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Thyroid nodules are commonly faced by clinicians as palpable nodules or incidentally identified on imaging. Nodules that are found to be suspicious by imaging can be biopsied by fine needle aspiration, which can yield material for molecular testing to refine the diagnosis.The current literature concerning molecular testing in thyroid nodules including available commercial assays was reviewed and summarized.Commonly encountered alterations include mutations in RAS, BRAF, TERT promoter, PTEN, and DICER1 as well as fusions of RET, ALK, PAX8-PPARγ, and NTRK. This article provides a summary of these molecular alterations, commercially available molecular assays, and general considerations for thyroid epithelial malignancies and benign thyroid nodules.

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;AtrxKO genetically engineered mouse model (GEMM). To validate the impact of a different Cre-driver line, we used similar methodologies and characterised the Pdx1-Cre;AtrxKO (P.AtrxKO) 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.AtrxWT, P.AtrxHOM males were heavier during the entire study period, hyperglycaemic between 3 and 12 mo., and glucose intolerant only from 6 mo.; in contrast, P.AtrxHOM 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.

DICER1 protein is a member of the ribonuclease (RNAse) III family with a key role in the biogenesis of microRNAs (miRNA) and in microRNA processing, potentially affecting gene regulation at the post-transcriptional level. The role of DICER1 and its relevance to thyroid cellular processes and tumorigenesis have only recently been explored, following the acknowledgement that DICER1 germline and somatic changes can contribute not only to non-toxic multinodule goiter (MNG) lesions detected in individuals of affected families but also to a series of childhood tumours, including thyroid neoplasms, which can be identified from early infancy up until the decade of 40s. In a context of DICER1 germline gene mutation, thyroid lesions have recently been given importance, and they may represent either an index event within a syndromic context or the isolated event that may trigger a deeper and broader genomic analysis screening of individuals and their relatives, thereby preventing the consequences of a late diagnosis of malignancy. Within the syndromic context MNG is typically the most observed lesion. On the other hand, in a DICER1 somatic mutation context, malignant tumours are more common. In this review we describe the role of DICER protein, the genomic events that affect the DICER1 gene and their link to tumorigenesis as well as the frequency and pattern of benign and malignant thyroid lesions and the regulation of DICER1 within the thyroidal environment.

“Small-cell malignancies of thyroid” is an unsolved dilemma. This term represents an umbrella terminology in thyroid, encompassing for a small group of tumors in which some of them are well-recognized tumors like medullary thyroid carcinoma, poorly differentiated thyroid carcinoma, and primary thyroid lymphomas and teratoma, whereas the remaining are less known as primary neuroendocrine carcinoma of thyroid, primary extraskeletal Ewing family tumors, and adamantinoma-like Ewing sarcoma. When the issue comes to evaluate a cytological sample predominantly composed of small-cell morphology, metastatic small-cell carcinomas to thyroid also should be excluded. In this review, our group focused on the main cytomorphological and clinical clues of each entity that help to set up a correct differential diagnosis. The literature discussions were also included for the entities that are not yet recognized by the mother publication WHO. A key point of the issue’s simple algorithm based on FNAC with small-cell morphology of thyroid was suggested by the authors.

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.

The International Academy of Cytology has joined with the International Agency for Research on Cancer (IARC) to bring together a group of experts in lung cytopathology to develop a WHO Reporting System for Lung Cytopathology (WHO System). This WHO System defines five categories for reporting lung cytopathology, that is, “Insufficient”/“Inadequate”/“Non-diagnostic,” “Benign,” “Atypical,” “Suspicious for malignancy,” and “Malignant,” each with a clear descriptive term for the category, a definition, a risk of malignancy and a suggested management algorithm. The key diagnostic cytopathology features of each of the lesions within each category have been established by consensus and will be presented more fully in a subsequent IARC e-book and published hard cover book.The WHO System provides the best practice application of ancillary testing, including immunocytochemistry and molecular pathology, and provides a review to guide sampling and processing techniques to optimize the handling and preparation of the cytopathology sample emphasizing the cytomorphological differential diagnosis to aid low-resourced settings. The authors recognize that local medical and pathology resources will vary, particularly in low- and middle-income countries, and have developed the WHO System to make it applicable worldwide based on cytomorphology with options for further diagnostic management of the patient.The online WHO System provides a direct link to the WHO Tumour Classification for Thoracic Tumours 5th Edition. It will raise the profile and use of cytopathology by increasing awareness of its current role and its potential role in the era of personalized medicine based on molecular pathology utilizing “small biopsies.” Ultimately, the System will improve patient care and outcomes.This System aims to improve and standardize the reporting of cytopathology, facilitate communication between cytopathologists and clinicians and improve patient care. The System is based on the current role of lung cytopathology and synthesizes the existing evidence while highlighting areas requiring further research and the future potential role of lung cytopathology.

