thyroid tumor progression. TP53 mutation has been detected only in few well differentiated thyroid carcinomas and is absent in benign conditions., Methods: A total of 162 prospective thyroid cytology and corresponding histological samples diagnosed from atypia of indeterminate significance (AUS) to malignant, were studied via immunocytochemistry for p53. Hence, 50 benign lesions (B) were used as negative control. Molecular analysis for p53 only was performed., Results: The cytology resulted in 50 B, 48 AUS, 40 follicular neoplasms (FNs), 23 suspicious for malignancy (SFM), and 1 malignant (M) case. The authors reported 102 negative and 60 positive p53 cases. The 60 positive cases included 27 cases with weak and/or focal cytoplasmic positivity (+1) and 33 with cases moderate (2+) to strong (3+) cytoplasmic and/or nuclear expression. Overall, 71 cases had histology (2 B, 11 AUS, 37 FN, 20 SFM, and 1 M) including 61.7% benign and 38.2% malignant diagnoses. Only 16 of 71 (5 FN, 10 SFM, and 1 M) were p53-positive. Furthermore, 100% AUS and 86.5% FN cases were p53-negative, none of which had malignant histology. All p53-positive cases were associated with a larger nodule size, tall-cell variant subtype, multifocality, extra thyroidal infiltration, and nodal metastases. Noninvasive follicular thyroid neoplasm with papillary like nuclear features were negative for p53. Few discrepancies in p53 intensity were observed on histology; there were no differences with the molecular testing., Conclusions: p53 might be useful in discriminating thyroid follicular lesions. p53 is likely to be a useful diagnostic marker in recognizing indeterminate lesions that are well-differentiated thyroid cancers., (© 2023 The Authors. Cancer Cytopathology published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Background: Mutational analysis contributes to the diagnosis and prognosis of thyroid nodules analyzed with fine-needle aspiration cytology (FNAC). Although several advanced molecular tests based on multiple molecular markers are available for clinical use and have increased their impact on clinical management of patients, they are not widely available. Among them is BRAF V600E, one of the most studied mutations. Other genetic alterations, such as TERT promoter mutations, may coexist in thyroid carcinomas. Previous studies have demonstrated that this duet might be involved in the aggressiveness of thyroid cancer, although its prognostic value related to mortality remains undefined. The detection of such genetic alterations in thyroid liquid-based cytology (LBC) thus may assist with patient management., Methods: From January 2013 to June 2014, 356 thyroid FNAC samples were processed by LBC, including 174 surgical follow-up samples. BRAF V600E and TERT mutation analyses were performed on both LBC and histopathology., Results: The study included 119 samples categorized as atypia of undetermined significance, 42 categorized as follicular neoplasms, 61 categorized as suspicious for malignancy, and 34 categorized as positive for malignancy. BRAF V600E mutation was detected in 10.4% of all cases, whereas TERT promoter mutations were identified in 1.1%. TERT-mutated cases belonged to the positive for malignancy category, with a histologic diagnosis of tall cell variant of papillary thyroid carcinoma. These genetic alterations correlated with lymph node metastases (P = .0349) and higher disease stage., Conclusions: BRAF V600E and TERT analysis can be performed on LBC. TERT mutations are rarely identified in well differentiated thyroid carcinoma but are associated with higher stage. Although a larger molecular panel may offer more information, analyzing these few point mutations is still likely to be useful for managing potentially more aggressive thyroid carcinomas., (© 2021 American Cancer Society.)

Purpose: In presence of indeterminate lesions by fine needle aspiration (FNA), thyroid cancer cannot always be easily diagnosed by conventional cytology. As a consequence, unnecessary removal of thyroid gland is performed in patients without cancer based on the lack of optimized diagnostic criteria. Aim of this study is identifying a molecular profile based on long noncoding RNAs (lncRNAs) expression capable to discriminate between benign and malignant nodules., Methods: Patients were subjected to surgery (n = 19) for cytologic suspicious thyroid nodules or to FNA biopsy (n = 135) for thyroid nodules suspicious at ultrasound. Three thyroid-specific genes (TG, TPO, and NIS), six cancer-associated lncRNAs (MALAT1, NEAT1, HOTAIR, H19, PVT1, MEG3), and two housekeeping genes (GAPDH and P0) were analyzed using Droplet Digital PCR (ddPCR)., Results: Based on higher co-expression in malignant (n = 11) but not in benign (n = 8) nodules after surgery, MALAT1, PVT1 and HOTAIR were selected as putative cancer biomarkers to analyze 135 FNA samples. Cytological and histopathological data from a subset of FNA patients (n = 34) were used to define a predictive algorithm based on a Naïve Bayes classifier using co-expression of MALAT1, PVT1, HOTAIR, and cytological class. This classifier exhibited a significant separation capability between malignant and benign nodules (P < 0.0001) as well as both rule in and rule out test potential with an accuracy of 94.12% and a negative predictive value (NPV) of 100% and a positive predictive value (PPV) of 91.67%., Conclusions: ddPCR analysis of selected lncRNAs in FNA biopsies appears a suitable molecular tool with the potential of improving diagnostic accuracy.

