Neuroendocrine tumors

Last updated date: 29-Aug-2023

Originally Written in English

Neuroendocrine tumors

Overview

Neuroendocrine cells are found throughout the body and respond to signals from the Central nervous system, or the brain and nerves, by releasing hormones into the blood. When a tumor forms in the cells, it changes the way the cells function and how well they release or maintain hormones.

 

What are Neuroendocrine Tumors (NETs)?

The neuroendocrine system is a network of glands and nerve cells responsible for hormone production and release into the circulation. These hormones aid in the regulation of regular bodily activities, such as digestion. Neuroendocrine cells may be found throughout the body, although they are most common in the gastrointestinal tract (large and small bowel), pancreas, and lungs.

While the term "neuroendocrine tumor" suggests that these tumors include both nerve cells and hormones, they are assumed to be primarily caused by endocrine cells. The "neuro-" is more of a historical oddity. Neuroendocrine tumors are tumors that can form anyplace there are endocrine cells. Endocrine cells aid in the regulation of several bodily activities, including growth, reproduction, and metabolism. They are found throughout the body, although the lungs, small intestines, and pancreas are the most prevalent sites for tumor development.

They are most frequent in the gastrointestinal tract (48%), lung (25%), and pancreas (9%), although they can also grow in the breast, prostate, thymus, and skin.

Unfortunately, when individuals are eventually identified with a NET, many will have metastases; population-based studies have indicated that 21% of patients have metastases at the time of diagnosis, but retrospective chart analyses have recorded rates as high as 56%-69%.

 

What Causes NETs?

 NETs

There is no single cause or unique risk factor for NETs. However, there are other variables that may increase a person's chance of acquiring a NET, such as:

 

Inherited syndromes:

Multiple endocrine neoplasia type 1 (MEN1) is a genetic disorder linked with NETs such as NETs, GI tract NETs, and pancreatic NETs. Von Hippel-Lindau syndrome, neurofibromatosis type 1, multiple endocrine neoplasia type 2 (MEN2), and tuberous sclerosis complex are all genetic disorders associated with NETs.

 

Other medical conditions:

Certain disorders can increase a person's chance of getting certain types of NETs. People with disorders that harm the stomach and limit acid production, for example, are more likely to develop a stomach NET.

 

Environment and diet: 

According to available research, there is no link between NETs and the environment or food.

 

How are Neuroendocrine Tumors Classified?

Neuroendocrine Tumors Classified

There are three clinicopathologic features that drive the biological behaviour of NETs: grade, differentiation and stage.

 

Grade

The biological aggressiveness of the tumor is reflected in the histologic grade. The Ki67 index, which quantifies the percentage of cancer cells that stain positive for Ki67, a marker of cell proliferation, and the mitotic rate, which chronicles the number of mitoses per 10 high-power microscopic fields, are the two key aspects of grade.

The significance of correct grading cannot be overstated because it is the most important driver of prognosis. Patients with a grade 1, 2, or 3 tumor have a median survival of 124 months, 64 months, and 10 months, respectively.

 

Differentiation

The degree to which neoplastic cells resemble their nonneoplastic counterparts in the tissue from whence they emerged is referred to as differentiation. Cancer cells that are well-differentiated resemble nonneoplastic cells, but poorly differentiated cancer cells do not. Low-grade tumors (grades 1 and 2) are often well-differentiated, but high-grade tumors (grade 3) are poorly differentiated.

 

Stage

The Tumor Node Metastasis (TNM) system is utilized, as it does for other malignancies, to determine the amount of tumor dissemination throughout the body. However, for practical purposes, NETs can be classified as either early stage (totally resectable) or advanced stage (either locally advanced and unresectable or metastatic).

 

Types of Neuroendocrine Cancer

 

Neuroendocrine Cancer

      1. Carcinoid Tumor

This kind of neuroendocrine carcinoma is extremely uncommon, typically affecting the gastrointestinal (GI) system. The GI system is part of the digestive system of the body, which also includes the stomach, small intestine, colon, rectum, and appendix. GI neuroendocrine cells produce hormones that aid in digesting regulation. Carcinoid tumors also can be found in the lungs.

