Belge.docx

AAA - Definition - ICD-O coding - ICD-11 coding - Related terminology - Subtype(s) - Localization - Clinical features - Epidemiology - Etiology - Pathogenesis - Macroscopic appearance - Histopathology - Cytology - Diagnostic molecular pathology - Essentia...

AAA - Definition - ICD-O coding - ICD-11 coding - Related terminology - Subtype(s) - Localization - Clinical features - Epidemiology - Etiology - Pathogenesis - Macroscopic appearance - Histopathology - Cytology - Diagnostic molecular pathology - Essential and desirable diagnostic criteria - Staging - Prognosis and prediction #### **Add Personal Note** Send us Feedback **Authors** **[Responsible Editor]** - **[Co-editor(s)]** - **[Responsible author(s)]** - **[Co-author(s)]** - - - - - - - - - - #### Pilocytic astrocytoma  **Definition  ** Pilocytic astrocytoma is an astrocytic neoplasm with variable proportions of bipolar hair-like (pilocytic) cells, compact and loose or myxoid regions, Rosenthal fibres, and eosinophilic granular bodies. Pilocytic astrocytoma is associated with MAPK pathway gene alterations (most often *KIAA1549*::*BRAF* gene fusions) (CNS WHO grade 1). **ICD-O coding  ** 9421/1 Pilocytic astrocytoma **ICD-11 coding  ** 2A00.0Y & XH29Q5 Other specified gliomas of brain & Pilomyxoid astrocytoma **Related terminology  ** *Not recommended (obsolete):* juvenile pilocytic astrocytoma. **Subtype(s)  ** Pilomyxoid astrocytoma; pilocytic astrocytoma with histological features of anaplasia **Localization  ** Pilocytic astrocytomas can arise throughout the neuraxis, but they are most common in the cerebellum, especially in children {[[ 32424575 ]](https://www.ncbi.nlm.nih.gov/pubmed/32424575); [[25792358 ]](https://www.ncbi.nlm.nih.gov/pubmed/25792358)}. Other preferred sites are the optic nerve, midline locations (brainstem, optic chiasm / hypothalamus, basal ganglia), and spinal cord. Tumours in the cerebral hemispheres are rare in children, but in adults they occur here with equal frequency as in the cerebellum {[[ 25792358 ]](https://www.ncbi.nlm.nih.gov/pubmed/25792358)}. **Clinical features  ** Presenting signs and symptoms, which are usually due to mass effect or ventricular obstruction, include macrocephaly, headache, endocrinopathy, and evidence of increased intracranial pressure. The slow growth sometimes leads to diagnostic delay because symptoms are subtle. Focal neurological signs relate to tumour location. Optic pathway tumours often produce visual loss {[[ 5386369 ]](https://www.ncbi.nlm.nih.gov/pubmed/5386369); [[8021787 ]](https://www.ncbi.nlm.nih.gov/pubmed/8021787)}. Brainstem pilocytic astrocytomas most often cause hydrocephalus or signs of brainstem dysfunction. Patients with thalamic and other supratentorial tumours present with focal motor deficiencies or movement disorders, whereas spinal cord lesions are associated with back pain, paresis, and kyphoscoliosis. Hypothalamic/pituitary dysfunction, including obesity and diabetes insipidus, is often apparent in patients with large hypothalamic tumours {[[ 2308672 ]](https://www.ncbi.nlm.nih.gov/pubmed/2308672)}. Especially in infants, midline tumours can be associated with emaciation and failure to thrive (diencephalic syndrome), with a poor clinical outcome {[[ 24039013 ]](https://www.ncbi.nlm.nih.gov/pubmed/24039013); [[9210720 ]](https://www.ncbi.nlm.nih.gov/pubmed/9210720)}. Primary dissemination at diagnosis may also be more common in this age group {[[ 24039013 ]](https://www.ncbi.nlm.nih.gov/pubmed/24039013); [[9210720 ]](https://www.ncbi.nlm.nih.gov/pubmed/9210720)}. However, neuraxis seeding does not necessarily indicate aggressive growth {[[ 8194029 ]](https://www.ncbi.nlm.nih.gov/pubmed/8194029)}. Seeding