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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 Keap1 flox/flox (Keap1 knock-down [Keap1 KD ]) 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: Keap1 KD 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. Keap1 KD 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 Keap1 KD 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 Keap1 KD 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: Keap1 KD 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.

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

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 in pathology to date. A 12 point event-based checklist for error in diagnostic accuracy in histopathology and cytopathology is proposed derived from Dupont’s ‘Dirty Dozen’ human factor checklist, as utilised in the aerospace industry for aircraft maintenance. This human factor checklist comprises 12 human factors implicated in defects in aircraft maintenance; (i) failure of communication, (ii) complacency, (iii) lack of knowledge, (iv) distractions, (v) lack of teamwork, (vi) fatigue, (vii) lack of resources, (viii) pressure, (ix) lack of assertiveness, (x) stress, (xi) norms, and (xii) lack of awareness. The accompanying article explains practical examples of how each of these 12 human factors may cause errors in diagnostic accuracy in pathology. This checklist could be used as a template for analysis of accuracy and risks 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 human factor checklist and similar systems for categorisation of diagnostic errors and diagnostic accuracy in pathology based on human factor principles.

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.

INTRODUCTION The UK Royal College of Pathologists (RCPath) Thy terminology is an internationally recognised system for reporting thyroid fine needle aspiration. The terminology has been used throughout the UK and Ireland, in some parts of Italy and Switzerland, and elsewhere in the world. There is no systematic review of the literature specifically addressing the use of the non-diagnostic for cytological diagnosis-Thy1/Thy 1c category in the UK RCPath terminology. METHODS A comprehensive literature search of online databases was conducted in October 2019 specifically examining overall reported rates of Thy1 and Thy1c in aspirates classified according to the UK Thy terminology. RESULTS Twenty-five articles were identified showing a Thy1 rate of 13.4% (2540/18 920). The studies were then stratified according to whether or not the patients underwent rapid on-site evaluation (ROSE): 6.0% (353/5841; range 3.0%-10.9%) of ROSE aspirates were Thy1 whereas 18.5% (2072/11 204; range 7.9%-43.3%) of non-ROSE patients were Thy1; (P

Context.— Solid pseudopapillary neoplasm of the pancreas is a low-grade malignant tumor generally associated with a good prognosis. Solid pseudopapillary neoplasms show peculiar morphologic features, but sometimes the differential diagnosis with other pancreatic neoplasms (ie, pancreatic neuroendocrine tumors) can be a challenging task, especially in cytologic or biopsy specimens. In these cases immunohistochemistry is a useful tool, but the diagnostic utility of several proposed immunohistochemical markers is questionable. In recent years, despite several attempts to characterize the pathogenetic, molecular, and prognostic features of solid pseudopapillary neoplasms, they still remain unclear. Objective.— To give the reader a comprehensive update on this entity. Data Sources.— The PubMed database (US National Library of Medicine) was searched using the following string: pseudopapillary tumor [AND/OR] neoplasm [AND/OR] pancreas. All articles written in English were included. In addition, because a heterogeneous terminology has been used in the past to define solid pseudopapillary neoplasms, the reference lists of each paper selected in the PubMed database were also reviewed. Conclusions.— This review gives a comprehensive update on the pathologic, clinical, and molecular features of solid pseudopapillary neoplasms, particularly addressing issues and challenges related to diagnosis. In addition, we have tried to correlate the molecular alterations with the morphologic and clinical features.

BACKGROUND Thyroid fine-needle aspiration (FNA) is a reliable and cost-effective diagnostic tool for establishing the nature of thyroid nodules, although up to 30% of FNAs are still classified as "indeterminate." Molecular testing of FNAs could improve preoperative diagnosis, thereby reducing unnecessary surgery. In this multicenter prospective study the authors investigated, using a 7-gene assay, the distribution and diagnostic impact of BRAF, RAS, RET/PTC, and PAX8/PPARg, the most frequent genomic alterations occurring during thyroid oncogenesis. METHODS In total, of 1172 routine FNAs from 7 centers in southern Italy were classified according to the Bethesda System for Reporting Thyroid Cytopathology. Each specimen was tested, and molecular data were compared with available histology or cytologic follow-up. RESULTS In particular, for atypia of undetermined significance/follicular lesion of undetermined significance cases, the 7-gene test confirmed the high positive predictive value of BRAFV600E and BRAF-like mutations (80%) and the moderate positive predictive value of RAS-like alterations (32.4%), suggesting different surgical management, depending on the type of mutation. The rate of mutation-positive FNAs was strictly related to the risk of malignancy of each diagnostic class, supporting the identification of prognostically relevant diagnostic categories. CONCLUSIONS The 7-gene panel test improves the preoperative risk stratification of indeterminate thyroid FNAs, especially when considering the biologic significance of the different types of mutations. Moreover, the rate of mutation-positive FNAs is related to the risk of malignancy of each diagnostic class.

The hyalinizing trabecular adenoma/tumor is a rare and poorly characterized follicular-derived thyroid neoplasm recently shown to harbor recurrent PAX8-GLIS1 or PAX8-GLIS3 gene fusions. Here we sought to define the repertoire of genetic alterations of hyalinizing trabecular tumors, and whether PAX8-GLIS3 fusions are pathognomonic for hyalinizing trabecular tumors. A discovery series of eight hyalinizing trabecular tumors was subjected to RNA-sequencing (n = 8), whole-exome sequencing (n = 3) or targeted massively parallel sequencing (n = 5). No recurrent somatic mutations or copy number alterations were identified in hyalinizing trabecular tumor, whereas RNA-sequencing revealed the presence of a recurrent genetic rearrangement involving PAX8 (2q14.1) and GLIS3 (9p24.2) genes in all cases. In this in-frame fusion gene, which comprised exons 1-2 of PAX8 and exons 3-11 of GLIS3, GLIS3 is likely placed under the regulation of PAX8. Reverse transcription RT-PCR and/or fluorescence in situ hybridization analyses of a validation series of 26 hyalinizing trabecular tumors revealed that the PAX8-GLIS3 gene fusion was present in all hyalinizing trabecular tumors (100%). No GLIS1 rearrangements were identified. Conversely, no PAX8-GLIS3 gene fusions were detected in a cohort of 237 control thyroid neoplasms, including 15 trabecular thyroid lesions highly resembling hyalinizing trabecular tumor from a morphological standpoint, as well as trabecular/solid follicular adenomas, solid/trabecular variants of papillary carcinoma, and Hurthle cell adenomas or carcinomas. Our data provide evidence to suggest that the PAX8-GLIS3 fusion is pathognomonic for hyalinizing trabecular tumors, and that the presence of the PAX8-GLIS3 fusion in thyroid neoplasms may be used as an ancillary marker for the diagnosis of hyalinizing trabecular tumor, thereby avoiding overtreatment in case of misdiagnoses with apparently similar malignant tumors.

