The term neuroendocrine denotes to the properties of “neuro”—based on the identification of dense core granules which store monoamines and “endocrine”—referring to the synthesis and secretion of these monoamines [1]. The most common primary site is the gastrointestinal tract (gastroenteropancreatic NEN: GEP-NEN) (62–67%) and the lungs (22–27%) [2]. We further divide GEP-NEN into neuroendocrine neoplasm of the luminal gastrointestinal tract and pancreatic neuroendocrine neoplasm (PNEN). We report two cases of PNEN with different rare presentations and stage of the disease. Based on our developing experience, we put forward our approach to diagnosing and managing these tumors.

Case 1

Mr. M, a 30-year-old gentleman with 10 packyears of smoking, presented with a three-day history of obstructive jaundice and abdominal pain and an acute episode of melena. Besides jaundice, the rest of the physical examination was unremarkable. He was anemic, and liver function test showed an obstructive picture. An esophagogastroduodenoscopy (OGDS) by us revealed a bleeding ampullary tumor which we temporarily arrested with argon plasma coagulation (APC). Ultrasonography (USG) and computed tomography (CT) pancreatic protocol showed a bulky pancreas with a duodenal tumor and dilated biliary and pancreatic duct. The pancreas and the duodenal mass showed arterial enhancement and portal venous washout with no evidence of intraabdominal metastases. The tumor did not encase the coeliac, superior mesenteric artery, superior mesenteric vein, and portal vein. We did an angiogram; however, no specific point of bleeding was identified to proceed for angioembolization. As his symptoms did not improve, and we could not proceed with any further investigation, we decided to perform a total pancreatectomy and splenectomy after discussing with our local NEN multidisciplinary team. Intraoperatively the entire pancreas was enlarged, hard, and nodular (Figure 1). His recovery was uneventful and was discharged home a week after surgery with subcutaneous insulin. Histopathological examination of the resected specimen revealed a Grade 1, well-differentiated NEN involving the whole length of the pancreas. Three out of 30 lymph nodes harvested were positive for NEN. The entire specimen showed strong positivity for synaptophysin and chromogranin A, and the Ki67 index was 3%. A postoperative serum chromogranin A (CgA) taken four weeks after surgery was 160.6 ng/ml. We organized a 68Ga-DOTATATE positron emission tomography (PET) scan for completion of staging.

Case 2

Madam S, a 48-year-old lady, with no known previous medical illness, presented with a history of progressive abdominal distension and lethargy for six months. Upon examination, we found a palpable mass encompassing the epigastric, the left hypochondrium and the left lumbar region. Computed tomography of the thorax, abdomen, and pelvis revealed a large mass arising from the entire pancreas, invading the splenic hilum and left pararenal space and displacing the stomach anteriorly with multiple liver and peritoneal metastases and ascites (Figure 2) and (Figure 3). A USG-guided biopsy of the mass showed a Grade 2, well-differentiated neuroendocrine 180 degrees encasement of the portal vein. We sent her for a 68Ga-DOTATOC PET scan in West Malaysia which revealed somatostatin-receptor-avid extensive disease in the abdomen with peritoneal, mesenteric, and liver metastasis. After a thorough discussion with our local NEN multidisciplinary team and the patient, we decided for best medical therapy with long-acting somatostatin analogues-lanreotide.

Pancreatic neuroendocrine neoplasms are rare tumors, with an incidence of approximately 0.2/100,000 in the United States and 2.2/100,000 in Asians and only accounts for 1–2% of all pancreatic neoplasms [2],[3]. These tumors commonly occur between the ages of 40 and 60 and have an equal gender distribution [3]. The neoplasm presents in a wide spectrum, ranging from clinically indolent to highly aggressive malignancy. These rare tumors arise from pancreatic islet cells. They present as either functional (hormone secreting) or non-functional neoplasm [4]. Functioning PNENs are associated with hormone secretion related to the pancreas (insulin, glucagon, and somatostatin) and those related to extra-pancreatic tissues (gastrin, vasoactive intestinal peptide, growth hormone releasing factor, and adrenocorticotropic hormone). The commonest type is that of insulin-producing tumors (insulinoma) with an annual incidence of 1–3/million per year, followed by gastrin-producing tumors (gastrinoma) associated with Zollinger–Ellison syndrome [5]. The majority of PNENs are sporadic, non-functioning, with an annual incidence estimated to be 0.07–0.1/100,000 [6],[7]. A small proportion is associated with genetic diseases—commonly related to multiple endocrine neoplasia type 1, Von Hippel–Lindau syndrome, tuberous sclerosis, and neurofibromatosis [4]. Some may present with obstruction, perforation, and even rarer as bleeding neoplasm, as reported in our first case. To our knowledge, very few case reports are available in the literature on bleeding pancreatic NEN [8],[9],[10].

