Circumscribed Astrocytic Gliomas

Main Text

Preamble

In the 2021 5th edition WHO, circumscribed astrocytic gliomas are a separate group within gliomas, glioneuronal and neuronal tumors.

Circumscribed Astrocytomas

Preamble

Six neoplasms comprise the group of circumscribed astrocytic gliomas: Pilocytic astrocytoma (PA), high-grade astrocytoma with piloid features (a newly recognized neoplasm in the 5th edition WHO), pleomorphic xanthoastrocytoma (PXA), subependymal giant cell astrocytoma (SEGA), chordoid glioma (CG), and astroblastoma (AB), MN1-altered. For purposes of discussion, we also include an uncommon variant of PA—pilomyxoid astrocytoma (PMA)—and discuss it separately in this group of circumscribed astrocytic gliomas.

Only two of these circumscribed astrocytomas, PA and SEGA, are designated as CNS WHO grade 1 neoplasms. WHO grade 1 tumors have low proliferative potential, can often be cured with surgical resection alone, and do not display an inherent tendency to malignant progression. Remote metastases are very rare, and, in the uncommon instances when they occur, the metastases generally maintain their bland (i.e., grade 1) histologic features.

Pilocytic Astrocytoma

The most common of the circumscribed astrocytomas is pilocytic astrocytoma (PA). A rare PA subvariant—pilomyxoid astrocytoma (PMA)—is considered separately.

Terminology

PA is a well-circumscribed, typically slow-growing astrocytic neoplasm associated with MAPK pathway gene alterations.

Etiology

MAPK pathway mutations are basically universal. Approximately 60% of PAs have BRAF duplications or rearrangements, especially p. V600E mutations and KIAA1549::BRAF fusions.

Specific alterations in PAs vary with anatomic location. KIAA1549::BRAF fusion is more common in cerebellar PAs, whereas BRAF p.V600E mutations are common in supratentorial tumors. Less common mutations include FGFR1 alterations and NF1 mutations, both found mainly in midline tumors. Approximately 15% of neurofibromatosis type 1 (NF1) patients develop PAs, most commonly in the optic nerves/tracts (“optic pathway gliomas”).

Pathology

Location

PAs may arise anywhere in the neuraxis but have a distinct predilection for certain sites. The cerebellum is the most common location, accounting for nearly 60% of all PAs (20-1).

The second most common site is in and around the optic nerve/chiasm and hypothalamus/third ventricle, which together account for between 1/4 and 1/3 of all PAs. The third most common location is the pons and medulla. PAs also occasionally occur in the tectum, where they may cause aqueductal stenosis.

The cerebral hemispheres are a reported but uncommon location of PA. When they occur outside the posterior fossa, optic pathway, or suprasellar region, PAs tend to be cortically based cysts with a tumor nodule.

Gross Pathology

PAs are typically well-circumscribed, grayish tumors with both firm and softer mucoid areas. Focal calcification may be present.

Sometimes PAs form a mural nodule in association with a cyst (20-1). The walls of most PA-associated cysts usually consist of compressed but otherwise normal brain parenchyma with the neoplastic element confined to the mural tumor nodule (20-2). Cyst contents are typically a protein-rich xanthochromic fluid.

Cystic PAs are preferentially located in the cerebellum and (less commonly) the cerebral hemispheres. A solid, more infiltrative appearance is common in the optic pathways and hypothalamus. Frank invasion of surrounding brain is typically absent or limited to a narrow border immediately adjacent to the neoplasm.

Microscopic Features

The classic PA is composed of a biphasic pattern of two distinct astrocyte populations. The dominant type is composed of compact, hair-like (“pilocytic”) bipolar cells with Rosenthal fibers [electron-dense glial fibrillary acidic protein (GFAP)-positive cytoplasmic inclusions]. Intermixed are loosely textured, hypocellular, GFAP-negative areas that contain multipolar cells with microcysts. Telangiectatic or glomeruloid vascular proliferation is common. Myxoid background with microcystic change is common. Ki-67/MIB-1 is typically < 5%, indicating low proliferative potential.

Staging, Grading, and Classification

PA is a CNS WHO grade 1 tumor. PAs generally maintain their CNS WHO grade 1 status over many years. Tumor dissemination occasionally occurs but is rare.

