WHO The classification of tumors of the digestive system was revised in 2019. There were no major changes in pancreatic ductal adenocarcinoma (PDAC), though there are several minor changes including the addition of invasive micropapillary carcinoma as a subtype of PDAC and a revision of the subtypes of undifferentiated carcinoma. However, the role of pathology is not limited to organizing tumor classifications. Pathology has multiple roles in clinical care and basic research for PDAC. In this article, the histopathological features, subtypes, precursor lesions, and characteristics of cancerous stroma of PDAC are described. The current situation and future directions concerning with EUS-FNA, TNM classification and evaluation of tumor regression after neoadjuvant therapy in resected pancreatic cancer are discussed.

Based on current classification systems, intraductal neoplasms of the pancreas are classified into two categories, intraductal papillary mucinous neoplasms (IPMN) and intraductal tubulopapillary neoplasms (ITPN). IPMNs are mucin-hypersecreting neoplasms with various degrees of dysplasia from low grade to high grade. IPMNs are further subdivided into four subtypes: gastric type, intestinal type, pancreatobiliary type and oncocytic type, based on their morphological and immunohistochemical features. ITPNs are non-mucinous tumors with uniform high-grade neoplastic cells which lack a low-grade component. To differentiate these two neoplasms, it is important to correctly recognize their characteristics including macroscopic, microscopic, immunohistochemical and molecular findings.

The clinicopathological features of typical serous cystic neoplasms (SCN), mucinous cystic neoplasms (MCN), and solid pseudopapillary neoplasms (SPN) have been established, but pathological issues related to diagnosis and treatment remain. The majority of SCNs have a benign course, but it should be noted that detailed examination of the surgical specimens may reveal local extension/invasion. It is desirable to consider how to deal with MCNs when the ovarian-like stroma is unclear, and consider criteria for follow-up or indications for surgery. Studies of SPNs that metastasize and SPNs with high-grade malignant transformation are desired.

The number of patients with pancreatic neuroendocrine neoplasm (PanNEN) has increased more than 5 times in the past 30 years due to progress in diagnostic imaging and biopsy methods. Along with this, the clinical and pathological diversity of PanNENs has been recognized. PanNEN are classified into well-differentiated (neuroendocrine tumor: NET) and poorly differentiated (neuroendocrine carcinoma: NEC) neoplasms according to their histological differentiation. They are different in aggressiveness, hormonal activity, and association with hereditary syndromes and the patients are treated differently. Recent comprehensive genetic studies have revealed the detailed molecular features of PanNETs although the cellular origin in terms of association with endocrinological activity has not yet been fully elucidated. In addition, the clinicopathologic characteristics of hereditary tumor syndromes, as well as molecular pathological characteristics of PanNEC are not well-understood.

For the diagnosis of type 1 autoimmune pancreatitis (AIP) by biopsy, it is important to understand the histological features of capsule-like lesions in the peripheral pancreas and lobular lesions. A capsule-like lesion in the peripheral pancreas is likely to be inflamed adipose tissue. Storiform fibrosis is observed frequently, but not always. These lesions may also consist of simple lymphoplasmacytic infiltration or fibrosis. The lobular contour is preserved in AIP, but acinar cells in the lobules are markedly decreased in number and are replaced by inflammatory cells and acinar-ductal metaplasia (ADM). Storiform fibrosis may be present, and the lobules tend to be enlarged. Atrophic and fibrotic lobules are also focally admixed. It is important to distinguish ADM from pancreatic cancers, and the concept of ADM should be acknowledged. Obliterative phlebitis, perineural inflammation, and periarteritis are also characteristic features of AIP. Numerous IgG4-positive plasma cells are seen (>10/high-power field), and a diffuse distribution of IgG4-positive cells and a high IgG4/IgG-positive cell ratio (>40%) are also helpful in establishing the diagnosis.

Neoadjuvant therapy is increasingly used for patients with pancreatic cancer to reduce the size of the primary tumor, treat micrometastases, and eventually improve overall survival. Pathology specimens after neoadjuvant treatment contain accurate information regarding the amount and viability of residual cancer cells and fibrosis. Thus, pathologic assessment of treatment effects may be important to predict patient outcomes after tumor resection. There has been recent progress in molecular pathology research focusing on genetic and protein changes in specimens after neoadjuvant therapy. There are several methods of pathological assessment of treatment effects, but their objectivity, reproducibility and prognostic utility are still controversial.

