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pilocytic_astrocytoma

Pilocytic astrocytoma

Pilocytic astrocytoma (PA) is a neoplasia which is considered as a WHO Grade I.

Epidemiology

Pilocytic astrocytoma (PA) is the most frequent pediatric brain tumor.

Its most common location is the cerebellum and it develops during the first two decades of life., and is one of the commonest subtypes of glioma to affect children.

They are rarely diagnosed in patients over the age of 18 years.

In adults, these tumours appear more frequently supratentorially than in the cerebellum and some reports suggest a different clinical course in adults.

Etiology

Activation of the MAPK pathway is well established as the oncogenic driver of the disease. It is most frequently caused by KIAA1549:BRAF fusions, and leads to oncogene induced senescence (OIS). OIS is thought to be a major reason for growth arrest of PA cells in vitro and in vivo, preventing establishment of PA cultures 1).

Molecular heterogeneity

For tumors originating in the supra-or infratentorial location, a different molecular background was suggested, but plausible correlations between the transcriptional profile and radiological features and/or clinical course are still undefined.

It is a clinically and molecularly heterogeneous disease that occurs most often in the cerebellum and hypothalamic and chiasmatic regions. Classically, pilocytic astrocytomas are driven by the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway.

Genetic aberrations involving this pathway are critical for tumorigenesis. Tandem duplication of 7q34 encodes BRAF and produces several KIAA1549-BRAF novel oncogenic fusions. Activating point mutations of BRAF, such as BRAF (V600E), also lead to pilocytic astrocytoma. Loss of the NF1 gene allows hyperactivation of the oncogene KRAS.

A better understanding of the evolving molecular heterogeneity of pilocytic astrocytomas offers hope for developing molecularly targeted therapeutic armamentariums 2).

Pilocytic astrocytomas of different locations can be precisely differentiated on the basis of their gene expression level, but their transcriptional profiles does not strongly reflect the radiological appearance of the tumor or the course of the disease 3).

Types

Cerebellar pilocytic astrocytoma

Anaplastic pilocytic astrocytoma.

Cervicomedullary pilocytic astrocytoma.

Pilocytic astrocytomas in the supratentorial compartment make up 20 % of all brain tumours in children with only 5 % of these arising in the suprasellar region.

Suprasellar pilocytic astrocytomas are challenging to manage surgically with high morbidity rates from surgical resection.


Recent studies suggest that the behavior and biology of WHO grade I pilocytic astrocytomas (PAs) in adults is different than that associated with grade I PAs in children.

Diagnosis

Pricola Fehnel et al., report the use of urinary biomarkers as a novel, noninvasive technique to detect juvenile pilocytic astrocytomas (JPAs), capable of distinguishing JPAs from other CNS diseases, including other brain tumors. Preliminary screening of an array of tumors implicated proteases (including matrix metalloproteinases [MMPs]) and their inhibitors (tissue inhibitors of metalloproteinase [TIMPs]) as well as growth factors (including basic fibroblast growth factor [bFGF]) as candidate biomarkers. These data led the authors to hypothesize that tissue inhibitor of metalloproteinase 3 (TIMP3) and bFGF would represent high-probability candidates as JPA-specific biomarkers.

Urine was collected from 107 patients, which included children with JPA (n = 21), medulloblastoma (n = 17), glioblastoma (n = 9), arteriovenous malformations (n = 25), moyamoya (n = 14), and age- and sex-matched controls (n = 21). Biomarker levels were quantified with enzyme-linked immunosorbent assay, tumor tissue expression was confirmed with immunohistochemical analysis, and longitudinal biomarker expression was correlated with imaging. Results were subjected to univariate and multivariate statistical analyses.

Using optimal urinary cutoff values of bFGF > 1.0 pg/μg and TIMP3 > 3.5 pg/μg, multiplexing bFGF and TIMP3 predicts JPA presence with 98% accuracy. Multiplexing bFGF and MMP13 distinguishes JPA from other brain tumor subtypes with up to 98% accuracy. Urinary biomarker expression correlated with both tumor immunohistochemistry and in vitro tumor levels. Urinary bFGF and TIMP3 decrease following successful tumor treatment and correlate with changes in tumor size.

This study identifies 2 urinary biomarkers-bFGF and TIMP3-that successfully detect one of the most common pediatric brain tumors with high accuracy. These data highlight potential benefits of urinary biomarkers and support their utility as diagnostic tools in the treatment of children with JPA 4).

Prognosis

Prognosis is mostly excellent if gross-total resection can be achieved, with 10-year survival rates of up to 95%.

Case series

2016

Pricola Fehnel et al., report the use of urinary biomarkers as a novel, noninvasive technique to detect juvenile pilocytic astrocytomas (JPAs), capable of distinguishing JPAs from other CNS diseases, including other brain tumors. Preliminary screening of an array of tumors implicated proteases (including matrix metalloproteinases [MMPs]) and their inhibitors (tissue inhibitors of metalloproteinase [TIMPs]) as well as growth factors (including basic fibroblast growth factor [bFGF]) as candidate biomarkers. These data led the authors to hypothesize that tissue inhibitor of metalloproteinase 3 (TIMP3) and bFGF would represent high-probability candidates as JPA-specific biomarkers.

Urine was collected from 107 patients, which included children with JPA (n = 21), medulloblastoma (n = 17), glioblastoma (n = 9), arteriovenous malformations (n = 25), moyamoya (n = 14), and age- and sex-matched controls (n = 21). Biomarker levels were quantified with enzyme-linked immunosorbent assay, tumor tissue expression was confirmed with immunohistochemical analysis, and longitudinal biomarker expression was correlated with imaging. Results were subjected to univariate and multivariate statistical analyses.

