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This review addresses new reporting systems for lung and pancreatobiliary cytopathology as well as the most recent edition of The Bethesda Reporting System for Thyroid Cytopathology. The review spans past, present, and future aspects within the context of the intricate interplay between traditional morphological assessments and cutting-edge molecular diagnostics. For lung and pancreas, the authors discuss the evolution of reporting systems, emphasizing the bridge between past directives and more recent collaborative efforts of the International Academy of Cytology and the World Health Organization in shaping universal reporting systems. The review offers a brief overview of the structure of these novel systems, highlighting their strengths and pinpointing areas that require further refinement. For thyroid, the authors primarily focus on the third edition of The Bethesda System for Reporting Thyroid Cytopathology, also considering the two preceding editions. This review serves as an invaluable resource for cytopathologists, offering a panoramic view of the evolving landscape of cytopathology reporting and pointing out the integrative role of the cytopathologist in an era of rapid diagnostic and therapeutic advancements.

Serous effusion cytology is a pivotal diagnostic and staging tool in clinical pathology, valued for its simplicity and cost-effectiveness. Staining techniques such as Giemsa and Papanicolaou are foundational, yet the search for rapid and efficient alternatives continues. Our study assesses the efficacy of an in-house-developed BlueStain, a toluidine blue variant, within the International System for Reporting Serous Fluid Cytopathology (TIS), aiming to optimize diagnostic clarity and resource use., Materials and Methods: This section provides details on the cohort of 237 patients with serous effusions, the ethical approval process, sample collection, and staining procedures with BlueStain, Papanicolaou, and Giemsa. It also describes the microscopic evaluation criteria, scoring system, and statistical methods used to compare the stains., Results: BlueStain demonstrated notable performance, particularly in identifying malignant cells, presenting a competitive alternative to the Papanicolaou stain, which, despite higher quality indices in other categories, requires more resources and time. The study revealed that BlueStain might offer a valuable balance between quality and efficiency, especially in cases where rapid diagnostic turnaround is essential., Conclusions: Our findings suggest that BlueStain is a viable staining method in the context of serous effusions, capable of providing detailed cytomorphological analysis. While traditional stains hold their place for their established diagnostic clarity, BlueStain offers a rapid and resource-optimized alternative. The absence of definitive diagnostic criteria in the atypical category and the inherent sample heterogeneity underscores the necessity for adaptable staining methods like BlueStain. The study highlights the potential trade-offs between detail and practicality in staining techniques, advocating for further research into innovative methods that do not compromise diagnostic precision for cost and time efficiency.

Introduction: The repertoire of microRNAs (miRNAs) in thyroid carcinomas starts to be elucidated. Among differentiated thyroid carcinomas (DTCs), papillary thyroid carcinoma (PTC) is the most frequent. The assessment of miRNAs expression may contribute to refine the pre-surgical diagnosis in order to obtain a personalized and more effective treatment for patients., Aims: This study aims to evaluate (1) the miRNAs in a series of DTCs, and their association with the presence of selected genetic mutations in order to improve diagnosis and predict the biologic behavior of DTC/PTC. (2) The reliability of molecular tests in Ultrasound-guided Fine Needle Aspiration Cytology (US-FNAC) for a more precise preoperative diagnosis., Material and Methods: This series includes 176 samples (98 cytology and 78 histology samples) obtained from 106 patients submitted to surgery, including 13 benign lesions (controls) and 93 DTCs (cases). The microRNA expression was assessed for miR-146b, miR-221, miR-222, and miR-15a through quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). The results were analyzed by the 2 -ΔΔCT method, using miR16 as an endogenous control. Regarding PTC diagnosis, the discriminative ability of miRNAs expression was assessed by the area under the Receiver Operating Characteristic Curve (AUC). In PTCs, the association of miRNAs expression, clinicopathological features, and genetic mutations ( BRAF , RAS, and TERTp ) was evaluated., Results/discussion: All the analyzed miRNAs presented a tendency to be overexpressed in DTCs/PTCs when compared with benign lesions, both in cytology and histology samples. In cytology, miRNAs expression levels were higher in malignant tumors than in benign tumors. In histology, the discriminative abilities regarding PTC diagnosis were as follows: miR-146b (AUC 0.94, 95% CI 0.87-1), miR-221 (AUC 0.79, 95% CI 0.68-0.9), miR-222 (AUC 0.76, 95% CI 0.63-0.89), and miR-15a (AUC 0.85, 95% CI 0.74-0.97). miR-146b showed 89% sensitivity (se) and 87% specificity (sp); miR-221 se = 68.4, sp = 90; miR-222 se = 73, sp = 70; and mi-R15a se = 72, sp = 80. MicroRNAs were associated with worst-prognosis clinicopathological characteristics in PTCs ( p < 0.05), particularly for miR-222. Our data reveal a significant association between higher expression levels of miR-146b, miR-221, and miR-222 in the presence of the BRAF mutation ( p < 0.001) and miR-146b ( p = 0.016) and miR-221 ( p = 0.010) with the RAS mutation, suggesting an interplay of these mutations with miRNAs expression. Despite this study having a relatively small sample size, overexpression of miRNAs in cytology may contribute to a more precise preoperative diagnosis. The miRNAs presented a good discriminative ability in PTC diagnosis. The association between the miRNAs expression profile and genetic alterations can be advantageous for an accurate diagnosis of DTCs/PTCs in FNAC.

