The group of neuroendocrine neoplasias (NEN) includes both benign and malignant tumours.

The origin of these tumours is found in the neuro-ectoderm (neural crest). NENs can be found primarily in the gastrointestinal tract, the pancreas or the bronchial system (airways/lungs). Within the NENs, those of the gastrointestinal tract are the most common entity (approx. 75-85%). These are called gastroenteropancreatic neuroendocrine neoplasia (GEP-NEN) in medical terminology.

GEP-NENs develop from endocrine (=hormone-producing) cells, which are distributed throughout the gastrointestinal tract and produce hormones to control the digestive process. According to their characteristics, these cells are also similar to nerve cells (=neuro). To summarise, the term neuroendocrine can be derived from this. In terms of their clinical behaviour, GEP-NENs exhibit a broad spectrum, varying from low proliferative (slow-growing) to highly proliferative (fast-growing) forms. In addition, NENs differ in their hormonal activity.

Neuroendocrine tumours of the gastrointestinal tract occur at a rate of 1 to 2 per 100,000 inhabitants per year, with an increasing frequency in recent decades. These tumours predominantly affect patients aged between 50 and 70 years. There are no differences in terms of gender distribution.

The causes for the development of neuroendocrine tumours are still largely unknown. A special form is MEN 1 (multiple endocrine neoplasia type 1) syndrome. In this case, several (multiple) tumours originating from the endocrine glands usually occur at a younger age (< 40 years). There are different variants of this disease, which occur more frequently in families, as they are caused and inherited by mutations (changes) in the genetic material. This mutation is inherited in such a way that it occurs again in the genetic material of half of the offspring of an affected parent. Unaffected children do not pass on this mutation. If MEN 1 syndrome is specifically suspected, MEN 1 genetic diagnostics are recommended.

The symptoms of neuroendocrine tumours depend on the primary location, the tumour stage, the growth rate and whether they are hormonally active or inactive. In approx. 60% of cases, these tumours are hormonally inactive (non-functional tumours) and usually present with non-specific symptoms (e.g. abdominal pain, weight loss, bleeding), which usually occur late in the course of the disease. Some tumours are able to produce and release hormones/hormonal mediators (functionally active tumours). The respective clinical picture is then characterised by the effect of the hormone released. The tumours are named according to the hormone/hormonal mediators produced, and are therefore referred to as insulinomas, gastrinomas, somatostatinomas, glucagenomas, VIPomas, etc. In the initial stage, hormones secreted into the bloodstream are usually metabolised and broken down by the liver. If the hormone concentration increases, which is usually caused by metastases of the original tumour in the liver, a so-called carcinoid syndrome can develop.

Typical symptoms of carcinoid syndrome are

1. Seizure-like reddening of the face (flushing), this reddening can also extend beyond the facial area to the upper body and be accompanied by palpitations and sweating; very rare are pronounced circulatory reactions up to collapse;
2. Cramp-like abdominal pain and diarrhoea;
3. Breathing difficulties (bronchospasms);
4. Heart problems, changes in the heart valves (insufficiencies, stenoses) in the case of a long course of the disease,
5. telangiectasias (visible dilation of superficially located tiny blood vessels).

The flushing symptoms usually last from a few seconds to a few minutes; triggering factors can include food intake, alcohol, mental stress or examinations. A carcinoid crisis is a sudden, particularly pronounced onset of these symptoms; this condition can also be potentially life-threatening. The massive release of hormones from the tumour is characterised by shock symptoms (drop in blood pressure, circulatory weakness) and swelling of the face and other parts of the body, including severe asthma attacks. Triggering factors are the mobilisation of the tumour during an operation, pressure on the tumour (during examinations) or excessive physical exertion. Pre-treatment must therefore be carried out before medical interventions.

Other defined syndromes are Zollinger-Ellison syndrome in gastrinomas (gastric ulcers, duodenal ulcers, diarrhoea), hypoglycaemia syndrome in insulinomas (hypoglycaemia) and Verner-Morrison syndrome in VIPomas (watery diarrhoea with changes in blood salts).

