Faculty Bibliography

OBJECTIVE:To compare laparoscopic distal pancreatectomy (LDP) versus open distal pancreatectomy (ODP) by using meta-analytical techniques. BACKGROUND:LDP is increasingly performed as an alternative approach for distal pancreatectomy in selected patients. Multiple studies have tried to assess the safety and efficacy of LDP compared with ODP. METHODS:A systematic review of the literature was performed to identify studies comparing LDP and ODP. Intraoperative outcomes, postoperative recovery, oncologic safety, and postoperative complications were evaluated. Meta-analysis was performed using a random-effects model. RESULTS:Eighteen studies matched the selection criteria, including 1814 patients (43% laparoscopic, 57% open). LDP had lower blood loss by 355 mL (P < 0.001) and hospital length of stay by 4.0 days (P < 0.001). Overall complications were significantly lower in the laparoscopic group (33.9% vs 44.2%; odds ratio [OR] = 0.73, 95% confidence interval [CI] 0.57-0.95), as was surgical site infection (2.9% vs 8.1%; OR = 0.45, 95% CI 0.24-0.82). There was no difference in operative time, margin positivity, incidence of postoperative pancreatic fistula, and mortality. CONCLUSIONS:LDP has lower blood loss and reduced length of hospital stay. There was a lower risk of overall postoperative complications and wound infection, without a substantial increase in the operative time. Although a thorough evaluation of oncological outcomes was not possible, the rate of margin positivity was comparable to the open technique. The improved complication profile of LDP, taken together with the lack of compromise of margin status, suggests that this technique is a reasonable approach in selected cancer patients.

OBJECTIVE:Autoimmune pancreatitis (AIP) is an inflammatory, IgG4-associated condition that often overlaps clinically and radiographically with pancreatic ductal adenocarcinoma. We reviewed our institutional experience with fine needle aspiration (FNA) cytology in patients subsequently diagnosed with AIP. STUDY DESIGN/METHODS:A retrospective review was conducted of FNA results correlating to all surgical pancreatic specimens diagnosed as AIP or lymphoplasmacytic sclerosing pancreatitis from 1984 to 2011. RESULTS:AIP was diagnosed in 15 cases by surgical resection and in 2 by combined clinical findings and nondiagnostic biopsies. Of 20 aspirates from 17 patients, 1 was diagnosed as malignant, 1 as neoplasm (mucinous), 10 as atypical, 5 as benign, and 3 as scant or nondiagnostic. Of the 10 aspirates diagnosed as atypical, 1 was suspicious for malignancy, 1 could not exclude neuroendocrine neoplasm, 1 was markedly atypical, and 7 demonstrated scattered ductal atypia. Common morphologic features included hypocellularity, focal-to-marked ductal epithelial atypia, fibrous tissue fragments, and a smear background lacking red blood cells. CONCLUSION/CONCLUSIONS:On FNA, AIP most often leads to an 'atypical' cytopathologic interpretation and rarely may be diagnosed as adenocarcinoma. Thus, caution is warranted to avoid overdiagnosis on FNA when a mass lesion is reported in a patient with clinical or radiographic suspicion of AIP.

