Neuroendocrine Carcinoma

Neuroendocrine Carcinoma

The neuroendocrine cells are specialized nerve cells or neurons that receive signals from other neurons and release hormones (called neurohormones) in response to that signal. They do not form a specific gland; rather they are distributed in many organs throughout the body. Cancers which originate from these cells are called neuroendocrine carcinomas and can occur in any organs where these cells are found. Neuroendocrine carcinomas are most frequently detected in the digestive system (stomach, appendix, ileum, rectum, colon) and the lung (bronchi). They are also detected in the pancreas and brain.

Types of neuroendocrine tumors

There are many kinds of neuroendocrine tumors (NETs). They are named based on their site of origin and histology. A pancreatic neuroendocrine tumor originates in the pancreas whereas a pulmonary neuroendocrine carcinoma develops in the lungs. Histologically neuroendocrine tumors can be of two types: well differentiated and poorly differentiated.

Neuroendocrine tumors can also be either functioning or nonfunctioning. Functioning tumors produce more hormones than normal cells. The kind of hormone produced is related to the site of tumor. Nonfunctioning tumors do not produce excess hormones, but their continuous growth can cause blockages.

Neuroendocrine carcinoma is a form of neuroendocrine tumor. The term carcinoma refers to both well-differentiated and poorly differentiated neuroendocrine tumors. In some systems, before 2001 and 2004 versions of the WHO classifications of digestive and pancreatic NETs, the term “carcinoma” was used instead of tumor to indicate malignancy. Some researchers suggested using the term carcinoma for all NETs, but others were against the use of same term for all grades of neuroendocrine tumors. It is important to understand that grade or differentiation should always be mentioned while using the terms neuroendocrine carcinoma and neuroendocrine tumor in pathology reports.

Some well-known forms of neuroendocrine tumors are:

  • Carcinoids
  • Functioning and Non-Functioning Pancreatic Tumors
  • Multiple Endocrine Neoplasias
  • Gastrinomas
  • Insulinomas
  • Glucagonomas
  • Pheochromocytomas

Nomenclature and Classification of Neuroendocrine Tumors

Differentiation andGrade Traditional Classification ENETS/WHO Classification Moran et al
Well differentiated
Low grade(grade 1) Carcinoid, islet cell, pancreatic (neuro)endocrine tumor Neuroendocrine tumor, grade 1 Neuroendocrine carcinoma, grade 1
Intermediate grade(grade 2) Carcinoid, atypical carcinoid, islet cell, pancreatic neuroendocrine tumor Neuroendocrine tumor, grade 2 Neuroendocrine carcinoma, grade 2
Poorly differentiated
High grade(grade 3) Small-cell carcinoma Neuroendocrine carcinoma, grade 3, small cell Neuroendocrine carcinoma, grade 3
Large-cell neuroendocrinecarcinoma Neuroendocrine carcinoma, grade 3, large cell Neuroendocrine carcinoma, grade 3

Epidemiology

Neuroendocrine tumors are rare and accounts for less than one percent of all cancers in the United States. 35,618 tumors were identified between 1973 and 2004 in the United States. The disease is equally frequent in both males and females. The average age at diagnosis is of 53 years. Neuroendocrine carcinomas are possibly under-reported because they grow at very slow rate and do not produce dramatic symptoms.

Risk factors

Age: The chance of neuroendocrine carcinoma increases with age.

Family history: Some of the neuroendocrine cancers can be hereditary.

Immune suppression: People with human immunodeficiency virus (HIV) or acquired immune deficiency syndrome (AIDS), and who have suppressed immune systems from organ transplantation have a higher risk for developing neuroendocrine cancers.

Inherited conditions: Neuroendocrine tumors may associate with the following conditions inherited genetically:

  • Multiple endocrine neoplasia (MEN) types 1 and 2
  • von Hippel-Lindau (VHL) disease
  • von Recklinghausens neurofibromatosis (NF)
  • Tuberculous sclerosis (TSC)

Symptoms

Excessive hormones released by the cancerous neuroendocrine cells may affect many organs and many different symptoms may appear. Some neuroendocrine cancers may not show any symptoms at all. Symptoms may include:

  • Fluctuation in blood sugar levels: hyperglycemia or hypoglycemia
  • Diarrhea
  • Continuous pain
  • Loss of appetite
  • Sudden loss or gain in weight
  • Cough that lasts for a long time
  • Hoarseness in voice
  • Flushing of the skin
  • Wheezing or shortness of breath
  • Lump in any part of the body
  • Changes in bowel habits
  • Frequent urination or problems with urination
  • Jaundice (yellowing of the skin)
  • Unusual bleeding or discharge
  • Fever or night sweats that continues
  • Headache
  • Palpitations (“racing heart”) and anxiety
  • Gastric ulcers

Diagnosis

General clinical examination: A general physical examination is conducted by the doctor to look for lumps and other symptoms related to cancer. Besides this, the patient’s history should be taken into account before suggesting other diagnostic tests.

