Medulloblastoma: what is it, symptoms, treatment, prognosis

What are medulloblastomas?

Medulloblastoma is the most common malignant brain tumor in children. Medulloblastomas, by definition, occur in the cerebellum, which is the part of the brain located at the base of the skull, just above the brainstem. The cerebellum is involved in many functions, including coordinating voluntary movements (eg, walking, fine motor skills) and regulating balance and posture.

Medulloblastomas arise from primitive, undeveloped brain cells. Most medulloblastomas occur in infants and children. Less commonly, these tumors can develop in adults. Symptoms associated with medulloblastoma include headaches in the morning that get worse as the day progresses, intermittent vomiting, difficulty walking, and balance. Medulloblastomas can spread to other parts of the central nervous system. The exact cause of medulloblastoma is unknown.

Signs and symptoms

The specific symptoms associated with medulloblastoma will vary from one person to the next in depending on the exact location and size of the medulloblastoma and whether the tumor has spread to other areas. Affected people may not have all of the symptoms discussed below. Affected people should talk to their doctor and medical team about their specific case, associated symptoms, and overall prognosis.

Medulloblastoma symptoms usually occur due to increased pressure in the skull (intracranial pressure). Medulloblastomas usually occur at or near the base of the skull, in an area known as the posterior fossa. The posterior fossa contains the brainstem and cerebellum.

Medulloblastomas usually involve a fluid-filled fourth cavity (ventricle) in the brain. The brain has four cavities called the ventricles, which are filled with cerebrospinal fluid (CSF) and are connected by channels through which CSF circulates. Because the tumor often fills the fourth ventricle, CSF circulation is obstructed, resulting in hydrocephalus. Hydrocephalus - a condition in which the accumulation of excess CSF in the brain causes various symptoms, including repeated, often severe vomiting, lethargy, and headaches that often occur in the morning and improve with throughout the day. Additional symptoms may include:

• irritability;
• an increase in the size of the head;
• paralysis (paresis) of the muscles that help control eye movements (extraocular muscles).

Many infants and children with medulloblastoma develop papilloedema, a condition in which the optic disc swells due to increased intracranial pressure. The optic nerve is a nerve that transmits impulses from the retina to the brain. Papilloedema can cause blurred vision. Since many of the symptoms associated with medulloblastoma are nonspecific and often subtle, papilloedema may be the first sign that a neurologist might be suspicious.

Children with medulloblastoma often show signs of cerebellar dysfunction. Symptoms may include poor coordination, difficulty walking, and clumsiness (ataxia). Affected children may fall frequently and develop an erratic, awkward gait (unsteady gait). They can stand with their legs wide apart, stagger or hesitate when walking, and easily lose their balance.

As the tumor grows or spreads, additional symptoms may appear. Such symptoms may include double vision (diplopia), fast, sharp eye movements (nystagmus), facial weakness, ringing in the ears (noise in ears), hearing loss and neck stiffness. Some children with double vision may tilt their heads to try to align the two images.

Causes

The exact underlying cause of medulloblastoma is unknown. Most cases happen by chance for no apparent reason (sporadically).

Many cases of medulloblastoma are associated with chromosomal abnormalities. These abnormalities are not inherited (i.e., not transmitted from one generation to the next), but occur at some unknown point during the development of the child, even during the development of the fetus or embryo. Although medulloblastomas are associated with chromosomal changes, they are not inherited.

In people with cancer, malignant neoplasms can develop due to abnormal changes in the structure and orientation of certain cells. As mentioned above, the specific cause or factors behind these changes are not known. However, studies show that abnormalities in DNA (deoxyribonucleic acid) that is the carrier of the organism's genetic code, underlies the malignant cellular transformation. Depending on the type of cancer you have and a number of other factors, these abnormal genetic changes can occur spontaneously for unknown reasons (sporadically).

