Sudan Journal of Medical Sciences Volume 12, Issue no. 3, DOI 10.18502/sjms.v12i3.1001 Production and Hosting by Knowledge E Research Article Rare Suprasellar Chordoid Meningioma with INI1 gene mutation Imad Fadl-Elmula1, Rania Giha2, Sawsan A. H. Deaf2, Lamyaa Ahmed El Hassan3, Ahmed M. Hassan4, and Mohamed A. R. Arbab5 1Department of Histopathology, Faculty of Medical Laboratory Sciences, Al Neelain University, Khartoum, Sudan 2National Centre of Neurological Sciences, Khartoum, Sudan 3Department of Pathology, Faculty of Medicine, Ahfad University for Women, Omdurman, Sudan 4Institute of Endemic Diseases, University of Khartoum, Khartoum, Sudan 5Department of Surgery, Faculty of medicine, University of Khartoum, Khartoum, Sudan Abstract Background: Chordoid Meningioma is a rare brain tumour characterized genetically by loss of genetic material from chromosome 22q at cytogenetic level resulting in mutation of NF2 gene. Objectives and case report: In the present report, we described a rare case of suprasellar chordoid meningioma, which presented in a 32-year-old-woman. Her only complain was throbbing headache. Neurological examination showed left temporal hemianopia, decreased visual acuity (3/6), and no physical abnormalities related to Castleman syndrome were noted. Cranial magnetic resonance (MR) images demonstrated a 28x15 mm mass in the sellar region, which showed iso-to low intensity that enhanced vividly after gadolinium with upwards displacement of the Optic chiasm. Total surgical excision of the tumour was performed and subsequent histological examination of the tumour showed typical histology pattern of chordoid meningioma grade II according to the WHO classification system of meningiomas. Genomic DNA was extracted and mutation analysis for INI1 gene using primer of exon 4, 5, 7, and 9 showed mutation involving exon 9. DNA sequencing showed heterozygosity C-T mutation in exon 9 of INI1 gene leading to change of amino acid serine to phenylalanine at (codon 63). The details of this case are presented with a review of the literature. Keywords: Chordoid Meningioma, Brain tumours, INI1 gene How to cite this article: Imad Fadl-Elmula, Rania Giha, Sawsan AH Deaf, Lamyaa Ahmed El Hassan, Ahmed M. Hassan, and Mohamed A. R. Arbab, (2017) “Rare Suprasellar Chordoid Meningioma with INI1 gene mutation,” Sudan Journal of Medical Sciences, vol. 12 (2017), issue no. 3, 198–206. DOI 10.18502/sjms.v12i3.1001 Page 198 Corresponding Author: Imad Fadl-Elmula; email: Imad@fadl-elmula.com Received: 15 June 2017 Accepted: 1 July 2017 Published: 4 July 2017 Production and Hosting by Knowledge E Imad Fadl-Elmula et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited. Editor-in-Chief: Prof. Mohammad A. M. Ibnouf http://www.knowledgee.com mailto:Imad@fadl-elmula.com https://creativecommons.org/licenses/by/4.0/ https://creativecommons.org/licenses/by/4.0/ Sudan Journal of Medical Sciences Production and Hosting by Knowledge E 1. Introduction Chordoid meningioma, accounts for 0.5% of all intracranial meningiomas. It was first described by Kepes et al., in 1988, and accepted as meningiomas variants by the WHO classification of the central nervous system tumour in 19931,2. Association of the tumour with haematologic abnormality such as microcytic anaemia and dysgammaglobulinemia and/or Castleman syndrome have been repeat- edly reported, especially, in paediatric patients [1], although chordoid meningioma with no hematological abnormalities have also been reported [3, 4]. Microscopically chordoid meningiomas have features of meningioma similar to chor- doma which is usually characterized by epitheliod cord like tumour cells. It is classified as WHO grade II tumour [5]. There are eosinophilic vacuolated cells within a myxoid stroma and a lymphoplasmocytic infiltrate is often apparent and might be associated with haematological abnormalities [6]. Cytogenetic analysis revealed that monosomy 22 is a common, early, and perhaps primary event in the genesis of meningioma. Molecular analysis has identified several important candidate genes. Of those, Neurofibromatosis 2 (NF2), Tumour Suppressor in Lung Cancer-1 (TSLC1), and TP53 are the most commonly reported. The INI1 (SMARCB1/hSNF5) gene, maps to chromosome 22q11.2, is