PAs with anaplastic features are rare and most commonly occur in adults. These tumors are now considered a distinct type, “high-grade astrocytoma with piloid features” (discussed later in this chapter).

Clinical Issues

Epidemiology

PA accounts for 5-10% of all gliomas and is the most common primary brain tumor in children. PAs represent nearly 25% of all CNS neoplasms and 85% of posterior fossa astrocytomas in this age group. PAs in the cerebral hemisphere are rare and tend to affect an older group of patients than the cerebellar or optic pathway PAs.

Demographics

More than 80% of PAs occur in patients under 20 years old. The peak incidence is in “middle-aged” children between the ages of 5-15 years. There is no sex predilection.

Presentation

Symptoms vary with location. Cerebellar PAs often present with headache, morning nausea, and vomiting, as intraventricular obstructive hydrocephalus is common. Ataxia, visual loss, and cranial nerve palsies also occur.

Optic pathway PAs typically present with visual loss. An uncommon presentation of a PA involving the hypothalamus is diencephalic syndrome, a rare but potentially lethal cause of failure to thrive despite adequate caloric intake.

Pontine and medullary PAs are uncommon but typically present with multiple cranial nerve palsies.

Natural History

PAs generally grow slowly. Ten-year survival exceeds 90%, even with partially resected tumors. Almost 1/2 of residual tumors show spontaneous regression or arrested long-term growth.

PAs generally maintain their CNS WHO grade 1 status over decades (20-9). Anaplastic features rarely develop and predominately occur in adults. These tumors must be distinguished from high-grade astrocytoma with piloid features, a distinct type of neoplasm with a unique DNA methylation profile (discussed later in this chapter).

Imaging

Similar to clinical presentation, imaging findings vary with PA location. The most common appearance of a posterior fossa PA is a well-delineated cerebellar cyst with a mural nodule.

PAs in and around the optic nerve, chiasm, third ventricle, and tectum tend to be solid, infiltrating, and less well marginated (20-4). When they occur in these locations, PAs tend to expand the affected structures, which maintain their underlying anatomic configuration.

PAs in the tectum expand the collicular plate and may cause aqueductal obstruction. The rare hemispheric PA typically presents as a cortically based lesion, usually a cyst with a mural nodule (20-7).

CT Findings

NECT scans show a mixed cystic/solid or solid lesion with focal mass effect and little, if any, adjacent edema. Calcification occurs in 10-20% of cases. Hemorrhage is uncommon; if present, the tumor may be a PMA rather than PA.

Most PAs enhance on both CT and MR scans. The most common pattern, seen in approximately 1/2 of all cases, is a nonenhancing cyst with a strongly enhancing mural nodule. A solid enhancing mass with central necrosis is seen in 40%, and 10% show solid homogeneous enhancement. If delayed scans are obtained, a contrast-fluid level may accumulate within the cyst.

MR Findings

Cystic PAs are usually well delineated and appear slightly hyperintense to CSF on both T1- and T2WI (20-6A). They do not suppress completely on FLAIR. The mural nodule is iso-/hypointense on T1WI and iso-/hyperintense on T2WI. Solid PAs appear iso- or hypointense to parenchyma on T1WI and hyperintense on T2/FLAIR. Posterior extension along the optic radiations is not uncommon with a suprasellar PA and does not denote malignancy.

PAs contain numerous capillaries with fenestrations and open endothelial tight junctions that permit the escape of large macromolecules across the blood-brain barrier. They may therefore show striking enhancement following contrast administration. Intense but heterogeneous enhancement of the nodule in a cystic PA is typical (20-3) (20-6B). Enhancement of the cyst wall itself varies from none to moderate (20-9). A variant pattern is a solid mass with central necrosis and a thick peripherally enhancing “rind” of tumor.

PAs in the optic nerve (20-4), optic chiasm, and hypothalamus/third ventricle show quite variable enhancement (from none to striking) (20-5), whereas hemispheric PAs generally present with a cyst + an enhancing mural nodule (20-7).

MRS in PAs often shows elevated Cho, low NAA, and a lactate peak (20-8). pMR shows low to moderate rCBV.

Differential Diagnosis

The differential diagnosis of PA depends on location and imaging appearance. A posterior fossa PA in a child with the classic cyst + tumor nodule appearance is relatively pathognomonic. A cerebellar hemangioblastoma (HGBL) can resemble PA, but HGBLs are tumors of middle-aged adults rather than children.

