Comparison of residual cancer burden, American Joint Committee on Cancer staging and pathologic complete response in breast cancer after neoadjuvant chemotherapy: results from the I-SPY 1 TRIAL (CALGB 150007/150012; ACRIN 6657).

PURPOSE: Several pathologic staging systems characterize residual tumor in patients undergoing neoadjuvant chemotherapy for breast cancer. Pathologic complete response (pCR) is now accepted by the Food and Drug Administration as an endpoint for granting accelerated drug approval. Two other systems of post-neoadjuvant pathologic tumor staging-residual cancer burden (RCB) and the American Joint Committee on Cancer post-neoadjuvant therapy staging system (yAJCC)-have been developed to characterize residual tumors when patients do not achieve pCR. The optimal system and the ways in which these systems complement each other have not been fully determined. METHODS: Using data from the I-SPY 1 TRIAL, we compared pCR, RCB, and yAJCC as predictors of early recurrence-free survival (RFS) to identify ways to improve post-neoadjuvant pathologic evaluation. RESULTS: Among 162 patients assessed, pCR identified patients at lowest risk of recurrence, while RCB and yAJCC identified patients at highest risk. Hormone-receptor (HR) and HER2 subtypes further improved risk prediction. Recursive partitioning indicated that triple-negative or HER2+ patients with yAJCC III or RCB 3 have the highest recurrence risk, with an RFS of 27%. Our analysis also highlighted discrepancies between RCB and yAJCC stratification: 31% of patients had discrepant RCB and yAJCC scores. We identified differential treatment of lymph node involvement and tumor cellularity as drivers of these discrepancies. CONCLUSIONS: These data indicate that there is benefit to reporting both RCB and yAJCC for patients in order to identify those at highest risk of relapse.

Chemotherapy response and recurrence-free survival in neoadjuvant breast cancer depends on biomarker profiles: results from the I-SPY 1 TRIAL (CALGB 150007/150012; ACRIN 6657).

Neoadjuvant chemotherapy for breast cancer allows individual tumor response to be assessed depending on molecular subtype, and to judge the impact of response to therapy on recurrence-free survival (RFS). The multicenter I-SPY 1 TRIAL evaluated patients with ≥ 3 cm tumors by using early imaging and molecular signatures, with outcomes of pathologic complete response (pCR) and RFS. The current analysis was performed using data from patients who had molecular profiles and did not receive trastuzumab. The various molecular classifiers tested were highly correlated. Categorization of breast cancer by molecular signatures enhanced the ability of pCR to predict improvement in RFS compared to the population as a whole. In multivariate analysis, the molecular signatures that added to the ability of HR and HER2 receptors, clinical stage, and pCR in predicting RFS included 70-gene signature, wound healing signature, p53 mutation signature, and PAM50 risk of recurrence. The low risk signatures were associated with significantly better prognosis, and also identified additional patients with a good prognosis within the no pCR group, primarily in the hormone receptor positive, HER-2 negative subgroup. The I-SPY 1 population is enriched for tumors with a poor prognosis but is still heterogeneous in terms of rates of pCR and RFS. The ability of pCR to predict RFS is better by subset than it is for the whole group. Molecular markers improve prediction of RFS by identifying additional patients with excellent prognosis within the no pCR group.

Papillary thyroid carcinomas with and without BRAF V600E mutations are morphologically distinct.

