Setting Of Neurofibromatosis Type Research Articles

NF1-Driven Rhabdomyosarcoma Phenotypes: A Comparative Clinical and Molecular Study of NF1-Mutant Rhabdomyosarcoma and NF1-Associated Malignant Triton Tumor.

Alterations of the NF1 tumor suppressor gene is the second most frequent genetic event in embryonal rhabdomyosarcoma (ERMS), but its associations with clinicopathologic features, outcome, or coexisting molecular events are not well defined. Additionally, NF1 alterations, mostly in the setting of neurofibromatosis type I (NF1), drive the pathogenesis of most malignant peripheral nerve sheath tumor with divergent RMS differentiation (also known as malignant triton tumor [MTT]). Distinguishing between these entities can be challenging because of their pathologic overlap. This study aims to comprehensively analyze the clinicopathologic and molecular spectrum of NF1-mutant RMS compared with NF1-associated MTT for a better understanding of their pathogenesis. We investigated the clinicopathologic and molecular landscape of a cohort of 22 NF1-mutant RMS and a control group of 13 NF1-associated MTT. Cases were tested on a matched tumor-normal hybridization capture-based targeted DNA next-generation sequencing. Among the RMS group, all except one were ERMS, with a median age of 17 years while for MTT the mean age was 39 years. Three MTTs were misdiagnosed as ERMS, having clinical impact in one. The most frequent coexisting alteration in ERMS was TP53 abnormality (36%), being mutually exclusive from NRAS mutations (14%). MTT showed coexisting CDKN2A/B and PRC2 complex alterations in 38% cases and loss of H3K27me3 expression. Patients with NF1-mutant RMS exhibited a 70% 5-year survival rate, in contrast to MTT with a 33% 5-year survival. All metastatic NF1-mutant ERMS were associated with TP53 alterations. Patients with NF1-mutant ERMS lacking TP53 alterations may benefit from dose-reduction chemotherapy. On the basis of the diagnostic challenges and significant treatment and prognostic differences, molecular profiling of challenging tumors with rhabdomyoblastic differentiation is recommended.

Cell-Free DNA Fragmentomics for Early Detection of Malignant Transformation in NF1 Patients Harboring Plexiform Neurofibromas

Malignant peripheral nerve sheath tumors (MPNST) are aggressive soft tissue sarcomas that are resistant to radiotherapy and chemotherapy, and are associated with poor survival. MPNST typically arise from benign or atypical plexiform neurofibromas (PN) in the setting of neurofibromatosis type 1 (NF1). Unfortunately, early detection by imaging and clinical examination remains very challenging. We hypothesize that cell-free DNA fragmentomic analysis can be used to precisely detect the risk for developing MPNST in NF1 patients, which could significantly improve clinical outcomes in the future through early cancer detection. We performed low-pass whole genome sequencing of plasma cell-free DNA samples from healthy controls (n = 21), patients with PN (n = 113), AN (n = 39) and MPNST (n = 71). Cell-free DNA was analyzed at a per-fragment level by tracking 4-nucleotide end motifs, and using a bin-wise fragmentomic machine learning approach called DELFI, which integrates across ratios of short (100-150 bp) versus long (151-220 bp) fragments in 5 megabase bins across the genome. End motif frequencies were compared between MPNST and PN patients, and receiver operating characteristic (ROC) analysis was used to classify disease states using DELFI fragmentomic scores. Using DELFI for genome-wide fragmentomics, followed by ROC analysis, we obtained the following accuracies: MPNST vs. AN (acc 0.62), MPNST vs. PN (acc 0.83), MPNST vs. healthy (acc 0.86), AN vs. PN (acc 0.87), AN vs. healthy (acc 0.72) and PN vs. healthy (acc 0.88). DELFI-based cell-free DNA fragmentomics was superior to the ichor CNA-based copy number alteration classifier that we published previously (Szymanski et al. PLOS Medicine, 2021) for all the aforementioned group comparisons (p < 0.001 by McNemar's test). Strikingly, the two AN cases with DELFI scores most closely resembling MPNST were separately identified by independent clinical care teams to have very high-risk features and recent history warranting short-interval follow up. Specifically, one patient had a paraspinal AN exhibiting new onset pain and rapid growth on imaging, while the other had increased FDG uptake of multiple AN lesions in a supraclavicular field treated years earlier with radiotherapy. We also measured fragment end motifs across different patient groups, and found that the CTCA end motif was more commonly present in cell-free DNA from MPNST and PN patients compared to healthy donors (Bonferroni-corrected p-value < 0.001). This study suggests that fragmentomic analysis of cell-free DNA can accurately risk-stratify NF1 patients with plexiform neurofibromas. Cell-free DNA fragmentomics outperformed our previously published copy number alteration method for distinguishing closely related patient subgroups with different malignancy risks. Atypical neurofibroma patients with cell-free DNA fragmentomic scores suggestive of MPNST were deemed clinically very high-risk for malignant transformation.

