Faculty Bibliography

OBJECTIVE:The criteria for resection of solitary pancreatic side-branch intraductal papillary mucinous neoplasm (IPMN) have been well described by the Sendai consensus statement. However, the management of multiple pancreatic cystic lesions is less certain, with no clear guidelines in the literature to date. The purpose of this study was to evaluate the histopathologic findings in pancreatic IPMNs in patients with multiple (≥ 4) pancreatic cysts. MATERIALS AND METHODS/METHODS:The CT scans of all patients with a pathologically proven IPMN at our institution were reviewed, and a total of 52 patients with four or more pancreatic cysts were found. Each case was reviewed for the number of cysts and the presence of signs of invasive malignancy including a coexistent solid pancreatic mass, pancreatic ductal dilatation, and mural nodularity. RESULTS:A total of 52 patients (19 men, 33 women; mean age, 71.8 years) were found to have multifocal IPMNs, defined as four or more cysts, on CT. Of these 52 patients, nine also had evidence of a solid pancreatic mass on CT. Retrospective review of the pathologic results for the remaining 43 patients (17 men, 26 women; mean age, 71.76 years) showed 18 cases of an IPMN with either high-grade dysplasia or a coexistent invasive carcinoma. Most important, 37% (7/19 patients) had no CT findings of an invasive malignancy according to the Sendai criteria (i.e., cysts ≥ 3 cm in the axial plane, main pancreatic ductal dilatation ≥ 6 mm, or mural nodularity within a cyst) but were found to have an IPMN with either high-grade dysplasia or invasive carcinoma. When the pancreas contained 10 or more cysts, high-grade dysplasia or invasive carcinoma tended to be more likely than low- or intermediate-grade dysplasia (odds ratio, 3.83; 95% CI, 0.87-16.8; p = 0.075). CONCLUSION/CONCLUSIONS:The presence of multiple pancreatic cysts should be looked on with suspicion, particularly when there are a large number of cysts, even when none of the cysts individually meet the imaging criteria for resection according to the Sendai consensus recommendations. At the very least, these patients need to be followed very closely.

OBJECTIVE:The objective of our study was to determine the prevalence and CT appearance of cystlike changes of pancreatic neuroendocrine tumor (NET), particularly of small (≤ 3 cm) tumors. MATERIALS AND METHODS/METHODS:The clinical records, images, and pathologic reports of 74 consecutive patients (average age, 55.5 years) with surgically resected pancreatic NETs who underwent preoperative CT were retrospectively reviewed. The size and location of the pancreatic NETs were recorded. The tumors were classified on the basis of CT appearance as small (≤ 3 cm) or large (> 3 cm) and as solid, partially (≤ 50% or > 50%) cystic, or purely (≈ 100%) cystic. Peripheral contrast enhancement on CT was characterized, and lymph node and liver metastases found by pathologic examination were recorded. RESULTS:A total of 78 pancreatic NETs were reviewed. Five were not visualized on CT, leaving 73 pancreatic NETs in 69 patients (multiple tumors were visualized on CT of three patients) for analysis. The mean size of the 73 tumors was 3.0 ± 2.6 (SD) cm (range, 0.7-13.1 cm); 52 tumors were 3 cm or smaller and 21 tumors were larger than 3 cm. Gross pathologic results confirmed that 13 of the 73 (17.8%) tumors were predominantly (> 50% or ≈ 100%) cystic: 10 of the 52 (19.2%) tumors 3 cm or smaller and three of the 21 (14.3%) tumors larger than 3 cm. Peripheral contrast enhancement was seen in 11 of the 13 (85%) predominantly cystic pancreatic NETs. Compared with solid pancreatic NETs, predominantly cystic pancreatic NETs were less commonly associated with lymph node and liver metastases. CONCLUSION/CONCLUSIONS:Cystic pancreatic NETs are not rare and should be included in the differential diagnosis of a cystic pancreatic mass, particularly if the cystic mass is associated with peripheral contrast enhancement. A minority of cystic pancreatic NETs can present with no peripheral enhancement.