Introduction: Molecular tests can contribute to improve the preoperative diagnosis of thyroid nodules. Tests available are expensive and not adapted to different populations., Aim: This study aimed to compare the cyto-histological genetic profile and to evaluate the reliability of molecular tests using ultrasound-guided fine needle aspiration cytology (US-FNAC) in accurately diagnosing differentiated thyroid carcinomas (DTCs) and predicting biologic behavior of papillary thyroid carcinomas (PTCs)., Materials and Methods: The series included 259 patients with paired cyto-histological samples totaling 518 samples. The genetic alterations were analyzed via PCR/Sanger sequencing. The association with clinicopathologic features was evaluated in PTCs., Results/discussion: From the 259 patients included, histologies were 50 (19.3%) benign controls and 209 (80.7%) DTC cases, from which 182 were PTCs; cytologies were 5.8% non-diagnostic, 18.2% benign, 39% indeterminate, and 37.1% malignant. In histology, indeterminate nodules ( n = 101) were 22.8% benign and 77.2% malignant. Mutation frequencies in cytology and histology specimens were, respectively, TERTp : 3.7% vs. 7.9%; BRAF : 19.5% vs. 25.1%; and RAS : 11% vs. 17.5%. The overall cyto-histological agreement of the genetic mutations was 94.9%, with Cohen's k = 0.67, and in indeterminate nodules agreement was 95.7%, k = 0.64. The identified mutations exhibited a discriminative ability in diagnosing DTC with a specificity of 100% for TERTp and BRAF , and of 94% for RAS , albeit with low sensitivity. TERTp and BRAF mutations were associated with aggressive clinicopathological features and tumor progression in PTCs ( p < 0.001). The obtained good cyto-histological agreement suggests that molecular analysis via US-FNAC may anticipate the genetic profile and the behavior of thyroid tumors, confirming malignancy and contributing to referring patients to surgery.

Summary: We report a 61-year-old male patient without personal history of thyroid carcinoma or radiation exposure. In 2011, he presented with a cervical mass whose biopsy diagnosed a papillary thyroid carcinoma (PTC) in a lymph node metastasis (LNM). Total thyroidectomy with lymphadenectomy of central and ipsilateral compartment was performed. Histopathology identified a 2 mm follicular variant of PTC and LNM in 25/25 lymph nodes. The patient was treated with 150 mCi of radioactive iodine (RAI), followed by levothyroxine suppressive therapy. In 2016, a retrotracheal mass was diagnosed, suggesting local recurrence; patient was submitted to surgical excision and RAI therapy (120 mCi). Due to seizures, in 2019, a brain CT was performed that diagnosed brain metastases. The patient underwent debulking of the main lesion. Histopathology analysis confirmed a metastatic lesion with variated morphology: classical PTC and follicular pattern and hobnail and tall cell features. Molecular analysis revealed BRAFV600E in LNM at presentation and BRAFV600E and TERT promoter (TERTp) mutations in the recurrent LNM and brain metastasis. Based upon this experience we review the reported cases of subcentimetric PTC with brain metastases and discuss the molecular progression of the present case., Learning Points: Papillary microcarcinoma (PMCs) usually have very good prognosis with low impact on patient survival. PMCs presenting in elderly patients with LNM at diagnosis may carry a guarded outcome. Brain metastasis although rare indicate aggressive phenotypic features. Patient risk stratification of PMCs based on histopathological analysis and genetic testing may have a significant impact on prognosis providing therapeutic markers, that may predict disease progression and overall outcome.

