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Context.—: Cytologic-histologic correlation (CHC) is a Clinical Laboratory Improvement Amendments-mandated requirement for gynecologic cytology, but no similar requirement exists for nongynecologic cytology. This study presents the findings from a College of American Pathologists survey of nongynecologic cytology practice patterns., Objective.—: To survey the current CHC practices for nongynecologic cytology., Design.—: Data were analyzed from a survey developed by the committee and distributed to participants in the Nongynecologic Cytopathology Education Program mailing., Results.—: Adoption of CHC for nongynecologic cytology cases is worldwide, with 88.5% of institutions performing CHC on these specimens, a substantial increase from previous years. Performance of CHC varied by institution type, with clinic or regional/local independent laboratories and national/corporate laboratories performing CHC significantly less frequently than hospitals, university hospitals/academic medical centers, and Veterans Administration/Department of Defense hospital institutions. Most CHC was performed concurrently in real time, when the corresponding surgical specimen was reviewed. Selection for real-time concurrent CHC was by the interpreting pathologist, the pathologist diagnosing the surgical biopsy sample or cytopathology case, or both. Sampling was by far the most common reason for discordance. A 2-step difference was the most frequent threshold for discordance between cytology and surgical specimens, but this criterion varied among institutions, with no majority definition. The positive predictive value of a positive cytology finding was calculated rarely in North American institutions but was calculated more frequently in international institutions., Conclusions.—: CHC practices for nongynecologic cytopathology mirror those found for CHC of gynecologic cytopathology., (© 2024 College of American Pathologists.)

Context.—: Pleural effusion cytology has been widely used in the investigation of pathologic fluid accumulation in pleural spaces. However, up to one-tenth of the cases were not given a definitive diagnosis. These cases have largely been neglected in the bulk of the literature., Objective.—: To provide real-world data on indefinite diagnoses including "atypia of uncertain significance" (AUS) and "suspicious for malignancy" (SFM) in pleural effusion cytology and to investigate pathologists' practice patterns on using these diagnostic categories., Design.—: We reported the diagnoses of 51 675 cases. Descriptive statistics and correlation coefficients were used to analyze the relationships between different diagnostic categories and pathologists' practice patterns and possible explanatory variables., Results.—: The diagnoses AUS and SFM were reported in 4060 cases (7.86%) and 1554 cases (3.01%) in the cohort, respectively. The mean rates for these indefinite diagnoses varied up to 3-fold between pathologists. Correlations were found between AUS and SFM, as well as between indefinite diagnoses and negative for malignancy (NFM). No correlations were found between pathologists' years of experience or case volume and the rates of indefinite diagnosis or diagnostic certainty., Conclusions.—: A real-world baseline for the rates of indefinite diagnoses in pleural effusion cytology is provided in this large retrospective study. Pathologists show significant variation in their use of indefinite diagnostic categories, and the tendency to use these ambiguous terms was not correlated with individuals' experience or case volume. How to untangle the intertwined relationship between the uncertainty of indefinite diagnoses and that of NFM requires future prospective studies., (© 2024 College of American Pathologists.)

Context.—: The College of American Pathologists (CAP) surveys provide national benchmarks of pathology practice., Objective.—: To investigate pancreaticobiliary cytology practice in domestic and international laboratories in 2021., Design.—: We analyzed data from the CAP Pancreaticobiliary Cytology Practice Supplemental Questionnaire that was distributed to laboratories participating in the 2021 CAP Nongynecologic Cytopathology Education Program., Results.—: Ninety-three percent (567 of 612) of respondent laboratories routinely evaluated pancreaticobiliary cytology specimens. Biliary brushing (85%) was the most common pancreaticobiliary cytology specimen evaluated, followed by pancreatic fine-needle aspiration (79%). The most used sampling methods reported by 235 laboratories were 22-gauge needle for fine-needle aspiration (62%) and SharkCore needle for fine-needle biopsy (27%). Cell block was the most used slide preparation method (76%), followed by liquid-based cytology (59%) for pancreatic cystic lesions. Up to 95% (303 of 320) of laboratories performed rapid on-site evaluation (ROSE) on pancreatic solid lesions, while 56% (180 of 320) performed ROSE for cystic lesions. Thirty-six percent (193 of 530) of laboratories used the Papanicolaou Society of Cytopathology System for Reporting Pancreaticobiliary Cytology in 2021. Among all institution types, significant differences in specimen volume, specimen type, ROSE practice, and case sign-out were identified. Additionally, significant differences in specimen type, slide preparation, and ROSE practice were found., Conclusions.—: This is the first survey from the CAP to investigate pancreaticobiliary cytology practice. The findings reveal significant differences among institution types and between domestic and international laboratories. These data provide a baseline for future studies in a variety of practice settings., Competing Interests: The authors are or were members of the College of American Pathologists Cytopathology Committee. Nwosu and Souers are employees of the College of American Pathologists., (© 2024 College of American Pathologists.)

Context: In recent years, several reporting systems have been developed by national and international cytopathology organizations to standardize the evaluation of specific cytopathology specimen types., Objective: To assess the current implementation rates, implementation methods, and barriers to implementation of commonly used nongynecologic reporting systems in cytopathology laboratories., Design: Data were analyzed from a survey developed by the College of American Pathologists Cytopathology Committee and distributed to participants in the College of American Pathologists Nongynecologic Cytopathology Education Program mailing., Results: Nongynecologic reporting systems with the highest rate of adoption were the Bethesda System for Reporting Thyroid Cytopathology, 2nd edition (74.1%; 552 of 745); the Paris System for Reporting Urinary Cytology (53.9%; 397 of 736); and the Milan System for Reporting Salivary Gland Cytopathology (29.1%; 200 of 688). The most common reason given for not adopting a reporting system was satisfaction with a laboratory's current system. Implementation varied among laboratories with regard to which stakeholders were involved in deciding to implement a system and the amount of education provided during the implementation process., Conclusions: The implementation of nongynecologic reporting systems in cytopathology laboratories was highly variable., (© 2024 College of American Pathologists.)

Context.—: Pseudocarcinomatous urothelial hyperplasia (PCUH) architecturally and cytologically mimics cancer. The urine cytology features of PCUH have not been described., Objective.—: To describe PCUH features in urine cytology., Design.—: We reviewed urine cytology cases with concurrent PCUH tissue specimens from 5 academic institutions and classified them by using The Paris System criteria., Results.—: Thirty-nine patients included 31 men and 8 women with a mean age of 67 years (range, 39-87 years). All patients had prior pelvic irradiation, and most presented with hematuria (n = 27). The specimens included voided urine (n = 16); bladder washing (n = 11); and urine, not otherwise specified (n = 12). The specimen preparation included cytospin (n = 29) and ThinPrep (n = 10). Original interpretations were negative for high-grade urothelial carcinoma (n = 28), atypical urothelial cells (AUCs; n = 10), and high-grade urothelial carcinoma (HGUC; n = 1). Twenty-five urine specimens (64%) had findings of PCUH. These specimens were moderately cellular and composed of sheets, cohesive groups, or isolated urothelial cells. Nucleoli were present in 23 cases. The nuclear membrane was smooth to irregular (n = 9), smooth (n = 8), and irregular (n = 8). The chromatin was glassy (n = 8), vesicular (n = 7), hyperchromatic (n = 7), and vesicular to finely granular (n = 3). The cytoplasm varied from dense squamoid, to finely vacuolated, to vacuolated. Nucleomegaly was observed in all 25 specimens, and nuclear-cytoplasmic ratio greater than 0.5 was seen in 11 of 25 cases (44%). The background contained acute inflammation (n = 14), was clean (n = 9), and contained red blood cells (n = 2). All cases originally interpreted as AUCs and HGUC had PCUH features., Conclusions.—: PCUH urine features can overlap with AUCs, HGUC, and other nonurothelial malignancies. In our cohort, 44% (11 of 25) of urine specimens with PCUH changes were initially misclassified. Recognition of cytologic features of PCUH is important to avoid overcalling reactive changes., (© 2023 College of American Pathologists.)

