A great deal of knowledge about intraductal papillary mucinous neoplasms (IPMNs) has been accumulated, ranging from their natural history to associated molecular abnormalities. In addition to genetic abnormalities (KRAS, GNAS, PI3KCA, BRAF, hTERT, Sonic Hedgehog (SHH), SKT11/LKB1, etc. ), many epigenetic and protein expression abnormalities have also been reported. Recently, attempts to use liquid biopsies to detect very small amounts of fragments of genes in blood, etc., as well as the establishment and analysis of organoids of IPMN cells, have been reported. However, from a clinical standpoint, it is difficult in many cases to accurately evaluate disease status including tumor grading, to predict postoperative recurrence and development of concomitant pancreatic carcinoma. In the future, it will be necessary to integrate various findings that have been accumulated so far and make them useful for medical treatment, of which the findings regarding genetic abnormalities will be the key. This review will outline the latest findings on genetic abnormalities in IPMN.

The mechanism of malignant progression of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas using multi-region sequencing focused on multi-step tumorigenesis and the divergent intra-tumor heterogeneity of intraductal neoplasms is being developed. Three patterns of molecular pathways are associated with the development of IPMN-related pancreatic cancers; a sequential pathway, corresponding to IPMN-derived carcinoma; a de novo pathway, corresponding to concomitant carcinoma; and a branch-off pathway, that is an inevitable molecular basis of adjacent invasive carcinoma.

Intraductal papillary mucinous neoplasms (IPMN) of the pancreas are categorized into four distinct types: gastric, intestinal, pancreatobiliary, and oncocytic types. Each is associated with specific clinicopathological features. The aim of this study was to uncover the molecular mechanisms underlying the development of these types of IPMNs. We obtained 103 specimens with lesions of various types, including 49 gastric, 26 intestinal, 22 pancreatobiliary, and 6 oncocytic lesions, from 43 IPMNs, including 36 with multiple types. Comparative analysis was performed by targeted sequencing of 37 genes in the different lesion types within each pancreas. Gastric-type low-grade lesions were observed in all 36 tumors with multiple types, with 245 mutations identified across all samples. The average number of mutations was significantly different between different lesion grades and types including 1.88 for low-grade lesions, 2.77 for high-grade lesions, and 2.38 for invasive lesions. By type, there were 1.96 for gastric-type, 2.92 for intestinal-type, 2.73 for pancreatobiliary-type, and 2.17 for oncocytic-type lesions. Tracing the mutations between lesions containing multiple types in the same pancreas suggested three developmental pathways, denoted as "progressive", "divergent", and "independent". These findings suggest that gastric-type low-grade lesions have a risk of progression into high-grade lesions of other types. Therefore, patients with low-grade gastric-type IPMNs should be under constant surveillance.

Pancreatic cancers related to intraductal papillary mucinous neoplasms (IPMN) include IPMN-derived carcinomas and concomitant carcinomas. Data from our institution shows that the cumulative incidence of pancreatic cancer was 3.3%, 6.6%, and 15.0% at 5, 10, and 15 years, respectively. The standardized incidence ratio of pancreatic cancer was 10.8. The size of IPMNs and the diameter of the main pancreatic duct in patients diagnosed with IPMN were risk factors for IPMN-derived carcinoma. However, neither of these was a risk factor for concomitant carcinoma. Therefore, for the early diagnosis of pancreatic cancer, periodic imaging is recommended for patients with IPMNs, regardless of the features of the IPMN. Some IPMNs develop into pancreatic carcinoma after 5-years of surveillance; continued surveillance beyond 5 years is recommended for patients with branch-duct IPMNs as long as they remain fit for major surgery.

In the International Consensus Guidelines 2017 for the management of intraductal papillary mucinous neoplasms (IPMNs), high risk stigmata (HRS) and worrisome features (WF) were revised to be more clinically relevant. However, the specificity and positive predictive value to establish a malignant diagnosis remain insufficient. Patients with IPMNs are often elderly with comorbidities. Even for patients with high-risk IPMNs with HRS or WF, follow-up is often chosen instead of surgery. Recently, a few reports on the medium- to long-term outcomes of patients with unresected high-risk IPMNs have shown that progression to IPMN-derived invasive cancer is rare, and disease-specific survival rates are relatively high. However, patients with mural nodules ≥10mm, main pancreatic duct diameter ≥15mm, and multiple HRS factors have lower disease-specific survival rates and should be followed carefully. Further elucidation of the clinical course of patients with unresected high-risk IPMNs and the development of predictive models based on disease-specific mortality and surgery-associated mortality and morbidity is expected in the future.

