Giovanni Marchegiani

Radiological and surgical implications of neoadjuvant treatment with FOLFIRINOX for locally advanced and borderline resectable pancreatic cancer.

PURPOSE On the basis of the ACCORD trial, FOLFIRINOX is effective in metastatic pancreatic adenocarcinoma (PDAC), making it a rational choice for locally advanced PDAC (LA). Aims of this study are to evaluate the accuracy of imaging in determining the resectability of PDAC and to determine the surgical and clinicopathologic outcomes of pancreatic resections after neoadjuvant FOLFIRINOX therapy. PATIENTS AND METHODS Clinicopathologic data were retrospectively collected for surgical PDAC patients receiving neoadjuvant FOLFIRINOX or no neoadjuvant therapy between April 2011 and February 2014. Americas Hepato-Pancreato-Biliary Association/Society of Surgical Oncology/Society for Surgery of the Alimentary Tract consensus guidelines defined LA and borderline. Imaging was reviewed by a blinded senior pancreatic surgeon. RESULTS Of 188 patients undergoing resection for PDAC, 40 LA/borderline received FOLFIRINOX and 87 received no neoadjuvant therapy. FOLFIRINOX resulted in a significant decrease in tumor size, yet 19 patients were still classified as LA and 9 as borderline. Despite post-FOLFIRINOX imaging suggesting continued unresectability, 92% had an R0 resection. When compared with no neoadjuvant therapy, FOLFIRINOX resulted in significantly longer operative times (393 vs 300 minutes) and blood loss (600 vs 400 mL), but significantly lower operative morbidity (36% vs 63%) and no postoperative pancreatic fistulas. Length of stay (6 vs 7 days), readmissions (20% vs 30%), and mortality were equivalent (1% vs 0%). On final pathology, the FOLFIRINOX group had a significant decrease in lymph node positivity (35% vs 79%) and perineural invasion (72% vs 95%). Median follow-up was 11 months with a significant increase in overall survival with FOLFIRINOX. CONCLUSIONS After neoadjuvant FOLFIRINOX imaging no longer predicts unresectability. Traditional pathologic predictors of survival are improved, and morbidity is decreased in comparison to patients with clearly resectable cancers at the time of presentation.

The 2016 update of the International Study Group (ISGPS) definition and grading of postoperative pancreatic fistula: 11 Years After

Background. In 2005, the International Study Group of Pancreatic Fistula developed a definition and grading of postoperative pancreatic fistula that has been accepted universally. Eleven years later, because postoperative pancreatic fistula remains one of the most relevant and harmful complications of pancreatic operation, the International Study Group of Pancreatic Fistula classification has become the gold standard in defining postoperative pancreatic fistula in clinical practice. The aim of the present report is to verify the value of the International Study Group of Pancreatic Fistula definition and grading of postoperative pancreatic fistula and to update the International Study Group of Pancreatic Fistula classification in light of recent evidence that has emerged, as well as to address the lingering controversies about the original definition and grading of postoperative pancreatic fistula. Methods. The International Study Group of Pancreatic Fistula reconvened as the International Study Group in Pancreatic Surgery in order to perform a review of the recent literature and consequently to update and revise the grading system of postoperative pancreatic fistula. Results. Based on the literature since 2005 investigating the validity and clinical use of the original International Study Group of Pancreatic Fistula classification, a clinically relevant postoperative pancreatic fistula is now redefined as a drain output of any measurable volume of fluid with an amylase level >3 times the upper limit of institutional normal serum amylase activity, associated with a clinically relevant development/condition related directly to the postoperative pancreatic fistula. Consequently, the former “grade A postoperative pancreatic fistula” is now redefined and called a “biochemical leak,” because it has no clinical importance and is no longer referred to a true pancreatic fistula. Postoperative pancreatic fistula grades B and C are confirmed but defined more strictly. In particular, grade B requires a change in the postoperative management; drains are either left in place >3 weeks or repositioned through endoscopic or percutaneous procedures. Grade C postoperative pancreatic fistula refers to those postoperative pancreatic fistula that require reoperation or lead to single or multiple organ failure and/or mortality attributable to the pancreatic fistula. Conclusion. This new definition and grading system of postoperative pancreatic fistula should lead to a more universally consistent evaluation of operative outcomes after pancreatic operation and will allow for a better comparison of techniques used to mitigate the rate and clinical impact of a pancreatic fistula. Use of this updated classification will also allow for more precise comparisons of surgical quality between surgeons and units who perform pancreatic surgery.

