A neuroendocrine cell tumor, or NET, is a relatively rare neoplasm that can develop in all body regions where the hormone-producing cells are present. Tumors that develop from the neuroendocrine cells preserve the ability to produce hormones and respond to the impulses from the autonomic nervous system. In addition to unusual and variable clinical picture due to the hormones overproduction, NETs can develop features of malignant neoplasms, invading healthy tissues and requiring active therapy. In a number of cases patients need to treatment abroad in order to find a competent doctor and specialized healthcare facility.
- Pathohistology and causes of neuroendocrine tumors
- Types of neuroendocrine tumors
- Clinical manifestations and complaints
- Diagnostic procedures
- Choosing between invasive and conservative treatment methods
- Treating neuroendocrine tumors in the leading hospitals with Booking Health
Pathohistology and causes of neuroendocrine tumors
A group of neuroendocrine tumors unites heterogeneous neoplasms that arise from lungs, adrenal glands, appendix, rectum, pancreas, and other organs of the digestive tract. Their common feature is combining properties of hormone-producing cells and nerve cells. Neuroendocrine tumors are able to accept electric signals from the nervous system and discharge hormones into the bloodstream in response to such stimuli. Pathohistology of such tumors depends on the type on the progenitor cell.
What are neuroendocrine tumors?
Neuroendocrine tumors are rare neoplasms that arise from the specialized cells of neuroendocrine system. The neuroendocrine system is present in many organ systems, as it controls and coordinates a number of body’s functions. NETs are usually considered malignant neoplasms, despite the fact that many of them grow slowly and need years to develop.
Depending on the speed of growth, tendency to metastasizing and invading neighboring organs, all NETs can be divided into the benign and malignant ones. Benign, or non-cancerous, tumors grow slowly and manifest themselves mainly with unexplainable hormonal changes. Malignant, or cancerous, ones tend to spread through the organism, invade nearby organs and cause both local and hormonal symptoms.
Is neuroendocrine cancer hereditary?
Fortunately, neuroendocrine cancer has not demonstrated hereditary nature and parents with this condition may give birth to healthy children. Nevertheless, it should be noted that certain hereditary conditions are associated with higher risks of NET development. Thus, in presence of MEN-1, MEN-2, etc. attention should be paid to NET screening.
The majority of NET tumors are sporadic. This means that they are not transmitted from parents to children, but arise as the newly onset conditions. Nevertheless, few hereditary syndromes increase chances of developing neurocarcinoma. These are multiple endocrine neoplasia type 1, multiple endocrine neoplasia type 2, neurofibromatosis, von Hippel-Lindau syndrome, and tuberous sclerosis.
Types of neuroendocrine tumors
Neuroendocrine tumors classification depends, first of all, on the localization and hormonal activity. The following tumor types are distinguished regarding these parameters.
Gastroenteropancreatic neuroendocrine tumors are most often found at age 50-60, by accident (during surgical interventions for other reasons). This is connected with absence of acute and specific clinical manifestations. Gastroenteropancreatic neuroendocrine tumors include the following subtypes:
- Appendiceal neoplasms are typically found postoperatively, during the histological examination of the removed during appendectomy tissue specimens. Appendiceal neoplasms are benign and rarely cause the carcinoid syndrome (in less than 1% of cases).
- Gastric neoplasms may be associated with chronic atrophic gastritis, Zollinger-Ellison syndrome, MEN-1, or be sporadic. These are usually the sporadic tumors that produce actively histamine and serotonin, causing an atypical carcinoid syndrome.
- Colorectal neoplasms are divided into small-cell and moderately differentiated carcinomas. The first ones are somewhat similar to small-cell lung cancer and require chemotherapy. The second ones resemble large-cell lung carcinoma and are successfully treated surgically.
- Pancreatic neoplasms originate from the diverse cells of pancreatic islets.
Due to the diversity of secreted hormones, the pancreatic NETs are divided into numerous subtypes:
- Insulinoma is a beta-cell neoplasm that is capable of the excessive insulin secretion. This is the most widespread pancreatic NET.
- Gastrinoma typically arises in the pancreas or duodenum and is responsible for the development of Zollinger-Ellison syndrome or peptic ulcers against the background of high gastrin levels.
