This pediatric tumor entity shares many of the gross and microscopic features of pilocytic astrocytomas. Like pilocytic astrocytomas, these tumors tend to occur in midline structures, with a predominance for the suprasellar/hypothalamic region [7]. Their increased tendency to recur and less favorable prognosis have resulted in designating pilomyxoid astrocytoma as a distinct WHO grade II entity rather than simply as a rare morphologic variant of pilocytic astrocytoma [7].

Grossly, pilomyxoid astrocytomas are well-circumscribed, solid, gelatinous, or cystic lesions that are difficult to distinguish macroscopically from pilocytic astrocytoma. On microscopic examination however, unlike its close relative, pilomyxoid astrocytoma is a monophasic tumor in a predominantly myxoid background matrix (Fig. 6.2a). Embedded within the myxoid matrix are bland bipolar cells that have a tendency to form an angiocentric pattern (Fig. 6.2b). Other histological findings that may help in distinguishing this entity from pilocytic astrocytoma are its lack of protoplasmic cells, Rosenthal fibers or calcifications, and rare eosinophilic granular bodies. Neither immunohistochemistry nor molecular testing has been helpful thus far in distinguishing pilomyxoid from pilocytic astrocytoma.

This entity was added to the WHO 2007 classification as a WHO grade I lesion and carries a good prognosis [2, 8]. They are cortically based, typically occurring in the frontoparietal and temporal lobes (including the hippocampal region), and present clinically with seizures. Microscopically, angiocentric gliomas are variably infiltrative and characterized by monomorphous bipolar cells with a prominent angiocentric growth pattern (Fig. 6.3a). They also frequently display subpial palisading. As for most astrocytic neoplasms, GFAP is diffusely positive. There is also an intracytoplasmic dot-like pattern of staining with epithelial membrane antigen (EMA) (Fig. 6.3b).

Diffuse astrocytomas (WHO grade II) are infiltrating glial tumors that occur throughout the pediatric CNS. Unlike in adults, diffuse astrocytomas in children rarely progress to higher grade lesions. Grossly, this tumor forms an ill-defined and occasionally cystic mass that causes enlargement and distortion of the involved anatomical structures.

Microscopically, diffuse astrocytomas are composed of hypercellular sheets of cells with oval to elongate nuclei within a fibrillar background (Fig. 6.4a). The entrapment of nonneoplastic neurons (Fig. 6.4b) and features such as perineuronal, perivascular, subpial, and subependymal aggregates of neoplastic cells (the so-called secondary structures) are evidence of their infiltrative growth. The presence of atypical nuclei that are angular, hyperchromatic, and mildly pleomorphic can help differentiate these neoplasms from reactive astrocytes. Mitoses, however, are rare or absent. GFAP is the main immunohistochemical stain that highlights the neoplastic astrocytic cells. Neurofilament is helpful for highlighting the infiltrative nature of the tumor cells (Fig. 6.4c).

Morphological variants of diffuse astrocytomas include protoplasmic and gemistocytic variants. The former is a rare hypocellular, mucoid, and microcystic lesion that is predominantly composed of cells with small nuclei, low content of glial filaments, and scant GFAP expression. The gemistocytic variant shows a predominant population of cells with abundant eosinophilic cytoplasm, nuclei that are displaced to the periphery and strong, consistent GFAP expression.

Recently, a study applying whole-genome sequencing to low-grade gliomas found a high rate (53 %) of either intragenic duplication of the tyrosine kinase domain of the FGFR1 or rearrangements of MYB in WHO grade II diffuse gliomas [9]. In a similar analysis of grade II gliomas, 28 % were shown to have partial duplication of the transcription factor MYBL1 [10]. Given the availability of specific therapeutic inhibitors of such pathways, histopathological diagnosis with supplemental molecular analysis of tumors may one day offer more patient-specific treatments and prognostication for these tumors.

Anaplastic astrocytomas (WHO grade III) show increased cellularity, nuclear pleomorphism, and hyperchromasia when compared to WHO grade II diffuse astrocytomas. Grossly, it is difficult to differentiate between diffuse astrocytoma WHO grade II and anaplastic astrocytoma.

The presence of mitoses is a key distinguishing feature that favors a diagnosis of anaplastic astrocytoma over the lower grade astrocytic neoplasms already discussed (Fig. 6.4d). Though the finding of pyknotic nuclei is still consistent with this category, geographic areas of necrosis or microvascular proliferation are usually indicative of glioblastoma.

Glioblastoma (GBM) is a malignant astrocytic tumor (WHO grade IV) that can occur throughout the CNS. It is less common in the pediatric population than in adults. As its former name “glioblastoma multiforme” suggests, the tumor exhibits tremendous phenotypic heterogeneity from one region of the tumor to another. Grossly, it usually shows areas of necrosis, hemorrhage, peritumoral edema as well as occasional pseudocapsule formation, in addition to a yellowish discoloration from myelin breakdown. GBMs also exhibit variable architectural patterns and cellular morphologies at the microscopic level that include multinucleated giant cells, small cells, granular cells, and lipidized cells. In addition to sharing features such as hypercellularity, diffuse infiltration, pleomorphism, and mitoses with anaplastic astrocytoma, GBMs also show either necrosis, typically with pseudopalisading of tumor cells (Fig. 6.5a) or microvascular proliferation (Fig. 6.5b).

Exome sequencing of pediatric supratentorial/hemispheric GBMs has revealed differences in the biology that governs tumorigenesis between pediatric/young adult GBMs and those seen in adults. In the young age group somatic mutations in the H3.3-ATRX-DAXX chromatin remodeling pathway can be found. Mutations in the tumor suppressor TP53 are found in approximately half of GBMs and 86 % of GBMs with H3.3 or ATRX mutations. Mutations in H3.3 were also highly specific for GBMs when compared to low-grade lesions and thus provide additional tools to help differentiate between the different tumor grades in small biopsies [11]. Although extremely rare in the pediatric population, IDH1 mutations may be encountered in the adolescent age group [12].

Pleomorphic Xanthoastrocytoma (PXA) is a relatively rare astrocytic, low-grade tumor (WHO grade II) with distinctive morphologic features. It is a supratentorial lesion that classically involves the superficial cortex and leptomeninges of the temporal lobe of children and young adults with medically refractory epilepsy. Grossly, PXAs are discrete lesions with leptomeningeal involvement and may be cystic lesions. Microscopically, as its name suggests, PXAs are composed of highly pleomorphic, fibrillary astrocytes, some of which may show lipidization (Fig. 6.6a). Large, bizarre, multinucleated cells are an additional feature. Reticulin positivity is a characteristic feature (Fig. 6.6b). Eosinophilic granular bodies, perivascular infiltration by lymphocytes, and a solid component within the subarachnoid space are key features that can help with diagnosis. Due to its significant pleomorphism, differentiation of PXA from more malignant astrocytic tumors such as anaplastic astrocytoma or GBM is critical given the difference in prognosis. In fact, even when PXAs show “anaplastic features” (5 or more mitoses per 10 high power fields) or necrosis, the prognosis still remains more favorable than that of high-grade gliomas [13]. The neoplastic cells in PXA are positive for S100 and variably positive for GFAP and CD34 [14]. There may also be focal areas with a neuronal phenotype suggesting a multipotential precursor cell as its cell of origin [15]. Approximately two-thirds of PXAs harbor the V600E BRAF mutation [16].