Sarah P. Thayer

Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis

Hedgehog signalling—an essential pathway during embryonic pancreatic development, the misregulation of which has been implicated in several forms of cancer—may also be an important mediator in human pancreatic carcinoma. Here we report that sonic hedgehog, a secreted hedgehog ligand, is abnormally expressed in pancreatic adenocarcinoma and its precursor lesions: pancreatic intraepithelial neoplasia (PanIN). Pancreata of Pdx–Shh mice (in which Shh is misexpressed in the pancreatic endoderm) develop abnormal tubular structures, a phenocopy of human PanIN-1 and -2. Moreover, these PanIN-like lesions also contain mutations in K-ras and overexpress HER-2/neu, which are genetic mutations found early in the progression of human pancreatic cancer. Furthermore, hedgehog signalling remains active in cell lines established from primary and metastatic pancreatic adenocarcinomas. Notably, inhibition of hedgehog signalling by cyclopamine induced apoptosis and blocked proliferation in a subset of the pancreatic cancer cell lines both in vitro and in vivo. These data suggest that this pathway may have an early and critical role in the genesis of this cancer, and that maintenance of hedgehog signalling is important for aberrant proliferation and tumorigenesis.

Main-Duct Intraductal Papillary Mucinous Neoplasms of the Pancreas: Clinical Predictors of Malignancy and Long-term Survival Following Resection

Objective:To describe clinical characteristics and outcomes of a large cohort of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas affecting the main pancreatic duct. Summary Background Data:IPMNs are being diagnosed with increasing frequency. Preoperative determination of malignancy remains problematic, and reported results of long-term survival following resection are conflicting. Methods:The combined databases from the Massachusetts General Hospital and the Pancreatic Unit of the University of Verona were analyzed. To avoid confusing overlap with mucinous cystic neoplasms, only patients with tumors of the main pancreatic duct (with or without side branch involvement) were included. A total of 140 tumors consecutively resected between 1990 and 2002 were classified as either benign (adenoma and borderline tumors) or malignant (carcinoma in situ or invasive cancer) to compare their characteristics and survival. Results:Men and women were equally affected (mean age 65 years). Seven patients (12%) had adenomas, 40 (28%) borderline tumors, 25 (18%) carcinoma in situ, and 58 (42%) invasive carcinoma. The median age of patients with benign IPMN was 6.4 years younger than those with malignant tumors (P = 0.04). The principal symptoms were abdominal pain (65%), weight loss (44%), acute pancreatitis (23%), jaundice (17%), and onset or worsening of diabetes (12%); 27% of patients were asymptomatic. Jaundice and diabetes were significantly associated with malignant tumors. Five- and 10-year cancer-specific survival for patients with noninvasive tumors was 100%, and comparable survival of the 58 patients with invasive carcinoma was 60% and 50%. Conclusions:Cancer is found in 60% of patients with main-duct IPMNs. Patients with malignant tumors are 6 years older than their benign counterparts and have a higher likelihood of presenting with jaundice or new onset diabetes. No patients with benign tumors or carcinoma in situ died of their disease following resection, and those with invasive cancer had a markedly better survival (60% at 5 years) than pancreatic ductal adenocarcinoma. These findings support both the concept of progression of benign IPMNs to invasive cancer and an aggressive policy of resection at diagnosis.

Mucinous cystic neoplasm of the pancreas is not an aggressive entity: lessons from 163 resected patients.

Objective:Mucinous cystic neoplasms (MCNs) of the pancreas have often been confused with intraductal papillary mucinous neoplasms. We evaluated the clinicopathologic characteristics, prevalence of cancer, and prognosis of a large series of well-characterized MCNs in 2 tertiary centers. Methods:Analysis of 163 patients with resected MCNs, defined by the presence of ovarian stroma and lack of communication with the main pancreatic duct. Results:MCNs were seen mostly in women (95%) and in the distal pancreas (97%); 25% were incidentally discovered. Symptomatic patients typically had mild abdominal pain, but 9% presented with acute pancreatitis. One hundred eighteen patients (72%) had adenoma, 17 (10.5%) borderline tumors, 9 (5.5%) in situ carcinoma, and 19 (12%) invasive carcinoma. Patients with invasive carcinoma were significantly older than those with noninvasive neoplasms (55 vs. 44 years, P = 0.01). Findings associated with malignancy were presence of nodules (P = 0.0001) and diameter ≥60 mm (P = 0.0001). All neoplasms with cancer were either ≥40 mm in size or had nodules. There was no operative mortality and postoperative morbidity was 49%. Median follow-up was 57 months (range, 4–233); only patients with invasive carcinoma had recurrence. The 5-year disease-specific survival for noninvasive MCNs was 100%, and for those with invasive cancer, 57%. Conclusions:This series, the largest with MCNs defined by ovarian stroma, shows a prevalence of cancer of only 17.5%. Patients with invasive carcinoma are older, suggesting progression from adenoma to carcinoma. Although resection should be considered for all cases, in low-risk MCNs (≤4 cm/no nodules), nonradical resections are appropriate.