Context.—: The approval of pembrolizumab for treatment of patients with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) advanced cancers has led to increased requests for MSI and/or MMR immunoperoxidase (IPOX) testing. Diagnoses for patients with advanced-stage cancer are frequently made from cytology specimens., Objective.—: To investigate the feasibility of using cell block (CB) preparations of effusions for MMR IPOX evaluation., Design.—: Surgical pathology cases of colorectal and endometrial carcinomas with known MMR/MSI status and matched effusions with available CBs were identified. Cell block sections were evaluated for adequacy and stained with MMR IPOX (MSH2, MSH6, MLH1, and PMS2). The CBs were reviewed, the number of tumor cells quantified, and MMR IPOX was interpreted as retained, lost, suboptimal, or noncontributory., Results.—: We identified 748 cases with MMR/MSI testing on surgical specimens having matched effusions. Of these, 131 cases (17.5%) had an available CB and 53 were deemed adequate for MMR IPOX staining. MMR IPOX results between effusion CBs and surgical pathology specimens were concordant in 45 of 53 (85%), inconclusive in 6 of 53 (11%), and discordant in 2 of 53 (4%) cases., Conclusions.—: There was high concordance of MMR IPOX testing between cytologic and surgical specimens, with no false-positive and 2 false-negative CB results. Limited tumor cells, staining in cells indefinite as tumor, tumor staining heterogeneity, and lack of internal control staining were problematic in some cases. Our findings indicate that cytologic effusion specimens may be suitable substrates for MMR IPOX biomarker testing; however, inconclusive cases need to be interpreted with caution., (© 2021 College of American Pathologists.)

Context.—: Mitotic count is an important histologic criterion for grading and prognostication in phyllodes tumors (PTs). Counting mitoses is a routine practice for pathologists evaluating neoplasms, but different microscopes, variable field selection, and areas have led to possible misclassification., Objective.—: To determine whether 10 high-power fields (HPFs) or whole slide mitotic counts correlated better with PT clinicopathologic parameters using digital pathology (DP). We also aimed to find out whether this study might serve as a basis for an artificial intelligence (AI) protocol to count mitosis., Design.—: Representative slides were chosen from 93 cases of PTs diagnosed between 2014 and 2015. The slides were scanned and viewed with DP. Mitotic counting was conducted on the whole slide image, before choosing 10 HPFs and demarcating the tumor area in DP. Values of mitoses per millimeter squared were used to compare results between 10 HPFs and the whole slide. Correlations with clinicopathologic parameters were conducted., Results.—: Both whole slide counting of mitoses and 10 HPFs had similar statistically significant correlation coefficients with grade, stromal atypia, and stromal hypercellularity. Neither whole slide mitotic counts nor mitoses per 10 HPFs showed statistically significant correlations with patient age and tumor size., Conclusions.—: Accurate mitosis counting in breast PTs is important for grading. Exploring machine learning on digital whole slides may influence approaches to training, testing, and validation of a future AI algorithm., (© 2020 College of American Pathologists.)

Context.—: The Management Guidelines for Children with Thyroid Nodules and Differentiated Thyroid Cancer from The American Thyroid Association recommends fine-needle aspiration (FNA) as an essential tool for evaluation and management of pediatric thyroid nodules, and The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) as a guideline to categorize FNA cytologic findings. A few publications have focused on TBSRTC categorization in children., Objective.—: To evaluate our institutional experience of using TBSRTC in the pediatric population., Design.—: We conducted a retrospective data search for thyroid FNA specimens from patients younger than 21 years who were assessed by using TBSRTC categorization between January 1, 2011, and September 30, 2017. Cytologic and histologic diagnoses, rate of surgical follow-up, rate of histology-proven malignancy, and cytologic-histologic concordance were assessed in comparison with our previously published adult experience., Results.—: Among a total of 201 specimens, benign category accounted for 103 (51.2%), followed by 35 (17.4%) malignant, 30 (14.9%) atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS), 14 (7.0%) nondiagnostic, 10 (5.0%) follicular neoplasm/suspicious for follicular neoplasm (FN/SFN), and 9 (4.5%) suspicious for malignancy (SFM) categories. Surgeries were subsequently performed in 100 of the 201 cases (49.8%). All surgically removed nodules categorized as malignant and SFM by FNA showed malignancy, while malignancy was evident in various proportions of specimens classified as AUS/FLUS (5 of 16; 31.3%), FN/SFN (1 of 9; 11.1%), and nondiagnostic (1 of 7; 14.2%). No malignancy was identified in the benign category. Cytologic-histologic concordance achieved 100% in malignant, SFM, and FN/SFN categories, and exceeded beyond 85% and 50% for benign and AUS/FLUS categories, respectively., Conclusions.—: TBSRTC is effective for appropriate categorization of pediatric thyroid nodules. Risk of malignancy in thyroid nodules is higher for the pediatric than adult population. Understanding the difference in TBSRTC categorization between children and adults may aid in achieving more appropriate evaluation and management of pediatric thyroid nodules.

Context.—: Fine-needle aspiration cytology (FNAC) of pulmonary nodules is usually guided by computed tomography (CT), whereas ultrasonography (US) is generally considered not applicable for such purposes., Objective.—: To evaluate the clinical applicability and diagnostic utility of US-guided transthoracic FNAC of peripheral pulmonary nodules., Design.—: Ultrasonography-guided transthoracic FNAC was obtained from 40 selected patients with peripheral, subpleural, and paravertebral pulmonary nodules. Air-dried and Diff-Quik-stained smears were used for rapid on-site evaluation; additional smears were alcohol fixed for Papanicolaou staining. Cell blocks were set up for immunocytochemical and molecular studies; in 2 cases, a flow cytometry evaluation was also performed. The series was compared to 40 CT-guided pulmonary FNAC samples from patients with pleural, peripheral, and paravertebral pulmonary nodules, to evaluate differences in terms of diagnostic rate, time of execution, safety, and cost., Results.—: The US-guided FNAC samples had results that were adequate and representative in 95% of cases. No significant differences were observed between the 2 groups in terms of diagnostic rate, number of passes, and cellularity of both smears and cell blocks. The mean time needed for the execution of US-guided FNAC was 13.1 minutes, whereas the mean time for CT-guided FNAC was 23.6 minutes. Thus, US-guided FNAC was significantly more rapid than CT-guided pulmonary FNAC. Because pneumothorax occurred in 1 individual who underwent US-guided FNAC and in 9 who underwent CT-guided FNAC, we might conclude that US-guided FNAC is a significantly safer procedure. Finally, comparing the costs of both procedures, US-guided FNAC is less expensive., Conclusions.—: Our experience showed an elevated clinical applicability and diagnostic utility of US-guided transthoracic FNAC for selected pulmonary nodules.

Context.—: Histopathologic diagnosis of adenocarcinoma of the prostate is based on light-microscopic examination of hematoxylin-eosin-stained tissue sections. Multiple factors, including preanalytic and analytic elements, affect the ability of the pathologist to accurately diagnose prostatic adenocarcinoma. False-negative diagnosis, that is, failure to diagnose prostatic adenocarcinoma, may have serious clinical consequences. It is important to delineate and understand those factors that may affect and cause histopathologic false-negative diagnoses of prostatic adenocarcinoma., Objectives.—: To review common factors involved in histopathologic underdiagnosis of prostatic adenocarcinoma, including the following: (1) tissue processing and sectioning artifacts, (2) minimal adenocarcinoma, (3) deceptively benign appearing variants of acinar adenocarcinoma, (4) single cell adenocarcinoma, and (5) treatment effects., Data Sources.—: Data sources included published, peer-reviewed literature and personal experiences of the senior author., Conclusions.—: Knowledge of the reasons for histopathologic false-negative diagnosis of adenocarcinoma of the prostate is an important component in the diagnostic assessment of prostate tissue sections. Diagnostic awareness of the histomorphologic presentations of small (minimal) adenocarcinoma; deceptively benign appearing variants including atrophic, foamy gland, microcystic, and pseudohyperplastic variants; single cell carcinoma; and treatment effects is critical for establishment of a definitive diagnosis of adenocarcinoma and the prevention of false-negative diagnoses of prostate cancer.

