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Pilocytic Astrocytoma
Definition and Characteristics: Pilocytic astrocytoma is an astrocytic neoplasm characterized by varying proportions of bipolar hair-like (pilocytic) cells, compact and loose or myxoid regions, Rosenthal fibers, and eosinophilic granular bodies. It is most commonly associated with MAPK pathway gene alterations, particularly KIAA1549::BRAF gene fusions, and is classified as CNS WHO grade 1. Subtypes include pilomyxoid astrocytoma and pilocytic astrocytoma with histological features of anaplasia.
Locations: Pilocytic astrocytomas can develop anywhere along the neuraxis, but they most commonly occur in the cerebellum, especially in children. Other common locations include the optic nerve, midline regions such as the brainstem, optic chiasm/hypothalamus, and basal ganglia, as well as the spinal cord. In children, these tumors are rare in the cerebral hemispheres, whereas in adults, they occur with similar frequency in the cerebral hemispheres and the cerebellum.
Signs and Symptoms: The presenting signs and symptoms of pilocytic astrocytomas are typically due to mass effect or ventricular obstruction, including macrocephaly, headache, endocrinopathy, and signs of increased intracranial pressure. The slow growth of these tumors can sometimes delay diagnosis because symptoms may be subtle.
Focal neurological signs depend on the tumor location:
- Optic pathway tumors often lead to visual loss.
- Brainstem tumors usually cause hydrocephalus or signs of brainstem dysfunction.
- Thalamic and other supratentorial tumors often present with focal motor deficits or movement disorders.
- Spinal cord lesions are associated with back pain, paresis, and kyphoscoliosis.
- Hypothalamic/pituitary tumors can cause dysfunctions such as obesity and diabetes insipidus. Large hypothalamic tumors in infants may lead to emaciation and failure to thrive (diencephalic syndrome), often resulting in poor clinical outcomes.
Primary dissemination at diagnosis may be more common in infants, but neuraxis seeding does not necessarily indicate aggressive growth. Seeding may be asymptomatic, and long-term survival is possible even without adjuvant treatment.
Imaging Features: Pilocytic astrocytomas exhibit a wide range of imaging features. Approximately two-thirds of these tumors appear as well-circumscribed cystic lesions with an enhancing mural nodule on MRI. The remainder often presents either as a cyst-like mass with a central non-enhancing zone or as a predominantly solid mass. The enhancement of the cyst wall is variable and does not necessarily indicate tumor involvement. Calcification may also be present.
Pilocytic astrocytomas are often contrast-enhancing, with the solid tumor component typically appearing isointense to hypointense on T1-weighted imaging and hyperintense on T2-weighted imaging. These imaging characteristics are often not specific enough to allow a definitive diagnosis without a biopsy.
Imaging Characteristics of Optic Nerve Tumors: Neurofibromatosis type 1 (NF1)-associated tumors: Rarely extend beyond the optic pathway and often appear solid. Non-NF1 tumors: May involve the optic chiasm, extend beyond the optic pathway, and frequently appear cystic.
Incidence and Demographics: Pilocytic astrocytoma accounts for 5% of all primary brain tumors. It is most common during the first two decades of life, with an average annual age-adjusted incidence rate of 0.91 cases per 100,000 population. It represents 17.6% of all childhood primary brain tumors and is the most common glioma in children. The incidence rate is highest in young children and decreases with age. Pilocytic astrocytoma is rare in older adults.
Genetic Mutations: Although most cases are sporadic, pilocytic astrocytomas are also the principal CNS tumor type in a group of neurodevelopmental diseases associated with germline mutations in MAPK pathway genes. These diseases include neurofibromatosis type 1 (NF1), Noonan syndrome, and encephalocraniocutaneous lipomatosis. NF1 is caused by NF1 germline mutations, Noonan syndrome is most frequently caused by mutations in PTPN11 or RAF1, and encephalocraniocutaneous lipomatosis is associated with FGFR1 germline mutations.
Pilocytic astrocytomas are linked to genetic mutations in genes that code for components of the MAPK pathway. The most common mutation, present in about 60% of cases, is a duplication or rearrangement of a roughly 2 Mb segment at 7q34, which includes the BRAF gene. This leads to gene fusions involving different combinations of KIAA1549 and BRAF exons, making it challenging to identify all potential fusions through RT-PCR.
Nearly all pilocytic astrocytomas analyzed genomically exhibit genetic alterations affecting the MAPK pathway. These alterations include NF1 mutations, primarily germline in patients with NF1; hotspot BRAF p.V600E mutations; BRAF fusions with partners other than KIAA1549; BRAF insertions; KRAS mutations; FGFR1 mutations or fusions; infrequent NTRK family receptor tyrosine kinase fusions; and RAF1 gene fusions, typically with SRGAP3 but occasionally with other partners. NTRK genes fuse with various 5′ partners containing a dimerization domain, which is believed to cause constitutive dimerization of the NTRK fusion proteins and activation of the kinase.