Introduction: Thyroid fine-needle aspiration (FNA) is a well-established technique in the cytology literature. Through the introduction of rapid stains in cytology practice, the ever-increasing utility of rapid on-site evaluation (ROSE) has strengthened the place of FNA as a primary diagnostic method in patient management. There are few stain variants available in the market for ROSE, namely Diff-Quik (DQ), Toluidine blue, and ultrafast Papanicolaou stains. Recently, our group developed a new staining variant labeled as original “BlueStain®” technique that was not previously tested in this context. Methods: 40 FNA thyroid cases were studied. At least two slides were prepared from each patient: one stained by DQ and the other by BlueStain®. Simultaneously, a ROSE diagnosis was performed as the two staining methods were compared, evaluating the parameters of background, cellularity, details of colloid presence, cell morphology, nuclear details, cytoplasmic details, and overall staining, scored on a scale from 1 to 3, representing poor, average, and good, respectively. Results: The quality index was slightly better for BlueStain® (53% vs. 47%) but not significantly different between the two stains. BlueStain® provides better details in both the presence and type of colloid as well as nuclear details, which are regarded as very important for diagnosis in thyroid cytology. There were eight cases with discordant diagnosis when compared between two stains from the same patient. In five cases of indeterminate cases, BlueStain® allows to bring them to the benign category, probably because this staining method allows a clear observation of the colloid in the background of the smears. However, since we are observing two different slides, we cannot rule out that these differences are a question of sample collecting and/or smearing. Conclusions: Our data demonstrates that BlueStain® is suitable to provide good-quality slides for primary assessments of thyroid aspirates studied by ROSE. In fact, in some aspects, this new staining method shows better preservation of colloid and cell details, revealing itself as an alternative to the DQ stain variant, upholding performance level while being 10 times cheaper and simpler because it requires just one step of staining.

This review presents an overview on molecular diagnostic in lung cancer using cytologic samples. Every patient with advanced non-small cell lung cancer (NSCLC) should be tested for targetable driver mutations and gene arrangements. If a mutation is found, this may open an option for targeted therapy. As most of the NSCLC patients in advanced stage of disease are no candidates for surgery, these tests have to be performed on small biopsies or cytology samples. The most common and treatable gene alterations should be tested in every patient: EGFR, ALK, ROS1. A growing number of other genetic changes with targetable mutations may become treatable in the near future. To find patients who might profit from inclusion into clinical studies, relevant additional markers may be tested in an appropriate context. Another important approach for treatment is immunotherapy of lung cancer, which is guided by status of PD-L1 expression on tumour cells. The use of cytology samples carries considerable advantages: often, DNA of high quality is extracted thus enabling easy and precise analysis, and samples may be easily obtained. In case of effusions, effusion fluid seldom is not aspirated for immediate patient relief, so no additional dedicated procedure is needed. Some challenges exist: If the tumour cell count is low, mutations with a low allelic frequency may be missed. In cellblocks formalin-induced DNA, damage may obviate any DNA analysis. In very cellular smears, FISH may be impossible due to massive overlapping of nuclei. Autofluorescence may impede FISH analysis. Although there is no real universal test for genomic profiling for lung cancer, the pathology laboratory must be prepared to offer different assays on different specimens in order to address turnaround time and optimise detections of difficult tumour alterations such as gene fusions. The data from the literature demonstrate that cytology show consistent results, and it is a good alternative for lung cancer molecular testing.

