European Journal of Medical Genetics 57 (2014) 269e274
Contents lists available at ScienceDirect
European Journal of Medical Genetics journal homepage: http://www.elsevier.com/locate/ejmg
Clinical report
Turner syndrome and meningioma: Support for a possible increased risk of neoplasia in Turner syndrome Danielle B. Pier a,1, Fabio P. Nunes b, 2, Scott R. Plotkin b, c, Anat O. Stemmer-Rachamimov d, James C. Kim d, Helen A. Shih e, Priscilla Brastianos f, g, h, Angela E. Lin a, * a
Medical Genetics Unit, MassGeneral Hospital for Children, Boston, MA, USA Stephen E. & Catherine Pappas Center for Neuro-Oncology, Department of Neurology, Massachusetts General Hospital, Boston, MA, USA Department of Neurology, Massachusetts General Hospital, Boston, MA, USA d Department of Pathology, Massachusetts General Hospital, Boston, MA, USA e Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA f Department of Medicine, Massachusetts General Hospital, Boston, MA, USA g Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA h Broad Institute of MIT and Harvard, Boston, MA, USA b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 18 June 2013 Accepted 14 March 2014 Available online 25 March 2014
Neoplasia is uncommon in Turner syndrome, although there is some evidence that brain tumors are more common in Turner syndrome patients than in the general population. We describe a woman with Turner syndrome (45,X) with a meningioma, in whom a second neoplasia, basal cell carcinomas of the scalp and nose, developed five years later in the absence of therapeutic radiation. Together with 7 cases of Turner syndrome with meningioma from a population-based survey in the United Kingdom, and 3 other isolated cases in the literature, we review this small number of patients for evidence of risk factors related to Turner syndrome, such as associated structural anomalies or prior treatment. We performed histological and fluorescent in situ hybridization (FISH) of 22q (NF2 locus) analyses of the meningeal tumor to search for possible molecular determinants. We are not able to prove causation between these two entities, but suggest that neoplasia may be a rare associated medical problem in Turner syndrome. Additional case reports and extension of population-based studies are needed. Ó 2014 Elsevier Masson SAS. All rights reserved.
Keywords: Aortic dissection Meningioma NF2 Pseudocoarctation Sex chromosome abnormality syndrome Turner syndrome
1. Introduction One in 2000 liveborn females is affected with Turner syndrome [Stochholm et al., 2006], a familiar sex chromosome abnormality in which there is an absent or structurally abnormal X chromosome, and less frequently, mosaicism [Bondy, 2007]. The well-delineated features of Turner syndrome include short stature, webbed neck, lymphedema, premature ovarian failure in infancy, left-sided cardiac anomalies, aortic dilation and dissection,
* Corresponding author. Genetics Unit, CPZN-2222, Massachusetts General Hospital, 185 Cambridge St., Boston, MA 02114, USA. Tel.: þ1 617 726 1561; fax: þ1 617 726 1566. E-mail address: [email protected] (A.E. Lin). 1 Current address: Department of Neurology, Boston Children’s Hospital, Boston, MA, USA. 2 Current address: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA. http://dx.doi.org/10.1016/j.ejmg.2014.03.005 1769-7212/Ó 2014 Elsevier Masson SAS. All rights reserved.
renal malformations, otitis media and hearing loss, and multiple nevi [Bondy, 2007]. The risk for cancer in Turner syndrome traditionally focuses on the development of gonadoblastoma in women who carry Y chromosome material [Bondy, 2007]. However, a population-based survey [Schoemaker et al., 2008] noted various malignancies in this population, including an increased risk of central nervous system (CNS) tumors, also noted in case reports [Iacono et al., 1981; Kido et al., 1994; Nozza et al., 2005]. It is unclear whether these are coincidental, related to the absent X chromosome, or to the treatment of associated medical problems such as short stature, estrogen deficiency and reduced fertility. To further explore this association, we report a 44-year-old woman with 45,X Turner syndrome, bicuspid aortic valve, and pseudocoarctation, who delivered a child using oocyte donation-assisted reproductive technology (ART). She developed multiple meningiomas, required resection of a large right frontal meningioma, and subsequently developed basal cell carcinoma of the scalp and nose.
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2. Clinical report 2.1. Present history A 44-year-old woman with Turner syndrome presented to an outside hospital with two brief episodes of altered mental status. A computed tomography (CT) scan of her head showed a 4.1-cm right frontal mass with surrounding edema, midline shift, sulbfalcine and uncal herniation, and hyperostosis of the sella turcica. She received high dose corticosteroids and an antiepileptic medication and was transferred to our emergency department. Neurological exam on presentation was only remarkable for a disconjugate gaze when looking to the left, but was otherwise non-focal. Abnormal laboratory values included a random glucose 161 mg/dL and alkaline phosphatase 136 U/L. The remaining tests were within normal limits, including electrolytes, renal function, thyroid function, prolactin, total and direct bilirubin, pancreatic enzymes, white blood count, platelets, and hematocrit. Magnetic resonance imaging (MRI) of the brain showed a dural based, extra-axial, homogenously enhancing mass measuring 4.4cm by 4.2-cm by 5.0-cm located in the right anterior cranial fossa, which extended across the midline, encased both carotid arteries, and invaded the cavernous sinuses. There was marked vasogenic edema in the right frontal and temporal lobes causing mass effect, compression of the right lateral ventricle, and 1.1-cm midline shift. Subfalcine and right uncal herniation was again evident. There was no evidence of infarction or hemorrhage, but the right anterior and middle cerebral arteries were displaced away from the mass. Detailed ophthalmologic exam showed chronic atrophic papilledema of the right eye and mild disc swelling of the left eye, indicating elevated intracranial pressure. She underwent subtotal tumor resection with right optic nerve decompression. There was bulky residual tumor along the skull base involving the left sphenoid wing, left cavernous sinus, prepontine space, and retroclival regions. Minimal residual tumor persisted along the right medial anterior temporal fossa and orbital apex. Postoperatively, she was maintained on high dose corticosteroids and antiepileptic prophylaxis. Her remaining neurological deficits after surgery include a non-reactive right surgical pupil, a third cranial nerve palsy with right ptosis and lateral deviation of the right eye, and mild reduced hearing in the right ear. Pathologic review of the tumor specimen showed a meningothelial meningioma, WHO Grade I, with atypical features of sheeting and high cell density. Based on the low-grade histology and extensive radiation fields that would likely incur some