What’s new in nerve sheath tumors Meyer, Anders; Billings, Steven D.
Virchows Archiv : an international journal of pathology,
2020/1, Letnik:
476, Številka:
1
Journal Article
Recenzirano
Peripheral nerve sheath tumors are commonly encountered and frequently pose challenges to the pathologist and the clinician. This review discusses the wide range of entities with an emphasis on new ...discoveries in the past decade. Clinical, histologic, immunohistochemical, and pathogenetic findings are discussed with an emphasis on clinical implications and differential diagnosis.
Oligodendrocyte pathology is increasingly implicated in neurodegenerative diseases as oligodendrocytes both myelinate and provide metabolic support to axons. In multiple sclerosis (MS), demyelination ...in the central nervous system thus leads to neurodegeneration, but the severity of MS between patients is very variable. Disability does not correlate well with the extent of demyelination
, which suggests that other factors contribute to this variability. One such factor may be oligodendrocyte heterogeneity. Not all oligodendrocytes are the same-those from the mouse spinal cord inherently produce longer myelin sheaths than those from the cortex
, and single-cell analysis of the mouse central nervous system identified further differences
. However, the extent of human oligodendrocyte heterogeneity and its possible contribution to MS pathology remain unknown. Here we performed single-nucleus RNA sequencing from white matter areas of post-mortem human brain from patients with MS and from unaffected controls. We identified subclusters of oligodendroglia in control human white matter, some with similarities to mouse, and defined new markers for these cell states. Notably, some subclusters were underrepresented in MS tissue, whereas others were more prevalent. These differences in mature oligodendrocyte subclusters may indicate different functional states of oligodendrocytes in MS lesions. We found similar changes in normal-appearing white matter, showing that MS is a more diffuse disease than its focal demyelination suggests. Our findings of an altered oligodendroglial heterogeneity in MS may be important for understanding disease progression and developing therapeutic approaches.
Malignant Peripheral Nerve Sheath Tumors Farid, Mohamad; Demicco, Elizabeth G.; Garcia, Roberto ...
The oncologist (Dayton, Ohio),
February 2014, Letnik:
19, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Learning Objectives
Explain the characteristics and treatment of malignant peripheral nerve sheath tumors, both in relation to neurofibromatosis type I and otherwise.
Cite the unique challenges in ...optimal management of malignant peripheral nerve sheath tumors.
Appraise the large amount of new data surrounding the potential molecular drivers, possible targets for therapy in this disease.
Malignant peripheral nerve sheath tumors (MPNST) are uncommon, biologically aggressive soft tissue sarcomas of neural origin that pose tremendous challenges to effective therapy. In 50% of cases, they occur in the context of neurofibromatosis type I, characterized by loss of function mutations to the tumor suppressor neurofibromin; the remainder arise sporadically or following radiation therapy. Prognosis is generally poor, with high rates of relapse following multimodality therapy in early disease, low response rates to cytotoxic chemotherapy in advanced disease, and propensity for rapid disease progression and high mortality. The last few years have seen an explosion in data surrounding the potential molecular drivers and targets for therapy above and beyond neurofibromin loss. These data span multiple nodes at various levels of cellular control, including major signal transduction pathways, angiogenesis, apoptosis, mitosis, and epigenetics. These include classical cancer‐driving genetic aberrations such as TP53 and phosphatase and tensin homolog (PTEN) loss of function, and upregulation of mitogen‐activated protein kinase (MAPK) and (mechanistic) target of rapamycin (TOR) pathways, as well as less ubiquitous molecular abnormalities involving inhibitors of apoptosis proteins, aurora kinases, and the Wingless/int (Wnt) signaling pathway. We review the current understanding of MPNST biology, current best practices of management, and recent research developments in this disease, with a view to informing future advancements in patient care.
Malignant peripheral nerve sheath tumors are amongst the most challenging mesenchymal malignancies to treat. Their frequent association with a seemingly simple genetic aberration—the loss of the tumor suppressor gene neurofibromin—belies genomic complexity that has rendered effective therapy elusive to date. This review aims to detail elements of current optimal clinical management and summarize recent data on potential molecular drivers and targets, with a view to charting the course for future progress in patient care.
Observing the structure and regeneration of the myelin sheath in peripheral nerves following injury and during repair would help in understanding the pathogenesis and treatment of neurological ...diseases caused by an abnormal myelin sheath. In the present study, transmission electron microscopy, immunofluorescence staining, and transcriptome analyses were used to investigate the structure and regeneration of the myelin sheath after end-to-end anastomosis, autologous nerve transplantation, and nerve tube transplantation in a rat model of sciatic nerve injury, with normal optic nerve, oculomotor nerve, sciatic nerve, and Schwann cells used as controls. The results suggested that the double-bilayer was the structural unit that constituted the myelin sheath. The major feature during regeneration was the compaction of themyelin sheath, wherein the distance between the 2 layers of cell membrane in the double-bilayer became shorter and the adjacent double-bilayers tightly closed together and formed the major dense line. The expression level of myelin basic protein was positively correlated with the formation of the major dense line, and the compacted myelin sheath could not be formed without the anchoring of the lipophilin particles to the myelin sheath.
Purpose
Malignant peripheral nerve sheath tumors are extremely rare in the general population and display a predilection for metastasis to the lungs. Here, we present a rare case of a malignant ...peripheral nerve sheath tumor located in the paraspinal region and highlight the importance of preoperative biopsy in diagnosis of spinal epidural peripheral nerve sheath tumors.