Angiotensin-Converting Enzyme 2 (ACE2), Transmembrane Serine Protease 2 (TMPRSS2), and Furin were known to be key players in the SARS-CoV-2 infection, and the thyroid gland was revealed to be one of the relevant targets of the virus. Regardless of the viral infection, the expression of these molecules in the thyroid gland and their putative role in the neoplastic transformation of the thyrocytes has not been thoroughly explored. In this work, we aimed to characterize the mRNA and protein expression pattern of ACE2, TMPRSS2, and Furin in a series of patients with thyroid lesions. Our main results revealed a significantly decreased expression of ACE2 mRNA in the thyroid neoplasms in comparison to normal adjacent tissue. Furin mRNA was significantly increased in thyroid neoplasms when compared to normal adjacent tissue. In addition, a higher Furin mRNA level in thyroid carcinomas was associated with the presence of lymph node metastasis. Furin mRNA expression revealed a high discriminatory power between adjacent tissue and neoplasms. Protein expression of these molecules did not correlate with mRNA expression. Our study shows the mRNA downregulation of ACE2 and overexpression of Furin in thyroid neoplasms. Further studies are required to clarify if Furin expression can be a potential diagnostic indicator in thyroid neoplasia.

Atrx loss was recently ascertained as insufficient to drive pancreatic neuroendocrine tumour (PanNET) formation in mice islets. We have identified a preponderant role of Atrx in the endocrine dysfunction in a Rip-Cre;Atrx KO genetically engineered mouse model (GEMM). To validate the impact of a different Cre -driver line, we used similar methodologies and characterised the Pdx1-Cre;Atrx KO ( P.Atrx KO ) GEMM to search for PanNET formation and endocrine fitness disruption for a period of up to 24 months. Male and female mice presented different phenotypes. Compared to P.Atrx WT , P.Atrx HOM males were heavier during the entire study period, hyperglycaemic between 3 and 12 mo., and glucose intolerant only from 6 mo.; in contrast, P.Atrx HOM females started exhibiting increased weight gains later (after 6 mo.), but diabetes or glucose intolerance was detected by 3 mo. Overall, all studied mice were overweight or obese from early ages, which challenged the histopathological evaluation of the pancreas and liver, especially after 12 mo. Noteworthily, losing Atrx predisposed mice to an increase in intrapancreatic fatty infiltration (FI), peripancreatic fat deposition, and macrovesicular steatosis. As expected, no animal developed PanNETs. An obese diabetic GEMM of disrupted Atrx is presented as potentially useful for metabolic studies and as a putative candidate for inserting additional tumourigenic genetic events.

DGCR8 emerged recently as miRNAs biogenesis pathway protein with a highlighted role in thyroid disease. This study aimed to characterize this miRNA biogenesis component, in particular the p.(E518K) mutation and DGCR8 expression in a series of thyroid lesions. The series of thyroid lesions was genotyped for the c.1552G>A p.(E518K) mutation. When frozen tissue was available, DGCR8 mRNA expression was analysed by qPCR. Formalin-fixed paraffin-embedded tissues were studied for DGCR8 immunoexpression. We present for the first time the p.(E518K) mutation in a case of poorly differentiated thyroid carcinoma and present the deregulation of DGCR8 expression at mRNA level in follicular-patterned tumours. The obtained data solidify DGCR8 as another important player of miRNA-related gene mutations in thyroid tumorigenesis, particularly in follicular-patterned thyroid tumours.

ATRX is a chromatin remodeller that maintains telomere homeostasis. Loss of ATRX is described in approximately 10% of pancreatic neuroendocrine tumours (PanNETs) and associated with poorer prognostic features. Here, we present a genetically engineered mouse model (GEMM) addressing the role of Atrx loss ( Atrx KO ) in pancreatic β cells, evaluating a large cohort of ageing mice (for up to 24 months (mo.)). Atrx loss did not cause PanNET formation but rather resulted in worsening of ageing-related pancreatic inflammation and endocrine dysfunction in the first year of life. Histopathological evaluation highlighted an exacerbated prevalence and intensity of pancreatic inflammation, ageing features, and hepatic steatosis in Atrx KO mice. Homozygous floxed mice presented hyperglycaemia, increased weights, and glucose intolerance after 6 months, but alterations in insulinaemia were not detected. Floxed individuals presented an improper growth of their pancreatic endocrine fraction that may explain such an endocrine imbalance. A pilot study of BRACO-19 administration to Atrx KO mice resulted in telomere instability, reinforcing the involvement of Atrx in the maintenance of β cell telomere homeostasis. Thereby, a non-obese dysglycaemic GEMM of disrupted Atrx is here presented as potentially useful for metabolic studies and putative candidate for inserting additional tumourigenic genetic events.