late effects such as hypopituitarism, the patient declined adjuvant radiation therapy. The tumor was monitored with serial MRIs. Definitive fractionated radiation therapy of the meningioma was carried out over 5 years, with total dose field radiation of 57.8 Gy. The patient then presented 5 years later with the development of a new vertex scalp lesion, which had grown over the past three months. The 2.6 cm lobulated lesion was mildly erythematous and slightly raised; the lesion correlated with MRI findings of an enhancing scalp lesion along the left scalp without clear evidence of erosion into the skull. She also was noted to have a smaller lesion of similar character on her nose. Biopsy of the scalp lesion revealed a 2.5 2.5 cm hyperkeratotic basal cell carcinoma, infiltrating type, which was resected at another institution. She had the lesion on the nose resected three months after the scalp resection at that same outside institution. Pathology of both lesions reportedly revealed findings consistent with basal cell carcinomas. The meningioma bed at the time of the scalp basal cell carcinoma diagnosis showed subtle, but definitive interval increase in the size of the tumor nodule located near the inferior clivus. Although asymptomatic since her initial surgery, she experienced a
generalized seizure two weeks after her scalp biopsy. Her antiepileptic medication, levetiracetam, was subsequently adjusted to reduce further risk of seizures. Two MRI scans performed in the sixth postoperative year have not shown increase in skull base tumor size, and possibly, a slight reduction. The patient had declined requests to have a CT angiogram of the aorta for more detailed monitoring. 2.2. Past medical history The patient had been diagnosed with Turner syndrome as a newborn and received endocrinologic treatment in childhood. She was not aware of her chromosome complement until a karyotype was obtained during treatment for her meningioma. This showed 45,X in 10 out of 10 metaphases examined, excluding mosaicism greater than 26% at a 95% confidence limit. The patient had typical physical features of Turner syndrome with short stature (height 150 cm), multiple nevi, low posterior hairline, short neck with webbing (surgical scars on right), large and low set ears, subjective hypertelorism, down-slanting eyes, small chin, pectus excavatum, dysplastic toenails, and chronic lymphedema of legs. She was not known to have a congenital heart defect in childhood, and had a unilateral nephrectomy as a child for probable obstructive uropathy. She received growth hormone at age 10 years, and was treated for hypothyroidism since early adolescence. The patient also started hormone replacement therapy in late adolescence; which was not resumed after her first and only pregnancy. She did well academically in school without learning disabilities or extra services, attended junior college and subsequently nursing school. She reports red/green color-blindness. The patient reported frequent unprotected sun exposure in the summer (e.g. used baby oil instead of sun-blocking agents). The patient married, and at age 35 years achieved pregnancy after several cycles of in vitro fertilization (IVF) with an anonymous egg donor. Her only biologic child was a male born at full term with multiple congenital anomalies. He had a normal chromosomal analysis, a right clubfoot, and bilateral ulnar deviation of the hands consistent with distal arthrogryposis (possibly consistent with FreemaneSheldon syndrome by review of A.E.L.). He died at 6 weeks of age, which was attributed to Sudden Infant Death Syndrome (SIDS). There is no family history of known chromosomal abnormalities, birth defects, genetic syndromes (other than red/ green color blindness), or brain or skin cancers. Her mother died of breast cancer at age 41. Because of the detection of a heart murmur in the third trimester of her sole pregnancy, she had a cardiac MRI scan at another institution, which diagnosed a pseudocoarctation of the aorta (image not available for review). The most recent echocardiogram performed at another hospital approximately 4 ½ years after the meningioma was detected reported mild aortic regurgitation. The descending aorta was not described, and the aortic valve opened during this study, but was not well seen. The aortic root diameter was 2.9 cm (BSA 1.5 m2). 2.3. Pathologic analysis of tumor Fresh and frozen sections of the tumor revealed a meningioma with some atypical features. The H&E paraffin-embedded sections showed a meningioma of the meningothelial histological subtype (Fig. 1A). There were a few foci with moderately increased cell density. In some areas, tumor cells had an appearance reminiscent of “rhabdoid” features, with enlarged cells and eccentric nuclei (Fig. 1B). No other atypical features were present, (such as necrosis, prominent nucleoli, or increased nucleuse cytoplasm ratio) and mitotic figures were rare (75% of nuclei to contain at least one NF2 signal. Paraffin sections were immunostained for estrogen receptor (ER) and progesterone receptor (PR) using the following primary antibodies: 6F11 (mouse monoclonal, prediluted, Leica Biosystems, Newcastle, UK) and 16 (mouse monoclonal, prediluted, Leika Biosystems, Newcastle, UK). Immunostaining was performed in a Bond III automatic immunostaining device (Leika Biosystems) using heat induced antigen retrieval in EDTA (pH 9.0) for 10 min (ER) or 20 min (PR). 3. Results 3.1. Clinical reports: new patient and literature Table 1 summarizes the new patient, individual case reports [Iacono et al., 1981; Kido et al., 1994; Nozza et al., 2005] and the population-based series from Great Britain [Schoemaker et al., 2008]. Three of the four patients were 31 years and older; ages were not available for 7 of the patients. The karyotype data was incomplete, but the frequency of 45,X (36%) is similar to the general Turner syndrome population [Bondy, 2007]. The absence of clinical information from the population-based survey precludes commentary about congenital heart disease, although the finding of one patient with aortic dissection and one with pseudocoarctation is worth noting. The significance of the frequency of patients with 45,X karyotype who undertook ART with egg donation (1 in 11, 9%) and subsequently developed cancers cannot be assessed due to small numbers. 3.2. Cytogenetic molecular analysis and immunostaining FISH analysis showed retention of the NF2 locus in all the blocks analyzed. Slides were evaluated for ER and PR positivity by a pathologist (ASR) using a semiquantitative system based on the proportion of positive cells and staining intensity. All cells were positive for PR (5/5) and were strongly positive (3/3). All cells were negative for ER (Fig 2). 4. Discussion This new patient adds important information to a small body of literature about women with Turner syndrome and neoplasm, including ten other cases with meningioma. Meningioma is the most common adult brain tumor, accounting for just over one-third of all primary CNS tumors diagnosed in the United States from 2005 to 2009, and is much more common in females [Dolecek et al., 2012]. Thus, the presence of meningioma in Turner syndrome patient may be coincidental, since meningiomas are found incidentally in 0.6% of all brain MRI scans performed for other reasons [Rocque et al., 2008]. However, a population-based study of 3425 women with Turner syndrome suggested that the risk of