Approximately 45% of sporadic well-differentiated pancreatic neuroendocrine tumors harbor mutations in either ATRX (alpha thalassemia/mental retardation X-linked) or DAXX (death domain-associated protein). These novel tumor suppressor genes encode nuclear proteins that interact with one another and function in chromatin remodeling at telomeric and peri-centromeric regions. Mutations in these genes are associated with loss of their protein expression and correlate with the alternative lengthening of telomeres phenotype. Patients with multiple endocrine neoplasia-1 (MEN-1) syndrome, genetically defined by a germ line mutation in the MEN1 gene, are predisposed to developing pancreatic neuroendocrine tumors and thus represent a unique model for studying the timing of ATRX and DAXX inactivation in pancreatic neuroendocrine tumor development. We characterized ATRX and DAXX protein expression by immunohistochemistry and telomere status by telomere-specific fluorescence in situ hybridization in 109 well-differentiated pancreatic neuroendocrine lesions from 28 MEN-1 syndrome patients. The study consisted of 47 neuroendocrine microadenomas (<0.5 cm), 50 pancreatic neuroendocrine tumors (≥0.5 cm), and 12 pancreatic neuroendocrine tumor lymph node metastases. Expression of ATRX and DAXX was intact in all 47 microadenomas, and none showed the alternative lengthening of telomeres phenotype. ATRX and/or DAXX expression was lost in 3 of 50 (6%) pancreatic neuroendocrine tumors. In all three of these, tumor size was ≥3 cm, and loss of ATRX and/or DAXX expression correlated with the alternative lengthening of telomeres phenotype. Concurrent lymph node metastases were present for two of the three tumors, and each metastasis displayed the same changes as the primary tumor. These findings establish the existence of ATRX and DAXX defects and the alternative lengthening of telomeres phenotype in pancreatic neuroendocrine tumors in the context of MEN-1 syndrome. The observation that ATRX and DAXX defects and the alternative lengthening of telomeres phenotype occurred only in pancreatic neuroendocrine tumors measuring ≥3 cm and their lymph node metastases suggests that these changes are late events in pancreatic neuroendocrine tumor development.

The international consensus guidelines for management of intraductal papillary mucinous neoplasm and mucinous cystic neoplasm of the pancreas established in 2006 have increased awareness and improved the management of these entities. During the subsequent 5 years, a considerable amount of information has been added to the literature. Based on a consensus symposium held during the 14th meeting of the International Association of Pancreatology in Fukuoka, Japan, in 2010, the working group has generated new guidelines. Since the levels of evidence for all items addressed in these guidelines are low, being 4 or 5, we still have to designate them "consensus", rather than "evidence-based", guidelines. To simplify the entire guidelines, we have adopted a statement format that differs from the 2006 guidelines, although the headings are similar to the previous guidelines, i.e., classification, investigation, indications for and methods of resection and other treatments, histological aspects, and methods of follow-up. The present guidelines include recent information and recommendations based on our current understanding, and highlight issues that remain controversial and areas where further research is required.

INTRODUCTION/BACKGROUND:Assessing patient-specific risk factors for long-term mortality following resection of pancreatic adenocarcinoma can be difficult. Sarcopenia--the measurement of muscle wasting--may be a more objective and comprehensive patient-specific factor associated with long-term survival. METHODS:Total psoas area (TPA) was measured on preoperative cross-sectional imaging in 557 patients undergoing resection of pancreatic adenocarcinoma between 1996 and 2010. Sarcopenia was defined as the presence of a TPA in the lowest sex-specific quartile. The impact of sarcopenia on 90-day, 1-year, and 3-year mortality was assessed relative to other clinicopathological factors. RESULTS:Mean patient age was 65.7 years and 53.1 % was male. Mean TPA among men (611 mm²/m²) was greater than among women (454 mm²/m²). Surgery involved pancreaticoduodenectomy (86.0 %) or distal pancreatectomy (14.0 %). Mean tumor size was 3.4 cm; 49.9 % and 88.5 % of patients had vascular and perineural invasion, respectively. Margin status was R0 (59.0 %) and 77.7 % patients had lymph node metastasis. Overall 90-day mortality was 3.1 % and overall 1- and 3-year survival was 67.9 % and 35.7 %, respectively. Sarcopenia was associated with increased risk of 3-year mortality (HR = 1.68; P < 0.001). Tumor-specific factors such as poor differentiation on histology (HR = 1.75), margin status (HR = 1.66), and lymph node metastasis (HR = 2.06) were associated with risk of death at 3-years (all P < 0.001). After controlling for these factors, sarcopenia remained independently associated with an increased risk of death at 3 years (HR = 1.63; P < 0.001). CONCLUSIONS:Sarcopenia was a predictor of survival following pancreatic surgery, with sarcopenic patients having a 63 % increased risk of death at 3 years. Sarcopenia was an objective measure of patient frailty that was strongly associated with long-term outcome independent of tumor-specific factors.

