Meningiomas May Be a Component Tumor of Multiple Endocrine Neoplasia Type 1

Vol. 10, 869–880, February 1, 2004 Clinical Cancer Research 869

Featured Article Meningiomas May Be a Component Tumor of Multiple Endocrine Neoplasia Type 1

Behnam Asgharian,1 Yuan-Jia Chen,1 with meningiomas. Meningiomas were asymptomatic and Nicholas J. Patronas,2 Paolo L. Peghini,1 60% showed no growth. A resected meningioma showed loss James C. Reynolds,3 Alexander Vortmeyer,4 of heterozygosity at 11q13 and 1p, including at p73 and 4 5 ARHI/NOEY2 locus, but not at the neurofibromatosis 2 Zhengping Zhuang, David J. Venzon, gene locus. 1 1 Fathia Gibril, and Robert T. Jensen Conclusions: These results show meningiomas are not 1Digestive Diseases Branch, National Institute of Diabetes and an infrequent occurrence in MEN 1, and loss of the function 2 Digestive and Kidney Diseases, NIH; Diagnostic Radiology of the MEN1 gene product plays a role in their pathogenesis Department, Warren Grant Magnuson Clinical Center, NIH; 3Nuclear Medicine Department, Warren Grant Magnuson Clinical Center, NIH; in these patients. 4Molecular Pathogenesis Unit, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, NIH; and 5Biostatistics and Data Management Section, National Cancer Introduction Institute, NIH, Bethesda, Maryland Multiple endocrine neoplasia type 1 (MEN 1) is an auto- somal dominant disorder caused by mutations in the MEN1 gene Abstract on chromosome 11q13 (1, 2). Patients characteristically develop Purpose: Recently, an increased incidence of some non- tumors of the parathyroid, enteropancreatic tissue, and anterior endocrine tumors are reported in patients with multiple pituitary (1–4). More recently, an increased occurrence of other endocrine neoplasia type 1 (MEN 1). There are rare reports endocrine tumors as well as nonendocrine tumors are reported in of meningiomas and other central nervous system tumors in patients with MEN 1, including skin tumors (melanomas, col- these patients, but it is unknown if they are more frequent or lagenomas, and angiofibromas), carcinoids (thymus, lung, and if allelic loss of the MEN1 gene is important in their patho- gastric), lipomas, as well as tumors of the adrenal and smooth genesis. The aim of this study was to address these two latter muscle (1, 2, 5–15). Some of these tumors [parathyroid, pitui- questions. tary, pancreatic endocrine tumors (PETs), carcinoids, smooth Experimental Design: Results from a prospective study muscle, and skin tumors] have allelic losses at the MEN1 locus of 74 MEN 1 patients with suspected/proven pancreatic on 11q13; therefore, alterations in the MEN1 gene play a key endocrine tumors (PETs) were analyzed, as well as molecu- role in their pathogenesis, whereas with others (thymic carci- lar studies performed on a resected meningioma. All pa- noids, and adrenal), this is not the case (1, 2, 5–15) and their tients had serial brain imaging studies (computed tomogra- pathogenesis remains unclear. phy, magnetic resonance imaging, and octreoscanning since Central nervous system (CNS) tumors, including ependy- 1994) and yearly studies evaluating MEN 1 involvement momas (16, 17), schwannomas (9, 18, 19), and meningiomas with a mean follow-up of 7.2 years. Results were compared (20, 21), have rarely been reported in patients with MEN 1 or with 185 patients with sporadic Zollinger-Ellison syndrome. MEN 1-variant syndromes. However, some of the tumors such Results: Six patients (8%) had meningiomas. Meningi- as meningiomas are common CNS tumors in the general pop- omas were single and found late in the MEN 1 course (mean ulation with an annual rate of 7.8/100,000, comprising 20% of years). Magnetic resonance imaging/computed all CNS tumors (22) and have rarely been reported in MEN 1 51 ؍ age tomography were more sensitive than octreoscanning. Their (20, 21). Therefore, whether meningiomas or any of these CNS diagnosis averaged 18 years after the onset of hyperpara- tumors occur with increased frequency in patients with MEN 1 thyroidism, 10–15 years after pituitary disease or PETs. is unknown. It is also unknown if they do occur whether allelic Meningiomas were 11 times more frequent in patients with losses in the MEN1 gene are found in these tumors, and there- -No fore, alterations in this gene plays a central role in their patho .(0.017 ؍ PETs with MEN 1 than without MEN 1 (P clinical, laboratory, or MEN 1 feature distinguished patients genesis in MEN 1 patients. In our ongoing prospective study of patients with possible PETs with MEN 1, in addition to serial evaluations of MEN 1 involvement, CNS assessments using brain magnetic resonance imaging (MRI) and computed tomography (CT) are performed Received 6/17/03; revised 10/8/03; accepted 10/22/03. initially and at yearly evaluations. This study reports the anal- The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked ysis of this prospective study and reveals that 8% of the 74 advertisement in accordance with 18 U.S.C. Section 1734 solely to patients with MEN 1 followed up to 19 years developed men- indicate this fact. ingiomas. A comparison with similar patients without MEN 1 Note: B. A. and Y-J. C. contributed equally to this work. with PETs showed this was a highly significant increase and Requests for reprints: Robert T. Jensen, NIH/NIDDK/DDB, Building 10, Room 9C-103, 10 Center Drive MSC 1804, Bethesda, MD 20892- molecular studies of a meningioma from a MEN 1 patient 1804. Phone: (301) 496-4201; Fax: (301) 402-0600; E-mail: robertj@ revealed allelic loss at 11q13 at the MEN1 locus as well as at bdg10.niddk.nih.gov. chromosome 1p but not at the neurofibromatosis 2 (NF2) locus. Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2004 American Association for Cancer Research. 870 Meningiomas in MEN 1

