Pleomorphic xanthoastrocytomas (PXAs) are rare tumors accounting for less than 1% of astrocytomas. They commonly occur in young patients and have relatively favorable prognosis. However, they are well known to have heterogenous morphology and biological behavior with the potential to recur and disseminate throughout the central nervous system, especially their anaplastic counterparts. Recent advances in the molecular characterization have discovered BRAFp.V600E mutations in conjunction with CDKN2A/B deletions and TERTp mutations to be the most frequent alterations in PXAs. These tumors can present a diagnostic challenge as they share overlapping histopathological, genomic as well as methylation profile with various other tumor types, particularly epithelioid glioblastomas (eGBs). This review provides the spectrum of evolution of PXAs from their genesis to recent molecular insights and attempts to review pathogenesis and relationship to other tumors that they mimic especially eGB. It is postulated based on evidence from literature that PXA and eGB are possibly related and not distinct entities, being two ends of a continuous spectrum of malignant progression (grade 2–grade 4) with anaplastic PXA (grade 3) lying in between. Future WHO classifications will have to possibly redefine these tumors using more confirmatory data from larger studies.
Your institute does not have access to this article
Subscribe to Journal
Get full journal access for 1 year
We are sorry, but there is no personal subscription option available for your country.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Kepes, J. J., Rubinstein, L. J. & Eng, L. F. Pleomorphic xanthoastrocytoma: a distinctive meningocerebral glioma of young subjects with relatively favorable prognosis. A study of 12 cases. Cancer 44, 1839–1852 (1979).
Weldon-Linne, C. M., Victor, T. A., Groothuis, D. R. & Vick, N. A. Pleomorphic xanthoastrocytoma. Ultrastructural and immunohistochemical study of a case with a rapidly fatal outcome following surgery. Cancer 52, 2055–2063 (1983).
Iwaki, T., Fukui, M., Kondo, A., Matsushima, T. & Takeshita, I. Epithelial properties of pleomorphic xanthoastrocytomas determined in ultrastructural and immunohistochemical studies. Acta Neuropathol. 74, 142–150 (1987).
Kepes, J. J., Rubinstein, L. J., Ansbacher, L. & Schreiber, D. J. Histopathological features of recurrent pleomorphic xanthoastrocytomas: further corroboration of the glial nature of this neoplasm. A study of 3 cases. Acta Neuropathol. 78, 585–593 (1989).
Kleihues, P., Burger, P. C. & Scheithauer, B. W. The new WHO classification of brain tumours. Brain Pathol. 3, 255–268 (1993).
Kleihues, P. et al. The WHO classification of tumors of the nervous system. J. Neuropathol. Exp. Neurol. 61, 215–225 (2002).
Louis, D. N. et al. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 114, 97–109 (2007).
Okazaki, T. et al. Primary anaplastic pleomorphic xanthoastrocytoma with widespread neuroaxis dissemination at diagnosis-a pediatric case report and review of the literature. J. Neurooncol. 94, 431–437 (2009).
Kyritsis, A. P. et al. Mutations of the p16 gene in gliomas. Oncogene 12, 63–67 (1996).
Giannini, C. et al. Pleomorphic xanthoastrocytoma: what do we really know about it? Cancer 85, 2033–2045 (1999).
Giannini C., et al. Anaplastic pleomorphic xanthoastrocytoma. in WHO Classification of Tumours of the Central Nervous System (eds Louis, D. N., Ohgaki, H., Wiestler, O. D., Cavenee, W. K.) 4th edn, 98–99 (IARC, 2016).
Dias-Santagata, D. et al. BRAF V600E mutations are common in pleomorphic xanthoastrocytoma: diagnostic and therapeutic implications. PLoS ONE 6, e17948 (2011).
Schindler, G. et al. Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma. Acta Neuropathol. 121, 397–405 (2011).