Thyroid nodules are a common worldwide health problem and a diagnostic challenge for clinicians and cytopathologists. Follicular growth pattern constitutes the majority of thyroid lesions. Thyroid nodules can be neoplastic or non-neoplastic, and neoplastic nodules can be classified as benign, malignant, or gray zone. Gray zone lesions include different benign and malignant entities that might be resulted in unnecessary thyroidectomies with risk of morbidity and higher health care costs. Depending on the cellularity, most cases might fall into the follicular neoplasia (FN)/ suspicious for FN (SFN) category or follicular lesion of undetermined significance (FLUS) in The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC). Pathologists must be aware of the relationship between this diagnostic category and follow-up patient management and avoid over-diagnosing by mastering the diagnostic criteria.

Background: To evaluate the performance of TBSRTC through multi-institutional experience in the paediatric population and questioning the management recommendation of ATA Guidelines Task Force on Paediatric Thyroid Cancer; Methods: A retrospective search was conducted in 4 institutions to identify consecutive thyroid FNAC cases in paediatric population between 2000 and 2018. Following the 2nd TBSRTC, the risk of malignancy ratios (ROMs) was given in ranges and calculated by 2 different ways. Sensitivity, specificity, PPV, NPV and DA ratios were calculated using histologic diagnosis as the gold standard; Results: Among a total of 405 specimens, the distribution of cases for each category was, 44 (11%) for ND, 204 (50%) for B category, 40 (10%) for AUS/FLUS, 36 (9%) for FN/SFN, 24 (6%) for SFM and 57 (14%) for M categories. 153 cases have a histological diagnosis. The ratio of surgery was 23% in ND, 16% in the B, 45% for AUS/FLUS, 75% for SFN/FN and 92% for SFM and 75% in M categories; Conclusions: The data underlines the high ROM values in paediatric population which might be clinically meaningful. The high rate of malignancy of the cohort of operated patients (50%) also underlines the need of better preoperative indicators for stratification. Considering that more than half of the nodules in AUS/FLUS category were benign, direct surgery recommendation could be questionable as proposed in ATA 2015 guidelines.

In fine-needle aspirations (FNA) of thyroid, Hürthle cells can be found in a broad spectrum of lesions, ranging from non-neoplastic conditions to aggressive malignant tumors. Recognize them morphologically, frequently represents a challenging for an adequately diagnosis and are associated with a significant interobserver variability. Although the limitations of the morphologic diagnosis still exist, the interpretation of the context where the cells appear and the recent advances in the molecular knowledge of Hürthle cells tumors are contributing for a more precise diagnosis. This review aims to describe the cytology aspects of all Hürthle cells neoplastic and non-neoplastic thyroid lesions, focusing on the differential diagnosis and reporting according to The Bethesda System for Reporting Thyroid Cytology (TBSRTC). New entities according to the latest World Health Organization (WHO) classification are included, as well as an update of the current molecular data., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Thodou, Canberk and Schmitt.)

It has been widely described that cancer genomes have frequent alterations to the epigenome, including epigenetic silencing of various tumor suppressor genes with functions in almost all cancer-relevant signalling pathways, such as apoptosis, cell proliferation, cell migration and DNA repair. Epigenetic alterations comprise DNA methylation, histone modification, and microRNAs dysregulated expression and they play a significant role in the differentiation and proliferation properties of TC. In this review, our group assessed the published evidence on the tumorigenic role of epigenomics in Hurthle cell neoplasms (HCN), highlighting the yet limited, heteregeneous and non-validated data preventing its current use in clinical practice, despite the well developed assessment techniques available. The identified evidence gaps call for a joint endeavour by the medical community towards a deeper and more systematic study of HCN, aiming at defining epigenetic markers in early diagnose, allowing for accurate stratification of maligancy and disease risk and for effective systemic treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Canberk, Lima, Pinto, Soares and Máximo.)

The awareness of epigenetic alterations leading to neoplasia attracted the attention of researchers toward its potential use in the management of cancer, from diagnosis to prognosis and prediction of response to therapies. Our group has focused its attention on the epigenomics of thyroid neoplasms. Although most of the epigenetic studies have been applied on histological samples, the fact is that cytology, through fine-needle aspiration, is a primary diagnostic method for many pathologies, of which thyroid nodules are one of the most paradigmatic examples. This has led to an increasing literature report of epigenetic studies using these biological samples over the past decade. In this review, our group aimed to document recent research of epigenetic alterations and its associated assessment techniques, based on cytology material. Our review covers the main epigenetic categories-DNA methylation, histone modification, and RNA-silencing-whose evidence in thyroid cytology samples may represent solid soil for future prospectively designed studies aiming at validating patterns of epigenetic alterations and their potential use in the clinical management of thyroid neoplasms., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Canberk, Lima, Pinto and Máximo.)