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.

Objective The second version of The Bethesda System for Reporting Thyroid Cytopathology endorsed the introduction of non-invasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP) as a distinct entity with low malignant potential into clinical practice. Consequently, the risk of malignancy (ROM) of cytological diagnoses has changed, but the magnitude of the change remains uncertain. The present systematic review was undertaken to obtain more robust information about the true impact of NIFTP on the ROM among patients undergoing surgery following a fine-needle aspiration cytology (FNAC) diagnosis of suspicious for malignancy (Bethesda V) or malignant (Bethesda VI). As they are managed surgically, these two diagnostic categories are the primary entities that are clinically impacted by the advent of NIFTP. Design Systematic review and meta-analysis. Methods A comprehensive literature search of online databases was performed in November 2018. The search was conducted looking for data of histologically proven NIFTP with preoperative FNAC. Results One-hundred fifty-seven articles were identified and nine were included in the study. Overall, there were 13,752 thyroidectomies with a cancer prevalence of 45.7%. When NIFTP was considered non-malignant, the pooled risk difference for ROM was 5.5%. Applying meta-analysis, the pooled prevalence of NIFTP among nodules with FNAC of Bethesda V or Bethesda VI was 14 and 3%, respectively. Conclusion This meta-analysis shows that the inclusion of NIFTP leads to a reduction in the ROM for the Bethesda V and Bethesda VI FNAC diagnostic categories by 14 and 3%, respectively. Clinicians should be aware of these data to avoid overtreatment.

The indeterminate thyroid nodules diagnosed by fine-needle aspiration cytology (FNAC)represents a problem for both cytopathologists and clinicians. The former sometimes use this diagnostic category as a sort of basket, putting in cases that they do not know exactly how to classify. The latter are faced with a highly variable risk of malignancy and consequently the management remains a challenge. On the histopathological side, the new WHO classification of tumors of the thyroid introduced the concept of tumors with uncertain and low malignant potential, and the concept of non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), whose prognosis and management are still to be completely elucidated. While the risk of malignancy of the indeterminate diagnostic category has decreased due to the re-classification of certain types of papillary thyroid carcinomas of the follicular variant into a low malignant potential form (the NIFTP), cases diagnosed cytologically as indeterminate will probably increase in the future to avoid false positive diagnosis. Thus, the indeterminate thyroid diagnostic category still remains a challenge, both at the diagnostic level and for its management. The new version of the Bethesda system for reporting thyroid cytopathology suggests managing these patients with a repeat FNA, diagnostic lobectomy and/or molecular testing.

Acinar cell carcinomas (ACCs) of the pancreas are a heterogeneous group of neoplasms showing a wide spectrum of morphological features including acinar, solid, glandular, and trabecular architecture. In addition, uncommon cytological aspects have recently been described and include oncocytic, spindle, clear, and pleomorphic cell types. This wide histological spectrum represents a challenge in the diagnostic task for pathologists. Molecular mechanisms involved in the onset and progression of ACCs are not completely known, but, in general, they differ from those observed in ductal adenocarcinomas or neuroendocrine neoplasms of the pancreas and frequently include alterations in the APC/β-catenin pathway. In the present paper, we describe a new variant of ACC showing thyroid-like follicular features and CTNNB1 mutation. This phenotype needs to be included in the spectrum of morphological presentation of ACC.

Cytology is a modern, fast, secure, and cost-effective method to render a diagnosis of neoplastic processes throughout the body, including neuroendocrine neoplasms. Fine-needle aspiration and exfoliative cytology specimens show a good sensitivity and specificity in detecting neuroendocrine neoplasms. Increased imaging has led to an increased and earlier detection of neuroendocrine neoplasms. In addition, the easy accessibility of both endoscopic procedures and a fast-diagnostic workup by cytology allow for earlier diagnoses on less invasively obtained material, increasingly in an outpatient setting. Thus, cytology has contributed to the decrease in the mortality of neuroendocrine neoplasms. This chapter focuses on general and site-specific cytology of neuroendocrine neoplasms to make the reader familiar with the spectrum of the cytology of neuroendocrine neoplasms. In addition, differential diagnoses and the use of ancillary techniques such as immunocytochemisty and immunohistochemistry are discussed. Finally, the widely accepted organ system-based, specific classification systems to facilitate the conversation among members of multidisciplinary endocrine oncology team are discussed.