AIMS: The BRAF V600E mutation resulting in the production of an abnormal BRAF protein has emerged as the most frequent genetic alteration in papillary thyroid carcinomas (PTCs). This study was aimed at identifying distinctive features in tumours with and without the mutation. METHODS AND RESULTS: Thirty-four mutation-positive and 22 mutation-negative tumours were identified by single-strand conformation polymorphism of the amplified BRAF V600E region in the tumour DNA. Mutation-positive tumours were more common in patients older than 45 years (24/33, P = 0.05), in classic (23/30, P = 0.01), tall cell (4/5) and oncocytic/Warthin-like (2/2) variants of PTC, and in subcapsular sclerosing microcarcinomas (4/4). In contrast, all 12 follicular variants (P < 0.0001) and two diffuse sclerosing variants were negative for the mutation. Mutation-positive tumours displayed infiltrative growth (32/34, P = 0.02), stromal fibrosis (33/34, P < 0.001), psammoma bodies (17/34, P = 0.05), plump eosinophilic tumour cells (22/34, P = 0.01), and classic fully developed nuclear features of PTC (33/34, P = 0.0001). Encapsulation was significantly associated with mutation-negative tumours (15/22, P = 0.02). CONCLUSIONS: BRAF V600E mutation-positive and negative PTCs are morphologically different. Recognition of their morphology may help in the selection of appropriate tumours for genetic testing.

BRAF mutation testing of thyroid fine-needle aspiration specimens enhances the predictability of malignancy in thyroid follicular lesions of undetermined significance.

BACKGROUND/OBJECTIVE: The Bethesda 2007 Thyroid Cytology Classification defines atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) as a heterogeneous category of cases that are neither convincingly benign nor sufficiently atypical for a diagnosis of follicular neoplasm or suspicious for malignancy. At our institution, we refer to these cases as 'indeterminate' and they are further subclassified into two categories. BRAF mutation occurs in 40-60% of papillary thyroid carcinoma (PTC). In this study, we examined cases in the AUS/FLUS category in correlation with BRAF mutation analysis and surgical pathology outcome. STUDY DESIGN: Thyroid fine-needle aspiration (FNA) cytology specimens interpreted as 'indeterminate' were selected from our files, and available remnants of thin-layer processed specimens were used for BRAF mutation analysis. Surgical pathology reports were reviewed for the final outcomes in these patients. RESULTS: Of the 84 indeterminate cases with BRAF mutation analysis, only 49 had follow-up with surgical intervention. Sixteen cases had BRAF mutation. All of the BRAF-positive cases had a final diagnosis of PTC. CONCLUSIONS: The sensitivity and specificity of BRAF mutation in detecting PTC in FNA specimens with indeterminate diagnosis was 59.3 and 100%, respectively, while the positive and negative predictive values were 100 and 65.6%, respectively. The limited data supports the use of BRAF mutation analysis to predict the risk of malignancy in patients with indeterminate thyroid FNAs.

Validating cell-free DNA from supernatant for molecular diagnostics on cytology specimens.

BACKGROUND: Cytology specimens are often used for biomarker testing in the setting of neoplasia. On occasion, formalin-fixed paraffin-embedded (FFPE) cell blocks unfortunately may not yield sufficient material for testing. Recent studies have suggested that residual supernatant fluid from cell block preparation is a valuable source of DNA: both cellular and cell-free DNA (cfDNA). In the present study, the use of cfDNA from supernatant is compared against DNA from FFPE materials. METHODS: cfDNA was extracted prospectively from residual supernatants of 30 cytology samples (29 neoplastic cases and 1 benign ascitic fluid from a patient with a history of melanoma). Samples were tested using clinically validated next-generation-sequencing platforms and the results were compared with data from paired FFPE cell blocks in a real-time prospective clinical setting. Thirteen samples were tested on an amplicon-based assay (Solid Tumor Hotspot), and 17 samples were tested using a comprehensive capture-based assay (UW-Oncoplex). RESULTS: Neoplastic content was estimated by mutational variant allele fraction, with a mean content of 24.0% and 25.8% in supernatant and FFPE, respectively. The variant concordance between paired samples was 90%, and identical results were detected in both supernatant and FFPE samples in 74% of cases. CONCLUSIONS: This study confirmed that cfDNA from supernatant is a viable alternative to FFPE cell blocks for molecular biomarker testing using both amplicon-based and capture-based assays with potential for decreasing additional tissue sampling and faster turnaround time.

Anal-rectal cytology: correlation with human papillomavirus status and biopsy diagnoses in a population of HIV-positive patients.

