Other Astrocytomas
Pilocytic Astrocytoma (WHO Grade I)
Clinical Context
General
Pilocytic astrocytomas are the most common primary CNS neoplasms in childhood, accounting for about 17% of all such lesions (1). No significant sex predilection exists. The incidence of pilocytic astrocytomas remains level through childhood and tapers to occasional cases after the age of 30 years (2). Rare examples are found in the elderly, up to 85 years old (3). Patients with neurofibromatosis type 1 (NF1) have a predisposition to develop gliomas, which are most often pilocytic astrocytomas (4). Although many cases present classically as a circumscribed posterior fossa lesion, pilocytic astrocytomas can occur anywhere in the neuraxis. Other common sites include the optic chiasm/hypothalamus, thalamus, cerebral hemisphere, and brainstem. Although the histology of pilocytic astrocytomas has a large degree of overlap between all anatomic sites, their clinical contexts are distinct and discussed separately below.
Cerebellar
The vast majority of astrocytomas that occur in the cerebellum are pilocytic and occur in children, the remaining minority being diffusely infiltrative and nonpilocytic in older patients (5). Patients present with signs and symptoms similar to other cerebellar neoplasms, with incoordination/ataxia and increased intracranial pressure. The vast majority of cerebellar cases are cystic with about half of those being the classic cyst with mural nodule. Treatment consists of simple surgical resection in most cases. Long-term survival is good, almost 80% at 20 years from diagnosis in one series (5).
Optic Pathway
The optic nerves, chiasm, and tracts are common sites for pilocytic astrocytomas in infants and young children and are sometimes referred to as optic gliomas or optic pathway gliomas. About 60% of cases occur in the setting of NF1. Unlike in other locations, optic pathway pilocytic astrocytomas infiltrate the native substance of the optic apparatus and extend longitudinally within the nerve, forming a tapered, fusiform outline. Radiology may also show a characteristic “buckling” of the optic nerve (6). Many patients present with decreased visual acuity or nystagmus, but those with NF1 are frequently diagnosed when asymptomatic, as
part of clinical workup of their syndrome (7). Cases that are bilateral or involve the optic nerve proper are more characteristic of patients with NF1, whereas sporadic cases tend to be centered on the chiasm (8,9). Chiasmatic lesions frequently involve the superjacent hypothalamus and for that reason cannot be completely resected.
part of clinical workup of their syndrome (7). Cases that are bilateral or involve the optic nerve proper are more characteristic of patients with NF1, whereas sporadic cases tend to be centered on the chiasm (8,9). Chiasmatic lesions frequently involve the superjacent hypothalamus and for that reason cannot be completely resected.
Optic gliomas in patients with NF1 most often present with decreased visual acuity, but are also found incidentally in the clinical workup for NF1. Two large series found a significant female majority (∼3:2, female:male) among optic glioma patients with NF1 (10,11). The clinical approach to, and natural history of, optic pathway gliomas depends heavily on the patient’s NF1 status. Syndromic lesions are indolent and tend to stabilize around puberty, whereas sporadic cases are more likely to continually progress. Observation with surveillance imaging is the initial approach for many NF1 patients, reserving more aggressive care for the minority of cases that progress. Sporadic optic pathway gliomas and NF1-related cases that progress are treated with multiagent chemotherapy. Radiation is less commonly used due to long-term complications, especially in NF1 patients (12).
Because of the intimate association of the tumor to optic nerve axons, surgical resection is avoided in favor of a small diagnostic biopsy. Debulking surgery can be undertaken when vision is already severely compromised, when the tumor grows exophytically from the chiasm, or to relieve hydrocephalus, but is no longer considered a primary treatment option for most optic pathway gliomas.
Cerebral Hemispheres
Only a few percent of supratentorial gliomas are pilocytic astrocytomas, but recognition of those few is essential because of their drastically different biology from infiltrating gliomas. Age of incidence in cerebral cases parallels that of cerebellar pilocytic astrocytomas and greatly overlaps that of infiltrating gliomas, making the prospect of having to distinguish the two likely. Most cases localize to the temporal and parieto-occipital lobes. Circumscription, strong contrast enhancement, and cystic spaces strongly favor pilocytic astrocytoma over diffuse glioma (14). Among published cases of cerebral pilocytic astrocytomas, long-term survival is high after surgical resection, about 80% of 102 cases with mean follow-up of around 15 years (14,15). The major risk factor for recurrence was subtotal resection in both of those studies.