may be asymptomatic, and long-term survival is possible, even without adjuvant treatment {[[ 8194029 ]](https://www.ncbi.nlm.nih.gov/pubmed/8194029)}. ##### **Imaging** Pilocytic astrocytomas have a wide spectrum of imaging features, but about two thirds appear as a well-circumscribed cystic lesion with an enhancing mural nodule on MRI. The remainder often appear either as a cyst-like mass with a central non-enhancing zone or as a predominantly solid mass {[[ 7630212 ]](https://www.ncbi.nlm.nih.gov/pubmed/7630212); [[9950497 ]](https://www.ncbi.nlm.nih.gov/pubmed/9950497)}. The cyst wall enhancement is variable, and enhancement does not necessarily indicate tumour involvement. Calcification may be present. Pilocytic astrocytomas are often contrast enhancing, with the solid tumour component typically isointense to hypointense on T1 imaging and hyperintense on T2. Imaging characteristics are often not specific enough to allow a diagnosis without biopsy. Imaging characteristics of optic nerve tumours vary, with neurofibromatosis type 1 (NF1)-associated tumours rarely extending beyond the optic pathway and often appearing solid, and non-NF1 counterparts involving the optic chiasm, extending beyond the optic pathway, and frequently being cystic {[[ 11733333 ]](https://www.ncbi.nlm.nih.gov/pubmed/11733333)}. **Epidemiology  ** Pilocytic astrocytoma accounts for 5% of all primary brain tumours {[[ 31675094 ]](https://www.ncbi.nlm.nih.gov/pubmed/31675094)}. 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 {[[ 31675094 ]](https://www.ncbi.nlm.nih.gov/pubmed/31675094)}. Pilocytic astrocytoma accounts for 17.6% of all childhood primary brain tumours and is the most common glioma in children. The incidence rate is highest in young children and decreases with advancing age {[[ 31675094 ]](https://www.ncbi.nlm.nih.gov/pubmed/31675094)}. Pilocytic astrocytoma is rare in older adults {[[ 31675094 ]](https://www.ncbi.nlm.nih.gov/pubmed/31675094)}. **Etiology  ** Although most cases are sporadic {[[ 21989351 ]](https://www.ncbi.nlm.nih.gov/pubmed/21989351)}, pilocytic astrocytomas are also the principal CNS tumour type in a group of neurodevelopmental diseases with germline mutations in MAPK pathway genes, including NF1, Noonan syndrome, and encephalocraniocutaneous lipomatosis. NF1 (see [section ]*Neurofibromatosis type 1*) is caused by *NF1* germline mutations, whereas Noonan syndrome is most frequently caused by mutations in *PTPN11* or *RAF1* {[[ 19621452 ]](https://www.ncbi.nlm.nih.gov/pubmed/19621452)}, and encephalocraniocutaneous lipomatosis by *FGFR1* germline mutations {[[ 26942290 ]](https://www.ncbi.nlm.nih.gov/pubmed/26942290); [[30143858 ]](https://www.ncbi.nlm.nih.gov/pubmed/30143858)}. **Pathogenesis  ** Pilocytic astrocytomas are associated with genetic abnormalities in genes encoding members of the MAPK pathway. The most frequent abnormality (found in \~60% of all cases) is a duplication/rearrangement of approximately 2 Mb at 7q34, encompassing the *BRAF* gene {[[ 18716556 ]](https://www.ncbi.nlm.nih.gov/pubmed/18716556); [[21745356 ]](https://www.ncbi.nlm.nih.gov/pubmed/21745356); [[18398503 ]](https://www.ncbi.nlm.nih.gov/pubmed/18398503); [[32289278 ]](https://www.ncbi.nlm.nih.gov/pubmed/32289278)} and resulting in gene fusions involving various combinations of *KIAA1549* and *BRAF* exons, which makes it difficult to comprehensively detect all possible fusions by RT-PCR. Essentially all pilocytic astrocytomas studied genomically had a genetic alteration affecting the MAPK pathway {[[ 23817572 ]](https://www.ncbi.nlm.nih.gov/pubmed/23817572); [[23583981 ]](https://www.ncbi.nlm.nih.gov/pubmed/23583981); [[30575814 ]](https://www.ncbi.nlm.nih.gov/pubmed/30575814)}. These alterations include *NF1* mutations, which are mostly germline mutations in patients with NF1 {[[ 23222849 ]](https://www.ncbi.nlm.nih.gov/pubmed/23222849)}; hotspot *BRAF* p.V600E mutations; *BRAF* fusions with partners other than *KIAA1549*; *BRAF* insertions; *KRAS* mutations; *FGFR1* mutations or fusions; very occasional NTRK family receptor tyrosine kinase fusions; and *RAF1* gene fusions, usually with *SRGAP3* but exceptionally with other partners {[[ 27810072 ]](https://www.ncbi.nlm.nih.gov/pubmed/27810072); [[32082673 ]](https://www.ncbi.nlm.nih.gov/pubmed/32082673)}. NTRK genes fuse with several different 5′ partners that contain a dimerization domain. This is presumed to lead to constitutive dimerization of the NTRK fusion proteins and activation of the kinase {[[ 23817572 ]](https://www.ncbi.nlm.nih.gov/pubmed/23817572); [[23583981 ]](https://www.ncbi.nlm.nih.gov/pubmed/23583981)}. The *FGFR1* alterations seen in pilocytic astrocytomas overlap with those seen in other paediatric low-grade glial and glioneuronal tumours. They include hotspot point mutations (p.N546K and p.K656E) {[[ 31673897 ]](https://www.ncbi.nlm.nih.gov/pubmed/31673897)}, *FGFR1*::*TACC1* fusions, and an internal tandem duplication of the kinase domain of *FGFR1* {[[ 23817572 ]](https://www.ncbi.nlm.nih.gov/pubmed/23817572)}. The incidence of MAPK pathway gene alterations identified to date is summarized in [[\#17012]](https://tumourclassification.iarc.who.int/attachment/45/19/17012)Table 2.03. Polysomies (in particular of chromosomes 5, 6, 7, 11, and 15) are reportedly more common in tumours of teenagers and adults {[[ 17086101 ]](https://www.ncbi.nlm.nih.gov/pubmed/17086101)}. The incidence of the various gene alterations varies with anatomical location {[[ 23817572 ]](https://www.ncbi.nlm.nih.gov/pubmed/23817572); [[23583981 ]](https://www.ncbi.nlm.nih.gov/pubmed/23583981)}, and distinct anatomical subsets of tumours may be distinguished on the basis of gene expression and DNA methylation profiles {[[ 23660940 ]](https://www.ncbi.nlm.nih.gov/pubmed/23660940); [[17283119 ]](https://www.ncbi.nlm.nih.gov/pubmed/17283119); [[19336457 ]](https://www.ncbi.nlm.nih.gov/pubmed/19336457); [[29539639 ]](https://www.ncbi.nlm.nih.gov/pubmed/29539639)}. The *KIAA1549*::*BRAF* fusion is common in cerebellar tumours, but less common supratentorially. *FGFR1* alterations are widely distributed, whereas *BRAF* p.V600E mutations are more common in supratentorial tumours. Infratentorial and supratentorial tumours may also be distinguishable on the basis of their gene expression or DNA methylation signatures {[[ 23660940 ]](https://www.ncbi.nlm.nih.gov/pubmed/23660940); [[17283119 ]](https://www.ncbi.nlm.nih.gov/pubmed/17283119); [[19336457 ]](https://www.ncbi.nlm.nih.gov/pubmed/19336457)}. The average mutation burden is low. **Macroscopic appearance  ** Most pilocytic astrocytomas are soft, grey, and relatively discrete. Intratumoural or paratumoural cyst formation, including mural tumour nodules, is common. Chronic lesions may be calcified. Spinal tumours may be associated with syrinx formation {[[ 7674006 ]](https://www.ncbi.nlm.nih.gov/pubmed/7674006)}. Optic nerve tumours often circumferentially infiltrate the optic sheath {[[ 7066671 ]](https://www.ncbi.nlm.nih.gov/pubmed/7066671)}. **Histopathology  ** Pilocytic astrocytomas have low to moderate cellularity. Neoplastic cells range widely in their morphology and include varying proportions of piloid and oligodendrocyte-like cells. Nuclei are round to elongate. Multinucleated cells with horseshoe-shaped nuclear clusters (pennies-on-a-plate pattern) are often seen. In some