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

Background: Familial non-toxic multinodular goiter (MNG) is a rare disease. KEAP1 gene (Kelch-like ECH-associated protein 1) that encodes the main inhibitor of nuclear factor erythroid 2-related transcription factor 2 (Nrf2), a central mediator of antioxidant responses, has been found to be one of the mutated genes that lead to familial MNG. The proposed association of KEAP1 with familial MNG is based on only two loss-of-function mutations in respective Japanese families, only one of which included proper phenotyping and demonstration of co-segregation of phenotype and mutation. To date, there is no experimental evidence from model organisms to support that decreased Keap1 levels can cause goiter. Hypothesis: We hypothesized that enhanced Nrf2 signaling induced by loss of Keap1 function in mice can lead to goiter. Methods: To this end, male Keap1 hypomorphic C57BL/6J mice that express ~80% less Keap1 in their tissues (Keap1 knockdown mice:“Keap1KD”) were studied at 3 and 12 months of age and compared to wild-type mice (WT). Plasma, thyroids and pituitary glands were collected for assessment of thyroid function by radioimmunoassays and for histology as well as gene and protein expression by quantitative PCR and immunoblotting respectively. Results: Keap1KD showed diffuse goiter that began to develop in early adult life and became highly prominent at the age of 12 months when the thyroids of Keap1KD were 6-fold heavier than WT. Histomorphometry assessment of thyroids showed that Keap1KD had ~3-fold larger follicle area and colloid compartment but no thyroid nodules or hyperplasia was detected. Keap1KD also showed primary hypothyroidism already in early adult life that was eventually well-compensated over time by increased TSH levels (at age of 12 months: WT TSH=47.7±9.1 mU/L, Keap1KD TSH=460±74 mU/L). This was also reflected in the pituitary gland of Keap1KD where Tshb mRNA was ~3-fold higher than WT. Despite a known stimulatory effect of Nrf2 on Tg gene transcription and Tg protein abundance, these measures were decreased in the thyroid of Keap1KD mice. No clear patterns were observed in the expression profiles of other thyroid hormone synthesis-specific factors, such as Duox1, Duoxa1, Duox2, Duoxa2, Tpo, Nis, Dio1, Dio2, Dehal1 mRNA levels, 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 showed age-dependent diffuse goiter and compensated hypothyroidism. The precise mechanism accounting for the thyroidal phenotype remains to be elucidated, but it may involve enhanced Tg solubilization and excessive lysosomal Tg degradation. This study unravels novel roles of the druggable Keap1/Nrf2 pathway in thyroid function and economy. Subclinical hypothyroidism in Keap1KD mice may have broader implications regarding their use in metabolic research.

Italian consensus for the classification and reporting of thyroid cytology has proposed to discriminate the cancer prevalence of high (Tir 3B) vs. low (Tir 3A) risk indeterminate nodules. To obtain more robust evidence on this topic, we performed a meta-analysis of the Odds Ratio (OR) of malignancy of Tir 3B vs. Tir 3A nodules. A comprehensive literature exploration of online databases was conducted until May 2018. Original articles reporting histology of nodules cytologically classified as Tir 3A and Tir 3B were eligible. Pooled cancer prevalence in Tir 3A and Tir 3B, and OR of Tir 3B vs. Tir 3A were calculated. The search revealed 95 articles, and 10 were included for the meta-analysis. Overall, 1168 indeterminate lesions were reported (441 Tir 3A and 727 Tir 3B), of which 391 were cancers. The pooled cancer prevalence was 17% in Tir 3A and 47% in Tir 3B. The OR of Tir 3B vs. Tir 3A was 4.24 (95% CI 2.75 to 6.53) with mild heterogeneity and without publication bias. When we considered non-invasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP) as non-malignant, cancer rate was lower, and OR of Tir 3B against Tir 3A was 2.93 (95% CI 1.60 to 5.37), with no heterogeneity but with publication bias. The Italian system for thyroid cytology is reliable to assess indeterminate lesions at low and high risk, being Tir 3B associated with a cancer risk significantly higher than Tir 3A, also when considering NIFTP as non-malignant entity.

OBJECTIVE In 2016, there were an estimated 56 870 new cases of thyroid cancer (TC) in the USA. Fine needle aspiration cytology (FNAC) is the most safe, accurate and cost-effective method for the initial investigation of thyroid nodules. FNAC is limited by the inability to diagnose malignancy in follicular-patterned lesions accurately and, as a result, 20%-30% of cases under investigation for TC are classified as cytologically indeterminate, illustrating a problem with current FNAC procedure. Raman spectroscopy has shown promising results for the detection of many cancers; however, to date there has been no report on the performance of Raman spectroscopy on thyroid cytological samples. The aim of this study was to examine whether Raman spectroscopy could be used to correctly classify cell lines representing benign thyroid cells and various subtypes of TC. METHODS A benign thyroid cell line and seven TC cell lines were prepared as ThinPrep® cytology slides and analysed with Raman spectroscopy. Principal components analysis and linear discriminant analysis were implemented to develop effective diagnostic algorithms for classification of Raman spectra of different TC subtypes. RESULTS The spectral differences separating benign and TC cell lines were assigned to differences in the composition of nucleic acids, lipids, carbohydrates and protein in the benign and cancer cells. Good sensitivities (74%-85%), specificities (65%-93%) and diagnostic accuracies (71%-88%) were achieved for the identification of TC. CONCLUSION These findings suggest that Raman spectroscopy has potential for preoperative TC diagnosis on FNAC samples.

Objective The management of occult lymph node metastasis (LNM) in head and neck squamous cell carcinoma has been a matter of controversy for decades. The vascular density within the tumor microenvironment, as an indicator of ongoing angiogenesis, could constitute an attractive predictor of LNM. The use of the panvascular endothelial antibody CD31 as a marker of occult LNM has never been reported. The aim of this study was to assess the predictive value of CD31 microvascular density for the detection of occult LNM in squamous cell carcinoma of the oral cavity and oropharynx. Study Design Case series with chart review. Setting Tertiary university hospital. Subjects and Methods Intra- and peritumoral microvascular density values were determined in 56 cases of squamous cell carcinoma of the oral cavity (n = 50) and oropharynx (n = 6) with clinically negative necks using the CD31 marker. Statistical associations of CD31 microvascular densities with clinicopathologic data were then established. Results Peritumoral CD31 microvascular density was significantly associated with occult LNM in multivariate analysis (P < .01). Recursive partitioning analysis for this parameter found a cutoff of 19.33, which identified occult LNM with a sensitivity of 91%, a specificity of 65%, a positive predictive value of 40%, a negative predictive value of 97%, and an overall diagnostic accuracy of 71%. Conclusion Peritumoral CD31 microvascular density in primary squamous cell carcinoma of the oral cavity and oropharynx allows accurate prediction of occult LNM.

