The WHO 2010 classification has been widely employed to classify gastro-enteric-pancreatic neoplasms because of its close correlation with clinicopathological parameters of patients including clinical outcomes. However, since its publication, some problems have been raised regarding its three tier classification, NET or neuroendocrine tumor G1, G2 and G3. Based on these issues, a novel classification of pancreatic neuroendocrine neoplasms was proposed as WHO 2017. In this review, an outline of this new WHO 2017 classification will be reviewed with emphasis upon the differentiation between NET and NEC (neuroendocrine carcinoma) and the standardization of Ki67 labeling index.

To clarify the relationship between the degree of histopathological differentiation in pancreatic neuroendocrine neoplasms (PNEN) and various imaging findings, we classified PNEN lesions as well-differentiated (NET G1/G2/G3) or poorly differentiated (neuroendocrine carcinoma; NEC G3) based on the World Health Organization 2017 classification and compared the imaging findings among these classifications. All lesions with only typical diagnostic imaging findings were classified as highly differentiated, with NET G1 tumors being particularly frequent. Among atypical findings, in the arterial phase, no enhancement/irregular shape was observed more frequently in lesions classified as NET G3 and NEC G3, suggesting high grade PNEN. Mineralization/cyst formation was only observed in NET G1 and G2 lesions, suggesting high differentiation. The positron emission tomography-computed tomography-positive rate increased with an increase in the degree of malignancy, and the positive rate was significantly higher in poorly differentiated lesions, although the maximum standardized uptake value was not significantly different between well-differentiated and poorly differentiated lesions. These findings indicate a relationship between imaging findings and PNEN grade, suggesting that diagnostic prediction of the degree of malignancy by imaging studies is possible to some extent. However, differentiation between NET G3 and NEC G3 is difficult using only imaging findings. In addition to imaging diagnosis, sufficient histopathological examination is required.

Although pancreatic neuroendocrine neoplasms (PanNENs) are rare, the number of patients with PanNENs is increasing with advances in the development of imaging modalities. Multi-detector computed tomography (MDCT) is a standard technique to detect pancreatic tumors, however, endoscopic ultrasound (EUS) is superior to MDCT for the detection of pancreatic tumors, especially small PanNENs. Pathological diagnosis is essential to differentiate PanNENs with atypical imaging from other tumors. EUS-guided fine needle aspiration (EUS-FNA) is a standard technique to obtain tumor samples from the pancreas. EUS-FNA allows appropriate diagnosis of PanNENs and yields important information to determine grading or aggressiveness needed to consider treatment options.

Somatostatin receptor scintigraphy (SRS) using ¹¹¹In-pentetreotide has been available in Japan since January 2016 and is widely used for the initial diagnosis of neuroendocrine neoplasms (NEN), search for metastases, follow-up, and confirmation of expression of somatostatin receptor (SSTR). However, SSTR is expressed in tumors other than NEN as well, there are NEN in which SSTR is not expressed or does not accumulate, and physiological accumulation of SRS occurs in the pancreatic head. Therefore, there is a need for a comprehensive evaluation, including other image modalities, based on the findings of the SRS. It is important to ascertain the presence of SSTR expression and to confirm the application of peptide receptor radionuclide therapy (PRRT) based on SRS observations and it is expected that the importance of SRS will increase in the future.

According to a nationwide survey in 2007, pancreatic neuroendocrine tumors have synchronous metastases in about 60% of patients. Metachronous liver metastases after primary resection occur at a high rate of 30 to 85%, and the overall five-year survival rate is very poor at about 40%. Before 2010, reductive surgery and palliative therapy were the only treatments for patients with advanced disease. However, after 2011, molecular targeted therapies such as everolimus, sunitinib, somatostatin analog, and streptozocin were eligible for reimbursement by the national health insurance system one after another in Japan, and tumors that were impossible to resect completely before 2010 could be excised. In 2017 a clinical trial of PRRT targeting SSTR 2 was started. In this paper, we will summarize the treatment strategies and WHO 2017 classification.

Pancreatic Neuroendocrine Neoplasms (PNEN) vary greatly among different pathological conditions and prognoses due to hormone production and grade classification. PNEN often recur, but there is no evidence for administration of postoperative adjuvant therapy in patients with PNEN, especially well-differentiated PNEN, and it is not recommended in the Japanese guidelines. It is important to identify patients with a high risk of postoperative recurrence and clarify whether postoperative adjuvant therapy improves the prognosis in patients with PNEN.

The incidence of pancreatic neuroendocrine neoplasms (panNENs; pancreatic neuroendocrine neoplasms) has increased in recent years, of which nonfunctional PanNENs account for more than half. The treatment policy for nonfunctional PanNENs is in principle surgical resection. Several reports recently recommend watchful waiting for patients with small sporadic nonfunctional PanNENs. However, other investigators reported that nonfunctional PanNENs had a high rate of lymph node metastases even if the lesion is small. Nonfunctional PanNENs which have been recognized to have a a good prognosis also have a risk of metastases and postoperative recurrence. A limited number of patients have distant metastases at the time of diagnosis. Aggressive surgical treatment is recommended for recurrent and distant metastatic lesions in patients with resectable disease, but surgical treatment strategies are changing with an accumulation of cases and the development of novel drugs. With reference to representative guidelines, we review surgical treatment strategies for nonfunctional PanNENs.

A 62-year-old man was referred for further evaluation of a dilated main pancreatic duct with cystic lesions in the pancreatic tail detected on abdominal ultrasonography. He had complained of dyspnea and chest back pain. Chest X-ray showed a massive left pleural effusion. Computed tomography revealed a low-density mass in the pancreatic body with a dilated main pancreatic duct and pseudocysts in the tail of the pancreas. Thoracentesis yielded red-brown pleural fluid with a high amylase level (26,775U/l). Cytologic examination of the pleural fluid was not consistent with malignancy. Endoscopic retrograde pancreatography (ERP) revealed an occluded main pancreatic duct, and biopsy from the ERP was suspicious for adenocarcinoma. The preoperative diagnosis was pancreatic body cancer with a pancreatic pleural effusion. Thoracic drainage, endoscopic naso-pancreatic drainage, and administration of antibiotics were performed. Twenty days later, pancreaticooduodenectomy was performed with curative intent. The postoperative course was uneventful, and the patient was discharged on postoperative day 18. Although the most common underlying cause of a pancreatic pleural effusion is chronic pancreatitis, this is a rare case of pancreatic cancer presenting as a pancreatic pleural effusion.

A 67-year-old man was admitted with abdominal distension and left-sided abdominal pain. Abdominal computed tomography scan revealed a 20 cm tumor of the pancreatic body and tail with both cystic and solid components. The left abdominal cavity was occupied by the tumor, and the tumor was in contact with multiple organs including the stomach, transverse colon, and left kidney. In addition, it was close to the superior mesenteric artery and abdominal aorta. Based on the diagnosis, radical resection of the malignant pancreatic tumor was planned because there were no distant metastases. The tumor appeared mobile and was easily separated from the retroperitoneum and we performed a distal pancreatectomy and left hemicolectomy. Pathological examination revealed proliferation of undifferentiated malignant cells and CD68-positive osteoclast-like multinucleated giant cells. The diagnosis was anaplastic carcinoma with osteoclast-like giant cells. The patient was treated with postoperative adjuvant chemotherapy with gemcitabine and S-1, but multiple lung metastases appeared 6 months after surgery. We changed the chemotherapy regimen to gemcitabine and nab-paclitaxel, but it was not effective and the patient died 13 months after resection.