The current WHO classification recognizes three grades of well-differentiated PNENs—pancreatic neuroendocrine tumor (PanNET) of low, intermediate, or high grade. Poorly differentiated high-grade PNENs are all referred to as pancreatic neuroendocrine carcinoma (PanNEC Grade 3) [11],[12].

The critical management step in all neuroendocrine tumors includes diagnosing the disease, identifying associated genetic disorders, hormonal control if functioning tumor, localizing the tumor, deciding on the role of surgical resection if possible, adjuvant therapy and follow-up. First line tools to localize tumors involve high-resolution multiphase CTs or magnetic resonance imaging (MRI) [13],[14]. Positron emission tomography scan with specific radiotracers is a sensitive method for the detection of the primary tumor and its metastases—most frequently used are somatostatin analogue labeled positron emitters, for example 68Ga-DOTATOC, 68Ga-DOTANOC, and 68Ga-DOTATATE [15],[16] . In the subject of tumor markers, serum CgA and urinary 5-hydroxyindoleacetic acid (5-HIAA) are two widely available markers in current practice. We preferentially use serum CgA as it is released in abnormal amounts by many neoplastic neuroendocrine cells—concentration in the circulation can be measured to provide information for the diagnosis, prognosis, and monitoring of patients with these tumors [17].

Surgery is a curative modality for malignant, sporadic PNEN, as resection of primary tumor improves patient survival [18],[19]. Current guidelines from National Comprehensive Cancer Network (NCCN) and European Neuroendocrine Tumour (ENET) recommend excision of tumors >2 cm [20],[21]. However, for some patients with tumors [21]. For high grade, poorly differentiated PNEN, we offer surgery in conjunction with chemotherapy or radiotherapy. Resecting, both primary and metastatic sites, can be attempted for PNENs with potentially resectable metastatic disease, for example liver metastasis [22]. We advocate medical therapy for unresectable metastatic disease—long-acting somatostatin analogues as the first line and systemic treatment (chemotherapy [oxaliplatin-based regimens], peptide receptor radionuclide therapy [PRRT], tyrosine kinase [sunitinib], inhibitors of mTOR [everolimus]) [23]. Cytoreductive surgery or palliative debulking is an option for clinically significant progressive disease and to alleviate local symptoms. Additionally, we control any functional PNENs with appropriate medical support before any resection. Following resection, surveillance would comprise of serum CgA level monitoring with multiphasic CT/MRI or DOTATOC scan as clinically indicated [24],[25].

The patient in our second case underwent a wellorchestrated flow of investigation protocol, adhering to the current guidelines of management for metastatic NEN; however, the first patient did not. The reason for the unconventional approach for our first patient is due to the lack of facilities and specific specializations which are not available in Sarawak, East Malaysia, on the island of Borneo. In an ideal situation, this patient should have undergone a DOTATOC scan, but because of the nature of the case is an upper gastrointestinal bleed, not amenable to endoscopic and endovascular intervention and no DOTATOC scan was available in our center in Sarawak, the decision was made to proceed with emergency surgery. Although this may not be the best approach for patients with pancreatic neoplasm, in a young, healthy patient with imaging suggestive of a NEN, we would suggest an aggressive strategy of surgical intervention as we can successfully treat the extrapancreatic lesions later with adjuvant therapy.

Pancreatic NEN is a heterogeneous group of disorders with varied presentations. Treatment must be planned on a case by case basis, as each patient presents with a clinical problem and diagnostic challenge of its own. Prompt investigation with appropriate intervention is an integral part of the multidisciplinary care of patients with these tumors. In keeping with the purpose of this article, as evidenced by the relevant instances presented, bleeding pancreatic NEN, a rare occurrence, is best managed with surgery, while unresectable metastatic NEN would benefit from appropriate medical therapy.