Cytogenetics and molecular genetics of childhood brain tumors

Considerable progress has been made toward improving survival for children with brain tumors, and yet there is still relatively little known regarding the molecular genetic events that contribute to tumor initiation or progression. Nonrandom patterns of chromosomal deletions in several types of childhood brain tumors suggest that the loss or inactivation of tumor suppressor genes are critical events in tumorigenesis. Deletions of chromosomal regions 10q, 11 and 17p, and example, are frequent events in medulloblastoma, whereas loss of a region within 22q11.2, which contains the INI1 gene, is involved in the development of atypical teratoid and rhabdoid tumors. A review of the cytogenetic and molecular genetic changes identified to date in childhood brain tumors will be presented.     

Cytogenetics and molecular genetics of childhood leukemia

Childhood leukemia is the commonest form of childhood cancer and represents clonal proliferation of transformed hemopoietic cells as a result of genetic changes. Molecular characterization of these changes, in particular chromosomal translocations, has yielded a wealth of information on the mechanisms of leukemogenesis. These findings have also allowed the development of sensitive assays for the identification of underlying molecular defects, which is applicable to disease diagnosis and to monitor response to treatment. Genetic alterations in childhood leukemia are powerful prognostic indicators. TEL-AML1 fusion and hyperdiploidy >50 chromosomes are associated with a good prognosis in childhood acute lymphoblastic leukemia, whereas BCR-ABL fusion and MLL rearrangements are associated with a poor prognosis. Hence cytogenetic and molecular genetic classification of childhood leukemia will significantly improve the ability of clinicians to predict therapeutic response and prognosis, which paves the way for risk stratification based on clinical and genetic features. Finally, deciphering of genetic lesions in leukemia has allowed elucidation of the molecular basis of current treatment, as typified by the success of all-trans retinoic treatment in acute promyelocytic leukemia, and has identified targets for novel therapeutic approaches. It is envisaged that efforts in characterization of molecular defects in childhood leukemia will ultimately be translated into better clinical outcome for patients.     

Molecular genetics of pediatric central nervous system tumors

Recent advances in molecular biology have enhanced our understanding of the pathogenesis of brain tumors, particularly in children. The use of molecular diagnostic tools is quickly becoming a standard component in the diagnosis and classification of brain tumors in children, in addition to providing insight leading to treatment stratification and improved outcome prediction. All new protocols involving treatments for brain tumors in children include studies of biomarkers and biologic correlates as a means to identify new targets for therapeutics and possible intervention strategies.     

Genetics of nervous system tumors.

Genetic aberrations are being defined for the various glial tumors. Astrocytic tumors can evolve by two different pathways. The genetic aberrations now being defined for these two pathways are different and can be associated with the grade of malignancy. In oligodendrogliomas, the genetic lesions differ from the astrocytic tumors, and several markers have been linked to chemosensitivity response and survival. Genetic aberrations in ependymomas also differ from the astrocytic tumors or oligodendrogliomas. Although additional cases are needed to study the genetic aberrations, the abnormalities identified suggest that spinal cord tumors carry different markers than intracranial tumors and that the markers within the cranium may be different based on their location.     

Molecular biology of nervous system tumors.

Many genetic alterations that contribute to CNS tumorigenesis and progression have been identified. One goal of such studies is to identify loci that would serve as diagnostic prognostic markers or both. A significant advance is the observation that chromosome 1p loss identified anaplastic oligodendroglioma and a subset of high-grade glioma patients who responded to chemotherapy and had longer survival times. Combined 1p and 19q loss was a predictor of prolonged survival of patients having pure oligodendrogliomas. Such markers eventually may be used to identify patients upfront who would benefit from treatment, while sparing patients who would not benefit. Although many molecular participants involved in the biologic pathways that promote proliferation, angiogenesis, and invasion have been elucidated, there are still many gaps in clinicians' knowledge. It is expected that the use of the human genome project information and databases such as SAGEmap, in combination with techniques such as cDNA arrays and proteomics, will facilitate greatly the identification of novel genes that contribute to CNS tumors. cDNA arrays and tissue arrays will permit the construction of CNS-specific screening tools that will permit the identification of tumor-specific mutations and alterations so that patient-specific therapies can be designed.     

