Supratentorial Primitive Neuroectodermal Tumors
Primitive neuroectodermal tumors (PNETs) of the central nervous system (CNS) are a diverse group of malignant embryonal tumors of neuroectodermal origin that account for 20 to 25% of all childhood brain tumors. Cerebral PNET was first described by Hart and Earle1 in 1973. These tumors are composed of un-differentiated or poorly differentiated neuroepithelial cells that may show divergent differentiation along neuronal, astrocytic, or ependymal lines. Medulloblastoma is the most common form of CNS PNET and shares some similarities with the other CNS PNETs; however, significant differences in the clinical, pathological, and molecular characteristics enable the various subtypes to be characterized and distinguished from medulloblastoma.1
Central nervous system PNET most commonly arises from the cerebral hemispheres. But rarely they can arise from the suprasellar region,2 brainstem,3,4 or the spinal cord.5
World Health Organization Classification and Nomenclature
The World Health Organization (WHO) classification of CNS PNETs has evolved over the past decade. The term CNS PNET not otherwise specified (NOS) is now used to describe undifferentiated or poorly differentiated embryonal tumors arising from any extracerebellar site in the CNS. This diagnostic category is synonymous with, and has replaced, the category of supratentorial PNET, and includes similar undifferentiated or poorly differentiated embryonal tumors occurring elsewhere in the CNS including the brainstem and spinal cord. Less common subgroups of CNS PNETs include CNS neuroblastomas, showing only neuronal differentiations, and CNS ganglioneuroblastomas if ganglion cells are present. Subgroups of embryonal origin within the category of CNS PNET include medulloepitheliomas that demonstrate neural tube formation and ependymoblastomas that demonstrate ependymoblastic rosettes ( Table 20.1 ).
Primitive neuroectodermal tumors can arise from sites outside the CNS. To enhance diagnostic clarity, the WHO Working Group proposed to add the prefix “CNS” to these tumors to avoid confusion ( Table 20.2 ).
Central nervous system PNETs, along with other embryonal tumors, correspond histologically to WHO grade IV.
Epidemiology
Central nervous system PNETs are uncommon tumors comprising approximately 1 to 3% of all pediatric CNS tumors.6,7 They occur slightly more commonly in males, with a male/female ratio of 1.2:1.6,7 The age range at presentation is broad, ranging from birth to older adults, but with a mean age at presentation of 5.5 years1; 80% are diagnosed before age 10 years and 25% present within the first 2 years of life. More precise epidemiological data are hampered by historically divergent classifications and varying terminology such as “cerebral medulloblastoma” and “cerebral neuroblastoma.”
Clinical Features
Presenting signs and symptoms vary with the age of the child, tumor location, rate of growth, obstruction of the ventricular system, and extent of dissemination at diagnosis. Infants may present more or less specific and sometimes insidious features, including vomiting, irritability, listlessness, hydrocephalus and increasing head circumference, failure to thrive, and loss of developmental milestones.8 The majority of the children present with signs and symptoms of raised intracranial pressure (ICP). The duration of the symptoms is usually short, with headache or irritability lasting for 2 to 4 weeks, followed by nausea and vomiting.9,10 Tumors arising from the cerebral hemispheres often present with seizures, lateralizing motor deficits, disturbances in consciousness, and raised ICP. Lesions in the suprasellar region may be associated with visual loss or visual field deficits, endocrinopathies, or behavioral/neuropsychiatric changes ( Table 20.3 ).10
Imaging
Central nervous system PNETs typically appear on neuroimaging as a complex hemispherical mass with minimal peritumoral edema. More commonly they appear well defined rather than infiltrative.11 The most common locations are hemispheric (cortical, subcortical, or thalamic); suprasellar, brainstem, and spinal cord lesions are less common.6,12 The size of the lesion at diagnosis is variable; hemispheric masses have a mean diameter of 5 cm, whereas suprasellar lesions tend to be smaller due to early presentation6 ( Table 20.4 ).