OBJECTIVES: We describe the cytological distribution of disease, correlate cytological diagnoses with human papillomavirus (HPV) DNA status and surgical biopsy diagnoses, determine if CD4 counts correlate with lesion severity, and compare anal-rectal data of HIV-infected patients (primarily men) with cervical data. MATERIALS AND METHODS: A retrospective search of the computerized database identified 118 HIV-positive patients who had anal-rectal cytology. Cytology results were compared with available follow-up data including repeat anal-rectal cytology tests, surgical biopsy, CD4 counts, and HPV DNA polymerase chain reaction-based genotyping. RESULTS: Cytological diagnoses included 3% unsatisfactory for diagnosis, 41% negative for intraepithelial lesion or malignancy (NILM), 23% atypical squamous cells of undermined significance (ASC-US), 31% low-grade squamous intraepithelial lesion (LSIL), and 2% high-grade squamous intraepithelial lesion (HSIL) (ASC-US/squamous intraepithelial lesion, 0.7:1). Two anal intraepithelial neoplasia (AIN) II, 10 AIN III, and 1 invasive squamous cell carcinoma were histologically detected (11%). The majority of AIN II was preceded by LSIL, 54%; ASC-US, 15%; and HSIL, 8%. The false-negative fraction was 23%. Sensitivity, specificity, negative predictive value, and positive predictive value were 92%, 8%, 33%, and 67%, respectively. Of those HPV tested concurrent with the first cytology specimen, 48% NILM, 78% ASC-US, and 100% LSIL were HPV positive. Mean CD4 counts (per microliter) were lower in patients with HSIL (243 [SD, 65]) compared with LSIL (400 [SD, 261]) and NILM (428 [SD, 232]). CONCLUSIONS: Anal-rectal cytology is a useful screening test. A high percentage of AIN II lesions were detected in this at-risk population, and the majority was detected following cytological abnormality.

Moving forward-the 2019 ASCCP Risk-Based Management Consensus Guidelines for Abnormal Cervical Cancer Screening Tests and Cancer Precursors and beyond: implications and suggestions for laboratories.

The 2019 ASCCP Risk Based Management Consensus Guidelines for prevention of cervical cancer promote clinical management recommendations aligned with our increased understanding of HPV biology and cervical carcinogenesis. They employ HPV-based testing as the basis for risk estimation, allow for personalized risk-based management by incorporating knowledge of current results with prior results, and streamline incorporation of new test methods as they are validated. They continue to support the principles of "equal management for equal risk" and "balancing harms and benefits" adopted in the 2012 version of the guidelines. These updated guidelines will be able to adjust for decreasing CIN3+ risks as more patients who received HPV vaccination reach screening age. Pathology organizations were closely involved in the development of these guidelines. Herein the pathologists who served as representatives to the 2019 ASCCP guidelines steering committee and workgroups, summarize the changes that are relevant to laboratories, pathologists, and cytotechnologists. Prior relevant screening and reporting recommendations that have not been widely and/or inconsistently adopted by laboratories are also discussed and considerations for modification of laboratory practices offered.

Rapid Validation of Telepathology by an Academic Neuropathology Practice During the COVID-19 Pandemic.

CONTEXT.­: The coronavirus disease 19 (COVID-19) pandemic is placing unparalleled burdens on regional and institutional resources in medical facilities across the globe. This disruption is causing unprecedented downstream effects to traditionally established channels of patient care delivery, including those of essential anatomic pathology services. With Washington state being the initial North American COVID-19 epicenter, the University of Washington in Seattle has been at the forefront of conceptualizing and implementing innovative solutions in order to provide uninterrupted quality patient care amidst this growing crisis. OBJECTIVE.­: To conduct a rapid validation study assessing our ability to reliably provide diagnostic neuropathology services via a whole slide imaging (WSI) platform as part of our departmental COVID-19 planning response. DESIGN.­: This retrospective study assessed diagnostic concordance of neuropathologic diagnoses rendered via WSI as compared to those originally established via traditional histopathology in a cohort of 30 cases encompassing a broad range of neurosurgical and neuromuscular entities. This study included the digitalization of 93 slide preparations, which were independently examined by groups of board-certified neuropathologists and neuropathology fellows. RESULTS.­: There were no major or minor diagnostic discrepancies identified in either the attending neuropathologist or neuropathology trainee groups for either the neurosurgical or neuromuscular case cohorts. CONCLUSIONS.­: Our study demonstrates that accuracy of neuropathologic diagnoses and interpretation of ancillary preparations via WSI are not inferior to those generated via traditional microscopy. This study provides a framework for rapid subspecialty validation and deployment of WSI for diagnostic purposes during a pandemic event.

