Stefano Partelli

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.

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.

Tumor size correlates with malignancy in nonfunctioning pancreatic endocrine tumor

BACKGROUND Tumor size is a criterion of staging in nonfunctioning pancreatic endocrine tumors as well as a predictor of outcome after curative resection. This study analyzes the correlation between tumor size and malignancy in patients with nonfunctioning pancreatic endocrine tumors. METHODS All patients with nonfunctioning pancreatic endocrine tumors who underwent curative resection (R0) at our institution between 1990 and 2008 were considered. Their clinicopathologic characteristics were compared among 3 different groups according to tumor size. Univariate and multivariable analyses were performed. RESULTS Over the study period, 177 patients were identified. Overall, 90 patients (51%) had a tumor size ≤2 cm (group 1), 46 (26%) had tumor size between >2 cm and ≤4 cm (group 2), and 41 (23%) had tumor size >4 cm (group 3). Tumors ≤2 cm were more frequently incidentally discovered (group 1, 57% vs group 2, 51% vs group 3, 32%; P = .014) and benign (group 1, 81% vs group 2, 65% vs group 3, 5%; P < .0001). The presence of a nonfunctioning pancreatic endocrine tumor >2 cm and a nonincidental diagnosis of the tumor were independent predictors of malignancy at multivariable analysis. None of the 51 patients (29%) with a pancreatic endocrine tumor ≤2 cm that was incidentally diagnosed died of disease. CONCLUSION A strict correlation between tumor size and malignancy in nonfunctioning pancreatic endocrine tumors was demonstrated. A nonoperative management could be advocated for tumors ≤2 cm when discovered incidentally.

Observational Study of Natural History of Small Sporadic Nonfunctioning Pancreatic Neuroendocrine Tumors

CONTEXT Asymptomatic sporadic nonfunctioning, well-differentiated pancreatic neuroendocrine tumors (NF-PNETs) are increasingly diagnosed, and their management is controversial because of their overall good but heterogeneous prognosis. OBJECTIVE The objective of the study was to assess the natural history of asymptomatic sporadic NF-PNETs smaller than 2 cm in size and the risk-benefit balance of nonoperative management. EXPERIMENTAL DESIGN From January 2000 to June 2011, 46 patients with proven asymptomatic sporadic NF-PNETs smaller than 2 cm in size were followed up for at least 18 months with serial imaging in tertiary referral centers. RESULTS Patients were mainly female (65%), with a median age of 60 years. Tumors were mainly located in the pancreatic head (52%), with a median lesion size of 13 mm (range 9-15). After a median follow-up of 34 months (range 24-52) and an average of four (range 3-6) serial imaging sessions, distant or nodal metastases appeared on the imaging in none of the patients. In six patients (13%), a 20% or greater increase in size was observed. Overall median tumor growth was 0.12 mm per year, and neither patients nor tumor characteristics were found to be significant predictors of tumor growth. Overall, eight patients (17%) underwent surgery after a median time from initial evaluation of 41 months (range 27-58); all resected lesions were European Neuroendocrine Tumor Society T stage 1 (n = 7) or 2 (n = 1), grade 1, node negative, with neither vascular nor peripancreatic fat invasion. CONCLUSIONS In selected patients, nonoperative management of asymptomatic sporadic NF-PNETs smaller than 2 cm in size is safe. Larger and prospective multicentric studies with long-term follow-up are now needed to validate this wait-and-see policy.

Malignant pancreatic neuroendocrine tumour: Lymph node ratio and Ki67 are predictors of recurrence after curative resections

INTRODUCTION Malignant pancreatic neuroendocrine tumours (PNENs) are generally associated with a good prognosis after radical resection. In other pancreatic malignancies predictors of recurrence and the role of lymph node ratio (LNR) are well known, but both have been scarcely investigated for malignant PNETs. METHODS The prospective database from the surgical Department of Verona University was queried. Clinical and pathological data of all patients with resected malignant PNET between 1990 and 2008 were reviewed. Univariate and multivariate analysis were performed. RESULTS Fifty-seven patients (male/female ratio=1) with a median age of 58 years (33-78) entered in the study. Twenty-nine (51%) patients underwent pancreaticoduodenectomy and 28 (49%) distal pancreatectomy. Postoperative mortality was nil with a 37% morbidity rate. There were 36 (63%) patients with lymph node metastases (N1). Of these, 23 (64%) had a lymph node ratio (LNR) >0 and ≤0.20 and 13 (36%) had a LNR >0.20. The median overall survival and the median disease free survival (DFS) were 190 and 80 months, respectively. Recurrent disease was identified in 24 patients (42%) with a 2 and 5-year DFS rate of 82% and 49%, respectively. On multivariate analysis, LNR >0.20 (HR=2.75) and a value of Ki67 >5% (HR=3.39) were significant predictors of recurrence (P<0.02). CONCLUSIONS After resection for malignant PNETs, LNR and a Ki67 >5% are the most powerful predictors of recurrence. The presence of these factors should be considered for addressing patients to adjuvant treatment in future clinical trials.