The recent update of The Bethesda System for Reporting Thyroid Cytology (TBSRTC) is a very important development in the evaluation of thyroid nodules. Clinical experience and scientific literature both show that practitioners performing thyroid fine-needle aspiration are accustomed to basing the clinical management of patients on reports using TBSRTC. Specifically, clinicians are familiar with the percent risk of malignancy corresponding to each TBSRTC diagnostic category (DC), as well as with the respective recommendation for clinical management. However, most clinicians are much less familiar with the specific considerations that lie between a given DC, on the one end, and the respective risk of malignancy and associated management recommendation, on the other end.A deeper understanding of the system can enlighten the clinician's thinking about the specific nodule under examination and can guide the decision-making process in a more meaningful way. Such an understanding can only be developed via close two-way communication between cytopathologists and clinicians. Through this type of interaction in the authors' tertiary medical center, recurring issues of particular importance for clinical practice were identified, which are reported here in the form of 16 frequently asked questions posed by the clinician to the cytopathologist.For each frequently asked question, an answer is provided based on the literature, the authors' experience, the new version of TBSRTC, and the new World Health Organization classification of tumors of endocrine organs.

HPV-positive head and neck squamous cell carcinoma (HNSCC) is increasingly frequent. Management is particularly debated in the case of postsurgical high-risk features, that is, positive surgical margins and extracapsular spread (ECS). In this increasingly complex emerging framework of HNSCC treatment, representative preclinical models are needed to support future clinical trials and advances in personalized medicine. Here, we present an immunocompetent mouse model based on the implantation of mouse tonsil epithelial HPV16-E6/E7-expressing cancer cells into the submental region of the floor-of-the-mouth. Primary tumors were found to replicate the patterns of human HNSCC local invasion and lymphatic dissemination. To study disease progression after surgery, tumors were removed likely leaving behind residual disease. Surgical resection of tumors was followed by a high rate of local recurrences (>90%) within the first 2-3 weeks. While only 50% of mice had lymph node metastases (LNM) at time of primary tumor excision, all mice with recurrent tumors showed evidence of LNM. To study the consecutive steps of LNM progression and distant metastasis development, LNs from tumor-bearing mice were transplanted into naive recipient mice. Using this approach, transplanted LNs were found to recapitulate all stages and relevant histological features of regional metastasis progression, including ECS and metastatic spread to the lungs. Altogether, we have developed an immunocompetent HPV-positive HNSCC mouse model of postsurgical local recurrence and regional and distant metastasis progression suitable for preclinical studies.

Enterobiasis is one of the most common human parasitic infections. It is considered an intestinal parasite, but cases of extra-intestinal affections exist, notably infections of the female genital tract. Enterobius vermicularis (EV) eggs (or ova) have been found in the cervical smears of two patients in our institute during the last 16 years. No gynaecological or gastrointestinal symptoms were reported, and there was no known intestinal infection in these two cases. A review of the available literature revealed rare cases of vaginal enterobiasis, with a wide range of clinical presentations, many patients being asymptomatic. The diagnosis may sometimes be difficult, mainly because of the lack of clinical suspicion. However, cytological identification of EV in cervico-vaginal smears is important, especially when considering the risk of ascending infections of the genital tract associated with severe complications.

Hyalinizing trabecular tumour (HTT) is a rare thyroid neoplasm of follicular cell origin characterised by a trabecular growth pattern and prominent intratrabecular and intertrabecular hyalinisation. These peculiar histological features allow the prompt recognition of this neoplasm in surgical specimens. However, cytological diagnosis of HTT remains elusive and misleading because of overlapping characteristics with other thyroid tumours, particularly papillary thyroid carcinoma (PTC), medullary thyroid carcinoma (MTC) and the newly described non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). Nevertheless, the proper recognition of this neoplasm on preoperative cytological preparations is important to avoid unnecessary overtreatment of this indolent lesion. A thorough review of the literature has revealed that the correct diagnosis of HTT in cytological smears is achieved in only 8% of cases. In a further 6% of cases, diagnostic doubt has been indicated. Sixty percent of published cases of HTT have been misdiagnosed as suggestive, suspicious or positive for PTC. These findings underline the difficulties of a cytological-based diagnosis of such entity. In this article we review the cytomorphological features of HTT and their correlation to histological features to provide the reader with the tools to improve diagnostic performance in the identification of HTT on preoperative cytology.

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: Follicular-patterned thyroid nodules predominantly composed of macrofollicular structures without nuclear atypia are generally regarded as benign (i.e., hyperplastic nodules or follicular adenomas). In line with this concept, fine-needle aspiration cytology (FNAC) also assigns a benign connotation to the presence of macrofollicular structures, unless thyrocytes present papillary thyroid carcinoma (PTC)-related nuclear features that raise the possibility of a macrofollicular variant of PTC. However, cases showing macrofollicular architecture, capsular invasion, and no PTC features can also be observed. Methods: We describe the clinical, cytological, histological, and molecular genetic features of four cases of encapsulated follicular neoplasms that presented histologically with a predominant (>70%) macrofollicular architecture, but which also showed clear signs of capsular invasion, and thus were classified as macrofollicular variant of follicular thyroid carcinoma (MV-FTC). Results: Cytologically, macrofollicular structures were identified in all cases, leading to a benign FNAC diagnosis in three of the four cases. Due to increasing nodule size, thyroidectomy was performed in all cases. Histology showed focal and limited capsular invasion, without vascular invasion. Next-generation sequencing (custom 394 gene panel) of each tumor compared with matched normal DNA revealed a total of 7 somatic variants, including dual (likely biallelic) mutations in the DICER1 gene in 2 patients. The clinical outcome was excellent in all cases. Conclusions: Similar to the classical minimally invasive follicular thyroid carcinoma, MV-FTC appears to behave indolently. MV-FTC has a high rate of false-negative FNAC results, but MV-FTC is very rare (

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.

