NENs are commonly called neuroendocrine tumours or carcinoids, but the correct term is NENs as tumours and carcinoid refer to specific NET subtypes. The term neuroendocrine refers to specific aspects of the cell and does not allow us to understand what kind of cancer we face, how it will respond to treatments and how aggressive it will be.

NENs originate from the diffuse neuroendocrine system, that is from a set of cells with similar morphological characteristics (they have aspects in part neurological and in part endocrine). Since this system spreads throughout the body, NENs can occur anywhere. In two thirds of cases, they arise in the gastro-enteric-pancreatic (GEP) tract, especially in the small intestine.

NENs include various diseases that differ in clinical and biological terms. Their management requires the expertise of several specialists (pathologist, medical oncologist, surgeon, nuclear medicine physician, endocrinologist, gastroenterologist, interventional radiologist, nutritionist, radiation oncologist). It is crucial that these professionals cooperate as part of a multidisciplinary team that establishes a comprehensive therapeutic strategy appropriate for the individual patient.

At IEO, we have been involved in clinical management and clinical research in patients with NENs for about 20 years. Our approach has always been multidisciplinary. Dedicated professionals have been created for each diagnostic and therapeutic specialty. We use various competencies to characterise the disease, define the patient clinical frame and the immediate and late objectives of care.

It is crucial that a dedicated pathologist is certain of the diagnosis and of some features which indicate the aggressiveness of the disease. Therefore, when possible, patients who have already had a histological diagnosis elsewhere are asked for a review by our pathologists.

From a clinical perspective, NENs are divided into two groups, functioning and non-functioning, depending on whether there is a presence or absence of a clinical syndrome related to the production and release into the circulation of one or more hormones by the tumour.

Syndromes associated with functioning NENs are various, the best known is the carcinoid syndrome, that most often appears as redness of the face (so-called flushing) and diarrhoea.

From am anatomic-pathological perspective, GEP NENs are classified into three groups, based on the proliferation index (that is the amount of tumour cells in the reproduction phase). Ki67 <2% and/or mitotic index <2 HPF (high power fields) = G1; Ki67 3-20% and/or mitotic index 2-20 HPF = G2; and Ki67> 20% and/or mitotic index> 20 HPF = G3. The first two groups, G1 and G2, are also called NEUROENDOCRINE TUMOURS (NET), while the third group, G3, forms the NEUROENDOCRINE CARCINOMAS (NEC).

Pulmonary NENs have a different classification, also prepared by WHO, which breaks them down as follows; typical carcinoid and atypical carcinoid (less aggressive forms), large cell neuroendocrine carcinoma and small cell neuroendocrine carcinoma (the most aggressive).

Carcinomas usually evolve rapidly and are treated with chemotherapy. G1 tumours and typical carcinoid tumours are generally slow in evolution, and are treated with non-intensive medical therapies, such as somatostatin analogues (octreotide or lanreotide). G2 tumours and atypical carcinoid tumours can behave differently and are treated according to their specific characteristics.

Approximately 5-10% of GEP-NENs are hereditary and may occur as part of syndromes such as MEN-1, MEN-2, von Hippel-Lindau’s disease (VHL), neurofibromatosis type 1 (von Recklinghausen's disease, NF1) and tuberous sclerosis. These syndromes may be suspected on the basis of family history, age of NEN onset and/or characteristic clinical details. The clinician works with the geneticist and the prevention expert for the right framing and eventual discussion of genetic testing.

Multiple endocrine neoplasia (MEN)

They represent familial forms of neuroendocrine neoplasms and include two types, MEN-1 and MEN-2. The MEN-1 is characterised by the three "p" (pituitary, pancreas and parathyroid), because it is an association of pituitary adenomas, endocrine neoplasms of the pancreas, and hyperparathyroidism. Hypercalcaemia due to hyperparathyroidism is the most frequent clinical manifestation of MEN-1. The MEN-2 syndrome is correlated with medullary thyroid carcinoma (MTC). Among the MEN-2, the most common form is the MEN-2A which occurs with MTC in 90% of cases, with pheochromocytoma in 50%, and with hyperparathyroidism. In MEN-2B, in addition to CMT and pheochromocytoma, the marfanoid habitus and ganglioneuromatosis of the mucous membranes and the gastrointestinal tract are observed.

The vast majority of NENs are not hereditary; they are defined as sporadic. For these, there is no specific prevention. It is generally believed that for the correct diagnosis of MEN, it is vital to know what it is and therefore to suspect it exists. 

For patients diagnosed with NEN who turn to IEO for treatment planning, an algorithm of reasoning can define at least three aspects:

1. certain diagnosis
2. adequate staging
3. prognostic estimation

1. Certain NEN diagnosis is only anatomic-pathological. It is the pathologist who will tell if it is a "pure" NEN (that is a totally or almost totally neuroendocrine neoplasm),  an "adenocarcinoma with neuroendocrine aspects" or a "mixed carcinoma". It should be emphasised that only in cases of pure NE will staging and specific therapy for a neuroendocrine tumour be carried out. In cases with external anatomic-pathological diagnosis, IEO usually requires a review of the histopathological preparation to be carried out by the IEO reference pathologist for neuroendocrine neoplasms.
2. It is necessary to perform two types of test, one morphological (ACT or magnetic resonance) and one functional (searching of the somatostatin receptors using either scintigraphy with labelled octreotide, or octreoscan ®, or using PET with Gallium 68 in the case of well-differentiated NENs); possibly PET/CT with FDG can be used in case of neuroendocrine carcinomas.
3. Finally, it is appropriate to acquire two pieces of anatomic-pathological data such as differentiation and proliferation index (Ki67 or mitotic index); it is also appropriate to acquire two pieces of functional data (PET with FDG and octreoscan ® or PET with Gallium 68 ) and one piece of radiological data (namely how two radiological examinations carried out at different times are different).

