Case Report

Meningioma in Down Syndrome Takahiro Yamamoto1,2, Naoki Shinojima2, Tatemi Todaka1, Shigeyuki Nishikawa1, Shigetoshi Yano2, Jun-ichi Kuratsu2

Key words Chromosome 21 - Down syndrome - Intracranial tumor - Meningioma -

Abbreviations and Acronyms Ab: Antibody DSCR1: Down syndrome candidate region-1 FISH: Fluorescence in situ hybridization NF2: Neurofibromin 2 From the 1Division of Neurosurgery, Nobeoka Hospital, Miyazaki and 2Department of Neurosurgery, Kumamoto University Hospital, Kumamoto, Japan To whom correspondence should be addressed: Naoki Shinojima, M.D., Ph.D. [E-mail: [email protected]] Citation: World Neurosurg. (2015). http://dx.doi.org/10.1016/j.wneu.2015.03.065 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2015 Elsevier Inc. All rights reserved.

INTRODUCTION Down syndrome comprises multiple malformations and is due to trisomy of chromosome 21. Epidemiologic evidence shows that individuals with Down syndrome are at reduced risk for cancer and solid and brain tumors, whereas the incidence of leukemia is high (6, 17, 18, 26). Genes with increased expression on the extra copy of chromosome 21 may act as tumor suppressor genes against solid tumors and protect against tumorigenesis (6, 17). However, no investigations on the status of chromosome 21 or the status of genes on chromosome 21 in tumors from individuals with Down syndrome have been published. We report the first case to our knowledge of a patient with Down syndrome with intracranial meningioma, in which the status of chromosome 21 was examined, and speculate on mechanisms underlying the reduced tumor incidence in Down syndrome. MATERIALS AND METHODS Written informed consent was obtained from the patient’s family. The gene and

- BACKGROUND:

Down syndrome comprises multiple malformations and is due to trisomy of chromosome 21. There is epidemiologic evidence that individuals with Down syndrome are at decreased risk for solid tumors including brain tumors. It has been suggested that some genes expressed on the extra copy of chromosome 21 act as tumor suppressor genes and contribute to protection against tumorigenesis.

- CASE

DESCRIPTION: We report the first case to our knowledge of a patient with Down syndrome, an 8-year-old boy, with an intracranial meningioma, in which the status of chromosome 21 was examined. The diagnosis was based on histologic examination of the surgically resected tumor. Postoperatively, the patient’s neurologic status improved, and there was no tumor regrowth in the next 2 years. Fluorescence in situ hybridization for chromosome 22 confirmed high allele loss involving the neurofibromin 2 gene locus, a finding typical in meningiomas. Fluorescence in situ hybridization also revealed chromosome 21 heterogeneity in tumor cells; not only cells with trisomy 21 but also cells with disomy and monosomy 21 were present. All blood cells from the patient manifested trisomy 21.

- CONCLUSIONS:

Deletion of the chromosome 21 allele may be associated with tumorigenesis of meningioma in Down syndrome. This supports the hypothesis that some genes whose expression is increased on the extra copy of chromosome 21 function as tumor suppressor genes and that they contribute to the reduced tumor incidence in individuals with Down syndrome.

molecular analysis in this study was conducted under our protocol (#231) approved by the Research Ethics Committee of the Institutional Review Board of Kumamoto University Hospital as previously reported (22). Immunohistochemistry Immunohistochemical results were validated with positive and negative controls (21, 23). Formalin-fixed, paraffin-embedded tumor tissue samples were used, and 4-mmthick serial sections were stained. The primary antibodies were anti-human vimentin antibody (Ab) (mouse, 1:400; Dako Corp., Denmark), anti-human CD31 Ab (mouse, 1:50; Dako Corp.), and anti-human Ki-67 (MIB-1) (mouse, 1:100; Dako Corp.). Fluorescence In Situ Hybridization Fluorescence in situ hybridization (FISH) was performed by use of formalin-fixed, paraffin-embedded tissue samples and

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the following probes in the Cytogenic Testing Group, Molecular Genetic Testing Department, Clinical Testing Center, Mitsubishi Chemical Medicine Corporation, Tokyo, Japan (22). TUPLE1 [22q11.2] SpectrumOrange (Abbott Laboratories, Abbott Park, Illinois, USA) and ARSA [22q13.3] SpectrumGreen probes (Abbott Laboratories) were used to detect q12 on chromosome 22 where the neurofibromin 2 (NF2) gene resides, and Vysis LSI 21 SpectrumOrange probes (Abbott Laboratories) were used for the centromere 21q22.13-q22.2 region. FISH for chromosome 21 in blood cells was also performed. The detection of 1 signal was taken to indicate monosomy, the detection of 2 signals was taken to indicate disomy, and the detection of 3 signals was taken to indicate trisomy. Signals from 200 cells were counted, and their percentage in each chromosome was calculated.