Available evidence suggests that in about one third to half of people with medulloblastoma, tumor cells may have a specific chromosomal abnormality known as the 17q isochromosome, with the associated loss or inactivation of a particular genetic information. Chromosomes, which are present in the nucleus of human cells, carry the genetic characteristics of each person. Pairs of human chromosomes are numbered 1 through 22, with an unequal 23rd pair of X and Y chromosomes in males and two X chromosomes in females. Each chromosome has a short arm, designated "p," a long arm, designated "q," and a narrowed region where two arms (centromere) are connected.

An isochromosome is an abnormal chromosome with identical arms on each side of the centromere. More specifically, in some cases of medulloblastoma, there is a duplication of the long arm and removal of the short arm of chromosome 17. Some researchers suggest that such structural abnormalities of chromosome 17 may lead to inactivation of the gene in chromosome, which usually acts as a tumor suppressor, potentially leading to malignant transformation of certain cells. However, the implications of such findings remain unclear.

Additional chromosomal abnormalities have been identified in individuals with medulloblastoma, including abnormalities on chromosomes 1, 7, 8, 9, 10q, 11, and 16. How these various abnormalities play a role in the development of medulloblastoma is unknown. Further research is needed to determine the complex mechanisms underlying the development of medulloblastoma.

In people with cancer, including medulloblastoma, malignant neoplasms can develop due to abnormal changes in the structure and orientation of certain cells, known as oncogenes or tumor suppressor genes. Oncogenes control cell growth; Tumor suppressor genes control cell division and ensure their timely death. Oncogenes associated with medulloblastoma include ERBB2, MYCC and OTX2. Many medulloblastomas are characterized by changes in specific molecular signaling pathways that lead to uncontrolled cell growth. Pathways involved in medulloblastoma include the Wnt pathway, the SHH pathway, and the myc pathway.

In extremely rare cases, medulloblastomas occur in people with certain inherited disorders, including:

• Gorlin-Goltz syndrome (hereditary primary multiple basal cell carcinoma of the skin);
• Turkot's syndrome;
• Lee syndrome Fraumeni;
• Rubinstein-Teibi syndrome;
• Nijmegen injury syndrome;
• neurofibromatosis;
• ataxia-telangiectasia.

People with these disorders have an increased risk of developing medulloblastoma.

Researchers speculate that medulloblastoma comes from immature cells that interfere with maturation in some way (ie, differentiation) into more specialized cells that have "intended" specific functions in the considered fabrics. Such immature or incompletely differentiated cells can grow and divide with extraordinary fast, uncontrolled speed that cannot be controlled by natural immune defenses organism. Eventually, this proliferation of abnormal cells can lead to the formation of a mass known as a tumor (neoplasm).

According to the classification of the World Health Organization (WHO classification), medulloblastomas are divided, depending on histological features / signs, into several types:

• classic medulloblastoma reduction CMB)
• desmoplastic / nodular medulloblastoma reduction DMB; you can also find the name of this type of tumor "desmoplastic / nodular medulloblastoma")
• medulloblastoma with pronounced nodularity reduction MBEN; you can also find the name of this type of tumor "medulloblastoma with extensive nodularity")
• anaplastic medulloblastoma reduction AMB)
• large cell medulloblastoma reduction LCMB)

The different subtypes of medulloblastoma appear to be different at the cellular level, but do not yet affect treatment options. However, in the future, such differences can be used to develop new targeted treatments based on a specific subtype and other factors.

Extensive transcriptional profiling of human medulloblastomas has recently led to a second or more a precise classification system that stratifies medulloblastomas according to their expression profiles mRNA. These are WNT medulloblastomas (i.e. medulloblastomas with activation of the WNT signaling pathway), SHH medulloblastomas (i.e. medulloblastoma with activation of the SHH signaling pathway), medulloblastoma group 3 and medulloblastoma 4 groups.

Medulloblastomas in the WN subgroupT cells are characterized by genetic changes that affect members of the Wnt signaling pathway that are associated with the processes of embryogenesis and tumorigenesis. Mutations in the ß-catenin gene and monosomy 6 are among the most common genetic events that define this subgroup, and the incidence is similar in men and women. Medulloblastomas of the WNT subgroup tend to affect older children and are rare in adults. Among the various subgroups, WNT tumors have the best prognosis and clinical outcomes.

