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Dear current and future ASC members, Welcome to the inaugural issue of American Society of Cytopathology’s journal, JASC! The society is proud to launch this effort and believes that the journal will become a valuable membership benefit that will be educative, and foster research and advocacy for cytopathology. We are in great handsdan awesome editorial team, a respected publisherdand contributions from all of us will ensure that this will be a successful ASC endeavor. I would like to take this opportunity to review where the ASC has been, where we are today, and where we are going. Let me begin, however, with some background on the current state of the nation’s health care as it pertains to members of our profession. The basic challenges in the rapidly evolving health care arena are not unique to pathology or cytopathologynamely, a relatively new and evolving health care system, workforce shortages, and economic pressures. With the implementation of the Affordable Healthcare Act, there will be changes in consumer demographics and new delivery systems. These changes, along with an increased emphasis on health Ritu Nayar, MD

This statement from the Cytopathology Education and Technology Consortium summarizes appropriate and inappropriate uses of human papillomavirus testing in cervical cancer screening based on guidelines from the American Society for Colposcopy and Cervical Pathology and the American Cancer Society. © 2014 S. Karger AG, Basel.

This statement from the Cytopathology Education and Technology Consortium summarizes appropriate and inappropriate uses of human papillomavirus testing in cervical cancer screening based on guidelines from the American Society for Colposcopy and Cervical Pathology and the American Cancer Society. © 2014 S. Karger AG, Basel.

The aim of this study was to compare radiological and pathological changes and test the adjunct efficacy of Sorafenib to Y90 as a bridge to transplantation in hepatocellular carcinoma (HCC). 15 patients with 16 HCC lesions were randomized to Y90 without (Group A, n = 9) or with Sorafenib (Group B, n = 7). Size (WHO, RECIST), enhancement (EASL, mRECIST) and diffusion-weighted imaging criteria (apparent diffusion coefficient, ADC) measurements were obtained at baseline, then at 1 and every 3 months after treatment until transplantation. Percentage necrosis in explanted tumors was correlated with imaging findings. 100%, 50%-99% and

BACKGROUND The diagnosis of malignant mesothelioma (MM) in effusion specimens is controversial. At the study institution (Northwestern University), a primary diagnosis of MM is made on fluid cytology specimens. In an effort to estimate the practice at other institutions, a survey was disseminated regarding cytologic diagnosis of MM. The authors also evaluated their own institution's experience with primary cytologic diagnosis of MM. METHODS Patients with MM at the study institution were identified from 1992 through 2011. Fluid cytology specimens preceding histologic diagnoses were reviewed. A survey was sent to a number of cytology laboratories to assess practice patterns regarding the diagnosis of MM. RESULTS At the study institution, 20 cases of MM had effusion specimens preceding the diagnostic histologic material. In 6 cases (30%), a definitive diagnosis of MM was rendered via cytology alone. There were no false-positive diagnoses of MM. Of 55 laboratories that responded to the survey, 36 reported making a definitive diagnosis of MM after cytologic analysis. Almost all laboratories (35) willing to diagnose MM in effusions reported performing immunohistochemistry to distinguish adenocarcinoma from MM. A smaller proportion (18) of these laboratories reported doing additional immunohistochemistry or fluorescence in situ hybridization for p16 to help distinguish benign from malignant mesothelial proliferations. Those who do not definitively diagnose MM in fluid specimens state inability to identify invasion and overlap with reactive mesothelial proliferation as factors supporting their practice. Most respondents (32) felt that the clinicians at their institution would manage a patient based on a cytologic diagnosis of MM. CONCLUSIONS The majority of respondents reported making a definitive diagnosis of MM in effusion cytology specimens. The diagnosis of MM in effusions, although not sensitive, is extremely specific. Cancer (Cancer Cytopathol) 2013;121:703–707. © 2013 American Cancer Society.

Endoscopic ultrasound (EUS) with fine needle aspiration (FNA) is a safe and effective way to sample lesions in the gastrointestinal tract. Rapid on-site specimen evaluation (ROSE) improves the accuracy of EUS–FNA. While data suggests that EUS with fine-needle biopsy (EUS–FNB) is effective, it remains unclear if ROSE is predictive of a final diagnosis when obtaining core specimens. The aim of this study was to investigate the utility of ROSE in achieving a final diagnosis for EUS–FNB core specimens. We evaluated 60 consecutive patients referred for EUS guided sampling of lesions within or adjacent to the gastrointestinal tract. All patients underwent EUS–FNB to evaluate the additive value of ROSE to the diagnostic accuracy of specimens obtained using a core biopsy needle. EUS–FNA was also performed in a majority of cases. EUS–FNB was feasible in all 60 cases; on-site specimen adequacy and final diagnostic accuracy was 58 % [95 % confidence intervals (CI) 45.1–71.2] and 83 % (95 % CI 71.9–91.5), respectively. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value of ROSE for core biopsies were 65, 100, 100, and 39 %, respectively. On-site adequacy and diagnostic accuracy for EUS–FNA was 38 % (95 % CI 22.2–53.5) and 63 % (95 % CI 50.1–75.8), respectively. There were no significant complications. EUS–FNB is safe, feasible, and effective. ROSE of the core biopsy provides excellent PPV; however, an inadequate ROSE appears to be of limited value. Further prospective studies are needed to assess the optimal handling and onsite processing of core specimens to determine whether ROSE is beneficial for EUS–FNB.

