Martha B. Pitman

Branch duct intraductal papillary mucinous neoplasms: Does cyst size change the tip of the scale? A critical analysis of the revised international consensus guidelines in a large single-institutional series

Objective:The aim of this study was to critically analyze the safety of the revised guidelines, with focus on cyst size and worrisome features in the management of BD-IPMN. Background:The Sendai guidelines for management of branch duct (BD) intraductal papillary mucinous neoplasm (IPMN) espouse safety of observation of asymptomatic cysts smaller than 3 cm without nodules (Sendai negative). Revised international consensus guidelines published in 2012 suggest a still more conservative approach, even for lesions of 3 cm or larger. By contrast, 2 recent studies have challenged the safety of both guidelines, describing invasive carcinoma or carcinoma in situ in 67% of BD-IPMN smaller than 3 cm and in 25% of “Sendai-negative” BD-IPMN. Methods and Results:Review of a prospective database identified 563 patients with BD-IPMN. A total of 240 patients underwent surgical resection (152 at the time of diagnosis and 88 after being initially followed); the remaining 323 have been managed by observation with median follow-up of 60 months. No patient developed unresectable BD-IPMN carcinoma during follow-up. Invasive cancer arising in BD-IPMN was found in 23 patients of the entire cohort (4%), and an additional 21 patients (3.7%) had or developed concurrent pancreatic ductal adenocarcinoma. According to the revised guidelines, 76% of resected BD-IPMN with carcinoma in situ and 95% of resected BD-IPMN with invasive cancer had high-risk stigmata or worrisome features. The risk of high-grade dysplasia in nonworrisome lesions smaller than 3 cm was 6.5%, but when the threshold was raised to greater than 3 cm, it was 8.8%, and 1 case of invasive carcinoma was found. Conclusions:Expectant management of BD-IPMN following the old guidelines is safe, whereas caution is advised for larger lesions, even in the absence of worrisome features.

Cyst fluid carcinoembryonic antigen is an accurate diagnostic marker of pancreatic mucinous cysts.

Objectives: Endoscopic ultrasound (EUS) may offer a diagnostic tool through the combination of imaging and guided fine-needle aspiration of pancreatic cysts. The purpose of this investigation was to determine the most accurate test for differentiating mucinous from nonmucinous cysts. Methods: The results of EUS imaging, cytology, and cyst fluid biochemical markers were prospectively collected and compared in a large single-center study (776 patients) using histology or malignant cytology as the final diagnostic standard in 198 patients. Results: The mean cyst fluid carcinoembryonic antigen (CEA) was greater in mucinous cysts (4703.0 ng/mL) compared with nonmucinous cysts (25.8 ng/mL) (P = 0.008). When using the optimal cutoff value of 109.9 ng/mL, the CEA was more accurate (86%, receiver operating characteristic area = 0.928) than EUS imaging (48%) and cytology (58%) in predicting a mucinous cyst (P < 0.0001). Malignant cysts had a mean cyst fluid CEA value (2558.2 ng/mL) similar to benign cysts (4700.2 ng/mL). Cytology (75%) more accurately diagnosed malignant cysts than EUS (66%) and CEA (62%) (P < 0.05). Conclusions: Cyst fluid CEA concentration provides a highly accurate test for the diagnosis of a mucinous cyst, but does not distinguish benign from malignant cysts. Cytology is the most accurate test for the diagnosis of a malignant cyst.Abbreviations: EUS - endoscopic ultrasound, CEA - carcinoembryonic antigen, MCN - mucinous cystic neoplasm, IPMN - intraductal papillary mucinous neoplasm

Prognosis of invasive intraductal papillary mucinous neoplasm depends on histological and precursor epithelial subtypes