Context.—: The Paris System for Reporting Urinary Cytology has been disseminated since its inception in 2013; however, the daily practice patterns of urinary tract cytopathology are not well known., Objective.—: To assess urinary tract cytopathology practice patterns across a variety of pathology laboratories to aid in the implementation and future update of the Paris System for Reporting Urinary Cytology., Design.—: A questionnaire was designed to gather information about urinary tract cytopathology practices and mailed in July 2014 to 2116 laboratories participating in the College of American Pathologists interlaboratory comparison program. The participating laboratories' answers were summarized., Results.—: Of the 879 of 2116 laboratories (41%) that participated, 745 (84.8%) reported processing urinary tract specimens in house. The laboratories reported processing various specimen types: voided urine, 735 of 738 (99.6%); bladder washing/barbotage, 639 of 738 (86.6%); and catheterized urine specimens, 653 of 738 (88.5%). Some laboratories used multiple preparation methods, but the most commonly used preparation techniques for urinary tract specimens were ThinPrep (57.4%) and Cytospin (45.5%). Eighty-eight of 197 laboratories (44.7%) reported preparing a cell block, but with a low frequency. Adequacy criteria were used by 295 of 707 laboratories (41.7%) for voided urine, and 244 of 707 (34.5%) assessed adequacy for bladder washing/barbotage. More than 95% of the laboratories reported the use of general categories: negative, atypical, suspicious, and positive. Polyomavirus was classified as negative in 408 of 642 laboratories (63.6%) and atypical in 189 of 642 (29.4%). One hundred twenty-eight of 708 laboratories (18.1%) performed ancillary testing, and of these, 102 of 122 (83.6%) reported performing UroVysion., Conclusions.—: Most laboratories use the ThinPrep method followed by the Cytospin technique; therefore, the criteria published in The Paris System for Reporting Urinary Cytology , based mostly on ThinPrep and SurePath, should be validated for Cytospin, and relevant information should be included in the revised edition of The Paris System for Reporting Urinary Cytology .

Context.—: Respiratory cytology continues to play an important role in the diagnosis of lower respiratory tract infections. Prompt, accurate diagnosis of causative organisms is of paramount importance, particularly in immunosuppressed patients. In addition, a rapidly expanding arsenal of ancillary testing is now available, aiding tremendously in organism identification., Objective.—: To provide an updated review on the cytomorphologic features of common organisms in lower respiratory tract infection. Relevant ancillary tests, differential diagnoses, and potential pitfalls of organism identification will also be discussed., Data Sources.—: Data for this review were gathered from PubMed searches of infectious diseases of the lower respiratory tract, especially related to the diagnoses., Conclusions.—: The lower respiratory tract is subject to infection by a wide variety of infectious agents. Pathologists should be familiar with common organisms, including their general clinical characteristics, cytomorphologic features, differential diagnoses, and ancillary methods of detection. Above all, correlation with microbiologic and clinical information is necessary to make a confident diagnosis of infection.

Context.—: The production of whole slide images is the most advanced form of digital pathology, in which a high-resolution digital scanner is used to rapidly scan glass microscope slides and produce a computer-generated whole slide image that can be saved, stored in a network-attached storage device, and accessed through slide management software within the hospital domain and remotely by authorized users. Digital transformation of glass slides has revolutionized the practice of anatomic pathology by facilitating and expediting consultative services, improving clinical workflow, and becoming an indispensable tool in education and research., Objective.—: To highlight the institutional need of Cleveland Clinic Abu Dhabi (Abu Dhabi, United Arab Emirates) and the cultural background for obtaining the United Arab Emirates' first comprehensive digital pathology program; to describe a multiphase road map for achieving full implementation of this platform; and to describe the system's clinical applications and its future potential growth., Data Sources.—: At Cleveland Clinic Abu Dhabi, we prioritized our efforts to initiate digital consultations (eConsultations) and digital immunohistochemistry services (eIHC) with Cleveland Clinic Laboratories (Cleveland, Ohio). After this, we established an internal archiving system together with a subspecialty-based, organ-specific digital library of pathologic diseases., Conclusions.—: We describe the strategic adoption and implementation of digital pathology into the clinical workflow of the pathology and laboratory medicine institute of Cleveland Clinic Abu Dhabi, and we highlight its impact on clinical operations, educational activities, and patient care.

Context: - Integration of the analysis of genetic markers with endoscopic ultrasound-guided fine-needle aspiration and cytologic evaluation has increased the accuracy of the preoperative diagnosis of pancreatic lesions. The application of high-throughput gene panel analysis using next-generation sequencing platforms is now offering a great opportunity for further improvements., Objective: - To review the application of next-generation sequencing to the preoperative diagnosis of pancreatic lesions., Data Sources: - For data acquisition, a PubMed search using the terms next-generation sequencing, pancreas, pancreatic lesions, pancreatic tumors, and EUS-FNA was performed covering the years 2000-2017., Conclusions: - KRAS remains the gene most widely studied for preoperative single-gene tests. Next-generation sequencing reliably allows analysis of multiple gene markers starting from limited amounts of DNA. The study of multigene panels has become a very attractive option for the management and preoperative risk stratification of patients with pancreatic cancer.

Context: - The rapid advances in targeted therapies in non-small cell lung cancer (NSCLC) make the optimization and implementation of cytology specimens for molecular testing a priority. Up to 70% of patients with NSCLC are diagnosed at advanced stages and tissue biopsies often cannot be taken. Although cytology samples provide high-quality material for molecular testing, molecular cytopathology is not yet well known or widely used., Objective: - To report the many advances in molecular cytopathology and the suitability and utility of cytology samples in molecular and genetic testing of NSCLC., Data Sources: - Data sources comprised published peer-reviewed literature and personal experience of the authors., Conclusions: - Molecular testing can be performed on cytologic specimens, especially on direct smears. Rapid on-site evaluation by cytopathologists has improved the adequacy and the management of cytology samples for molecular testing. Mutational profiling of NSCLC using next-generation sequencing can be performed on cytology samples from very small amounts of DNA. Fluorescence in situ hybridization assays on cytology specimens, including stained direct smear, offer some distinct advantages over their histologic counterpart, and are used to detect ALK and ROS1 rearrangements in NSCLC. Cytology specimens allow assessment of the entire tumor cell nucleus, avoiding signal loss from truncation artifacts. The use of cytology samples for assessing programmed death ligand-1 protein expression is currently being developed. Protocols for bisulfite conversion and DNA droplet digital polymerase chain reaction assays have been optimized for cytology smear to investigate aberrant DNA methylation of several NSCLC-related genes.

Context: - Thyroid nodules have a prevalence of approximately 70% in adults. Fine-needle aspiration (FNA) is a minimally invasive, cost-effective, standard method to collect tissue from thyroid nodules for cytologic examination. However, approximately 15% of thyroid FNA specimens cannot be unambiguously diagnosed as benign or malignant., Objective: - To investigate whether clinically actionable data can be obtained using next-generation sequencing of residual needle rinse material., Design: - A total of 24 residual needle rinse specimens with malignant (n = 6), indeterminate (n = 9), or benign (n = 9) thyroid FNA diagnoses were analyzed in our clinical molecular diagnostics laboratory using next-generation sequencing assays designed to detect gene mutations and translocations that commonly occur in thyroid cancer. Results were correlated with surgical diagnoses and clinical outcomes., Results: - Interpretable data were generated from 23 of 24 residual needle rinse specimens. Consistent with its well-known role in thyroid malignancy, BRAF V600E mutations were detected in 4 malignant cases. An NRAS mutation was detected in 1 benign case. No mutations were detected from specimens with indeterminate diagnoses., Conclusions: - Our data demonstrate that residual thyroid FNA needle rinses are an adequate source of material for molecular diagnostic testing. Importantly, detection of a mutation implicated in thyroid malignancy was predictive of the final surgical diagnosis and clinical outcome. Our strategy to triage thyroid nodules with indeterminate cytology with molecular testing eliminates the need to perform additional FNA passes into dedicated media or to schedule additional invasive procedures. Further investigation with a larger sample size to confirm the clinical utility of our proposed strategy is underway.

