Molecular genetics of intraductal papillary–mucinous neoplasms of the pancreas

Intraductal papillary–mucinous neoplasms of the pancreas show characteristic clinicopathological and molecular pathobiological features which are distinct from those of conventional ductal adenocarcinomas. Alterations of KRAS, AKT/PKB, CDKN2A, TP53, SMAD4, STK11/LKB1, and DUSP6, and other molecular alterations, including global expression studies as well as their clinical implications, are discussed.     

Intraductal papillary mucinous neoplasms of the pancreas: is the puzzle solved?

Intraductal papillary mucinous neoplasms (IPMN) are drawing more attention and being detected more frequently. This review focuses on current understanding of the management of IPMN, regarding morphological classification, subclassification by cell lineage features, molecular abnormalities, radiological and imaging evaluation, progression to cancer, incidence and risk factors for malignancy, risk of distinct pancreatic adenocarcinoma and extrapancreatic malignancies, treatment strategy, and types of surgical resection. In particular, missing links in solving the IPMN puzzles are described with regard to differential diagnosis, role of cyst fluid analysis, multifocal IPMN, histological evaluation of the surgical specimen, observation without resection, follow up of patients after resection, role of adjuvant therapy for invasive carcinoma, screening for other neoplasms in patients with IPMN on follow up, prognostic factors influencing long-term outcomes, and role of endoscopic therapy.     

Side-branch intraductal papillary mucinous neoplasms of the pancreatic head/uncinate: resection or enucleation?

Introduction

Side-branch intraductal papillary mucinous neoplasms (IPMN) of the pancreatic head/uncinate are an increasingly common indication for pancreaticoduodenectomy (PD). However, enucleation (EN) may be an alternative to PD in selected patients to improve outcomes and preserve pancreatic parenchyma.

Aim

To determine peri-operative outcomes in patients with side-branch IPMN of the pancreatic head/uncinate undergoing EN or PD compared with a cohort of patients with pancreatic adenocarcinoma (PA) undergoing PD.

Methods

Retrospective review of a prospectively collected, combined, academic institutional series from 2005 to 2008. Of 107 pancreatic head/uncinate IPMN, enucleation was performed in 7 (IPMN EN) and PD was performed in 100 (IPMN PD) with 17 of these radiographically amenable to EN (IPMN PD^en). During the same time period, 281 patients underwent PD for PA (Control PD).

Results

Operative time was shorter (p < 0.05) and blood loss (p < 0.05) was less in the IPMN EN group compared with all other groups. Peri-operative mortality and morbidity of all IPMN groups (IPMN EN, IPMN PD^en) were similar to the Control PD group. Overall pancreatic fistulae rate in the IPMN EN group was higher than in the IPMN PD^en and Control PD groups; however, the rate of grade C pancreatic fistulae was the same in all groups.

Conclusions

Pancreaticoduodenectomy for side-branch IPMNs can be performed safely. Compared with PD, enucleation for IPMN has less blood loss, shorter operative time and similar morbidity, mortality, hospital length of stay (LOS) and readmission rate. Enucleation should be considered more frequently as an option for patients with unifocal side-branch IPMN.     

Intraductal papillary neoplasm of the bile duct: A biliary equivalent to intraductal papillary mucinous neoplasm of the pancreas?

Intraductal papillary neoplasm of the bile duct (IPNB) is a variant of bile duct carcinoma characterized by intraductal growth and better outcome compared with the more common nodular-sclerosing type. IPNB is a recognized precursor of invasive carcinoma, but its pathogenesis and natural history are ill-defined. This study examines the clinicopathologic features and outcomes of IPNB. A consecutive cohort of patients with bile duct cancer (hilar, intrahepatic, or distal) was reviewed, and those with papillary histologic features identified. Histopathologic findings and immunohistochemical staining for tumor markers and for cytokeratin and mucin proteins were used to classify IPNB into subtypes. Survival data were analyzed and correlated with clinical and pathologic parameters. Thirty-nine IPNBs were identified in hilar (23/144), intrahepatic (4/86), and distal (12/113) bile duct specimens between 1991 and 2010. Histopathologic examination revealed 27 pancreatobiliary, four gastric, two intestinal, and six oncocytic subtypes; results of cytokeratin and mucin staining were similar to those of intraductal papillary mucinous neoplasm (IPMN) of the pancreas. Invasive carcinoma was seen in 29/39 (74%) IPNBs. Overall median survival was 62 months and was not different between IPNB locations or subtypes. Factors associated with a worse median survival included presence and depth of tumor invasion, margin-positive resection, and expression of MUC1 and CEA. Conclusion: IPNBs are an uncommon variant of bile duct cancer, representing approximately 10% of all resectable cases. They occur throughout the biliary tract, share some histologic and clinical features with IPMNs of the pancreas, and may represent a carcinogenesis pathway different from that of conventional bile duct carcinomas arising from flat dysplasia. Given their significant risk of harboring invasive carcinoma, they should be treated with complete resection. (HEPATOLOGY 2012).     

