What are Neuroendocrine Neoplasms (NENs)
NENs are relatively rare and heterogenous neoplasms that develop mostly in the gastrointestinal (stomach, pancreas, bowel) and respiratory (lungs) system but can be found virtually in every tissue of the human body. All NENs are considered as potentially malignant albeit the majority (70-80%) is of lower malignant potential compared to other cancers as even in the presence of metastatic disease their evolution is slower and outcomes are better compared to other cancers.
NENs are derived from neuroendocrine cells that belong to the diffuse endocrine system that have common links with the nervous and endocrine system and are characterized by their ability to synthesize and secrete compounds that when are bioactive can cause distinct clinical syndromes (such NENs are called functioning and can cause the carcinoid and other syndromes).
NENs are considered to be relatively rare affecting approximately 1/2000 inhabitants. However, during the last decades their overall prevalence has substantially increased although it is believed that a significant number still remains underdiagnosed. This is probably related to the absence or presence of non-specific symptoms related to NENs as the majority are non-functioning and thus not related to a secretory syndrome. Furthermore, related symptoms can be extremely common and non-specific, encountered in many diseases with increased prevalence such as gastritis, peptic ulcer, irritable bowel syndrome, asthma, disorders of glucose metabolism, menopause and others. For a subset of NENs (functioning NENs), approximately 20%, symptoms may be relatively specific leading to their prompt diagnosis.
NENs can be diagnosed at any age but are mostly present in the 5-6 decade of life and may develop along with other endocrine neoplasms in the context of familial syndromes that are associated with specific chromosomal abnormalities (such as Multiple Endocrine Neoplasia Syndrome 1 and others).
Common Clinical Presentation
Functioning NENs can be diagnosed because of the presence of a secretory syndrome such as in the case of carcinoid syndrome (diarrhea, flushing episodes, rashes, cramps, dyspnea and heart valvular problems). Pancreatic NENs can cause symptoms secondary to the secretion of insulin, gastrin and other hormones causing hypoglycemia and peptic ulcer disease.
Non-functioning NENs are not related to a secretory syndrome and are associated with non-specific symptoms such as abdominal pain, nausea, loss of appetite and loss of weight.
In some cases, NENs are asymptomatic and are diagnosed during imaging studies for other purposes.
In the majority of NENs, besides functioning ones, the diagnosis is made with a relative delay mainly due to the absence of specific symptoms and the slow growth of the NEN.
When the diagnosis is made at the initial stages of NEN development these neoplasms are of relatively small size usually localized and the prognosis is the most optimal. However, in their majority NENs are diagnosed relatively late when the disease has already spread to nearby (usually lymph node) or distant tissues (usually the liver). Although in such cases complete cure of the patients’ is not feasible patients can exhibit a protracted course maintaining a good quality of life with the use of different therapeutic approaches.
Blood tests give us information on general blood count, biochemistry profile, calcium, fasting gut hormones, chromogranin A, ACTH, cortisol, calcitonin, pituitary hormone screen and oncology markers.
A number of NENs secrete substances that are excreted in the urine such a 5-hyroxy-indoloacetic-acid (from serotonin metabolism) particularly those derived from the small bowel and have developed metastases to the liver. You will be asked to collect all your urine produced within 24 hours and at the same time to avoid consuming foods and drinks that may affect the measurement such as chocolates, bananas, vanilla, tomatoes and drinking coffee and alcohol.
Inspection of the upper (stomach, duodenum) and lower (large bowel, rectum and lower small bowel) gastrointestinal tract with gastroscopy and colonoscopy or their modifications. Occasionally, an endoscopic ultrasound is needed to identify the precise size and depth of bowel wall invasion from the NEN in lesions of the stomach and duodenum and identify or confirm pancreatic lesions. The investigation allows biopsy taking to verify the diagnosis further histologically. A camera can also be used to identify small bowel lesions not visible to advanced endoscopy.
Radiology- Nuclear Medicine
The localization of a NEN is best undertaken through computerized tomography (CT) or magnetic resonance imaging (MRI) for lung and abdominal (upper or lower) lesions. MRI is superior to CT to identify liver lesions using specific sequences. Radionuclear imaging with 111In-labelled octreotide or more recent with 68Gallium-DOTATATE PET/CT is used to detect the presence of somatostatin receptors that are found in the majority of NETs as their presence can predict prognosis and affect therapeutic decisions. Recently 18FDG-PET is also used to identify lesions that they have a higher proliferative capacity and can thus herald a more aggressive course.
