Faculty Bibliography

PURPOSE/OBJECTIVE:To determine if serotonin production by pancreatic endocrine neoplasms is associated with the pancreatic duct stenosis seen in patients with stenosis that is out of proportion to the size of the tumors seen on computed tomographic images. MATERIALS AND METHODS/METHODS:Institutional approval was obtained for this HIPAA-compliant study. Informed consent was waived. Clinical and radiologic findings in six patients were reviewed. Gross and histologic findings in the resected pancreata were also assessed. Formalin-fixed paraffin-embedded tumor sections were immunolabeled with antibodies to serotonin. Tissue microarrays constructed from 47 pancreatic endocrine neoplasms from the institutional tissue bank served as controls. Histologic and serotonin immunoreactivity findings were compared between the two groups. The Fisher exact test was used to compare serotonin immunoreactivity. RESULTS:Only one of the six study patients had a large dominant tumor (4 cm in the pancreatic head). All others were 2.5 cm or smaller. Four of the six pancreatic endocrine neoplasms with associated pancreatic duct stricture had prominent stromal fibrosis. Serotonin immunoreactivity was present in five (83%) patients, and this labeling was strong and diffuse in the four patients with prominent fibrosis. By contrast, stromal fibrosis was minimal in the nonimmunoreactive case. Only three (6%) of the 47 control pancreatic endocrine neoplasms were immunoreactive for serotonin (P < .01, Fisher exact test). CONCLUSION/CONCLUSIONS:These data suggest that serotonin produced by pancreatic endocrine neoplasms may be associated with local fibrosis and stenosis of the pancreatic duct. Clinicians should be aware that small pancreatic endocrine neoplasms can produce pancreatic duct stenosis resulting in ductal dilatation and/or upstream pancreatic atrophy out of proportion to the size of the tumor.

INTRODUCTION/BACKGROUND:National Comprehensive Cancer Network (NCCN) guidelines recommend hepatic resection and lymphadenectomy (LND) for gallbladder adenocarcinoma (GBA). We sought to evaluate compliance with these recommendations and to assess trends in the management and survival of patients with GBA. METHODS:Using Surveillance, Epidemiology and End Results (SEER)-Medicare-linked data, we identified 2,955 patients with GBA who underwent cancer-directed surgery from 1991 to 2005. We assessed clinicopathologic data, trends in surgical management, and survival. RESULTS:From 1991 to 2005, preoperative evaluation included CT (62%), MRI (6%), and PET (2%). Only 383 (13%) patients underwent radical resection/hepatectomy with a temporal increase over the study period (1991-1995, 12%; 1996-1999, 10%; 2000-2002, 12.0%; 2003-2005, 16%; P < 0.001). For patients undergoing radical resection/hepatectomy, LND ≥ 3 nodes was performed in 96 (3%) patients. Among patients who had LND, 47% had nodal metastasis. The overall 1-, 3-, and 5-year survival was 56%, 30%, and 21%. On multivariate analysis, radical resection/hepatectomy (hazard ratio (HR) = 0.71) and LND ≥ 3 nodes (HR = 0.56) were independently associated with increased survival. There was no significant improvement in survival over time (P = 0.60). CONCLUSIONS:Compliance with NCCN guidelines for GBA remains poor. Survival of patients with surgically managed GBA has not improved over time.

INTRODUCTION/BACKGROUND:The management of patients with peri-ampullary liver metastasis remains controversial. We sought to assess the safety and efficacy of curative intent surgery for peri-ampullary liver metastasis. METHODS:Between 1993 and 2009, 40 patients underwent curative intent surgery (resection and/or radiofrequency ablation (RFA)) for peri-ampullary liver metastasis. Clinicopathologic and outcome data were collected and analyzed. RESULTS:Location of the primary tumor was pancreas head (n = 20), ampulla of Vater (n = 10), distal bile duct (n = 5), or duodenum (n = 5). Most patients (n = 27) presented with synchronous disease, while 13 patients presented with metachronous disease following a median disease-free interval of 22 months. Most patients (n = 25) presented with hepatic metastasis from pancreaticobiliary origin (pancreatic or distal common bile duct) compared with 15 patients who had metastasis from an intestinal-type primary (ampullary or duodenal). There were no differences in metastatic tumor number or size between these groups (P > 0.05). Post-operative morbidity and mortality was 30% and 5% respectively. Overall 1- and 3-year survival was 55% and 18%. Patients who underwent resection of liver metastasis from intestinal-type tumors experienced a longer survival compared with patients who had pancreaticobiliary lesions (median: 13 months vs. 23 months; P = 0.05). CONCLUSION/CONCLUSIONS:Curative intent surgery for peri-ampullary liver metastasis was associated with post-operative morbidity and a 5% mortality rate. Although the overall survival benefit was modest, patients with liver metastasis from intestinal-type tumors experienced improved survival following resection of liver metastasis compared with pancreaticobiliary lesions.