Implementation of proficiency testing for gynecologic cytology was delayed 20 years because of challenges addressing the subjective nature of cytologic interpretation and replicating normal working conditions. Concern remains regarding test scoring, slide validation, test environment, and other issues. How these test results are, or should be, used in quality management has never been explored.To provide information on good laboratory practices for gynecologic cytology proficiency testing based on findings from the College of American Pathologists' survey-based project funded by the Centers for Disease Control and Prevention.An expert working group evaluated results from a Web-based, national laboratory survey plus responses from follow-up questions and findings from the literature. The group created statements on good laboratory practices pertinent to proficiency testing and its role in quality management, which were discussed and voted on at a consensus conference.Two-thirds of laboratories report having an individual with an unsuccessful proficiency testing score. More than 90% did not initiate any remedial action for 1 or 2 unsuccessful tests; 84% of laboratories reported they actively monitored results from proficiency testing, but most laboratories did not initiate any remedial action for cytotechnologists (81.4%; 376 of 462) or pathologists (87.7%; 405 of 462) who passed a proficiency test but who did not score 100%. Proficiency testing pass-fail rates should be monitored globally for the laboratory and for each individual. Proficiency testing slides should be prescreened by cytotechnologists for pathologists who are not primary screeners. Remedial action should not be required for a passed, but imperfect, test. No remedial action is required for an unsuccessful, first proficiency test result before retesting.

The Bethesda System for Reporting Thyroid Cytology (TBSRTC) was proposed in 2007 at the National Cancer Institute Thyroid Fine Needle Aspiration State of the Art and Science Conference held in Bethesda, Maryland. The aim was to address the inconsistent and sometimes confusing reporting terminologies used for thyroid FNA throughout the world. The TBSRTC consists of 6 diagnostic categories, each associated with an implied risk of malignancy that translates directly into a clinical management algorithm. Since the publication of the TBSRTC cytology Atlas in January 2010, considerable experience has been gained regarding its application in cytology practice, clinical impact, and limitations. In conjunction with the International Academy of Cytology (IAC), an international panel composed of sixteen cytopathologists and an endocrinologist with special interest in thyroid cytology, including several co-authors of the 2010 TBSRTC Atlas, was created to: (1) analyze the current worldwide impact of TBSRTC, (2) report on the current state of TBSRTC based upon a review of the published literature, and (3) provide possible recommendations for a future update of TBSRTC. Herein, we summarize the panel's deliberations and key recommendations that our panel hopes will be useful during the preparation of the second edition of TBSRTC.

A. Mahajan, X. Lin and R. Nayar Thyroid Bethesda reporting category, ‘suspicious for papillary thyroid carcinoma’, pitfalls and clues to optimize the use of this category Objective: The Bethesda System of Reporting Thyroid Cytopathology classifies the indeterminate categories based on their differing risks of malignancy, as atypia of undetermined significance (AUS), follicular neoplasm/suspicious for follicular neoplasm (FLUS) and suspicious for malignancy. The vast majority of cases of the last category are suspicious for papillary thyroid carcinoma (PTC). The aim of the present study was to identify the pitfalls and clues to improve the usage of the suspicious category as well as improve its outcome of malignancy. Methods: We reviewed the cytological features on air dried Diff-Quik® and alcohol-fixed Papanicolaou smears from 54 thyroid fine needle aspirates (FNAs) with surgical follow-up that were originally diagnosed as suspicious. Procedure data/specimen adequacy was correlated and follow-up histology reports were reviewed after our cytological review was completed. Incidental PTC that was not the target of the FNA was excluded from the calculations for correlation. Results: In our cytological review, we retained a diagnosis of suspicious in 18 of the 54 cases and the remaining 36 were re-categorized as follows: 6 malignant, 10 neoplasm (which is used in our centre instead of FLUS) and 20 AUS. The reasons for overcall of suspicious cases included pseudopapillae, syncytial sheets, nuclear grooves and pinpoint nucleoli in chronic lymphocytic thyroiditis and Hurthle cell neoplasms, and intranuclear inclusions in parathyroid adenoma, hyalinizing trabecular adenoma and mesenchymal repair. The primary reasons for undercall of PTC as suspicious included cystic aspirates with minor features of PTC such as histiocytoid cells, bubblegum colloid, syncytial sheets and cellular swirls. Cases with cytoplasm similar to Hurthle cells were also noted to cause difficulty in accurate classification. Conclusions: Recognition of these pitfalls and clues can help improve diagnosis, patient treatment and consequently reduce the number of unnecessary thyroidectomies.

The purpose of this study is to examine subcentimeter thyroid nodules to determine their rate of malignancy, the accuracy of various ultrasound features in prediction of malignancy, and the utility of ultrasound-guided biopsy of these nodules.Included in this retrospective study were 104 patients in whom 108 thyroid nodules smaller than 1 cm had been biopsied. Diagnostic ultrasound examinations were reviewed, and nodules were evaluated for the following ultrasound features: internal echogenicity, margins, height-to-width ratio, presence of calcifications, posterior acoustic features, solid-to-cystic ratio, presence of a halo, and color Doppler characteristics. In addition, a subjective assessment of level of suspicion was assigned to each nodule. Each feature was correlated with the pathologic results to determine the accuracy of the feature for predicting malignancy.Adequate cytologic specimens were obtained in 97 of the 108 subcentimeter biopsies (90%) performed. The average size of malignant nodules was significantly smaller than the average size of benign nodules (6.4 ± 2.1 vs 7.7 ± 1.4 mm, p = 0.041). The rate of carcinoma among nodules with a final diagnosis was 19% (16/85). The most accurate features significantly associated with malignancy were posterior acoustic shadowing (87%), many diffuse calcifications (82%), rim calcifications (81%), and taller than wide shape (79%). The subjective level of suspicion correlated well with the presence of malignancy (76%).Subcentimeter nodules are significantly associated with the risk of malignancy and can be accurately and safely biopsied with a very high diagnostic rate. Certain ultrasound features can be used to accurately stratify risk of malignancy, although no single feature replaces the clinician's overall impression.

