Primitive Neuroectodermal Tumour

Primitive neuroectodermal tumours are rare, aggressive cancers that develop from immature nerve cells left over from early development. While these tumours present significant treatment challenges, advances in medical understanding and treatment approaches are providing new hope for patients.

Table of contents

• What is a primitive neuroectodermal tumour?
• Classification and reclassification
• Where these tumours form
• Symptoms and warning signs
• What causes these tumours
• How doctors diagnose PNETs
• Tumour grading
• Who is affected
• Treatment approaches
• How these tumours spread

What is a primitive neuroectodermal tumour?

A primitive neuroectodermal tumour, often called PNET, is a rare type of cancer that develops from immature nerve cells in the body. These are cells that began to form when a person was still developing as an embryo, before they were born, but did not develop normally as they should have^[1].

The term “primitive” refers to the fact that these cells are undeveloped or undifferentiated—they have not matured into the specialized nerve cells they were meant to become^[3]. These tumours are considered highly aggressive, meaning they grow quickly and can spread to other parts of the body^[2].

PNETs can develop in two main areas: in the central nervous system (brain and spinal cord), called central PNETs, or outside the central nervous system in areas like the chest wall, pelvis, or limbs, called peripheral PNETs^[2].

Classification and reclassification

The way doctors classify and name primitive neuroectodermal tumours has changed significantly in recent years. In 2016, the World Health Organization published a revised classification system for central nervous system tumours that uses molecular parameters—specific genetic characteristics of the tumours—to classify them more accurately^[4].

As a result of this new classification, the term PNET is no longer used as a single category. Instead, tumours previously called PNETs are now classified into several more specific groups based on their genetic features^[1]. The group that was formerly known as PNETs now includes specific diagnoses such as:^[1]

• Medulloepithelioma
• CNS neuroblastoma
• CNS ganglioneuroblastoma
• Embryonal tumour with multilayered rosettes
• Other unspecified embryonal tumours

This reclassification helps doctors provide more accurate diagnoses and better targeted treatments. Using molecular analysis, many tumours that were previously reported as PNET can now be reclassified into known tumour types with specific genetic characteristics^[4].

Where these tumours form

PNETs can form in different locations throughout the body. Central nervous system PNETs are most commonly found in the brain, particularly in the outer layer called the cortex, or in the upper part of the brain known as the cerebrum^[1][7]. In rare cases, they can also be found in the brainstem or spinal cord^[1].

These tumours develop from the ectoderm, which is the outermost layer of cells surrounding a developing embryo during early development^[1]. The primitive nerve cells that give rise to PNETs are leftovers from the development of the nervous system during pregnancy^[6].

Peripheral PNETs can occur at sites outside the central nervous system, usually in bones or soft tissues. Common locations include the extremities (arms and legs), the pelvis, and the chest wall^[9].

• Brain (cerebrum, cortex)
• Brainstem
• Spinal cord
• Chest wall
• Pelvis
• Extremities

Symptoms and warning signs

The symptoms of a primitive neuroectodermal tumour depend largely on where the tumour is located in the body. Because these tumours tend to grow quickly and can become quite large, many symptoms result from increased pressure inside the skull or from the tumour pressing against nearby structures^[6].

Common symptoms of PNETs in the brain include^[1][6]:

• Headaches, particularly in the morning
• Seizures
• Problems with thinking or memory
• Weakness or numbness
• Problems with balance and movement
• Nausea and vomiting
• Fatigue or unusual sleepiness
• Changes in personality or behavior
• Unexplained weight loss or gain

For tumours located in the spine, symptoms may include^[1]:

• Loss of bowel or bladder control
• Pain in the back and legs

More advanced symptoms can include loss of coordination, problems with walking and balance, dizziness, and double vision^[6].

What causes these tumours

The exact cause of primitive neuroectodermal tumours is not fully understood. Like many cancers, PNETs are considered a genetic disease, meaning they are caused by certain changes to genes that control how cells function, grow, and die^[1].

These genetic changes, called mutations, can cause cells to grow and divide at an abnormal rate, leading to cancer. In many types of cancer, genes may be mutated in ways that increase the growth and spread of cancer cells^[1].

Some PNETs are related to specific genetic changes. Based on molecular analysis, both peripheral PNETs and a related group of tumours called Ewing family tumours share similar genetic alterations, most commonly involving a rearrangement between chromosomes 11 and 22^[2].

However, scientists have not been able to identify specific risk factors or causes for these tumours. There does not appear to be a genetic predisposition, meaning these diseases do not seem to run in families^[3].

