Primitive Neuroectodermal Tumor - Symptoms, Types, Causes & Diagnosis

Introduction

The central nervous system ("CNS") was reclassified by the World Health Organization (WHO) in 2016. Tumor with molecular parameters. In this classification, several tumors previously recognized in the 2007 classification have been renamed or deleted. Primitive neuroectodermal tumors (PNETs) are no longer recognized.

Embryonic CNS tumors are currently classified based on specific genetic/molecular features. Using molecular analysis, many tumors previously reported as PNETs are now reclassified as known tumors with specific genetic features.

Medulloblastoma is the most common embryonic tumor and has its own genetic/molecularly defined group (SHH-activated TP53 mutant, SHH-activated TP53 wild-type, WNT-activated, non-SHH/WNT group 3, and non-SHH/WNT groups). 4) In addition to histologically defined groups (classic, desmoplastic/nodular, significant nodularity, big cells, and anaplastic medulloblastoma.

A combination of genetic profile and histology determines the prognosis of these tumors. The Sonic Hedgehog protein, which is important for cell specialization and cell proliferation, is encoded by the SHH gene on chromosome 7. The WNT gene family on chromosome 12q13 region encodes signaling proteins that control cell proliferation, cell fate, and embryogenesis.

Immunohistochemical staining for INI1 or BRG1 expression is used to distinguish them. The WHO 9508/3 classifies tumors or tumors with rhabdoid traits including those that do not have INI1 or BRG1 mutations. These embryonic tumors without C19MC amplification, without INI1 or BRG1 alterations, and rosettes are called embryonic tumors, NOS (WHO 9473/3).

This last group, formerly known as He PNET, is a tumor trash category and cannot be assigned to a gene/molecule group. Some of these tumors were previously called embryonic tumors with abundant neuropil and true rosettes.

Concurrent with the release of his WHO classification in 2016, the group recognized his four new categories on PNET. They reviewed his previously classified PNET database and found that, based on molecular analysis of tumor specimens, most of them were indistinguishable from known supratentorial CNS tumors and classified among those known supratentorial CNS tumors.

A small group of other tumors not assignable to supratentorial CNS tumors is known to be grouped into four new categories. The CNS neuroblastoma with forkhead box R2 (FOXR2) activation, Ewing sarcoma family CNS tumors with the CIC alteration, high-grade CNS neuroepithelial tumors with meningioma 1 gene alteration (MN1), and high-grade CNS neuroepithelial tumors with the BCL6 corepressor (BCOR) change are new categories.

A few tumors that did not display molecular specificity for inclusion in a particular category were termed CNS embryonic tumors, NOS. This group is similar to the 'garbage' category of the 2016 WHO classification. The significance of these results has not yet been analyzed and will be included in future WHO classifications. These four new groups are also confirmed in a 2020 Polish study.

Etiology

The PNET term was removed from CNS tumors by the new 2016 WHO revised classification. They were aggressive tumors of poorly differentiated germ cells in infants, but rarely affected adolescents or adults.

Tumors are currently classified according to their molecular properties. Embryonal tumors are classified primarily by the presence of amplification of her C19MC region (19q13.42) on chromosome 19. Atypical teratoid/rhabdoid tumors show alterations in INI1 or rarely BRG1. Other embryonic tumors show FOXR2 activation, CIC alterations, MN1 alterations, and BCOR alterations.

SMARCB1 (also known as INI1, BAF47, hSNF5) on chromosome 22 at locus 22q11.2 is critical for the SWI/SNF chromatin remodeling complex. The ATPase subunit SMARCA4 (BRG1) on chromosome 19p13.2 is another SWI/SNF chromatin remodeling complex member.

Embryonal tumors without confirmed C19MC amplification, INI1 or BRG1 alterations, or rosettes are referred to as embryonic tumors, NOS (WHO 9473/3). There are currently no molecular or genetic alterations associated with it.

These embryonal tumors should be thoroughly examined. Diagnosis of exclusion. They must be distinguished from supratentorial ependymomas, high-grade gliomas, embryonic tumors with multilamellar rosettes, and ATRT because of specific genetic alterations.

Epidemiology

Primary CNS tumors are the second most common tumors in children and adolescents after leukemia. Approximately 20% of childhood brain tumors are fetal CNS tumors. This number includes all medulloblastomas and all other embryonic tumors. Embryonal CNS tumors most commonly occur in children under the age of 4 and are more common in women.

