Faculty Bibliography

OBJECTIVE:To develop and validate a risk score to predict the 30- and 90-day mortality after a pancreaticoduodenectomy or total pancreatectomy on the basis of preoperative risk factors in a high-volume program. DESIGN/METHODS:Data from a prospectively maintained institutional database were collected. In a random subset of 70% of patients (training cohort), multivariate logistic regression was used to develop a simple integer score, which was then validated in the remaining 30% of patients (validation cohort). Discrimination and calibration of the score were evaluated using area under the receiver operating characteristic curve and Hosmer-Lemeshow test, respectively. SETTING/METHODS:Tertiary referral center. PATIENTS/METHODS:The study comprised 1976 patients in a prospectively maintained institutional database who underwent pancreaticoduodenectomy or total pancreatectomy between 1998 and 2009. MAIN OUTCOME MEASURES/METHODS:The 30- and 90-day mortality. RESULTS:In the training cohort, age, male sex, preoperative serum albumin level, tumor size, total pancreatectomy, and a high Charlson index predicted 90-day mortality (area under the curve, 0.78; 95% CI, 0.71-0.85), whereas all these factors except Charlson index also predicted 30-day mortality (0.79; 0.68-0.89). On validation, the predicted and observed risks were not significantly different for 30-day (1.4% vs 1.0%; P = .62) and 90-day (3.8% vs 3.4%; P = .87) mortality. Both scores maintained good discrimination (for 30-day mortality, area under the curve, 0.74; 95% CI, 0.54-0.95; and for 90-day mortality, 0.73; 0.62-0.84). CONCLUSIONS:The risk scores accurately predicted 30- and 90-day mortality after pancreatectomy. They may help identify and counsel high-risk patients, support and calculate net benefits of therapeutic decisions, and control for selection bias in observational studies as propensity scores.

Paragangliomas are rare neuroendocrine neoplasms arising in extra-adrenal chromaffin cells of the autonomic nervous system. In rare instances, paragangliomas present around and involve the pancreas, thereby mimicking one of the more common primary pancreatic lesions. These neoplasms present considerable diagnostic difficulty not only for the clinician and radiologist but also for the pathologist. We have collected a series of 9 peripancreatic paragangliomas clinically simulating a primary pancreatic lesion. The paragangliomas were diagnosed in 4 men and 5 women with an age range of 37 to 78 years (mean, 50 y). Patients presented clinically either with diffuse epigastric and abdominal pain (7 of 9, 78%) or with an incidental mass (2 of 9, 22%) discovered on routine radiographic imaging. All patients were found to have mass lesions suspicious for a primary pancreatic neoplasm on radiographic examination. The lesions were predominantly located in the body of the pancreas (5 of 9, 56%) and ranged in size from 5.5 to 17.0 cm (mean, 10.0 cm). Five of 9 (56%) neoplasms also demonstrated cystic change. Fine-needle aspiration (FNA) was performed on 6 cases; however, the diagnostic accuracy was low, with 3 of 6 (50%) neoplasms misdiagnosed as pancreatic neuroendocrine tumor (PanNET) (n=1), spindle cell neoplasm (n=1), or pseudocyst (n=1). In addition, 2 of 8 (25%) surgically resected tumors were misdiagnosed by the referring pathologist as a PanNET. Immunohistochemistry was performed on all cases, confirming the characteristic 2-cell populations: chief cells (synaptophysin positive and chromogranin A positive) and sustentacular cells (S-100 protein positive). Follow-up information was available for all patients and ranged from 2 months to 11.6 years (mean, 2.7 y). Three of 9 (33%) patients developed metastatic disease, and 2 of these 3 died of their disease at 2.8 and 4.6 years after diagnosis. In summary, in unsuspected cases, interpretation of FNA and surgical pathology resections can be diagnostically challenging. Awareness and proper recognition of this entity, including differential diagnosis, are imperative in establishing the correct diagnosis. Further, close follow-up of these cases should be considered because of the significant risk of metastatic disease.