Classification schemes for reporting thyroid cytology of fine needle aspiration (FNA) of thyroid nodules are largely used in clinical practice, but the level of inter-observer agreement among cytopathologists is poorly acknowledged. The present study aimed to explore the inter-observer agreement among the experienced authors of the 2014 Italian Consensus for Classification and Reporting of Thyroid Cytology (ICCRTC). A stratified randomization was performed in order to obtain a sample homogeneously distributed and representative of all ICCRTC classes. Four high-experience raters were randomly selected among the extensors of the Italian consensus. They independently reviewed 60 FNA samples blindly of the initial cytological report and clinical features. Their overall agreement was evaluated according to Fleiss' kappa. The overall inter-observer agreement was moderate (κ 0.46). Specifically, a good agreement was found when the samples were consistent for malignancy (TIR5) or were not adequate for diagnosis (TIR1) (κ 0.67 and κ 0.73, respectively). A moderate agreement was present for suspicious-for-malignant category (TIR4), and a fair agreement was recorded in the two intermediate ones (TIR3A and TIR3B) (κ 0.36 and κ 0.35, respectively). For clinical purposes, the agreement was good (κ 0.74) in differentiating cases with surgical indication (TIR4/TIR5) from those in which surgery is not essential or requires limited extension (TIR3B/TIR3A/TIR2). In conclusion, the present study confirms the reliability of ICCRTC. These data represent a reference for cytopathologists using this system and are useful for the practice of clinicians and surgeons.

Purpose: The identification of somatic mutations in cancer specimens enables detection of molecular markers for personalized treatment. We recently developed a novel molecular assay and evaluated its clinical performance as an ancillary molecular method for indeterminate thyroid nodule cytology. Herein we describe the analytical validation of the novel targeted next-generation sequencing (NGS) assay in thyroid samples from different sources., Methods: We present validation data of a novel NGS-based panel on 463 thyroid samples, including 310 fine-needle aspiration (FNA) specimens from different sources (FNA collected in preservative solution, liquid-based, and stained smears), 10 fresh frozen, and 143 formalin-fixed paraffin-embedded (FFPE) thyroid tissue specimens. Sequencing performance in the different samples was evaluated along with reproducibility, repeatability, minimum nucleic acid input to detect variants, and analytical sensitivity of the assay., Results: All thyroid samples achieved high sequencing performance, with a mean base coverage depth ranging from 2228 × (in liquid-based FNA) to 3661 × (in FNA stained smears), and coverage uniformity ranging from 86% (in FFPE) to 95% (in FNA collected in preservative solution), with all target regions covered above the minimum depth required to call a variant (500×). The minimum nucleic acid input was 1 ng. Analytic sensitivity for mutation detection was 2-5% mutant allele frequency., Conclusions: This validation study of a novel NGS-based assay for thyroid nodules demonstrated that the assay can be reliably used on multiple thyroid sample types, including FNA from different sources and FF and FFPE thyroid samples, thus providing a robust and reliable assay to genotype thyroid nodules, which may improve thyroid cancer diagnosis and care.

Purpose: Deciding whether patients with a cytologically indeterminate thyroid nodule should be referred for surgery or for active surveillance is an important challenge for clinicians. The aim of this study was to evaluate the performance of a novel dual-component molecular assay as an ancillary molecular method for resolving indeterminate thyroid nodule cytology., Methods: We selected 156 thyroid nodules from those that had undergone fine-needle aspiration processed by liquid-based cytology and surgical resection between June 2016 and December 2017. The sample set included 63 nodules cytologically classified as indeterminate, and 93 other nodules randomly selected from those with non-diagnostic, benign, suspicious, or malignant cytology. Nucleic acids from each nodule were subjected to next-generation sequencing analysis for mutation detection in 23 genes and to digital polymerase chain reaction (PCR) evaluation for miR-146b-5p expression levels., Results: Used alone, mutation analysis in the indeterminate subset (cancer prevalence: 22.5%) displayed high sensitivity (89%) and NPV (96%). In contrast, the miR-146b-5p assay offered high specificity (93%) and PPV (93%). Combined use of both analyses improved panel performance by eliminating false-negative results., Conclusions: These preliminary data suggest that a dual-component molecular test can increase the diagnostic accuracy of thyroid cytology alone by reducing the number of nodules that will be classified as indeterminate and increasing those that can be reliably classified as benign. If these findings are confirmed, this test can be considered for use in clinical practice and is expected to reduce diagnostic surgery and health care costs, and to improve patient quality of life.