Perioperative CA19-9 Levels Can Predict Stage and Survival in Patients With Resectable Pancreatic Adenocarcinoma

PURPOSE Different prognostic factors stratify patients with pancreatic adenocarcinoma. The purpose of this study was to determine whether preoperative CA19-9 levels can predict stage of disease or survival and whether a change in preoperative to postoperative CA19-9 or the postoperative CA19-9 predicts overall survival. PATIENTS AND METHODS Four hundred twenty-four consecutive patients with pancreatic adenocarcinoma underwent resection between January 1, 1985 and January 1, 2004. Of the patients with a bilirubin less than 2 mg/dL, 176 had preoperative CA19-9 values, and 111 had pre- and postoperative CA19-9 values. Survival was measured from the first postoperative CA19-9 level measured (median, 39 days) until death or last follow-up. A multivariate failure time model was fit using clinical, operative, pathologic, and adjuvant treatment characteristics, and a categorization was defined by the values and changes in CA19-9 before and after surgery. RESULTS Of the 176 patients, 128 (73%) had T3 lesions, and 99 (56%) had N1 disease; 138 patients (78%) underwent pancreaticoduodenectomy. Median preoperative CA19-9 levels were lower in N0 patients compared with patients with positive nodes (nine v 164 U/mL, respectively; nonparametric P = .06) and in T1/T2 patients versus T3 patients (41 v 162 U/mL, respectively; P = .03). Median follow-up time (n = 111) was 1.8 years (range, 1 to 12.9 years), with overall actuarial 1-, 3-, and 5-year survival rates of 70%, 36%, and 30%, respectively. Significant predictors of survival on multivariate analysis included a decrease in CA19-9 (P = .0005), negative lymph nodes (P = .001), lower T stage (P = .0008), and postoperative CA19-9 less than 200 U/mL (P = .0007). CONCLUSION In patients with pancreatic adenocarcinoma, preoperative CA19-9 correlates with stage of disease. Both a postoperative decrease in CA19-9 and a postoperative CA19-9 value of less than 200 U/mL are strong independent predictors of survival, even after adjusting for stage. CA19-9 levels should be included in a patients perioperative care and should be considered for prognostic nomograms.

Debridement and closed packing for sterile or infected necrotizing pancreatitis: insights into indications and outcomes in 167 patients.

Objective:To examine the surgical indications and clinical outcomes of a large cohort of patients with necrotizing pancreatitis. Summary Background Data:Mortality after debridement for necrotizing pancreatitis continues to be inordinately high. The clinical experience with patients who underwent uniform surgical treatment for necrotizing pancreatitis at the Massachusetts General Hospital over a 15-year period is described. Methods:Retrospective review of 167 patients with necrotizing pancreatitis who required intervention and were treated with single stage debridement and a closed packing technique. Particular emphasis was placed on the indication for surgery and the presence of infected necrosis. Multiple logistic regression models were used to identify predictors of mortality. Results:The primary preoperative indication for operation was infected necrosis (51%), but intraoperative cultures proved that 72% of the entire cohort was infected. The rate of reoperation was 12.6%, and 29.9% of patients required percutaneous interventional radiology drainage after initial debridement. Overall operative mortality was 11.4% (19/167), but higher in patients who were operated upon before 28 days (20.3% vs. 5.1%, P = 0.002). Other important predictors of mortality included organ failure ≥3 (OR = 2.4, P = 0.001), postoperative intensive care unit stay ≥6 days (OR = 15.9, P = 0.001), and female gender (OR = 5.41, P = 0.02). Conclusions:Open, transperitoneal debridement followed by closed packing and drainage results in the lowest reported mortality and reoperation rates, and provides a standard for comparing other methods of treatment. A negative FNA does not reliably rule out infection. The clinical status of the patients and not proof of infection should determine the need for debridement.