OBJECTIVE:Evaluation of the imaging features of pathology-proven acinar cell carcinomas (ACCs) of the pancreas using computed tomography (CT). METHODS:We reviewed the CT features, clinical presentations, and clinical outcomes of 15 patients (9 men, 6 women, mean age 62.3) with pathology-proven pancreatic ACCs. An abdominal radiologist retrospectively evaluated each patient's initial imaging study with respect to the lesion's size, location, attenuation (Hounsfield units) on arterial and venous phase images, peripancreatic lymphadenopathy, and distant metastases. Additional parameters studied included biliary and pancreatic ductal dilatation, intratumoral hemorrhage, calcification, the presence of cystic/necrotic components, and whether the tumor was intraparenchymal or exophytic. RESULTS:The ACCs in this series were evenly distributed between the head/uncinate and the tail, were predominantly exophytic (73%), tended to be large (average size 5.1 cm), and were mostly hypodense to the surrounding pancreas on both the arterial and venous phase images. A sizeable proportion demonstrated a cystic or necrotic component (53%) and/or an enhancing capsule (53%). Of those lesions in the head or uncinate process, very few resulted in pancreatic (28%) or biliary (14%) ductal dilatation. None of the lesions in this series showed internal calcification or intratumoral hemorrhage. CONCLUSION/CONCLUSIONS:While a prospective diagnosis is difficult, ACCs have several features which can differentiate them from ductal adenocarcinoma, including their large size, lack of biliary or pancreatic ductal dilatation, exophytic nature, and the presence of an enhancing capsule.

BACKGROUND:The median age of pancreatic ductal adenocarcinoma (PDAC) patients is 71 years. PDAC rarely affects individuals under the age of 45. We investigated features of PDAC occurring in young patients (≤45 years) who underwent surgical resection in order to determine if any difference exists in comparison to elderly patients (≥70 years). METHODS:A retrospective analysis of patients with PDAC who were ≤ 45 years on the date of surgery between 1975 and 2009 was performed. This cohort was compared with PDAC patients whose ages were over 70 years on the date of surgery over the same time interval. Information reviewed included demographics, Charlson Age-Comorbidity Index (CACI), pathological staging, surgical management, and death or last follow-up. RESULTS:Seventy five patients with PDAC of age ≤ 45 years at surgery were identified. The reference group consisted of 870 patients with a median age of 75. The most common symptoms of young patients were jaundice (45 %), abdominal pain (32 %), or weight loss (33 %). This did not differ significantly from older patients. Among the younger patients, 7 (9 %) underwent total pancreatectomy, 60 (80 %) underwent pancreaticoduodenectomy, and 8 (11 %) had distal pancreatectomy. The distribution of type of surgery was similar between two groups. Fifty-two of the young patients (69 %) had an R0 resection and this did not differ from the older age group (n = 616; 71 %). The rate of lymph node positivity was 68 % for younger patients and 74 % for older patients (p = 0.27). Of the younger patients, 11, 13, 49, and 2 were classified as stage I, IIA, IIB, and III, respectively, and did not differ from the older age group. The median overall survival for the young patients cohort was 19 months (95 % CI 15-22 months) which is longer than 16 months (95 % CI 14-17 months) of the older group (p = 0.007). The actual 5- and 10- year survival in young age group (24 and 17 %) was longer than that in old age group (11 and 3 %) (p < 0.05). The median CACI of the younger patients was 0.5 and was lower than 4.1 of the older patients (p < 0.0001). CONCLUSIONS:The demographic, pathologic, and treatment characteristics of PDAC patients younger than 45 years were similar to those older than 70 years. Younger patients had fewer complications after curative resections. The better survival among younger patients is likely related to fewer comorbidities in this group. These findings will be useful in counseling young patients with resectable pancreatic cancer.

