What are the other Names for this Condition? (Also known as/Synonyms)

• Cerebral Ganglioneuroblastoma
• Cerebral GNB
• CNS Ganglioneuroblastoma

What is Central Nervous System Ganglioneuroblastoma? (Definition/Background Information)

• A Central Nervous System Ganglioneuroblastoma is a tumor that may form anywhere within the central nervous system (CNS). The brain along-with the spinal cord constitute the central nervous system (CNS) of the body. A CNS/brain tumor may be described as a mass of abnormally growing cells arising from the brain tissue (brain parenchyma and meninges) or the spinal cord (central spine)
• Broadly, these tumors are classified as benign (non-cancerous) and malignant. Malignant tumors are cancerous and can spread or metastasize to other regions of the body. They generally exhibit rapid growth and, in some cases, may present symptoms during the early stages of development
• The World Health Organization (WHO) classifies central nervous system tumors according to their grade and histological subtypes. A tumor subtype is determined by a pathologist after examining a tissue biopsy of the tumor under the microscope. This WHO classification system is used by healthcare professionals all over the world in diagnosing and treating these tumors
• Central Nervous System Ganglioneuroblastoma (CNS GNB) is an uncommon tumor of moderate aggression and having the potential for a malignant transformation. The tumor specimen shows the presence of both benign ganglion cells and neuroblasts. As the name suggests, the ganglioneuroblastoma (GNB) tumor is a combination of ganglion nerve cells (mature nerve cells) and neuroblasts (young nerve cells)
• In general, ganglioneuroblastomas are abdominal (adrenal gland) tumors that develop in young children; the other locations include the chest cavity, legs, or neck. The central nervous system is therefore an unusual location for the tumor. Thus, due to their relative rarity and generally asymptomatic nature, CNS Ganglioneuroblastomas make for a challenging diagnosis
• Ganglioneuroblastoma (GNB), which is of intermediate grade, belongs to the family of neuroblastic tumors; with the other family members being neuroblastoma (a highly-aggressive tumor) and ganglioneuroma (a benign and low-grade tumor). It is also described in the literature as a variant of neuroblastoma. Both ganglioneuroblastoma and neuroblastoma are sympathetic nervous system tumors
• According to WHO, CNS Ganglioneuroblastoma is part of a group designated “embryonal tumors”, which are all high-grade malignancies. It is a histologic subtype of a primitive neuroectodermal tumor (PNET). High-grade tumors are known to exhibit aggressive behavior and grow rapidly. These tumors are known to infiltrate widely and destroy tissues, causing necrosis. They are also known to recur sooner following treatment
• The cause of formation of Central Nervous System Ganglioneuroblastoma is not well-established. Generally, it is reported that a combination of several factors may play a role in the formation of brain tumors, including genetic, environmental, and lifestyle-related. The risk factors for such tumors may include presence of certain genetic disorders, exposure to ionized radiation, viral infections, and head trauma
• The signs and symptoms of Central Nervous System Ganglioneuroblastoma depend on the location of the tumor. Individuals may experience headaches, weakness in different parts of the body, convulsions, vision and speech disturbances. Large-sized tumors may compress adjacent brain tissue resulting in complications. Infrequently, metastatic tumors may spread outside the brain and spinal cord
• The treatment modalities for Central Nervous System Ganglioneuroblastoma may include a combination of surgery, radiation therapy, and chemotherapy. The prognosis is determined by a wide variety of factors, such as age of the individual, tumor size, and overall health status. Nevertheless, the prognosis is generally favorable with adequate treatment, but may vary across patients

Who gets Central Nervous System Ganglioneuroblastoma? (Age and Sex Distribution)

• Although rare, Central Nervous System Ganglioneuroblastoma is a common type of embryonal tumor of infancy. Typically, ganglioneuroblastoma constitutes nearly 10% of all childhood malignancies
• Most of the tumors are diagnosed in children less than 5 years old; the median age of presentation being 4 years
• CNS Ganglioneuroblastomas are not common in children over 14 years, and are very rare in adults
• Both boys and girls are affected, but a slight predilection for girls is noted (girl-boy ratio of 7:5)
• Worldwide, individuals of all racial and ethnic groups may be affected

What are the Risk Factors for Central Nervous System Ganglioneuroblastoma? (Predisposing Factors)

Infants and young children report a higher incidence of Central Nervous System Ganglioneuroblastoma formation. Apart from this, no other clearly identified risk factors are evident for CNS GNB.

