Neuroendocrine Cancer

Neuroendocrine cancer is a relatively rare and heterogeneous type of malignancy. It comprises approximately 2% of all malignancies, with a prevalence of 5.25 cases per 100,000 population. Though neuroendocrine cancers are rare in occurrence, they can develop anywhere in the body. Due to the marked heterogeneity in risk factors, biological behaviors, and response to treatment, the management of these cancers is complex.

What is neuroendocrine cancer?

Neuroendocrine cancers are carcinomas that arise from specialized body cells called neuroendocrine cells. These are the cells that interact with the nervous system or glands that produce hormones. They release hormones into the blood in response to signals from the nervous system.

Neuroendocrine carcinomas develop when these hormone-producing cells undergo any sudden mutation (changes) and grow out of control, forming a tumor. These neuroendocrine tumors (NET) can be either benign (non-cancerous) or malignant (cancerous). Some tumor cells can produce excess hormones while others don't release hormones or cause any symptoms.

Types:

Though there are many types of neuroendocrine tumors, the most common types are:

• Carcinoid tumors: NETs that arise in the digestive tract, lungs, appendix, or thymus.
• They can also grow in the lymph nodes, brain, bone, ovaries, and testes or skin.
• Pancreatic neuroendocrine tumors: Also called islet cell tumors, these arise in the cells of the pancreas.
• Pheochromocytoma: These are rare types of NET that usually develops in the adrenal glands.

Signs and Symptoms

Because neuroendocrine cancer originates at different locations, the signs and symptoms vary depending on where the tumor is located, and the kind of hormones released.

The general symptoms related to the size and/or location of the tumor are:

• Persistent pain in a specific area
• Thickening or a lump in any part of the body
• Nausea or vomiting
• A cough or hoarseness that does not go away
• Changes in the bowel or bladder habits
• Jaundice, yellowing of the skin and whites of the eyes
• Unusual bleeding or discharge

Symptoms related to the release of excess hormones are:

• Diarrhea
• Facial flushing, usually without sweating
• Hyperglycemia, a high level of glucose in the blood
• Hypoglycemia, low level of glucose in the blood
• Gastric ulcer disease
• Skin rash
• Confusion
• Anxiety

Neuroendocrine Tumor Causes/ Risk factors

The exact cause of neuroendocrine tumors is not clear. However, some factors are known to increase the risk of developing such cancers. 

Risk factors associated with neuroendocrine cancers are:

Inherited syndromes, such as:

• Multiple endocrine neoplasia type I (MEN I) and type II (MEN II)
• Neurofibromatosis type I
• Tuberous sclerosis complex
• Von Hippel-Lindau syndrome

Conditions that affect how the stomach makes digestive juices, including:

• Atrophic gastritis
• Pernicious anemia
• Zollinger-Ellison syndrome
• Race/ethnicity: African Americans are more likely to develop carcinoid tumors in certain areas of the body than Caucasians.
• Gender: This cancer is more common in women than in men
• Age: A person of any age can develop a neuroendocrine tumor, however, children rarely develop this cancer
• Smoking tobacco

Diagnosis

Making a diagnosis of a rare malignancy like neuroendocrine cancer can often be challenging. Most NETs are found unexpectedly during any medical procedure done for reasons unrelated to the tumor. If a doctor suspects a NET, the medical and family history is initially reviewed followed by a complete physical examination.

The following tests are recommended for detailed diagnosis:

Blood/urine tests:

• Complete blood count (CBC) and blood chemistry studies to check certain substances in the blood
• 24-hour urine collection to detect the level of serotonin in the body
• Tumor marker test to measure the level of chromogranin A, a protein released from the neuroendocrine cells

Endoscopy: In this procedure, a small endoscope (a thin flexible tube with a video camera at the end) is inserted into the area suspected to have the tumor. It allows visualization of the inside of the body and checks for abnormalities. 

Imaging tests: Tests such as ultrasound, computerized tomography (CT) scan, and magnetic resonance imaging (MRI) is done to examine the suspicious area to determine the extent of the cancer spread. Specialized scans like the octreotide scan and PET scan help in determining the neuroendocrine tumors. 