Introduction: DICER1 is a member of RNase III family that has a pivotal role in the biogenesis of microRNAs, being important for normal development. Dysregulation of DICER1 has been described in different human tumours; however, there is insufficient data on the risk of thyroid cancer in the presence of germline DICER1 variants, particularly when focusing on the background of papillary thyroid carcinoma (PTC). For this purpose, we ascertained the presence of DICER1 variants in 502 (PTC) cases available from The Cancer Genome Atlas (TCGA) research network in a well-characterized pathological context., Material and Methods: in this study we analyzed 502 samples from 502 patients, described as PTC in the TCGA database. Tumour diagnoses were re-evaluated by 2 pathologists (S.C. and M.S.-S.) on slides available from the database, and clinicopathological and demographic data was examined. Data concerning germline and sporadic DICER1 gene variants as well as frequent mutations in the genes involved in thyroid carcinogenesis (e.g., RAS and BRAF V600E) was retrieved from the database., Results and Discussion: We report 1 new germline possibly pathogenic variant, besides 15 others already been identified in ClinVar. We found that the DICER1-positive PTC group more frequently includes PTC variants, namely the oncocytic, follicular, and aggressive (hobnail variant of PTC) variants. A previous association of DICER1 had been demonstrated, mainly with the follicular variant of PTC and follicular thyroid carcinomas. Tumours harbouring germline DICER1 mutations were more frequently "bilateral" and "encapsulated." The frequent association of DICER1 germline variants with other mutations associated with thyroid cancer can reflect an haploinsufficiency tumour suppressor gene function of DICER1, as suggested from the study of animal models., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2020 by European Thyroid Association Published by S. Karger AG, Basel.)

Research on the primary thyroid lymphoma (PTL) diagnosis is limited, with only a few large sample size studies, reported from Asian countries. The aim of the present study was to clarify the current prevalence and challenges in PTL diagnosis, and recommended ancillary studies for PTL in non-Western countries. PTL (n = 153) cases were retrieved from 10 institutions in non-Western countries and analyzed. Ultrasound examination (UE) and fine needle aspiration cytology (FNAC) were used as main preoperative diagnostic tools in all participating institutions. Flow cytometry (FCM) was performed in the 5 institutions (50%). Lobectomy was the most common histological procedure to confirm the PTL diagnosis. All institutions routinely performed immuno-histochemical analysis. PTL was 0.54% of malignant thyroid tumor cases, with mucosa-associated lymphoid tissue lymphoma (MALTL) and diffuse large B-cell lymphoma (DLBCL) being 54.9% and 38.6%, respectively. Kuma Hospital, where the frequency of MALTL was highest (83.7%), routinely performed FCM using the materials obtained by FNAC. UE and FNAC sensitivities were 62.5% and 57.8%, respectively. In both UE and FNAC, sensitivity of MALTL was lower than of DLBCL. The study elucidated that the prevalence of PTL in non-Western countries was lower than previously reported. We propose that FCM should be more actively used to improve the preoperative diagnosis of MALTL. Our data predicted that the MALTL proportion will increase with improved diagnostic tools, while observation of PTL-suspected nodules without histological examination remains a viable option.

The precursor lesions of thyroid neoplasms can arise from either C cells or follicular cells. Although MTC has an established and recognized precursor lesion, the C-cell hyperplasia, the same does not occur for the follicular cell-derived tumors, which are much more frequent. One of the significant obstacles to recognizing follicular cell-derived precursor lesions (FCPL) is the lack of refinement of the morphological spectrum and biology of these putative premalignant lesions. What are the "gold standard" histological criteria in thyroid pathology to identify the progression of dysplasia to cancer? Diagnostical irreproducibility and misnomer in the terminology of some FCPLs have been lying behind the answer to this question. The last past decades' advances in molecular pathology allow us to transform the knowledge in thyroid pathology to cancer prevention and early detection, which will only be possible by improving our understanding of the nature of thyroid precursor and borderline lesions. This review, amassed with the augmented expertise of thyroid pathology documented in the literature, is an attempt at underlining the present understanding of precursor and borderline lesions of the thyroid, with a particular highlight on practice differences in Asian and Western geographies., Competing Interests: Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/gs-20-429). The editorial office commissioned the series “Asian and Western Practice in Thyroid Pathology: Similarities and Differences” without any funding or sponsorship. The author has no other conflicts of interest to declare., (2020 Gland Surgery. All rights reserved.)