BACKGROUND:The role of adjuvant chemoradiation therapy for ampullary carcinoma is unknown. Previous literature suggests that certain populations with high risk factors for recurrence may benefit from adjuvant chemoradiation. We combined the experience of two institutions to better delineate which patients may benefit from adjuvant chemoradiation. METHODS:Patients who underwent curative surgery for ampullary carcinoma at the Johns Hopkins Hospital (n=290; 1992-2007) and at the Mayo Clinic (n=130; 1977-2005) were reviewed. Patients with <60 days of follow-up, metastatic disease at surgery, or insufficient pathologic data were excluded. The final combined study consisted of 186 patients (n=104 Johns Hopkins, n=82 Mayo). Most patients received 5-FU based chemoradiation with conformal radiation. Cox proportional hazards models were used for survival analysis. RESULTS:Median overall-survival was 39.9 months with 2- and 5-year survival rates of 62.4% and 39.1%. On univariate analysis, adverse prognostic factors for overall survival included T3/T4 stage disease (RR=1.86, p=0.002), node positive status (RR=3.18, p<0.001), and poor histological grade (RR=1.69, p=0.011). Patients who received adjuvant chemoradiation (n=66) vs. surgery alone (n=120) showed a higher rate of T3/T4 stage disease (57.6% vs. 30.8%, P<0.001), lymph node involvement (72.7% vs. 30.0%, P<0.001), and close or positive margins (4.6% vs. 0.0%, P=0.019). Five year survival rates among node negative and node positive patients were 58.7% and 18.4% respectively. When compared with surgery alone, use of adjuvant chemoradiation improved survival among node positive patients (mOS 32.1 vs. 15.7 mos, 5 yr OS: 27.5% vs. 5.9%; RR=0.47, P=0.004). After adjusting for adverse prognostic factors on multivariate analysis, patients treated with adjuvant chemoradiation demonstrated a significant survival benefit (RR=0.40, P<0.001). Disease relapse occurred in 37.1% of all patients, most commonly metastatic disease in the liver or peritoneum. CONCLUSIONS:Node-positive patients with resected ampullary adenocarcinoma may benefit from 5-FU based adjuvant chemoradiation. Since a significant proportion of patients develop metastatic disease, there is a need for more effective systemic treatment.

Only a minority of patients who undergo surgical resection for pancreatic ductal adenocarcinoma are cured. Since patient outcome is not reliably predicted using pathological factors (tumor stage, differentiation, and resection margin status) alone, markers of tumor behavior are needed. One candidate predictor of pancreatic cancer outcome is E-cadherin status. CDH1 is a tumor suppressor gene encoding an important cell adhesion molecule (E-cadherin). The aim of this study was to determine if, among patients undergoing pancreaticoduodenectomy for pancreatic adenocarcinoma, loss of E-cadherin expression was an independent predictor of poor outcome. We examined patterns of loss of E-cadherin by immunohistochemistry in tissue microarrays of 329 surgically resected pancreatic ductal adenocarcinomas. E-cadherin expression was then correlated with outcome. Kaplan-Meier analysis and Cox proportional hazards regression modeling were used to assess the mortality risk. One hundred forty-one pancreatic adenocarcinomas (43%) had partial or complete loss of E-cadherin expression within the analyzed tissue cores. In most instances (134 cases, 41%), this loss was partial. Patients whose pancreatic adenocarcinomas had either complete loss (n=7; median survival, 5.5 months) or partial loss (n=134; 12.7 months) of E-cadherin expression had significantly worse median survival than those with uniformly intact E-cadherin expression (n=188; 18.5 months) by univariate (P=0.002) and multivariate (P=0.006) analyses. In subgroup analysis, patients with poorly differentiated cancers had a worse prognosis if their cancers had partial loss of E-cadherin expression (P=0.02). Among patients undergoing pancreaticoduodenectomy for pancreatic ductal adenocarcinoma, partial loss of tumoral E-cadherin expression is an independent predictor of poor outcome.

