In considering this subject, one of the first problems is with the definition of neoplasia. It is well known that a number of lesions may simulate brain tumors in their clinical manifestations and histologic appearance but are really developmental hamartomas and not true neoplasms. A hamartoma is a “tumor-like formation that has its basis in maldevelopment” (Russell) and undergoes little change during the life of the host. The difficulty one encounters in distinguishing it from a true neoplasm, whose constituent cells multiply without restraint, is well illustrated by tuberous sclerosis and von Recklinghausen neurofibromatosis, where hamartomas and neoplasms are both found. Similarly, in a number of mass lesions—such as certain cerebellar astrocytomas, bipolar astrocytomas of the pons and optic nerves, von Hippel-Lindau cerebellar cysts, and pineal teratomas—a clear distinction between neoplasms and hamartomas is often not possible.
The understanding of the pathogenesis of brain tumors has evolved greatly. Johannes Müller (1838), in his atlas Structure and Function of Neoplasms, first enunciated the appealing idea that tumors might originate in embryonic cells left in the brain during development. This idea was elaborated upon by Cohnheim in 1878, who postulated that the source of tumors was an anomaly of the embryonic anlage. Ribbert, in 1904, extended this hypothesis by postulating that the potential for differentiation of these stem cells would favor blastomatous growth, an idea that has now been resurrected.
For many years, thinking about the pathogenesis of primary CNS tumors was dominated by the histogenetic theory of Bailey and Cushing, which was based on the assumed embryology of nerve and glia cells. Although it is no longer held to be valid, Bailey and Cushing attached the suffix blastoma to indicate all tumors composed of primitive-looking cells, such as glioblastoma and medulloblastoma. One prominent theory was that most tumors arise from neoplastic transformation of mature adult cells (dedifferentiation). A normal astrocyte, oligodendrocyte, microgliocyte, or ependymocyte is transformed into a neoplastic cell and, as it multiplies, the daughter cells become variably anaplastic, more so as the degree of malignancy increases. (Anaplasia refers to the more primitive undifferentiated state of the constituent cells.)
In fact, the cells of origin of the major types of brain tumors have not been unequivocally identified or, in many cases, they appear to arise from pluripotential stem cells that reside in the brain, a concept not known in Bailey’s time. If this is indeed the case, it may be that the apparent dedifferentiation of both the cells of origin and of tumor cells is not a fundamental property of brain tumors.
The factor of age plays a central role in the biology of brain tumors. Medulloblastomas, optic nerve gliomas, and pinealomas occur mainly before the age of 20 years, and meningiomas and glioblastomas are most frequent in the sixth decade of life. A number of mutations, some somatic and some inherited, underlie the genesis of certain tumors, particularly retinoblastomas, neurofibromas, and hemangioblastomas. The gliomas associated with neurofibromatosis and tuberous sclerosis and the cerebellar hemangioblastomas of von Hippel-Lindau are the best examples of a germline determinant. The rare familial disorders of multiple endocrine neoplasia and multiple hamartomas are associated with an increased incidence of anterior pituitary tumors and meningiomas, respectively. Glioblastomas and cerebral astrocytomas have also been reported occasionally in more than one member of a family and with one exception so far (POT1, Bainbridge et al); the study of such families has not disclosed the operation of an identifiable genetic factor.