Diagnostic utility of IDH1- and p53-mutation analysis in secondary gliosarcoma.

We report on a 47-year-old woman in whom an anaplastic astrocytoma was resected in 2006. Postoperative radiation had to be interrupted because of a wound infection necessitating explantation of the infected bone flap and implantation of a titanium mesh. Subsequently, radiation therapy was completed and temozolomide was administered for 45 cycles. In the beginning of 2010 a new contrast enhancing mass was seen in the former tumor region. The mass was subtotally excised and showed no histomorphological similarity to the first lesion but represented a highly pleomorphic and mainly sarcomatoid differentiated malignant tumor. The lack of expression of GFAP or MAP-2 raised the question of a secondary malignancy, however, molecular genetic analysis of IDH1 and p53 revealed the same mutations in the anaplastic astrocytoma from 2006 as in the sarcomatoid tumor operated in 2010. Furthermore, accumulation of mutated IDH1 and TP53 protein could be demonstrated immunohistochemically. Thus, the second tumor represented the rare instance of recurrence of an anaplastic astrocytoma as a secondary gliosarcoma and a second malignant neoplasm was ruled out. The postoperative therapy and the inflammation might have contributed to the severe change in morphological phenotype of the glioma.

Precursor T-lymphoblastic lymphoma within a recurrent pituitary adenoma.

Only single examples of lymphoma associated with pituitary adenoma have been reported. In our patient, a precursor T-lymphoblastic lymphoma developed within a recurrent pituitary adenoma 17 years after the first resection. Histomorphologically, lymphoma and adenoma components were tightly admixed. The features harbour remarkable similarity to the previous report by Kuhn et al.. In both patients the lymphomas were composed of T-cells, there was no evidence of further sites involved, and both adenomas expressed follicle-stimulating hormone. The hormone may have posed a proliferative and transforming effect on lymphatic cells and could have played a crucial role in "lymphomagenesis" as an exceptional phenomenon.

Long-term results with Matrix coils vs. GDC: an angiographic and histopathological comparison.

INTRODUCTION: The aim of the study was to compare standard platinum Guglielmi detachable coils (GDC) with coated platinum coils (Matrix; both Boston Scientific, Fremont, CA) regarding handling, complications, occlusion and recanalization rate after 3 and 6A months. METHODS: Aneurysms in the right common carotid artery were created in 25 rabbits. The animals were divided into five groups of five animals each. The animals of group 1 (the control group) received no treatment of the induced aneurysms, the animals of groups 2 and 3 (killed at 3 and 6A months) were treated with standard GDC, and the animals of groups 4 and 5 (killed at 3 and 6A months) were treated with Matrix coils. RESULTS: Histopathological evaluation showed organized thrombus formation and connective tissue with neovascularization around the implanted coils in all the treated groups. The achieved occlusion rates in groups 2 and 3 were identical to those in groups 4 and 5. Thus the long-term results of aneurysm treatment with GDC and Matrix coils show no differences regarding occlusion and recanalization rates. The only noticeable difference was the difference in handling. More force was required to pushing the Matrix coils forward through the microcatheter and there was more friction in coil interaction in the aneurysm. CONCLUSION: The bioactive coating of the Matrix coil produces no significant benefit in achieving higher occlusion and lower recanalization rates, and the coil is more difficult to handle. Future bioactive coils must be shown to produce significantly better long-term results than GDC and their ease of handling has to be improved.

[Classification and documentation of diffuse gliomas]. / Klassifikation und Dokumentation diffuser Gliome.

Most current grading systems of diffuse gliomas are based solely on the microscopic evaluation of surgical specimens and the TNM classification does not have a value for brain tumors. Here additional parameters are presented, which are suitable for a classification and documentation of diffuse gliomas. As additional parameters to the WHO typing and grading we discuss age groups, different tumor devolutions, circumstances such as a second malignant neoplasm or hereditary tumors, tumor expansion based on anatomically defined brain regions, Karnofsky Scale, eloquence of the brain regions, diag-nostic certainty and informativity of tissue samples. This work shows that clinical data and imaging studies can contribute substantially to the classification of diffuse gliomas. The additional parameters presented here constitute a significant improvement of glioma documentation. Especially complex courses of long duration and repeated therapeutic interventions can be better surveyed and digitally processed.