Context: - Body fluid cytology is an important diagnostic tool used to identify various conditions. However, an accurate diagnosis in this setting can sometimes be challenging., Objective: - To identify the performance characteristics of body fluid cytology by analyzing participant responses from the College of American Pathologists Interlaboratory Comparison Program in Nongynecologic Cytopathology., Design: - Participant responses from 5102 slides were analyzed for concordance to the general category (GC) and to the reference diagnosis (RD). Nonlinear mixed models were used to analyze concordance., Results: - The overall GC concordance was 95.2%. The GC type, participant type, and preparation type were significantly associated with GC concordance ( P < .001). Concordance for malignant cases was higher than it was for benign cases. Cytotechnologists had better GC concordance compared to pathologists. ThinPrep (Hologic, Marlborough, Massachusetts) slides had the highest GC concordance. Participant type, fluid type, preparation type, and participant interpretation were significantly associated with RD concordance ( P < .001). Pathologists performed better than cytotechnologists did for RD concordance. Pericardial fluid had the lowest RD concordance, especially for cases with normal or reactive findings. Modified Giemsa-stained slides performed best for lymphoma and hematopoietic malignancy. Small cell carcinoma had the highest GC concordance, and its RD concordance was higher in pleural than in peritoneal fluids. Adenocarcinoma showed the highest concordance rates for both GC and RD., Conclusions: - This study illustrates the challenges associated with interpreting body fluid cytology, particularly in pericardial fluid, and the factors that may affect accurate diagnoses. The results also highlight the value of using multiple preparation types in challenging cases.

Context: - Malignant mesothelioma (MM) is an uncommon tumor that can be difficult to diagnose., Objective: - To provide updated, practical guidelines for the pathologic diagnosis of MM., Data Sources: - Pathologists involved in the International Mesothelioma Interest Group and others with an interest and expertise in the field contributed to this update. Reference material included up-to-date, peer-reviewed publications and textbooks., Conclusions: - There was discussion and consensus opinion regarding guidelines for (1) distinguishing benign from malignant mesothelial proliferations (both epithelioid and spindle cell lesions), (2) cytologic diagnosis of MM, (3) recognition of the key histologic features of pleural and peritoneal MM, (4) use of histochemical and immunohistochemical stains in the diagnosis and differential diagnosis of MM, (5) differentiating epithelioid MM from various carcinomas (lung, breast, ovarian, and colonic adenocarcinomas, and squamous cell and renal cell carcinomas), (6) diagnosis of sarcomatoid MM, (7) use of molecular markers in the diagnosis of MM, (8) electron microscopy in the diagnosis of MM, and (9) some caveats and pitfalls in the diagnosis of MM. Immunohistochemical panels are integral to the diagnosis of MM, but the exact makeup of panels employed is dependent on the differential diagnosis and on the antibodies available in a given laboratory. Depending on the morphology, immunohistochemical panels should contain both positive and negative markers for mesothelial differentiation and for lesions considered in the differential diagnosis. Immunohistochemical markers should have either sensitivity or specificity greater than 80% for the lesions in question. Interpretation of positivity generally should take into account the localization of the stain (eg, nuclear versus cytoplasmic) and the percentage of cells staining (>10% is suggested for cytoplasmic and membranous markers). Selected molecular markers are now being used to distinguish benign from malignant mesothelial proliferations. These guidelines are meant to be a practical diagnostic reference for the pathologist; however, some new pathologic predictors of prognosis and response to therapy are also included.

Context: - At our medical center, cytopathologists perform rapid on-site evaluation for specimen adequacy of fine-needle aspiration and touch imprint of needle core biopsy lung cancer samples. Two years ago the molecular diagnostics laboratory at our institution changed to next-generation sequencing using the Ion Torrent PGM and the 50-gene AmpliSeq Cancer Hotspot Panel v2 for analyzing mutations in a 50-gene cancer hot spot panel. This was associated with a dramatic fall in adequacy rate (68%)., Objective: - To improve the adequacy rate to at least 90% for molecular testing using next-generation sequencing for all specimens collected by rapid on-site evaluation by the cytology laboratory., Design: - After baseline data on adequacy rate of cytology specimens with rapid on-site evaluation for molecular testing had been collected, 2 changes were implemented. Change 1 concentrated all the material in one block but did not produce desired results; change 2, in addition, faced the block only once with unstained slides cut up front for molecular testing. Data were collected in an Excel spreadsheet and adequacy rate was assessed., Results: - Following process changes 1 and 2 we reached our goal of at least 90% adequacy rate for molecular testing by next-generation sequencing on samples collected by rapid on-site evaluation including computed tomography-guided needle core biopsies (94%; 17 of 18) and fine-needle aspiration samples (94%; 30 of 32)., Conclusion: - This study focused on factors that are controllable in a pathology department and on maximizing use of scant tissue. Optimizing the adequacy of the specimen available for molecular tests avoids the need for a second procedure to obtain additional tissue.

Context: -The National Cancer Care Network and the combined College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology guidelines indicate that all lung adenocarcinomas (ADCs) should be tested for epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements. As the majority of patients present at a later stage, the subclassification and molecular analysis must be done on cytologic material., Objective: -To evaluate the accuracy and interobserver variability among cytopathologists in subtyping non-small cell lung carcinoma using cytologic preparations., Design: -Nine cytopathologists from different institutions submitted cases of non-small cell lung carcinoma with surgical follow-up. Cases were independently, blindly reviewed by each cytopathologist. A diagnosis of ADC or squamous cell carcinoma was rendered based on the Diff-Quik, Papanicolaou, and hematoxylin-eosin stains. The specimen types included fine-needle aspiration from lung, lymph node, and bone; touch preparations from lung core biopsies; bronchial washings; and bronchial brushes. A major disagreement was defined as a case being misclassified 3 or more times., Results: -Ninety-three cases (69 ADC, 24 squamous cell carcinoma) were examined. Of 818 chances (93 cases × 9 cytopathologists) to correctly identify all the cases, 753 correct diagnoses were made (92% overall accuracy). Twenty-five of 69 cases of ADC (36%) and 7 of 24 cases of squamous cell carcinoma (29%) had disagreement (P = .16). Touch preparations were more frequently misdiagnosed compared with other specimens. Diagnostic accuracy of each cytopathologist varied from 78.4% to 98.7% (mean, 91.7%)., Conclusion: -Lung ADC can accurately be distinguished from squamous cell carcinoma by morphology in cytologic specimens with excellent interobserver concordance across multiple institutions and levels of cytology experience.

Spindle cell lesions of the gastrointestinal tract are relatively uncommon compared with the frequency of their epithelial counterparts. Although gastrointestinal stromal tumors and leiomyomas are the most commonly encountered spindle cell lesions in the stomach and esophagus, respectively, there are other less common diagnostic entities that should be considered for accurate diagnoses as well as appropriate patient treatment and clinical follow-up. Given the morphologic overlap of low-grade spindle cell lesions on cytologic preparations, ancillary studies play a key role in differentiating these lesions from one another.

Context: Body fluids submitted to the hematology laboratory for cell counts may also be examined for the presence of malignancy. Previous studies evaluating the hematology laboratory's performance at detecting malignancy in body fluids have reached conflicting conclusions., Objective: To investigate the hematology laboratory's ability to detect malignancy in body fluids by comparison with cytology., Design: Retrospective analysis of 414 body fluid samples during an 18-month period, with introduction of new quality assurance measures after the first 210 cases. If no concurrent cytology was ordered, results were compared with recent previous and/or subsequent cytologic, histologic, or flow cytometric diagnoses., Results: Of the initial 210 cases, the hematology laboratory detected 3 of 13 malignancies diagnosed by concurrent cytology (23% sensitivity), with no false-positives (100% specificity). Malignancy was not identified on retrospective review of the hematology slides in the 10 discrepant cases. After the initial study, educational sessions on morphology for the medical technologists and a more thorough hematology-cytology correlation policy were implemented. The subsequent 204 hematology laboratory cases had increased sensitivity for the detection of malignancy (60%; 6 of 10). Definitive features of malignancy were seen in only one discrepant hematology laboratory slide on retrospective review. This case had not been flagged for hematopathologist review. None of the discrepancies before or after implementation of the additional quality assurance measures impacted patient care., Conclusions: Body fluid processing by the hematology laboratory is not optimized for the detection of malignancy. Concurrent cytologic examination is critical for the detection of malignancy, and needs to be considered as cost-saving measures are increasingly implemented.