CNS tumors is 8.2 times greater than the normal population in women with complete 45,X (95% CI 3.55e16.2), with meningioma being the highest risk (standardized incidence ratio of 12) [Schoemaker et al., 2008]. The risk is less with mosaic forms, and greater with 45,X [Schoemaker et al., 2008]. It is possible that the increased risk of meningioma in women with Turner syndrome may be due to haploinsufficiency of the X chromosome, or the result of the hormonal treatments required for their condition, which include growth hormone, estrogen replacement, and progesterone replacement. The use of growth hormone in patients with Turner Syndrome, which is used to treat short stature, has not been shown to contribute directly to the increased incidence of meningioma [Jostel et al., 2005], however there is conflicting data about the effect of sex hormones on meningioma, namely progesterone and estrogen therapies. Case reports show meningioma occurrence or progression in women treated with progesterone agonists [Gruber et al., 2004; Piper et al., 1994], and tumor regression after treatment cessation [Vadivelu et al., 2010]. Although meningioma expression of progesterone receptors (PR) had been well demonstrated [Roser et al., 2004a, 2004b], the biology of the hormone and hormone receptors indicate that expression of PR is associated with low tumor vascularity and Low Ki-67-labeling index [Roser et al., 2004a]. PR expression levels are also comparable between genders and age groups, and are inversely correlated to tumor grade, which speak against a functional importance to the presence of the receptors in tumor tissue [Roser et al., 2004b]. Concerning exogenous estrogen, a common source of exposure to estrogen in women with Turner syndrome is the need for hormone replacement therapy (HRT) in association with artificial reproductive technologies (ART). Spontaneous pregnancy in women with Turner syndrome is approximately 10%, usually occurring in those with mosaicism [Bondy, 2007]. Rates of infertility and premature ovarian failure are high, leading some women with Turner syndrome opt for oocyte or embryo donation. This requires exogenous HRT in order to prepare the uterus to successfully tolerate a pregnancy. The typical hormonal dosing required in this population to achieve adequate endometrial thickness is typically 4e8 mg of 17-beta estradiol in addition to a gestagen [Bondy, 2007]. In our review of 10 reported cases [Iacono et al., 1981; Kido et al., 1994; Nozza et al., 2005; Schoemaker et al., 2008] and this new patient with meningioma (Table 1), details of HRT dose, onset and duration were not available, but we suspect that most received exogenous sex hormone therapy at some point. Whether HRT increases the risk of cranial meningioma in patients without Turner syndrome has been supported by several recent European studies [Andersen et al., 2013 Jun 22; Korhonen et al., 2012 Feb 15; Michaud et al., 2010 Oct], whereas other studies have not shown a clinically significant association [Claus et al., 2013 Mar; Pines and 2011 Apr]. Exogenous estrogen exposure, rather than
Fig. 2. Genetic Features of Meningioma. A. Meningioma cells are completely negative for ER (mouse monoclonal 6F11) and B. diffusely and strongly positive for PR (16, monoclonal mouse antibody). C. Meningioma cells show retention of two copies of NF2 gene (arrows) and 2 copies of control gene (circled) by FISH. There is no evidence of NF2 deletion.
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estrogen-progesterone in combination, appears to be the greater risk factor [Korhonen et al., 2012 Feb 15]. It is unknown whether Turner syndrome further increases the risk for development of meningiomas in the setting of HRT. An alternative hypothesis to explain the two neoplasias in this particular patient is the presence of a co-occurring oncogenic gene unrelated to Turner syndrome. The molecular basis for meningioma formation and progression is incompletely understood. The NF2 gene, located on chromosome 22q12, has been implicated as the causative gene in up to 60% of sporadic meningiomas [Ruttledge et al., 1994]. Most patients with familial multiple meningioma syndrome (FMMS) are women, with very few well-documented men [Heinrich et al., 2003]. FMMS is characterized by the presence of multiple meningiomas without any other evidence of neurofibromatosis 2, and the causative gene for FMMS is not entirely clear. A recent report suggested that loss of SUFU (located on 10q24) in one family function led to multiple meningioma occurrences [Aavikko et al., 2012]. In this patient with Turner syndrome, the FISH analysis of the tumor paraffin block showed retention of the NF2 gene locus. Meningiomas with NF2 loss are more commonly of the fibroblastic subtype [Ruttledge et al., 1994], whereas this tumor was meningothelial. Molecular involvement of the NF2 gene in patients with Turner syndrome has not been reported previously, and a more comprehensive analysis with mutation analysis of the NF2 gene sequence in a cohort of tumors from Turner syndrome patients is needed to better address this issue. A subset of meningiomas lacking NF2 alterations harbor recurrent oncogenic mutations in AKT1 (p.Glu17Lys) and SMO (p.Trp535Leu) and exhibited immunohistochemical evidence of activation of these pathways [Brastianos et al., 2013]. These mutations were present in therapeutically challenging tumors of the skull base and higher grade. Furthermore, the SMO and AKT1-mutated tumors tend to have a meningothelial histology, which is the histologic subtype of our patient’s meningioma [Brastianos et al., 2013]. To determine the possible role of oncogenic genes, we presented the patient a strategy of tiered testing for both targeted genes (e.g. PTCH1) and whole genome sequencing, using both commercial and research methodology; she declined genetic testing. Five years after the meningioma was diagnosed, our patient developed an infiltrating basal cell carcinoma (BCC), one of the most common cancers in the US. The exact incidence is unknown because there are no cancer registries dedicated to BCCs specifically. They are more common in males and persons with lighter skin [Rogers et al., 2010]. It has been suggested that hormone replacement therapy increases the incidence of non-melanoma type skin cancers in the general population as well [BirchJohansen et al., 2012]. Given the frequent occurrence in the general population, and this patient’s well-acknowledged sun exposure history, we cannot be certain if this patient’s lifetime exposures contributed to the development of this second cancer. Also, notably, mutations in the hedgehog pathway (including SMO and PTCH1) are pathognomonic for basal cell carcinoma, [Sekulic et al., 2012 Jun 7]. Furthermore, familial basal cell carcinoma (Gorlin syndrome), a predisposition to multiple cancer types including basal cell carcinoma and meningiomas, is associated with alterations in the Hedgehog pathway [Dahmane et al., 1997 Oct 23]. Thus, it is possible that the patient had a germline mutation in the Hedgehog pathway, but in the absence of sequencing, we cannot determine this definitively. Following guidelines for adult women with Turner syndrome, [Bondy, 2007] our patient is being monitored for aortic dilation, which has been observed in up to 30% using magnetic resonance imaging [Bondy, 2007]. Although she does not have a bicuspid aortic valve or coarctation, she is considered at higher risk for
