Molecular pathogenesis of craniopharyngioma: switching from a surgical approach to a biological one

Craniopharyngioma has long been considered a benign tumor because of its pathological aspect. This primordial view of craniopharyngioma fit with the primitive treatment attempts based on blind resection of the tumor each time it recurred. The limits of this management strategy were proven early by the high morbidity related to the resection and recurrence risk despite radical lesion removal. Nowadays, craniopharyngioma must be considered a complex molecular disease, and a detailed explanation of the mechanisms underlying its aggressive biological and clinical behavior, despite some benign pathological features, would be the first step toward defining the best management of craniopharyngioma. Indeed, advances in the knowledge of the molecular mechanisms at the base of craniopharyngioma oncogenesis will lead to comprehension of the critical checkpoints involved in neoplastic transformation. The final research target will be the definition of new biological agents able to reverse the neoplastic process by acting on these critical checkpoints. This biological approach will lead to a refined therapy combining higher efficacy and safety with lower morbidity. In this paper the authors reveal state-of-the-art comprehension of the molecular biology of craniopharyngioma and the consequent therapeutic implications

Preoperative and postoperative neurological, neuropsychological and behavioral impairment in children with posterior cranial fossa astrocytomas and medulloblastomas: the role of the tumor and the impact of the surgical treatment

Introduction: The aim of the present study was to prospectively investigate if a correlation might exist between preoperative and postoperative neurological conditions, neuroradiological/intraoperative findings and results of a complete neuropsychological evaluation in children with posterior fossa medulloblastomas and astrocytomas. Materials and methods: Of the 65 children admitted at the Pediatric Neurosurgery of the UCSC of Rome between January 2005 and October 2009, 41 were selected; the only two exclusion criteria were represented by age under 24 months and severe neurological conditions, seen that in both cases it would not have been a possible reliable evaluation. All children underwent a preoperative and immediate postoperative complete MR study. Hydrocephalus was graded on the Evans score; brainstem infiltration was defined on intraoperative findings. Neuropsychological assessment consisted of a battery of tests tailored on the patient's age, cognitive level, and level of cooperation. Post operative neuropsychological evaluation was performed at a mean time of 2.5 min (2 mos, max 4.5 mos) from the operation, before any eventually needed adjuvant treatment (i.e., chemotherapy, radiotherapy). Results: Concerning neurological status, we found a statistically significant relation between the presence of oculomotor impairment and both verbal fluency deficits (p = 0.044) and imagery disorders (p = 0.03); also, the presence of ataxia/dysmetria was significantly correlated to attention dysfunction (p = 0.01) and, more tightly, to planning dysfunction (p = 0.006). For neuroradiological/intraoperative features, Intelligence Quotient (IQ) impairment was significantly correlated to the intraoperative evidence of tumor infiltration of the brainstem (p = 0.003), a severe hydrocephalus at diagnosis (p = 0.001) and the histological diagnosis of medulloblastoma (MB) (p = 0.002). For selective skills, a significant correlation was found between linguistic processing deficits and the evidence of dentate nuclei infiltration (blindly defined on MR); procedural memory defects and imagery disorders related to the severity of the hydrocephalus (p = 0.02), infiltration of the brain stem (p = 0.01) and a histological diagnosis of MB (p = 0.01). After surgery no patient showed a worsening of his/her cognitive profile; the relationships between clinical, intraoperative, and radiological findings were substantially confirmed. Discussion: Our results support the hypothesis that when present, neuropsychological impairment is already present at diagnosis and that the most statistically significant factors, which might be related with cognitive deficits in the preoperative as well as in the postoperative period, are tumor infiltration of the brainstem, the severity of hydrocephalus, and a histological diagnosis of MB

Endoscopic third ventriculostomy for the management of Chiari I and related hydrocephalus: outcome and pathogenetic implications

Hydrocephalus affects 7% to 10% of patients with Chiari I malformation (CIM). It can be successfully treated by endoscopic third ventriculostomy (ETV), possibly improving related CIM and syringomyelia

5-year-old boy with a clival mass.

Epithelioid sarcoma is a rare tumor originating from mesenchymal cells, usually involving the extremities of young adults and is found only sporadically in the head and neck region. Only one case involving the central nervous system has been described so far. We report a 5 year-old boy with a large solid, osteolytic lesion of the clivus with a wide soft tissue component expanding into the intracranial compartment and obliterating the prepontine cistern. Histopathological examination revealed epithelioid neoplastic cells with abundant eosinophilic cytoplasm, rounded nuclei and prominent nucleoli. Areas of geographic necrosis and numerous mitoses were present. Neoplastic cells immunostained for vimentin, cytokeratin, and epithelial membrane antigen (EMA). No immunostaining was observed for glial fibrillary associated protein (GFAP), S-100, PLAP, \u3b1-fetoprotein, CD 117, CD 34, CD 31, BAF-47 (INI1). The Ki67 proliferation index exceeded 40%. These histological findings favor a diagnosis of epithelioid sarcoma. This report adds epithelioid sarcoma to the differential diagnosis of both clival tumors and pediatric skull base tumors

The role of inflammation in the genesis of the cystic component of craniopharyngiomas.

Craniopharyngioma accounts for 5-10% of childhood tumors and, despite of the benign histological features, its clinical course can be malignant because of critical anatomical relationships with neural and vascular structures and the possible morbidity associated to resection. Only a few studies have addressed the molecular characterization of the cyst fluid so far and the mechanisms of action of intracystic agents are not clearly understood yet. The acidic soluble proteins contained in the cystic fluid of six patients with cystic craniopharyngioma, three of them treated with intratumoral interferon-alpha, were analyzed. A high performance liquid chromatography electrospray ionization mass spectrometry analysis was performed. The antimicrobial peptides alpha-defensins 1-3 relevant for innate immunity were detected in the cystic fluid before the intratumoral treatment. Amount of peptides significantly decreased in cystic fluid during pharmacological treatment. Detection of alpha-defensins 1-3 excludes that cyst fluid formation can derive from disruption of blood-brain barrier and suggests the involvement of innate immune response in pathology of craniopharyngioma cyst formation. The reduction of alpha-defensins could derive both from direct antitumoral effect of interferon-alpha on squamous epithelial cells of craniopharyngioma cyst and from its immuno-modulatory effects on the recruitment of cells of innate immune systems. Interestingly, the clinical patient outcome well correlates with the gradual reduction of alpha-defensins 1-3 amount. Additional studies will be necessary to establish the role of these molecules in the pathogenesis of craniopharyngioma, and further investigations will be necessary to confirm the efficacy of the antitumoral activity of interferon-alpha

Primer sequences.

<p>Primer sequences.</p

Consistent anomalies observed in ET and BAT by a-CGH.

*<p>further amplification in ET, with respect to BAT.</p><p>In bold: anomalies limited to ETs.</p><p>In square bracket: genomic positions (according to NCBI 36 build) of the observed anomalies.</p><p>In round brackets: mosaicism degree of the observed anomaly. The percentage of abnormal cells was inferred using the formula proposed by Valli et al. That formula cannot be applied to the amplified segments (EGFR, CDK4, MDM2 and 15q24.1) since their ploidy status is unknown.</p

Selection of the genes significantly different between ET and BAT with a 10<i>-</i>fold difference in expression levels.

<p>Selection of the genes significantly different between ET and BAT with a 10<i>-</i>fold difference in expression levels.</p