Context: The use of p16 in cervical biopsies improves the accuracy of cervical intraepithelial neoplasia (CIN) diagnosis and grading and decreases its interpathologist variability., Objective: To determine the impact of the frequency of use of p16 immunostains in cervical biopsies on pathologists' diagnoses of CIN grade 1 and grade 2 or above (CIN1 and CIN2+) and on cytohistologic correlations., Design: We identified all cervical biopsy specimens with cytologic correlations subjected or not to p16 staining from January 1, 2005, to September 30, 2010; calculated each pathologist's percentage of p16 use; and correlated it with their major cytohistologic discrepancy rates, CIN2+ diagnoses, and CIN1/CIN2+ ratios., Results: During the study period, each of the 23 pathologists interpreted 59 to 1811 (mean, 518) of 11 850 cervical biopsy specimens, used p16 for 0% to 21.31% (mean, 10.14%) of these, had CIN2+ detection rates of 9.5% to 24.1% (mean, 18.9%), and CIN1/CIN2+ ratios of 0.7 to 4.5 (mean, 1.5). Compared to the 12 "low users" of p16, who used p16 fewer times than the institution's mean for p16 use, the 11 "high users" of p16 diagnosed more biopsies (8391 versus 3459), had a lower rate of major cytohistologic discrepancies (12.62% versus 14.92%, P < .001), a higher rate of CIN2+ diagnoses (19.9% versus 16.4%, P < .001), a lower range of CIN2+ rates (15.0%-23.1% versus 9.5%-24.1%), and lower CIN1/CIN2+ ratios (1.2 versus 2.3)., Conclusions: We found a high intrainstitutional variability of p16 use in cervical biopsies, CIN2+ rates, and CIN1/CIN2+ ratios. Use of p16 for greater than 10% of cervical biopsies was associated with improved cytohistologic correlation rates and with lower variability in the frequencies of histologic diagnoses.

Context: Experiences at our institution show that flow cytometry analysis (FCA) has become routine clinical practice in the workup of patients with altered mental status, even if risk factors are low., Objective: To assess diagnostic accuracy of combined FCA and cytology in the diagnosis of central nervous system lymphoma in an unselected patient population with neurologic symptoms, including patients with no history of lymphoma or suspicious radiology., Design: Between 2001 and 2011, cerebrospinal fluid was submitted from 373 patients for lymphoma screening by FCA. The medical records were reviewed for patient symptomatology, history of malignancy, brain imaging, FCA results, cytology results, brain biopsy, and clinical follow-up., Results: A lymphoid malignancy was detected by FCA in 4% of cases. A positive diagnosis was more likely in patients with either a history of hematologic malignancy and/or a suspicious radiology result (P = .009). All patients with no history of lymphoma and no suspicious radiology (n = 102) had negative cytology, and none had a correspondingly positive FCA result. The positive and negative predictive values of combined cytology and FCA in the patients with history of lymphoma and/or abnormal imaging results were 92% and 89%, respectively, when compared with open brain tissue biopsy, and 89% and 86%, respectively, when compared with clinical follow-up. When low-risk patients were included, the positive predictive value remained at 92%, but the negative predictive value dropped to 52% with the open brain biopsy as the reference, and values did not change significantly for the group with clinical follow-up., Conclusions: Concurrent FCA and cytology are most useful in the appropriate clinical setting, and we propose a triage algorithm for how FCA on cerebrospinal fluid is best used.

Context: The usefulness of spontaneous nipple discharge analysis is controversial. Nipple discharge preparations are rare in clinical practice and malignant cases are exceptional. The College of American Pathologists Interlaboratory Comparison Program in Nongynecologic Cytopathology has included nipple discharge preparations since its inception., Objectives: To evaluate participant responses in the College of American Pathologists Interlaboratory Comparison Program in Nongynecologic Cytopathology to assess the accuracy of cytologic interpretation of nipple discharge preparation., Design: General diagnostic category (benign, suspicious, malignant), participant type (pathologist, cytotechnologist), stain (Papanicolaou, modified Giemsa), and program year (2005-2009) were analyzed using χ(2) and a nonlinear mixed model for slide factor correlation structure., Results: Of 2506 responses, 1280 (51%) were malignant, 171 (7%) were papillary, and 1055 (42%) were benign. There were 222 discordant general category responses with a false-positive/suspicious rate of 12.8% and a false-negative rate of 3.4%. The most common false-negative diagnosis was mastitis/abscess (125 of 1272 responses; 9.8%). The most common false-positive response was papillary lesion (26 of 457 responses; 5.7%). There were no differences between stains or years. Cytotechnologists performed better than pathologists; pathologists had a higher false-negative rate than cytotechnologists (15.3% versus 7.9%, P < .001)., Conclusions: There is poor accuracy in evaluating nipple discharge preparation in the College of American Pathologists Interlaboratory Comparison Program in Nongynecologic Cytopathology. If the findings in the program parallel clinical practice, nipple discharge preparations may adversely impact patient care. A benign nipple discharge cytologic diagnosis does not exclude malignancy, and the false-positive/suspicious rate requires confirmation of a malignant nipple discharge prior to definitive patient management.

Context: Cytology relies heavily on morphology to make diagnoses, and morphologic criteria have not changed much in recent years. The field is being shaped predominantly by new techniques for imaging and for acquiring and processing samples, advances in molecular diagnosis and therapeutics, and regulatory issues., Objective: To review the importance of classical morphology in the future of cytopathology, to identify areas in which cytology is expanding or contracting in its scope, and to identify factors that are shaping the field., Data Sources: Literature review., Conclusions: Five stories paint a picture in which classical cytomorphology will continue to have essential importance, both for diagnosis and for improving our understanding of cancer biology. New endoscopy and imaging techniques are replacing surgical biopsies with cytology samples. New molecularly targeted therapies offer a chance for cytology to play a major role, but they pose new challenges. New molecular tests have the potential to synergize with, but not replace, morphologic interpretation of thyroid fine-needle aspirations. Ultrasound-guided fine-needle aspiration performed by cytopathologists is opening a new field of "interventional cytopathology" with unique value. For the productive evolution of the field, it will be important for cytopathologists to play an active role in clinical trials that document the ability of cytology to achieve cost-effective health care outcomes.

Context: Digital whole slide imaging is the anticipated future of anatomic pathology, where sign-out of glass slides will be replaced by scanned images. Whole slide imaging has been successfully used in surgical pathology, but its usefulness and clinical application have been limited in cytology for several reasons, including lack of availability of z-axis depth focusing and large file size. Recently, several systems have become available in the United States for whole slide imaging with z-axis technology., Objective: To determine the accuracy and efficiency of whole slide imaging, as compared with traditional glass slides, for use in cervicovaginal diagnostic cytology., Design: Eleven cervicovaginal cytology cases (ThinPrep and SurePath) scanned at ×20, ×40, and ×40 z-stack magnifications using the BioImagene iScan Coreo Au 3.0 scanner were evaluated by 4 cytotechnologists and 3 pathologists in a blinded study. Different magnification scans were recorded as separate cases and presented in a randomized sequence. Corresponding glass slides were also reviewed. For each case, the diagnoses and total time to reach each diagnosis were recorded., Results: Diagnostic accuracy was higher and average time per case was lower with glass slides as compared with all digital images. Among the digital images, the ×40 or ×40 z-stack had the highest diagnostic accuracy and lowest interpretation time., Conclusions: Whole slide imaging is a viable option for the purposes of teaching and consultations, and as a means of archiving cases. However, considering the large file size and total time to reach diagnosis on digital images, whole slide imaging is not yet ready for daily cervicovaginal diagnostic cytology screening use.