Background: The CUT score is a thyroid nodule scoring system that has become recently available as a smartphone application. It has been created on the basis of a clinical (C) and ultrasonographic (U) meta-analysis of suspicious thyroid nodule features to help clinicians with the preoperative malignancy risk assessment of thyroid nodules. The aim of the present study was to analyze the C + U sum of the CUT score for cytologically indeterminate TIR3A and TIR3B thyroid nodules, comparing the results obtained from the two groups. Methods: The CUT score was applied to 201 cytologically indeterminate thyroid nodules, 78 categorized as TIR3A and 123 as TIR3B. The Mann-Whitney test was applied to compare the C + U score values of the two groups, and a receiver operating characteristic (ROC) curve analysis was performed to validate the C + U score as a diagnostic test. Results: In both groups, the median C + U value of all nodules was significantly higher in case of malignant (4.37 TIR3A, 4.50 TIR3B) versus benign nodules (2.75 TIR3A, 3.00 TIR3B). Through ROC curve analysis within the TIR3A group, a C + U value ≥4.00 was determined as diagnostic cutoff for the detection of malignant nodules (56% sensitivity, 77% specificity, area under the curve [AUC] = 0.714); and for the TIR3B group, a cutoff of C + U value of ≥3.75 was identified (65% sensitivity, 78% specificity, AUC = 0.744). Conclusion: The CUT score could represent a valid aid for the clinician in the management of indeterminate nodules with follicular proliferation.

Background: Hyalinizing trabecular tumors (HTTs) are rare, essentially benign, follicular cell-derived thyroid neoplasms characterized by a trabecular growth pattern and nuclear pseudoinclusions. Their cytological findings are misleading, because these tumors are often misinterpreted on fine needle aspirate cytology as malignant lesions, such as papillary thyroid cancer and/or medullary thyroid cancer, leading to unnecessary total thyroidectomy. The aim of this study was to analyze the cytomorphological features and application of ancillary techniques in a series of HTTs., Methods: Of 26 histological cases of HTT collected from September 2001 to December 2018, 18 cases had concomitant cytopathology. Cytological cases were processed with liquid-based cytology (LBC). Immunocytochemistry for HBME-1 and galectine-3 as well as molecular testing for BRAF V600E mutation were performed on both LBC and histological specimens., Results: The 18 lesions with fine needle aspirate cytology ranged in size from 5 to 45 mm. Cytological diagnoses included: 1 benign lesion favoring goiter (5.5%), 4 atypia of undetermined significance (22.2%), 6 follicular neoplasms (33.3%), 5 suspicious for malignancy favoring papillary thyroid cancer (28%), and 2 malignant (11%). Hence, 89% HTT had a negative concordant immunopanel, and they were 100% wild-type BRAF V600E ., Conclusion: The majority of our HTTs (83.3%) were diagnosed in the indeterminate Bethesda categories, suggesting that their cytomorphological features pose issues for reaching a conclusive cytological diagnosis. The ancillary test results in our series support the fact that HTT is a benign neoplasm., (© 2019 American Cancer Society.)

Introduction: Several authors have underlined the limits of morphological analysis mostly in the diagnosis of follicular neoplasms (FN). The application of ancillary techniques, including immunocytochemistry (ICC) and molecular testing, contributes to a better definition of the risk of malignancy (ROM) and management of FN. According to literature, the application of models, including the evaluation of ICC, somatic mutations (ie, BRAF V 600E ), micro RNA analysis is proposed for FNs. This study discusses the validation of a diagnostic algorithm in FN with a special focus on the role of morphology then followed by ancillary techniques., Methods: From June 2014 to January 2016, we enrolled 37 FNs with histological follow-up. In the same reference period, 20 benign nodules and 20 positive for malignancy were selected as control. ICC, BRAF V 600E mutation and miR-375 were carried out on LBC., Results: The 37 FNs included 14 atypia of undetermined significance/follicular lesion of undetermined significance and 23 FN. Specifically, atypia of undetermined significance/follicular lesion of undetermined significance resulted in three goitres, 10 follicular adenomas and one NIFTP whereas FN/suspicious for FN by seven follicular adenomas and 16 malignancies (nine non-invasive follicular thyroid neoplasms with papillary-like nuclear features, two invasive follicular variant of papillary thyroid carcinoma [PTC] and five PTC). The 20 positive for malignancy samples included two invasive follicular variant of PTC, 16 PTCs and two medullary carcinomas. The morphological features of BRAF V 600E mutation (nuclear features of PTC and moderate/abundant eosinophilic cytoplasms) were associated with 100% ROM. In the wild type cases, ROM was 83.3% in presence of a concordant positive ICC panel whilst significantly lower (10.5%) in a negative concordant ICC. High expression values of MirR-375 provided 100% ROM., Conclusions: The adoption of an algorithm might represent the best choice for the correct diagnosis of FNs. The morphological detection of BRAF V 600E represents the first step for the identification of malignant FNs. A significant reduction of unnecessary thyroidectomies is the goal of this application., (© 2018 John Wiley & Sons Ltd.)