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dissection because she had two cycles of ART and a successful pregnancy, has mild aortic regurgitation, and incompletely defined aortic valve morphology. Published data is insufficient at present to suggest that there is a direct role between the loss of the X chromosome in the pathogenesis of neoplasia, although this review supports the hypothesis of an association. There is some evidence to suggest an association with exogenous hormone exposure and certain types of neoplasia, but current data are insufficient to allow us to decide between the two hypotheses: X-chromosome genes, haploinsufficiency, or HRT effect. Given that women with Turner Syndrome are likely to require hormone replacement therapy during their lives, and most need artificial reproductive technologies to conceive, we suggest that additional research is needed to determine whether this may be a more important risk factor for certain types of neoplasia in this population. Acknowledgments We thank Takako Yanagisawa from Toho University, Faculty of Medicine in Tokyo, Japan for providing translation. Dr. Paolo Nozza, Anatomic Pathologist at the Istituto Giannina Gaslini in Genoa, Italy provided supplemental clinical information to the report of Nozza et al. (2005). Meaghan Muir from the Brigham and Women’s Hospital library provided assistance. References Aavikko M, Li S-P, Saarinen S, Alhopuro P, Kaasinen E, Morgunova E, et al. Loss of SUFU function in familial multiple meningioma. Am J Hum Genet 2012;91(3): 520e6. Andersen L, Friis S, Hallas J, Ravn P, Schrøder HD, Gaist D. Hormone replacement therapy increases the risk of cranial meningioma. Eur J Cancer 2013;49(15):3303e10. Birch-Johansen F, Jensen A, Olesen AB, Christensen J, Tjønneland A, Kjær SK. Does hormone replacement therapy and use of oral contraceptives increase the risk of non-melanoma skin cancer? Cancer Causes Control 2012;23(2):379e 88. Bondy CA. Care of girls and women with Turner syndrome: a guideline of the Turner Syndrome Study Group. J Clin Endocrinol Metab 2007;92:10e25. Brastianos PK, Horowitz PM, Santagata S, Jones RT, McKenna A, Getz G, et al. Genomic sequencing of meningiomas identifies oncogenic SMO and AKT1 mutations. Nat Genet 2013;45(3):285e9. Claus EB, Calvocoressi L, Bondy ML, Wrensch M, Wiemels JL, Schildkraut JM. Exogenous hormone use, reproductive factors, and risk of intracranial meningioma in females. J Neurosurg 2013 Mar;118(3):649e56. Dahmane N, Lee J, Robins P, Heller P, Ruiz i Altaba A. Activation of the transcription factor Gli1 and the Sonic hedgehog signalling pathway in skin tumours. Nature 1997 Oct 23;389(6653):876e81. Dolecek TA, Propp JM, Stroup NE, Kruchko C. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2005e2009. Neuro-Oncology 2012;14(Suppl. 5):1e49. Gruber T, Dare AO, Balos LL, Lele S, Fenstermaker RA. Multiple meningiomas arising during long-term therapy with the progesterone agonist megestrol acetate. Case report. J Neurosurg 2004;100(2):328e31. Heinrich B, Hartmann C, Stemmer-Rachamimov AO, Louis DN, MacCollin M. Multiple meningiomas: investigating the molecular basis of sporadic and familial forms. Int J Cancer 2003;103(4):483e8. Iacono RP, Apuzzo ML, Davis RL, Tsai FY. Multiple meningiomas following radiation therapy for medulloblastoma. Case report. J Neurosurg 1981;55(2):282e6. Jostel A, Mukherjee A, Hulse PA, Shalet SM. Adult growth hormone replacement therapy and neuroimaging surveillance in brain tumour survivors. Clin Endocrinol (Oxf) 2005;62(6):698e705. Kido G, Miyagi A, Shibuya T, Miyagami M, Tsubokawa T, Sawada T. Turner’s syndrome with pituitary hyperplasia: a case report. No Shinkei Geka 1994;22(4): 333e8. Korhonen K, Auvinen A, Lyytinen H, Ylikorkala O, Pukkala E. A nationwide cohort study on the incidence of meningioma in women using postmenopausal hormone therapy in Finland. Am J Epidemiol 2012 Feb 15;175(4):309e14. Matsuno A, Fujimaki T, Sasaki T, Nagashima T, Ide T, Asai A, et al. Clinical and histopathological analysis of proliferative potentials of recurrent and nonrecurrent meningiomas. Acta Neuropathol. 1996;91(5):504e10. Michaud DS, Gallo V, Schlehofer B, Tjønneland A, Olsen A, Overvad K, et al. Reproductive factors and exogenous hormone use in relation to risk of glioma and meningioma in a large European cohort study. Cancer Epidemiol Biomarkers Prev 2010 Oct;19(10):2562e9.
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Nozza P, Raso A, Rossi A, Milanaccio C, Pezzolo A, Capra V, et al. Rhabdoid meningioma of the tentorium with expression of desmin in a 12-year-old Turner syndrome patient. Acta Neuropathol 2005;110(2):205e6. Pines A. Hormone therapy and brain tumors. Climacteric 2011 Apr;14(2):215e6. Piper JG, Follett KA, Fantin A. Sphenoid wing meningioma progression after placement of a subcutaneous progesterone agonist contraceptive implant. Neurosurgery 1994;34(4):723e5. Rocque BG, Baskaya MK, Kuo JS. Incidental findings on brain MRI. N Engl J Med 2008;358(8):853 [author reply 854e855]. Rogers HW, Weinstock MA, Harris AR, Hinckley MR, Feldman SR, Fleischer AB, et al. Incidence estimate of nonmelanoma skin cancer in the United States, 2006. Arch Dermatol 2010;146(3):283e7. Roser F, Samii M, Ostertag H, Bellinzona M. The Ki-67 proliferation antigen in meningiomas. Experience in 600 cases. Acta Neurochir (Wien) 2004;146(1): 37e44 [discussion 44]. Roser F, Nakamura M, Bellinzona M, Rosahl SK, Ostertag H, Samii M. The prognostic value of progesterone receptor status in meningiomas. J Clin Pathol 2004;57(10):1033e7.
Ruttledge MH, Sarrazin J, Rangaratnam S, Phelan CM, Twist E, Merel P, et al. Evidence for the complete inactivation of the NF2 gene in the majority of sporadic meningiomas. Nat Genet 1994;6(2):180e4. Schoemaker MJ, Swerdlow AJ, Higgins CD, Wright AF, Jacobs PA. Cancer incidence in women with Turner syndrome in Great Britain: a national cohort study. Lancet Oncol 2008;9(3):239e46. Sekulic A, Migden MR, Oro AE, Dirix L, Lewis KD, Hainsworth JD, et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med 2012 Jun 7;366(23):2171e9. Stochholm K, Juul S, Juel K, Naeraa RW, Gravholt CH. Prevalence, incidence, diagnostic delay, and mortality in Turner syndrome. J Clin Endocrinol Metab 2006;91:3897e902. Vadivelu S, Sharer L, Schulder M. Regression of multiple intracranial meningiomas after cessation of long-term progesterone agonist therapy. J Neurosurg 2010;112(5):920e4.
