Cell block practices in European cytopathology laboratories.

BACKGROUND: There are numerous methods and procedures described for the preparation of cell blocks (CBs) from cytological samples. The objective of this study was to determine current practices and issues with CBs in European laboratories. METHODS: A link to an online survey, with 11 questions about CB practices, was distributed to cytology laboratories via participants of United Kingdom National External Quality Assurance Service for Cellular Pathology Techniques and national representatives in the European Federation of Cytology Societies. RESULTS: A total of 402 laboratories responded completely (337/402, 84%) or partially (65/402, 16%) to the survey by February 4, 2022. The most common CB practice is embedding cell pellets using plasma and thrombin (23.3%), agar (17.1%), Shandon/Epredia Cytoblock (11.4%), HistoGel (7.9%), and Cellient (3.5%). Other methods such as CytoFoam, albumin, gelatin, Cytomatrix, and collodion bags are rarely used (1.0%, 0.7%, 0.7%, 0.3%, and 0.2%, respectively). CBs are also prepared from naturally occurring clots or tissue fragments (29.5%) and cells scraped from unstained or prestained smears (4.4%). The most frequent issues with the CBs in a daily cytology practice are low cellularity (248/402, 62%) and dispersed cells (89/402, 22%), regardless of the CBs preparation method or how the samples for embedding were selected. CONCLUSIONS: There is a great variability in CB practices in European laboratories with low cellular CBs as the main issue. Additional studies are mandatory to evaluate and improve performance and cellular yield of CBs.

Impact of the 3rd Edition of the Bethesda System for Reporting Thyroid Cytopathology on Grey Zone Categories.

INTRODUCTION: Thyroid Bethesda Reporting System is a six-tiered system that aims to bring uniformity in reporting thyroid cytology and improve the communication with clinicians. The system has achieved its goal as a presurgical diagnostic method; however, it remains a screening method in the grey zone categories, namely atypia of undetermined significance (AUS) and follicular neoplasm (FN). The book recently released the 3rd edition, following the recent changes in thyroid pathology. One of the most important novelties is subgrouping AUS category and FN to be able to make a better risk stratification in these categories. Our group aims to retrospectively analyze a large dataset based on the new TBSRTC, with a focus on the grey zone categories. METHODS: Only patients who underwent lobectomy or total thyroidectomy were included, allowing for direct comparison between cytological and histopathological results. Cytological evaluations, based on the TBSRTC 3rd edition, were methodically compared with their respective histopathological results, enabling a comprehensive analysis. RESULTS: Of the 244 patients (female:male ratio = 8.8:1, mean age = 56), a total of 252 nodules were evaluated. A distinction was noted with 79 nodules (31%) diagnosed as AUS and 173 nodules (69%) as FN. Intriguingly, the risk of malignancy (ROM) for AUS-overall stood at 44.3%, with AUS-nuclear atypia at 50% and AUS-other at 43.2%. Although the AUS subdivisions did not demonstrate statistical significance, a significant disparity was observed in their distribution, with 15% as AUS-nuclear atypia compared to 85% as AUS-other. This disparity raises the question: Could AUS-other be considered the new waste-basket category in the TBSRTC 3rd edition? Using the TBSRTC 3rd edition as a base, we added a subclassification for FN nodules based on the presence or absence of papillary thyroid carcinoma (PTC) nuclear features. Our findings showed that differentiating FN with oncocytic characteristics correlated well with histological outcomes and ROMs. Though retrospective in design with inherent bias potential, our data suggest a possible improvement in PTC case segregation in the FN category when differentiating between FN nodules with and without PTC nuclear features. CONCLUSION: Our retrospective study sheds light on the potential advantages of the TBSRTC 3rd edition, particularly in refining the AUS and FN categories for thyroid nodules. The clear disparity in AUS subcategories raises important questions about their classification and potential future refinements. Moreover, the differentiation of FN nodules based on PTC nuclear features holds a promising approach for better risk stratification.

Delphi expert consensus for whole slide imaging in thyroid cytopathology.

