- Email: [email protected]
Cerebellar pleomorphic xanthoastrocytoma in a patient with neurofibromatosis type 1 – Molecular study and review of literature
Human Pathology: Case Reports 11 (2018) 39–42
Contents lists available at ScienceDirect
Human Pathology: Case Reports journal homepage: http://www.humanpathologycasereports.com
Case Report
Cerebellar pleomorphic xanthoastrocytoma in a patient with neurofibromatosis type 1 – Molecular study and review of literature Shira Ronen, MD a, Mohit Agarwal, MD b, Alexander C. Mackinnon, MD, PhD a, Elizabeth Cochran, MD a,⁎ a b
Medical College of Wisconsin, Department of Pathology, 9200 W. Wisconsin Avenue, Milwaukee, WI 53226, United States Medical College of Wisconsin, Department of Radiology, 9200 W. Wisconsin Avenue, Milwaukee, WI 53226, United States
a r t i c l e
i n f o
Article history: Received 5 June 2017 Received in revised form 25 September 2017 Accepted 5 October 2017 Available online xxxx
1. Introduction Pleomorphic xanthoastrocytoma (PXA) is a rare astrocytic neoplasm, constituting b 1% of all astrocytic neoplasms and usually found in children and young adults. Patients usually present with long history of seizures and occasionally headaches. With surgical resection, the patient has a relatively favorable outcome. The most common location for PXAs is the cerebral hemispheres. Tumors originating in the cerebellum are extremely rare [1–3]. The majority of PXAs behave as low-grade tumors without recurrence or metastases. However, up to 20% of cases may show progression to a higher grade astrocytic neoplasm [2,4–6]. We present a case of cerebellar PXA in a patient with neurofibromatosis type 1 (NF1) that recurred 6 months after resection. The clinical, radiographic, histopathologic and molecular features of this case are described.
2. Case report 2.1. Clinical presentation This patient is an 18-year-old male who presented with recent onset nausea and emesis and severe bifrontal headache which was present for several months. He also complained of off-balance gait and right hand tremor with fine movements. On physical examination, numerous café-au-lait spots and axillary freckling was noted. On neurologic examination, the only abnormality was bilateral mild dysmetria on finger-tonose testing. MRI of brain with and without contrast identified an enhancing lesion in the right cerebellar hemisphere with mass effect on ⁎ Corresponding author. E-mail address: [email protected] (E. Cochran).
the fourth ventricle, hydrocephalus, cerebellar tonsillar herniation, and a syrinx in the spinal cord. (Fig. 1) An incomplete resection of the cerebellar mass was performed and a right ventriculostomy catheter placed. Due to the presence of multiple cafe au lait spots and axillary freckling, there was concern for the presence of a syndrome, and genetic testing was performed. A pathogenic mutation of the NF1 gene was detected by sequence analysis, specifically c.3198-2AN G. Following identification of this mutation, Lisch nodules were identified on the iris by ophthalmological examination. Postoperatively, the first cycle of chemotherapy (procarbazine, lomustine, and vincristine) was started but several months later, MRI brain scan showed enlargement of the right cerebellar lesion with heterogeneous enhancement and significant mass effect with right to left midline shift, superior transtentorial herniation and cerebellar tonsillar herniation. (Fig. 2). Therefore, a second surgery to debulk the tumor was performed with postoperative radiotherapy. 