PURPOSE/OBJECTIVE:The diagnosis of pancreatic cystic lesions has increased dramatically. Most are benign, whereas some, such as intraductal papillary mucinous neoplasms (IPMN), represent precursors of pancreatic adenocarcinoma. Therapeutic stratification of IPMNs is challenging without precise information on dysplasia grade and presence of invasion. We assessed the diagnostic benefit of using miRNAs as biomarkers in pancreatic cyst fluid, focusing on IPMNs because of their frequency and malignant potential. EXPERIMENTAL DESIGN/METHODS:RNA was extracted from 55 microdissected formalin-fixed, paraffin-embedded (FFPE) IPMN specimens, and 65 cyst fluid specimens aspirated following surgical resection. Expression of 750 miRNAs was evaluated with TaqMan miRNA Arrays using 22 FFPE and 15 cyst fluid specimens. Differential expression of selected miRNA candidates was validated in 33 FFPE and 50 cyst fluid specimens using TaqMan miRNA Assays. RESULTS:We identified 26 and 37 candidate miRNAs that distinguish low-grade from high-grade IPMNs using FFPE and cyst fluid specimens, respectively. A subset of 18 miRNAs, selected from FFPE and cyst fluid data, separated high-grade IPMNs from low-grade IPMNs, serous cystadenomas (SCA) and uncommon cysts, such as solid pseudopapillary neoplasms (SPN) and cystic pancreatic neuroendocrine tumors (PanNET). A logistic regression model using nine miRNAs allowed prediction of cyst pathology implying resection (high-grade IPMNs, PanNETs, and SPNs) versus conservative management (low-grade IPMNs, SCAs), with a sensitivity of 89%, a specificity of 100%, and area under the curve of 1. CONCLUSIONS:We found candidate miRNAs that helped identify patients with high-grade IPMN and exclude nonmucinous cysts. These classifiers will require validation in a prospective setting to ultimately confirm their clinical usefulness.

The overall 5 year survival rate for pancreatic ductal adenocarcinoma (i.e., PDAC) is a dismal 5%, although patients that have undergone surgical resection have a somewhat better survival rate of up to 20%. Very long-term survivors of PDAC (defined as patients with ≥ 10 year survival following apparently curative resection), on the other hand, are considerably less frequent. The molecular characteristics of very long-term survivors (VLTS) are poorly understood, but might provide novel insights into prognostication for this disease. In this study, a panel of five VLTS and stage-matched short-term survivors (STS, defined as disease-specific mortality within 14 months of resection) were identified, and quantitative proteomics was applied to comparatively profile tumor tissues from both cohorts. Differentially expressed proteins were identified in cancers from VLTS vs. STS patients. Specifically, the expression of galectin-1 was 2-fold lower in VLTS compared with STS tumors. Validation studies were performed by immunohistochemistry (IHC) in two additional cohorts of resected PDAC, including: 1) an independent cohort of VLTS and 2) a panel of sporadic PDAC with a considerable range of overall survival following surgery. Immunolabeling analysis confirmed that significantly lower expression of stromal galectin-1 was associated with VLTS (p = 0.02) and also correlated with longer survival in sporadic, surgically-treated PDAC cases (hazard ratio = 4.9, p = 0.002). The results from this study provide new insights to better understand the role of galectin-1 in PDAC survival, and might be useful for rendering prognostic information, and developing more effective therapeutic strategies aimed at improving survival.