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CASE REPORT TAKAHIRO YAMAMOTO ET AL.

CASE DESCRIPTION The patient was an 8-year-old boy with Down syndrome and progressive dysphagia and right hemiparesis. Neither he nor any of his family members had any history of malignancy. Magnetic resonance imaging showed a mass lesion measuring 50 mm in maximum diameter in the left cerebellopontine angle. It compressed the brainstem and fourth ventricle and produced obstructive hydrocephalus (Figure 1). T1-weighted magnetic resonance imaging with gadolinium-diethylenetriamine pentaacetic acid showed contrast enhancement with the dural tail sign (Figure 1AeC). The preoperative diagnosis was meningioma. Using the left lateral suboccipital approach, the tumor was partially resected. The mass lesion was well demarcated from

MENINGIOMA IN DOWN SYNDROME

the cerebellum, adhered to the brainstem, and was attached to the dura mater of the petrous bone. There was a small amount of intraoperative bleeding. To avoid iatrogenic damage to the brainstem and the cranial nerve VIIeVIII complex, as much of the mass as possible was removed for decompression. Postoperatively, his neurologic status improved. Magnetic resonance imaging demonstrated that the mass reduction was adequate for brainstem decompression, and his hydrocephalus was improved (Figure 1D). Without adjuvant therapy, he was symptom-free at 2-year follow-up examination, and there was no tumor regrowth. Microscopically, the tumor was composed of spindle-shaped cells arranged in short fascicles and concentric whorls; it manifested

the typical meningothelial pattern. There was no evidence of malignancy such as abundant pleomorphic nuclei; few mitotic features were observed (Figure 2A). The diagnosis was meningothelial meningioma. Immunohistochemistry showed strong immunostaining for vimentin (Figure 2B). The MIB-1 labeling index did not exceed 7.3% (Figure 2C). CD31 staining revealed little vessel formation in the tumor (Figure 2D). As is typical for meningioma, FISH for chromosome 22 showed a high incidence of allelic loss involving the NF2 locus (86.0%) (Figure 2E). In tumor cells, chromosome 21 exhibited heterogeneity; 43% of the cells manifested trisomy, 50% manifested disomy, and 7% manifested monosomy. All blood cells displayed trisomy 21 (Figure 2F and G). DISCUSSION

Figure 1. (A and B) T1-weighted and T2-weighted magnetic resonance imaging performed on admission. The mass manifested hypointensity (A) and hyperintensity (B). (C) Gadolinium-enhanced axial T1-weighted magnetic resonance imaging performed on admission. Note contrast enhancement with the dural tail sign. (D) Postoperative gadolinium-enhanced T1-weighted magnetic resonance imaging.

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To date, brain tumors have been reported in only 62 individuals with Down syndrome. Data on the earlier cases and our patient are summarized in Table 1 (2-5, 7, 8, 11, 12, 14, 16, 17, 19, 20, 24, 25). There is a sex difference with male predominance; of the 63 patients, 38 were male, and 13 were female. The sex of the other 12 patients was not disclosed. The median age of 53 patients whose age was reported was 9 years (range, 0e54 years). There were 43 patients younger than 14 years, and age range was 15e19 years in 3 patients, suggesting that brain tumors in patients with Down syndrome tend to arise during childhood. Of the 56 identified tumors, 24 each (42.9%) were germ cell tumors or gliomas, 4 (7.1%) were angiomas, 2 (3.6%) were lipomas, and 1 (1.8%) was a medulloblastoma. Ours is the first meningioma reported in a patient with Down syndrome. Most pediatric brain tumors tend to be gliomas and medulloblastomas (9, 13); 14.3% of Japanese children with brain tumors have been reported to have germ cell tumors (9). Epidemiologic studies showed that individuals with Down syndrome are at decreased risk for solid tumors (6, 17, 18, 26). Miller (10) reported that among 56,199 individuals with Down syndrome, 5 (0.009%) developed brain tumors, making the estimated prevalence of brain tumors in that population almost 9 per 100,000. According to Porter et al. (15),

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CASE REPORT TAKAHIRO YAMAMOTO ET AL.