2.2. Pathological finding The original resection showed low or moderately cellular neoplasm composed of scattered astrocytic appearing cells infiltrating brain parenchyma. (Fig. 3A–B) The cells frequently exhibited markedly pleomorphic nuclei with intranuclear cytoplasmic inclusions; no eosinophilic granular bodies, Rosenthal fibers, or xanthomatous cytoplasm was seen. Mitoses were very sparse and no necrosis or endothelial proliferation was seen. Immunohistochemistry showed the following results: MIB-1: sparse positive nuclei (Fig. 3.C), Neurofilament: preservation of axons with neoplastic cells interspersed confirming infiltrative nature (Fig. 3D), CD45: occasional positive lymphocytes and macrophages, GFAP: positive neoplastic cells, p53: sparse lightly positive neoplastic nuclei, and IDH1 (R132H): negative in the neoplastic cells. FISH for codeletions 1p and 19q was negative. Diagnosis of diffuse astrocytoma, WHO grade 2 was made. Histological features of the specimen received from the second surgery showed moderate to high cellularity and were composed predominantly of cells with markedly pleomorphic, hyperchromatic nuclei. (Fig. 4A–B) Eosinophilic granular bodies and occasional xanthomatous change to the cell cytoplasm were seen. Mitoses were very sparse and no endothelial proliferation or necrosis was seen. Reticulin was limited to the blood vessels, PAS highlighted eosinophilic granular bodies (Fig. 4C), CD34 immunohistochemistry was negative in the neoplastic cells and MIB-1 was increased (Fig. 4D). The morphology of the second
https://doi.org/10.1016/j.ehpc.2017.10.001 2214-3300/Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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S. Ronen et al. / Human Pathology: Case Reports 11 (2018) 39–42
Fig. 1. Axial FLAIR (A), axial T2W (B), Gadolinium-enhanced axial T1W (C) and Gadolinium-enhanced sagittal T1W (D) images show a long TR hyperintense heterogeneously enhancing mass in the right cerebellum with significant surrounding vasogenic edema. There is mass effect with effacement of the fourth ventricle (arrow in B). Mass effect caused inferior cerebellar tonsillar herniation (arrow in D). Altered CSF flow dynamics caused syrinx formation in the spinal cord (chevron in D). Left anterior temporal arachnoid cyst is incidental.
resection suggested a pleomorphic xanthoastrocytoma, WHO grade 2 without increased mitoses to support an anaplastic neoplasm. 2.3. Molecular analysis Highly purified DNA was extracted from paraffin sections of the recurrent tumor. DNA and library concentrations were quantified by spectrofluorometry methods (Qubit). Purified DNA was used to prepare a library following the Ion AmpliSeq Library Kit (Life Technologies)
Fig. 3. Photomicrograph, first surgery: A Sections show a neoplasm of low cellular density composed of astrocytic-appearing cells with multinucleation and pleomorphism. (40×). B. MIB-1 immunohistochemistry shows sparse positive nuclei indicating a low proliferation index (40×). C. Neurofilament immunohistochemistry highlights the preservation of axons with interspersed neoplastic cells confirming infiltrative nature (40×).
Fig. 2. Axial T2W (A), Gadolinium-enhanced axial T1W (B) and pre-contrast sagittal T1W (C) MRI images approx. 5 months after the first surgery and treatment with chemotherapy. Despite treatment the mass has increased in size. Note increased extent in the cerebellum and the brainstem (chevron in A). There is increased effacement of the fourth ventricle (arrow in A). Extent of enhancement in the mass has also increased (arrow in B and compare to Fig. 1C). There is increased mass effect on the posterior aspect of brainstem (arrow in C and compare to Fig. 1D) and increased cerebellar tonsillar herniation (chevron in C).
S. Ronen et al. / Human Pathology: Case Reports 11 (2018) 39–42
41
Fig. 4. Photomicrograph, second surgery: A. Sections show moderate to high cellularity with marked nuclear multinucleation and pleomorphism (H&E, 20×). B. Perivascular lymphocytes are present (H&E, 40×). C. Eosinophilic granular body is seen which is a frequent finding in PXA (H&E, 60×). D. A xanthomatous cell with bubbly cytoplasm is in the center of the field (H&E, 60×). E. MIB-1 immunohistochemistry shows higher proliferative index in comparison to the first resection (40×).