BACKGROUND:To examine the effect of body mass index (BMI) on clinicopathologic factors and long-term survival in patients undergoing pancreaticoduodenectomy for pancreatic adenocarcinoma. METHODS:Data on BMI, weight loss, operative details, surgical pathology, and long-term survival were collected on 795 patients who underwent pancreaticoduodenectomy. Patients were categorized as obese (BMI > 30 kg/m(2)), overweight (BMI 25 to <30 kg/m(2)), or normal weight (BMI < 25 kg/m(2)) and compared using univariate and multivariate analyses. RESULTS:At the time of surgery, 14% of patients were obese, 33% overweight, and 53% normal weight. Overall, 32% of patients had preoperative weight loss of >10%. There were no differences in operative times among the groups; however, higher BMI was associated with increased risk of blood loss (P < 0.001) and pancreatic fistula (P = 0.01). On pathologic analysis, BMI was not associated with tumor stage or number of lymph nodes harvested (both P > 0.05). Higher BMI patients had a lower incidence of a positive retroperitoneal/uncinate margin versus normal weight patients (P = 0.03). Perioperative morbidity and mortality were similar among the groups. Obese and overweight patients had better 5-year survival (22% and 22%, respectively) versus normal weight patients (15%; P = 0.02). After adjusting for other prognostic factors, as well as preoperative weight loss, higher BMI remained independently associated with improved cancer-specific survival (overweight: hazard ratio, 0.68; obese: hazard ratio, 0.72; both P < 0.05). CONCLUSION/CONCLUSIONS:Obese patients had similar tumor-specific characteristics, as well as perioperative outcomes, compared with normal weight patients. However, obese patients undergoing pancreaticoduodenectomy for pancreatic cancer had an improved long-term survival independent of known clinicopathologic factors.

OBJECTIVES/OBJECTIVE:To analyze the perioperative and long-term outcomes of patients undergoing liver-directed therapy after pancreaticoduodenectomy in a large dual-center cohort of patients. BACKGROUND:Although aggressive liver-directed therapy may be beneficial, liver-directed therapy may be associated with a high risk of complications after pancreaticoduodenectomy. METHODS:Of 5025 patients who underwent pancreaticoduodenectomy at the Johns Hopkins Hospital and the Mayo Clinic between 1970 and 2008, 126 (2.5%), patients were identified who were also treated with either simultaneous or staged liver-directed therapy. Data on demographics, primary tumor, and hepatic metastasis characteristics, as well as details of the liver-directed therapy were collected and analyzed. RESULTS:Primary tumor histology included neuroendocrine carcinoma (34.9%), pancreatic ductal adenocarcinoma (33.4%), distal cholangiocarcinoma (8.7%), ampullary carcinoma (7.1%), duodenal carcinoma (4.0%), or other (11.9%). Liver-directed therapies included hepatic resection alone (45.2%), hepatic resection plus ablation (11.1%), ablation alone (7.9%), transarterial chemoembolization (9.5%), and whole-liver irradiation (22.2%). The overall morbidity following liver-directed therapy was 34.1% and overall mortality was 2.4%. Patients undergoing staged liver-directed therapy (14.5%) versus simultaneous pancreaticoduodenectomy plus liver-directed therapy (7.0%) were more likely to develop a liver abscess (P < 0.05). Of those patients who developed complications, the majority (55.8%) were major (Clavien grade >or=3). CONCLUSIONS:Pancreaticoduodenectomy plus liver-directed therapy is associated with considerable morbidity. The incidence of hepatic abscess is increased in patients undergoing staged pancreaticoduodenectomy followed by liver-directed therapy.

