Peripheral nerve sheath tumors are common neoplasms, with classic identifiable features, but on occasion, they are diagnostically challenging. Although well-defined subtypes of peripheral nerve ...sheath tumors were described early in the history of surgical pathology, controversies regarding the classification and grading of these tumors persist. Advances in molecular biology have provided new insights into the nature of the various peripheral nerve sheath tumors, and have begun to suggest novel targeted therapeutic approaches. In this review, we discuss current concepts and problematic areas in the pathology of peripheral nerve sheath tumors. Diagnostic criteria and differential diagnosis for the major categories of nerve sheath tumors are proposed, including neurofibroma, schwannoma, and perineurioma. Diagnostically challenging variants, including plexiform, cellular and melanotic schwannomas are highlighted. A subset of these affects the childhood population, and has historically been interpreted as malignant, although current evidence and outcome data suggest they represent benign entities. The growing current literature and the author's experience with difficult to classify borderline or “hybrid tumors” are discussed and illustrated. Some of these classification gray zones occur with frequency in the gastrointestinal tract, an anatomical compartment that must always be entertained when examining these neoplasms. Other growing recent areas of interest include the heterogeneous group of pseudoneoplastic lesions involving peripheral nerve composed of mature adipose tissue and/or skeletal muscle, such as the enigmatic neuromuscular choristoma. Malignant peripheral nerve sheath tumors (MPNST) represent a diagnostically controversial group; difficulties in grading and guidelines to separate “atypical neurofibroma” from MPNST are provided. There is an increasing literature of MPNST mimics which neuropathologists must be aware of, including synovial sarcoma and ossifying fibromyxoid tumor. Finally, we discuss entities that are lacking from the section on cranial and paraspinal nerves in the current WHO classification, and that may warrant inclusion in future classifications. In summary, although the diagnosis and classification of most conventional peripheral nerve sheath tumors are relatively straightforward for the experienced observer, yet borderline and difficult-to-classify neoplasms continue to be problematic. In the current review, we attempt to provide some useful guidelines for the surgical neuropathologist to help navigate these persistent, challenging problems.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Bale TA et al., summarize and address the challenges inherent to the expanding group of low-grade glial and glioneuronal tumors that affect children, another category of tumors where molecular ...diagnostics has played an important role in outlining new types. Kresbach C. et al., cover important advances in the classification of ependymal neoplasms, a tumor group that best illustrates the updated model of the WHO classification, merging anatomic, histologic, immunohistochemical, sequencing, and epigenetic data into a powerful classification approach that has significantly improved prognostication. In the spirit of the prior WHO, “not otherwise specified” options and long diagnostic comments are still available when thorough profiling resulting from large-scale groundbreaking studies are not possible in the individual case. ...creativity in the design of surrogate markers and practical diagnostic approach guidelines should continue to be encouraged at the present time.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Abstract
Neoplasms of the peripheral nervous system represent a heterogenous group with a wide spectrum of morphological features and biological potential. They range from benign and curable by ...complete excision (schwannoma and soft tissue perineurioma) to benign but potentially aggressive at the local level (plexiform neurofibroma) to the highly malignant (malignant peripheral nerve sheath tumors MPNST). In this review, we discuss the diagnostic and pathologic features of common peripheral nerve sheath tumors, particularly those that may be encountered in the intracranial compartment or in the spine and paraspinal region. The discussion will cover schwannoma, neurofibroma, atypical neurofibromatous neoplasms of uncertain biological potential, intraneural and soft tissue perineurioma, hybrid nerve sheath tumors, MPNST, and the recently renamed enigmatic tumor, malignant melanotic nerve sheath tumor, formerly referred to as melanotic schwannoma. We also discuss the diagnostic relevance of these neoplasms to specific genetic and familial syndromes of nerve, including neurofibromatosis 1, neurofibromatosis 2, and schwannomatosis. In addition, we discuss updates in our understanding of the molecular alterations that represent key drivers of these neoplasms, including neurofibromatosis type 1 and type 2, SMARCB1, LZTR1, and PRKAR1A loss, as well as the acquisition of CDKN2A/B mutations and alterations in the polycomb repressor complex members (SUZ12 and EED) in the malignant progression to MPNST. In summary, this review covers practical aspects of pathologic diagnosis with updates relevant to neurosurgical practice.
More complete brain cancer resection can prolong survival and delay recurrence. However, it is challenging to distinguish cancer from noncancer tissues intraoperatively, especially at the ...transitional, infiltrative zones. This is especially critical in eloquent regions (for example, speech and motor areas). This study tested the feasibility of label-free, quantitative optical coherence tomography (OCT) for differentiating cancer from noncancer in human brain tissues. Fresh ex vivo human brain tissues were obtained from 32 patients with grade II to IV brain cancer and 5 patients with noncancer brain pathologies. On the basis of volumetric OCT imaging data, pathologically confirmed brain cancer tissues (both high- and low-grade) had significantly lower optical attenuation values at both cancer core and infiltrated zones when compared with noncancer white matter, and OCT achieved high sensitivity and specificity at an attenuation threshold of 5.5 mm(-1) for brain cancer patients. We also used this attenuation threshold to confirm the intraoperative feasibility of performing in vivo OCT-guided surgery using a murine model harboring human brain cancer. Our OCT system was capable of processing and displaying a color-coded optical property map in real time at a rate of 110 to 215 frames per second, or 1.2 to 2.4 s for an 8- to 16-mm(3) tissue volume, thus providing direct visual cues for cancer versus noncancer areas. Our study demonstrates the translational and practical potential of OCT in differentiating cancer from noncancer tissue. Its intraoperative use may facilitate safe and extensive resection of infiltrative brain cancers and consequently lead to improved outcomes when compared with current clinical standards.