In general, the following factors may increase one’s risk for brain tumors:

• Advancing age is an important risk factor
• In general, males are at a higher risk for brain tumors than females
• Positive family history: It is reported that certain genetic (hereditary) factors are responsible for the formation of certain brain tumors. Such hereditary conditions include:
  • Li-Fraumeni syndrome
  • Neurofibromatosis types 1 or 2 (NF1 or NF2)
  • Tuberous sclerosis
  • Turcot syndrome
  • Von Hippel-Lindau disease
• Environmental factors such as ionized radiation exposure (both high-dose and low-dose)
• Individuals who have undergone radiation therapy for other cancers involving the head and neck region are at an increased risk
• Viral infections involving pathogens, such as Epstein-Barr virus (EBV) and cytomegalovirus (CMV), have been implicated
• Exposure to certain chemicals, pesticides, or products, either at work or at home
• Some reports indicate that the use of mobile phones may increase one’s risk due to exposure to electromagnetic waves. However, the scientific research community is presently divided on this factor
• Head injuries
• History of seizures
• Hormonal factors: Studies have shown a correlation between hormones and some types of brain tumors
• Intake of N-nitroso compounds, either in one’s diet (such as cured meat) or via vitamin supplements may increase one’s risk

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Central Nervous System Ganglioneuroblastoma? (Etiology)

The exact cause of development of Central Nervous System Ganglioneuroblastoma is not well-understood. Research scientists believe that the cause of brain tumors may involve a combination of several factors including genetic, environmental, and occupational factors.

A few genetic abnormalities have been identified in ganglioneuroblastoma, in general, and some of these include:

• Amplification of MYCN gene
• Involvement of the ALK gene is observed in some cases
• Loss of genetic material on chromosome 1p
• Chromosome 17q amplification

In general, it is known that cancers form when normal, healthy cells begin transforming into abnormal cells - these cancer cells grow and divide uncontrollably (and lose their ability to die), resulting in the formation of a mass or a tumor.

What are the Signs and Symptoms of Central Nervous System Ganglioneuroblastoma?

The signs and symptoms of brain tumors may be significantly different from one individual to another. It may be mild or severe, depending on several factors. The onset of symptoms and speed of progression of the tumor can vary. In many individuals, tumors that grow slowly and remain asymptomatic, are only diagnosed during certain radiological imaging studies of the head and neck region, which are performed for unrelated health conditions.

The signs and symptoms of Central Nervous System Ganglioneuroblastoma primarily depend on the location and size of the tumor. The tumor may develop in any part of brain or spinal cord, including in the neck. In many cases, during the initial stages, the tumors do not present any significant symptoms. Although, some tumors are known to be present widespread in the region.

The signs and symptoms may include:

• Headaches that may increase in intensity and be persistent
• Nausea and vomiting
• Irritability
• Numbness and tingling sensation
• Muscle weakness; loss of strength in the arms of legs
• Neck pain
• Visual impairment such as blurred vision, double vision or poor eyesight
• Ringing in the ears (tinnitus)
• Hearing impairment or hearing loss
• Speech problems
• Insomnia or loss of sleep, or excessive sleepiness (usually during daytime)
• Damage to peripheral nerves
• Tremors
• Seizures or convulsions
• Lack of coordination; unsteadiness and loss of balance (vertigo)
• Dizziness and fainting
• Confusion
• Changes in one’s behavior; personality changes
• Mental impairment
• Memory loss

When the spinal cord is involved, the following may be noted (based on tumor location):

• Back pain and/or chest pain
• Numbness and tingling sensation
• Weakness of the body or lower extremities; loss of strength in the arms of legs
• Pain in the arms and legs, depending on the nerves that are compressed by the tumor
• Severe cases may result in loss of bowel and bladder control; especially observed in lower spine tumors

Large tumors can cause significant signs and symptoms. Most of the tumors are single; but occasionally, multiple tumors can be detected growing simultaneously in the brain or spinal cord region, particularly in individuals with genetic disorders. The associated symptoms of the underlying condition, if any present, may be noted.

