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BACKGROUND The introduction of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) affects the risk of malignancy (ROM) mostly in the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) categories. In this multi-institutional, retrospective study, the authors investigated variations in the impact of an NIFTP diagnosis on the associated ROM for each TBSRTC category with an emphasis on the influence of pathologist and institutional diagnostic thresholds on the ROM. METHODS Baseline data on cytology and histology diagnostic categories were collected over a 3-year period at 3 academic center hospitals (institutions A, B, and C). Histology slides for all cases diagnosed as follicular variant of papillary thyroid carcinoma (FVPTC) were re-reviewed at each institution, and those that qualifying as NIFTP were separated from other PTCs. RESULTS The collective case cohort from the 3 institutions included 15,973 thyroid fine-needle aspiration cytology (FNAC) specimens and 5090 thyroid surgical resection specimens. Significant differences in baseline cytology and histology data were noted among the 3 institutions. The number of cases classified as NIFTP compared with FVPTC was highly variable (institution A, 14%; institution B, 39%; and institution C, 12%). For 3250 resected thyroid nodules with a previous FNAC diagnosis, the average decrease in ROM after the exclusion of NIFTP for all TBSRTC categories was as follows: institution A, 9.8%; institution B, 3.9%; and institution C, 1.3%. CONCLUSIONS The institutional frequency of NIFTP histopathology diagnosis and cytology baseline data will impact the ROM associated with specific FNAC diagnoses, especially among the indeterminate TBSRTC categories. The range of ROM for each TBSRTC diagnostic category is reflective of the inherent diagnostic thresholds and interobserver and interinstitutional variability in the diagnosis of thyroid lesions. Cancer Cytopathol 2018;126:20-6. © 2017 American Cancer Society.

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.

BACKGROUND Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) represents a challenge for the diagnosis and management of thyroid carcinoma. Some authors have proposed histological criteria that are able to distinguish NIFTPs from invasive follicular variant of papillary thyroid carcinoma (I-FVPTC). Hence, NIFTPs may have repercussions in the diagnostic categories on fine-needle aspiration. In the current study, the authors evaluated the criteria for NIFTPs on liquid-based cytology samples. METHODS The authors recorded all 61 liquid-based cytology samples proved to be histological FVPTC between January 2013 and March 2016 and analyzed the architectural, cytoplasmic, and nuclear parameters. They compared them with a cohort of 40 PTC cases and 20 follicular adenoma cases. RESULTS The authors reported 37 NIFTP cases and 24 I-FVPTC cases at histology. The cytological diagnoses of follicular nodules in the NIFTP cases were twice those found in the I-FVPTC cases (54.1% vs 29.2%). The number of positive for malignancy cases among the NIFTPs were approximately half those of I-FVPTC cases. When compared with I-FVPTCs, 70% of the NIFTP cases demonstrated a nuclear size .05). A predominant microfollicular pattern was recognized in both NIFTPs and I-FVPTCs (97.3% vs 100%). CONCLUSIONS The majority of NIFTPs appear to be devoid of nuclear pseudoinclusions and papillary structures, thereby allowing the inclusion in the follicular nodule cases. Nuclear size and microfollicular clusters may suggest the discrimination between NIFTPs and I-FVPCs. Cancer Cytopathol 2016. © 2016 American Cancer Society.

BACKGROUND The current study compared ThinPrep urinary cytology and conventional cytospin urinary cytology in the diagnosis of bladder cancer, applying the Paris System for Reporting Urinary Cytology. METHODS Between January 2010 and December 2011, a total of 3659 urine samples were processed using conventional cytospin methods. Between January 2012 and December 2013, a total of 4186 urine cytological cases were analyzed using ThinPrep methods. In 131 cases (65 processed by conventional cytospin and 66 processed by ThinPrep), a subsequent biopsy was performed. The authors reclassified these cases according to the Paris System and an analysis between the 2 methods with regard to bladder biopsies was performed. RESULTS No significant differences were observed in terms of sensitivity and specificity between the 2 methods in cases with positive cytology for high-grade carcinoma. According to the Paris System, cases of atypical urothelial cells (AUC) and atypical urothelial cells suspicious for high-grade carcinoma (AUC-H) that were processed using cytospin did not correlate with urothelial carcinoma or with negative biopsies; conversely, the AUC cases processed using ThinPrep appeared to correlate with negative histological biopsies or low-grade urothelial carcinoma. CONCLUSIONS The results of the current study demonstrated that according to the Paris System, there were no significant differences in sensitivity or specificity for the diagnosis of high-grade urothelial carcinoma or AUC-H between the 2 methods. Cases of AUC should be easy to recognize using Thin Prep rather than cytospin and only AUCs diagnosed with ThinPrep were found to be statistically linked to negative cases for carcinoma or with low-grade urothelial carcinoma. Cancer Cytopathol 2016;124:519–23. © 2016 American Cancer Society.