Hyperplasia of Arachnoid Trabecular Cells: A Hitherto Undescribed Lesion Observed in the Setting of Neurofibromatosis Type 1.

Central nervous system manifestations, a variety of benign and malignant tumors as well as non-neoplastic abnormalities, are found in over 70% of neurofibromatosis type 1 (NF1) patients. Herein, we report hitherto undescribed space-occupying lesions in the setting of NF1. We aimed to clarify their characteristics, especially whether they represent neoplastic or non-neoplastic (hyperplastic) lesions. All 3 cases were preoperatively assessed as non-neoplastic; 2 and 1 cases were suspected to be arachnoid cysts and dilation of subarachnoid space, respectively. However, all lesions were revealed to be whitish jelly-like masses by operation, and the histology composed of spindle cells resembling arachnoid trabecular cells with moderate cellularity and cellular uniformity gave an impression that these lesions may be neoplastic. In contrast, electron microscopic analysis showed that the characteristics of these cells were compatible with those of normal arachnoid trabecular cells. Furthermore, whole-exome sequencing and array comparative genomic hybridization did not show any obvious alterations suggestive of their neoplastic nature. DNA methylation analysis demonstrated that these lesions were epigenetically distinct not only from meningiomas but also from normal healthy meninges. In conclusion, considering the clinicopathologic aspects of the present lesions and the results of the molecular analysis that failed to suggest their neoplastic nature, they may represent previously unrecognized rare hyperplasia of arachnoid trabecular cells, which may be associated with NF1.

RRM2 as a novel prognostic and therapeutic target of NF1-associated MPNST.

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas that typically develop in the setting of neurofibromatosis type 1 (NF1) and cause significant morbidity. Conventional therapies are often ineffective for MPNSTs. Ribonucleotide reductase subunit M2 (RRM2) is involved in DNA synthesis and repair, and is overexpressed in multiple cancers. However, its role in NF1-associated MPNSTs remains unknown. Our objective was to determine the therapeutic and prognostic potential of RRM2 in NF1-associated MPNSTs. Identification of hub genes was performed by using NF1-associated MPNST microarray datasets. We detected RRM2 expression by immunochemical staining in an MPNST tissue microarray, and assessed the clinical and prognostic significance of RRM2 in an MPNST cohort. RRM2 knockdown and the RRM2 inhibitor Triapine were used to assess cell proliferation and apoptosis in NF1-associated MPNST cells in vitro and in vivo. The underlying mechanism of RRM2 in NF1-associated MPNST was revealed by transcriptome analysis. RRM2 is a key hub gene and its expression is significantly elevated in NF1-associated MPNST. We revealed that high RRM2 expression accounted for a larger proportion of NF1-associated MPNSTs and confirmed the correlation of high RRM2 expression with poor overall survival. Knockdown of RRM2 inhibited NF1-associated MPNST cell proliferation and promoted apoptosis and S-phase arrest. The RRM2 inhibitor Triapine displayed dose-dependent inhibitory effects in vitro and induced significant tumor growth reduction in vivo in NF1-associated MPNST. Analysis of transcriptomic changes induced by RRM2 knockdown revealed suppression of the AKT-mTOR signaling pathway. Overexpression of RRM2 activates the AKT pathway to promote NF1-associated MPNST cell proliferation. RRM2 expression is significantly elevated in NF1-associated MPNST and that high RRM2 expression correlates with poorer outcomes. RRM2 acts as an integral part in the promotion of NF1-associated MPNST cell proliferation via the AKT-mTOR signaling pathway. Inhibition of RRM2 may be a promising therapeutic strategy for NF1-associated MPNST.