In patients with thyroid fine-needle aspiration (FNA) report of suspicious for malignancy (SFM), both lobectomy and thyroidectomy might be considered. BRAF mutation analysis could guide towards accurate surgical therapy. The primary outcome was the reliability of BRAF (V600E) in detecting malignancy in nodules with FNA reading of SFM. The secondary outcome was to analyze its positive predictive value (PPV) and negative predictive value (NPV) considering the surgical histology as gold standard. A literature search of online databases was performed in June 2019. BRAF prevalence among thyroid nodules with FNA read as SFM according to the most popular classification systems (i.e., Bethesda V, Thy4, TIR4 category) was searched. The random-effects model was used. Three hundred sixty original articles were identified and 34 were finally included in the study. There were 1428 thyroid nodules with FNA read as SFM and 1287 (90.1%) lesions underwent surgery with a cancer rate 89.6%. The pooled prevalence of BRAF (V600E) mutation among all nodules with SFM cytology was 47% (95% CI = 40 to 54, I2 = 85.5%). Pooled PPV and NPV of BRAF testing were 99% (95% CI, 97-99) and 24% (95% CI, 16-32), respectively. BRAF (V600E) mutation was found in about one in two nodules with thyroid FNA read as SFM, its PPV to detect cancers was excellent, and its NPV was very poor. The routine BRAF testing in FNA read as SFM cannot be recommended. BRAF (V600E) test may be useful to extend surgical approach in selected cases with further suspicious clinical/ultrasound features.

Background The UK Royal College of Pathologists Thy terminology for reporting thyroid fine-needle aspiration cytology (FNAC), first published in 2009 is used throughout the United Kingdom and Ireland, in some parts of Italy and Switzerland and elsewhere. There is no review of the literature or meta-analysis of the risk of malignancy (ROM) in the various categories of the UK Thy terminology. The goal of this study was to establish the published ROM for each Thy category and compare the results with other existing terminology systems for which similar meta-analyses are available. Methods A comprehensive literature search of online databases was conducted in May 2019 to examine the ROMs for histologically proven nodules with preoperative FNAC classified according to the UK Thy terminology. Results Twenty-five articles were identified that showed results of both cytology and histology. Twelve of these articles were excluded to prevent a selection bias because they showed data in just 1 Thy category. In the remaining 13 articles, the pooled ROMs were as follows: Thy1, 12% (95% confidence interval [CI], 5%-22%); Thy2, 5% (95% CI, 3%-9%); Thy3, 22% (95% CI, 18%-26%); Thy3a, 25% (95% CI, 20%-31%); Thy3f, 31% (95% CI, 24%-39%); Thy4, 79% (95% CI, 70%-87%); and Thy5, 98% (95% CI, 97%-99%). Conclusions This meta-analysis shows results comparable to those of meta-analyses of other internationally recognized reporting terminologies for the pooled ROMs for surgically excised nodules in the various Thy reporting categories. There is comparatively little difference (only 6%) between the pooled ROMs of Thy3a and Thy3f surgically excised nodules.

More than 70 years ago, Prof. Pierre Masson, a renowned French-Canadian pathologist (1880–1959), advised us that “No classification is more difficult to establish than that of thyroid carcinomas…Of all cancers, they teach, perhaps, the greatest lessons of humility to histopathologists.” Almost 70 years later, the recent evidence-based reclassification of the non-invasive encapsulated follicular variant of papillary thyroid carcinoma (FVPTC) as non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), has demonstrated that this problematic is still ongoing. For about 30 years, it was wrongly assumed that the encapsulated FVPTC behaved and spread like its classical counterpart and, therefore, that it should be treated likewise. As such, the renaming of a malignant entity as a nonmalignant (albeit not benign) neoplasm has contributed to optimizing patient care by deescalating treatment and follow-up for an indolent neoplasm, decreasing medical expense and complications possibly caused by further treatment including radioactive iodine, and reassuring patients with this diagnosis. At the same time, NIFTP has significant implications not only for the practice of thyroid cytopathology but also for surgical pathology and for molecular tests, creating significant new challenges. NIFTP has rigorous histopathologic diagnostic criteria, including papillary-like nuclear features, and submission of the entire tumor capsule and content is required to exclude both invasion and presence of papillary structures. Cytologically, because of the morphological overlap with other follicular neoplasms and with papillary thyroid carcinoma (PTC), most NIFTP are diagnosed into one of the indeterminate Bethesda categories (III–V) and can be adequately triaged for surgery. From a molecular view, NIFTP are most often characterized by RAS-type mutations, similar to other follicular-patterned lesions, and molecular testing can be helpful to suggest NIFTP preoperatively. In this review, we focus on the impact of NIFTP on the diagnosis of thyroid nodules.

Background There have been few recent advances in the identification of occult lymph node metastases (OLNM) in oral squamous cell carcinoma (OSCC). This study aimed to develop, compare, and validate several machine learning models to predict OLNM in clinically N0 (cN0) OSCC. Methods The biomarkers CD31 and PROX1 were combined with relevant histological parameters and evaluated on a training cohort (n = 56) using four different state-of-the-art machine learning models. Next, the optimized models were tested on an external validation cohort (n = 112) of early-stage (T1-2 N0) OSCC. Results The random forest (RF) model gave the best overall performance (area under the curve = 0.89 [95% CI = 0.8, 0.98]) and accuracy (0.88 [95% CI = 0.8, 0.93]) while maintaining a negative predictive value >95%. Conclusions We provide a new clinical decision algorithm incorporating risk stratification by an RF model that could significantly improve the management of patients with early-stage OSCC.