The FGFR1 alterations observed in pilocytic astrocytomas are similar to those found in other pediatric low-grade glial and glioneuronal tumors. These include hotspot point mutations (p.N546K and p.K656E), FGFR1::TACC1 fusions, and an internal tandem duplication of the FGFR1 kinase domain. Polysomies, particularly involving chromosomes 5, 6, 7, 11, and 15, are reported to be more frequent in tumors occurring in teenagers and adults.
The incidence of the various gene alterations varies with anatomical location, and distinct anatomical subsets of tumors may be distinguished based on gene expression and DNA methylation profiles. The KIAA1549::BRAF fusion is common in cerebellar tumors, but less common supratentorially. FGFR1 alterations are widely distributed, whereas BRAF p.V600E mutations are more common in supratentorial tumors. Infratentorial and supratentorial tumors may also be distinguishable based on their gene expression or DNA methylation signatures. The average mutation burden is low.
Histological Features: Most pilocytic astrocytomas are soft, grey, and relatively well-defined. Intratumoral or peritumoral cyst formation, including mural tumor nodules, is common. Chronic lesions may become calcified. Spinal tumors are often associated with syrinx formation, and optic nerve tumors frequently infiltrate the optic sheath circumferentially.
Pilocytic astrocytomas typically exhibit low to moderate cellularity. The neoplastic cells display a wide range of morphologies, including various proportions of piloid and oligodendrocyte-like cells. The nuclei are generally round to elongated, and multinucleated cells with horseshoe-shaped nuclear clusters (pennies-on-a-plate pattern) are frequently observed. While some cases show hyperchromasia and pleomorphism, mitotic figures are rare. However, in rare instances, brisk mitotic activity can be observed, suggesting aggressive behavior. Rosenthal fibers and eosinophilic granular bodies are commonly present but vary in prominence. A myxoid background with microcystic changes is typical, along with degenerative changes such as calcifications, hyalinized vessels, and hemorrhages.
Histological Patterns: Pilocytic astrocytomas can exhibit various histological patterns:
- A biphasic pattern, characterized by alternating compact areas rich in bipolar cells and Rosenthal fibers, and loose, microcystic regions abundant in oligodendrocyte-like cells.
- A predominantly compact, piloid pattern with numerous Rosenthal fibers.
- A more dispersed pattern, rich in oligodendrocyte-like cells, mimicking oligodendroglioma.
The biphasic pattern is commonly found in cerebellar tumors. The compact pattern is often seen in adults, while the oligodendrocyte-like pattern may be associated with FGFR1 alterations. Occasionally, typical pilocytic astrocytomas contain foci resembling pilomyxoid astrocytoma, known as intermediate tumors. Rare cases demonstrate a regimented palisaded (spongioblastoma) pattern.
Pilocytic astrocytomas also show highly vascular areas with thin glomerular capillaries, often arranged linearly and associated with cystic structures, or with thick-walled, hyalinized vessels and regressive changes. Glomeruloid microvascular proliferations line the cyst wall but should not prompt a higher-grade designation. Infarct-like necrosis can occur, though palisading necrosis is rare. Leptomeningeal involvement can happen at any location, sometimes with extensive desmoplastic reaction. Some tumors may mimic diffuse astrocytomas histopathologically due to significant infiltration, despite often appearing solid radiologically. Entrapped neurons can be mistaken for a neuronal component, such as in ganglioglioma.
Immunohistochemistry: Immunohistochemistry for pilocytic astrocytomas reveals strong, diffuse positivity for GFAP, S100, and OLIG2. Many cases also show positivity for synaptophysin but are negative for NFP, NeuN, and chromogranin. CD34 is generally negative, although expression has been reported in tumors located in the hypothalamic/chiasmatic region. IDH1 p.R132H expression is absent, and the H3 p.K28M (K27M) stain is negative, with rare exceptions. Most tumors exhibit strong and diffuse staining for SOX10 and p16, with SOX10 and OLIG2 positivity aiding in the differentiation of pilocytic astrocytoma from ependymoma. The Ki-67 index is typically low, with only focal areas of increased activity.
Pilomyxoid Astrocytoma: Pilomyxoid astrocytoma shares many characteristics with classic pilocytic astrocytoma but has distinct clinicopathological differences. Pilomyxoid astrocytoma typically presents in infancy within the hypothalamic/chiasmatic region. Compared to pilocytic astrocytoma, pilomyxoid astrocytoma has a higher recurrence rate, poorer prognosis, and a tendency for cerebrospinal spread. It is characterized by monomorphic piloid cells, a myxoid background, and increased cellularity, lacking Rosenthal fibers and eosinophilic granular bodies. Neuroimaging shows pilomyxoid astrocytomas as solid and uniformly enhancing lesions, similar to PAs. Some pilomyxoid astrocytomas may transform into classic pilocytic astrocytomas upon recurrence, and rare hybrid pilomyxoid astrocytoma/pilocytic astrocytomas tumors have been observed, though their biological behavior is not well understood. Molecular studies reveal MAPK pathway gene alterations similar to those in PA, but distinct differences exist, necessitating further research to clarify the pilomyxoid astrocytomas molecular profile.
