Intraoperative confocal laser endomicroscopy for brain tumors - potential and challenges from a neuropathological perspective

Confocal laser endomicroscopy (CLE) represents a new non-invasive in vivo imaging technique that holds considerable promise in neurosurgery and neuropathology. CLE is based on the principle of optical sectioning which uses pinholes placed in the light path to selectively image photons of a specific focal plane by filtering out photons above and below the focal plane. Potential indications of CLE in neurosurgery and neuropathology include intraoperative tumor diagnosis and staging as well as assessment of tumor resection margins notably in the case of diffusely infiltrating gliomas. CLE-based tumor analysis in near-real time may also have a significant impact on future tumor resection strategies. We here discuss the technical features of CLE, its potential for wide-field imaging, its role in comparison to established histological techniques for intraoperative tumor assessment and its position in digital pathology and telepathology. Based on our group’s experience with a commercially available confocal laser endomicroscope (ZEISS CONVIVO), we critically address the current state of intraoperative CLE in brain tumor surgery, the applicability of classical histological criteria and the strategies required to further improve the diagnostic accuracy of CLE. We finally discuss how a widespread use of CLE in neurosurgery may modify the role of neuropathologists in intraoperative consultation, generating both new opportunities and new challenges

Nestin, PDGFRbeta, CXCL12 and VEGF in glioma patients: different profiles of (pro-angiogenic) molecule expression are related with tumor grade and may provide prognostic information.

Angiogenesis is a key event in the natural progression of gliomas. Nestin, a marker for multipotential neuroepithelial stem cells, is detected in neuroepithelial tumors and in proliferating endothelial cells (ECs) and is involved in the early stages of lineage commitment, proliferation and differentiation. Nestin expression is correlated with proangiogenic chemokines (CXCL12 and its receptor CXCR4) and growth factors (VEGF, PDGF-B and its receptor PDGFRbeta). VEGF expression upregulates CXCR4 on endothelial cells, binding the chemokine SDF1/CXCL12 (Stromal Derived Factor) that has a role on angiogenesis and chemotaxis of endothelial cells; PDGF (platelet-derived growth factor) and PDGFRbeta are also crucial by increasing the expression of VEGF. We performed a retrospective study on the presence and role of nestin-expressing cells in 102 patients with glioma, relating the findings to VEGF, CXCL12, PDGFRbeta expression and to clinical outcome (time to tumor progression-TTP and survival time-ST). Our results suggest that in gliomas the detection of proliferating ECs expressing nestin correlates to histological malignancy grade and clinical outcome. Also, the expression of CXCL12 in low-grade gliomas was the only factor associated with a significantly shorter TTP, suggesting a role of this chemokine in angiogenic shift and/or disease progression

Confocal laser imaging in neurosurgery: A comprehensive review of sodium fluorescein-based CONVIVO preclinical and clinical applications.

Given the established direct correlation that exists among extent of resection and postoperative survival in brain tumors, obtaining complete resections is of primary importance. Apart from the various technological advancements that have been introduced in current clinical practice, histopathological study still remains the gold-standard for definitive diagnosis. Frozen section analysis still represents the most rapid and used intraoperative histopathological method that allows for an intraoperative differential diagnosis. Nevertheless, such technique owes some intrinsic limitations that limit its overall potential in obtaining real-time diagnosis during surgery. In this context, confocal laser technology has been suggested as a promising method to have near real-time intraoperative histological images in neurosurgery, thanks to the results of various studies performed in other non-neurosurgical fields. Still far to be routinely implemented in current neurosurgical practice, pertinent literature is growing quickly, and various reports have recently demonstrated the utility of this technology in both preclinical and clinical settings in identifying brain tumors, microvasculature, and tumor margins, when coupled to the intravenous administration of sodium fluorescein. Specifically in neurosurgery, among different available devices, the ZEISS CONVIVO system probably boasts the most recent and largest number of experimental studies assessing its usefulness, which has been confirmed for identifying brain tumors, offering a diagnosis and distinguishing between healthy and pathologic tissue, and studying brain vessels. The main objective of this systematic review is to present a state-of-the-art summary on sodium fluorescein-based preclinical and clinical applications of the ZEISS CONVIVO in neurosurgery

Genetic alterations and in vivo tumorigenicity of neurospheres derived from an adult glioblastoma

Pediatric brain tumors may originate from cells endowed with neural stem/precursor cell properties, growing in vitro as neurospheres. We have found that these cells can also be present in adult brain tumors and form highly infiltrating gliomas in the brain of immunodeficient mice. Neurospheres were grown from three adult brain tumors and two pediatric gliomas. Differentiation of the neurospheres from one adult glioblastoma decreased nestin expression and increased that of glial and neuronal markers. Loss of heterozygosity of 10q and 9p was present in the original glioblastoma, in the neurospheres and in tumors grown into mice, suggesting that PTEN and CDKN2A alterations are key genetic events in tumor initiating cells with neural precursor properties

Prognostic value of CXCL12 expression in 40 low-grade oligodendrogliomas and oligoastrocytomas.