BACKGROUND Fine-needle aspiration cytology (FNAC) has proven its value as an essential step in the diagnosis of salivary gland lesions. Although the majority of salivary gland lesions, especially those that are common and benign, can be diagnosed with ease on FNAC, limited cellularity and morphologic lesion heterogeneity can pose diagnostic challenges and lead to false-positive and false-negative diagnoses. This study presents the institutional experience of FNAC of salivary gland lesions from 2 academic centers. METHODS A retrospective analysis was conducted on 1729 salivary gland FNAC specimens that were diagnosed over an 8-year period from January 2008 to March 2015. All samples were processed either with liquid-based cytology alone or in combination with air-dried, Diff-Quik–stained or alcohol-fixed, Papanicolaou-stained smears. RESULTS Surgical excision was performed in 709 of 1749 FNACs (41%) that were diagnosed as nondiagnostic/inadequate (n = 29), benign (n = 111), neoplasm (n = 453), atypical (n = 15), suspicious for malignancy (n = 28), and malignant (n = 73). The overall concordance between cytologic and histologic diagnoses was 92.2%, with 91.8% concordance in the benign category and 89.5% concordance in cases diagnosed as suspicious for malignancy and malignant. The most frequent benign and malignant lesions were pleomorphic adenoma and squamous cell carcinoma, respectively. There were 46 false-negative and 13 false-positive results, leading to an overall specificity of 97.6% and diagnostic accuracy of 91.3%. CONCLUSIONS FNAC is a reliable diagnostic modality for the diagnosis and management of salivary gland lesions based on its high specificity and diagnostic accuracy. Cancer Cytopathol 2016. © 2016 American Cancer Society.

BACKGROUND Mutational analysis is reshaping the practice of fine-needle aspiration cytology for the diagnosis of thyroid nodules. The v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) valine (V) to glutamic acid (E) substitution at codon 600 (BRAFV600E) is the most effective diagnostic/prognostic marker and is used mainly for papillary thyroid carcinomas (PTCs). Although BRAFV600E represents 95% of all BRAF mutations, uncommon BRAF mutations have been identified in thyroid carcinomas. For the current study, the authors evaluated morphologic (plump pink cells and sickle-shaped nuclei) anti-BRAFV600E antibody (VE1) immunocytochemical and molecular findings of BRAF mutations in PTCs and in the follicular variant of PTC (FVPC). METHODS Between January 2013 and June 2014, there were 150 cytologic samples with surgical follow-up at the authors' institution. BRAF mutations, which were identified using liquid-based cytology, were classified into wild-type BRAF, BRAFV600E, and uncommon BRAF mutations. All clinicopathologic correlations between BRAF and FVPCs were analyzed. RESULTS Forty-four of 150 samples were identified as benign histologic lesions, and the authors focused on the 106 cytologic samples from patients who had malignant outcomes (60 PTCs and 46 FVPCs). The series included 16 follicular neoplasms, 36 samples diagnosed as suspicious of malignancy, and 54 samples diagnosed as positive for malignancy. The BRAFV600E mutation was detected in 17.4% of FVPCs and in 66.6% of PTCs, whereas uncommon BRAF mutations were detected only in FVPCs. Plump pink cells and VE1 expression were not identified in samples that had uncommon BRAF mutations. VE1 immunocytochemistry yielded positive results in all 36 samples that had the BRAFV600E mutation. CONCLUSIONS Uncommon BRAF mutations were observed only in FVPCs and were linked to less aggressive behavior. Negative/weak VE1 expression was observed in both wild-type and uncommon BRAF mutations. The current investigation did not reveal any plump cells or morphologic BRAF findings in samples that had uncommon BRAF mutations. In the authors' experience, BRAF mutations detected by DNA methods were more accurate in identifying FVPCs. Cancer (Cancer Cytopathol) 2015;123:593–602. © 2015 American Cancer Society.