Materials and Methods pituitary disease, symptomatic PET, detection of a PET, or the One hundred twenty-eight consecutive patients with MEN time of first detection of an abnormal laboratory value compat- 1 with or without Zollinger-Ellison syndrome (ZES) evaluated ible with MEN 1 hormonal overactivity in an asymptomatic between July 1975 and August 2002 at NIH were considered for patient with known family history of MEN 1. The time of this study. Patients were eligible for the study if they had regular diagnosis of MEN 1 was the time of confirmation of MEN 1 at pituitary and whole brain imaging with CT scanning or MRI. the initial visit or the time of first diagnosis before NIH pres- This study is part of an ongoing prospective study of entation at an outside institution. In patients with multiple par- patients with ZES with or without MEN 1 since 1975 and is athyroidectomies, the initial parathyroid surgery was taken for approved by the Clinical Research Committee of the National measurement of years from parathyroidectomy. Institute of Diabetes, Digestive, and Kidney Diseases. All patients had brain imaging with a CT scan or MRI as Diagnostic criteria for MEN 1, as previously described (23, well as imaging of the pituitary fossa initially and during each 24), included presence of a combination of PET, pituitary dis- subsequent evaluation. MRI was generally used with CT scan- ease, hyperparathyroidism, positive genetic test for MEN 1, or ning performed in patients with a contraindication to MRI. In the presence of any of the above with a known family history of patients with any abnormality, both studies were done. MRI MEN 1. Of the 74 patients with MEN1, we have completed scans were performed using a 1.5-T magnet (General Electric, sequencing of the MEN1 gene in 62 patients, of which, 90% had Milwaukee, WI). T1-weighted (repetition time in ms/echo time a germ-line mutation. We have not sequenced all of the patients in ms, 415-550/11-16) and T2-weighted (2500-4384/90-110) with sporadic ZES; however, we have sequenced 35 consecutive spin-echo images were obtained, with a 5-mm section of thick- cases of sporadic ZES, including 1 patient with sporadic ZES ness. The T1-weighted scans were repeated after the adminis- with a meningioma and none had MEN1 gene mutations. The tration of 0.1 mmol of gadopentetate dimeglumine/kg body presence or absence of a PET was determined by surgical weight (Magnevist; Berlex Laboratories, Wayne, NJ). CT scans exploration or by imaging alone. The diagnosis of ZES was were performed using Isovue (Bracco Diagnostic, Inc., Prince- made biochemically as described previously (25). Serum gastrin ton, NJ). The time of diagnosis of a meningioma was deter- concentrations were measured by Bioscience Laboratories (New mined as the first time it was identified on imaging. An expe- York, NY) and by Mayo Clinic Laboratories (Rochester, MN). rienced neuroradiologist (N. P.) diagnosed all meningiomas. Study Protocol. During the initial evaluation at the NIH, The radiological diagnosis of meningioma was made by the all patients underwent studies to determine the extent of in- presence of an extra axial dural-based mass that was uniformly volvement of MEN 1 as described previously (23, 24). These and markedly enhanced with contrast materials (22, 29, 30). included a detailed review of symptoms compatible with gastric Possible symptoms of the meningioma were evaluated by a acid hypersecretion, a personal or family history of MEN 1- detailed review of likely CNS symptoms. The largest diameter related symptoms, and laboratory studies to assess for presence of each meningioma was determined initially and compared of hormonal activity (parathyroid, pituitary, adrenal, and pan- with the diameter in the last study to assess change in size of the creas). Laboratory studies included measurement of serum par- meningioma. athyroid hormone (intact and mid-molecule), prolactin, fasting All patients had serial studies with all but 1 patient in the serum gastrin, calcium (ionized and total), proinsulin, insulin present study having serial follow-up evaluations at least yearly. and simultaneous glucose, growth hormone, glucagon, adreno- During the follow-up visits, in addition to brain and pituitary corticorticotropic hormone, thyrotropin, chromogranin A, pan- imaging, abdomen imaging, as well as the plasma hormone creatic polypeptide, albumin, and urinary cortisol. For the diag- assays listed above that were performed on the initial study, nosis of ZES, the patients had assessment of gastric acid were all repeated. Patients with metastatic disease had follow-up secretory rate, measurement of fasting serum gastrin concentra- visits every 3–6 months to assess changes in extent of the tion on 3 separate days (25), and secretin provocative testing metastases as described previously (31, 32). (when secretin was available) with a bolus injection of 2 clinical The frequency of meningiomas in the 65 patients with units of secretin/kg body weight (25, 26). To define the extent MEN 1 with ZES was compared with that of 185 patients with and location of PETs, all patients underwent abdominal imaging ZES without MEN 1 (i.e., sporadic ZES) who had undergone as previously described (27, 28) with ultrasound, CT scanning similar brain imaging studies. with i.v. contrast, MRI, and selective abdominal angiography if Statistics. Continuous variables were compared using the results were unclear. Somatostatin receptor scintigraphy the Mann-Whitney U test and discontinuous variables using (SRS) was performed routinely since 1994 by injection of Fisher’s exact test or ␹2 test. P Ͻ 0.05 was considered signifi- 111 1 ( In-DTPA-D-Phe ) octreotide followed by whole body as cant. Results are reported as mean Ϯ SE. well as single-photon emission computed tomography images as DNA Samples. Tumor tissue from the meningioma of 1 described previously (27, 28). The onset of a PET was deter- of the patients with MEN 1 was obtained by microdissection mined either as the time of onset of symptoms in the patients from the formalin-fixed, paraffin-embedded sample. Tumor tis- with functional PETs or as the time of the first imaging diag- sue was microdissected from four different areas on one slide nosis with a nonfunctional PET. The duration of the PET was and was digested in four tubes to release tumor genomic DNA determined as the time of onset of the PET until their last by a 3-day incubation in 30 ␮l of TE solution [10 mM Tris (pH follow-up or death. 8.0)-1 mM EDTA, 0.5 mg/ml proteinase K, 0.5% Tween 20] at The onset of MEN 1 was determined as the time of onset 37°C. Normal genomic DNA from the patient as well as from of symptoms compatible with MEN 1, including nephrolithiasis, her mother was isolated from peripheral blood leukocytes using

