Differential NF1, p16, and EGFR patterns by interphase cytogenetics (FISH) in malignant peripheral nerve sheath tumor (MPNST) and morphologically similar spindle cell neoplasms

Malignant peripheral nerve sheath tumors (MPNSTs) are diagnostically challenging neoplasms for which sensitive and specific immunohistochemical markers are lacking. Although limited to date, previous studies have suggested that NF1 (17q), NF2 (22q), p16 (9p), and EGFR (7p) alterations may be involved in MPNST tumorigenesis. To determine whether specific genetic changes differentiate between MPNST and morphologically similar neoplasms, we assessed these chromosomal regions in 22 MPNSTs (9 NF1-associated, 13 sporadic), 13 plexiform neurofibromas, 5 cellular schwannomas, 8 synovial sarcomas, 6 fibrosarcomas, and 13 hemangiopericytomas by 2-color FISH. NF1 deletions, often in the form of monosomy 17, were found in MPNSTs (76%). neurofibromas (31%), hemangiopericytomas (17%), and fibrosarcomas (17%), but not in synovial sarcomas or cellular schwannomas. NF1 losses were encountered more frequently in MPNSTs versus other sarcomas (p < 0.001), as were p16 homozygous deletions (45% vs 0%; p < 0.001), EGFR amplifications (26% vs 0%; p = 0.006), and polysomies for either chromosomes 7 (53% vs 12%; p = 0.003) or 22 (50% vs 4%; p < 0.001). Hemizygous or homozygous p16 deletions were detected in 75% of MPNSTs, but not in benign nerve sheath tumors (p < 0.001). Thus, FISH analysis identifies relatively specific genetic patterns that may be useful in selected cases, for which the differential diagnosis includes low- or high-grade MPNST.     

Tumor suppressor mutations and growth factor signaling in the pathogenesis of NF1-associated peripheral nerve sheath tumors: II. The role of dysregulated growth factor signaling

Patients with neurofibromatosis type 1 (NF1), one of the most common genetic disease affecting the nervous system, develop multiple neurofibromas that can transform into aggressive sarcomas known as malignant peripheral nerve sheath tumors (MPNSTs). Studies of human tumors and newly developed transgenic mouse models indicate that Schwann cells are the primary neoplastic cell type in neurofibromas and MPNSTs and that development of these peripheral nerve sheath tumors involves mutations of multiple tumor suppressor genes. However, it is widely held that tumor suppressor mutations alone are not sufficient to induce peripheral nerve sheath tumor formation and that dysregulated growth factor signaling cooperates with these mutations to promote neurofibroma and MPNST tumorigenesis. In Part I of this review, we discussed findings demonstrating that a loss of NF1 tumor suppressor gene function in neoplastic Schwann cells is a key early step in neurofibroma formation and that progression from neurofibroma to MPNST is associated with abnormalities of additional tumor suppressor genes, including p53, INK4A, andp27(kip1). In Part II of this review, we consider evidence that dysregulated signaling by specific growth factors and growth factor receptors promotes the proliferation, migration, and survival of neoplastic Schwann cells in neurofibromas and MPNSTs.     

Tumor suppressor mutations and growth factor signaling in the pathogenesis of NF1-associated peripheral nerve sheath tumors. I. The role of tumor suppressor mutations

Patients with neurofibromatosis type 1 (NF1), a common autosomal dominant tumor predisposition syndrome, develop benign cutaneous, intraneural, and plexiform neurofibromas and malignant peripheral nerve sheath tumors (MPNSTs), an aggressive form of Schwann cell neoplasm that frequently arises from plexiform neurofibromas. Impressive advances have been made in defining the molecular mechanisms responsible for neurofibroma and MPNST tumorigenesis, including the identification of key tumor suppressor gene mutations, an improved understanding of the functions of these tumor suppressors, and the production of transgenic mouse models in which tumor suppressor gene mutations predispose animals to the development of neurofibromas and MPNSTs. It has also become apparent that dysregulated growth factor signaling cooperates with tumor suppressor mutations to promote neurofibroma and MPNST tumorigenesis. In Part I of this two-part review, we consider findings demonstrating that Schwann cells are the primary neoplastic cell type in neurofibromas and MPNSTs and that specific tumor suppressor gene mutations promote the development of these tumors. In Part II, which will be published in a later issue, we will review evidence indicating that inappropriate growth factor signaling contributes to this process by stimulating the proliferation, survival, and migration of Schwann cells whose regulatory mechanisms have been crippled by a loss of tumor suppressor function.     

Bilateral spinal neurofibromas in patients with neurofibromatosis 1

Neurofibromatosis 1 (NF1) is a neurocutaneous syndrome that can be inherited as autosomal dominant or may appear due to a de novo mutation. We present 8 patients (5 M and 3 F) with sporadic or non-familial spinal neurofibromatosis 1 (non-FSNF1) associated with bilateral spinal neurofibromas involving all of the paraspinal nerves. To our knowledge, this is the first series of such association described in the literature. Their ages ranged from 6 months to 20 years (average 9.8 years) at the time of radiological diagnosis. This presentation appears to be earlier than in familial spinal neurofibromas in NF1 (FSNF1). Predisposition to malignancy probably is greater in the non-FSNF1 type. MRI studies were performed routinely in all patients with NF1 and these were complemented with MRI enhanced with gadolinium and repeated at different ages in cases with paraspinal tumors. Coronal views provided the best evidence for the presence of neurofibromas in every spinal nerve. The size of the tumors and the clinical complications increased with advancing age in most patients. Giant plexiform tumors were often seen in the cervico-thoracic region. Malignant peripheral nerve sheath tumors (MPNST) were found in one patient with a sciatic tumor and another patient died suddenly at home without necropsy or pathological study. Voluminous paraspinal neurofibromas can be at risk for malignancy. More frequent neuroimaging studies may be necessary for an earlier detection. Early surgical treatment to anticipate the occurrence of MPNST during surveillance could be an option. Bilateral spinal neurofibromas are found in both patients who inherited the NF1 and in those due to de novo mutations.     