BACKGROUND: Fine-needle aspiration cytology (FNAC) of serous membrane effusions may fulfil a challenging role in the diagnostic analysis of both primary and metastatic disease. From this perspective, liquid-based cytology (LBC) represents a feasible and reliable method for empowering the performance of ancillary techniques (ie, immunocytochemistry and molecular testing) with high diagnostic accuracy. METHODS: In total, 3171 LBC pleural and pericardic effusions were appraised between January 2000 and December 2013. They were classified as negative for malignancy (NM), suspicious for malignancy (SM), or positive for malignancy (PM). RESULTS: The cytologic diagnoses included 2721 NM effusions (2505 pleural and 216 pericardic), 104 SM effusions (93 pleural and 11 pericardic), and 346 PM effusions (321 pleural and 25 pericardic). The malignant pleural series included 76 unknown malignancies (36 SM and 40 PM effusions), 174 metastatic lesions (85 SM and 89 PM effusions), 14 lymphomas (3 SM and 11 PM effusions), 16 mesotheliomas (5 SM and 11 SM effusions), and 3 myelomas (all SM effusions). The malignant pericardic category included 20 unknown malignancies (5 SM and 15 PM effusions), 15 metastatic lesions (1 SM and 14 PM effusions), and 1 lymphoma (1 PM effusion). There were 411 conclusive immunocytochemical analyses and 47 molecular analyses, and the authors documented 88% sensitivity, 100% specificity, 98% diagnostic accuracy, 98% negative predictive value, and 100% positive predictive value for FNAC. CONCLUSIONS: FNAC represents a primary diagnostic tool for effusions and a reliable approach with which to determine the correct follow-up. Furthermore, LBC is useful for ancillary techniques, such as immunocytochemistry and molecular analysis, with feasible diagnostic and predictive utility. Cancer (Cancer Cytopathol) 2015;000:000-000. V C 2015 American Cancer Society.

The introduction of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) affects the risk of malignancy (ROM) mostly in the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) categories. In this multi-institutional, retrospective study, the authors investigated variations in the impact of an NIFTP diagnosis on the associated ROM for each TBSRTC category with an emphasis on the influence of pathologist and institutional diagnostic thresholds on the ROM.Baseline data on cytology and histology diagnostic categories were collected over a 3-year period at 3 academic center hospitals (institutions A, B, and C). Histology slides for all cases diagnosed as follicular variant of papillary thyroid carcinoma (FVPTC) were re-reviewed at each institution, and those that qualifying as NIFTP were separated from other PTCs.The collective case cohort from the 3 institutions included 15,973 thyroid fine-needle aspiration cytology (FNAC) specimens and 5090 thyroid surgical resection specimens. Significant differences in baseline cytology and histology data were noted among the 3 institutions. The number of cases classified as NIFTP compared with FVPTC was highly variable (institution A, 14%; institution B, 39%; and institution C, 12%). For 3250 resected thyroid nodules with a previous FNAC diagnosis, the average decrease in ROM after the exclusion of NIFTP for all TBSRTC categories was as follows: institution A, 9.8%; institution B, 3.9%; and institution C, 1.3%.The institutional frequency of NIFTP histopathology diagnosis and cytology baseline data will impact the ROM associated with specific FNAC diagnoses, especially among the indeterminate TBSRTC categories. The range of ROM for each TBSRTC diagnostic category is reflective of the inherent diagnostic thresholds and interobserver and interinstitutional variability in the diagnosis of thyroid lesions. Cancer Cytopathol 2018;126:20-6. © 2017 American Cancer Society.

