Low-grade Rhabdoid Meningioma: Morphological Characteristics

Low-grade Rhabdoid Meningioma: Morphological Characteristics Arvids Jakovlevs, Andrejs Vanags, Janis Gardovskis, Ilze Strumfa SUMMARY Rhabdoid meningioma (RM) is a rare type of meningioma. It is classified as a grade III tumour (anaplastic meningioma) in the recent World Health Organization (WHO) classification of the tumours of the central nervous system (CNS). Here we describe a unique case of RM lacking any features of malignancy. Few cases of low-grade RMs are described in the literature in contrast with the grading of this entity in WHO classification. Key words: meningioma, rhabdoid, low-grade AIM OF THE DEMONSTRATION The aim of our article is to report a case of unusual RM lacking malignant features in regard to the issue about the prognostic significance of rhabdoid morphology in meningiomas. CASE REPORT A 37-year-old woman was admitted to the hospital due to progressive headaches over previous 1.5 years. The magnetic resonance imaging of head and brain revealed a well-demarcated intracranial lesion measuring 3.53.63.6 cm (Figure 1A). The mass was located adjacent to the frontal bone and was attached to the dura mater. The patient underwent a craniotomy and total tumour resection. Histological examination of the neoplasm revealed cells consistent with rhabdoid morphology. The tumour was almost entirely composed of polygonal, rather large cells that possessed eccentric nuclei, strongly eosinophilic cytoplasm with abundant pale globular inclusions and prominent cytoplasmic granularity (Figure 1B). The nuclei of neoplastic cells were slightly pleomorphic. Mitoses were absent in the whole specimen. In addition, the tumour had well-developed fibrous capsule that demarcated it from normal brain tissues. Psammoma bodies were found in some areas of the tumour. Immunohistochemical visualizati on (IHC) showed intense cytoplasmic expression of vimentin and epithelial membrane antigen (Figure 1C-D) as well as strong nuclear expression of progesterone receptors in the tumour cells. The neoplastic cells did not express smooth muscle actin, desmin, HMB-45, S-100 protein, kappa and lambda light chains. Ki-67 proliferation index was as low as 1.5 %. Thus, the morphological appearance and immunohistochemical features were consistent with RM and low-grade cellular characteristics. DISCUSSION Tumours with rhabdoid morphology were first described in 1978 in relation to malignant renal tumours of children (1). Nowadays, many tumours with rhabdoid morphology are known in different localizations including CNS and meninges. Rhabdoid cells have no evidence of myogenic origin. The term „rhabdoid† is used to denote close histological resemblance of tumour cells to rhabdomyoblasts. Rhabdoid cells are characterized by typical light microscopic morphology: round cells with eccentric, vesicular nuclei, prominent nucleoli and eosinophilic cytoplasm with paranuclear globular inclusions (3). Meningiomas developing from the meninges are among the most common intracranial tumours. Regarding these tumours, surgery is the mainstay of treatment, and neurosurgeon also is involved in the planning of further observation and treatment in accordance to the tumour grade (5). Meningiomas show wide range of histopathological appearances. While the majority of meningiomas are benign tumours (WHO grade I meningiomas), some meningiomas have increased risk of local recurrences (WHO grade II meningiomas) and the minority are truly malignant and have a risk of metastatic dissemination; these are classified as WHO grade III meningiomas (2). RM is an uncommon type of meningioma which was described for the first time in 1998 (3). It was found that rhabdoid morphology in meningiomas was associated with a worse prognosis (3). Soon after this finding RM was separated as a distinct entity in WHO classification of CNS tumours published in 2000. RM has been classified as a grade III neoplasm by WHO (2). Consistent with the malignant behaviour, significant mitotic activity, anaplasia and other atypical features are usually found in RMs (2, 4). However, there are some isolated