Diagnosis and Treatment of Peripheral and Cranial Nerve Tumors with Expert Recommendations: An EUropean Network for RAre CANcers (EURACAN) Initiative

The 2021 WHO classification of the CNS Tumors identifies as "Peripheral nerve sheath tumors" (PNST) some entities with specific clinical and anatomical characteristics, histological and molecular markers, imaging findings, and aggressiveness. The Task Force has reviewed the evidence of diagnostic and therapeutic interventions, which is particularly low due to the rarity, and drawn recommendations accordingly. Tumor diagnosis is primarily based on hematoxylin and eosin-stained sections and immunohistochemistry. Molecular analysis is not essential to establish the histological nature of these tumors, although genetic analyses on DNA extracted from PNST (neurofibromas/schwannomas) is required to diagnose mosaic forms of NF1 and SPS. MRI is the gold-standard to delineate the extension with respect to adjacent structures. Gross-total resection is the first choice, and can be curative in benign lesions; however, the extent of resection must be balanced with preservation of nerve functioning. Radiotherapy can be omitted in benign tumors after complete resection and in NF-related tumors, due to the theoretic risk of secondary malignancies in a tumor-suppressor syndrome. Systemic therapy should be considered in incomplete resected plexiform neurofibromas/MPNSTs. MEK inhibitor selumetinib can be used in NF1 children ≥2 years with inoperable/symptomatic plexiform neurofibromas, while anthracycline-based treatment is the first choice for unresectable/locally advanced/metastatic MPNST. Clinical trials on other MEK1-2 inhibitors alone or in combination with mTOR inhibitors are under investigation in plexiform neurofibromas and MPNST, respectively

Primary Meningeal Melanocytic Tumors of the Central Nervous System:A Review from the Ultra-Rare Brain Tumors Task Force of the European Network for Rare Cancers (EURACAN)

Background: Primary meningeal melanocytic tumors are ultra-rare entities with distinct histological and molecular features compared with other melanocytic or pigmented lesions, such as brain and leptomeningeal metastases from metastatic melanoma. Methods: The European Network for Rare Cancers (EURACAN) Task Force on Ultra-Rare Brain Tumors (domain 10, subdomain 10) performed a literature review from January 1985 to December 2023 regarding the epidemiologic and clinical characteristics, histological and molecular features, radiological findings, and efficacy of local treatments (surgery and radiotherapy) and systemic treatments for these entities. Results: Molecular analysis can detect specific mutations, including GNAQ, GNA11, SF3B1, EIF1AX, BAP1, that are typically found in circumscribed primary meningeal melanocytic tumors and not in other melanocytic lesions, whereas NRAS and BRAF mutations are typical for diffuse primary meningeal melanocytic tumors. The neuroimaging of the whole neuroaxis suggests a melanocytic nature of a lesion, depicts its circumscribed or diffuse nature, but cannot predict the tumor’s aggressiveness. Gross-total resection is the first choice in the case of circumscribed meningeal melanocytoma and melanoma; conversely, meningeal biopsy may be reserved for patients with diffuse and multinodular leptomeningeal spread to achieve a definitive diagnosis. High-dose radiotherapy is rarely indicated in diffuse melanocytic tumors except as palliative treatment to alleviate symptoms. Last, a definitive advantage of a specific systemic treatment could not be concluded, as most of the data available derive from case reports or small cohorts. Conclusions: As primary meningeal melanocytic tumors are extremely rare, the correlations between the clinical characteristics, molecular profile, radiological findings at diagnosis and progression are weak, and poor evidence on the best therapeutic approach is available. There is a need to develop shared platforms and registries to capture more knowledge regarding these ultra-rare entities.</p

CRX Is a Diagnostic Marker of Retinal and Pineal Lineage Tumors

Background: CRX is a homeobox transcription factor whose expression and function is critical to maintain retinal and pineal lineage cells and their progenitors. To determine the biologic and diagnostic potential of CRX in human tumors of the retina and pineal, we examined its expression in multiple settings. Methodology/Principal Findings: Using situ hybridization and immunohistochemistry we show that Crx RNA and protein expression are exquisitely lineage restricted to retinal and pineal cells during normal mouse and human development. Gene expression profiling analysis of a wide range of human cancers and cancer cell lines also supports that CRX RNA is highly lineage restricted in cancer. Immunohistochemical analysis of 22 retinoblastomas and 13 pineal parenchymal tumors demonstrated strong expression of CRX in over 95% of these tumors. Importantly, CRX was not detected in the majority of tumors considered in the differential diagnosis of pineal region tumors (n = 78). The notable exception was medulloblastoma, 40% of which exhibited CRX expression in a heterogeneous pattern readily distinguished from that seen in retino-pineal tumors. Conclusions/Significance: These findings describe new potential roles for CRX in human cancers and highlight the general utility of lineage restricted transcription factors in cancer biology. They also identify CRX as a sensitive and specific clinical marker and a potential lineage dependent therapeutic target in retinoblastoma and pineoblastoma