BACKGROUND The BRAFV600E mutation is the most common diagnostic/prognostic marker in papillary thyroid carcinoma (PTC). Its evaluation is typically performed with DNA-based techniques; nonetheless, a few articles have recently proposed the morphological prediction of BRAFV600E in histological PTCs. We investigated this morphological parameter in our cytological series. METHODS We re-analyzed all 72 cytohistological samples diagnosed as positive for malignancy (favoring PTC) on fine-needle aspiration cytology from January 2012 to December 2013. We included 22 male patients and 50 female patients. The cytological cases were processed with liquid-based cytology. We performed molecular analysis and immunocytochemistry for the VE1 BRAFV600E antibody. RESULTS We reported 47 mutated cases and 25 wild-type (WT) cases with 100% cytohistological concordance. The cytological evaluations revealed plump cells (abundant eosinophilic cytoplasm and PTC nuclei) in all 47 mutated cases, with only 6 having a focal plump cell component (≤20% cells). Furthermore, 5 of the 25 WT cases showed focal plump cells. A distinctive sickle nuclear shape was found only in the mutated cases. VE1 yielded 100% positivity for all 24 mutated cases that were tested, including 3 cases with focal plump cells. CONCLUSIONS We demonstrated that the BRAFV600E mutation might be predicted in cytological samples on the basis of some specific morphological features. Although the detection of plump cells (mainly focal) was also observed in WT cases, the detection of sickle-shaped nuclei provided the highest specificity and sensitivity as a predictive mutational parameter. These morphological features might be a valid tool for selecting cases for molecular analysis. Cancer (Cancer Cytopathol) 2014;122:883–891. © 2014 American Cancer Society.

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.A search of the pathology database from 6 academic institutions identified 184 FNAB cases of nonlymphomatous SMSG.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.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.

Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) represents a challenge for the diagnosis and management of thyroid carcinoma. Some authors have proposed histological criteria that are able to distinguish NIFTPs from invasive follicular variant of papillary thyroid carcinoma (I-FVPTC). Hence, NIFTPs may have repercussions in the diagnostic categories on fine-needle aspiration. In the current study, the authors evaluated the criteria for NIFTPs on liquid-based cytology samples.The authors recorded all 61 liquid-based cytology samples proved to be histological FVPTC between January 2013 and March 2016 and analyzed the architectural, cytoplasmic, and nuclear parameters. They compared them with a cohort of 40 PTC cases and 20 follicular adenoma cases.The authors reported 37 NIFTP cases and 24 I-FVPTC cases at histology. The cytological diagnoses of follicular nodules in the NIFTP cases were twice those found in the I-FVPTC cases (54.1% vs 29.2%). The number of positive for malignancy cases among the NIFTPs were approximately half those of I-FVPTC cases. When compared with I-FVPTCs, 70% of the NIFTP cases demonstrated a nuclear size20 μm (P = .025) and rarely exhibited grooves (13% vs 42%; P = .009). The authors found 100% of cases with wild-type BRAF gene in NIFTP cases versus 38.4% in mutated I-FVPTC cases (P = .046). The cytoplasmic features might help to discriminate NIFTPs from follicular adenomas but not from I-FVPTCs (P.05). A predominant microfollicular pattern was recognized in both NIFTPs and I-FVPTCs (97.3% vs 100%).The majority of NIFTPs appear to be devoid of nuclear pseudoinclusions and papillary structures, thereby allowing the inclusion in the follicular nodule cases. Nuclear size and microfollicular clusters may suggest the discrimination between NIFTPs and I-FVPCs. Cancer Cytopathol 2016;124:699-710. © 2016 American Cancer Society.