If GEP-NEN is suspected, a number of investigations are required to make a diagnosis, which are briefly described below.

Medical history and physical examination

During a detailed consultation, you will tell the doctor about all your symptoms and previous illnesses. A thorough physical examination will then be carried out.

Laboratory tests

A series of blood tests will be carried out on you to provide information about your general condition and certain organ functions. In addition, specific laboratory values, so-called tumour markers, are determined, which can usually be detected in functional NENs. Chromogranin A/synaptophysin are very sensitive tumour markers, but do not provide any information about the underlying NET type, localisation or extent of the disease. In functional NENs with carcinoid syndrome, a 24-hour urine sample is collected to verify serotonin-induced symptoms and the 5-hydroxyindoleacetic acid concentration is determined. Other specific parameters are determined according to the suspected NEN type (gastrin, glucose, insulin, glucagon, VIP, somatostatin, ACTH, GnRH).

Transabdominal ultrasound (sonography)

Due to its inexpensive availability and the absence of side effects or radiation exposure, sonography is now an important examination for suspected GEP-NEN. The assessment is often made more difficult by the localisation and size of the tumour, so that further imaging procedures must be used. One advantage of sonography is the ability to assess the spread of the tumour to other organs or to detect existing metastases (tumour metastases), e.g. in the liver.

Gastroscopy (gastroscopy) (depending on individual requirements)

If there are indications of NEN in the stomach/duodenum/pancreas, a gastroscopy with endosonography should be performed. In addition to the possibility of confirming the diagnosis by taking a biopsy from the tumour, the examiner should provide a precise description of the localisation and extent of the process. Pronounced inflammation of the gastric mucosa with ulceration can be indicative of a gastrinoma. If imaging does not provide reliable evidence of a tumour, a gastroscopy is recommended.

Colonoscopy (depending on individual requirements)

A colonoscopy is performed to investigate the cause of abdominal complaints and to find a possible source of bleeding in the bowel in the event of anaemia or blood in the stool. During this examination, biopsies can also be taken from conspicuous areas of the intestinal mucosa to clearly identify a colon tumour. If imaging does not provide reliable evidence of a tumour, a colonoscopy is recommended.

Endosonography (EUS) (depending on individual requirements)

Endosonography involves an endoscopy of the oesophagus/stomach/small intestine/rectum using a device with an ultrasound probe at the tip. This ultrasound probe can be guided directly to the tumour in the stomach/small intestine/rectum. This examination can also be used to detect small pancreatic tumours. Endosonography therefore allows a precise assessment of the local spread of the tumour, e.g. into neighbouring organs or lymph nodes, as well as the depth of penetration of the tumour.

Computer tomography (CT)

Computed tomography is a painless X-ray examination in which a contrast medium is administered intravenously. The relevant part of the body is examined layer by layer so that the location and size of the tumour can be determined. The exact spread of the tumour and any existing metastases, e.g. in the liver, lungs or lymph nodes, can be determined.

Magnetic resonance imaging (magnetic resonance imaging = MRI)

You may also have a magnetic resonance imaging (MRI) scan. MRI is not an X-ray examination, but is based on the effects of magnetic fields. In terms of assessing the tumour stage and operability, the procedure is comparable to computer tomography.

PET/CT for neuroendocrine tumours with various radiopharmaceuticals

- Ga-68-DOTATOC
A somatostatin receptor ligand (Ga-68-DOTATOC) is used for localisation diagnostics. It can be used to visualise specific surface receptors (somatostatin receptors) that occur in GEP-NET. As with the standard method, somatostatin receptor scintigraphy with In-111 octreotide, receptor subtypes 2 and 5 are visualised. Somatostatin receptor scintigraphy is a recognised procedure and initial results show that Ga-68-DOTATOC-PET is superior to this standard method, primarily due to the significantly higher resolution and the additional anatomical information provided by CT.