Having achieved a clear idea of the tumour characteristics and the patient has been clinically profiled, the early and late treatment objectives are set. The therapeutic decision comes almost always from a multidisciplinary discussion. The group is critical in determining the overall therapeutic strategy rather than each single treatment, its clinical indication and the technical feasibility of that specific treatment.

Over the years, there has been an increase in available therapies thanks to research and they are now numerous. They include chemotherapy, interferon, somatostatin analogues, molecular targeted agents (in particular, everolimus and sunitinib), radioreceptor therapy, local hepatic treatments using interventional radiology (TACE, TAE, TARF, HIFU, DEB-TACE), stereotactic radiotherapy, surgical resection of metastases and/or primary tumour, and even liver transplantation, in very selected cases. Many of these therapies are in the experimental stage.

Chemotherapy used in NENs includes different medications and it is offered when the disease is metastatic or if radical resection cannot be performed. Chemotherapy has a primary a role in aggressive NENs; however, certain types of chemotherapy may also be offered in less aggressive forms, in which drugs at low dosage are usually used with daily oral administration, even if in this case there is no chemotherapy that can be defined as "standard".

Ongoing trials at IEO are for patients with unresectable or metastatic disease.

Among the molecular target drugs, Everolimus (m-TOR inhibitor) and Sunitinib (inhibitor of VEGFR, PDGFR, KIT, FLT3, and RET) have been approved by the Italian Medicines Agency (AIFA) for advanced pancreatic NETs that are progressing. To date, however, only Everolimus can be prescribed through the National Healthcare System (SSN).

Everolimus is also being studied in lung and thymic carcinoids. At IEO, the LUNA trial is currently ongoing, in which Everolimus can be administered alone or in combination with Pasireotide (a somatostatin analogue having a spectrum of activity broader than octreotide and lanreotide). The combination of everolimus/pasireotide is extremely innovative and we have already studied this combination in patients with pancreatic NET (international COOPERATE-2 study), with some of them still in treatment. Similarly some other patients are still in treatment with Everolimus, which has been studied for non-functioning NEN (international study RADIANT-4) or associated with octreotide in first-line (Italian multicentre ITMO study).

Patients with advanced pancreatic NET in progression phase can be evaluated at IEO for therapy with sunitinib as part of an international phase IV study (IEO is the only Italian participant centre).

Patients with advanced NET on octreotide or lanreotide therapy, who have radiological progression (for example, at CT or magnetic resonance), functional progression (for example octreoscan or PET), biochemical progression (for example, blood chromogranin-A) or clinical progression (for example syndrome rising) can be evaluated for a multicentre Italian study with Lanreotide at high dose (LANDH), which schedules the administration of lanreotide autogel at a dose of 180 mg every 4 weeks.

Patients who have NET associated with uncontrolled carcinoid syndrome under somatostatin analogue treatment at maximum dosage can be evaluated for an experimental therapy with Telotristat (oral inhibitor of the enzyme tryptophan hydroxylase), which reduces the production of serotonin, a substance believed to be responsible for the severe diarrhoea and possible damage to the heart valve and mesenteric fibrosis in patients with carcinoid syndrome.

The radio-receptor therapy (PRRT) is an innovative and very promising therapy. It is applied to unresectable or metastatic NENs that express somatostatin receptors. These receptors, identified with the methods of nuclear medicine (octreoscan ® or PET/T with Gallium 68-Dota), are the target of a drug consisting of a somatostatin analogue binded to a radioisotope (Yttrium-90 or more recently Lutetium-177). PRRT can be proposed in the context of a clinical trial (NETTER-1 study) conducted in patients with NET of the small intestine, unresectable or metastatic, octreoscan® positive, that are in radiological progression during therapy with octreotide LAR at the dosing of 30 mg every 4 weeks.

Treatments of interventional radiology, partly still at the experimental stage, are divided into ablative, such as radiofrequency thermal ablation (RFA), and vascular, such as chemo-embolisation (TACE, TAE, DEB-TACE) and radio-embolisation performed by the intra-arterial infusion of microspheres preloaded with Yttrium-90 (SIRT). The indication to this kind of treatment is always given after group discussion within the context of our multidisciplinary group.

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For over ten years, the multidisciplinary NET group (IEO NET Study Group) has met weekly to discuss clinical cases. The number of cases discussed has been increasing over the years exceeding the 300 discussions/year in the last few years, with about 200 new patients per year.

Some members of the IEO NET Study Group have also participated in the drafting of the AIOM/ITANET NEN National Guidelines, 2013 version, available at the website of the Italian Society of Medical Oncology (AIOM).

Every year we organise national training courses aimed at spreading the multidisciplinary approach to the NENs. The members of the IEO NET Study Group interact with a predetermined number of groups of Italian clinicians.

Finally, there is an association of patients affected by NENs. Its name is “NET Italy” and it involves volunteers who express participation, solidarity and pluralism to the patient, families and acquaintances of NEN patients. Another purpose is to act for the benefit of the whole community with the aim of promoting health education, with particular emphasis to NENs, favouring the dissemination of research and its results for the benefit of the community.