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The recently published WHO Reporting System for Pancreaticobiliary Cytopathology (World Health Organization [WHO] System) is an international approach to the standardized reporting of pancreaticobiliary cytopathology, updating the Papanicolaou Society of Cytopathology System for Reporting Pancreaticobiliary Cytology (PSC System). Significant changes were made to the categorization of benign neoplasms, intraductal neoplasms, mucinous cystic neoplasms, and malignant neoplasms considered low grade. Benign neoplasms, such as serous cystadenoma, categorized as Neoplastic: benign in the PSC system, are categorized as Benign/negative for malignancy in the WHO system. Pancreatic neuroendocrine tumor, solid-pseudopapillary neoplasm, and gastrointestinal stromal tumor, categorized as Neoplastic: other in the PSC system, are categorized as Malignant in the WHO System in accord with their classification in the 5th edition WHO Classification of Digestive System Tumours (2019). The two new categories of Pancreaticobiliary Neoplasm Low-risk/grade and Pancreaticobiliary Neoplasm High-risk/grade are mostly limited to intraductal neoplasms and mucinous cystic neoplasms. Low-risk/grade lesions are mucinous cysts, with or without low-grade epithelial atypia. High-risk/grade lesions contain neoplastic epithelium with high-grade epithelial atypia. Correlation with clinical, imaging, and ancillary studies remains a key tenet. The sections for each entity are written to highlight key cytopathological features and cytopathological differential diagnoses with the pathologist working in low resource setting in mind. Each section also includes the most pertinent ancillary studies useful for the differential diagnosis. Sample reports are provided for each category. Finally, the book provides a separate section with risk of malignancy and management recommendations for each category to facilitate decision-making for clinicians., (© 2024 American Cancer Society.)

Cytologic examination of epithelial cells in cyst fluids from pancreatic mucinous cysts is the optimal method for identifying high-grade atypia (HGA), which may represent histologic high-grade dysplasia (HGD) or invasive carcinoma and thereby classify the cyst as high risk, warranting surgical resection. Cytologic features of HGA were previously described at our institution in 2013 and implemented thereafter, but performance of grading with these criteria has not yet been reported. In total, 1322 pancreatic cyst fluid specimens (2014-2021) were identified; all pathology reports and relevant clinical data were reviewed in detail; and 230 unique cysts (217 patients) contained neoplastic mucinous epithelium. Of the 230 cysts, 178 had low-grade atypia (LGA), and 52 had HGA. Ninety-seven cysts had histologic follow-up: 77 (79%) were resections and 20 (21%) were diagnostic surgical biopsies only. Moreover, 92 (95%) were confirmed neoplastic mucinous cysts, 3 were adenocarcinomas, and 2 were benign entities. Among histologically confirmed neoplastic mucinous cysts, 58 had low-grade dysplasia (LGD); 34 had HGD, of which 14 also had invasive carcinoma. A significantly higher proportion of cysts with HGA (63%) demonstrated at least HGD on follow-up compared to those with LGA (26%, P < .001). The sensitivity and specificity of HGA for accurately classifying a high-risk cyst were 54% and 81%, respectively. Of the 230 cysts, 146 (64%) cysts had corresponding next-generation sequencing results; 31% of HGA cysts harbored a high-risk mutation (TP53, CDKN2A, and/or SMAD4) vs 7% of LGA cysts (P < .001). Among cysts without histologic confirmation, 25% of HGA cysts had high-risk mutation vs 7% of LGA cysts. The grade of cytologic atypia was predictive of overall survival and recurrence-free survival (P < .001 and P = .020, respectively). Implementation of cytologic criteria for HGA in pancreatic mucinous cysts has relatively low sensitivity but modest specificity for classifying a high-risk cyst. Although high-risk mutations were more commonly found in cysts with HGA, their frequency is overall low. Thus, evaluating the degree of cytologic atypia, which is predictive of patient survival, provides significant value and informs patient outcomes., (Copyright © 2024 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Biopsy of benign and low-risk tumors of the kidney can be grouped into three distinct categories with different levels of risk, and the suggested diagnoses of these tumors should be tailored to their respective category., (© 2023 American Cancer Society.)

The risks of malignancy for cytologic categories in renal biopsy specimens differ from the risks in most other sites. There are obvious areas in which cytopathologists can do better at classifying these cases, and the routine use of immunohistochemistry and core-needle biopsy may improve the accuracy of the classification of these specimens., (© 2023 American Cancer Society.)

Introduction: Endoscopic biopsy procedures increasingly generate multiple tissue samples from multiple sites, and frequently retrieve concurrent cytologic specimens and small core needle biopsies. There is currently lack of consensus in subspecialized practices as to whether cytopathologists or surgical pathologists should review such samples, and whether the pathology findings should be reported together or separately., Materials and Methods: In December 2021, the American Society of Cytopathology convened the Re-Imagine Cytopathology Task Force to examine various workflows that would facilitate unified pathology reporting of concurrently obtained biopsies and improve clinical care., Results and Conclusions: This position paper summarizes the key points and highlights the advantages, challenges, and resources available to support the implementation of such workflows that result in "one procedure-one report"., (Copyright © 2023 American Society of Cytopathology. Published by Elsevier Inc. All rights reserved.)

Background: Intraductal papillary mucinous neoplasms (IPMNs) are a cystic precursor to pancreatic cancer. IPMNs deemed clinically to be at high-risk for malignant progression are frequently treated with surgical resection, and pathological examination of the pancreatectomy specimen is a key component of the clinical care of IPMN patients., Methods: Systematic literature reviews were conducted around eight topics of clinical relevance in the examination of pathological specimens in patients undergoing resection of IPMN., Results: This review provides updated perspectives on morphological subtyping of IPMNs, classification of intraductal oncocytic papillary neoplasms, nomenclature for high-grade dysplasia, assessment of T stage, distinction of carcinoma associated or concomitant with IPMN, role of molecular assessment of IPMN tissue, role of intraoperative assessment by frozen section, and preoperative evaluation of cyst fluid cytology., Conclusions: This analysis provides the foundation for data-driven approaches to several challenging issues in the pathology of IPMNs., (Copyright © 2023. Published by Elsevier B.V.)

The World Health Organization (WHO), the International Academy of Cytology, and the International Agency for Research on Cancer have developed an approach to standardized reporting of pancreaticobiliary cytopathology. The WHO Reporting System for Pancreaticobiliary Cytopathology (WHO System) revises the Papanicolaou Society of Cytopathology (PSC) System for Reporting Pancreaticobiliary Cytology published in 2015 and replaces the 6 PSC categories with 7 categories: "Insufficient/Inadequate/Nondiagnostic"; "Benign/Negative for malignancy"; "Atypical"; "Pancreaticobiliary neoplasm, low risk/grade (PaN-low)"; "Pancreatic neoplasm, high risk/grade (PaN-High)"; "Suspicious for malignancy"; and "Malignant". In the PSC system, there is a single category for "Neoplastic" lesions that includes 2 groups, 1 for benign neoplasms and 1 named "Neoplastic-other", dominated by premalignant intraductal neoplasms primarily intraductal papillary mucinous neoplasms and low-grade malignant neoplasms (pancreatic neuroendocrine tumors (PanNET) and solid pseudopapillary neoplasms (SPN). In the WHO System, benign neoplasms with virtually no risk of malignancy are included in the "Benign" category and low-grade malignancies (PanNET and SPN) are included in the "Malignant" category, as per the 5th edition of the WHO Classification of Digestive System Tumors, while the non-invasive pre-malignant lesions of the ducts are divided by the cytomorphological grade of the epithelium into PaN-low and PaN-high with distinctly different risks of malignancy. Within each category, key diagnostic cytopathologic features and the ancillary studies for diagnostic and prognostic evaluation, as well as the implications of diagnosis for patient care and management, are outlined. Reporting and diagnostic management options recognize the variations in the availability of diagnostic and prognostic ancillary testing modalities in low- and middle-income countries., (Copyright © 2023. Published by Elsevier Inc.)

