Gastroenteropancreatic Neuroendocrine Tumors- Classification, Symptoms, Diagnosis, and Treatment

Introduction:

Gastro-Entero-Pancreatic (GEP) Neuroendocrine Tumors (NETs) are uncommon growths that have become more prevalent in the last thirty years. There is better awareness and understanding of these tumors, which can vary greatly in behavior and progression. While most NETs release hormones causing specific symptoms, some remain hidden until they cause physical effects. Treatment approaches should be personalized, considering the tumor's likely progression and the patient's overall health. Options include surgery for cure or symptom relief, various methods to reduce tumor size, and medical interventions like chemotherapy and biotherapy to manage hormone-related symptoms and tumor growth.

What Are Gastroenteropancreatic Neuroendocrine Tumors?

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) originate from neuroendocrine cells found throughout the gastrointestinal tract. They form a diverse group with varying clinical behaviors. Despite being considered rare, recent US data from the surveillance epidemiology and results reveal a significant over 400% rise in GEP-NET incidence from 1973 to 2004.GEP-NETs are more prevalent than combined stomach and pancreatic carcinomas. Typically diagnosed in the fifth decade, these tumors can emerge sporadically or due to hereditary predisposition syndromes like multiple endocrine neoplasia type-1, Von Hippel-Lindau's disease, or neurofibromatosis type-1.

NETs arising from the GEP system are rare and uncommon and emerge from the diffuse endocrine system in the gastrointestinal tract, referred to as carcinoids, and the pancreas (insular tumors), displaying diverse clinical presentations. GEP-NETs constitute around two percent of all GI tumors. While GEP-NETs originate within the GI tract, NETs can also emerge in other locations such as the bronchus and lung, thyroid, hypophysis, thymus, medulla, and adrenal cortex. In the case of GEP-NETs, they can enhance the activity of their source cells, leading to the secretion of various peptides and neurotransmitters. This secretion can result in distinct clinical syndromes in 'functioning' tumors, or the tumors can remain biologically inactive as non-functioning tumors. The latter can occur due to defects in hormonal synthesis or secretion, rapid hormone degradation, production of inactive hormone precursors, or simultaneous secretion of opposing hormones.

How Are GEP-NETs Classified?

1. GEP-NETs are classified as:

• Embryonic origin-based classification:

• Carcinoids from foregut: Stomach, proximal duodenum, biliary tract, and pancreas.

• Carcinoids from midgut: Distal duodenum, small intestine, appendix, right colon.

• Carcinoids from hindgut: Descending colon, sigmoid colon, rectum.

2. Recent WHO classification (clinical pathological criteria):

• Well-differentiated endocrine tumors: Benign or uncertain behavior.

• Well-differentiated endocrine carcinomas: Low-grade malignant behavior.

• Poorly differentiated endocrine carcinomas (small cell carcinomas): High-grade malignant behavior.

• Mixed endocrine-exocrine carcinomas: Display characteristics of both endocrine and exocrine tumors.

Each category can include functioning (hormone-producing) and non-functioning tumors.

What Are the Symptoms of GEP-NETs?

The clinical features or symptoms vary depending on the site, size, and hormone production. These include:

1. Carcinoid Syndrome Symptoms: In cases where the tumor produces excess hormones (such as serotonin), symptoms like skin flushing, diarrhea, wheezing, and heart palpitations can occur.

2. Abdominal Pain: Many GEP-NETs are asymptomatic, but larger tumors or those affecting the gastrointestinal tract can cause abdominal pain.

3. Bowel Obstruction: Tumors located in the small intestine or colon can cause bowel obstruction, leading to symptoms like nausea, vomiting, and abdominal distention.

4. Change in Bowel Habits: Diarrhea, constipation, or changes in stool consistency can occur due to hormonal imbalances caused by the tumor.

5. Unexplained Weight Loss: Advanced tumors might lead to weight loss due to decreased appetite and malabsorption.

6. Gastrointestinal Bleeding: Tumors in the digestive tract can cause bleeding, leading to symptoms like dark stools or blood in the stool.

7. Fatigue: Generalized weakness and fatigue can result from chronic illness and hormone imbalances caused by the tumor.

8. Hyperglycemia: Some GEP NETs produce insulin-like hormones that can lead to low blood sugar levels (hypoglycemia) or high blood sugar levels (hyperglycemia).

9. Cardiac Issues: Carcinoid tumors can affect the heart valves, causing symptoms like murmurs or, in severe cases, heart failure.

10. Neurological Symptoms: Rarely, tumors producing hormones might cause neurological symptoms such as confusion, dizziness, or fainting.