Weber, R. G. et al. Frequent loss of chromosome 9, homozygous CDKN2A/p14(ARF)/CDKN2B deletion and low TSC1 mRNA expression in pleomorphic xanthoastrocytomas. Oncogene 26, 1088–1097 (2007).
Lassaletta, A. et al. Therapeutic and prognostic implications of BRAF V600E in pediatric low-grade gliomas. J. Clin. Oncol. 35, 2934–2941 (2017).
Mistry, M. et al. BRAF mutation and CDKN2A deletion define a clinically distinct subgroup of childhood secondary high-grade glioma. J. Clin. Oncol. 33, 1015–1022 (2015).
Vaubel, R. A. et al. Recurrent copy number alterations in low-grade and anaplastic pleomorphic xanthoastrocytoma with and without BRAF V600E mutation. Brain Pathol. 28, 172–182 (2018).
Giannini, C. et al. Pleomorphic xanthoastrocytoma. in The WHO Classification of Tumors of the Central Nervous System (eds Reifenberger, G. & Perry A.) 5th edn (IARC) (2007).
Dono, A. et al. Predictors of outcome in pleomorphic xanthoastrocytoma. Neurooncol. Pract. 8, 222–229 (2020).
Ostrom, Q. T. et al. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2010-2014. Neuro Oncol. 19, v1–v88 (2017).
Ida, C. M. et al. Pleomorphic xanthoastrocytoma: natural history and long-term follow-up. Brain Pathol. 25, 575–586 (2015).
Dolecek, T. A., Propp, J. M., Stroup, N. E. & Kruchko, C. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2005-2009. Neuro Oncol. 14(Suppl 5), v1–v49 (2012).
Fouladi, M. et al. Pleomorphic xanthoastrocytoma: favorable outcome after complete surgical resection. Neuro Oncol. 3, 184–192 (2001).
Gil-Gouveia, R. et al. Pleomorphic xanthoastrocytoma of the cerebellum: illustrated review. Acta Neurochir. 146, 1241–1244 (2004).
Nakamura, M., Chiba, K., Matsumoto, M., Ikeda, E. & Toyama, Y. Pleomorphic xanthoastrocytoma of the spinal cord. Case report. J. Neurosurg. Spine 5, 72–75 (2006).
Zarate, J. O. & Sampaolesi, R. Pleomorphic xanthoastrocytoma of the retina. Am. J. Surg. Pathol. 23, 79–81 (1999).
McNatt, S. A., Gonzalez-Gomez, I., Nelson, M. D. & McComb, J. G. Synchronous multicentric pleomorphic xanthoastrocytoma: case report. Neurosurgery 57, E191 (2005).
Lubansu, A. et al. Cerebral anaplastic pleomorphic xanthoastrocytoma with meningeal dissemination at first presentation. Childs Nerv. Syst. 20, 119–122 (2004).
Passone, E. et al. Non-anaplastic pleomorphic xanthoastrocytoma with neuroradiological evidences of leptomeningeal dissemination. Childs Nerv. Syst. 22, 614–618 (2006).
Davies, K. G., Maxwell, R. E., Seljeskog, E. & Sung, J. H. Pleomorphic xanthoastrocytoma-report of four cases, with MRI scan appearances and literature review. Br. J. Neurosurg. 8, 681–689 (1994).
Crespo-Rodríguez, A. M., Smirniotopoulos, J. G. & Rushing, E. J. MR and CT imaging of 24 pleomorphic xanthoastrocytomas (PXA) and a review of the literature. Neuroradiology 49, 307–315 (2007).
Osborn A. G., Blaser S. I. & Salzman K. L. (eds) Diagnostic Imaging: Brain 1st edn (Amirsys, 2004).
Yu, S., He, L., Zhuang, X. & Luo, B. Pleomorphic xanthoastrocytoma: MR imaging findings in 19 patients. Acta Radiol. 52, 223–228 (2011).
Yoshino, M. T. & Lucio, R. Pleomorphic xanthoastrocytoma. Am. J. Neuroradiol. 13, 1330–1332 (1992).