Using available data on CNS tumors diagnosed in the United States between 2012 and 2016 and excluding medulloblastoma, the incidence of PNET was 0.15 per 100,000 children aged 0–4 years, 0.04 per 100,000 children aged 9, and 0.04 per 100,000 children aged 10-9. 14 and 0.03 per 100,000 adolescents aged 15-19 years. The estimated 10-year survival rate for PNET is 30%.

Very few cases are diagnosed after 9 years. ATRT has an estimated 10-year survival rate of 37%. Between 0 and 14 years old, there is no discernible difference in the incidence of ATRT between boys and females.

High-grade neuroepithelial tumors with altered BCOR are very rare tumors with only 24 reported cases. The 4-year survival rate is 50%. They are treated like other embryonic tumors.

A study that previously examined histologic supratentorial PNETs & reanalyzed using molecular parameters found a 71% change in diagnosis. Supratentorial lesions, when confused with supratentorial PNETs, are more likely to be high-grade gliomas or ependymomas. DNA methylation profile defines diagnosis. For infratentorial disease, medulloblastoma and ependymoma must be ruled out first.

They studied brain magnetic resonance imaging (MRI) features of embryonic tumors to distinguish them from other molecularly diagnosed tumors and found that embryonic tumors had similar edema changes to non-embryonic tumors. Found that it has margin and size definitions. indistinguishable.

Histopathology

All embryonic tumors are classified as WHO IV. No longer in use is the term PNET. Each tumor must be subjected to a genetic or molecular investigation. Histopathological changes remain important for early tumor detection and intraoperative consultation.

Immunohistochemical staining reveals specific features of each tumor. Embryonal tumors with lamellar rosettes show abundant neuropil and true rosettes and show amplification of the C19MC region on chromosome 19. They show small multi-layered rounded blue cells with a pseudostratified neuroepithelium surrounding a central lumen that may be empty or contain eosinophilic debris.

The nucleus is removed from the lumen. Vimentin, cytokeratin, and CD99 have positive histochemistry. Epithelial membrane antigen could be present focally. (EMA). Positive markers of neuropils include synaptophysin, neuron-specific protein, and neurofilament protein.

Embryonal tumors, classified as NOS, need to be studied closely because they can be classified into other tumor entities using current diagnostic techniques. The Ki-67 has a very high marking index. ATRT usually shows a loss of immunoreactivity of the SMARCB1 (INI1) protein.

There are three groups of them (ATRT-TYR common in the infratentorial area in very young children, predominantly in the supratentorial area in older children, and ATRT-SHH in both age groups). They could be positive for her EMA and vimentin.

CNS neuroblastomas with FOXR2 activation are highly cellular and have small cells with hyper-stained nuclei surrounded by distinct halos. Areas of nerve nets, neurons, or ganglion cells can be seen. Vascular pseudorosettes, nuclear palisades, and Homer-Wright rosettes are commonly seen. Microvascular proliferation may occur.

CNS tumors of the Ewing sarcoma family with CIC alterations are dense cells with small round cells. Tumors display both alveolar and fascicular growth patterns. No distinguishing features.

High-grade CNS neuroepithelial tumors with MN1 alterations show a mixed solid and pseudopapillary pattern with pericellular hyalinization. Commonly expressed glial fibrillary acidic protein (GFAP).

High-grade CNS neuroepithelial tumors with BCOR alterations show a combination of the spindle to ellipsoidal cells and perivascular pseudorosettes and fibrous processes. Commonly expressed GFAP.

They are highly cellular with a thin-walled capillary network.

Medulloepithelioma shows neuroepithelial cells with papillary arrangements that can mimic the embryonic neural tube. Necrosis and bleeding may occur.

History and Physical

Patients with embryonic tumors usually show signs of increased intracranial pressure. This may include headaches with decreasing frequency, nausea, vomiting, irritability, and lethargy. It may also present with visual disturbances, seizures, hemiplegia, cerebellar symptoms, and cranial nerve palsies.

The location of the supratentorial or infratentorial tumor is important for symptom development. Persons in an infratentorial position usually develop hydrocephalus with headache, vomiting, irritability, and lethargy. Ataxia or other cerebellar signs and cranial nerve palsies are common. They rarely have seizures.