f v T l c c U l w ( u H s l c A o n o a p s a q n w Subepithelial mass lesions are detected frequently during clinical care, often incidentally seen in the stomach during endoscopy performed for other indications. Alteratively, they may be seen on radiographic imaging or ecause of symptoms. Evaluation of these lesions may be hallenging because superficial biopsies will rarely be iagnostic. After evaluation of these lesions with EUS to haracterize their layer of origin, tissue acquisition is often erformed. There are multiple modalities to sample these lesions, ncluding EUS-guided FNA (EUS-FNA), EUS-guided core eedle biopsy, bite-on-bite forceps biopsies, and endocopic resection.2 EUS-FNA cytology alone may be inadequate or inaccurate in nearly half of these patients.3-5 Although EUS-guided core needle biopsy is intended to provide histology, the rigid needle can be difficult to use and does not reliably obtain tissue and, thus, may be inadequate.6 For lesions that create an impression on the astric lumen, bite-on-bite forceps biopsies by using umbo forceps allow the creation of a tunnel through the ucosa into the underlying lesion.7 However, for deep lesions, it may be unclear whether adequate tissue has been obtained, in contrast to EUS-FNA, in which on-site cytology is often used. In this study, we describe our results with using the bite-on-bite technique with jumbo forceps and touch

Background & Aims We sought to study receiver-operating characteristics (ROC) of the European Association for the Study of the Liver (EASL), Response Evaluation Criteria in Solid Tumors (RECIST), and World Health Organization (WHO) guidelines for assessing response following locoregional therapies individually and in various combinations. Methods Eighty-one patients with hepatocellular carcinoma underwent liver explantation following locoregional therapies. Response was assessed using EASL, RECIST, and WHO. Kappa statistics were used to determine inter-method agreement. Uni/multivariate logistic regression analyses were performed to determine the variables predicting complete pathologic necrosis. Numerical values were assigned to the response classes: complete response=0, partial response=1, stable disease=2, and progressive disease=3. Various mathematical combinations of EASL and WHO were tested to calculate scores and their ROCs were studied using pathological examination of the explant as the gold standard. Results Median times (95% CI) to the WHO, RECIST, and EASL responses were 5.3 (4–11.5), 5.6 (4–11.5), and 1.3months (1.2–1.5), respectively. Kappa coefficients for WHO/RECIST, WHO/EASL, and RECIST/EASL were 0.78, 0.28, and 0.31, respectively. EASL response demonstrated significant odds ratios for predicting complete pathologic necrosis on uni/multivariate analyses. Calculated areas under the ROC curves were: RECIST: 0.63, WHO: 0.68, EASL: 0.82, EASL+WHO: 0.82, EASL×WHO: 0.85, EASL+(2×WHO): 0.79 and (2×EASL)+WHO: 0.85. An EASL×WHO Score of ⩽1 had 90.2% sensitivity for predicting complete pathologic necrosis. Conclusions The product of WHO and EASL demonstrated better ROC than the individual guidelines for assessment of tumor response. EASL×WHO scoring system provides a simple and clinically applicable method of response assessment following locoregional therapies for hepatocellular carcinoma.

Oncogenic osteomalacia (OO) is a rare paraneoplastic condition in which a bone or soft tissue tumor induces biochemical and clinical signs and symptoms of osteomalacia (or rickets) most often by the production of the phosphaturic protein, fibroblast growth factor-23. Phosphaturic mesenchymal tumor, mixed connective tissue type (PMTMCT) is a rare, histologically distinct tumor that represents the most common cause of OO. As the clinical diagnosis of OO is typically suspected on the basis of clinical and biochemical features and the presence of a bone or soft tissue tumor, cytologic examination might potentially provide the necessary pathologic confirmation of OO. In this case of a 46-year-old female with clinical stigmata of OO and a right distal humeral mass, we report that the fine-needle aspiration findings of short, cytologically bland spindled cells embedded in a fine, fibrillary stromal-rich matrix and the presence of osteoclast-type giant cells associated with the stromal matrix provide strong pathological evidence for PMTMCT and assist in pathologically confirming the clinical impression of OO, thus alleviating the need for a more invasive diagnostic surgical procedure Diagn. Cytopathol. 2012. © 2011 Wiley Periodicals, Inc.

Background & Aims Despite the widespread use of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) to sample pancreatic lesions and the standardization of pancreaticobiliary cytopathologic nomenclature, there are few data on inter-observer agreement among cytopathologists evaluating pancreatic cytologic specimens obtained by EUS-FNA. We developed a scoring system to assess agreement among cytopathologists in overall diagnosis and quantitative and qualitative parameters, and evaluated factors associated with agreement. Methods We performed a prospective study to validate results from our pilot study that demonstrated moderate to substantial inter-observer agreement among cytopathologists for the final cytologic diagnosis. In the first phase, 3 cytopathologists refined criteria for assessment of quantity and quality measures. During phase 2, EUS-FNA specimens of solid pancreatic lesions from 46 patients were evaluated by 11 cytopathologists at 5 tertiary care centers using a standardized scoring tool. Individual quantitative and qualitative measures were scored and an overall cytologic diagnosis was determined. Clinical and EUS parameters were assessed as predictors of unanimous agreement. Inter-observer agreement (IOA) was calculated using multi-rater kappa (κ) statistics and a logistic regression model was created to identify factors associated with unanimous agreement. Results The IOA for final diagnoses, based on cytologic analysis, was moderate (κ = 0.56; 95% CI, 0.43–0.70). Kappa values did not increase when categories of suspicious for malignancy, malignant, and neoplasm were combined. IOA was slight to moderate for individual quantitative (κ = 0.007; 95% CI, –0.03 to –0.04) and qualitative parameters (κ = 0.5; 95% CI, 0.47–0.53). Jaundice was the only factor associated with agreement among all cytopathologists on multivariate analysis (odds ratio for unanimous agreement, 5.3; 95% CI, 1.1–26.89). Conclusions There is a suboptimal level of agreement among cytopathologists in the diagnosis of malignancy based on analysis of EUS-FNA specimens obtained from solid pancreatic masses. Strategies are needed to refine the cytologic criteria for diagnosis of malignancy and enhance tissue acquisition techniques to improve diagnostic reproducibility among cytopathologists.