Diagnosis and Treatment of Pineal Region Tumors in Adults: A EURACAN Overview

Pineal region tumors are rare intracranial tumors, accounting for less than 1% of all adult intracranial tumor lesions. These lesions represent a histologically heterogeneous group of tumors. Among these tumors, pineal parenchymal tumors and germ cell tumors (GCT) represent the most frequent types of lesions. According to the new WHO 2021 classification, pineal parenchymal tumors include five distinct histotypes: pineocytoma (PC), pineal parenchymal tumors of intermediate differentiation (PPTID), papillary tumor of the pineal region (PTPR), pinealoblastoma (PB), and desmoplastic myxoid tumor of the pineal region, SMARCB1-mutant; GCTs include germinoma, embryonal carcinoma, yolk sac tumor, choriocarcinoma, teratoma, mixed GCTs. Neuroradiological assessment has a pivotal role in the diagnostic work-up, surgical planning, and follow-up of patients with pineal masses. Surgery can represent the mainstay of treatment, ranging from biopsy to gross total resection, yet pineal region tumors associated with obstructive hydrocephalus may be surgically managed via ventricular internal shunt or endoscopic third ventriculostomy. Radiotherapy remains an essential component of the multidisciplinary treatment approach for most pineal region tumors; however, treatment volumes depend on the histological subtypes, grading, extent of disease, and the combination with chemotherapy. For localized germinoma, the current standard of care is chemotherapy followed by reduced-dose whole ventricular irradiation plus a boost to the primary tumor. For pinealoblastoma patients, postoperative radiation has been associated with higher overall survival. For the other pineal tumors, the role of radiotherapy remains poorly studied and it is usually reserved for aggressive (grade 3) or recurrent tumors. The use of systemic treatments mainly depends on histology and prognostic factors such as residual disease and metastases. For pinealoblastoma patients, chemotherapy protocols are based on various alkylating or platinum-based agents, vincristine, etoposide, cyclophosphamide and are used in association with radiotherapy. About GCTs, their chemosensitivity is well known and is based on cisplatin or carboplatin and may include etoposide, cyclophosphamide, or ifosfamide prior to irradiation. Similar regimens containing platinum derivatives are also used for non-germinomatous GCTs with very encouraging results. However, due to a greater understanding of the biology of the disease's various molecular subtypes, new agents based on targeted therapy are expected in the future. On behalf of the EURACAN domain 10 group, we reviewed the most important and recent developments in histopathological characteristics, neuro-radiological assessments, and treatments for pineal region tumors

Anaplastic oligodendrogliomas with 1p19q codeletion have a proneural gene expression profile

<p>Abstract</p> <p>Background</p> <p>In high grade gliomas, 1p19q codeletion and <it>EGFR </it>amplification are mutually exclusive and predictive of dramatically different outcomes. We performed a microarray gene expression study of four high grade gliomas with 1p19q codeletion and nine with <it>EGFR </it>amplification, identified by CGH-array.</p> <p>Results</p> <p>The two groups of gliomas exhibited very different gene expression profiles and were consistently distinguished by unsupervised clustering analysis. One of the most striking differences was the expression of normal brain genes by oligodendrogliomas with 1p19q codeletion. These gliomas harbored a gene expression profile that partially resembled the gene expression of normal brain samples, whereas gliomas with <it>EGFR </it>amplification expressed many genes in common with glioblastoma cancer stem cells. The differences between the two types of gliomas and the expression of neuronal genes in gliomas with 1p19q codeletion were both validated in an independent series of 16 gliomas using real-time RT-PCR with a set of 22 genes differentiating the two groups of gliomas (<it>AKR1C3</it>, <it>ATOH8</it>, <it>BMP2</it>, <it>C20orf42</it>, <it>CCNB1</it>, <it>CDK2</it>, <it>CHI3L1</it>, <it>CTTNBP2</it>, <it>DCX, EGFR, GALNT13, GBP1, IGFBP2, IQGAP1, L1CAM, NCAM1, NOG, OLIG2, PDPN, PLAT, POSTN, RNF135</it>). Immunohistochemical study of the most differentially expressed neuronal gene, alpha-internexin, clearly differentiated the two groups of gliomas, with 1p19q codeletion gliomas showing specific staining in tumor cells.</p> <p>Conclusion</p> <p>These findings provide evidence for neuronal differentiation in oligodendrogliomas with 1p19q codeletion and support the hypothesis that the cell of origin for gliomas with 1p19q codeletion could be a bi-potential progenitor cell, able to give rise to both neurons and oligodendrocytes.</p

Thrombocytopenia limits the feasibility of salvage lomustine chemotherapy in recurrent glioblastoma: a secondary analysis of EORTC 26101