Solid PAs can resemble medulloblastoma, especially when they are mostly solid midline tumors. Medulloblastomas typically restrict on DWI, whereas PAs do not. Ependymoma is a plastic-appearing tumor that extrudes out the foramen of Magendie and lateral recesses.

The major differential diagnosis of hypothalamic PAs is an IDH-mutant astrocytoma. The hypothalamus is a relatively uncommon site for these tumors, which are generally adult-type neoplasms.

The differential diagnosis of a hemispheric PA with a nodule + cyst appearance is ganglioglioma. Gangliogliomas are generally cortically based and often calcify. Pleomorphic xanthoastrocytomas (PXA) can present with a solid “nodule + cyst” but are tumors of young adults, not children. PXAs often incite meningeal reaction (dural tail sign).

Pilomyxoid astrocytoma (PMA) is a subtype/variant of PA. PMAs tend to occur in younger children or infants and are generally larger and more bulky than PAs. Hemorrhage is rare in PA but relatively common in PMA.

Visual pathway PAs must be distinguished from demyelinating disease and postviral inflammation.

Pilomyxoid Astrocytoma

In the 5th edition WHO, pilomyxoid astrocytoma (PMA) is considered a rare subtype of pilocytic astrocytoma (PA). PMAs share many features with classic PA but differ in some important clinicopathologic respects. PMAs are generally noninfiltrative and have a myxoid background with monomorphic piloid cells and angiocentric arrangement. MAPK pathway alterations are common, most often BRAF mutations and fusions.

PMAs often present in infancy but have been reported in adults. They are generally more clinically aggressive than PAs with a higher rate of recurrence and propensity for CSF dissemination.

Although PMAs may occur anywhere along the neuraxis, they have a strong geographic predilection for the suprasellar region (20-10). Almost 60-75% center in the hypothalamus/optic chiasm, often extending into both temporal lobes. PMAs are generally large, bulky, but relatively well-circumscribed masses (20-11). A glistening appearance caused by the myxoid component is common. Hemorrhage and necrosis are more common than with PA.

PMAs look quite different from classic PAs on imaging studies. PMAs are more often solid and are primarily hypodense on NECT. Intratumoral hemorrhage is seen in nearly 1/2 of all cases; calcification is rare.

PMAs are iso- to hypointense on T1WI, and nearly all are hyperintense on T2, reflecting the high proportion of myxoid matrix in these tumors. Peritumoral edema is minimal or absent. Approximately 20% of PMAs demonstrate evidence of intratumoral hemorrhage on T2* (GRE, SWI), which is very rare in PAs.

PMAs demonstrate strong, generally homogeneous enhancement after contrast administration. Occasionally, large lesions may exhibit heterogeneous enhancement (20-12). High ADC values are common, most likely because of the mucinous component. pMR shows higher rCBV compared to PAs.

CSF dissemination is common with PMA, so the entire neuraxis should be imaged prior to surgical intervention.

High-Grade Astrocytoma With Piloid Features

High-grade astrocytoma with piloid features (HGAP) is a rare astrocytoma with a distinct DNA methylation profile. High-grade piloid &/or glioblastoma-like histologic features are common. In the past, these uncommon neoplasms were called “anaplastic astrocytoma with piloid features” or “anaplastic pilocytic astrocytoma.” They are now recognized as a distinct tumor entity in the 5th edition WHO and (perhaps inexplicably) included in the group of circumscribed astrocytomas.

In most cases, HGAP occurs as a de novo neoplasm rather than developing from a preexisting lower grade astrocytoma. HGAPs have numerous chromosomal alterations. MAPK pathway activating mutations are common as are CDKN2A&/or CDKN2B inactivations.

HGAPs are tumors of adults and are vanishingly rare in children. The median age of reported patients is 40 years. The five-year overall survival rate is ~ 50%.

Histopathology shows pleomorphic astrocytic characteristics, often resembling glioblastoma or pleomorphic xanthoastrocytoma. Thin, hair-like “piloid” features may be present. Currently, DNA methylation profiling is the only method for establishing the definitive diagnosis of HGAP.

