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Show Clinical Observation Suprasellar Primitive Neuroectodermal Tumor in an Adult Angelina Espino Barros Palau, MD, Khurrum Khan, Michael L. Morgan, MD, PhD, Suzanne Z. Powell, MD, Andrew G. Lee, MD Abstract: Primitive neuroectodermal tumors (PNET) of the central nervous system (CNS) are a heterogeneous group of embryonal malignancies that are composed of undifferentiated or poorly differentiated neuroepithelial cells. Supratentorial PNET is the second most common CNS embryonal malignancy in children, but it is rare in adults. We report the case of a 31-year-old woman with bilateral vision loss and a bitemporal hemianopia. Neuroimaging revealed a suprasellar mass, and pathology was consistent with PNET. After surgical debulking of the tumor followed by radiation therapy and chemotherapy, the patient had significant visual recovery and remained stable over 14 months of follow-up. Journal of Neuro-Ophthalmology 2016;36:299-303 doi: 10.1097/WNO.0000000000000312 © 2015 by North American Neuro-Ophthalmology Society categorized separately. This includes neuroblastoma, ganglioneuroblastoma, medulloepithelioma, ependymoblastoma, embryonal tumor with abundant neurophil and true rosettes, and not otherwise specified PNET tumor. Supratentorial PNET (S-PNET) is primarily a childhood malignancy that affects the cerebral hemispheres with equal distribution among the frontal, temporal, and parietal lobes, and represents 2%-3% of all primary cerebral hemisphere tumors in the pediatric age group (3). S-PNET is extremely rare in adults (4-7) and usually causes signs of increased intracranial pressure (ICP), seizures, and focal neurological deficits. Our patient's only symptom was bilateral visual failure. CASE REPORT P rimitive neuroectodermal tumors (PNET) of the central nervous system (CNS), a term coined in 1973 by Hart and Earle (1), have been defined as "a heterogeneous group of tumors occurring predominantly in children and adolescents that may arise in the cerebral hemispheres, brainstem, or spinal cord, and are composed of undifferentiated or poorly differentiated neuroepithelial cells, which may display divergent differentiation along neuronal, astrocytic, and ependymal lines" (2). In the revised World Health Organization (WHO) classification, many of these neoplasms are now Department of Ophthalmology (AEBP), Centro Médico Zambrano Hellion-Tec Salud, Monterrey, Mexico; Department of Ophthalmology (KK, AGL), Baylor College of Medicine, Houston, Texas; Department of Ophthalmology, Houston Methodist Hospital, Houston, Texas; Department of Pathology and Genomic Medicine (MLM, AGL), Houston Methodist Hospital, Houston, Texas; Departments of Ophthalmology (AGL), Neurology, and Neurosurgery, Weill Cornell Medical College, Houston, Texas; Department of Ophthalmology (AGL), UTMB Galveston, Texas; The UT M.D. Anderson Cancer Center (AGL), Houston, Texas; and The University of Iowa Hospitals and Clinics (AGL), Iowa City, Iowa. The authors report no conflicts of interest. Address correspondence to Andrew G. Lee, MD, Department of Ophthalmology, Houston Methodist Hospital, 6560 Fannin Street, Scurlock 450, Houston, TX 77030; E-mail: AGLee@ HoustonMethodist.org Espino Barros Palau et al: J Neuro-Ophthalmol 2016; 36: 299-303 A previously healthy 31-year-old woman experienced painless, progressive bilateral (right greater than left) vision loss over 4 weeks. Her medical history and family history were unremarkable. She was prescribed new glasses and artificial tears. Because her vision continued to deteriorate, she was ultimately referred for neuro-ophthalmic assessment and admitted to hospital. Visual acuity was 20/400, for right eye and 20/50, for left eye. Color vision was reduced bilaterally, and there was a right relative afferent pupillary defect. Ocular motility was full and the patient was orthophoric without nystagmus. Funduscopy was unremarkable but automated visual fields showed bitemporal hemianopic loss (Fig. 1). Magnetic resonance imaging (MRI) of the brain showed an intrasellar and suprasellar mass originating from the region of the lamina terminalis and suprasellar cistern. It demonstrated both downward extension into the sella and upward extension into the anterior-inferior third ventricle causing mild outflow obstruction of cerebrospinal fluid. The