How is Central Nervous System Ganglioneuroblastoma Diagnosed?

The tumors may be detected when there is a sudden worsening of the symptoms prompting the healthcare provider to perform radiological studies of the brain and/or spinal cord.

Generally, it is not possible to establish a pre-operative diagnosis of Central Nervous System Ganglioneuroblastoma through symptomatic assessment or radiological imaging studies alone; a tumor biopsy following a surgical tumor removal is necessary to make a definitive diagnosis.

The diagnosis of CNS Ganglioneuroblastoma may involve the following tests and examinations:

• Complete physical examination with thorough evaluation of the individual’s medical history (including family history of any genetic disorder)
• Assessment of the presenting signs and symptoms
• Visual field tests; tests to assess visual acuity
• Neurological, motor skills, and cognitive assessment:
  • Checking intellectual ability, memory, mental health and function, language skills, judgment and reasoning, coordination and balance, reflexes, sensory perceptions (space, sight, hearing, touch)
  • The healthcare provider/neurologist may use the Karnofsky Performance Scale in order to assess the neurological functioning of the individual’s central nervous system (CNS)
• Catecholamines urine test: It is a test to assess the levels of catecholamine hormones in urine. It is used to diagnose hormone-releasing tumors (or neuroendocrine tumors). An elevated level of catecholamines may indicate the presence of a ganglioneuroblastoma in the body
• Electroencephalography (EEG)
• Electromyography with nerve conductivity tests
• Imaging studies that may be performed include:
  • X-ray of head and neck
  • Computerized tomography (CT) scan of the head and neck region; CT with contrast - the scans may reveal calcifications
  • Magnetic resonance imaging (MRI) scan of the central nervous system (brain and spine); MRI with contrast agents such as gadolinium
  • Cerebral angiographic studies or MR angiography: An angiogram involves injecting dye into the bloodstream, which makes the blood vessels to appear visually on X-rays. The X-ray may show a tumor in the brain or the blood vessels leading into the tumor
  • Magnetic resonance spectroscopy: This radiological technique is used to study the chemical profile of the tumor. It is often performed with and compared to corresponding MRI scan images of the affected region
  • Positron emission tomography (PET scan): A PET scan is a nuclear medicine imaging technique that uses three-dimensional images to show how tissue and organs are functioning. It may be performed to detect any malignancy, and if there is a metastasis (spread) of the tumor to other regions
• Iodine-123 metaiodobenzylguanidine scan (123-I-MIBG): In a MIBG scan, a radioactive substance is injected into blood, which will then bind to the neuroblastoma cells. This test helps in determining whether the tumor has spread to other regions of the body or not
• Cerebrospinal fluid analysis, where a spinal tap or lumbar puncture procedure may be performed: This diagnostic test is used to remove a sample of cerebrospinal fluid (CSF) from the spaces in and around the brain and spinal cord. The sample is removed from the lower spinal cord using a thin needle, and it is then checked for the presence of cancer cells
• Molecular testing to determine genetic mutations, if any

Tissue biopsy: A biopsy of the affected region is performed and sent to a laboratory for a pathological examination. A pathologist examines the biopsy sample under a microscope. After putting together clinical findings, special studies on tissues (if needed) and with microscope findings, the pathologist arrives at a definitive diagnosis. Examination of the biopsy sample under a microscope by a pathologist is considered to be gold standard in arriving at a conclusive diagnosis.

