Muriel Genevay

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.

High‐grade atypical epithelial cells in pancreatic mucinous cysts are a more accurate predictor of malignancy than “positive” cytology

The Sendai guidelines for risk assessment of malignancy in patients with mucinous cysts lists “positive” cytology as a high‐risk feature. In the current study, the authors hypothesized that a cytological threshold of high‐grade atypical epithelial cells (AEC) is a more accurate predictor of malignancy.

Standardized terminology and nomenclature for pancreatobiliary cytology: The Papanicolaou Society of Cytopathology guidelines: Pancreatobiliary Cytology Terminology and Nomenclature

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 postbiopsy treatment and management. All documents are based on the expertise of the authors, a review of the literature, discussions of the draft document at several national and international meetings 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.

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

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.

Trends in Presentation and Survival for Gallbladder Cancer During a Period of More Than 4 Decades: A Single-Institution Experience

OBJECTIVES To determine the prevalence of incidentally found cases of gallbladder cancer, the incidence of residual disease at reexploration, and the changes in the mode of presentation, treatment, and survival of patients with gallbladder cancer during a period of more than 4 decades. DESIGN Retrospective case series. SETTING University-affiliated tertiary care center. PATIENTS Between January 1, 1962, and March 1, 2008, 402 patients with gallbladder cancer were identified and their clinicopathologic data were analyzed. INTERVENTIONS Surgical treatment, radiotherapy, and chemotherapy. MAIN OUTCOME MEASURES Incidentally discovered gallbladder cancer, incidence of residual disease, and differences in presentation, treatment, and survival. RESULTS Surgical exploration was performed in 260 patients (64.7%), of whom 151 (58.1%) underwent resection. The median age of the patients was 72 years, and 72.3% were female. Between January 1, 1994, and March 1, 2008, 6881 laparoscopic cholecystectomies were performed, and there were 17 incidentally discovered cases of gallbladder cancer (0.25%). Residual disease on reexploration was identified in 0 of 2 patients with T1 tumor, 3 of 13 patients with T2 tumor, and 8 of 10 patients with T3 tumor (P = .01). Patients with stage IV disease (34 [13.1%] diagnosed from 1962-1979; 34 [13.1%] diagnosed from 1980-1997; and 22 [8.5%] diagnosed from 1998-2008) had a median survival of 4 months (range, 0-37 months). Concomitant liver resections increased in the third study period (11.1%, 10.1%, and 54.3%; P < .001), with an increase in negative margins (33.3%, 42.0%, and 63.0%; P = .01). Cox regression analysis identified T stage and surgical margin status as significant prognostic factors. CONCLUSIONS Gallbladder cancer is incidentally found during 0.25% of laparoscopic cholecystectomies. As T stage increases, the likelihood of residual disease on reexploration increases. Although many patients with gallbladder cancer present with incurable disease and have very poor survival, the overall prognosis is improving, likely because of more extensive operations.

Grasp or brush for biliary sampling at endoscopic retrograde cholangiography? A blinded randomized controlled trial.

OBJECTIVES Brushing, the standard sampling method at endoscopic retrograde cholangiography (ERC), lacks sensitivity for cancer detection. We assessed a novel sampling method using a grasping basket.METHODS Fifty-six patients with a suspected malignant biliary stricture were randomized to biliary sampling at ERC using a basket (basket group, N = 30) or a brush (brush group, N = 26), followed by the alternate device. When deemed necessary, strictures were dilated (using 6-mm balloons exclusively). The primary end point was sensitivity for cancer detection at cytopathological examination of the first sample collected in each patient; the cytopathologist was blinded to clinical details and sampling method. All analyses followed an intention-to-treat principle.RESULTS All 56 patients had successful sampling with both techniques; 50 (89%) had a final diagnosis of malignant stricture. Sensitivity for cancer detection with the first sample collected in each patient was significantly higher in the basket compared to brush group (20/25 [80%] vs 12/25 [48%], respectively, P = 0.018, OR 4.33, 95% CI 1.24–15.21). Seventeen (34%) of the 50 sample pairs collected from malignant cases showed discordant cytopathological results: 15 patients had a positive basket and a negative brush result while two had the inverse association (P = 0.002, OR 7.5, 95% CI 1.65–47.44). Basketting more frequently yielded positive samples from malignant strictures in case of presampling balloon dilation (27/32 [84%] vs 10/18 [56%], respectively, P = 0.043, OR 4.32, 95% CI 1.14–16.37). Specificity was 100% (both methods).CONCLUSION Biliary sampling at ERC using a dedicated basket provided a significantly higher sensitivity for cancer detection than brushing; presampling stricture dilation significantly increased sensitivity.