Contents lists available at ScienceDirect
European Journal of Medical Genetics journal homepage: http://www.elsevier.com/locate/ejmg
Clinical report
Turner syndrome and meningioma: Support for a possible increased risk of neoplasia in Turner syndrome Danielle B. Pier a,1, Fabio P. Nunes b, 2, Scott R. Plotkin b, c, Anat O. Stemmer-Rachamimov d, James C. Kim d, Helen A. Shih e, Priscilla Brastianos f, g, h, Angela E. Lin a, * a
Medical Genetics Unit, MassGeneral Hospital for Children, Boston, MA, USA Stephen E. & Catherine Pappas Center for Neuro-Oncology, Department of Neurology, Massachusetts General Hospital, Boston, MA, USA Department of Neurology, Massachusetts General Hospital, Boston, MA, USA d Department of Pathology, Massachusetts General Hospital, Boston, MA, USA e Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA f Department of Medicine, Massachusetts General Hospital, Boston, MA, USA g Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA h Broad Institute of MIT and Harvard, Boston, MA, USA b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 18 June 2013 Accepted 14 March 2014 Available online 25 March 2014
Neoplasia is uncommon in Turner syndrome, although there is some evidence that brain tumors are more common in Turner syndrome patients than in the general population. We describe a woman with Turner syndrome (45,X) with a meningioma, in whom a second neoplasia, basal cell carcinomas of the scalp and nose, developed five years later in the absence of therapeutic radiation. Together with 7 cases of Turner syndrome with meningioma from a population-based survey in the United Kingdom, and 3 other isolated cases in the literature, we review this small number of patients for evidence of risk factors related to Turner syndrome, such as associated structural anomalies or prior treatment. We performed histological and fluorescent in situ hybridization (FISH) of 22q (NF2 locus) analyses of the meningeal tumor to search for possible molecular determinants. We are not able to prove causation between these two entities, but suggest that neoplasia may be a rare associated medical problem in Turner syndrome. Additional case reports and extension of population-based studies are needed. Ó 2014 Elsevier Masson SAS. All rights reserved.
Keywords: Aortic dissection Meningioma NF2 Pseudocoarctation Sex chromosome abnormality syndrome Turner syndrome
1. Introduction One in 2000 liveborn females is affected with Turner syndrome [Stochholm et al., 2006], a familiar sex chromosome abnormality in which there is an absent or structurally abnormal X chromosome, and less frequently, mosaicism [Bondy, 2007]. The well-delineated features of Turner syndrome include short stature, webbed neck, lymphedema, premature ovarian failure in infancy, left-sided cardiac anomalies, aortic dilation and dissection,
* Corresponding author. Genetics Unit, CPZN-2222, Massachusetts General Hospital, 185 Cambridge St., Boston, MA 02114, USA. Tel.: þ1 617 726 1561; fax: þ1 617 726 1566. E-mail address: [email protected] (A.E. Lin). 1 Current address: Department of Neurology, Boston Children’s Hospital, Boston, MA, USA. 2 Current address: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA. http://dx.doi.org/10.1016/j.ejmg.2014.03.005 1769-7212/Ó 2014 Elsevier Masson SAS. All rights reserved.
renal malformations, otitis media and hearing loss, and multiple nevi [Bondy, 2007]. The risk for cancer in Turner syndrome traditionally focuses on the development of gonadoblastoma in women who carry Y chromosome material [Bondy, 2007]. However, a population-based survey [Schoemaker et al., 2008] noted various malignancies in this population, including an increased risk of central nervous system (CNS) tumors, also noted in case reports [Iacono et al., 1981; Kido et al., 1994; Nozza et al., 2005]. It is unclear whether these are coincidental, related to the absent X chromosome, or to the treatment of associated medical problems such as short stature, estrogen deficiency and reduced fertility. To further explore this association, we report a 44-year-old woman with 45,X Turner syndrome, bicuspid aortic valve, and pseudocoarctation, who delivered a child using oocyte donation-assisted reproductive technology (ART). She developed multiple meningiomas, required resection of a large right frontal meningioma, and subsequently developed basal cell carcinoma of the scalp and nose.
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2. Clinical report 2.1. Present history A 44-year-old woman with Turner syndrome presented to an outside hospital with two brief episodes of altered mental status. A computed tomography (CT) scan of her head showed a 4.1-cm right frontal mass with surrounding edema, midline shift, sulbfalcine and uncal herniation, and hyperostosis of the sella turcica. She received high dose corticosteroids and an antiepileptic medication and was transferred to our emergency department. Neurological exam on presentation was only remarkable for a disconjugate gaze when looking to the left, but was otherwise non-focal. Abnormal laboratory values included a random glucose 161 mg/dL and alkaline phosphatase 136 U/L. The remaining tests were within normal limits, including electrolytes, renal function, thyroid function, prolactin, total and direct bilirubin, pancreatic enzymes, white blood count, platelets, and hematocrit. Magnetic resonance imaging (MRI) of the brain showed a dural based, extra-axial, homogenously enhancing mass measuring 4.4cm by 4.2-cm by 5.0-cm located in the right anterior cranial fossa, which extended across the midline, encased both carotid arteries, and invaded the cavernous sinuses. There was marked vasogenic edema in the right frontal and temporal lobes causing mass effect, compression of the right lateral ventricle, and 1.1-cm midline shift. Subfalcine and right uncal herniation was again evident. There was no evidence of infarction or hemorrhage, but the right anterior and middle cerebral arteries were displaced away from the mass. Detailed ophthalmologic exam showed chronic atrophic papilledema of the right eye and mild disc swelling of the left eye, indicating elevated intracranial pressure. She underwent subtotal tumor resection with right optic nerve decompression. There was bulky residual tumor along the skull base involving the left sphenoid wing, left cavernous sinus, prepontine space, and retroclival regions. Minimal residual tumor persisted along the right medial anterior temporal fossa and orbital apex. Postoperatively, she was maintained on high dose corticosteroids and antiepileptic prophylaxis. Her remaining neurological deficits after surgery include a non-reactive right surgical pupil, a third cranial nerve palsy with right ptosis and lateral deviation of the right eye, and mild reduced hearing in the right ear. Pathologic review of the tumor specimen showed a meningothelial meningioma, WHO Grade I, with atypical features of sheeting and high cell density. Based on the low-grade histology and extensive radiation fields that would likely incur some late effects such as hypopituitarism, the