A Novel Somatic Mouse Model to Survey Tumorigenic Potential Applied to the Hedgehog Pathway

We report a novel mouse model for the generation of sporadic tumors and show the efficiency of this approach by surveying Hedgehog (Hh)-related tumors. Up-regulation of the Hh pathway is achieved by conditionally regulated expression of an activated allele of Smoothened (R26-SmoM2) using either sporadic leakage or global postnatal induction of a ubiquitously expressed inducible Cre transgene (CAGGS-CreER). Following postnatal tamoxifen induction, CAGGS-CreER; R26-SmoM2 mice developed tumors with short latency and high penetrance. All mice exhibited rhabdomyosarcoma and basal cell carcinoma; 40% also developed medulloblastoma. In addition, mice showed a novel pancreatic lesion resembling low-grade mucinous cystic neoplasms in humans. In contrast, widespread activation of SmoM2 in the postnatal prostate epithelium results in no detectable morphologic outcome in 12-month-old mice. Comparison of gene expression profiles among diverse tumors identified several signature genes, including components of platelet-derived growth factor and insulin-like growth factor pathways, which may provide a common mechanistic link to the Hh-related malignancies. This experimental model provides a robust tool for exploring the process of Hh-dependent tumorigenesis and the treatment of such tumors. More generally, this approach provides a genetic platform for identifying tumorigenic potential in putative oncogenes and tumor suppressors and for more effective modeling of sporadic cancers in mice.

Mucin-Producing Neoplasms of the Pancreas: An Analysis of Distinguishing Clinical and Epidemiologic Characteristics

BACKGROUND & AIMS Mucin-producing neoplasms (MPNs) of the pancreas include mucinous cystic neoplasms (MCNs) and main-duct, branch-duct, and combined intraductal papillary mucinous neoplasms (IPMNs). MCNs and branch-duct IPMNs are frequently confused; it is unclear whether main-duct, combined, and branch-duct IPMNs are a different spectrum of the same disease. We evaluated their clinical and epidemiologic characteristics. METHODS Patients who underwent resection for histologically confirmed MPNs were identified (N = 557); specimens were reviewed and eventually reclassified. RESULTS One hundred sixty-eight patients (30%) had MCNs, 159 (28.5%) had branch-duct IPMNs, 149 (27%) had combined IPMNs, and 81 (14.5%) had main-duct IPMNs. Patients with MCNs were significantly younger and almost exclusively women; 44% of patients with main-duct or combined IPMNs and 57% of those with branch-duct IPMNs were women. MCNs were single lesions located in the distal pancreas (95%); 11% were invasive. IPMNs were more frequently found in the proximal pancreas; invasive cancer was found in 11%, 42%, and 48% of branch-duct, combined, and main-duct IPMNs, respectively (P = .001). Patients with invasive MCN and those with combined and main-duct IPMNs were older than those with noninvasive tumors. The 5-year disease-specific survival rate approached 100% for patients with noninvasive MPNs. The rates for those with invasive cancer were 58%, 56%, 51%, and 64% for invasive MCNs, branch-duct IPMNs, main-duct IPMNs, and combined IPMNs, respectively. CONCLUSIONS MPNs comprise 3 different neoplasms: MCNs, branch-duct IPMNs, and main-duct IPMNs, including the combined type. These tumors have specific clinical, epidemiologic, and morphologic features that allow a reasonable degree of accuracy in preoperative diagnosis.

Branch duct intraductal papillary mucinous neoplasms: Does cyst size change the tip of the scale? A critical analysis of the revised international consensus guidelines in a large single-institutional series