Identification of predictive biomarkers for ovarian cancer (OC) treatment, particularly in the platinum-resistant/refractory setting, is highly relevant for clinical management. E-cadherin, vimentin, and osteopontin (OPN) are proteins associated with tumor microenvironment (TME) remodelling that play key roles in cancer. This study aimed to evaluate the association between the staining patterns of these proteins with survival outcomes in a series of OC patients, namely in patients with platinum-resistant/refractory disease. Low E-cadherin expression and high vimentin expression in all patient groups (as well as for E-cadherin in the platinum-resistant arm) were significantly associated with longer overall survival (OS). Low cytoplasmic OPN expression (and cytoplasmic and membrane OPN in the platinum-resistant arm) were significantly associated with longer OS. In patients that responded to treatment (pegylated liposomal doxorubicin (PLD) or other), low cytoplasmic OPN expression was also associated with longer progression-free survival (PFS). In the other hand, high nuclear OPN-c expression in patients that respond to treatment was associated with longer OS and longer PFS. Longer PFS was also associated with high expression of both nuclear and cytoplasm OPN-c, in platinum-resistant patients and in those that responded to PLD. Our study indicates that the expression of E-cadherin, vimentin, and OPN may have prognostic implications. Nuclear OPN-c and cytoplasm OPN expression are putative predictive markers in platinum-resistant (PLD treated) ovarian cancer patients.

The presence of TERT promoter ( TERT p) mutations in thyroid cancer have been associated with worse prognosis features, whereas the extent and meaning of the expression and activation of TERT in thyroid tumours is still largely unknown. We analysed frozen samples from a series of benign and malignant thyroid tumours, displaying non-aggressive features and low mutational burden in order to evaluate the presence of TERT p mutations and TERT mRNA expression in these settings. In this series, TERT p mutations were found in 2%, only in malignant cases, in larger cancers, and from older patients. TERT mRNA expression was detected in both benign and malignant tumours, with increased frequencies in the malignant tumours with aggressive histotypes, larger tumours, and from older patients. In benign tumours, TERT mRNA expression was found in 17% of the follicular thyroid adenoma (FTA) with increased levels of expression in smaller tumours and associated with the presence of thyroiditis. TERT p mutations and TERT mRNA expression are correlated with worse prognosis features in malignant thyroid tumours, whereas TERT mRNA expression in the benign tumours is associated with the presence of thyroiditis.

Aim of the Study: While the rate of thyroid incidentaloma detected on positron emission tomography (PET) was reported as 4%, the malignancy rate was 14%-50%. We evaluated the thyroid nodules which were detected by PET-computerized tomography (CT) in cancer patients and analyzed the pathological results of those thyroid nodules diagnosed by fine needle aspiration biopsy (FNAB) and their correlation with the maximum standardized uptake (SUV max ) value and PET imaging features., Materials and Methods: FNAB were performed for 40 thyroid incidentalomas. We analyzed the relationship between the histopathological findings and radiological features by Pearson's correlations and Chi-square-Fisher's exact tests to evaluate the factors associated with SUV max ., Results: The median SUV max values were 5.4 for thyroid nodules. Totally, 14 malignancies were detected by FNAB (35%).The sensitivity and specificity of SUV max value for diagnosis of malignancy were 87.5% and 52%, respectively. Positive and negative predictive values were 36.8% and 92.8%. The most common malignant and benign pathologies were classic variant papillary carcinoma and benign colloidal nodule. The median SUV max was the higher in colon cancer thyroid metastasis and oncocytic neoplasia (SUV max 14.5 and 13.6, respectively). Histopathological type was not related with nodule size but positively associated with categorical SUV max (r = 0.318, P = 0.04) and negatively correlated with both the density of the thyroid nodule in PET-CT (r = -0.0042, P = 0.01) and density of nodule in ultrasound (USG) (r = -0.305, P = 0.05). Margin of the thyroid nodule in USG (P = 0.007) and internal component of the nodule in PET (P = 0.03) were found to be important factors to differentiate benign or malignant lesion., Conclusion: If the thyroid nodule is detected with flouro-2-deoxy-D-glucose uptake, to differentiate benign nodule from malignant, cytological examination is noteworthy to diagnose the more aggressive type of thyroid nodule and also thyroid metastasis from primary cancer., Competing Interests: None

Detection of thyroid carcinoma has been steadily increased in the past few decades. After the recognition of NIFTP, also gain importance to differentiate benign tumors (follicular adenoma) from follicular patterned variants of papillary thyroid carcinoma (invasive and infiltrative follicular variant papillary thyroid carcinoma), and low-risk lesions of thyroid (NIFTP). Follicular patterned proliferations of thyroid still persists as a battle for pathologists. In this study, we aimed to analyze the most commonly used immunohistochemical stains "HBME1, CK19, Galectin-3", adding the new ones "CD56, CD57, and p63". Study groups were; nodular hyperplasia, follicular adenoma, NIFTP, infiltrative follicular variant PTC, classical variant PTC (CVPTC) and follicular carcinoma. Each group consisted of twenty cases. The sections were stained with CD56, CD57, p63, CK19, HBME1 (Mesotel cell), Galectin-3 antibody. Although the expression of CD56 was high in benign follicular lesions, FC could not be excluded in this group. CD57 was high in malignant follicular group and NIFTP. Interestingly, p63 was found highly expressed in FVPTC, which might be promising to predict invasiveness in follicular group of lesions. CK19, Galectin-3 and HBME1 were found quietly prominent in CVPTC in concordance with the previous reports.