Using optimal urinary cutoff values of bFGF > 1.0 pg/μg and TIMP3 > 3.5 pg/μg, multiplexing bFGF and TIMP3 predicts JPA presence with 98% accuracy. Multiplexing bFGF and MMP13 distinguishes JPA from other brain tumor subtypes with up to 98% accuracy. Urinary biomarker expression correlated with both tumor immunohistochemistry and in vitro tumor levels. Urinary bFGF and TIMP3 decrease following successful tumor treatment and correlate with changes in tumor size.

This study identifies 2 urinary biomarkers-bFGF and TIMP3-that successfully detect one of the most common pediatric brain tumors with high accuracy. These data highlight potential benefits of urinary biomarkers and support their utility as diagnostic tools in the treatment of children with JPA 5).

2015

Eighty six children (55 males and 31 females) with histologically verified pilocytic astrocytoma were included in a study. Their age at the time of diagnosis ranged from fourteen months to seventeen years, with a mean age of seven years. There were 40 cerebellar, 23 optic tract/hypothalamic, 21 cerebral hemispheric, and two brainstem tumors. According to the radiological features presented on MRI, all cases were divided into four subtypes: cystic tumor with a non-enhancing cyst wall; cystic tumor with an enhancing cyst wall; solid tumor with central necrosis; and solid or mainly solid tumor. In 81 cases primary surgical resection was the only and curative treatment, and in five cases progression of the disease was observed. In 47 cases the analysis was done by using high density oligonucleotide microarrays (Affymetrix HG-U133 Plus 2.0) with subsequent bioinformatic analyses and confirmation of the results by independent RT-qPCR (on 39 samples).

Bioinformatic analyses showed that the gene expression profile of pilocytic astrocytoma is highly dependent on the tumor location. The most prominent differences were noted for IRX2, PAX3, CXCL14, LHX2, SIX6, CNTN1 and SIX1 genes expression even within different compartments of the supratentorial region. Analysis of the genes potentially associated with radiological features showed much weaker transcriptome differences. Single genes showed association with the tendency to progression.

Here the authors shown that pilocytic astrocytomas of three different locations can be precisely differentiated on the basis of their gene expression level, but their transcriptional profiles does not strongly reflect the radiological appearance of the tumor or the course of the disease 6).

2012

A study included 21 males and 11 females with a median age of 10.5 years. Tumors demonstrated predilection for infratentorial location (74.9%), especially the cerebellum (59.3%), followed by cerebral ventricles (15.6%), supratentorial location (12.5%) and optic pathway (3.12%). Gross total resection was achieved in 14 tumors only. On histopathology, moderate cellularity (68.7%), microcystic changes (71.9%), Rosenthal fibers (62.5%) and eosinophilic granular bodies (53.2%) were present in the majority of cases. Atypia was present in 62.5% of cases, while endothelial proliferation and necrosis was noted in 3 and 2 cases, respectively. Median follow-up for all patients was 24 months. Four patients died in the postoperative period, one of whom was 62-year-old men and two others had brainstem location or invasion. Recurrence was observed in a 56-year-old patient whom first tumor was locally invasive. The patient died after the second surgery and anaplastic features was found in the recurrent tumor without previous radiotherapy. PA is a benign tumor, but some clinicopathological factors, such as partial resection, brainstem location and adult age have a worse prognosis 7).

1)
Selt F, Hohloch J, Hielscher T, Sahm F, Capper D, Korshunov A, Usta D, Brabetz S, Ridinger J, Ecker J, Oehme I, Gronych J, Marquardt V, Pauck D, Bächli H, Stiles CD, von Deimling A, Remke M, Schuhmann MU, Pfister SM, Brummer T, Jones DT, Witt O, Milde T. Establishment and application of a novel patient-derived KIAA1549:BRAF-driven pediatric pilocytic astrocytoma model for preclinical drug testing. Oncotarget. 2016 Dec 17. doi: 10.18632/oncotarget.14004. [Epub ahead of print] PubMed PMID: 28002790.
2)
Sadighi Z, Slopis J. Pilocytic astrocytoma: a disease with evolving molecular heterogeneity. J Child Neurol. 2013 May;28(5):625-32. doi: 10.1177/0883073813476141. Epub 2013 Feb 25. Review. PubMed PMID: 23439714.
3) , 6)
Zakrzewski K, Jarząb M, Pfeifer A, Oczko-Wojciechowska M, Jarząb B, Liberski PP, Zakrzewska M. Transcriptional profiles of pilocytic astrocytoma are related to their three different locations, but not to radiological tumor features. BMC Cancer. 2015 Oct 24;15:778. doi: 10.1186/s12885-015-1810-z. PubMed PMID: 26497896; PubMed Central PMCID: PMC4619381.
4) , 5)
Pricola Fehnel K, Duggins-Warf M, Zurakowski D, McKee-Proctor M, Majumder R, Raber M, Han X, Smith ER. Using urinary bFGF and TIMP3 levels to predict the presence of juvenile pilocytic astrocytoma and establish a distinct biomarker signature. J Neurosurg Pediatr. 2016 Oct;18(4):396-407. PubMed PMID: 27314542.
7)
Cyrine S, Sonia Z, Mounir T, Badderedine S, Kalthoum T, Hedi K, Moncef M. Pilocytic astrocytoma: a retrospective study of 32 cases. Clin Neurol Neurosurg. 2013 Aug;115(8):1220-5. doi: 10.1016/j.clineuro.2012.11.009. Epub 2012 Dec 21. PubMed PMID: 23265563.
pilocytic_astrocytoma.txt · Last modified: 2017/06/14 13:59 by administrador