PURPOSE/OBJECTIVE:Little information is available on genetic and epigenetic changes in duodenal adenocarcinomas. The purpose was to identify possible subsets of duodenal adenocarcinomas based on microsatellite instability (MSI), DNA methylation, mutations in the KRAS and BRAF genes, clinicopathologic features, and prognosis. EXPERIMENTAL DESIGN/METHODS:Demographics, tumor characteristics, and survival were available for 99 duodenal adenocarcinoma patients. Testing for KRAS and BRAF mutations, MSI, MLH1 methylation, and CpG island methylator phenotype (CIMP) status was conducted. A Cox proportional hazard model was built to predict survival. RESULTS:CIMP(+) was detected in 27 of 99 (27.3%) duodenal adenocarcinomas and was associated with MSI (P = 0.011) and MLH1 methylation (P < 0.001), but not with KRAS mutations (P = 0.114), as compared with CIMP(-) tumors. No BRAF V600E mutation was detected. Among the CIMP(+) tumors, 15 (55.6%) were CIMP(+)/MLH1-unmethylated (MLH1-U). Kaplan-Meier analysis showed that tumors classified by CIMP, CIMP/MLH1 methylation status, or CIMP/MSI status could predict overall survival (OS; P = 0.047, 0.002, and 0.002, respectively), whereas CIMP/MLH1 methylation status could also predict time-to-recurrence (TTR; P = 0.016). In multivariate analysis, CIMP/MLH1 methylation status showed a significant prognostic value in both OS (P < 0.001) and TTR (P = 0.023). Patients with CIMP(+)/MLH1-U tumors had the worst OS and TTR. CONCLUSIONS:Our results showed existence of CIMP in duodenal adenocarcinomas. The combination of CIMP(+)/MLH1-U seems to be independently associated with poor prognosis in patients with duodenal adenocarcinomas. This study also suggests that BRAF mutations are not involved in duodenal tumorigenesis, MSI, or CIMP development.

OBJECTIVE:This pictorial essay reviews the imaging appearance of pancreatic neuroendocrine tumors, as well as a number of mimics on CT. CONCLUSION/CONCLUSIONS:Pancreatic neuroendocrine tumors have a distinct appearance, typically characterized by a well-defined hypervascular mass best visualized on arterial phase images. However, a number of other lesions can mimic the CT appearance of pancreatic neuroendocrine tumors, including pancreatic metastases, acinar cell carcinoma, pancreatoblastoma, solitary fibrous tumor, pancreatic hamartoma, serous adenoma, intrapancreatic splenules, exophytic gastrointestinal stromal tumors, and peripancreatic paragangliomas.

BACKGROUND:Criteria for resectability of colon cancer liver metastases (CLM) are evolving, yet little is known about how physicians choose a therapeutic strategy for potentially resectable CLM. METHODS:Physicians completed a national Web-based survey that consisted of varied CLM conjoint tasks. Respondents chose among three treatment strategies: immediate liver resection (LR), preoperative chemotherapy followed by surgery (C → LR), or palliative chemotherapy (PC). Data were analyzed by multinomial logistic regression, yielding odds ratios (OR). RESULTS:Of 219 respondents, 79 % practiced at academic centers and 63 % were in practice ≥10 years. Median number of cases evaluated was four per month. Surgical training varied: 51 % surgical oncology, 44 % hepato-pancreato-biliary/transplantation, 5 % no fellowship. Although each factor affected the choice of CLM therapy, the relative effect differed. Hilar lymph node disease predicted a strong aversion to LR with surgeons more likely to choose C → LR (OR 8.92) or PC (OR 49.9). Solitary lung metastasis also deterred choice of LR, with respondents favoring C → LR (OR 4.43) or PC (OR 6.97). After controlling for clinical factors, surgeons with more years in practice were more likely to choose PC over C → LR (OR 1.94) (P = 0.005). Surgical oncology-trained surgeons were more likely than hepatobiliary/transplant-trained surgeons to choose C → LR (OR 2.53) or PC (OR 4.15) (P < 0.001). CONCLUSIONS:This is the first nationwide study to define the relative impact of key clinical factors on choice of therapy for CLM. Although clinical factors influence choice of therapy, surgical subspeciality and physician experience are also important determinants of care.