Brainstem
A small subset of pilocytic astrocytomas occur in the brainstem, where they are often dorsally exophytic from the medulla or midbrain (16). Formerly classified among other brainstem gliomas, pilocytic astrocytoma is recognized to have a much better prognosis than the more common diffuse brainstem gliomas, which occur mostly in the ventral
pons (17). Progression-free survival in brainstem pilocytic astrocytomas is favorable with complete surgical resection, 74% at 5 years versus 20% for incompletely resected lesions (18). Imaging characteristics are similar to pilocytic astrocytomas occurring elsewhere.
pons (17). Progression-free survival in brainstem pilocytic astrocytomas is favorable with complete surgical resection, 74% at 5 years versus 20% for incompletely resected lesions (18). Imaging characteristics are similar to pilocytic astrocytomas occurring elsewhere.
 FIGURE 4-1 Pilocytic astrocytomas usually present as “cyst with mural nodule” lesions in children, as shown in this T2-weighted/FLAIR magnetic resonance imaging (MRI). |
Radiologic Features
Neuroimaging shows a circumscribed round or oval lesion that usually contains cystic areas and produces little edema in surrounding tissue. The “cyst with mural nodule” configuration is typical of cerebellar pilocytic astrocytomas (Figure 4-1). The solid portions of tumor are hypo- to isointense on CT scan and exhibit widespread contrast enhancement. On MRI, pilocytic astrocytomas are hypointense in T1-weighted sequences and hyperintense on T2 (19). Circumscription, cyst formation, and bright contrast enhancement help to separate pilocytic astrocytomas from infiltrating (grades II to IV) astrocytomas radiologically.
Meningeal Dissemination
Leptomeningeal dissemination, either as diffuse or discrete lesions, occurs in a small number of patients with pilocytic astrocytoma. Hypothalamic/chiasmatic lesions account for about 70% of those patients (20). Many cases of dissemination result from mobilization of tumor cells into the CSF at the time of resection, but a few present with this finding: 5 out of 126 in one large institutional review (21). Patients will often show signs and symptoms of increased intracranial pressure and hydrocephalus, possibly due to clogging of the arachnoid villi by tumor cells. The clinical significance of dissemination is not completely understood, but it has a generally favorable outcome (20,22).
Pilomyxoid Astrocytoma
Pilomyxoid astrocytoma is a variant subcategory of pilocytic astrocytoma that until the 2016 WHO update was considered grade II due to its reportedly more aggressive clinical course (23). They are most common in the first 3 years of life, and, like pilocytic astrocytomas,
occur in progressively lower frequencies as age increases. Rare examples have been described in adults (24,25). Most cases are centered in the chiasmatic/hypothalamic area, yet pilomyxoid astrocytoma can be found anywhere in the neuraxis. It has been suggested that this tendency for hypothalamic location prevents their complete excision, thus explaining the less favorable outcomes, rather than it being due to the inherent biology of the tumor. Several cases from the spinal cord have been described (25,26). Neuroimaging fails to reveal any consistent differences between pilocytic and pilomyxoid astrocytomas (27). Several series have shown that the pilomyxoid variant is more aggressive and has a higher rate of recurrence and lower rate of survival, although the effect is difficult to separate from that of location (28,29,30). Nevertheless, evidence does at least seem to indicate that pilomyxoid astrocytoma has a higher rate of leptomeningeal dissemination, supporting a more intrinsically aggressive nature (31,32).
occur in progressively lower frequencies as age increases. Rare examples have been described in adults (24,25). Most cases are centered in the chiasmatic/hypothalamic area, yet pilomyxoid astrocytoma can be found anywhere in the neuraxis. It has been suggested that this tendency for hypothalamic location prevents their complete excision, thus explaining the less favorable outcomes, rather than it being due to the inherent biology of the tumor. Several cases from the spinal cord have been described (25,26). Neuroimaging fails to reveal any consistent differences between pilocytic and pilomyxoid astrocytomas (27). Several series have shown that the pilomyxoid variant is more aggressive and has a higher rate of recurrence and lower rate of survival, although the effect is difficult to separate from that of location (28,29,30). Nevertheless, evidence does at least seem to indicate that pilomyxoid astrocytoma has a higher rate of leptomeningeal dissemination, supporting a more intrinsically aggressive nature (31,32).