protocol. The library was quantified and diluted, and a barcode was applied to the library. The library was then clonally amplified onto Ion Sphere Particles (ISPs) using Ion OneTouch 200 Template Kit (Life Technologies) protocol. Templated ISPs were sequenced on the Ion PGM system following the manufacturer's instructions, and genetic variants were identified using the Ion Torrent Server software. Variants were further reviewed and annotated using the GenomOncology Clinical Workbench software. The following genes were examined for alterations of know or potential pathogenicity and all were negative; BRAF, IDH1, IDH2, ABL1, AKT1, ALK, APC, ATM, CDH1, CDKN2, CSF1R, CTNNB1, EGFR, ERBB2, ERBB4, EZH2, FBXW7, FGFR1, FGFR2, FGFR3, FLT3, GNA11, GNAQ, GNAS, HNF1A, HRAS, JAK2, JAK3, KDR, KIT, KRAS, MET, MLH1, MPL, NOTCH1, NPM1, NRAS, PDGFRA, PIK3CA, PTEN, PTPN11, RB1, RET, SMAD4, SMARCB1, SMO, SRC, STK11, TP53 and VHL. 3. Discussion PXAs are most frequently low grade (WHO grade II) glial neoplasms, predominantly affecting children and young adults with no sex predilection. They are characterized by giant cells with pleomorphic nuclei, prominent eosinophilic granular bodies, cytoplasmic protein droplets, abundant reticulin fibers, and occasional intracytoplasmic lipid accumulation. Mitotic activity and necrosis are usually absent or inconspicuous with MIB-1 proliferation index is generally b1%. Rarely, PXAs behave
more aggressively and are characterized by increased mitoses (equal or N 5 mitoses per 10 high-power fields). These PXAs are designated as anaplastic PXA, WHO grade III [7]. PXAs most commonly occur in cerebral hemispheres, most commonly in the temporal lobe, with cyst formation and involvement of adjacent leptomeninges. Very few cases have been described arising in deep gray matter, cerebellum, spinal cord, sella, suprasellar region, olfactory groove and retina [8–13]. Neurofibromatosis type 1 is an autosomal dominant disorder caused by mutations in the NF1 gene. NF1 is characterized by café au lait macules, skin fold freckling, optic pathway gliomas, neurofibromas and plexiform neurofibromas, osseous lesions, and iris hamartomas (Lisch nodules). Cerebral involvement by the disease is characterized by optic pathway gliomas (seen in 15–20%) and brainstem gliomas [14]. The most common histopathologic type of glioma reported in NF1 is pilocytic astrocytoma, with a smaller representation of diffuse gliomas and glioblastoma. PXA does not commonly occur in NF1; there are fourteen reported cases [1,2,15–17] of PXA in patients with NF1, and only four cases of PXA in NF1 occurring in the cerebellum, including the current patient. (Table 1) [1–3]. The most common gene mutation in PXA is BRAF (V600E) which is seen up to 60% of PXA [6,18]. However, in our case it was not present. Takei at el. also recently reported a case of PXA in a patient with NF1 in the cerebellum without a BRAF (V600E) mutation [2]. The remaining reported cases of PXA of the cerebellum associated with NF1 have not
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S. Ronen et al. / Human Pathology: Case Reports 11 (2018) 39–42
Table 1 The current documented cases of PXA-NF1-cerebellar location in the literature. Authors & year
Age (years), Gender
Symptoms
Imaging Finding
Histological features
Treatment
Follow Up
Molecular analysis
Naidich, et al., 2004
51, Female
Worsening ataxia
WHO grade 2
Surgery and radiotherapy
(Discharge to rehabilitation in good condition)
N/A
Saikali, et al., 2005
36, Female
Headache
Anaplastic features
Surgery, radiotherapy and chemotherapy
Died 3 years after 1st surgery
N/A
Takei, et al., 2015
33, Female
Headache
WHO grade 2
Surgery and radiotherapy
N/A
BRAF (V600E) negative
Present case
18, Male
Headache, nausea & emesis, tremor
Abnormal hyperintensity in the vermis, extending into both cerebellar hemispheres. Iso- to hypointense occipital cystic tumor and multiple iso- to hypointense signals in the right cerebellar hemisphere 3.4 cm ill-defined lesion with a gyriform enhancing pattern in the left cerebellum Enhancing lesion in the right cerebellar hemisphere with mass effect on the fourth ventricle and hydrocephalus
WHO grade 2
Surgery, chemotherapy and radiotherapy
Alive without second recurrence two years after second surgery
BRAF (V600E) negative IDH1 (R132H) negative
been evaluated for a BRAF mutation. There are also cases reported of PXA, associated with NF1, occurring in the cerebrum where BRAF(V600E) mutation is not present [15]. These reports suggest the possibility of a different pathogenesis of PXAs that occur in patients with NF1. In summary, we have described the fourth case of cerebellar PXA in NF1 patient. We performed molecular testing on 50 cancer associated genes to look for the mechanism that can lead to the different biological behavior seen in PXA-NF1. However, variants in these genes were not identified, including BRAF, which is the most common mutation in PXA. Further analysis is necessary to increase the understanding of PXA in patients with NF-1. References [1] S. Saikali, et al., Multicentric pleomorphic xanthoastrocytoma in a patient with neurofibromatosis type 1. Case report and review of the literature, J. Neurosurg. 102 (2) (2005) 376–381. [2] H. Takei, E. Rouah, M.B. Bhattacharjee, Cerebellar pleomorphic xanthoastrocytoma in a patient with neurofibromatosis type 1: a case report and literature review, Int. J. Clin. Exp. Pathol. 8 (6) (2015) 7570–7574. [3] M.J. Naidich, et al., Cerebellar pleomorphic xanthoastrocytoma in a patient with neurofibromatosis type 1, Neuroradiology 46 (10) (2004) 825–829. [4] C. Giannini, et al., Pleomorphic xanthoastrocytoma: what do we really know about it? Cancer 85 (9) (1999) 2033–2045. [5] Y. Schmidt, et al., Anaplastic PXA in adults: case series with clinicopathologic and molecular features, J. Neuro-Oncol. 111 (1) (2013) 59–69.