Biopsy: It involves the removal of some tumor tissues from the suspicious area using a needle and its analysis under a microscope. The procedure is guided by CT or MRI scanning. 

Molecular testing of the tumor: This is a laboratory test on the tumor cells to identify specific genes, proteins, and other features of the tumor.

Staging

Staging of cancer provides a uniform way to describe the location of the tumor, its size, and if or where it has spread. Neuroendocrine tumor staging depends on the location of the tumor. For E.g., staging of NETs of the GI tract and pancreas will be different from the lung NET.

Grading of the tumor according to the World Health Organization (WHO) is as follows:

• Grade 1: Low-grade tumor that divides at a low rate
• Grade 2: an intermediate-grade tumor that divides at an intermediate rate
• Grade 3: High-grade tumor that divides at a fast rate and grows quickly

Treatment

Treatment options and recommendations for NETs usually depend on several factors, including:

• The type of NET
• Stage and grade
• Possible side effects
• Overall health of the patient

In general, neuroendocrine tumor treatment modalities may include:

• Surgery: It is often the first-line treatment for patients with localized NETs and some metastatic cases. Most common neuroendocrine tumor surgeries include:
• Excision: removal of a tumor along with a small amount of surrounding healthy tissues
• Resection: removal of the organ in which the tumor originated
• Fulguration: surgical destruction of tumors using electrical currents
• Cryosurgery: the destruction of cancerous tissue through exposure to extreme cold temperature
• Radiofrequency ablation: surgical destruction of tumors using high-energy radio waves
• Hepatic artery embolization: blocking the blood supply to cancerous cells causing them to starve and die.

Possible side effects of surgery include bleeding, infection, anesthesia risks, and the risk of blood clots post-surgery.

• Chemotherapy: For treating neuroendocrine tumors, chemo drugs are used either:
• Before surgery (neoadjuvant therapy) to help shrink a tumor
• After surgery to help destroy any residual cancer cells and to prevent the reoccurrence of cancer

Chemotherapy is usually given in several cycles, which involves a period of treatment followed by a rest period, allowing the body to recover from its side effects. There is no standard chemotherapy regimen for neuroendocrine tumor therapy. The drugs or drugs combinations are recommended based on the site of tumor occurrence and grade.

Common side effects of chemotherapy are fatigue, nausea and vomiting, loss of appetite, hair loss, and diarrhea.

• Targeted drug therapy: Targeted drugs work by interfering with substances like genes or proteins that contribute to the growth and survival of cancer. For advanced neuroendocrine tumors, targeted drug therapy is combined with chemotherapy for better results. The side effects differ for each patient depending on the type of tumor and the drugs used.
• Radiation therapy: Radiation therapy is recommended for the NETs in the advanced stage and if the location of the tumor would likely complicate the surgical procedures. It involves the use of high-energy radiation to kill cancer cells. The treatment approach can vary for each patient depending on the grade and location of the tumor. Side effects from the radiation therapy may include mild skin reactions, fatigue, hair loss, nausea and vomiting, and diarrhea.
• Peptide receptor radionuclide therapy (PRRT): PRRT is a drug therapy in which the drugs that target the cancer cells are combined with radioactive substances. These radioactive drugs specifically act on the cancer cells and destroy them by emitting radiation. This is usually recommended for advanced GI tract NETs and pancreatic NETs. Possible side effects include low white blood cell count, high enzyme levels in some organs, high blood sugar level, low level of potassium, and nausea and vomiting.
• Medications to control excess hormones: Somatostatin analogs are drugs that are similar to somatostatin - a hormone that controls the release of several other hormones, such as insulin and glucagon. These drugs help manage the symptoms due to the hormone-like substances released by a NET.

Outlook

It is difficult to predict the prognosis of neuroendocrine tumors because each patient responds differently to the treatment. However, the prognosis and survival rate of NETs depend on the primary tumor sites. Other factors that affect the prognosis are the stage and characteristics of cancer, the treatments are chosen, and the overall health of the patient. The difficulty in diagnosing these rare malignancies also contributes to mortality.