1025449 research-article2021 JOR0010.1177/20551169211025449Journal of Feline Medicine and Surgery Open ReportsOrgonikova et al Case Report Journal of Feline Medicine and Surgery Open Intracranial meningioma in two Reports 1­–7 © The Author(s) 2021 coeval adult cats from the same litter Article reuse guidelines: sagepub.com/journals-permissions https://doi.org/10.1177/20551169211025449 DOI: 10.1177/20551169211025449 journals.sagepub.com/home/jfmsopenreports This paper was handled and processed by the European Editorial Office (ISFM) Ivona Orgonikova1 , Lorenzo Mari1 , for publication in JFMS Open Reports Chiara Giannasi1, Martí Pumarola i Batlle2, Sebastien Behr3 and Josep Brocal1 Abstract Case summary In this report we describe the occurrence of intracranial meningioma in two adult cats from the same litter. The location of the meningioma varied: one tumour was at the level of the brainstem, and the other was affecting the temporal and piriform lobes. The cat with the brainstem meningioma was treated with radiotherapy and the littermate had a rostrotentorial craniectomy for tumour removal. Both cats had a histopathological diagnosis of grade I meningioma of a predominantly fibrous subtype. Relevance and novel information Cases of familial meningioma in cats have not previously been described in the veterinary literature. However, familial meningioma is well described in humans and it is possible that cases are underestimated in animals. We discuss the possible genetic background and other causes, as well as challenges we may face in veterinary medicine in identifying these associations. Keywords: Familial; siblings; brain tumour; seizures; neoplasia Accepted: 27 May 2021 Case description Considering the suspected focal epileptic seizures and Case 1 the neurological examination findings, the neuroana- A 13-year-old male neutered Norwegian Forest Cat tomical localisation was to the left forebrain and the para­ (weight 6.6 kg) was presented with a 5-month history of sympathetic component of the left oculomotor nerve. jaw-chattering episodes lasting a few seconds, followed Neoplasia (ie, primary brain tumour) was considered by sudden jerks of the head and limbs. Episodes were the most likely differential diagnosis. associated with touching the mouth and eating. As a Haematology and biochemistry were unremarkable. result, the cat was hyporexic. These episodes were sus- MRI (1.5 T, Siemens Magnetom Essenza; Siemens) of the pected to be focal epileptic seizures and myoclonus, and brain revealed a large, round, well-defined extra-axial less likely to be a consequence of hyperaesthesia or par- space-occupying lesion on the left side of the brainstem aesthesia. Previously diagnosed conditions included at the level of mesencephalon and pons, causing mass suspected triaditis, grade II right medial patellar luxa- tion and left cruciate ligament rupture, feline asthma 1Wear Referrals Veterinary Hospital, Bradbury, Stockton-on-Tees, and T11–T12 vertebral canal stenosis. The cat was being UK treated with ursodeoxycholic acid (10 mg/kg q24h 2Department of Animal Medicine and Surgery, Murine and [Ursodiol; Zydus]), prednisolone (0.4 mg/kg q48h Comparative Laboratory Unit, Autonomous University of [Prednicortone; Le Vet Beheer]), liver supplement q24h Barcelona, Bellaterra (Cerdanyola del Vallès), Barcelona, Spain (Hepatosyl Plus, VSL laboratories) and a gastrointestinal 3Willows Veterinary Centre and Referral Service, Solihull, UK diet (Veterinary Gastrointestinal Cat; Royal Canin). Corresponding author: Neurological examination revealed mildly decreased Ivona Orgonikova MVDr, MRCVS, Wear Referrals Veterinary postural reactions in the right thoracic limb, mild mydri- Hospital, Bradbury, Stockton-on-Tees TS21 2ES, UK asis and reduced pupillary light reflex in the left eye. Email: iorgonikova@gmail.com Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). 