The molecular genetics of gastroenteropancreatic neuroendocrine tumors

The pathobiology of neuroendocrine tumors (NETs) is hampered by the lack of scientific tools that define their mechanisms of secretion, proliferation, and metastasis; and, currently, there are no accurate means to assess tumor behavior and disease prognosis. Molecular biologic techniques and genetic analysis may facilitate the delineation of the molecular pathology of NETs and provide novel insights into their cellular mechanisms. The current status and recent advances in assessment of the molecular basis of tumorigenesis of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) were reviewed (1981-2004). The objectives of this retrospective study were to provide a cohesive overview of the current state of knowledge and to develop a molecular understanding of these rare tumor entities to facilitate the establishment of therapeutic targets and rational management strategies. Multiple differences in chromosomal aberration patterns were noted between gastrointestinal (GI) neuroendocrine and pancreatic endocrine tumors (PETs). Divergence in gene expression patterns in the development of GI carcinoids and PETs was identified, whereas examination of the PET and GI carcinoid data demonstrated only few areas of overlap in the accumulation of genetic aberrations. These data suggest that the recent World Health Organization classification of GEP-NETs may require updating. In addition, previous assumptions of tumor similarity (pancreatic vs. GI) may be unfounded when they are examined at a molecular level. On the basis of the evolution of genetic information, enteric neuroendocrine lesions (carcinoids) and PETs may need to be classified as two distinct entities rather than grouped together as the single entity "GEP-NETs."     

Central nervous system tumors in children.

Of 488 central nervous system neoplasms occurring in children over a 39-year period, 467 were intracranial and 21 were intraspinal. The most common intracranial neoplasms were astrocytoma (28%), medulloblastoma (25%), ependymal neoplasm (9%), craniopharyngioma (9%), and glioblastoma multiforme (9%). The median age at diagnosis was 6 years with a male-to-female ratio of 1.3:1. Overall mean survival was 53.4 months and varied greatly relative to the type of tumor and the location. Of the intraspinal neoplasms the most frequently noted were the astrocytoma (47%) and the ependymal neoplasma (24%). The median age at diagnosis was 10 years with a male-to-female ratio of 1:1. The average survival from diagnosis (54.1 months) was comparable to that of intracranial neoplasms. Detailed analyses of each histological type of tumor relative to age at diagnosis, sex, anatomical location and survival from diagnosis are reported for both intracranial and intraspinal neoplasms.     

Cytogenetics of cranial base tumors

Summary Many different tumor types can arise in or invade the skull base. The more common tumors include, but are not limited to, angiofibromas, chondrosarcomas, chordomas, hemangiopericytomas, meningiomas, carcinomas, olfactory neuroblastomas, paragangliomas, pituitary adenomas, and rhabdomyosarcomas. Several of these tumors, including meningiomas, hemangiopericytomas, and rhabdomyosarcomas are characterized by nonrandom cytogenetic abnormalities. In this paper, we review the recognized chromosomal aberrations in cranial base tumors and illustrate the insights that can be gained into the genetic basis of tumor formation using karyotypes from skull base tumors that we have examined. As in tumors in other locations, chromosomal findings may be of diagnostic and prognostic value in cranial base tumors.     

Neuroimaging for central nervous system tumors

Advances in neuroimaging techniques have now provided clinicians with the ability to detect CNS neoplasms at an earlier stage and to measure responses to therapy. However, errors in performing or interpreting these studies can lead to erroneous conclusions that may subsequently influence therapeutic decisions. The exact delineation of areas of tumor involvement in the brain has improved with newer imaging techniques, but this too is problematic in some patients. Evaluations of response to treatment can also be complicated by technical artifacts that can lead to inadequate differentiation of tumor from non-neoplastic tissues. Nevertheless, MRI and CT have helped clinicians to redefine the natural history of CNS tumors, reach earlier diagnoses, improve the accuracy of radiotherapy, explain adverse treatment responses, and exclude conditions that are not related directly to the tumor but that can be responsible for clinical deterioration. Newer tests that have the ability to assess tumor metabolism will further increase our understanding of these pathological processes.     

Pathology and genetics of primary central nervous system and intraocular lymphoma

Ongoing studies based on gene expression profile analysis using microarrays have provided preliminary evidence for significant molecular distinctions between primary central nervous system lymphoma (PCNSL) and nodal lymphomas of the large B-cell type. The application of array-based comparative genomic hybridization techniques attempts to identify genomic distinctions between PCNSL and nodal lymphomas and to identify the molecular markers that relate to prognosis. It is possible that insights gained from these studies will facilitate the development of targeted therapies, which address the fundamental genetic mutations that drive PCNSL and intraocular lymphoma growth.     