Serous cystic neoplasm of the pancreas: a multinational study of 2622 patients under the auspices of the International Association of Pancreatology and European Pancreatic Club (European Study Group on Cystic Tumors of the Pancreas)

Objectives Serous cystic neoplasm (SCN) is a cystic neoplasm of the pancreas whose natural history is poorly known. The purpose of the study was to attempt to describe the natural history of SCN, including the specific mortality. Design Retrospective multinational study including SCN diagnosed between 1990 and 2014. Results 2622 patients were included. Seventy-four per cent were women, and median age at diagnosis was 58 years (16–99). Patients presented with non-specific abdominal pain (27%), pancreaticobiliary symptoms (9%), diabetes mellitus (5%), other symptoms (4%) and/or were asymptomatic (61%). Fifty-two per cent of patients were operated on during the first year after diagnosis (median size: 40 mm (2–200)), 9% had resection beyond 1 year of follow-up (3 years (1–20), size at diagnosis: 25 mm (4–140)) and 39% had no surgery (3.6 years (1–23), 25.5 mm (1–200)). Surgical indications were (not exclusive) uncertain diagnosis (60%), symptoms (23%), size increase (12%), large size (6%) and adjacent organ compression (5%). In patients followed beyond 1 year (n=1271), size increased in 37% (growth rate: 4 mm/year), was stable in 57% and decreased in 6%. Three serous cystadenocarcinomas were recorded. Postoperative mortality was 0.6% (n=10), and SCNs related mortality was 0.1% (n=1). Conclusions After a 3-year follow-up, clinical relevant symptoms occurred in a very small proportion of patients and size slowly increased in less than half. Surgical treatment should be proposed only for diagnosis remaining uncertain after complete workup, significant and related symptoms or exceptionally when exists concern with malignancy. This study supports an initial conservative management in the majority of patients with SCN. Trial registration number IRB 00006477.

Pancreatic resections for cystic neoplasms: From the surgeon's presumption to the pathologist's reality

BACKGROUND Current guidelines for the management of pancreatic cystic neoplasms are based on the assumption that these lesions can be classified correctly on the basis of features of cross-sectional imaging. However, a certain degree of overlap between different lesions exists, and little is known about the rate of inaccurate preoperative diagnoses. To address this issue, preoperative and final pathologic diagnoses of patients resected for a presumed pancreatic cystic neoplasm were compared. METHODS Retrospective analysis was undertaken of patients managed operatively between 2000 and 2010. Preoperative workup was reviewed to identify diagnostic pitfalls and potential risk factors for incorrect preoperative characterization of cystic lesions presumed to be neoplastic. RESULTS We analyzed 476 patients. Final pathologic diagnosis matched the preoperative diagnosis in 78% of cases. The highest accuracy was reached for solid pseudopapillary neoplasms (95%) and for main duct/mixed duct intraductal papillary mucinous neoplasms (81%). Surprisingly, 23 cysts (5%) were found to be ductal adenocarcinoma, whereas 45 patients (9%) underwent a pancreatic resection for a non-neoplastic condition. The use of a routine radiologic workup, including contrast-enhanced ultrasonography and magnetic resonance imaging, was associated with a favorably correct characterization of the cystic lesion. Endoscopic ultrasonography did not seem to improve diagnostic accuracy. Increased levels of serum carbohydrate antigen (CA)19-9 resulted as risk factors for an incorrect diagnosis as well as for a final diagnosis of a ductal adenocarcinoma. CONCLUSION The overall rate of inaccurate preoperative diagnoses in a tertiary care center with a broad experience in pancreatology approached 22%. Serum CA19-9 is an important complementary tool within the context of preoperative investigation of cystic neoplasms of the pancreas.