Fine-needle aspiration cytology (FNAC) has proven its value as an essential step in the diagnosis of salivary gland lesions. Although the majority of salivary gland lesions, especially those that are common and benign, can be diagnosed with ease on FNAC, limited cellularity and morphologic lesion heterogeneity can pose diagnostic challenges and lead to false-positive and false-negative diagnoses. This study presents the institutional experience of FNAC of salivary gland lesions from 2 academic centers.A retrospective analysis was conducted on 1729 salivary gland FNAC specimens that were diagnosed over an 8-year period from January 2008 to March 2015. All samples were processed either with liquid-based cytology alone or in combination with air-dried, Diff-Quik-stained or alcohol-fixed, Papanicolaou-stained smears.Surgical excision was performed in 709 of 1749 FNACs (41%) that were diagnosed as nondiagnostic/inadequate (n = 29), benign (n = 111), neoplasm (n = 453), atypical (n = 15), suspicious for malignancy (n = 28), and malignant (n = 73). The overall concordance between cytologic and histologic diagnoses was 92.2%, with 91.8% concordance in the benign category and 89.5% concordance in cases diagnosed as suspicious for malignancy and malignant. The most frequent benign and malignant lesions were pleomorphic adenoma and squamous cell carcinoma, respectively. There were 46 false-negative and 13 false-positive results, leading to an overall specificity of 97.6% and diagnostic accuracy of 91.3%.FNAC is a reliable diagnostic modality for the diagnosis and management of salivary gland lesions based on its high specificity and diagnostic accuracy. Cancer Cytopathol 2016;124:388-96. © 2016 American Cancer Society.

The current study compared ThinPrep urinary cytology and conventional cytospin urinary cytology in the diagnosis of bladder cancer, applying the Paris System for Reporting Urinary Cytology.Between January 2010 and December 2011, a total of 3659 urine samples were processed using conventional cytospin methods. Between January 2012 and December 2013, a total of 4186 urine cytological cases were analyzed using ThinPrep methods. In 131 cases (65 processed by conventional cytospin and 66 processed by ThinPrep), a subsequent biopsy was performed. The authors reclassified these cases according to the Paris System and an analysis between the 2 methods with regard to bladder biopsies was performed.No significant differences were observed in terms of sensitivity and specificity between the 2 methods in cases with positive cytology for high-grade carcinoma. According to the Paris System, cases of atypical urothelial cells (AUC) and atypical urothelial cells suspicious for high-grade carcinoma (AUC-H) that were processed using cytospin did not correlate with urothelial carcinoma or with negative biopsies; conversely, the AUC cases processed using ThinPrep appeared to correlate with negative histological biopsies or low-grade urothelial carcinoma.The results of the current study demonstrated that according to the Paris System, there were no significant differences in sensitivity or specificity for the diagnosis of high-grade urothelial carcinoma or AUC-H between the 2 methods. Cases of AUC should be easy to recognize using Thin Prep rather than cytospin and only AUCs diagnosed with ThinPrep were found to be statistically linked to negative cases for carcinoma or with low-grade urothelial carcinoma. Cancer Cytopathol 2016;124:519-23. © 2016 American Cancer Society.

Fine-needle aspiration cytology (FNAC) of serous membrane effusions may fulfil a challenging role in the diagnostic analysis of both primary and metastatic disease. From this perspective, liquid-based cytology (LBC) represents a feasible and reliable method for empowering the performance of ancillary techniques (ie, immunocytochemistry and molecular testing) with high diagnostic accuracy.In total, 3171 LBC pleural and pericardic effusions were appraised between January 2000 and December 2013. They were classified as negative for malignancy (NM), suspicious for malignancy (SM), or positive for malignancy (PM).The cytologic diagnoses included 2721 NM effusions (2505 pleural and 216 pericardic), 104 SM effusions (93 pleural and 11 pericardic), and 346 PM effusions (321 pleural and 25 pericardic). The malignant pleural series included 76 unknown malignancies (36 SM and 40 PM effusions), 174 metastatic lesions (85 SM and 89 PM effusions), 14 lymphomas (3 SM and 11 PM effusions), 16 mesotheliomas (5 SM and 11 SM effusions), and 3 myelomas (all SM effusions). The malignant pericardic category included 20 unknown malignancies (5 SM and 15 PM effusions), 15 metastatic lesions (1 SM and 14 PM effusions), and 1 lymphoma (1 PM effusion). There were 411 conclusive immunocytochemical analyses and 47 molecular analyses, and the authors documented 88% sensitivity, 100% specificity, 98% diagnostic accuracy, 98% negative predictive value, and 100% positive predictive value for FNAC.FNAC represents a primary diagnostic tool for effusions and a reliable approach with which to determine the correct follow-up. Furthermore, LBC is useful for ancillary techniques, such as immunocytochemistry and molecular analysis, with feasible diagnostic and predictive utility.