Context: Diagnoses rendered as atypical/suspicious for malignancy on fine-needle aspiration (FNA) of pancreatic mass lesions range from 2% to 29% in various studies. We have identified the expression of 3 genes, MUC4, MUC16, and NGAL that are highly upregulated in pancreatic adenocarcinoma. In this study, we analyzed the expression of these markers in FNA samples to determine whether they could improve sensitivity and specificity., Objective: To evaluate the utility of MUC4, MUC16, and NGAL in the evaluation of pancreatic FNA specimens., Design: Records of pancreatic FNAs performed during 10 consecutive years were reviewed. Unstained sections from corresponding cell blocks were immunostained for MUC4, MUC16, and NGAL (polyclonal). Immunostaining was assessed using the H-score (range, 0-3). Any case with an H-score of >0.5 was considered positive., Results: Cases were classified using cytomorphologic criteria as adenocarcinoma (31 of 64; 48.4%), benign (17 of 64; 26.6%), and atypical/suspicious (16 of 64; 25%). On follow-up, all cases (100%; 31 of 31) diagnosed as carcinoma on cytology were confirmed on biopsy/resection samples or by clinical follow-up (such as unresectable disease). Of the cases diagnosed as atypical/suspicious, 69% (11 of 16) were found to be positive for adenocarcinoma and 31% (5 of 16) were benign on subsequent follow-up. Overall sensitivity and specificity, respectively, for the various markers for the detection of pancreatic adenocarcinoma were as follows: MUC4 (74% and 100%), MUC16 (62.9% and 100%), and NGAL (61.3% and 58.8%). In cases that were atypical/suspicious on cytology, expression of MUC4 and MUC16 was 100% specific for carcinoma with sensitivities of 63.6% and 66.7%, respectively., Conclusion: Immunocytochemistry for MUC4 and MUC16 appears to be a useful adjunct in the classification of pancreatic FNA samples, especially in cases that are equivocal (atypical/suspicious) for adenocarcinoma on cytomorphologic assessment.

Context: Little has been reported on changes in pancreatic pathology practice after implementation of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA)., Objectives: We assessed the impact of EUS-FNA on cytologic diagnosis replacing histologic diagnosis for pancreatic disease and determined whether it fulfills Christensen criteria of a disruptive innovation effect., Design: Pattern of utilization during 20 years, diagnostic categories, and diagnostic accuracy of pancreatic cytology were compared before and after implementation of EUS-FNA. The disruptive effect of cytology relevant to biopsy was assessed by comparing the utilization trends and the accuracy of diagnosis over time., Results: The mean annual volume (standard deviation) of cytologic specimens increased from 24 (11) to 231 (10) after implementation of EUS-FNA, and that of histologic specimens increased from 97 (42) to 377 (148). The average percentage of annual cases managed by following cytology alone was 19% (10) before versus 51% (8) after implementation. The percentage managed by histology alone was 56% before versus 23% after implementation. Non-endoscopic ultrasound-guided fine-needle aspiration cytology decreased from 36% to 1%. Needle biopsies decreased from 7% to 1%, and other biopsy types from 29% to 9%. Unsatisfactory (7% versus 1%), atypical (16% versus 4%), and suspicious (16% versus 3%) diagnoses were significantly reduced. The accuracy of cytologic diagnosis significantly improved: the sensitivity (confidence interval) and specificity (confidence interval) for cancer diagnosis were 55% (38%-70%) and 78% (58%-89%) before versus 88% (84%-91%) and 96% (93%-98%) after implementation, respectively., Conclusions: Endoscopic ultrasound-guided fine-needle aspiration improved the accuracy of cytologic diagnosis, reduced the number of indeterminate diagnoses, and replaced the need for tissue biopsy. Given its cost and simplicity as compared with tissue biopsy, this trend represents a disruptive innovation effect.

Context: The advent of new endoscopic optical techniques is likely to change pathologists' role in diagnosis., Objective: To describe how confocal laser endomicroscopy (CLE) works, show its advantages and limitations compared to cytohistologic biopsy, and explore how it may affect the practice of pathology., Data Sources: Literature review., Conclusions: Confocal laser endomicroscopy is proving its ability to provide histology-like images of tissues in vivo to help avoid risks and costs of conventional biopsies. Confocal imaging restricts light to 1 plane, emulating a paraffin section, and topical or systemic optical contrast agents allow subcellular resolution. New contrast agents could theoretically permit molecular characterization. In vivo imaging has begun to demonstrate novel, dynamic types of diagnostic features. Decreased histologic biopsies can be anticipated for a few scenarios. Significant limitations of CLE include the inability to create a tissue archive for broad molecular classification, suboptimal contrast agents, small fields of view and shallow penetration, paucity of clinical validation studies, and problems with reimbursement. Confocal laser endomicroscopy exposes new opportunities for pathologists: CLE technologies can be exploited in pathology, and diagnostic criteria expanded based on endoscopists' discoveries. Potential synergy exists between CLE and cytology, allowing the low-magnification diagnostic architectural changes by CLE and cytomorphology to emulate the full diagnostic information in a histologic biopsy while providing an archive of material for molecular or immunohistochemical studies. Confocal laser endomicroscopy will decrease some types of biopsies, but offers an opportunity for pathologists to find new ways to provide value and improve patient care.

Context: Mucosal leishmaniasis (ML) is a rare disease in the world, even in endemic areas such as Iran. Clinical, histologic, or cytologic assessment may help in the diagnosis of ML., Objective: To describe clinical, histologic, and cytologic findings in ML., Design: Review of our files showed 11 patients diagnosed with ML, of whom 7 patients had oral lesions, 1 of whom was a known patient with oral leishmaniasis with recurrence of oral lesions; 2 had laryngeal lesions; and 3 had nasal lesions. One case of laryngeal leishmaniasis was a recurrence of prior oral lesions. Cytologic smears were prepared by scraping the lesions with a scalpel or cytobrush. Histology on the biopsies was done for 7 patients. In 2 patients with nasal lesions, exfoliative cytology was made by washing the nasal cavity. Smears were both air dried and fixed in alcohol and stained., Results: Cytologic findings showed free Leishman-Donovan bodies, intrahistiocytic Leishman-Donovan bodies, atypical organisms, granuloma, acute and chronic inflammatory cells, histiocytes, multinucleated giant cells, mast cells, binucleated histiocytes (Reed-Sternberg-like cells), and plasma cells. In 6 of the patients, biopsy was inconclusive and in subsequent cytology the organism was detected. In 3 cases, findings from clinical and cytologic examinations were suggestive for leishmaniasis; however, with response to treatment, the diagnosis was confirmed. In 5 patients a malignant tumor was suspected because of clinical or histologic findings, but cytology helped to diagnose leishmaniasis., Conclusions: Clinically or histologically, ML can be mistaken for benign and malignant lesions. Scraping or exfoliative cytology is an easy, reliable, and cost-effective method for diagnosing ML. Thus, clinical, histologic, and cytologic features together may help in ML diagnosis.

Context: Surgical pathology is unavailable in most of sub-Saharan Africa because of equipment costs and lack of expertise. Cytopathology is an inexpensive and reliable alternative., Objective: To explore the utility of cytopathology in a rural hospital setting in Africa., Design: A cytopathologist and a pathology resident from Calgary, Alberta, Canada, went to Cameroon to provide a cytopathology service at the Banso Baptist Hospital. Both performed the fine-needle aspiration procedures. Direct smears were fixed in alcohol and stained with hematoxylin-eosin. Surgical specimens subsequently obtained from the patients were processed and reported at Calgary Laboratory Services, Canada. The histopathologic diagnoses were the gold standard for determining the accuracy of the cytologic diagnoses., Results: Fifty-nine patients were examined during a 5-week period, 33 females (56%) and 26 males (44%). Sixteen (27%) were known to be HIV positive. Forty-four fine-needle aspiration procedures were performed for 43 patients (73%). The cost of each procedure was approximately US $10. Head and neck and breast were the sites most frequently sampled for aspirates. Cervical smears from 5 patients were also assessed, as were 8 fluid specimens and 2 touch preparations of prostatic core biopsies. The most frequent diagnoses for malignancy were carcinoma and lymphoma. Tuberculous lymphadenitis was diagnosed in 6 patients, 4 of whom were HIV positive. Surgical specimens were received from 18 patients (30%). Cytohistologic and clinicopathologic correlation revealed 1 false-positive (1.6%) and 1 false-negative (1.6%) diagnosis., Conclusion: Cytopathology is a reliable alternative for tissue diagnosis in low-resource settings.

