Pilocytic astrocytoma pa is the most frequent pediatric brain tumor. Pilocytic astrocytoma pa is the most common tumor of the pediatric central nervous system cns. More developments in being familiar with the biology of pilocytic astrocytoma, particularly in further elucidating the precise roles and downstream effects of mapk pathway activation, even have the probable to enormously boost analysis and prognostication of pas, and likewise to provide additional targets for novel therapeutic strategies. In the majority of cases, oncogenic braf fusions or braf v600e mutations are observed, while raf1 or nf1 alterations are more rarely found. Similar to pilocytic astrocytoma but no rosenthal fibers brain tumor pathol 2019. A new gtf2ibraf fusion mediating mapk pathway activation. Pilocytic astrocytomas of the optic nerve and their relation to pilocytic. Genetic aberrations leading to mapk pathway activation. Pdf mapk pathway activation in pilocytic astrocytoma.
Recent studies have identified alterations in the braf serinethreonine kinase gene as the likely causative mutation in these childhood brain tumors. Under nonpathological conditions, mapkerk signaling components are expressed in most regions of the brain, and show a largely overlapping expression pattern with the exception of mek2, which is almost completely absent. Rosenthal fibers were present in 15 79% of cases, 6 of which 40% also. Pilocytic astrocytoma pa was initially described as spongioblastoma by bailey and cushing 1 in 1926 as a group of tumors that occur in the cerebellar region in children and show a longterm postoperative survival. A recurrent feature of pa is deregulation of the mitogen activated protein kinase mapk pathway most often through kiaa1549braf fusion, but also by other braf or raf1gene fusions and point mutations e. One of the upstream activators of the mapk pathway is the oncogene braf, and many studies have documented braf alterations in pilocytic astrocytoma. Mapk pathway activation in pilocytic astrocytoma mapk pathway activation in pilocytic astrocytoma. Frequent gains at chromosome 7q34 involving braf in pilocytic astrocytoma. Mapk pathway activation in pilocytic astrocytoma ncbi nih. Most common alteration is the braf duplication fusion resulting in. A novel git2braf fusion in pilocytic astrocytoma diagnostic.
The word pilocytic hair cell refers to the fiberlike appearance of the tumor cells and their fibrillary stroma, but large parts of these tumors, especially in the loose areas, do not fit this description. Pilocytic astrocytoma pa is the most common pediatric brain tumor. Fusions of braf with other partner genes, as well as other genetic alterations not involving braf but also leading to mapk pathway activation have been described rarely. Several mechanisms lead to activation of this pathway in. Genetic alterations resulting in constitutive activation of braf, a key tyrosine kinase in the mitogenactivated protein kinase mapk pathway, are the defining abnormality in most pediatric lowgrade gliomas. Pilocytic astrocytoma pa is the most common type of primary brain tumor in children and. Pilocytic astrocytoma pa is the most frequently encountered glial tumor. Pilocytic astrocytoma pa is one of the most common brain cancers among children and activation of the mitogenactivated protein kinase mapk pathway is. Oncogenic raf1 rearrangement and a novel braf mutation as alternatives to kiaa1549. Several mechanisms lead to activation of this pathway in pa, mostly in a mutually. The histologic features and clinical history of rgnt resemble those of pilocytic astrocytoma pa. Rosenthal fibers are a frequent feature of pilocytic astrocytomas and may be numerous b. Pilocytic astrocytoma, involving the optic pathways, optic nerve, and chiasm. A body of research over recent years has demonstrated a key role for mitogenactivated protein kinase mapk pathway signaling in the development and behavior of pas.
Somatic genetic abnormalities affecting this pathway occur in the majority of pilocytic astrocytomas pa, the most prevalent brain neoplasm in children. A followup tissue evaluation using immunohistochemistry showed alterations in mapk signaling pathway. An array of proteins comprise the 4 major mapk cascades that include erk, p38, jnk, and erk5. Mitogenactivated protein kinase in gliosis and pilocytic. Takeuchi h, neishi h, higashino y, kitai r, kikuta ki, imamura y. Novel braf alteration in a sporadic pilocytic astrocytoma. Pa is a tumor of low to moderate cellularity with compact, densely fibrillated areas rich in rosenthal fibers, consisting of cells with long bipolar hairlike processes and elongated cytologically bland nuclei fig. Braf fusions, and leads to oncogene induced senescence ois. Pubmed abstract korshunov a, meyer j, capper d, et al combined molecular analysis of braf and idh1 distinguishes pilocytic astrocytoma from diffuse astrocytoma. The term pilocytic to describe astrocytoma variants has been used since the 1930s 8, 18 to indicate cells with hairlike, bipolar processes.
Heterogeneity of histopathological presentation of. The mapk pathway mitogenactivated protein kinase pathway also known as the rasmapk pathway is an oncogenic pathway and is most commonly involved in human cancers it consists of a membrane receptor tyrosine kinase which when bound to by a growth factor results in activation of the signal transducer ras 1. The ras cellular proliferation pathway is inhibited by. Mitogenactivated protein kinase in gliosis and pilocytic astrocytoma. Functionally, this signaling pathway has been implicated in. Bilateral fusiform enlargement of the optic nerve is virtually diagnostic of neurofibromatosis type 1 a. Mapk cell signaling pathway thermo fisher scientific uk.