[6] C. Koelsche, et al., BRAF-mutated pleomorphic xanthoastrocytoma is associated with temporal location, reticulin fiber deposition and CD34 expression, Brain Pathol. 24 (3) (2014) 221–229. [7] D.N. Louis, et al., WHO classification of Tumours of the Central Nervous System, 4th ed. International Agency for Research on Cancer (IARC), Lyon, 2016. [8] M.V. Kaku, et al., Pleomorphic xanthoastrocytoma arising from olfactory groove: a rare location for a rare tumor, Pediatr. Neurosurg. 49 (5) (2013) 292–296. [9] D.J. Yeh, et al., Composite pleomorphic xanthoastrocytoma-ganglioglioma presenting as a suprasellar mass: case report, Neurosurgery 52 (6) (2003) 1465–1468 (discussion 1468-9). [10] K. Arita, et al., Intrasellar pleomorphic xanthoastrocytoma: case report, Neurosurgery 51 (4) (2002) 1079–1082 (discussion 1082). [11] X. Zhao, X. Jiang, X. Wang, Spinal pleomorphic xanthoastrocytoma companied with periventricular tumor, Int. J. Clin. Exp. Pathol. 8 (1) (2015) 1036–1040. [12] J.O. Zarate, R. Sampaolesi, Pleomorphic xanthoastrocytoma of the retina, Am. J. Surg. Pathol. 23 (1) (1999) 79–81. [13] S. Yu, et al., Pleomorphic xanthoastrocytoma: MR imaging findings in 19 patients, Acta Radiol. 52 (2) (2011) 223–228. [14] N.J. Ullrich, Neurocutaneous syndromes and brain tumors, J. Child Neurol. 31 (12) (2016) 1399–1411. [15] M.A. Vizcaino, et al., Pleomorphic xanthoastrocytoma: report of two cases with unconventional clinical presentations, Clin. Neuropathol. 33 (6) (2014) 380–387. [16] A.O. Adeleye, et al., Cerebral pleomorphic xanthoastrocytoma associated with NF1: an updated review with a rare atypical case from Africa, Neurosurg. Rev. 35 (3) (2012) 313–319 (discussion 319). [17] M.T. Neal, T.L. Ellis, C.A. Stanton, Pleomorphic xanthoastrocytoma in two siblings with neurofibromatosis type 1 (NF-1), Clin. Neuropathol. 31 (1) (2012) 54–56. [18] G. Schindler, 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 (3) (2011) 397–405.
