Werner Paulus

Primary central nervous system lymphomas—an update

SummaryPrimary CNS lymphomas (PCNSL), until recently representing about 1% of all brain tumors, show dramatically increased incidence both in high-risk groups (immunocompromised, AIDS) and in the general population. They are extranodal diffuse non-Hodgkins lymphomas, the morphology and classification of which are identical to those of systemic lymphomas, although PCNSL show different biological behavior and diagnosis according to the New Working Formulation and updated Kiel classification may be difficult. The majority are large B cell variants of high-grade malignancy; lowgrade subtypes and T cell lymphomas are rare. Sixty per cent occur in the supratentorial space (hemispheres, periventricular) and 12% in the posterior fossa; 30% are multiple (50%–70% in AIDS). PCNSL show a male preponderance with a peak incidence in the 5th–7th decade (3rd–4th in AIDS). The duration of diffuse or focal clinical symptoms averages 1–2 months. Computed tomography and magnetic resonance imaging scans show single or multiple or diffuse, often typical lesions. Diagnosis is achieved by evaluation of stereotactic biopsy material or cerebrospinal fluid cytology using immunocytological markers. Current therapy in immunocompetent patients, radiation plus corticosteroids and pre- or postradiation polychemotherapy, shows response rates of 85% with a median survival of 17–44 months, a prognosis similar to that for glioblastoma. Meningeal PCNSL is treated with intrathecal methotrexate or cytosine arabinoside. Transliquoral seeding of PCNSL is frequent, distant metastases occurring in 6%–8%. Therapy of AIDS-related PCNSL makes use of radiation and corticosteroids, and rarely of chemotherapy. The pathogenesis of PCNSL is unknown, but Epstein-Barr virus may be a contributory factor.

Clinico-pathological correlations in Parkinson's disease.

Based on comparative clinical and morphometric studies in 45 autopsy cases of Parkinsons disease (PD), 27 clinically presenting with akinesia and rigidity (AR-type), 18 with predominant resting tremor (T-type), the neurobiological basis of the major clinical subtypes in PD is discussed. The AR-type showed higher neuronal losses in locus coeruleus (LC) and in medial and lateral parts of substantia nigra (SNM, SNL), suggesting lesion patterns different from the T-type. More severe cell loss in the serotonergic dorsal raphe nucleus was observed in PD patients with depression than in non-depressed ones. Demented PD subjects showed higher cell loss in SNM than non-demented ones indicating dysfunction of the mesocortical dopamine system, and significantly more severe Alzheimer lesions in isocortex and hippocampus. These and other recent data from the literature indicate that some major clinical features of PD are related to lesions of distinct neuronal systems.

Pleomorphic xanthoastrocytoma: report of six cases with special consideration of diagnostic and therapeutic pitfalls.

BACKGROUND Pleomorphic xanthoastrocytoma (PXA) is a rare clinicopathologic entity that occurs typically in young patients. Improved neuroradiologic techniques, especially gadolinium-enhanced magnetic resonance imaging (MRI), reveal a characteristic tumor appearance. METHODS We present six cases of PXA operated on with unusual clinical course, elucidating different clinical implications. RESULTS Two patients showed subsequent progression into a malignant glioma, one case was a primary anaplastic PXA. The latter case had not previously been reported in the literature. Increased mitotic activity seems to indicate a worse clinical course; whereas focal infiltration of the brain does not necessarily lead to malignant transformation. CONCLUSIONS Surgical removal is the treatment of choice. A consequent follow-up is mandatory in order to detect a potentially malignant recurrence as early as possible and to select patients who need additional therapy.

Interphase cytogenetics of glioblastoma and gliosarcoma

Interphase cytogenetics, i.e., in situ hybridization using probes to chromosome-specific DNA, enables histological identification of cells bearing numerical chromosome aberrations and cytogenetic analysis of composite tumors. We studied routinely processed tissues from seven glioblastomas and three gliosarcomas using biotinylated probes to pericentromeric alpha-satellite sequences on chromosomes 10, 17 and X. By applying various pretreatment protocols, an evaluable compromise between morphology and signal intensity was obtained in most cases. Compared to vascular cells with normal chromosomal counts, a significant subpopulation of glioblastoma cells showed monosomy 10 (four of five cases), monosomy 17 (one of seven cases) and loss of one X chromosome (one of seven cases). All monosomy 10 cases comprised additional areas where two copies of chromosome 10 were retained. Among the gliosarcomas, both the glioma and the sarcoma portion showed monosomy 10 in one case and monosomy 17 in another case. In contrast, in the third case of gliosarcoma, monosomy 10 was found only in the glioma portion, whereas a gain of chromosome X was observed in the sarcoma portion. We conclude that: (1) numerical chromosome aberrations can be detected in routinely processed brain tumor biopsy specimens using interphase cytogenetics, making retrospective studies feasiblel (2) glioblastomas show intratumoral cytogenetic heterogeneity with formation of monoclonal cell clusters; and (3) sarcoma and glioma elements in gliosarcomas may exhibit the same or different numerical chromosome aberrations, suggesting various histogenetic pathways of the sarcoma-like portion.

