Primitive Neuroectodermal Tumors of the Central Nervous System 

Primitive neuroectodermal tumors (PNET) are neoplasms of which medulloblastoma is the prototype. These are small cell, malignant embryonal tumors showing divergent differentiation of variable degree along neuronal, glial, or rarely mesenchymal lines.

The most recent WHO categorization of embryonal tumors is as follows:[1]

• Medulloblastoma
• CNS primitive neuroectodermal tumor (PNET)

  • CNS neuroblastoma
  • CNS ganglioneuroblastoma
  • Medulloepithelioma
  • Ependymoblastoma
• Atypical teratoid/rhabdoid tumor

Only tumors of the CNS are discussed here. Peripheral primitive neuroectodermal tumors are regarded as distinct entities.[2]

PNET of the CNS can be divided grossly into infratentorial tumors (medulloblastoma or iPNET) and supratentorial tumors (sPNET).

Considerable controversy exists regarding the histogenesis of these tumors. Initially, these dense, cellular, embryonal tumors were thought to have a common origin from primitive neuroectodermal cells and to differ only in their location, type, and degree of differentiation. In the revised World Health Organization (WHO) classification, however, many of these tumors are given a separate niche on the basis of the assumption that these embryonal tumors also could arise from cells already committed to differentiation.[3]

Regardless of the controversy, these tumors are discussed as infratentorial (medulloblastoma) and supratentorial. The latter occur rarely (25:1) and are more common in young adults than infratentorial tumors.

Spinal dissemination via the cerebrospinal fluid (CSF) is the most common form of metastatic spread of PNETs.

Frequency

United States

Medulloblastoma represents the most common type of primary solid malignant brain tumor in children (as many as 30% of all solid brain tumors). In contrast, only 1% of brain tumors in adults are medulloblastomas. The overall annual incidence is approximately 0.5 case per 100,000 children. Seventy-five percent arise in the midline (vermis), while 25% occur in the lateral cerebellum.

International

The Swedish Cancer Registry reported, as part of a population-based study, that medulloblastomas represented 21% of all primary brain tumors in children. Similar figures were provided by the British Tumor Registry and from the United States (Surveillance, Epidemiology and End Results Program).

Mortality/Morbidity

Risk of sudden death secondary to obstructive hydrocephalus has been hypothesized; however, it is not often observed clinically.

Race-, sex-, and age-related characteristics

National Cancer Survey suggests a slightly higher incidence in white than in blacks.

A slight male preponderance is observed (male-to-female ratio 1.8:1).

Three fourths of these tumors appear in children younger than 15 years, and 50% are seen in the first decade of life. A second, smaller peak occurs in young adults (aged 21-40 y).[2] Children are 4.6 times as likely to be afflicted by a PNET than adults.[4] Cerebellar medullobastoma occurs rarely in the elderly.[5]

The overall 5 year survival rate is about 53%.[6]

No pathognomonic signs or symptoms exist. The onset at presentation is insidious.

The observed symptoms are due to the neuroanatomical location of the tumor or are a consequence of increased intracranial pressure. They include the following:

• Irritability, lethargy, and decreased social interaction (60%)

• Intermittent vomiting (40%)

• Headache (40%) (usually worse in the morning)

• Visual blurring/change (30%)

• Nausea - Unusual as a distinct symptom, unless the tumor infiltrates the floor of the fourth ventricle (5%)

• Imbalance (40%)

Physical characteristics include the following:

• Papilledema (60%)

• Ataxia (50%)

• Nystagmus with or without gaze palsy (40%)

• Lower cranial nerve palsy (20%)

• Dysdiadochokinesia, hypotonia, dysmetria, particularly in lateralized lesions of the cerebellum (20%)

• Increased head circumference in children younger than 2 years (30%)

Isolated PNET is sporadic in nature, and only 14 familial cases have been reported in the literature.

Loss of the short arm of chromosome 17 (17p13.3) is the most frequent abnormality (particularly with medulloblastoma, in which it is found in 30-40% of cases), the presence of which also affects prognosis. This site is, however, distinct from the common tumor suppressor gene, TP53. Other genetic loci of interest in the pathogenesis of medulloblastoma include PAX genes and sonic hedgehog (SHH) genes, the roles of which are under intense investigation.