Table 1 Comparison of clinical and laboratory characteristics of patients with multiple endocrine neoplasia type 1 (MEN 1) with and without meningiomas Number (percentage)a Meningioma present Meningioma absent Total Patient number 6 68 74 Age at onset of MEN 1 (yrs)b 33.2 Ϯ 5.9 29.8 Ϯ 1.2 30.1 Ϯ 1.2 Age at diagnosis of MEN 1 (yrs) 41.8 Ϯ 9.2 36.0 Ϯ 1.4 36.5 Ϯ 1.5 Age at diagnosis of hyperparathyroidism (yrs) 40.0 Ϯ 9.9 35.4 Ϯ 1.3 35.7 Ϯ 1.3 Male gender 2 (33%) 32 (47%) 34 (46%) Follow-up duration at NIH (yrs)c 7.6 Ϯ 4.2 7.2 Ϯ 0.8 7.2 Ϯ 0.8 MEN 1 duration (yrs)d 20.5 Ϯ 6.2 18.4 Ϯ 1.4 18.6 Ϯ 1.4 MEN 1-related death during follow-up 0 (0%) 2 (3%) 2 (3%) Family history of MEN 1 5 (83%) 50 (73%) 55 (74%) Fasting serum gastrin (pg/ml)e Mean Ϯ SE 425 Ϯ 297f 23,500 Ϯ 14,000 21,675 Ϯ 12,800 Median 165 735 577 (Range) (28–1,900) (24–930,000) (24–930,000) Serum chromogranin A (ng/ml)e Mean Ϯ SE 227 Ϯ 110 470 Ϯ 149 448 Ϯ 136 (Range) (12–582) (4.3–6,639) (4.3–6,639) Serum prolactin (␮g/liter)e Mean Ϯ SE 27.5 Ϯ 8.4 26.9 Ϯ 5.9 26.9 Ϯ 5.5 (Range) (11–68) (2–377) (2–377) a Percentage of MEN 1 patients with the characteristic in the indicated meningioma category. b Age at first MEN 1 symptom or discovery of abnormal laboratory value. c Time from first NIH evaluation to present. d Time from MEN 1 onset to present. e Normal reference values: fasting serum gastrin (Ͻ200 pg/ml), chromogranin A (Ͻ5.6 ng/ml), and prolactin (Ͻ11 ␮g/liter). f P Ͻ 0.02 compared with patients without meningiomas.

the Puregene DNA isolation kit (Gentra System, Minneapolis, INT-2) spanning the MEN1 locus (33, 34) and 5 markers span- MN). DNA was stored at 4°C until PCR amplification. ning the NF2 suppressor gene (D22S268, D22S1163, D22S929, Microsatellite DNA Markers. Six polymorphic markers D22S280, and D22S282; Ref. 35) as well as 12 markers span- (D11S480, D1S1883, PYGM, D11S4946, D11S449, and ning chromosome 1p were ordered from Invitrogen, ResGen

Table 2 Comparison of MEN 1 features in patients with or without meningioma Number (percentage)a Meningioma present (n ϭ 6) Meningioma absent (n ϭ 68) Total Hyperparathyroidism present 5 (83%) 68 (100%) 73 (98%) Parathyroidectomy 4 (67%) 58 (85%) 62 (84%) Years from parathyroidectomyb 15.8 Ϯ 7.0 12.5 Ϯ 1.4 12.7 Ϯ 1.3 Pancreatic endocrine tumor (PET) present 4 (67%) 61 (90%) 65 (96%) Zollinger-Ellison syndrome 4 (67%) 61 (90%) 65 (96%) Duration of PETc 11.2 Ϯ 5.8 11.0 Ϯ 1.0 11.0 Ϯ 1.0 PET extentd Localized 4 (67%) 47 (69%) 51 (69%) Liver metastasis 0 (0%) 14 (20%) 14 (19%) PET Resection 3 (50%) 39 (57%) 42 (57%) Years from PET resectionb 5.6 Ϯ 3.9 7.4 Ϯ 1.0 7.3 Ϯ 0.9 Pituitary adenoma present 3 (50%) 27 (40%) 30 (40%) Pituitary adenoma resection 1 (17%) 9 (13%) 10 (14%) Years from adenoma resectionb 37.8 10.3 Ϯ 2.6 13.0 Ϯ 3.6 Other tumorse 1 (17%) 16 (24%) 17 (23%) a Percentage in each meningioma category. b Years from surgery to present. c Years from diagnosis of PET to present. d Extent determined by surgical pathology (n ϭ 42) or radiological imaging (n ϭ 32). ‘Localized’ refers to presence of a PET without distant metastasis (i.e., bone, liver). e Other tumors include: papillary thyroid cancer (n ϭ 1); prostate cancer (n ϭ 1); renal cell papillary cancer (n ϭ 1); basal cell cancer (n ϭ 2); uterine fibroid (n ϭ 1); renal cystadenoma (n ϭ 1); renal angiolipoma (n ϭ 1); esophageal leiomyoma (n ϭ 2); esophageal cancer (n ϭ 1); melanoma (n ϭ 3); uterine leiomyosarcoma (n ϭ 1); bladder cancer (n ϭ 1); uterine adenocarcinoma (n ϭ 1); rhabdomyosarcoma sarcoma (n ϭ 1); and colon cancer (n ϭ 1).

