Familial Tuberculum Sellae Meningiomas.

OBJECTIVES: The aim of this study was to study and explore the genetic mechanism of familial meningiomas through 3 cases of familial tuberculum sellae meningioma.
METHODS: A retrospective analysis of clinical data of 3 cases of familial tuberculum sellae meningioma patients, and the pathological results of types and immunohistochemical results of the 3 patients were compare. REULTS: Three cases of postoperative pathology were meningiomas (mixed type), immunohistochemical examination showed that Vimentin, epithelial membrain antigen , and Ki67 were positive.
CONCLUSIONS: The occurrence of meningiomas is associated with ≥1 chromosomal deletions, and the absence of certain tumor suppressor genes may be the genetic basis for the familial growth of meningiomas.

This report focuses on a family of 7 siblings, with 5 sisters and 2 brothers. Among the sisters, 3 suffer from tuberculum sellae meningiomas, which has been confirmed via pathological analysis. The remaining 4 siblings all underwent brain magnetic resonance imaging (MRI) scanning while they accompanied their sisters to hospital, and no meningioma was found. The 3 cases of familial tuberculum sellae meningioma are detailed in the following section.

CLINICAL STUDY

Patient 1, female, age 71. The patient was admitted to the Department of Neurosurgery at the First People's Hospital of Changzhou in July 2011 after repeated episodes of intermittent dizziness, ongoing for 2 months. A brain MRI scan suggested meningioma in the sella area. Right pterional craniotomy was performed to remove the tumor. Follow-up visits to the hospital in the subsequent 4 years found no neurological dysfunction. Post-surgery pathologic analysis showed the mixed meningioma rich in cells and actively growing. Immunochemistry assays revealed negative staining of the glial fibrillary acidic protein (GFAP) and human hematopoietic progenitor cell antigen (CD34), and positive staining of Vimentin, epithelial membrain antigen (EMA), and proliferation marker Ki-67 (< 2%).

Patient 2, female, age 69. The patient was admitted to the Department of Neurosurgery at the First People's Hospital of Changzhou in July 2015 after progressive vision loss in the left eye for 30 years with acute headaches during the preceding 2 months. A brain MRI scan suggested bilateral sella meningiomas. Presurgical examinations showed no perception of light in the left eye and 4.8 vision in the right eye. Right pterional craniotomy was performed to remove the tumors. During follow-up visits during the subsequent 6 months, the patient still had no perception of light in the left eye and 4.8 vision in the right. Post-surgery pathologic analysis showed mixed meningioma with abundant cells and angiogenesis. Immunochemistry assays revealed negative staining of monoclonal anti-Pan-Cytokeratin (AE1/AE3), GFAP, and S-100, and positive staining of CD34, EMA, Vimentin, and Ki-67 (<2%).

Patient 3, female, age 68. This patient was the first to be diagnosed with meningioma among the 3. She was admitted to the Huashan Hospital of the Fudan University in November 2005 due to progressive loss of vision in both eyes for 10 years. A brain MRI scan suggested meningioma in the sella area. Presurgical examinations showed only the right eye capable of light perception and 4.5 vision in the left eye. Craniotomy was performed to remove the tumor. In the subsequent 6 years of follow-ups, the patient had no perception of light in the right eye and 4.4 vision in the left. The post-surgery pathologic analysis showed mixed meningioma, part of which had abundant cells and was actively growing. Immunochemistry assays revealed negative staining of GFAP and positive staining of Vimentin, EMA, CD34, and Ki-67 (<2%).

All 3 cases of tuberculum sellae meningioma had soft tumors, medium supply of blood, and a mixed histological type according to the post-surgery pathology reports.

DISCUSSION

Meningiomas are neoplasms that arise from the meninges and the subarachnoid space. They may grow from cells of the dura mater, the pia mater, and in most cases, the arachnoid mater, and may be present in any area that contains arachnoid cells. Meningiomas are not caused by any single factor, but may correlate with internal changes and gene mutations. Familial meningiomas are not common, and 3 cases within 1 family with tumors in the same area are extremely rare.