The status of biopsy and cytology of pancreatic tumors has changed significantly since the advent of endoscopic ultrasound-guided fine needle aspiration (EUS-FNA). Unlike pancreatic juice and pancreatic duct brush cytology, which is mainly used for tumors involving the pancreatic ducts, diagnosis by EUS-FNA includes tumors not involving the pancreatic ducts. However, pancreatic juice and pancreatic duct brush cytology remain useful for the diagnosis of early pancreatic cancer and pancreatic ductal lesions. Attempts have been made to improve diagnostic accuracy by examination of serial pancreatic juice aspiration cytology specimens. Immunohistochemistry and genetic analysis to distinguish between benign and malignant disease and determine the histological type are more easily performed on samples obtained by EUS-FNA than on those obtained from pancreatic juice and pancreatic ductal brush cytology. Rapid on-site cytologic evaluation and other procedures are needed to reduce the inadequate sampling rate of EUS-FNA and increase the amount of tissue collected.

Comprehensive studies of the pancreatic cancer genome have revealed that most genetic alterations are associated with specific core signaling pathways, and these are driven by the KRAS, CDKN2A, TP53, and SMAD4 genes that are frequently mutated as well as several low-frequency mutated genes. In addition to these mutations, other molecular abnormalities that include variations in gene expression, protein levels, and metabolic markers may be applied as new diagnostic tools for pancreatic cancer. Liquid biopsy-based molecular testing that reflects intratumor heterogeneity can be used not only for selecting smart drugs for advanced cancers but also as a tool to identify early-stage disease and screen individuals at high-risk. To apply these detailed molecular profiles in precision medicine, it is crucial to understand the biological features of tumor pathogenesis including the presence of multicentric lesions in the pancreas, intra-tumor heterogeneity, and their clonal evolution. This review outlines the molecular abnormalities that occur during the early development of pancreatic cancer and introduces the latest innovative technologies that may be relevant to clinical practice.

Clinical implementation of cancer genomic medicine using the cancer genomic profiling test reimbursed by national health insurance is proceeding in Japan. The principal purpose of the study is to obtain useful genomic profiles for the treatment of patients with cancer. Performing the cancer genomic profiling test under the health insurance system is only for patients with cancer with no standard chemotherapy, such as certain rare malignancies and cancer of unknown primary. This also includes patients with already well-treated solid tumors who would be expected to have a good performance status even after the cancer genomic profiling test. The results of the genomic profile and treatment strategies based on genomic information for patients are discussed in the conference by an expert panel. However, only about 10% of patients can eventually receive genotype-matched treatment based on the results of the cancer genomic profiling test based on the current system in Japan. For the maximum utilization of data from the cancer genomic profiling test, we have to consider the proper timing to perform it and develop an accessible system for taking genotype-matched treatment including off-label use of various anticancer agents.

The incidence of pancreatic cancer in families with at least two affected first-degree relatives who have pancreatic cancer is significantly higher than in the general population. In 2014, the Japan Pancreas Society started the nationwide Japan Familial Pancreatic Cancer Registry to investigate familial pancreatic cancer in Japan. The aim of this paper is to describe an expert consensus for surveillance in people with an increased risk using the Japan Familial Pancreatic Cancer Registry. A working group constituted by experts in imaging and genetic diagnosis of pancreatic cancer first proposed 22 statements regarding (1) the definition of those at high risk, (2) initial work-up and (3) follow-up of the high-risk group. Agreement of the councilors of Japan Pancreas Society was obtained for the 21 of the 22 statements by a vote. We expect that this expert consensus will contribute to the early diagnosis and an improved prognosis in people with familial pancreatic cancer.

Although the prognosis of patients with pancreatic ductal adenocarcinoma (PDAC) with postoperative recurrence is poor, lung metastases may have a relatively better prognosis than other sites of recurrence. Among 112 patients who underwent surgery for PDAC in our department between 2006 and 2017, 5 had recurrence in the lung alone, and 3 underwent resection of the lung metastases. All 5 patients were male, and the 2 who did not undergo resection of the lung metastases included one with unresectable multiple lung lesions and one with respiratory dysfunction. Primary tumor resection was performed after preoperative adjuvant chemotherapy in all 5 patients, and postoperative adjuvant chemotherapy was given to 4 patients. Pathologically, 4 had lymph node metastases, and an R0 resection was performed in 4 patients. Regardless of the presence of lung metastasis, all 5 patients have an overall survival more than 4 years, and only one patient died due to the lung metastases. There are many reports that resection of lung metastases in patients with pancreatic cancer improves their prognosis. However, it is necessary to accumulate and review more patients in future studies to show the effectiveness of metastasectomy.