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.

Patterns of Recurrence After Resection of IPMN: Who, When, and How?

Objective: To describe the patterns of recurrence after resection of intraductal papillary mucinous neoplasms (IPMN) of the pancreas. Background: IPMNs represent an increasing indication for pancreatic resection, but little is known about the actual incidence and the patterns of recurrence after surgical excision. Methods: Retrospective review of 412 resected IPMNs from 1990 to 2013 who have had near-complete follow-up. Results: Median age of the cohort was 68 years, 56% had branch duct (BD)-IPMN and 21% had invasive cancers. Nineteen patients (5%) had distinct pancreatic ductal adenocarcinoma (PDAC) and were excluded from the recurrence analysis. After a median of 58 months, 65 of 381 patients (17%) experienced recurrence of the IPMN, and 5- and 10-year disease-free survival (DFS) was 82% and 78%, respectively. Only 2 patients (0.5%) developed metachronous PDAC. In 33 patients (9%), a residual BD-IPMN was left in the pancreatic remnant, but none of these significantly grew or required reoperation. Invasive component and resection margin positive for IPMN were predictors of recurrence (P < 0.05). Invasive IPMN recurred in 45% of cases, whereas noninvasive in only 9% and later (P < 0.001), but patterns depended on IPMN subtypes. Only 9 patients required reoperation for recurrence, with good long-term outcome particularly for oncocytic IPMNs. Conclusions: Recurrence of noninvasive BD-IPMN is infrequent and surveillance may be avoided in selected cases. In invasive IPMN recurrence depends on N status, pancreatic margin, and invasive type.

IPMN involving the main pancreatic duct: biology, epidemiology, and long-term outcomes following resection.

OBJECTIVES To describe the characteristics of intraductal papillary mucinous neoplasms (IPMNs) with predominant involvement of the main pancreatic duct (MPD), analyzing predictors for survival and recurrence. BACKGROUND IPMNs involving the MPD harbor a high likelihood of malignancy and different biological features. The appropriateness of including cases with minimal noncircumferential MPD involvement has been challenged because these show clinicopathological features that are similar to branch duct IPMN. Accordingly, their exclusion has led to a redefinition of MPD IPMN (MD-IPMN). METHODS Retrospective review of resected MD-IPMN from 1990 to 2013. All slides were reviewed by a single pancreatic pathologist and classified on the basis of epithelial type and invasive component. RESULTS A total of 223 patients underwent resection for IPMN involving the MPD. Of these, 50 were excluded because of minimal MPD involvement. Among the 173 patients analyzed, median age was 68 years and 55% were males. Predominant epithelial phenotype was intestinal (50%). Forty-eight patients (28%) had low- or intermediate-grade dysplasia, whereas 125 (72%) had either high-grade dysplasia (33%) or invasive carcinoma (39%). Of the 67 invasive IPMNs, 39 were tubular carcinomas (58%) and invasion was minimal (<5 mm) in 28 (42%). The 5-year overall survival rate was 69% and the disease-specific survival rate was 83%. The estimated recurrence rate at 10 years was 25%. Size and type of the invasive component, lymph node positivity, and a positive resection margin were predictors for both survival and recurrence (P < 0.05). CONCLUSIONS MD-IPMN is mainly intestinal-type and malignant. After resection, it has a very favorable prognosis, especially in the absence of macroscopic invasive carcinoma.

Pancreaticoduodenectomy for pancreatic cancer: the Verona experience.

Pancreatic ductal adenocarcinoma is the fourth leading cause of cancer-related mortality in the Western world. The current treatment is multimodal, and in resectable patients radical surgery represents the key-step toward long-term survival. Pancreaticoduodenectomy (PD) is the most widely performed operation, because the majority of ductal carcinomas arise in the head of the pancreas. Once considered extremely hazardous, PD has evolved into a safe procedure, with mortality below 5% and morbidity rates in the range from 20% to 60% at high-volume centers. Verona is regarded as one of the most prominent institutions for pancreatic surgery in Europe. More than 5500 patients with pancreatic diseases have been managed, and the surgical case load has increased substantially, with more than 1350 PDs performed. This review discusses this center’s experience in surgical treatment of pancreatic head cancer. Furthermore, the preliminary results of radiofrequency thermal ablation of locally advanced ductal cancer are presented.

