The Art and Science of Cytopathology

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

Standardized terminology and nomenclature for pancreatobiliary cytology: The Papanicolaou Society of Cytopathology Guidelines.

Liquid-based preparations (LBP) are increasingly being used both for gynecologic (gyn) and non-gynecologic (non-gyn) cytology including fine needle aspirations (FNA). The two FDA-approved LBP currently in use include ThinPrep (TP), (Cytyc Corp, Marlborough, MA) and SurePath (SP), (TriPath Imaging Inc., Burlington, NC). TP was approved for cervico-vaginal (Pap test) cytology in 1996 and SP in 1999 and both have since also been used for non-gyn cytology. In the LBP, instead of being smeared, cells are rinsed into a liquid preservative collection medium and processed on automated devices. Even after a decade of use, the morphological interpretation of LBP remains a diagnostic challenge because of somewhat altered morphology and artifacts or facts resulting from the fixation and processing techniques. These changes include cleaner background with altered or reduced background and extracellular elements; architectural changes such as smaller cell clusters and sheets, breakage of papillae; altered cell distribution with more dyscohesion and changes in cellular morphology with enhanced nuclear features, smaller cell size and slightly more three-dimensional (3-D) clusters. Herein, we review the published literature on morphological aspects of LBP for non-gyn cytology. Diagn. Cytopathol. 2007;35:621–634. © 2007 Wiley-Liss, Inc.

Non-gynecologic cytology on liquid-based preparations: A morphologic review of facts and artifacts.

http://www.tara.tcd.ie/bitstream/handle/2262/68233/Asbun--When%20to%20Perform%20a%20Pa.pdf;sequence=1

When to perform a pancreatoduodenectomy in the absence of positive histology? A consensus statement by the International Study Group of Pancreatic Surgery

Fluorescence in situ hybridization in diagnostic cytology.

BACKGROUND
Duct brushing cytology is an important tool in evaluation of the extrahepatic biliary tract and large pancreatic ducts. The emergence of neoadjuvant therapies underscores the importance of accurate preoperative diagnosis by noninvasive means. Liquid-based preparation methods, such as ThinPrep, have become popular for nongynecologic cytology specimens.

METHODS
Findings from bile and pancreatic duct brushings were reviewed over the 10-year period of 1994-2003. Cytologic material, imaging reports, and clinical data were reviewed and pathologic and clinical follow-up data were obtained. The slides were prepared by direct smear only (18.8%), direct smear plus cytospin (14.4%), or direct smear plus ThinPrep (66.8%).

RESULTS
A total of 1118 specimens were identified (1008 bile duct, 110 pancreatic duct) from 864 patients. The cytologic findings were: 53.5% negative, 16.5% malignant, 18.2% suspicious for malignancy, 11% atypical/inconclusive, 0.8% inadequate. Follow-up in the form of either histology or at least 6 months clinical observation was available for 82.2% of cases (n = 971). Overall operating characteristics were: 52.6% sensitivity, 99.4% specificity, 98.9% positive predictive value, 67.1% negative predictive value, and 75.7% accuracy. Diagnostic agreement between cytology and follow-up was the main variable analyzed. Agreement was significantly affected by characteristics of the sampled lesion, with ductal narrowing having the lowest rate of malignancy. In addition, the ThinPrep method showed superior sensitivity and accuracy compared with other preparation methods (P = .02). Nonsignificant associations were noted for patient age and gender, site of lesion, and the presence of either stones or prior stent.

CONCLUSION
In a large dataset from a single institution, brushing cytology showed modest sensitivity and high specificity. Diagnostic agreement was considerably better for benign cases. The combination of direct smear and the ThinPrep method showed superior sensitivity and accuracy. Cancer (Cancer Cytopathol) 2006. © 2006 American Cancer Society.

Pancreatic and bile duct brushing cytology in 1000 cases: Review of findings and comparison of preparation methods

Yolk sac tumors (YST) in extragonadal locations are rare. Cytologic diagnosis of YST on fine-needle aspiration (FNA) smears may be a challenge to the cytopathologist. Further neo-adjuvant therapy may be based on cytologic diagnosis making accuracy important. We studied FNA material from a hepatic mass in a pediatric patient to further define the cytomorphologic features of hepatic YST. Features include large pleomorphic balls of tumor cells with high nuclear to cytoplasmic ratios, papillary or microglandular pattern of growth, cytoplasmic and intranuclear vacuoles, and prominent nucleoli. Positive immunohistochemical studies included alpha-fetoprotein, cytokeratin AE1/AE3, and CAM 5.2, which are useful in supporting the diagnosis. We report a pediatric patient in whom the diagnosis of hepatic YST was made by cytologic, histologic, and immunohistochemical studies. The subsequent liver biopsy was consistent with the FNA diagnosis. Our findings may further help to characterize the cytomorphologic features of this rare lesion.

Cytomorphology of yolk sac tumor of the liver in fine-needle aspiration: a pediatric case.

Recent work suggests the ThinPrep® method can improve diagnostic sensitivity and accuracy in bile duct brushings. However, the proportion of atypical and suspicious diagnoses remains high. The aim of this study was to identify the most useful morphologic features in ThinPrep® bile duct cytology and evaluate interobserver reliability.



We evaluated 100 bile duct brushings prepared by ThinPrep®, all with either histology or long term clinical follow-up (55 malignant, 45 benign). Morphologic features were evaluated by four experienced cytopathologists blind to clinical information and follow-up diagnoses. These features included cellularity, blood or diathesis, mitoses, inflammation, three-dimensional groups, discohesive atypical cells, macronucleoli, well-defined cytoplasmic borders, and nuclear features of malignancy (nuclear membrance irregularity, chromatin clumping). The data were analyzed by intraclass correlation (ICC) and stepwise multiple logistic regression.



Reviewers showed unanimous agreement in 29% of cases, one degree of disagreement in 58% of cases, and full disagreement in 13% of cases. Of benign cases, 38% were thought to be diagnostic of malignancy by at least one of the four reviewers. Sensitivity for the morphologic parameters varied from 18 to 67%; the highest sensitivity was for discohesive atypical cells, well-defined cytoplasmic borders, nuclear features of malignancy, and cellularity (67, 62, 51 and 46%, respectively). Specificity of parameters varied from 16 to 100%; the highest specificity was for mitoses, three-dimensional groups, nuclear features of malignancy, and macronucleoli (100, 98, 93, and 93%, respectively). Interobserver reliability (ICC) was very good for specimen cellularity (0.72) and nuclear features of malignancy (0.60). In logistic regression analysis, only nuclear features of malignancy and increasing patient age separated benign from malignant.



On ThinPrep® bile duct brushings, nuclear features of malignancy are most useful in distinguishing benign from malignant, and interobserver reliability for this parameter is very good. Discohesive atypical cells show moderate sensitivity and specificity, while three dimensional clusters and macronucleoli are specific but not sensitive for malignancy, and are not significant in multivariate logistic regression models. The relatively high proportion of benign cases thought to be diagnostic of malignancy by at least one reviewer argues for a consensus approach to this diagnosis. Diagn. Cytopathol. 2008;36:651–656. © 2008 Wiley-Liss, Inc.

Use of the ThinPrep® method in bile duct brushings: Analysis of morphologic parameters associated with malignancy and determination of interobserver reliability

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Papers

Pancreatic and bile duct brushing cytology in 1000 cases: Review of findings and comparison of preparation methods

Cytomorphology of yolk sac tumor of the liver in fine-needle aspiration: a pediatric case.

Use of the ThinPrep® method in bile duct brushings: Analysis of morphologic parameters associated with malignancy and determination of interobserver reliability