part of the SWI/SNF complex participating in transcriptional regulation by remodeling chromatin in an ATP-dependent manner [7]. The SWI/SNF complex seems to be involved in DNA replication [8]. These features characterize members of the SWI/SNF complex as interesting targets for genes which may be involved in tumour formation. Recently, INI1 has been shown to carry mutations predominately in some central nervous system tumours such as meningiomas [9], schwannomas [10], astrocy- tomas11, ependymomas12 and glioblastomas11). INI1, therefore, is an interesting candidate gene for brain tumours, especially those entities that exhibit allelic loss on chromosome 22. 2. Material and Methods 2.1. The Case A 32-year-old-female lady presented with four months history of throbbing headache and left visual field and acuity defect that worsened over the last three weeks. Neuro- logical examination showed left temporal hemianopia, decreased visual acuity (3/6), and no physical abnormalities related to Castleman disease. DOI 10.18502/sjms.v12i3.1001 Page 199 Sudan Journal of Medical Sciences Production and Hosting by Knowledge E Routine laboratory investigations including Hb, MCV, MCH, total protein, albumen, and globulin were all normal. MRI revealed large iso-intense sellar mass measuring 2.8?1.5 X1.5 cm that enhanced vividly after gadolinium with upwards displacement of the Optic chiasm (Figure F1-A). A provisional preoperative diagnosis of a pituitary macro adenoma was made. Preoperative assessment of T3, T4, TSH and prolactin was normal. The patient was then operated upon through right sub frontal surgical approach. Intraoperatively, a firm, circumscribed fibrous tumour with numerous vas- cular feeders was found. Using the operating microscope, total excision of the tumour and its dural attachment was attained according to Simpson classification grade I13. Part of the tumour was fixed in 10% neutral formalin for histopathology examination. The other part was kept for molecular studies. 2.2. Molecular Analysis Genomic DNA was isolated using chloroform phenol extraction methods. PCR was performed under standard conditions using dNTPs, Taq DNA polymerase (Promega, Madison, Wisconsin, USA), and a Biometra UNO Thermoblock (Biometra, Gottingen, Germany). Primers of exon 4, 5, 7, and 9 for INI1 gene, were analyzed by SSCP and direct sequencing employing a set of primers specified Exon 4 forward primer, 5‘-TCA GGT CCT ATA CTG ACT GG-3‘. Exon 4 reverse primer, 5‘-AGA ACT AAG GCG GAA TCA GC-3‘. Exon 5 forward primer, 5‘-GCT TCC ATT TCA CTT TCA GC-3‘. Exon 5 reverse primer, 5‘-GTT CCC ACG TAA CAC ACA GG-3‘. Exon 7 forward primer, 5‘-CCTGGGCTGCAAAAGCTCTA-3‘ Exon 7 reverse primer, 5‘-GGAGGGAGAGACTCATGCAT-3‘ Exon 9 forward primer, 5‘-TGT TCC CAC CCC TAC ACT TG-3‘. Exon 9 reverse primer, 5‘-ATG AAT GGA GAC GCG CGC TCT-3‘ PCR was performed in a final volume of 25 𝜇l containing 100 ng DNA, 50 mM KCl, 20 mM TRIS-HCl pH 8.4, 200 𝜇M of each dNTP, 0.1% gelatin, 10 pmol of each primer, 1.0–2.0 mM MgCl2 and 0.25 U Taq polymerase. Using touchdown programmed initial denaturation at 94∘C for 1 min was followed by 40 cycles on an automated thermal cycler (Biometra, Germany). These included denaturation at 94∘C for 35 s, annealing at temperatures ranging from 58∘C to 62∘C depending on the primer pair for 40 s, and extension at 72∘C for 40s followed by the final extension step at 72∘C for 10 min. The DOI 10.18502/sjms.v12i3.1001 Page 200 Sudan Journal of Medical Sciences Production and Hosting by Knowledge E Figure 1 PCR products on acrylamide gel using SSCP analysis was performed on apparatus using 12% acrylamide gels. Electrophoresis was run at 2–6 W and variable temperatures. DOI 10.18502/sjms.v12i3.1001 Page 201 Sudan Journal of Medical Sciences Production and Hosting by Knowledge E Figure 2 2.3. Sequencing The same primers used for PCR analysis were used for sequencing. PCR products samples were sent for commercial sequencing at Macrogen, Seoul, Republic of Korea. The BLAST (Basic Local Alignment Search Tool) programmer at the site of National Center for biotechnology Information (NCBI) was used for individual alignment of our samples. 