What is Primitive Neuroectodermal Tumor?
In 2016, the World Health Organization (WHO) used modern scientific tools to revamp its classification system for central nervous system (CNS) tumors. This revised system now includes molecular parameters, which are characteristics at the genetic level. As a result, some tumors from the 2007 system were renamed or removed, including a type known as primitive neuroectodermal tumor (PNET).
Now, CNS embryonal tumors (these develop from cells that are present whilst the baby grows in the womb), are categorized based on their unique genetic/molecular properties. Using this new approach, many tumors that were previously termed as PNET have been renamed and grouped with known tumors that exhibit specific genetic characteristics.
Of all the embryonal tumors, medulloblastomas are the most common. Their classification is now split into specific genetic groups aside from their histological groups (groups formed looking the cells under the microscope) like classic, desmoplastic/nodular, medulloblastoma with extensive nodularity, and large cell/anaplastic. Your prognosis or outlook depends on both the genetic type and what the cells look like under the microscope.
All other embryonal tumors are classified depending on whether they have an amplification, which is an increase in the number of copies of a specific region of chromosome 19 known as C19MC. If they do have this, they’re named as embryonal tumor with multilayered rosettes, C19MC-altered. If they don’t, they’re called embryonal tumor with multilayered rosettes, NOS. There are other embryonal tumors called medulloepithelioma, CNS neuroblastoma, CNS ganglioneuroblastoma, and atypical teratoid/rhabdoid tumor (ATRT) – these have alterations in certain genes, namely INI1 or in rare cases BRG1.
The expression of either the INI1 or BRG1 gene is checked using a laboratory test called immunohistochemical staining. Tumors without alterations of either INI1 or BRG1 are classified as embryonal tumors with rhabdoid features. Some tumors which don’t amplify the C19MC, lack alterations of INI1 or BRG1, and don’t form rosettes are named embryonal tumor, NOS. This is the group for tumors that don’t fit any genetic/molecular criteria and were previously known as PNET.
Around the same time as the WHO 2016 classification, a set of scientists recognized four new categories for PNET. After reviewing a database of previously classified PNETs, they found that, based on genetic analysis, the majority of tumors were no different from known CNS supratentorial tumors (tumors that occur in the upper part of the brain). The few tumors that were not matched to known CNS supratentorial tumors were put under the four new categories.
Few tumors that weren’t grouped into any particular category were named CNS embryonal tumors, NOS, similar to WHO 2016’s classification. The importance of these findings is still being analyzed and may be included in future WHO classifications. This grouping system has also been supported by a research study conducted in Poland in 2020.
What Causes Primitive Neuroectodermal Tumor?
In simpler terms, the term PNET, which refers to a type of brain tumor, is no longer used in the medical community since a 2016 update to the World Health Organization’s (WHO) classification system. PNET tumors were aggressive and usually formed from poorly formed cells in young kids but occasionally showed up in teenagers and adults too.
Nowadays, tumors are grouped based on their specific molecular features – in other words, what’s going on in their genes. For instance, certain tumors are labeled depending on whether they show a change in a specific area of chromosome 19, known as the C19MC region. Other tumors might show changes in genes like INI1, BRG1, FOXR2, CIC, MN1 and BCOR.
Some tumors also involve genes such as SMARCB1 and SMARCA4, whose roles are in chromatin remodeling, a vital process wherein the structure of the chromatin (the material in our cells that includes our DNA) is modified.
There are also tumors that don’t have any changes in the C19MC, INI1 or BRG1 genes, and in these cases, they’re labelled as “embryonal tumor, NOS” (which is just short for ‘Not Otherwise Specified’). Currently, these tumors don’t have any recognized genetic changes connected to them. These types of embryonal tumors need in-depth study. Figuring out whether a tumor is an embryonal tumor, NOS involves ruling out other types of tumors, such as ependymomas or high-grade gliomas, based on their specific genetic changes.
Risk Factors and Frequency for Primitive Neuroectodermal Tumor
Primary tumors in the central nervous system (CNS), or brain, are the second most common type of cancer in children and adolescents, following leukemia. About 20% of these are embryonal tumors, which can affect children at any age, but are most common in kids aged 0 to 4 years. The average age for these cases is roughly 8.4 years, and they are more common in girls than boys.
- About 20% of pediatric brain tumors are CNS embryonal tumors, including medulloblastomas and other embryonal tumors.
- Embryonal tumors are the most common CNS tumor in children aged 0–4 years.
- Such tumors are the fifth most common in children and adolescents aged 0 to 19 years.