Dynamin-related protein 1 (DRP1), a mitochondrial fission protein, and its active form phosphorylated at Serine 616 (S616-p-DRP1) have been increasingly associated with tumorigenesis and invasion in various tumor models, including oncocytic thyroid cancer (TC). In this study, the expression of DRP1 and S616-p-DRP1 and its relationship with patients’ clinicopathological characteristics, tumor genetic profiles, and clinical outcomes were assessed in a large series of follicular cell-derived TC (FCDTC). Retrospective biomarker study characterizing the clinicopathological and immunochemistry DRP1 and S616-p-DRP1 expression of a series of 259 patients with FCDTC followed in two University Hospitals. DRP1 expression was positive in 65.3% (169/259) of the cases, while the expression of the S616-p-DRP1 was positive in only 17.3% (17/98). DRP1-positive expression was significantly associated with differentiated tumors (67.7 vs. 48.0%; P = 0.049), non-encapsulated tumors (73.8 vs. 57.4%; P = 0.011) and thyroid capsule invasion (73.4 vs. 57.5%; P = 0.013). S616-p-DRP1-positive expression was significantly associated with tumor infiltrative margins (88.9 vs. 11.1%; P = 0.033), thyroid capsule invasion (29.8 vs. 3.1%; P = 0.043), lymph node metastases (23.3 vs. 8.1%; P = 0.012), and higher mean cumulative radioiodine dosage (317.4 ± 265.0 mCi vs. 202.5 ± 217.7 mCi; P = 0.038). S616-p-DRP1 expression was negatively associated with oncocytic phenotype (0.0 vs. 26.2%; P = 0.028). S616-p-DRP1 is a better candidate than DRP1 to identify tumors with locally invasive behavior. Prospective studies should be pursued to assess S616-p-DRP1 role as a molecular marker of malignancy in TC and in patients’ risk assessment.

BACKGROUND: To the authors' knowledge, the impact of the coronavirus disease 2019 (COVID-19) pandemic on cytopathology practices worldwide has not been investigated formally. In the current study, data from 41 respondents from 23 countries were reported. METHODS: Data regarding the activity of each cytopathology laboratory during 4 weeks of COVID-19 lockdown were collected and compared with those obtained during the corresponding period in 2019. The overall number and percentage of exfoliative and fine-needle aspiration cytology samples from each anatomic site were recorded. Differences in the malignancy and suspicious rates between the 2 periods were analyzed using a meta-analytical approach. RESULTS: Overall, the sample volume was lower compared with 2019 (104,319 samples vs 190,225 samples), with an average volume reduction of 45.3% (range, 0.1%-98.0%). The percentage of samples from the cervicovaginal tract, thyroid, and anorectal region was significantly reduced (P < .05). Conversely, the percentage of samples from the urinary tract, serous cavities, breast, lymph nodes, respiratory tract, salivary glands, central nervous system, gastrointestinal tract, pancreas, liver, and biliary tract increased (P < .05). An overall increase of 5.56% (95% CI, 3.77%-7.35%) in the malignancy rate in nongynecological samples during the COVID-19 pandemic was observed. When the suspicious category was included, the overall increase was 6.95% (95% CI, 4.63%-9.27%). CONCLUSIONS: The COVID-19 pandemic resulted in a drastic reduction in the total number of cytology specimens regardless of anatomic site or specimen type. The rate of malignancy increased, reflecting the prioritization of patients with cancer who were considered to be at high risk. Prospective monitoring of the effect of delays in access to health services during the lockdown period is warranted. ispartof: CANCER CYTOPATHOLOGY vol:128 issue:12 pages:885-894 ispartof: location:United States status: published

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. Through FCT – Fundação para a Ciência e a Tecnologia – in the framework of a PhD grant to SC (SFRH/ BD/147650/2019).