2 Journal of Feline Medicine and Surgery Open Reports  Figure 1 Head MRI of the cat from case 1. T2-weighted (a) transverse and (b) dorsal image of the large, round, well-defined extra-axial isohyperintense mass (arrows) located to the left of the mesencephalon and pons; and T1-weighted (c) transverse and (d) dorsal post-contrast images at the same levels showing the homogeneous contrast enhancement (arrows) effect (Figure 1). The mass was isohyperintense in As the reflex nature of the suspected seizures, treat- T2-weighted (T2W), and isointense in fluid-attenuated ment with levetiracetam (20 mg/kg q8h [Levetiracetam; inversion recovery and T1-weighted (T1W) sequences, Zentiva]) was initiated. Prednisolone was maintained at compared with the grey matter, and presented marked 0.4 mg/kg q48h. The cat underwent palliative radiother- homogeneous contrast enhancement. Routine analysis apy within 10 weeks of presentation. The protocol con- of cerebrospinal fluid collected from the cerebellomedul- sisted of 12 fractions of 4 Gy (total dose 48 Gy), delivered lary cistern, including cell count, protein quantification using a three coplanar beam plan (at 6 mV; Johnson and cytology, was normal. A presumptive diagnosis of Foundation Radiotherapy Unit). Treatment was deliv- intracranial meningioma was made. ered on a Monday–Wednesday–Friday basis. Orgonikova et al 3 gabapentin (4 mg/kg q12h [Gabapentin; Accord-UK]), amantadine (1 mg/kg q24h [Symmetrel; Auden McKenzie]), albuterol sulfate inhaler (108 µg q12h [Ventolin; GlaxoSmithKline]) and levothyroxine (5 µg/kg q12h [Leventa; MSD Animal Health]). The portosystemic shunt was an incidental finding upon abdominal imaging for triaditis. No medical therapy was therefore initiated for the portosystemic shunt. Clinical examination revealed grade II/VI left-sided systolic heart murmur. Neurological examination showed decreased postural reactions on the right tho- racic and pelvic limb and decreased-to-absent menace response bilaterally. The neurolocalisation was focal left- sided forebrain. The most likely differential diagnosis was neoplasia (ie, primary brain tumour). Haematology was unremarkable. Comprehensive Figure 2 Histopathology of the brainstem tumour of case 1. biochemistry revealed markedly elevated creatine kinase Transitional meningioma with a predominant fibrous (1421 µkat/l; reference interval [RI] 10–290) and alanine pattern; some concentric structures and multiple basophilic mineralised foci are present (haematoxylin and eosin stain) aminotransferase (ALT; 2339 U/l [RI 1–120]), and mildly elevated total protein (78 g/l [RI 53–77]) and total thyrox- ine (46.3 U/l [RI 13.3–44.7]). The rest of the parameters Jaw-chattering episodes recurred after completion of were within normal limits. Creatine kinase and ALT the radiotherapy but with markedly reduced severity returned to normal 3 weeks later, suggesting that their and frequency, and did not affect the cat’s appetite. The transient increase was most likely the consequence of the neurological abnormalities resolved. At follow-up re- recent epileptic activity. Feline immunodeficiency virus examinations, owing to the persistent hyperglycaemia and feline leukaemia virus SNAP testing was negative. combined with glucosuria, diabetes mellitus was diag- Toxoplasma serum titres were negative. Abdominal ultra- nosed, and insulin treatment was initiated shortly after sound findings were consistent with choledocholithiasis. the radiotherapy, initially with protamine zinc insulin (1 MRI of the head showed a large, rounded, well-defined, unit SC q12h [ProZinc; Boehringer Ingelheim]), then extra-axial space-occupying lesion at the level of the left lente insulin (2 units q12h [Caninsulin; MSD Animal piriform and temporal lobes causing severe mass effect Health]). Eleven months after radiotherapy the cat devel- with midline shift, caudotentorial