CONTEXT/BACKGROUND: Of the 200 million adults worldwide who undergo noncardiac surgery each year, more than 1 million will die within 30 days. OBJECTIVE:To determine the relationship between the peak fourth-generation troponin T (TnT) measurement in the first 3 days after noncardiac surgery and 30-day mortality. DESIGN, SETTING, AND PARTICIPANTS/METHODS: A prospective, international cohort study that enrolled patients from August 6, 2007, to January 11, 2011. Eligible patients were aged 45 years and older and required at least an overnight hospital admission after having noncardiac surgery. MAIN OUTCOME MEASURES/METHODS: Patients' TnT levels were measured 6 to 12 hours after surgery and on days 1, 2, and 3 after surgery. We undertook Cox regression analysis in which the dependent variable was mortality until 30 days after surgery, and the independent variables included 24 preoperative variables. We repeated this analysis, adding the peak TnT measurement during the first 3 postoperative days as an independent variable and used a minimum P value approach to determine if there were TnT thresholds that independently altered patients' risk of death. RESULTS: A total of 15 133 patients were included in this study. The 30-day mortality rate was 1.9% (95% CI, 1.7%-2.1%). Multivariable analysis demonstrated that peak TnT values of at least 0.02 ng/mL, occurring in 11.6% of patients, were associated with higher 30-day mortality compared with the reference group (peak TnT≤0.01 ng/mL): peak TnT of 0.02 ng/mL (adjusted hazard ratio [aHR], 2.41; 95% CI, 1.33-3.77); 0.03 to 0.29 ng/mL (aHR, 5.00; 95% CI, 3.72-6.76); and 0.30 ng/mL or greater (aHR, 10.48; 95% CI, 6.25-16.62). Patients with a peak TnT value of 0.01 ng/mL or less, 0.02, 0.03-0.29, and 0.30 or greater had 30-day mortality rates of 1.0%, 4.0%, 9.3%, and 16.9%, respectively. Peak TnT measurement added incremental prognostic value to discriminate those likely to die within 30 days for the model with peak TnT measurement vs without (C index = 0.85 vs 0.81; difference, 0.4; 95% CI, 0.2-0.5; P < .001 for difference between C index values). The net reclassification improvement with TnT was 25.0% (P < .001). CONCLUSIONS:Among patients undergoing noncardiac surgery, the peak postoperative TnT measurement during the first 3 days after surgery was significantly associated with 30-day mortality.

PURPOSE/OBJECTIVE:Genetic alterations of KRAS, CDKN2A, TP53, and SMAD4 are the most frequent events in pancreatic cancer. We determined the extent to which these 4 alterations are coexistent in the same carcinoma, and their impact on patient outcome. EXPERIMENTAL DESIGN/METHODS:Pancreatic cancer patients who underwent an autopsy were studied (n = 79). Matched primary and metastasis tissues were evaluated for intragenic mutations in KRAS, CDKN2A, and TP53 and immunolabeled for CDKN2A, TP53, and SMAD4 protein products. The number of altered driver genes in each carcinoma was correlated to clinicopathologic features. Kaplan-Meier estimates were used to determine median disease free and overall survival, and a Cox proportional hazards model used to compare risk factors. RESULTS:The number of genetically altered driver genes in a carcinoma was variable, with only 29 patients (37%) having an alteration in all 4 genes analyzed. The number of altered driver genes was significantly correlated with disease free survival (P = 0.008), overall survival (P = 0.041), and metastatic burden at autopsy (P = 0.002). On multivariate analysis, the number of driver gene alterations in a pancreatic carcinoma remained independently associated with overall survival (P = 0.046). Carcinomas with only 1 to 2 driver alterations were enriched for those patients with the longest survival (median 23 months, range 1 to 53). CONCLUSIONS:Determinations of the status of the 4 major driver genes in pancreatic cancer, and specifically the extent to which they are coexistent in an individual patients cancer, provides distinct information regarding disease progression and survival that is independent of clinical stage and treatment status.

Pancreatic cancer is a highly lethal malignancy with few effective therapies. We performed exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical cohort (n = 142) of early (stage I and II) sporadic pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative tumours identified substantial heterogeneity with 2,016 non-silent mutations and 1,628 copy-number variations. We define 16 significantly mutated genes, reaffirming known mutations (KRAS, TP53, CDKN2A, SMAD4, MLL3, TGFBR2, ARID1A and SF3B1), and uncover novel mutated genes including additional genes involved in chromatin modification (EPC1 and ARID2), DNA damage repair (ATM) and other mechanisms (ZIM2, MAP2K4, NALCN, SLC16A4 and MAGEA6). Integrative analysis with in vitro functional data and animal models provided supportive evidence for potential roles for these genetic aberrations in carcinogenesis. Pathway-based analysis of recurrently mutated genes recapitulated clustering in core signalling pathways in pancreatic ductal adenocarcinoma, and identified new mutated genes in each pathway. We also identified frequent and diverse somatic aberrations in genes described traditionally as embryonic regulators of axon guidance, particularly SLIT/ROBO signalling, which was also evident in murine Sleeping Beauty transposon-mediated somatic mutagenesis models of pancreatic cancer, providing further supportive evidence for the potential involvement of axon guidance genes in pancreatic carcinogenesis.