In June 2019, a lung symposium was held at the 42nd European Congress of Cytology in Malmö, Sweden. Due to the current importance of cytological samples in the diagnoses and molecular analysis to set up the utmost management of lung cancer patients, cytologists from different countries shared the experience of their institutions. The place of the cytological samples gains more and more importance on the potential long-term survival gain through personalized medicine and this harbors the improvement of the guidelines both in pathology and cytology field. In this symposium, the new 6-tiered reporting system for pulmonary cytology proposed by the Papanicolaou Society of Cytopathology and detailed cytomorphological approach to lung carcinoma including lookalike lesions and DNA- and RNA-based analysis of cytology material have been discussed. The cytopathologist plays a pivotal role in ensuring success of a correct triage for the cytology material to be sure of the adequacy and quality of the yield from the rapid on-site evaluation till the report which should encompass molecular profile in rational patient management.

Background: In a previous worldwide survey, the authors showed a drastic reduction in the number of cytological specimens processed during the coronavirus disease 2019 “lockdown” period along with an increase in malignancy rates. To assess the continued impact of the pandemic on cytological practices around the world, they undertook a second follow-up worldwide survey collecting data from the post-lockdown period (2020). Methods: Participants were asked to provide data regarding their cytopathology activity during the first 12 weeks of their respective national post-lockdown period (2020), which ranged from April 4 to October 31. Differences between the post-lockdown period and the corresponding 2019 period were evaluated, and the authors specifically focused on rates of malignant diagnoses. Results: A total of 29 respondents from 17 countries worldwide joined the survey. Overall, a lower number of cytological specimens (n = 236,352) were processed in comparison with the same period in 2019 (n = 321,466) for a relative reduction of 26.5%. The overall malignancy rate showed a statistically significant increase (12,442 [5.26%] vs 12,882 [4.01%]; P

Background: Thyroid cancer accounts for 1% of cancer cases in developed countries, in which papillary thyroid carcinoma (PTC) is the most common type. There are multiple variants of PTC described to date, some of them with aggressive behavior and poor clinical outcome. These variants are well described and accepted in recent guidelines of many international societies, and the prognostic and management implications are well laid out. Due to their established clinical importance and to guide appropriate surgical management, it is now imperative in clinical practice, including cytopathology, to differentiate aggressive variants from nonaggressive ones. This review aims to describe the variants of PTC and to provide a practical algorithmic approach to facilitate the cytological diagnosis of these variants. Summary: Subtyping PTC variants on fine needle aspiration cytology (FNAC) is challenging even for the most experienced cytopathologist. To facilitate a correct subtyping on FNAC, we propose a stepwise approach that is mainly designed for conventional smear methodology. This approach requires first to stratify the lesions into oncocytic and nononcocytic features before analyzing further details in cell morphology and pattern. Key Messages: (1) Subtyping in PTC is possible on cytopathology. (2) The main aim of the cytopathologist is to differentiate aggressive from nonaggressive variants. (3) The subtyping of PTC can help in the surgical management of the patients.

The recent update of the 4th edition of the World Health Organization's Classification of Tumors of Endocrine Organs introduced important changes in the nomenclature of follicular-cell thyroid tumors, namely, regarding mitochondrion-rich neoplasms (In this review, for the practical purposes, the words Hurthle and oncocytic are synonymous in the field of thyroid pathology.) According to the last edition, oncocytic thyroid neoplasms, with follicular architecture and no typical nuclei of papillary carcinoma, – are now included in a separate group - the Hurthle cell neoplasms. Whenever thus categorized-while keeping oncocytic variant of papillary, medullary and poorly differentiated carcinoma-, a sort of tidal phenomenon has occurred about oncocytic tumors known for decades. Through this categorization, pathologists and researchers need to progress in the discussion about etiopathogenesis of oncocytic neoplasms (ONs). This review provides an attempt to balance the facts and doubts by questioning the recent changes based on what is known about oncocytic tumors.

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.