Contents lists available at ScienceDirect
Human Pathology: Case Reports journal homepage: http://www.humanpathologycasereports.com
Case Report
Cerebellar pleomorphic xanthoastrocytoma in a patient with neurofibromatosis type 1 – Molecular study and review of literature Shira Ronen, MD a, Mohit Agarwal, MD b, Alexander C. Mackinnon, MD, PhD a, Elizabeth Cochran, MD a,⁎ a b
Medical College of Wisconsin, Department of Pathology, 9200 W. Wisconsin Avenue, Milwaukee, WI 53226, United States Medical College of Wisconsin, Department of Radiology, 9200 W. Wisconsin Avenue, Milwaukee, WI 53226, United States
a r t i c l e
i n f o
Article history: Received 5 June 2017 Received in revised form 25 September 2017 Accepted 5 October 2017 Available online xxxx
1. Introduction Pleomorphic xanthoastrocytoma (PXA) is a rare astrocytic neoplasm, constituting b 1% of all astrocytic neoplasms and usually found in children and young adults. Patients usually present with long history of seizures and occasionally headaches. With surgical resection, the patient has a relatively favorable outcome. The most common location for PXAs is the cerebral hemispheres. Tumors originating in the cerebellum are extremely rare [1–3]. The majority of PXAs behave as low-grade tumors without recurrence or metastases. However, up to 20% of cases may show progression to a higher grade astrocytic neoplasm [2,4–6]. We present a case of cerebellar PXA in a patient with neurofibromatosis type 1 (NF1) that recurred 6 months after resection. The clinical, radiographic, histopathologic and molecular features of this case are described.
2. Case report 2.1. Clinical presentation This patient is an 18-year-old male who presented with recent onset nausea and emesis and severe bifrontal headache which was present for several months. He also complained of off-balance gait and right hand tremor with fine movements. On physical examination, numerous café-au-lait spots and axillary freckling was noted. On neurologic examination, the only abnormality was bilateral mild dysmetria on finger-tonose testing. MRI of brain with and without contrast identified an enhancing lesion in the right cerebellar hemisphere with mass effect on ⁎ Corresponding author. E-mail address: [email protected] (E. Cochran).
the fourth ventricle, hydrocephalus, cerebellar tonsillar herniation, and a syrinx in the spinal cord. (Fig. 1) An incomplete resection of the cerebellar mass was performed and a right ventriculostomy catheter placed. Due to the presence of multiple cafe au lait spots and axillary freckling, there was concern for the presence of a syndrome, and genetic testing was performed. A pathogenic mutation of the NF1 gene was detected by sequence analysis, specifically c.3198-2AN G. Following identification of this mutation, Lisch nodules were identified on the iris by ophthalmological examination. Postoperatively, the first cycle of chemotherapy (procarbazine, lomustine, and vincristine) was started but several months later, MRI brain scan showed enlargement of the right cerebellar lesion with heterogeneous enhancement and significant mass effect with right to left midline shift, superior transtentorial herniation and cerebellar tonsillar herniation. (Fig. 2). Therefore, a second surgery to debulk the tumor was performed with postoperative radiotherapy. 2.2. Pathological finding The original resection showed low or moderately cellular neoplasm composed of scattered astrocytic appearing cells infiltrating brain parenchyma. (Fig. 3A–B) The cells frequently exhibited markedly pleomorphic nuclei with intranuclear cytoplasmic inclusions; no eosinophilic granular bodies, Rosenthal fibers, or xanthomatous cytoplasm was seen. Mitoses were very sparse and no necrosis or endothelial proliferation was seen. Immunohistochemistry showed the following results: MIB-1: sparse positive nuclei (Fig. 3.C), Neurofilament: preservation of axons with neoplastic cells interspersed confirming infiltrative nature (Fig. 3D), CD45: occasional positive lymphocytes and macrophages, GFAP: positive neoplastic cells, p53: sparse lightly positive neoplastic nuclei, and IDH1 (R132H): negative in the neoplastic cells. FISH for codeletions 1p and 19q was negative. Diagnosis of diffuse astrocytoma, WHO grade 2 was made. Histological features of the specimen received from the second surgery showed moderate to high cellularity and were composed predominantly of cells with markedly pleomorphic, hyperchromatic nuclei. (Fig. 4A–B) Eosinophilic granular bodies and occasional xanthomatous change to the cell cytoplasm were seen. Mitoses were very sparse and no endothelial proliferation or necrosis was seen. Reticulin was limited to the blood vessels, PAS highlighted eosinophilic granular bodies (Fig. 4C), CD34 immunohistochemistry was negative in the neoplastic cells and MIB-1 was increased (Fig. 4D). The morphology of the second
https://doi.org/10.1016/j.ehpc.2017.10.001 2214-3300/Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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S. Ronen et al. / Human Pathology: Case Reports 11 (2018) 39–42
Fig. 1. Axial FLAIR (A), axial T2W (B), Gadolinium-enhanced axial T1W (C) and Gadolinium-enhanced sagittal T1W (D) images show a long TR hyperintense heterogeneously enhancing mass in the right cerebellum with significant surrounding vasogenic edema. There is mass effect with effacement of the fourth ventricle (arrow in B). Mass effect caused inferior cerebellar tonsillar herniation (arrow in D). Altered CSF flow dynamics caused syrinx formation in the spinal cord (chevron in D). Left anterior temporal arachnoid cyst is incidental.