3. Results Following surgery the patient had an uneventful postoperative recovery; the headache subsided and the visual acuity markedly improved to 5\6. Postoperative values of T3, T4, TSH and prolactin were within normal ranges. Microscopic examination of the tumour specimen revealed cluster of cohesive cells with dark regular nuclei and tapering cytoplasm arranged in a fibrous stroma showing an intense lymphocytic and plasma cells infiltration. There were scattered Russell bod- ies in the inflammatory reaction (Figure 2). The diagnosis of chordoid meningioma with DOI 10.18502/sjms.v12i3.1001 Page 202 Sudan Journal of Medical Sciences Production and Hosting by Knowledge E inflammatory reaction WHO Grade II was made and hence the patient was submitted to conformal radiotherapy [14, 15]. The postoperative MRI revealed total removal of the tumour (Figure F1-B). 3.1. Molecular results The sequencing indicated that the mutation was heterozygotic with heterozygosity C- T mutation in exon 9 of INI1 gene, the mutation changed in the amino acid serine to phenylalanine in (codon 63) in this polymorphism data not reported in data analysis programmer. 4. Discussion Schmitz and co-workers have suggested an important role of INI1 gene in the patho- genesis of meningioma16. This suggestion led many to speculate that NF2 is not the only important gene in the pathogenesis of meningioma17. However, INI1 mutations were seen in only four tumours out of 126 meningiomas16. Interestingly, INI1 muta- tions in all four cases were in the same position: nucleotide 377 (Arg to His substitu- tion). This intriguing finding prompted others to check the status of INI1 hot spots of exons 4, 5, 7 and 9 in meningioma. However, all these studies were based in Europe and USA, thus no such a study was performed in African population. Considering the differences in clinical, histopathological, and the natural history of meningiomas in the two populations, one may anticipate differences in the genetic profile as well. Meningiomas can potentially occur at any site in the meninges. However, the most common locations known are the parasagittal and falcine tumours that account for around 24% of meningiomas, convexity tumours in 18%, olfactory groove, and tuber- cular sellae seen in 10% each. Suprasellar chordoid meningioma is a rare tumour that may mimic pituitary adenomas. In the present case, the clinical presentation was dom- inated by headache and visual deterioration. The MRI finding was consistent with a pituitary adenoma. Association of chordoid meningioma and Castleman syndrome has been reported [18, 19]. The present case did not show features of Castleman syndrome. Chordoid meningioma is a rare variant of meningioma; the differential diagnosis includes glioma, myxoid chondrosarcoma, chondroid chordoma, and other variants of meningiomas [4, 19–21]. Usually they show trabeculae or cords of eosinophilic vacuo- lated cells in myxoid matrix [22]. The fact that the tumour proved to be chordoid meningioma should alert attention to this possibility in interpretation of suprasellar tumours. More-over, WHO grade II DOI 10.18502/sjms.v12i3.1001 Page 203 Sudan Journal of Medical Sciences Production and Hosting by Knowledge E meningiomas are considered to have an aggressive course. In the present report, there were no features of an aggressive behavior; this might be due to early detection of the tumour. The aggressive behaviour and the fibrous texture of these tumours with its close anatomical relation to the vital structures in the sellar region render tumour recurrence a potential risk. Use of post-operative radio therapy lessens the chance of recurrence. Close and regular follow up of these patients is mandatory to detect such recurrence. conclusion: The general belief from the clinical point of view that meningiomas are benign tumours has to be accepted with great care, since only the histological diagnosis can verify the potential aggressive behaviour of the tumour and the subsequent liability for recurrence. References [1] J. J. Kepes, W. Y. Chen, M. H. Connors, and F. S. Vogel, ““Chordoid” meningeal tumors in young individuals with peritumoral lymphoplasmacellular infiltrates causing systemic manifestations of the castleman syndrome. A report of seven cases,” Cancer, vol. 62, no. 2, pp. 391–406, 