CT scan: The CT scan is a procedure by which images of the internal organs of the body can be obtained with a help of x-rays. A contrasting dye is injected in the veins so that the images are clearly understood. The images can be viewed with the help of a computer.

Blood tests: A blood test called chromogranin A can indicate neuroendocrine tumors.

Echocardiogram: An echocardiogram is a test in which ultrasound is used to examine the heart.

24hour urine collection and analysis: 5-hydroxyindoleacetic acid (5-HIAA) levels in urine can indicate neuroendocrine tumors.

X-ray scan: The x-ray remains probably the most valuable tool in diagnosing whether cancer has spread to other organs.

Bone scan: A bone scan is a nuclear imaging test for detecting cancer that has spread (metastasized) to the bone from a tumor that started in a different organ.

MRI scan: This imaging procedure is based on the use of radiowaves in the presence of a magnet. The images produced can be viewed with the help of a computer attached to the machine.

Ultrasound imaging: This procedure with sound waves gives an image of the internal parts on a computer screen. This technique is most often used to detect lumps and swellings in testicles.

Biopsies: Cells or tissues removed from the affected tissue are examined under a microscope in the laboratory to check for signs of cancer. These tumors can only be accurately diagnosed when a pathologist examines a tissue sample using specialized stains that help clarify the cells’ subtype.

Capsule endoscopy: In this technique a capsule containing a wireless camera, called capsule endoscopy camera, is given to the patient. When the patient swallows the capsule the wireless camera takes pictures of the digestive tract which are transmitted to a recorder which the patient wears on a belt around his/her waist.

Endoscopy: Endoscopy is a way of looking inside the body using a flexible tube that has a small camera on the end of it. This instrument is called an endoscope.

Metaiodobenzylguanidine (MIBG) imaging: It is an imaging procedure in which a tracer radiolabeled meta-iodobenzyl-guanidine (MIBG) helps to make the tumor visible. The images of the tumor can be obtained by a scanner. The tracer used for this purpose is.

Positron emission tomography (PET) scans: The PET scanner is an imaging technique, which helps to find out the spread of the disease.

Specialized laboratory hormone and peptide tests: Presence of certain hormones and peptides in the blood or urine in excess can be a sign for a particular type of neuroendocrine carcinoma. Therefore, specific tests are conducted to confirm the type of cancer.

Grading system of neuroendocrine carcinoma

Grading of the neuroendocrine tumor is done based on microscopic studies of the cells obtained through biopsy from the patient. Grading considers two important aspects:

  • Proliferative index (Percentage of cells which Ki 67 protein positive as detected by immunohistochemistry)
  • Mitotic rate (number of mitoses per 10 high-power microscopic fields)

There can be three grades for a neuroendocrine tumor:

  • Low-grade neuroendocrine tumor (slow rate of growth)
  • Intermediate-grade neuroendocrine tumor (moderate rate of growth)
  • High-grade neuroendocrine tumor (high rate of growth)

Well-differentiated neuroendocrine carcinomas are designated as low grade and intermediate grade, whereas poorly differentiated ones are designated as high grade.

Staging

The SEER database uses the terms localized, regional and distant to stage neuroendocrine cancers. These terms describe the extent of metastasis of neuroendocrine cancer. However, AJCC has proposed that TNM staging system should be applicable for staging neuroendocrine cancers, too.

Treatment

Surgery: Surgery is the main treatment for neuroendocrine carcinoma. The tumor is removed along with a small amount of healthy tissue around the tumor, called the margin. Surgery for palliation can be done even after the cancer has spread. This kind of surgery helps to enhance the time of survival of the patient.

Radiation therapy: High-energy rays are used to kill cancer cells and reduce the size of neuroendocrine tumors. This can be done in two ways:

External radiation therapy: Radiation is given by a machine from outside the body at the affected region.