OBJECTIVE: Despite an increase in thyroid fine needle aspiration (FNA) and advances in whole slide imaging (WSI) adoption, digital pathology is still considered inadequate for primary diagnosis of these cases. Herein, we aim to validate the utility of WSI in thyroid FNAs employing the Delphi method strategy. METHODS: A panel of experts from seven reference cytology centres was recruited. The study consisted of two consecutive rounds: (1) an open-ended, free-response questionnaire generating a list of survey items; and (2) a consensus analysis of 80 selected shared WSIs from 80 cases by six investigators answering six morphological questions utilising a 1 to 5 Likert scale. RESULTS: High consensus was achieved for all parameters, with an overall average score of 4.27. The broad majority of items (84%) were ranked either 4 or 5 by each physician. Two badly scanned cases were responsible for more than half of the low-ranked (≤2) values (57%). Good to excellent (≥3) diagnostic confidence was reached in more than 95.2% of cases. For most cases (78%) WSI assessment was not limited by technical issues linked to the image acquisition process. CONCLUSION: This systematic Delphi study indicates broad consensus among participating physicians on the application of DP to thyroid cytopathology, supporting expert opinion that WSI is reliable and safe for primary diagnostic purposes.

Current picture of anaplastic thyroid cancer patients' care and meetable needs: A survey of 94 Institutions from the EORTC Endocrine and Head and Neck Cancer Groups.

Anaplastic thyroid carcinoma (ATC) is a rare cancer accounting for 40% of thyroid cancer-specific deaths. In the last 5 years, improved insights into molecular pathways led the Food and Drug Administration to license BRAF/MEK inhibitors (B/Mi) in BRAFV600E-mutant ATC, and pembrolizumab in solid cancer with high tumour mutational burden (TMB-H) (≥10 mutations/megabase) (mut/Mb). In Europe, clinicians face challenges in prescribing novel treatments, as the European Medical Association (EMA) has not licensed B/Mi nor immunotherapy (IO) for ATC so far. Some patients manage to receive these drugs through alternative ways. We investigated the extent of this phenomenon launching an online survey from March 12th to 19th 2021 open to 239 Institutions in the EORTC Endocrine and Head & Neck Cancer Groups. Questions enquired about the number of ATC patients evaluated/year, feasibility of BRAF assessment, accessibility to B/Mi-IO, availability of clinical trials and interest in new studies. Colleagues from 94 Institutions (20 Countries) joined: 30 centres evaluated ≥5 ATC patients/year, with an overall incidence >200 patients/year. 80.8% tested BRAF status, 43.6% by next-generation sequencing. 62.7% and 70% of responders reported limitations in prescribing B/Mi and IO, respectively: either the impossibility of offering them, or drugs accessibility exclusively under certain conditions (e.g. health insurance, clinical trials, compassionate use, off-label). Only 13.8% had clinical trials ongoing while 91.5% of sites claimed ATC-dedicated trials. Disparities in access to novel treatments are diffuse. Access to cutting-edge therapies is an urgent issue in this setting, and clinical trials seem feasible within an appropriate network.

Position paper from the Endocrine Task Force of the European Organisation for Research and Treatment of Cancer (EORTC) on the management and shared decision making in patients with low-risk micro papillary thyroid carcinoma.

The incidence of differentiated thyroid cancer (DTC) has been increasing worldwide, mostly, as an increase in the incidental detection of micro papillary thyroid carcinomas (microPTCs), many of which are potentially overtreated, as suggested by the unchanged mortality. Several international guidelines have suggested a less aggressive approach. More recently, it has been shown that active surveillance or minimally invasive treatments (MIT) are good alternatives for the management of these patients. In this context, patient participation in the decision-making process is paramount. The Endocrine Task Force of the European Organisation for Research and Treatment of Cancer (EORTC) has undertaken the task to establish consensus and define its position based on the scientific evidence concerning, 1) the current state of diagnostic and management options in microPTCs, including the current opinion of physicians about shared decision making (SDM), 2) the available evidence concerning patients' needs and the available decision instruments, and 3) to provide practical suggestions for implementation of SDM in this context. To improve SDM and patients' participation, knowledge gaps and research directions were highlighted.