Early liver biopsy, intraparenchymal cholestasis, and prognosis in patients with alcoholic steatohepatitis

BackgroundAlcoholic steatohepatitis (ASH) is a serious complication of alcoholic liver disease. The diagnosis of ASH requires the association of steatosis, evidence of hepatocellular injury with ballooning degeneration, and polynuclear neutrophil infiltration on liver biopsy. Whether these lesions, in addition to other histological features observed in liver tissue specimens, have prognostic significance is unclear.MethodsWe studied 163 patients (age 55 yrs [35-78], male/female 102/61) with recent, heavy (> 80 gr/day) alcohol intake, histologically-proven ASH (97% with underlying cirrhosis, Maddreys score 39 [13-200], no sepsis), who had a liver biopsy performed 3 days [0-10] after hospital admission for clinical decompensation. A semi-quantitative evaluation of steatosis, hepatocellular damage, neutrophilic infiltration, periportal ductular reaction, intraparenchymal cholestasis, and iron deposits was performed by two pathologists. All patients with a Maddreys score ≥ 32 received steroids. The outcome at 3 months was determined. Statistical analysis was performed using the Wilcoxon and Fishers exact tests, Kaplan-Meier method, and the Cox proportional hazard model.Results43 patients died after 31 days [5-85] following biopsy. The 3-month survival rate was 74%. Mean kappa value for histological assessment by the two pathologists was excellent (0.92). Univariate analysis identified age, the Maddreys score, the Pughs score, the MELD score and parenchymal cholestasis, but not other histological features, as factors associated with 3-month mortality. At multivariate analysis, age (p = 0.029, OR 2.83 [1.11-7.2], intraparenchymal cholestasis (p = 0.001, OR 3.9 [1.96-7.8], and the Maddreys score (p = 0.027, OR 3.93 [1.17-13.23] were independent predictors of outcome. Intraparenchymal cholestasis was more frequent in non survivors compared to survivors (70% versus 25%, p < 0.001). Serum bilirubin was higher in patients with severe compared to those with no or mild intraparenchymal cholestasis (238 [27-636] versus 69 [22-640] umol/l, p < 0.001).ConclusionsIn this large cohort of patients with histologically documented ASH early after admission and no sepsis, liver biopsy identified marked intraparenchymal cholestasis as an independent predictor of poor short term outcome together with age and the Maddreys score. It may be hypothesized that incorporation of this particular variable into existing disease severity scores for ASH would improve their performance.

Islet Autotransplantation After Extended Pancreatectomy for Focal Benign Disease of the Pancreas