Thyroid fine-needle aspiration (FNA) biopsy has been widely accepted as an accurate and cost-effective tool in the management of thyroid nodules. To avoid unnecessary FNAs and provide appropriate management, patient evaluation should be based on a multidisciplinary approach. For this purpose, the Thyroid Imaging Reporting and Data System (TI-RADS) and strain elastography (SE) were proposed as tools for the risk assessment of malignancy in thyroid nodules. The aim of the present study was to analyze the utility of TI-RADS system and SE, along with FNA, and prospectively evaluate 369 consecutive patients referred for FNA of a thyroid nodule. TI-RADS was tested against The Bethesda System for Reporting Thyroid Cytopathology to determine whether there was an agreement between the two classification systems; statistically, some agreement was observed. Medians of the maximum SE values (E-max) were obtained for benign and malignant FNA results and found to be 1.97 [interquartile range (IQR): 1.87] and 2.8 (IQR: 3.42), respectively (P=0.004). The number of studies investigating the utility of TI-RADS and SE along with TBSRCT is currently limited. Our study demonstrated that a multidisciplinary approach with the use of TI-RADS and SE may mildly improve the management of thyroid nodules.

Objective: To determine the malignancy rate in the non-diagnostic (ND) category of the Bethesda System for Reporting Thyroid Cytopathology (BSRTC) based on a different approach in relation to histopathology diagnoses., Study Design: All ND fine needle aspirations (FNAs) that were performed under ultrasound guidance by an interventional radiologist with rapid on-site evaluation were included in the study. Slides were reevaluated to identify the cause of inadequacy as "qualitative" or "quantitative." The malignancy rate of the ND category was assessed. Nodule/patient characteristics were compared between benign and malignant cases within the study cohort., Results: The study cohort consisted of 192 ND aspirations. Overall there were 156 (81.3%) women and 36 (18.7%) men with a mean age of 50.6 years (range 24-82 years). The malignancy rate was 4.7%. None of the nodules (size, consistency, and number) or patient characteristics (gender and age) were found to be predictive of malignancy., Conclusion: The malignancy rate of the ND category was high when compared to BSRTC predictions, but at the low end of the reported malignancy rates in the literature. Our results revealed that cyto-histopathologic correlation and method of malignancy rate estimation could have an effect on a wide range of reported malignancy rates. Furthermore, patient/nodule dependent factors were not statistically found to be predictive of malignancy., Competing Interests: The authors have declared that no competing interests exist.

Introduction: DOG1 is a transmembrane protein originally "discovered on gastrointestinal stromal tumors," works as a calcium-activated chloride channel protein. There is a limited number of studies on the potential usage of this antibody in the diagnosis of salivary gland tumors on routine practice in cell blocks. The aim of this study was to search for the usefulness of K9 clone in oncocytic type tumors and review of the literature., Materials and Methods: Sixty-nine fine needle aspiration (FNA) cytologic materials of predominantly oncocytic morphology salivary gland tumors; acinic cell carcinoma (AciCC) (n = 8), adenoid cystic carcinoma (n = 2), pleomorphic adenoma (PA) (n = 22), Warthin tumor (WT) (n = 20), myoepithelioma (ME) (n = 5), benign oncocytoma (BeO) (n = 3), mucoepidermoid carcinoma (MEC) (n = 7), mammary analog salivary gland carcinoma (n = 2) were immunostained with DOG1 (clone K9) stain., Results: Of the 8 AciCCs, 7 were observed apical-luminal positive staining, demonstrating 1-3 + intensity, and involving 40-70% of the tumor cells. One MEC of 7 (14%), 1 ME of 5 (20%), and 4 PA of 22 (18%) showed weak (1+) cytoplasmic granular staining in 5-10% of the tumor cells. Pure oncocytic neoplasms (WT, BeO) showed no expression with DOG1-K9., Conclusions: FNA is a common tool in the diagnosis and management of salivary gland tumors. DOG1-K9 clone was very useful with a unique staining pattern of apical-luminal positivity in the differential diagnosis of AciCC from other oncocytic salivary gland tumors.

