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Molecular Genetics of Supratentorial Primitive Neuroectodermal Tumors and Pineoblastoma

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Molecular Genetics of Supratentorial Primitive Neuroectodermal Tumors and Pineoblastoma Neurosurg Focus 19 (5):E3, 2005 Molecular genetics of supratentorial primitive neuroectodermal tumors and pineoblastoma MEI HUA LI, PH.D., ERIC BOUFFET, M.D., CYNTHIA E. HAWKINS, M.D., PH.D., JEREMY A. SQUIRE, PH.D., AND ANNIE HUANG, M.D., PH.D. Arthur and Sonia Labatt Brain Tumor Research Centre, Cancer Research Program, Division of Hematology and Oncology, and Department of Pediatric Laboratory Medicine, Hospital for Sick Children, Toronto; Ontario Cancer Institute, Toronto; and Department of Pathobiology and Laboratory Medicine, University of Toronto, Ontario, Canada The supratentorial primitive neuroectodermal tumors (PNETs) are a group of highly malignant lesions primarily affecting young children. Although these tumors are histologically indistinguishable from infratentorial medulloblas- toma, they often respond poorly to medulloblastoma-specific therapy. Indeed, existing molecular genetic studies indi- cate that supratentorial PNETs have transcriptional and cytogenetic profiles that are different from those of medullo- blastomas, thus pointing to unique biological derivation for the supratentorial PNET. Due to the rarity of these tumors and disagreement about their histopathological diagnoses, very little is known about the molecular characteristics of the supratentorial PNET. Clearly, future concerted efforts to characterize the molecular features of these rare tumors will be necessary for development of more effective supratentorial PNET treatment protocols and appropriate disease models. In this article the authors review existing molecular genetic data derived from human and mouse studies, with the aim of providing some insight into the putative histogenesis of these rare tumors and the underlying transforming pathways that drive their development. Studies of the related but distinct pineoblastoma PNET are also reviewed. KEY WORDS • supratentorial primitive neuroectodermal tumor • pineoblastoma • molecular genetics OVERVIEW PNETs have molecular features that are unique from those of The supratentorial PNET and pineoblastoma are high- medulloblastoma. Nevertheless, because of the rarity of su- grade, relatively undifferentiated tumors arising from the pratentorial PNETs, only limited molecular studies of small cerebral hemispheres and the pineal regions, respectively. numbers of supratentorial PNETs have been conducted to Although they are histologically very similar to medullo- date. Clearly, comprehensive knowledge of the molecular blastoma, supratentorial PNETs have markedly different genetic features of supratentorial PNETs will be essential in clinical behavior and are generally considered to represent future studies to advance diagnosis, therapy, and prognosis a more aggressive tumor group than medulloblastoma, with in this rare but challenging tumor group. We review existing a frequently massive tumor burden and a higher incidence molecular studies of supratentorial PNETs with a view to of disseminated disease at diagnosis, as reviewed in Jakac- improving our current understanding of putative signaling ki.85 Because cerebral supratentorial PNETs may often be defects and molecular abnormalities in supratentorial deep-seated in paraventricular, thalamic, and hypothalamic PNETs. We also review molecular studies of pineoblasto- 94 sites,44 they pose significant challenges to safe resection and mas, a WHO Grade IV pineal parenchymal tumor that has the delivery of limited radiation. Thus, despite their small- often been considered collectively with the supratentorial er numbers, supratentorial PNETs are a significant thera- PNET in molecular and therapeutic studies. Nevertheless, peutic problem because these highly aggressive, therapy- existing data suggest distinct histogenesis and unique mole- resistant tumors primarily affect younger children, who are cular genetics for the pineoblastoma, and they are therefore the most likely to suffer long-term damage due to radiation. discussed separately. Existing data support the suggestion that supratentorial Abbreviations used in this paper: cdk = cyclin-dependent kinase; SUPRATENTORIAL PNETS CGH = comparative genomic hybridization; CNS = central nervous system; mRNA = messenger RNA; PNET = primitive neuroecto- Collectively, supratentorial PNETs are relatively rare, rep- dermal tumor; Shh = Sonic hedgehog; WHO = World Health Or- resenting approximately one tenth the frequency of medul- ganization. loblastoma, and 3 to 7% of pediatric CNS tumors.91,97 They Neurosurg. Focus / Volume 19 / November, 2005 1 Unauthenticated | Downloaded 10/02/21 11:19 PM UTC M. H. Li, et al. are diagnosed at a younger median age than medulloblasto- gest intrinsic