OBJECTIVES/OBJECTIVE:This study was conducted to determine if pulmonary metastasectomy (PM) for isolated pancreatic cancer metastases is safe and effective. METHODS:This was a retrospective case-control study of patients undergoing PM at our institution from 2000 to 2009 for isolated lung metastasis after resection for pancreatic cancer. Clinical and pathologic data were compared with a matched reference group. Resected neoplasms were immunolabeled for the Dpc4 protein. Kaplan-Meier analysis compared overall survival and survival after relapse. RESULTS:Of 31 patients with isolated lung metastasis, 9 underwent 10 pulmonary resections. At initial pancreas resection, all patients were stage I or II. Other baseline characteristics were similar between the two groups. Median time from pancreatectomy to PM was 34 months (interquartile range 21-49). During the study, 29/31(90.6%) patients died. There were no in-hospital mortalities or complications after PM. Median cumulative survival was significantly improved in the PM group (51 vs. 23 months, p = 0.04). There was a trend toward greater 2-year survival after relapse in the PM group (40% vs. 27%, p = 0.2). CONCLUSIONS:In patients with isolated lung metastasis from pancreatic adenocarcinoma, this is the first study to show that pulmonary resection can be performed safely with low morbidity and mortality. The improved survival in the PM group may result in part from selection bias but may also represent a benefit of the procedure.

OBJECTIVES/OBJECTIVE:The majority of pancreatic serous cystic neoplasms (SCNs) are benign. However, these neoplasms can cause symptoms and rarely can be aggressive. Identification of factors associated with symptomatic or aggressive SCNs may aid management decisions. The aim of this study was to identify variables that predict aggressive SCNs. METHODS:Prospective pathology database was queried for SCNs that were surgically resected at Johns Hopkins Hospital. Tumors were considered aggressive if they invaded surrounding structures and/or vessels or if they metastasized to lymph nodes or distant organs. The associations of gender, tumor size, and tumor location, with the presence or absence of symptoms and tumor behavior were examined using Fisher's exact test, logistic regression, and multivariate analyses. RESULTS:A total of 257 patients with SCNs underwent surgical resection. Mean tumor diameter was 4.9 cm. Tumor location in the head of pancreas (HOP) was associated with symptoms (odds ratio (OR) 1.87, 95% confidence interval (CI) 1.1-3.3). Computed tomography (CT) predicted the diagnosis of SCN in approximately a quarter of patients. Thirteen tumors (mean 10.5 cm) were considered aggressive. Multivariate analysis showed that tumor diameter (OR 1.53, 95% CI 1.24-1.89) and location of tumor in pancreatic head (OR 10.44, 95% CI 1.73-63.04) were independently associated with aggressive behavior. CONCLUSIONS:We describe the largest case series of patients with pathologically proven SCNs. CT performed poorly in preoperative diagnosis of SCNs. Large tumor size and head location predicted aggressive behavior. These factors should be considered in the management of patients with SCN.

More than 2% of the adult U.S. population harbors a pancreatic cyst. These often pose a difficult management problem because conventional criteria cannot always distinguish cysts with malignant potential from those that are innocuous. One of the most common cystic neoplasms of the pancreas, and a bona fide precursor to invasive adenocarcinoma, is called intraductal papillary mucinous neoplasm (IPMN). To help reveal the pathogenesis of these lesions, we purified the DNA from IPMN cyst fluids from 19 patients and searched for mutations in 169 genes commonly altered in human cancers. In addition to the expected KRAS mutations, we identified recurrent mutations at codon 201 of GNAS. A larger number (113) of additional IPMNs were then analyzed to determine the prevalence of KRAS and GNAS mutations. In total, we found that GNAS mutations were present in 66% of IPMNs and that either KRAS or GNAS mutations could be identified in 96%. In eight cases, we could investigate invasive adenocarcinomas that developed in association with IPMNs containing GNAS mutations. In seven of these eight cases, the GNAS mutations present in the IPMNs were also found in the invasive lesion. GNAS mutations were not found in other types of cystic neoplasms of the pancreas or in invasive adenocarcinomas not associated with IPMNs. In addition to defining a new pathway for pancreatic neoplasia, these data suggest that GNAS mutations can inform the diagnosis and management of patients with cystic pancreatic lesions.