A 66-year-old female with lesions in the body of the pancreas and liver on computed tomography (CT) scan was diagnosed with adenocarcinoma by endoscopic ultrasound-guided fine needle aspiration (EUS-FNA). She was treated with gemcitabine plus nab-paclitaxel combination therapy (GnP). She presented to our hospital with dysarthria and right hemiparesis eight days later. Magnetic resonance imaging (MRI) scan revealed multiple cerebral infarctions and she was diagnosed with Trousseau's syndrome. Since her neurological symptoms improved spontaneously, we continued systemic chemotherapy and no new neurological symptoms developed. Hypercoagulability was ameliorated by combination chemotherapy with GnP. The pancreatic lesions and hepatic metastases responded partially to systemic chemotherapy. However, metastases to the spine were found 4 months later after 5 courses of GnP. Therefore, we changed the regimen to modified FOLFIRINOX (mFOLFIRINOX). Nausea, appetite loss and vesicorectal disturbances developed 3 months later following 4 courses of mFOLFIRINOX. Meningeal carcinomatosis was diagnosed by cerebrospinal fluid cytology. Her general condition deteriorated and she died three weeks later.

A 59-year-old woman presented with upper abdominal pain. Imaging studies showed a 30mm polycystic tumor in the head of the pancreas. ERCP showed dilation of the main pancreatic duct, and pancreatic fluid cytology and brushing cytology were both class V. The diagnosis was intraductal papillary mucinous carcinoma (IPMC). The patient underwent pancreato-duodenectomy. The final pathological diagnosis was IPMC. Twelve months after resection, the patient had elevated serum CA19-9 levels. CT scan showed recurrence at the pancreato-intestinal anastomosis, and the patient underwent further resection. Histopathological examination showed the same pattern as that observed in the previously resected specimen. IPMC with residual pancreatic recurrence was diagnosed. The serum CA19-9 levels were again elevated 51 months after re-excision. CT scan showed a 20mm mass in the abdominal wall. Abdominal metastasis from IPMC was suspected, and resection was performed. The resected mass was white and well-defined. Based on histopathological findings, abdominal wall metastasis from IPMC was diagnosed. The patient remains alive 88 months after the first resection. We report a patient for whom long-term survival was achieved by resection of the residual pancreatic recurrence and abdominal wall metastasis after resection of IPMC in the head of the pancreas.

Annular pancreas is a congenital anomaly in which pancreatic parenchyma surrounds the second part of the duodenum, with a frequency of 0.015%. Pancreatic cancer is extremely rare in patients with annular pancreas. We report a patient with invasive ductal carcinoma of the head of the pancreas in an annular pancreas. A 76-year-old woman was diagnosed with branch duct intraductal papillary mucinous neoplasm and annular pancreas and was admitted with fatigue and anorexia. Laboratory data showed elevation of serum bilirubin and hepatobiliary enzymes. Contrast-enhanced CT scan revealed dilatation of the intrahepatic and common bile ducts, and showed a 2cm hypovascular tumor in the head of the pancreas. Pancreatography showed disruption of the main pancreatic duct in the head, and dilatation of the caudal main pancreatic duct. Cholangiography showed stenosis of the distal bile duct and the diagnosis was obstructive jaundice due to carcinoma of the head of the pancreas. A subtotal stomach preserving pancreaticoduodenectomy was performed. Pathology revealed invasive ductal carcinoma of the pancreas. Ph, TS2 (33mm), pT3, pN1, M0, pStage IIB.

A 43-year-old female presented with a tumor in the head of the pancreas. She had a history of a synovial sarcoma in the left axilla resected 4 years previously. The pancreatic tumor was 4.5cm in diameter with showed cystic and solid components and enhancement on contrast CT scan. The pancreas tumor showed intermediate signal intensity on T2-weighted images and low signal intensity on T1 weighted images on MRI. There was no evidence of main pancreatic duct dilatation suggestive of pancreatic cancer on either CT or MRI. The ERP also showed a normal main pancreatic duct. Laboratory data and tumor makers were all normal. Based on examinations, the pancreatic head tumor was diagnosed as a metastasis from the synovial sarcoma. We performed a pylorus-preserving pancreaticoduodenectomy. The final pathologic diagnosis was a metastasis from the synovial sarcoma. She has been well for 83 months without recurrence. Pancreatic metastasis from synovial sarcoma is quite rare. The CT/MRI findings of synovial sarcoma are varied because both synovial sarcomas and their metastases usually include calcification, cystic component and hemorrhage. If patients have only a pancreatic metastasis, pancreatic tumor resection may be associated with a good prognosis.