Neuroendocrine neoplasms (NENs) constitute a heterogeneous group of cancers arising from neuroendocrine cells, which can most commonly be found in gastroenteropancreatic (GEP) structures or respiratory tracts, where these cells are numerous. [1], [2]. However, most NENs are well-differentiated neuroendocrine tumors (NETs) and possess a more indolent disease biology, around 10–20% of NENs are poorly differentiated neuroendocrine carcinomas (NECs), which have a highly proliferative index and are characterized by more rapid disease progression [3].The incidence and prevalence of NENs continues to rise globally, with the greatest rates of increase in nations such as the USA, Canada, and Norway [4]. GEP NENs represent the most common NEN subtype, constituting 55–70% of all NENs [5].In Europe, the incidence of GEP-NENs has also increased and ranges between 1.33 and 2.33/100 000 population, with small intestinal and pancreatic NENs tending to be most prevalent [4], [6], [7], [8].

Over the past four decades, the incidence of NENs has increased 6.4-fold over the past four decades from 1.09 (1973) to 6.98 (2012) new cases per 100,000 inhabitants annually [5]. This may be related to extensive use of somatostatin receptor-based functional imaging, upgrading in nuclear techniques (68Ga‐DOTATOC), which improves detecting occult NENs, and pathological diagnostic methods [2].

To date, five somatostatin receptor subtypes (sst1–sst5) have been identified, all of which are expressed with differing frequencies in GEP-NETs. For example, sst2 and sst5 are expressed at a high density in 70–100% of GEP-NETs. Poorly differentiated NECs hardly express somatostatin receptors [9]. Somatostatin receptor PET tracers have a higher lesion detection rate than is achieved with 18F-fluorodihydroxyphenyl-l-alanine PET, somatostatin receptor SPECT, CT, or MRI. Peptides labeled with 68Ga-DOTA bind to somatostatin receptors, especially type 2, although each may have different affinities for other receptors. The most commonly used radiopharmaceuticals are 68Ga-DOTA-TOC (DOTA-Tyr3-octreotide), 68Ga-DOTA-NOC (DOTA-1-NaI-octreotide), and 68Ga-DOTA-TATE (DOTA. Tyr3-octreotate) [10]. This studies are routinely performed for localizing the primary tumor, evaluating disease extension, monitoring treatment effects, determining the receptor status as a predictor of response to octreotide therapy, and selecting patients for targeted radionuclide therapy [11].

Survival for all NENs seems to be improving, particularly for advanced-stage pancreatic and gastrointestinal NENs. However, it broadly varies by primary tumor site, proliferative index (ki-67 or mitotic index), histological differentiation, and stage [12]. According to the Surveillance Epidemiology and End Results (SEER) database, rectum (24.6 years) and appendix (> 0.0 years) NENs had the best prognosis, while pancreatic NENs (3.6 years) and lung NENs (5.5 years) had the worst survival. Survival by grade also broadly ranged from 16.2 for grade 1, 8.3 years for grade 2 and 10 months for grade 3 tumors.

About 20–25% of NENs are functioning tumors and are associated with a clinical syndrome due to excessive hormone production such as carcinoid syndrome. Of special note is the relatively high carcinoid crisis risk, beyond high tumor burden metastatic NENs who undergo invasive treatment procedures. Prevalence of this essentially hemodynamic instability syndrome represents 25-32% of surgical NEN patients [13]. Previous carcinoid syndrome, high serotonin levels, elderly patients and longer anesthetic duration, are major risk factors. Thus, when selected treatment modality of metastatic disease is surgery, special anesthetic care must be considered. Nevertheless, the proportion of functioning NENs seems to be falling with time due to earlier diagnosis, improved symptomatic and antineoplastic therapy.

They are generally diagnosed in the fifth decade of life, and about 5% of them are associated with hereditary predisposition syndromes [14]. Although there are large studies on the general epidemiology of NEN very little is known about the epidemiology of metastatic disease [15]. NENs represents a complex and heterogenous family of tumors with challenging clinical management. In this review, we aim to provide synthetical and practical guidelines regarding the management of bone metastases and uncommon sites of spread of the NEN that includes the brain, orbital and myocardial metastases.