- VIPoma is a component of MEN-1 syndrome. VIPoma autonomously and uncontrollably synthesizes the vasoactive intestinal peptide.
- Glucagonoma is responsible for the overproduction of hormone glucagon. Due to its potent action, the excess of glucagon causes a paraneoplastic phenomenon with diabetes mellitus, dermatitis, depression, and deep vein thrombosis.
- Somatostatinoma is the rarest pancreatic NET. High levels of hormone somatostatin suppress the work of the gastrointestinal tract, and the diagnosis is easily confirmed by the elevated somatostatin blood levels.
- Pancreatic polypeptide-secreting tumor is a rather common NET type, although it is not associated with any clinical syndrome. Non-specific symptoms, like abdominal pain or jaundice, may be associated with the tumor presence.
Adrenal cancer and pheochromocytoma. Pheochromocytoma is a benign neoplasm that arises from the adrenal gland. This is a rather common condition that is characterized by the excessive secretion of catecholamines and is often found in young patients with arterial hypertension. On the contrary, adrenal cancer is a malignant pathology that tends to metastasizing to the distant body parts.
Merkel cell carcinoma is a rare skin malignant neoplasm that arises on head, neck or face. The condition is typically diagnosed in older people, as well as in people with weak immunity. The tumor may be superficial or may spread deeper, beyond the skin.
Tumors of the genitourinary tract appear in kidneys and bladder, ovaries and cervix uteri (women), prostate and testicles (men). Due to the weak hormonal activity, they are rarely diagnosed (except for testicular and ovarian ones).
Pulmonary tumors comprise typical and atypical carcinoids, large cell neuroendocrine carcinoma, and small-cell lung carcinoma. The pathologies are listed in order of aggressiveness increasing and prognosis worsening. It should be noted, that pulmonary endocrine neuro cancer has the same cell of origin with small cell lung cancer.
What are most common endocrine tumors?
The most common endocrine tumors are found in the organs that synthesize hormones actively, i.e. pancreas and the adrenal glands. Such neoplasms are accompanied by bright clinical picture and require surgical treatment. Fortunately, they rarely invade the nearby organs or metastasize, so the surgical removing of the primary tumor is often curative.
Clinical manifestations and complaints
Due to the heterogeneity of the cellular progenitors of NETS, neuroendocrine cancer symptoms include a bunch of specific and non-specific clinical manifestations. Patients with pancreatic neoplasms may suffer from:
- Unusual hunger and weight loss
- Stomach pain
- Headache and dizziness
- Fast heartbeat
- Trembling hands and body
Carcinoid tumors with an excessive secretion of histamine and serotonin manifest themselves with the following complaints:
- Red and warm skin of the face and neck
- Itching skin of the face and neck
- Trouble breathing
- Pain in the chest, coughing
- Unintended body mass changes
- Other neuroendocrine cancer symptoms include:
- Nausea or vomiting
- Pain of different localization and intensity
- Fast heart rate, sweating, night sweats
- Yellowish skin and / or eyes
- Bleedings without any obvious cause
- Unintended body mass changes (both gain and loss)
However, in NETs sole symptoms cannot be the basis for the diagnosis making. Comprehensive clinical, laboratory and visualizing studies are required for the final diagnosis establishment.
Neuroendocrine cell tumors are hard to detect, as they may be tiny, up to few millimeters in size, but cause severe symptoms. This is explained by the biological activity of hormones that are produced by such tumors. Even few molecules of a hormone may launch the biological process. Thus, the diagnosis of NET is often the exclusion diagnosis – a physician looks for more typical causes of the symptoms first and proceeds to looking for NET only in absence of such causes.
Physical examination is important in terms of receiving information about general patient’s health state. Unfortunately, there are no clinical signs that could be pathognomonic for NETs. Thus, the laboratory examination is the obligatory next diagnostic step. Laboratory analyses include both general (complete blood count, renal and liver function tests, coagulogram, etc.) and special (hormone levels, tumor markers, etc.) ones. Depending on the tumor suspected, special analyses may include:
- Blood tests for insulin, somatostatin, glucagon and other hormones
- Urine analysis for metanephrine and normetanephrine
- Serum chromogranin A
- Urinary 5-HIAA excretion
Visualizing studies comprise CT scan, MRI, and specific octreotide scan. In octreotide scan, a patient receives an intravenous injection of radiopharmaceutical that is bound to NET cells and makes them visible for the scanner. When the tumor is found or its localization is suspected, a biopsy may be performed in order to investigate properties of the tumor better. Biopsy allows for the most precise diagnosis making and elaborating the most suitable treatment regimen.