BACKGROUND:Survival for pancreatic ductal adenocarcinoma is low, the role of adjuvant therapy remains controversial, and recent data suggest adjuvant chemoradiation (CRT) may decrease survival compared with surgery alone. Our goal was to examine efficacy of adjuvant CRT in resected pancreatic adenocarcinoma compared with surgery alone. MATERIALS AND METHODS/METHODS:Patients with pancreatic adenocarcinoma at Johns Hopkins Hospital (n = 794, 1993-2005) and Mayo Clinic (n = 478, 1985-2005) following resection who were observed (n = 509) or received adjuvant 5-FU based CRT (median dose 50.4 Gy; n = 583) were included. Cox survival and propensity score analyses assessed associations with overall survival. Matched-pair analysis by treatment group (1:1) based on institution, age, sex, tumor size/stage, differentiation, margin, and node positivity with N = 496 (n = 248 per treatment arm) was performed. RESULTS:Median survival was 18.8 months. Overall survival (OS) was longer among recipients of CRT versus surgery alone (median survival 21.1 vs. 15.5 months, P < .001; 2- and 5-year OS 44.7 vs. 34.6%; 22.3 vs. 16.1%, P < .001). Compared with surgery alone, adjuvant CRT improved survival in propensity score analysis for all patients by 33% (P < .001), with improved survival when stratified by age, margin, node, and T-stage (RR = 0.57-0.75, P < .05). Matched-pair analysis demonstrated OS was longer with CRT (21.9 vs. 14.3 months median survival; 2- and 5-year OS 45.5 vs. 31.4%; 25.4 vs. 12.2%, P < .001). CONCLUSIONS:Adjuvant CRT is associated with improved survival after pancreaticoduodenectomy. Adjuvant CRT was not associated with decreased survival in any risk group, even in propensity score and matched-pair analyses. Further studies evaluating adjuvant chemotherapy compared with adjuvant chemoradiation are needed to determine the most effective combination of systemic and local-regional therapy to achieve optimal survival results.

Sclerosing mesenteritis (SM), also known as mesenteric lipodystrophy, rarely involves the parenchyma of the pancreas. When SM does involve the pancreas, it can mimic pancreatic carcinoma both clinically and radiographically with pain, obstructive jaundice, a mass lesion, and even the appearance of vascular invasion. We report 6 patients with SM involving the pancreas (mean age 43.2 y, 5 female), and review their clinical presentation, radiographic findings, pathology, and outcome. Five of these 6 patients were originally thought to have a primary pancreatic neoplasm. Initial presenting clinical information was available for each patient: all 6 reported abdominal or epigastric pain, 3 reported weight loss, and 2 reported one or more of the following: back pain, fever, abdominal bloating/distention, nausea with/without vomiting, and anorexia. The lesions formed masses with an infiltrative pattern and all had 3 key histologic features: fibrosis, chronic inflammation, and fat necrosis-without a known etiology. The inflammatory infiltrate was composed of a mixture of lymphocytes, plasma cells, and scattered eosinophils. Of the 5 patients with post-treatment clinical information available, 4 had at least a partial response to treatment with steroids, tamoxifen, azathioprine, resection, or a combination of these, and 1 did not respond. A dramatic response to immunosuppressive therapy is illustrated by the case of a 46-year-old woman who presented with the presumptive diagnosis of an unresectable pancreatic cancer. Distinguishing SM from pancreatic carcinoma is crucial to appropriate management, as patients with SM may benefit from immunosuppressive therapy.

PURPOSE/OBJECTIVE:Intraductal papillary mucinous neoplasms are mucin-producing cystic neoplasms of the pancreas. One-third are associated with invasive carcinoma. We examined the benefit of adjuvant chemoradiotherapy (CRT) for this cohort. METHODS AND MATERIALS/METHODS:Patients who had undergone pancreatic resection at Johns Hopkins Hospital between 1999 and 2004 were reviewed. Of these patients, 83 with a resected pancreatic mass were found to have an intraductal papillary mucinous neoplasm with invasive carcinoma, 70 of whom met inclusion criteria for the present analysis. RESULTS:The median age at surgery was 68 years. The median tumor size was 3.3 cm, and invasive carcinoma was present at the margin in 16% of the patients. Of the 70 patients, 50% had metastases to the lymph nodes and 64% had Stage II disease. The median survival was 28.0 months, and 2- and 5-year survival rate was 57% and 45%, respectively. Of the 70 patients, 40 had undergone adjuvant CRT. Those receiving CRT were more likely to have lymph node metastases, perineural invasion, and Stage II-III disease. The 2-year survival rate after surgery with vs. without CRT was 55.8% vs. 59.3%, respectively (p = NS). Patients with lymph node metastases or positive surgical margins benefited significantly from CRT (p = .047 and p = .042, respectively). On multivariate analysis, adjuvant CRT was associated with improved survival, with a relative risk of 0.43 (95% confidence interval, 0.19-0.95; p = .044) after adjusting for major confounders. CONCLUSION/CONCLUSIONS:Adjuvant CRT conferred a 57% decrease in the relative risk of mortality after pancreaticoduodenectomy for intraductal papillary mucinous neoplasms with an associated invasive component after adjusting for major confounders. Patients with lymph node metastases or positive margins appeared to particularly benefit from CRT after definitive surgery.