Distinguishing between solid-pseudopapillary neoplasms (SPNs) and pancreatic neuroendocrine tumors (PanNETs) may pose a diagnostic dilemma. Both can demonstrate solid growth patterns, and both can be immunoreactive with neuroendocrine markers such as synaptophysin and CD56. One well-established feature of SPNs is the presence of hyaline globules, which in contrast has only rarely been reported in PanNETs. Clinicopathologic features of 361 cases originally classified as PanNETs were examined. Of these, 24 tumors (6.6%) had hyaline globules, raising the possibility of SPN. Immunohistochemistry for β-catenin was performed on these 24 neoplasms, and showed nuclear labeling in 6 cases. These 6 cases, which also demonstrated cytoplasmic CD10 staining, were reclassified as SPNs. The remaining 18 cases maintained their original diagnosis as PanNETs, and the hyaline globules in these cases were periodic acid-Schiff (PAS) positive, diastase resistant, and immunoreactive with α-1-antitrypsin. All 24 cases were histologically re-evaluated, and the pattern of invasion, presence of clear cells, and nuclear grooves were found to be helpful in distinguishing SPNs from PanNETs. We conclude that the presence of hyaline globules should raise SPNs in the differential diagnosis of a solid cellular neoplasm of the pancreas. However, this should not be used as the sole criterion in the diagnosis of SPNs, as hyaline globules may also be seen in 5% of PanNETs. Immunohistochemical and histologic features supporting the diagnosis of SPNs over PanNETs include CD10 and nuclear β-catenin labeling, an insidious pattern of invasion, clear cells, and nuclear grooves.

BACKGROUND:As indications for liver resection expand, objective measures to assess the risk of peri-operative morbidity are needed. The impact of sarcopenia on patients undergoing liver resection for colorectal liver metastasis (CRLM) was investigated. METHODS:Sarcopenia was assessed in 259 patients undergoing liver resection for CRLM by measuring total psoas area (TPA) on computed tomography (CT). The impact of sarcopenia was assessed after controlling for clinicopathological factors using multivariate modelling. RESULTS:Median patient age was 58 years and most patients (60%) were male. Forty-one (16%) patients had sarcopenia (TPA ≤ 500 mm(2) /m(2) ). Post-operatively, 60 patients had a complication for an overall morbidity of 23%; 26 patients (10%) had a major complication (Clavien grade ≥3). The presence of sarcopenia was strongly associated with an increased risk of major post-operative complications [odds ratio (OR) 3.33; P= 0.008]. Patients with sarcopenia had longer hospital stays (6.6 vs. 5.4 days; P= 0.03) and a higher chance of an extended intensive care unit (ICU) stay (>2 days; P= 0.004). On multivariate analysis, sarcopenia remained independently associated with an increased risk of post-operative complications (OR 3.12; P= 0.02). Sarcopenia was not significantly associated with recurrence-free [hazard ratio (HR) = 1.07] or overall (HR = 1.05) survival (both P > 0.05). CONCLUSIONS:Sarcopenia impacts short-, but not long-term outcomes after resection of CRLM. While patients with sarcopenia are at an increased risk of post-operative morbidity and longer hospital stay, long-term survival is not impacted by the presence of sarcopenia.

OBJECTIVES/OBJECTIVE:Defining perioperative mortality as death that occurs within 30 days of surgery may underestimate 'true' mortality among patients undergoing hepatic resection. To better define perioperative mortality, trends in the risk for death during the first 90 days after hepatectomy were assessed. METHODS:Surveillance, Epidemiology and End Results (SEER) Medicare data were used to identify 2597 patients who underwent hepatic resection during 1991-2006. Data on their clinicopathological characteristics, surgical management and perioperative mortality were collected and survival was assessed at 30, 60 and 90 days post-surgery. RESULTS:Overall, 5.7% of patients died within the first 30 days. Postoperative mortality at 60 and 90 days were 8.3% and 10.1%. In-hospital mortality after hepatic resection was greater among patients with hepatocellular carcinoma (HCC) than among those with colorectal liver metastases (CRLM) (8.9% and 3.8%, respectively; P < 0.001). In CRLM patients, mortality increased from 4.3% at 30 days to 8.4% at 90 days, whereas mortality in HCC patients increased from 9.7% at 30 days to 15.0% at 90 days (both P < 0.05). Patients with HCC were twice as likely as CRLM patients to die within 30 days [odds ratio (OR) 2.03], 60 days (OR = 1.74) and 90 days (OR = 1.71) (all P < 0.001). Differences in 30- and 90-day mortality were greatest among HCC patients undergoing major hepatic resection (P < 0.05). CONCLUSIONS:Reporting deaths that occur within a maximum of 30 days of surgery underestimates the mortality associated with hepatic resection. Traditional 30-day definitions of mortality are misleading and surgeons should report all perioperative outcomes that occur within 90 days of hepatic resection.