reports of RMs with no evidence of cellular atypia (6). In our case diagnosis of RM was established due to pure rhabdoid morphology along with meningothelial origin that was clearly demonstrated by IHC. Absence of atypia in the tumour cells and low Ki-67 proliferation index was consistent with low-grade meningioma in the present case. In conclusion, rhabdoid meningioma occasionally lacks histological features of malignancy that can lead to confusion if the rhabdoid morphology is always associated with malignant behaviour. Increased awareness of low-grade rhabdoid meningiomas is necessary to estimate the prognosis and to plan the treatment appropriately. REFERENCES Beckwith JB, Palmer NF. Histopathology and prognosis of Wilms tumors: results from the First National Wilms’ Tumor Study // Cancer, 1978; 41:1937 – 1948 Cooper WA, Shingde M, Lee VK, Allan RS, Wills EJ, Harper C. â€Å"Rhabdoid meningioma† lacking malignant features. Report of two cases // Clin Neuropathol, 2004; 23(1):16 – 20 Louis DN, Ohgaki H, Wiestler OD, Cavenee WK. Meningeal tumors // In: Bosman FT, Jaffe ES, Lakhani RS, Ohgaki H. WHO Classification of tumours of the central nervous system. 4th edition. Lyon: IARC; 2007; 164-180 Perry A, Scheithauer BW, Stafford SL, Abell-Aleff PC, Meyer FB. Rhabdoid meningioma: an aggressive variant // Am J Surg Pathol, 1998; 22:1482 – 1490 Walcott BP, Nahed BV, Brastianos PK, Loeffler JS. Radiation treatment for WHO grade II and III meningiomas // Front Oncol, 2013; 3:227, doi:10.3389/fonc.2013.00227 Zhou Y, Xie Q, Gong Y, Mao Y, Zhong P, Che X, Jiang C, Huang F, Zheng K, Li S, Gu Y, Bao W, Yang B, Wu J, Wang Y, Chen H, Xie L, Zheng M, Tang H. Clinicopathological analysis of rhabdoid meningiomas: Report of 12 cases and a systematic review of the literature // World Neurosurg, 2013; 79(5-6):724 – 732 3t-Alkyl-2r,6c-diarylpiperidin-4-ones: Synthesis 3t-Alkyl-2r,6c-diarylpiperidin-4-ones: Synthesis 3t-Alkyl-2r,6c-diarylpiperidin-4-ones Synthesis A very convenient and non-laborious one-pot synthesis method developed by Noller and Baliah [50] has been used successfully for the synthesis of 3t-alkyl-2r, 6c-diarylpiperidin-4-ones 32 by the condensation of methyl ketones, aromatic aldehydes and ammonium acetate in 1:2:1 molar ratio (Scheme 13). It’s a non-laborious one-pot synthesis of 3t-alkyl-2r, 6c-diarylpiperidin-4-ones 32. Various substituted piperidin-4-ones were also synthesized by adapting the above method [53-,57]. Often used typical procedure reported by Baliah and Jeyaraman was adapted to synthesis several substituted 3t-alkyl-2r,6c-difuranylpiperidin-4-ones 33 and 3t-benzyl-2r,6c-diarylpiperidin-4-ones 34 with convenient modification [58,59]. Seven r(2),c(4)-bis(isopropoxycarbonyl)-t(3)-aryl-c(5)-hydroxy-t(5)-methylcyclohexano-nes (aryl = C6H5, p-ClC6H4, p-FC6H4, p-OMeC6H4, p-Me2NC6H4, m-O2NC6H4 and m-C6H5OC6H4) have been synthesized by condensing isopropyl acetoacetate with aromatic aldehydes in the presence of methylamine [53]. Aridoss et al have synthesized an array of novel N-morpholinoacetyl-2,6-diarylpiperidin-4-ones as well as imidazo(4,5-b) pyridinylethoxypiperidones and Structure and stereochemistry of all the N-morpholinoacetyl-2,6-diarylpiperidin-4-ones have been analyzed using 1H and 13C NMR spectroscopic techniques [54,55]. 1H and 13C NMR spectra have been recorded for 2r,6c-diarylpiperidin-4-one (3_-hydroxy-2_naphthoyl)hydrazones and 3,3-dimethyl-2r,6c-bis(p-methoxyphenyl)piperidin-4-one [56-57]. Conversion to other derivatives Other derivatives from piperidin-4-ones have been obtained which includes oximes 35 [60-73], hydrazones 36 [57,74], semicarbazones 37 [75], thiosemicarbazones 38 [69], and phenylhydrazones 39 [76] by the reaction of the carbonyl group with suitable reagents. 