Neurofibromatosis 1 (NF1) is an autosomal dominant genetic disorder that presents with variable phenotypes as a result of mutations in the neurofibromatosis type 1 (
NF1
) gene and subsequently, ...abnormal function of the protein product, neurofibromin. Patients with NF1 are at increased risk for central nervous system (CNS) manifestations including structural, functional, and neoplastic disease. The mechanisms underlying the varied manifestations of NF1 are incompletely understood, but the loss of functional neurofibromin, resulting in sustained activation of the oncoprotein RAS, is responsible for tumorigenesis throughout the body, including the CNS. Much of our understanding of NF1-related CNS manifestations is from a combination of data from animal models and natural history studies of people with NF1 and CNS disease. Data from animal models suggest the importance of both
Nf1
mutations and somatic genetic alterations, such as
Tp53
loss, for development of neoplasms, as well as the role of the timing of the acquisition of such alterations on the variability of CNS manifestations. A variety of non-neoplastic structural (macrocephaly, hydrocephalus, aqueductal stenosis, and vasculopathy) and functional (epilepsy, impaired cognition, attention deficits, and autism spectrum disorder) abnormalities occur with variable frequency in individuals with NF1. In addition, there is increasing evidence that similar appearing CNS neoplasms in people with and without the NF1 syndrome are due to distinct oncogenic pathways. Gliomas in people with NF1 show alterations in the RAS/MAPK pathway, generally in the absence of
BRAF
alterations (common to sporadic pilocytic astrocytomas) or IDH or histone H3 mutations (common to diffuse gliomas subsets). A subset of low-grade astrocytomas in these patients remain difficult to classify using standard criteria, and occasionally demonstrate morphologic features resembling subependymal giant cell astrocytomas that afflict patients with tuberous sclerosis complex (“SEGA-like astrocytomas”). There is also emerging evidence that NF1-associated high-grade astrocytomas have frequent co-existing alterations such as
ATRX
mutations and an alternative lengthening of telomeres (ALT) phenotype responsible for unique biologic properties. Ongoing efforts are seeking to improve diagnostic accuracy for CNS neoplasms in the setting of NF1 versus sporadic tumors. In addition, MEK inhibitors, which act on the RAS/MAPK pathway, continue to be studied as rational targets for the treatment of NF1-associated tumors, including CNS tumors.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Biodegradable polymeric nanoparticles have the potential to be safer alternatives to viruses for gene delivery; however, their use has been limited by poor efficacy in vivo. In this work, we ...synthesize and characterize polymeric gene delivery nanoparticles and evaluate their efficacy for DNA delivery of herpes simplex virus type I thymidine kinase (HSVtk) combined with the prodrug ganciclovir (GCV) in a malignant glioma model. We investigated polymer structure for gene delivery in two rat glioma cell lines, 9L and F98, to discover nanoparticle formulations more effective than the leading commercial reagent Lipofectamine 2000. The lead polymer structure, poly(1,4-butanediol diacrylate-co-4-amino-1-butanol) end-modified with 1-(3-aminopropyl)-4-methylpiperazine, is a poly(β-amino ester) (PBAE) and formed nanoparticles with HSVtk DNA that were 138 ± 4 nm in size and 13 ± 1 mV in zeta potential. These nanoparticles containing HSVtk DNA showed 100% cancer cell killing in vitro in the two glioma cell lines when combined with GCV exposure, while control nanoparticles encoding GFP maintained robust cell viability. For in vivo evaluation, tumor-bearing rats were treated with PBAE/HSVtk infusion via convection-enhanced delivery (CED) in combination with systemic administration of GCV. These treated animals showed a significant benefit in survival (p = 0.0012 vs control). Moreover, following a single CED infusion, labeled PBAE nanoparticles spread completely throughout the tumor. This study highlights a nanomedicine approach that is highly promising for the treatment of malignant glioma.