Abstract 997: Cell-free DNA fragmentomics distinguish between benign, pre-malignant and malignant peripheral nerve sheath tumors in neurofibromatosis type 1

Abstract Background: Malignant peripheral nerve sheath tumors (MPNST) are aggressive soft tissue sarcomas that, in the setting of neurofibromatosis type 1 (NF1), arise within pre-malignant atypical neurofibroma (AN) and benign plexiform neurofibroma (PN). Early surgical resection improves prognosis, however, early detection by imaging and tissue biopsies is challenging due to tissue heterogeneity. In this multi-institutional study we analyze fragmentomic profiles of plasma cell free DNA (cfDNA) to non-invasively distinguish between NF1 associated PN, AN and MPNST. Accurate classification would inform clinical care: standards of care for PN is observation, AN is narrow-margin resection, and MPNST is wide-margin resection. Methods: We performed whole genome sequencing of plasma cfDNA samples from healthy controls (n = 21), patients with PN (n = 113), AN (n = 39) and MPNST (n = 71). cfDNA fragment profiles were analyzed using two complementary approaches. First, we used unsupervised non-negative matrix factorization (NMF) to obtain global fragment length signatures to infer tumor fragment length distributions. The optimal cutpoint was determined after receiver operating characteristic analysis by Youden’s index in one-versus-one (OVO) disease state comparisons. Additionally, we implemented a bin-wise fragmentomic analysis based on DELFI, training a classifier on the ratios of short (100-150bp) and long (151-220bp) fragments in 5 megabase regions across the genome and arm-level features. Results: NMF accurately distinguished disease states on OVO comparisons: MPNST v AN (acc 0.71), MPNST v PN (acc 0.75), MPNST v healthy (acc 0.84), AN v PN (acc 0.70), AN v healthy (acc 0.80) and PN v healthy (acc 0.87). Accuracies were moderately improved in nearly all conditions with bin-wise fragmentomics: MPNST v AN (acc 0.62), MPNST v PN (acc 0.83), MPNST vs healthy (acc 0.86), AN v PN (acc 0.87), AN vs healthy (acc 0.72) and PN vs healthy (acc 0.88). Strikingly, the two AN with the DELFI scores most closely resembling MPNST were separately identified by independent clinical care teams to have very high-risk features and recent history warranting short-interval follow up. Conclusions: This study demonstrates that the spectrum of benign, pre-malignant and malignant peripheral nerve sheath tumors have distinct, disease state specific fragmentomic signatures. Fragmentomics alone outperformed our previously published copy number based cfDNA classifier in all conditions, most notably in low mutational burden healthy, PN and AN states. Finally, preliminary clinical vignettes suggest that this approach may be able to inform surveillance intervals by identifying higher risk premalignant lesions. Together, this work has the potential to enable earlier detection of clinically actionable AN and early-stage MPNST, thereby improving survival outcomes. Citation Format: Alex C. Pan, Russell Taylor Sundby, Jeffrey J. Szymanski, Paul A. Jones, Peter K. Harris, Aadel A. Chaudhuri, Angela C. Hirbe, Jack F. Shern. Cell-free DNA fragmentomics distinguish between benign, pre-malignant and malignant peripheral nerve sheath tumors in neurofibromatosis type 1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 997.

Malignant peripheral nerve sheath tumor in children: A clinicopathologic and molecular study with parallels to the adult counterpart.