cases, hyperchromasia and pleomorphism are obvious but mitotic figures are rare {[[ 10068313 ]](https://www.ncbi.nlm.nih.gov/pubmed/10068313)}. Rare cases have brisk mitotic activity, which may imply aggressive behaviour {[[ 20061938 ]](https://www.ncbi.nlm.nih.gov/pubmed/20061938)}. Rosenthal fibres and eosinophilic granular bodies are common, but they vary in prominence. Myxoid background with microcystic change is common, as are degenerative changes, including calcifications, hyalinized vessels, and haemorrhages {[[ 25792358 ]](https://www.ncbi.nlm.nih.gov/pubmed/25792358)}. Various histological patterns can be seen in pilocytic astrocytomas: (1) a biphasic pattern, in which compact areas rich in bipolar cells and Rosenthal fibres alternate with loose and microcystic regions rich in oligodendrocyte-like cells; (2) a predominantly compact, piloid pattern, with abundant Rosenthal fibres; and (3) a more dispersed pattern, rich in oligodendrocyte-like cells, mimicking oligodendroglioma. The biphasic pattern is common in cerebellar tumours. The compact pattern is often seen in adults, and the oligodendrocyte-like pattern may be associated with *FGFR1* alterations {[[ 32289278 ]](https://www.ncbi.nlm.nih.gov/pubmed/32289278)}. Occasionally, typical pilocytic astrocytomas have foci that resemble pilomyxoid astrocytoma; these are called intermediate tumours. Rare examples also demonstrate the regimented palisaded (spongioblastoma) pattern. Pilocytic astrocytomas show highly vascular areas with thin glomerular capillaries often arranged in a linear fashion and associated with cystic structures, or they have thick-walled, hyalinized vessels and regressive changes. Glomeruloid microvascular proliferations line the cyst wall and should not prompt a higher grade designation. Infarct-like necrosis can occur, but palisading necrosis is exceptional. Leptomeningeal involvement can occur in any location, sometimes with extensive desmoplastic reaction. Some tumours may mimic diffuse astrocytomas on histopathology because of a surprising degree of infiltration, despite often appearing solid radiologically. Entrapped neurons can also be mistaken for a neuronal component (e.g. ganglioglioma). ##### **Immunophenotype** Immunohistochemistry demonstrates strong diffuse positivity for GFAP, S100, and OLIG2. Many cases are positive for synaptophysin but negative for NFP, NeuN, and chromogranin. CD34 is usually negative, although expression has been reported in the hypothalamic/chiasmatic region {[[ 23442159 ]](https://www.ncbi.nlm.nih.gov/pubmed/23442159)}. IDH1 p.R132H expression is absent and the H3 p.K28M (K27M) stain is negative, with rare exceptions. Most tumours show strong and diffuse SOX10 and p16 staining, with SOX10 and OLIG2 positivity helping to distinguish pilocytic astrocytoma from ependymoma {[[ 26945037 ]](https://www.ncbi.nlm.nih.gov/pubmed/26945037)}. The Ki-67 index is usually low, with only focal increases. ##### **Subtypes** ###### **Pilomyxoid astrocytoma** Pilomyxoid astrocytoma {[[ 10515229 ]](https://www.ncbi.nlm.nih.gov/pubmed/10515229)} shares many features with classic pilocytic astrocytoma but differs in some important clinicopathological respects {[[ 14683543 ]](https://www.ncbi.nlm.nih.gov/pubmed/14683543); [[12943571 ]](https://www.ncbi.nlm.nih.gov/pubmed/12943571)}. It is a tumour of infancy occurring in the hypothalamic/chiasmatic region, has a higher rate of recurrence and a poorer outcome than classic pilocytic astrocytoma, and shows a propensity for cerebrospinal dissemination {[[ 14683543 ]](https://www.ncbi.nlm.nih.gov/pubmed/14683543); [[18622384 ]](https://www.ncbi.nlm.nih.gov/pubmed/18622384)}. Pilomyxoid astrocytoma is defined as a