2r,6c-diarylpiperidin-4-ones have been reduced to obtain 4t-Hydroxy-2r, 6c-diphenylpiperidines 40a and 4c-hydroxy-2r,6c-diphenylpiperidines 40b. N-substituted 2r,6c-diarylpiperidin-4-ones 41-51 was obtained by the reaction of the NH function with suitable reagents have been reported (Scheme 13) [77-84]. Physico-chemical studies Several physico-chemical studies have been performed for 3t-Alkyl-2r,6c-diarylpiperidin-4-ones and their derivatives [64-91]. Several studies have documented the conformations of various substituted 2,6-diarylpiperidin-4-ones [78,86]. Pandiarajan et al. [88] have elaborately discussed the conformations of 32 and suggested chair conformation to these compounds with equatorial disposition of the aryl and alkyl substituents based on their NMR spectral data. Substitution of alkyl group at C-3 position of the piperidine ring causes the ring to flatten slightly about C(2)-C(3) bond probably to decrease gauche interaction between aryl and alkyl groups at C(2) and C(3). Stereochemistry of N-acetyl and N-benzoyl-2r,6c-diphenylpiperidin-4-one oximes 5256 has been already reported [89]. Synthesis and conformation of 3t-chloro-2r,6c-diarylpiperidin-4-ones 57 also been reported [90,91]. Manimekalai et al. [92] demonstrated the conformation of benzyl group in 4-benzyl-4-hydroxypiperidines 58. Pharmacological studies Many piperidine derivatives possess pharmacological activities including antimicrobial, antioxidant and anticancer activities and to form an essential part of the molecular structure of important drugs [9, 93-97]. Piperidin-4-ones have been used for development of compounds with selective biological activities include antiviral [98], antitumor [99], analgesic [100], local anesthetic [101,102], bactericidal [103], fungicidal [103], herbicidal [103], insecticidal [104], antihistaminic [104], anti-inflammatory [104], anticancer [105], CNS stimulant [105], antitubercular and depressant [106] activities. Earlier reports have clearly established that the biological activities[R1] of piperidin-4-ones were improved by incorporation of the substituents at C-2, C-3 and C-6 [106,107]. Ferguson documented that N-nitrosopiperidines are carcinogenic in nature and blocking of one of the à ¯Ã‚ Ã‚ ¡ position by an alkyl group significantly reduces the carcinogenic activity [108]. Lijinsky and Taylo r have also supports that blocking of à ¯Ã‚ Ã‚ ¡ positions to the N-nitroso group by methyl groups reduces the carcinogenic activity [109]. 3t,5t-Dimethyl-2r,6c-diarylpiperidin-4-one hydrochlorides 59-61 have shown anti-histaminic activity [110]. Furthermore, 3t,5t-dimethyl-2r,6c-bis(4-hydroxyphenyl)piperidin-4-one 62 and 3t-methyl-5-substitutedphenyl-2r,6c-diarylpiperidin-4-ones 63 showed antimicrobial, insecticidal and antihistaminic activities [111]. 2,3,6-Triarylpiperidin-4-ones 64 and their oximes exhibits marked bactericidal, fungicidal and herbicidal activities [104]. N-Substituted piperidin-4-one 65 and its derivatives 66 and 67 exhibited potential Juvenile hormone activity on Bombyx mori [112]. N-methyl-3E,5E-bis(arylidine)piperidin- 4-ones 68, possessing a variety of aryl and heteroaryl groups, showed antiviral and antitumor activities [98]. 3E,5E-Bis(benzylidene)piperidin-4-one 69, 1-acryloyl derivatives of 69, and 70 the adduct of 2-mercaptoethanesulfonic acid 71 as well as 3E,5E-Bis(thienylidene)-piperidin-4-ones 72 have shown antitumor activity towards human carcinoma cell lines Caov3, Scov3 and A549 [113]. Furthermore, modification of position 3 of the piperidin-4-one nucleus as well as a substitution of certain functional groups in the para position of phenyl ring attached to C-2 and C-6 carbons of the piperidine moiety would result in compounds of potent biological activities. Hydrazones Hydrazones are a class of organic compounds with azomethine -NHN=CH- proton that constitutes an important class of compounds for new drug development [10,97,98]. Hydrazone are formed usually by the action of hydrazine on ketones or aldehydes. Hydrazide-hydrazone derivatives receive the attention of various medicinal chemists as a result of their effectual biological potencies viz., antimicrobial, anti-tubercular, and also anticonvulsant actions [10,114-116]. Some hydrazones is known to act as herbicides, insecticides, nematocides, rodenticides and plant growth regulators. Several studies have documented the spasmolytic activity, hypotensive action and activity against leukaemia, sarcomas and other malignant neoplasms [114-116]. Many of the physiologically active hydrazones have applications in diseases like tuberculosis, leprosy and mental disorder are characterized by the presence of the triatomic group (>C=N–N73 [117]. Hydrazones are also useful in detection, determination and isolation of compounds containing the carbonyl group and many other metals [10]. Syringaldehyde hydrazones 74 and 6-nitro-3,4-methylene-dioxophenyl-N-acylhydrazone 75 exhibits antioxidant properties [118,119]. Hydrazone and its substituted derivatives showed good antibacterial, antifungal, anticonvulsant, antitubercular, anticancer and antitumor activities. 