Malignant peripheral nerve sheath tumors (MPNST) are aggressive neoplasms, arising either sporadically, in the setting of neurofibromatosis type I (NF1) or post radiation. Most MPNST occur in adults and their pathogenesis is driven by the loss of function mutations in the PRC2 complex, regardless of their clinical presentation. In contrast, pediatric MPNST are rare and their pathogenesis has not been elucidated. In this study, we investigate a large cohort of 64 MPNSTs arising in children and young adults (younger than the age of 20 years) to better define their clinicopathologic and molecular features. Sixteen (25%) cases were investigated by MSK-IMPACT, a targeted NGS panel of 505 cancer genes. Most patients (80%) were aged 11-20 years. A history of NF1 was established in half of the cases. Mean tumor size was 8.5cm. The most common locations included the extremities (34%) and abdomen/pelvis (27%). Histologically, 89% of high-grade MPNST showed conventional features, while the remaining three cases showed a predominant epithelioid phenotype. Heterologous differentiation occurred in 25% of high grade cases, with half showing rhabdomyoblastic differentiation. Tumors arose in a background of a plexiform neurofibroma (16%), neurofibroma (13%), and schwannoma in two cases (3%). Immunohistochemically, H3K27me3 expression was lost in 82% of conventional high-grade MPNST analyzed, while loss of SMARCB1 expression was seen in one epithelioid MPNST. Genomically, all cases showed more than one genetic abnormality, with 53% showing mutations in EED / SUZ12 genes, and 47% of cases harboring alterations in NF1 and CDKN2A/CDKN2B genes. At the last follow-up, 30% patients died of disease, 28% were alive with disease and 42% had no evidence of disease. NF1 status did not correlate with overall survival. In conclusion, half of pediatric and young adult MPNST were NF1-related and showed loss of function alterations in PRC2 complex, NF1, and CDKN2A, similar to the adult counterpart. Thus, H3K27me3 loss of expression may be used in the diagnosis of high grade MPNSTs in children. Moreover, a small subset of pediatric MPNST have an epithelioid morphology with different pathogenesis.

56. Chr8 gain is associated with MPNST transformation

Malignant Peripheral Nerve Sheath Tumors, or MPNST, are a rare and aggressive tumor accounting for 4% of all sarcomas that often arise from transformation of a benign precursor tumor (Plexiform Neurofibroma or PN). The majority arise sporadically or in the setting of Neurofibromatosis type 1 (NF1), and when advanced or unresectable, can be difficult to treat effectively. Despite advances in our understanding of MPNST pathobiology, there exist few effective therapeutic options, and clinical trials have not identified any successful investigational agents. Hence, there is a pressing need to better understand the molecular drivers underlying MPNST development and progression. Though our work aimed to better understand the genomic heterogeneity of MPNST, we identified Chr8q gain as a near universal event in MPNST. Chr8q gain was observed in >90% of the cells and was associated with poor overall survival (OS) in soft tissue sarcomas. We found six known cancer drivers residing on Chr8q (RECQL4, SOX17, HEY1, C-MYC, RAD21, and UBR5) that were highly expressed in MPNST, but not benign precursor PN by bulk RNA-seq data. Through CRISPR knockdown experiments, we found that UBR5 is critical for MPNST proliferation and migration. These data suggest that chr8q gain is a critical event in MPNST pathogenesis, at least in part due to expression of UBR5, and may account for the aggressive nature and poor clinical outcomes in this sarcoma subtype.

Metastatic Bilateral Internal Auditory Canal Invasion Mimicking Neurofibromatosis Type 2

Bilateral internal auditory canal (IAC) tumors are usually pathognomonic for vestibular schwannomas in the setting of neurofibromatosis type 2 (NF2). Descriptions of bilateral nonschwannomatous IAC tumors, such as metastasis that may mimic NF2, are limited to case reports. Here, we report a case of unusual metastatic bilateral IAC tumor originating from the ovary with a rapidly progressive pattern, which we initially suspected to be NF2.