and foramen magnum oped chronic small intestinal diarrhoea, polydipsia, herniation. The mass was T2W iso-hyperintense and pelvic limb weakness with plantigrade stance and leth- T1W isohypointense, compared with grey matter, and argy that progressed to intermittent collapse and abnor- was strongly homogenously contrast enhancing (Figure mal mentation. Further investigations were declined by 3). A presumptive diagnosis of intracranial meningioma the owner and humane euthanasia was elected. was made. The brain of the cat was submitted for histopathology. A left sided rostrotentorial craniectomy was performed A full post-mortem examination was not performed. and the tumour was removed by en-bloc resection. Histopathological diagnosis of transitional meningioma Recovery from the surgery was uneventful. A tapering (grade I) was made.1 The predominant pattern was dose over 12 weeks of prednisolone (Prednicortone; Le fibrous with psammoma bodies and abundant areas of Vet Beheer) starting at 0.4 mg/kg q24h was initiated along mineralisation (Figure 2). with levetiracetam (30 mg/kg q8h [Levetiracetam; Zentiva]). Histopathological diagnosis was a fibrous Case 2 meningioma (grade I) with rare foci of mineralisation A 13-year-old male neutered Norwegian Forest Cat (Figure 4). (weight 7.4 kg) from the same litter and same household Three months after surgery the cat was diagnosed with as case 1 was presented to the same referral centre 4 alimentary, small-cell lymphoma after presenting with months later with a cluster of generalised tonic–clonic recurrent constipation and hyporhexia. The diagnosis epileptic seizures. The cat had been previously diagnosed was obtained based on the gastroduodenoscopy and colo- with lumbosacral intervertebral disc protrusion, sus- noscopy findings, as well as on histopathology of the pected triaditis, feline asthma, hypothyroidism following endoscopically biopsied tissues. Treatment with chloram- radioiodine (I131) treatment for hyperthyroidism, mild bucil (0.3 mg/kg q48h [Leukeran; GlaxoSmithKline hypertrophic cardiomyopathy and a left gastric-phrenic Pharmaceuticals]) was initiated alongside the previously portosystemic shunt, and was on treatment with prescribed medical therapy. Six months postoperatively 4 Journal of Feline Medicine and Surgery Open Reports  Figure 3 Head MRI of case 2. T2-weighted (a) sagittal and (b) transverse image of the isohyperintense extra-axial rounded mass at the level of the left piriform and temporal lobe (arrows), and post-contrast T1-weighted (T1W) (c) transverse and (d) T1W fat-saturated dorsal image at the same levels showing its marked homogeneous contrast enhancement (arrows) the cat had a cluster of generalised tonic–clonic epileptic reported in cats. The possibility that these two cats seizures. Repeat MRI was declined. The cat continued to simultaneously developed the same meningioma sub- do well 18 months after the initial presentation, without type by random chance has been considered. This was further epileptic activity. deemed unlikely, taking into the account that Norwegian Forest Cats were not an over-represented breed in previ- Discussion ous studies of cat meningioma .2,3 We described the occurrence of intracranial meningioma Meningioma is the most common extra-axial intracra- (grade I)1 in two adult cats from the same litter and nial brain tumour in cats (32.8–73%)2–4 and people.5–8 household that presented 4 months apart. To our knowl- Human family history studies suggest a role for inher- edge, familial meningioma has not previously been ited susceptibility to many central nervous system (CNS) Orgonikova et al 5 subtype, but are most often of the fibrous variant,22 which was diagnosed in both cases presented herein. The rea- son behind the development of fibrous morphology in NF2-deficient tumours is not entirely clear. Relation to the dysregulation of cell–cell