Faculty Bibliography

BACKGROUND:Surgical resection remains the only potentially curative option for patients with pancreatic adenocarcinoma (PAC). Advances in surgical technique and perioperative care have reduced perioperative mortality; however, temporal trends in perioperative morbidity and the use of adjuvant therapy on a population basis remain ill-defined. STUDY DESIGN/METHODS:Using Surveillance, Epidemiology, and End Results-Medicare data, 2,461 patients with resected PAC were identified from 1991 to 2005. We examined trends in preoperative comorbidity indices, adjuvant treatment, type of pancreatic resection, and changes in morbidity and mortality during 4 time intervals (ie, 1991-1996, 1997-2000, 2001-2003, and 2003-2005). RESULTS:The majority of patients underwent pancreaticoduodenectomy (n = 1,945; 79%). There was a temporal increase in mean patient age (p < 0.05) and the number of patients with multiple preoperative comorbidities (Elixhauser comorbidities ≥3: 1991-1996, 10% vs 2003-2005, 26%; p < 0.001). Perioperative morbidity (53%) did not, however, change over time (p = 0.97) and 30-day mortality decreased by half (1991-1996: 6% vs 2003-2005: 3%; p = 0.04). Overall, 51% (n = 1,243) of patients received adjuvant therapy, with the majority receiving chemoradiation (n = 817; 33%). Among patients who received adjuvant therapy, factors associated with receipt of adjuvant chemotherapy alone relative to chemoradiation included older patient age (odds ratio = 1.75; p < 0.001) and ≥3 medical comorbidities (odds ratio = 1.57; p = 0.007). Receipt of adjuvant chemotherapy alone also increased over time (2003-2005 vs 1991-1996, odds ratio = 2.21; p < 0.001). CONCLUSIONS:Perioperative 30-day mortality associated with resection for PAC decreased by one-half from 1991 to 2005. Although patients undergoing resection for PAC were older and had more preoperative comorbidities, the incidence of perioperative complications remained stable. The relative use of adjuvant chemotherapy alone vs chemoradiation therapy for PAC has increased in the United States during the 15 years examined.

Although vascular invasion is a well-established indicator of poor prognosis for patients with infiltrating ductal adenocarcinoma of the pancreas (PDAC), the histopathologic characteristics of vascular invasion are not well described. Hematoxylin and eosin-stained slides from 209 surgically resected infiltrating PDACs were systematically evaluated for the presence or absence of microscopic vascular invasion. For the cases with vascular invasion, we further categorized the histologic pattern of invasion into conventional and pancreatic intraepithelial neoplasia-like (PanIN-like). In addition, several histopathologic factors in the surrounding blood vessels, including lymphocytic infiltration and luminal fibrosis, were carefully assessed. Data were compared with clinicopathologic variables, including patient survival. Microscopic vascular invasion was observed in 136 of the 209 PDACs (65.1%). Vascular invasion mimicking pancreatic intraepithelial neoplasia (PanIN-like invasion) was observed in 94 of the 136 cases (69.1%) with vascular invasion. Microscopic vascular invasion was associated with increased tumor size (P=0.04), higher pT classification (P=0.003), lymph node metastasis (P<0.0001), and perineural invasion (P=0.005). Vascular invasion was inversely correlated with neo-adjuvant therapy (P<0.0001). Examination of adjacent blood vessels revealed that peritumoral blood vessels with intimal lymphocytes (P=0.002), intimal (P=0.007) and medial (P=0.001) fibrosis, and cancer cells in vascular wall (P<0.0001) were all highly associated with the intraluminal vascular invasion. In univariate analysis, patients whose cancers had microscopic vascular invasion (median survival, 15.3 mo) had a significantly worse survival than did patients with carcinomas without vascular invasion (25.1 mo; P=0.01, log-rank test). Microscopic vascular invasion is a poor prognostic indicator and can histologically mimic PanIN.

OBJECTIVE:To examine the clinicopathologic features and clonal relationship of multifocal intraductal papillary mucinous neoplasms (IPMNs) of the pancreas. BACKGROUND:Intraductal papillary mucinous neoplasms are increasingly diagnosed cystic precursor lesions of pancreatic cancer. Intraductal papillary mucinous neoplasms can be multifocal and a potential cause of recurrence after partial pancreatectomy. METHODS:Thirty four patients with histologically documented multifocal IPMNs were collected and their clinicopathologic features catalogued. In addition, thirty multifocal IPMNs arising in 13 patients from 3 hospitals were subjected to laser microdissection followed by KRAS pyrosequencing and loss of heterozygosity (LOH) analysis on chromosomes 6q and 17p. Finally, we sought to assess the clonal relationships among multifocal IPMNs. RESULTS:We identified 34 patients with histologically documented multifocal IPMNs. Synchronous IPMNs were present in 29 patients (85%), whereas 5 (15%) developed clinically significant metachronous IPMNs. Six patients (18%) had a history of familial pancreatic cancer. A majority of multifocal IPMNs (86% synchronous, 100% metachronous) were composed of branch duct lesions, and typically demonstrated a gastric-foveolar subtype epithelium with low or intermediate grades of dysplasia. Three synchronous IPMNs (10%) had an associated invasive cancer. Molecular analysis of multiple IPMNs from 13 patients demonstrated nonoverlapping KRAS gene mutations in 8 patients (62%) and discordant LOH profiles in 7 patients (54%); independent genetic alterations were established in 9 of the 13 patients (69%). CONCLUSIONS:The majority of multifocal IPMNs arise independently and exhibit a gastric-foveolar subtype, with low to intermediate dysplasia. These findings underscore the importance of life-long follow-up after resection for an IPMN.

