Faculty Bibliography

Quantitative determination of the degree of vascularity has been shown to be independently prognostically significant in many human tumor types. In particular, tumor vascularity has known importance in astrocytomas, in which endothelial proliferation is a criterion for anaplasia in many grading schemes. This chapter summarizes the known associations of quantitated microvessel parameters obtained from histologic sections of human brain tumors with clinical outcome, or other pathobiologic factors that have been examined. Among the conclusions are 1) brain tumors have the unique feature of complex "glomeruloid" vessels, as well as heterogeneity of microvascular distribution and caliber; 2) lower-grade astrocytomas incorporate pre-existing vessels, while glioblastomas develop new vessels; 3) quantitation may have additional independent prognostic value over and above routine histologic grade in low-grade astrocytomas with low tumor cell proliferative indices. These findings have implications for the appropriateness of antiangiogenic therapies

Periventricular leukomalacia (PVL), the major substrate of cerebral palsy in survivors of prematurity, is defined as focal periventricular necrosis and diffuse gliosis in immature cerebral white matter. We propose that nitrosative and/or oxidative stress to premyelinating oligodendrocytes complicating cerebral ischemia in the sick premature infant is a key mechanism of injury interfering with maturation of these cells to myelin-producing oligodendrocytes and subsequent myelination. Using immunocytochemical markers in autopsy brain tissue from 17 PVL cases and 28 non-PVL controls, we found in the PVL cases: 1) selective regionalization of white matter injury, including preferential involvement of the deep compared to intragyral white matter; 2) prominent activation of microglia diffusely throughout the white matter; 3) protein nitration and lipid peroxidation in premyelinating oligodendrocytes in the diffuse component; 4) preferential death of premyelinating oligodendrocytes diffusely; and 5) virtual sparing of the overlying cerebral cortex, as demonstrated by markers of activated astrocytes and microglia. These data establish that PVL is primarily a white matter disease that involves injury to premyelinating oligodendrocytes, potentially through activation of microglia and release of reactive oxygen and nitrogen species. Agents that prevent nitrosative and oxidative stress may play a key role in ameliorating PVL in premature infants in the intensive care nursery.

OBJECTIVE: We encountered 3 organizing tentorial hematomas simulating posterior fossa lesions such as Dandy-Walker, dermoid, or arachnoid cysts. We sought to correlate the clinical and pathologic features that allow distinction of developmental cysts from hematomas in the posterior fossa on imaging. METHODS. Prenatal sonograms in all fetuses and fetal magnetic resonance scans in 2 of the 3 were reviewed. One case proceeding to term had serial imaging up to age 11 months. Two cases had complete neuropathologic evaluation after termination. Maternal records were reviewed. RESULTS: In each case, the ultrasonographic findings were reminiscent of a developmental cyst but with echogenic debris, a rim, or both. Magnetic resonance imaging suggested tentorial hemorrhage in 2, 1 also with falcine hemorrhage. Serial prenatal and postnatal imaging showed resolution in the surviving case. Pathologically, 2 fetuses had organizing tentorial hematomas causing brain displacement. Calcifications, white matter damage, germinal matrix hemorrhage, and brain stem necrosis were also present. One mother had von Willebrand disease. CONCLUSIONS: Tentorial hematomas, with or without maternal coagulopathy, should be considered in the prenatal ultrasonographic diagnosis of cystlike posterior fossa abnormalities containing echogenic material. Fetal magnetic resonance imaging can suggest blood products. Hypoxic-ischemic brain damage may be concurrent; however, resolution of the hematoma, with no apparent neurologic sequelae, can occur.

Glioblastomas only rarely metastasize to sites outside the central nervous system, for reasons that are poorly understood. We report the clinicopathological and molecular genetic findings in 6 patients with metastatic glioblastoma. Four patients were under the age of 32 and all but 1 patient died within 2 yr of diagnosis. The number of metastases ranged from 1 to 3. At the time of death, 3 patients had apparent tumor control at their primary site. We evaluated DNA from both primary and metastatic glioblastomas for genetic alterations commonly found in glioblastomas: TP53 mutations, CDKN2A/p16 deletions, EGFR amplification, and allelic loss of chromosomes 1p, 10q and 19q. Four of 6 cases had TP53 mutations and only single cases had EGFR amplification, CDKN2A/p16 deletions, or allelic loss of 1p, 10q and 19q; 2 cases had no detectable genetic alterations. In 2 cases, the primary and metastatic tumors had identical genotypes. Remarkably, however, 2 cases had different TP53 alterations in the primary and metastatic lesions, or among the metastatic tumors, which suggests that some metastatic deposits may represent emergence of subclones that were not necessarily dominant in the primary tumor. The present observations and a review of the recent literature demonstrate that metastatic glioblastomas tend to occur in younger adults who do not follow long clinical courses, and may be characterized by TP53 mutations and differential clonal selection.

Quantitative determination of the degree of vascularity has been shown to be independently prognostically significant in many human tumor types. In particular, tumor vascularity has known importance in astrocytomas, in which endothelial proliferation is a criterion for anaplasia in many grading schemes. This review analyzes reports of microvessel quantification performed on histologic sections of human brain tumors, and in which correlations with clinical outcome, or other pathobiologic factors have been made. Among the conclusions are: (1) brain tumors have the unique feature of complex 'glomeruloid' vessels, as well as heterogeneity of microvascular distribution and caliber; (2) lower-grade astrocytomas may incorporate pre-existing vessels, while glioblastomas may develop new vessels; (3) quantification may have additional independent prognostic value over and above routine histologic grade in low-grade astrocytomas with low tumor cell proliferative indices. These findings have implications for the appropriateness of antiangiogenic therapies.

OBJECTIVE: It is not well appreciated that the clinical presentation of amyloid myopathy can mimic that of polymyositis. By retrospective clinicopathologic analysis we determined distinctive features of amyloid myopathy that differentiate the 2 diseases. METHODS: Two patients with clinical and histologic evidence of an inflammatory myopathy had fatal outcomes despite appropriate treatment for polymyositis. Their clinical course and original pathologic specimens were reviewed. In addition, original tissue samples were obtained and analyzed using Congo red staining and immunoperoxidase. RESULTS: The initial diagnosis of polymyositis was supported in both cases by muscle biopsies showing inflammatory infiltrates and elevations of creatine phosphokinase and by classic electromyography. Retrospective evaluation of the initial muscle biopsies disclosed subtle but incontrovertible evidence of vascular amyloid. Further analysis of the original specimens confirmed the presence of immunoglobin light chain (AL) amyloid. CONCLUSION: Amyloid myopathy can mimic polymyositis. Both can have similar clinical symptoms, as well as inflammatory infiltrates on muscle biopsy. Failure to recognize amyloid myopathy deprives patients of potentially life prolonging treatment. Congo red staining and immunohistochemical analysis of tissue could prevent misdiagnosis.