Hemorrhage
A recently recognized tendency of pilocytic astrocytomas is to develop intracranial hemorrhage at the site of the tumor. Two large series found the rate of clinically apparent hemorrhage to be about 8% to 11%, higher than any other category of glial neoplasm within the same time period (33,34). Cerebellar cases are much less likely to hemorrhage than those in other locations. The tendency to hemorrhage may be linked to the abnormally proliferating vasculature seen in these lesions.
Histopathology
 FIGURE 4-2 Pilocytic astrocytomas are usually biphasic at low magnification, with dense fibrillar areas and looser myxoid areas. |
No one description captures the spectrum of appearances in pilocytic astrocytomas, but several features remain constant through the vast majority. A biphasic pattern (Figure 4-2) of loose myxoid glial tissue alternating
with areas of densely fibrillar tissue is present at least subtly in the most cases. The loose areas contain monotonous round to oval nuclei with a few processes suspended in a mucoid material, creating a spongy microcystic look (Figure 4-3). The compact areas of fibrillar tissue are composed of elongate cells with thick fibrillar processes (Figure 4-4) that give the impression of matted hair, the origin of the tumor’s name (Latin: pilus—hair). The
nuclei in fibrillar areas are uniform and oval to elongate. Calcifications and vascular hyalinization, common in low-grade lesions, are seen, but the former is uncommon. However, calcification may be more common in cases that spontaneously hemorrhage (33). Large parts of some pilocytic astrocytomas show a nodular nested pattern in superficial areas (Figure 4-5).
with areas of densely fibrillar tissue is present at least subtly in the most cases. The loose areas contain monotonous round to oval nuclei with a few processes suspended in a mucoid material, creating a spongy microcystic look (Figure 4-3). The compact areas of fibrillar tissue are composed of elongate cells with thick fibrillar processes (Figure 4-4) that give the impression of matted hair, the origin of the tumor’s name (Latin: pilus—hair). The
nuclei in fibrillar areas are uniform and oval to elongate. Calcifications and vascular hyalinization, common in low-grade lesions, are seen, but the former is uncommon. However, calcification may be more common in cases that spontaneously hemorrhage (33). Large parts of some pilocytic astrocytomas show a nodular nested pattern in superficial areas (Figure 4-5).
 FIGURE 4-3 The loose areas in pilocytic astrocytomas are generally rich in myxoid material that frequently pools into microcysts. |
 FIGURE 4-4 Smear preparations of pilocytic astrocytoma show oval to elongate, bipolar glial cells, many of which contain a single prominent eosinophilic thread through the cytoplasm. |
 FIGURE 4-5 Pilocytic astrocytomas grow in a nested, fibrotic pattern in superficial areas involving the leptomeninges. |
Some cases of pilocytic astrocytoma display a resemblance to oligodendrogliomas, with apparently infiltrative elements containing uniform cells with round nuclei and perinuclear haloes (Figure 4-6). When such tissue comes from a cystic cerebellar mass in a child, the diagnosis is straightforward, but in the cerebrum of older children and young adults, cautious review of all available evidence, including genetic characterization, should guide this distinction. Some have noted an increased incidence of recurrence in cerebellar cases with this feature (35).
Eosinophilic granular bodies (EGBs) may be seen in the microcystic portions of pilocytic astrocytomas and provide histologic evidence of the lesion’s low-grade nature. EGBs are brightly eosinophilic, spherical protein droplets that occur in aggregates (Figure 4-7) or as larger single globules. Also seen in pleomorphic xanthoastrocytomas (PXAs) and gangliogliomas, EGBs develop intracytoplasmically within astrocytes and are composed of ubiquitinated alpha-1 chymotrypsin and alpha-1 antitrypsin (36). As with Rosenthal fibers, EGBs are neither specific nor sufficient for a diagnosis of pilocytic astrocytoma and can rarely be seen in higher-grade lesions, even glioblastoma (37). Like the hepatocellular inclusions of mutant alpha-1 antitrypsin in alpha-1 antitrypsin deficiency, EGBs are accentuated by PAS staining.