Objective:The aim of this study was to critically analyze the safety of the revised guidelines, with focus on cyst size and worrisome features in the management of BD-IPMN. Background:The Sendai guidelines for management of branch duct (BD) intraductal papillary mucinous neoplasm (IPMN) espouse safety of observation of asymptomatic cysts smaller than 3 cm without nodules (Sendai negative). Revised international consensus guidelines published in 2012 suggest a still more conservative approach, even for lesions of 3 cm or larger. By contrast, 2 recent studies have challenged the safety of both guidelines, describing invasive carcinoma or carcinoma in situ in 67% of BD-IPMN smaller than 3 cm and in 25% of “Sendai-negative” BD-IPMN. Methods and Results:Review of a prospective database identified 563 patients with BD-IPMN. A total of 240 patients underwent surgical resection (152 at the time of diagnosis and 88 after being initially followed); the remaining 323 have been managed by observation with median follow-up of 60 months. No patient developed unresectable BD-IPMN carcinoma during follow-up. Invasive cancer arising in BD-IPMN was found in 23 patients of the entire cohort (4%), and an additional 21 patients (3.7%) had or developed concurrent pancreatic ductal adenocarcinoma. According to the revised guidelines, 76% of resected BD-IPMN with carcinoma in situ and 95% of resected BD-IPMN with invasive cancer had high-risk stigmata or worrisome features. The risk of high-grade dysplasia in nonworrisome lesions smaller than 3 cm was 6.5%, but when the threshold was raised to greater than 3 cm, it was 8.8%, and 1 case of invasive carcinoma was found. Conclusions:Expectant management of BD-IPMN following the old guidelines is safe, whereas caution is advised for larger lesions, even in the absence of worrisome features.

Middle pancreatectomy : Indications, short-and long-term operative outcomes

Objective:To evaluate the indications, perioperative, and long-term outcomes of a large cohort of patients who underwent middle pancreatectomy (MP). Summary Background Data:MP is a parenchyma-sparing technique aimed to reduce the risk of postoperative exocrine and endocrine insufficiency. Reported outcomes after MP are conflicting. Methods:Patients who underwent MP between 1990 and 2005 at the Massachusetts General Hospital and at the University of Verona were identified. The outcomes after MP were compared with a control group that underwent extended left pancreatectomy (ELP) for neoplasms in the mid pancreas. Results:A total of 100 patients underwent MP. The most common indications were neuroendocrine neoplasms, serous cystadenoma, and branch-duct IPMNs. Comparison with 45 ELP showed that intraoperative blood loss and transfusions were significantly higher for ELP. The 2 groups showed no differences in overall morbidity, abdominal complications, overall pancreatic fistula, and grade B/C pancreatic fistula rate (17% in MP and 13% in ELP), but the mean hospital-stay was longer for MP patients (P = 0.005). Mortality was zero. In the MP group, 5 patients affected by IPMNs had positive resection margins and 3 had recurrence. After a median follow-up of 54 months, incidence of new endocrine and exocrine insufficiency were significantly higher in the ELP group (4% vs. 38%, P = 0.0001 and 5% vs. 15.6%, P = 0.039, respectively). Conclusions:MP is a safe and effective procedure for treatment of benign and low-grade malignant neoplasms of the mid pancreas and is associated with a low risk of development of exocrine and endocrine insufficiency. MP should be avoided in patients affected by main-duct IPMN.

851 resected cystic tumors of the pancreas: a 33-year experience at the Massachusetts General Hospital.

BACKGROUND The objective of this study was to identify trends in the diagnosis and treatment of cystic neoplasms of the pancreas using a retrospective review of patients from a surgical database at an academic referral center during a 33-year period. METHODS Patient characteristics, including demographics, pathology, and survival, were analyzed over 5 time periods between 1978 and 2011. RESULTS A total of 851 consecutive patients underwent resection for a cystic neoplasm of the pancreas during a 33-year period. Sixty-five percent of patients were female, and mean age was 60 years. The most common pathologic diagnoses were intraductal papillary mucinous neoplasm (38%), mucinous cystic neoplasm (23%), serous cystadenoma (16%), and cystic neuroendocrine neoplasm (7%). There was a stepwise increase in the number of resections across time periods (67 between 1978 and 1989; 376 between 2005 and 2011), with a parallel increase in the proportion of incidentally discovered lesions (22% to 50%). Diagnosis of intraductal papillary mucinous neoplasm was very uncommon in the first 2 time periods (before the first recognition of intraductal papillary mucinous neoplasm as a distinct entity) but predominated in the last 2 (41% and 49%), and cystic neuroendocrine neoplasms, which constituted 3% of the cystic neoplasms in the first time-period, now comprise more than 8% of pancreatic cystic neoplasms. The proportion of malignant neoplasms decreased over time (41% between 1978 and 1989; 12% between 2005 and 2011), reflecting probably the earlier diagnosis and treatment of premalignant neoplasms. Although operative mortality was minimal (4/849, 0.5%), the postoperative complication rate was 38%. Overall 5-year survival for all mucinous lesions was 87%. CONCLUSION Cystic neoplasms of the pancreas are being diagnosed and treated with increasing frequency. At present, most are incidentally discovered intraductal papillary mucinous neoplasms.