Neuropathology
Since 1979, tumors of the central nervous system (CNS) have been classified according to guidelines promulgated by the World Health Organization (WHO), which merged several earlier schemes into a single system. The most recent update in 2007 has been substantially modified and expanded by incorporating advances in histopathological classification and the molecular characterization of CNS tumors. For the management of adult patients, this system provides a widely accepted, common language that facilitates diagnostic and prognostic reproducibility.1
Although it is generally acknowledged that CNS tumors in children differ in many respects from those in adults, the development of a useful and comprehensive taxonomic system has been a slow process. In 1985, Rorke et al2 pioneered an adaptation of the 1979 WHO scheme for pediatric CNS tumors. They pointed out the importance of tumor location for accurate prognosis, and thus recognized that not only the histopathological diagnosis but also multiple and often interrelated variables are likely to affect clinical behavior. In fact, microscopic features alone often fail to reflect accurately the biological behavior of tumors. For example, the prognosis for children with pilocytic astrocytoma (PA) in the cerebellum is more favorable than for the same tumor localized in the diencephalon. Similarly, the author of the neuropathology chapter in the first edition of this book championed an approach that avoided established “pigeon holes” and favored a comprehensive system that gave full consideration to a catalogue of histopathological features.3 The validation of this system would depend on comparison of data from multiple institutions that would be subjected to rigorous statistical analysis. Perhaps this approach was considered too complex for practical purposes, because it failed to garner wide acceptance despite the obvious need for more uniform diagnostic criteria for CNS tumors in children. Yet all grading systems may be thought of as works in progress that through data gleaned from collective experience will eventually evolve into a more refined tool.3 Accordingly, the 2007 WHO “blue book” remains the standard classification system for both adult and pediatric tumors.4
Table 5.1 provides a shorthand version of the WHO 2007 classification. This chapter focuses on the salient features of the most common entities in pediatric practice. For a more detailed description of the more than the 100 tumors in WHO 2007, the reader is directed to standard textbooks of neuropathology and the WHO publication.
The vast majority of pediatric neoplasms are tumors of neuroepithelial origin, whereas metastatic disease accounts for a vanishingly small proportion. Similarly, high-grade glial tumors (anaplastic astrocytomas and glioblastoma multiformes [GBMs]), meningiomas, and tumors of cranial and paraspinal nerves are rare entities in children. The 2006 Central Brain Tumor Registry of the United States (CBTRUS) reported that embryonal tumors, which encompass medulloblastomas, primitive neuroectodermal tumors, and atypical teratoid/rhabdoid tumors (AT/RTs), are more prevalent among infants and children (0–4 years of age). The predominant tumor in children 5 to 19 years of age is pilocytic astrocytoma. Of 1,593 nervous system tumors diagnosed at the Children′s Hospital of Philadelphia from 1979 to 2005, primary neuroepithelial neoplasms accounted for 1,351 cases, whereas only 242 represented craniopharyngiomas, germ cell tumors, meningioma, pituitary tumors, miscellaneous entities, and metastases.5 As might be expected, the most frequent neuroepithelial neoplasms were of glial origin (56.4%), including pilocytic astrocytomas and ependymomas. Embryonal tumors, either medulloblastomas or AT/RTs, accounted for 22.4%. Finally, mixed neuroglial tumors contributed 16.7% and choroid plexus neoplasm 3.1%, respectively.