- These tumors more commonly appear in children below the age of 4 and are more frequent in females.
- Embryonal tumors in older children, on average, are diagnosed at 8.4 years of age and are predominantly found in females compared to males (ratio of 2.3:1).
As per recent data from the USA, between 2012 to 2016, the number of new cases (incidence rate) of certain types of these tumors was found to be 0.15 to 0.03 per 100,000 children aged from 0 to 19. Survival rates after 10 years from diagnosis were approximately 30%.
Another type of tumor called ATRT was found to occur in 0.32 per 100,000 children aged between 0 and 4 and in very few children aged 5 to 9. Survival rates after 10 years for ATRT patients were approximately 37%. It’s important to note that there was no significant difference between boys and girls in the chances of getting ATRT.
High-grade neuroepithelial tumor with BCOR alteration is a very rare type, with only 24 reported cases. A half of these patients survive for at least four years from diagnosis. These tumors are treated in a similar way to other embryonal tumors.
In a study of supratentorial PNET, a particular subtype of these tumors, the diagnosis was changed in 71% of cases when examined with molecular techniques. If a supratentorial lesion is mistaken for a supratentorial PNET, it’s more likely to be a high-grade glioma or ependymoma. In the case of lesions in the infratentorial region of the brain, medulloblastoma and ependymoma should be ruled out first. It’s challenging to distinguish embryonal tumors from non-embryonal ones based on MRI scans, as they often have similar changes in the affected brain tissue, size, and margins.
Signs and Symptoms of Primitive Neuroectodermal Tumor
Embryonal tumors are a type of brain cancer often identified by increasing pressure in the brain. The common symptoms typically include headache, nausea, vomiting, irritability, and lethargy. Patients may also have visual issues, seizures, or experience weakness on one side of the body. Certain symptoms such as problems with coordination, balance, or other nervous system functions may also be apparent. It’s important to note that symptoms can depend on where the tumor is located in the brain, how old the patient is, and whether the tumor is of a high grade.
For instance, a tumor in the lower part (infratentorial) of the brain often leads to increased brain fluid, causing symptoms like headache, vomiting, irritability, and lethargy. There might also be issues with balance and muscle coordination, and problems related to the functioning of cranial nerves, which affect areas of the body like the face, eyes, tongue, and throat. Seizures are rare with these tumors. On the other hand, tumors in the upper (supratentorial) region of the brain commonly cause vomiting, seizures, and headaches. If they impact the motor areas, the patient may experience hemiparesis, or weakness on one side of the body.
Children with these tumors may show different symptoms. For instance, younger children often show irritability, vomiting, and visual issues, while those older than three years usually exhibit headaches, vomiting, and balance problems.
These aggressive tumors are typically detected within a short time, about 20 days, from the first observable symptom. Tumors in the lower part of the brain, high-grade tumors, and those in younger patients tend to be diagnosed quickest.
A comprehensive physical assessment, with a focus on neurological examination, is crucial. A nerve and eyes specialist should evaluate any visual symptoms, as these can be especially hard to identify in children.
Testing for Primitive Neuroectodermal Tumor
When doctors use MRI (Magnetic Resonance Imaging) on the brain, they can often spot a large, clearly defined, solid lump with fluid build-up around it. This can also create a significant mass effect, where the growth puts pressure on the surrounding brain tissue. On a specific type of MRI called T1-weighted images, these lumps usually appear darker, but can sometimes look the same color as brain tissue. On T2-weighted images, another type of MRI, they usually look the same color or brighter than brain tissue. When contrast (a special dye) is used with T1-weighted images, the tumor usually lights up unevenly.
Some tumors can show signs of blood products (that’s blood that leaked out of the tumor into nearby tissue), tiny bits of calcium, and areas that are dead or filled with cysts (fluid-filled sacs). The tumor cells are so packed together that water can’t move around freely – this is called “restricted diffusion”. These characteristics are similar to those of high-grade gliomas, a type of brain cancer, which make it vital to accurately identify the types of cells on the molecular level.
Magnetic resonance spectroscopy, another type of MRI, shows an increase in a substance called choline and a decrease in N-acetyl-aspartate. The ratio of choline to aspartate is usually high. This can help doctors in diagnosing the type of tumor.
A MRI of the spine is also usually necessary. This helps doctors spot if the tumor has spread and helps to predict what might happen in the future.
Treatment Options for Primitive Neuroectodermal Tumor
The most successful treatment for these types of tumors typically involves three methods: surgical removal of the tumor, radiation treatment, and chemotherapy. Surgeons usually aim to remove the entire tumor because complete removal has been linked to more positive outcomes.