Glioneuronal tumors of the central nervous system

Advances in the immunohistochemical detection of neuron-specific and neuronal-associated antigens have resulted in the discovery of neuronal elements in certain primary human brain tumors. The results have been not only to expand what neuropathologists commonly recognize as gangliogliomas, including the tumors now known as glioneurocytic tumor with neuropil rosettes and papillary ganglioneuroma, but also to expand the spectrum of tumor types to now include tumors such as central neurocytoma, dysembryoplastic neuroepithelial tumor, and desmoplastic infantile ganglioglioma. These discoveries have helped us to better understand the biology of these tumors and to refine our classification of them. Distinctions among these tumors include sites of predilection, such as the temporal lobe with the dysembryoplastic neuroepithelial tumors, and a spectrum of clinical aggressiveness that spans indolent “quasihamartomatous” lesions, such as the dysembryoplastic neuroepithelial tumor, to high-grade, highly aggressive tumors, such as the supratentorial primitive neuroectodermal tumor (World Health Organization Grade IV). Many of these tumors also commonly exhibit a glial component, as determined by both their histologic appearance and their immunoreactivity for glial fibrillary acidic protein. This review covers these recently described lesions, including the desmoplastic infantile ganglioglioma, the dysembryoplastic neuroepithelial tumor, the papillary glioneuronal tumor, the glioneuronal tumor with neuropil rosettes, and the mixed glioblastoma-cerebral neuroblastoma (supratentorial primitive neuroectodermal tumor), as well as the known tumors, ganglioglioma, medulloepithelioma, and medulloblastoma. For pathologists confronted by this growing array of tumors and subtypes, it is appropriate to focus on them and understand the differential diagnosis to be considered when confronted by them.     

Medulloblastomas and central nervous system primitive neuroectodermal tumors

Opinion statement Significant advances in the treatment of medulloblastoma and primitive neuroectodermal tumors have been made in the past three decades. Maximal surgical resection is a mainstay of therapy. However, unlike many other central nervous system neoplasms, medulloblastoma and primitive neuroectodermal tumors are radiation and chemotherapy responsive. Despite this response, the prognosis for patients with these tumors remains variable and is relatively poor in infants and patients with metastatic disease. These tumors most commonly arise in children, thus most clinical trials emphasize the reduction of long-term sequelae, in addition to improving survival. All newly diagnosed patients who are eligible should be offered participation in a clinical trial. If a patient is ineligible or declines consent/ assent for a clinical trial, the best current treatment approach is surgical resection, followed by radiation therapy (except for children younger than 3 years) with weekly vincristine. For high-risk patients, 36 Gy of craniospinal irradiation should be delivered plus a boost of 19.8 Gy to the posterior fossa/primary tumor bed and sites of bulk metastatic disease. For average-risk patients, the craniospinal irradiation dose may be lowered to 23.4 Gy plus 32.4 Gy to the posterior fossa/tumor bed. After radiation therapy, intensive multimodal chemotherapy should be used for all patients.     

Differentiation in embryonal neuroepithelial tumors of the central nervous system.

Ninety-six embryonal neuroectodermal tumors were studied histologically and immunohistologically with a panel of antibodies including glial, neuronal, epithelial, mesodermal, and myelin markers. In 71 tumors there was glial and neuronal differentiation and expression both of an S (photoreceptor) antigen and vimentin. In five tumors there was only glial differentiation and in 20 tumors only neuronal differentiation. No reactivity for myelin and epithelial markers was found. Histologic and immunohistologic findings identified various degrees of differentiation in different tumors, which was bipolar (glial and neuronal) in most tumors and unipolar in the remainder. The authors suggest that their findings may be the result of normal or aberrant oncogenic differentiation, agreeing with the nomenclature of the World Health Organization classification for these tumors with and the inclusion of a category for ependymoblastoma.     

Radiotherapy, hyperthermia, and phototherapy for central nervous system tumors.

Many new modalities and increasing data have become available in the treatment of brain tumors. We will review the growing experience with newer treatment modalities such as brachytherapy, radiosurgery, hyperthermia, and photodynamic therapy.     

Primary central nervous system germ cell tumors

Opinion statement The prognosis of primary germ cell tumors (germinal neoplasms) of the central nervous system varies, depending on the histology and size of tumor and the extent of disease at diagnosis. Although some patients receive therapy without a tissue diagnosis, it is strongly recommended that tumor tissue samples be obtained for accurate histologic diagnosis. Modern neurosurgical navigation techniques have made tissue sampling by stereotactic biopsy a safe and rapid method of determining tumor histology. Depending on tumor location, open surgical biopsy may be required in some patients. Typically, germinomas are exquisitely radiosensitive, although pre-irradiation chemotherapy reduces the total radiation exposure and may increase the cure rate. Induction cisplatin-based chemotherapy, followed by low-dose involved field radio-therapy, has excellent overall and relapse-free survival rates and is the optimal treatment for patients with germinomas. This combined chemoradiotherapy approach is associated with minimal endocrinopathy and minimal neurocognitive dysfunction. Patients with relapses after low-dose radiation therapy can respond well to salvage therapy (chemotherapy or chemoradiotherapy) without significant sequelae. Patients with nongerminomas respond best to chemotherapy combined with radiation, although the response and cure rates are lower compared to germinomas. Patients with residual masses and normal tumor markers after primary therapy should have a second-look resection because most patients have residual teratoma or necrotic tissue and can be spared additional chemotherapy or radiation. Pure mature teratomas are cured only by surgical extirpation. Immature central nervous system teratomas appear to benefit from radical surgical resection, but higher doses of locally directed radiotherapy are required with no benefit from the usual chemotherapy.