Objective: FNA biopsy is considered as the most accurate method for the selection of patients with thyroid nodules that need for surgery or for the wait and see management. The aim of the present study is to clarify the risk of malignancy for the cytological data classified according to the 2014 Italian reporting system., Methods: We report a retrospective analysis of 4043 patients in our institution's experience during the period April 2014 through December 2016 with the Italian reporting system for thyroid cytology., Results: The diagnostic incidences of the 4043 cases were as follows: 9.8% TIR1; 1.3% TIR1C; 70% TIR2; 6.6% TIR3A; 4.5% TIR3B; 2.4% TIR4; 5.2% TIR5. A repeated aspiration was carried out in 68 out of 269 cases (25%) classified as TIR3A. A total of 407 cases with cytology underwent surgical resection. A malignant neoplasm was detected in 261 out of 407 (64%) cases. Regarding TIR3B, surgical excision was undertaken in 109 cases, which included 42 high-risk lesions and 67 Hürthle cell neoplasms. The risk of malignancy was significantly higher in the former compared to the latter (50% vs 9%; P<.05)., Conclusions: This investigation emphasises the reliability of the 2014 Italian Reporting System concerning the mutual frequency of the diagnostic categories. The risk of malignancy is perfectly within the range of the estimated values., (© 2017 John Wiley & Sons Ltd.)

BRAF mutations represent the most common genetic alteration in papillary thyroid carcinoma (PTC). The p.V600E mutation is specific for the classic and tall-cell variants of PTC and has been associated with a more aggressive biologic behavior. On the other hand, the p.K601E mutation is peculiar to the follicular variant of PTC, and seems to be a favorable prognostic indicator. A 12-year-old boy presented with a 10-mm left-sided thyroid nodule. Fine-needle aspiration cytology reported the lesion as suspicious for a follicular neoplasm (Bethesda category IV). The patient underwent lobectomy, and histopathology revealed a follicular adenoma with normal surrounding tissue. The cytological smear was found to be positive for BRAF p.K601E mutation, and this was later confirmed on the corresponding paraffin block. This case was independently revised by 4 expert pathologists, all of whom confirmed the benign nature of the thyroid lesion. This article describes the presence of a BRAF mutation in a benign thyroid lesion. To the authors' knowledge, this is the fourth case of follicular adenoma carrying BRAF K601E reported in literature to date. BRAF K601E mutation can occur in benign thyroid lesions. This finding, in the context of the current literature and the recently proposed reclassification of the noninvasive encapsulated follicular variant of papillary thyroid carcinoma into a benign lesion, confirms the importance of preoperative BRAF p.K601E testing in offering patients a tailored treatment plan and avoiding overtreatment.

Objective: In fine needle aspiration cytology (FNAC), the category of benign thyroid lesions (BTL), which constitutes 65-70% of all thyroid FNAC, and can be correctly diagnosed by morphology alone, is an important entity. A diagnosis of BTL denotes a lesion managed with follow-up unless found in conjunction with compressive symptoms. Although this diagnosis can be quite simple, there are cases in which the scant cellular or colloid component may pose diagnostic issues. Herein, we describe the experiences of evaluating BTL at two large academic institutions. We evaluated the clinical importance of a correct diagnosis of BTL to define the exact inherent risk of a false-negative result (FNR)., Methods: From January 2008 through to June 2013, 506 (3.6%) out of 15 850 patients with BTL underwent surgery. All nodules were sampled under sonographic guidance (US) and processed either with liquid-based cytology (LBC), Diff-Quik® smears or alcohol-Papanicolaou staining methods., Results: The histological follow-up of 506 BTL series included 493 benign and 13 malignant lesions. The latter group included four follicular carcinomas (FC), two classic variants of papillary thyroid carcinoma (PTC), one macrofollicular PTC and six follicular variants of PTC (FVPC). The malignancy rate for the BTL category was 2.5%., Conclusions: When diagnosed by expert cytopathologists, BTL represents a robust diagnosis and might reduce the number of FNR. Additional diagnostic experience and a large case series could enable cytopathologists to recognise all the morphological entities of BTL. An important additional aid is the extensive sampling of the lesions to reduce issues related to a low cellularity., (© 2015 John Wiley & Sons Ltd.)

We assess the role of thyroid fine needle aspiration cytology(FNAC) in our series of elderly patients. The growing subset of people aged older than 70 years has shown an increased incidence of thyroid diseases which need to be studied in order to reduce the percentage of surgical treatments in patients with higher likelihood of co-morbidities and associated life risk. We compared Follicular/Indeterminate Neoplasms(FN) and suspicious of malignancy(SM) with pediatric and adult cohorts. We discussed the role of immunocytochemistry-ICC to refine diagnoses. Four hundred and eighty out of 3539FNACs(13.5%) in elderly patients, were surgical followed-up. They included: 35Inadequate, 188benign(BL), 164FN/AUS, 49SM and 44positive for malignancy (PM). All PM and 95.7%BL were histological confirmed. The malignant rate was 24.3% mostly diagnosed as papillary thyroid carcinomas. An ICC panel (HBME-1 and Galectin-3) was carried out on liquid based cytology (LBC) and performed on FN/AUS, SM and PM.We found concordant positive ICC in 69.3%malignancies and concordant negative ICC in 97.6%benign follicular adenomas. Among FNs, 42.9%malignant histologic cases had concordant positivity whilst 97.4%benign histology had negative panel.Thyroid FNAC shows high feasibility in elderly patients. ICC helps in reducing the number of useless thyroidectomies and providing a more adequate clinical and/or surgical selection in elderly patients.