Table 3 Characteristics of multiple endocrine neoplasia type 1 (LOH) was defined as a reduction of at least 50% observed in (MEN 1) patients with meningiomas the allelic ratio between the tumor and normal DNA (37, 38). Number (%) Age (yrs) at diagnosis of meningioma Results Mean Ϯ SE 50.8 Ϯ 7.6 Seventy-four patients met the study criteria in that they all (Range) (29–76) had brain and pituitary imaging on admission and subsequent Onset of MEN 1 to meningioma Mean Ϯ SE 17.6 Ϯ 6.1 follow-ups. In these 74 patients, 92% had an initial MRI, and the (Range) (2–37.8) remainder had an initial CT either because MRI was not avail- Onset of hyperparathyroidism to meningioma able at the time or was contraindicated. The 74 patients had a Mean Ϯ SE 18.2 Ϯ 5.8 mean age of onset and diagnosis of MEN 1 in the fourth decade, (Range) (2–30.9) and mean duration of total follow-up from MEN 1 onset was 19 Onset of ZES to meningioma Mean Ϯ SE 13.9 Ϯ 6.0 years with 7.2 years occurring at NIH (Table 1). (Range) (1.5–25.7) A meningioma was identified in 6 of the 74 patients by Onset of pituitary disease to meningiomaa imaging (Table 1). In the 6 patients with meningiomas, 5 of 6 Ϯ Ϯ Mean SE 14.1 11.4 (83%) had hyperparathyroidism, 4 of 6 (67%) had a PET with (Range) (0.5–37) Years from pancreatic endocrine tumor ZES, and 3 of 6 (50%) had a pituitary adenoma (Table 2). resection to meningiomab Meningioma was found late in the course of the MEN 1 with a Mean Ϯ SE 4.0 Ϯ 4.1 mean time of 17.6 years after the onset of the MEN 1 (Table 3) (Range) (0.4–12) at a mean age of 51 years. However, there was a wide range in Pituitary resection 1 (17%) age at diagnosis of the meningioma, varying from 29 to 76 years Years from pituitary resection to meningioma 36.7 Parathyroidectomyc 4 (66%) (Table 3). The meningioma was diagnosed on the average 18 Years from parathyroidectomy to meningioma years after the onset of hyperparathyroidism and 14 years after Mean Ϯ SE 11.5 Ϯ 6.6 the onset of ZES and pituitary disease (Table 3). Meningiomas (Range) (2.6–27.7) were also diagnosed after patients had been treated for the more a Three of the 6 patients with meningiomas had pituitary disease. common manifestations of MEN 1 with parathyroidectomies, b Four of the 6 patients had a pancreatic endocrine tumor. pituitary surgery, or resection of a PET (Table 3). In no case was c Five of the 6 patients had hyperparathyroidism. the meningioma diagnosed caused by symptoms, instead in all 6 cases, it was found on routine imaging studies (Table 4). MEN 1 patients with or without meningiomas did not differ (Carlsbad, CA) based on the published papers (36) and online in their age at onset or at diagnosis of MEN 1, age at diagnosis data.6 of hyperparathyroidism, percentage with male gender, duration PCR. The tumor DNA and leukocyte DNA of the pa- of follow-up for MEN 1-related disorders, percentage with a tient, as well as the leukocyte DNA of her mother, were ampli- family history of MEN 1, the mean serum prolactin, or the mean fied by PCR using a GeneAmp PCR system 9700 Thermo- chromogranin A levels (Table 1). The mean serum gastrin level cycler (PE Applied Biosystems, Foster City, CA) with the following conditions: 94°C for 5 min; 94°C for 45 s; annealing at 59°C for 45 s; and extension at 72°C for 45 s for total 35 Table 4 Characteristics of meningiomas in the six MEN 1 patients cycles. Each reaction contained 1.5 ␮lof10ϫ PCR buffer, 1.5 ␮l of tumor DNA or normal control DNA (ϳ10–20 ng), 10 Number (%) pmol of each primer, 2.5 units of Gold Taq polymerase (PE Symptoms related to meningioma 0 Applied Biosystems), and 130 ␮M each of deoxynucleoside Location 2ϩ Frontal lobe 2 (33%) triphosphate. The final concentration of Mg was 1.5 mM, and Planum sphenoidale 3 (50%) ␣ 32 ␮ Ͼ -P -dCTP (0.1 l/reaction; 3000 Ci/mmol) was included in Intraosseous 1 (17%) each PCR reaction. Posterior fossa 1 (17%) Analysis of Allele Loss. After PCR, products were Octreotide scan positivea 3 (60%) ϭ Follow-up of meningioma (yrs) 3.6 Ϯ 1.8 mixed with loading dye (v/v 1/1), denatured at 95°C for 10 b ␮ Initial size (mm) min, then chilled immediately at 4°C. Four l of products were Mean Ϯ SE 16.0 Ϯ 3.2 analyzed by electrophoresis througha6or8%denaturing poly- (Range) (8–30) acrylamide gel in 1ϫ Tris-borate EDTA buffer. The gels were Increase in size during follow-upc,d 2 (40%) then dried and exposed to X-ray films (Kodak X-Omat AR; Extent increase in size (mm) 1.4 Ϯ 1.2 Ϯ Eastman Kodak Company, Rochester, NY) with or without an % increase in size (mm) 16.7 14.7 % increase in size/year 17.3 Ϯ 13.7 intensive screen for8hto3days. The intensity of signals in the a films was analyzed and quantified by using Kodak Image station Five of 6 patients had octreotide scan. b Size was determined as the largest diameter with computed to- 440 system (Eastman Kodak Company). Loss of heterozygosity mography scan or magnetic resonance imaging at initial discovery. c Change in size was determined from serial computed tomography scan and magnetic resonance imaging and is expressed as mm change in diameter over the follow-up period. d Five of 6 patients had follow-up imaging. One patient had me- 6 Internet address: http://www.gdb.org. ningioma recently discovered.