- F-18-FDG and F-18-DOPA
F-18-FDG is also used to visualise the distribution of neuroendocrine tumours with positron emission tomography (PET). F-18-FDG is a useful diagnostic tool if there is a suspicion of a dedifferentiated tumour with a high cell division rate based on histological examinations or the spread of the tumour.
An amine precursor (F-18-DOPA) is used for more specific visualisation. F-18-DOPA exploits the biological property of neuroendocrine tumours to take up more biogenic amines and then accumulate them in specific intracellular stores (vesicles). NETs show an uptake of the amine precursor F-18-DOPA in comparison to the surrounding normal tissue, allowing even the smallest metastases or even the primary tumour to be reliably visualised. In the case of de-differentiated NET, the biological property of the increased glucose utilisation rate compared to the surrounding tissue is used.
Ga-68-DOTATOC-PET/CT is indicated for assessing whether therapy with a somatostatin analogue (e.g. Sandostatin or radiopeptide therapy) is promising, as well as for monitoring the course of therapy.

Histological typing

The histological (histological) classification of neuroendocrine neoplasms/tumours/carcinomas is based on the current WHO (World Health Organisation) classification. Neuroendocrine neoplasms serve as an umbrella term and are further subdivided into neuroendocrine tumours (NET) and neuroendocrine carcinomas (NEC). The subdivision criterion is grading, which is determined by the pathologist based on the mitotic rate (cell division activity) and the proliferation index (growth activity). The grading and the cell division rate correlate with the prognosis and are decisive for determining the therapy. NETs are so-called grade 1 (low malignant) and grade 2 (intermediate malignant) tumours, NECs are grade 3 (highly malignant) tumours. According to their biological behaviour, NETs are slow-growing, partially hormone-secreting tumours. NEC are aggressive, fast-growing tumours that tend to metastasise early and have a poorer prognosis.

Tumour stage/classification

In order to determine the optimal therapy, the exact spread of the tumour must be determined in the form of the so-called TNM formula, which should result from the staging examinations. The TNM classification guarantees a determination of the anatomical extent of the tumour. Three different components are taken into account: The extent of the primary tumour (T), the absence or presence, as well as the extent of lymph node metastases (N), and the absence or presence of distant metastases (M).

Furthermore, the microscopic examination of the tumour tissue is necessary for the determination of the therapy concept to assess the malignancy, see histological typing.

Finally, the resection stage (R) is determined postoperatively (after surgery), which provides information on the absence or presence of residual tumour.

Clinical-prognostic classification

In the case of GEP-NENs, the original localisation proves to be of additional prognostic significance. There is a correlation between survival rates and the location of the primary tumour.

• Tumours of the foregut: Bronchus, esophagus, stomach, pancreas, liver, gallbladder, anterior section of the small intestine
• Tumours of the midgut: rest of the small intestine, anterior section of the large intestine
• Tumours of the hindgut (hindgut): remaining colon, rectum

The treatment of NET depends on the histological type, grading, localisation and spread. As before, only radical resection (complete surgical removal) of the NET offers a chance of cure. For NETs of the stomach/rectum (rectum) that do not exceed the mucosal level, endoscopic mucosectomy (mucosal resection) can be performed.

Primary surgery should only be performed with the aim of achieving an R0 resection. An indication for palliative resection (palliative = disease-mitigating, without the aim of a cure) is given in individual cases and is justified by the occurrence of tumour complications. The results of the investigations into the spread and stage of the tumour determine the procedure to be followed. Patients often undergo different therapies during the course of the disease. Every case of a patient with NEN is discussed in our interdisciplinary tumour conference

• Surgical therapy

As a cure can only be achieved through complete resection, all patients in whom surgery appears possible must be presented to an experienced visceral surgeon. In the case of neuroendocrine carcinomas, subsequent chemotherapy (adjuvant chemotherapy) is the standard treatment even after complete resection of the tumour.