Bucciero, A. et al. Pleomorphic xanthoastrocytoma: clinical, imaging and pathological features of four cases. Clin. Neurol. Neurosurg. 99, 40–45 (1997).
Kepes, J. J., Kepes, M. & Slowik, F. Fibrous xanthomas and xanthosarcomas of the meninges and the brain. Acta Neuropathol. 23, 187–199 (1973).
Burger P. C. & Scheithauer B. W. Tumors of the Central Nervous System (American Registry of Pathology in collaboration with the Armed Forces Institute of Pathology, 2007).
Perry A. & Brat D. J. Practical Surgical Neuropathology: a Diagnostic Approach (Elsevier, 2018).
Primavera, J. et al. Clear cell pleomorphic xanthoastrocytoma: case report. Acta Neuropathol. 102, 404–408 (2001).
Xiong, J., Chu, S. G., Mao, Y. & Wang, Y. Pigmented pleomorphic xanthoastrocytoma: a rare variant and literature review. Neuropathology 31, 88–92 (2011).
Furuta, T. et al. Clinicopathological and genetic association between epithelioid glioblastoma and pleomorphic xanthoastrocytoma. Neuropathology 38, 218–227 (2018).
Alexandrescu, S. et al. Epithelioid glioblastomas and anaplastic epithelioid pleomorphic xanthoastrocytomas-same entity or first cousins? Brain Pathol. 26, 215–223 (2016).
Wang, J. et al. Evaluation of EZH2 expression, BRAF V600E mutation, and CDKN2A/B deletions in epithelioid glioblastoma and anaplastic pleomorphic xanthoastrocytoma. J. Neurooncol. 144, 137–146 (2019).
Hirose, T. et al. Pleomorphic xanthoastrocytoma: a comparative pathological study between conventional and anaplastic types. Histopathology 52, 183–193 (2008).
Giannini, C., Hebrink, D., Scheithauer, B. W., Dei Tos, A. P. & James, C. D. Analysis of p53 mutation and expression in pleomorphic xanthoastrocytoma. Neurogenetics 3, 159–162 (2001).
Paulus, W. et al. Molecular genetic alterations in pleomorphic xanthoastrocytoma. Acta Neuropathol. 91, 293–297 (1996).
Kaulich, K. et al. Genetic alterations commonly found in diffusely infiltrating cerebral gliomas are rare or absent in pleomorphic xanthoastrocytomas. J. Neuropathol. Exp. Neurol. 61, 1092–1099 (2002).
Vaubel, R. et al. Biology and grading of pleomorphic xanthoastrocytoma-what have we learned about it? Brain Pathol. 31, 20–32 (2021).
Nakajima, N. et al. BRAF V600E, TERT promoter mutations and CDKN2A/B homozygous deletions are frequent in epithelioid glioblastomas: a histological and molecular analysis focusing on intratumoral heterogeneity. Brain Pathol. 28, 663–673 (2018).
Phillips, J. J. et al. The genetic landscape of anaplastic pleomorphic xanthoastrocytoma. Brain Pathol. 29, 85–96 (2019).
Korshunov, A. et al. Epithelioid glioblastomas stratify into established diagnostic subsets upon integrated molecular analysis. Brain Pathol. 28, 656–662 (2018).
Zou, H. et al. Molecular features of pleomorphic xanthoastrocytoma. Hum. Pathol. 86, 38–48 (2019).
Koelsche, C. et al. Distribution of TERT promoter mutations in pediatric and adult tumors of the nervous system. Acta Neuropathol. 126, 907–915 (2013).
Pratt, D. et al. BRAF activating mutations involving the β3-αC loop in V600E-negative anaplastic pleomorphic xanthoastrocytoma. Acta Neuropathol. Commun. 6, 24 (2018).