Appearance on Computed Tomography
The appearances of CNS PNETs are diverse, ranging from homogeneous to heterogeneous; tumors display a range of attenuation characteristics. Hemorrhage and necrosis is common, and 50 to 70% of tumors have calcifications.13 Contrast-enhanced computer tomography (CT) scan shows heterogeneous enhancement.12
CNS PNET not otherwise specified (NOS) | 9473/3 |
CNS neuroblastoma | 9500/3 |
CNS ganglioneuroblastoma | 9490/3 |
Medulloepithelioma | 9501/3 |
Ependymoblastoma | 9392/3 |
Magnetic Resonance Findings (Figs. 20.1 and 20.2)
On T1-weighted magnetic resonance imaging (MRI), these tumors are hypo- to isointense to the gray matter and may be homogeneous or heterogeneous.14 On T2-weighted images, solid elements are iso- to slightly hyperintense to the gray matter. Heterogeneity is common, and there is sparse peritumoral edema. In contrast to most CNS tumors, these tumors are hyperintense on diffusion-weighted images. T1 contrast images demonstrate heterogeneous enhancement and are useful to delineate cerebrospinal fluid (CSF) pathway seeding. Magnetic resonance spectroscopy demonstrates the following: ↓NAA/Cho, ↓NAA/Cr, ↓Cr, -↑Cho/Cr, +Lac/Lipid, and +taurine.11,12,15
Positron Emission Tomography Scan
Fluorodeoxyglucose positron emission tomography (FDG-PET) is useful in the characterization of brain tumors in pediatric patients, and has a role in evaluating therapy and monitoring recurrence. Hoffman et al16 analyzed 17 patients with posterior fossa tumors with FDG-PET, and found that FDG uptake was higher in more malignant and aggressive tumor types. Holthoff et al,17 based on their experience in 15 children with different tumors, concluded that PET with FDG may be a useful tool to evaluate metabolic activity of pediatric brain tumors over time and to assess response to treatment. O′Tuama et al,18 in a study of 13 children with brain tumors with [11C]L-methionine, were able to delineate tumor extent and uptake correlated with tumor grade.
At the time of diagnosis, comprehensive imaging of the entire neuraxis is required because of the propensity of these tumors to disseminate along CSF pathways. The most common region for dissemination is along the posterior surface of the spinal cord in the thoracolumbar region and the caudal tip of the thecal sac.14 Metastatic deposits may be identified on post-gadolinium T1-weighted images as enhancing nodules or a diffuse coating of the meningeal surfaces of the brain and the spinal cord. Nonenhancing deposits may be identified on T2 images as areas of distortion adjacent to the subarachnoid spaces or as areas of abnormal signal on fluid-attenuated inversion recovery (FLAIR) or diffusion images.11
Increased intracranial pressure |
Irritability |
Listlessness |
Vomiting |
Headaches |
Failure to thrive |
Macrocephaly |
Loss of developmental milestones |
Seizures |
Focal neurologic deficits/hemiparesis |
Visual field loss/deficit |
Neuroendocrine dysfunction |
Behavioral disturbance |
Appetite disturbance |
Cranial neuropathies |
Long tract signs (paraparesis, hyperreflexia) |
Spinal cord symptoms |
The most common imaging differential diagnoses include glioblastoma multiforme, ependymoma, oligodendroglioma, atypical teratoid/rhabdoid tumor (AT/RT), and choroid plexus carcinoma. These tumors are staged based predominantly on tumor extent at diagnosis, although up to 20% of patients have evidence of dissemination ( Table 20.5 ).19,20
Histopathology1,21 (Fig. 20.3)
Typically CNS PNETs appear to be poorly differentiated tumors composed of small to medium-sized cells with a high nuclear/cytoplasmic ratio and hyperchromatic nuclei. Mitoses are usually abundant, and proliferation, as measured by the immunohistochemical marker Ki-67, may range from near zero to over 80%. Necrosis of individual cells is common. Homer Wright rosettes can be seen but are rarer than in medulloblastomas. Foci of large-cell and anaplastic transformation similar to those seen in aggressive medulloblastomas may also be seen. Calcification is common in degenerating areas. Vascular endothelial proliferation may also be seen. Tumors with greater degrees of differentiation may demonstrate neuronal features such as oval to elongated nuclei with vacuolation and Nissl substance. A more eosinophilic, spindle cell appearance may be seen in the areas of glial differentiation ( Table 20.6 ).
Well defined, minimal peritumoral edema |
Computed tomography features: |
Homo/heterogeneous |
Hemorrhage/necrosis/calcification common |
Heterogeneous contrast enhancement |
Magnetic resonance imaging features: |
T1 hypo/isointense, contrast enhances |
T2 iso/slightly hyperintense |
Magnetic resonance spectroscopy features: |
↓NAA/Cho, ↓NAA/Cr, ↓Cr, ↑Cho/Cr, +Lac/Lipid, +taurine |
Some CNS PNETs primarily express neuronal lineage antigens on initial presentation but show more glial phenotype on recurrence.22 In such cases similar genetic mutations have been identified in both the astrocytic and neuronal elements, suggesting a common origin for both components.
Proliferation
All CNS PNETs are WHO grade IV by definition. PNETs at any site show variable proliferation activity (measured by Ki-67 immunohistochemical staining). The proportion of cells undergoing division is generally high, but varies from 0 to 85% in different fields.1
Histological Variants
Variants expressing only neuronal lineage have been termed either cerebral neuroblastoma or cerebral ganglioneuroblastoma. Medulloepithelioma and ependymoblastoma are other variants of CNS PNET.