Context: Standard histology services in geographically remote areas are often not available or have long turn-around time, resulting in delayed diagnosis or inappropriate treatment due to incomplete diagnostic data. The use of rapid tissue processing and a portable microtome technique may offer timely, point-of-care histologic diagnosis to patients in a low resources setting, such as medical missions., Objective: To present an alternative to the conventional histologic processing that will permit point-of-care histopathology service., Design: A total of 21 tissue samples from a variety of sites were collected and subjected to a protocol of rapid manual tissue processing, lightweight portable field microtome sectioning, and hematoxylin-eosin staining. The histologic preparations were evaluated for diagnostic quality. The scoring of the preparations was based on completeness and uniformity of the sections, integrity of architectural features, cytologic detail, staining quality, and overall adequacy for diagnosis., Results: Diagnostic quality microscopic slides were obtained from each of the 21 samples that included lesions of the skin, uterus, colon, and breast. The average preparation time, including routine hematoxylin-eosin staining, was 1.5 hours., Conclusions: We validated a point-of-care field histology technique that will be useful in settings of low resources, such as medical missions. Actual field testing of the procedure with special staining for fungi and acid-fast bacilli is the next step in the validation of the methodology.

Context: The false-positive rate for fine-needle aspirates of the lung has been cited as less than 1% for granulomatous inflammation, comprising one of the known causes of false-positive diagnoses., Objective: To determine the rate of false-positive diagnoses of granulomatous inflammation for lung fine-needle aspirates by assessing the false-positive response rate in the context of the College of American Pathologists Nongynecologic Cytopathology Interlaboratory Comparison Program., Design: We performed a retrospective review of 1092 participant responses for lung fine-needle aspirate challenges with the reference diagnosis of specific infections/granulomatous inflammation from 1998 to 2008 from the College of American Pathologists Nongynecologic Cytopathology Interlaboratory Comparison Program. False-positive rates by participant type (pathologist versus cytotechnologist), general diagnosis category, reference diagnosis, and preparation type were analyzed for the pathologists' responses., Results: Of the 502 general category responses for pathologists, 428 (85.3%) were benign, 55 (11%) were malignant, and 19 (3.8%) were suspicious. There was no difference in the false-positive rate between preparations (P  =  .76) or participants (P  =  .39). Of those responses by pathologists that were benign, only 68.7% (292 of 425) were an exact match to granulomatous inflammation. Non-small cell carcinoma, adenocarcinoma, and squamous carcinoma represented 64% of false-positive/suspicious responses, while small cell carcinoma and carcinoid comprised 13%., Conclusion: In an interlaboratory comparison program, granulomatous inflammation represents an important cause of false-positive/suspicious responses in lung fine-needle aspirates (14.8%) and is much higher than false-positive rates reported historically in clinical studies. These results highlight the importance of granulomatous inflammation as a mimic of carcinoma.

Context: Differences in participant responses for ThinPrep (TP) and non-ThinPrep (NTP) preparations for gastrointestinal cytology challenges, which circulated in the College of American Pathologists Interlaboratory Comparison Program in Nongynecologic Cytology (CAP NGC), may help to identify performance variations between preparation types., Objective: To compare the performance of TP-prepared slides of gastrointestinal exfoliative cytology specimens to that of NTP preparations in the CAP NGC program., Design: Participant responses between 2000 and 2007 were evaluated for esophageal wash/brush, gastric wash/brush, and biliary tract brush specimens with a reference diagnosis of adenocarcinoma, squamous cell carcinoma, carcinoid, or spindle cell neoplasm. ThinPrep challenges were compared with NTP preparations (conventional smears, cytospins) for discordant responses., Results: In all, 6023 pathologist responses and 3825 cytotechnologist responses were reviewed. Non-ThinPrep preparations comprised 93% (n = 11 588) of the challenges, while 7% (n = 912) were TP material. A match for a "positive/suspicious" diagnosis was seen in 88.5% of NTP and 95.9% of TP preparations (P < .001). These results were statistically significant when the specific reference diagnosis was adenocarcinoma (P < .001). Overall performance of cytotechnologists was not different from that of pathologists (89.2% versus 89.0%; P = .75). Cytotechnologists had better performance for detecting squamous cell carcinoma (96.3% versus 92.6%; P < .001), while pathologists had better performance for detecting spindle cell neoplasm (79.7% versus 42.9%; P < .001)., Conclusions: ThinPrep preparations performed significantly better than NTP preparations in gastrointestinal cytology specimens circulated in an interlaboratory comparison program. Performance varied by reference interpretation, with the best performance for the interpretation of adenocarcinoma. Cytotechnologists and pathologists performed at the same level overall, but with differences for the diagnosis of spindle cell neoplasm and squamous carcinoma.

Context: -Minimum cellular criteria for satisfactory Papanicolaou tests were established with the Bethesda System in 2001, and unsatisfactory rates are used as a quality-reporting measure., Objective: -To evaluate practices and unsatisfactory rates from laboratories responding to the 2007 College of American Pathologists supplemental questionnaire survey., Design: -In 2007, a supplemental questionnaire was mailed to 1621 laboratories enrolled in the 2006 College of American Pathologists Interlaboratory Comparison Program in Gynecologic Cytology (PAP Education), requesting data from the 2006 calendar year. Unsatisfactory rates, reasons for unsatisfactory specimens, laboratory size, and specimen preparation type were analyzed., Results: -A total of 42% of the laboratories responded to the survey. Most of those laboratories (637 of 674; 94.5%) used the Bethesda System minimum cellularity criteria. Of those laboratories responding, 79% (527 of 667) used the Bethesda System criteria for atrophic or postirradiation specimens. Unsatisfactory rates have increased since 1996. SurePath preparations were associated with the lowest unsatisfactory rate (50th percentile, 0.30; 95th percentile, 1.3), conventional Papanicolaou tests had the highest 95th percentile rates (50th percentile, 1.0; 95th percentile, 5.90), and ThinPrep specimens had the highest median percentile (50th percentile, 1.1; 95th percentile, 3.4). The most-common reason for unsatisfactory Papanicolaou tests was too few squamous cells. Air-drying artifact was the least-common reason for unsatisfactory reporting for liquid-based preparations., Conclusions: -Use of the Bethesda System criteria for unsatisfactory specimens is widespread. Unsatisfactory rates have increased since 1996; however, the median rates are 1.1% or less for all preparations. Results from the College of American Pathologists PAP Education supplemental questionnaire continue to provide valuable benchmarking data for cytologic quality-improvement programs in laboratories.

Context: -The increasing use of contrast-enhanced magnetic resonance imaging (MRI) of the breast as a valuable adjunct to mammography and ultrasound in the detection of breast lesions, in association with needle core biopsy taken from the suspicious areas, has major workload implications for histopathology laboratories wherever breast MRI is practiced., Objective: -To establish the number of histologic levels necessary for the evaluation of breast MRI-guided needle core biopsy specimens taken from suspicious areas on breast MRI examination., Design: -Retrospective histologic review of a series of breast MRI-guided core needle biopsies, initially examined routinely at 4 levels, in the Pathology Department at Mount Sinai School of Medicine in New York, New York., Results: -Accurate diagnostic classification was possible after examination of the first level in 95.4% of cases. For a small group of patients (4.4%), 4 levels were considered to provide additional useful information, although this information did not alter the diagnosis. In only a single case (0.2%) was it likely that routine examination of 4 levels could have led to an incidental finding of a very small intraductal papilloma (0.15 cm) present only at the second histologic level. However, this incidental finding would have not changed the patient outcome., Conclusions: -Needle core biopsies for MRI-detected abnormalities should be routinely examined at only 1 level. Further levels may be needed in occasional cases to identify more conclusively an associated pathologic abnormality and may be of particular value when assessing atypical intraductal proliferative epithelial lesions.

Context: Gynecologic cytology terminology and report formatting have been nationally standardized since the implementation of The Bethesda System of 1988, but standard reporting for nongynecologic cytology has never been formally addressed on the same scale., Objectives: To promote patient safety through uniform reporting in nongynecologic cytology (including fine-needle aspiration cytology) and to improve communication between laboratories and health care providers., Data Sources: Sources include the College of American Pathologists Cytopathology Resource Committee; the College of American Pathologists Council on Scientific Affairs Ad Hoc Committee on Pathology Report Standardization; the College of American Pathologists Laboratory Accreditation Program inspection checklists; the Joint Commission for Accreditation of Healthcare Organizations; and the Clinical Laboratory Improvement Amendments of 1988., Conclusions: We describe the major elements of quality nongynecologic cytology reporting and discuss areas of controversy in cytology reporting. Standardized nongynecologic specimen reporting will expand the concept of common report elements already widely implemented in gynecologic cytology reporting. The intent is to improve communication with the health care team while remaining in compliance with federal mandates and accreditation guidelines.