Outcomes after resection of locally advanced or borderline resectable pancreatic cancer after neoadjuvant therapy

BACKGROUND Neoadjuvant treatment frequently is performed in unresectable/borderline resectable pancreatic cancer. The aim of this study was to retrospectively compare postoperative outcomes and survival of patients who underwent pancreatectomy after neoadjuvant treatment for locally advanced/borderline resectable pancreatic cancer (neoadjuvant treatment group) with those of patients with resectable disease who underwent upfront surgery. METHODS Between 2000 and 2008, there were 403 patients who underwent pancreatic cancer resection, 41 (10.1%) patients after neoadjuvant treatment for initially unresectable tumors and 362 (89.9%) patients had upfront surgery. Univariate and multivariable analyses were performed. RESULTS Mortality/morbidity rates were similar in the 2 groups. Nodal metastases were significantly lower in the neoadjuvant treatment group (31.7% vs 86.2%; P < .001). A complete pathologic response was observed in 13.6% after neoadjuvant treatment. Median disease-specific survival from resection was 35 and 27 months in the neoadjuvant treatment and upfront groups, respectively (P = .74). In the neoadjuvant treatment group survival rates were similar in N0/N1 patients. CONCLUSIONS Postoperative mortality and morbidity do not significantly increase after neoadjuvant treatment. Neoadjuvant treatment in locally advanced pancreatic cancer can lead to an objective pathologic response, but this does not significantly improve survival after resection.

Intraductal papillary mucinous neoplasms of the pancreas with multifocal involvement of branch ducts

INTRODUCTION The appropriate management of patients with branch-duct intraductal papillary mucinous neoplasm (BD-IPMN) with multiple involvements of branch ducts (multifocal BD-IPMN) remains challenging. PATIENTS AND METHODS Our database of patients affected by IPMN was queried to identify patients with a clinicoradiologic or a pathologic diagnosis of multifocal BD-IPMN between January 1990 and December 2006. RESULTS One hundred thirty-one patients (52 male and 79 female; median age 67 years) had a clinicoradiologic or a histopathologic diagnosis of multifocal BD-IPMN. Ten patients (7.6%) underwent surgery. After a median follow-up of 40 months (range 12 to 127) all the 121 patients conservatively managed are alive, and none underwent surgery during follow-up. One patient with invasive carcinoma developed hepatic metastases and died of disease 88 months after surgery. COMMENTS Patients with branch-side IPMN can be conservatively managed, but when multifocality is present follow-up may be problematic because of the number of lesions to be evaluated. The nonoperative management of well-selected patients with BD-IPMN, even in the multifocal setting, seems to be safe and reliable.

Low progression of intraductal papillary mucinous neoplasms with worrisome features and high-risk stigmata undergoing non-operative management: a mid-term follow-up analysis

Objective To evaluate mid-term outcomes and predictors of survival in non-operated patients with pancreatic intraductal papillary mucinous neoplasms (IPMNs) with worrisome features or high-risk stigmata as defined by International Consensus Guidelines for IPMN. Reasons for non-surgical options were physicians’ recommendation, patient personal choice or comorbidities precluding surgery. Methods In this retrospective, multicentre analysis, IPMNs were classified as branch duct (BD) and main duct (MD), the latter including mixed IPMNs. Univariate and multivariate analysis for overall survival (OS) and disease-specific survival (DSS) were obtained. Results Of 281 patients identified, 159 (57%) had BD-IPMNs and 122 (43%) had MD-IPMNs; 50 (18%) had high-risk stigmata and 231 (82%) had worrisome features. Median follow-up was 51 months. The 5-year OS and DSS for the entire cohort were 81% and 89.9%. An invasive pancreatic malignancy developed in 34 patients (12%); 31 had invasive IPMNs (11%) and 3 had IPMN-distinct pancreatic ductal adenocarcinoma (1%). Independent predictors of poor DSS in the entire cohort were age >70 years, atypical/malignant cyst fluid cytology, jaundice and MD >15 mm. Compared with MD-IPMNs, BD-IPMNs had significantly better 5-year OS (86% vs 74.1%, p=0.002) and DSS (97% vs 81.2%, p<0.0001). Patients with worrisome features had better 5-year DSS compared with those with high-risk stigmata (96.2% vs 60.2%, p<0.0001). Conclusions In elderly patients with IPMNs that have worrisome features, the 5-year DSS is 96%, suggesting that conservative management is appropriate. By contrast, presence of high-risk stigmata is associated with a 40% risk of IPMN-related death, reinforcing that surgical resection should be offered to fit patients.