To correlate posttreatment radiologic and pathologic findings in patients who underwent transarterial chemoembolization before transplantation or resection. Thirty-five patients with postchemoembolization follow-up imaging underwent liver transplantation/resection. Pre- and posttreatment contrast-enhanced magnetic resonance imaging were used to evaluate radiologic findings. Imaging characteristics using World Health Organization (WHO) and European Association for the Study of the Liver (EASL) criteria after treatment were evaluated. Treated lesions were examined by pathology (gold standard) for the assessment of necrosis. Radiologic findings on magnetic resonance imaging were correlated to pathologic findings to assess the predictability by imaging of actual necrosis. Kappa (κ) statistics were used to determine intermethod agreement between WHO and EASL criteria. Fourteen (40%) of 35 lesions had biopsy-proven hepatocellular carcinoma. Thirteen (37%) of 35 target lesions showed complete pathologic necrosis. Complete pathologic necrosis was seen in 35% of lesions with pretreatment size

S. Zhang, D. V. S. DeFrias, R. Alasadi and R. Nayar Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA): experience of an academic centre in the USA Objectives: Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) has become widely accepted as an effective modality for obtaining tissue for primary diagnosis and staging. We have been using EUS-FNA since July 2001 and herein we summarize our experience over a 5-year period. Methods: A computer-based search for in-house EUS-FNA was performed in the pathology database from July 2001 to October 2006. To calculate the sensitivity, specificity and accuracy of EUS-FNA, the cytology diagnosis was compared with the surgical follow-up. Results: A total of 951 EUS-FNAs were performed during the study period and included 279 pancreatic solid lesions, 186 pancreatic cyst lesions, 249 lymph node aspirations, 111 gastrointestinal (GI) tract submucosal lesions, and 126 miscellaneous lesions. EUS-FNA had a very high sensitivity and accuracy for solid pancreatic lesions (94.7 and 97.7%, respectively), low sensitivity and accuracy but high specificity (47, 64.8 and 95%, respectively) for cystic lesions. Cyst fluid carcinoembryonic (CEA) levels were significantly higher in mucinous neoplasms than non-neoplastic cysts. EUS-FNA also had very high sensitivity and specificity for detecting metastatic carcinoma in lymph nodes (95 and 100%, respectively). GI submucosal spindle cell tumours were further classified with immunohistochemical stains performed either on a cell block or a core biopsy obtained via EUS guidance. Conclusions: EUS-FNA has a very high sensitivity and accuracy for pancreatic solid lesions, but the sensitivity for cystic lesions is generally low. Cyst fluid chemical analysis for CEA is helpful, but the overlap between mucinous neoplasm and non-neoplastic cysts is significant. Recognizing GI contamination is important and immunohistochemical stains are useful for GI submucosal spindle cell lesions.

BACKGROUND: To date, thyroid fine-needle aspiration (FNA) has been used by clinicians as the screening test of choice to determine whether surgery is required and this is what the pathology report should communicate. Standard terminology for reporting thyroid FNA has not been implemented yet, and pathologists have used various reporting systems to communicate results. A significant source of confusion among both pathologists and clinicians has been the use of the indeterminate category. On the basis of an analysis of 1150 thyroid FNAs in 2000, this institution modified the reporting of thyroid biopsy results into 6 categories, including unsatisfactory. The indeterminate category was separated into 3 subroups: 1) indeterminate for neoplasia (IND), 2) follicular neoplasm (FN), and 3) suspicious for malignan cy (SUSP). Repeat FNA in 6m onths to 12 months was recommended for IND and surgery for FN and SUSP categories. METHODS: To determine the validity of this approach, the outcomes of this reporting system from July of 2000 to December of 2006 were analyzed. The IND category was used for 2 subsets of cases: (a) those that morphologically fall into the gray zone between adenomatoid nodule (AN) and FN, for Hurthle cell nodule (hyperplasia vs neoplasm), and chronic lymphocytic thyroiditis with concern for neoplasia; and (b) for suboptimal specimens due to low epithelial cellularity or collection artifacts. RESULTS: Among 5194 thyroid nodules, the IND category comprised 18%. FNA follow-up was done in 21% of IND cases: 58% were benign/negative and did not require surgery based on cytology alone. Surgical follow-up in 46% of IND showed 52% were benign/negative, and 42% were follicular/Hurthle cell adenomas. The surgical yield of malignancy in IND was low (6%) when compared with the FN category, which was 14% (more than 2 that of the IND category), and the SUSP category, which was 53% (almost 9 that of the IND category). CONCLUSIONS: A 6-tier reporting system for thyroid FNA was effective for determining which patients needed surgery versus follow-up FNA and also guided the clinician on the extent of surgery. Cancer (Cancer Cytopathol) 2009;117:195–202. V C 2009 American Cancer Society.

Purpose: In a pilot study of women with pathologic nipple discharge (PND) undergoing ductoscopy, we tested quantitative assessment of gene promoter hypermethylation using quantitative multiplex methylation–specific PCR (QM-MSP) to enhance detection of duct carcinoma in situ (DCIS). Experimental Design: Women with PND underwent ductoscopy; ducts with significant lesions were surgically resected (36 ducts in 33 women) and those with minimal findings were not (28 ducts in 16 women). QM-MSP was done on ductoscopy cell samples. Results were compared with cytology and tissue histology. Results: Cells from ducts with significant lesions on ductoscopy had significantly higher levels of methylation than those with minimal findings. Furthermore, cells from ducts with DCIS displayed higher levels of methylation than those with benign lesions such as papilloma (P = 0.006); or ducts with minimal findings on ductoscopy (P = 0.0001). Cumulative RASSF1A, TWIST1, and HIN1 gene methylation accurately distinguished ducts with cancerous versus benign lesions (100% sensitivity, 72% specificity, and area under the curve of 0.91 according to receiving operating characteristic analyses). QM-MSP analysis was more informative than cytology (100% versus 29% sensitivity, respectively), for detecting DCIS. In a validation set of paraffin-embedded DCIS and papilloma samples from women presenting with PND, QM-MSP was significantly higher in DNA from DCIS than papilloma sections (P = 0.002). Conclusion: The positive predictive value of ductoscopy was more than doubled (19% versus 47%) with the addition of QM-MSP, demonstrating the benefit of targeting ducts having both high methylation and significant abnormalities on ductoscopy for surgical excision. Future large-scale studies to validate this approach are needed.