adhesion (due to merlin deficiency) leading to a more ‘mesenchymal’ spindled phenotype is hypothesised.14 Likelihood of an identical histology of meningioma in two family members in humans is around 46%,11 with low-grade tumours (World Health Organization grade I)23 more likely to occur in familial cases, compared with sporadic cases.24 Experimental models have suggested that NF2 muta- tions alone may not be sufficient to promote tumorigen- esis, and additional genetic alterations are likely required.25 Other genetic mutations associated with meningioma exist in human medicine, affecting, for Figure 4 Histopathology of the lesion in the left temporal and example, genes encoding enzymes involved in apoptotic piriform lobe of case 2. Fibrous meningioma. Intersecting mechanisms, cell-cycle control or DNA repair.13 These streams of spindle cells amidst a prominent collagenous stroma. Haematoxylin and eosin ×100 mutations may predispose to other tumours as well.26–30 For example, abnormalities in the tumour suppressor gene PTEN were found to play a role in the pathogenesis tumours, including intracranial meningiomas.5,6,9,10 of meningiomas, as well as haematological malignan- There is a proven increased risk of intracranial meningi- cies.31 Case 2 was also diagnosed with alimentary small- oma in humans with a first-degree family history of cell lymphoma, further supporting a possible underlying meningioma,5,9,11 and the association is even stronger genetic background predisposing to tumours. Genomic when the diagnosis is made in people <55 years of age.5 profiling has the potential to differentiate between spo- Children, parents and siblings are considered first- radic and familial meningiomas, and define the risk of degree family members,5,9 like the two cats described occurrence in family members.24 The pedigrees of the herein. reported cats were analysed to identify other affected In humans, many genetic syndromes predisposing to subjects in the family line and assess consanguinity, meningioma exist, with neurofibromatosis type 2 (NF2) which was not detected in the five preceding genera- being the most reported.6,12,13 However, even when tions. We unsuccessfully attempted to collect clinical patients with NF2 are excluded from the population, information and DNA samples from relatives for whole- familial relations for meningiomas remain evident.5,6,9 genome sequencing by contacting the Norwegian Forest NF2 is a tumour predisposition syndrome character- Cat Club in the UK, making further genetic investiga- ised by the development of distinctive nervous system tions impossible. Pedigrees containing information lesions (eg, schwannomas, meningiomas and ependymo- about diseases in individuals are lacking, likely making mas).12–20 Although the typical lesions generally include the occurrence of familial meningioma in cats underesti- vestibular schwannomas, and tend to present more in mated. Such informative pedigree analysis would have children, meningiomas are detected in approximately a great potential to identify the genetic background 50% of patients with NF2,15 concurrently with, or occa- in familial and sporadic cases of meningioma in cats. sionally also independently from, the presence of vestib- A possible connection between genetic defects and ular schwannomas, and the disease can manifest at older feline meningioma has previously been hypothesised in age.12–20 NF2 results from germline mutations in the NF2 a study describing meningioma in young cats in associa- tumour suppressor gene located on chromosome 22q12 tion with mucopolysaccharidosis (MPS) I. The authors of with autosomal dominant inheritance.15 Apart from the study hypothesised that a gene locus important in inherited NF2, in up to 60% of sporadic meningioma meningioma tumorigenesis and the locus of the enzyme cases spontaneous mutations in NF2 were found.16–19 