Objective Invasive cancers arising from intraductal papillary mucinous neoplasm (IPMN) are recognised as a morphologically and biologically heterogeneous group of neoplasms. Less is known about the epithelial subtypes of the precursor IPMN from which these lesions arise. The authors investigate the clinicopathological characteristics and the impact on survival of both the invasive component and its background IPMN. Design and patients The study cohort comprised 61 patients with invasive IPMN (study group) and 570 patients with pancreatic ductal adenocarcinoma (PDAC, control group) resected at a single institution. Multivariate analyses were performed using a stage-matched Cox proportional hazard model. Results The histology of invasive components of the IPMN cohort was tubular in 38 (62%), colloid in 16 (26%), and oncocytic in seven (12%). Compared with PDAC, invasive IPMNs were associated with a lower incidence of adverse pathological features and improved mortality by multivariate analysis (HR 0.58; 95% CI 0.39 to 0.86). In subtype analysis, this favourable outcome remained only for colloid and oncocytic carcinomas, while tubular adenocarcinoma was associated with worse overall survival, not significantly different from that of PDAC (HR 0.85; 95% CI 0.53 to 1.36). Colloid and oncocytic carcinomas arose only from intestinal- and oncocytic-type IPMNs, respectively, and were mostly of the main-duct type, whereas tubular adenocarcinomas primarily originated in the gastric background, which was often associated with branch-duct IPMN. Overall survival of patients with invasive adenocarcinomas arising from gastric-type IPMN was significantly worse than that of patients with non-gastric-type IPMN (p=0.016). Conclusions Tubular, colloid and oncocytic invasive IPMNs have varying prognosis, and arise from different epithelial subtypes. Colloid and oncocytic types have markedly improved biology, whereas the tubular type has a course that resembles PDAC. Analysis of these subtypes indicates that the background epithelium plays an equally, if not more, important role in defining the biology and prognosis of invasive IPMNs.

Fine-Needle Aspiration Biopsy in the Diagnosis and Classification of Primary and Recurrent Lymphoma: A Retrospective Analysis of the Utility of Cytomorphology and Flow Cytometry

We retrospectively reviewed our experience with the fine-needle aspiration biopsy (FNAB) diagnosis of primary and recurrent lymphoma to assess the ability of cytomorphology with and without ancillary flow cytometry (FCM) analysis to diagnose and subclassify these tumors according to the Revised European-American Lymphoma/World Health Organization classifications. We reviewed 139 consecutive FNABS of 84 primary and 55 recurrent lymphomas. FCM was successful in 105 (75%) cases. The overall results, including cases without FCM, included 93/139 (67%) true positive, 7 (5%) false negative, and 39 indeterminate (27 [19%] suspicious and 12 [9%] atypical) diagnoses of lymphoma. In cases with FCM, there were 80/105 (77%) true positive, no false negative, and 25 indeterminate diagnoses (15 [14%] suspicious and 10 [9%] atypical). The overall results of the 84 primary lymphomas were 55 (67%) true positive, 5 (5%) false negative, and 24 indeterminate (14[16%] suspicious and 10 [12%] atypical) diagnoses for lymphoma. Of the 68 primary lymphomas analyzed with FCM, 50 [74%] were true positives, and 28 were indeterminate (11 [16%] suspicious and 7 [10%] atypical). There were no false negatives. Diagnostic accuracy varied among lymphoma subtypes. Subclassification of the positive cases were initially conclusive in only 55/93 cases (59%). However, a retrospective review of the morphologic together with FCM data in 15 of the 23 unclassified cases improved the overall subclassification of positive cases to 77%. Subclassification was best in small lymphocytic lymphoma/chronic lymphocytic leukemia, lymphoplasmacytic lymphoma, Burkitts lymphoma, mantle cell lymphoma, and plasmacytoma (all 100%). Subclassification was poor in marginal-zone lymphoma (33%), and initially as well in diffuse large B-cell lymphoma (62%), but it improved on review (95%), as did subclassification of follicular lymphoma (77 to 100% on review). Hodgkins disease was recognized as malignant in only 44% of the cases (7/16) and was classified as such based on morphology alone.This review of our early efforts to diagnose and subclassify lymphoma with FNAB and FCM indicates that although a diagnosis and proper subclassification of lymphoma can be made with certainty in the majority of cases, recurrent or primary, it requires close coordination of cytomorphology and immunophenotyping data, which often comes with close cooperation of cytopathologists and hematopathologists. A mere cytological diagnosis of positive for lymphoma is no longer acceptable if FNAB is to become an independent diagnostic tool for lymphoma.

Serous Cystadenoma of the Pancreas : Limitations and Pitfalls of Endoscopic Ultrasound-Guided Fine-Needle Aspiration Biopsy

Expectant management of serous cystadenoma (SCA) of the pancreas requires an accurate preoperative diagnosis. Previously published cytologic diagnostic sensitivities have ranged widely, from 10% to 100%. In the current study, the authors evaluated the diagnostic sensitivity of endoscopic ultrasound (EUS)‐guided fine‐needle aspiration biopsy (FNAB) and cross‐sectional imaging for SCA.