Micropapillary carcinoma (MPC) is a rare aggressive tumor, which generally accompanies the primary carcinoma of the organ of its origin, while the pure form is extremely uncommon. Angiolymphatic involvement is widespread and a considerable proportion of the cases present with metastases. The current study presents eight pure MPC cases arising from the breast (n=3), urinary bladder (n=3), parotid gland (n=1) and lung (n=1, presenting with pericardial effusion), with the cytological findings. The eight patients included three female and five male cases aged between 48 and 74 years. The most common cytological findings were three-dimensional aggregates, cell clusters with angulated or scalloped borders, single cells with a columnar configuration and eccentric nuclei, and high-grade nuclear features. Histopathological sections showed accompanying in situ ductal carcinoma in the cases of MPC arising in the parotid gland and breast (n=3), and one case in the bladder exhibited only in situ MPC. The average follow-up period was 20 months (range, 6-54 months) and, during this period, three patients succumbed to the disease. At present, four patients are alive with disease and one patient is alive and disease-free. In conclusion, cytology is an important tool for the diagnosis and management of MPC.

Background: Oncocytic follicular (OF) cells can be a prominent component of fine needle aspiration (FNA) specimens from neoplasms (adenomas and carcinomas) and nodules arising in multinodular goiter and chronic lymphocytic thyroiditis (CLT). Because OF cells can be present in non-neoplastic and neoplastic thyroid lesions it can be challenging to differentiate between these two in FNA specimens. The aims of this study were to determine the risk of malignancy in cases diagnosed as either oncocytic follicular neoplasm (OFN) or hyperplastic/adenomatoid nodule with OF on FNA and to identify clinicopathologic features that may help in predicting malignancy in such cases, especially the presence or absence of CLT., Design: We retrospectively searched the computerized laboratory information system at our institution between 1998 and 2009 for thyroid US guided FNA specimens in which the term "oncocytic/oncocytes" was mentioned in the final cytopathologic diagnosis. A total of 340 cases were selected for this study. The following data points were collected: Patient demographics, site of thyroid biopsy, size of lesion, FNA diagnosis, histopathologic follow-up and presence of CLT. Surgical pathology follow-up (SPFU) was available in 269 (79%) cases., Results: Two hundred and sixty patients were females and 80 males (average age 53 years). The lesion size was <3.0 cm in 241 (71%) and ≥ 3.0 cm in 99 (29%) cases. Cytologic diagnoses included: Follicular neoplasm with oncocytic features (FNOF) 321 and suggestive of FNOF 19 cases; a secondary cytologic diagnosis of CLT was made in 20 cases. SPFU was available in 269 (79%) cases; it was benign in 213 (213/267 = 79%) and malignant in 56 (56/269 = 21%) cases. The background thyroid showed CLT in 67 (25%) cases; 24% (48/196) neoplasms occurred with versus 76% (147/196) without CLT. The rate of malignancy was lower in nodules measuring less than 3.0 cm as compared to those equal or greater than 3.0 cm in size (17% vs. 28% respectively). The presence of CLT did not significantly alter the rate of malignancy in both FNA and surgical pathology specimens., Conclusions: Based on this study, nodule size and not CLT appears to be an important clinicopathologic features in the management of thyroid FNA specimens diagnosed as OFN.

Giant cell tumor, excluding its prototype in bone, is usually a benign but local aggressive neoplasm originating from tendon sheath or soft tissue. Malignant behavior is uncommon. Visceral organ involvement including urinary bladder is rare. Giant cell tumors in visceral organs usually accompany epithelial tumors and the clinical behavior of giant cell tumor in urinary bladder is similar to its bone counterpart. Here, we report two cases of giant cell tumor located in urinary bladder in comparison with nine reported cases in the English literature. Concurrent noninvasive urothelial carcinoma was also described in all these previous reports and only one patient with follow-up died of disease. One of the two cases we present had no concurrent urothelial tumor at the time of diagnosis but had a history of a low grade noninvasive urothelial carcinoma with three recurrences. The histology of these two cases was similar to the giant cell tumor of bone and composed of oval to spindle mononuclear cells with evenly spaced osteoclast-like giant cells. Immunohistochemically, the giant cells showed staining with osteoclastic markers including CD68, TRAP, and LCA. Immunohistochemical expression of vimentin, CD68, LCA, and smooth muscle actin in mononuclear cells supported a mesenchymal origin with histiocytic lineage. The histologic and immunohistochemical properties in our cases as well as their clinical courses were consistent with a giant cell tumor. Consequently, tumors in urinary bladder showing features of giant cell tumor of bone may also be considered and termed "giant cell tumor".