S3416 Gastrointestinal Stromal Tumor Presenting as Small Bowel Obstruction in the Setting of Neurofibromatosis Type 1

S3416 Gastrointestinal Stromal Tumor Presenting as Small Bowel Obstruction in the Setting of Neurofibromatosis Type 1

Multiplatform molecular analyses refine classification of gliomas arising in patients with neurofibromatosis type 1

Gliomas arising in the setting of neurofibromatosis type 1 (NF1) are heterogeneous, occurring from childhood through adulthood, can be histologically low-grade or high-grade, and follow an indolent or aggressive clinical course. Comprehensive profiling of genetic alterations beyond NF1 inactivation and epigenetic classification of these tumors remain limited. Through next-generation sequencing, copy number analysis, and DNA methylation profiling of gliomas from 47 NF1 patients, we identified 2 molecular subgroups of NF1-associated gliomas. The first harbored biallelic NF1 inactivation only, occurred primarily during childhood, followed a more indolent clinical course, and had a unique epigenetic signature for which we propose the terminology “pilocytic astrocytoma, arising in the setting of NF1”. The second subgroup harbored additional oncogenic alterations including CDKN2A homozygous deletion and ATRX mutation, occurred primarily during adulthood, followed a more aggressive clinical course, and was epigenetically diverse, with most tumors aligning with either high-grade astrocytoma with piloid features or various subclasses of IDH-wildtype glioblastoma. Several patients were treated with small molecule MEK inhibitors that resulted in stable disease or tumor regression when used as a single agent, but only in the context of those tumors with NF1 inactivation lacking additional oncogenic alterations. Together, these findings highlight recurrently altered pathways in NF1-associated gliomas and help inform targeted therapeutic strategies for this patient population.

PATH-40. SPORADIC NF2 WILD-TYPE MULTIPLE MENINGIOMAS HARBOR DISTINCT DRIVER MUTATIONS

Abstract OBJECTIVE Multiple meningiomas (MM) are rare and present a unique management challenge. While the mutational landscape of single meningiomas has been extensively studied, understanding the molecular pathogenesis of sporadic MM remains incomplete. The objective of this study is to elucidate the genetic features of sporadic MM. METHODS We identified nine patients with MM (n=19) defined as ≥2 spatially separated synchronous or metachronous meningiomas. We profiled genetic changes in these tumors using next-generation sequencing (NGS) assay that covers a large number of targetable and frequently mutated genes in meningiomas including AKT1, KLF4, NF2, PIK3CA/PIK3R1, POLR2A, SMARCB1, SMO, SUFU, TRAF7, and the TERT promoter. RESULTS Most of MM were WHO grade 1 (n= 16, 84.2%). Within individual patients, no driver mutation was shared between separate tumors. All but two cases harbored different hot spot mutations in known meningioma-driver genes like TRAF7 (n= 5), PIK3CA (n= 4), AKT1 (n= 3), POLR2A (n=1) and SMO (n= 1). Moreover, individual tumors differed in histologic subtype in 8/9 patients. The low frequency of NF2 mutations in our series stands in contrast to previous studies that included hereditary cases arising in the setting of neurofibromatosis type 2 (NF2). CONCLUSIONS Our findings provide evidence for genomic inter-tumor heterogeneity and an independent molecular origin of sporadic NF2 wild-type MM. Furthermore, these findings suggest that genetic characterization of each lesion is warranted in sporadic MM.

P04.14 Sporadic wild-type multiple meningiomas harbor distinct driver mutations

Abstract BACKGROUND Multiple meningiomas (MM) are rare and present a unique management challenge. While the mutational landscape of single meningiomas has been extensively studied, understanding of the molecular pathogenesis of sporadic MM remains incomplete. The objective of this study is to elucidate the genetic features of sporadic MM. MATERIAL AND METHODS We identified eight patients with MM (n=17) defined as ≥2 spatially separated synchronous or metachronous meningiomas. We profiled genetic changes in these tumors using a next generation sequencing (NGS) assay that covers a large number of targetable and frequently mutated genes in meningiomas including AKT1, KLF4, NF2, PIK3CA/PIK3R1, POLR2A, SMARCB1, SMO, SUFU, TRAF7, and the TERT promoter. RESULTS Most of MM were WHO grade 1 (n= 14, 82.3%). Within individual patients, no driver mutation was shared between separate tumors. All but two cases harbored different hot spot mutations in known meningioma-driver genes like TRAF7 (n= 5), PIK3CA (n= 3), AKT1 (n= 3) and SMO (n= 1). Moreover, individual tumors differed in histologic subtype in 7/8 patients. The low frequency of NF2 mutations in our series stands in contrast to previous studies that included hereditary cases arising in the setting of neurofibromatosis type 2 (NF2). CONCLUSION Our findings provide evidence for genomic inter-tumor heterogeneity and an independent molecular origin of sporadic NF2 wild-type MM. Furthermore, these findings suggest that genetic characterization of each lesion is warranted in sporadic MM.