A Proposal for the Performance, Classification, and Reporting of Lymph Node Fine-Needle Aspiration Cytopathology: The Sydney System.

BACKGROUND: The evaluation of lymph nodes (LN) by fine-needle aspiration cytology (FNAC) is routinely used in many institutions but it is not uniformly accepted mainly because of the lack of guidelines and a cytopathological diagnostic classification. A committee of cytopathologists has developed a system of performance, classification, and reporting for LN-FNAC. METHODS: The committee members prepared a document that has circulated among them five times; the final text has been approved by all the participants. It is based on a review of the international literature and on the expertise of the members. The system integrates clinical and imaging data with cytopathological features and ancillary techniques. The project has received the endorsement and patronage of the International Academy of Cytology and the European Federation of the Cytology Societies. RESULTS: Clinical, imaging, and serological data of lymphadenopathies, indications for LN-FNAC, technical procedures, and ancillary techniques are evaluated with specific recommendations. The reporting system includes two diagnostic levels. The first should provide basic diagnostic information and includes five categories: inadequate/insufficient, benign, atypical lymphoid cells of undetermined/uncertain significance, suspicious, and malignant. For each category, specific recommendations are provided. The second diagnostic level, when achievable, should produce the identification of specific benign or malignant entities and additional information by utilizing ancillary testing. CONCLUSION: The authors believe that the introduction of this system for performing and reporting LN-FNAC may improve the quality of the procedure, the report, and the communication between cytopathologists and the clinicians. This system may lead to a greater acceptance and utilization of LN-FNAC and to a better interdisciplinary understanding of the results of this procedure.

Specimen radiographs assist in identifying and assessing resection margins of occult breast carcinomas.

For carcinoma specimens with non-grossly identifiable lesions such as microcalcifications, difficulties may be encountered in locating these abnormalities and sampling the margins that are at risk. This is magnified in the case of skin-sparing procedures where the margin is a much greater surface area and is the operation of choice in patients with diffuse microcalcifications and/or multifocal in situ disease. The objective of this study was to determine the efficacy of specimen radiographs of mastectomy in identifying occult carcinoma associated with microcalcifications and assessing the resection margins. We reviewed the histology and corresponding specimen radiographs of 16 patients with diffuse and widespread microcalcifications and who underwent skin-sparing mastectomy. After the specimens were serially sectioned, specimen radiographs of each section of the specimens were obtained with digital mammography equipment. Findings in the specimen radiographs were used to direct the histologic sampling of the specimens. On gross examination, two (12.5%) mastectomy specimens had identifiable discreet masses; the lesions were 4 and 7 mm, respectively. Histologic examination revealed the presence of carcinoma in 13 (81%) cases; seven with both infiltrating and in situ carcinoma and six with in situ carcinoma alone. The remaining three patients demonstrated only changes of biopsy site without any residual carcinoma. Microcalcifications were associated with in situ carcinoma in all malignant cases. Among the 12 cases with microcalcifications present at or within 2 mm of the margins, in situ carcinoma was present at the margins in three cases and located within 2 mm of the margins in two cases. All margins were negative in all cases with microcalcifications that were at least 1 cm away from the resection margins. The average number of tissue blocks examined was 16.6 +/- 5.4. The average number of tissue blocks sampled among randomly selected mastectomy specimens was 15.2 +/- 5.4. There was no statistically significant difference in the number of blocks between mastectomy cases with specimen radiographs taken and those without (t-test). Our study suggests that specimen radiographs may assist in identifying occult breast carcinoma associated with microcalcifications and assessing the resection margins without increased sampling.