BACKGROUND:Duodenal adenocarcinoma is a rare cancer usually studied as a group with periampullary or small bowel adenocarcinoma; therefore, its natural history is poorly understood. METHODS:Patients with duodenal adenocarcinoma were identified from a single-institution pancreaticoduodenectomy database. Patients with adenocarcinoma arising from the ampulla of Vater were excluded. Univariate and multivariate analyses were performed to identify clinicopathologic variables associated with survival and recurrence after resection. RESULTS:From 1984 to 2006, a total of 122 patients with duodenal adenocarcinoma underwent pancreaticoduodenectomy. Overall survival after resection was 48% at 5 years and 41% at 10 years. Five-year survival decreased as the number of lymph nodes involved by metastasis increased from 0 to 1-3 to ≥ 4 (68%, 58%, 17%, respectively, P < 0.01) and as the lymph node ratio increased from 0 to >0-0.2 to >0.2-0.4 to >0.4 (68%, 57%, 14%, 14%, respectively, P < 0.01). Lymph node metastasis was the only independent predictor of decreased survival in multivariate analysis. Recurrence after resection was predominantly distant (81%). Adjuvant chemoradiation did not decrease local recurrence or prolong overall survival; however, patients who received chemoradiation more commonly had nodal metastasis (P = 0.03). CONCLUSIONS:The prognostic significance of both the absolute number and ratio of involved lymph nodes emphasizes the need for adequate lymphadenectomy to accurately stage duodenal adenocarcinoma. The mostly distant pattern of recurrence underscores the need for the development of effective systemic therapies.

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.

Poorly differentiated neuroendocrine carcinomas (NECs) of the pancreas are rare malignant neoplasms with a poor prognosis. The aim of this study was to determine the clinicopathologic and genetic features of poorly differentiated NECs and compare them with other types of pancreatic neoplasms. We investigated alterations of KRAS, CDKN2A/p16, TP53, SMAD4/DPC4, DAXX, ATRX, PTEN, Bcl2, and RB1 by immunohistochemistry and/or targeted exomic sequencing in surgically resected specimens of 9 small cell NECs, 10 large cell NECs, and 11 well-differentiated neuroendocrine tumors (PanNETs) of the pancreas. Abnormal immunolabeling patterns of p53 and Rb were frequent (p53, 18 of 19, 95%; Rb, 14 of 19, 74%) in both small cell and large cell NECs, whereas Smad4/Dpc4, DAXX, and ATRX labeling was intact in virtually all of these same carcinomas. Abnormal immunolabeling of p53 and Rb proteins correlated with intragenic mutations in the TP53 and RB1 genes. In contrast, DAXX and ATRX labeling was lost in 45% of PanNETs, whereas p53 and Rb immunolabeling was intact in these same cases. Overexpression of Bcl-2 protein was observed in all 9 small cell NECs (100%) and in 5 of 10 (50%) large cell NECs compared with only 2 of 11 (18%) PanNETs. Bcl-2 overexpression was significantly correlated with higher mitotic rate and Ki67 labeling index in neoplasms in which it was present. Small cell NECs are genetically similar to large cell NECs, and these genetic changes are distinct from those reported in PanNETs. The finding of Bcl-2 overexpression in poorly differentiated NECs, particularly small cell NEC, suggests that Bcl-2 antagonists/inhibitors may be a viable treatment option for these patients.

INTRODUCTION/BACKGROUND:Solid pseudopapillary neoplasms are rare pancreatic neoplasms with low malignant potential and favorable prognosis that are typically seen in young women. PRESENTATION OF CASE/METHODS:We report a case of two large solid pseudopapillary neoplasms in a 23-year old woman who was treated successfully with a total pancreatectomy. CONCLUSION/CONCLUSIONS:To the best of our knowledge, this is the first report of two discrete solid pseudopapillary neoplasms in the same patient.