The International Academy of Cytology has joined with the International Agency for Research on Cancer to bring together a group of experts in lung cytopathology to develop a WHO Reporting System for Lung Cytopathology (WHO System). This System aims to improve and standardize the reporting of cytopathology, facilitate communication between cytopathologists and clinicians, and improve patient care. The WHO System describes 5 categories for reporting lung cytopathology: 'Insufficient/Inadequate/Nondiagnostic', 'Benign', 'Atypical', 'Suspicious for malignancy', and 'Malignant', each one with a clear descriptive term, a definition, a risk of malignancy, and a suggested management algorithm. The key diagnostic cytopathologic features of each of the lesions within each category have been established by consensus through an Expert Editorial Board, who are also the authors of this review and selected for each reporting system and chosen based on their expertise in the field and/or diversity of geographical representation. Many other co-authors from around the world also contributed. The assignment of writing and editing responsibilities used the same model as that used for the WHO Classification of Tumours (https://whobluebooks.iarc.fr/about/faq/). The WHO System provides the best practice application of ancillary testing, including immunocytochemistry and molecular pathology, and guides in sampling and processing techniques to optimize the handling and preparation of specimens. The WHO System was created by the authors to be applicable globally and is based on cytomorphology with possibilities for additional diagnostic management of the patient. The authors are aware that local medical and pathology resources would differ, especially in low- and middle-income countries. The WHO Tumour Classification for Thoracic Tumors, Fifth Edition, is directly accessible through the online WHO System., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: The aim of this study was to describe our institutional experience with resected cystic tumors of the pancreas with emphasis on changes in clinical presentation and accuracy of preoperative diagnosis., Summary Background Data: Incidental discovery of pancreatic cystic lesions has increased and has led to a rise in pancreatic resections. It is important to analyze surgical outcomes from these procedures, and the prevalence of malignancy, pre-malignancy and resections for purely benign lesions, some of which may be unintended., Methods: Retrospective review of a prospective database spanning 3 decades. Presence of symptoms, incidental discovery, diagnostic studies, type of surgery, postoperative outcomes, and concordance between presumptive diagnosis and final histopathology were recorded., Results: A total of 1290 patients were identified, 62% female with mean age of 60 years. Fifty-seven percent of tumors were incidentally discovered. Ninety-day operative mortality was 0.9% and major morbidity 14.4%. There were 23 different diagnosis, but IPMN, MCN, and serous cystadenoma comprised 80% of cases. Concordance between preoperative and final histopathological diagnosis increased by decade from 45%, to 68%, and is presently 80%, rising in parallel with the use of endoscopic ultrasound, cytology, and molecular analysis. The addition of molecular analysis improved accuracy to 91%. Of misdiagnosed cases, half were purely benign and taken to surgery with the presumption of malignancy or premalignancy. The majority of these were serous cystadenomas., Conclusions: Indications and diagnostic work-up of cystic tumors of the pancreas have changed over time. Surgical resection can be performed with very low mortality and acceptable morbidity and diagnostic accuracy is presently 80%. About 10% of patients are still undergoing surgery for purely benign lesions that were presumed to be malignant or premalignant. Further refinements in diagnostic tests are required to improve accuracy., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

The International Academy of Cytology has joined with the International Agency for Research on Cancer (IARC) to bring together a group of experts in lung cytopathology to develop a WHO Reporting System for Lung Cytopathology (WHO System). This WHO System defines five categories for reporting lung cytopathology, that is, "Insufficient"/"Inadequate"/"Non-diagnostic," "Benign," "Atypical," "Suspicious for malignancy," and "Malignant," each with a clear descriptive term for the category, a definition, a risk of malignancy and a suggested management algorithm. The key diagnostic cytopathology features of each of the lesions within each category have been established by consensus and will be presented more fully in a subsequent IARC e-book and published hard cover book.The WHO System provides the best practice application of ancillary testing, including immunocytochemistry and molecular pathology, and provides a review to guide sampling and processing techniques to optimize the handling and preparation of the cytopathology sample emphasizing the cytomorphological differential diagnosis to aid low-resourced settings. The authors recognize that local medical and pathology resources will vary, particularly in low- and middle-income countries, and have developed the WHO System to make it applicable worldwide based on cytomorphology with options for further diagnostic management of the patient.The online WHO System provides a direct link to the WHO Tumour Classification for Thoracic Tumours 5th Edition. It will raise the profile and use of cytopathology by increasing awareness of its current role and its potential role in the era of personalized medicine based on molecular pathology utilizing "small biopsies." Ultimately, the System will improve patient care and outcomes.This System aims to improve and standardize the reporting of cytopathology, facilitate communication between cytopathologists and clinicians and improve patient care. The System is based on the current role of lung cytopathology and synthesizes the existing evidence while highlighting areas requiring further research and the future potential role of lung cytopathology., (© 2022 S. Karger AG, Basel.)

The World Health Organization (WHO), the International Academy of Cytology, and the International Agency for Research on Cancer, with expert contributors from around the world, present an international approach to standardized reporting of pancreaticobiliary cytopathology. This reporting system is one of the first in a series from various body sites that mirror the WHO Classification of Tumours series and provides an evidence-based terminology system with associated risk of malignancy and diagnostic management recommendation per diagnostic category. The WHO Reporting System for Pancreaticobiliary Cytopathology (WHO system) revises the Papanicolaou Society of Cytopathology (PSC) system for Reporting Pancreaticobiliary Cytology published in 2015 and replaces the six-tiered system with a seven-tiered system: "insufficient/inadequate/nondiagnostic"; "benign (negative for malignancy)," "atypical," "pancreaticobiliary neoplasm of low risk/low grade," "pancreatic neoplasm of high risk/high grade," "suspicious for malignancy," and "malignant." The principal differences between the WHO and the PSC systems revolve around the classification of neoplasia. In the PSC system, there was a single category for "neoplastic" lesions that includes two groups, one for "benign neoplasms" [primarily serous cystadenoma] and one named "other," dominated by premalignant intraductal neoplasms (primarily intraductal papillary mucinous neoplasms) and low-grade malignant neoplasms [pancreatic neuroendocrine tumors (PanNETs) and solid pseudopapillary neoplasms (SPNs)]. In the WHO system, benign neoplasms with virtually no risk of malignancy are included in the "benign" category and low-grade malignancies (PanNET and SPN) are included in the "malignant" category, as per the WHO Classification of Digestive System Tumours, thus leaving in the "neoplasm" category primarily those noninvasive premalignant lesions of the ductal system. These neoplasms are divided by the cytomorphological grade of the epithelium into low risk/low-grade and high risk/high-grade, with distinctly different risks of malignancy. As with the PSC system, the WHO system advocates close correlation with imaging and encourages incorporation of ancillary testing into the final diagnosis, such as biochemical (CEA and amylase) and molecular testing of cyst fluid and bile duct brushings. Key diagnostic cytopathological features of specific lesions or neoplasms, ancillary studies for diagnostic and prognostic evaluation, and implications of diagnosis for patient care and management are discussed. In addition, the WHO system includes reporting and diagnostic management options that recognize the variations in the availability of diagnostic and prognostic ancillary testing modalities in low- and middle-income countries, where cytopathology is particularly useful and is increasingly available in the absence of histopathological services., (© 2022 S. Karger AG, Basel.)

Background: Quality and safety are the foundation of the practice of cytopathology. Review of key performance indicator (KPI) data can shine a light on laboratory vulnerabilities and potential areas for targeted improvement. The rate and content of amendment reports is a frequently monitored KPI in anatomic pathology, but few have studied its value in cytopathology. The goal of this study was to examine the frequency, classification, and outcome of amendments for a large cytopathology laboratory., Methods: All amendment reports issued for cases during a 2-year period from July 2019 to June 2021 were included in the study. Amendments were classified into three error type root causes: Specimen Identification Error, General Report Defects, and Diagnostic Error., Results: A total of 202 amendment reports were issued equating to a rate of 0.275%. A total of 83 (41.1%) were gynecologic cases and 119 (58.9%) were nongynecologic cases. Within the gynecologic cases, 13 (15.7%) cases were due to Specimen Identification Error, 13 (15.7%) cases were due to Diagnostic Error, and 57 (68.7%) cases were due to General Report Defects. Within the nongynecologic cases, 15 (12.6%) cases were due to Specimen Identification Error, 30 (25.2%) cases were due to General Report Defects, and 74 (62.2%) cases were due to Diagnostic Error with 32 of these due to true diagnostic change. Discovery methods included following re-review after additional clinical information was provided, reinterpretation after additional ancillary testing was performed, or conference review. There was no correlation with years in practice., Conclusions: Studying amendment reports is an underrecognized and valuable quality assurance tool. Amendments can help provide information about types of errors, monitor laboratory processes, and help guide quality improvement endeavors., (© 2022 American Cancer Society.)

Cervical cytology has remained a diagnostically challenging area despite its long and widespread use. At least part of this challenge has stemmed from the cytomorphologic overlap between benign and neoplastic processes. The present review has highlighted select benign processes that present diagnostic pitfalls. For each of these, we have discussed the pertinent cytologic features and emphasized the morphologic clues that will aid in distinguishing the benign entities from the neoplastic processes they mimic., (Copyright © 2020 American Society of Cytopathology. Published by Elsevier Inc. All rights reserved.)