Inter- and intraobserver agreement in whole-slide digital ThinPrep samples of low-grade squamous lesions of the cervix uteri with known high-risk HPV status: A multicentric international study.

BACKGROUND: High-risk human papilloma virus (HR HPV) testing and liquid-based cytology are used for primary cervical screening. Digital cytology, based on whole-slide scanned samples, is a promising technique for teaching and diagnostic purposes. The aim of our study was to evaluate the interobserver and intraobserver variation in low-grade squamous lesions, HR HPV status bias, and the use of whole-slide scanned digital cervical cytology slides. METHODS: Fifteen expert cytopathologists evaluated 71 digitalized ThinPrep slides (31 atypical squamous cells of undetermined significance [ASC-US], 21 negative for intraepithelial lesion or malignancy, and 19 low-grade squamous intraepithelial lesion cases). HR HPV data were accessible only in the second round. RESULTS: In interobserver analysis, Kendall's coefficient of concordance was 0.52 in the first round and 0.58 in the second round. Fleiss' kappa values were 0.29 in the first round and 0.31 in the second round. In the ASC-US category, Fleiss kappa increased from 0.19 to 0.22 in the second round and the increase was even higher expressed by Kendall's coefficient: from 0.42 to 0.52. In intraobserver analysis, personal scores were higher in the second round. CONCLUSIONS: The interobserver and intraobserver variability in low-grade squamous lesions was within fair agreement values in the present study, in line with previous works. The comparison of two rounds showed that expert cytopathologists are generally unbiased by the knowledge of HR HPV data, but that being informed of the HR HPV status leads to a better agreement. Stain quality and back discomfort were highlighted as factors affecting digital cytopathology use.

Performance of the Bethesda System for Reporting Thyroid Cytology in Multi-Institutional Large Cohort of Pediatric Thyroid Nodules: A Detailed Analysis.

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.

Small-Cell Malignancies of Thyroid: Challenge Solved?

"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.

COVID-19 pandemic impact on cytopathology practice in the post-lockdown period: An international, multicenter study.

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 < .001) during the same time period. Similar results were obtained if both malignancy and suspicious for malignancy rates were considered together (15,759 [6.58%] vs 16,011 [4.98%]; P < .001). CONCLUSIONS: The data showed a persistent reduction in the cytological specimen volume during the post-lockdown period (2020). However, the relative increase in the cytological workload in the late part of the post-lockdown is a promising finding of a slow return to normality.

Papillary Thyroid Carcinoma with Desmoid-Type Fibromatosis: Review of Published Cases.

Desmoid-type fibromatosis (DTF) is a very rare variant of papillary thyroid carcinoma (PTC). It is essentially a dual tumor with a component of classical PTC with malignant epithelial proliferation (BRAF-mutated) and another component of mesenchymal proliferation (CTNNB1-mutated). We conducted a literature review on PTC-DTF. In total, 31 articles were identified, that together reported on 54 patients. The mean age was 47 years, with a 2.2:1 female predominance. No ultrasound features were found to be helpful in differentiating PTC-DTF from other PTC variants. Of the 43 cases that reported histological details, 60% had locally infiltrative disease (T3b or T4). Around 48% had cervical lymph node metastases, but none had distant metastases. While PTC-DTF may be locally more aggressive than classic PTC, its overall behavior is similar and can include extrathyroidal extension and lymph node metastases, which may contain a stromal component and show extranodal invasion. The mainstay of treatment for PTC-DTF is surgery, and the DTF component is not expected to be sensitive to radioactive iodine. External radiotherapy, non-steroidal anti-inflammatory drugs, tyrosine kinase inhibitors and chemotherapy have also been used in selected cases. Due to the rarity of these tumors and the lack of specific treatment guidelines, management should be discussed in a multidisciplinary team.

Denosumab for the Treatment of Hypercalcemia in a Patient With Parathyroid Carcinoma: A Case Report.