alpha-L-iduronidase (defective in MPS I) may be closely NF2 is responsible for expression of the protein merlin located. Another hypothesis was that accumulation of (membrane-associated protein).15,21 Abnormal or absent the metabolite products can be associated with tumori- merlin function can disrupt tumour suppression via vari- genesis of the arachnoid cells and therefore predispose ous mechanisms affecting the membrane organisation of to meningioma.32 proteins, cell–cell adhesion, cytoskeletal architecture or The possibility that the meningioma in these two cats interaction with cytosolic proteins.15 Interestingly, NF2- from the same household was environmentally related has associated meningiomas may be of any histological been considered. A human study found that spouses 6 Journal of Feline Medicine and Surgery Open Reports  (genetically unrelated people exposed to similar environ- patient were always followed and/or this work involved the ments) of people with brain tumours were not at higher use of cadavers. Ethical approval from a committee was there- risk of brain tumours, while first-degree relatives were.9 fore not specifically required for publication in JFMS Open The role of specific environmental risk factors in humans Reports. Although not required, where ethical approval was still obtained, it is stated in the manuscript. (eg, cigarette smoking, mobile phone use, exposure to elec- tromagnetic fields or to lead) has been investigated and Informed consent Informed consent (either verbal or writ- was found to be insignificant or inconsistent.33 All these ten) was obtained from the owner of all animal(s) described in findings support a predominant role of genetic factors vs this work (either experimental or non-experimental animals, environmental factors in the occurrence of primary brain including cadavers) for all procedure(s) undertaken (either tumours in people, and make an environmental cause for prospective or retrospective studies). For any animals or peo- simultaneous development of meningioma in these two ple individually identifiable within this publication, informed cats less likely. consent (verbal or written) for their use in the publication was Apart from genetic associations, other risk factors for obtained from the people involved. the development of meningioma in humans exist such as exposure to ionising radiation.34–39 Interestingly, devel- ORCID iD Ivona Orgonikova https://orcid.org/0000- 0001-8821-1467 oping meningioma after exposure to radiotherapy in humans appears to have an inherited component.40 Lorenzo Mari https://orcid.org/0000-0002-5732-1011 Neither repor­ted cat underwent radiotherapy before the Josep Brocal https://orcid.org/0000-0002-3019-1317 occurrence of the meningioma. The cat described in case 2 had radioactive iodine treatment 2 years before the References meningioma diagnosis. An association between radioio- 1 Higgins RJ, Bollen AW, Dickinson PJ, et al. Tumors of the dine treatment and meningioma has not been confirmed nervous system. In: Tumors in domestic animals. 5th ed. Chichester: Wiley-Blackwell, 2016, pp 834–891. in humans or in cats.41–43 In human meningiomas, female 2 Tomek A, Cizinauskas S, Doherr M, et al. Intracranial neo- sex is another risk factor;8 whereas, male cats (as the cats plasia in 61 cats: localisation, tumour types and seizure described herein) are more commonly reported in the patterns. J Feline Med Surg 2006; 8: 243–253. veterinary literature.3 3 Troxel MT, Vite CH, Van Winkle TJ, et al. Feline intracra- nial neoplasia: retrospective review of 160 cases (1985– Conclusions 2001). J Vet Intern Med 2003; 17: 850–859. 