Background: Mutational analysis is reshaping the practice of fine-needle aspiration cytology for the diagnosis of thyroid nodules. The v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) valine (V) to glutamic acid (E) substitution at codon 600 (BRAF(V600E)) is the most effective diagnostic/prognostic marker and is used mainly for papillary thyroid carcinomas (PTCs). Although BRAF(V600E) represents 95% of all BRAF mutations, uncommon BRAF mutations have been identified in thyroid carcinomas. For the current study, the authors evaluated morphologic (plump pink cells and sickle-shaped nuclei) anti-BRAF(V600E) antibody (VE1) immunocytochemical and molecular findings of BRAF mutations in PTCs and in the follicular variant of PTC (FVPC)., Methods: Between January 2013 and June 2014, there were 150 cytologic samples with surgical follow-up at the authors' institution. BRAF mutations, which were identified using liquid-based cytology, were classified into wild-type BRAF, BRAF(V600E), and uncommon BRAF mutations. All clinicopathologic correlations between BRAF and FVPCs were analyzed., Results: Forty-four of 150 samples were identified as benign histologic lesions, and the authors focused on the 106 cytologic samples from patients who had malignant outcomes (60 PTCs and 46 FVPCs). The series included 16 follicular neoplasms, 36 samples diagnosed as suspicious of malignancy, and 54 samples diagnosed as positive for malignancy. The BRAF(V600E) mutation was detected in 17.4% of FVPCs and in 66.6% of PTCs, whereas uncommon BRAF mutations were detected only in FVPCs. Plump pink cells and VE1 expression were not identified in samples that had uncommon BRAF mutations. VE1 immunocytochemistry yielded positive results in all 36 samples that had the BRAF(V600E) mutation., Conclusions: Uncommon BRAF mutations were observed only in FVPCs and were linked to less aggressive behavior. Negative/weak VE1 expression was observed in both wild-type and uncommon BRAF mutations. The current investigation did not reveal any plump cells or morphologic BRAF findings in samples that had uncommon BRAF mutations. In the authors' experience, BRAF mutations detected by DNA methods were more accurate in identifying FVPCs., (© 2015 American Cancer Society.)

Background: Fine needle aspiration Cytology (FNAC) fulfills a reliable role in the evaluation of thyroid lesions. Although the majority of nodules are quite easily diagnosed as benign or malignant, 30% of them represent an indeterminate category whereby the application of ancillary techniques (i.e. immunocytochemistry-ICC and molecular testing) has been encouraged. The search for a specific immunomarker of malignancy sheds light on a huge number of ICC stains although none of them attempt to yield 100% conclusive results. Our aim was to define in a pilot study on thyroid FNAC whether CD56 might be a valid marker also in comparison with HBME-1 and Galectin-3., Materials and Methods: Inasmuch as this is the largest pilot study using only liquid based cytology (LBC), we selected all the cases only in the categories of benign nodules (BN) and positive for malignancy (PM) for validation purposes. Eighty-five consecutive (including 50 PM and 35 BN) out of 950 thyroid FNACs had surgical follow-up. The ICC panel (HBME-1, Galectin-3 and CD56) was carried out on LBC and histology., Results: All BNs and PMs were histological confirmed. CD56 was negative in 96% of the PM while 68.5% of the BNs showed cytoplasmic positivity for this marker, with an overall high sensitivity (96%) but lower specificity (69%). In specific, our 96% of the PMs did not show any follicular cell with CD56 expression. Different ICC combinations were evaluated showing that the panel made up of CD56 plus HBME-1 and Galectin-3 had the highest sensitivity (98%) and specificity (86%)., Conclusions: Our pilot study suggests that CD56 may be a good marker for ruling out PTC and its variants. The low specificity suggests that an immunopanel including also HBME-1 and Galectin-3 could obtain the highest diagnostic accuracy in thyroid lesions. Our results suggest that CD56 may be a feasible additional marker for identifying malignancies also in the FNs and SMs.