biological differences between supratentorial mas; more than 65% of supratentorial PNETs are reported in PNET and medulloblastoma. patients younger than 5 years of age with no significant sex predominance (reviewed in Jakacki, et al.86). In a Pediatric Histopathological Diagnosis of Supratentorial PNET Oncology group trial for delayed radiation in children Histopathological classification of supratentorial PNET younger than 3 years of age, supratentorial PNETs repre- remains a contentious issue. Based on the indistinguishable sented the second most common tumor (13 of 19).44 Supra- 39,64,113 histological features of supratentorial PNET and medul- tentorial PNETs can present as congenital tumors. Al- loblastoma, a common histopathological grouping of all though supratentorial PNET is generally considered almost PNETs with a presumed common histogenesis was pro- exclusively a pediatric tumor, rare adult series have been 140 109 91,155 posed and remains disputed. Current WHO criteria described. There is currently insufficient literature to identify supratentorial PNET as a Grade IV tumor with un- judge whether supratentorial PNETs in adults differ from differentiated or poorly differentiated neuroepithelial cells, those in children. It is notable, however, that one study re- and with the capacity for divergent differentiation along ported a 3-year survival rate of 75% for a series of 12 pa- multiple lineages, including neuronal, astrocytic, ependy- tients, a rate far superior to any reported in pediatric supra- 142 91 mal, muscular, or melanocytic lines. Because specific tentorial PNETs. These observations, together with reports marker(s) for supratentorial PNET do not exist, these le- of a high frequency of p53 mutations in adult supratentorial 74 sions are still diagnosed primarily on the basis of a supra- PNETs, suggest they are likely to represent distinct dis- tentorial location and histological features of a predomi- eases. nantly undifferentiated neuroepithelial tumor with focal High-grade glial tumors are well recognized as potential areas of divergent differentiation. The inclusion of supra- late complications of the craniospinal radiation treatment tentorial neuronal tumors with more distinct neuronal dif- used in childhood leukemias. Interestingly, supratentorial ferentiation, such as the cerebral neuroblastoma, or the gan- PNETs can also present as secondary malignancies after glioneuroblastoma with its distinct ganglionic features, therapy for hematological as well as primary intracranial remains controversial.12,14 When supratentorial PNETs dem- neoplasms. To date, seven cases of secondary supratentori- onstrate very little morphological or immunohistochemical al PNET arising after treatment for childhood acute lym- signs of differentiation, they pose diagnostic challenges phocytic leukemia, acute myeloid leukemia, or lymphoma 102 with respect to other high-grade supratentorial tumors such have been reported. Secondary supratentorial PNETs the “round” or “small cell” glioblastoma variants, which have been reported in the context of cancer predisposition 94 syndrome in two patients. One child presented with supra- may also exhibit a similarly undifferentiated phenotype. tentorial PNET 5 years after treatment for unilateral retino- For polyphenotypic supratentorial PNETs presenting in a young child with expression of epithelial or muscular anti- blastomas,50 and in another with neurofibromatosis Type 1, supratentorial PNET developed after radiation treatment for gens such as epithelial membrane antigen and smooth-mus- 132 cle actin, the differentiation from the highly aggressive a brainstem astrocytoma. Supratentorial PNETs can also 141 occur as secondary malignancies in both children and adults CNS rhabdoid tumors may pose significant challenges, because INI1 mutation has been reported in supratentorial with no genetic condition. Tumors occurring up to 18 years 150 after radiation treatment for low-grade primary intracranial tumors without typical histological “rhabdoid” features. neoplasms such as cerebellar pilocytic astrocytoma and In a recent survey, pathologists identified histopatho- 34,69 logical diagnosis of supratentorial PNET as an area of sig- low-grade astrocytoma have been described. 7 A supratentorial PNET most commonly arises in the ce- nificant challenge. The continuing uncertainties about the rebrum, and is seen less frequently in deep paraventricular precise histological criteria required for diagnosis and the or midline locations such as the diencephalon and basal relative rarity of these tumors means that published genet- ganglia.47 Rarely, PNETs can present in the leptomeninges ic and molecular genetic data, particularly in small series, without evidence of primary tumor in the supra- or infraten- may be difficult to interpret, and may have included high- torial compartments.13 These are proposed
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