This review presents an overview on molecular diagnostic in lung cancer using cytologic samples. Every patient with advanced non-small cell lung cancer (NSCLC) should be tested for targetable driver mutations and gene arrangements. If a mutation is found, this may open an option for targeted therapy. As most of the NSCLC patients in advanced stage of disease are no candidates for surgery, these tests have to be performed on small biopsies or cytology samples. The most common and treatable gene alterations should be tested in every patient: EGFR, ALK, ROS1. A growing number of other genetic changes with targetable mutations may become treatable in the near future. To find patients who might profit from inclusion into clinical studies, relevant additional markers may be tested in an appropriate context. Another important approach for treatment is immunotherapy of lung cancer, which is guided by status of PD-L1 expression on tumour cells. The use of cytology samples carries considerable advantages: often, DNA of high quality is extracted thus enabling easy and precise analysis, and samples may be easily obtained. In case of effusions, effusion fluid seldom is not aspirated for immediate patient relief, so no additional dedicated procedure is needed. Some challenges exist: If the tumour cell count is low, mutations with a low allelic frequency may be missed. In cellblocks formalin-induced DNA, damage may obviate any DNA analysis. In very cellular smears, FISH may be impossible due to massive overlapping of nuclei. Autofluorescence may impede FISH analysis. Although there is no real universal test for genomic profiling for lung cancer, the pathology laboratory must be prepared to offer different assays on different specimens in order to address turnaround time and optimise detections of difficult tumour alterations such as gene fusions. The data from the literature demonstrate that cytology show consistent results, and it is a good alternative for lung cancer molecular testing.

Dynamin-related protein 1 (DRP1), a mitochondrial fission protein, and its active form phosphorylated at Serine 616 (S616-p-DRP1) have been increasingly associated with tumorigenesis and invasion in various tumor models, including oncocytic thyroid cancer (TC). In this study, the expression of DRP1 and S616-p-DRP1 and its relationship with patients' clinicopathological characteristics, tumor genetic profiles, and clinical outcomes were assessed in a large series of follicular cell-derived TC (FCDTC).Retrospective biomarker study characterizing the clinicopathological and immunochemistry DRP1 and S616-p-DRP1 expression of a series of 259 patients with FCDTC followed in two University Hospitals.DRP1 expression was positive in 65.3% (169/259) of the cases, while the expression of the S616-p-DRP1 was positive in only 17.3% (17/98). DRP1-positive expression was significantly associated with differentiated tumors (67.7 vs. 48.0%; P = 0.049), non-encapsulated tumors (73.8 vs. 57.4%; P = 0.011) and thyroid capsule invasion (73.4 vs. 57.5%; P = 0.013). S616-p-DRP1-positive expression was significantly associated with tumor infiltrative margins (88.9 vs. 11.1%; P = 0.033), thyroid capsule invasion (29.8 vs. 3.1%; P = 0.043), lymph node metastases (23.3 vs. 8.1%; P = 0.012), and higher mean cumulative radioiodine dosage (317.4 ± 265.0 mCi vs. 202.5 ± 217.7 mCi; P = 0.038). S616-p-DRP1 expression was negatively associated with oncocytic phenotype (0.0 vs. 26.2%; P = 0.028).S616-p-DRP1 is a better candidate than DRP1 to identify tumors with locally invasive behavior. Prospective studies should be pursued to assess S616-p-DRP1 role as a molecular marker of malignancy in TC and in patients' risk assessment.

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. FEEI (Fundos Europeus Estruturais e de Investimento), FEDER (Fundo Europeu de Desenvolvimento Regional) funds through the COMPETE 2020, Operational Programme for Competitiveness and Internationalisation (POCI), Portugal 2020, and by Portuguese funds through FCT (Fundação para a Ciência e a Tecnologia), in the framework of the project: Predicting patient’s response to liposomal anticancer drugs: focusing on LRP1B endocytic activity—PTDC/MEC-ONC/31520/2017. Further funding by the European Regional Development Fund (ERDF) through the Operational Programme for Competitiveness and Internationalization (COMPETE) 2020, and Portuguese national funds via FCT, under the project “POCI-01-0145-FEDER-016390: CANCEL STEM”.