patient declined adjuvant radiation therapy. The tumor was monitored with serial MRIs. Definitive fractionated radiation therapy of the meningioma was carried out over 5 years, with total dose field radiation of 57.8 Gy. The patient then presented 5 years later with the development of a new vertex scalp lesion, which had grown over the past three months. The 2.6 cm lobulated lesion was mildly erythematous and slightly raised; the lesion correlated with MRI findings of an enhancing scalp lesion along the left scalp without clear evidence of erosion into the skull. She also was noted to have a smaller lesion of similar character on her nose. Biopsy of the scalp lesion revealed a 2.5 2.5 cm hyperkeratotic basal cell carcinoma, infiltrating type, which was resected at another institution. She had the lesion on the nose resected three months after the scalp resection at that same outside institution. Pathology of both lesions reportedly revealed findings consistent with basal cell carcinomas. The meningioma bed at the time of the scalp basal cell carcinoma diagnosis showed subtle, but definitive interval increase in the size of the tumor nodule located near the inferior clivus. Although asymptomatic since her initial surgery, she experienced a
generalized seizure two weeks after her scalp biopsy. Her antiepileptic medication, levetiracetam, was subsequently adjusted to reduce further risk of seizures. Two MRI scans performed in the sixth postoperative year have not shown increase in skull base tumor size, and possibly, a slight reduction. The patient had declined requests to have a CT angiogram of the aorta for more detailed monitoring. 2.2. Past medical history The patient had been diagnosed with Turner syndrome as a newborn and received endocrinologic treatment in childhood. She was not aware of her chromosome complement until a karyotype was obtained during treatment for her meningioma. This showed 45,X in 10 out of 10 metaphases examined, excluding mosaicism greater than 26% at a 95% confidence limit. The patient had typical physical features of Turner syndrome with short stature (height 150 cm), multiple nevi, low posterior hairline, short neck with webbing (surgical scars on right), large and low set ears, subjective hypertelorism, down-slanting eyes, small chin, pectus excavatum, dysplastic toenails, and chronic lymphedema of legs. She was not known to have a congenital heart defect in childhood, and had a unilateral nephrectomy as a child for probable obstructive uropathy. She received growth hormone at age 10 years, and was treated for hypothyroidism since early adolescence. The patient also started hormone replacement therapy in late adolescence; which was not resumed after her first and only pregnancy. She did well academically in school without learning disabilities or extra services, attended junior college and subsequently nursing school. She reports red/green color-blindness. The patient reported frequent unprotected sun exposure in the summer (e.g. used baby oil instead of sun-blocking agents). The patient married, and at age 35 years achieved pregnancy after several cycles of in vitro fertilization (IVF) with an anonymous egg donor. Her only biologic child was a male born at full term with multiple congenital anomalies. He had a normal chromosomal analysis, a right clubfoot, and bilateral ulnar deviation of the hands consistent with distal arthrogryposis (possibly consistent with FreemaneSheldon syndrome by review of A.E.L.). He died at 6 weeks of age, which was attributed to Sudden Infant Death Syndrome (SIDS). There is no family history of known chromosomal abnormalities, birth defects, genetic syndromes (other than red/ green color blindness), or brain or skin cancers. Her mother died of breast cancer at age 41. Because of the detection of a heart murmur in the third trimester of her sole pregnancy, she had a cardiac MRI scan at another institution, which diagnosed a pseudocoarctation of the aorta (image not available for review). The most recent echocardiogram performed at another hospital approximately 4 ½ years after the meningioma was detected reported mild aortic regurgitation. The descending aorta was not described, and the aortic valve opened during this study, but was not well seen. The aortic root diameter was 2.9 cm (BSA 1.5 m2). 2.3. Pathologic analysis of tumor Fresh and frozen sections of the tumor revealed a meningioma with some atypical features. The H&E paraffin-embedded sections showed a meningioma of the meningothelial histological subtype (Fig. 1A). There were a few foci with moderately increased cell density. In some areas, tumor cells had an appearance reminiscent of “rhabdoid” features, with enlarged cells and eccentric nuclei (Fig. 1B). No other atypical features were present, (such as necrosis, prominent nucleoli, or increased nucleuse cytoplasm ratio) and mitotic figures were rare (75% of nuclei to contain at least one NF2 signal. Paraffin sections were immunostained for estrogen receptor (ER) and progesterone receptor (PR) using the following primary antibodies: 6F11 (mouse monoclonal, prediluted, Leica Biosystems, Newcastle, UK) and 16 (mouse monoclonal, prediluted, Leika Biosystems, Newcastle, UK). Immunostaining was performed in a Bond III automatic immunostaining device (Leika Biosystems) using heat induced antigen retrieval in EDTA (pH 9.0) for 10 min (ER) or 20 min (PR). 3. Results 3.1. Clinical reports: new patient and literature Table 1 summarizes the new patient, individual case reports [Iacono et al., 1981; Kido et al., 1994; Nozza et al., 2005] and the population-based series from Great Britain [Schoemaker et al., 2008]. Three of the four patients were 31 years and older; ages were not available for 7 of the patients. The karyotype data was incomplete, but the frequency of 45,X (36%) is similar to the general Turner syndrome population [Bondy, 2007]. The absence of clinical information from the population-based survey precludes commentary about congenital heart disease, although the finding of one patient with aortic dissection and one with pseudocoarctation is worth noting. The significance of the frequency of patients with 45,X karyotype who undertook ART with egg donation (1 in 11, 9%) and subsequently developed cancers cannot be assessed due to small numbers. 3.2. Cytogenetic molecular analysis and immunostaining FISH analysis showed retention of the NF2 locus in all the blocks analyzed. Slides were evaluated for ER and PR positivity by a pathologist (ASR) using a semiquantitative system based on the proportion of positive cells and staining intensity. All cells were positive for PR (5/5) and were strongly positive (3/3). All cells were negative for ER (Fig 2). 4. Discussion This new patient adds important information to a small body of literature about women with Turner syndrome and neoplasm, including ten other cases with meningioma. Meningioma is the most common adult brain tumor, accounting for just over one-third of all primary CNS tumors diagnosed in the United States from 2005 to 2009, and is much more common in females [Dolecek et al., 2012]. Thus, the presence of meningioma in Turner syndrome patient may be coincidental, since meningiomas are found incidentally in 0.6% of all brain MRI scans performed for other reasons [Rocque et al., 2008]. However, a population-based study of 3425 women with Turner syndrome suggested that the risk of