GEP-NETs are also associated with the following syndromes:

• Carcinoid Syndrome: Characterized by flushing, diarrhea, wheezing, and heart palpitations. It occurs when tumors produce excessive serotonin and other vasoactive substances.

• Zollinger-Ellison Syndrome: Caused by gastrin-secreting tumors, leading to excessive stomach acid production, ulcers, and recurrent abdominal pain.

• Insulinoma Syndrome: Results from insulin-secreting tumors, causing low blood sugar levels, leading to confusion, tremors, and fainting.

• Glucagonoma Syndrome: Associated with tumors producing glucagon, leading to high blood sugar levels, skin rash, weight loss, and anemia.

• VIPoma Syndrome: Linked to tumors producing vasoactive intestinal peptide (VIP), causing profuse diarrhea, electrolyte imbalances, and dehydration.

• Somatostatinoma Syndrome: Occurs with tumors releasing excess somatostatin, leading to symptoms like diabetes, steatorrhea (fatty stools), and gallstones.

• Multiple Endocrine Neoplasia (MEN) Syndromes: Some GEP-NETs are associated with inherited conditions like MEN-1 and MEN-2, which can lead to multiple tumors in different endocrine glands.

What Is the Diagnostic Procedure for GEP-NETs?

The diagnosis of GEP-NETs involves:

Clinical Evaluation: A physician will assess medical history, symptoms, and potential risk factors. They will inquire about symptoms such as abdominal pain, changes in bowel habits, flushing, and other related issues.

Laboratory Tests:

• Blood Tests: These include measuring hormone levels (like serotonin, gastrin, insulin) and biomarkers associated with GEP-NETs.

• Chromogranin A: A blood test to detect the presence of neuroendocrine tumors.

Imaging Tests:

• CT (Computed Tomography) Scan: CT scans provide detailed images of the abdomen and other areas, helping identify the location, size, and extent of the tumor.

• MRI (Magnetic Resonance Imaging): MRI provides additional information about the tumor's characteristics and its relation to nearby structures.

• Octreotide Scan: A specialized imaging test using a radioactive substance attached to a hormone called octreotide, which binds to neuroendocrine tumor cells and can be detected by a scanner.

• Somatostatin Receptor Scintigraphy (SRS): Similar to an octreotide scan, this test helps visualize the presence of somatostatin receptors on tumor cells.

Endoscopy: If the tumor is suspected to be in the GIT, an endoscopy might be performed to directly visualize and obtain tissue samples (biopsies) for analysis.

Biopsy: Tissue samples obtained through endoscopy, surgery, or other methods are examined under a microscope to confirm the presence of a GEP-NET and determine its type and grade.

Pathological Examination: A pathologist will analyze the tissue samples to assess the tumor's histology, grade, and potential hormone production.

Genetic Testing: Genetic testing might be performed in cases of suspected inherited syndromes like MEN-1 or MEN-2.

What Is the Treatment of GEP-NETs?

Treatment approaches include:

Surgery: Surgical tumor removal is often the primary treatment, especially for localized tumors. The extent of surgery may vary from tumor excision to removal of an organ portion.

Medical Therapies:

• Somatostatin Analogs: Drugs like octreotide and lanreotide can control hormone-related symptoms and slow tumor growth by blocking hormone release.

• Targeted Therapies: Medications that target specific pathways involved in tumor growth, such as Everolimus and Sunitinib.

• Peptide Receptor Radionuclide Therapy (PRRT): A radioactive substance is attached to a somatostatin analog and delivered to tumor cells, destroying them.

Chemotherapy: Used primarily for poorly differentiated or aggressive tumors, chemotherapy aims to slow tumor growth and manage symptoms.

Embolization: Blocking blood vessels that supply the tumor, cutting off and shrinking the blood supply.

Radiation Therapy: Used to target localized tumors or manage symptoms in cases where surgery is not an option.

Liver-Directed Therapies: Treatments like radioembolization and chemoembolization can be considered for tumors that have spread to the liver.

Biological Therapies: These involve using the body's immune system to fight the tumor, including immunotherapy approaches.

Combination Therapies: Different treatment modalities may achieve the best outcome depending on the tumor's characteristics.

Supportive Care: Managing symptoms and maintaining overall health through nutritional support, pain management, and addressing hormonal imbalances.

Conclusion:

Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs) present a diverse group of tumors originating from neuroendocrine cells in the gastrointestinal tract and pancreas. The clinical features of GEP-NETs vary widely, influenced by factors such as tumor size, location, and hormone production. Additionally, these tumors are associated with distinct syndromes due to the secretion of hormones that can lead to a range of systemic effects. Diagnosis involves clinical evaluation, lab tests, imaging, and biopsies. Treatment options include surgery, medical therapies, and targeted treatments, often personalized based on tumor characteristics.