Typing of inflammatory lesions of the pituitary

Pituitary - Inflammatory pituitary lesions account for 1.8% of all specimens from the German Pituitary Tumor Registry. They occure in 0.5% of the autoptical specimens and in 2.2% of the surgical...     

Adamantinomatous craniopharyngiomas express tumor stem cell markers in cells with activated Wnt signaling: further evidence for the existence of a tumor stem cell niche?

Introduction

Early disease onset, clinical manifestation, histomorphology, and increased tendency to relapse distinguish the adamantinomatous craniopharyngioma (adaCP) from the more favorable papillary variant (papCP). A molecular hallmark of adaCP is the activated Wnt signaling pathway indicated by nuclear β-catenin accumulation in a subset of tumor cells. A mouse model recently illustrated that these cells are the driving force in tumorigenesis of adaCP. This observation and the peculiar growth pattern points to the existence of a specific tumor stem cell (TSC) population in human CP.

Materials and Methods

To prove this hypothesis, the TSC markers CD133 (Prominin1) and CD44 were examined in papCP (n = 8) and adaCP (n = 25) on mRNA level using quantitative real time PCR of total tumor RNA. Furthermore, we investigated protein expression performing immunohistochemical analyses of formalin-fixed paraffin embedded tumor samples.

Results

PapCP revealed a homogenous CD44 expression pattern predominantly at the cell membrane, whereas CD133 labeling was hardly detectable. In adaCP, on the other hand all markers were consistently and predominantly co-expressed in nuclear β-catenin accumulating cell clusters, which was confirmed by double immunofluorescence staining. Overall expression of CD44 was significantly decreased in adaCP versus papCP, whereas CD133 showed significantly higher protein and mRNA levels in adaCP.

Conclusions

Our results indicate tumor stem cell-like characteristics of β-catenin accumulating cell clusters in adaCP, which may represent a tumor stem cell niche and might contribute to tumor recurrence. The potential impact of these special cell groups in regard to future CP management, including postoperative follow-up and additional treatment remains to be explored.     

Intraperitoneal treatment with S100B enhances hippocampal neurogenesis in juvenile mice and after experimental brain injury

Background

Neurogenesis is documented in adult mammals including humans, is promoted by neurotrophic factors, and constitutes an innate repair mechanism following brain injury. The glial neurotrophic protein S100B is released following various types of brain injuries, enhances hippocampal neurogenesis and improves cognitive function following brain injury in rats when applied intrathecally. The present study was designed to elucidate whether the beneficial effect of S100B on injury-induced neurogenesis can be confirmed in mice when applied intraperitoneally (i.p.), and whether this effect is dose-dependent.

Methods

Male juvenile mice were subjected to a unilateral parietal cryolesion or sham injury, and treated with S100B at 20nM, 200nM or vehicle i.p. once daily. Hippocampal progenitor cell proliferation was quantified following labelling with bromo-deoxyuridine (BrdU, 50 mg/KG i.p.) in the germinative area of the dentate gyrus, the subgranular zone (SGZ), on day 4 as well as on cell survival and migration to the granular cell layer (GCL) on day 28. Progenitor cell differentiation was assessed following colabelling with the glial marker GFAP and the neuronal marker NeuN.

Results

S100B enhanced significantly the early progenitor cell proliferation in the SGZ as well as cell survival and migration to the GCL, and promoted neuronal differentiation. While these effects were predominately dose-dependent, 200nM S100B failed to enhance the proliferation in the SGZ on day 4 post-injury.

Conclusion

We conclude that S100B participates in hippocampal neurogenesis after injury at lower nanomolar concentrations. Therefore S100B may serve as a potential adjunct treatment to promote neuroregeneration following brain damage.     

Common mutations of β-catenin in adamantinomatous craniopharyngiomas but not in other tumours originating from the sellar region

Dysregulation of the Wnt signalling pathway contributes to developmental abnormalities and carcinogenesis of solid tumours. Here, we examined -catenin and adenomatous polyposis coli (APC) by mutational analysis in pituitary adenomas (n=60) and a large series of craniopharyngiomas (n=41). Furthermore, the expression pattern of -catenin was immunohistochemically analysed in a cohort of tumours and cysts of the sellar region including pituitary adenomas (n=58), craniopharyngiomas (n=57), arachnoidal cysts (n=8), Rathkes cleft cysts (n=10) and xanthogranulomas (n=6). Whereas APC mutations were not detectable in any tumour entity, -catenin mutations were present in 77% of craniopharyngiomas, exclusively of the adamantinomatous subtype. All mutations affected exon 3, which encodes the degradation targeting box of -catenin compatible with an accumulation of nuclear -catenin protein. In addition, a novel 81-bp deletion of this exonic region was detected in one case. Immunohistochemical analysis confirmed a shift from membrane-bound to nuclear accumulation of -catenin in 94% of the adamantinomatous tumours. Aberrant distribution patterns of -catenin were never observed in the other tumour entities under study. We conclude that -catenin mutations and/or nuclear accumulation serve as diagnostic hallmarks of the adamantinomatous variant, setting it apart from the papillary variant of craniopharyngioma.     