Background: Thyroid Metastases (TM) represent a rare entity with an estimated variability ranging between 0 and 24%. Fine needle aspiration cytology (FNAC) might be useful in discriminating between primary and TM nodules especially when ancillary techniques (i.e., immunocytochemistry-ICC) are carried out., Methods: We herein appraised a series of 20 TM on FNAC analyzed between 2000 and 2013. We included eight male and 12 female patients. The cytological cases were processed with both liquid based (LBC) and conventional cytology., Results: We reported 2.2% TM out of 910 malignancies. Our TM cases resulted as: six lung (LG), five gastro-intestinal (GI), five breast (B), three larynx (LX), and one clear cell renal carcinoma (CCRC) metastases. All the patients had a previous known cancer history. Although the cytological features were likely to suspect a TM, the application of ICC panels was contributive in 100% cases. None of TMs resulted as a unique localization whereby two cases underwent total thyroidectomy (including one B and one CCRC) and 18 TM were treated with radio-chemotherapy approaches., Conclusions: FNAC empowered the diagnostic workup of patients with TM avoiding useless surgical approach. The low sensitivity of cytology might be reinforced by the application of ancillary techniques. In contrast with the reported predominant rate of kidney metastatic carcinomas, our findings underlined that intestinal cancer as well as lung and breast are the most common TM. TM are frequently multifocal and in a contest of a systemic disease so that a tailored therapy seems to be the best treatment., (© 2014 Wiley Periodicals, Inc.)

Background: The current study was conducted to investigate the role of thyroid fine-needle aspiration cytology (FNAC) in the authors' pediatric series. Thyroid pediatric FNAC has been reported to have conflicting sensitivity and specificity in different series. The authors evaluated their thyroid cytological series mainly for the categories of 1) follicular/indeterminate neoplasms with atypical cells of indeterminate significance (FN/AUS) and 2) suspicious for malignancy (SM). In this setting, the application of immunocytochemistry (ICC) is likely to allow a correct diagnosis., Methods: A total of 64 of 247 pediatric FNACs (26%) that were processed with liquid-based cytology had surgical follow-up. An ICC panel (Hector Battifora mesothelial cell-1 [HBME-1] and galectin-3) was performed on liquid-based cytology. A positive immunopanel was defined by a concordant positivity., Results: These 64 cases were cytologically diagnosed as 4 cases of cystic hemorrhagic lesions, 23 benign lesions (BL), 17 FN/AUS cases, 11 SM cases, and 9 positive for malignancy (PM) cases. All PM and BL cases were histologically confirmed. The rate of malignancy was 31.2%, including 1 case of follicular carcinoma, 9 cases of classic papillary thyroid carcinomas (PTC), and 10 PTC variants (7 follicular variant of PTC, 1 macrofollicular variant, and 2 sclerosing diffuse variants). The immunopanel was performed on the categories of FN/AUS, SM, and PM. The data highlighted a concordant positive ICC in 87% of malignancies and a concordant negative ICC in 100% of benign follicular adenomas., Conclusions: Thyroid FNAC represents a valuable/feasible tool in childhood. The higher incidence of histological malignancies justifies the cytological application of ancillary techniques (ie, ICC or molecular panels), thereby enabling a more adequate surgical selection based on the effective distinction of high-risk and low-risk lesions mainly for the categories of FN/AUS and SM., (© 2014 American Cancer Society.)

Objective: Thyroid nodules are a common finding in the general population, including both nonneoplastic and neoplastic entities. Fine-needle aspiration cytology (FNAC) is the first tool for evaluating thyroid nodules. In spite of its high diagnostic accuracy, 25% of nodules result in the category of follicular neoplasms (FN), with varying risk of malignancy and different management strategies., Study Design: The use of ancillary techniques is reshaping the practice of FNAC. These tools can significantly empower the morphological diagnosis and prognosis of thyroid nodules, allowing a more accurate prediction of the nature of the lesion. Several studies have underlined the role of single or multiple testing for the category of FN as strong indicators of cancer. Every cytological preparation can be used for the application of ancillary techniques but the introduction of liquid-based cytology (LBC) might facilitate the application., Results: Our experience involving an immunocytochemical panel made up of HBME-1 and galectin-3 pointed to an 81% overall diagnostic accuracy in discriminating between low and high risk of malignancy in FN., Conclusions: The application of these techniques on LBC represents an adjunct to the morphological evaluation of FN. They represent a critical and challenging, but also a feasible, tool in the preoperative diagnoses, allowing specific prognostic and predictive details regardless of the cytological preparation. © 2014 S. Karger AG, Basel.

The presence of ectopic thyroid tissue is a frequent diagnostic feedback related to a possible histogenetic abnormality or a result of post-surgical seeding. The important challenge is the diagnostic definition of its nature, which could lead to a different therapeutic approach. We describe a case with all the possible implications and differential diagnoses supported by the application of immunohistochemistry and BRAF-V600E molecular detection. A 36-year-old girl with a left thyroid nodule underwent surgery with a diagnosis of angio-invasive tall cell variant of papillary carcinoma without lymph-node metastases. The patient history revealed a previous right lobectomy in another institution ten years before. The right neck dissection was histologically characterized by the presence of thymic residual and evidence of microfollicular microfoci (less than 1mm) of thyroid tissue. Thyroid tumor cells were positive for thyroglobulin, TTF-1, HBME-1 and Galectin-3, while the residual ectopic thyroid tissue showed positivity only for TTF-1 and thyroglobulin. The molecular tests on the thyroid nodule revealed the presence of BRAF-V600E mutation, but wild type BRAF in the ectopic tissue. The histo-morphological definition of these remnants plays the most important role, but the application of immunohistochemistry and molecular biology may help to reach a conclusive diagnosis., (Copyright © 2012 Elsevier GmbH. All rights reserved.)