1988. [2] P. Kleihues, D. N. Louis, B. W. Scheithauer et al., “The WHO Classification of Tumors of the Nervous System,” Journal of Neuropathology & Experimental Neurology, vol. 61, no. 3, pp. 215–225, 2002. [3] H. Yano, A. Hara, K. Takenaka et al., “Differential expression of β-catenin in human glioblastoma multiforme and normal brain tissue,” Neurological Research, vol. 22, no. 7, pp. 650–656, 2000. [4] M. E. Couce, F. V. Aker, and B. W. Scheithauer, “Chordoid meningioma: A clinicopathologic study of 42 cases,” American Journal of Surgical Pathology, vol. 24, no. 7, pp. 899–905, 2000. [5] P. C. W. Lui, T. K. F. Chau, S. S. Wong et al., “Cytology of chordoid meningioma: A series of five cases with emphasis on differential diagnoses,” Journal of Clinical Pathology, vol. 60, no. 9, pp. 1024–1028, 2007. [6] S. Nagao, N. Kawai, T. Ohomoto, and T. Oohashi, “A case of intrasellar and suprasellar meningioma with hypopituitarism,” Neurological Surgery, vol. 18, no. 7, pp. 637–642, 1990. [7] J. A. Armstrong, J. J. Bieker, and B. M. Emerson, “A SWI/SNF-related chromatin remodeling complex, E-RC1, is required for tissue-specific transcriptional regulation by EKLF in vitro,” Cell, vol. 95, no. 1, pp. 93–104, 1998. DOI 10.18502/sjms.v12i3.1001 Page 204 Sudan Journal of Medical Sciences Production and Hosting by Knowledge E [8] J. F. Flanagan and C. L. Peterson, “A role for the yeast SWI/SNF complex in DNA replication,” Nucleic Acids Research, vol. 27, no. 9, pp. 2022–2028, 1999. [9] J. P. Dumanski, V. P. Collins, M. Nordenskjold, and G. A. Rouleau, “Molecular Genetic Analysis of Chromosome 22 in 81 Cases of Meningioma,” Cancer Research, vol. 50, no. 18, pp. 5863–5867, 1990. [10] B. R. Seizinger, R. L. Martuza, and J. F. Gusella, “Loss of genes on chromosome 22 in tumorigenesis of human acoustic neuroma,” Nature, vol. 322, no. 6080, pp. 644– 647, 1986. [11] C. D. James, E. Carlbom, J. P. Dumanski et al., “Clonal Genomic Alterations in Glioma Malignancy Stages,” Cancer Research, vol. 48, no. 19, pp. 5546–5551, 1988. [12] C. D. James, J. He, E. Carlbom et al., “Loss of genetic information in central nervous system tumors common to children and young adults,” Genes, Chromosomes and Cancer, vol. 2, no. 2, pp. 94–102, 1990. [13] D. Simpson, “The recurrence of intracranial meningiomas after surgical treatment,” Journal of Neurology, Neurosurgery, and Psychiatry, vol. 20, no. 1, pp. 22–39, 1957. [14] W. Stenzel, G. Röhn, H. Miletic, H. Radner, M. Deckert, and R.-I. Ernestus, “Diagnostic impact of ornithine decarboxylase in meningiomas,” Journal of Neuro-Oncology, vol. 66, no. 1-2, pp. 59–64, 2004. [15] P. Kleihues and W. K. Cavenee, WHO Classification of Tumours Pathology and Genetics of Tumours of Nervous System, IARC press, Lyon, 2000. [16] U. Schmitz, W. Mueller, M. Weber, N. Sévenet, O. Delattre, and A. V. Deimling, “INI1 mutations in meningiomas at a potential hotspot in exon 9,” British Journal of Cancer, vol. 84, no. 2, pp. 199–201, 2001. [17] M. Peyrard, I. Fransson, Y.-G. Xie et al., “Characterization of a new member of the human /-adaptin gene family from chromosome 22q12, a candidate meningioma gene,” Human Molecular Genetics, vol. 3, no. 8, pp. 1393–1399, 1994. [18] F. C. Stam, H. A. M. van Alphen, and D. M. Boorsma, “Meningioma with conspicuous plasma cell components - A histopathological and immunohistochemical study,” Acta Neuropathologica, vol. 49, no. 3, pp. 241–243, 1980. [19] H. Kobata, A. Kondo, K. Iwasaki, H. Kusaka, H. Ito, and S. Sawada, “Chordoid meningioma in a child. Case report,” Journal of Neurosurgery, vol. 88, no. 2, pp. 319– 323, 1998. [20] G. W. Mierau and D. A. Weeks, “Chondroid chordoma,” Ultrastructural Pathology, vol. 11, no. 5-6, pp. 731–737, 1987. [21] D. J. Brat, The elusive origin of chordoid glioma. Arch Pathol Lab Med, 130, 437-438, 2006. DOI 10.18502/sjms.v12i3.1001 Page 205 Sudan Journal of Medical Sciences Production and Hosting by Knowledge E [22] M. E. Couce, F. V. Aker, and B. W. Scheithauer, “Chordoid meningioma: A clinicopathologic study of 42 cases,” American Journal of Surgical Pathology, vol. 24, no. 7, pp. 899–905, 2000. DOI 10.18502/sjms.v12i3.1001 Page 206 Introduction Material and Methods The Case Molecular Analysis Sequencing Results Molecular results Discussion References