Faculty Bibliography

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.

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.

BACKGROUND:Malignant melanoma only rarely metastasizes to the pancreas. As such, there is limited medical literature on the clinical course and outcomes for patients who have undergone surgical management of these tumors. The aim of our study was to review our experience with the surgical resection of melanoma metastatic to the pancreas. METHODS:The records of five patients (four females, one male) with surgically resected melanoma metastatic to the pancreas were retrospectively reviewed. Tumor characteristics, patient presentation, operative details, and follow-up data were evaluated. RESULTS:The primary site of melanoma was known in three cases and unknown in two cases. Four patients were symptomatic at presentation, including abdominal pain (n = 3), jaundice (n = 2), abdominal distension (n = 1), bleeding metastases (n = 1), and fatigue (n = 1). In one patient, the metastasis was an incidental discovery. Surgical resection was accomplished by pylorus-preserving pancreaticoduodenectomy in four patients and distal pancreatectomy in one patient. Single-site resection was done in two patients while the other three underwent synchronous multiple-site resections. Complications developed post-operatively in three patients. Two patients had progression of disease in the form of new metastatic lesions and received subsequent chemotherapy. The median survival was 11.4 months (range, 3-26 months). CONCLUSIONS:Aggressive surgical management of pancreatic metastases provides palliative relief of symptoms and may be considered in appropriately selected candidates.

Pancreatic cancer is caused by inherited and acquired mutations in specific cancer-associated genes. The discovery of the most common genetic alterations in pancreatic cancer has provided insight into the fundamental pathways that drive the progression from a normal cell to noninvasive precursor lesions and finally to widely metastatic disease. In addition, recent genetic discoveries have created new opportunities to develop gene-based approaches for early detection, personalized treatment, and molecular classification of pancreatic neoplasms.

OBJECTIVES: Management of liver metastasis (LM) from a non-colorectal, non-neuroendocrine primary carcinoma remains controversial. Few data exist on the management of hepatic metastasis from primary renal cell carcinoma (RCC). This study sought to determine the safety and efficacy of surgery for RCC LM. METHODS: A total of 43 patients who underwent surgery for RCC hepatic metastasis between 1994 and 2011 were identified in a multi-institution hepatobiliary database. Clinicopathologic, operative and outcome data were collected and analysed. RESULTS: Mean patient age was 62.4 years and most patients (67.4%) were male. The mean tumour size of the primary RCC was 6.9 cm and most tumours (72.1%) were designated as clear cell carcinoma. Nine patients (20.9%) presented with synchronous LM. Among the patients with metachronous disease, the median time from diagnosis of the primary RCC to treatment of LM was 17.2 months (range: 2.1-189.3 months). The mean size of the RCC LM was 4.0 cm and most patients (55.8%) had a solitary metastasis. Most patients (86.0%) underwent a minor resection (up to three segments). Final pathology showed margin status to be negative (R0) in 95.3% of patients. Postoperative morbidity was 23.3% and there was one perioperative death. A total of 69.8% of patients received perioperative chemotherapy. Overall 3-year survival was 62.1%. Three-year recurrence-free survival was 27.3% and the median length of recurrence-free survival was 15.5 months. CONCLUSIONS: Resection of RCC hepatic metastasis is safe and is associated with low morbidity and near-zero mortality. Although recurrence occurs in up to 50% of patients, resection can be associated with long-term survival in a well-selected subset of patients.

Pancreatic neuroendocrine tumors with prominent stromal fibrosis are often clinically, radiographically, and grossly indistinguishable from ductal adenocarcinoma. We recently described a small series of fibrotic pancreatic neuroendocrine tumors that express serotonin. To understand better the relationship between histopathologic patterns and serotonin expression, we reviewed 361 pancreatic neuroendocrine tumors to identify those with prominent stromal fibrosis exceeding 30% of total tumor area. We identified 52 cases and immunolabeled these neoplasms with antibodies to serotonin and Ki-67. Two predominant histologic subtypes were identified: 14 (26.9%) of 52 had a trabecular or trabecular-glandular cellular pattern with interspersed fibrosis, whereas 38 (73.1%) of 52 had solid architecture. Of the 52, 14 (26.9%) pancreatic neuroendocrine tumors showed at least focal serotonin immunoreactivity. Tumors with predominantly trabecular architecture were significantly more likely to express serotonin than those with solid architecture (P < .01). Only 2 of 34 pancreatic neuroendocrine tumors with fibrosis less than 30% of total tumor area expressed serotonin. The 14 serotonin-expressing tumors were less likely to have lymph node metastases (P = .016) and more likely to involve large pancreatic ducts (P < .01) than were the 38 serotonin-negative tumors. The serotonin-expressing tumors were also found in a younger patient population (P < .01). There was no significant association of serotonin immunoreactivity with Ki-67 proliferation index, tumor size, or distant metastases. Our data demonstrate a strong correlation between trabecular architecture and serotonin immunoreactivity in pancreatic neuroendocrine tumors with stromal fibrosis. Serotonin-expressing tumors are also less likely to have lymph node metastases and more likely to involve large pancreatic ducts.

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.

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.

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 AND PURPOSE/OBJECTIVE:This study seeks to: (a) quantify radiologic-pathologic discrepancy for pancreatic adenocarcinoma by comparing tumor size on conventional computed tomography (C-CT) and 3-dimensional CT (3D-CT) to corresponding pathologic specimens; and (b) to identify clinico-pathologic characteristics predictive of radiologic-pathologic discrepancy to assist radiotherapy planning. MATERIALS AND METHODS/METHODS:Sixty-three patients with pancreatic adenocarcinoma and preoperative C-CT and volume-rendered 3D-CT imaging within 6 weeks of resection were identified. Maximum tumor diameter (MTD) was measured on pathology, C-CT, and 3D-CT and compared for each patient as well as among different clinico-pathologic subgroups. RESULTS:There was a trend toward C-CT underestimation of MTD compared to final pathology (p=0.08), but no significant difference between 3D-CT MTD and pathology (p=0.54). Pathologic tumor size was significantly underestimated by C-CT in patients with larger pathologic tumor size (>3.0 cm, p=0.0001), smaller tumor size on C-CT (<3.0 cm, p=0.003), higher CA19-9 (>90 U/mL, p=0.008), and location in the pancreatic head (p=0.015). A model for predicting pathologic MTD using C-CT MTD and CA19-9 level was generated. CONCLUSIONS:3D-CT may allow for more accurate contouring of pancreatic tumors than C-CT. Patients with the above clinico-pathologic characteristics may require expanded margins relative to tumor size estimates on C-CT during radiotherapy planning.