Hsiao, S. J. et al. A novel, potentially targetable TMEM106B-BRAF fusion in pleomorphic xanthoastrocytoma. Cold Spring Harb. Mol. Case Stud. 3, a001396 (2017).
Zhang, J. St. Jude Children’s Research Hospital–Washington University Pediatric Cancer Genome Project. et al. Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas. Nat. Genet. 45, 602–612 (2013).
Bettegowda, C. et al. Exomic sequencing of four rare central nervous system tumor types. Oncotarget 4, 572–583 (2013).
Phillips, J. J. et al. Activating NRF1-BRAF and ATG7-RAF1 fusions in anaplastic pleomorphic xanthoastrocytoma without BRAF p.V600E mutation. Acta Neuropathol. 132, 757–760 (2016).
Lim, S. et al. Prognostic factors and therapeutic outcomes in 22 patients with pleomorphic xanthoastrocytoma. J. Korean Neurosurg. Soc. 53, 281–287 (2013).
Korshunov, A. & Golanov, A. Pleomorphic xanthoastrocytomas: immunohistochemistry, grading and clinico-pathologic correlations. An analysis of 34 cases from a single Institute. J. Neurooncol. 52, 63–72 (2001).
Perkins, S. M., Mitra, N., Fei, W. & Shinohara, E. T. Patterns of care and outcomes of patients with pleomorphic xanthoastrocytoma: a SEER analysis. J. Neurooncol. 110, 99–104 (2012).
Ng, W. H., Lim, T. & Yeo, T. T. Pleomorphic xanthoastrocytoma in elderly patients may portend a poor prognosis. J. Clin. Neurosci. 15, 476–478 (2008).
Reis, G. F. et al. CDKN2A loss is associated with shortened overall survival in lower-grade (World Health Organization Grades II-III) astrocytomas. J. Neuropathol. Exp. Neurol. 74, 442–452 (2015).
Pahapill, P. A., Ramsay, D. A. & Del Maestro, R. F. Pleomorphic xanthoastrocytoma: case report and analysis of the literature concerning the efficacy of resection and the significance of necrosis. Neurosurgery 38, 822–829 (1996).
Byun, J., Hong, S. H., Kim, Y.-H., Kim, J. H. & Kim, C. J. Peritumoral edema affects the prognosis in adult pleomorphic xanthoastrocytoma: retrospective analysis of 25 patients. World Neurosurg. 114, e457–e467 (2018).
Macaulay, R. J., Jay, V., Hoffman, H. J. & Becker, L. E. Increased mitotic activity as a negative prognostic indicator in pleomorphic xanthoastrocytoma: case report. J. Neurosurg. 79, 761–768 (1993).
Koga, T. et al. Long-term control of disseminated pleomorphic xanthoastrocytoma with anaplastic features by means of stereotactic irradiation. Neuro Oncol. 11, 446–451 (2009).
van Roost, D., Kristof, R., Zentner, J., Wolf, H. K. & Schramm, J. Clinical, radiological, and therapeutic features of pleomorphic xanthoastrocytoma: report of three patients and review of the literature. J. Neurol. Neurosurg. Psychiatry 60, 690–692 (1996).
Khalafallah, A., Rakovec, M. & Mukherjee, D. Association between adjuvant radiation therapy and overall survival in pleomorphic xanthoastrocytoma. Clin. Neurol. Neurosurg. 196, 106042 (2020).
Hosona, J. et al. Role of a promoter mutation in TERT in malignant transformation of pleomorphic xanthoastrocytoma. World Neurosurg. 126, 624–630 (2019).
Saikali, S. et al. Multicentric pleomorphic xanthoastrocytoma in a patient with neurofibromatosis type 1: case report and review of the literature. J. Neurosurg. 102, 376–381 (2005).
Mallick, S., Benson, R., Melgandi, W., Giridhar, P. & Rath, G. K. Grade II pleomorphic xanthoastrocytoma: a meta-analysis of data from previously reported 167 cases. J. Clin. Neurosci. 54, 57–62 (2018).