MENINGIOMA IN DOWN SYNDROME

Figure 2. (AeD) Representative photographs of hematoxylin-eosinestained and immunostained specimens (magnification 100). (A) Hematoxylin-eosin stain. (B) Immunostaining for vimentin. (C) Immunostaining for Ki-67. (D) Immunostaining for CD31. (EeG) Fluorescence in situ hybridization was performed using probes to detect q12 on chromosome 22 (set of red and green signals) and chromosome 21 (red signal). Most of the tumor cells exhibited monosomy 22 (red [arrow] and green [arrowhead] signals were observed) (E). The tumor specimen contained cells with trisomy 21 (3 red signals), cells with disomy (2 signals [arrow]), and cells with monosomy (1 signal [arrowhead]) (F). All blood cells manifested trisomy 21. Representative photograph of a blood cell nucleus shows 3 red signals (arrow) indicating trisomy 21 and 2 green signals (arrowhead) elicited by the control probes (G).

the estimated incidence of brain tumors in North American patients 0e19 years old was 35.4 per 100,000 in 2004. Overall,

these studies suggest that brain tumors are extremely rare in individuals with Down syndrome.

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In our patient, FISH showed heterogeneity of chromosome 21 in tumor tissues. Although all blood cells manifested trisomy, 43% of tumor cells revealed trisomy 21, 50% showed disomy, and 7% showed monosomy. There is epidemiologic evidence that some genes expressed on the extra copy of chromosome 21 may function as tumor suppressor genes and protect against tumorigenesis (6, 17). Baek et al. (1), who reported Down syndrome candidate region-1 (DSCR1, also known as RCAN1), one of the genes on chromosome 21, found that DSCR1 protein inhibited tumor angiogenesis via the suppression of vascular endothelial growth factoremediated angiogenic signaling by the calcineurin pathway in murine and induced pluripotent stem cell models of Down syndrome. These investigators suggested that decreased tumor angiogenesis by genes on chromosome 21 such as DSCR1 was responsible for the lower cancer incidence in individuals with Down syndrome. Working under the hypothesis that abundant vascular formation mediated by vascular endothelial growth factor should be observed in our patient’s tumor, we assessed its vascularity by immunostaining for CD31. We found that the tumor was hypovascular. FISH for chromosome 22 showed a high degree of allelic loss involving the NF2 locus in the meningioma. We now propose that in the presence of Down syndrome, tumor development facilitated by loss of function of tumor suppressor genes such as NF2 is impossible unless the extra copy of chromosome 21 in the solid tumor is absent—in other words, unless trisomy changes to disomy or monosomy. In this context, our findings may support the epidemiology-based speculation that some genes with increased expression on the extra copy of chromosome 21 function as tumor suppressor genes and contribute to the protection from tumorigenesis of solid tumors in individuals with Down syndrome. However, further investigations of the status of chromosome 21 in the tumors of individuals with Down syndrome are needed. CONCLUSIONS We report the first case to our knowledge of a patient with Down syndrome with

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Table 1. Brain Tumors Reported in Patients with Down Syndrome (2-5, 7, 8, 11, 12, 14, 16, 17, 19, 20, 24, 25) Case Number