Histologic grading of invasive lobular carcinoma: does use of a 2-tiered nuclear grading system improve interobserver variability?

The Nottingham histologic grade (NHG) is a prognostic marker for infiltrating ductal carcinoma. Its usefulness for invasive lobular carcinoma (ILC) has been less clear, given that 2 of the 3 parameters, tubule formation and mitotic activity, show little variation in ILC, placing much of the emphasis on nuclear grade. We have previously reported a trend for improved overall and relapse-free survival in patients with ILC of low nuclear grade, as classified by a 2-tiered nuclear grading system. Given the inherent potential for interobserver variability with any grading system, the goal of this study is to compare interobserver variability in the grading of ILC using a 2-tiered nuclear grade vs the NHG. Thirty-eight cases of ILC were graded independently by 5 pathologists using NHG criteria. Tumors were also categorized by a nuclear grading system as low grade (grade 1 nuclei) or high grade (grades 2-3 nuclei). Pairwise kappa values and interobserver agreement rates were calculated for both NHG and nuclear grade. Results were compared using the paired t test. Mean interobserver agreement rates and kappa values improved with use of the nuclear grading system as compared to NHG (83% vs 70%, 0.4738 vs 0.3228, respectively). The differences between the 2 were statistically significant. Because histologic grade has significant prognostic implications for patients with breast cancer, accurate reporting is paramount. For ILC, where use of the NHG places substantial weight on nuclear pleomorphism, a 2-tiered nuclear grading system may reduce interobserver variability yet still provide useful prognostic information.

p16 Improves interobserver agreement in diagnosis of anal intraepithelial neoplasia.

OBJECTIVES: Evaluation of anal intraepithelial neoplasia (AIN) is subjective. Previous studies have shown p16 and Ki-67 expressions to correlate with AIN grade. Biomarkers like p16 and Ki-67 may improve interobserver agreement. The objectives were (1) to determine the extent of interobserver agreement in evaluating AIN on routine hematoxylin and eosin (H&E) sections and (2) to test whether p16 and/or Ki-67 staining improve interobserver diagnostic agreement. MATERIALS AND METHODS: Seventy-seven anal specimens were retrieved. Sections were stained with monoclonal antibodies against p16 and Ki-67. Blind to the original diagnoses, 4 pathologists assessed H&E alone, p16 alone, Ki-67 alone, and all 3 simultaneously. Diagnoses were normal/reactive, AIN I/HPV, AIN II, and AIN III. Agreement was calculated using kappa and S statistics. RESULTS: Pathologists were board certified and had 2 to 25 years (mean = 13.6 years) of experience. Fair agreement was observed using H&E diagnosis alone (kappa = 0.38, S = 0.56). The p16 diagnostic evaluation demonstrated the highest agreement (kappa = 0.57, S = 0.73). Interobserver agreement for Ki-67 alone and for H&E/p16/Ki-67 combined were comparable to that of H&E alone (kappa = 0.4, S = 0.54 and kappa = 0.44, S = 0.62, respectively). When the pathologists' diagnoses for all diagnostic evaluations were compared with consensus diagnoses, the lowest average magnitude of disagreement was seen with Ki-67 alone, followed by p16 alone, H&E/p16/Ki-67 combined, and H&E alone. CONCLUSIONS: Interobserver agreement for diagnosis of AIN was fair when based solely on H&E preparation. p16 alone improved interobserver agreement and demonstrated superior agreement when compared with H&E, Ki-67, and H&E/p16/Ki-67 combined.

Cytological features of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP).