CNS tumors is 8.2 times greater than the normal population in women with complete 45,X (95% CI 3.55e16.2), with meningioma being the highest risk (standardized incidence ratio of 12) [Schoemaker et al., 2008]. The risk is less with mosaic forms, and greater with 45,X [Schoemaker et al., 2008]. It is possible that the increased risk of meningioma in women with Turner syndrome may be due to haploinsufficiency of the X chromosome, or the result of the hormonal treatments required for their condition, which include growth hormone, estrogen replacement, and progesterone replacement. The use of growth hormone in patients with Turner Syndrome, which is used to treat short stature, has not been shown to contribute directly to the increased incidence of meningioma [Jostel et al., 2005], however there is conflicting data about the effect of sex hormones on meningioma, namely progesterone and estrogen therapies. Case reports show meningioma occurrence or progression in women treated with progesterone agonists [Gruber et al., 2004; Piper et al., 1994], and tumor regression after treatment cessation [Vadivelu et al., 2010]. Although meningioma expression of progesterone receptors (PR) had been well demonstrated [Roser et al., 2004a, 2004b], the biology of the hormone and hormone receptors indicate that expression of PR is associated with low tumor vascularity and Low Ki-67-labeling index [Roser et al., 2004a]. PR expression levels are also comparable between genders and age groups, and are inversely correlated to tumor grade, which speak against a functional importance to the presence of the receptors in tumor tissue [Roser et al., 2004b]. Concerning exogenous estrogen, a common source of exposure to estrogen in women with Turner syndrome is the need for hormone replacement therapy (HRT) in association with artificial reproductive technologies (ART). Spontaneous pregnancy in women with Turner syndrome is approximately 10%, usually occurring in those with mosaicism [Bondy, 2007]. Rates of infertility and premature ovarian failure are high, leading some women with Turner syndrome opt for oocyte or embryo donation. This requires exogenous HRT in order to prepare the uterus to successfully tolerate a pregnancy. The typical hormonal dosing required in this population to achieve adequate endometrial thickness is typically 4e8 mg of 17-beta estradiol in addition to a gestagen [Bondy, 2007]. In our review of 10 reported cases [Iacono et al., 1981; Kido et al., 1994; Nozza et al., 2005; Schoemaker et al., 2008] and this new patient with meningioma (Table 1), details of HRT dose, onset and duration were not available, but we suspect that most received exogenous sex hormone therapy at some point. Whether HRT increases the risk of cranial meningioma in patients without Turner syndrome has been supported by several recent European studies [Andersen et al., 2013 Jun 22; Korhonen et al., 2012 Feb 15; Michaud et al., 2010 Oct], whereas other studies have not shown a clinically significant association [Claus et al., 2013 Mar; Pines and 2011 Apr]. Exogenous estrogen exposure, rather than
Fig. 2. Genetic Features of Meningioma. A. Meningioma cells are completely negative for ER (mouse monoclonal 6F11) and B. diffusely and strongly positive for PR (16, monoclonal mouse antibody). C. Meningioma cells show retention of two copies of NF2 gene (arrows) and 2 copies of control gene (circled) by FISH. There is no evidence of NF2 deletion.
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estrogen-progesterone in combination, appears to be the greater risk factor [Korhonen et al., 2012 Feb 15]. It is unknown whether Turner syndrome further increases the risk for development of meningiomas in the setting of HRT. An alternative hypothesis to explain the two neoplasias in this particular patient is the presence of a co-occurring oncogenic gene unrelated to Turner syndrome. The molecular basis for meningioma formation and progression is incompletely understood. The NF2 gene, located on chromosome 22q12, has been implicated as the causative gene in up to 60% of sporadic meningiomas [Ruttledge et al., 1994]. Most patients with familial multiple meningioma syndrome (FMMS) are women, with very few well-documented men [Heinrich et al., 2003]. FMMS is characterized by the presence of multiple meningiomas without any other evidence of neurofibromatosis 2, and the causative gene for FMMS is not entirely clear. A recent report suggested that loss of SUFU (located on 10q24) in one family function led to multiple meningioma occurrences [Aavikko et al., 2012]. In this patient with Turner syndrome, the FISH analysis of the tumor paraffin block showed retention of the NF2 gene locus. Meningiomas with NF2 loss are more commonly of the fibroblastic subtype [Ruttledge et al., 1994], whereas this tumor was meningothelial. Molecular involvement of the NF2 gene in patients with Turner syndrome has not been reported previously, and a more comprehensive analysis with mutation analysis of the NF2 gene sequence in a cohort of tumors from Turner syndrome patients is needed to better address this issue. A subset of meningiomas lacking NF2 alterations harbor recurrent oncogenic mutations in AKT1 (p.Glu17Lys) and SMO (p.Trp535Leu) and exhibited immunohistochemical evidence of activation of these pathways [Brastianos et al., 2013]. These mutations were present in therapeutically challenging tumors of the skull base and higher grade. Furthermore, the SMO and AKT1-mutated tumors tend to have a meningothelial histology, which is the histologic subtype of our patient’s meningioma [Brastianos et al., 2013]. To determine the possible role of oncogenic genes, we presented the patient a strategy of tiered testing for both targeted genes (e.g. PTCH1) and whole genome sequencing, using both commercial and research methodology; she declined genetic testing. Five years after the meningioma was diagnosed, our patient developed an infiltrating basal cell carcinoma (BCC), one of the most common cancers in the US. The exact incidence is unknown because there are no cancer registries dedicated to BCCs specifically. They are more common in males and persons with lighter skin [Rogers et al., 2010]. It has been suggested that hormone replacement therapy increases the incidence of non-melanoma type skin cancers in the general population as well [BirchJohansen et al., 2012]. Given the frequent occurrence in the general population, and this patient’s well-acknowledged sun exposure history, we cannot be certain if this patient’s lifetime exposures contributed to the development of this second cancer. Also, notably, mutations in the hedgehog pathway (including SMO and PTCH1) are pathognomonic for basal cell carcinoma, [Sekulic et al., 2012 Jun 7]. Furthermore, familial basal cell carcinoma (Gorlin syndrome), a predisposition to multiple cancer types including basal cell carcinoma and meningiomas, is associated with alterations in the Hedgehog pathway [Dahmane et al., 1997 Oct 23]. Thus, it is possible that the patient had a germline mutation in the Hedgehog pathway, but in the absence of sequencing, we cannot determine this definitively. Following guidelines for adult women with Turner syndrome, [Bondy, 2007] our patient is being monitored for aortic dilation, which has been observed in up to 30% using magnetic resonance imaging [Bondy, 2007]. Although she does not have a bicuspid aortic valve or coarctation, she is considered at higher risk for