1-[4=[(2-[(4-Substitutedphenyl)methylene]hydrazine] carbonyl)phenyl]-3-substituted thioureas 76 exhibited good clinically active tuberculostat [120]. Some coupling products from 4-aminobenzoic acid hydrazones 77 and (7-Hydroxy-2-oxo-2H-chromen-4-yl)acetic hydrazide 78 showed antimicrobial activity [121,122]. A series of 4-fluorobenzoic acid (substituted methylene/ ethylidine) hydrazide derivatives 79 showed the chemotherapeutic antituberculosis activities [123]. Hemalatha et al have documented the antibacterial and antifungal activities of N-nitroso-2,6-diarylpiperidin-4-one semicarbazones [124]. Some bicyclic semicarbazones and thiosemicarbazones 81 showed a wide variety of biological activities [124]. The significance of fusing heterocycles Heterocycles possess an enormously diverse group of compounds, are widely distributed in nature. Heterocycles can be easily manipulated and modified by organic synthetic methods to increase or decrease reactivity. They are used extensively as intermediates in various reactions as well as building blocks in organic synthesis. Novel libraries of biologically diverse heterocyclic compounds have been synthesized by incorporation and substitution of a wide range of functional groups (ring activators or deactivators) and their positions around the ring of heterocycles. Several studies provide evidence that combination of two bio-active heterocyclic moieties together leads to the production of novel and biologically important compounds with the anticipation of several promising pharmacological agents [4,125]. Based on the above features discussed under 3t-Alkyl-2r,6c-diarylpiperidin-4-ones, 2r,4c-Diaryl-3-azabicyclo[3.3.1]nonan-9-ones and hydrazones, we have developed the system that fuse 3 -azabicyclonones/piperidin-4-one pharmacophore and hydrazide moieties together to produce the corresponding hydrazones with the anticipation of several promising antioxidant, anticancer and antimicrobial agents arising. The relevant technique used to elucidate the structure of the newly synthesized compounds Specialized spectroscopic instruments can be used to generate information that enables the determination of the structure of an unknown organic compound. This includes Infrared spectrometry (IR), nuclear magnetic spectrometry (NMR) and elemental analysis. Among all available spectrometric methods, NMR is the only technique which offers a complete analysis and interpretation of the entire spectrum [126,127]. A few of the strategies of NMR experiments that are used in determination of different compounds are described as follows. NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY Nuclear magnetic resonance spectroscopy, one of the most versatile techniques for elucidation of structure of organic compounds, has shown a tremendous progress due to improved experimental technology and novel approaches. In NMR, the most useful information comes from the interactions between two nuclei, either through the bonds which connect them (J-coupling interaction) or directly through space (NOE interaction) [126-128]. Interpretation of NMR spectra is well understood from the following basic information gathered from NMR spectra. 