The strongest prognostic factor after resection of intraductal papillary mucinous neoplasms (IPMN) is the presence of invasive cancer. After resection of non-invasive IPMNs, the long-term prognosis is favorable, while extra-pancreatic recurrence or a residual pancreatic lesion might occur in some patients. Although patients with invasive IPMNs have shorter survival compared to those with non-invasive IPMNs, they have been reported to have a more favorable prognosis compared to conventional pancreatic ductal adenocarcinoma. This is probably due to detection at an earlier stage and a higher proportion of colloid carcinoma among invasive IPMNs. Residual pancreatic lesions after resection of IPMNs have increasingly been reported recently and several investigators reported risk/predictive factors. Among these, high-grade or invasive IPMNs were reported to be specific risk/predictive factors for lesions requiring resection. Regarding surveillance after resection of IPMNs, long-term surveillance considering development of residual pancreatic lesions is recommended although there are some differences in available guidelines.

An international consensus guideline for the management of patients with intraductal papillary mucinous neoplasm (IPMN) classified IPMNs pathologically into low-grade dysplasia, high-grade dysplasia, and invasive intraductal papillary mucinous carcinoma (IPMC). Once an IPMN has invasive components, lymph node metastases can occur and recurrence is often found even after complete surgical resection. In this event, the survival of patients with invasive IPMC is worse than that of patients with noninvasive IPMN. Therefore, lymphadenectomy during operation is essential for invasive IPMC to improve survival, similar to common pancreatic ductal adenocarcinoma. With regard to postoperative adjuvant therapy, some studies reported its effectiveness for patients with invasive IPMC to prolong the survival, while other studies did not. It is controversial whether adjuvant therapy should be administered to patients with invasive IPMC. This paper will introduce a project of the Japan Pancreas Society to evaluate the efficacy of postoperative adjuvant therapy for patients with invasive IPMC.

A 49-year-old man was treated with FOLFIRINOX (5-fluorouracil, oxaliplatin, irinotecan, and leucovorin) for pancreatic tail cancer with multiple liver metastases, and had a partial response. However, bleeding gastric varices due to sinistral portal hypertension associated with pancreatic tail cancer developed. While repeated endoscopic variceal ligation and endoscopic injection sclerotherapy were performed, the gastric variceal bleeding was difficult to manage endoscopically. Therefore, partial splenic artery embolization (PSE) was performed to treat the bleeding gastric varices, with control of the bleeding. Compared with splenectomy, PSE is less invasive and can be performed with short-term interruption of chemotherapy. PSE is considered effective to control gastric variceal bleeding in patients with bleeding due to left portal hypertension.

A 58-year-old woman was found to have dilatation of the main pancreatic duct at screening ultrasonography performed for renal impairment. Evaluation showed stenosis of the main pancreatic duct in the head of the pancreas, a hypovascular region with ill-defined borders on contrast-enhanced computed tomography scan, and a slightly ill-defined hypoechoic region on endoscopic ultrasonography. Serial pancreatic juice aspiration cytologic examination (SPACE) and endoscopic ultrasound-fine needle aspiration showed no malignant findings. Pancreatic cancer could not be ruled out, and subtotal stomach-preserving pancreaticoduodenectomy was performed. Pathological examination revealed high-grade pancreatic intraepithelial neoplasia in the pancreatic duct branches in the head of the pancreas. Fibrosis surrounded the pancreatic duct branches where the lesions were located. Postoperatively, endoscopic ultrasound performed with an increase in serum tumor markers revealed a hypoechoic mass with a long diameter of 7mm in the residual pancreas. Atypical cells were detected by SPACE, and local recurrence in the residual pancreas was strongly suspected. Total pancreatectomy was performed 59 months after the initial resection. Pathological examination revealed an invasive ductal carcinoma with a long diameter of 8mm in the background of high-grade pancreatic intraepithelial neoplasia, which frequently occurs in the residual pancreas.