Author, Year

Age(years)/Sex

Site of Lesion

Diagnosis

1

Henschen et al., 1955

27/F

Corpus callosum, choroid plexus

Lipoma

2

Carter et al., Stewart et al., 1958

4/M

Brain

Glioma

3

Holland et al., 1962

13/M

Brain

Angioma

4

Turner et al., 1962

8 months/—

Brain

Glioma

5

Turner et al., 1962

49/—

Brain

Glioblastoma

6

Jackson et al., 1968

8/M



Astrocytoma

7

Foley et al., 1968

17/F

Basicranium

Rhabdomyosarcoma

8

Miller et al., 1970





Angioma

9

Komiya et al., 1975

2/M

Cerebellum

Teratoma

10

Nakato et al., 1982

7/M

Third ventricle

Teratoma

11

Scholl et al., 1982







12

Jonakin et al., 1983

12/M

Optic nerve

Glioma

13

Fukushima et al., 1985



Brain

Malignant tumor

14

Yamasaki et al., 1985

4 months/F

Basal ganglia, posterior fossa

Teratoma

15

Buchin et al., 1986





Glioblastoma

16

Isaacs et al., 1987

0/F

Thalamus

Myxolipoma

17

Hokezu et al., 1987

11/M

Basal ganglia



18

Rueda-Pedraza et al., 1987

27 months/M

Cerebellum

Yolk sac tumor

19

Morayati et al., 1990

54/M

Pituitary

Pituitary adenoma

20

Narod et al., 1991



Brain

Glioma

21

Narod et al., 1991



Brain

Glioma

22

Fujita et al., 1992

9/M

Basal ganglia

Germinoma

23

Zagzag et al., 1992

13/M

Brainstem

Glioblastoma multiforme

24

Hori et al., 1992

24/M

Choroid plexus

Papilloma

25

Oshita et al., 1993

12/F

Basal ganglia

Yolk sac tumor

26

Wada et al., 1995

6/M

Cerebellopontine angle

Yolk sac tumor

27

Hashimoto et al., 1995

12/M

Basal ganglia

Seminoma

28

Tanabe et al., 1997

10/M

Basal ganglia

Germinoma

29

Nakashima et al., 1997

12/M

Frontal lobe, basal ganglia

Germinoma

30

Robson et al., 1997

0/F

Pineal region

Mature teratoma

31

Matsumura et al., 1998

10/M

Basal ganglia, thalamus

Germinoma

32

Matsumura et al., 1998

20/M

Pineal region

Germinoma

33

Chik et al., 1999

9/M

Basal ganglia

Germinoma

34

Chik et al., 1999

3/M

Cerebellum

Yolk sac tumor

35

Hasle et al., 2000





Glioblastoma

36

Satgé et al., 2001

19/M

Frontal lobe

Astrocytoma

37

Ishiyama et al., 2001

12/M

Basal ganglia



38

Rickert et al., 2002

0/F

Fourth ventricle

Ependymoma

39

Tan et al., 2004

22/M

Pineal region

Yolk sac tumor

40

Murphy et al., 2006





— Continues

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Table 1. Continued Case Number

Author, Year

Age(years)/Sex

Site of Lesion

Diagnosis

41

Patja et al., 2006







42

Patja et al., 2006







43

Benesch et al., 2009

4/M

Cerebellum

Medulloblastoma

44

Nakamura et al., 2011

11/M

Basal ganglia

Germ cell tumor

45

Maeda et al., 2011

13/M

Basal ganglia

Yolk sac tumor

46

Satoh et al., 2012

35/M

Cerebellopontine cistern

Germ cell tumor

47

Ehara et al., 2012

1 month/F



Teratoma

48

Ehara et al., 2012

6/M



Yolk sac tumor

49

Ehara et al., 2012

2/M





50

Bakhtiar et al., 2012

2 months/M

Cerebellum

Teratoma

51

Sugimoto et al., 2013

17/F

Basal ganglia

Yolk sac tumor

52

Endo et al., 2013

2/M

Posterior fossa

Yolk sac tumor

53

Satgé et al., 2013

5/M

Third ventricle

Astrocytoma

54

Satgé et al., 2013

8/F

Temporal region

Xanthoastrocytoma

55

Satgé et al., 2013

9/M

Occipital region

Astrocytoma

56

Satgé et al., 2013

4/F

Brainstem

Glioma

57

Satgé et al., 2013

8/M

Brainstem

Glioma

58

Satgé et al., 2013

4/M

Corpus callosum

Gliomatosis cerebri

59

Satgé et al., 2013

10/F

Fourth ventricle

Pilocytic astrocytoma

60

Satgé et al., 2013

10/M

Pons

Glioma

61

Satgé et al., 2013

8/F

Thalamus

Anaplastic astrocytoma

62

Satgé et al., 2013

13/M

Fourth ventricle

Astrocytoma

63

Present case

8/M

Posterior fossa

Meningioma

F, female; M, male.

meningioma. This is the first investigation of the status of chromosome 21 in a tumor specimen from a patient with Down syndrome. Our investigation hints at the mechanism underlying the reduced incidence of solid tumors in individuals with Down syndrome. REFERENCES 1. Baek KH, Zaslavsky A, Lynch RC, Britt C, Okada Y, Siarey RJ, Lensch MW, Park IH, Yoon SS, Minami T, Korenberg JR, Folkman J, Daley GQ, Aird WC, Galdzicki Z, Ryeom S: Down’s syndrome suppression of tumour growth and the role of the calcineurin inhibitor DSCR1. Nature 459:1126-1130, 2009.

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Conflict of interest statement: This work was supported by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (JSPS KAKENHI Grant Number 25462272). The authors declare no conflict of interest. Received 19 January 2015; accepted 11 March 2015 Citation: World Neurosurg. (2015). http://dx.doi.org/10.1016/j.wneu.2015.03.065 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2015 Elsevier Inc. All rights reserved.

WORLD NEUROSURGERY, http://dx.doi.org/10.1016/j.wneu.2015.03.065

Meningioma in Down Syndrome.

Down syndrome comprises multiple malformations and is due to trisomy of chromosome 21. There is epidemiologic evidence that individuals with Down synd...
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