Case report gene alteration of rosetteforming glioneuronal tumor. Jones dt, gronych j, lichter p, witt o, pfister sm. Novel braf alteration in a sporadic pilocytic astrocytoma hindawi. Alternative mechanism of mitogenactivated protein kinase pathway activation that leads to pilocytic astrocytoma formation. Pilocytic astrocytoma, the most common pediatric brain tumor, is a clinically and molecularly heterogeneous disease that occurs most often in the cerebellum and hypothalamic and chiasmatic regions. Activation of the hedgehog pathway in pilocytic astrocytomas.
A new gtf2ibraf fusion mediating mapk pathway activation in. Mapk signaling in normal brain and highgrade astrocytomas. A pilocytic astrocytoma and its variant juvenile pilomyxoid astrocytoma is a brain tumor that occurs more often in children and young adults in the first 20 years of life. Recent progress in the pathology and genetics of pilocytic. Today, what we call pilocytic astrocytoma pa has had a number of names before the who classification system became generally accepted. Mapk pathway activation in pilocytic astrocytoma, so far reported in only a few cases, is fusion of a second raf kinase family member, raf1 or craf 61, 62, 81. The majority of these genetic changes involve chromosome 7q34 tandem duplication, resulting in aberrant. Therapeutic targets in pilocytic astrocytoma based on. Activation of the mapk pathway is well established as the oncogenic driver of the disease. Therefore, we investigated the expression of mapk in reactive gliosis associated with cavernous angiomas. Growth factorinitiated signaling is associated with the erk pathway, whereas the jnk, p38, and erk5 pathways are activated by cytokines, environmental stress including osmotic shock and ionizing radiation and other stimuli 6. Pfister s, janzarik wg, remke m, et al braf gene duplication constitutes a mechanism of mapk pathway activation in lowgrade astrocytomas. A body of research over recent years has demonstrated a key role for mitogenactivated protein kinase mapk pathway signaling in. The tumor typically extends into the leptomeningeal space, expanding the dural sheath and compressing the remaining optic nerve proper, which is atrophic b.
The tumor cells often contain rosenthal fibers and eosinophilic granular bodies. Rosenthal fibers and eosinophilic granular bodies, socalled protein droplets, were interspersed. Most pas harbor rosenthal fibers within their compact or fibrillary areas. Alternative lengthening of telomeres, atrx loss and h3. Pas demonstrate mapk signaling pathway activation through. Abstract pilocytic astrocytoma pa is the most common tumor of the pediatric central nervous system cns.
Relative adc and location differ between posterior fossa. Kiaa1549braf fusion is the most common genetic event in pilocytic astrocytoma pa, and leads to activation of the mitogen activated protein kinase mapk signaling pathway. Oncogenic brafras or nf1 loss can potentially trigger oncogeneinduced senescence ois through activation of the mitogenactivated protein kinase mapk pathway. Pilocytic astrocytoma pa, featuring activation of the mitogenactivated protein kinase mapk pathway, is the most common tumor of the pediatric central nervous system. A complete cross section of the optic nerve is shown in the inset. The second architectural pattern of pa is characterized by loose stroma, containing microcysts c and occasionally. The tumor tissue biopsy showed characteristic cells that look like fibers called rosenthal fibers.
In the gs group, histopathologic features of pa piloid cells, rosenthal fibers, microcysts with. Pilocytic means hairlike, due to long, bipolar processes. Pilocytic astrocytoma pa represents the most frequent primary brain tumor in children, and accounts for 15. Pilocytic astrocytoma pa, featuring activation of the mitogenactivated protein kinase mapk pathway, is the most. Pilocytic astrocytoma pa is one of the most common brain cancers among children and activation of the mitogenactivated protein kinase mapk pathway is considered the hallmark. Jones dtw, kocialkowski s, liu l, pearson dm, ichimura k, collins vp. Occasional rosenthal fibers and eosinophilic granular bodies were. Braf fusion in activating the mapk pathway in pilocytic astrocytoma. They usually arise in the cerebellum, near the brainstem, in the hypothalamic region, or the optic chiasm, but they may occur in any area where astrocytes are present, including the cerebral hemispheres and the. Pa is histologically characterized by the presence of neoplastic bipolar astrocytes in compact areas a. Pilocytic astrocytoma is a rare type of brain tumor that occurs mostly in children and young adults under age 20. To determine the distinction of pilocytic astrocytoma of the optic nerve from.
Recent findings implicate aberrant activation of the mapk pathway, due to braf gene rearrangements or mutations, in 66%85% of sporadic pilocytic astrocytomas. Webpathology is a free educational resource with 10304 high quality pathology images of benign and malignant neoplasms and related entities. Most commonly arises during the first two decades of life peak age 8 years. Pilocytic astrocytomas of the optic nerve and their. Cns brain tumors 1 questions and study guide quizlet. Oncogenic fam1bbraf fusion resulting from 7q34 deletion comprises an alternative mechanism of mapk pathway. Better prognosis than diffuse types, particularly if resectable such as cerebellar tumors most common cns neoplasm of childhood. A mitogenactivated protein kinase mapk or map kinase is a type of protein kinase that is specific to the amino acids serine and threonine i.
Pilocytic astrocytoma key concepts a subgroup of astrocytomas who grade i with better prognosis 10year survival. Pilocytic astrocytoma, g it2braf, fusion, braf background pa is the most common glioma in the pediatric population 1 and it represents 5. Rosenthal fibres strongly eosinophilic structures of unknown composition and granular bodies are also frequently observed, but are neither. A recurrent feature of pa is deregulation of the mitogen activated protein kinase mapk pathway most. Oncogenic fam1bbraf fusion resulting from 7q34 deletion comprises an alternative mechanism of mapk pathway activation in pilocytic astrocytoma. Raf1 fusion activating the mapk pathway in pilocytic.
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