Therapeutic strategies for gastroenteropancreatic neuroendocrine neoplasms: State-of-the-art and future perspectives

Abstract

Although gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) have always been considered rare tumors, their incidence has risen over the past few decades. They represent a highly heterogeneous group of neoplasms with several prognostic factors, including disease stage, proliferative index (Ki67), and tumor differentiation. Most of these neoplasms express somatostatin receptors on the cell surface, a feature that has important implications in terms of prognosis, diagnosis, and therapy. Although International Guidelines propose algorithms aimed at guiding therapeutic strategies, GEP-NEN patients are still very different from one another, and the need for personalized treatment continues to increase. Radical surgery is always the best option when feasible; however, up to 80% of cases are metastatic upon diagnosis. Regarding medical treatments, as GEP-NENs are characterized by relatively long overall survival, multiple therapy lines are adopted during the lifetime of these patients, but the optimum sequence to be followed has never been clearly defined. Furthermore, although new molecular markers aimed at predicting the response to therapy, as well as prognostic scores, are currently being studied, their application is still far from being part of daily clinical practice. As they represent a complex disease, with therapeutic protocols that are not completely standardized, GEP-NENs require a multidisciplinary approach. This review will provide an overview of the available therapeutic options for GEP-NENs and attempts to clarify the possible approaches for the management of these patients and to discuss future perspectives in this field.

Keywords: Future perspectives; Gastroenteropancreatic neuroendocrine neoplasms; Medical treatments; Overview; Radical surgery; Therapeutic strategies.

Figure 1

Elettra Merola, MD, PhD, Department of Gastroenterology, Santa Chiara Hospital, Azienda Provinciale per i Servizi Sanitari (APSS), Largo Medaglie D’Oro 9, Trento 38122, Italy

Figure 2

Endoscopic management of gastric neuroendocrine tumors presentation of a clinical case referred to our hospital. A 78-year-old female patient was referred to our Endoscopy Unit for resection of a lesion of the gastric fundus. Staging by endoscopic ultrasound showed hypoechoic lesion of 19 mm × 12 mm, with well-defined margins, originating from the third hyperechoic layer. Fine-needle cytology diagnosed a NET G1 (Ki67 < 2%). The lesion was then resected by endoscopic submucosa dissection (ESD). Histological evaluation described a gastric NET (g-NET) G1, associated with autoimmune gastritis (Type I). During follow-up, another minor lesion (< 10 mm) suspected for NET was reported along the greater curvature, and resected by Band-ligation endoscopic mucosal resection (EMR-L). Histological report confirmed a Type I g-NET. A: Cardial area reflexed view; B: Resection base after ESD; C: Oriented and pinned specimen; D: Hematoxylin-eosin stain showing monomorphic cells in a nested architecture without necrosis; E: Corresponding Chromogranin A immunostain (20 × magnification); F: Corresponding Ki67 immunostain (20 × magnification); G: Endoscopic appearance of the lesion detected during follow-up; H: EMR-L: Rubber band release; I: Resection base after EMR-L.

Figure 3

Locoregional treatments for neuroendocrine liver metastases-presentation of a clinical case referred to our hospital, with progressive liver disease after multiple systemic treatments. A: ⁶⁸Ga-DOTATOC-positron emission tomography/computed tomography (CT) whole-body maximum intensity projection image reveals multiple liver metastases involving both hepatic lobes, the left lobe being almost completely replaced by tumor. Bone and lymph nodal small metastases are also evident; B: Selective angiography of the right hepatic artery performed before lobar chemoembolization shows multiple hypervascular liver lesions; C: Selective angiography of the right hepatic artery performed 1 mo after two sessions of degradable starch microsphere transarterial chemoembolization (DSM-TACE). A marked reduction of the liver metastases enhancement is visible, preserved patency of the arterial intra-hepatic branches; D: Portal-phase CT scan before arterial chemoembolization: Multiple confluent hypodense lesions compared to liver parenchyma are detected in the right liver lobe; E: Portal-phase CT scan control after two DSM-TACE: Partial response of the liber metastases, which appear reduced in size and without contrast enhancement. Right portal vein branch narrowing represents an initial sign of liver/biliary toxicity.