4 Troxel MT, Vite CH, Massicotte C, et al. Magnetic reso- To our knowledge, this is the first report to describe two nance imaging features of feline intracranial neoplasia: cases of meningioma in cats from the same litter pre- retrospective analysis of 46 cats. J Vet Intern Med 2004; 18: sented at the same age. Familial meningiomas are well 176–189. documented in humans, and predisposing genetic fac- 5 Claus EB, Calvocoressi L, Bondy ML, et al. Family and per- tors, such as NF2 mutation, are described. No similar sonal medical history and risk of meningioma. J Neurosurg predisposing factors have been identified in felids and 2011; 115: 1072–1077. further investigations in this field would be of great 6 Hemminki K, Tretli S, Sundquist J, et al. Familial risks interest and may lead to a better understanding of this in nervous-system tumours: a histology-specific analysis common feline primary CNS tumour pathogenesis. from Sweden and Norway. Lancet Oncol 2009; 10: 481–488. Genetic analysis of feline relatives with meningioma 7 Sun C, Dou Z, Wu J, et al. The preferred locations of may be challenging given that first-degree family mem- meningioma according to different biological character- istics based on voxel-wise analysis. Front Oncol 2020; 10: bers rarely stay in the same household. This is also a rea- 1412. DOI: 10.3389/fonc.2020.01412. son to suspect that the prevalence of familial meningioma 8 Saraf S, McCarthy BJ and Villano JL. Update on meningio- in cats might be underestimated. Accessible, clinically mas. Oncologist 2011; 16: 1604–1613. updated pedigrees might be helpful. 9 Malmer B, Henriksson R and Grönberg H. Familial brain tumours-genetics or environment? A nationwide cohort Conflict of interest The authors declared no potential study of cancer risk in spouses and first-degree relatives conflicts of interest with respect to the research, authorship, of brain tumour patients. Int J Cancer 2003; 106: 260–263. and/or publication of this article. 10 Hemminki K, Li X and Collins VP. Parental cancer as a risk factor for brain tumors (Sweden). Cancer Causes Control Funding The authors received no financial support for the 2001; 12: 195–199. research, authorship, and/or publication of this article. 11 Hemminki K and Li X. Familial risks in nervous system tumors. Cancer Epidemiol Biomark Prev 2003; 12: 1137–1142. Ethical approval The work described in this manuscript 12 Kerr K, Qualmann K, Esquenazi Y, et al. Familial syn- involved the use of non-experimental (owned or unowned) dromes involving meningiomas provide mechanis- animals. Established internationally recognised high standards tic insight into sporadic disease. Neurosurgery 2018; 83: (‘best practice’) of veterinary clinical care for the individual 1107–1118. Orgonikova et al 7 13 Huntoon K, Toland AMS and Dahiya S. Meningioma: banding, comparative genomic hybridization, and spec- a review of clinicopathological and molecular aspects. tral karyotyping. J Neurosurg 2000; 93: 437–448. Front Oncol 2020; 10: 579599. DOI: 10.3389/fonc.2020.579599. 29 Weng L-P, Brown JL, Baker KM, et al. PTEN blocks 14 Coy S, Rashid R, Stemmer-Rachamimov A, et al. An update insulin-mediated ETS-2 phosphorylation through MAP on the CNS manifestations of neurofibromatosis type 2. kinase, independently of the phosphoinositide 3-kinase Acta Neuropathol (Berl) 2020; 139: 643–665. pathway. Hum Mol Genet 2002; 11: 1687–1696. 15 Asthagiri AR, Parry DM, Butman JA, et al. Neurofibroma- 30 Cairns P, Okami K, Halachmi S, et al. Frequent inactivation tosis type 2. Lancet 2009; 373: 1974–1986. of PTEN/MMAC1 in primary prostate cancer. Cancer Res 16 Seizinger BR, de la Monte S, Atkins L, et al. Molecular 1997; 57: 4997–5000. genetic approach to human meningioma: loss of genes on 31 Dahia PLM, Aguiar RCT, Alberta J, et al. PTEN is inversely chromosome 22. Proc Natl Acad Sci U S A 1987; 84: 5419–5423. correlated with the cell survival factor Akt/PKB and is 17 Wellenreuther R, Kraus JA, Lenartz D, et al. Analysis of inactivated via multiple mechanisms in haematological the neurofibromatosis 2 gene reveals molecular variants malignancies. Hum Mol Genet 1999; 8: 185–193. of meningioma. Am J Pathol 1995; 146: 827–832. 