Glioblastoma multiforme |
Ependymoma |
Oligodendroglioma |
AT/RT |
Choroid plexus carcinoma |
Medulloepithelioma
Medulloepithelioma is a rare CNS PNET subtype characterized by an immature tubular, trabecular, or sometimes papillary arrangement of neuroepithelial cells that resemble the embryonic neural tube.1,21 This variant is usually seen in the supratentorial region, particularly in children younger than 5 years of age. Rarely they contain mesenchymal elements such as cartilage, bone, or immature skeletal muscle, and require differentiation from immature teratoma.23
Ependymoblastoma
Ependymoblastoma is rarer variant of CNS PNET, characterized by the presence of multilayered ependymoblastic rosettes, with the outer layers of the rosette formation appearing to merge with the surrounding area of PNET-like histology.1,21 These true rosettes have a central lumen lined by tumor cells that contain the basal bodies of cilia (blepharoplasts). This variant should not be confused with anaplastic ependymomas that may contain single-layer rosettes of mitotically inactive cells.
Embryonal Tumor with Abundant Neuropil and True Rosettes
Recently another CNS PNET variant has been identified. Embryonal tumor with abundant neuropil and true rosettes (ETANTR) shares features with both ependymoblastomas (having well-developed true rosettes) and cerebral neuroblastomas (having foci of extensive neuronal differentiation with neuropil formation). Whether this is a variant of CNS PNET or a distinct pathological entity remains controversial.24,25
Poorly differentiated, hyperchromatic nuclei |
Abundant mitoses, Ki-67 (0–80%) |
Grade IV by WHO definition |
Necrosis common with associated Ca+ |
May manifest neuronal and glial lineage |
Immunostaining
Central nervous system PNETs express neuronal markers such as synaptophysin, class III β-tubulin and neurofilament protein.1 They may also express neurone specific enolase (NSE), S-100, and CD57. Glial elements of CNS PNET are immunoreactive for glial fibrillary acidic protein (GFAP).18 Ki-67(MIB-1) labeling is variable, but commonly high. They retain INI1 staining, differentiating them from AT/RTs.
Differential Diagnosis
Glioblastoma: CNS PNET requires careful differentiation from the small-cell and PNET-like variants of glioblastoma. Glioblastomas are relatively uncommon in children and are characterized by pseudopalisading necrosis and vascular endothelial proliferation. Typically, they do not express neuronal antigens. On imaging, glioblastomas are characterized by extensive vasogenic edema and calcification is uncommon.
Atypical teratoid/rhabdoid tumor (AT/RT): This is an important differential diagnosis particularly in children younger than 3 years of age. AT/RTs arise more commonly in the posterior fossa and often demonstrate extensive necrosis on light microscopy, cystic changes, and extensive vasogenic edema on imaging. Diagnosis of AT/RT may be confirmed by the lack of immunostaining for the nuclear expression of INI1, the only recognized tumor suppressor gene abnormality with a role in CNS tumors in children. CNS PNETs express INI1 in a normal pattern.
Ependymoma: Usually ependymomas arise from the lateral or the third ventricle, are large at presentation, and necrosis and hemorrhage are uncommon. They are distinguished easily based on immunohistochemical staining.
Ganglioglioma and central neurocytoma: Both tumors are uncommon in young children and have a tendency to arise from characteristic locations—the superficial temporal lobe for ganglioma and the lateral ventricles for central neurocytoma. They also demonstrate a higher level of neuronal differentiation.