Status and Recommendations for Incorporating Biomarkers for Cutaneous Neurofibromas Into Clinical Research.

To summarize existing biomarker data for cutaneous neurofibroma (cNF) and to inform the incorporation of biomarkers into clinical trial design for cNFs. The cNF working group, a subgroup of the Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) consortium, was formed to review and inform clinical trial design for cNFs. Between June 2018 and February 2020, the cNF working group performed a review of existing data on genetic biomarkers for cNFs in the setting of neurofibromatosis type 1. We also reviewed criteria for successful biomarker application in the clinic. The group then held a series of meetings to develop a consensus report. Our systematic literature review of existing data revealed a lack of validated biomarkers for cNFs. In our report, we summarize the existing signaling, genomic, transcriptomic, histopathologic, and proteomic data relevant to cNF. Finally, we make recommendations for incorporating exploratory aims for predictive biomarkers into clinical trials through biobanking samples. These recommendations are intended to provide both researchers and clinicians with best practices for clinical trial design to aid in the identification of clinically validated biomarkers for cNF.

High Expression of Solute Carrier Family 2 Member 1 (SLC2A1) in Cancer Cells Is an Independent Unfavorable Prognostic Factor in Pediatric Malignant Peripheral Nerve Sheath Tumor.

Malignant peripheral nerve sheath tumor (MPNST) in children is a rare mesenchymal malignancy developing predominantly in the setting of neurofibromatosis type 1. The prognosis in advanced MPNST is poor therefore new prognostic markers are highly needed for optimal therapeutic decisions. In many solid tumors, the bidirectional interactions between hypoxia and inflammation in the tumor microenvironment via functions of tumor-associated cells, like neutrophils, lymphocytes and macrophages, have been investigated recently. There is no data whether in MPNST hypoxic microenvironment may translate into systemic inflammation, which is a well-established factor for worse prognosis in cancer patients. Therefore, we investigated the prognostic significance of markers of tumor hypoxia and systemic inflammation in 26 pediatric malignant peripheral nerve sheath tumors (MPNST). Tumor tissue microarrays were stained for hypoxia-inducible factor-1α (HIF1A), solute carrier family 2 member 1 (SLC2A1, also known as glucose transporter 1 (GLUT1)), carbonic anhydrase 9 (CA9), and vascular endothelial growth factor A (VEGFA) and classified into low- or high-expression groups. Baseline complete blood counts and C-reactive protein (CRP) levels were collected for all cases. Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) were calculated from age-adjusted complete blood count parameters. Both 10-year RFS and OS were significantly lower in patients with high NLR values (17% vs. 75%, p = 0.009, q = 0.018; and 31% vs. 100%, p = 0.0077, q = 0.014; respectively). Ten-year-OS was significantly lower in patients with high expression of SLC2A1 (20.00% vs. 94%, p < 0.001, log-rank), high expression of HIF1A (23% vs. 79%, p = 0.016, log-rank), and CRP higher than 31 mg/L (11% vs. 82%, p = 0.003, q = 0.009). Cox’s proportional hazard regression analysis revealed that high expression of SLC2A1 (HR = 3.31, 95% CI = 1.08–10.09, p = 0.036) and VEGFA (HR = 4.40, 95% CI = 0.95–20.34, p = 0.058) were the independent factors predicting relapse, whereas high SLC2A1 was identified as the independent risk factor for death (HR = 12.20, 95% CI = 2.55–58.33, p = 0.002). Patients with high expression of hypoxic markers and low or high NLR/CRP values had the highest events rate, patients with low hypoxic markers and high NLR/CRP had intermediate events rate, while patients with low hypoxic markers and low NLR/CRP had the lowest events rate. SLC2A1 and VEGFA are promising novel prognostic factors in pediatric MPNST. Correlations between hypoxic and systemic inflammatory markers suggest the interplay between local tumor hypoxia and systemic inflammation.