Choosing between invasive and conservative treatment methods
When treating low-to-intermediate NETs, doctors start from curative surgeries (if possible) and medical management aimed at relieving symptoms, suppressing tumor growth and metastasizing prevention. The following systemic treatments are applied in different clinical cases:
- Somatostatin analogs (lanreotide and octreotide) are administered to patients with carcinoid syndrome and gastroenteropancreatic tumors.
- Peptide receptor radionuclide therapy (PRRT). The majority of gastroenteropancreatic neoplasms express receptors to somatostatin on their surface. Thus, radioactive substances that bind to the same receptors are able to destroy such tumors.
- Interferon alpha reduces the hormone output and alleviates clinical manifestations significantly. In addition, long-term drug intake leads to the improvement of tumor marker levels.
- Everolimus affects the signal pathway mTOR (mechanistic pathway of rapamycin) that is involved into the NETs development. It may be prescribed in combination with somatostatin analogs.
- Sunitinib inhibits vascular endothelial growth factor receptor (VEGFR) of the 1, 2 and 3 type. This prevents tumor from growing large and metastasizing.
- Bevacizumab is a humanized monoclonal antibody to vascular endothelial growth factor A. Similar to sunitinib, bevacizumab suppresses growth of tumor blood vessels and reduces its blood supply.
- Cytotoxic agents, including nitrosourea streptozocin, capecitabine, 5-FU, temozolomide and others, destroy the malignant cells directly.
When treating aggressive high-grade neuroendocrine tumors (the extrapulmonary ones) healthcare specialists may perform surgeries, administer diverse chemotherapeutic regimens, selective internal radiation therapy, and radionuclide therapy (e.g. I-131 MIBG, Y-90 DOTA octreotide).
Since January 2018, an innovative method for the treatment of gastroenteropancreatic neuroendocrine tumors has been implemented into the clinical practice – the radionuclide therapy with the Lutetium-177 isotope. 177Lu-DOTATATE has been approved by the Food and Drug Administration (FDA) for its proven efficacy, i.e. reducing tumor size, eliminating hormone-related symptoms, and improving quality of life. At the moment, the use of 177Lu-DOTATATE demonstrates the highest efficiency among all known methods of treatment. Radionuclide therapy with the Lutetium-177 is used as monotherapy, as well as in combination with somatostatin analogues in patients with somatostatin receptor positive neoplasms.
After the stage of active treatment and selecting the proper consolidating therapy, it is better to undergo rehabilitation. Timely professional rehabilitation improves patient’s health state and the quality of life. One can undergo an individual rehabilitation program in the following German hospitals:
- Rehabilitation Clinic Benedictus Krankenhaus Feldafing
- Neurological Rehabilitation Clinic RehaNova Cologne
- Maternus Rehabilitation Clinic Bad Oeynhausen
- St. Mauritius Therapieklinik Meerbusch
- Neurological Rehabilitation Clinic Godeshöhe Bonn
Treating neuroendocrine tumors in the leading hospitals with Booking Health
Making the diagnosis of a neuroendocrine tumor requires from healthcare professionals extensive practical experience and profound clinical thinking. In addition, precise laboratory, instrumental and genetic tests should be available in the healthcare institution. University hospitals in Germany offer the whole range of diagnostic and therapeutic options for patients with NETs of different localizations.
Patients from all world’s countries can receive medical help from German healthcare practitioners due to services of Booking Health. Booking Health is the only company with the international quality control certificate ISO 9001:2015 in the field of medical tourism. The company offers all-inclusive assistance in the diverse aspects of undergoing treatment abroad:
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Should you fill in the "Send request" form on the Booking health website and a medical advisor or patient case manager will contact you the same day and provide with further guidance.
Choose treatment abroad and you will for sure get the best results!
Author: Dr. Nadezhda Ivanisova