32 Haskins ME and McGrath JT. Meningiomas in young cats 18 Ueki K, Wen-Bin C, Narita Y, et al. Tight association of loss with mucopolysaccharidosis I. J Neuropathol Exp Neurol of merlin expression with loss of heterozygosity at chro- 1983; 42: 664–670. mosome 22q in sporadic meningiomas. Cancer Res 1999; 33 Barnholtz-Sloan JS and Kruchko C. Meningiomas: causes 59: 5995–5998. and risk factors. Neurosurg Focus 2007; 23: E2. 19 Ruttledge MH, Sarrazin J, Rangartnam S, et al. Evidence for 34 Al-Mefty O, Topsakal C, Pravdenkova S, et al. Radiation- the complete inactivation of the NF2 gene in the majority induced meningiomas: clinical, pathological, cytokinetic, of sporadic meningiomas. Nat Genet 1994; 6: 180–184. and cytogenetic characteristics. J Neurosurg 2004; 100: 20 Halliday D, Emmanouil B, Pretorius P, et al. Genetic Sever- 1002–1013. ity Score predicts clinical phenotype in NF2. J Med Genet 35 Harrison MJ, Wolfe DE, Lau TS, et al. Radiation-induced 2017; 54: 657–664. meningiomas: experience at the Mount Sinai Hospi- 21 Torp SH and Scheie D. Advances in research on human tal and review of the literature. J Neurosurg 1991; 75: meningiomas. Cancers 2020; 12: 2702. DOI: 10.3390/cancers 564–574. 12092702. 36 Hijiya N, Hudson MM, Lensing S, et al. Cumulative inci- 22 Baser ME, Friedman JM, Aeschliman D, et al. Predictors dence of secondary neoplasms as a first event after child- of the risk of mortality in neurofibromatosis 2. Am J Hum hood acute lymphoblastic leukemia. JAMA 2007; 297: Genet 2002; 71: 715–723. 1207–1215. 23 Louis DN, Perry A, Reifenberger G, et al. The 2016 World 37 Mack EE and Wilson CB. Meningiomas induced by high- Health Organization Classification of Tumors of the Cen- dose cranial irradiation. J Neurosurg 1993; 79: 28–31. tral Nervous System: a summary. Acta Neuropathol (Berl) 38 Moss SD, Rockswold GL, Chou SN, et al. Radiation- 2016; 131: 803–820. induced meningiomas in pediatric patients. Neurosurgery 24 Shen Y, Nunes F, Stemmer-Rachamimov A, et al. Genomic 1988; 22: 758–761. profiling distinguishes familial multiple and sporadic 39 Neglia JP, Robison LL, Stovall M, et al. New primary neo- multiple meningiomas. BMC Med Genomics 2009; 2: 42. plasms of the central nervous system in survivors of DOI: 10.1186/1755-8794-2-42. childhood cancer: a report from the Childhood Cancer 25 Woods R, Friedman JM, Evans DGR, et al. Exploring the Survivor Study. J Natl Cancer Inst 2006; 98: 1528–1537. “two-hit hypothesis” in NF2: tests of two-hit and three- 40 Flint-Richter P and Sadetzki S. Genetic predisposition for hit models of vestibular schwannoma development. Genet the development of radiation-associated meningioma: Epidemiol 2003; 24: 265–272. an epidemiological study. Lancet Oncol 2007; 8: 403–410. 26 Sestini R, Vivarelli R, Balestri P, et al. Neurofibromatosis 41 Damle NA, Bal C, Peepre K, et al. Occurrence of symptom- type 2 attributable to gonosomal mosaicism in a clinically atic meningioma as a second neoplasm in patients with normal mother, and identification of seven novel muta- differentiated thyroid cancer treated with radioiodine. tions in the NF2 gene. Hum Genet 2000; 107: 366–371. Indian J Endocrinol Metab 2012; 16: 612–613. 27 Li D-M and Sun H. PTEN/MMAC1/TEP1 suppresses the 42 Metso S, Auvinen A, Huhtala H, et al. Increased cancer tumorigenicity and induces G1 cell cycle arrest in human incidence after radioiodine treatment for hyperthyroid- glioblastoma cells. Proc Natl Acad Sci 1998; 95: 15406–15411. ism. Cancer 2007; 109: 1972–1979. 28 Bayani J, Zielenska M, Marrano P, et al. Molecular cyto- 43 Carney HC, Ward CR, Bailey SJ, et al. 2016 AAFP guide- genetic analysis of medulloblastomas and supratentorial lines for the management of feline hyperthyroidism. primitive neuroectodermal tumors by using conventional J Feline Med Surg 2016; 18: 400–416.