INTRODUCTION: The noninvasive encapsulated follicular variant of papillary carcinoma (EFVPC) was recently renamed a noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) because of its unique genetic alterations and biological behavior. The objective of this report is to help cytopathologists and cytotechnologists improve diagnostic accuracy and determine the need for cytogenetic studies during adequacy evaluation of thyroid fine-needle aspirations. MATERIALS AND METHODS: Fifty-five cases of surgery-proven noninvasive EFVPC with corresponding cytology material were reviewed. These cases were collected over 17 years, from 1999 to 2016. RESULTS: Thirty-four of 55 (61.8%) cases were diagnosed as follicular neoplasm or suspicious for follicular neoplasm on cytology. Eighty to ninety percent of cases showed scant colloid, cellular smears with small clusters of follicular cells with nuclear atypia including enlarged nuclei, oval-shaped nuclei, nuclear grooves, mild chromatin powdering, and rare nuclear pseudo-inclusions. CONCLUSIONS: NIFTP has unique features: cytologically similar to follicular neoplasms, and nuclear atypia falling between atypia of undetermined significance (category III) and suspicious for/and papillary thyroid carcinoma (category V/VI) (The Bethesda System for Reporting Thyroid Cytopathology).

Using a higher cutoff for the percentage of HER2+ cells decreases interobserver variability in the interpretation of HER2 immunohistochemical analysis.

The effect of using a 30% cutoff for the proportion of HER2+ cells on the interobserver variability in the interpretation of HER2 immunohistochemical results was evaluated. Immunostained sections from 96 cases of breast carcinoma were reviewed by 10 pathologists and scored as positive (3+) when uniform strong membranous staining was identified in at least 10% of tumor cells; the actual percentage of cells with such staining was also estimated. The agreement rates and the kappa values using a 30% cutoff were compared with those using a 10% cutoff. These proved to be higher in 62% and 66% of measurements, respectively, with average interobserver rates and kappa values of 72% and 0.54 using the 30% cutoff and 70% and 0.49 using the 10% cutoff (P=.001 for all comparisons). Using a 30% cutoff for the percentage of HER2+ cells by immunohistochemical analysis modestly decreased interobserver variability in the interpretation of HER2 immunohistochemical results.

The effect of neoadjuvant chemotherapy on histologic grade, hormone receptor status, and HER2/neu status in breast carcinoma.

The use of neoadjuvant chemotherapy prior to surgical resection for breast cancer is no longer restricted to patients with locally advanced disease. As preoperative treatment becomes more common, the question arises whether or not such therapy changes important tumor characteristics. The objective of our study is to compare histological grade, hormone receptor status, and HER2/neu expression pre- and post-therapy patients receiving preoperative neo-adjuvant chemotherapy. Forty patients status post-neoadjuvant treatment who had available archived pathologic material pre- and post-therapy were identified. Glass slides were reviewed retrospectively, and tumor grade, hormone receptor status, and HER2/neu expression were compared between the pre- and post-therapy specimens. No significant differences were noted between the pre- and post-specimens for two of the three parameters comprising the modified Bloom-Richardson grade, including degree of tubule formation (p = 0.062) and nuclear pleomorphism (p = 0.086). For mitotic activity, a decrease in score was observed between pre- and post-therapy specimens which was statistically significant (p = 0.021). However, there was no significant difference in the overall modified Bloom-Richardson grade (p = 0.118). Information was available regarding hormone receptor and HER2/neu status in 26 patients (65%). There was no significant difference between pre- and post-treatment specimens for hormone receptor status. However, there were more patients with HER2/neu overexpression after receiving neoadjuvant therapy (p = 0.027). Neoadjuvant therapy resulted in a significant decrease in mitotic count and an increase in the proportion of patients with HER2/neu overexpression. No significant changes were noted for the degree of tubule formation, nuclear pleomorphism, overall Bloom-Richardson score, and hormone receptor status. However, small sample size may be a limitation of these results.

Endoscopic ultrasound-guided fine needle aspiration is useful for nodal staging in patients with pleural mesothelioma.