Prognosis and Anaplastic Features: Pilocytic astrocytomas maintain their CNS WHO grade 1 status over decades. Terms like “anaplastic pilocytic astrocytoma” and “pilocytic astrocytoma with histological anaplasia” are used for pilocytic astrocytomas with significant mitotic activity and sometimes necrosis. These anaplastic features may be present at diagnosis or recurrence. In a study of 36 histologically defined anaplastic PAs, these tumors mostly appeared in adults (mean age: 32 years; range: 3–75 years), primarily affecting the posterior fossa. They displayed diverse genetic features, including BRAF duplications (30%), NF1 mutations (33%), loss of nuclear ATRX expression (57%), and alternative lengthening of telomeres (69%). Factors linked to worse overall survival included necrosis, subtotal resection, alternative lengthening of telomeres, and ATRX loss (P < 0.05). The overlap between histologically anaplastic pilocytic astrocytomas and rare midline pilocytic astrocytomas with double mutant FGFR1, BRAF, or NF1 and H3 p.K28M (K27M) mutations remains to be fully understood, though both exhibit aggressive behavior.
In a cohort of predominantly adult patients across more than 20 institutions worldwide, 81% of tumors histologically identified as anaplastic pilocytic astrocytomas showed a unique methylome signature, now classified as “high-grade astrocytoma with piloid features.” This methylation profile was also found in 36% of histologically defined cerebellar glioblastomas. Although this methylation class aligns with neoplasms diagnosed as anaplastic PAs, the categories do not completely overlap, and their relationship requires further investigation.
Histological and molecular diagnostic criteria established for pilocytic astrocytoma with anaplasia in adults may not apply to children. In one study of 31 pediatric patients (aged < 16 years), on multivariate analysis, only young age (< 6 years) and partial resection were associated with decreased progression-free survival. Necrosis and high mitotic activity were not significantly associated with survival. Nuclear ATRX expression was preserved in all tumors, and only one tumor matched the methylation class of high-grade astrocytoma with piloid features, with an additional case showing homozygous deletion of CDKN2A and/or CDKN2B.
Differential Diagnosis: A relevant differential diagnosis in the presence of microvascular proliferation and/or necrosis is a high-grade astrocytic glioma, including glioblastoma. Solid growth patterns, low mitotic activity, and bipolar cells, in addition to molecular features, help resolve this differential diagnosis. Rosenthal fiber–rich piloid gliosis may also mimic pilocytic astrocytoma, but it lacks the loose component. In the midline, an H3 K27–altered diffuse midline glioma must be excluded, although rare pilocytic astrocytomas acquire an H3 p.K28M (K27M) mutation in addition to their MAPK gene alteration. Other differential diagnoses include ganglioglioma, dysembryoplastic neuroepithelial tumor, pleomorphic xanthoastrocytoma, rosette-forming glioneuronal tumor, ependymoma (especially tanycytic), and diffuse leptomeningeal glioneuronal tumor. Some tumors of this last type may be virtually indistinguishable from pilocytic astrocytoma on routine histology.
A note of caution is warranted concerning anaplastic transformation after radiation therapy, especially with a long interval and without the presence of a pilocytic component: some of these tumors may instead be a second primary, i.e., radiation-induced high-grade glioma.
Intraoperative Smears: Intraoperative smears of pilocytic astrocytoma typically feature cells with long, fine, hair-like processes. These cells generally have uniform, round to spindled nuclei with minimal atypia. Rosenthal fibers, eosinophilic granular bodies, and glomeruloid vessels can also be present.
Genetic Alterations: The most common genetic alteration in pilocytic astrocytoma is a rearrangement of chromosome 7q34, leading to a KIAA1549::BRAF tandem duplication and fusion. In a small number of cases, other BRAF fusions have been identified, resulting from various genetic rearrangements (such as deletions and translocations). These rearrangements consistently cause the loss of the N-terminal regulatory region of the BRAF protein while retaining the kinase domain. Alterations in other genes of the MAPK pathway also occur.
The presence of the KIAA1549::BRAF fusion (or other MAPK gene alterations) supports the diagnosis of pilocytic astrocytoma in the appropriate morphological context. However, the KIAA1549::BRAF fusion is also found in diffuse leptomeningeal glioneuronal tumors, and other MAPK gene alterations similarly overlap with other tumor types.
Staging and Prognosis: For infratentorial and spinal tumors, staging of pilocytic astrocytoma includes both cerebral and spinal MRI. In the case of supratentorial tumors, spinal MRI is conducted only when there is evidence of intracranial dissemination. Cerebrospinal fluid cytology is performed solely if radiological findings suggest disseminated disease.
In most large studies, pilocytic astrocytomas show favorable overall survival rates even after multiple recurrences. Complete resection of these tumors results in rare cases of recurrence. Due to their generally positive outcomes, radiation-sparing treatments are often recommended. Since most tumors exhibit alterations in MAPK pathway genes, they may respond well to targeted MEK inhibitors. The long-term outcomes of these approaches are still being studied. For tumors that behave aggressively and resist chemotherapy, a biopsy may be needed for molecular characterization. It is important to note that pilomyxoid astrocytomas tend to act more aggressively. The prognostic significance of histological anaplasia in pilocytic astrocytomas still needs to be established.
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