Ankle Malignant Peripheral Nerve Sheath Tumor in A Neurofibromatosis I Patient: A Case Report and Review the Literature

1.1. Introduction: Malignant Peripheral Nerve Sheath Tumors (MPNST) are rare and aggressive sarcomata’s tumors with an overall incidence of 0.001% [1] derived from Schwann cells or pluripotent cells of the neural crest [2-8]. MPNSTs are typically seen in patients aged 20-50 years, and usually in the setting of Neuro Fibromatosis Type 1(NF1) and following radiation therapy [8]. The most common sites are the trunk and extremities followed by the head and neck area [7, 8]. 1.2. Presentation of The Case: This case reports a 50-year-old man with a previous diagnosis five years ago of a Plexiform Neuro Fibroma (NF) in the posterior distal third of the right leg and ankle. In this case, we review the most important pathological findings and review the literature by reason of the rarity of this lesion. Actually, the patient is currently on regular follow-up and ongoing disease extension study in another hospital for surgical or oncologic treatment decision. 1.3. Discussion: The majority of MPNSTs are derived from neuro fibroma or they arise de novo in normal peripheral nerves [9, 2]. It is important to focus on the correct diagnosis and especially in the differential diagnosis with other tumors that can mimic MPNST, which include desmoplastic and metastatic melanomas, as well as synovial sarcoma and fibrosarcomatous dermatofibrosarcoma protuberans [10, 11]. In this article, we discuss a case of a patient with a previous diagnosis of plexiform neuro fibroma that some years later presents as an enlarging painful mass that extends to the ankle, a rare location for these tumors as described on the pathological findings and review in the literature. 1.4. Conclusion: MPNSTs are very rare sheath tumors that must be suspected in patients with NF1, especially with a previous diagnosis or another benign lesion, because this is very aggressive and rapidly growing disease.

Intra-Orbital Meningioma Causing Loss of Vision in Neurofibromatosis Type 2: Case Series and Management Considerations.

Objectives: Little evidence exists regarding the management of orbital meningioma causing vision loss in the setting of neurofibromatosis Type 2 (NF2). We review here our experience with patients at risk for blindness due to intra-orbital meningioma.Design/Setting/Participants/Main Outcome Measures: The charts of patients with NF2 presenting for evaluation of intra-orbital meningioma and vision impairment between 2008 and 2013 were retrospectively reviewed in accordance with institutional IRB policies. Patients with primarily extra-orbital tumors and minimal intra-orbital extension were excluded. Charts were analyzed for the presence and/or imaging progression of intra-orbital tumor, presence of other optic apparatus pathology, presence and/ or progression of vision impairment, and intervention performed (if any).Results: Seven patients with intra-orbital meningioma on MRI and bilateral vision loss and/or unilateral visual impairment due to tumor and contralateral blindness of any etiology were identified. Patients without salvageable vision in either eye were excluded (n = 3). Diagnosis of meningioma was obtained either by biopsy or based on imaging assessment.Conclusion: Conservative management of orbital tumors in NF2 may be preferred in asymptomatic patients but may not be acceptable in patients with progressive visual decline. Radiation is a reasonable option for meningiomas of the orbit and optic nerve sheath. Finally, although the benefit of cranial nerve decompression in NF2 for preservation of facial nerve and hearing has previously been established, the role of optic nerve decompression for preservation of vision in NF2 remains poorly defined.

Composite Pheochromocytoma/Paraganglioma-Ganglioneuroma: A Clinicopathologic Study of Eight Cases with Analysis of Succinate Dehydrogenase.