Delayed gastric emptying after pylorus-preserving pancreaticoduodenectomy: validation of International Study Group of Pancreatic Surgery classification and analysis of risk factors

OBJECTIVES This study evaluates the incidence and clinical features and associated risk factors of delayed gastric emptying (DGE) after pancreaticoduodenectomy, employing the International Study Group of Pancreatic Surgery (ISGPS) consensus definition. METHODS Demographic, pathological and surgical details for 260 consecutive patients who underwent pylorus-preserving pancreaticoduodenectomy at a single institution were analysed using univariate and multivariate models. RESULTS Postoperative complications occurred in 108 (41.5%) and DGE was diagnosed in 36 (13.8%) of 260 patients. Among the 36 DGE patients, 16 had grade A, 18 grade B and two grade C DGE. Resumption of a solid diet (P < 0.001), time to passage of stool (P= 0.002) and hospital discharge (P < 0.001) occurred later in DGE patients. The need for total parenteral nutrition was significantly higher in DGE grade B/C patients (P < 0.001). In the univariate analysis, abdominal collections (P≤ 0.001), pancreatic fistula (PF) grades B and C (P < 0.001), biliary fistula (P= 0.002), pulmonary complications (P < 0.001) and sepsis (P= 0.002) were associated with DGE. Only abdominal collections (P= 0.009), PF grade B/C (P < 0.001) and sepsis (P= 0.024) were associated with clinically relevant DGE. In the multivariate analysis, PF grade B/C (P= 0.004) and biliary fistula (P= 0.039) were independent risk factors for DGE. CONCLUSIONS The ISGPS classification and grading systems correlate well with the clinical course of DGE and are feasible for patient management. The principal risk factors for DGE seem to be pancreatic and biliary fistulas.

Total pancreatectomy: Indications, different timing, and perioperative and long-term outcomes

BACKGROUND Total pancreatectomy (TP) has been performed rarely in the past because of its high morbidity and mortality. Because outcomes of pancreatic surgery as well as management of pancreatic insufficiency have improved markedly, enthusiasm for TP has an increased. METHODS Between 1996 and 2008, 65 patients (33 females, 32 males; median age, 63 years) underwent TP at a single, high-volume center. Indications, timing, and perioperative and long-term results were analyzed. RESULTS Twenty-five patients (38.5%) underwent a planned, elective TP and 25 patients underwent a single-stage unplanned TP after an initial partial pancreatectomy that required TP because of intraoperative hemorrhage (n = 1) or positive pancreatic resection margin (n = 24). The remaining 15 patients (23%) underwent a 2-stage pancreatectomy for tumor recurrence in the remnant. No completion TP for postoperative complications were performed. There was no mortality; the overall morbidity was 39% and the reoperation rate was 5%. Overall, 48% of patients had intraductal papillary mucinous neoplasms, and 29% pancreatic ductal adenocarcinoma. The R1 resection rate was 12%. Four of 23 patients (17%) who underwent single-stage, unplanned TP for positive resection margin had R1 resection (positive retroperitoneal margin). The median follow-up was 34 months. The overall 5-year survival was 71%. No deaths owing to hypoglycemia were observed. Median insulin was 32 U/d, and the median lipase was 80,000 U/d. CONCLUSION TP can be performed safely with no mortality and acceptable morbidity. Postoperative pancreatic insufficiency can be managed safely. To achieve an R0 during TP, both the resection and retroperitoneal margin should be evaluated intraoperatively. TP is an effective operation in selected patients.