      2. Pancreatic Neuroendocrine Tumor

The pancreas is a gland located just beneath the stomach. Neuroendocrine cells in the pancreas influence hormone synthesis, including insulin, which regulates blood sugar. Islet cell tumors are another name for pancreatic neuroendocrine tumors.

     3. Medullary Thyroid Cancer

Medullary thyroid cancer is a rare but fast developing malignancy that affects neuroendocrine cells in the thyroid gland. The thyroid gland is located near the bottom of the throat. The cells, known as C cells, contribute to the production of calcitonin, a hormone that regulates calcium levels in the blood.

    4. Pheochromocytoma

A pheochromocytoma is a rare neuroendocrine tumor that develops in the adrenal glands' core. An adrenal gland is positioned above each kidney and produces catecholamine chemicals that assist control heart rate.

    5. Merkel Cell Carcinoma

This aggressive neuroendocrine tumor develops in Merkel cells, which are found in the top layer of the skin near nerve endings that sense touch. Merkel cell carcinoma is also known as neuroendocrine skin cancer. It is more common in sun-exposed regions of skin.

    6. Neuroendocrine Tumor, Non-small Cell Lung

This form of cancer grows quickly in neuroendocrine cells in the lungs.

    7. Neuroendocrine Tumor, Small Cell Lung

Neuroendocrine tumors are similar to small-cell lung cancers in that they start in neuroendocrine cells. They are as follows:

  • Low-grade typical carcinoid
  • Intermediate-grade atypical carcinoid
  • High-grade neuroendocrine tumors including large-cell neuroendocrine carcinoma and small-cell lung cancer

 

How do Neuroendocrine Tumors Present?

Neuroendocrine tumors disrupt hormone synthesis, resulting in greater levels of hormones in the blood than is normal. The symptoms are connected to increased hormone levels, although they might differ depending on the kind of neuroendocrine carcinoma and the cells involved.

 

Carcinoid Tumor

Carcinoid Tumor

In the early stages, some gastrointestinal carcinoid tumors show no signs or symptoms. The tumor's development and the hormones it produces may induce signs and symptoms. Some tumors, particularly those of the stomach or appendix, may not produce any symptoms. Carcinoid tumors are frequently discovered through tests or therapies for other diseases.

Carcinoid tumors of the small intestine (duodenum, jejunum, and ileum), colon, and rectum can cause signs or symptoms as they develop or as a result of the hormones they produce. Other conditions may have similar signs or symptoms.

Check with your doctor if you have any of the following:

Duodenum

Signs and symptoms of GI carcinoid tumors in the duodenum (first part of the small intestine, that connects to the stomach) may include the following:

  • Abdominal pain
  • Constipation
  • Diarrhea
  • Change in stool color
  • Nausea
  • Vomiting
  • Jaundice (yellowing of the skin and whites of the eyes)
  • Heartburn

 

Jejunum and Ileum

The following are signs and symptoms of GI carcinoid tumors in the jejunum (middle part of the small intestine) and ileum (final section of the small intestine that attaches to the colon):

  • Abdominal pain
  • Weight loss for no known reason
  • Feeling very tired
  • Feeling bloated
  • Diarrhea
  • Nausea
  • Vomiting

 

Colon

Signs and symptoms of GI carcinoid tumors in the colon may include the following:

  • Abdominal pain
  • Weight loss for no known reason

 

Rectum

Signs and symptoms of GI carcinoid tumors in the rectum may include the following:

  • Blood in the stool
  • Pain in the rectum
  • Constipation

Carcinoid syndrome might develop if the tumor spreads to the liver or other organs. Hormones produced by gastrointestinal carcinoid tumors are typically eliminated in the blood by liver enzymes. If the tumor has grown to the liver and the liver enzymes are unable to remove the additional hormones produced by the tumor, large levels of these hormones may persist in the body, resulting in carcinoid syndrome. This can also occur if tumor cells reach the bloodstream.

Signs and symptoms of carcinoid syndrome include the following:

  • Redness or a feeling of warmth in the face and neck
  • Abdominal pain
  • Feeling bloated
  • Diarrhea
  • Wheezing or other trouble breathing
  • Fast heartbeat

If you experience any of these symptoms, consult your doctor since they might be caused by gastrointestinal carcinoid tumors or other diseases.