Endoscopic Ultrasound Guided Fine Needle Aspiration Biopsy of Autoimmune Pancreatitis: Diagnostic Criteria and Pitfalls

Autoimmune pancreatitis (AIP) is a benign inflammatory disease of the pancreas that mimics pancreatic malignancy both clinically and radiologically. The fine needle aspiration biopsy (FNAB) features of AIP have not previously been documented. We report our experience with AIP, highlight pitfalls, and perform a comprehensive analysis of the cytomorphologic features of this condition. We identified 16 patients with AIP, initially evaluated by endoscopic ultrasound (EUS)-guided FNAB, 11 of whom subsequently underwent a pancreatoduodenectomy. We compared these to a cohort of EUS-guided aspirates from ductal carcinoma of the pancreas (n = 16) and chronic pancreatitis, not otherwise specified (NOS) (n = 19). On all 51 cases, we semiquantitatively evaluated presence and atypia of ductal cells, presence and cellularity of stromal fragments, and inflammatory cells, type and distribution. Fifty percent (8 of 16) of the AIP cases presented as obstructive jaundice. EUS and CT scan showed mass lesions in 10 and 6 cases, respectively. There were three false-positive cytologic diagnoses, an adenocarcinoma, a solid-pseudopapillary tumor and a mucinous neoplasm. Ductal epithelium was inconspicuous and was seen in 6 cases. The FNAB samples showed background lymphocytes in three AIP cases, a feature absent in the control cohort. Stromal fragments with embedded lymphocytes (greater than 30 per 60×) were seen in 37.5% of AIP cases and only rarely with adenocarcinoma (12.5%) and pancreatitis, NOS (0%). The cellularity of stromal fragments was significantly higher in AIP than in the control group. The presence of stromal fragments of high cellularity with a lymphoid infiltrate in conjunction with clinical and radiology findings could potentially both establish a diagnosis of AIP and exclude carcinoma, thus preventing pancreatic resection.

EUS-guided FNA for the diagnosis of GI stromal cell tumors: sensitivity and cytologic yield.

BACKGROUND EUS-guided FNA has been well documented to aid in the diagnosis of subepithelial lesions by providing cytologic material. Studies to date evaluating the sensitivity of EUS-FNA for the diagnosis of GI stromal cell tumors (GIST) have been small, and few have relied on surgical histologic diagnosis as the reference standard. OBJECTIVE Our purpose was to determine the diagnostic yield and sensitivity of EUS-FNA for the diagnosis of GIST and to identify EUS features of GIST that are predictive of the ability to obtain adequate tissue by EUS-FNA. DESIGN All patients with histologically confirmed, c-kit-positive GIST who underwent EUS-FNA from 1998 to 2006 were reviewed. EUS images were examined for mass size, shape, location, wall layer, heterogeneity, echogenicity, cystic spaces, lobulation, ulceration, and central umbilication. Needle gauge, number of needle passes, and presence of a cytologist during the EUS-FNA were recorded. RESULTS A total of 37 patients (29 with diagnostic FNA cytology; 8 with nondiagnostic cytology) met the inclusion criteria. The diagnostic yield and sensitivity of EUS-FNA cytology for the diagnosis of GIST was 78.4% (29/37). The sensitivity was 84.4% (27/32) for GISTs located in the stomach, but poor for lesions located in the duodenum because none of these tumors yielded diagnostic cytology (n = 3). An increase in size up to 10 cm, round/oval shape, and identification of the origin of GIST within a specific sonographic wall layer were statistically significant in their ability to predict adequate tissue yield. CONCLUSIONS The sensitivity of EUS-FNA cytology for the diagnosis of GIST is 78.4% and is influenced by size, location, shape, and layer of origin.

Techniques for thyroid FNA: a synopsis of the National Cancer Institute Thyroid Fine-Needle Aspiration State of the Science Conference.