mass had a lobulated contour and enhanced heterogeneously (Fig. 2). MRI of cervical, thoracic, and lumbar spine was normal. A right frontotemporal craniotomy revealed a suprasellar mass infiltrating between the optic nerves. Frozen section showed a malignant appearing blue cell tumor, and flow 299 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Observation FIG. 1. Automated visual fields (Humphrey 24-2). A bitemporal hemianopic field defect is evident using a V test object in the right eye and III test object in the left eye. cytometry revealed atypical large cells CD45-/CD56+ suggestive of a nonhematolymphoid neoplasm. Pathology demonstrated dyshesive pleomorphic tumor cells with scant cytoplasm (Fig. 3A, B). Neurofilament protein and synaptophysin stains disclosed moderately strong, but patchy staining (Fig. 3C, D). Pancytokeratin and glial fibrillary acidic protein (GFAP) stains did not show immunoreactivity, arguing against a glial-derived tumor (Fig. 3E, F). Oct-3/4 staining was also negative, making a germ cell tumor unlikely (Fig. 3G). Most of the tumor cell nuclei (.50%) were MIB-1 immunoreactive (Fig. 3H). No calcium was found on any biopsy specimens. Final diagnosis was a high-grade neuroepithelial tumor consistent with a CNS PNET. After tumor debulking by right frontal craniotomy, the patient was referred for total craniospinal radiation and chemotherapy. Conformal intensity-modulated radiotherapy 1.8 Gy per fraction was given for a total of 36 Gy to the whole brain and spine with a 18 Gy boost to the tumor bed. Chemotherapy consisted of cisplatin and etoposide followed by cyclophosphamide and vincristine. Full-body positron emission tomographic scan did not reveal metastatic or recurrent disease. A repeat visual field showed resolution of bitemporal hemianopia and acuity recovered to 20/25 bilaterally. On her last brain MRI, 14 months after surgical resection, no evidence of residual sellar, parasellar, or suprasellar tumor was noted. DISCUSSION FIG. 2. Postcontrast coronal T1 magnetic resonance imaging reveals a 3.0 · 3.0-cm intrasellar and suprasellar mass with a lobulated contour, which enhances heterogeneously. 300 S-PNET is a rare malignancy in adults with a PubMed search yielding less than 100 reported cases. Mean age at diagnosis is 32.5 years with the most between the ages of 20-30 years (4), with a slight male predominance (male: female = 4:3) (4,5). The location PNET has been equally Espino Barros Palau et al: J Neuro-Ophthalmol 2016; 36: 299-303 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Observation FIG. 3. Biopsy histopathology. There are dyshesive pleomorphic tumor cells with scant cytoplasm, neuroendocrine nuclear features, apoptotic material, and conspicuous mitoses along with rare rosette-like formations (A, hematoxylin and eosin, ·200; B, touch preparation, ·200). Neurofilament protein (C) and synaptophysin (D) stains show moderately strong but patchy staining (C, D, ·200). Pancytokeratin (E) and GFAP (F) stains do not show immunoreactivity (E, F, ·100). Oct-3/4 staining (G) is negative, whereas most of the tumor cell nuclei are MIB-1 immunoreactive (H) (G, H, ·100). distributed among the frontal, temporal, and parietal lobes. Cerebrospinal dissemination at the time of diagnosis has been found in 10% of cases. Most patients present with symptoms and signs of increased ICP (4,8-11). S-PNET also can present with focal neurologic signs corresponding with tumor location. To our knowledge, there is only 1 previous report of PNET presenting as a suprasellar mass. Berwaerts et al (7) Espino Barros Palau et al: J Neuro-Ophthalmol 2016; 36: 299-303 described a 55-year-old woman with unilateral visual loss and personality changes. The patient underwent 2 surgical procedures. The first by right frontal craniotomy was performed to debulk the tumor and relieve compression of the optic nerves and chiasm, and the second, used a transsphenoidal approach to resect the intrasellar component of the tumor. The patient had multiple postoperative complications including cerebrospinal fluid leakage, postoperative 301 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Observation hydrocephalus, cognitive changes, and dementia, and died of a respiratory tract infection 6 months after the initial surgical procedure. The differential diagnosis of a suprasellar mass in