While a definitive WHO grade for HGAPs has not been assigned, the 5th edition WHO suggests that the clinical behavior roughly corresponds to that of a CNS WHO grade 3 neoplasm.

Imaging shows an infiltrating, poorly marginated neoplasm that is T2/FLAIR hyperintense and generally exhibits strong but heterogeneous enhancement (20-13).

The main differential diagnosis of HGAP is glioblastoma, IDH-wildtype. Many adult posterior fossa parenchymal tumors originally diagnosed as “cerebellar glioblastoma” are likely HGAPs. Midline or juxta-midline HGAPs must also be distinguished from H3 K27-altered diffuse midline glioma.

Pleomorphic Xanthoastrocytoma

Terminology

Pleomorphic xanthoastrocytoma (PXA) is a rare astrocytic glioma that accounts for < 1% of primary CNS tumors. PXAs are characterized by large pleomorphic, frequently multinucleated cells and xanthomatous change.

Pathology

Location

Over 95% of PXAs are supratentorial hemispheric masses. Most are superficial cortically based, seizure-associated neoplasms. The temporal lobe is the most common site (40-50%), and involvement of the adjacent leptomeninges is common. Other frequent locations include the frontal (33%) and parietal (20%) lobes. Cerebellar and spinal cord PXAs have been reported but are very rare.

Size and Number

PXAs are usually solitary lesions. Most are small; lesions > 3 cm are uncommon.

Gross Pathology

The most common gross appearance is that of a relatively discrete, partially cystic, superficial cortical, yellowish mass with a mural nodule that abuts or is attached to the leptomeninges (20-14). Dural invasion is rare. The deep tumor margins may be indistinct with focal parenchymal infiltration into the adjacent subcortical white matter.

Microscopic Features

The most striking features of PXA are its highly pleomorphic histology, dense reticulin network, compact architecture, and lipidization of tumor cells. Fibrillary and giant, multinucleated, neoplastic astrocytes are intermixed with large, lipid-containing, GFAP-positive cells (20-15).

Staging, Grading, and Classification

The majority of PXAs are CNS WHO grade 2 tumors. PXAs that display anaplastic features (aPXAs), including higher cellularity and ≥ 5 mitoses/10 HPF, are designated WHO grade 3 tumors (the term “anaplastic pleomorphic xanthoastrocytoma” is not recommended) (20-17).

Diagnostic Molecular Pathology

Almost all PXAs have MAPK pathway alterations with 60-80%BRAF p.V600E mutations. Up to 95% have homozygous deletion of CDKN2A&/or CDKN2B.

Clinical Issues

Demographics

PXA is a rare tumor, accounting for slightly < 1% of all astrocytomas. PXAs are generally tumors of children and young adults; mean age at diagnosis is 22 years.

Natural History

CNS WHO grade 2 PXAs tend to recur and disseminate in the CSF. Approximately 20% progress to higher grade tumors (CNS WHO grade 3). Resection extent is the most significant prognostic factor. Five-year survival is ~ 70% for grade 2 tumors and 50% for grade 3 lesions.

Imaging

CT Findings

NECT scans show a well-delineated, peripheral, cortically based mass that contacts the leptomeninges. Two imaging patterns are common. A “cyst + nodule” configuration is present in 70% of cases (20-16A), and a predominantly solid mass with intratumoral cysts is seen in 30%. The overlying skull may be thinned and remodeled on bone CT. Calcifications are present in 40% of cases, but gross intratumoral hemorrhage is rare.

The mural nodule of a PXA shows moderate to intense enhancement on CECT.

MR Findings

The solid component of a PXA is heterogeneously hypo- or isointense relative to cortex on T1WI (20-16B). Over 90% of the tumor nodules demonstrate heterogeneous hyperintensity on T2WI and FLAIR. If calcifications or hemorrhage is present, “blooming” on T2* can be seen. The cystic portions of PXA are usually hyperintense relative to CSF on T2WI and FLAIR sequences (20-16C).

Moderate enhancement of the tumor nodule is typical following contrast administration (20-16D). Over 90% of PXAs abut the pia and may incite reactive thickening of the adjacent dura. A dural tail sign was seen in 15-50% of cases in a reported series.