We present the correlation between radiologic and pathologic findings in HCC patients who underwent radioembolization with yttrium-90 (90Y) microspheres prior to resection or transplantation. Thirty-five patients with a total of 38 lesions who underwent liver explantation after 90Y radioembolization were studied. Imaging surrogates following treatment were evaluated; the explants were examined for assessment of necrosis by pathology. The correlation betwen radiologic and histologic findings of the treated lesions was analyzed. Twenty-three of 38 (61%) target lesions showed complete pathologic necrosis. All target lesions demonstrated some degree of histologic necrosis at explant. Complete histologic necrosis was seen in 89% of lesions with pretreatment size

Background Ductal lavage (DL) allows repeat sampling of breast epithelium for serial observation in a chemoprevention setting; however, the reproducibility of duct cannulation, cell yield and cytology has not been addressed. Methods We conducted a Phase 2 trial, wherein high risk women chose tamoxifen treatment or observation following an entry DL procedure. We present data from the non-intervention arm of our study to assess the reproducibility of cannulation, cell yield, and cytologic diagnosis from DL of the same duct at two time-points. Inter-observer variability was assessed by a blinded review of Papanicoloau-stained slides by two cytopathologists. Results Sixty-five women had a successful lavage of 187 ducts at baseline and chose observation; 63/65 (97%) had a successful lavage 6 months later. Successful recannulation of the same duct was accomplished in 63 women (97%) and162 ducts (87%). Total epithelial cell yields ≥100 were obtained from 57/65 women (88%) and 129/187 ducts (69%) at baseline, and 46/63 women (73%) and 80/162 ducts (49%) at both time-points. Cytologic diagnosis was reproducible in 27/63 (43%) women and 77/162 (48%) ducts. Inter-observer variability for cytologic diagnosis between two observers showed good agreement (κ = 0.62). Conclusions Recannulation and lavage of the same duct after a 6 month interval can be achieved with high frequency; however, reproducibility of cell yield and cytologic findings from the same duct is sub-optimal, leading to significant attrition of evaluable subjects. The utility of DL for the serial monitoring of breast epithelium is therefore limited.

Objective. Studies of cervical cancer and its immediate precursor, cervical intraepithelial neoplasia 3 (CIN3), have identified genes that often show aberrant DNA methylation and therefore represent candidate early detection markers. We used quantitative PCR assays to evaluate methylation in five candidate genes (TNFRSF10C, DAPK1, SOCS3, HS3ST2 and CDH1) previously demonstrated as methylated in cervical cancer. Methods. In this analysis, we performed methylation assays for the five candidate genes in 45 invasive cervical cancers, 12 histologically normal cervical specimens, and 23 liquid-based cervical cytology specimens confirmed by expert review as unequivocal demonstrating cytologic high-grade squamous intraepithelial lesions, thus representing the counterparts of histologic CIN3. Results. We found hypermethylation of HS3ST2 in 93% of cancer tissues and 70% of cytology specimens interpreted as CIN3; hypermethylation of CDH1 was found in 89% of cancers and 26% of CIN3 cytology specimens. Methylation of either HS3ST2 or CDH1 was observed in 100% of cervical cancer tissues and 83% of CIN3 cytology specimens. None of the five genes showed detectable methylation in normal cervical tissues. Conclusion. Our data support further evaluation of HS3ST2 and CDH1 methylation as potential markers of cervical cancer and its precursor lesions.

BACKGROUND Meningiomas, tumors that often affect middle-aged and elderly people, occasionally arise in the spine, typically at the thoracic level. The cytologic findings in meningiomas include whorls and syncytial clusters of bland-looking cells with scattered, psammomatous calcifications and intranudclear cytoplasmic inclusions. However, in many cases, not all these findings are seen, and in rare cases, unusual cytomorphologic features are observed. CASE A case of spinal meningioma was located in the extradural compartment and composed predominantly of singly scattered cells with a plasmacytoid appearance, demonstrated on fine needle aspiration biopsy smear preparations. The cell block showed more typical features of meningioma, and the diagnosis was supported by the results of immunohistochemical staining. CONCLUSION The diagnosis of spinal meningioma is readily made by employing magnetic resonance imaging. The diagnosis can be difficult to confirm pathologically when atypical histologic findings are present, as in this case, with prominent plasmacytoid features. Sections from the cell block and immunohistochemical stains as well as clinical and radiologic findings were extremely helpful in arriving at the final diagnosis.