Proximal chromosome 11p contiguous gene deletion syndrome phenotype: case report and review of the literature.

The proximal chromosome 11p contiguous gene deletion syndrome (P11pDS), also known as Potocki-Shaffer syndrome (PSS) or DEFECT 11 (OMIM 601224), is a disorder associated with foramina parietalia permagna and multiple osteochondroma (exostoses). Additional features include mental retardation, craniofacial anomalies, seizures and genitourinary abnormalities. Here, clinico-pathological findings of a unique patient with all of these features and, additionally, enlarged ventricles, hypertrophic obstructive cardiomyopathy and adipositas are described. The brain showed malformative lesions with hallmarks of disturbed bulk growth including micrencephaly, periventricular nodular heterotopias and focal cortical dysplasia in the nodulus of the cerebellar vermis. In addition, symmetric foci with vacuolation of the underlying neuropil, intermingled macrophages and large bizarre, partially vacuolated, reactive astrocytes were found. The proximal short arm of chromosome 11 harbors several candidate genes that could explain the patient's signs and symptoms including ALX4 and EXT2, which are always present in the interstitial deletion of the short arm of chromosome 11 in PSS. In addition, MYBPC3 would be a good candidate for the hypertrophic cardiomyopathy. Furthermore, adipositas might be related to the MAPK8IP1 gene. To the best of our knowledge, the present patient is the oldest one so far described with PSS phenotype and the only case that has undergone detailed neuropathological investigation.

Altered expression of beta-catenin/E-cadherin in meningiomas.

AIMS: Meningiomas are generally slow-growing benign tumours representing approximately 20% of all primary intracranial tumours. The hallmark of tumorigenesis of meningiomas is the loss of chromosome 22, including loss of heterozygosity of the neurofibromatosis type 2 (NF2) gene. The NF2 encoded protein merlin appears to function as a tumour suppressor gene by controlling cadherin-mediated cell-cell adhesion. The E-cadherin cell adhesion system includes beta-catenin that indirectly connects cadherin to actin filaments. The aim of this study was to analyse the expression and the subcellular location of E-cadherin and beta-catenin in human meningiomas, including meningiomas of different histomorphological subtypes and different World Health Organization (WHO) grades. METHODS AND RESULTS: Immunohistochemical analysis revealed lack of E-cadherin expression at the cell membrane in 34% of meningiomas independent of their WHO grade. Loss of membranous beta-catenin occurred in 79% of meningiomas. An intense perinuclear granular immunoreactivity of beta-catenin without nuclear location was detected in the majority of meningiomas. Both immunofluorescence and Western blot analysis of fractionated meningioma cells located beta-catenin mostly on the Golgi apparatus and ER/Golgi intermediate compartment (ERGIC). Cytogenetic analysis of meningiomas showed no correlation between NF2 loss and the loss of the proper location of beta-catenin. CONCLUSIONS: The lack of membranous beta-catenin and/or membranous E-cadherin in meningiomas may indicate an altered interaction between meningioma cells independent of loss of NF2 and independent of the tumour grade.

Automated nuclear segmentation in the determination of the Ki-67 labeling index in meningiomas.