The National Cancer Institute (NCI) sponsored the NCI Thyroid fine‐needle aspiration (FNA) State of the Science Conference on October 22–23, 2007 in Bethesda, MD. The 2‐day meeting was accompanied by a permanent informational website and several on‐line discussion periods between May 1 and December 15, 2007 (http://thyroidfna.cancer.gov). This document summarizes matters addressing manual and ultrasound guided FNA technique and related issues. Specific topics covered include details regarding aspiration needles, devices, and methods, including the use of core needle biopsy; the pros and cons of anesthesia; the influence of thyroid lesion location, size, and characteristics on technique; the role of ultrasound in the FNA of a palpable thyroid nodule; the advantages and disadvantages of various specialists performing a biopsy; the optimal number of passes and tissue preparation methods; sample adequacy criteria for solid and cystic nodules, and management of adverse reactions from the procedure. (http://thyroidfna.cancer.gov/pages/info/agenda/) Diagn. Cytopathol. 2008;36:407–424.

Cytology Adds Value to Imaging Studies for Risk Assessment of Malignancy in Pancreatic Mucinous Cysts

Objective:Evaluate the value of cytology relative to imaging features in risk assessment for malignancy as defined in the Sendai Guidelines. Background:The Sendai Guidelines list symptoms, cyst size >30 mm, dilated main pancreatic duct (MPD) >6 mm, mural nodule (MN) and “positive” cytology as high risk stigmata for malignancy warranting surgical triage. Methods:We reviewed clinical, radiological and cytological data of 112 patients with histologically confirmed mucinous cysts of the pancreas evaluated in a single tertiary medical center. Cytology slides were blindly re-reviewed and epithelial cells grouped as either benign or high-grade atypia (HGA) [≥high-grade dysplasia]. Histologically, neoplasms were grouped as benign (low-grade and moderate dysplasia) and malignant (in situ and invasive carcinoma). Performance characteristics of cytology relative to other risk factors were evaluated. Results:Dilated MPD, MN, and HGA were independent predictors of malignancy (p < 0.0001), but not symptoms (p = 0.29) or cyst size >30 mm (p = 0.51). HGA was the most sensitive predictor of malignancy in all cysts (72%) and in small (⩽30 mm) branch-duct intraductal papillary mucinous neoplasm (BD IPMN; 67%), whereas also being specific (85 and 88%, respectively). MN and dilated MPD were highly specific (>90%), but insensitive (39%–44%). Cytology detected 30% more cancers in small cysts than dilated MPD or MN and half of the cancers without either of these high-risk imaging features. Conclusions:Cytology adds value to the radiological assessment of predicting malignancy in mucinous cysts, particularly in small BD IPMN.

Thyroid Fine-Needle Aspiration Biopsy: Variability in Reporting

BACKGROUND The low incidence of thyroid cancer despite the high prevalence of thyroid nodules necessitates a screening tool to determine which patients require surgical management. The utility of fine-needle aspiration biopsy (FNAB) for this purpose requires a low false-negative (FN) rate and an acceptable sensitivity and specificity for the detection of malignancy. While reviewing our institutions experience with thyroid FNAB, we found significant discrepancies in how statistics of thyroid FNAB were tabulated and reported in the literature. Here we examine the sources of these discrepancies by evaluating large series of thyroid FNAB with regard to cytopathologic reporting and statistical calculation. METHODS Published series of thyroid FNAB with >200 FNAB and available histological data with sufficient raw data to recalculate statistics were analyzed. Considering indeterminate and malignant results to be positive FNAB results, since, in a four-tier system, both lead to surgical management, specificity, sensitivity, accuracy, positive predictive value, negative predictive value, FN, and false-positive (FP) rates were recalculated. Differences between reported and recalculated statistics were then evaluated for significance. RESULTS Nineteen studies and 20 series were identified. The following are reported and recalculated means, respectively: for sensitivity, 81% and 86%; for specificity, 81% and 62%; for accuracy, 77% and 71%; for positive predictive value, 65% and 50%; for negative predictive value, 84% and 93%; for FN rates, 13% and 14%; for FP rates, 10% and 38%. FP rates had a mean of 1.4% when recalculated considering only malignant FNAB as positive tests. Specificity and FP rates had statistically significant differences between the means of reported and recalculated values. CONCLUSIONS Thyroid FNAB remains the screening tool of choice in the evaluation of thyroid nodules. However, the variability in the calculation of reported thyroid FNAB statistics highlights the need for uniformity in statistical reporting for accurate understanding of thyroid FNABs clinical utility.