Patients with malignant pleural mesothelioma and negative N2 stage lymph nodes may benefit from extrapleural pneumonectomy with adjuvant therapy. The objective of this study is to describe the use of EUS-FNA to determine N2 stage status in patients with mesothelioma and its impact in the management of such patients. Six patients (mean age, 62 yr; median age, 63 yr; range, 52-70 yr; 5 men; 1 woman) underwent EUS-FNA for staging of N2 lymph nodes from July 2000 to July 2006. Follow-up included operative notes, treatment summaries, and surgical pathology. Eight sites were aspirated: four subcarinal lymph nodes, three aorto-pulmonary window lymph nodes, and one paraesophageal mass. Two of 8 (25%) aspirates were positive for metastatic disease in two different patients. Two false negative EUS-FNAs were observed and were attributed to sampling error not diagnostic error. No complications were observed. EUS-FNA is a safe N2 node staging technique in patients with mesothelioma. A positive N2 lymph node by EUS-FNA may be a contraindication to definitive surgery in patients with malignant mesothelioma.

The Value of Negative Diagnosis in Thyroid Fine-Needle Aspiration: a Retrospective Study with Histologic Follow-Up.

The Bethesda System for reporting thyroid cytopathology (BSRTC) predicts an incidence of malignancy of less than 5% in thyroid nodules with a benign diagnosis on fine-needle aspiration (FNA). However, recent series have suggested that the true rate of malignancy might be significantly higher in this category of patients. We reviewed our experience by performing a retrospective analysis of patients with benign thyroid FNA results who underwent thyroidectomy between 2008 and 2013 at a large academic center. Information including demographics, ultrasound features, FNA diagnosis, and surgical follow-up information were recorded. Slides were reviewed on cytology-histology discrepant cases, and it was determined whether the discrepancy was due to sampling or interpretation error. A total of 802 FNA cases with a benign diagnosis and surgical follow-up were identified. FNA diagnoses included 738 cases of benign goiter and 64 cases of lymphocytic thyroiditis. On subsequent surgical resection, 144 cases were found to be neoplastic, including 117 malignant cases. False negative, defined as interpretation error and inadequate biopsy of the nodule harboring malignancy, was 6%. When cases of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) were excluded from the analysis, false-negative rate was 5%. When microPTC cases were excluded, false-negative rate was 3% and was slightly less than 3% when both microPTC and NIFTP cases were excluded from the analysis. Retrospective review of neoplastic cases showed that 57% were due to sampling error and 43% were due to interpretation error. Interpretation error was more likely to occur in follicular patterned neoplasms (75%), while sampling error was more common in non-follicular variants of papillary thyroid carcinoma (non-FVPTC) (61%). With the exclusion of microPTC, interpretation errors were still more likely to occur in follicular neoplasms (79%) but there was no significant difference in sampling error between non-FVPTC (37%) and follicular patterned neoplasms (42%). Tumor size was larger in cases with interpretation error (mean = 2.3 cm) compared to cases with sampling error (mean = 1.4 cm). This study shows that the false-negative rate of thyroid FNA at our institution is not significantly above the rate suggested by the BSRTC. Interpretation errors were more likely to occur in follicular patterned neoplasms, while non-FVPTC was more frequently found in false negative cases due to inadequate sampling.

Well differentiated grade 3 pancreatic neuroendocrine tumors compared with related neoplasms: A morphologic study.