OBJECTIVE:To identify pathologic features that may account for the favorable survival after resection of invasive pancreatic adenocarcinoma arising in the setting of intraductal papillary mucinous neoplasm (IPMN) compared with standard pancreatic ductal adenocarcinoma (PDA) in the absence of IPMN. SUMMARY BACKGROUND DATA/BACKGROUND:The 5-year survival after resection of IPMN-associated invasive adenocarcinoma is reported to be between 40% and 60%, which is superior to the 10-25%, typically cited after resection of standard PDA. It remains unclear whether this represents distinct biology or simply a tendency for earlier presentation of IPMN-associated invasive adenocarcinoma. METHODS:A single institution's prospective pancreatic resection database was retrospectively reviewed to identify patients with invasive pancreatic adenocarcinoma who underwent pancreatectomy with curative intent. Log rank and Cox regression analysis were used to identify factors associated with survival. RESULTS:From 1995 to 2006, 1260 consecutive patients were identified, 132 (10%) with IPMN-associated invasive adenocarcinoma and 1128 (90%) with standard PDA. Actuarial 5-year survival was 42% after resection for IPMN-associated versus 19% for standard PDA (P < 0.001). However, compared with standard PDA, invasive adenocarcinoma arising within an IPMN was associated with a lower incidence of (1) advanced T stage (T2-T4, 96% vs. 73%, P < 0.001); (2) regional lymph node metastasis (78% vs. 51%, P < 0.001); (3) poor tumor differentiation (44% vs. 26%, P < 0.001); (4) vascular invasion (54% vs. 33%, P < 0.001); (5) perineural invasion (92% vs. 63%, P < 0.001); and (6) microscopic margin involvement (28% vs. 14%, P < 0.001). Specifically, in the presence of any one of the aforementioned adverse pathologic characteristics, outcomes after resection for IPMN-associated and standard PDA were not significantly different. CONCLUSION/CONCLUSIONS:The favorable biologic behavior of IPMN-associated compared with standard PDA is based on its lower rate of advanced T stage, lymph node metastasis, high tumor grade, positive resection margin, perineural, and vascular invasion. In the presence of any one of the aforementioned adverse pathologic characteristics, however, survival outcomes after resection of IPMN-associated and after resection of standard pancreatic adenocarcinoma are similar.

BACKGROUND:Whether ampullary neoplasms are best surgically managed by pancreaticoduodenectomy versus local ampullectomy is controversial. We sought to examine the outcome of patients undergoing pancreaticoduodenectomy versus ampullectomy, as well as to identify factors predictive of lymph node metastasis in patients with ampullary neoplasms. METHODS:Between 1970 and 2007, 450 patients who underwent surgical resection of ampullary adenoma or adenocarcinoma were identified from a prospective, single-institution database. Data on clinicopathologic factors, morbidity, mortality, and survival were analyzed. RESULTS:The initial surgical procedure was pancreaticoduodenectomy in 96.7% patients and ampullectomy in 3.3%. Final diagnosis was invasive adenocarcinoma (77.1%) or adenoma (22.9%). Median tumor size was similar for adenomas associated with an adenocarcinoma (2.5 cm) versus adenomas without invasive cancer (2.9 cm; P=0.71). Morbidity was comparable with pancreaticoduodenectomy (52.2%) versus ampullectomy (33.3%; P=0.15), as was 30-day mortality (pancreaticoduodenectomy, 2.1% versus ampullectomy, 0%; P=0.6). Metastatic disease to regional lymph nodes was present in 54.5% patients with adenocarcinoma. Factors associated with presence of lymph node metastasis included tumor size > or = 1 cm (OR 2.1), poor histologicgrade (OR 4.8), perineural invasion (OR 3.0), microscopic vessel invasion (OR 6.6), and depth of invasion > pT1 (OR 4.3; all P<0.05). Specifically, risk of lymph node metastasis increased with T stage (T1, 28.0%; T2, 50.9%; T3, 71.7%; T4, 77.3%; P<0.001). CONCLUSION/CONCLUSIONS:When surgery is indicated, radical resection is required for early invasive adenocarcinoma of the ampulla of Vater, as lymph node metastases are present in nearly 30% of patients with T1 disease. Pancreaticoduodenectomy should be the preferred approach for most ampullary neoplasms that require surgical resection.