Uterine tumors resembling ovarian sex-cord tumors (UTROSCTs) are rare uterine neoplasms of uncertain etiology that resemble the sex cord tumors of the ovary and display a combined sex cord, epithelial, and smooth muscle immunophenotype. Most tumors are associated with a benign clinical course. We report the first cytological description of uterine UTROSCTs in liquid-based cervical cytology (LBC). A menopausal woman was discovered to have a uterine intraluminal polypoid mass protruding through the vagina. A Pap test was performed, and the LBC preparation showed isolated tumor cells with scant cytoplasm and slightly irregular, ovoid nuclei with fine chromatin and small nucleoli. Final histological evaluation identified a UTROSCT. This diagnostic possibility, albeit rare, should be included in the differential diagnosis when isolated malignant-appearing adenocarcinomatous cells are seen in women in the above scenario. As these features are not specific, they may result in misinterpretation with tumors that are more common and aggressive.

Recently, the immunohistochemistry (IHC) for N-RAS Q61R has been developed and commercialized for clinical practice. Here, we investigated the reliability of IHC to identify N-RAS Q61R mutated thyroid neoplasia. A series of 24 consecutive thyroid lesions undergone surgery following indeterminate cytology were enrolled. Paraffin sections were stained for IHC using the rabbit monoclonal anti-human N-RAS Q61R, clone SP174. N-RAS mutations in codon 61 were also investigated by automated sequencing. At histology, 12 cases of follicular carcinoma, cytologically defined as follicular lesions, 1 papillary cancer, 7 follicular adenomas, and 4 hyperplastic nodules were found. Of these, 4 showed a positive IHC for anti N-RAS antibody where N-RAS expression was detected mainly at cytoplasmic level with similar intensity of reaction. The remaining cases had negative IHC. A 100% concordance between IHC and molecular analysis for N-RAS Q61R was observed. In conclusion, this study shows high reliability of IHC to identify N-RAS Q61R mutated thyroid lesions with high cost-effectiveness. These data indicate the reliability of IHC to identify N-RAS Q61R mutated thyroid neoplasia and suggest to adopt this approach for a more accurate management of patients, when indicated.

The aim of the present study was to analyze in vivo the role of zinc finger protein SNAI1 (SNAI1) on renal fibrosis. Unilateral ureteral obstruction injury was induced in Snai1 knockout mice. Snai1 gene deletion was, however, only partial and could therefore not be correlated to reduced fibrosis. Expression of SNAI1 protein and epithelial-mesenchymal transformation markers was then assessed in human chronic allograft nephropathy biopsy specimens. Significant up-regulation of SNAI1 protein was detected within cytoplasm of proximal tubules localized, for some of them, near foci of fibrosis and tubular atrophy. No concomitant epithelial-mesenchymal transformation could, however, be demonstrated analyzing the expression of the fibroblast markers vimentin, α-smooth muscle actin, and S100A4. SNAI1 cytoplasmic up-regulation was particularly evident in biopsy specimens obtained from calcineurin inhibitor–treated patients, which might be because of, as suggested by in vitro experiments, a decrease of the proteasome chimotrypsin activity. Deeper analysis on chronic allograft nephropathy biopsy specimens suggested that SNAI1 cytoplasmic up-regulation was preceded by a transient increase of phosphorylated heat shock protein 27, p38 mitogen-activated protein kinase, and glycogen synthase kinase 3β. Concomitant down-regulation of the polyubuquitinylated conjugates was detected in SNAI1 + tubules. Altogether, these results might suggest that calcineurin inhibitor–induced tubular SNAI1 protein cytoplasmic accumulation, possibly because of impaired SNAI1 proteasomal degradation and nuclear translocation, might be a sign of a diseased profibrotic epithelial phenotype.

BACKGROUND Secondary malignancies of salivary glands (SMSGs) are among the most common malignant neoplasms to involve the salivary glands. Fine-needle aspiration biopsy (FNAB) of SMSG can present diagnostic challenges. The current report presents the largest such FNAB series to date. METHODS A search of the pathology database from 6 academic institutions identified 184 FNAB cases of nonlymphomatous SMSG. RESULTS Of the 184 cases, 171 were of the parotid glands, and 13 were of the submandibular glands; 130 patients were men, and 54 were women, and the mean patient age at diagnosis was 68 years. Metastatic squamous cell carcinoma (SCC) from all sites (n = 87) and melanoma (n = 67) constituted the majority of SMSGs. Less frequent SMSGs were comprised of metastatic carcinomas from distant organs (n = 16), including sites in the breast, lung, kidney, thyroid, pancreatobiliary, prostate, and bladder. Other uncommon SMSGs, including nasopharyngeal carcinoma (n = 3), sarcoma (n = 4), other metastatic skin-derived carcinomas (n = 6), and metastatic chordoma (n = 1), also were observed. Ancillary tests were performed on 37 FNAB specimens (20.1%) to aid the evaluation. One hundred forty-seven specimens (79.9%) had a definitive diagnosis with accurate tumor subtyping, 21 (11.4%) had a definitive malignant diagnosis but without specifying subtype, 9 (4.9%) had an indeterminate diagnosis, and 7 (3.8%) had a false-negative diagnosis. CONCLUSIONS SMSGs originate predominately from the head and neck and are more common in older men. Overall, the FNAB diagnosis of SMSG is accurate, but diagnostic challenges can be encountered, especially in SCC types of SMSG. Ancillary studies are needed for the definitive diagnosis of challenging cases. Cancer Cytopathol 2017;125:91-103. © 2016 American Cancer Society.