Can the location of the mural nodule indicate benign or malignant in branch duct-type intraductal papillary mucinous neoplasm of the pancreas?

Background/ObjectivesIntraductal papillary mucinous neoplasms (IPMNs) are classified into main duct (MD)-type IPMNs, branch duct (BD)-type IPMNs, and mixed type IPMNs. While MD-type IPMN has a high risk of malignancy and should therefore be considered for resection if the patient is fit, BD-type IPMN needs to be carefully judged for surgical indication. The decision to resect BD-type IPMN is often based on international consensus Fukuoka guidelines 2017, but further investigation is required. In this study, we focused on whether the location of the mural nodule (MN) could be an indicator of malignancy.MethodsWe enrolled 17 cases who had been diagnosed BD-type IPMNs which were surgically resected from January 2016 to December 2019. These cases were classified into benign and malignant group. Subsequently, a clinicopathological study was conducted based on the localization of MN (MN-central type or MN-peripheral type).ResultsAlthough MN was found in 57% (4/11) in the benign group, 88% (7/8) was noted in the malignant group, indicating the presence of MN to be more common in the malignant group. Those with MN consisted of 6 cases of MN-central type and 5 cases of MN-peripheral type. All cases of central type were malignant compared to only one case of the peripheral group being confirmed on histology as cancer.ConclusionBD-IPMN with central mural nodule should be considered high risk for malignancy.     

Intraductal papillary mucinous neoplasms of the pancreas – a cost-effectiveness analysis of management strategies for the branch-duct subtype

Background

Branch-duct intraductal papillary mucinous neoplasm (BD-IPMN) presents a clinical conundrum. Rigorous long-term surveillance or surgical resection is recommended. The economic consequences of the management have not been fully investigated.

Should non-invasive diffuse main-duct intraductal papillary mucinous neoplasms be treated with total pancreatectomy?

BackgroundMain-duct (MD) intraductal papillary mucinous neoplasm (IPMN) is associated with malignancy risk. There is a lack of consensus on treatment (partial or total pancreatectomy) when the MD is diffusely involved. We sought to characterize the pancreatic remnant fate after partial pancreatectomy for non-invasive diffuse MD-IPMN.MethodsConsecutive patients with partial pancreatectomy for non-invasive MD-IPMN from 2004 to 2016 were analyzed. Diffuse MD-IPMN was defined by preoperative imaging as dilation of the MD in the head of the pancreas more than 5 mm and involving the whole gland.ResultsOf 127 patients with resected non-invasive MD-IPMN, 47 (37%) had diffuse MD involvement. Eleven of 47(23%) patients developed imaging evidence of progression or new cystic disease in the pancreatic remnant. Patients with diffuse MD-IPMN were older (73yrs vs 67yrs, p = 0.009), more likely to receive a pancreaticoduodenectomy (96% vs 56%, p < 0.001) and have high-grade dysplasia (51% vs 31%, p = 0.025) than those with focal MD involvement. Diffuse MD involvement was not associated with shorter PFS following partial pancreatectomy (p = 0.613).ConclusionPartial pancreatectomy is an appropriate surgical approach for diffuse MD-IPMN, and is not associated with earlier progression after surgery as compared to partial pancreatectomy for focal dilation.     

Value of repeated cytology for intraductal papillary mucinous neoplasms of the pancreas with high risk potential of malignancy: Is it a promising method for monitoring a malignant transformation?

ObjectivesThe efficacy of and indications for cytological reexamination to detect malignant changes in branch duct type intraductal papillary mucinous neoplasms (BD-IPMNs) have not been studied in detail. We conducted a retrospective study to evaluate the efficacy and indications of cytological reexamination by using pancreatic juice (repeated cytology) for BD-IPMNs.MethodsForty-five patients who underwent repeated cytology after a diagnosis of benignancy by using initial cytology were recruited for this study.ResultsThirty-eight patients, excluding 7 patients with lack of surveillance period after the final cytology, were classified into Malignancy (n = 13) and Benignancy groups (n = 25) on the bases of the findings from resected specimens or changes in BD-IPMNs after repeated cytology. The sensitivity and specificity to detect malignant changes in BD-IPMNs by using repeated cytology were 62% and 100%, respectively. For the 12 patients with mural nodules (MNs) ≥ 5 mm (67% of them were malignant), the sensitivity was 50%, whereas, for the 26 patients without MNs ≥ 5 mm (19% of them were malignant), it was 80%. In addition, malignant changes in BD-IPMNs after initial cytology occurred in 62% of the patients with changes in the MNs and 27% of the patients with an increase in the cyst size.ConclusionRepeated cytology can play a role in the determination for surgery even after a diagnosis of benignancy by using initial cytology, especially for BD-IPMNs without MNs ≥5 mm. In addition, changes in the MNs or cyst size may be appropriate indications for repeated cytology.