BACKGROUND Thrombocytopenia represents the main cause of stopping alkylating chemotherapy for toxicity. Here, we explored the incidence, and the consequences for treatment exposure and survival, of thrombocytopenia induced by lomustine in recurrent glioblastoma. METHODS We performed a retrospective analysis of the associations of thrombocytopenia with treatment delivery and outcome in EORTC 26101, a randomised trial designed to define the role of lomustine versus bevacizumab versus their combination in recurrent glioblastoma. RESULTS A total of 225 patients were treated with lomustine alone (median 1 cycle) (group 1) and 283 patients were treated with lomustine plus bevacizumab (median 3 lomustine cycles) (group 2). Among cycle delays and dose reductions of lomustine for toxicity, thrombocytopenia was the leading cause. Among 129 patients (57%) of group 1 and 187 patients (66%) of group 2 experiencing at least one episode of thrombocytopenia, 36 patients (16%) in group 1 and 93 (33%) in group 2 had their treatment modified because of thrombocytopenia. Lomustine was discontinued for thrombocytopenia in 16 patients (7.1%) in group 1 and in 38 patients (13.4%) in group 2. On adjusted analysis accounting for major prognostic factors, dose modification induced by thrombocytopenia was associated with inferior progression-free survival in patients with MGMT promoter-methylated tumours in groups 1 and 2. This effect was noted for overall survival, too, but only for group 2 patients. CONCLUSION Drug-induced thrombocytopenia is a major limitation to adequate exposure to lomustine chemotherapy in recurrent glioblastoma. Mitigating thrombocytopenia to enhance lomustine exposure might improve outcome in patients with MGMT promoter-methylated tumours

DGKI Methylation Status Modulates the Prognostic Value of MGMT in Glioblastoma Patients Treated with Combined Radio-Chemotherapy with Temozolomide

International audienceBackgroundConsistently reported prognostic factors for glioblastoma (GBM) are age, extent of surgery, performance status, IDH1 mutational status, and MGMT promoter methylation status. We aimed to integrate biological and clinical prognostic factors into a nomogram intended to predict the survival time of an individual GBM patient treated with a standard regimen. In a previous study we showed that the methylation status of the DGKI promoter identified patients with MGMT-methylated tumors that responded poorly to the standard regimen. We further evaluated the potential prognostic value of DGKI methylation status.Methods399 patients with newly diagnosed GBM and treated with a standard regimen were retrospectively included in this study. Survival modelling was performed on two patient populations: intention-to-treat population of all included patients (population 1) and MGMT-methylated patients (population 2). Cox proportional hazard models were fitted to identify the main prognostic factors. A nomogram was developed for population 1. The prognostic value of DGKI promoter methylation status was evaluated on population 1 and population 2.ResultsThe nomogram-based stratification of the cohort identified two risk groups (high/low) with significantly different median survival. We validated the prognostic value of DGKI methylation status for MGMT-methylated patients. We also demonstrated that the DGKI methylation status identified 22% of poorly responding patients in the low-risk group defined by the nomogram.ConclusionsOur results improve the conventional MGMT stratification of GBM patients receiving standard treatment. These results could help the interpretation of published or ongoing clinical trial outcomes and refine patient recruitment in the future

A new landscape for systemic pharmacotherapy of recurrent glioblastoma?

Glioblastoma is the most common and aggressive primary malignant brain tumor in adult patients [...

ASPM-associated stem cell proliferation is involved in malignant progression of gliomas and constitutes an attractive therapeutic target

<p>Abstract</p> <p>Background</p> <p>ASPM (<it>Abnormal Spindle-like Microcephaly associated</it>) over-expression was recently implicated in the development of malignant gliomas.</p> <p>Results</p> <p>To better characterize the involvement of ASPM in gliomas, we investigated the mRNA expression in 175 samples, including 8 WHO Grade II, 75 WHO Grade III and 92 WHO Grade IV tumors. <it>Aspm </it>expression was strongly correlated with tumor grade and increased at recurrence when compared to the initial lesion, whatever the initial grade of the primary tumor. ASPM expression also increased over serial passages in gliomaspheres <it>in vitro </it>and in mouse xenografts <it>in vivo</it>. Lentivirus-mediated shRNA silencing of ASPM resulted in dramatic proliferation arrest and cell death in two different gliomasphere models.</p> <p>Conclusion</p> <p>These data suggest that ASPM is involved in the malignant progression of gliomas, possibly through expansion of a cancer stem cell compartment, and is an attractive therapeutic target in glioblastoma multiforme.</p

Recurrent glioblastoma: From molecular landscape to new treatment perspectives

Glioblastoma is the most frequent and aggressive form among malignant central nervous system primary tumors in adults. Standard treatment for newly diagnosed glioblastoma consists in maximal safe resection, if feasible, followed by radiochemotherapy and adjuvant chemotherapy with temozolomide; despite this multimodal treatment, virtually all glioblastomas relapse. Once tumors progress after first-line therapy, treatment options are limited and management of recurrent glioblastoma remains challenging. Loco-regional therapy with re-surgery or re-irradiation may be evaluated in selected cases, while traditional systemic therapy with nitrosoureas and temozolomide rechallenge showed limited efficacy. In recent years, new clinical trials using, for example, regorafenib or a combination of tyrosine kinase inhibitors and immunotherapy were performed with promising results. In particular, molecular targeted therapy could show efficacy in selected patients with specific gene mutations. Nonetheless, some molecular characteristics and genetic alterations could change during tumor progression, thus affecting the efficacy of precision medicine. We therefore reviewed the molecular and genomic landscape of recurrent glioblastoma, the strategy for clinical management and the major phase I-III clinical trials analyzing recent drugs and combination regimens in these patients