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dissection because she had two cycles of ART and a successful pregnancy, has mild aortic regurgitation, and incompletely defined aortic valve morphology. Published data is insufficient at present to suggest that there is a direct role between the loss of the X chromosome in the pathogenesis of neoplasia, although this review supports the hypothesis of an association. There is some evidence to suggest an association with exogenous hormone exposure and certain types of neoplasia, but current data are insufficient to allow us to decide between the two hypotheses: X-chromosome genes, haploinsufficiency, or HRT effect. Given that women with Turner Syndrome are likely to require hormone replacement therapy during their lives, and most need artificial reproductive technologies to conceive, we suggest that additional research is needed to determine whether this may be a more important risk factor for certain types of neoplasia in this population. Acknowledgments We thank Takako Yanagisawa from Toho University, Faculty of Medicine in Tokyo, Japan for providing translation. Dr. Paolo Nozza, Anatomic Pathologist at the Istituto Giannina Gaslini in Genoa, Italy provided supplemental clinical information to the report of Nozza et al. (2005). Meaghan Muir from the Brigham and Women’s Hospital library provided assistance. References Aavikko M, Li S-P, Saarinen S, Alhopuro P, Kaasinen E, Morgunova E, et al. Loss of SUFU function in familial multiple meningioma. Am J Hum Genet 2012;91(3): 520e6. Andersen L, Friis S, Hallas J, Ravn P, Schrøder HD, Gaist D. Hormone replacement therapy increases the risk of cranial meningioma. Eur J Cancer 2013;49(15):3303e10. Birch-Johansen F, Jensen A, Olesen AB, Christensen J, Tjønneland A, Kjær SK. Does hormone replacement therapy and use of oral contraceptives increase the risk of non-melanoma skin cancer? Cancer Causes Control 2012;23(2):379e 88. Bondy CA. Care of girls and women with Turner syndrome: a guideline of the Turner Syndrome Study Group. J Clin Endocrinol Metab 2007;92:10e25. Brastianos PK, Horowitz PM, Santagata S, Jones RT, McKenna A, Getz G, et al. Genomic sequencing of meningiomas identifies oncogenic SMO and AKT1 mutations. Nat Genet 2013;45(3):285e9. Claus EB, Calvocoressi L, Bondy ML, Wrensch M, Wiemels JL, Schildkraut JM. Exogenous hormone use, reproductive factors, and risk of intracranial meningioma in females. J Neurosurg 2013 Mar;118(3):649e56. Dahmane N, Lee J, Robins P, Heller P, Ruiz i Altaba A. Activation of the transcription factor Gli1 and the Sonic hedgehog signalling pathway in skin tumours. Nature 1997 Oct 23;389(6653):876e81. Dolecek TA, Propp JM, Stroup NE, Kruchko C. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2005e2009. Neuro-Oncology 2012;14(Suppl. 5):1e49. Gruber T, Dare AO, Balos LL, Lele S, Fenstermaker RA. Multiple meningiomas arising during long-term therapy with the progesterone agonist megestrol acetate. Case report. J Neurosurg 2004;100(2):328e31. Heinrich B, Hartmann C, Stemmer-Rachamimov AO, Louis DN, MacCollin M. Multiple meningiomas: investigating the molecular basis of sporadic and familial forms. Int J Cancer 2003;103(4):483e8. Iacono RP, Apuzzo ML, Davis RL, Tsai FY. Multiple meningiomas following radiation therapy for medulloblastoma. Case report. J Neurosurg 1981;55(2):282e6. Jostel A, Mukherjee A, Hulse PA, Shalet SM. Adult growth hormone replacement therapy and neuroimaging surveillance in brain tumour survivors. Clin Endocrinol (Oxf) 2005;62(6):698e705. Kido G, Miyagi A, Shibuya T, Miyagami M, Tsubokawa T, Sawada T. Turner’s syndrome with pituitary hyperplasia: a case report. No Shinkei Geka 1994;22(4): 333e8. Korhonen K, Auvinen A, Lyytinen H, Ylikorkala O, Pukkala E. A nationwide cohort study on the incidence of meningioma in women using postmenopausal hormone therapy in Finland. Am J Epidemiol 2012 Feb 15;175(4):309e14. Matsuno A, Fujimaki T, Sasaki T, Nagashima T, Ide T, Asai A, et al. Clinical and histopathological analysis of proliferative potentials of recurrent and nonrecurrent meningiomas. Acta Neuropathol. 1996;91(5):504e10. Michaud DS, Gallo V, Schlehofer B, Tjønneland A, Olsen A, Overvad K, et al. Reproductive factors and exogenous hormone use in relation to risk of glioma and meningioma in a large European cohort study. Cancer Epidemiol Biomarkers Prev 2010 Oct;19(10):2562e9.
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Nozza P, Raso A, Rossi A, Milanaccio C, Pezzolo A, Capra V, et al. Rhabdoid meningioma of the tentorium with expression of desmin in a 12-year-old Turner syndrome patient. Acta Neuropathol 2005;110(2):205e6. Pines A. Hormone therapy and brain tumors. Climacteric 2011 Apr;14(2):215e6. Piper JG, Follett KA, Fantin A. Sphenoid wing meningioma progression after placement of a subcutaneous progesterone agonist contraceptive implant. Neurosurgery 1994;34(4):723e5. Rocque BG, Baskaya MK, Kuo JS. Incidental findings on brain MRI. N Engl J Med 2008;358(8):853 [author reply 854e855]. Rogers HW, Weinstock MA, Harris AR, Hinckley MR, Feldman SR, Fleischer AB, et al. Incidence estimate of nonmelanoma skin cancer in the United States, 2006. Arch Dermatol 2010;146(3):283e7. Roser F, Samii M, Ostertag H, Bellinzona M. The Ki-67 proliferation antigen in meningiomas. Experience in 600 cases. Acta Neurochir (Wien) 2004;146(1): 37e44 [discussion 44]. Roser F, Nakamura M, Bellinzona M, Rosahl SK, Ostertag H, Samii M. The prognostic value of progesterone receptor status in meningiomas. J Clin Pathol 2004;57(10):1033e7.
Ruttledge MH, Sarrazin J, Rangaratnam S, Phelan CM, Twist E, Merel P, et al. Evidence for the complete inactivation of the NF2 gene in the majority of sporadic meningiomas. Nat Genet 1994;6(2):180e4. Schoemaker MJ, Swerdlow AJ, Higgins CD, Wright AF, Jacobs PA. Cancer incidence in women with Turner syndrome in Great Britain: a national cohort study. Lancet Oncol 2008;9(3):239e46. Sekulic A, Migden MR, Oro AE, Dirix L, Lewis KD, Hainsworth JD, et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med 2012 Jun 7;366(23):2171e9. Stochholm K, Juul S, Juel K, Naeraa RW, Gravholt CH. Prevalence, incidence, diagnostic delay, and mortality in Turner syndrome. J Clin Endocrinol Metab 2006;91:3897e902. Vadivelu S, Sharer L, Schulder M. Regression of multiple intracranial meningiomas after cessation of long-term progesterone agonist therapy. J Neurosurg 2010;112(5):920e4.