Context The College of American Pathologists periodically surveys laboratories to determine changes in cytopathology practices. We report the results of a 2011 gynecologic cytology survey. Objective To provide a cross-sectional survey of gynecologic cytology practices in 2010. Design In 2011, a survey was sent to 1604 laboratories participating in the College of American Pathologists gynecologic cytology interlaboratory comparison education program and proficiency testing programs requesting data from 2010 on the following topics: terminology/reporting, cytotechnologist workload, quality assurance, reagents, and ancillary testing. Results Six hundred and twenty-five laboratories (39%) replied to the survey. The nonstandard use of “low-grade squamous intraepithelial lesion cannot exclude high-grade squamous intraepithelial lesion” is used by most laboratories to report the presence of low-grade squamous intraepithelial lesion with possibility of high-grade squamous intraepithelial lesion. Most laboratories also report the presence or absence of cells from the transformation zone. Most respondents do not limit cytotechnologist screening workload during the work shift. Only about one-third of laboratories (188 of 582; 32%) use image-assisted screening devices. Rapid prescreening as a quality assurance measure is used by only 3.5% (21 of 594) of the laboratories. When used for screening, most laboratories use the imager for retrospective review of slides to detect human locator and interpretive errors. Most laboratories receive both liquid-based cytology samples (mainly ThinPrep, Hologic, Marlborough, Massachusetts) and conventional Papanicolaou tests. Expiration dates of liquid-based cytology test vials are not usually recorded. Conclusions The field of gynecologic cytology is evolving rapidly. These survey results offer a snapshot of national gynecologic cytology practices in 2010.

Introduction The College of American Pathologists (CAP, Northfield, Illinois) monitors performance in cytologic analysis to evaluate the standard of practice and consider strategies for method improvement. Materials and methods 5700 responses to 97 pancreatobiliary tract brushing slide challenges were collected by the CAP Non-Gynecologic Cytopathology (NGC) Program, between 2000 and 2011. Analysis examined participant agreement with the general diagnostic categories of benign or malignant. Suspicious responses were classified as concordant with slides having a positive general diagnosis. Conventional smears with Pap stain and Romanowsky stain were evaluated in addition to CytoSpin, ThinPrep, and SurePath preparations. A nonlinear mixed model was fit with 3 factors—general diagnosis, participant type, and preparation type. Results Overall concordance rate was 91.7%. Preparation type and general diagnosis were significantly associated with the concordance rate. The interaction term between these two factors was also statistically significant, with ThinPrep performing marginally better for positive cases and CytoSpin performing better for negative cases. Conventional smears did not perform as well as CytoSpin, ThinPrep, or SurePath. Conclusions Participants performed well with greater than 90% agreement with the target diagnostic category. There was no significant difference between cytotechnologists and pathologists. Small significant differences were found between preparations types. The statistical differences between concentration techniques may be due to dissimilarities in the quantity of cells and quality of cytomorphology, thus affecting the interpretations by participating laboratories.

Automated screening devices have the potential to increase both the sensitivity and the specificity of the cervical cancer screening process. In addition, productivity gains may be achieved with their use. In the era of HPV vaccine use, when prevalence of high-grade squamous intraepithelial lesions in the population is expected to decline, the sensitivity of manual screening will also decline. Thus, automation with its potentially superior sensitivity for rare-event detection may play an important role in morphology-based screening and triage. The increase in the prevalence of disease as presented to the screener via focused selection of important fields of view, or via selection of high-risk slides for manual review, has the potential to maintain the level of sensitivity needed to continue effective manual-based morphologic screening. Several new US Food and Drug Administration approvals in the field of automated cervical cytology screening have occurred in the past decade. These have included the so called “location-guided screening” devices that identify areas at highest risk for containing potential abnormalities—essentially providing a prescreened slide. This chapter provides an overview of the currently used systems and updates recommendations, which now include the reporting items for “location-guided screening” devices in addition to those previously covered in the second edition of this atlas.

Effective communication between laboratories and clinical providers is a key element of successful cervical cancer screening. Laboratorians and clinicians have a shared responsibility to remain current in their field and communicate significant changes in their respective disciplines to one another. When pathologists serve as consultants to health-care providers, giving appropriate advice on screening and follow-up tests, the patient is the beneficiary. The use of written recommendations and/or comments in cervical cytology reports is optional. When included in the cytology report, they must be worded carefully and relay clear, concise, current, evidence-based information. In the second edition of the Bethesda atlas, it was recommended that such comments be directed to the clinician and that the laboratorian/laboratory not communicate directly with the patient unless specifically instructed to do so. In the United States, as of 2014, there are changes to the rules regarding patient access to test reports. In addition, standardization of reports to facilitate widespread electronic health record implementation has been encouraged. These changes may have further implications for the use of recommendations in pathology reports, and a relevant discussion is now included.

Our understanding of preinvasive HPV-associated squamous lesions supports only two conceptual divisions: HPV infection and true precancer. Transient infections generally regress over the course of 1–2 years, and lesions with HPV persistence are associated with an increased risk of developing a cancer precursor (precancer) or invasive cancer. This concept led to the introduction of the two-tiered nomenclature of low-grade squamous intraepithelial lesion (LSIL) and high-grade squamous intraepithelial lesion (HSIL), by the Bethesda System (TBS) in 1988. The 2014 Bethesda update maintains this dichotomous reporting terminology for the squamous intraepithelial lesions. Since the focus of cervical cancer screening is primarily the detection of HSIL, this chapter has been substantially expanded to include problematic patterns and mimics that may lead to locator and/or interpretation errors of non-neoplastic changes as HSIL/ASC-H or vice versa.

The category “negative for intraepithelial lesion or malignancy” is used for specimens that show a spectrum of nonneoplastic changes, including those associated with protective and reactive responses to inflammation, hormonal alterations, and colonizing or infectious organisms. Recognition of the wide variety of normal cellular presentations is key for the accurate discrimination from neoplastic conditions. Many characteristic patterns of reaction in normal cells can be important clues to the underlying causative process. Some of these patterns have features which are also seen in neoplasia, hence recognition of the key reactive changes is essential for overall accuracy. An expanded variety of “normal” findings as well as non-neoplastic mimics of classic epithelial abnormalities are included in this chapter, providing a more complete representation of the morphologic variations that can be encountered in cervical cytology preparations.