Subgroup SHH characterized by increased activity of members of the SHH signaling family. Common genetic events excluding this subgroup are mutations in genes PTCH, the SHH receptor, and SUFU, a negative regulator of the SHH signaling pathway. SHH tumors are the most common subgroup of medulloblastoma found in children and adults, and have an intermediate prognosis. As with the WNT subgroup, the incidence of SHH tumors is the same for men and women.

Tumors of group 3 characterized by excessive amplification of MYC and genes associated with phototransduction and glutamate signaling. These tumors are also known for their high rates of metastasis and have a poorer prognosis for any subtype of medulloblastoma. Group 3 tumors are extremely rare in adults and are more common in men than women. The last subgroup currently known as group 4is characterized by the activation of genes associated with neuronal or glutameminergic signaling. Although these tumors are common in all age groups, relatively little is known about them. Like group 3, group 4 tumors are more common in men and have a high tendency to metastasize. Their prognosis is considered intermediate.

Medulloblastoma is sometimes classified as a primary neuroectodermal tumor or PNET. PNETs are a group of tumors that arise from primitive nerve cells in the brain. Medulloblastoma is sometimes called the primary neuroectodermal tumor of the posterior fossa.

Affected populations

Medulloblastomas can affect people of any age, but are most common in children under 15 years of age, with a peak incidence between 3 and 9 years of age. Medulloblastomas are the most common malignant brain tumor in children. Approximately 80 percent of those affected are under 15 years of age. Medulloblastomas are extremely rare in adults, accounting for 1–2 percent of all adult brain tumors. In adults, most medulloblastomas occur between the ages of 20 and 44. Medulloblastomas are extremely rare in people over 45.

Among children, boys get sick more often than girls. However, in adults, this ratio is the same. The exact incidence of medulloblastomas is unknown, and there are many different estimates in the medical literature. Typically, medulloblastomas account for 2 percent of all primary brain tumors and 18 percent of all brain tumors in children.

Symptomatic disorders

Symptoms of the following disorders may be similar to those of medulloblastoma. Comparisons can be useful for differential diagnosis.

Various types of brain tumors can lead to increased intracranial pressure and generalized symptoms similar to those potentially associated with medulloblastomas such as vomiting, headaches, gait disturbances, changes in consciousness, visual impairment, head enlargement in young children, and / or others abnormalities. Such tumors can also lead to additional generalized or more localized symptoms not usually associated with medulloblastomas; differ in the average duration of symptoms before diagnosis; and / or have other clinical characteristics not usually seen in medulloblastomas. Confirming the presence of a brain tumor and identifying a specific type of tumor usually requires clinical and neurological examination, complete medical history, advanced imaging techniques and others diagnostic measures.

Diagnostics

Medulloblastoma is diagnosed on the basis of careful clinical and neurological evaluation, identifying characteristic symptoms and physical signs, medical history and special diagnostic tests. Such tests may include blood tests; assessment of visual acuity, visual fields and eye movements; using an instrument (ophthalmoscope) that visualizes the inside of the eyes (i.e., to detect papilloedema); advanced imaging techniques (MMR, CT); and or other diagnostic tests.

The main specialized imaging technique used to diagnose medulloblastoma is magnetic resonance imaging (MRI) of the brain and spine. MRI uses a magnetic field and radio waves to create detailed cross-sectional images of organs and tissues. Experts point out that, if available, MRI is preferred over computed tomography (CT) as a diagnostic tool for medulloblastoma, as it may provide a better indication of the extent of the tumor, possible penetration into the meninges, and involvement spine. An MRI is done before and after the patient receives an intravenous injection of gadolinium contrast agent. The contrast agent causes the tumor to appear as a bright mass (much brighter than the surrounding tissue) on the screen. When MRI is not available, a CT scan can be performed. Computed tomography uses a computer and X-rays to create a snapshot of internal structures.