Background: Refractory hypercalcemia is one of the major complications of parathyroid carcinoma. Case report: An 84-year old female patient presented with an acute confusional state due to hypercalcemia. This led to the diagnosis of primary hyperparathyroidism for which she underwent surgery. The initial histological diagnosis was interpreted as atypical parathyroid adenoma; the resection was microscopically incomplete. One year later, the patient presented with elevated calcium levels up to 3.89 mmol/l. Recurrent severe hypercalcemia required multiple hospitalizations. Review of the histology slides revealed that the initially resected lesion was in fact a parathyroid carcinoma. Treatment with the calcimimetic drug cinacalcet was poorly tolerated. Repeated administration of zoledronic acid only had transient effects on calcium levels, and bisphosphonate treatment was ultimately discontinued because of chronic renal failure. The patient then received denosumab (60 or 120 mg) when needed (nine doses over twenty months), the last dose in November 2020, which led to a reduction and control of here calcium levels. Currently, at three years after initial surgery, calcium levels are stable between 2.7-2.8 mmol/l and the patient has not required hospitalization for hypercalcemia for 10 months. Discussion: In case of parathyroid carcinoma, en-bloc resection is the first treatment. Denosumab has proven its efficiency in treating hypercalcemia in malignancy. Several case reports studied denosumab in hypercalcemia due to parathyroid carcinoma, and the treatment were efficient to decrease levels of calcium when repeated as needed or monthly. We report another case of refractory hypercalcemia treated with several doses of denosumab in a patient with parathyroid carcinoma.

Mice Hypomorphic for Keap1, a Negative Regulator of the Nrf2 Antioxidant Response, Show Age-Dependent Diffuse Goiter with Elevated Thyrotropin Levels.

Background: Familial nontoxic multinodular goiter (MNG) is a rare disease. One of the associated genes is Kelch-like ECH-associated protein 1 (KEAP1), which encodes the main inhibitor of nuclear factor erythroid 2-related transcription factor 2 (Nrf2), a central mediator of antioxidant responses. The association of KEAP1 with familial MNG is based on only two loss-of-function mutations identified in two families, only one of which included proper phenotyping and adequate demonstration of co-segregation of the phenotype and the mutation. There is no experimental evidence from model organisms to support that decreased Keap1 levels can, indeed, cause goiter. This study used mice hypomorphic for Keap1 to test whether decreased Keap1 expression can cause goiter, and to characterize the activation status of Nrf2 in their thyroid. Methods: C57BL/6J Keap1flox/flox (Keap1 knock-down [Keap1KD]) mice were studied at 3 and 12 months of age. Plasma and thyroid glands were harvested for evaluation of thyroid function tests and for gene and protein expression by real-time polymerase chain reaction and immunoblotting, respectively. Results: Keap1KD mice showed diffuse goiter that began to develop in early adult life and became highly prominent and penetrant with age. The goiter was characterized by a markedly increased size of thyroid follicles, most notably of the colloid compartment, and by absence of thyroid nodules or hyperplasia. Keap1KD mice also showed decreased T4 levels in early adult life that were eventually well compensated over time by increased thyrotropin (TSH) levels. Nrf2 was activated in the thyroid of Keap1KD mice. Despite a known stimulatory effect of Nrf2 on thyroglobulin (Tg) gene transcription and Tg protein abundance, the expression levels were decreased in the thyroid of Keap1KD mice. No clear patterns were observed in the expression profiles of other thyroid hormone synthesis-specific factors, with the exception of Tg-processing and Tg-degrading cathepsins, including an increase in mature forms of cathepsins D, L, and S. Conclusions: Keap1KD mice develop age-dependent diffuse goiter with elevated TSH levels. The precise mechanism accounting for the thyroidal phenotype remains to be elucidated, but it may involve enhanced Tg solubilization and excessive lysosomal Tg degradation.

Global impact of the COVID-19 pandemic on cytopathology practice: Results from an international survey of laboratories in 23 countries.

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.

A human factor event-based learning assessment tool for assessment of errors and diagnostic accuracy in histopathology and cytopathology.