Observational study of the incidence of pancreatic and extrapancreatic malignancies during surveillance of patients with branch-duct intraductal papillary mucinous neoplasm

OBJECTIVE This observational analysis assessed the incidence of pancreatic and extrapancreatic malignancies in BD-IPMN patients. BACKGROUND Previous studies showed that progression to malignancy of pancreatic branch-duct (BD) intraductal papillary mucinous neoplasm (IPMN) is infrequent and that extrapancreatic malignancies (EPMs) occur with unusual frequency in IPMN patients. METHODS Patients observed from 2000 to 2012 and enrolled in a surveillance protocol according to the current guidelines were considered eligible for the study. Only patients with follow-up of more than 12 months were evaluated. The incidence of EPM was calculated only in patients who were free of them at the time of IPMN diagnosis. Data were compared with Italian cancer statistics. The standardized incidence ratios (SIRs) and the 5- and 10-year incidence rates were estimated. RESULTS The study population consisted of 569 patients. At a median follow-up of 56 months, 9 patients developed a pancreatic malignancy. Of these, 5 were unresectable. The SIR was 9.21 [95% confidence interval (CI), 1.85-26.91] in males, and 11.94 (95% CI, 4.36-26.0) in females, with a 5-year cumulative incidence of 1.4%. The EPM incidence analysis was performed in 456 patients. Thirty EPMs developed during the follow-up. The SIR was 1.40 (95% CI, 0.72-2.45) in males and 1.37 (95% CI, 0.81-2.16) in females. The 5-year rate of developing any EPM was 5.7%. CONCLUSIONS BD-IPMN patients are at risk of pancreatic carcinogenesis. Although the 5-year incidence rate was as low as 1.4%, the surveillance protocol based on the current guidelines failed to identify a small subset of patients who progressed to advanced disease. Patients with BD-IPMN are not at risk of extrapancreatic carcinogenesis.

Oncocytic-Type Intraductal Papillary Mucinous Neoplasms: A Unique Malignant Pancreatic Tumor with Good Long-Term Prognosis

BACKGROUND The different epithelial phenotypes of intraductal papillary mucinous neoplasms (IPMNs) are predictors of tumor biology and post-surgical outcomes. Oncocytic-type IPMN (O-IPMN) seems to have a unique natural history, but not much information is available because of its rarity. We sought to describe the characteristics of a cohort of patients resected for O-IPMNs, focusing on their long-term outcomes after surgery. STUDY DESIGN We conducted a retrospective review of the demographics, clinical presentation, pathology, and survival of a cohort of patients resected for IPMN between 1990 and 2013, comparing O-IPMN with other IPMN subtypes. RESULTS Eighteen of 400 patients (4.5%) who underwent resection for IPMN had the oncocytic subtype. Compared with other IPMN patients, those with O-IPMNs were more likely to be male (72% vs 45%; p = 0.02) and to have main pancreatic duct involvement (72% vs 42%; p = 0.01). Oncocytic IPMNs occurred in asymptomatic individuals in 67% of cases. They had either invasive carcinoma (61%) or high-grade dysplasia (39%), and the proportions in other epithelial subtypes were 19% and 21%, respectively (p < 0.001). After resection, the 10-year recurrence rate for O-IPMNs was 46%. Recurrences occurred up to 11 years after the initial resection and a completion total pancreatectomy was performed in 4 patients. At a median follow-up of 7 years, no patients with O-IPMN had died from the disease. CONCLUSIONS Oncocytic IPMN is a unique tumor subtype that occurs mostly in the main pancreatic duct and is malignant. Recurrences after resection are not uncommon and can occur more than 10 years after the initial resection. Reoperations for recurrent O-IPMN are often feasible and have excellent results in terms of survival.