Radiation treatment is commonly used because these tumors frequently spread to other parts of the brain and spinal cord. However, studies have shown that when this treatment lasts for a long duration, it can lead to a worse prognosis, especially for a type of tumor called medulloblastomas. This is thought to occur because tumors that grow quickly can re-grow during long radiation treatment periods. Usually, radiation dosage between 50 to 60 Gy is used, but this can vary based on other factors.
Chemotherapy, a treatment using certain drugs to fight the tumor cells, is usually used in combination with other treatments. The drug combination most often includes vincristine, cisplatinum, cyclophosphamide, and etoposide. Bevacizumab is also used to block a specific protein that promotes the growth of new blood vessels in tumors. Other drugs, like methotrexate and topotecan, can be given within the spinal canal, an area surrounding the brain and spinal cord, to treat or prevent spread of the tumor in this area. In some cases, an intense form of chemotherapy that destroys the bone marrow is used, followed by a procedure to restore the bone marrow using stem cells. However, the specific combination and sequence of these treatments can vary depending on the particular circumstances of the patient.
What else can Primitive Neuroectodermal Tumor be?
When it comes to diagnosing different kinds of brain tumors, age and specific characteristics play a role:
- ATRT: Mostly observed in patients who are younger than two years old.
- Ependymomas: Generally, there are no limitations as to who can have these.
- High-grade gliomas: These are often indistinguishable based solely on their appearance, diagnosis is usually made based on their molecular properties. Some may exhibit increased growth of blood vessels and abnormal cell death.
- Medulloblastomas: These are distinguished by their own unique genetic or molecular groups.
- Medulloepitheliomas: These tend to be found in very young patients.
What to expect with Primitive Neuroectodermal Tumor
The outlook for patients with leptomeningeal dissemination (cancer spread to the membranes surrounding the brain and spinal cord) and possible extraneural metastasis (cancer spread to areas outside the nervous system) is generally not good. Approximately 32% of cases involving supratentorial embryonal tumors, which originate in the upper part of the brain, are found to have spread to the spine.
There are several factors that can indicate a worse prognosis or outlook. These include a delay in diagnosis, poor overall health, and an inadequate initial response to treatment. Larger tumors and those with unclear edges tend to have the worst overall survival.
The survival rate for patients with supratentorial high-grade glioma, a type of brain cancer, is quite low, with only 12% of patients living five years past their diagnoses. This is noticeably worse than for patients with embryonal tumors (including pineoblastomas), where the five-year survival rate is 78.5%. This significant difference makes it crucial to get an accurate molecular diagnosis to guide the patient and their family about the likely prognosis. For patients with Atypical Teratoid Rhabdoid Tumor (ATRT), a rare type of brain tumor, the median survival is unfortunately less than two years.
Possible Complications When Diagnosed with Primitive Neuroectodermal Tumor
Tumors can have a significant impact on a patient’s life, leading to numerous serious complications. These complications can come from the tumor itself or from the triple therapy treatment, which includes surgery, radiation, and chemotherapy. The surgery can be very difficult and sometimes even complex. Radiation and chemotherapy treatments also cause a lot of health issues due to the harmful effects of ionizing radiation and the negative side effects of chemotherapeutic drugs.
Common Side Effects:
- Motor deficits (trouble with movements)
- Sensory deficits (problems with sensing)
- Seizures
- Neurocognitive problems (brain function issues)
- Developmental delay
- Learning delays
- Neuroendocrine deficit (issues like delayed puberty, low thyroid activity, low growth hormone levels)
Preventing Primitive Neuroectodermal Tumor
The previously known Central Nervous System (CNS) Primitive Neuroectodermal Tumor (PNET) is no longer a recognized type of tumor. With modern techniques, most tumors can now be categorized more accurately based on their molecular properties, which is determined by lab tests. Because of this improved identification approach, a detailed examination of the tumor’s structure and cells, also known as histopathological examination, is required. On a brighter note, the process of identifying tumors has now led to the exclusion of many high-grade gliomas, a hard-to-treat kind of brain tumor. This has resulted in a better overall prognosis, or likelihood of recovery, for patients.
Despite the improvements in medical technology, the prognosis for these tumors still leaves a lot of room for optimism. For this reason, it’s vital for both patients and their parents or caregivers to receive counseling. Living with a tumor is a significant challenge, and many patients and their families will need emotional support to cope with the disease.