Ki-M1P as a marker for microglia and brain macrophages in routinely processed human tissues

SummaryThe monoclonal antibody Ki-M1P recognizes a formalin/paraffin-resistant differentiation epitope of monocytes and their macrophage derivatives [Radzun et al., Lab Invest 65:306, 1991]. To evaluate its usefulness for neuropathology, we examined a variety of routinely processed tissues using immunohistochemistry. In normal brains, positivity was restricted to ramified microglial cells. Intense labeling of macrophages, ramified and ameboid microglial cells, and rod cells was seen in brains with various degenerative and inflammatory disorders. Astrocytes were negative as determined by double-immunofluorescence labeling using Ki-M1P and anti-glial fibrillary acidic protein (GFAP). Histiocytic lesions (histiocytosis X, xanthogranulomas, granulomatous inflammation) were immunopositive. Among 107 tumors, reactivity of Ki-M1P was observed with some schwannoma and meningioma tumor cells. In addition to macrophages, most gliomas contained small, elongated Ki-M1P-positive cells, which were negative for GFAP. Positivity was also found in two glioblastoma cell lines. Immunoblotting performed on spleen, meningioma and glioblastoma specimens revealed one to three bands in the range of 110 to 130 kDa. We conclude that Ki-M1P can serve as a reliable marker for brain macrophages and microglial cells in routinely processed normal and non-neoplastic tissues, whereas due to the unexpected immunoreactivities results obtained with neoplastic tissues should be carefully interpreted.

Comparison of integrin adhesion molecules expressed by primary brain lymphomas and nodal lymphomas

The expression of 17 adhesion molecules was immunohistochemically examined in 5 primary cerebral lymphomas (PCL) and in 5 histologically similar nodal lymphomas (NL) to evaluate their possible involvement in selective targeting of lymphoma cells to the brain. PCL and NL tumor cells showed very similar expression patterns: they were consistently positive for α3, α4 and β1 integrin chains; negative for α2, α6, β3 and β4 integrin chains; and heterogeneous for α5, αL, αM, αX, β2 and β7 integrin chains, as well as for intercellular adhesion molecule-1 (ICAM-1) and the selectin LECAM-1. Loosely infiltrating PCL showed lower levels of the αLβ2 integrin than compact cell clusters. Vessels stained for ICAM-1 and vascular cell adhesion molecule-1 (VCAM-1). We conclude that the adhesion molecules implicated in the extravasation of non-neoplastic leukocytes (α4β1/VCAM-1 and αLβ2/ICAM-1) are also expressed by both PCL and NL. The adhesion molecules examined are apparently not selective mediators of lymphoma cell homing to the brain, but at least αLβ2 integrin might be related to the infiltration pattern of PCL within the brain parenchyma.

Interactions of glioma cells and extracellular matrix

SummaryThe communication between tumor cells and extracellular matrix (ECM) is responsible for clinically important features of malignant gliomas, such as cerebral invasion and leptomeningeal spread. The synthesis of ECM components, ECM-degrading activities and ECM receptors as well as the interaction between ECM components and their receptors represents the molecular basis for these processes. Recent studies have shown that proteases and integrins, the major group of ECM receptors, may be over-expressed by astrocytic tumor cells. Furthermore, integrins and the hyaluronate receptor CD44 have been found to be involved in adhesion and basement membrane invasion of glioma cells. Critical issues which are poorly understood so far include the ECM composition of the normal human brain and of brain tumors, the function of individual ECM components and receptors in a neuro-oncological context, and the molecular processes mediating the diffuse invasion of glioma cells into the brain.

Microglial reaction in Pick's disease

Number and morphology of microglial cells (MC) were compared in 6 cases each of Picks disease (PD), Alzheimers disease (AD) and controls using immunohistochemistry with the monoclonal antibody Ki-M1P. The severely involved neocortex of both PD and AD, and in particular the white matter subjacent to spongy PD lesions showed a marked increase of MC density, whereas non-affected PD areas and AD white matter showed no MC changes. The PD hippocampus, particularly the dentate gyrus, showed reduction of MC density and processes. We conclude that (1) MC reaction represents a major element of PD histopathology, and (2) density, morphology and distribution of MC are different in AD and PD.

Mesenchymal, IMon-Meningothelial Tumors of the Central Nervous System

The spectrum of non‐meningothelial mesenchymal tumors that may arise within the central nervous system is presented, based on the current classification of soft tissue tumors. Among malignant types, hemangiopericytoma, rhabdomyosarcoma, mesenchymal chondrosarcoma, and malignant fibrous histiocytoma are the most frequent ones. Rare tumor entities are mentioned. As in soft tissue sarcomas, diagnosis is mainly based on light and electron microscopy, while immunohistochemistry can improve accuracy of diagnosis.

Progesterone Receptors in Tumor Fragment Spheroids of Human Meningiomas

Progesterone receptors (PgR) are detectable in about 60-70% of tissue specimens of human meningiomas. Despite these data, PgR are hardly to be found in monolayer tissue culture of meningiomas. Aim of this study was to elucidate whether PgR might be preserved in tumor fragment spheroids of meningiomas maintained in organ culture since the morphological appearance of the original tumor is preserved by this culture technique. Aliquots of meningioma specimens of 25 patients (17 females) were snap frozen in liquid nitrogen immediately after removal. Additionally, monolayer tissue cultures of the same specimen were obtained as primary culture and passage #3. Tumor fragment spheroids were kept on medium-agar with liquid medium overlay and harvested after 1 and 3 weeks in culture. PgR were detected by immunohistochemistry using a rat monoclonal antibody. 18/25 meningioma tissue specimens were positive for PgR. In 8 out of 15 PgR-positive tumors which formed spheroids we could detect PgR in fragment spheroids after 1 and 3 weeks in culture. In contrast, none of the monolayers depicted PgR. PgR is preserved in a considerable amount of tumor fragment spheroids of PgR-positive meningiomas. They remain detectable after 3 weeks of culture whereas monolayer tissue cultures are PgR-negative. Thus, tumor fragment spheroids seem to be a suitable tool to investigate progesterone/antiprogesterone effects in vitro.