 

Pancreatic Neuroendocrine Tumor

Pancreatic Neuroendocrine Tumor

Pancreatic neuroendocrine tumors (NETs) present with a variety of signs and symptoms. Symptoms may be induced by tumor development and hormones produced by the tumor. Some cancers may not produce any symptoms.

 

Signs and Symptoms of a Nonfunctional Pancreatic NET

A nonfunctional pancreatic NET can develop over an extended period of time without presenting symptoms. Before causing symptoms, it may become big or spread to other regions of the body, such as:

  • Diarrhea
  • Indigestion
  • A lump in the abdomen
  • Pain in the abdomen or back
  • Yellowing of the skin and whites of the eyes

 

Signs and Symptoms of a Functional Pancreatic NET

The symptoms of a functioning pancreatic NET are determined by the kind of hormone produced.

Too much gastrin may cause:

  • Stomach ulcers that keep coming back
  • Pain in the abdomen, which may spread to the back (and may come and go, or go away after taking an antacid)
  • The flow of stomach contents back into the esophagus (gastroesophageal)
  • Diarrhea

Too much insulin may cause:

  • Low blood sugar; this can cause blurred vision, headache and feeling lightheaded, tired, weak, shaky, nervous, irritable, sweaty, confused or hungry
  • Fast heartbeat

Too much glucagon may cause:

  • Skin rash on the face, stomach or legs
  • High blood sugar, which may cause headaches, frequent urination, dry skin and mouth or feeling hungry, thirsty, tired or weak
  • Blood clots, which can cause shortness of breath, coughing, or discomfort in the chest if formed in the lungs; clots in the arm or leg can cause pain, swelling, warmth, or redness of the arm or leg if formed in the arm or leg.
  • Diarrhea
  • Weight loss for no known reason
  • Sore tongue or sores at the corners of the mouth

Too much vasoactive intestinal peptide (VIP) may cause:

  • Very large amounts of watery diarrhea
  • Dehydration. This can cause feeling thirsty, making less urine, dry skin and mouth, headaches, dizziness or feeling tired
  • Low potassium level in the blood. This can cause muscle weakness, aching or cramps, numbness and tingling, frequent urination, fast heartbeat and feeling confused or thirsty
  • Cramps or pain in the abdomen
  • Weight loss for no known reason

Too much somatostatin may cause:

  • High blood sugar levels can induce headaches, frequent urination, dry skin and mouth, and feelings of hunger, thirst, tiredness, or weakness.
  • Diarrhea
  • Steatorrhea
  • Gallstones
  • Yellowing of the skin and whites of the eye
  • Weight loss for no known reason

 

How are Neuroendocrine Tumors Diagnosed?

Neuroendocrine Tumors Diagnosed

A NET diagnosis necessitates a multidisciplinary team effort comprising medical oncologists, surgeons, interventional radiologists, and pathologists. Pathology, hormonal, and diagnostic and functional imaging results are used to give a complete diagnostic picture.

  • Pathology

Tissue collection for pathological testing is required for the diagnosis of NETs. When surgical excision is not an option, core needle biopsy is favored over fine needle aspiration to get a complete picture of the tumor architecture.

Biochemical tests should be tailored to the individual illness in patients who come with signs of a functional NET. A 24-hour urine 5-hydroxyindole acetic acid (5-HIAA) test should be conducted for individuals who arrive with a small intestinal tumor or carcinoid syndrome symptoms. To avoid false-positive findings, patients should avoid consuming serotonin-rich foods (such as bananas, pineapples, avocados, kiwi fruits, or almonds) for at least three days before testing.

 

Nonsyndrome-specific biochemical testing

Chromogranin A is the preferred diagnostic biomarker for NETs. Proton-pump inhibitors, renal insufficiency, adenocarcinomas, and severe arterial hypertension are the most prevalent causes of spurious increases.

 

Diagnostic imaging

Diagnostic imaging methods used in conjunction to diagnose NETs fall into two broad groups. The first is conventional cross-sectional imaging using computed tomography (CT) or magnetic resonance imaging (MRI). According to Canadian consensus recommendations, all patients with a suspected NET should have CT scans of the chest, abdomen, and pelvis for staging, as well as an MRI of the liver or pancreas if additional characterization is necessary.