Methods
We describe the clinical course of the patient as well as the radiological and pathological findings of the tumor.
Results
A 14-year-old girl presented with a six-month history of sacral pain. Occasionally she experienced left leg pain and abnormal gait. General physical examination revealed sensorial loss in the L5–S1 regions. T1-weighted sagittal MRI showed a hypointense oval mass and the contrast-enhanced T1-weighted axial MRI image showed heterogeneous enhancement of the tumor. On CT imaging, this tumor characteristically appears as a dumbbell-like mass with punctate calcification and widening L5–S1 intervertebral foramen. Complete resection was performed using an anterior approach. Intraoperative pathological examination revealed evidence of malignancy and subsequent immunohistochemical analysis of the tumor confirmed the diagnosis of MPNST. The postoperative course was uneventful and the patient has had significant improvement in her symptoms 1 month postoperatively.
Conclusions
Preoperative biopsy should be routinely performed for pathological differential diagnosis of spinal epidural PNSTs as well as surgical decision-making. Furthermore a combination of clinical manifestation, radiological findings and biopsy should also be pursued for diagnosing these tumors.
Age-associated decline in regeneration capacity limits the restoration of nervous system functionality after injury. In a model for demyelination, we found that old mice fail to resolve the ...inflammatory response initiated after myelin damage. Aged phagocytes accumulated excessive amounts of myelin debris, which triggered cholesterol crystal formation and phagolysosomal membrane rupture and stimulated inflammasomes. Myelin debris clearance required cholesterol transporters, including apolipoprotein E. Stimulation of reverse cholesterol transport was sufficient to restore the capacity of old mice to remyelinate lesioned tissue. Thus, cholesterol-rich myelin debris can overwhelm the efflux capacity of phagocytes, resulting in a phase transition of cholesterol into crystals and thereby inducing a maladaptive immune response that impedes tissue regeneration.
Oligodendrocytes wrap nerve fibres in the central nervous system with layers of specialized cell membrane to form myelin sheaths
. Myelin is destroyed by the immune system in multiple sclerosis, but ...myelin is thought to regenerate and neurological function can be recovered. In animal models of demyelinating disease, myelin is regenerated by newly generated oligodendrocytes, and remaining mature oligodendrocytes do not seem to contribute to this process
. Given the major differences in the dynamics of oligodendrocyte generation and adaptive myelination between rodents and humans
, it is not clear how well experimental animal models reflect the situation in multiple sclerosis. Here, by measuring the integration of
C derived from nuclear testing in genomic DNA
, we assess the dynamics of oligodendrocyte generation in patients with multiple sclerosis. The generation of new oligodendrocytes was increased several-fold in normal-appearing white matter in a subset of individuals with very aggressive multiple sclerosis, but not in most subjects with the disease, demonstrating an inherent potential to substantially increase oligodendrocyte generation that fails in most patients. Oligodendrocytes in shadow plaques-thinly myelinated lesions that are thought to represent remyelinated areas-were old in patients with multiple sclerosis. The absence of new oligodendrocytes in shadow plaques suggests that remyelination of lesions occurs transiently or not at all, or that myelin is regenerated by pre-existing, and not new, oligodendrocytes in multiple sclerosis. We report unexpected oligodendrocyte generation dynamics in multiple sclerosis, and this should guide the use of current, and the development of new, therapies.
•Both radiation-induced and neurofibromatosis-associated MPNSTs have poorer prognosis than sporadic MPNSTs.•Complete resection of the tumor is a significant prognostic factor for MPNST.•Surgery with ...adjuvant radiotherapy is related to improved local control in patients with positive surgical margins.
Malignant peripheral nerve sheath tumors (MPNST) may be sporadic or associated with neurofibromatosis or prior radiation. MPNST may behave aggressively with a high rate of local recurrence and distant metastasis.
In an IRB approved protocol, we reviewed the clinical characteristics, treatment, and outcomes of 280 patients treated for MPNST at Massachusetts General Hospital (MGH) between 1960 and 2016.
There were 138 men and 142 women with a median age of 41 (range: 3–95) years. Tumors were classified as neurofibromatosis-associated (nfMPNST, n = 77), radiation-induced (rMPNST, n = 21), or sporadic (sMPNST, n = 182) MPNST. The median time to development of rMPNST from prior radiation was 15 years. With a median follow-up of 43.1 months, the median overall survival (OS) was 65.3 months. Older age, nfMPNST, rMPNST, increased tumor size, lymph node involvement, metastatic disease, intermediate to high grade, radiotherapy alone, and R2 resection were related to worse OS, whereas surgery with radiotherapy was associated with improved OS. Among the 251 patients without metastasis, nfMPNST, rMPNST, and increased tumor size were correlated with worse metastasis-free survival; nfMPNST, radiotherapy alone, and R1/R2 resection were associated with local recurrence, whereas surgery with adjuvant radiotherapy was related to improved local control in patients with R1/R2 resection.
Both radiation-induced and neurofibromatosis-associated MPNSTs have poorer prognosis than sporadic MPNSTs. Complete resection of the tumor is a significant prognostic factor for MPNST. The addition of radiotherapy after surgery should be considered especially when the surgical margins are positive.
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