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 presence of TERT promoter (TERTp) 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 TERTp mutations and TERT mRNA expression in these settings. In this series, TERTp 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. TERTp 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. This study was supported by FCT, the Portuguese Foundation for Science and Technology through a PhD grant to AP SFRH/BD/110617/2015 and RB SFRH/BD/111321/2015. This work was financed by FEDER—Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020—Operacional Programme for Competitiveness and Internationalization (POCI), Portugal 2020, and by Portuguese funds through FCT-Fundação para a Ciência e a Tecnologia/Ministério da Ciência, Tecnologia e Inovação in the framework of the project “Institute for Research and Innovation in Health Sciences” (POCI-01-0145-FEDER-007274). Additional funding by the European Regional Development Fund (ERDF) through the Operational Programme for Competitiveness and Internationalization—COMPETE2020, and Portuguese national funds via FCT, under project POCI-01-0145-FEDER-016390: CANCEL STEM and from the FCT, under the project POCI-01-0145-FEDER-031438: The other faces of telomerase: Looking beyond tumour immortalization (PDTC/MED_ONC/31438/2017).

The presence of TERT promoter (TERTp) 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 TERTp mutations and TERT mRNA expression in these settings. In this series, TERTp 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. TERTp 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.

BACKGROUND Recently a new system for reporting salivary gland fine-needle aspiration (FNA) cytology was proposed, the Milan System for Reporting Salivary Gland Cytopathology (MSRSGC). Herein, we evaluated diagnostic accuracy of salivary gland FNA, comparing the system previously used in our hospital with the Milan system. METHODS Salivary gland specimens obtained between 2011 and 2017 were reclassified according to MSRSGC. Risk of malignancy for each diagnostic category was determined. Diagnostic yield of both classifications was evaluated. RESULTS The cases (n = 388) were classified according to the old system: nondiagnostic (n = 28), benign (n = 246), atypical (n = 36), neoplastic (n = 57), suspicious for malignancy (n = 7) and malignant (n = 14). The lesions were distributed according to the MSRSGC: nondiagnostic (n = 28), non-neoplastic (n = 89), atypia of undetermined significance (n = 39), benign neoplasm (n = 156), neoplasm of uncertain malignant potential (n = 55), suspicious for malignancy (n = 7) and malignant (n = 14). When considering only benign and malignant cases, both classifications showed the same sensitivity (62.5%), specificity (100%) and similar accuracy (95.8%). Comparison between the two systems showed no significant difference. CONCLUSIONS Salivary gland FNA has high diagnostic accuracy and assists clinical management independently of the reporting system used, however, in some cases, the use of Milan system could be beneficial, since it allows an enhanced category stratification.

Fine-needle aspiration (FNA) plays a key role in the early evaluation of patients with thyroid nodules; however, from 15% to 30% of FNA specimens are cytologically indeterminate. Molecular testing has proven useful when applied to indeterminate thyroid FNAs, and its use has been endorsed in the American Thyroid Association guidelines. In addition to the noncommercial ("in-house") application of v-Raf murine sarcoma viral oncogene homolog B1 (BRAF), rat sarcoma (RAS), rearranged in transformation/papillary thyroid carcinoma (RET/PTC), and peroxisome proliferator-activated receptor γ/paired box gene 8 (PPARγ/PAX8) testing, there are currently 3 commercially available molecular panels that vary in their relative reported performances, strengths, and limitations. Here, we discuss the role of molecular testing for indeterminate thyroid aspirates, taking into consideration the recent reclassification of the encapsulated follicular variant of papillary thyroid carcinoma (PTC) as "noninvasive follicular neoplasm with papillary-like nuclear features (NIFTP)." Cancer Cytopathol 2017;125(6 suppl):477-85. © 2017 American Cancer Society.