Introduction: Oil Red O (ORO) staining on cytologic specimens with calculation of the lipid-laden macrophage index (LLMI) is used as a part of the workup in a number of clinical settings, particularly when aspiration is of concern. As a part of ongoing internal quality improvement measures, the objective of the present study was to evaluate the interobserver agreement of the LLMI calculation and to identify factors that affect the variability of the calculation., Materials and Methods: There were 9 study participants, which included 3 trainees, 3 cytotechnologists, and 3 cytopathologists. Each participant reviewed 100 ORO-stained bronchoalveolar lavage slides and assigned an LLMI score to each case. The scores were categorized into 3 groups according to the associated aspiration risk: low, LLMI <40; intermediate, LLMI 40 to 90; and high, LLMI >90. The participants were also requested to note any challenges to the calculation for each case., Results: The interobserver agreement among all participants was fair (κ = 0.23). Stratified by participant group, the interobserver agreement among the trainees was fair (κ = 0.24), among cytotechnologists was fair (κ = 0.32), and among cytopathologists was moderate (κ = 0.60). In 70 cases, at least one participant scored the case at least one category higher than the other participants; in 47 cases there was a two category difference. A primary diagnostic challenge reported by participants was macrophage pigmentation (hemosiderin, anthracosis)., Conclusions: We found only fair interobserver agreement among all 9 participants in the study. Hemosiderin and anthracotic pigmentation was a major factor impeding LLMI calculation resulting in overestimation of the LLMI., (Copyright © 2020 American Society of Cytopathology. Published by Elsevier Inc. All rights reserved.)

Introduction: Cytology of bile duct brushings (BDBs) is a specific, but insensitive, test for malignancy. Next-generation sequencing (NGS) of BDBs has recently been shown to improve sensitivity. We analyzed the cytologic features of NGS-positive (NGS + ) and NGS-negative (NGS - ) BDBs and correlated the morphology with the presence of mutations., Materials and Methods: A total of 96 BDBs were analyzed for 29 cytologic features by 2 pathologists who were unaware of the original diagnosis and NGS results. Clinicopathologic follow-up was used to determine the patient outcomes (ie, benign, low-grade neoplasm, malignant [carcinoma/high-grade dysplasia])., Results: We analyzed 74 NGS + BDBs from 66 patients and 22 NGS - BDBs from 22 patients. During follow-up, 58 of 66 NGS + patients (88%) had malignancy compared with 0% of NGS - patients (P < 0.001). Fewer than 50% of the malignant cases had been interpreted as malignant on cytology; however, 100% had demonstrated mutations using NGS. Within the NGS + cases, 53% showed late mutations (TP53, SMAD4, and CDKN2A) supportive of a high-risk stricture. Significant morphologic differences were seen in the background appearance, presence of single cells, architectural disarray, nucleomegaly, anisonucleosis, irregular nuclear borders, increased nuclear/cytoplasmic ratio, nuclear hyperchromasia, nucleoli, abnormal groups, clusters, and/or single cells, and overall impression. Naked nuclei, nucleomegaly, anisonucleosis, and coarse chromatin were more common in BDBs with late mutations than in those with KRAS/GNAS (Kirsten rat sarcoma viral oncogene homolog/guanine nucleotide binding protein, α-stimulating complex locus) mutations only. Cytology had a sensitivity of 16% and a specificity of 100% for malignancy. In contrast, NGS had a sensitivity of 100% and a specificity of 73%. Late mutations were 100% specific for malignancy compared with mutations in KRAS/GNAS only, of which 69% were malignant., Conclusions: We found significant overlap in the cytomorphologic features between neoplastic and non-neoplastic BDBs, and more than one half of cancer cases had been interpreted as "nonmalignant" on cytology. NGS showing late mutations was 100% specific for malignancy. Adding genetic testing to BDB cytology would be a valuable ancillary test for the detection of malignancy, and reflex testing should be considered., (Copyright © 2020. Published by Elsevier Inc.)

Background/aim: The presence of circulating tumor cells (CTC) has been reported to have an impact on prognosis in different tumor entities. Little is known about CTC morphology and heterogeneity., Patients and Methods: In a multicenter setting, pre-therapeutic peripheral blood specimens were drawn from patients with non-metastatic esophageal adenocarcinoma (EAC). CTCs were captured by size-based filtration (ScreenCell®), subsequently Giemsa-stained and evaluated by two trained readers. The isolated cells were categorized in groups based on morphologic criteria., Results: Small and large single CTCs, as well as CTC-clusters, were observed in 69.2% (n=81) of the 117 specimens; small CTCs were observed most frequently (59%; n=69), followed by large CTCs (40%; n=47) and circulating cancer-associated macrophage-like cells (CAMLs; 34.2%, n=40). Clusters were rather rare (12%; n=14). CTC/CAML were heterogeneous in the cohort, but also within one specimen. Neither the presence of the CTC subtypes/CAMLs nor the exact cell count were associated with the primary clinical TNM stage., Conclusion: Morphologically heterogenic CTCs and CAMLs are present in patients with non-metastatic, non-pretreated EAC., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Introduction: Pancreatic endoscopic ultrasound-guided fine needle biopsy (EUS-FNB) acquires both direct smear and small core biopsy specimens. The triage protocols for pancreatic FNBs to cytopathology (CP) or gastrointestinal surgical pathology (GIP) are controversial and vary by institution., Material and Methods: Pancreatic EUS-FNBs obtained with the SharkCore FNB were reviewed from January 2014 to June 2019. The specimen characteristics and pathology data, including tissue triage, were obtained from the electronic medical records. We assessed the diagnostic yield, defined as malignant, specific neoplastic, or benign, and the operating characteristics at the time of rapid on-site evaluation (ROSE) and final diagnosis., Results: We reviewed 324 pancreatic FNBs from 313 patients. Of the 324 FNBs, 260 (80%) obtained concurrent direct smear and core biopsy specimens, 30 (12%) of which were divided between CP and GIP. Of the 51 core-only specimens, 47 (92%) were reviewed by CP and 4 (8%) by GIP. ROSE improved the overall diagnostic yield by 10% and accuracy by 9%. When core specimens were reviewed independently, the diagnostic accuracy was 93% for CP (n = 248) and 100% for GIP (n = 33). All false-negative results of the CP-reviewed cores were due to sampling error. Concurrent smear review improved EUS-FNB performance, increasing the negative predictive value by 10% and accuracy by 3% compared with core review alone., Conclusions: CP and GIP can accurately interpret pancreatic EUS-FNB specimens. However, triage of concurrent EUS-FNB-acquired smear and core specimens to CP may be most efficient as CPs are trained to assess adequacy at the time of ROSE, as well as interpret all parts of the biopsy, minimizing the risk of discordant pathology reports., (Copyright © 2020 American Society of Cytopathology. Published by Elsevier Inc. All rights reserved.)

Introduction: The introduction of a new generation of core needle biopsies (CNBs) for endoscopic procedures has prompted reconsideration of the role of cytopathologists in the handling of small biopsies. The American Society of Cytopathology (ASC) has therefore conducted a survey with the intention of elucidating current practices regarding the handling of small CNBs., Materials and Methods: The membership of the ASC was invited by email to participate in an online survey over a 2-month period. The survey consisted of 20 multiple choice questions with 2-8 possible responses per question., Results: Of 2651 members contacted by e-mail, 282 (10.6%) responded to the survey questions, including 196 pathologists (69.5%) and 86 cytotechnologists (30.5%). Of these, 265 respondents were from the US/Canada (94.0%), with 156 from academic institutions (58.9%) and 109 from non-academic practices (41.1%); 17 were from other countries (6.0%). In 18.8% of all practices, cytopathologists sign out >90% of small CNBs from endoscopic and radiologically guided procedures; in 36.5% of practices >90% are signed out by surgical pathologists; the remainder have such cases divided more evenly between cytopathologists and surgical pathologists. Responses show that 78.0% of all respondents are interested in signing out more small biopsies in the future, and 80.5% desire increased small biopsy-related resources from the ASC., Conclusions: The survey responses indicate that practices currently vary widely across institutions. Most indicated an interest in greater incorporation of small biopsies into the practice of cytopathology., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Solitary fibrous tumor (SFT) of the pancreas is rare, with only 16 reported cases in English studies. The cytologic features of pancreatic SFT have not been well described. We report 2 cases of SFT (1 primary and 1 metastatic) involving the pancreas and discuss the cytomorphologic findings, including the first primary SFT of the pancreas specifically diagnosed using cytology., Materials and Methods: The cases of 2 patients with a diagnosis of SFT of the pancreas from material obtained via fine needle aspiration (FNA) are reported. Clinical information was retrieved from the patients' medical records. The FNA cytology slides, previous relevant surgical pathologic findings, and findings from subsequent pancreatic resections were reviewed., Results: Of the 2 patients, 1 had had secondary involvement of the pancreas from a primary central nervous system SFT, and 1 had had a primary pancreatic SFT diagnosed by FNA. Immunohistochemistry for STAT6 was crucial for establishing the diagnosis using FNA., Conclusions: We have reported 2 cases of SFT involving the pancreas, including the first reported case of primary pancreatic SFT diagnosed preoperatively using FNA. Metastatic SFT from central nervous system primaries should be considered when diagnosing SFT of the pancreas., (Copyright © 2020 American Society of Cytopathology. Published by Elsevier Inc. All rights reserved.)