1) Chemical shift, which identifies the type of proton based on their electronic environment, 2) Spin-Spin splitting patterns, which identifies neighbouring protons, 3) Peak Area, which is proportional to the number of protons giving a particular resonance line, 4) The observation of a triplet and a quartet spin state confirming usually the presence of an ethyl group (CH3CH2) and 5) The observation of ÃŽ ´ values between 7.2-8.0 indicates that the structure contains a benzene ring (benzyl proton) [126-130]. Generally, three approaches are used in NMR spectroscopy methods. These include one dimension (1D), two dimensions (2D) and three dimensions (3D). The first approach of 1D-NMR (1H DEPT, 13C, 15N, 19F, 31P, etc.) generates good information about the structure of simple organic compounds. However, it is overcrowded in case e of larger molecules. The second approach of 2D-NMR (COSY, DQFCOSY, MQFCOSY, HETCOR, HSQC, HMQC, HMBC, TOCSY, NOESY, EXSY, etc.) is used for the further larger molecules. A 2D-NMR spectrum also becomes complex and overlapping in case of further very large molecules like proteins. Therefore, multi-Dimensional-NMR (Homonuclear and Heteronuclear) are generally used to achieve high resolution and reduced overlapping in spectra of very large molecules [126,128,129]. This section further describes the general interpretation of structure of different organic compounds by different NMR techniques. 1D NMR SPECTROSCOPY 1H-NMR: Spin transitions of only hydrogen nuclei are observed in in 1H-NMR spectroscopy. Table 1 represents different ÃŽ ´ values, couplings, coupling constants and chemical shifts of 1H nuclei processing in different chemical environments. Commonly, ÃŽ ´ value scale of 1H-NMR ranges from 0-10 ppm with respect to Tetra methyl Silane (TMS) as internal standard. 1H-NMR spectral interpretation can be best understood from table 4 [126,131]. 1H Chemical shifts Because of variations in the electron distribution, the variation of nuclear magnetic resonance frequencies of the same kind of nucleus is referred to as chemical shift (symbolized by ÃŽ ´). Quantitative chemical shift are measured in frequency (Hertz) relative to a standard, Tetra methyl silane (TMS). Characterization of the structure of a molecule is depending upon the position and number of chemical shifts [111,112,115]. The chemical shift range of 1H nuclei can also be understood from a chart given in figure 1 [126].The chemical shift values for methyl protons attached to groups of varied electronegativity are given below [127]: CH3I-2.16 CH3Br-2.18 CH3Cl-3.05 and CH3F-4.26 ppm, The electron density around the proton affects its chemical shift. Because of the e- density around the H nuclei, the CH3 protons come to resonance at higher ÏÆ' values as the electronegativity of a functional group is increased. Electronic charge surrounded to H nuclei shields the nucleus to some extent from the influence of the applied field. The magnetic flux overcomes this shielding effect in order to bring a proton to resonance. Thus, the higher the electron density around the proton, the greater the induced diamagnetic effect and the greater the external field required to overcome the shielding effect. Electro-ve groups like fluorine in CH3F withdraws e- density from the CH3 group (-inductive effect). This leads to de-shielding by lower value of an applied magnetic field in order bring the methyl proton to resonance. Fluorine is more electro-ve than Cl, thus the proton in CH3F appears at a higher ÃŽ ´ values than those in CH3Cl. The chemical shift positions for protons attache d to C=C in alkenes is higher compared to that of accounted by electronegative effect alone. Alkene and aromatic protons appear at high ÏÆ' values while alkyne C≠¡C protons appear at a relatively low ÃŽ ´ value [126,127,132]. The magnetic field created by pi electrons or rings is referred to as Magnetic anisotropy, which describes an environment where different magnetic fields are found at different points in space. Since Pi electrons are held less strongly than sigma electrons, pi electrons are more able to move in response to the magnetic field. The anisotropic effects of the à ¯Ã‚ Ã‚ ³ electrons of C-C bond is low compared to those of the circulating à ¯Ã‚ Ã‚ °-electrons. The equatorial protons in cyclohexane resonate at 0.5 ppm higher than the axial protons. This is due to the anisotropic effect of the à ¯Ã‚ Ã‚ ³-electron in the CÃŽ ²-Cà ¯Ã‚ Ã‚ § bonds [127,133] (Figure. 2). [R1]Specify which biological activity