Gadolinium-based MRI of the spine can also be performed to determine if medulloblastoma has spread into the cerebrospinal fluid and spine. In some cases, a lumbar puncture may also be recommended for the analysis of tumor cells in the CSF. (During a lumbar puncture, a cannula is inserted into the spinal canal to extract CSF for analysis.) However, experts may advise that lumbar puncture is inappropriate (contraindicated) in most cases prior to resection tumors.

Surgical removal and microscopic examination (biopsy) of the affected tissue may be done to confirm the diagnosis of medulloblastoma. In some cases, other diagnostic tests can be performed.

Standard treatments

Treatment of medulloblastoma may require a coordinated effort by a team of healthcare professionals, including pediatricians; specialists in diseases of the nervous system (neurologists), diagnosis and treatment of cancer (medical oncologists) and the use of radiation in the treatment of cancer (radiation oncologists); pediatric oncologists; oncology nurses; neurosurgeons; and / or other healthcare professionals. Specific treatment approaches may depend on the size, location, nature, stage and / or development of the tumor; the patient's age and general health and other factors.

Aggressive surgery followed by radiation therapy and chemotherapyd, which can be used alone or in combination, are the current standard used to treat patients with medulloblastoma. A therapy that is effective in one group may not be effective in another group. For example, chemotherapy that has been effective in children and adolescents may not be effective or less well tolerated in adults.

To obtain a biopsy sample, reduce pressure on the brain by draining accumulated CSF, and for the maximum possible removal of the tumor without damaging the surrounding brain tissue can be performed surgery. Surgery is aimed at removing the tumor completely or removing as much of it as possible. Some studies have shown that the result is improved when the entire tumor visible to the surgeon is removed (complete resection). However, total total resection is not always possible. Advanced imaging techniques (such as computed tomography and magnetic resonance imaging) and others can be done shortly after surgery diagnostic methods to determine how much of the tumor remains and to help determine the appropriate postoperative approaches to treatment.

In rare cases, it may be recommended bypass before surgery to remove the tumor. Bypass surgery will help remove excess fluid and reduce intracranial pressure. Shunts are specialized devices that divert excess CSF from the brain to another part of the body for absorption by the bloodstream. However, preoperative CSF bypass surgery is usually not performed due to certain risks (e.g. hernia, possible facilitation of the spread of cancer cells), and hydrocephalus in some patients is facilitated by the removal of tumors. Some patients may need a shunt after surgery to remove the tumor.

Standard postoperative care often includes radiation therapy (radiotherapy) of the brain and spine (craniospinal irradiation), starting approximately 2-4 weeks after surgery. During radiation therapy, radiation (through X-rays or other sources of radioactivity) is passed through specific areas of the body to destroy cancer cells and shrink tumors. Radiation therapy is given in carefully defined dosages to help minimize damage to normal cells in the body. Radiation therapy is an important adjunctive therapy because it can destroy microscopic cancer cells that are too small to be seen and that may remain after operations. These microscopic cells can lead to tumor recurrence.

In advanced cases, the recommended therapy may also include treatment with certain anticancer drugs (chemotherapy) during or after radiation therapy. Doctors may recommend combination therapy with multiple chemotherapy drugs, which have different modes of action in destroying and / or preventing tumor cells reproduction. Chemotherapy drugs that have been used to treat medulloblastoma include vincristine, lomustine, cisplatin, cyclophosphamide, carboplatin, or etoposide.

Chemotherapy can be given to infants and children under three years of age instead of radiation therapy to avoid the potential long-term side effects of radiation therapy. In some cases, radiation therapy may be recommended when these children grow up.

Since there are fewer adults with medulloblastoma than children, effective treatment regimens for adults have not yet been developed. Various chemotherapy drugs used to treat children have been shown to be less effective in adults, who often have worse side effects.

Forecast

Over the past decades, children and adolescents with medulloblastoma have significantly increased the chances of being cured of the disease. Modern diagnostic methods and treatment, which became combined and intensive, and began to be carried out according to standards, led to the fact that five years after the diagnosis is made, about 75% of the sick live (in medical statistics, the figures of 5-year survival). The 10-year survival rate is just under 70% of the total number of children and adolescents affected.