Introduction: Bronchoalveolar lavage (BAL) has a useful role in the detection of infectious diseases. Grocott methenamine silver (GMS) and acid-fast bacilli (AFB) are ancillary stains that aid in the cytologic detection of fungal and mycobacterial organisms. However, the utility of these stains in conjunction with microbiological testing is unclear., Materials and Methods: BAL specimens from lung transplant patients between January 1, 2018, to December 31, 2018, were evaluated. Inclusion criteria included cases with both GMS and AFB stains and concurrent fungal and mycobacterial microbiology testing. The staining findings were correlated with concurrent microbiology findings, including cultures and immunofluorescent smears., Results: A total of 231 BAL specimens were identified. GMS stain was positive in 19.5% and AFB in 1.3%. Fungal microbiology was positive in 23.4% and mycobacterial microbiology in 6.1%. A total of 87.9% of cases had concordant findings between cytology stains and microbiology tests and 12.1% had discrepant findings. Notably of the discrepancies, 3.0% had positive GMS and negative fungal microbiology and 6.9% had positive fungal microbiology and negative GMS. No cases had positive AFB with negative mycobacterial microbiology whereas 4.8% had positive mycobacterial microbiology and negative AFB stain., Conclusions: We show that staining for AFB on BAL material in lung transplant patients had limited benefit when concurrent microbiology was performed. GMS staining shows a small benefit. We recommend reflex testing for fungal organisms but not mycobacterial organisms in lung transplant patients., (Copyright © 2020 American Society of Cytopathology. Published by Elsevier Inc. All rights reserved.)

The Papanicolaou Society of Cytopathology developed a set of guidelines for reporting pancreaticobiliary cytology in 2014 (PB System), with a six-tiered system: Nondiagnostic, Negative, Atypical, Neoplastic (Benign or Other), Suspicious, and Positive. This proposed scheme incorporates ancillary testing such as biochemical testing of cyst fluids for diagnosis and provides terminology that standardizes the category of the various diseases of the pancreas, some of which are difficult to diagnose specifically by cytology alone. Since its initial publication five and half years ago, several groups have published their experiences on the use of the PB System and have shown that most objectives proposed by the original publication have been achieved. They have shown that there is a better understanding and definition of the diagnostic categories with an associated distribution and risk of malignancy. The diagnostic categories of Neoplastic: Other, Suspicious, and Malignant show a high sensitivity and specificity for the diagnosis of malignancy. The System also provides a multi-specialist view of pancreatic lesions, with biochemical and radiological findings being incorporated into the final pathological report. The present review summarizes these findings and discusses the future perspectives and foreseen changes that are to be incorporated to a second edition of the reporting System., (© 2020 Wiley Periodicals, Inc.)

Introduction: Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is the standard diagnostic procedure for many intrathoracic and intra-abdominal lesions. Next-generation fine-needle biopsies (FNBs) can increase diagnostic yield by procuring tissue suitable for histological processing. We evaluate the diagnostic yield and operating characteristics of the SharkCore (SC; Medtronic Corp., Minneapolis, MN) FNB in a tertiary referral facility., Materials and Methods: We performed a single-center retrospective review of SC-FNB-acquired tissue between January 2014 and March 2018. Patient demographic data, endoscopic features, and pathology data were obtained from the electronic medical record. Diagnostic yield was assessed by the ability to obtain a definitive diagnosis, defined as malignant or benign interpretations. Operating characteristics were also calculated., Results: A total of 179 lesions were sampled with the SC-FNB in 157 patients (mean age: 63 years, 57% male). Of these, 31 lesions were concomitantly sampled with a conventional FNA needle. Most lesions were pancreatic (49%). Diagnostic yield was 86%, which was independent of lesion location, lesion size and needle gauge. Diagnostic accuracy was highest when both histology and cytology specimens were analyzed concurrently (96.5%). In patients with a history of chronic pancreatitis, accuracy, sensitivity, and negative predictive value were reduced (71.4%, 20.0%, and 69.2%, respectively). Rapid onsite evaluation (ROSE) occurred in 64.8% of cases and was more likely to be diagnostic at the time of rapid evaluation if SC-acquired tissue was utilized versus FNA-acquired tissue (P = 0.03); however, final diagnostic yield did not differ between needles (P = 0.13)., Conclusions: SC-FNB shows high diagnostic yield and accuracy and provides diagnostic tissue for ROSE. SC-FNB is an effective alternative to conventional FNA., (Copyright © 2019 American Society of Cytopathology. Published by Elsevier Inc. All rights reserved.)

Background: Management of pancreatic lesions depends on the risk of malignancy, which is primarily determined from the cytologic and radiologic evaluation findings. The Papanicolaou Society of Cytopathology (PSC) published a classification system for reporting pancreaticobiliary cytology. However, the "neoplastic: other" category can be further stratified by high-grade atypia (HGA). Studies on the risk of malignancy using the PSC system have been limited., Materials and Methods: All patients who had undergone endoscopic ultrasound-guided fine-needle aspiration (FNA) for a pancreatic lesion at Massachusetts General Hospital from January 2016 to December 2016 were prospectively classified. The clinical, radiographic, and endoscopic findings, cytologic and histologic diagnoses, and follow-up data from 334 FNA biopsies from 322 patients were reviewed. The neoplastic: other category was subclassified as low-grade atypia or HGA. The absolute risk of malignancy was determined by the histologic outcome or follow-up of ≥6 months., Results: The absolute risk of malignancy was 7.7% for the nondiagnostic category; 1.0% for negative; 28.0% for atypical; 0.0% for neoplastic: benign; 30.3% for neoplastic: other; 90.0% for neoplastic: other with HGA; 100% for suspicious; and 100% for positive. When the neoplastic: other with HGA, suspicious, and positive cytologic diagnoses were considered positive, the sensitivity, specificity, positive predictive value, and negative predictive value for pancreatic FNA biopsy was 92.2%, 98.8%, 98.3%, and 94.3%, respectively., Conclusions: Categories of the PSC system each carry an implied absolute risk of malignancy, increasing from the negative to positive categories. The presence of HGA identifies lesions at the greatest risk of malignancy in the neoplastic: other category, and its inclusion with suspicious and positive as positive diagnoses optimizes the diagnostic performance of identifying high-risk lesions that warrant surgical excision., (Copyright © 2019 American Society of Cytopathology. Published by Elsevier Inc. All rights reserved.)

The diagnostic approach to pancreaticobiliary disease requires a multidisciplinary team in which the cytopathologist plays a crucial role. Fine-needle aspiration, obtained by endoscopic ultrasound, is the diagnostic test of choice for pancreatic lesions. Preoperative clinical management depends on many factors, many of which rely on accurate cytologic assessment. Pancreaticobiliary cytology is wrought with diagnostic pitfalls. Clinical history, imaging studies, cytology samples, and ancillary tests, including immunohistochemistry, biochemical analysis, and genetic sequencing, are integral to forming a complete diagnosis and guiding optimal patient management. This article reviews clinical aspects and the diagnostic work-up of commonly encountered diagnostic entities within the field of pancreatic cytology., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background and Aims: The tissue acquisition and diagnostic yield of cyst fluid cytology is low-to-moderate and rarely provides a specific diagnosis. The aim of this study was to compare the tissue acquisition and diagnostic tissue yield of microforceps biopsy (MFB) with cyst fluid cytology., Methods: In this multicenter study, data of 42 patients who had cysts both aspirated by EUS-guided FNA (EUS-FNA) and biopsy specimens were then obtained with an MFB device, were collected. Cytology analysis of cyst fluid and histologic analysis of biopsy specimens were done. Acquisition yield was defined as percentage of patients with tissue present in the aspirate or biopsy. Diagnostic tissue yield was evaluated at 3 levels: the ability of differentiation between mucinous and/or nonmucinous cysts, detection of high risk for malignancy, and specific cyst type diagnosis., Results: The mean patient age was 69 years. Sixteen pancreatic cysts (38.1%) were located in the head, 17 (40.5%) in the body, and 9 (21.4%) in the tail. The mean cyst size was 28.2 mm (12-60 mm); 25 of 42 (60%) were septated. The EUS-FNA tissue (fluid) acquisition yield was 88.1% (37/42). The MFB tissue acquisition yield was 90.4% (38/42). The diagnostic cytology yield to differentiate between mucinous and/or nonmucinous cysts was 47.6% (20/42), and the MFB histologic yield to differentiate between mucinous and/or nonmucinous cysts was 61.9% (26/42) (P = .188). The percentage of cysts at high risk for malignancy by cytology was 54.7% (23/42), and MFB was 71.5% (30/42) (P = .113). However, the ability of MFB to provide a specific cyst type diagnosis was 35.7% (15/42), and that for cytology was 4.8% (2/42) (P = .001). Surgical histology was concordant with that of MFB in 6 of 7 patients (85%), and with that of cytology in 1 of 7 patients (15%)., Conclusion: The cyst tissue acquisition yield for MFBs was 90%. Although cytology of cyst fluid and MFB were comparable in distinguishing mucinous and nonmucinous cysts and detecting cysts at high risk for malignancy, MFB was far superior to cytology for providing a specific cyst diagnosis., (Published by Elsevier Inc.)