Objectives: Fine-needle aspiration biopsy is regarded as the most important diagnostic tool for thyroid lesions because of its simplicity, safety, and cost-effectiveness. However, its pivotal role in the correct characterization of the majority of nodules is impaired by the difficulties in discriminating benign from malignant follicular-patterned lesions., Study Design: Liquid-based cytology (LBC) is a semiautomated device that has recently become widely available and has gained popularity as a method of collecting and processing both gynecologic and nongynecologic cytologic specimens. It achieves a diagnostic sensitivity as accurate as conventional preparations, especially for its excellent cell preservation and lack of background which decrease the amount of inadequate diagnoses., Results: In many cases the cytologic features are similar in both methods, but the colloid film and the lymphocytic component are more easily evaluated on direct smears whereas nuclear details and colloid globules are better evaluated in LBC slides. The material stored in the preservative solution could be effectively used for the application of immunocytochemical and molecular techniques., Conclusions: LBC-processed biopsies represent a valid alternative to conventional cytology. The possibility of applying additional techniques enhances the efficacy of the cytologic diagnosis of thyroid lesions., (Copyright © 2011 S. Karger AG, Basel.)

Objective: The isthmus represents a peculiar, as yet partially unexplored, thyroid gland area., Aim of the Study: To assess i) the prevalence and clinico-pathological features of solitary thyroid isthmic nodules (STIN); ii) the frequency of medullary thyroid carcinoma (MTC) arising from the isthmus; and iii) the C-cell distribution in the isthmus of patients with MTC and benign nodular thyroid disease (NTD)., Subjects and Methods: Patients referred from 2006 to 2008 for STIN were prospectively recruited, and underwent serum calcitonin (C(t)) measurement and fine needle aspiration cytology (FNAC). MTCs diagnosed from 1993 to 2005 were retrospectively searched. Immunohistochemistry was performed using anti-C(t) antibodies on lateral lobes and isthmi of 50 benign NTD and 50 MTC cases., Results: From 1993 to 2005, 150 patients underwent surgery for MTC. All patients had the neoplasm located in lateral thyroid lobes, none in the isthmus. In the 3 years following, 192 STIN patients (40 (21%) males, 152 (79%) females; mean age: 46.2+/-7.1 years; 6.4% of NTD subjects) were recruited. All had normal C(t) concentrations. FNAC was malignant or suspicious for malignancy in 14 (7.3%) patients. Histology found malignancy in 17 (9%) cases, MTC in none. C cells were disclosed in lateral thyroid lobes of 100% MTC and 77% benign NTD patients; isthmi were free of C cells in either group., Conclusions: STINs are significantly less likely to be MTC in patients presenting with sporadic disease. Therefore, C(t) screening is not warranted in these subjects. Nonetheless, STINs are more likely to be neoplastic and deserve equal attention as those of the lateral lobes.

Background: The routine measurement of serum calcitonin (CT) has been proposed for patients with nodular thyroid disease (NTD), to detect unsuspected medullary thyroid carcinoma (MTC) before surgery., Objective: To assess the prevalence of hypercalcitoninemia and MTC in NTD patients; to compare the ability of CT measurement and fine needle aspiration cytology (FNAC) to predict MTC; to identify age groups of NTD patients who should be better candidates than others to undergo routine measurement of CT., Patients and Methods: 1425 consecutive patients, referred from April 1, 2003, through March 31, 2004, to four Italian endocrine centers due to NTD, were grouped depending on age, and underwent basal and, in some cases, pentagastrin (Pg)-stimulated CT measurement, FNAC and, when indicated, surgery. Serum CT concentrations were measured by an immunoluminometric assay (ILMA)., Results: Hypercalcitoninemia was found in 23 out of 1425 patients. MTC was discovered in 9 patients, all >40 yr old and showing high CT levels. Sensitivity of basal and Pg-stimulated CT to predict MTC before surgery was 100% for both tests, whereas specificity was 95 and 93%, respectively. CT specificity reached 100% when a cutoff value of 20 pg/ml was taken. FNAC showed an overall 86% sensitivity. When >10 mm MTC nodules were considered, FNAC sensitivity approached 100%. On the contrary, a correct cytological diagnosis was obtained in only one out of five patients with <10 mm MTC nodules (microMTC); in one patient with histologically proved microMTC, FNAC even demonstrated a benign lesion. Hypercalcitoninemia or MTC were associated with chronic thyroiditis in 30 or 33% of cases, respectively. C-cell hyperplasia was found in 57% of hypercalcitoninemic patients without MTC., Conclusions: Basal CT measurement detects elevated CT values in 1.6% of NTD patients. Although CT is not a specific marker of MTC, its routine measurement represents a useful tool in the pre-operative evaluation of NTD patients, particularly those >40 yr old presenting with nodules <10 mm, even when FNAC does not show malignant features. To our knowledge, this is the first trial using ILMA to assess the ability of pre-operative CT measurement to predict MTC in a large series of NTD patients.