This review article summarises systems for categorisation of diagnostic errors in pathology and cytology with regard to diagnostic accuracy and the published information on human factors (HFs) in pathology to date. A 12-point event-based checklist for errors of diagnostic accuracy in histopathology and cytopathology is proposed derived from Dupont's 'Dirty Dozen' HF checklist, as used in the aerospace industry for aircraft maintenance. This HF checklist comprises 12 HFs; (1) Failure of communication. (2) Complacency. (3) Lack of knowledge. (4) Distractions. (5) Lack of teamwork. (6) Fatigue. (7) Lack of resources. (8) Pressure. (9) Lack of assertiveness. (10) Stress. (11) Norms. (12) Lack of awareness. The accompanying article explains practical examples of how each of these 12 HFs may cause errors in diagnostic accuracy in pathology. This checklist could be used as a template for analysis of accuracy and risk of diagnostic error in pathology either retrospectively 'after the event' or prospectively at the time of diagnosis. There is a need for further evaluation and validation of this proposed 12-point HF checklist and similar systems for categorisation of diagnostic errors and diagnostic accuracy in pathology based on HF principles.

Immunocytochemistry practices in European cytopathology laboratories-Review of European Federation of Cytology Societies (EFCS) online survey results with best practice recommendations.

BACKGROUND: Variability in preanalytical and analytical steps for immunocytochemistry (ICC) on cytology samples is poorly defined. The objective of this study was to evaluate current practices for ICC on cytology samples in European laboratories. METHODS: A link to an online survey with 19 questions about ICC practices was distributed to cytology laboratories through national representatives in the European Federation of Cytology Societies. RESULTS: In total, 245 laboratories responded to the survey by January 30, 2019. Cell blocks, cytospins, liquid-based cytology (LBC) preparations, and smears alone or in combination with other preparations were used for ICC in 38%, 22%, 21%, and 19% of laboratories, respectively. In general, various combinations of preparations were used for ICC in greater than one-half of laboratories (147 of 245; 60%), whereas only 1 specific type of cytology preparation was used in the remaining 98 of 245 laboratories (40%) laboratories. The majority of laboratories (217 of 226; 96%) performed ICC on automated platforms using protocols that were the same as those used for formalin-fixed, paraffin-embedded samples (238 of 527 laboratories; 45%), either optimized (138 of 527 laboratories; 26%) or optimized and validated (151 of 527 laboratories; 29%) for cytology preparations. Positive control slides, negative control slides, and external quality control were used in 174 of 223 (78%), 112 of 223 (50%), and 111 of 120 (50%) laboratories, respectively. Greater than 1000 ICC tests were performed yearly in 34% of laboratories (65 of 191; average, 1477 tests; median, 500 tests). CONCLUSIONS: ICC is extensively performed in European laboratories using variously prepared cytology preparations on automated platforms, mostly without quality-assurance measures.

Measures to reduce diagnostic error and improve clinical decision making in thyroid FNA aspiration cytology: A proposed framework.

Thyroid fine-needle aspiration cytology (FNA) and histopathology can be subjective areas of medical diagnosis and subject to different interpretations. On the basis of the authors' personal experience, 12 recommendations with potential to improve clinical decision making, ensure quality, and reduce diagnostic error in thyroid FNAC and histopathology are presented. 1) use a standardized reporting terminology for thyroid FNAC; 2) understand and explain to service users the limitations of cytology and the standardized thyroid FNAC reporting terminology used; 3) the cytopathologist should review all relevant clinical and ultrasound findings, if feasible; 4) include the risk of malignancy in all FNAC reports if feasible; 5) collect data to calculate the local institutional risk of malignancy for FNAC if feasible; 6) accept that nondiagnostic FNAC will include small numbers of carcinomas; 7) use rapid on-site evaluation and/or educational sessions for aspirators if the nondiagnostic aspiration rate is high; 8) know the diagnostic pitfalls of both cytology and histopathology; 9) use special immunohistochemical and molecular techniques that are evidence-based; 10) make use of second opinions, either in-house or interinstitutional; 11) multidisciplinary discussion of cases before surgery or therapy is invaluable; and, finally, 12) manage patient and clinician expectations of thyroid cytology and histopathology. These 12 recommendations may assist in quality-improvement initiatives and may reduce diagnostic errors in thyroid cytology and histopathology. Thyroid multidisciplinary case discussion remains the principal, overarching method for error reduction and for providing high-quality clinical decision making.