• Drug therapy

The aims of drug therapy are

1. Improvement/control of symptoms (reduction of hormone secretion),
2. Influencing tumour growth,
3. Maintaining/improving the quality of life.

Somatostatin is a hormone produced naturally in the body; it acts as a natural antagonist of growth hormone and can reduce hormone production in various body cells. Somatostatin analogues (SSA) are used as first-line therapy for patients with functional NET and intestinal NET in stage G1/G2. These substances have a targeted and specific effect on the somatostatin receptors of the NET and inhibit both tumour growth (antiproliferative) and the sprouting and growth of tumour-related blood vessels (antiangiogenic). As a rule, therapy with SSAs is very well tolerated.

Interferons are substances produced by the body that play a controlling role in the body's

defence system (immune system) of the body. They can trigger defence mechanisms against viruses and tumour cells via various cascades. The drug interferon α has been shown to be effective against NETs, but it has more side effects than SSAs and is therefore not the drug of first choice.

New targeted therapies are increasingly being considered as an option for metastasised NETs in stage G1/G2, particularly NETs of the pancreas. These drugs interrupt certain signalling chains in the tumour cell and can thus inhibit its growth.

Systemic chemotherapies are used for growing pancreatic tumours and poorly differentiated, fast-growing NEN of any location.

• Treatment of carcinoid syndrome

The aim of therapy here is to control the symptoms of the clinical complaints caused by serotonin, see above. The substances generally used for this purpose are called somatostatin analogues (SSA). By inhibiting the production of hormones by the tumour cells, SSAs can significantly alleviate existing symptoms.

• Nuclear medicine therapies

Nuclear medicine methods extend the treatment spectrum with radioreceptor therapy (radionuclide therapy, peptide receptor radiotherapy (PRRT)). Well-differentiated NETs largely express somatostatin receptors. For treatment, radiolabelled SSAs can be coupled with a therapeutically effective radioactive source, e.g. 177 lutetium or 90 yttrium. These radionuclides are then selectively absorbed into the tumour cells via the somatostatin receptor and expose them to radiation, which leads to cell death. The prerequisite for this therapy is a high level of somatostatin receptors in the tumour and adequate liver/kidney/bone marrow function.

Selective internal radiotherapy (SIRT, radioembolisation) is a procedure for the treatment of metastases in the liver; it is a local ablative procedure, see below. Tiny beads containing the radioactive emitter 90Yttrium are introduced into the tumour via a probe inserted into the hepatic artery. This allows local irradiation of the tumour cells to be achieved. There are currently no prospective comparative studies available for this type of therapy, especially with regard to NENs.

• Radiological procedures

Local ablative treatment procedures:

These procedures are used for the targeted treatment of individual tumour metastases under imaging control. Within this group, there are different approaches for the treatment of metastases in the liver (transarterial chemoembolisation, embolisation, radiofrequency ablation, laser-induced interstitial thermotherapy, cryotherapy).

If a recurrence (recurrence of the tumour in the former tumour area) occurs, treatment should be repeated, although the restrictions on treatment described above also apply here.

The patient may eat and drink anything that is good for them and does not cause any discomfort. As functional NENs differ in terms of the hormones they secrete, specific nutritional counselling should be provided depending on the type. In addition to drug therapy, appropriate behavioural measures for symptom control can be learned. In the case of carcinoid syndromes, triggering factors such as alcohol, extraordinary psychological strain/stress should be avoided as far as possible.

Interdisciplinary patient care by a team experienced in the treatment of these rare diseases is crucial for successful therapy. A presentation in an interdisciplinary tumour board should take place prior to the initiation of treatment and in the event of planned changes to the treatment strategy. This ensures optimised individual care for the patient and takes into account the many facets of these diseases.

As this is a heterogeneous group of tumours, the prognosis varies from individual to individual. Factors that generally influence the prognosis are the tumour stage (tumour size, metastases), histological type, grading, presence of vascular invasion and location of the primary tumour.