Neuroendocrine tumors (NETs) are a distinct group of neoplasms that arise from cells in the diffuse neuroendocrine system. At least 17 different types of neuroendocrine cells are found in the pancreas and gastrointestinal tract, and in the pancreas, they are located in the islets of Langerhans.9 pNETs first described in 1869, are a subset of NENs that exhibit relatively distinct biologic behaviour and clinical management compared to pancreatic adenocarcinoma. pNETs account for less than 10% of all NETs and have an approximate incidence of 0.5 per 100,000 people per year.10,11Although they represent only 1–2% of pancreatic neoplasms, their incidence is increasing.12 The proportion of pNETs out of gastroenteropancreatic tumours in our study was found to be 27.8%.
Originally described by Nicholls in 1902 as tumours arising from the pancreatic islet cell line, these tumours are often associated with the clinical syndrome associated with the hormone secreted by the tumour.13 These neoplasms are known as functional pNETs and include insulinomas, gastrinomas, glucagonomas, and somatostatinomas. Non-functioning pNETs (NF-pNETs) are not associated with any functional syndrome, therefore their symptoms at presentation are due to the tumour and include abdominal pain (35–55%), jaundice (25–40%), weight loss (30–45%) and/or an abdominal mass (10–40%).14,15,16 Owing to their non-specific symptoms, NF-pNETs are usually diagnosed late in their disease course with large primary tumours, with most having metastatic disease to the liver (40–90%).14,15,16 The term NF-pNETs is a misnomer as these tumours secrete many peptides that do not cause clinical syndromes, including pancreatic polypeptide (25–70%) (also known as PPomas), chromogranin-A (60–100%), neuron-specific enolase (31%), ghrelin, neurotensin and subunits of human chorionic gonadotropin (20%).14,15,16
pNETs are generally grossly well-demarcated and range in colour from grey-white to yellow and have a solid, homogenous appearance. They can be vascular and congested, with areas of haemorrhage. They can be cystic in rare cases, and radiologically, can be mistaken with other non-neoplastic, benign, and neoplastic cystic lesions in the pancreas.17 All tumours in our series were well-circumscribed and solid in gross appearance. Multiple tumours could be seen in genetic syndromes. In our case of Von-Hippel Lindau syndrome, the tumour was located at the uncinate process with bilateral pheochromocytoma.
Several studies have discussed the clinical and pathological features, surgical management, and adjuvant radionuclide chemotherapy of pNEN, which have led to continuous changes in histological classification and hence treatment protocols. The 2017 WHO classification introduced some changes to the classification of pNEN. The first was the introduction of well-differentiated pNEN grade-3 (G3) for well-differentiated pNEN with high proliferation indices (Ki-67 > 20% and/or mitotic rate > 20/10 hpf). This change has in turn led to confusion regarding terminology and the distinction between pNEN-G3 and pancreatic neuroendocrine carcinoma (pNEC). A second important point was that instead of the previous Ki-67 cutoff of 2%, less than 3% cutoff is now used for G1 pNETs.18 A third change was the introduction of the term 'neuroendocrine-non neuroendocrine neoplasm' for mixed neoplasms that may occasionally contain well-differentiated components and non-neuroendocrine components in addition to adenocarcinoma.18
Pancreatic NETs G3 are well-differentiated pNEN with a mitotic count greater than 20/10 hpf or a Ki-67 index greater than 20% according to 2017 WHO classification. The histological features of pancreatic NET G3 are comparable to those of well-differentiated NET G1/G2, although these tumours are not pNEC. A higher Ki-67 index is considered a determining factor when the Ki-67 index and the mitotic count are inconsistent. According to Basturk et al, patients with a G2 mitotic count and a G3 Ki-67 index had a longer survival time than patients with poorly differentiated pNEC, but a shorter survival time than patients with G2.19 Poorly differentiated pancreatic NECs are histologically divided into small and large cell types.
Despite the histomorphological differences between NETs G3 and NECs, they are sometimes difficult to distinguish. Loss of nuclear expression for DAXX and ATRX and retention of expression for Rb and p53 help identify NETs G3 and NECs, respectively. Somatostatin receptors are commonly expressed in well-differentiated pNET.20 The liver was the most common site of distant metastases according to several studies.21,22,23 This was seen in four of our cases. Apart from the WHO 2017 classification of pNEN, TNM staging is also important for management.
Treatment of pNET is a multidisciplinary effort that includes surgery, somatostatin analogues (SSAs), targeted therapy, and chemotherapy. Several recent studies have greatly added to the therapeutic options, and treatment guidelines are constantly evolving. Surgery is the mainstay of treatment for pNET.24 Resection is often curative for patients with localized disease, and even patients with distant metastases may benefit from surgical debulking in terms of symptom control and survival.24 The surgical approach to pNET depends on the size and location of the tumour, functional status, and the presence or absence of distant metastases. Distal pancreatectomy, pancreaticoduodenectomy, central pancreatectomy, enucleation, or observation are the treatment modalities in cases where pNET are limited to the pancreas and regional lymph nodes. All pNET larger than 2 cm and functional tumours, regardless of size, should be resected.24
Surgical excision remains the only possible curative treatment for people with pNET in the majority of cases. Several guidelines (NCCN, ENETS, Chinese Society of Clinical Oncology, and NANETS) recommend surgical resection for all functioning pNET and localized NF-pNETs (without extensive metastases), with surgical options including simple enucleation, central pancreatectomy, distal pancreatectomy with or without splenectomy and pancreatoduodenectomy depending on tumour location.25 Tumours of the head of the pancreas are resected by pancreaticoduodenectomy, whereas tumours located in the body or tail with or without spleen preservation are performed by distal pancreatectomy.24
A treatment algorithm for pNET based on functionality and localized or metastatic disease was proposed by Akirov et al.26 Liver metastases are found in approximately 40–45 percent of pNETs, but they are not a contraindication for surgical excision. Indeed, if a comprehensive examination reveals no sites of metastasis other than the liver, surgical resection is indicated based on the pNET grade and the surgical resectability of liver metastases. In the case of pNET G1-G2 with resectable liver metastases, a prior surgical approach is advocated and G3 pNETs are treated. Although controversial, a palliative debulking operation can be considered in inoperable liver metastases, especially if life-threatening and/or obstructive consequences (bleeding, severe pancreatitis, jaundice or gastric obstruction). are present.27