Patient’s summary
Neuroendocrine tumors or NETs are rare cancers that arise from specialized Neural (Related to nerves) and Endocrine (Related to hormones ) cells. They can occur anywhere in the body but more common in the Gastrointestinal Tract (The food Pathway). Outside the GI Tract, they occur in the Lungs, adrenal, thyroid, skin, and parathyroid glands.
Since these tumors arise from specialized cells, some NETs produce various hormones and substances in excess amounts. These are called functional neuroendocrine tumors. Others lose their hormone-producing ability and are called non-functioning neuroendocrine tumors.
Most neuroendocrine tumors are found incidentally in imaging or endoscopy. Others present with symptoms like vague abdominal pain, Anaemia, or Symptoms caused by an excess amount of various hormones.
NETs are investigated with CT scan, MRI scan PET scans, and a specialized blood test called Chromogranin A. Endoscopies are done depending on the site of the lesion.
Treatment of Neuroendocrine tumors depends on stage of the tumor and site of origin. Best results are achieved with the complete removal of the tumor. Cytoreduction (partial removal of the tumor) also gives a reasonable outcome when complete removal is not possible.
Medications such as Octreotide and everolimus are given depending on the stage of the tumor.
What are Neuroendocrine tumors/cancers?
Neuroendocrine tumors (NETs) are rare neoplasms that occur from the neural and endocrine cells of the body. Although they are common in the gastrointestinal tract, they occur outside the gastrointestinal tract as well. The majority of the neuroendocrine tumors are discovered incidentally. However, some present with unique symptoms and signs.
Neuroendocrine cells are specialized hormone-producing cells. These cells have an embryological ectodermal origin and are found in different body systems. Neuroendocrine cells comprise 1% of gut mucosa (inner covering of the gut)
Intestinal NETs are found in the Small intestine, Appendix, Large bowel, Pancreas Rectum, Stomach, and Bile ducts.
Extra-intestinal (outside the intestinal tract)Neuroendocrine tumors are found in the Lungs, Adrenal gland, Skin, Thyroid, Testis, Parathyroids, etc.
When neuroendocrine tumors develop, some stop secreting hormones and other substances. These are called non-functioning neuroendocrine tumors, Whereas others continue to produce an excess amount of various substances and hormones. These types of neuroendocrine tumors are called functional neuroendocrine tumors.
Incidence
Neuroendocrine tumors are rare. Only find 1 case per 100000. However, the incidence is increasing
What causes neuroendocrine tumors
There is no definite underlying cause for neuroendocrine cancers. However, people with following genetic syndromes have a very high risk for neuroendocrine tumors
- multiple endocrine neoplasia type 1 (MEN1)
- multiple endocrine neoplasia type 2 (MEN2)
- multiple endocrine neoplasia type 4 (MEN4)
- neurofibromatosis type 1
- Von Hippel-Lindau syndrome (VHL)
- Carney complex
- Familial pheochromocytoma syndrome
- familial paraganglioma syndrome
| Type of tumor | hormone | site |
| Carcinoid tumors | Serotonin | small and large intestine, Stomach Appendix Pancreas Bile duct, Ampulla of Vater |
| Insulinoma | insulin | Pancreatic neuroendocrine cells |
| Gastrinoma | gastrin | Stomach . Pancrease Small intestine. |
| Glucagonoma | glucagon | Pancrease |
| Somatostatinoma | Somatostatin | Small intestine Pancreas. |
| VIPoma | VIP | Pancrease |
Clinical presentation
Non-functioning
Non-functioning neuroendocrine tumors rarely cause symptoms in the early stages. Nonspecific abdominal pain and anemia caused by gut bleeding are the most common presentations to doctors.
When the tumors grow bigger, they cause blockage f intestine and bile duct result in jaundice or bowel obstruction.
Functioning
These types of tumors continue to secrete a large amount of hormones and patients may present with symptoms related to the hormones they produce.
However, functioning NETs that arise in the intestinal tract will not cause symptoms in the early stages as the liver breaks down the hormones by a process called the first-pass metabolism. Once the metastatic spread of the tumor damages the liver, these hormones will release into the body, and the patient will develop symptoms
| type of tumor | Symptoms and signs |
| carcinoid | diarrhea skin flushing shortness of breath Right-sided heart valvular disease, Right heart failure. |
| Insulinoma | Symptoms of hypoglycemia fatigue anxiety sweating unsteadiness pale skin new-onset cardiac arrhythmias Whipple triad |
| Glucagonoma | Necrolytic migratory erythema, Stomatitis weight loss Diabetes. |
| Gastrinoma: | Zollinger-Ellison syndrome Gastric ulcer Gastroesophageal reflux Watery diarrhea. |
| Vasoactive intestinal polypeptide(VIP) Oma | hypersecretory diarrhea Weight loss Acute kidney injury. |
| Somatostatinoma | Hypochlorhydria Steatorrhea Diabetes |
Carcinoid syndrome
This is a syndrome Characterized by Symptoms and signs Due to excess Serotonin secreted by Tumor cells.
Occurs in (10%) of NET patients.
These symptoms include Excess sweating, Flushes, diarrhea etc
For carcinoid syndrome to occur, excess Serotonin should reach systemic circulation, Which occurs in the following situations.
- Liver damage caused by secondary deposits
- Extraintestinal NETS
Diagnosis of neuroendocrine tumors
Diagnostic workup should be planned according to the clinical presentation of the patient. The ultimate diagnosis is made with a combination of blood tests and imaging.