OBJECTIVE: Assessing the Ki-67 labeling index (LI) is laborious and time consuming. Therefore, an automated computer-based method was developed, which is able to identify and analyze immunolabeled and hematoxylin-stained nuclei in digital images of routine immunohistochemical slides. MATERIAL AND METHODS: The method is based on a plugin for the public domain image analysis software ImageJ, which runs on every operating system (free download at http://rsb.info.nih.gov/ij/). Percentage of Ki-67 immunostained nuclei were determined in 5 high power fields (x40) of immunostained slides (DAB detection technique, hematoxylin counterstain) of 20 Grade I, 20 Grade II, and 10 Grade III meningiomas conventionally by two independent investigators and automatically, respectively. The time effort was measured for each counting procedure. RESULTS: Enumerating conventionally or automatically did not reveal any significant differences in the mean labeling indices. Ki-67 LIs discriminated sufficiently between meningiomas of Grade I (median 1.7% Investigator 1 and 1.5% Investigator 2 vs. 1.5% automatically), Grade II (7.6%, 8% vs. 7.3%), and Grade III meningiomas (22%, 21% vs. 22%). The computer-based results correlated very closely with those obtained by manual counting (correlation coefficient = 0.98). The mean time effort for counting procedure per image was 374 s (130 s-435 s) for the conventional and 11 s (7 s-12 s) for the automated method. CONCLUSIONS: The described method can reliably assess the Ki-67 LI much faster than conventional enumerating. The computerized method has the advantages of objectivity, accuracy, repeatability, and ease of use. There is no request for special stains nor special image acquiring systems. The plugin can be downloaded at the "Morphometrie" section of http://www.uniklinikum-saarland.de/neuropathologie.

Immunohistochemical detection of dUTPase in intracranial tumors.

The nuclear isoform of deoxyuridine 5'-triphosphate nucleotidohydrolase (dUTPase, OMIM *601266, EC 3.6.1.23) is immunohistochemically detectable in all proliferating tissues and may thus be a useful adjunct for the grading of tumors analogous to Ki-67 labeling. A hundred and twenty-seven human intracranial tumors, including 56 astrocytomas, 12 oligodendrogliomas, 8 oligoastrocytomas, 34 meningiomas, 7 ependymomas, and 10 metastatic carcinomas, were stained using the monoclonal rat anti-human dUTPase antibody (clone 3E6) with formalin-fixed and paraffin-embedded tissue. The labeling indices were compared with those obtained with the proliferation marker Ki-67 on parallel tissue sections. All tumors contained dUTPase-positive nuclei, whereas the percentage of positive tumor cells generally increased with grade of malignancy. Meningiomas of higher grades, i.e., World Health Organization (WHO) grades II and III, contained additional cells with cytoplasmic reactivity. There were usually fewer dUTPase- than Ki-67-positive nuclei detectable. Unlike Ki-67, dUTPase was not detectable in mitotic figures. Labeling indices for dUTPase, but not for Ki-67, showed significant differences between all 3 WHO grades of diffuse astrocytomas. In summary, dUTPase staining provides a useful measure of cell proliferation distinct from that offered by Ki-67 labeling. It proved particularly useful for the evaluation of diffuse astrocytomas.

[Diagnostic value of the monoclonal antibody to thyroid transcription factor -1(TTF-1) in CNS metastases. An immunohistochemical study of 65 cases]. / Diagnostischer Wert des monoklonalen Antikörpers TTF-1 bei ZNS-Metastasen. Immunhistochemische Studie an 65 Fällen.

Thyroid transcription factor-1 (TTF-1) is used as an immunohistochemical marker for the identification of the lungs or thyroid gland as the site of origin in patients with metastatic disease and unknown primary tumor. In this study the reliability of anti-TTF-1 was assessed in 65 metastases of the central nervous system (CNS), among which there were also small stereotactic biopsies (n = 22) and poorly preserved specimens. Eight out of nine CNS metastases of patients with known adenocarcinoma of the lungs, as well as seven adenocarcinoma metastases of patients with radiologically detected or anamnestically presumed pulmonary carcinoma, expressed TTF-1 immunohistochemically. One CNS metastasis from a follicular thyroid carcinoma was positive and one from an anaplastic thyroid carcinoma was negative. All CNS metastases from patients with known primary tumors outside the lungs or thyroid gland were negative. TTF-1 is a sensitive (up to 90%) and specific (100%) immunohistochemical marker for CNS metastases of adenocarcinomas of the lungs and also functions reliably on small or stereotactic biopsies and poorly preserved samples.