Neuroblastoma

Definitions & Key takeaways

Neuroblastoma is a type of tumor composed of neural crest cells, which are cells involved in the development of the sympathetic nervous system. It is most commonly found in the adrenal gland, but it can also occur in other parts of the body along the sympathetic chain, such as the neck, chest, or pelvis. Neuroblastoma most often affects children, and it is more common in males than in females.

Symptoms of neuroblastoma can vary depending on the location and size of the tumor. They may include abdominal pain, a lump in the abdomen, difficulty breathing, bone pain, weight loss, sweating, fatigue, and changes in bowel or bladder function. Treatment for neuroblastoma may include surgery to remove the tumor, chemotherapy, radiation therapy, and immunotherapy.

Chapters:

Watch video only

Introduction0:00–0:18

Neuroblastoma is a type of tumor composed of “neuroblasts,” specifically neural crest cells, which are cells involved in the development of the sympathetic nervous system.
Neuroblastoma is the most common cancer in infants, and it’s only rarely seen in children over five years old. When a fetus is in its 5th week of development, special cells called neural crest cells start migrating along the spine.

Physiology0:18–1:33

In the thoracic region of the spine, neural crest cells differentiate into the neurons of the sympathetic chain, lying on either side of the entire spinal cord.In the lumbar region, neural crest cells differentiate into the cells of the adrenal medulla, the inner part of the adrenal gland that sits atop the kidneys.
Together, the sympathetic chain and adrenal medulla form the sympathetic nervous system, connecting the brain and central nervous system to various organs including the heart and blood vessels.
So, when you’re under some sort of stress, like playing a competitive sport like badminton, the sympathetic nervous system kicks into action.
The sympathetic neurons releases norepinephrine, also called noradrenaline, and the cells of the adrenal medulla release norepinephrine and epinephrine, also called adrenaline.
These hormones bind to receptors in various tissues like the blood vessels, the heart, and the lungs, redirecting blood flow to your muscles, make your heart pump faster, and expanding the airways in your lungs, all of which can help you make the winning hit.
After the game is over, and the hormones are no longer needed, epinephrine and norepinephrine break down into metabolites like homovanillic acid or HMA, and vanillylmandelic acid, or VMA.
In neuroblastoma, some neural crest cells in the sympathetic chain or adrenal medulla don’t differentiate properly during fetal development, and these cells ultimately go on to form a tumor, which most often form in the adrenal medulla, but can also develop in other areas of the sympathetic chain.

Pathology1:33–4:17

While no one knows exactly how it happens, this abnormal cell differentiation has been associated with mutations in the MYCN oncogene, Anaplastic lymphoma kinase ALK fusion oncogenes, and mutations in tumor suppressor genes, like the Paired-like homeobox 2b or PHOX2B, and other tumor suppressor genes on chromosome 1 and 11.
Oncogenes help cells grow and proliferate, while tumor suppressor genes slow down cell growth and proliferation. So both an MYCN amplification or ALK gene fusion, where the oncogene is “turned on,” or a PHOX2B and chromosome 1 and 11 deletions, where tumor suppressor genes are “turned off,” can potentially cause uncontrolled cell growth.
There are three types of neuroblastomas, and they’re categorized based on the size and shape of the tumor cells: undifferentiated, poorly differentiated, and differentiating neuroblastoma.An undifferentiated neuroblastoma is mostly comprised of neural crest cells, which are sometimes called small round blue cells, due to a lack of cytoplasm, and a large blue nuclei.
A poorly differentiated neuroblastoma is composed of slightly more differentiated cells, with smaller nuclei and a bit more cytoplasm.
In addition, the cells of a poorly differentiated neuroblastoma may be surrounded by a substance called neuropil, which is a dense network of interwoven nerve fibers, like axon and dendrite branches.
Finally, a differentiating neuroblastoma is composed of cells with lots of cytoplasm, and is often surrounded by a substance called Schwannian stroma.
Schwannian stroma is a connective tissue from non-neuronal cells that forms myelin, which insulates the axons of the mature neurons.
When any type of neuroblastoma forms, cells in the surrounding tissue release chemokines called CXCL12 and that stimulates nearby immune cells.
CXCL12 is normally produced by some organs like the lymph nodes, liver, bones, and especially the bone marrow, but gets produced in higher amounts when tissue is damaged.When immune cells sense high levels of CXCL12, they get stimulated and move towards the area where it’s coming from.
As it turns out, neuroblastic tumor cells also get stimulated by CXCL12. If a neuroblastoma cell breaks away and gets into the blood or lymph, it will sometimes migrate towards the organs where CXCL12 is normally produced - creating metastatic tumors there.Symptoms of neuroblastoma result from the chemokine release, and include fever, weight loss, sweating, and fatigue.Other symptoms of neuroblastoma depend on where the tumor is located, and are usually a result of the tumor pressing up against surrounding organs.

Symptoms4:17–5:50

For example, if the tumor is in the thoracic region of the sympathetic chain, it can grow into the lungs, causing breathing difficulties.
A thoracic tumor that extends to the neck can press up against nerves originating there and heading towards the face, and it can cause Horner syndrome.
Horner syndrome involves miosis or constriction of the pupils, ptosis or the drooping of the eyelid, and anhidrosis which is an inability to sweat in the face.
Tumors on the sympathetic chain might also grow into the spine, causing neurologic symptoms, like muscle weakness or bowel and bladder problems.
Children with a tumor in the adrenal medulla can have a large, painful abdominal mass that causes abdominal swelling.About half of all neuroblastomas spread to the bones, causing bone pain and small fractures.
Classically, neuroblastomas can cause fractures at the base of the skull, just where the skull connects to the spine. With these fractures, fluid and blood to leak into the tissues around the eyes.
When that happens it can cause periorbital ecchymosis, also called raccoon eyes, because of the dark rings of blood that can be seen in the soft tissue around the eyes.
Neuroblastoma that invades the bone marrow can also affect the marrow’s ability to make healthy red blood cells, platelets, and white blood cells, leading to fatigue, easy bruising, and frequent infections.
Diagnosis of neuroblastoma usually starts with testing for HMA and VMA in the blood or urine, since high levels those metabolites may indicate tumors that secrete epinephrine and norepinephrine.A CT scan can show the location and size of the tumor, and a complete blood count can help determine whether neuroblastoma has spread to the bone marrow.

Diagnosis5:50–6:09

Treatment6:09–6:32

Treatment largely depends on the size and staging of the neuroblastoma--meaning how far the tumor has spread. Early on, surgery can be used to remove the tumor, but once it has started to spread it might require a combination of chemotherapy, medication, and even a stem-cell or bone marrow transplantation.
Generally speaking, the best treatment outcomes are among the youngest patients that have a differentiating neuroblastoma.##SummaryAlright, as a quick recap, neuroblastoma is a condition where neural crest cells of the developing sympathetic nervous system and adrenal medulla do not differentiate normally.

Review6:32–6:58

Rather, they continue to proliferate in an immature state, creating tumors that press on nearby organs, or spread to other organs causing complications like horner syndrome and raccoon eyes.
High levels of HMA and VMA are usually the first indication of neuroblastoma.