There are two ways to perform a biopsy:

• First, a biopsy can be performed as part of a surgical procedure to remove the brain tumor
• Second, a stereotactic needle biopsy can be performed when the tumor is deep within the brain or located in a sensitive area. In this procedure, the surgeon drills a small hole (called a burr hole) into the skull. A thin needle, guided by CT or MRI scanning, is then inserted through the hole to help in the removal of tissue

A differential diagnosis to eliminate other conditions or tumor types may be considered, before arriving at a definitive diagnosis. These may include:

Pathological differential diagnosis may include:

• Atypical teratoid/rhabdoid tumor of the central nervous system
• Desmoplastic small round cell tumor of the central nervous system
• Ganglioneuroma of the central nervous system
• Lymphoid malignancy of the central nervous system
• Metastatic melanoma to brain
• Neuroblastoma of the central nervous system
• Pharyngeal tumors extending to the central nervous system
• Primitive neuroectodermal tumors
• Schwannoma with neuroblastoma-like features of the central nervous system

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Central Nervous System Ganglioneuroblastoma?

The possible complications associated with Central Nervous System Ganglioneuroblastoma include:

• Emotional and mental stress for both the patients and the caretakers, due to the diagnosis and treatment of a malignant brain tumor
• Large undetected tumors can severely affect brain function and be disabling or even life-threatening, due to mass effect/compression of brain tissue
• Large tumors may also press against the skull (or other) bones causing it to expand, causing severe complications
• Spinal cord compression is another potential complication associated with a neuroblastoma located on the spine. As the tumor grows, it can press upon the spinal cord leading to paralysis of the arms/legs and pain
• Some tumors can secrete vasoactive intestinal peptide (VIP) hormone causing severe watery diarrhea
• Trouble with concentration
• Severe loss of memory
• Dementia including personality changes causing a reduced quality of life
• Bleeding in the brain (brain hemorrhage)
• Paralysis and coma
• Peritumoral brain edema (PTBE): Presence of fluid around the tumor region in the brain resulting in severe symptoms and complications
• The tumors may spread to other regions of the central nervous system through the cerebrospinal fluid, called CSF dissemination
• In rare cases, the tumor may spread (metastasize) to other sites of the body leading to severe complications and treatment challenges. CNS Ganglioneuroblastoma is known to metastasize outside the brain
• Complications due to an underlying genetic disorder, if any present

Complications may arise from surgery, radiation therapy, chemotherapy, or other treatment modalities.

Surgical complications:

• Damage to the muscles, vital nerves, and blood vessels, during surgery to remove the tumor; injury to unaffected brain tissue during surgery
• Post-surgical infection at the wound site is a potential complication
• Sometimes, removing the tumor can worsen the signs and symptoms in some individuals
• Recurrence of the tumor after surgery may be observed; malignant tumors often have very high recurrence rates

Chemotherapy side effects depend on the type of chemotherapy medication used and may include:

• Nausea and vomiting
• Hair loss
• Mouth sores
• Loss of appetite
• Diarrhea
• Fatigue
• Increased risk for infections
• Easy bruising

Radiation therapy can cause short-term side effects. It depends on the type used and may include:

• Nausea and vomiting
• Hair loss
• Dryness of mouth; loss of taste
• Headaches
• Fatigue
• Skin color changes; usually darkening of skin on the face and neck may be noted
• Speech and hearing difficulties
• Memory issues
• Seizures

Long-term side effects of radiation therapy (seen after 6 months or beyond) may include loss of memory, impaired brain function, and appearance of symptoms that mimic stroke.

How is Central Nervous System Ganglioneuroblastoma Treated?

The treatment modality for brain tumor is chosen, depending on the type, size, location, and stage of the tumor, tumor growth rate, age and health status of the individual. Often, a multidisciplinary team of specialists including ophthalmologists, neurologists, oncologists, surgeons, radiation therapy experts, and other healthcare professionals are involved in managing the condition.

Currently, there are no treatment protocols available for Central Nervous System Ganglioneuroblastoma, since it is a highly uncommon tumor. Some of the treatment measures may include:

• Symptomatic treatment that may involve the use of antiseizure medications, painkillers, steroids (to reduce inflammation), and administration of anti-depressants

Surgical treatment: Surgery to remove the entire tumor or just part of the tumor depends on several factors including the risk assessment by a neurosurgeon, with respect to the potential injury to nearby brain tissues. It is also considered based on the location, size, and overall health of the individual. A complete removal of the tumor can result in a cure in many patients. Although, in many cases, removal of the tumor offers a lot of surgical challenges to the healthcare providers, due to the complexity of the tumor site involved.