Contents Foreword by Robert J. Kurman Acknowledgments Contributors List of Abbreviations Introduction by Diane D. Davey and David C. Wilbur The 2001 Bethesda System in table format 1: Specimen Adequacy George G. Birdsong, Diane D. Davey, Teresa M. Darragh, Paul A. Elgert, and Michael Henry 2: Non-Neoplastic Findings Nancy A. Young, Marluce Bibbo, Sally-Beth Buckner, Terence J. Colgan, and Marianne U. Prey 3: Endometrial Cells: The How and When of Reporting Ann T. Moriarty and Edmund S. Cibas 4: Atypical Squamous Cells Mark E. Sherman, Fadi W. Abdul-Karim, Jonathan S. Berek, Celeste N. Powers, Mary K. Sidawy, and Sana O. Tabbara 5: Epithelial Abnormalities: Squamous Thomas C. Wright, Rose Marie Gatscha, Ronald D. Luff, and Marianne U. Prey 6: Epithelial Abnormalities: Glandular Jamie L. Covell, David C. Wilbur, Barbara Guidos, Kenneth R. Lee, David C. Chhieng, and Dina R. Mody 7: Other Malignant Neoplasms Sana O. Tabbara and Jamie L. Covell 8: Anal-Rectal Cytology Teresa M. Darragh, George G. Birdsong, Ronald D. Luff, and Diane D. Davey 9: Ancillary Testing Stephen S. Raab and Mark E. Sherman 10: Computer-Assisted Interpretation of Cervical Cytology Marianne U. Prey 11: Educational Notes and Suggestions Appended to Cytology Reports Dennis M. O'Connor Index

Purpose: The challenges of cytology for accurate diagnosis of breast cancer are well recognized. We previously showed that normal and tumor tissue can be distinguished using a technique called quantitative multiplex methylation-specific PCR (QM-MSP). We hypothesized that quantitative analysis of methylated genes will provide enhanced detection of cancer cells present in cytologic specimens.Experimental Design: QM-MSP was done on ductal lavage cells from a set of 37 ductal lavage samples from women undergoing mastectomy (27 with cancer and 3 without). Duct histology information was available for each lavaged duct. QM-MSP data was assessed by measuring cumulative methylation index and by receiver operating characteristic threshold analysis. To determine the baseline level of methylation for each gene in this population, cells from 60 ducts of women at high risk of developing breast cancer were analyzed.Results: QM-MSP findings on a panel of nine genes were correlated to duct histology and ductal lavage cytology. Cytology detected cancer in 33% (7 of 21 ducts) with a specificity of 99% (92 of 93). QM-MSP detected cancer as calculated by cumulative methylation index with a sensitivity of 62% (13 of 21) and specificity of 82% (62 of 76) and by receiver operating characteristic threshold analysis with a sensitivity of 71% (15 of 21) and specificity of 83% (63 of 76).Conclusions: Compared with cytology, QM-MSP doubled the sensitivity of detection of cancer. This study provides proof of principle by showing the advantages of using methylation analyses to query cytologic specimens and indicates its potential use in diagnosis and in stratifying risk.

Background Primary synovial sarcomas of the heart are aggressive and extremely rare tumors. At least 17 cases have been reported in the literature. In all the published cases the diagnosis was based on histoiogic sections. To our knowledge, this is the first case of primary synovial sarcoma of the heart diagnosed by fine needle aspiration (FNA). Case A 36-year-old male with an unremarkable past medical history presented with a 4.4-cm mass arising from the left ventricular wall of the heart. Endoscopic ultrasound guided fine needle aspiration biopsy of the mass revealed a high grade tumor showing an intimate admixture of spindle and epithelial cells. A diagnosis of undifferentiated sarcoma, favor synovial sarcoma, was rendered. Reverse transcription-polymerase chain reaction demonstrated the presence of a SYT-SSX fusion transcript. The patient received 6 cycles of chemotherapy followed by resection of the residual tumor. The histology of the viable tumor showed histotogic findings typical of biphasic synovial sarcoma. Conclusion Synovial sarcoma rarely presents as a primary tumor of the heart. Sampling by FNA allows demonstration of the cytomorphologic appearance typical of the tumor and other ancillary studies. The specific genetic abnormality of these tumors allows confirmation by cytogenetic and molecular studies.

Background Epithelioid angiosarcoma (EAS) is a mesembymal neoplasm that may appear indistinguishable from carcinoma, melanoma and other tumors with epithelioid/epithelial differentiation. We repart a case of metastain postradiation EAS to the lungs that was mistaken for adenocarcinoma. Case A 45-year-old women who received radiotherapy for ductal carcinoma in situ (DCIS) 5 years preciously bad a Iocal recurence a year carlier and recent development of bilateral small pulmonary nodules. Fine needle aspiration biopsy of the lung lesions showed round to oval tumor cells with amphophlic cytoplasm. An interpreta tion of adenocarcinoma was rendered during assessment for specimen adequacy. The original brcast tumor was typical of cribriform DCIS. Review of the recurrent breast tumor (initially reported as DCIS) and a prior wedge resection of the lung nodules (reporred as EAS) showed an cpithelial-appearing tumor exbihiting an endotbelial immunophenotype (CD31+, CD34+). Conclusion The cytologic features of EAS may resemble those of other neoplasms. In vealuating tumors with epithelioid morpholog, mesenchymal tumors should also be considered so that appropriate antibodies can be included in the panel for immunobistocbemistry. The importance of reviewing the patient's previous biopsy materials cannot be overemphasized.