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease. Circulating tumor cells (CTC) in the blood are hypothesized as the means of systemic tumor spread. Blood obtained from healthy donors and patients with PDAC was therefore subject to size-based CTC-isolation. We additionally compared Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations in pancreatic CTC and corresponding tumors, and evaluated their significance as prognostic markers. Samples from 68 individuals (58 PDAC patients, 10 healthy donors) were analyzed; CTCs were present in patients with UICC stage IA-IV tumors and none of the controls (p < 0.001). Patients with >3 CTC/ml had a trend for worse median overall survival (OS) than patients with 0.3–3 CTC/ml (P = 0.12). Surprisingly, CTCs harbored various KRAS mutations in codon 12 and 13. Patients with a KRAS G12V mutation in their CTC (n = 14) had a trend to better median OS (24.5 months) compared to patients with other (10 months), or no detectable KRAS mutations (8 months; P = 0.04). KRAS mutations in CTC and corresponding tumor were discordant in 11 of 26 “tumor-CTC-pairs” (42%), while 15 (58%) had a matching mutation; survival was similar in both groups (P = 0.36). Genetic characterization, including mutations such as KRAS, may prove useful for prognosis and understanding of tumor biology.

Acinar cell cystadenoma is a rare, benign cystic lesion of the pancreas. There have been only a few retrospective reports on its cytological features. We present the first case of acinar cell cystadenoma in a 65-year-old woman, diagnosed pre-operatively by pancreatic cyst fluid cytology and Moray ® micro-forceps biopsy. We emphasize possible diagnostic pitfalls of acinar cell cystadenoma cyst fluid cytology and suggest useful morphologic, immunohistochemical, and other clues to aid in diagnosis. Diagn. Cytopathol. 2017;45:557-560. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

Background: Mucinous cystic neoplasms (MCNs) of the pancreas present a management conundrum. The majority are benign but all are resected due to their malignant potential. Recent studies have recommended nonsurgical management. In the current study, the authors analyzed the preoperative imaging, cytology, and cyst fluid characteristics of 136 histologically confirmed MCNs to assess predictors of a high-risk (HR) cyst for surgical triage., Methods: MCNs resected at the Massachusetts General Hospital between 1990 and 2014 formed the study cohort. Patient demographics, cyst size, and mural nodules (MNs) by endoscopic ultrasound, cytology, and cyst fluid carcinoembryonic antigen and amylase levels were correlated with histological grade. A HR cyst was defined as high-grade dysplasia or invasive carcinoma on histology. Performance characteristics were assessed for each parameter, with a cyst size ≥3 cm or a MN on imaging and malignant cytology considered to be "true-positive" results for predicting malignancy., Results: Only 15 of the 136 cysts had HR histology (11%). On average, patients with HR cysts were older than those with low-risk cysts (55 years vs 49 years, respectively). High-grade cytology was the most accurate predictor of malignancy (95%) followed by MN and cyst size together (88%) and MN alone (83%). The average carcinoembryonic antigen level (in ng/mL) increased with the grade of dysplasia but the ranges overlapped between low risk and HR cysts., Conclusions: To the authors' knowledge, the current study is the largest series to date analyzing the cytological features of histologically confirmed MCN. Cytology is insensitive but very specific for detecting a HR MCN and outperformed imaging for the detection of HR MCN. Endoscopic ultrasound-guided fine-needle aspiration and cytology should be performed on any clinically suspected MCN that is being considered for conservative management. Cancer Cytopathol 2017;125:169-177. © 2016 American Cancer Society., (© 2016 American Cancer Society.)

Pancreatic ductal adenocarcinoma (PDAC) is most often diagnosed in a metastatic stage. Circulating tumor cells (CTC) in the blood are hypothesized as the means of systemic dissemination. We aimed to isolate and characterize CTC to evaluate their significance as prognostic markers in PDAC. Blood obtained from healthy donors and patients with PDAC before therapy was filtered with ScreenCell® filtration devices for size-based CTC isolation. Captured cells were analyzed by immunofluorescence for an epithelial to mesenchymal transition (EMT) marker (zinc finger E-box binding homebox 1 (ZEB1)) and an epithelial antigen (cytokeratin (CK)). Molecular analysis of parallel specimens evaluated the KRAS mutation status of the CTC. The survival of each patient after study was recorded. As demonstrated by either cytology or finding of a KRAS mutation, CTC were detected in 18 of 21 patients (86 %) with proven PDAC: 8 out of 10 patients (80 %) with early stage (UICC IIA/IIB) and 10 out of 11 (91 %) with late stage (UICC III/IV) disease. CTC were not found in any of the 10 control patients (p < 0.001). The presence of CTC did not adversely affect median survival: 16 months in CTC-positive (n = 18) vs. 10 months in CTC-negative (n = 3) patients. Neither ZEB1 nor cytological characteristics correlated with overall survival, although ZEB1 was found almost exclusively in CTC of patients with established metastases. Patients with a CTC KRAS mutation (CTC-KRAS (mut)) had a substantially better survival, 19.4 vs. 7.4 months than patients with wild type KRAS (p = 0.015). With ScreenCell filtration, CTC are commonly found in PDAC (86 %). Molecular and genetic characterization, including mutations such as KRAS, may prove useful for prognosis.

Background and Aims: Pancreatic cyst fluid (PCF) CEA has been shown to be the most accurate preoperative test for detection of cystic mucinous neoplasms (CMNs). This study aimed to assess the added value of PCF KRAS mutational analysis to CEA for diagnosis of CMNs., Patients and Methods: This is a retrospective study of prospectively collected endoscopic ultrasonography (EUS) fine-needle aspiration (FNA) data. KRAS mutation was determined by direct sequencing or equivalent methods. Cysts were classified histologically (surgical cohort) or by clinical (EUS or FNA) findings (clinical cohort). Performance characteristics of KRAS, CEA and their combination for detection of a cystic mucinous neoplasm (CMN) and malignancy were calculated., Results: The study cohort consisted of 943 patients: 147 in the surgical cohort and 796 in the clinical cohort. Overall, KRAS and CEA each had high specificity (100 % and 93.2 %), but low sensitivity (48.3 % and 56.3 %) for the diagnosis of a CMN. The positivity of KRAS or CEA increased the diagnostic accuracy (80.8 %) and AUC (0.84) significantly compared to KRAS (65.3 % and 0.74) or CEA (65.8 % and 0.74) alone, but only in the clinical cohort (P < 0.0001 for both). KRAS mutation was significantly more frequent in malignant CMNs compared to histologically confirmed non-malignant CMNs (73 % vs. 37 %, P = 0.001). The negative predictive value of KRAS mutation was 77.6 % in differentiating non-malignant cysts., Conclusions: The detection of a KRAS mutation in PCF is a highly specific test for mucinous cysts. It outperforms CEA for sensitivity in mucinous cyst diagnosis, but the data does not support its routine use.