Differential Diagnosis

The major differential diagnosis of PXA is ganglioglioma, which has a glial component that may resemble PXAs. A few gangliogliomas with anaplasia in the glial component have been reported, but molecular analysis reveals most of these are other neoplasms, most commonly PXA.

Giant cell glioblastoma shares many histopathologic features and imaging similarities with PXA but differs in molecular profile.

IDH-mutant diffuse astrocytoma usually involves the white matter and does not involve the meninges. Oligodendroglioma can present as a slow-growing cortical-white matter junction lesion that remodels the adjacent calvaria, but the cyst + nodule pattern is usually absent.

Besides ganglioglioma, other less common tumors with a cyst + nodule appearance that can mimic PXA include hemispheric pilocytic astrocytoma. Dysembryoplastic neuroepithelial tumor (DNET)has a similar presentation and age range but typically has a multicystic bubbly appearance.

Subependymal Giant Cell Astrocytoma

Subependymal giant cell astrocytoma (SEGA) is a localized, circumscribed, periventricular CNS WHO grade 1 astrocytic tumor that is strongly associated with tuberous sclerosis (TS) (20-18).

Terminology

SEGA is a circumscribed astrocytic glioma that arises from the subependymal tissue of the lateral ventricles adjacent to the foramen of Monro. Rare locations include the third ventricle and the retina.

Etiology

SEGA has a strong association with TS. Growth of a subependymal nodule (SEN) in TS into a SEGA is a gradual process that generally occurs in the first two decades of life. SEGAs only rarely arise after the age of 20-25 years.

Radiologic evidence supports the evolution of some SENs into SEGAs.

Genetics

It is uncertain whether SEGAs can occur outside the setting of TS or if the tumor harbors currently undetectable TS complex (TSC) gene alterations.

TSC-Associated SEGAs

The majority of SEGAs in patients with TSC have biallelic inactivation of the TSC1 (15%) or TSC2 (56%) genes. The TSC1 and TSC2 genes encode the tumor suppressor proteins hamartin and tuberin, respectively, leading to mammalian target of rapamycin genes (mTOR) upregulation. mTOR upregulation leads to uncontrolled cell growth and protein synthesis.

Nonsyndromic SEGAs

Examples of SEGAs in the absence of other clinical features of TSC have been reported, but these tumors may harbor currently undetectable TSC gene alterations. SEGAs with low levels of TSC1 or TSC2 somatic mosaicisms or large deletions may also occur without other clinical manifestations of the disease. In patients with solitary SEGA, mosaic mutations may be present in other organs, and TSC may clinically manifest later in life, so these patients should be followed up for prolonged periods.

Rare isolated nonsyndromic SEGAs have also been reported in patients without currently demonstrable germline or tumor mutations in TSC1 or TSC2 on sequencing.

Pathology

Location

Nearly all SEGAs are located in the lateral ventricles adjacent to the foramen of Monro (20-21).

Size and Number

SEGAs vary in size from tiny to lesions measuring several centimeters in diameter. The average tumor size is 10-15 mm. Most SEGAs are solitary lesions. So-called double SEGAs occur in up to 20% of cases.

Gross Pathology

SEGAs are sharply demarcated, well-circumscribed, multilobulated solid intraventricular masses that rarely hemorrhage or undergo necrosis (20-19). Calcification is common. Even large SEGAs generally do not invade the adjacent brain.

Microscopic Features

SEGA tumor cells display a wide spectrum of glial phenotypes that may be indistinguishable from SENs. Large pyramidal cells that resemble astrocytes or ganglion cells are typical. Nuclei are large, round, and usually eccentric with open chromatin and prominent nucleoli.

Staging, Grading, and Classification

SEGAs are CNS WHO grade 1 neoplasms. The presence of mitoses, vascular proliferation, or necrosis does not indicate anaplastic progression.

Diagnostic Molecular Pathology

DNA methylation-based classification studies support SEGA as a distinct tumor entity. Methylome profiling with analyses for TSC1 or TSC2 alterations may be helpful in histologically ambiguous cases. However, molecular analyses are usually not needed to establish the diagnosis of SEGA.

Clinical Issues

Epidemiology

SEGAs arise in a relatively small proportion (10-20%) of patients with TSC but cause up to 25% of the morbidity associated with this condition.

