The art of diagnosis in complex clinical cases: neuroendocrine tumors (NETs)

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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 the unusual and variable clinical picture due to the hormone overproduction, NETs can develop features of malignant neoplasms, invading healthy tissues and requiring active therapy. In many cases, patients need treatment abroad to find a competent doctor and specialized healthcare facility.

Content

1. Pathohistology and causes of neuroendocrine tumors
2. Types of neuroendocrine tumors
3. Clinical manifestations and complaints
4. Diagnostic procedures
5. Choosing between invasive and conservative treatment methods
6. 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 the 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 of the progenitor cell.

What are neuroendocrine tumors?

Neuroendocrine tumors are rare neoplasms that arise from the specialized cells of the neuroendocrine system. The neuroendocrine system is present in many organ systems, as it controls and coordinates a number of the body’s functions. NETs are usually considered malignant neoplasms, despite many of them growing slowly and needing years to develop.

Depending on the growth speed, tendency to metastasize, and invading neighboring organs, all NETs can be divided into 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 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 the 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 newly onset conditions. Nevertheless, few hereditary syndromes increase the 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 tumor 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 the absence of acute and specific clinical manifestations. Gastroenteropancreatic neuroendocrine tumors include the following subtypes:

1. Appendiceal neoplasms are typically found postoperatively, during the histological examination of the removed during appendectomy tissue specimens. Appendiceal neoplasms are benign and rarely cause carcinoid syndrome (in less than 1% of cases).
2. Gastric neoplasms may be associated with chronic atrophic gastritis, Zollinger-Ellison syndrome, MEN-1, or sporadic. These are usually the sporadic tumors that actively produce histamine and serotonin, causing an atypical carcinoid syndrome.
3. 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.
4. 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 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.
• 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 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 metastasize to distant body parts.

Merkel cell carcinoma is a rare skin malignant neoplasm that arises on the 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 and endocrine neuro cancer has the same cell of origin as small cell lung cancer.

What are the most common endocrine tumors?

The most common endocrine tumors are found in the organs that synthesize hormones actively, i.e., the pancreas and the adrenal glands. Such neoplasms are accompanied by a bright clinical picture and require surgical treatment. Fortunately, they rarely invade the nearby organs or metastasize, so the surgical removal 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
• Diarrhea
• Headache and dizziness
• Fast heartbeat
• Trembling hands and body
• Sweating
• Weakness

Carcinoid tumors with 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
• Diarrhea
• Unintended body mass changes
• Other neuroendocrine cancer symptoms include:
• Nausea or vomiting
• The pain of different localization and intensity
• Fast heart rate, sweating, night sweats
• Fever
• Yellowish skin and/or eyes
• Rash
• 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 made. Comprehensive clinical, laboratory, and visualizing studies are required for the final diagnosis establishment.

Diagnostic procedures

Neuroendocrine cell tumors are hard to detect, as they may be tiny, up to a few millimeters in size, but cause severe symptoms. This is explained by the biological activity of hormones produced by such tumors. Even a few molecules of a hormone may launch the biological process. Thus, diagnosis of NET is often the exclusion diagnosis – a physician looks for more typical causes of the symptoms first and proceeds to look for NET only in the absence of such causes.

Physical examination is important in receiving information about the 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, and other hormones
• Urine analysis for metanephrine and normetanephrine
• Serum chromogranin A
• Urinary 5-HIAA excretion

Visualizing studies comprise CT scans, MRI, and specific octreotide scans. In an octreotide scan, a patient receives an intravenous injection of radiopharmaceutical that is bound to NET cells and makes them visible to the scanner. When the tumor is found or its localization is suspected, a biopsy may be performed to investigate the properties of the tumor better. A biopsy allows for the most precise diagnosis and elaborates the most suitable treatment regimen.

 

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Choosing between invasive and conservative treatment methods

When treating low-to-intermediate NETs, doctors start with curative surgeries (if possible) and medical management to relieve symptoms, suppress tumor growth, and metastasize prevention. The following systemic treatments are applied in different clinical cases:

1. Somatostatin analogs (e.g., octreotide) are administered to patients with carcinoid syndrome and gastroenteropancreatic tumors.
2. 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.
3. Interferon alpha reduces the hormone output and alleviates clinical manifestations significantly. In addition, long-term drug intake leads to improved tumor marker levels.
4. Drugs that affect the signal pathway mTOR (mechanistic pathway of rapamycin) that is involved in the NETs development. It may be prescribed in combination with somatostatin analogs.
5. Sunitinib inhibits vascular endothelial growth factor receptor (VEGFR) of the 1, 2, and 3 types. This prevents the tumor from growing large and metastasizing.
6. Humanized monoclonal antibodies to vascular endothelial growth factor-A. Similar to sunitinib, such antibodies suppress the growth of tumor blood vessels and reduce their blood supply.
7. Cytotoxic agents that destroy the malignant cells directly.

When treating aggressive high-grade neuroendocrine tumors (the extrapulmonary ones), healthcare specialists may perform surgeries, administer various 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 treating 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 analogs 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 a patient’s health state and quality of life. One can undergo an individual rehabilitation program in the following German hospitals:

1. Rehabilitation Clinic Benedictus Krankenhaus Feldafing
2. Neurological Rehabilitation Clinic RehaNova Cologne
3. Maternus Rehabilitation Clinic Bad Oeynhausen
4. St. Mauritius Therapieklinik Meerbusch
5. Neurological Rehabilitation Clinic Godeshöhe Bonn

 

 

Find specialized hospital & treatment

Treating neuroendocrine tumors in the leading hospitals with Booking Health

Making the diagnosis of a neuroendocrine tumor requires extensive practical experience and profound clinical thinking from healthcare professionals. In addition, special laboratory, instrumental and genetic tests should be available in the healthcare institution. University hospitals in Germany offer a whole range of diagnostic and therapeutic options for patients with NETs of different localizations.

Patients from all world countries can receive medical help from German healthcare practitioners due to the services of Booking Health. The company offers all-inclusive assistance in the diverse aspects of undergoing treatment abroad:

• Choosing the clinic and physician based on the qualification profile and success rates
• Establishing communication with the selected physician
• Booking the appointment on the convenient date
• Preparing medical program in advance, explaining all the recommended procedures
• Providing favorable costs for medical and relevant services
• Excluding fees for foreign patients (saving up to 50%)
• Monitoring medical program implementation
• Organization of follow-up examinations
• Help in buying and/or forwarding medicines
• Communication with the clinic after medical program completion
• Checking invoices, returning unspent funds
• Travel service of the highest level: booking plane tickets and hotels, transfer organization
• Services of medical interpreter and translator

Should you fill in the "Send request" form on the Booking health website, a medical advisor or patient case manager will contact you the same day and provide further guidance.

 

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Choose treatment abroad and you will for sure get the best results!

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Authors:

The article was edited by medical experts, board certified doctors Dr. Nadezhda Ivanisova, Alexandra Solovey. For the treatment of the conditions referred to in the article, you must consult a doctor; the information in the article is not intended for self-medication!

 

Sources:

National Center for Biotechnology Information

National Library of Medicine

National Cancer Institute

American Cancer Society

 

 

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