Contrast-enhanced CT scan (CECT)
CECT is the key to the diagnosis. The lesions are hyper-enhancing in the arterial phase and iso-enhancing in the venous phase
Small bowel neuroendocrine tumors will give a typical cartwheel appearance in the CT scan.
MRI Scan
Apart from assessing the primary lesion, MRI scans help to assess the metastasis, particularly liver lesions.
Endoscopic Ultrasound Scans
Particularly useful in assessing pancreatic NET. and allows biopsy
Biopsy
NETs found on imaging or endoscopy should be biopsied either image-guided or endoscopically.
UGIE (Upper gastrointesinal Endoscopy)
For suspected Gastric neuroendocrine tumors.
LGIE ( Lower gastrointesinal Endoscopy)
For suspected Rectal and Large bowel neuroendocrine tumors
Staging of Neuroendocrine Tumors.
Rectal and appendicular NETs less than 2 cm have a very low potential for metastatic spread. So these are treated primarily without staging. All the other neuroendocrine tumors should be assessed for metastatic spread before treatment.
Somatostatin receptor (SSRT)-PET
this is the investigation of choice for NET staging. SSRT-PET has a very high sensitivity for NET staging.
Octreotide scintigraphy
Used to be the primary investigation for NET Staging and Localizing. Still used when SSRT-PET is not available.
Chromogranin A.
Chromogranin is a protein secreted by neuroendocrine cells. Serum chromogranin A level is done for diagnosis and to detect recurrences in the follow-up of the patients. Levels are elevated in both Functional and non-functional NETs.
also, there is evidence to suggest that elevated chromogranin A levels can be useful in prognosis
Pretreatment chromogranin A level greater than 5 times the upper limit of normal was associated with worse overall survival and recurrence-free survival.
Urine 5-HIAA Level
The liver breaks down Serotonin into a product called 5-HIAA. This is secreted in the urine, and urinary 5-HIAA level is measured to diagnose suspected neuroendocrine tumors.
Other tests
A serum c-peptide
Serum Gastrin levels
glucagon
Somatostatin
VIP
How to Treat Neuroendocrine Tumors
The ideal treatment of NETs is resection of all macroscopic disease seen at presentation.
Small Intestine
Small bowel neuroendocrine tumors usually present late. Complete removal of the primary tumor is the mainstay of treatment. Unfortunately, complete removal of the tumor is not possible in all cases due to the anatomical position of the tumor and the lymphatic and metastatic spread.
When possible tumor should be removed with the segment of the bowel, associated mesentery, and lymph nodes, it gives the best outcome. Cytoreduction ( Removal of part of the tumor ) has a place when complete removal is not possible. Cytoreduction increases overall survival to 161 months.
Neuroendocrine tumors presenting in the advanced stage have an overall survival of 56 months. Hyperthermic intraperitoneal chemotherapy is currently not recommended for Neuroendocrine tumors.
Appendix
NET of the appendix presents with symptoms suggestive of appendicitis. These tumors present early, so they have a better prognosis. Neuroendocrine tumors at the tip of the appendix, which are less than 2cm, are treated with appendectomy along. However, if they have the following risk factors, they need formal right hemicolectomy (removal of the right side of the colon)
- a tumor that involves the appendiceal base,
- positive resection margins after appendectomy
- more than 3 mm of mesoappendiceal extension
- Lymphovascular invasion
- Grade 2 (ki 67 3-20%)
tumors with the above features need proper staging with CECT, MRI, or Somatostatin receptor (SSRT)-PET
Pancreas
Non-functioning NETs which not associated with genetic disorders may be left alone after the MDT meeting and careful discussion with the patient as they may not cause any problem to the patient.
Others treated depending on the size and the site of the lesion.
Lesions in the pancreatic head – Formal Pancreaticoduodenectomy
Lesions in the tail of the pancreas – distal Pancraeatectomy
Central lesions – Subtotal or central pancreatectomy
Small lesions less than 2cm may be treated with enucleation if the main duct is not involved
Gastric Carcinoid
Gastric carcinoids arise from enterochromaffin-like cells in gastric mucosa.
There are 5 types of gastric carcinoids.
- Type I: the most common type.This type is more frequent.Type 1 gastric carcinoids arise in the background of chronic atropic gastritis. Account for 70-80% of gastric carcinoids
- Type II: associated with Zollinger-Ellison syndrome and multiple endocrine neoplasm type 1 disorders.1/3 of these metastasises.
- Type III: This type is the most aggressive type with high chance of metastasis.
- Type IV: These are poorly differentiated NET.Surgical resection is difficult
Liver Metastases
Resection (Removal) of liver Metastasis is indicated in NET. Complete resection of liver Mets gives the best outcome. However, cytoreduction also improves survival and is recommended when complete resection is not possible .Ablation can be combined to preserve liver volume.Complete liver resection gives an overall survival of 112.5 months.
Medical Treatment for Neuroendocrine tuomrs
Octreotide – First line for metastatic and symptomatic gastrointestinal NETS
Everolimus – improves outcome in metastatic gastrointestinal NETS
NET Grading System.
Extraintestinal neuroendocrine tumors
Adrenal Gland – Pheochromocytoma
Thyroid – Medullary thyroid ca
Lungs
Thymus
Parathyroid
Renal – Renal carcinoids
Skin – Merkel cell carcinoma
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