BACKGROUND The columnar cell variant of papillary thyroid carcinoma (PTC-CCV) is a rare entity that demonstrates a more aggressive clinical course compared with the more common subtypes of PTC. On histology, it is defined by papillae or gland-like structures lined by columnar cells displaying prominent nuclear stratification. Because to the authors' knowledge no characteristic cytomorphological features have been identified to date and typical features of PTC often are absent on cytology, the diagnosis of PTC-CCV by fine-needle aspiration (FNA) is challenging. This prompted the authors to evaluate a series of PTC-CCV cases to identify features that could facilitate its diagnosis by FNA. METHODS A total of 11 surgical specimens of PTC-CCV with corresponding preoperative cytology were identified over a 21-year period. The cytological features of the aspirated specimens, consisting mostly of Papanicolaou and Diff-Quick smears, were evaluated retrospectively. RESULTS All cases demonstrated the presence of papillary structures. The most important features observed in PTC-CCV FNA specimens were hypercellularity with nuclear superposition and a paucity of nuclear pseudoinclusions and grooves. CONCLUSIONS Although PTC-CCV may demonstrate features that overlap with those of the classic variant of PTC, hypercellular smears with papillary structures covered by cells with pseudostratified nuclei that show a paucity of nuclear pseudoinclusions and grooves should alert the cytopathologist to the possibility of this diagnosis. Cancer Cytopathol 2017. © 2017 American Cancer Society.

Background Fine needle aspiration (FNA) is commonly used for the preoperative evaluation of salivary gland tumors. Tumor grade is a key factor influencing clinical management of salivary gland carcinomas (SGCs). To assess the ability to grade nonbasaloid SGCs in FNA specimens, an international panel of cytopathologists convened to review and score SGC cases. Methods The study cohort included 61 cases of primary SGC from the pathology archives of 3 tertiary medical centers. Cases from 2005 to 2016 were selected, scanned, and digitized. Nineteen cytopathologists blinded to the histologic diagnosis reviewed the digitized cytology slides and graded them as low, high, or indeterminate. The panelists' results were then compared to the tumor grades based on histopathologic examination of the corresponding resection specimens. Results All but 2 of the 19 (89.5%) expert panelists review more than 20 salivary gland FNAs per year; 16 (84.2%) of the panelists work at academic medical centers, and 13 (68.4%) have more than 10 years' experience. Participants had an overall accuracy of 89.4% in the grading of SGC cases, with 90.2% and 88.3% for low- and high-grade SGC, respectively. Acinic cell carcinoma and mucoepidermoid carcinoma had the highest degree of accuracy, while epithelial-myoepithelial carcinoma and salivary duct carcinoma had the lowest degree of accuracy. As expected, the intermediate-grade SGC cases showed the greatest variability (high-grade, 42.1%; low-grade, 37.5%, indeterminate, 20.4%). Conclusion This study confirms the high accuracy of cytomorphologic grading of primary SGC by FNA as low- or high-grade. However, caution should be exercised when a grade cannot be confidently assigned.

Organotin compounds, such as tributyltin (TBT), are common environmental contaminants and suspected endocrine-disrupting chemicals. Tributyltin is found in antifouling paints, widely used in ships and other vessels. The present study evaluated whether a 15-day treatment with TBT at a dose of 100 ng/kg/day could induce histomorphological changes in the thyroid gland of rats. TBT promoted relevant alterations in the thyroid architecture, being the most relevant histological findings the presence of increased number of small-size follicles in the treated group. In qualitative analyses, colloid vacuolization, papillary budging structures, cystic degeneration and chronic thyroiditis, were observed. Moreover, histomorphometric analysis showed statistically significant changes in the follicular architecture of TBT-treated rats, mainly a decrease in the follicle area (colloid) and an increased epithelial height that resulted in an increased epithelial height/colloid ratio. Augmented collagen deposition was also seen in the thyroids of treated groups. In immunohistochemical (IHC) analyses, the localization of NIS protein was described and a significant increased proliferation index (evaluated by Ki67 positive cells) in the treated group was reported. As an indirect measurement of oxidative stress, mitochondrial protein SDHA was also analyzed by IHC analysis. Although the cytoplasmic expression of SDHA was observed in both groups, the staining intensity score was higher in TBT-treated group. Our results suggest that besides causing histomorphological changes, environmental relevant dose of TBT treatment can also induce oxidative alterations.