• Craniotomy: It is a surgical procedure wherein a tiny hole is created in the cranium to access and remove the tumor. The main goal of surgery is to remove as much tumor as possible without damaging the surrounding brain tissue
• Microsurgery: The surgery is performed using microsurgical techniques, which can help minimize damage to the accompanying nerve. Since the tumor mostly affects the covering around the nerves, it can be completely removed without affecting the nerve in most cases. The following techniques may be employed:
  • Subtotal removal; when the tumor is incompletely removed
  • Near total removal; when most of the tumor is removed and there is very little tumor remnants
  • Total tumor removal; when the tumor is removed completely
• In some cases, embolization of the tumor may be performed, in order to shrink the tumor size, before major invasive procedures are undertaken. In embolization, the blood supply to the tumor is cut-off, resulting in its shrinkage. This also helps reduce blood loss during a surgical resection
• Radiosurgery for individuals who cannot undergo surgery or have recurrent tumors
• Post-operative care is important: One must maintain minimum activity levels, until the surgical wound heals

Surgical procedures to remove brain tumors carry risks, including infection, possible damage to healthy brain tissue, swelling, or possible fluid build-up in the brain.

Radiation therapy: There are a variety of radiation therapy methods that can be used to treat the tumors. Radiation therapy is performed either after removal of the tumor (to destroy any remaining meningioma cells), or in individuals where surgical removal procedure is not an option. Radiation therapy is helpful to reduce the rate of recurrence. It is also recommended for individuals where the tumor is removed partially.

The types of radiation therapy include:

• Standard external radiation beam therapy using a beam of high-energy X-rays; it is the most common form of radiation therapy used to treat cancers
• 3-dimensional conformal radiation therapy, where 3-d images of the tumor are created using radiological imaging scans to help design appropriate radiation therapy beam size and angles
• Intensity modulated radiotherapy (IMRT): It is a procedure that uses computer-controlled linear accelerators to deliver precise radiation to a malignant tumor
• Stereotactic radiosurgery using Gamma Knife or CyberKnife technique
• Proton radiation therapy: It is a form of external beam therapy using high-energy proton beams to destroy the tumor cells
• Fractionated radiation therapy: It is a good option for individuals whose tumors are too large for radiosurgery, or if the tumor is in a sensitive location. In this therapy, small doses of radiation are administered for a certain set period

Some individuals may experience a few side effects, while others may experience none. These may include fatigue, headaches, hair loss, and scalp irritation. Radiation therapy beams may affect the pituitary gland causing it to dysfunction (bringing about hormonal changes in the body).

Chemotherapy: The response of the tumor to chemotherapy is an important consideration while using this treatment modality. Chemotherapy may be administered in CNS Ganglioneuroblastoma, particularly in very young children.

• Whether to use chemotherapy as a treatment modality is determined by healthcare provider on case-by-case basis
• Chemotherapy may be administered for those tumors that cannot be effectively treated by surgery or radiation therapy. The administration of some drugs may slow the rate of growth of the tumor

The following chemotherapy agents and methods have been used in higher grade tumors with varying beneficial results:

• Immunotherapy to stimulate an affected individual’s immune system
• Somatostatin analogs which prevent the release of growth hormones
• Hydroxyurea, epidermal growth factor receptor inhibitors, platelet-derived growth factor receptor inhibitors, and vascular endothelial growth factor inhibitors

There are side effects for chemotherapy, which depends upon the type and dose of drugs administered. The common chemotherapy side effects include nausea, vomiting, hair loss, loss of appetite, headache, fever, chills, and weakness.

Clinical trials: In certain advanced stage tumors, there may be some newer treatment options, currently on clinical trials, which can be considered for some patients depending on their respective risk factors.

Regular observation and periodic checkups to monitor the condition is strongly recommended following treatment. In order to avoid a relapse, or be prepared for a recurrence, the entire diagnosis, treatment process, drugs administered, healthcare recommendations post-treatment, etc. should be well-documented and follow-up measures initiated.

How can Central Nervous System Ganglioneuroblastoma be Prevented?