Background: Fine-needle aspiration biopsy (FNAB) is the most reliable diagnostic tool for thyroid nodules. A difficult cytologic diagnosis may be supported by an immunocytochemical study. The efficacy of a panel made up of RET, HBME-1, and Galectin-3 antibodies was evaluated in smears processed by thin-layer cytology (TLC)., Design: Thyroid FNABs (n = 99) with both conventional (CS) and thin-layer cytology (TLC) smears were studied. The cases were diagnosed as follows: 5 benign lesions (BL), 13 papillary carcinomas (PC), and 81 follicular proliferations (FP). The category of FP was divided into three subgroups according to nuclear features of follicular cells: Follicular neoplasm (FN NOS), oxyphilic follicular neoplasm (OFN), and follicular lesion with nuclear pleomorphism (FLWNP). Immunostains for HBME-1, Galectin-3, and RET were carried out on TLC slides., Results: Among 49 cases undergoing surgery, all 10 PC and 2 BL were histologically confirmed, whereas 15 out of 37 FP (40.5%) were malignant. The complete immunocytochemical panel (ICCP) was positive in 9 of 10 malignancies (90%) and negative in both BLs. Out of 37 FP, the ICCP yielded positive in 15 cases (4 benign, 11 malignant) and negative in 11 (all benign). In the FLWNP subgroup, the ICCP was positive in 11 (84.6%) and negative in 2 histologically benign cases., Conclusion: The combined panel of antibodies and the nuclear pleomorphism of follicular cells were effective in distinguishing between thyroid nodules requiring surgery from thyroid nodules requiring just follow-up., (2005 American Cancer Society.)

Background: Thyroid gland manipulation, surgical stress response, and postoperative outcome in cases of video-assisted thyroidectomy (VAT) and conventional thyroidectomy were compared to verify the safety of VAT., Methods: Twenty consenting patients were randomly assigned to undergo VAT or conventional thyroidectomy. Serum thyroglobulin levels were monitored as indicators of thyroid manipulation, and C-reactive protein and white blood cell count were monitored to assess surgical stress response. Thyroid capsule integrity and the presence of spilled cells in the thyroid bed were verified., Results: No significant differences were found in the indicators of thyroid gland manipulation and surgical stress response between groups. No thyroid capsules ruptured, and no spilled thyroid cells were found. Patients who had VAT experienced less pain, required fewer analgesics, and were more satisfied with the cosmetic result and the surgical outcome., Conclusions: VAT is as safe as conventional thyroidectomy and is characterized by a less painful postoperative course and by better cosmetic results and postoperative outcome., (Copyright 2004 Wiley Periodicals, Inc.)

Objective: Conventional fine-needle aspiration biopsy (FNAB) for cystic thyroid nodules (CTNs) has a high rate of nondiagnostic and false-negative results. Ultrasound-guided FNAB (UG-FNAB) permits direct sampling of the wall and/or the solid portion of CTNs, increasing the possibility of a representative sample. In this study we evaluated the role of UG-FNAB in CTNs management., Methods: Five-hundred-seventy-five UG-FNAB of CTNs were performed. Thyroidectomy was carried out in 119 of these cases. The medical records of these 119 patients were reviewed and form the basis of this report., Results: The nondiagnostic smear rate was 9.2%. Cytological diagnosis was benign nodule in 42 cases, predominantly follicular lesion in 50 cases, and suspicious or malignant lesion in 16 cases. The final pathology revealed a benign nodule in 98 cases (82.4%) and a carcinoma in 21 (17.6%). The overall accuracy of UG-FNAB was 88.0%. No significant differences were found in age, sex, lesion size, or echographic pattern (p = NS) comparing patients with benign CTNs to patients with malignant CTNs., Conclusion: UG-FNAB has a low rate of nondiagnostic smears and a high overall accuracy in CTNs. All CTNs should undergo UG-FNAB to select patients for surgery, since the malignancy rate is not negligible and no clinical parameter can reliably predict it.

We describe our technique of diagnostic lobectomy (DL) and the rationale it is based on. We define DL as a minimally invasive procedure consisting of total lobectomy and isthmusectomy, with preservation of the omolateral recurrent laryngeal nerve and parathyroid glands, but without digital exploration of the contralateral lobe. The fact that re-entry into the previously explored field to complete thyroidectomy increases the risk of complications must be taken into consideration. The subjects were 63 consecutive patients who underwent surgery for unilobar follicular neoplasms of the thyroid gland between January 1997 and December 2002. There were 49 follicular adenomas and 14 carcinomas. In the 14 patients with thyroid cancer, total thyroidectomy was performed within 2 weeks after the first operation in a sterile environment with normal anatomical cleavage plains, avoiding any risk of injury to the laryngeal nerves and parathyroid glands. It is concluded that DL is a safe and suitable surgical procedure for patients with follicular-structured lesions of the thyroid gland.