Myoepithelioma is a rare and usually benign salivary gland tumor derived from myoepithelial cells. Variability in cellular morphology and stromal composition leads to diagnostic pitfalls on fine-needle aspiration cytology; therefore, histology and immunohistochemistry are often required for definitive diagnosis. We describe a case of parotid gland myoepithelioma in a 76-year-old woman, which was discovered incidentally on cerebral magnetic resonance imaging. Fine-needle aspiration sampled cohesive aggregates of spindle-shaped cells embedded in a fibrillary matrix as well as abundant mature adipocytes, initially considered as part of normal salivary gland parenchyma. Histology of the resected specimen showed bundles of spindle-shaped cells embedded in loose connective tissue, admixed with numerous intralesional adipocytes. Immunohistochemical studies revealed a diffuse expression of p63 by this adipocytic population, an observation clearly indicating that myoepithelial cells can trans-differentiate and acquire the morphology of mature adipocytes. Knowledge of this phenomenon can be helpful in the work-up of salivary gland lesions. Diagn. Cytopathol. 2016;44:1090-1093. © 2016 Wiley Periodicals, Inc.

Background The correlation between podoplanin expression and extracapsular spread in head and neck squamous cell carcinoma (HNSCC) has never been reported. The purpose of this study was to assess the predictive value of podoplanin expression for this parameter. Methods Subjective immunoreactivity scores and semiquantitative image analysis of podoplanin expression were performed in 67 patients with primary oral squamous cell carcinoma and in their corresponding lymph nodes. Neck classification showed 34 cases (51%) of pN0 and 33 cases (49%) of pN+. Correlation between the levels of podoplanin expression and the histopathological data was established. Results In lymph nodes, a high level of podoplanin expression correlated with the presence of extracapsular spread by multivariate analysis (p = .03). A strong correlation between subjective and semiquantitative image analysis was observed (r = 0.77; p

Thyroid implants in the soft tissue of the neck are very rare findings of traumatic, iatrogenic, or neoplastic origins. We describe the clinico-pathological and molecular analysis of three cases with an initial diagnosis of follicular adenoma, Hürthle cell variant (FA-HCT), which developed cervical thyroid implants at 60, 59, and 36 months after thyroid surgery, followed by further neck recurrences, and, eventually, by distant metastases. A systematic review of all histopathological samples of both the primary lesions and the neck implants was performed. Molecular study included the analysis of pan-RAS and BRAF mutations and RET/PTC1, RET/PTC3, and PAX8/PPARγ rearrangements. The review of the original slides and of additional re-cuts of each block of the thyroid lesions did not show any sign of capsular and/or vascular invasion; thus, the original diagnoses of FA-HCT were confirmed. When sampling adequacy was considered, it turned out that the capsule was completely evaluable in case #3, whereas 85 % was evaluable for case #1 and less than 50 % for case #2. We cannot exclude that cases #1 and #2 were carcinomas that had not been completely sampled. The first occurring neck implants showed neither histological signs of malignancy nor the presence of lymphoid tissue. However, further neck recurrences had different histological aspects, with a clear infiltrative growth. Moreover, a mesenchymal reaction forming a sort of capsule was observed around oncocytic cells along with signs of vascular invasion. Molecular analysis revealed no alterations in the genes and rearrangements studied. Oncocytic thyroid implants in the neck soft tissue should be regarded as metastasis, even in the absence of clear-cut signs of malignancy and in the case of a bona fide diagnosis of Hürthle cells adenoma of the thyroid.

Background. The use of lymphatic vessel density as a predictor of occult lymph node metastasis (OLNM) in head and neck squamous cell carcinoma (HNSCC) has never been reported. Methods. Staining of the specific lymphatic endothelial cells nuclear marker, PROX1, as an indicator of lymphatic vessel density was determined by counting the number of positive cells in squamous cell carcinomas (SCCs) of the oral cavity and the oropharynx with clinically negative necks. Correlation with histopathological data was established. Results. Peritumoral PROX1 lymphatic nuclear count significantly correlated with the detection of OLNM in multivariate analysis (p

Background The Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) is a 6-tier diagnostic category system with associated risks of malignancy (ROMs) and management recommendations. Submandibular gland fine-needle aspiration (FNA) is uncommon with a higher frequency of inflammatory lesions and a higher relative proportion of malignancy, and this may affect the ROM and subsequent management. This study evaluated the application of the MSRSGC and the ROM for each diagnostic category for 734 submandibular gland FNAs. Methods Submandibular gland FNA cytology specimens from 15 international institutions (2013-2017) were retrospectively assigned to an MSRSGC diagnostic category as follows: nondiagnostic, nonneoplastic, atypia of undetermined significance (AUS), benign neoplasm, salivary gland neoplasm of uncertain malignant potential (SUMP), suspicious for malignancy (SM), or malignant. A correlation with the available histopathologic follow-up was performed, and the ROM was calculated for each MSRSGC diagnostic category. Results The case cohort of 734 aspirates was reclassified according to the MSRSGC as follows: nondiagnostic, 21.4% (0%-50%); nonneoplastic, 24.2% (9.1%-53.6%); AUS, 6.7% (0%-14.3%); benign neoplasm, 18.3% (0%-52.5%); SUMP, 12% (0%-37.7%); SM, 3.5% (0%-12.5%); and malignant, 13.9% (2%-31.3%). The histopathologic follow-up was available for 333 cases (45.4%). The ROMs were as follows: nondiagnostic, 10.6%; nonneoplastic, 7.5%; AUS, 27.6%; benign neoplasm, 3.2%; SUMP, 41.9%; SM, 82.3%; and malignant, 93.6%. Conclusions This multi-institutional study shows that the ROM of each MSRSGC category for submandibular gland FNA is similar to that reported for parotid gland FNA, although the reported rates for the different MSRSGC categories were variable across institutions. Thus, the MSRSGC can be reliably applied to submandibular gland FNA.

The presence of thyroid nodules represents a common finding in the general population. Their detection, evaluation, and diagnosis are mostly achieved with ultrasonographic examination and fine needle aspiration cytology (FNAC) analysis. The widespread use of ultrasound imaging permits the detection of deeply located and millimetric lesions. Thus, providing reliable diagnosis for the management of all these nodules represents a challenge for cytopathologists and cytotechnologists. Unfortunately, up to 30% of thyroid nodules fail to provide a definite FNAC diagnosis.