Programmed Death-Ligand 1 (PD-L1) Is a Potential Biomarker of Disease-Free Survival in Papillary Thyroid Carcinoma: a Systematic Review and Meta-Analysis of PD-L1 Immunoexpression in Follicular Epithelial Derived Thyroid Carcinoma.

The expression of programmed death-ligand 1 (PD-L1) is an established prerequisite for the administration of checkpoint inhibitor therapy and is of prognostic value in several cancer types. Data concerning the potential effect of PD-L1 on the prognosis of thyroid carcinoma are limited. Therefore, this study aimed to provide a systematic review of the published data on this topic. The literature was reviewed to gather and quantify evidence on the prognostic role of PD-L1 in follicular epithelial derived thyroid carcinomas and determine its association with clinicopathological parameters. A meta-analysis was performed using the DerSimonian-Laird random-effects model. The quality of studies was evaluated with the Newcastle-Ottawa Scale and a modified GRADE approach used to rate the quality of evidence. Out of 445 papers, 18 were included and 15 provided adequate data for meta-analysis. The quality of evidence ranged from low to high. PD-L1 expression was significantly associated with a reduced disease-free survival (DFS) (RR 1.63, CI 1.04-2.56, p = 0.03, I2 68%, τ2 0.19 and HR 1.90, CI 1.33-2.70, p< 0.001, I2 0%, τ2 0.00); however, no association was found with the overall survival (OS). Furthermore, a significant association was found with respect to underlying chronic lymphocytic thyroiditis and BRAFV600E mutation status in papillary thyroid carcinomas. In the subgroup analysis, the association of PD-L1 and DFS remained strong in papillary thyroid carcinoma when compared with dedifferentiated thyroid carcinomas (anaplastic and poorly differentiated thyroid carcinomas) that failed to demonstrate a significant association with respect to PD-L1. These findings underscore the role of PD-L1 immunohistochemistry as a potential prognostic biomarker of disease recurrence in patients with papillary thyroid carcinoma.

Papillary thyroid carcinoma with prominent myofibroblastic stromal component: clinicopathologic, immunohistochemical and next-generation sequencing study of seven cases.

Papillary thyroid carcinoma with desmoid-type fibromatosis or nodular fasciitis-like stroma is an extremely unusual and poorly understood subtype of papillary thyroid cancer. Although prior studies have demonstrated alterations in the Wnt/ß-catenin signaling pathway in some of these tumors, controversy still exists regarding the nature of the stromal spindle component. We have studied seven cases of papillary thyroid carcinoma with prominent myofibroblastic stroma, including six men and one woman aged 20-65 years (mean age = 44). All cases displayed areas consistent with conventional papillary thyroid carcinoma embedded in abundant myofibroblastic-like stroma. The myofibroblastic stroma in six cases resembled desmoid-type fibromatosis and in one case it more closely resembled nodular fasciitis. By immunohistochemical staining, the stromal spindle component showed positivity for SMA and low MIB1 proliferation index in all cases, and there was at least patchy strong nuclear positivity for beta-catenin in six/seven cases. Stains for cytokeratin AE1/AE3 and PAX8 were positive in the epithelial elements but negative in the stromal component. Next-generation sequencing was performed on six of seven cases. CTNNB1 gene mutations were identified in six/seven cases. The epithelial component showed BRAF mutations in two cases and an NRAS mutation in one case. The case with fasciitis-like stroma was negative for beta-catenin by sequencing and immunostaining as well as negative for USP6 gene rearrangement. Our findings indicate that papillary thyroid carcinoma with prominent myofibroblastic stroma may represent more than one category of lesions.

Cytologic grading of primary malignant salivary gland tumors: A blinded review by an international panel.

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.