Fig. 1 Magnetic resonance imaging (MRI) and somatostatin receptor scintigraphy (SRS) showing location of the meningioma in a patient (no. 5) with multiple endocrine neoplasia type 1. Left panel, coronal (top) and sagittal (bottom) after contrast views of the T1-weighted MRI images. An extracerebral mass is identified originating form the dura of the planum sphenoidale. The mass compresses the inferior aspect of the left frontal lobe and projects into the interhemispheric fissure. There is homogeneous enhancement present. These findings are typical for meningioma. Right panel, coronal (top) and transverse (bottom) views on SRS showing enhanced uptake of radionucleotide in the meningioma.

was significantly higher in patients without meningiomas (P Ͻ and colon) and less common MEN 1-related tumors (thyroid 0.02 without correction for multiple, highly correlated compar- cancer, angiolipoma, leiomyomata, melanoma, leiomyosarco- isons; Table 1). ma; Refs. 4–7) occurred in 23% of the patients, and their The manifestations of MEN 1 in patients with or without a frequency did not differ in patients with or without meningio- meningioma are compared in Table 2. Almost all patients in the mas (Table 2). nonmeningioma (83%) and meningioma (100%) groups had Two of the 6 meningiomas were in the frontal lobe, 3 in the hyperparathyroidism, and the percentage having a previous par- planum sphenoidale, and 1 in the posterior fossa (Table 4). Five athyroidectomy at the time the meningioma was diagnosed was of the 6 patients had an octreotide scan performed that included not significantly different (85 versus 67%, P ϭ 0.24) nor was whole body images, and in 3 patients, there was uptake in the the duration from the parathyroidectomy (Table 2). The majority brain area corresponding to the site of meningioma on the MRI. of the patients in the meningioma group (67%) had a PET with Examples of the somatostatin receptor scintigraphy and MRI ZES, as did the patients in the nonmeningioma group (90%), results in 2 patients are shown in Figs. 1 and 2. In the patient and the duration of the PET was not significantly different in the shown in Fig. 1, the meningioma in the dura of the planum two groups (i.e., 11.2 and 11.0 years; Table 2). The extent of the sphenoidole was seen on both the MRI and somatostatin recep- PET was similar in both groups with each having two-thirds of tor scintigraphy studies, whereas in the patient in Fig. 2, the the patients with localized disease (Table 2). Although there was meningioma seen in the left frontal lobe with the MRI was not a trend for patients without a meningioma to have more aggres- seen on the somatostatin receptor scintigraphy study. The mean sive PETs with liver metastases (20 versus 0%), this difference initial size of the meningiomas was 16 mm with a range of 8–30 did not reach significance. Patients with or without meningioma mm (Table 4). The average follow-up duration of the meningi- did not differ in the percentage who had previous PET resec- oma was 3.6 years with a range of 0.5–11 years. One patient tions (ϳ50%) or the time from these resections (Table 2). with a 30-mm meningioma underwent resection. Two of the 5 Pituitary adenomas occurred in 40% of all of the patients and meningiomas evaluated for changes in size over time showed an neither their frequency, percentage of the patients requiring increase in size with an average increase of 1.4 mm or 16.7% of pituitary surgery, nor the duration of time from that surgery their original length, which represented a 17.3% increase in their differed between the two groups (Table 2). Other non-MEN original length/year of follow-up (Table 4). The patient with the 1-related cancers (prostate, renal, uterine, esophageal, bladder, greater increase in size of the meningioma was a patient with

Fig. 2 Magnetic resonance imaging (MRI) but not somatostatin receptor scintigraphy (SRS) localization of the meningioma in a patient (no. 4) with MEN 1. Left panel, axial (top) and coronal (bottom) after contrast T1-weighted MRI images. An extracerebral mass (arrow) is identified in the left frontal region. The mass has a flat surface of attachment to the dura and compresses the adja- cent brain parenchyma. There is homogenous enhancement present. Right panel, transverse (top) and coronal (bottom) images on SRS showing no uptake in the region corresponding to the MRI finding.

two prior pituitary surgeries and postoperative radiation. He has NF2 tumor suppressor gene locus (28, 35, 39–48) in sporadic also had other MEN 1-related conditions, including hyperpara- meningiomas and in NF2-associated meningiomas (49), and thyroidism, ZES, and had an early age of presentation of the their presence correlates with an aggressive growth pattern, MEN 1. None of the other patients with meningiomas had tumor site, high histological grade, and decreased recurrence- received radiation. free survival (40, 41, 44–46). To assess these genetic alterations To compare the frequency of meningioma in patients with (NF2 and 1p) as well as possible LOH at the MEN1 locus on ZES with or without MEN 1, the rate of occurrence of menin- chromosome 11q13 in this MEN 1-associated meningioma, each giomas of 4 cases in 65 patients with ZES and MEN 1 was of these regions was examined with polymorphic microsatellite compared with that in 185 patients with ZES without MEN 1 markers (Figs. 3–5). On chromosome 11q13, LOH was identi- who also had repeated brain imaging. Each of the 185 patients fied by all six polymorphic markers over the MEN1 locus (Figs. with sporadic ZES (i.e., without MEN 1) were involved in a 3 and 5). No LOH was found on chromosome 22q in the region prospective protocol with yearly evaluations with biochemical of the NF2 gene (Figs. 3 and 5). LOH was identified in six loci and imaging studies similar to that outlined for the MEN 1 of 1p (Figs. 4 and 5). LOH in chromosome 1p at the D1S468 patients in “Materials and Methods.” locus indicated loss of p73 gene (50), the homologue of p53 (51, Meningiomas were significantly (P ϭ 0.017) more fre- 52). Loss of another novel putative tumor suppressor gene, quent in the patients with ZES and MEN 1 [6.2% (4 of 65) ARHI/NOEY2, on 1p31 (53), was identified with three markers versus 0.5% (1 of 185), respectively]. This difference occurred flanking the gene (D1S2638, D1S1665, and D1S500) and one although the 185 patients without MEN 1 were older (49.8 Ϯ intragenic marker (D1S2829; Ref. 36; Figs. 4 and 5). ARHI/ 0.8 versus 47.7 Ϯ 1.8 years, P Ͻ 0.058) and had a longer NOEY2 is a maternal imprinted gene (53), whereas p73 may be follow-up at the NIH (10.3 Ϯ 0.4 versus 8.0 Ϯ 0.9 years, P ϭ a paternal imprinted gene (51). By comparing the allelotyping 0.0011). Furthermore, this difference in frequency was not due data of the patient’s normal DNA with her mother’s normal to the difference in duration of the ZES (17.7 Ϯ 0.6 versus DNA amplified by PCR using marker D1S468, it was demon- 17.1 Ϯ 1.2 years, P ϭ 0.49), male gender (46 versus 57%, P ϭ strated that the paternal allele of p73 is lost in the tumor (i.e., the 0.09), or the severity of the ZES because fasting gastrin levels upper band disappeared in the tumor; Fig. 4). Similarly, loss of (median, 610 versus 1000 pg/ml, P ϭ 0.10) were not signifi- the paternal allele (functional allele) of ARHI/NOEY2 in this cantly different, and in fact, the basal acid output was higher in meningioma (T1) was shown with markers D1S2638 (data not the sporadic cases (44.9 versus 41.6 mEq/h, P ϭ 0.044). shown) and D1S1665 that flank ARHI/NOEY2 gene (Ref. 36; Previous studies have shown a high frequency of LOH on Fig. 4). These data demonstrated that ARHI/NOEY2 gene was chromosome 1p LOH (28–57%) and at 22q12 (44–100%) at the completely inactivated in the meningioma by loss of its func-