Vomiting, seizures, and headache are common in the supratentorial site. Hemiplegia is present if the tumor affects the cortical motor area or the descending tract. Presentation is also affected by age. Young patients present with hypersensitivity, vomiting, and vision problems. Patients over 3 years of age usually present with headaches, vomiting, and ataxia.

These high-grade tumors have a short interval between the first prediagnostic symptoms and his radiographic diagnosis, with a median of 20 days. Infratentorial tumors, high-grade tumors, and tumors in young patients have the shortest intervals.

A complete physical examination with an emphasis on neurological evaluation is essential. A neuro-ophthalmologist should evaluate vision problems. This is due to how challenging it is to detect in young individuals.

Evaluation

MRI of the brain shows large circumscribed solid masses with surrounding edema, often with significant mass effect. They can be isointense but are typically hypointense on T1-weighted imaging. On T2-weighted images, they are isointense to hypertonicity, and contrasting T1-weighted images show patchy contrast enhancement.

Some tumors may have areas of blood products, microcalcifications, and necro cystic components. Spread is limited due to the high cellularity of the tumor. These features resemble high-grade gliomas, making a molecular diagnosis of great importance. Magnetic resonance spectroscopy shows a choline peak with reduced N-acetyl aspartate and high choline.

A spine MRI is usually required to demonstrate dissemination and prognosis.

Treatment

The current most effective treatment for these tumors is triple therapy consisting of surgical resection and radiation and chemotherapy. Complete total excision is always attempted because it gives better results.

Because of the high incidence of distant leptomeningeal metastases and spinal dissemination, craniospinal irradiation is usually given. Long-term radiotherapy was found to produce the worst outcomes compared to short-term treatment, especially for medulloblastoma.

This has not yet been proven for other embryonic tumors. This phenomenon is thought to be due to the regrowth of rapidly growing tumors. Radiation therapy is given in the range of 50 to 60 Gy.

Chemotherapy varies by protocol, but a combination of vincristine, cisplatin, cyclophosphamide, and etoposide is common. Bevacizumab is used to block vascular endothelial growth factors. Topotecan and intrathecal methotrexate may be used in the therapeutic regimen. In some cases, myeloablative chemotherapy was used, followed by hematopoietic stem cell rescue.

Differential diagnosis

Attribute: Usually seen in patients under 2 years of age.

Ependymoma: Usually no limit.

High-grade glioma: Most are indistinguishable and diagnosis is based on molecular features. Some show vascular endothelial proliferation and necrosis.

Medulloblastoma: It has its own genetic/molecularly defined group.

Medulloepithelioma: Usually seen in very young patients.

Prognosis

The prognosis is poor due to leptomeningeal spread and possible extraneural metastasis. Approximately 32% of supratentorial embryonic tumors metastasize to the spine. Several factors influence the poor prognosis, including late diagnosis, poor performance status, and inadequate initial response to treatment. Larger, more extensive tumors and tumors with poorly defined boundaries have the lowest overall survival.

Supratentorial high-grade glioma has a 5-year overall survival rate of 12%, significantly worse than embryonic tumors (including pineoblastoma), which have a 5-year overall survival rate of 78.5%. This distinct difference is very important. Obtaining the correct molecular diagnosis is therefore essential to inform the prognosis of patients and families. Median ATRT survival is less than 2 years.

Complications

These tumors place a great burden on the patient and many serious complications occur as a result of the tumor and the triple therapy received. Surgery is challenging and sometimes tricky. Radiation and chemotherapy cause significant morbidity due to the effects of ionizing radiation and the side effects of chemotherapy drugs.

Movement disorders.
Sensory disturbance.
Seizure.
Neurocognitive problems.
Developmental delay.
Learning delay.
Neuroendocrine disorders (delayed puberty, hypothyroidism, low growth hormone).

Consultations

Consultations with neuropathologists, pediatricians, neurosurgeons, hematologist-oncologists, radiation oncologists, and endocrinologists may be necessary.

Patient Education and Disincentives

The so-called CNS PNET is no longer acknowledged. Nowadays, based on molecular analysis, the majority of tumors may be classified. It's necessary to do a thorough histological analysis. The prognosis for the patient is considerably better due to the exclusion of many high-grade gliomas. In any case, these tumors have a terrible outlook. Counseling is necessary because both the patient and the parents will be significantly impacted by the illness.