Thyroid fine-needle aspiration cytology (FNAC) is one of the most performed medical procedures worldwide. 1 It is used as a diagnostic test to separate benign thyroid nodules (colloidal and hyperplastic nodules) from thyroid malignancies, either primary (papillary thyroid carcinoma (PTC), medullary thyroid carcinoma (MTC), poorly differentiated thyroid carcinoma (PDTC), anaplastic thyroid carcinoma (ATC)) or less often metastatic. 2 The negative and positive predictive values (NPV and PPV) of this procedure in The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) are respectively 97% and 98% for the benign and malignant categories. This article is protected by copyright. All rights reserved.

Since borderline/precursor thyroid tumors are now established in the thyroid tumor classification, the next required step is to establish cytological categories to accomodate these tumors. How to handle these categories is the key for diagnostic system for thyroid FNA cytology. The Japanese diagnostic system is a histological-oriented classification by which the indeterminate category is sub-classifies into follicular adenoma/follicular carcinoma (RAS-like tumor) lineage and papillary carcinoma (BRAF-like tumor) lineage. The author proposed several histological type oriented classifications of thyroid FNA cytology in this chapter which were modified from the Japanese system. The author believes they are useful for selection of optimal molecular tests and/or ancillary tests for more definite diagnoses of indeterminate nodules. This is the key to solve the problems with the so-called indeterminate categories. With the aide of available clinical tests, including molecular tests, more definite diagnosis will help reduceing numbers of diagnostic surgery and over treatment of indolent thyroid tumors.

Once upon a time there was “free for all” thyroid reporting system. Each institution and each cytopathologist used an own terminology to describe the nature of a thyroid aspiration. In recent years, with the advent of national reporting systems, thyroid cytopathological reports are standardized, reproducible, and understandable by all stakeholders who gravitate around the problems of thyroid proliferation. It becomes easier to compare casuistic between institutions and to compare the accuracy of ancillary techniques and molecular test applied to thyroid fine-needle aspiration cytology. The most widespread reporting systems have been established in the United States, England, Italy, Japan, and Australia. Some of them are five-tiered and other six-tiered. Efforts have been done in the revised version of some of these reporting systems to homogenize diagnostic categories that have been differently named, in particular in the indeterminate categories, in order to make more super imposable each system.

The recent introduction of noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP) in the World Health Organization classification of thyroid tumors has significantly modified the risk of malignancy of cytological diagnoses. In fact, while this tumor was previously classified as a carcinoma (the encapsulated, noninvasive form follicular variant of papillary thyroid carcinoma), it is now considered a neoplasm with low malignant potential. Given that the cytological features of NIFTP are not specific and overlap with other pathologic entities, there is no specific cytological diagnostic category for NIFTP. To obtain more robust information about the cytological findings associated with NIFTP, published articles were systematically reviewed, and a meta-analysis of the data was conducted. The review was conducted according to PRISMA guidelines. A comprehensive literature search of the PubMed/MEDLINE and Scopus databases was conducted using a combination of terms "noninvasive," "encapsulated," "follicular variant," "NIFTP," and "thyroid cancer." The search was updated to June 2018, and references of the retrieved articles were also screened. Only original articles reporting the classification of histologically proven NIFTPs with cytological findings according to The Bethesda System for Reporting Thyroid Cytopathology were eligible for inclusion. The literature search revealed 117 articles, of which 15 were included in the study. All studies were retrospective. A total of 915 NIFTP cases were retrieved. The incidence of cases cytologically classified according to the Bethesda system was as follows: non-diagnostic 3%, benign 10%, atypia of undetermined significance or follicular lesion of undetermined significance 30%, follicular neoplasm or suspicious for a follicular neoplasm 21%, suspicious for malignancy 24%, and malignant 8%. Mild heterogeneity between the studies was found. Publication bias was absent. This meta-analysis shows that the cytological diagnoses associated with NIFTP by fine-needle aspiration cytology includes a wide spectrum of findings. The majority of cases are cytologically indeterminate, and the remainder may be read as non-diagnostic, benign, or malignant. In order to develop an accurate presurgical diagnosis of these cases, further cytological and/or molecular characteristics need to be identified.

Angiosarcoma and anaplastic carcinoma are the most lethal neoplasms of the thyroid worldwide and share some similarities, which have led to a longstanding controversy on their etiopathological relationship. Thyroid angiosarcomas are characterized by vessel formation and an immunophenotype common to endothelial cells, while anaplastic carcinomas are partially or wholly composed of mesenchymal-like cells that have lost the morphologic and functional features of normal thyroid follicular cells. To investigate whether angiosarcomas represent the endothelial extreme of the differentiation spectrum of carcinomas or they are bona fide vascular neoplasms, we studied the clinico-morphologic and genetic characteristics of a series of 10 angiosarcomas and 22 anaplastic carcinomas. Immunohistochemically, among the endothelial markers, CD31 and ERG were the most consistently expressed in angiosarcomas. Among the markers of thyroid origin, PAX8 was the most reliable in anaplastic carcinomas, while TTF-1 reactivity was found in only 5% of anaplastic carcinomas and thyroglobulin was always negative. Pankeratin reacted with most angiosarcomas and anaplastic carcinomas and is therefore not useful in the differential diagnosis. Interestingly a mutated pattern of p53 immunostaining prompted a diagnosis of anaplastic carcinoma. To compare the genetic profile, we used the NGS approach to sequence hotspot regions within a panel of 57 genes. As a result, only a few mutations were found in angiosarcomas and all of them were single events (no TP53 or TERT mutation). On the other hand, anaplastic carcinomas were characterized by a higher number of mutations, and TP53 and TERT promoter mutations were the most frequent genetic alterations. The lack in angiosarcomas of the common mutations identified in anaplastic carcinomas supports a different genetic origin and strongly suggests that, in spite of a shared sarcomatous morphology and a similar clinical aggressiveness, angiosarcomas and anaplastic carcinomas rely on a completely different set of genetic alterations during their evolution.