54). Also, the phenotype of MEN 1 knockout mice is similar to the features of the human MEN 1 disorder (55), suggesting that loss of this tumor suppressor gene plays a critical role in the pathogenesis of this disorder. However, in a subset of the tumors mentioned above, MEN1 LOH was not identified (5, 7–10, 54). Moreover, in some tumors that occur in MEN 1 patients such as most adrenocortical tumors, thyroid tumors, and all thymic carcinoids, no LOH of the MEN1 gene is identified (2, 5, 11, 14). These findings suggested that the molecular pathogenesis of these various tumors differ. In the present study, we demonstrated for the first time that a MEN 1-related meningioma had LOH at all six loci examined on the MEN1 gene. This result demonstrates that the meningioma occurring in this patient is an MEN 1 tumor and that alterations in the MEN1 gene play a role in its pathogenesis. Although this study is the first to establish the occurrence of meningioma as a specific MEN 1 tumor, two previous studies (20, 21) report a meningioma in a patient with MEN 1. Although MEN 1 was not proven, meningiomas have been reported in patients with hyperparathyroidism (56–59) and in patients with pituitary adenomas (57, 60–63). The association of meningiomas with pituitary adenomas is complicated by the recognition that intracranial irradiation for pituitary disease or other causes is associated with occurrence of meningiomas (60, 62, 64, 65). Patients with pituitary adenomas and meningiomas without previous radiation are described previously (60, 61, 63); however, in no case was the presence of MEN 1 investigated. Only 1 of our patients with MEN 1 had previous pituitary radiation, so this suggests pituitary irradiation is not necessary for the development of meningiomas in MEN 1 patients. However, these results do not exclude the possibility that meningiomas could be more frequent in MEN 1 patients receiving pituitary radiation. In addition to the above associations, a patient with a meningioma, gastric myofibroma, thyroid disease, and an ileal carcinoid tumor has been previously reported (66), as well as a patient Fig. 3 Assessment of chromosome 11q13 (left panel) and 22q (right with multiple lipomas, thyroid disease, prolactin-secreting pitu- panel) loss of heterozygosity (LOH) in a meningioma from a patient with multiple endocrine neoplasia type 1 (MEN 1). Shown are results itary adenoma, and meningioma (63). from normal tissue (N; i.e., leukocytes) and from tumor (T1). The thin Other CNS tumors, including spinal ependymomas (16, 17) arrows show the retained allele, and bold arrows show LOH. In the left and schwannomas (19, 20), are occasionally reported in patients panel are shown results of assessment for 11q13 LOH (MEN1 locus) with MEN 1 (16, 67) or MEN 1-variant syndromes (19). How- using marker D11S480, D11S1883, PYGM, and D11S449. MEN 1 LOH in the meningioma is seen with all four markers. In the right panel ever, in none of these tumors have studies established that they are shown results of assessment for LOH in 22q at the neurofibromatosis demonstrate LOH at the MEN1 locus as was shown in the 2 (NF2) loci with marker D22S280 and D22S929 (intragenetic marker). present study for meningiomas in MEN 1 patients. Although the No NF2 LOH is seen. exact factors are unknown that contribute to the development of meningiomas in MEN 1 patients and perhaps these other CNS tumors, a possible contributing factor in some patients could be elevated plasma levels of either gastrin or other gastrointestinal tional allele, i.e., paternal allele, whereas p73 might not be hormones that are frequently secreted by gastrinomas and other completely inactivated because it lost the imprinted paternal PETs these patients commonly develop (25, 68, 69). Gastrin has allele. LOH of NF2 gene, which was shown to be frequently been shown to cause the proliferation of meningiomas as well as present in sporadic meningiomas (35, 39–41), was not shown in other CNS tumors (70) and meningiomas and other CNS tumors this MEN 1-related meningioma (Figs. 3 and 5). shown to possess CCK/gastrin receptors (71, 72) as well as neurotensin receptors (73), a hormone frequently released by Discussion gastrinomas as well as other PETs (68, 74). The present study LOH at the MEN1 locus on chromosome 11q13 has been provides some insights into this possibility. Meningiomas were identified in many of the endocrine tumors that occur in patients 11 times more frequent in patients with ZES and MEN 1 than with MEN 1, including PETs, parathyroid tumors, pituitary with ZES alone. This difference was not because of the MEN 1 tumors, cutaneous angiofibromas, smooth muscle leiomyomas, patients being older, having higher serum gastrin levels, more lipomas, and carcinoids of the lung and stomach (2, 3, 5, 7–10, severe ZES, or longer follow-up. These results suggest that the