Background Birt-Hogg-Dube (BHD) syndrome is a rare autosomal dominant neoplastic syndrome characterized by multiple skin lesions, lung cysts and renal tumors. A variety of histologic types of renal tumors have been reported, including clear cell renal cell carcinoma (RCC), papillary RCC, chromophobe RCC, oncocytoma and a recently described hybrid oncocytic tumor, which is thought to be highly associated with BHD. Case We report a case of a 48-year-old woman with BHD who initially presented to our institution with spontaneous pneumothorax and was found to have multiple lung cysts and renal tumors on computed tomography. We describe the fine needle aspiration findings of one of the renal tumors, which was suggestive of so-called hybrid oncocytic tumor. We also describe the gross and histologic findings of the multiple kidney tumors that the patient subsequently had excised. Conclusion When multiple kidney tumors from a single patient appear oncycytic on fine needle aspiration, especially when focal clear cells are present, the possibility of oncocytomas and hybrid tumors associated with BHD must be entertained.

Background:The general cytologic features of the keratinizing form of squamous cell carcinoma are well characterized and include pleomorphic squamous cells present singly or in loosely cohesive aggregates. Abnormal shapes including tadpole/spindled or heavily keratinized cells and nuclear pleomorphi

Nipple discharge is responsible for approximately 5% of surgical referrals annually.1 Not all forms of spontaneous nipple discharge (SND) are associated with significant pathologic findings. The clinical features of SND that are associated with a high likelihood of intraductal neoplasia include unilaterality, persistence, emanation from a single duct, and watery, serous, or bloody appearance.2,3 Discharges with these characteristics are classified as pathologic and have traditionally been considered an indication for surgical excision of the involved duct. However, among women with SND who are evaluated surgically, 2% to 25% are diagnosed with either invasive or noninvasive cancer.2–5 When mammography shows significant findings in women with SND, the likelihood of malignancy increases,2 but mammographic imaging is often unhelpful. Galactography has been used to evaluate women with SND with variable success.6,7 When SND is caused by peripheral intraductal lesions, galactography provides localizing information and can also assess the likelihood of malignancy,4 although definitive diagnosis requires central or terminal duct excision (TDE). Duct excision is also therapeutic unless malignancy is discovered. Conventionally, this procedure has been performed blindly, guided by a lacrimal probe or blue dye instillation into the duct or by preoperative ductography and wire localization if the lesion is located more than 2 to 3 cm from the ductal orifice.2,8 Mammary endoscopy (ductoscopy) is a recently introduced technique, which may allow more precise identification and delineation of intraductal disease but is not currently a standard practice among most surgeons. Ductoscopy has been reported to result in improved localization of intraductal lesions9–11 and may avoid surgery in women with endoscopically normal ducts. However, ductoscopy adds to time and expense in the operating room, and the yield of significant pathologic lesions reported in separate series of women who are managed with and without ductoscopy at different institutions is reported to be in the range of 90%.2,9 There has not been a direct comparison of the results achieved with these 2 different approaches in terms of lesion yield or amount of tissue excised. We undertook a comparison of findings in women with SND who were managed with and without ductoscopy at the Lynn Sage Breast Program to assess the value of adding ductoscopy to the management of these patients.

OBJECTIVE: To compare the diagnostic criteria for cirrhosis and hepatocellular carcinoma (HCC) noted on liver fine needle aspirates (FNAs) and their corresponding liver needle core biopsies (NCBs). STUDY DESIGN: We reviewed FNA slides from 15 cases of cirrhosis and 6 cases of HCC and their corresponding NCBs. We compared a variety of specific nonarchitectural criteria, including small cell dysplasia (SCD) and large cell dysplasia (LCD), for distinguishing cirrhosis from HCC. RESULTS: FNA smears diagnostically correlated with NCBs. The cytologic criterion with the greatest correlation in predicting HCC on FNA was SCD. This was not noted in all the core biopsies, probably due to sampling error. LCD was seen more frequently in cirrhosis than HCC on both cytology and histology and therefore was not a criterion useful in establishing a diagnosis of malignancy. The remaining cytologic criteria had good correlations but did not aid in diagnosing HCC. CONCLUSION: FNA has good cytohistologic correlation with NCB for both cirrhosis and HCC. There is an association of SCD with HCC; however, LCD is not a reliable precancerous change as it is commonly seen in cirrhosis and HCC. Therefore, the presence of SCD on FNA should be reported and is an indication for close clinical follow-up to exclude HCC.

OBJECTIVE: To assess the role of brush cytology in the routine evaluation of patients with primary sclerosing cholangitis (PSC). STUDY DESIGN: From January 1995 to June 2000, 64 brush cytology specimens were obtained from 21 patients who had at least one cytologic sample obtained during endoscopic retrograde cholangiography. All patients had a diagnosis of primary sclerosing cholangitis. Cases were classified as benign, atypical or malignant according to major cytologic criteria (nuclear contour and chromatin irregularities) and minor cytologic criteria (polarity, cellularity, nuclear enlargement, mitosis, increased nuclear/cytoplasmic ratio) used by us to diagnose biliary brush cytology. Follow-up was available in all cases. RESULTS: Diagnoses were benign (13), atypical (5) and malignant (3) on cytology. Follow-up of the 13 benign cases showed bile duct stones (2), gallbladder adenocarcinoma at cholecystectomy (1), ascending cholangitis (1) and clinically/cytologically by benign follow-up (9). Five of 13 benign cases had subsequent liver transplantation for liver failure, with explants showing changes of primary sclerosing cholangitis. Of the 3 malignant cases, 1 had carcinoma in situ on biopsy, with the explanted liver showing high grade dysplasia; the second patient had cholangiocarcinoma on explant; and the third had hepatocellular carcinoma on liver five needle aspiration. The 5 patients with atypical cytology were reclassified on review as reactive (3) and atypical not otherwise specified (2). Follow-up showed benign disease in 3 of 3 atypical cases reclassified as reactive; 2 of 2 reclassified as atypical not otherwise specified showed low grade dysplasia in the explant. CONCLUSION: The overall incidence of malignancy was low (3 of 21) in patients with PSC. Bile duct brushing is a sensitive method of detecting neoplasia in the setting of PSC when well-defined cytologic criteria are applied.