Background and Aims: The value of next-generation sequencing (NGS) of pancreatic cyst fluid relative to the clinical and imaging impression has not been well-studied. The aim of this study was to assess the impact of NGS on the clinical diagnosis from imaging and carcinoembryonic antigen (CEA) and thus the management of pancreatic cysts., Methods: Ninety-two pancreatic cyst fluids from 86 patients were analyzed by cytology, CEA, and targeted NGS. Cysts were classified by imaging as nonmucinous, mucinous, or not specified. NGS results were compared with the imaging impression stratified by CEA and cytology., Results: NGS impacted the clinical diagnosis by defining a cyst as mucinous in 48% of cysts without elevated CEA levels. The VHL gene in 2 intraductal papillary mucinous neoplasms (IPMNs) supported a serous cystadenoma. Twenty percent of cysts that were nonmucinous by imaging were mucinous by NGS. Of the 14 not-specific cysts, CEA levels were not elevated in 12 (86%), and NGS established a mucinous etiology in 3 (25%). A KRAS or GNAS mutation supported an IPMN with nonmucinous CEA in 71%. A KRAS mutation reclassified 19% of nonneoplastic cysts with nonmucinous CEA as mucinous. Seven cyst fluids (8%) had either a TP53 mutation or loss of CDKN2A or SMAD4 in addition to KRAS and/or GNAS mutations; 5 of 7 (71%) were clinically malignant, and high-grade cytology was detected in all 5. Overall, CEA was more specific for a mucinous etiology (100%), but NGS was more sensitive (86% vs 57%)., Conclusions: NGS of pancreatic cyst fluid impacts clinical diagnosis and patient management by defining, supporting, or changing the clinical diagnosis based on imaging and CEA. NGS was most valuable in identifying mucinous cysts with nonmucinous CEA. An added benefit is the potential to detect mutations late in the progression to malignancy that may increase the risk classification of the cyst based on imaging and cytology., (Copyright © 2016 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Cytological evaluation of pancreatic or biliary duct brushings is a specific, but insensitive, test for malignancy. We compared adjunctive molecular testing with next-generation sequencing (NGS) relative to fluorescence in situ hybridization (FISH) for detection of high-risk neoplasia or malignancy. Bile duct brushings from 81 specimens were subjected to cytological analysis, FISH using the UroVysion probe set, and targeted NGS. Specimens were placed into negative/atypical (negative) or suspicious/positive (positive) categories depending on cytology and negative or positive categories on the basis of FISH and NGS results. Performance characteristics for each diagnostic modality were calculated on the basis of clinicopathologic follow-up and compared in a receiver operating characteristic analysis. There were 33 high-risk neoplasia/malignant strictures (41%) and 48 benign (59%). NGS revealed driver mutations in 24 cases (30%), including KRAS (21 of 24 cases), TP53 (14 of 24 cases), SMAD4 (6 of 24 cases), and CDKN2A (4 of 24 cases). Cytology had a sensitivity of 67% (95% CI, 48%-82%) and a specificity of 98% (95% CI, 89%-100%). When added to cytology, NGS increased the sensitivity to 85% (95% CI, 68%-95%), leading to a significant increase in the area under the curve in a receiver operating characteristic analysis (P = 0.03). FISH increased the sensitivity to 76% (95% CI, 58%-89%), without significantly increasing the area under the curve. These results suggest that ancillary NGS testing offers advantages over FISH, although studies with larger cohorts are needed to verify these findings., (Copyright © 2016 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.)

Background: Circulating epithelial cell (CEC) isolation has provided diagnostic and prognostic information for a variety of cancers, previously supporting their identity as circulating tumor cells in the literature. However, we report CEC findings in patients with benign, premalignant, and malignant pancreatic lesions using a size-selective filtration device., Study Design: Peripheral blood samples were drawn from patients found to have pancreatic lesions on preoperative imaging at a surgical clinic. Blood was filtered using ScreenCell devices, which were evaluated microscopically by a pancreatic cytopathologist. Pathologic data and clinical outcomes of these patients were obtained from medical records during a 1-year follow-up period., Results: Nine healthy volunteers formed the control group and were found to be negative for CECs. There were 179 patients with pancreatic lesions that formed the study cohort. Circulating epithelial cells were morphologically similar in patients with a variety of pancreatic lesions. Specifically, CECs were identified in 51 of 105 pancreatic ductal adenocarcinomas (49%), 7 of 11 neuroendocrine tumors (64%), 13 of 21 intraductal papillary mucinous neoplasms (62%), and 6 of 13 patients with chronic pancreatitis. Rates of CEC identification were similar in patients with benign, premalignant, and malignant lesions (p = 0.41). In addition, CEC findings in pancreatic ductal adenocarcinoma patients were not associated with poor prognosis., Conclusions: Although CECs were not identified in healthy volunteers, they were identified in patients with benign, premalignant, and malignant pancreatic lesions. The presence of CECs in patients presenting with pancreatic lesions is neither diagnostic of malignancy nor prognostic for patients with pancreatic ductal adenocarcinoma., (Copyright © 2015 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)

Background and Study Aims: Intraductal papillary mucinous neoplasm (IPMN) consists of four epithelial subtypes. There are limited data on the endoscopic ultrasound (EUS) findings and/or cyst fluid analysis of the epithelial subtypes. The objective of this study was to determine whether there are differences in EUS and cyst fluid characteristics (carcinoembryonic antigen [CEA] concentration and cytology) among the subtypes., Patients and Methods: The study cohort consisted of 85 patients (median age 68 years, 40 men) with resected and histologically confirmed branch-duct or mixed-type IPMNs who underwent preoperative EUS-guided fine-needle aspiration between 1999 and 2010 for the evaluation of pancreatic cysts. EUS and cyst fluid characteristics were analyzed retrospectively and correlated with the subtypes., Results: The numbers of evaluated cystic lesions were 1 in 79 patients, 2 in 5 patients, and 3 in 1 patient. Of 92 IPMNs analyzed, gastric-type IPMNs were the most common (n = 68, 73.9 %), followed by intestinal (n = 17, 18.5 %), oncocytic (n = 5, 5.4 %), and pancreatobiliary subtypes (n = 2, 2.2 %). Gastric-type IPMNs were significantly smaller (cutoff 30 mm; P = 0.002), and less likely than other subtypes to have a mass lesion or mural nodule (P = 0.046) on EUS. Cyst fluid CEA concentration varied among the subtypes (median concentrations for gastric, intestinal, oncocytic, and pancreatobiliary types 619.8, 83.0, 5.1, and 270.0 ng/mL, respectively; P = 0.012). The presence of neoplastic epithelial cells (P = 0.624) and extracellular mucin (P = 0.208) on cytology had no association with subtypes., Conclusions: Gastric-type IPMNs, the most common subtype, are characterized by high concentrations of cyst fluid CEA, small cyst diameter, and low risk EUS imaging features., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: Pancreatic cyst size >3 cm is a worrisome rather than high-risk feature for malignancy based on the 2012 International Guidelines for the management of mucinous cysts. The value of cytology in preoperative evaluation and surgical triage is unclear., Methods: All pancreatic cysts >3 cm resected over a 7-year period were evaluated for clinical, radiologic, and pathologic information. Performance of cytology for the detection of malignancy and surgical triage compared with imaging was assessed., Results: There were 93 histologically confirmed cysts, 52 of which were mucinous and 41 of which were nonmucinous. Of these, 37% were malignant, including 16 nonmucinous malignancies and 18 mucinous cysts (12 with invasive carcinoma, 6 with high-grade dysplasia). Thirty-nine cysts (41% malignant, 59% benign) were not subject to endoscopic ultrasound-fine needle aspiration (EUS-FNA) prior to resection (average size, 6.0 cm). Fifty-four were evaluated by EUS-FNA, with 35 available for review (average size, 5.4 cm). Cytology/cyst fluid analysis had the highest specificity (88.9%) compared with imaging, whereas magnetic resonance imaging (MRI) showed the highest sensitivity (100%). MRI had the highest predictive value for mucinous (100%) versus nonmucinous cysts (100%). MRI and EUS were able to predict malignancy from the presence of high-risk imaging features in all cases. Some benign cases also showed high-risk imaging features on MRI (28.6%), computed tomography (32.3%), and EUS (45.8%). Cytology correctly classified 5 of 6 benign cysts with high-risk imaging as benign., Conclusions: Preoperative evaluation of pancreatic cysts >3 cm is warranted, as many are nonmucinous cysts and not high-grade. Cytology is more specific than imaging for the detection of malignancy in cysts >3 cm., (© 2014 American Cancer Society.)

The Papanicolaou Society of Cytopathology has developed a set of guidelines for pancreatobiliary cytology including indications for endoscopic ultrasound (EUS) guided fine-needle aspiration (FNA) biopsy, techniques of EUS-FNA, terminology and nomenclature of pancreatobiliary disease, ancillary testing and post-biopsy treatment and management. All documents are based on the expertise of the authors, a review of the literature, discussion of the draft document at several national and international meetings over an 18 month period and synthesis of online comments of the draft document on the Papanicolaou Society of Cytopathology web site [www.papsociety.org]. This document selectively presents the results of these discussions and focuses on a proposed standardized terminology scheme for pancreatobiliary specimens that correlate cytological diagnosis with biological behavior and increasingly conservative patient management of surveillance only. The proposed terminology scheme recommends a six-tiered system: Non-diagnostic, negative, atypical, neoplastic [benign or other], suspicious and positive. Unique to this scheme is the "neoplastic" category separated into "benign" (serous cystadenoma) or "other" (premalignant mucinous cysts, neuroendocrine tumors and solid-pseudopapillary neoplasms (SPNs)). The positive or malignant category is reserved for high-grade, aggressive malignancies including ductal adenocarcinoma, acinar cell carcinoma, poorly differentiated neuroendocrine carcinomas, pancreatoblastoma, lymphoma and metastases. Interpretation categories do not have to be used. Some pathology laboratory information systems require an interpretation category, which places the cytological diagnosis into a general category. This proposed scheme provides terminology that standardizes the category of the various diseases of the pancreas, some of which are difficult to diagnose specifically by cytology. In addition, this terminology scheme attempts to provide maximum flexibility for patient management, which has become increasingly conservative for some neoplasms.