Demographics

SEGAs generally occur in the setting of TSC and typically develop during the first two decades of life. Mean age at diagnosis is 11 years. Sporadic SEGAs without obvious TS stigmata occur but are extremely rare.

Presentation

Epilepsy in TS patients is related to cortical tubers, not SEGAs. SEGAs are generally asymptomatic until they cause obstructive hydrocephalus. Headache, vomiting, and loss of consciousness are typical symptoms.

Natural History

Prognosis is generally good, as SEGAs are benign lesions that grow slowly and rarely infiltrate adjacent brain. Many patients with SEGAs have small lesions that may remain relatively stable. Median growth rate generally ranges from 2.5-5.6 mm per year.

The clinical course of SEGA, however, is not invariably so benign. The main concern is obstructive hydrocephalus, which may develop suddenly and result in rapidly rising intracranial pressure.

Treatment Options

When imaging findings are indeterminate and a lesion near the foramen of Monro cannot be clearly identified as an SEN or SEGA, close interval follow-up imaging (initially every 6 months, then annually if there is no evidence of growth) is recommended. A lesion in this location should be treated as soon as it shows evidence of enlargement.

Surgical resection has been the treatment of choice, as regrowth rates after complete tumor removal are very low. However, not all SEGAs can be resected completely. Biologically targeted pharmacotherapy with mTOR inhibitors, such as sirolimus and everolimus, has provided a safe and efficacious treatment option. SEGAs can recur a few months after drug discontinuation, so continued therapy may be necessary to avoid recurrence.

Imaging

The most important ancillary imaging findings to identify are those of TSC (see Chapter 44). In the absence of a known family history, intellectual disability, epilepsy, or cutaneous stigmata, imaging may provide the first clues to the diagnosis of TSC.

CT Findings

SEGAs are hypo- to isodense, variably calcified lesions near the foramen of Monro (20-20A). Calcified SENs may be seen along the lateral ventricle margins, especially the caudothalamic grooves. Hydrocephalus is present in 15% of cases. “Blurred” lateral ventricle margins indicate severe obstructive hydrocephalus with transependymal CSF migration.

SEGAs demonstrate strong but heterogeneous enhancement. An enhancing lesion at the foramen of Monro on CECT scan should be considered SEGA until proven otherwise.

MR Findings

SEGAs are hypo- to isointense compared with cortex on T1WI and heterogeneously iso- to hyperintense on T2WI. Larger SEGAs may have prominent “flow voids.” Strong but heterogeneous enhancement is typical.

FLAIR is especially useful for detecting subtle CNS features of TSC, such as SENs, cortical tubers, and white matter radial migration lines. Streaky linear hyperintensities extending through the white matter to the subjacent ventricle or wedge-shaped hyperintensities underlying expanded (“clubbed”) gyri are typical (20-20B).

SEN enhancement is much more visible on MR than on CT. Between 30-80% of SENs enhance following contrast administration (20-20C), so enhancement alone is insufficient to distinguish a SEN from a SEGA. Although a mass at the foramen of Monro > 10-12 mm in diameter is usually a SEGA (20-23), only progressive enlargement is sufficient to differentiate a SEGA from a SEN.

Differential Diagnosis

The major differential diagnosis of SEGA in a patient with TSC is a benign nonneoplastic SEN. SENs remain stable and do not need to be treated, whereas SEGAs gradually enlarge and eventually require surgical treatment. SEGAs arise only near the foramen of Monro, whereas SENs can be located anywhere around the ventricular wall, especially along the caudothalamic groove. Although SENs are much more common than SEGAs, a partially calcified, enhancing lesion at the foramen of Monro > 5 mm is more likely to be a SEGA than an SEN.

Other lateral ventricle masses that should be included in the differential diagnosis are subependymoma (a tumor of middle-aged and older adult patients) and central neurocytoma (a “bubbly” tumor that arises in the lateral ventricle body). Low-grade diffusely infiltrating astrocytoma can arise in the septi pellucidi or fornices, but these tumors typically neither calcify nor enhance.

SUBEPENDYMAL GIANT CELL ASTROCYTOMA

Etiology, Genetics

• 5-15% of patients with TSC develop SEGA

• Almost all SEGAs are associated with TSC

 Biallelic inactivation of TSC1 or TSC2 genes

 Loss of hamartin or tuberin immunoexpression

 Activation of mTOR pathway

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