Astrocytic Tumors
Pilocytic Astrocytoma, WHO Grade I
Pilocytic astrocytoma features a biphasic pattern ( Fig. 5.1a ) composed of hypercellular, compact areas populated by elongated, bipolar astrocytes, often with abundant Rosenthal fibers ( Fig. 5.1b ), alternating with cobweb-like microcystic areas that sometimes contain eosinophilic granular bodies (EGBs). In addition to this classic pattern, some tumors contain multinucleated cells that form a “pennies on the plate” arrangement. Vascular changes are consistently observed, either in the form of thickened, hyalinized vessels or “glomeruloid,” single-layered vessels with multiple lumina, mainly seen in regions abutting the cyst wall. Pseudopalisading necrosis is not a feature of PA; however, rarely, infarct-like necrosis may be seen. The benign nature of these tumors is apparent by the infrequency of mitoses, and the generally low proliferative index. On occasion, a few mitoses in an otherwise typical pilocytic astrocytoma are allowed. Rare cases of “malignant” or “atypical” PA have been reported and are characterized by hypercellularity, pseudopalisading necrosis, endothelial proliferation, and high numbers of mitoses.6
Of special interest is the pilomyxoid variant, which is more frequently seen in early childhood and usually arises in the hypothalamic region. These tumors lack the biphasic pattern and Rosenthal fibers, and possess abundant mucoid/myxoid matrix and the angiocentric arrangement of cells.7 It should be noted that still other examples of conventional PA show considerable morphological variation. There are variant forms that are largely microcystic tumors to predominantly compact and piloid examples. Microcystic PA may be difficult to differentiate from diffuse astrocytoma, especially if Rosenthal fibers or EGBs are not observed. When the lesion is hypothalamic and consists of exclusively compact areas and abundant Rosenthal fibers, piloid gliosis enters in the differential diagnosis. Piloid gliosis is a reactive process that can surround craniopharyngiomas and hemangioblastomas ( Tables 5.2, 5.3, 5.4 ). Children may develop the entire range of these tumors, although much less frequently than adults.
Tumors of neuroepithelial origin |
Tumors of cranial and spinal nerves |
Tumors of the meninges |
Lymphoma and hematopoietic neoplasms |
Germ cell tumors |
Tumors of the sellar region |
Metastatic tumors |
The so-called pontine glioma is most frequently a diffuse astrocytoma,8 whereas GBM in children has a distinctive genetic profile.1 Discrete, exophytic masses protruding from the medulla or midbrain are often PAs.8
Ependymal Tumors
Ependymoma, WHO Grade II, and Anaplastic Ependymoma, WHO Grade III
Ependymomas are well-circumscribed glial tumors that generally displace rather than infiltrate brain. Limited infiltration may be seen in anaplastic tumors. In children older than 1 year of age, most tumors are confined to the fourth ventricle. The next most common site is supratentorial, with only rare cases arising in the spinal cord. From 1989 to 2009 at Children′s Hospital of Philadelphia, only 21 spinal ependymomas were recently identified. In this series, 12 cases were classic ependymomas and nine were myxopapillary variants ( Table 5.5 ).
Prototype of circumscribed astrocytomas in children |
More often infratentorial (cerebellum, midbrain, medulla) |
Biphasic pattern |
Rosenthal fibers |
Pleomorphic xanthoastrocytoma (PXA), WHO grade II |
Rare, less than 1% of astrocytic tumors |
More frequently supratentorial (temporal lobe) |
Atypical/pleomorphic/multinucleated, lipidized cells and small/polygonal/fusiform forms |
Subependymal giant cell astrocytoma (SEGA), WHO grade I |
Less than 1% of astrocytic tumors |
Wall of lateral ventricles (vicinity of the foramen on Monro) |
Tightly linked to the tuberous sclerosis complex (TSC) |
Spindled/polygonal/globoid or ganglion-like cells |
Nearly all ependymomas show perivascular pseudorosettes ( Fig. 5.2 ). When this cardinal feature is absent, the diagnosis of ependymoma must be rendered with caution. Only a minority of ependymomas show epithelial features in the form of true ependymal rosettes, canals, or strips of ependymal epithelium. Sporadic ependymomas feature clear cell change that may be easily mistaken for oligodendroglioma. Attention to the neuro-imaging features of circumscription, cyst formation, and contrast enhancement should point to the correct diagnosis.
Ependymomas |
Third most common pediatric brain tumor |
Perivascular pseudorosettes and true ependymal rosettes |
Poor correlation between histological features and prognosis |
Other ependymal tumors |
Subependymoma, WHO grade I |
Myxopapillary ependymoma, WHO grade I |
Anaplastic ependymomas (WHO grade III) are marked by brisk mitoses, microvascular proliferation, and sometimes pseudopalisading necrosis. Frequently, only focal areas with hypercellularity and increased mitotic activity are present in otherwise classic ependymomas. The threshold at which “focal anaplasia” is considered sufficient to warrant the WHO III designation has yet to be determined.4 An ancillary difficulty with grading of this tumor is the poor correlation between histological features and prognosis.5 Although grading criteria for ependymoma are still controversial, a recent Children′s Oncology Group study determined that 5 to 10 mitoses per 10 high-power fields (hpf) is associated with more aggressive behavior.9
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