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IJS, KILJ, NUK, PNG, UL, UM
The tumor microenvironment (TME) is critical for tumor progression. However, the establishment and function of the TME remain obscure because of its complex cellular composition. Using a mouse ...genetic system called mosaic analysis with double markers (MADMs), we delineated TME evolution at single-cell resolution in sonic hedgehog (SHH)-activated medulloblastomas that originate from unipotent granule neuron progenitors in the brain. First, we found that astrocytes within the TME (TuAstrocytes) were trans-differentiated from tumor granule neuron precursors (GNPs), which normally never differentiate into astrocytes. Second, we identified that TME-derived IGF1 promotes tumor progression. Third, we uncovered that insulin-like growth factor 1 (IGF1) is produced by tumor-associated microglia in response to interleukin-4 (IL-4) stimulation. Finally, we found that IL-4 is secreted by TuAstrocytes. Collectively, our studies reveal an evolutionary process that produces a multi-lateral network within the TME of medulloblastoma: a fraction of tumor cells trans-differentiate into TuAstrocytes, which, in turn, produce IL-4 that stimulates microglia to produce IGF1 to promote tumor progression.
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•A small number of medulloblastoma cells trans-differentiated into TME astrocytes•Astrocytes in human SHH-subtype medulloblastoma share lineage with tumor cells•Tumor-derived astrocytes secret IL-4 to polarize microglia for IGF1 production•IGF1 from tumor associated microglia is critical for tumor progression
Tumors shape a microenvironmental network by acting as a source of tumor-associated astrocytes that provide paracrine stimulation to microglia to secret IGF1, which is critical for tumor progression in SHH-activated mouse medulloblastoma models.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
OBJECTIVETo determine the utility of quantitative metrics obtained from fMRI using diffusion-weighted imaging (DWI)/apparent diffusion coefficient (ADC) mapping compared with metabolic ...(F-fluorodeoxyglucose FDG-PET/CT) imaging in patients with neurofibromatosis type 1 (NF1) for the characterization of peripheral nerve sheath tumors (PNSTs) as benign or malignant.
METHODSThis Institutional Review Board–approved, Health Insurance Portability and Accountability Act–compliant study retrospectively reviewed imaging of 55 PNSTs in 21 patients with NF1. Imaging included anatomic (unenhanced T1, fluid-sensitive, contrast-enhanced T1-weighted), functional DWI (b = 50, 400, 800 s/mm) and ADC mapping, magnetic resonance sequences, and FDG-PET/CT imaging. Anatomic (size), functional (minimum ADC values), and metabolic (maximum standardized uptake values SUVmax) imaging characteristics were recorded. ADC values were correlated with SUVmax. With histologic correlation for all malignant PNSTs (MPNSTs) or clinical or imaging stability (>12 months) for benign lesions used as reference standards, diagnostic accuracy was calculated.
RESULTSOf 55 PNSTs, there were 19 (35%) malignant and 36 (65%) benign PNSTs. Benign PNSTs were overall smaller than MPNSTs (largest diameter 4.3 ± 1.3 vs 8.2 ± 3.3 cm, respectively, p = 0.014). Benign PNSTs had higher ADCmin (×10 mm/s) than MPNSTs (1.6 ± 0.4 vs 0.6 ± 0.2, respectively, p < 0.0001) and lower SUVmax than MPNSTs (3.2 ± 1.8 vs 8 ± 3.9, p < 0.0001, respectively). ADCmin correlated inversely with SUVmax (correlation coefficient r = −0.0.58, p < 0.0001). Maintaining a sensitivity of 100% with threshold values of ADCmin ≤1 or SUVmax >3.2, DWI yielded a specificity of 94% while FDG-PET/CT offered a specificity of 83%.
CONCLUSIONSBoth quantitative metabolic imaging and functional imaging offer high sensitivity for the characterization of PNSTs in NF1; however, DWI/ADC mapping offers increased specificity and may be a more useful modality.
CLASSIFICATION OF EVIDENCEThis study provides Class II evidence that for patients with NF1, MRI using DWI/ADC mapping accurately distinguishes malignant and benign PNSTs.
Prognostic significance of histological anaplasia and BRAF V600E mutation were retrospectively evaluated in 74 patients with pleomorphic xanthoastrocytoma (PXA). Median age at diagnosis was 21.5 ...years (31 pediatric, 43 adult) and median follow‐up 7.6 years. Anaplasia (PXA‐AF), defined as mitotic index ≥ 5/10HPF and/or presence of necrosis, was present in 33 cases. BRAF V600E mutation was detected in 39 (of 60) cases by immunohistochemical and/or molecular analysis, all negative for IDH1 (R132H). Mitotic index ≥ 5/10HPF and necrosis were associated with decreased overall survival (OS; P = 0.0005 and P = 0.0002, respectively). In all cases except two, necrosis was associated with mitotic index ≥ 5/10HPF. Patients with BRAF V600E mutant tumors had significantly longer OS compared with those without BRAF V600E mutation (P = 0.02). PXA‐AF patients, regardless of age, had significantly shorter OS compared with those without (P = 0.0003). Recurrence‐free survival was significantly shorter for adult PXA‐AF patients (P = 0.047) only. Patients who either recurred or died ≤3 years from diagnosis were more likely to have had either PXA‐AF at first diagnosis (P = 0.008) or undergone a non‐gross total resection procedure (P = 0.004) as compared with patients who did not. This study provides further evidence that PXA‐AF behaves more aggressively than PXA and may qualify for WHO grade III “anaplastic” designation.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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