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A 42-year-old man presented with progressive change in personality, confusion, and difficulty walking. MRI of the brain showed diffuse high T2 signal throughout the white matter bilaterally, with only focal enhancement. Following a brain biopsy, he received radiation therapy but declined neurologically and died 30 months after initial diagnosis. At autopsy, the deep cerebral white matter was expanded bilaterally and the gray-white junction was indistinct.
Archive Case and Diagnosis:
This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2007, Case 8 and is a gliomatosis cerebri.
Criteria for Diagnosis and Comments:
The diagnosis in this case is gliomatosis cerebri (GC). GC is a diffusely infiltrating glial tumor which involves more than two lobes, is frequently bilateral, and often extends into infratentorial structures. As such, correlation with clinical and radiographic findings is necessary to make an antemortem diagnosis. MRI with T2-weighted or FLAIR images is the most sensitive modality for diagnosis, revealing diffuse hyperintensity in more than two lobes. Recent studies have also suggested that magnetic resonance spectroscopy may be of value in diagnosis. Clinically, patients present with the insidious onset of headaches, seizures, corticospinal tract deficits, altered mental status and/or dementia.
Pathologically, GC most often involves the cerebral hemispheres (76% of cases), with the centrum semiovale always involved and less frequent infiltration of the cortex (19%) and leptomeninges (17%). The mesencephalon and pons are involved in 52% of cases, thalamus in 43%, basal ganglia in 34%, cerebellum in 29%, medulla oblongata in 13% and the spinal cord in 9%. Grossly, there is diffuse expansion of the white matter with loss of gray-white matter demarcation and relative preservation of the underlying architecture. In the classical form, designated type I by WHO, no circumscribed tumor masses are present. A secondary circumscribed tumor mass, usually with malignant features, may develop in some cases, classified as Type II GC by the WHO. Histologically, GC is characterized by diffuse white matter infiltration by elongated glial cells, which often form parallel rows among nerve fibers in myelinated tracts. Myelin sheaths may be destroyed, but axons and neurons are preserved. When the cortex is involved, perineuronal satellitosis and subpial infiltration may be prominent. The neoplastic cells have ovoid, hyperchromatic nuclei with indistinct nucleoli and mitotic activity is variable. In some cases, gemistocytic tumor cells may be present. In most cases, the neoplastic cells appear to be astrocytic, although they may be GFAP-negative. A smaller percentage of cases (22% in men and 13% in women) exhibit an oligodendroglial morphology and/or genotype. Some cases may exhibit TP53 mutations or p53 nuclear protein accumulation, similar to diffuse astrocytomas, but other molecular genetic alterations are rare. Chromosomal analysis suggests a clonal origin, with the findings not being typical of astrocytoma. As such, GC is classified under “Glial tumors of uncertain origin” by the WHO. The prognosis in GC is poor and it has been classified as WHO grade III. In a recent study, median survival was 14.5 months, with longer survival (36 months) for the oligodendroglial type. Infratentorial involvement and higher Ki-67 labelling index are associated with shorter survival. Some patients show a benefit from chemotherapy or whole brain radiotherapy.
In the current case, the neoplastic cells have an astrocytic appearance, with elongate, hyperchromatic nuclei in a fibrillary background. As such, the diagnosis of oligodendroglioma, which has uniform, round nuclei, is excluded. Although nuclear pleomorphism is present, this neoplasm lacks the mitotic activity seen in anaplastic astrocytoma and the vascular proliferation and necrosis seen in glioblastoma. Further, the radiologic and autopsy findings, with diffuse, bilateral white matter involvement, support the diagnosis of GC rather than diffuse astrocytoma. Late-delayed radiation necrosis, which usually develops 6 months to 2 years after completion of therapy, is characterized by white matter necrosis, fibrinoid angionecrosis, glomeruloid vascular proliferation, thickening and fibrosis of vascular walls, and reactive gliosis. Although this lesion may extensively involve white matter, it is usually contrast enhancing. Further, the current case lacks the necrosis and vascular changes seen with radiation necrosis.