Internal radiation therapy: Radioactive substance sealed in a needle or wire is placed near the larynx. Radiation emitted from this radioactive substance kills the cancer cells.

External-beam radiation therapy is most commonly used for this purpose. Radiation therapy is generally used when a neuroendocrine tumor has spread or is in a location that makes surgery difficult or impossible.

Chemotherapy: Chemotherapy refers to administration of drugs intravenously for killing cancer cells. The use of drugs depends on a number of factors. Cisplatin plus etoposide and streptozotocin in combination with 5-fluorouracil and doxorubicin is used most frequently. Everolimus (Afinitor, Novartis Pharmaceuticals) has recently shown promising results when administered in patients with pancreatic neuroendocrine tumors. Different combinations of chemotherapeutic drugs have been tried in the recent years. A combination of doxorubicin, 5-fluorouracil and dacarbazine has recently proved successful against neuroendocrine cancers in some cases.

Hormone-delivered radiotherapy: In this treatment, a peptide or a hormone is tagged with a radioisotopeand administered intravenously in the patient. The peptide or hormone is chosen based on their uptake by the cancer cells. This kind of radioisotherapy is called peptide receptor radionuclide therapy (PRRT), or hormone-delivered radiotherapy. This is done by tagging Octreotide Acid or Octreotate (octapeptide that is a potent somatostatin) to Lutetium-177, Ytrium-90 or Indium-111. The radiolabelled peptide or hormones kill the cancer cell after they are taken up.

Medical treatment: Medical treatment with certain drugs like octreotide, alfa-interferon, proton-pump inhibitors, etc. can be used to treat specific neuroendocrine cancers.

Chemoembolization: It refers to a method of delivering a relatively large dose of chemotherapeutic agent directly to the tumor.

Hepatic artery embolization (HAE): It is done when cancer has been detected in liver. This therapy blocks blood flow to the tumors, reducing the tumor size significantly.

Cryoablation: Cold probes can be used to freeze the tumor.

Nutritional modification: Dietary guidelines are provided by the doctor as a treatment option.

Radiofrequency ablation: The use of radiofrequency waves increases the temperature within the tumor tissue, breaking down the tumor.

Prognosis

Prognosis depends mainly on the primary site of the cancer and the type of cancer at the time of diagnosis. Usually neuroendocrine tumors, which have not spread from their site of origin, show good prognosis. Poorly differentiated neuroendocrine carcinomas have a worse prognosis in comparison to well-differentiated ones carcinomas. Large cell neuroendocrine carcinomas of the lungs are much more aggressive than the small cell carcinomas. Large cell neuroendocrine carcinomas of the lung have 5-year actuarial survivals ranging from 13% to 57%. Pancreatic neuroendocrine tumors are usually diagnosed at a late stage, with approximately 65% of patients presenting with unresectable or metastatic disease. Therefore, the prognosis is poor for this type of cancer.

Chances of survival decrease with the extent of metastasis of the disease. Therefore, it is very important that the patients be diagnosed early and correctly for the type of carcinoma.

References

  1. James C. Yao, Manisha H. Shah, Tetsuhide Ito, Catherine Lombard Bohas, et. Al (2011) Everolimus for Advanced Pancreatic Neuroendocrine Tumors. N Engl J Med; 364:514-523
  2. Lisa Hutchinson (2011) Targeted therapies: Radiopeptide therapy improves outcomes for neuroendocrine cancers. Nature Reviews Clinical Oncology 8, 384
  3. Klimstra, David S.; Modlin, Irvin R.; Coppola, Domenico; Lloyd, Ricardo V.; Suster, Saul (2010) The Pathologic Classification of Neuroendocrine Tumors: A Review of Nomenclature, Grading, and Staging Systems; NANETS Guidelines 39 (6):707-712
  4. Oberg K, Akerström G, Rindi G, Jelic S; ESMO Guidelines Working Group (2010) Neuroendocrine gastroenteropancreatic tumors: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol.;21 Suppl 5:v223-7.
  5. Castellano D, Salazar R, Raymond E. (2011) Future perspectives on neuroendocrine tumors.Cancer Metastasis Rev.;30 Suppl 1:35-40.
  6. This article was originally published on September 3, 2012 and last revision and update was 9/4/2015.