Fig. 4 Results of assessment for loss of heterozygosity (LOH) at 1p in a meningioma from a patient with multiple endocrine neoplasia type 1. In the left panel is shown the chromosome location of the loci identified by the different markers. In the middle panel are shown results from normal tissue (N; i.e., leukocytes) and from two different areas of the meningioma (T1 and T2). The thin arrows show the retained allele, and bold arrows show LOH. In the right panel are shown results from the leukocyte DNA of the patient with the meningioma (D) and from her mother (M). The arrows in the right panel show the paternal allele and maternal allele in the patient’s normal tissue. The middle panel shows that the top allele is lost in the meningioma at locus D1S468. Comparison with the D1S468 data in the right upper panel from the patient’s normal tissue (D) and her mother’s normal tissue (M) indicates that there is loss of the paternal allele at D1S468 (i.e., p73) in the meningioma. In the middle panel at locus D1S2638, D1S2829 (intragenetic marker), and D1S1665, the meningioma had LOH of the ARHI/NOEY2 gene. In the T18 meningioma, the top allele and bottom allele are lost at D1S2638 and D1S1665, respectively. Comparison with the data of D1S1665 from the patient and her mother’s normal tissue in the right panel indicates that there is loss of the paternal allele (functional allele) of ARHI/NOEY2 gene in the meningioma (T18). Also the lower allele is lost in the T20 meningioma, which indicates loss of the maternal allele (imprinted allele) of ARHI/ NOEY2 gene at this site in the meningioma (T20).

presence of the MEN 1 is the important contributing factor to MEN 1, the meningiomas were asymptomatic and detected by the increased frequency of meningiomas in MEN 1 patients. imaging studies, whereas 40–80% are symptomatic in patients Secondly, there was no correlation in our study with the pres- with sporadic meningiomas in different series (22, 75–77). In ence or absence of a meningioma and the magnitude of hyper- comparison to patients with asymptomatic sporadic meningio- gastrinemia. Thirdly, 2 of the 6 patients with MEN 1 with mas, the mean age of our patients with MEN 1 at the time of meningiomas in the present study did not have hypergastrinemia diagnosis of the meningioma was lower [51 versus 57–67 year or any PET imaged, demonstrating meningioma can occur with- (six studies; Refs. 29, 75, 77–80)]. However, the mean age in out associated ZES or another PET. our patients at diagnosis of the meningioma was not as low as The meningiomas in patients with MEN 1 have similarities the third or fourth decade usually seen in patients with NF2 (81). and differences from those reported in patients without MEN 1. The mean size of the meningioma in our patients at initial They resemble sporadic meningiomas with a female predomi- detection was smaller than those with asymptomatic sporadic nance of 2:1 in MEN 1 patients similar to the 2:1 or 3:2 ratio meningiomas [i.e., 1.6 versus 2.2 cm (29), 2.9 cm (75), 2.1 cm reported in sporadic meningiomas (22). In all patients with (78), or 2.6 cm (82)]. Although the numbers of meningiomas in

ingiomas in patients with MEN 1 also frequently possess high densities of these receptors, with 60% (3 of 5) of patients with meningiomas who underwent somatostatin receptor scintigraphy having a positive scan. This percentage may be lower than the 98–100% reported in studies of sporadic meningiomas (83– 87), possibly because of the smaller size of the meningiomas in our patients. Recently, studies imaging PETs with somatostatin receptor scintigraphy demonstrate the detection rate is propor- tional to tumor size and a similar relationship may exist for meningiomas (88). These results demonstrate that it is not sufficient to rely on somatostatin receptor scintigraphy to detect all patients with MEN 1 with meningiomas but instead an MRI of the brain should be performed at the time of evaluation for possible pituitary adenoma. A number of different endocrine (parathyroid, pituitary, PETs, and adrenal) and nonendocrine (cutaneous angiofibromas, smooth muscle leiomyomas, thymic and gastric carcinoids, and lipomas) tumors (4, 5, 7, 8, 54) can develop in patients with MEN 1, and the current study provides some insights into the frequency and temporal relationship between some of these tumors and meningiomas in these patients. Meningiomas were found in 8% of the MEN 1 patients studied, which was significantly less frequent than the frequency in the same patients of Fig. 5 Summary of loss of heterozygosity (LOH) assessment in chro- parathyroid hyperplasia (98%), PETs (96%), or pituitary adeno- mosome 1p, 11q13, and 22q in a meningioma from a patient with MEN mas (40%). This frequency, however, was similar to that for 1. Shown are the microsatellite markers as well as their chromosome location and their distance in centimorgans (cM). The results for the smooth muscle tumors (4%) in these patients and is approxi- tumor with each marker are shown. Results at each locus assessed are mately equal to that reported for bronchial or thymic carcinoids expressed as LOH and retention of heterozygosity (R), determined as (0–8%) in MEN 1 patients (2, 14, 15), less frequent than gastric described in “Materials and Methods.” cM data are from Marshfield 6 carcinoids (15–35%; Ref. 15), adrenocortical tumors (16–40%; chromosome sex-average linkage map. Refs. 2, 12), lipomas (20–34%; Refs. 2, 3), or cutaneous angiofibromas (88%; Ref. 2). The higher frequency of occurrence of meningiomas in females with MEN 1 (2:1) is similar to pituitary different locations in our study were low, the 50% distribution adenomas and bronchial carcinoids in MEN 1 patients, which in the sphenoid area in our study suggests a possible different are also more frequent in females (3) but differs from thymic distribution from patients with asymptomatic sporadic menin- carcinoids that occur almost exclusively in men (14), and hy- giomas in which 10–12% are found in the sphenoidal area (29, perparathyroidism or PETs, which occur with equal frequency 75, 78), with 54–66% instead found in the convexity and/or falx in MEN 1 patients of both sexes (3). In general, the development area (29, 75, 78). During follow-up over a mean of 3.6 years, in of a meningioma was a late feature of MEN 1, occurring 10–15 60% of the patients with MEN 1, the meningiomas demon- years later than the development of hyperparathyroidism, PETs, strated no growth. This compares to a similar percentage growth or pituitary disease. Its peak time of diagnosis at age 50 years is rate of 11–35% in six studies of patients with sporadic menin- similar to the late time course for the development of gastric giomas accidentally discovered followed over a mean 2.7–5 carcinoids and thymic carcinoid tumors in MEN 1 patients (14, years (29, 76, 76, 78, 80, 82). Similarly, the annual mean growth 89). Similar to that recently reported with the development of rate of the meningiomas in our patients was similar to that thymic carcinoids (14), no clinical parameter, laboratory value, reported in patients with sporadic meningiomas [i.e., 0.17 versus or other MEN 1 feature distinguished patients who did or did not 0.24–0.31 cm/year (29, 78)]. Of interest was the fact that the 1 develop a meningioma. Therefore, because it cannot be pre- patient receiving previous pituitary radiation had the highest dicted which patient with MEN 1 will develop a meningioma, it growth rate (i.e., 71% change in diameter/year). This result is will be necessary to perform routine brain MRIs to detect them. consistent with previous reports that meningiomas arise in this Because the youngest age any patient was first diagnosed with context may be more aggressive than sporadic tumors (64, 65). a meningioma in our study was 29 years old, we would recom- None of our patients developed symptoms from the meningioma mend an initial brain MRI be performed by age 25 years. At during follow-up, which is similar to the low rate (i.e., 0.5–3%) present, we have insufficient data to propose when brain MRIs reported in patients with accidentally discovered sporadic men- should be repeated if initially negative. ingiomas in four studies (29, 78–80) but different from another Previous studies in sporadic meningiomas show a high study where 12% became symptomatic (82). Lastly, recent frequency (44–100%) of LOH on chromosome 22q12 at NF2 studies demonstrate 100% of sporadic meningiomas have high gene locus (35, 39–44), and patients with NF2 develop meni- densities of somatostatin receptors which bind octreotide with giomas that have a high frequency of NF2 gene LOH (49). Our high affinity (i.e., sst2,3,5) and that radiolabeled octreotide can be results from allelotyping of 22q12 in the MEN 1-associated used to image these tumors (83–87). Our data show that men- meningioma show that there is no LOH on chromosome 22q12