BACKGROUND:Data on readmission as well as the potential impact of length of stay (LOS) after colectomy for colon cancer remain poorly defined. The objective of the current study was to evaluate risk factors associated with readmission among a nationwide cohort of patients after colorectal surgery. STUDY DESIGN/METHODS:We identified 149,622 unique individuals from the Surveillance, Epidemiology, and End Results-Medicare dataset with a diagnosis of primary colorectal cancer who underwent colectomy between 1986 and 2005. In-hospital morbidity, mortality, LOS, and 30-day readmission were examined using univariate and multivariate logistic regression models. RESULTS:Primary surgical treatment consisted of right (37.4%), transverse (4.9%), left (10.5%), sigmoid (22.8%), abdominoperineal resection (7.3%), low anterior resection (5.6%), total colectomy (1.2%), or other/unspecified (10.3%). Mean patient age was 76.5 years and more patients were female (52.9%). The number of patients with multiple preoperative comorbidities increased over time (Charlson comorbidity score ≥3: 1986 to 1990, 52.5% vs 2001 to 2005, 63.1%; p < 0.001). Mean LOS was 11.7 days and morbidity and mortality were 36.5% and 4.2%, respectively. LOS decreased over time (1986 to 1990, 14.0 days; 1991 to 1995, 12.0 days; 1996 to 2000, 10.4 days; 2001 to 2005, 10.6 days; p < 0.001). In contrast, 30-day readmission rates increased (1986 to 1990, 10.2%; 1991 to 1995, 10.9%; 1996 to 2000, 12.4%; 2001 to 2005, 13.7%; p < 0.001). Factors associated with increased risk of readmission included LOS (odds ratio = 1.02), Charlson comorbidities ≥3 (odds ratio = 1.27), and postoperative complications (odds ratio = 1.17) (all p < 0.01). CONCLUSIONS:Readmission rates after colectomies have increased during the past 2 decades and mean LOS after this operation has declined. More research is needed to understand the balance and possible trade off between these hospital performance measures for all surgical procedures.

PURPOSE/OBJECTIVE:The purpose of this study is to identify factors predictive of early mortality following palliative bypass in patients with previously unsuspected advanced pancreatic adenocarcinoma to provide a basis for the selection of appropriate therapies. METHODS:All patients with pancreatic adenocarcinoma who underwent a bypass procedure at our institution between 9/30/1994 and 1/31/2006 were reviewed. Patients with peri-operative mortality were excluded from the analysis. Univariate analysis was performed on peri-operative data to identify factors associated with early mortality (death within 6 months of surgery). Patients having multiple risk factors were assigned an overall prognostic score based on the sum of these factors. RESULTS:Of the 397 patients with pancreatic adenocarcinoma analyzed, four factors were found to predict early mortality following palliative bypass: Presence of distant metastatic disease (HR 2.59, P < 0.0001), poor tumor differentiation (HR 1.71, P = 0.009), severe pre-operative nausea and vomiting (HR 1.48, P = 0.013), and lack of previous placement of a biliary stent (HR 1.36, P = 0.048). Patients with a prognostic score of 0 were significantly more likely to survive past 6 months than patients with a prognostic score of 1 (HR 2.71, P < 0.0001), 2 (HR 3.70, P < 0.0001), or ≥3 (HR 5.63, P < 0.0001). CONCLUSIONS:In a cohort of patients undergoing a palliative bypass procedure, specific peri-operative factors can be used to identify patients who are at risk of early mortality. These factors may be helpful in selecting appropriate interventions for this group of patients.

BACKGROUND:Identifying pancreatic cancer patients at high risk of early mortality following pancreaticoduodenectomy (PD) is important for treatment decisions in a multidisciplinary setting. This study examines the preoperative predictors of early mortality following PD and combines these variables into an early mortality risk score (EMRS). METHODS:Medical records of patients who underwent PD for pancreatic adenocarcinoma at the Johns Hopkins Hospital between 30 August 1993 and 28 February 2005 were reviewed. Cox proportional hazards analysis was performed to identify predictors of early mortality, defined as death at 9 and 12 months. EMRS was constructed from univariate associated risk factors (age >75 years, tumor size ≥ 3 cm, poor differentiation, co-morbid diseases) with each factor assigned 1 point (range of 0-4). EMRS was evaluated as an independent predictor of death at 9 and 12 months. RESULTS:On univariate analysis, risk factors for death at 9 months included age ≥ 75 years (RR, 1.6; p = .009), comorbid disease (RR, 1.5; p = 0.020), tumor ≥ 3 cm (RR, 1.4; P = 0.050), and poor differentiation (RR, 2.1; P < 0.001). EMRS was associated with early mortality among those who did (p = 0.038) and did not receive adjuvant treatment (p < 0.001). A modified EMRS without tumor differentiation was also associated with early mortality (p < 0.001). Results persisted when reanalyzed using death at 12 months. CONCLUSIONS:EMRS may identify patients at risk of early mortality following PD who may be candidates for alternatively sequenced treatment protocols. Prospective validation of this EMRS is needed.