17p loss, MYC amplification/expression, and 1q gain are associated with poor prognosis; in contrast, monosomy 6, mutation of CTNNB1, and trkC expression identify tumors with a favorable outcome.[7]

Multiple signaling pathways have been associated with medulloblastoma formation and growth. These include the developmental pathways Hedgehog, (Hh) Notch, and Wnt, as well as the receptor tyrosine kinases (RTK) c-Met, erbB2, IGF-R, and TrkC, and the oncoprotein Myc.[8]

Studies on molecular characterization have identified 4-6 subgroups of medulloblastoma on the basis of molecular differences.[9] Despite the disparity in the number of subtypes, the studies have substantial common ground. All describe a subtype with aberrant sonic hedgehog pathway signaling (often PTCH1 mutations), which has a high incidence among desmoplastic tumors. Another subtype has aberrant signaling in the wingless (WNT) pathway (frequently, CTNNB1 mutations), a classic histology that commonly affects older children. Additionally, a less favorable subtype emerged from the latest studies, which associates MYC overexpression and amplification with poor prognostic features, such as high prevalence of metastatic disease and large-cell anaplastic histology.

The most current international consensus recognizes 4 core medulloblastoma subgroups namely, SHH, WNT, Group 3, and Group 4. This is adopted based on the knowledge of genomic complexity of medulloblastoma as analyzed by recent high-throughput genomic technology.[10]

Karyotypically, almost all PNETs are abnormal.

Certain conditions have increased associations with PNETs. They include the following:

• Gorlin syndrome, also known as nevoid basal cell carcinoma syndrome, is an autosomal dominant disorder with mutations of the PTCH gene.[11] It is characterized by a combination of neoplastic and malformative disorders including nevoid basal cell carcinoma, jaw keratocysts, skeletal abnormalities, ovarian fibromas, and ectopic calcifications. Approximately 5% of mutation carriers develop medulloblastoma at an early age.

• Turcot syndrome is a heterogenous group of autosomal dominant disorders with occurrence of multiple colorectal neoplasms and medulloblastomas or glioblastomas.

• Li-Fraumeni syndrome is an autosomal dominant disorder characterized by multiple tumors in children, including soft-tissue sarcomas, osteosarcomas, breast cancer, leukemias, and a higher incidence of brain tumors than in the general population.

Lab tests are not helpful in the diagnosis of primitive neuroectodermal tumors (PNET).

Diagnosis of these clinical entities is confirmed or excluded by lumbar puncture and CT scan and/or MRI. Presence of a mass lesion on an imaging study precludes lumbar puncture because of the risk of herniation.

Clinical diagnosis of these tumors is not possible. Radiologic features unique to each type of tumor may be helpful, but the only possible absolute confirmation is by pathologic examination of the surgical specimen.

MRI

MRI is the imaging technique of choice. The typical tumor is a heterogeneous mass with ill-defined margins arising from the vermis, which fills the fourth ventricle.

Typical findings include moderate to intense enhancement of the tumor, which is not homogenous (see image below).

Accompanying hydrocephalus is common (see image below), and associated cystic changes can occur (see image below).

The entire neuraxis should be imaged to detect spinal metastases, which may occur via subarachnoid dissemination.

CT scan

In emergent situations, CT scan is preferred over MRI because of its easy accessibility. However, CT scan resolution is inferior to that of MRI. The mass is typically midline, relatively heterogeneous, and variably contrast enhancing. (See the image below.)

CT myelogram may be used to rule out spinal dissemination in cases in which MRI is contraindicated.

MR spectroscopy

As compared to the normal cerebellum, these tumors on MR spectroscopy reveal a heterogeneous picture with decreased N- acetyl-aspartate (NAA) and creatine peaks and increased choline peaks.

The technique is still considered experimental.

See the list below:

• Ventriculostomy is rarely done preoperatively because of the risk of upward herniation.

• Preoperative lumbar puncture is avoided because of the risk of downward herniation.

See the list below:

• Primitive cells are observed growing in sheets or cords of dense cellularity with increased mitotic index and increased nuclear-cytoplasmic ratio.

• Formation of Homer-Wright rosettes (ie, neuroblastic rosettes consisting of tumor cell nuclei disposed in a circular fashion about tangled cytoplasmic processes) is typical but not always seen and is not essential for diagnosis. When present, it is frequently associated with marked nuclear pleomorphism and high mitotic activity.

• Associated gross pathologic findings may include cystic changes, although the tumors are usually solid. They may vary from soft to firm in consistency. Geographic areas of necrosis, vascular proliferation, or calcification are less common, while hemorrhage is rare.

• Immunohistochemical markers can confirm differentiation toward astrocytic or neuronal lineage.

• Unusual variants include those with melanin deposition, rhabdomyoblastic differentiation, or desmoplastic features, among others.