This method allows access to a sample of the NEN either in the form of cell blocks or tissue components. It can be done either during endoscopic procedures or following biopsies in lesions of either the primary neoplasm or a metastatic deposit through a specific needle and/or during radiological procedures (endoscopy, ultrasound, CT). The patient is explicitly described the procedure and gives his consent; all such procedures should be undertaken in centers and by operators with relevant experience.
Patients with NENs of the small bowel should also undergo an echogram of the heart to identify potential valvular lesions.
Ideally decisions for the management of patients with NENs should be taken in the context of a (Multidisciplinary Team, MDT). The MDT is formed by physicians with specialties relevant to the management of patients with NENs. Each patient has a specific therapeutic plan that depends on the tissue of origin of the NEN, stage of the disease and grade and considers the performance characteristics of the patient (condition of overall health). It is important that the patient is informed and participates in decision making.
|During the course of your disease you may come across with the following specialties|
|Radiologists, Interventional Radiologist|
|Nuclear Medicine Physicians|
|Dieticians, Nurses, Pain management teams|
If the NEN is of well-differentiation and lies in a specific anatomic area (localized disease) or there is limited spread to nearby or other areas (mostly to the liver) surgery is the treatment of choice and the best option of obtaining a ‘cure’. If following surgery, the lesion(s) are completely excised, in the majority of cases no further treatment is administered and the patient is followed up at regular intervals to identify potential early recurrences. In cases of extensive disease, surgery may still be utilized particularly in the presence of a difficult to control secretory syndrome in order to reduce the tumor load or in the presence of local compressing symptoms (such as bowel obstruction, jaundice) in order to debulk part of the tumor and ameliorate symptoms. In such cases there is still residual tumor tissue.
These agents are the cornerstone of treatment for the majority of well differentiated NENs and functioning NENs. They are administered as monthly injections and cause reduction of the secretory component of the NEN and thus amelioration of the related symptoms, such as the carcinoid syndrome, whereas they can cause stabilization of the disease for a considerable period of time although reduction of the tumor load is not usually seen.
Molecular targeted therapies
The most commonly used compounds are everolimus (afinitor) και sunitinib (sutent) although many more are under development and are been evaluated in phase III trials. These compounds act by inhibiting several molecular pathways that are activated in NENs and can control the disease for a significant period of time. They are usually associated with a variety of different adverse effects however the majority of patients can tolerate treatment with only a small minority discontinuing these agents.
Occasionally, when tumor load is considerable and/or in the presence of relatively rapid growth of the neoplasm a number of different chemotherapeutic agents can be used considering patients’ characteristics. There are several different schemes that can be administered either by mouth without the need of admission to the hospital and are not associated with the known chemotherapy related side effects such as hair loss and nausea although they may need specific monitoring of the patient.
Interferon stimulates the immune system to fight cancer and may be effective, especially in combination with somatostatin analogues. Its use has been restricted due to significant adverse events.
Treatment with radiopeptides (Peptide Receptor Radiotherapy, PRRT)
This form of treatment is based in the administration of radio-labelled compounds that are attached to a chelator and the whole complex to a somatostatin analog that binds selectively to the surface of the NENs harboring somatostatin receptors. As a result, following intravenous administration these compounds bind and can be internalized to the NEN leading to cellular damage without affecting nearby healthy tissues. PRRT has been shown to be efficacious in many different NENs leading to a significant number of them in substantial reduction and disease control for a prolonged period. The radioactivity administered does not cause side effects whereas the patients do not have to be admitted to hospital but receive their treatment as outpatients.
Liver embolization, that is, cutting off the blood supply to tumours in the liver with or without the addition of chemotherapy (chemoembolization), is useful for patients who have predominantly liver disease.
Thermal ablation such as radio-frequency ablation, i.e. probes that “burn” away the tumours, may be useful in patients who have a small number of liver tumours.
Rarely, liver transplantation is considered in patients who have disease confined to the liver and have had investigations to fully exclude disease outside the liver. Even so, other criteria will need to be met and the concern is of recurrence of disease after liver transplant.