in the region of the NF2 gene. This data suggested that LOH of 8. Debelenko, L. V., Zhuang, Z. P., Emmert-Buck, M. R., Chan- NF2 gene may not be involved in the tumorigenesis of MEN drasekharappa, S., Manickam, P., Guru, S. C., Marx, S. J., Skarulis, M., 1-associated meningioma. Spiegel, A. M., Collins, F. S., Jensen, R. T., Liotta, L. A., and Lubensky, I. A. Allelic deletions on chromosome 11q13 in multiple endocrine Chromosome 1p LOH is the second most common chro- neoplasia type-I-associated sporadic gastrinomas and pancreatic endo- mosomal abnormality (28–57%) reported in sporadic meningi- crine tumors. Cancer Res., 57: 2238–2243, 1997. omas (39, 44–46, 46–48). The present study demonstrated that 9. Pack, S., Turner, M. L., Zhuang, Z., Vortmeyer, A. O., Boni, R., 1p LOH occurred at 6 of 12 loci on chromosome 1p examined Skarulis, M., Marx, S. J., and Darling, T. N. Cutaneous tumors in in the MEN 1-related meningioma. Two tumor suppressor genes patients with multiple endocrine neoplasia type 1 show allelic deletion (p73 and ARHI/NOEY2) have been localized on 1p36 and 1p31, of the MEN1 gene. J. Investig. Dermatol., 110: 438–440, 1998. respectively (50, 53), and in our study, at each locus in the MEN 10. Debelenko, L. V., Emmert-Buck, M. R., Zhuang, Z., Epshteyn, E., Moskaluk, C. A., Jensen, R. T., Liotta, L. A., and Lubensky, I. A. The 1-associated meningioma, LOH was found. ARHI/NOEY2 is a multiple endocrine neoplasia type 1 gene locus is involved in the maternal imprinted tumor suppressor gene (53), and our data pathogenesis of type II gastric carcinoids. Gastroenterology, 113: 773– demonstrates that the paternal (functional) allele of ARHI/ 782, 1997. NOEY2 gene was lost in the MEN 1-associated meningioma. 11. Skogseid, B., Larsson, C., Lindgren, P. G., Kvanta, E., Rastad, J., This means that ARHI/NOEY2 gene is completely inactivated Theodorsson, E., Wide, L., Wilander, E., and Oberg, K. Clinical and in this meningioma, suggesting that loss of this tumor suppres- genetic features of adrenocortical lesions in multiple endocrine neoplasia type 1. J Clin. Endocrinol. Metab., 75: 76–81, 1992. sor gene could be contributing to the tumorigenesis of the 12. Komminoth, P., Heitz, P. U., and Kloppel, G. Pathology of MEN-1: meningioma in MEN 1 patients. However, with the paternal morphology, clinicopathologic correlations, and tumour development. imprinted gene p73 (51, 90), which is a homologue of p53 (51, J. Intern. Med., 243: 455–464, 1998. 52, 91), loss of the paternal allele was found, indicating that the 13. Solcia, E., Capella, C., Fiocca, R., Rindi, G., and Rosai, J. Gastric p73 gene might not be involved in the pathogenesis of menin- argyrophil carcinoidosis in patients with Zollinger-Ellison syndrome gioma in MEN 1 patients. due to type 1 multiple endocrine neoplasia. A newly recognized association. Am. J. Surg. Pathol., 14: 503–513, 1990. 14. 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