Background: Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) of pancreatic cysts obtains cyst fluid for cytologic and biochemical analysis, which may determine whether the cyst is mucinous and malignant, contributing to patient management. Despite this added value, EUS-FNA remains controversial in the preoperative assessment of pancreatic cysts. The objective of this study was to assess the utility of EUS-FNA in a cohort of small pancreatic cysts that were benign on imaging studies., Methods: All pancreatic cysts that underwent initial EUS-FNA in 2006 and 2007 were retrospectively analyzed. Ninety-two patients with pancreatic cysts met the inclusion criteria. Patients who had high-risk or worrisome features on imaging studies were excluded. Cytology, histology, and cyst fluid analysis data were collected. The main outcome measurements were radiologic and clinical follow-up as well as cytopathologic and histologic results., Results: EUS-FNA supported a diagnosis of a mucinous cyst in 38 of 92 patients (41%) by carcinoembryonic antigen (CEA) measurement and/or cytology. Cytology demonstrated an absence of high-grade atypia (HGA) in 89 of 92 patients (97%). The mean follow-up was 4.4 years (range, 0-7.7 years), during which 6 cysts were surgically resected and 16 cysts were resampled by at least 1 subsequent EUS-FNA. The overall negative predictive value of cytologic examination for HGA was 99%., Conclusions: EUS-FNA is a screening test that contributes to a triple-negative test for pancreatic cysts--no high-risk stigmata, no worrisome features, and no HGA on cytology--providing a negative predictive value of 99% for conservative management., (© 2013 American Cancer Society.)

The newest installment on state-of-the-art standards of practice in cytopathology from the Papanicolaou Society of Cytopathology (PSC) focuses on the pancreaticobiliary system. Similar to the National Cancer Institute recommendations for aspiration cytology of the thyroid, the PSC guidelines for pancreaticobiliary cytology addresses indications, techniques, terminology and nomenclature, ancillary studies, and postprocedure management. Each committee was composed of a multidisciplinary group of experts in diagnosing, managing, and treating patients with pancreaticobiliary disease. Draft documents were posted on an interactive Web-based forum hosted by the PSC Web site (www.papsociety.org) and the topics of terminology, ancillary testing, and management were presented at national and international meetings over an 18-month period for discussion and feedback from practicing pathologists around the world. This review provides a synopsis of these guidelines., (© 2014 American Cancer Society.)

Background: Cystic pancreatic neuroendocrine tumors (cPanNETs) account for 13% to 17% of PanNETs. Although the value of endoscopic ultrasound (EUS) imaging and cyst fluid analysis (CFA) in their preoperative diagnosis has been well described, limited information is available about the diagnostic role of cytology samples obtained from fine-needle aspiration (FNA)., Methods: Cytopathology records between 1992 and 2013 were searched for all reports of cysts interpreted as PanNET. Patient demographics, clinical and radiologic information, CFA, histopathology, and cytopathology findings were recorded. Performance characteristics of cytology and EUS for the accurate diagnosis of cPanNET were calculated., Results: In total, 35 FNAs from 33 patients with cPanNETs were identified, and 34 EUS were performed. Cytology made a specific diagnosis of a cPanNET in 71% of the biopsies compared with a specific diagnosis by EUS in 38% of cases. An interpretation of suspicious for cPanNET was given in 77% of cases by cytology and in 47% by EUS. Cytology identified 86% of the lesions as high-risk pancreatic cysts compared with 56% by EUS. Diagnostic morphology was present on both cytology and cell block preparations in 60% of aspirates, on cytology only in 20%, and on cell block only in 20%. CFA was performed on 51% cyst fluids. All cysts but 1 revealed low carcinoembryonic antigen levels (range, 0.2 to >500 ng/mL; mean, 29.5 ng/mL), and amylase levels were <500 U/L in all but 2 cases (range, 16-1493 U/L; mean, 205 U/L)., Conclusions: Cytology is the most accurate test for preoperative diagnosis of cPanNETs. EUS is insufficiently accurate for independent diagnosis, and carcinoembryonic antigen and amylase analyses are noncontributory., (© 2014 American Cancer Society.)

Intraductal papillary mucinous neoplasm (IPMN) of the pancreas is a relatively rare cystic neoplasm. Although most IPMNs appear to be benign and may be managed by surveillance, all IPMNs are considered premalignant lesions with malignant potential. As such, current efforts are focused on identifying those neoplasms that are at high risk for malignancy to optimize treatment strategy and outcome. IPMNs with invasive carcinoma have clinical outcomes that approach those of conventional pancreatic ductal adenocarcinoma. Management guidelines recommend surgical resection for IPMNs with high-risk imaging or cytologic features. The role of adjuvant therapy is unclear, and we review the evidence for chemoradiation here. Some studies suggest adjuvant chemoradiation may have the greatest impact in malignant IPMNs with adverse histologic features, that is, lymph node metastasis at the time of diagnosis or positive surgical margins. As more IPMNs are recognized and treated, more evidence will accumulate to guide clinicians regarding appropriate use of radiotherapy in the management of IPMN., (© 2013 Published by Elsevier Inc.)

The Papanicolaou Society of Cytopathology has developed a set of guidelines for pancreatobiliary cytology including indications for endoscopic ultrasound-guided fine-needle aspiration, terminology and nomenclature of pancreatobiliary disease, ancillary testing, and post-biopsy management. All documents are based on the expertise of the authors, a review of the literature, discussions of the draft document at several national and international meetings, and synthesis of selected online comments of the draft document. This document presents the results of these discussions regarding the use of ancillary testing in the cytologic diagnosis of biliary and pancreatic lesions. Currently, fluorescence in situ hybridization (FISH) appears to be the most clinically relevant ancillary technique for cytology of bile duct strictures. The addition of FISH analysis to routine cytologic evaluation appears to yield the highest sensitivity without loss in specificity. Loss of immunohistochemical staining for the protein product of the SMAD4 gene and positive staining for mesothelin support a diagnosis of ductal adenocarcinoma. Immunohistochemical markers for endocrine and exocrine differentiation are sufficient for a diagnosis of endocrine and acinar tumors. Nuclear staining for beta-catenin supports a diagnosis of solid-pseudopapilary neoplasm. Cyst fluid analysis for amylase and carcinoembryonic antigen aids in the preoperative classification of pancreatic cysts. Many gene mutations (KRAS, GNAS, VHL, RNF43, and CTNNB1) may be of aid in the diagnosis of cystic neoplasms. Other ancillary techniques do not appear to improve diagnostic sensitivity sufficiently to justify their increased costs., (Copyright © 2014 Wiley Periodicals, Inc.)

Background: Determining high-risk human papillomavirus (HR-HPV) status of head and neck squamous cell carcinoma (HNSCC) defines a tumor subset with important clinical implications. Cytologic sampling often provides the sentinel or sole diagnostic specimen. The authors assessed the performance characteristics for the Roche cobas 4800 HPV real-time polymerase chain reaction (PCR)-based system (cobas) on cytologic specimens of HNSCC compared with standard methods of in situ hybridization (ISH) for HR-HPV and immunohistochemistry (IHC) for p16 on formalin-fixed, paraffin-embedded (FFPE) tissue., Methods: Samples of HNSCC were collected by fine-needle aspiration and from surgical biopsies or resections, fixed, and processed with the cobas system. Available corresponding FFPE samples were synchronously evaluated for HR-HPV using ISH and IHC. Discrepant cases underwent additional PCR studies for adjudication., Results: Thirty-six samples from 33 patients were analyzed. Forty-two percent (n = 15) of tumors were positive for HR-HPV according to cobas. Corresponding histology with ISH (n = 30) was concordant in 91% of samples. Compared with the adjudication PCR standard, there were 3 false-positive cases according to cobas. Ninety-two percent (n = 12) of cases were the HPV16 subtype. The overall sensitivity for the cobas system was 100%, and the specificity was 86%., Conclusions: Concordance in HNSCC HR-HPV status between cobas and ISH/IHC was > 90%, and cobas demonstrated a sensitivity of 100% and a specificity of 86%, broadening options for HR-HPV testing of fine-needle aspiration samples. Advantages for this system include subtyping of HR-HPV and the ability to discern HR-HPV status earlier in a patient's treatment course., (© 2013 American Cancer Society.)