Rosenthal fibers are intensely eosinophilic, wormlike cords of aggregated protein that originate, like EGBs, within the cytoplasm of astrocytes
(Figure 4-8). Although Rosenthal fibers are a consistent feature of pilocytic astrocytomas, these structures are also typical components of the reactive piloid gliosis in compressed brain tissue around indolent mass lesions, such as a craniopharyngioma, hemangioblastoma, or syrinx. In pilocytic astrocytomas, Rosenthal fibers are generally restricted to the dense regions and can range in quantity from zero to numerous. Rosenthal fibers have
also been described in malignant CNS tumors but are extremely unusual in that setting (38).
(Figure 4-8). Although Rosenthal fibers are a consistent feature of pilocytic astrocytomas, these structures are also typical components of the reactive piloid gliosis in compressed brain tissue around indolent mass lesions, such as a craniopharyngioma, hemangioblastoma, or syrinx. In pilocytic astrocytomas, Rosenthal fibers are generally restricted to the dense regions and can range in quantity from zero to numerous. Rosenthal fibers have
also been described in malignant CNS tumors but are extremely unusual in that setting (38).
 FIGURE 4-6 Some posterior fossa pilocytic astrocytomas have areas with a monotonous population of haloed cells with round regular nuclei, imitating the appearance of oligodendrogliomas. |
 FIGURE 4-7 Eosinophilic granular bodies (EGBs) are common in the loose areas of pilocytic astrocytomas and in several other low-grade CNS neoplasms. |
 FIGURE 4-8 Rosenthal fibers are intensely eosinophilic vermiform structures that are seen in the dense areas of pilocytic astrocytomas. |
The circumscription of pilocytic astrocytomas on neuroimaging sometimes belies the extent of infiltration seen histologically (39). Mature nonneoplastic neurons can be entrapped well into the tumor, creating a potential nosologic crisis between pilocytic astrocytoma entrapping neurons and ganglioglioma with a piloid glial component. Fortunately, location separates most of these cases, and the consequences of misidentifying entrapped neurons as neoplastic are minimal.
Pilomyxoid Features
The pilomyxoid variant is architecturally monomorphic, lacking the densely fibrillar element and biphasic appearance of classic pilocytic astrocytoma, instead demonstrating a loose myxoid pattern throughout. Pilomyxoid astrocytoma also has a distinctive perivascular orientation of tumor cells (Figure 4-9), similar to the perivascular pseudorosettes of ependymomas. Rosenthal fibers are lacking, but rare EGBs are allowable (23). Infiltration of surrounding tissue is limited but reported to exceed that of classic pilocytic astrocytoma (40). To suffice for a diagnosis of pilomyxoid astrocytoma, the vast majority of the tumor should show typical pilomyxoid features. The significance of focal pilomyxoid features is unknown, and their presence can be communicated either in comment form, or as an appendage to the diagnosis of pilocytic astrocytoma. Pilomyxoid astrocytoma will recur with a more typical, classic pilocytic growth pattern (41).
Anaplasia
Anaplastic change is remarkably rare in pilocytic astrocytomas, occurring in less than 2% in one large series (42). That same series
also showed radiation to be a risk factor for anaplasia, although accounting for a smaller fraction of anaplastic tumors than what had been reported in the literature (42,43,44,45). The cases in that study, and most other reported cases were morphologically defined, so it’s unclear if those that developed anaplasia were genetically distinct or had any molecular risk factor for progression. Anaplastic pilocytic astrocytomas are generally considered WHO grade III and not equivalent to a diagnosis of glioblastoma. Histologic criteria associated with poor outcome include ≥4 mitotic figures in 10 (400×) fields and necrosis (42). The criterion of mitotic activity does not apply in cases of optic pathway glioma in the setting of NF1, as it has not been shown to convey increased risk (4).
also showed radiation to be a risk factor for anaplasia, although accounting for a smaller fraction of anaplastic tumors than what had been reported in the literature (42,43,44,45). The cases in that study, and most other reported cases were morphologically defined, so it’s unclear if those that developed anaplasia were genetically distinct or had any molecular risk factor for progression. Anaplastic pilocytic astrocytomas are generally considered WHO grade III and not equivalent to a diagnosis of glioblastoma. Histologic criteria associated with poor outcome include ≥4 mitotic figures in 10 (400×) fields and necrosis (42). The criterion of mitotic activity does not apply in cases of optic pathway glioma in the setting of NF1, as it has not been shown to convey increased risk (4).
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