These 3 cases of familial tuberculum sellae meningioma were all confirmed to be of mixed type by pathological analysis, and they all had positive staining of Vimentin, EMA, and Ki-67 in immunochemistry assays. Vimentin is an important cytoskeletal protein in mesenchymal cells. A multiphosphorylated form of this protein can be used as a discriminative marker for infiltrative and invasive meningiomas.[1] Abnormal expression of Vimentin in tumor cells may lead to changes in quality and quantity of cytoskeletal proteins, which may enable the cells to float about, modify their mobility and affinity, and finally induce changes to their biological characteristics. A previous study showed decreased expression of EMA and increased expression of Vimentin with malignant progression of meningioma. Although Vimentin was found to be expressed in both benign and malignant meningiomas, it only increased in 20% of the anaplastic types.[2] Ki-67 has been shown to be associated with different histological types of meningiomas, that is, its expression is different in different types and the difference may be due to whether the tumor is benign or malignant. Therefore, Ki-67 can be used as a diagnostic marker for meningioma subtypes. Takeuchi et al[3] found an increased risk of meningioma relapse when the Ki-67 labeling exceeded 2% even though the tumor was pathohistologically benign and thus, radiotherapy or stereotactic radiosurgery was recommended in this case.

Chromosomal aberration is an anomaly in chromosomes that is caused by missing, repetitive, or rearranged genetic material. It can be caused via atypical numbers of chromosomes or structural abnormalities. In meningiomas, chromosomal aberrations have been found in chromosomes 1, 3, 6, 7, 8, 10, 12, 14, 17, 18, 19, 22, X, and Y.[4] Among these, abnormalities in chromosome 22 are the most common, and they include missing, translocated, monoploidy, and polyploidy of the chromosome. The long arm of chromosome 22 contains the tumor suppressor gene NF2. A number of studies have suggested that mutations in NF2 might be associated with the carcinogenic aberrations of chromosome 22.[5,6] It has previously been proposed that missing chromosome 22 leads to NF2 mutations, which in turn causes meningioma, and changes the other chromosomes in combination with gene mutations, thus aggravating histological grades of the tumor.[6] Furthermore, Aavikko et al[7] reported an incidence of five cases of meningiomas among siblings in one family, four out of which were multiple meningiomas. With genome-wide linkage analysis and exome sequencing, the authors showed that a hereditary mutation in the tumor suppressor gene SUFU, predisposed to meningiomas, especially multiple meningiomas. The altered SUFU had significantly lower activity, resulting in abnormal expression of the Hedgehog signaling pathway, which might help explain the genetic etiology of familial meningiomas.[7]

Cranial injuries, radiation exposure, viral infection, and bilateral acoustic neuromas may all lead to mutations in chromosomes or acceleration in cell proliferation. Since each chromosome consists of thousands of genes, missing DNA on a single chromosome will result in loss of a considerable amount of genetic information. It is possible that meningioma is related to loss of one or multiple chromosomes and of tumor suppressor genes. We are currently trying to contact the 3 patients of tuberculum sellae meningiomas and the other members of their family. We plan to perform genome-wide sequencing of the whole family to search for genetic aberrations, underlying the meningiomas in the family. With in-depth analysis of molecular and genetic information, new paths and directions may be uncovered for the further exploration into mechanisms of mengioma occurrence and progression (Fig. 1).

FIGURE 1

(A) Tumor in the sella area shown by contrast-enhanced magnetic resonance imaging (MRI) imaging of brain, case 1, transverse section. (B) Tumor in the sella area shown by contrast-enhanced MRI imaging of brain, case 1, sagittal section. (C) Tumor in the sella area shown by contrast-enhanced MRI imaging of brain, case 1, coronal section. (D) Post-surgery pathology staining (H&E staining 10 × 10) showed mixed meningioma, case 1. (E) Immunochemistry staining (EMA +), 10 × 10, case 1. (F) Bilateral tumors in the sella area shown by contrast-enhanced MRI imaging of brain, case 2, transverse section. (G) Bilateral tumors in the sella area shown by contrast-enhanced MRI imaging of brain, case 2, sagittal section. (H) Bilateral tumors in the sella area shown by contrast-enhanced MRI imaging of brain, case 2, coronal section. (I) Post-surgery pathology staining (H&E staining 10 × 10) showed mixed meningioma, case 2. (J) Immunochemistry staining (EMA +), 10 × 10, case 2. (K) Tumor in the sella area shown by contrast-enhanced MRI imaging of brain, case 3 transverse section. (L) Tumor in the sella area shown by contrast-enhanced MRI imaging of brain, case 3 sagittal section. (M) Tumor in the sella area shown by contrast-enhanced MRI imaging of brain, case 3 coronal section. (N) Post-surgery pathology staining (H&E staining 10 × 10) showed mixed meningioma, case 3. (O) Immunochemistry staining (EMA +), 10 \× 10, case 3.