Thomas, A. et al. RARE-30. Anaplastic pleomorphic xanthoastrocytoma with leptomeningeal dissemination responsive to BRAF inhibition and bevacizumab. Neuro Oncol. 19, vi216 (2017). Suppl. 6.
Brown, N. F., Carter, T. & Mulholland, P. Dabrafenib in BRAFV600-mutated anaplastic pleomorphic xanthoastrocytoma. CNS Oncol. 6, 5–9 (2017).
Hyman, D. M. et al. Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations. N. Engl. J. Med. 373, 726–736 (2015).
Kaley, T. et al. BRAF inhibition in BRAFV600-mutant gliomas: results from the VE-BASKET Study. J. Clin. Oncol. 36, 3477–3484 (2018).
Lukas, R. V. & Merrell, R. T. BRAF inhibition with concomitant tumor treating fields for a multiply progressive pleomorphic xanthoastrocytoma. CNS Oncol. 7, CNS10 (2018).
Louis, D. N. et al. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol. 131, 803–820 (2016).
Tanaka, S. et al. Epithelioid glioblastoma arising from pleomorphic xanthoastrocytoma with the BRAF V600E mutation. Brain Tumor Pathol. 31, 172–176 (2014).
Matsumura, N. et al. Concurrent TERT promoter and BRAF V600E mutation in epithelioid glioblastoma and concomitant low-grade astrocytoma. Neuropathology 37, 58–63 (2017).
Broniscer, A. et al. Clinical, radiological, histological and molecular characteristics of paediatric epithelioid glioblastoma. Neuropathol. Appl. Neurobiol. 40, 327–336 (2014).
Kleinschmidt-DeMasters, B. K. et al. Epithelioid versus rhabdoid glioblastomas are distinguished by monosomy 22 and immunohistochemical expression of INI-1 but not claudin 6. Am. J. Surg. Pathol. 34, 341–354 (2010).
Nobusawa, S. et al. Intratumoral heterogeneity of genomic imbalance in a case of epithelioid glioblastoma with BRAF V600E mutation. Brain Pathol. 24, 239–246 (2014).
Khanna, G. et al. Immunohistochemical and molecular genetic study on epithelioid glioblastoma: series of seven cases with review of literature. Pathol. Res. Pract. 214, 679–685 (2018).
Kordek, R. et al. Pleomorphic xanthoastrocytoma with a gangliomatous component: an immunohistochemical and ultrastructural study. Acta Neuropathol. 89, 194–197 (1995).
Perry, A. et al. Composite pleomorphic xanthoastrocytoma and ganglioglioma: report of four cases and review of the literature. Am. J. Surg. Pathol. 21, 763–771 (1997).
Margetts, J. C. & Kalyan-Raman, U. P. Giant celled glioblastoma of brain: a clinico-pathological and radiological study of ten cases (including immunohistochemistry and ultrastructure). Cancer 63, 524–531 (1989).
Kozak, K. R. & Moody, J. S. Giant cell glioblastoma: a glioblastoma subtype with distinct epidemiology and superior prognosis. Neuro Oncol. 11, 833–841 (2009).
Meyer-Puttlitz, B. et al. Molecular genetic analysis of giant cell glioblastomas. Am. J. Pathol. 151, 853–857 (1997).
Ogawa, K. et al. Giant cell glioblastoma is a distinctive subtype of glioma characterized by vulnerability to DNA damage. Brain Tumor Pathol. 37, 5–13 (2020).
Nesvick, C. L. et al. Atypical teratoid rhabdoid tumor: molecular insights and translation to novel therapeutics. J. Neurooncol. 150, 47–56 (2020).
Ho, B. et al. Molecular subgrouping of atypical teratoid/rhabdoid tumors-a reinvestigation and current consensus. Neuro Oncol. 22, 613–624 (2020).