a young otherwise healthy woman includes pituitary adenoma, meningioma, craniopharyngioma, astrocytoma/glioma, and germinoma. The tumor in our patients was high grade, undifferentiated, showed neuroendocrine nuclei with molding (a cytologic feature of PNET), rosette formation, and a high MIB-1 labeling index, and expressed neural markers, such as CD56 and synaptophysin, and was negative for GFAP. In addition, there was no evidence of an extrasellar, disconnected lesion in our case that would suggest pituitary carcinoma. In our case, chromosomal studies of the tumor were not performed. These studies can aid in the differentiation between CNS PNET and medulloblastoma, and also indicate prognosis and clinical outcome. Recent genetic analysis has demonstrated that PNETs are characterized by MYNC or MYCC gene amplifications and polysomies of chromosomes 2, 8, and 22 (12). Although MYNC and MYCC amplifications have been associated with aggressive clinical behavior and poor prognosis in medulloblastoma patients (13-16), these amplifications have not been associated with anaplastic/large cell features on PNET histology, and shortened survival has not reached statistical significance (12). In contrast, polysomies of chromosomes 2 and 8 have been associated with decreased survival. It should be noted that most of the genetic characteristics have been described in pediatric cases due to the rarity of adult PNET. The same prognostic implications might be inaccurate in the latter group. Treatment of PNET includes surgery, radiation therapy, chemotherapy (4,5). An attempt at surgical resection is generally performed initially, but postoperative radiotherapy often is necessary (8). Gaffney et al (3) suggested a maximum radiation dose to the tumor site between 50 and 55 Gy over a 7 to 8-week period. Radiation of the whole craniospinal axis has also been recommended on the basis of CNS dissemination risk and improved prognosis (8,17). The role of chemotherapy in CNS PNET is controversial. The Packer chemotherapy regimen (vincristine, lomustine, and cisplatin) (18) has been used in pediatric and adult SPNET patients, but its efficacy is unproven (19). Unfortunately, the prognosis for adults (.20 years old) PNET is worse than that of children (1-9 years) and adolescents (10-19 years). Adults have been shown to have a 5-year cumulative relative survival (CRS) rate of 35%, whereas adolescents have a 5-year CRS of 57%, and children have a CRS of 64% (20). In adults, the most important prognostic factor is the Ki-67 index, a marker of cellular proliferation (21). In a series of 12 patients with S-PNET, Kim et al (8) found that a Ki-67 index greater than 30% to be a poor prognostic factor is with a mean postoperative survival time of 8 months. MIB-1 is an anti302 body directed against an epitope of the Ki-67 protein and is now used to determine the Ki-67 labeling index (22). In our patient, most of the tumor cell nuclei (.50%) were MIB-1 immunoreactive indicating a guarded prognosis. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: A. Espino Barros Palau, M. L. Morgan, and A. G. Lee; b. Acquisition of data: A. Espino Barros Palau, K. Khan, M. L. Morgan, and S. Powell; c. Analysis and interpretation of data: A. Espino Barros Palau, M. L. Morgan, A. G. Lee, and S. Powell. Category 2: a. Drafting the manuscript: A. Espino Barros Palau, K. Khan, and M. L. Morgan; b. Revising it for intellectual content: A. Espino Barros Palau, M. L. Morgan, S. Powell, and A. G. Lee. Category 3: a. Final approval of the completed manuscript: A. Espino Barros Palau, K. Khan, M. L. Morgan, S. Powell, and A. G. Lee. REFERENCES 1. Hart MN, Earle KM. Primitive neuroectodermal tumors of the brain in children. Cancer. 1973;32:890-897. 2. Louis DN, Ohgaki H, Weistler OD, Cavenee WK, eds. WHO Classification of Tumours of the Central Nervous System, 4th edition. Lyon, France: IARC Press, 2007:309. 3. Gaffney CC, Sloane JP, Bradley NJ, Bloom HJG. Primitive neuroectodermal tumors of the cerebrum: pathology and treatment. J Neurooncol. 1985;3:23-33. 4. Ohba S, Yoshida K, Hirose Y, Ikeda E, Kawase T. A supratentorial primitive neuroectodermal tumor in an adult: a case report and review of the literature. J Neurooncol. 2008;86:217-224. 5. Papadopoulos EK, Fountas KN, Brotis AG, Paterakis KN. 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