Background: The recognition of epithelial cells with high-grade atypia (HGA) in the cyst fluid of an intraductal papillary mucinous neoplasm (IPMN) identifies a cyst at high risk of invasive carcinoma. To the best of the authors' knowledge, the cytological features of HGA have not been systematically analyzed to define diagnostic criteria., Methods: Cell groups from patients with histologically confirmed branch-duct IPMNs were evaluated by 2 cytopathologists with expertise in pancreatic cytology. A consensus interpretation categorized the cell groups as having either low-grade (LG) or high-grade (HG) morphology. Characteristics regarding cell size and architecture, nuclear and cytoplasmic features, and background necrosis were analyzed. Performance characteristics were assessed using the Fisher exact test at 95% confidence intervals., Results: Sixty cell groups yielded 27 LG and 25 HG morphological groups. No consensus was reached for 8 groups, which were excluded from statistical analysis. Five features that were found to be significantly different between the LG and HG groups included: 1) cell size <  a 12-μm duodenal enterocyte for HG and size equal for LG; 2) an increased nuclear-to-cytoplasmic (N/C) ratio; 3) marked nuclear membrane abnormalities; 4) abnormal chromatin pattern; and 5) background necrosis. The 3 most accurate features for the identification of HGA were background necrosis (88%), abnormal chromatin pattern (84%), and an increased N/C ratio (82%)., Conclusions: IPMN cyst fluid at high-risk of malignancy can be recognized most accurately by the presence of epithelial cells with HGA showing an increased N/C ratio, an abnormal chromatin pattern, and background necrosis., (© 2013 American Cancer Society.)

Background: Preoperative cytological analysis of cyst fluid from intraductal papillary mucinous neoplasms (IPMN) contributes to risk stratification for malignancy. To the authors' knowledge, agreement among pathologists in grading epithelial atypia in IPMN cyst fluids has not been studied to date., Methods: Blinded to the histological grade, 4 observers independently graded 60 cell groups from endoscopic ultrasound-guided fine-needle aspiration samples of 24 IPMNs of various grades as either 0 (nonlesional), 1 (low-grade dysplasia), 2 (intermediate-grade dysplasia [IGD]), 3 (high-grade dysplasia), or 4 (invasive adenocarcinoma). The percentage of agreement and the kappa (k) coefficient were calculated for these 5 tiers and a reduced 2-tier grouping (low-grade [LG] [0-1 and 0-2] vs high-grade [HG] [2-4 and 3-4]). Agreement between the 2 most experienced reviewers established a consensus diagnosis that was compared with the histological grade., Results: Among the 4 reviewers there was poor agreement using a 5-tiered system and fair agreement with the 2-tiered system. LG and HG grouping of IGD did not appear to greatly affect agreement, with 54% agreement for grouping 0 to 2 and 3 to 4 (k = 0.45) and 52% agreement for grouping 0 to 1 and 2 to 4 (k = 0.44). The 2 most experienced reviewers had 87% agreement for the 0 to 2 and 3 to 4 grouping (k = 0.74) and 88% for the 0 to 1 and 2 to 4 grouping (k = 0.71). HG atypia on cytology with IGD grouped as LG yielded a sensitivity of 82%, with a specificity of 70% for detecting a cyst with HG morphology., Conclusions: Grading cellular atypia in cyst fluids requires experience, which results in very good interobserver agreement and good correlation with histology using a 2-tiered LG and HG grading system and IGD classified as LG., (© 2013 American Cancer Society.)

Background: Pancreatic cysts are aspirated to assess whether a cyst is mucinous on one hand and malignant on the other. The authors' retrospective data have indicated that high-grade atypical epithelial cells (AECs) identified on cytology are a high-risk feature and a better threshold than "positive" for detecting malignancy. The objective of the current study was to assess the accuracy of AECs in predicting malignancy in pancreatic cysts., Methods: Cysts aspirated by endoscopic ultrasound (EUS)-guided fine-needle aspiration (EUS-FNAs) obtained between January 2006 and June 2011 were evaluated. Cytologic, histologic, imaging, and cyst fluid analysis data were recorded. AECs were defined as cells that had an increased nuclear-to-cytoplasmic ratio and nuclear hyperchromasia with or without membrane abnormalities and with or without cytoplasmic vacuoles, but of insufficient quality and quantity for a "positive" interpretation. Malignancy included mucinous cysts with high-grade dysplasia and invasive carcinoma. Performance characteristics of cytology with AECs or worse (high-grade atypia [HGA]) for predicting malignancy were assessed., Results: There were 70 FNAs that had histologic confirmation from 404 EUS-FNAs in 352 patients. Excluding 4 nondiagnostic FNAs, the study cohort consisted of 66 FNAs for analysis. There were 24 malignant cysts with 20 true-positive, 4 false-negative, 36 true-negative, and 6 false-positive results. For the detection of malignancy, HGA had 83% sensitivity, 86% specificity, a positive predictive value of 77%, a negative predictive value of 90%, and 85% overall accuracy. The lower threshold for malignancy with AECs resulted in a 12% increase in the detection of malignancy., Conclusions: A finding of AECs on cytology is a high-risk feature for malignancy and is an accurate triage threshold for resection. Cancer (Cancer Cytopathol) 2013;121:29-36 © 2012 American Cancer Society., (Copyright © 2012 American Cancer Society.)

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Pancreatic Adenocarcinoma discuss the workup and management of tumors of the exocrine pancreas. These NCCN Guidelines Insights provide a summary and explanation of major changes to the 2012 NCCN Guidelines for Pancreatic Adenocarcinoma. The panel made 3 significant updates to the guidelines: 1) more detail was added regarding multiphase CT techniques for diagnosis and staging of pancreatic cancer, and pancreas protocol MRI was added as an emerging alternative to CT; 2) the use of a fluoropyrimidine plus oxaliplatin (e.g., 5-FU/leucovorin/oxaliplatin or capecitabine/oxaliplatin) was added as an acceptable chemotherapy combination for patients with advanced or metastatic disease and good performance status as a category 2B recommendation; and 3) the panel developed new recommendations concerning surgical technique and pathologic analysis and reporting.

Background: We report a case of Rosai-Dorfman disease (RDD) presenting as an oropharyngeal mass, and we provide a detailed discussion of this rare clinical entity., Methods: An initial biopsy, described as being consistent with lymphoma, was reviewed at a second outside institution and was thought to be reactive lymphoid hyperplasia. The patient then presented to our institution for a second opinion. Direct laryngoscopy revealed a firm 1- to 2-cm lesion involving the left soft palate and superior tonsillar pillar., Results: The diagnosis of RDD was confirmed with immunohistochemical staining on both cytology and histology. The patient elected conservative management and has remained asymptomatic for over 15 months., Conclusion: The diagnosis of RDD may be challenging in cases presenting initially with extranodal disease. Close follow-up and repeat biopsies may be necessary. Identification of Rosai-Dorfman cells with emperipolesis and confirmation with appropriate immunohistochemical staining on both cytology and histology is diagnostic of RDD. Conservative treatment is appropriate in select cases., (Copyright © 2010 Wiley Periodicals, Inc.)

Objective: Attenuation values on CT of less than 10 H are considered characteristic of adrenal adenomas. Adrenal pheochromocytomas can infrequently contain fat that could result in low attenuation on CT. The purpose of our study was to determine if pheochromocytomas could be confused with adenomas by virtue of their attenuation values on unenhanced CT., Materials and Methods: CT attenuation and size of nine adrenal nodules producing pheochromocytoma syndrome were measured on unenhanced CT in nine patients. For five patients who received IV contrast material, washout profiles were also calculated., Results: Two of the nine patients had adrenal lesions with attenuation values of less than 10 H; one had a pheochromocytoma with an attentuation of 9.0 H, and the other had a medullary hyperplasia with an attenuation of 1.8 H. These two nodules showed evidence of microscopic fat at histologic examination. No macroscopic fat was seen on the CT scans. The remaining seven patients had lesions with attenuation values exceeding 10 H (mean value, 25.6 H; range, 1.8-41 H). Mean diameter of the nine tumors (including the hyperplastic nodule) was 3.2 cm (range, 0.8-6.7 cm; SD, +/- 2.3 cm). The two low-attenuation lesions also mimicked adenomas by displaying more than 60% contrast washout on 10-min-delayed contrast-enhanced scans, unlike the other three pheochromocytomas for which we had washout data., Conclusion: On CT, pheochromocytomas may have attenuation values less than 10 H and also may display more than 60% washout of contrast agents on delayed scanning. Adrenal pheochromocytomas should be included with adenomas in the differential diagnosis both for masses with low attenuation on unenhanced CT and for lesions exhibiting a high percentage of contrast washout.

Diagnosis of dysplasia in the gastrointestinal tract has important clinical implications for management decisions. Although dysplasia is generally recognized by histology, cytologic specimens have been shown to increase the sensitivity of tissue diagnosis. The advantage of cytology is the ability to sample a much larger mucosal area. The relatively low specificity caused by the overlap in cytologic features of reactive atypia, dysplasia, and carcinoma is a disadvantage. This article reviews the cytology of squamous and glandular dysplasia in the alimentary tract as well as the studies that have evaluated the clinical utility of cytologic sampling of the gastrointestinal tract in the evaluation of dysplasia.