tumour with monomorphic piloid cytology, a diffusely myxoid background, and increased cellularity compared with that of classic pilocytic astrocytoma {[[ 10515229 ]](https://www.ncbi.nlm.nih.gov/pubmed/10515229)}. It also has a prominent angiocentric arrangement of tumour cells and typically lacks Rosenthal fibres and eosinophilic granular bodies. On neuroimaging, pilomyxoid astrocytomas appear similar to classic pilocytic astrocytomas, but they are more often solid and uniformly enhancing {[[ 25666233 ]](https://www.ncbi.nlm.nih.gov/pubmed/25666233); [[25666232 ]](https://www.ncbi.nlm.nih.gov/pubmed/25666232)}. Some pilomyxoid astrocytomas develop into a classic pilocytic astrocytoma on recurrence. Rare hybrid pilomyxoid/pilocytic astrocytomas have been reported, but their biological behaviour is poorly defined {[[ 21107083 ]](https://www.ncbi.nlm.nih.gov/pubmed/21107083)}. Molecular studies identify MAPK pathway gene alterations similar to those in classic pilocytic astrocytoma, but differences have been reported {[[ 18622384 ]](https://www.ncbi.nlm.nih.gov/pubmed/18622384); [[25521223 ]](https://www.ncbi.nlm.nih.gov/pubmed/25521223); [[30945015 ]](https://www.ncbi.nlm.nih.gov/pubmed/30945015)}. Further studies are needed to elucidate the precise molecular profile of pilomyxoid astrocytomas {[[ 29539639 ]](https://www.ncbi.nlm.nih.gov/pubmed/29539639)}. ###### **Pilocytic astrocytoma with histological features of anaplasia** Pilocytic astrocytomas are remarkable in that they maintain their CNS WHO grade 1 {[[ 12816259 ]](https://www.ncbi.nlm.nih.gov/pubmed/12816259)} status over decades. The terms "anaplastic pilocytic astrocytoma" and "pilocytic astrocytoma with histological anaplasia" have been proposed for tumours with morphological features of pilocytic astrocytoma but showing brisk mitotic activity with or without necrosis {[[ 20061938 ]](https://www.ncbi.nlm.nih.gov/pubmed/20061938)}. Anaplastic changes may be present at initial diagnosis or at recurrence. In a study of 36 pilocytic astrocytomas with anaplasia defined histologically, they predominantly occurred in adults (mean age: 32 years; range: 3--75 years), mostly involved the posterior fossa, and showed heterogeneous genetic features with alterations typical of pilocytic astrocytoma and other gliomas {[[ 30192422 ]](https://www.ncbi.nlm.nih.gov/pubmed/30192422)}, including *BRAF* duplications (30%), germline or somatic *NF1* mutations (33%), loss of nuclear ATRX expression (57%), and an alternative-lengthening-of-telomeres phenotype (69%). Features associated with worse overall survival included necrosis, subtotal resection, alternative lengthening of telomeres, and ATRX loss (*P* \ 20 institutions worldwide, who were considered to have histologically defined anaplastic pilocytic astrocytoma, 81% of the tumours harboured a distinct methylome signature, referred to as "DNA methylation class anaplastic astrocytoma with piloid features" {[[ 29564591 ]](https://www.ncbi.nlm.nih.gov/pubmed/29564591)}. These tumours are now considered a distinct type, designated as "high-grade astrocytoma with piloid features". A similar DNA methylation profile was found in 36% of histologically defined cerebellar glioblastomas {[[ 31661039 ]](https://www.ncbi.nlm.nih.gov/pubmed/31661039)}. Although this methylation class is enriched for neoplasms pathologically diagnosed as pilocytic astrocytoma with histological anaplasia, the two categories do not overlap completely and their relationship remains to be elucidated. Histological and molecular diagnostic criteria established for pilocytic astrocytoma with anaplasia in adults may not be applicable to children. In one study of 31 paediatric patients (aged \