resection suggested a pleomorphic xanthoastrocytoma, WHO grade 2 without increased mitoses to support an anaplastic neoplasm. 2.3. Molecular analysis Highly purified DNA was extracted from paraffin sections of the recurrent tumor. DNA and library concentrations were quantified by spectrofluorometry methods (Qubit). Purified DNA was used to prepare a library following the Ion AmpliSeq Library Kit (Life Technologies)
Fig. 3. Photomicrograph, first surgery: A Sections show a neoplasm of low cellular density composed of astrocytic-appearing cells with multinucleation and pleomorphism. (40×). B. MIB-1 immunohistochemistry shows sparse positive nuclei indicating a low proliferation index (40×). C. Neurofilament immunohistochemistry highlights the preservation of axons with interspersed neoplastic cells confirming infiltrative nature (40×).
Fig. 2. Axial T2W (A), Gadolinium-enhanced axial T1W (B) and pre-contrast sagittal T1W (C) MRI images approx. 5 months after the first surgery and treatment with chemotherapy. Despite treatment the mass has increased in size. Note increased extent in the cerebellum and the brainstem (chevron in A). There is increased effacement of the fourth ventricle (arrow in A). Extent of enhancement in the mass has also increased (arrow in B and compare to Fig. 1C). There is increased mass effect on the posterior aspect of brainstem (arrow in C and compare to Fig. 1D) and increased cerebellar tonsillar herniation (chevron in C).
S. Ronen et al. / Human Pathology: Case Reports 11 (2018) 39–42
41
Fig. 4. Photomicrograph, second surgery: A. Sections show moderate to high cellularity with marked nuclear multinucleation and pleomorphism (H&E, 20×). B. Perivascular lymphocytes are present (H&E, 40×). C. Eosinophilic granular body is seen which is a frequent finding in PXA (H&E, 60×). D. A xanthomatous cell with bubbly cytoplasm is in the center of the field (H&E, 60×). E. MIB-1 immunohistochemistry shows higher proliferative index in comparison to the first resection (40×).
protocol. The library was quantified and diluted, and a barcode was applied to the library. The library was then clonally amplified onto Ion Sphere Particles (ISPs) using Ion OneTouch 200 Template Kit (Life Technologies) protocol. Templated ISPs were sequenced on the Ion PGM system following the manufacturer's instructions, and genetic variants were identified using the Ion Torrent Server software. Variants were further reviewed and annotated using the GenomOncology Clinical Workbench software. The following genes were examined for alterations of know or potential pathogenicity and all were negative; BRAF, IDH1, IDH2, ABL1, AKT1, ALK, APC, ATM, CDH1, CDKN2, CSF1R, CTNNB1, EGFR, ERBB2, ERBB4, EZH2, FBXW7, FGFR1, FGFR2, FGFR3, FLT3, GNA11, GNAQ, GNAS, HNF1A, HRAS, JAK2, JAK3, KDR, KIT, KRAS, MET, MLH1, MPL, NOTCH1, NPM1, NRAS, PDGFRA, PIK3CA, PTEN, PTPN11, RB1, RET, SMAD4, SMARCB1, SMO, SRC, STK11, TP53 and VHL. 3. Discussion PXAs are most frequently low grade (WHO grade II) glial neoplasms, predominantly affecting children and young adults with no sex predilection. They are characterized by giant cells with pleomorphic nuclei, prominent eosinophilic granular bodies, cytoplasmic protein droplets, abundant reticulin fibers, and occasional intracytoplasmic lipid accumulation. Mitotic activity and necrosis are usually absent or inconspicuous with MIB-1 proliferation index is generally b1%. Rarely, PXAs behave