Ganglioneuromas represent the most well-differentiated spectrum of neoplasia arising from the sympathetic nervous system, while neuroblastomas represent the most poorly differentiated counterpart, and ganglioneuroblastomas represent intermediate stages of differentiation. Small series of cases have documented the co-occurrence of ganglioneuroma with a pheochromocytoma (Pheo)/paraganglioma (PGL) component. We report the clinicopathologic features of eight such cases, diagnosed between 2003 and 2015 with a mean follow-up of 22months (1-47), which were evaluated for syndrome associations, SDHB expression, and clinical outcome. Mutations of the succinate dehydrogenase (SDH) complex subunits (A, B, C, D, and SDHAF2) have been implicated in predicting metastatic behavior and in identifying possible paraganglioma syndromes. The proliferative index was calculated by manual quantification of Ki-67-positive cells at selected hot-spots using ImageJ (NIH). In our series, composite Pheo/PGL-ganglioneuromas predominantly involved the adrenal gland (Pheo 7, PGL 1). The cases had an equal gender distribution (males 4, females 4), with a mean age at diagnosis of 67years (range 53 to 86years), an average size of 5.2cm (range 2 to 8.2cm), an average weight of 49.3g (7.8 to 144.7g, n=6), and the majority were functionally active (7 of 8, 88%). The mean Ki67 proliferation rate was 2% (range 0.3 to 3%), and all cases retained SDHB expression (8/8, 100%). No patient (0/8, 0%) developed metastatic disease on follow-up. One patient had a retroperitoneal composite PGL-ganglioneuroma in the setting of neurofibromatosis type 1. No recurrent disease or other associations were identified. In our study, composite Pheo/PGL-ganglioneuromas predominantly affected the adrenal gland in older patients, showed no loss of SDHB, and no disease recurrence was identified.

Extradural spinal schwannoma in a 5 year old non NF child: A rare entity

Abstract Pediatric spinal schwannomas constitute 2.5-4% of all pediatric spinal tumors. They often occur in the setting of neurofibromatosis type 2 (NF-2) and are almost always intradural (with/without dumbbell extension). Rarely are they confined to extradural space alone. Till date only one case of totally extradural lumbosacral schwannoma in a non NF child has been reported. We here report the second case of totally extradural spinal schwannoma in a non NF child. A five year old female child presented with progressively increasing paraperesis and bladder symptoms, with no clinical features of Neurofibromatosis type I or II. Imaging revealed a dorsolumbar extradural lesion from DV11 to LV1. Patient underwent laminoplasty with total excision of tumour. Intraoperatively, the tumor was confined to extradural space alone. Histopathology confirmed Schwannoma. This case highlights that possibility of schwannomas should be considered as a differential diagnosis for intraspinal extradural tumors even in children without NF.

Acquired and Congenital Abnormalities of the Pediatric Globe and Optic Nerve

Abnormalities of the pediatric globe and optic nerve present with different clinical features than adults. While many of these lesions are benign, most have a significant impact on vision, and therefore, the radiologist can play a key role in patient care. This article will review the radiologic features of retinoblastoma, the most common pediatric orbital tumor, as well as other congenital abnormalities such as persistent hyperplastic primary vitreous, Coats disease, and retinopathy of prematurity. Abnormalities of globe development, such as coloboma and vascular lesions, will also be discussed, as these should prompt imaging of the entire neuroaxis due to association with systemic syndromes. Tumors of the optic nerve can also unmask an underlying syndrome, the most common being an optic nerve glioma occurring in the setting of neurofibromatosis type I.

Hippocampal Sclerosis Associated Temporal Lobe Epilepsy Surgery in the Setting of Neurofibromatosis

Objectives: Epilepsy is relatively uncommon in the setting of neurofibromatosis type I (incidence of 4%-7%) and usually amenable to pharmacotherapy. In those with refractory disease, resection of the epileptogenic focus can be helpful. Despite its high prevalence in the epilepsy surgery population, hippocampal sclerosis has only rarely been reported in the setting of neurofibromatosis type I. Methods: …