Background. Extended pancreatectomy is associated with the risk of surgical diabetes. Islet autotransplantation is successful in the prevention of diabetes after pancreas resection for chronic pancreatitis (CP), with insulin independence rates of 50% at 1 year. The aim of the present study is to demonstrate the safety and efficiency of islet autotransplantation after extended left pancreatectomy for benign disease. Methods. Between 1992 and 2009, 25 patients underwent extended pancreatectomy and islet autotransplantation for benign disease. Of these, 15 patients were operated for focal lesions located at the neck of the pancreas (14 benign tumors and 1 traumatic pancreatic section), the remainder being CP cases. After unequivocal diagnosis of benignity, the rest of the pancreas was processed and infused into the portal vein. Metabolic results were analyzed and isolation results were compared with those obtained from patients with CP or donors with brain death (DBD). Results. There was no mortality and a low morbidity (Streptococcus mitis bacteremia in 1 patient), no portal thrombosis or pancreatic fistula occurred. Median follow-up was 90 months. Actuarial patient survival was 100% at 10 years. Actuarial insulin independence was 94% at 10 years. All patients had positive basal and stimulated C-peptide levels and normal HbA1c. Mean islet yields were 5455 IEQ/gram vs. 1457 in CP (P=0.001) and 3738 in DBD (P=0.003). Conclusions. Islet autotransplantation after extensive pancreatic resection for benign disease is a safe and successful procedure. Islet yields after isolation, which are equivalent to the live donor situation, are significantly better than those from DBD donors.

Cytological analysis of small branch-duct intraductal papillary mucinous neoplasms provides a more accurate risk assessment of malignancy than symptoms

Objectives: The Sendai guidelines for management of patients with clinically suspected intraductal papillary mucinous neoplasms (IPMN) recommend resection of cysts > 30 mm, a dilated main pancreatic duct (MPD) > 6 mm, a mural nodule (MN), symptoms or positive cytology. Although sensitive, asymptomatic cysts, nonspecific symptoms, and a high threshold for positive cytology limit the specificity of the guidelines. We have assessed the value of cytology relative to symptom for predicting malignancy in IPMNs without high-risk imaging features. Materials and Methods: We retrospectively reviewed the clinical, radiological, and cytological data of 31 small branch-duct IPMNs without a MN. The cytological presence of high-grade atypical epithelial cells (HGA) was considered true positive, with a corresponding histology of high-grade dysplasia or invasive carcinoma. The performance of cytology versus symptoms was evaluated by calculating the sensitivity, specificity, negative predictive value (NPV), positive predictive value (PPV), and accuracy. Results: The sensitivity (0.80), specificity (0.85), and accuracy (0.84) of HGA were higher than the corresponding performance characteristics of symptoms (0.60, 0.45, and 0.48, respectively). The NPV of no HGA on cytology was > 95%. Conclusions: Cytology is a better predictor of malignancy than symptoms, for the conservative management of small branch-duct IPMNs. Cytology contributes to a highly accurate triple negative test for malignancy in small IPMN: No dilated MPD, MN or HGA.

Extensive biliary intraepithelial neoplasia (BilIN) and multifocal early intrahepatic cholangiocarcinoma in non-biliary cirrhosis

Biliary intraepithelial neoplasia (BilIN), a preneoplastic condition that may precede invasive intrahepatic cholangiocarcinoma (ICC), has been compared to pancreatic intraepithelial neoplasia (PanIN), a precursor lesion of pancreatic carcinoma. Biliary tract carcinoma development and progression is associated with several gene alterations, but BilIN lesions have yet to be studied in detail by molecular techniques. We describe a case of extensive intrahepatic biliary dysplasia, with lesions ranging from BilIN-1 to BilIN-3 lesions, and multifocal microscopic ICC in hepatitis C virus (HCV)- and alcohol-related cirrhosis. The small ICC foci had remained undetected prior to transplantation. Fluorescence in situ hybridization (FISH) analysis was performed on three foci of BilIN-3 lesions and on three microinvasive ICC foci with a combination of three FISH probes directed against genes frequently altered in pancreatic and biliary tract carcinomas. FISH analysis revealed a CDKNA2 heterozygous deletion in one BilIN-3 focus, and in one non-contiguous ICC focus, although the deletion was just above the chosen threshold. No deletions were detected in the genomic regions encoding TP53 and SMAD4. This report documents for the first time the development of multifocal ICC in the setting of extensive biliary dysplasia in a patient with three risk factors, HCV infection, alcohol abuse, and cirrhosis, and suggests heterogeneous carcinogenesis in ICC and possible involvement of the CDKNA2 gene.