more aggressively and are characterized by increased mitoses (equal or N 5 mitoses per 10 high-power fields). These PXAs are designated as anaplastic PXA, WHO grade III [7]. PXAs most commonly occur in cerebral hemispheres, most commonly in the temporal lobe, with cyst formation and involvement of adjacent leptomeninges. Very few cases have been described arising in deep gray matter, cerebellum, spinal cord, sella, suprasellar region, olfactory groove and retina [8–13]. Neurofibromatosis type 1 is an autosomal dominant disorder caused by mutations in the NF1 gene. NF1 is characterized by café au lait macules, skin fold freckling, optic pathway gliomas, neurofibromas and plexiform neurofibromas, osseous lesions, and iris hamartomas (Lisch nodules). Cerebral involvement by the disease is characterized by optic pathway gliomas (seen in 15–20%) and brainstem gliomas [14]. The most common histopathologic type of glioma reported in NF1 is pilocytic astrocytoma, with a smaller representation of diffuse gliomas and glioblastoma. PXA does not commonly occur in NF1; there are fourteen reported cases [1,2,15–17] of PXA in patients with NF1, and only four cases of PXA in NF1 occurring in the cerebellum, including the current patient. (Table 1) [1–3]. The most common gene mutation in PXA is BRAF (V600E) which is seen up to 60% of PXA [6,18]. However, in our case it was not present. Takei at el. also recently reported a case of PXA in a patient with NF1 in the cerebellum without a BRAF (V600E) mutation [2]. The remaining reported cases of PXA of the cerebellum associated with NF1 have not
42
S. Ronen et al. / Human Pathology: Case Reports 11 (2018) 39–42
Table 1 The current documented cases of PXA-NF1-cerebellar location in the literature. Authors & year
Age (years), Gender
Symptoms
Imaging Finding
Histological features
Treatment
Follow Up
Molecular analysis
Naidich, et al., 2004
51, Female
Worsening ataxia
WHO grade 2
Surgery and radiotherapy
(Discharge to rehabilitation in good condition)
N/A
Saikali, et al., 2005
36, Female
Headache
Anaplastic features
Surgery, radiotherapy and chemotherapy
Died 3 years after 1st surgery
N/A
Takei, et al., 2015
33, Female
Headache
WHO grade 2
Surgery and radiotherapy
N/A
BRAF (V600E) negative
Present case
18, Male
Headache, nausea & emesis, tremor
Abnormal hyperintensity in the vermis, extending into both cerebellar hemispheres. Iso- to hypointense occipital cystic tumor and multiple iso- to hypointense signals in the right cerebellar hemisphere 3.4 cm ill-defined lesion with a gyriform enhancing pattern in the left cerebellum Enhancing lesion in the right cerebellar hemisphere with mass effect on the fourth ventricle and hydrocephalus
WHO grade 2
Surgery, chemotherapy and radiotherapy
Alive without second recurrence two years after second surgery
BRAF (V600E) negative IDH1 (R132H) negative
been evaluated for a BRAF mutation. There are also cases reported of PXA, associated with NF1, occurring in the cerebrum where BRAF(V600E) mutation is not present [15]. These reports suggest the possibility of a different pathogenesis of PXAs that occur in patients with NF1. In summary, we have described the fourth case of cerebellar PXA in NF1 patient. We performed molecular testing on 50 cancer associated genes to look for the mechanism that can lead to the different biological behavior seen in PXA-NF1. However, variants in these genes were not identified, including BRAF, which is the most common mutation in PXA. Further analysis is necessary to increase the understanding of PXA in patients with NF-1. References [1] S. Saikali, et al., Multicentric pleomorphic xanthoastrocytoma in a patient with neurofibromatosis type 1. Case report and review of the literature, J. Neurosurg. 102 (2) (2005) 376–381. [2] H. Takei, E. Rouah, M.B. Bhattacharjee, Cerebellar pleomorphic xanthoastrocytoma in a patient with neurofibromatosis type 1: a case report and literature review, Int. J. Clin. Exp. Pathol. 8 (6) (2015) 7570–7574. [3] M.J. Naidich, et al., Cerebellar pleomorphic xanthoastrocytoma in a patient with neurofibromatosis type 1, Neuroradiology 46 (10) (2004) 825–829. [4] C. Giannini, et al., Pleomorphic xanthoastrocytoma: what do we really know about it? Cancer 85 (9) (1999) 2033–2045. [5] Y. Schmidt, et al., Anaplastic PXA in adults: case series with clinicopathologic and molecular features, J. Neuro-Oncol. 111 (1) (2013) 59–69.
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