Case 2 -

Astrocytoma, Grade 4 of 4 (WHO) Timothy Smith and Cynthia Welsh

High grade astrocytic tumors in adults can be seen at all ages, but tend to be more common with increasing age. The majority, as with most adult tumors, are supratentorial. On MRI scans, high grade tumors enhance and glioblastomas (GBM) usually enhance around necrosis (ring-enhancement). Glioblastoma is WHO grade 4 of 4. The differential diagnosis for the usual "ring-enhancing" lesion in an elderly adult consists of glioblastoma, metastasis, abscess, and lymphoma. During the intra-operative consultation, glial tumors are often designated as low or high grade glioma, with grades 3 and 4 considered together, and astrocytic lumped with oligodendroglial. Usually this information is enough for the neurosurgeon, although clinical research protocols may require more, such as being able to say "GBM"; this may necessitate additional tissue. As glial tumors increase in grade, nuclear differences between astrocytic and oligodendroglial tumors start to blur. Vessels become more alike also. A higher grade is usually heralded microscopically by increased cellularity and mitoses first. Generally the complex microvascular changes and necrosis are later than (in addition to) the mitoses. The mitoses, vascular changes, and necrosis can all be seen on both tissue sections and smears. There are many variants of GBM such as giant cell, spindle cell, and small cell (which can be mixtures), and therefore many malignant metastatic tumors enter the histologic differential. They all show astrocytic differentiation, which may show better on smears, because the processes may be better defined. Even gemistocytic astrocytomas have processes. Astrocytic tumors have finer chromatin than metastases. They may have chromocenters, but nucleoli if present at all should be inconspicuous (as opposed to many metastases). Metastatic tumors form clumps and are often accompanied by at least some neuroglial tissue (which has a fine fibrillated background), and will give the impression of two populations of tissue if both are present on smears. The complex microvascular changes in a smear are spread out into arborizing structures rather than being all cropped at a single level as in a tissue section. In both preparations, tumor cells tend to cling to the vessels. Abscesses also can have ring-enhancement, many mitoses, reactive blood vessels to be confused with tumor vessels and bizarre astrocytes. But the vessels within the brain are pushed aside by an abscess and are reactive not "glomeruloid", the reactive astrocytes have abundant cytoplasm, the level of inflammation is way over and above that of a GBM, and the GBM has a shaggier wall of enhancement. Metastases have a mass effect much more significant than their size alone would predict because of the surrounding edema, which is much more than seen with a primary tumor. They have a pushing border, not the T2-weighted infiltrative borders seen with primary tumors. Metastases tend to be multiple, but the smaller ones may not yet be in evidence at original presentation, while the GBM can have multiple sites of proliferation which mimic multifocality. The T2 and FLAIR images distinguish metastases from GBM. The metastasis will not generally show more than very little tendency to infiltrate at the edges on frozens and will show two cell populations on the smears (gliotic brain and balls of tumor usually). Primary CNS lymphomas may enhance, and if they do, it may be solid or ring-enhancement. They tend to be periventricular and are frequently multifocal. The peripheral zones of the tumor usually show "perivascular cuffing" which can be mistaken for "secondary structures of Scherer" – astrocyte tumor cells around vessels, or the other complex microvascular structures typical of high grade glioma. The central areas with sheets of back-to-back cells show nuclei generally larger than those of GBM with less nuclear membrane irregularities and nucleoli that are conspicuous. Single cell necrosis is typical, something not classical for GBM. Smears show the coarse chromatin, prominent nucleoli, and lack of processes better than frozen sections, and diff quik stains in particular highlight the lymphoid features. PML (progressive multifocal leukoencephalopathy) can have some of the most bizarre astrocytes you will ever see and necrosis is expected. It is not unusual for PML to appear to follow white matter tracts. But the macrophages and even distribution of the astrocytes should have you searching for infected oligodendroglial nuclei. Acute MS (multiple sclerosis) may show considerable necrosis. The lesions can be incredibly mitotically active in areas and show considerable reaction from surrounding vessels. But, this will be accompanied by macrophages, perivascular cuffs of lymphocytes and evenly scattered (though perhaps large and juicy) astrocytes. Infarcts may be mistaken on CT for tumor. At some point in time they will enhance around the central necrosis. The macrophages present at this point in time, or red neurons if it is earlier (and they are present) will make this diagnosis for you. PXA (pleomorphic xanthoastrocytoma) is a low grade tumor with enough pleomorphism that limited samples may be in the differential of GBM. The PXA is non-infiltrative on radiology and tissue sections; if the boundary with adjacent brain isn't available in the frozen section, the MRI scans will clinch the issue. Therapeutic effects in previously diagnosed gliomas include macrophages becoming prominent, vessels becoming hyalinized and possibly less cellular appearing, necrosis in areas of tumor (or surrounding brain) which aren't very cellular, a paucity of mitoses, and occasionally increased numbers of truly bizarre astrocytic nuclei with intranuclear cytoplasmic pseudoinclusions. Differential features of necrosis Dead vessels - GBM Pseudopalisading - GBM Pseudopapillary - metastasis Coagulative - tumor Liquefactive - infection or infarct Inflammation - neutrophils and/or macrophages should raise non-neoplastic "flags" Patterns of enhancement GBM - irregular "shaggy" ring enhancement Abscess - thinner, more uniform ring-enhancement Lymphoma - variable