Preoperative administration of steroids can help to alleviate some of the signs and symptoms of primitive neuroectodermal tumors (PNET) by reducing peritumoral edema.[2]

Radiation therapy

Radiation therapy, usually given adjuvantly, should be performed under the direction of a radiation oncologist.

Many series report a clear, dose-dependent relationship between postoperative radiation and local tumor control.

Adjuvant radiotherapy alone, with posterior fossa doses of 5000 cGy and neuraxis doses of 3000 cGy, results in a 5-year event-free survival rate of 50-70%. Lower than standard doses of radiation therapy, at least without chemotherapy, are less effective.

Craniospinal axis radiation is used for patients with spinal dissemination.

Newer methods, including stereotactic radiosurgery and high fractionation radiotherapy, are being evaluated.[12] These methods limit the dose of radiation to the local sites and avoid potential adverse effects in children, including cognitive dysfunction or delay in growth, that are seen frequently with conventional radiotherapy.

Chemotherapy

Chemotherapy should be administered under the direction of a medical oncologist.

Varying combinations of drugs used in these tumors include, but are not limited to, lomustine (CCNU), vincristine, cisplatin, etoposide (VP-16), and cyclophosphamide. Several trials, including those from the Pediatric Oncology Group (POG) and Children's Cancer Group (CCG), are underway, evaluating varying combinations of chemotherapy with and without radiotherapy. The best results, so far, have come from the Children's Hospital of Pennsylvania study, reporting a 5-year event-free survival rate of 80% among 51 patients.

CCNU has been shown to be of limited benefit, particularly in high-risk cases.

High-dose chemotherapy with stem cell rescue is being tried to improve survival and outcome.

The goals of surgery are to achieve radical tumor resection, when possible, and to restore normal CSF outflow.

For persistent lesions, second-look surgery is recommended to remove residual tumor.

Available studies have failed to show a significant advantage, in terms of event-free survival, of total resection as compared to near-total and less-aggressive resections.

Permanent CSF diversion in the form of ventriculoperitoneal shunt is required in as many as 30% of these cases.

Current treatment modalities include a combination of surgery, chemotherapy, and/or radiation. Ongoing worldwide research has explored nonconventional therapeutic strategies such as immunotherapy and gene therapy to improve outcome and survival, although their clinical efficacy is yet to be established.[13] Moreover, there is growing interest in proton therapy as a potential replacement for photon therapy, while high-dose chemotherapy and autologous stem cell rescue may improve therapeutic efficacies.

Consultation with the following may prove helpful:

• Neurosurgeon

• Neurologist/pediatric neurologist

• Radiation oncologist

• Medical oncologist

No specific medications are used for the treatment of PNET. Steroids may be used for decreasing peritumoral edema. (Chemotherapy is discussed in Treatment.)

Class Summary

These agents reduce edema around tumor, frequently leading to symptomatic and objective improvement.

Dexamethasone (Decadron)

Postulated mechanisms of action in brain tumors include reduction in vascular permeability and decreased CSF production.

See the list below:

• Radiation therapy

• Chemotherapy

• Follow-up care: Serial neuroimaging is used on an individual basis depending upon each patient's initial extent of disease and the extent of resection achieved. In general, MRI is indicated every 3 months for 6 months, followed by every 6 months and then every year. After 5 years, imaging intervals can be prolonged to 5 or 10 years as appropriate.

Patients with primitive neuroectodermal tumors (PNET) may need to be admitted for treatment of complications of surgery, chemotherapy, or tumor recurrence.

Complications may include the following:

• Meningitis (postoperative)

• Hydrocephalus

• Immunosuppression due to chemotherapy and/or radiotherapy

• Paralysis

• Cranial nerve palsy

• Hypothyroidism

• Cognitive dysfunction

• Growth retardation

The following factors worsen the prognosis:

• Presence of metastases at diagnosis

• Infiltrative nature, evidence of glial differentiation, and presence of TP53 mutation

• Recent genomic study reveals that cases in the WNT group showed a slightly better survival with more favorable prognosis than those in the SHH or non-WNT/SHH group.[14]

• Unfavorable location that prevents complete resection: Failure at the primary site continues to be the predominant barrier to cure in patients with medulloblastoma.

• Younger age at presentation: Age older than 4 years at the time of initial diagnosis is associated with more favorable prognosis than age younger than 4 years.

In recent series of low-risk cases, the 5-year survival rate has been reported to be 60-80% (or even higher).

Many tumors relapse at a period equal to the age at diagnosis plus 9 months (the Collin law).

Patients (and parents) should be referred for psychosocial counseling.