BACKGROUND: Pancreatic neuroendocrine neoplasms with a Ki-67 labeling index greater than 20% were reclassified in 2017 by the World Health Organization into well differentiated (WD) and poorly differentiated grade 3 neuroendocrine carcinoma (NEC). The authors describe the cytologic features of grade 3 WD pancreatic neuroendocrine neoplasms compared with grade 2 neoplasms and NEC. METHODS: Fine-needle aspirates from 65 pancreatic neuroendocrine neoplasms were reviewed, and their cytomorphologic features were compared across grade 2, WD grade 3, and PD small cell type (PD-S), large cell type (PD-L), and type not otherwise specified (PD-NOS) neoplasms. RESULTS: The 65 aspirates consisted of 19 grade 2 neoplasms, 32 WD grade 3 neoplasms, and 14 NECs (6 PD-S, 5 PD-L, and 3 PD-NOS). The medians Ki-67 proliferation index was 11% (range, 3.2%-17%) in grade 2 neoplasms, 40% (range, 21%-89%) in WD grade 3 neoplasms, 80% (range, 63%-95%) in PD-S neoplasms, 39% (range, 25%-61%) in PD-L neoplasms, and 70% (range, 30%-80%) in PD-NOS neoplasms. Both grade 2 and WD grade 3 neoplasms were associated with plasmacytoid morphology and smooth nuclear contours, but WD grade 3 neoplasms had significant increases in abundant cytoplasm (72% vs 17%; P = .007), nuclear tangles (75% vs 42%; P = .006), and apoptosis (86% vs 58%; P = .005). Compared with NECs, WD grade 3 neoplasms had increased plasmacytoid morphology (75% vs 7%; P < .001), smooth nuclear contours (94% vs 64%; P = .02), round nuclei (59% vs 21%; P = .01), and less pleomorphism (13% vs 50%; P = .004), molding (9% vs 79%; P < .001), and necrosis (13% vs 43%; P = .003). WD grade 3 neoplasms had less pleomorphism (13% vs 50%; P = .04), less necrosis (13% vs 60%; P = .04), and more plasmacytoid morphology (75% vs 20%; P = .03) than PD-L. CONCLUSIONS: The prevalence of cytologic features differs in WD grade 3 pancreatic neuroendocrine neoplasms compared with grade 2 neoplasms and NECs, and these differences assist in the recognition of this newly classified entity. Cancer Cytopathol 2018;126:326-35. © 2018 American Cancer Society.

Assessment of cytologic differentiation in high-grade pancreatic neuroendocrine neoplasms: A multi-institutional study.

BACKGROUND: Well-differentiated (WD) and poorly differentiated (PD) pancreatic neuroendocrine neoplasms are biologically distinct entities with different therapies and prognoses. WD neoplasms with elevated proliferation (Ki-67 > 20%) have been shown to have an overlapping histology with PD neuroendocrine carcinomas. This study compared expert cytomorphologic assessments of differentiation in pancreatic neuroendocrine neoplasms in a multi-institutional study. METHODS: Fine-needle aspiration specimens from pancreatic neuroendocrine neoplasms (grade 2 [G2] and grade 3 [G3] according to the 2017 World Health Organization classification; n = 72) were diagnosed independently by 3 cytopathologists as WD or PD (poorly differentiated large cell type [PD-L] or poorly differentiated small cell type [PD-S]) purely on the basis of cytomorphology. Their diagnoses were compared with a final classification supported by immunohistochemistry (retinoblastoma (RB), death domain- associated protein (DAXX), and α thalassemia/mental retardation syndrome X-linked (ATRX) protein expression), targeted mutation analysis (Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets), prior history of G1/G2 histology, and consensus. RESULTS: The rate of agreement on differentiation was 38% (15 WD cases and 12 PD cases) for the 70 cases included (55 WD cases [n = 19 G2, n = 31 G3, and n = 5 could not be graded] and 15 PD cases [n = 6 PD-S, n = 6 PD-L, and n = 3 PD, not otherwise specified). Two cases could not be classified by the employed methods. PD carcinomas had a higher rate of agreement (10 of 15 [67%]) than WD neoplasms (15 of 55 [27%]). Round nuclei and plasmacytoid cells were associated with agreement for WD cases, whereas apoptosis and angulated nuclei were associated with disagreement. Necrosis was associated with agreement for PD cases. CONCLUSIONS: A purely morphologic approach to the distinction between G2 and G3 pancreatic neuroendocrine neoplasms based on cytology can be challenging, with disagreement found among experienced cytopathologists. Cancer Cytopathol 2018;126:44-53. © 2017 American Cancer Society.