Context: Diagnosis and classification of primary intraocular lymphoma can be challenging because of the sparse cellularity of the vitreous specimens., Objective: To classify and clinically correlate intraocular lymphoma according to the World Health Organization (WHO) classification by using vitrectomy specimens., Design: Clinical history, cytologic preparations, flow cytometry reports, and outcome of 16 patients diagnosed with intraocular lymphoma were reviewed., Results: The study group included 10 women and 6 men. The mean age of the patients was 63 years (range, 19-79 years). Eleven patients had central nervous system involvement and 6 patients had systemic involvement. All cases were adequately diagnosed and classified according to the WHO classification by using combination of cytologic preparations and 4-color flow cytometry with a limited panel of antibodies to CD19, CD20, CD5, CD10, and kappa and lambda light chains. The cases included 9 primary diffuse large B-cell lymphomas of the CNS type; 2 diffuse large B-cell lymphomas, not otherwise specified; 1 extranodal, low-grade, marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT); 1 precursor B-lymphoblastic lymphoma; and 3 peripheral T-cell lymphomas, not otherwise specified. Of note, all 11 cases of diffuse large B-cell lymphoma were CD10-. All the patients received systemic chemotherapy and radiation therapy. Only 4 patients were free of disease at last follow-up (range, 18 months to 8 years), with severe visual loss., Conclusions: Intraocular lymphoma cases can be adequately classified according to the WHO classification. Diffuse large B-cell lymphoma, CD10- and most likely of non-germinal center B-cell-like subgroup, is the most common subtype of non-Hodgkin lymphoma in this site, in contrast to ocular adnexal lymphoma for which MALT lymphoma is the most common subtype.

Context: The presence of malignant cells in peritoneal washings leads to classification as International Federation of Gynecology and Obstetrics stage IC or higher in ovarian carcinomas and at least International Federation of Gynecology and Obstetrics stage IIIA in endometrial carcinomas. Unfortunately, the morphologic examination of cytologic specimens has not proven to be a sensitive or specific diagnostic tool. Malignant cells might be few in number and might be unrecognized among a large population of mesothelial cells and/or macrophages, or reactive mesothelial cells might be misinterpreted as neoplastic cells leading to unnecessary chemotherapy., Objective: To evaluate the main pitfalls in the evaluation of peritoneal washings in patients with gynecologic malignancies and analyze the ancillary studies that might be helpful to achieve the correct diagnosis with an emphasis on immunocytochemistry., Data Sources: A comprehensive review of the literature was performed., Conclusions: Peritoneal effusions may represent major challenges to the pathologist and can have important clinical implications. Immunostains for epithelial markers such as B72.3, MOC-31, and Ber-EP4 represent the best available markers to identify epithelial cells. Caution is advised to not overdiagnose endometriosis or endosalpingiosis as adenocarcinoma.

Context: Fluorescence in situ hybridization (FISH) of voided urine sediment is a sensitive and specific test for the detection of urothelial carcinoma. The time required for slide preparation using the conventional cytospin method is lengthy., Objective: To present an alternative to the conventional cytospin method., Design: We compared the results of an improved filter monolayer method with published results of the conventional cytospin method. A total of 624 patients with cytology and FISH analyses were followed with cystoscopy and/or bladder biopsy. Fluorescence in situ hybridization analysis was performed on 624 cases using fluorescence-labeled probes to the pericentromeric regions of chromosomes 3, 7, and 17 and band 9p21; cytology was also performed in all cases., Results: A total of 217 (34.7%) of 624 patients had follow-up bladder biopsies, and 170 of these (78.3%) had urothelial carcinoma. The sensitivity for cancer detection was higher for FISH than for urine cytology (92.9% [158/ 170] for FISH vs 72.9% [124/170] for urine cytology, P = <5%). The specificity was equivalent for FISH and urine cytology (97.5% [443/454] for FISH vs 92.2% [419/454] for cytology). The sensitivity for FISH was better (92.9% vs 81%), and there was no significant difference in specificity (97.5% vs 96%) between the filter method and the conventional cytospin method. Unlike the conventional cytospin method, the filter method did not require multiple centrifugation and decantation steps or investment in dedicated equipment., Conclusions: The improved filter method was faster, easier, and less expensive than published results with the conventional cytospin method with better sensitivity and equivalent specificity.

Context: Despite several publications attesting to its accuracy and value, cytology is rarely used for preliminary autopsy diagnosis in the United States. Postmortem cytodiagnosis has the potential to increase the accuracy and specificity of the provisional and final autopsy diagnoses, increase resident interest in cytodiagnostic techniques, and direct pathologists to request pertinent special studies, such as microbial cultures and special stains., Objective: To assess and illustrate the value of cytodiagnostic techniques for improving autopsy quality assurance and resident education., Design: Eighty-five samples were evaluated from 49 nonconsecutive autopsies. Sixty-five focal lesions were sampled by direct scraping. Diffuse lung consolidation was sampled by fine-needle aspiration (20 samples). Smears and cytocentrifuge preparations of fine-needle aspirations were routinely stained by both Papanicolaou and Romanowski methods. Cytologic diagnoses were compared with final autopsy diagnoses, and both cytology and pertinent histology were reviewed., Results: Clinical or radiographic antemortem site-specific diagnoses had been made in 28 (33%) of the 85 samples. A definite diagnosis was made by postmortem cytology in 68 (80%) of 85 samples, and these diagnoses could contribute to provisional autopsy diagnosis in 46 instances (68%). Resident and faculty enthusiasm for the use of cytology in the autopsy suite has increased during the 7 years following the study. Case examples illustrating the benefits of postmortem cytology are provided., Conclusions: Postmortem cytology benefits both autopsy quality and resident education.

Context: Case reports have described detection of candidemia by examination of peripheral blood smears. It is unclear whether this method has wider applicability for early detection of fungemia., Objective: To determine the sensitivity of smear review for detecting candidemia., Design: Normal and cytopenic blood was spiked with increasing concentrations of yeast. Smears were prepared and reviewed by a pathologist and by technical staff. Staff members blinded to the purpose of the study first performed a routine slide review and then a targeted review for yeast., Results: The pathologist detected isolated yeast forms at a concentration of 1 to 5 x 10(5) colony-forming units (CFU)/mL. When blinded to the purpose of the study, technical staff could detect Candida in most samples when the yeast concentration was 1 to 5 x 10(7) CFU/mL, but found it in only a small fraction of samples with lower concentrations. When asked to examine the smears specifically for yeast, they could detect it in most samples containing 1 to 5 x 10(6) CFU/mL., Conclusions: Detection of candidemia by peripheral blood smear examination requires a yeast concentration of 1 to 5 x 10(5) CFU/mL or greater. This degree of fungemia is unusual; therefore, detection of candidemia by blood smear review will not be possible in most cases. Sensitivity of smear review for yeast detection is greatly increased if the microscopist is specifically directed to look for the presence of yeast.

Context: Although the cytologic features of leukemia/lymphoma in cerebrospinal fluid specimens are well known, the correlation of these features with the ability of cytologists to identify this tumor have not been well studied., Objective: To identify the morphologic features of leukemia/lymphoma in cerebrospinal fluid that are associated with good performance and poor performance in an educational interlaboratory comparison program; and to identify the morphologic features associated with how well a slide performs with regard to its reference diagnosis., Design: The performance of 147 cases of leukemia/lymphoma in the College of American Pathologists Interlaboratory Comparison Program in Non-gynecologic Cytology was analyzed. The cytologic features of a subset of 31 cases composed of relatively equal numbers of Romanowsky-stained and Papanicolaou-stained specimens were further evaluated, and those that performed poorly (n = 12) were compared with those that performed extremely well (n = 19)., Results: For all cases of leukemia/lymphoma in the program, the rate of misclassification as benign for cases with Papanicolaou stain was significantly higher than for those with Romanowsky stain (9.5% vs 2.6%, P < .001). Compared with cases that performed well, slides that performed poorly were more likely to have less than 200 abnormal cells (42% vs 5%, P = .02). The size of the tumor cells and preservation were not significant., Conclusion: Cases of specimens of leukemia/lymphoma in cerebrospinal fluid are more likely to be misdiagnosed as benign if they are Papanicolaou-stained or have 200 abnormal cells.