The most common chromosomal abnormality in medulloblastomas is iso-chromosome 17q, in which most of the short arm is lost from two chromosomes 17 and they are then fused head-to-head producing a chromosome with two centromers, little 17p and two 17q arms.
This is observed in 30–50% of cases by using cytogenetic techniques. These findings have been confirmed by CGH and molecular genetic studies. Many other chromosomal aberrations have been identified using conventional cytogenetic, CGH or molecular genetic techniques—for example, loss of 10q (35%). In addition, several growth and transcription factors have been investigated, some reporting high expression in a subset of tumours for example, erbB2&4.
A major contribution to our understanding of medulloblastoma biology has come from the study of two genetic syndromes exhibiting a predisposition to medulloblastoma formation. Gorlin’s syndrome (hereditary naevoid basal cell carcinoma syndrome) and familial adenomatous polyposis (FAP) syndrome arise from mutations in the PTCH (9q) and APC (5q) genes, respectively, and both are associated with medulloblastoma formation.
The gene products of these two genes take part in two interconnected pathways that are fundamental to neural development and cell turnover. Hemizygous loss and mutations in the retained allele of PTCH in sporadic medulloblastomas have been shown. However, alterations in the PTCH and APC genes as well as other genes coding for components of these two pathways are involved in the development of less than 15% of sporadic medulloblastomas.
Other genes involved in the two pathways, including SMO and SUFU, have been studied and also show loss of wild type in only single, isolated cases. Other genes currently being investigated for their significance in medulloblastoma biology are the myc family and the PDGF receptors and ligands.
COMMON ADULT TUMOURS
Diffuse astrocytic tumours
The adult diffuse astrocytic tumours include the astrocytomas (malignancy grade II), the anaplastic astrocytomas (malignancy grade III), and the glioblastomas (malignancy grade IV). The astrocytoma malignancy grade II tumours have a peak incidence between 25 and 50 years of age, while the glioblastomas have a peak incidence between 45 and 70 years.
All are more common in males and most are located in the cerebral hemispheres. Glioblastomas are the most common form and are divided into those that develop from a previously diagnosed tumour of lower malignancy grade and those that appear to develop de novo. Both clinical and molecular data support the hypothesis that these tumours may develop from the mutation of different genes but affect the same cellular pathways.
The relevance of the histologically based malignancy grading scheme is indicated by patient survival. Patients with an astrocytoma (malignancy grade II) have an average survival of approximately seven years, patients with anaplastic astrocytomas have a median survival half that time, while glioblastoma patients have an average survival of between 9–11 months.
This is despite the best currently available treatments. The astrocytomas (malignancy grade II) and anaplastic astrocytomas have been well documented to progress to tumours of higher malignancy grade. The tumour cells of astrocytomas (malignancy grade II) resemble astrocytes, show little nuclear atypia, and have extensions producing a loosely textured matrix (fig 4). They generally express S-100 protein and glial fibrillary acidic protein.
Anaplastic astrocytomas (malignancy grade III) show increased cellularity but the tumour cells still show histological and immunocytochemical characteristics of astrocytes. The tumour cells are more pleomorphic than found in astrocytomas, show distinct nuclear atypia, and there is mitotic activity.
No evidence of spontaneous tumour necrosis or abnormal microvascular proliferation is permitted in anaplastic astrocytomas. Glioblastomas (malignancy grade IV) are more cellular than the anaplastic astrocytomas. The tumour cells show a wide spectrum of morphologies, can be very pleomorphic with giant forms, but generally retain some of the phenotypical characteristics of astrocytes.
Mitosis, spontaneous tumour necrosis with pseudopalisading of tumour cells, as well as florid endothelial proliferation, are inevitably found in some areas of a well sampled tumour (fig 4). A large central necrotic area with a ring-like zone of contrast enhancement, representing the viable tumour tissue, can often be identified by neuroimaging.