Solid haemangioblastomas of the CNS: a review of 17 consecutive cases

A retrospective study on solid central nervous system haemangioblastomas was performed to characterize clinical features, treatment strategies and outcome in these rare lesions. Between 1993 and 2006 23, solid haemangioblastomas were surgically removed in 17 patients. Eight lesions were located within pons Varolii and medulla oblongata, six within the cerebellar hemispheres and three in the cerebellopontine angle. Three haemangioblastomas were located supratentorially and three within the spinal cord. All patients except two underwent pre-operative magnetic resonance imaging (MRI). Post-operative digital subtraction angiography and/or MRI was performed in all surviving patients. Except for spinal cord lesions, rather unsystematic clinical symptoms were observed. Twenty-two tumours could be resected completely. Two patients with brainstem lesions died within 10 weeks after surgery from infectious complications. Persistent new neurological deficits occurred in two patients. Three patients underwent radiosurgery prior to or following the surgical procedure. Solid haemangioblastomas represent a surgical challenge due to their arteriovenous malformation-like vascularisation and their frequent location in eloquent areas. Surgery is the therapy of choice. Circumferential dissection with devascularization and en bloc removal yields good functional results. A location within the brainstem carries the most unfavourable prognosis.     

Hereditary neuropathy with liability to pressure palsy combined with schwannomas of the median and medial plantar nerves

A 42-year-old woman was surgically treated for carpal tunnel syndrome, revealing schwannoma of the median nerve. A year later, she developed a tarsal tunnel syndrome. At time of this diagnosis, hereditary neuropathy with liability to pressure palsies (HNPP) was diagnosed genetically and a schwannoma of the medial plantar nerve was treated surgically. The occurrence of HNPP and schwannomas in the same patient might be purely coincidental, but it is tempting to speculate that they share a common genetic basis.     

Towards a clinico-pathological classification of granule cell dispersion in human mesial temporal lobe epilepsies

The dentate gyrus (DG) plays a pivotal role in the functional and anatomical organization of the hippocampus and is involved in learning and memory formation. However, the impact of structural DG abnormalities, i.e., granule cell dispersion (GCD), for hippocampal seizure susceptibility and its association with distinct lesion patterns in epileptic disorders, such as mesial temporal sclerosis (MTS) remains enigmatic and a large spectrum of pathological changes has been recognized. Here, we propose a clinico-pathological classification of DG pathology based on the examination of 96 surgically resected hippocampal specimens obtained from patients with chronic temporal lobe epilepsy (TLE). We observed three different histological patterns. (1) A normal granule cell layer was identified in 11 patients (no-GCP; 18.7%). (2) Substantial granule cell loss was evident in 36 patients (referred to as granule cell pathology (GCP) Type 1; 37.5%). (3) Architectural abnormalities were observed in 49 specimens, including one or more of the following features: granule cell dispersion, ectopic neurons or clusters of neurons in the molecular layer, or bi-lamination (GCP Type 2; 51%). Cell loss was always encountered in this latter cohort. Seventy-eight patients of our present series suffered from MTS (81.3%). Intriguingly, all MTS patients displayed a compromised DG, 31 (40%) with significant cell loss (Type 1) and 47 (60%) with GCD (Type 2). In 18 patients without MTS (18.7%), seven displayed focally restricted DG abnormalities, either cell loss (n = 5) or GCD (n = 2). Clinical histories revealed a significant association between DG pathology patterns and higher age at epilepsy surgery (p = 0.008), longer epilepsy duration (p = 0.004), but also with learning dysfunction (p < 0.05). There was no correlation with the extent of pyramidal cell loss in adjacent hippocampal segments nor with postsurgical seizure relief. The association with long-term seizure histories and cognitive dysfunction is remarkable and may point to a compromised regenerative capacity of the DG in this cohort of TLE patients.     

Experimental therapy of malignant gliomas using the inhibitor of histone deacetylase MS-275

Inhibitors of histone deacetylases are promising compounds for the treatment of cancer but have not been systematically explored in malignant brain tumors. Here, we characterize the benzamide MS-275, a class I histone deacetylase inhibitor, as potent drug for experimental therapy of glioblastomas. Treatment of four glioma cell lines (U87MG, C6, F98, and SMA-560) with MS-275 significantly reduced cell growth in a concentration-dependent manner (IC(90), 3.75 micromol/L). Its antiproliferative effect was corroborated using a bromodeoxyuridine proliferation assay and was mediated by G(0)-G(1) cell cycle arrest (i.e., up-regulation of p21/WAF) and apoptotic cell death. Implantation of enhanced green fluorescent protein-transfected F98 glioma cells into slice cultures of rat brain confirmed the cytostatic effect of MS-275 without neurotoxic damage to the organotypic neuronal environment in a dose escalation up to 20 micromol/L. A single intratumoral injection of MS-275 7 days after orthotopic implantation of glioma cells in syngeneic rats confirmed the chemotherapeutic efficacy of MS-275 in vivo. Furthermore, its propensity to pass the blood-brain barrier and to increase the protein level of acetylated histone H3 in brain tissue identifies MS-275 as a promising candidate drug in the treatment of malignant gliomas.     

Alveolar rhabdomyosarcoma of the clivus with intrasellar expansion: Case report

Rhabdomyosarcomas are common tumors of the head and neck region in children. However, a primarily intracranial localization of this tumor entity is rare. We report on a 3-year-old boy presenting with double vision due to left VI (th) nerve palsy. No other neurological deficits were recognized by clinical inspection. MRI scans visualized an enhancing mass lesion in the upper clivus compressing the cavernous sinus and the pituitary gland. Transsphenoidal biopsy was performed and histopathological examination as well as molecular diagnostics confirmed the diagnosis of an alveolar rhabdomyosarcoma (ARMS). Staging identified a metastatic lesion in the fourth thoracic vertebra resulting in the diagnosis of stage IV disease. Treatment modality included stereotactic radio- and chemotherapy.