How doctors diagnose PNETs

Diagnosing a primitive neuroectodermal tumour involves several steps. The process typically begins with a physical examination and medical history, followed by a neurological examination to assess sensation, eye movements, hearing, motor function, balance, and coordination^[6].

Imaging studies are the most important tools for diagnosing PNETs. Magnetic resonance imaging (MRI) scans are primarily used because they can show the size and characteristics of the tumour, as well as the presence of fluid buildup in the brain called hydrocephalus^[6]. On an MRI scan, PNETs usually appear as a single mass, though sometimes more than one tumour can be identified. The tumours often show up clearly when a contrast agent is used, and they may contain fluid-filled areas called cysts^[1].

Computed tomography (CT) scans are also used. For both types of scans, a contrast enhancement can be administered so doctors can visualize the tumour against the normal brain tissue in the background^[6].

Since these tumours are known to spread through cerebrospinal fluid—the liquid that surrounds the brain and spinal cord—it is essential to scan both the brain and spine^[3].

To confirm the diagnosis, doctors need to examine tumour tissue. During surgery, a piece of tumour tissue is removed and sent for analysis. A neuropathologist, a doctor who specializes in diagnosing diseases of the nervous system, reviews the tissue under a microscope^[1]. PNETs have certain identifying features, including the presence of a genetic marker called CD99, which is found in 90% to 100% of cases^[2].

Tumour grading

Primary central nervous system tumours are assigned a grade based on analysis of tumour tissue performed by a neuropathologist. This grading system helps doctors understand how aggressive the tumour is and plan appropriate treatment^[1].

The group of tumours formerly known as PNETs are classified as grade 4 (also written as grade IV) tumours. This means they are malignant (cancerous) and fast-growing^[1]. Grade 4 tumours are the most aggressive type of brain tumour and require intensive treatment.

Who is affected

Primitive neuroectodermal tumours are very rare. They most commonly occur in children and young adults, though they can occur at any age^[1][2]. These tumours are more common in children than in adults^[1].

Because the classification system changed in 2016, and tumours previously called PNETs are now classified differently, it is difficult to estimate exact statistics for the number of people diagnosed per year or survival rates^[1]. Data captured between 2000 and 2014, before the reclassification, showed that an estimated 950 people were living with these tumours in the United States during that time period^[1].

The overall five-year survival rate for primitive neuroectodermal tumours has been reported as approximately 53 percent^[8].

Treatment approaches

Treatment for primitive neuroectodermal tumours typically involves a combination of approaches, as these are aggressive cancers that require intensive therapy. The main treatment methods include surgery, radiation therapy, and chemotherapy^[3][6].

Surgery is usually the first step in treatment. The primary goal is to remove as much of the tumour as possible and to restore normal flow of cerebrospinal fluid^[9]. However, because these tumours tend to be large and have an extensive blood supply, complete removal may not always be possible at the time of diagnosis^[7]. The surgery also provides tissue samples that doctors can use to obtain an accurate diagnosis^[9].

After surgery, treatment typically includes radiation therapy and chemotherapy. For children aged 3 and older, radiation is usually applied to both the brain and spinal cord, followed by chemotherapy^[7]. However, radiation therapy is generally delayed in very young children due to the risks to the developing brain. For infants and toddlers diagnosed with PNET, chemotherapy is used alone after surgery^[7].

In some cases, chemotherapy may be used before surgery to shrink the tumour and make surgical removal safer^[7].

If the tumour blocks the normal flow of cerebrospinal fluid and causes hydrocephalus, another procedure called endoscopic third ventriculostomy (ETV) may be necessary^[3].

Treatment planning requires a multidisciplinary team of cancer specialists who have experience treating brain tumours. The specific treatment plan depends on several factors, including the patient’s age, overall health, the type and location of the tumour, the amount of tumour remaining after surgery, and whether the cancer has spread^[9].

How these tumours spread

One of the concerning characteristics of primitive neuroectodermal tumours is their tendency to spread. Because these tumours are malignant and aggressive, they can spread easily through the cerebrospinal fluid that surrounds and cushions the brain and spinal cord^[6][9].

PNETs can spread to other areas of the central nervous system and, in some cases, to organs outside the nervous system^[1]. About one-third of patients have tumours that have already spread to other locations at the time of diagnosis^[1].

These tumours can also block the normal flow of cerebrospinal fluid, causing a condition called hydrocephalus. In hydrocephalus, fluid builds up in the brain, increasing pressure inside the skull^[6][9].

The tendency of these tumours to spread quickly and in an unpredictable manner makes complete surgical removal difficult and makes follow-up treatment with chemotherapy and radiation necessary^[9].

PNET, primitive neuroectodermal tumors, primitive neuro-ectodermal tumors