Peripheral-type Ewing sarcoma/PNET: This tumor can present in intracranial or intraspinal sites. Most reported cases have been meningeal-based, mimicking meningioma radiologically.26 However, these tumors may arise within the brain parenchyma, and differentiating them from CNS PNETs on morphology alone may be difficult. The peripheral PNETs are characterized by translocation t(11–22) and also express markers like FLI-1 and CD99, whereas CNS PNETs lack the expression of these markers.27,28
Genetics
In 2002, Pomeroy et al29 demonstrated distinct clustering of CNS PNETs from other embryonal tumors of the CNS based on expression analysis. These findings have been confirmed and extended by several workers. Molecular studies indicate that medulloblastoma and CNS PNETs are genetically distinct, despite similar histological features.29–31
The most common cytogenetic change observed in medulloblastoma, isochromosome 17q, is not a feature of CNS PNET. 30,32 However, recent studies have identified rare chromosome 17 aberrations in some CNS PNETs.33 Studies using high-resolution genomic arrays also suggest significant molecular genetic differences.31,34 Promoter methylation status and other studies on epigenetic regulation of gene expression have revealed differences among the CNS embryonal tumor types.29,35 However, CNS PNET and medulloblastoma share the same promoter methylation status of the RASSF1A gene.36 Also noted in a subset of CNS PNETs are myc gene amplifications; however, whereas c-myc is most common in medulloblastomas, N-myc is more common in CNS PNET. Some of the most common chromosomal aberrations seen in CNS PNET include gains on chromosomes 1q, 7, and 8q and losses on chromosomes 9, 13q, and 19q.30,32,33 Possibly due to the genetic heterogeneity of this disease, a host of additional cytogenetic changes have been described with variable consistency.30,32,33 Several focal amplifications and deletions have been described in CNS PNETs, including CDKN2A (correlated with the progression of the disease),31,33 PGDFRA and KIT,31 p14/ARF methylation,29 transcriptional silencing of DLC-1,37 expression of the Neuro D family of basic helix-loop-helix transcription factors, and expression of the related neurogenic transcription factor achaete scute.1 Recently, tumorassociated carbonic anhydrase (CA) II, IX, and XII expression was studied in a group of medulloblastomas and CNS PNETs, and CA IX was found to have prognostic significance.37 In a recent study, CNS PNETs expressed significantly higher levels of SOX2, NOTCH1, ID1, and ASCL-1 transcripts, whereas NEUROD1, NEUROG1, and NEUROG2 were unregulated in medulloblastomas. Also the proportion of phosphorylated STAT3α relative to STAT3α was significantly greater in CNS PNETs than in medulloblastomas, indicating JAK/STAT3 pathway activation in CNS PNETs.38 Absence of t(11–22) and other alterations in Ewing sarcoma of genes in CNS PNETs are helpful in differentiating peripheral Ewing sarcoma/PNET arising from the CNS.39 Table 20.7 demonstrates clinically important molecular alterations in CNS PNET, and Table 20.8 differentiates CNS PNET from other embryonal tumors.
Management
In general, CNS PNETs are associated with a more aggressive clinical course and relative resistance to therapy and high recurrence rates despite surgery, radiation, and chemotherapy. Prolonged survival after recurrence is uncommon. More recent reports suggest that high-dose multiagent chemotherapy strategies after gross total resection may result in long-term survival in some patients.40 Patients with CNS PNET are often treated using approaches similar to the ones used for children with high–risk medulloblastoma.
Molecular Alteration | Clinical Outcome |
MYC89 | High expression Unfavorable outcome |
CDKN2A33 | Deletion Metastatic disease and unfavorable outcome |
CAIX37 | CAIX expression Unfavorable outcome |
Polysome 2 and 890 | Unfavorable outcome |
Interpretation of published reports is made more difficult because of inconsistency and variations in the application of diagnostic criteria; heterogeneity within the tumors grouped under the heading of CNS PNET; relatively low numbers of patients, creating a barrier to clinical research studies; and variability of reporting time points for event-free survival (EFS) and overall survival (OS). All these factors have negative impact on the interpretation of outcome data in CNS PNET.
As in the case of medulloblastomas, the CNS PNETs require staging by CSF cytology and MRI of the spine for identification of the subarachnoid dissemination at the time of diagnosis. Research involving the prognostic significance of molecular genetic markers is increasing rapidly, emphasizing the importance of tumor banking as part of the surgical and pathological approach to these tumors. Recent work suggests that gene profile expression classification based on multigene models may be more useful.
Surgery
An attempt at complete surgical resection is important in the management of both medulloblastoma and CNS PNET. Resection also provides tissue for histopathological diagnosis, molecular analysis, and tumor banking. The importance of surgical resection has not been lessened by the introduction of aggressive chemotherapy protocols, even though surgery itself is not curative. However, as CNS PNETs are less common and there is limited information about these tumors, the importance of gross total surgical resection has not been resolved, and reports on the impact of the extent of surgical resection on survival vary. A prospective study by Cohen et al19 in 55 patients of ages 1.5 to 19.3 years, 17 with pineal tumors, 24 with nonpineal tumors, three with non-PNET tumors, and 11 with discordant tumors, showed no survival advantage in patients with supratentorial PNET (SPNET) undergoing 90 to 99% resection as compared with patients who had <90% tumor resection.19 Similarly, the prospective German Brain Tumor Trials (HIT 88/89 and HIT 91) involving 63 children did not show any significant differences in outcomes based on extent of surgical resection.41 However, studies by Massimino et al,42 Reddy et al,43 and Timmermann et al44 demonstrated that there was a trend toward better survival of those patients with complete or near complete resection compared with those with partial resection or biopsy, although the results were statistically not significant, probably due to low numbers of patients.42–44 Because these tumors frequently involve eloquent cortex or vascular structures, gross total resection may not be feasible in selected patients. In the Children′s Cancer Group (CCG)-921 trial and German HIT trial, gross re-section could be performed only in 40% of the patients with SPNETs.41,45
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