Presently, there are no specific methods or guidelines to prevent the formation of Central Nervous System Ganglioneuroblastoma. However, if it is associated with a genetic disorder, the following points may be considered:

• Genetic counseling and testing: If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
• Regular health check-ups might help those individuals with a history of the condition in the immediate family and help diagnose the tumor early

In general, the factors that may help reduce the incidence of brain tumor may include:

• Reducing exposure to ionizing radiation
• Avoiding cigarette smoke inhalation
• Weight loss, in case one is obese or overweight; maintaining a good BMI
• Availing early treatment for infections
• Using safety gear including wearing helmets when playing sports or while riding two-wheelers
• Wearing seatbelts while driving automobiles to minimize the risk for head/body injury

According to the U.S. Preventive Services Task Force (USPSTF), currently there is no standard testing protocols available for brain tumor.

Regular medical screening at periodic intervals with blood tests, scans, and physical examinations are mandatory. Often several years of active vigilance are crucial and necessary.

What is the Prognosis of Central Nervous System Ganglioneuroblastoma? (Outcomes/Resolutions)

The prognosis of Central Nervous System Ganglioneuroblastoma may vary considerably from one individual to another and is dependent on a set of factors.

• According to reports, the prognosis of CNS Ganglioneuroblastoma is better than that of a neuroblastoma (an aggressive malignancy), but much worse than a ganglioneuroma (a benign tumor). Hence, the tumor reportedly has an intermediate prognosis
• The 5-year survival rate is about 94%. However, this is highly dependent on the patient’s age at tumor diagnosis; tumors in children younger than 12 months have the best prognosis
• Factors that indicate poor prognosis include a poor response to treatment and progression to higher grade tumors. In about 1-2% of the tumors, regression is known to take place

In general, the prognosis may depend upon several factors, which include:

• Tumor histology or grade of the tumor: The lower the grade, the better is the prognosis
• Stage of tumor: With lower-stage tumors, when the tumor is confined to site of origin, the prognosis is usually excellent with appropriate therapy. In higher-stage tumors, such as tumors with metastasis, the prognosis is poor
• Age of the individual: Older individuals generally have poorer prognosis than younger individuals
• Overall health of the individual: Individuals with overall excellent health have better prognosis compared with those with poor health
• The size of the tumor: Individuals with small-sized tumors fare better than those with large-sized tumors
• Location of the tumor is an important prognostic factor: Tumors at certain sites involving the central nervous system are more difficult to surgically excise and remove. They can also cause considerable neurological damage at certain sites in the brain and/or spinal cord. Tumors located near vital structures of the brain have poor prognosis
• Tumors that are slow-growing have better prognosis than rapidly-growing tumors
• Presence of certain genetic abnormalities may result in a rapid progression of tumor growth and development
• Sporadic tumors have generally better prognosis than syndromic tumors; tumors in a background of genetic disorders/syndromes may have additional complications
• The ease of accessibility and surgical resectability of the tumor (meaning, if the primary tumor can be removed completely). This is an important prognostic factor
• Extent of residual tumor in the body following a surgical resection: A complete surgical excision with entire tumor removal presents the best outcome. In some cases, large portions of the tumor may be removed; or, only a small portion for tissue biopsy
• Individuals with bulky disease may have a poorer prognosis
• Involvement of other vital organs may complicate the condition
• Metastatic spread: Spread of the malignancy to other body sites portrays a poorer prognosis
• Whether the tumor is occurring for the first time or is a recurrent tumor. Recurring tumors have worse prognosis compared to tumors that do not recur 
• Response to treatment and absence of post-operative complications: Tumors that respond to treatment have better prognosis compared to tumors that do not respond to treatment
• Progression of the condition makes the outcome worse
• Functional neurologic status based on neurological evaluation of the patient: A higher score on the Karnofsky Performance Scale may indicate more favorable outcomes

An early diagnosis and prompt treatment of the tumor generally yields better outcomes than a late diagnosis and delayed treatment.

Additional and Relevant Useful Information for Central Nervous System Ganglioneuroblastoma:

The following DoveMed website link is a useful resource for additional information:

https://www.dovemed.com/diseases-conditions/cancer/