Louisiana Webs of Hope

Background

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

Pathophysiology

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 (Kleihues, 1993), 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.

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

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

Sex

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

Age

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).

History

• 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

• 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%)

Causes

• 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.
• Certain conditions have increased associations with PNETs.
• • Gorlin syndrome, also known as nevoid basal cell carcinoma syndrome, is an autosomal dominant disorder with mutations of the PTCH gene. 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.
• Other reported genetic abnormalities include isochromosome 17q (i17q), loss of segments of chromosome arms 10q and 9q, and amplification of the c-myc gene.
• Karyotypically, almost all PNETs are abnormal.

Other Problems to be Considered

Encephalitis
Meningitis
Other brain tumors such as ependymoma and astrocytoma

Lab Studies

• Lab tests are not helpful in the diagnosis of PNET.

Imaging Studies

• 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 1).
  • Accompanying hydrocephalus is common (see Image 2), and associated cystic changes can occur.
  • 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 Image 3).
  • CT myelogram may be employed 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.

Procedures

• Ventriculostomy is rarely done preoperatively because of the risk of upward herniation.
• Preoperative lumbar puncture is avoided because of the risk of downward herniation.

Histologic Findings

• 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.

Medical Care

• Preoperative administration of steroids can help to alleviate some of the signs and symptoms by reducing peritumoral edema.
• 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 employed for patients with spinal dissemination.
  • Newer methods, including stereotactic radiosurgery and high fractionation radiotherapy, are being evaluated. 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.

Surgical Care

• 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.

Consultations

• Neurosurgeon
• Neurologist/pediatric neurologist
• Radiation oncologist
• Medical oncologist