Uner, M., Saglam, A., Meydan, B. C., Aslan, K. & Soylemezoglu, F. Atypical teratoid rhabdoid tumor arising in a pleomorphic xanthoastrocytoma: a rare entity. Clinic Neuropathol. 36, 227–232 (2017).
Zacher, A. et al. Molecular diagnostics of gliomas using next generation sequencing of a glioma-tailored gene panel. Brain Pathol. 27, 146–159 (2017).
Gupta, K., Kalra, I., Salunke, P. & Vasishta, R. K. Lipidized glioblastoma: a rare differentiation pattern. Neuropathology 31, 93–97 (2011).
Arita, H. et al. A combination of TERT promoter mutation and MGMT methylation status predicts clinically relevant subgroups of newly diagnosed glioblastomas. Acta Neuropathol. Commun. 4, 79 (2016).
Ceccarelli, M. et al. Molecular profiling reveals biologically discrete subsets and pathways of progression in diffuse glioma. Cell 164, 550–563 (2016).
Reinhardt, A. et al. Anaplastic astrocytoma with piloid features, a novel molecular class of IDH wildtype glioma with recurrent MAPK pathway, CDKN2A/B and ATRX alterations. Acta Neuropathol. 136, 273–291 (2018).
Aldape K. D. & Rosenblum M. K. Astroblastoma. in WHO Classification of Tumours of the Central Nervous System (Louis, D. N., Ohgaki, H., Wiestler, O. D. & Cavenee, W. K.) 121–122 (International Agency for Research on Cancer, 2016).
Lehman, N. L. et al. Genomic analysis demonstrates that histologically-defined astroblastomas are molecularly heterogeneous and that tumors with MN1 rearrangement exhibit the most favorable prognosis. Acta Neuropathol. Commun. 7, 42 (2019).
Lehman, N. L. et al. Morphological and molecular features of astroblastoma, including BRAFV600E mutations, suggest an ontological relationship to other corticalbased gliomas of children and young adults. Neuro-Oncology 19, 31–42 (2017).
Boisseau, W. et al. Molecular profiling reclassifies adult astroblastoma into known and clinically distinct tumor entities with frequent mitogen-activated protein kinase pathway alterations. Oncologist 24, 1584–1592 (2019).
Wood, M. D. et al. Multimodal molecular analysis of astroblastoma enables reclassifcation of most cases into more specifc molecular entities. Brain Pathol. 28, 192–202 (2018).
Sturm, D. et al. New brain tumor entities emerge from molecular classification of CNS-PNETs. Cell 164, 1060–1072 (2016).
Capper, D. et al. DNA methylation-based classification of central nervous system tumours. Nature 555, 469–474 (2018).
Fukuoka, K. et al. Clinical impact of combined epigenetic and molecular analysis of pediatric low-grade gliomas. Neuro Oncol. 22, 1474–1483 (2020).
Korshunov, A. et al. Integrated analysis of pediatric glioblastoma reveals a subset of biologically favorable tumors with associated molecular prognostic markers. Acta Neuropathol. 129, 669–678 (2015).
Mackay, A. et al. Integrated molecular meta-analysis of 1,000 pediatric high-grade and diffuse intrinsic pontine glioma. Cancer Cell 32, 520–537 (2017).
Huillard, E. et al. Cooperative interactions of BRAFV600E kinase and CDKN2A locus deficiency in pediatric malignant astrocytoma as a basis for rational therapy. Proc. Natl Acad. Sci. USA 109, 8710–8715 (2012).
The authors wish to acknowledge Dr. Tejpal Gupta, Professor and Officer in charge, Department of Radiation Oncology, Tata Memorial Centre, Mumbai, India, for his inputs and edits in the treatment section of this review.
The authors declare no competing interests.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Mahajan, S., Dandapath, I., Garg, A. et al. The evolution of pleomorphic xanthoastrocytoma: from genesis to molecular alterations and mimics. Lab Invest 102, 670–681 (2022). https://doi.org/10.1038/s41374-021-00708-0