The second technique is functional imaging, which takes advantage of the somatostatin receptor upregulation found in NETs. To pinpoint tumors, radiolabeled somatostatin analogues are supplied intravenously, concentrate in NETs, and the emitted radiation is measured. The most often utilized radiotracer is 111Indium (In)-labelled pentetreotide.

 

Endoscopic imaging

The most sensitive diagnostic for detecting pancreatic NETs is endoscopic ultrasonography. Endoscopic ultrasonography is very helpful for detecting tumors smaller than 2 cm in size and for localizing insulinomas, and it is frequently used intraoperatively for this reason.

The neuroendocrine system is a network of glands and nerve cells responsible for hormone production and release into the circulation. These hormones aid in the regulation of regular bodily activities, such as digestion. Neuroendocrine cells may be found throughout the body, although they are most common in the gastro-intestinal tract (large and small bowel), pancreas, and lungs.

 

How are Neuroendocrine Tumors Treated?

Neuroendocrine Tumors Treated

Individualized treatment regimens are developed based on tumor characteristics such as location, stage, grade, differentiation, and symptoms, as well as patient characteristics such as age and comorbidities.

    1. Localized disease

Surgery 

To present, the only curative therapy option is a suitable oncologic procedure focusing on margin-negative resection and sufficient lymphadenectomy. It is critical that the surgeon thoroughly look for synchronous lesions during resection. A single-center retrospective investigation of 691 individuals with midgut NETs discovered multiple synchronous original tumors in 22% of patients, with a range of 2 to 26 tumors.

 

Adjuvant therapy (chemotherapy after surgery) 

There is no evidence that adjuvant treatment improves NET cure after surgery. However, based on extrapolation of small cell lung cancer data, consensus recommendations propose that patients with totally resected, poorly differentiated tumors be considered for adjuvant platinum-based treatment.

 

    2. Metastatic disease

Observation 

Observation with expectant care and serial diagnostic imaging is acceptable in select patients with low-volume, asymptomatic, nonfunctional metastatic illness; traditionally, many individuals remain well without disease progression for years.

 

Somatostatin analogues 

Somatostatin analogues are an important component of NET therapy. There are two long-acting somatostatin analogue formulations available: lanreotide and octreotide long-acting repeatable. Somatostatin analogues were first utilized in individuals with secretory symptoms and only had an anti-proliferative effect. The use of octreotide long-acting repeating was linked to a shorter time to progression.

There was no effect on median overall survival (84.7 months), however this was thought to be attributable to most patients switching from placebo to therapy. Similarly.

Somatostatin analogues can cause diarrhea, stomach discomfort, nausea, vomiting, and hyperglycemia. Furthermore, individuals receiving somatostatin analogues are at an increased risk of developing cholelithiasis and biliary sludge; consequently, preventive cholecystectomy should be considered for patients beginning long-term somatostatin analogue treatment. This suggestion, however, has never been tested in a prospective research and is based on retrospective investigations that found high rates of cholelithiasis and low rates of symptomatic gallbladder illness. 

 

Surgery 

Even in the case of metastatic illness, surgery plays a significant role. If the initial tumor is situated in the small intestinal, resection is frequently performed to prevent obstruction later, especially in low-grade tumors with a favorable prognosis. According to the findings of retrospective population-based research, this may also enhance survival. In the context of large-volume metastatic disease, surgical cytoreduction can be performed to better control of secretory symptoms that may be difficult to manage with somatostatin analogue alone; retrospective studies also suggest that this may increase survival.

 

Prognosis of Neuroendocrine Tumors

Prognosis of Neuroendocrine Tumors

A doctor cannot forecast the exact course of a disease since it is dependent on each person's unique circumstances. However, depending on the test findings, the rate of tumor growth, as well as your age, fitness, and medical history, your doctor may offer you a prognosis - the expected fate of the condition.

 

Conclusion 

Neuroendocrine tumors (NETs) are uncommon cancers that begin in neuroendocrine cells. Neuroendocrine tumors are becoming more common and more common. Awareness of this diverse entity may decrease diagnostic delays and promote expert interdisciplinary care. Treatment is determined on the kind of NET, the location of the tumor, its size, and if it has spread (the stage).