Gastroenteropancreatic neuroendocrine neoplasms: A clinical snapshot

Abstract

Our understanding about the epidemiological aspects, pathogenesis, molecular diagnosis, and targeted therapies of neuroendocrine neoplasms (NENs) have drastically advanced in the past decade. Gastroenteropancreatic (GEP) NENs originate from the enteroendocrine cells of the embryonic gut which share common endocrine and neural differentiation factors. Most NENs are well-differentiated, and slow growing. Specific neuroendocrine biomarkers that are used in the diagnosis of functional NENs include insulin, glucagon, vasoactive intestinal polypeptide, gastrin, somatostatin, adrenocorticotropin, growth hormone releasing hormone, parathyroid hormone-related peptide, serotonin, histamine, and 5-hydroxy indole acetic acid (5-HIAA). Biomarkers such as pancreatic polypeptide, human chorionic gonadotrophin subunits, neurotensin, ghrelin, and calcitonin are used in the diagnosis of non-functional NENs. 5-HIAA levels correlate with tumour burden, prognosis and development of carcinoid heart disease and mesenteric fibrosis, however several diseases, medications and edible products can falsely elevate the 5-HIAA levels. Organ-specific transcription factors are useful in the differential diagnosis of metastasis from an unknown primary of well-differentiated NENs. Emerging novel biomarkers include circulating tumour cells, circulating tumour DNA, circulating micro-RNAs, and neuroendocrine neoplasms test (NETest) (simultaneous measurement of 51 neuroendocrine-specific marker genes in the peripheral blood). NETest has high sensitivity (85%-98%) and specificity (93%-97%) for the detection of gastrointestinal NENs, and is useful for monitoring treatment response, recurrence, and prognosis. In terms of management, surgery, radiofrequency ablation, symptom control with medications, chemotherapy and molecular targeted therapies are all considered as options. Surgery is the mainstay of treatment, but depends on factors including age of the individual, location, stage, grade, functional status, and the heredity of the tumour (sporadic vs inherited). Medical management is helpful to alleviate the symptoms, manage inoperable lesions, suppress postoperative tumour growth, and manage recurrences. Several molecular-targeted therapies are considered second line to somatostatin analogues. This review is a clinical update on the pathophysiological aspects, diagnostic algorithm, and management of GEP NENs.

Keywords: Chemotherapy; Gastroenteropancreatic neuroendocrine neoplasms; Neuroendocrine carcinoma; Neuroendocrine tumours; Octreoscan; Targeted molecular therapy.

Figure 1

The distribution of neuroendocrine neoplasms based on the primary site of the neuroendocrine tumors^[11]. NENs: Neuroendocrine neoplasms.

Figure 2

Surgical and medical management of pancreatic and small intestinal neuroendocrine neoplasms^[80-91]. GEP: Gastroenteropancreatic; NENs: Neuroendocrine neoplasms; pNENs: Pancreatic NENs; NET: Neuroendocrine tumor; NEC: Neuroendocrine carcinoma; ZES/MEN1: Zollinger Ellison Syndrome with multiple endocrine neoplasia 1; STZ/5FU: Streptozotocin/5-fluorouracil; PRRT: Peptide receptor radionuclide therapy; SSA: Somatostatin analogues; SIRT: Selective internal radiotherapy; TAE: Transarterial embolisation; TACE: Transarterial chemoembolization; CAPTEM: Capecitabine and temozolomide; FOLFOX: Folinic acid, 5-fluorouracil and oxaliplatin; FOLFIRI: Folinic acid, fluorouracil, and irinotecan; CP: Central pancreatectomy; DP: Distal pancreatectomy; PD: Pancreaticoduodenectomy, TP: Total pancreatectomy; G1: Grade 1; G2: Grade 2; G3: Grade 3.