F. Becherini

Human brain tumors: multidrug-resistance P-glycoprotein expression in tumor cells and intratumoral capillary endothelial cells

Malignant brain tumor is a lethal disease with currently available treatment options having a limited impact on outcome. Nevertheless, novel therapeutic approaches combined with genetic prediction of chemosensitivity have, in the last decade, significantly improved clinical benefit for the treated patients. The fine characterization of the MDR1 gene encoding for P-glycoprotein (MDR1–Pgp) in brain tumors may be a crucial determinant for evaluating the long-term efficiency of specific anti-cancer compounds. By using a very high specific monoclonal antibody, the MDR1–Pgp was immunodetected in 34 out of 43 grade IV, 6 out of 10 grade III, 4 out of 7 grade II, and 1 out 3 grade I brain tumors. MDR1–Pgp resulted hyper-expressed, both in vessels and in neoplastic cells from the majority of tumors examined, compared to normal parenchyma. This study demonstrates that the MDR1 gene can be detected in all grade tumor brain malignancies and in endothelial cells of newly formed capillaries, thus, impairing drug access at the tumor cell level. Although the role of MDR1–Pgp in tumor blood vessels needs to be further examined and more clearly defined, drug resistance in malignant brain tumors may result from characteristics not only of tumor vasculature but also of neoplastic cells.

Choroid plexus carcinoma : a new case associated with a novel TP53 germ line mutation

The choroid plexus is a highly specialized structure projecting into the lateral ventricle and consisting of a vascularized fibrous stroma covered by epithelial cells of neuroectodermal origin. This specialized epithelium very rarely gives rise to neoplasms, which mainly affect young children and present in sporadic fashion. Choroid plexus tumours (CPT) are in fact rare epithelial brain neoplasms accounting for 0.4–0.8% of all brain tumours and for approximately 1% of paediatric brain tumours [1,2]. Histologically, CPT are classified into benign choroid plexus papilloma (CPP), atypical CPP and malignant choroid plexus carcinoma (CPC) [3]. The survival rate of patients with CPP is significantly higher; nevertheless, a few cases of CPP have been reported to pursue a more aggressive course with intracranial and/or spinal seeding; progression from CPP to CPC has also been reported [1,4]. Most CPT occur sporadically; nevertheless, they can also occur in association with hereditary syndromes such as Aicardi’s syndrome [5] or, more frequently, Li–Fraumeni syndrome (LFS) [3]. The p53 tumour suppressor gene (TP53) is the most commonly mutated gene in human cancers. It regulates cell proliferation and DNA repair by inhibiting the cell cycle at G1/S, so that loss of its function may lead to aberrant cell kinetics and tumour growth [6]. Germline mutations in TP53 characterize patients with LFS, a rare hereditary tumour syndrome commonly associated with a variety of malignancies including sarcoma, breast cancer, leukaemia and adrenal cortical carcinoma [7]. Among the paediatric cancers arising within the LFS, rhabdomyosarcoma and CPC are the two most frequent histotypes [8]. Up to date, 17 cases of CPC have been described in the literature occurring in association to a TP53 germline mutation [8–19]. We have identified a hitherto undescribed TP53 germline mutation associated with CPC in a 3-month-old boy, in the absence of a clear tumour predisposition syndrome. The infant presented with vomiting, weight loss and somnolence. The first, non-enhanced, CT scan demonstrated marked and active hydrocephalic enlargement of the supratentorial ventricular system and a lobulated hyperdense mass, with rare and minute calcified foci, arising within the occipital horn and the posterior atrium of the right lateral ventricle; magnetic resonance imaging (MRI) confirmed the intraventricular lobular neoplasm, occupying and enlarging the aforementioned ventricular sections and showing transverse largest diameters of about 3.4 ¥ 2.9 ¥ 2.9 cm (Figure 1). Moderate peri-trigonal vasogenic oedema was also present. The mass appeared iso-intense on T1 weighted images (T1 WI) and of intermediate signal, with multiple areas of signal void, on T2 gradient recalled echo images (GRE-T2*), showing marked and spreading enhancement after administration of paramagnetic contrast material. Diffusion weighted imaging (DWI) and MR spectroscopy (MRS) complemented MRI: DWI revealed an iso-intense mass with multiple small hypo-intense ‘cystic-like’ areas; MRS demonstrated a pathological alteration of the spectral pattern, with complete absence of N-Acetyl Aspartate, marked depletion of Creatine compounds, elevated levels of Choline and lipids. According to the previously reported findings [20], a radiologic diagnosis compatible with CPC was made. The tumour was completely removed through a transparietal route to the lateral ventricle, even if a local invasion of the brain parenchyma was present at the lateral wall of the ventricle. The post-surgical period was uneventful and, 42 months after the surgery, the child is alive and well. Histologically, the lesion demonstrated the typical morphology of CPC with irregular papillae (Figure 2A) lined by cytologically malignant cells and surrounded by sheets of epithelioid-looking cells occasionally forming perivascular rosettes. Mitotic figures, including atypical mitoses, were often observed, as well as necrotic areas. By immunoperoxidase staining (Ventana Medical Systems, Inc.), the tumour cells showed positivity for cytokeratin 8 and 18, S100, vimentin, and focally for synaptophysin. The MIB-1 proliferative index was about 20% and strong p53 nuclear staining was seen in the overwhelming majority of tumour cells (Figure 2B).

Progressive hemispheric shrinking in hemimegalencephaly: a possible role for seizure‐related neuronal loss

Hemimegalencephaly (HME) is a developmental brain lesion consisting of a unilateral enlarged, dysplastic, and often highly epileptogenic cerebral hemisphere. Most patients exhibit early onset intractable seizures, status epilepticus, hemiplegia, hemianopsia, and developmental delay. Major surgical procedures are advocated for limiting the devastating consequences of epilepsy. We studied a female with HME, early onset intractable seizures and recurrent status epilepticus, in whom progressive hemiatrophy of the enlarged hemisphere and normal growth of the contralateral hemisphere, exceeding the size of the dysplastic hemisphere, was demonstrated by magnetic resonance imaging. Histopathology, following functional hemispherectomy at the age of 7 years, demonstrated severe neuronal loss with an elevated number of cells exhibiting the morphological and biochemical features of apoptosis. Eighteen months after surgery the patient was seizure‐free (Engel class I) and exhibited improved motor and language skills, alertness and social behaviour. We hypothesize that nearly continuous seizure activity might sustain seizure‐induced brain injury in the dysplastic hemisphere but causal heterogeneity and associated anatomical factors may influence differently the individual predisposition to atrophic changes.

Primary intra-diploic meningioma in a child

BackgroundPrimary intra-diploic meningiomas are uncommon in childhood and, at the clinical onset, may be confused with other and more frequent bone tumours because they lack specific clinical and radiological characteristics. Surgery is indicated not only to remove the lesion but also to obtain an accurate histological diagnosis.Case reportWe report the case of a young girl who presented with a recently developed subcutaneous hard mass in the left pterional region. Neuroradiological investigations revealed an intra-osseous lytic mass with a sclerotic reaction. Diagnosis was possible only after the total removal of the tumour and its histological examination.