Introduction: The Acibadem Health Group (AHG) has been using telepathology/digital pathology stations since 2006. In 2013, the system was changed from videoconferencing to digital pathology (whole-slide imaging) utilizing 3DHISTECH scanners and software. In 2017, digital cytology started to be used for routine cytopathologic diagnosis for thyroid fine-needle aspiration (FNA) cases. Material and Methods: Two hundred and twenty-seven thyroid cases were received for analysis using telecytology (TC) during the period from November 2017 to May 2018. Rapid on-site evaluation was performed at the Atakent Hospital of the AHG by a cytotechnologist and scanned on the same day. For every case, there were Diff-Quik- and Papanicolaou-stained FNA smears. Each glass slide was digitized with a 3DHISTECH whole-slide scanner in 1 focal Z-plane at ×40 magnification. Results: Two hundred and twenty-seven thyroid FNA specimens were retrieved, of which 25 had histologic follow-up. Samples were classified as nondiagnostic in 3%, benign in 74%, atypia of undetermined significance/follicular lesion of undetermined significance in 13%, suspicious for follicular neoplasia/follicular neoplasia in 3%, suspicious for malignancy in 4%, and malignant in 3%. When only the “suspicious for malignancy” and “malignancy” categories were considered positive tests, cytology sensitivity and specificity using TC for diagnosis was 100%. Conclusions: Our data demonstrate that TC is suitable to provide a primary diagnosis in daily routine cytology practice. Despite the promising results, there were some challenges stemming from the novelty of using TC for the primary diagnosis. The study also addresses both advantages and disadvantages of TC in daily practice to increase the efficiency of the technique in primary diagnosis.

WOS: 000470851300023 PubMed ID: 31169225 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%u50%. 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 (SUVmax) 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 SUVmax. Results: The median SUVmax values were 5.4 for thyroid nodules. Totally, 14 malignancies were detected by FNAB (35%).The sensitivity and specificity of SUVmax 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 SUVmax was the higher in colon cancer thyroid metastasis and oncocytic neoplasia (SUVmax 14.5 and 13.6, respectively). Histopathological type was not related with nodule size but positively associated with categorical SUVmax(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.

Fibromuscular dysplasia is rarely biopsied. Progesterone receptor expression in myofibroblastic cells is useful for the histopathological evaluation in difficult-to-diagnose cases. Herein, we report two unusual cases of fibromuscular dysplasia in which progesterone receptor expression was shown in vessel sections.

Thyroid cancer has increased more than any other malignancy including cervix uteri, breast, colon, and prostate cancer. In those, papillary thyroid carcinoma is the most common thyroid malignancy, and the number of variants of papillary carcinoma has increased compared to the past decades. Some of them has been proved with the poor clinical outcome that defined aggressive variants and already has been placed in the recent manifestos of many international societies with the comprehensive therapy managements. For those practicing cytology, it is now a necessity to differentiate aggressive variants from non-aggressive ones in the name of providing appropriate surgery. This chapter aims to emphasize and make a practical cytomorphological and pathological summary of the variants based on an algorithmic approach.

Background: The encapsulated follicular variant (EFV) of papillary thyroid carcinoma (PTC) is the most discussed entity in thyroid pathology. Recently, the question of whether or not EFV-PTC is a malignant entity has been the subject of renewed discussion in the light of recent molecular and clinical studies. The aim of this study was to analyze the malignancy ratios of each category of the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) if EFV-PTC is no longer considered as a malignant entity. Materials and Methods: Data on thyroid fine-needle aspirations (n = 1,886) with surgical follow-up between 1999 and 2014 were studied. EFV-PTC cases constituted 27% (94/343) of the malignant cases. Results: Malignancy ratios were determined as nondiagnostic, benign, atypia/follicular lesion of undetermined significance, suspicious for follicular neoplasm/follicular neoplasm, suspicious for malignancy, and malignant categories of the TBSRTC in 13, 7, 45, 30, 72 and 98%, respectively. If EFV-PTC was not regarded as malignant, malignancy ratios would decrease to 6.5, 6, 30, 10, 48, and 87% for each category in the same order. Conclusions: The current study showed that the most significant decrease in relative malignancy ratios was seen in the suspicious for follicular neoplasm/follicular neoplasm category (66% relative decrease), but all categories represented a considerable decrease.