Both clinical and biological features have been reported as prognostic factors in low-grade gliomas. Among these, histotype, tumor size, enhancement, age and genetic pattern. Microvessel density (MVD) has been correlated to clinical outcome in astrocytomas, but its impact in oligodendrogliomas and mixed tumors is not sure. The pro-angiogenic chemokine stromal cell-derived factor (SDF-1/CXCL12) and its receptor CXC chemokine receptor 4 (CXCR4) have been described in low-grade gliomas, with a correlation between CXCL12 expression and shorter time to progression (TTP). The intermediate filament Nestin is expressed in proliferating vessels. Platelet-derived growth factor B (PDGF-B) and its receptor PDGFR-beta are also involved in angiogenesis and malignant progression in gliomas

VIPERS: Stellar population properties of early-type galaxies

We present stellar population properties of early-type galaxies from the VIMOS Public Extragalactic Redshift Survey (VIPERS) based on the spectral measurements of ∼ 4000 galaxies with stellar masses from 10^{10} to 10^{12} {[M_{☉}]} in the redshift range 0.4 < z < 1.0. We quantify relations between their age, stellar metallicity, duration of star burst, and stellar mass. We compare the properties of VIPERS intermediate redshift galaxies with galaxies found in the Local Universe

Diffuse glioblastoma resembling acute hemorrhagic leukoencephalitis

We report the case of a young man with sudden onset of diplopia after an upper respiratory tract infection. Based on the first radiological findings acute hemorrhagic leukoencephalitis, a variant of acute disseminated encephalomyelitis, was suspected and treatment with high dose intravenous dexamethasone was started but it was stopped for intolerance. The patient clinically worsened, developing gait instability, ataxia and ophthalmoplegia; brain MRI performed 20 days later showed severe progression of the disease with subependymal dissemination. After brain biopsy of the right temporal lesion the histological diagnosis was glioblastoma. These findings suggest that MRI features of acute hemorrhagic leukoencephalitis may dissimulate the diagnosis of diffuse glioma/glioblastoma. This case underscores the importance of considering diffuse glioma in the differential diagnosis of atypical signs and symptoms of acute hemorrhagic leukoencephalitis and underlines the relevant role of integrating neuroradiologic findings with neuropathology

Case report: Multiple brain intravascular papillary endothelial hyperplasia: incidence, diagnostic challenges, and management approach

Multiple hemorrhagic brain lesions are mainly diagnosed based on clinico-radiological features integrated with histological data. Intravascular papillary endothelial hyperplasia (IPEH), or Masson's tumor, is a very rare entity, particularly when localized in the brain. In this study, we describe a case of multiple recurrent brain IPEHs and provide details on the diagnostic phase, therapeutic approaches, and related challenges. A 55-year-old woman presented with a relapsing neurological deficit. Brain magnetic resonance imaging (MRI) revealed a hemorrhagic right frontal-parietal lesion. When new neurological symptoms occurred, subsequent MRI scans detected more bleeding cerebral lesions. She underwent a series of single hemorrhagic lesion debulking. For any samples that underwent histopathological examination, the first results were not informative; the second and the third results revealed hemangioendothelioma (HE); and the fourth results led to the IPEH diagnosis. Interferon alpha (IFN-α) and subsequently sirolimus were prescribed. Both were well tolerated. Clinical and radiological features remained stable 43 months after starting sirolimus therapy and 132 months after the first diagnosis. To date, 45 cases of intracranial IPEH have been reported, mostly as single lesions without parenchymal location. They are usually treated by surgery and sometimes by radiotherapy upon recurrence. Our case is notable for two main reasons: because of the consecutive recurrent multifocal exclusively cerebral lesions and the therapeutic approach we used. Based on multifocal brain recurrence and good performance, we propose pharmacological therapy, including IFN-α and sirolimus, to stabilize IPEH

Final results of the second prospective AIEOP protocol for pediatric intracranial ependymoma

BACKGROUND: This prospective study stratified patients by surgical resection (complete = NED vs incomplete = ED) and centrally reviewed histology (World Health Organization [WHO] grade II vs III). METHODS: WHO grade II/NED patients received focal radiotherapy (RT) up to 59.4 Gy with 1.8 Gy/day. Grade III/NED received 4 courses of VEC (vincristine, etoposide, cyclophosphamide) after RT. ED patients received 1-4 VEC courses, second-look surgery, and 59.4 Gy followed by an 8-Gy boost in 2 fractions on still measurable residue. NED children aged 1-3 years with grade II tumors could receive 6 VEC courses alone. RESULTS: From January 2002 to December 2014, one hundred sixty consecutive children entered the protocol (median age, 4.9 y; males, 100). Follow-up was a median of 67 months. An infratentorial origin was identified in 110 cases. After surgery, 110 patients were NED, and 84 had grade III disease. Multiple resections were performed in 46/160 children (28.8%). A boost was given to 24/40 ED patients achieving progression-free survival (PFS) and overall survival (OS) rates of 58.1% and 68.7%, respectively, in this poor prognosis subgroup. For the whole series, 5-year PFS and OS rates were 65.4% and 81.1%, with no toxic deaths. On multivariable analysis, NED status and grade II were favorable for OS, and for PFS grade II remained favorable. CONCLUSIONS: In a multicenter collaboration, this trial accrued the highest number of patients published so far, and results are comparable to the best single-institution series. The RT boost, when feasible, seemed effective in improving prognosis. Even after multiple procedures, complete resection confirmed its prognostic strength, along with tumor grade. Biological parameters emerging in this series will be the object of future correlatives and reports