Genetic and phenotypic characterization of tumor cells derived from malignant peripheral nerve sheath tumors of neurofibromatosis type 1 patients

Neurofibromatosis type 1 (NF1) patients have an 8-13% lifetime risk of developing malignant peripheral nerve sheath tumors (MPNST) which have a very poor prognosis. In this study, cells from eight MPNSTs (six primary and two recurrences) of six clinically and genetically well-characterized NF1 patients were taken into culture. Tracing of loss of heterozygosity (LOH) of the NF1, p53, and p16 gene regions or of abnormal karyotypes enabled identification of tumor cells from five MPNSTs. In two other MPNST-derived cell cultures, LOH of the relevant regions in the original tumors could not be detected, indicating that the obtained cells were nonneoplastic cells. Cells from most MPNSTs grew only under standard culture conditions but not under conditions optimized for Schwann cells. These cells were S100-negative and did not exhibit spindle shape which is a characteristic of Schwann cells. Drastically increased proliferation rates were found for most of the MPNST cells in comparison to Schwann cells derived from benign neurofibromas. Our study demonstrates that genetic analysis is effective and essential for verification of MPNST tumor cells in culture. These verified MPNST cells are valuable for further investigations of the biology and pathogenesis of this malignancy as well as for in vitro pharmacologic studies essential for the development of new therapies.     

How does the Schwann cell lineage form tumors in NF1?

Neurofibromas are benign tumors of peripheral nerve that occur sporadically or in patients with the autosomal dominant tumor predisposition syndrome neurofibromatosis type 1 (NF1). Multiple neurofibroma subtypes exist which differ in their site of occurrence, their association with NF1, and their tendency to undergo transformation to become malignant peripheral nerve sheath tumors (MPNSTs), the most common malignancy associated with NF1. Most NF1 patients carry a constitutional mutation of the NF1 tumor suppressor gene. Neurofibromas develop in these patients when an unknown cell type in the Schwann cell lineage loses its remaining functional NF1 gene and initiates a complex series of interactions with other cell types; these interactions may be influenced by aberrant expression of growth factors and growth factor receptors and the action of modifier genes. Cells within certain neurofibroma subtypes subsequently accumulate additional mutations affecting the p19(ARF)-MDM2-TP53 and p16INK4A-Rb signaling cascades, mutations of other as yet unidentified genes, and amplification of growth factor receptor genes, resulting in their transformation into MPNSTs. These observations have been validated using a variety of transgenic and knockout mouse models that recapitulate neurofibroma and MPNST pathogenesis. A new generation of mouse models is also providing important new insights into the identity of the cell type in the Schwann cell lineage that gives rise to neurofibromas. Our improving understanding of the mechanisms underlying the pathogenesis of neurofibromas and MPNSTs raises intriguing new questions about the origin and pathogenesis of these neoplasms and establishes models for the development of new therapies targeting these neoplasms.     

Evaluation of (18)fluorodeoxyglucose positron emission tomography ((18)FDG PET) in the detection of malignant peripheral nerve sheath tumours arising from within plexiform neurofibromas in neurofibromatosis 1

OBJECTIVES: The ability of (18)fluorodeoxyglucose positron emission tomography ((18)FDG PET) to detect malignant change in plexiform neurofibromas from patients with neurofibromatosis 1 (NF1) was evaluated. METHODS: Eighteen NF1 patients who presented with pain, increase in size, or neurological deficit associated with a plexiform neurofibroma were assessed. Magnetic resonance imaging determined the site and extent of the lesion. Qualitative(18)FDG PET was performed and the standard uptake value (SUV) measured the regional glucose metabolism. Histological confirmation of the diagnosis was obtained in 10 patients. RESULTS: Twenty three plexiform neurofibromas were detected in 18 patients. Seven malignant peripheral nerve sheath tumours, four high grade and three low grade tumours, occurred in five patients. In one patient the clinical and radiological characteristics of the tumour suggested malignancy, but histology was inconclusive. Fifteen benign plexiform neurofibromas were identified in 12 patients and these findings were confirmed histologically in five lesions from four patients. Ten plexiform neurofibromas occurring in eight patients were considered benign on(18)FDG PET and the patients did not undergo surgery. They remained stable or their symptoms improved on clinical follow up (median 9 months). The results of qualitative (18)FDG PET were interpreted as indicating that 13 plexiform neurofibromas were benign and 10 were malignant. No malignant tumours were classified as benign, but two benign tumours were reported as malignant. The SUV was calculated for 20 tumours and was significantly higher in five malignant tumours 5.4 (SD 2.4), than in 15 benign tumours 1.54 (SD 0.7), p=0.002. There was an overlap between benign and malignant tumours in the SUV range 2.7-3.3. CONCLUSIONS: (18)FDG PET is helpful in determining malignant change in plexiform neurofibromas in NF1. Increased separation between benign and malignant lesions could be obtained by calculating the SUV at about 200 minutes after injection of (18)FDG, when the peak activity concentration is obtained in malignant tumours.     

Genetically engineered mouse models shed new light on the pathogenesis of neurofibromatosis type I-related neoplasms of the peripheral nervous system

Neurofibromatosis type 1 (NF1), the most common genetic disorder affecting the human nervous system, is characterized by the development of multiple benign Schwann cell tumors in skin and large peripheral nerves. These neoplasms, which are termed dermal and plexiform neurofibromas respectively, have distinct clinical courses; of particular note, plexiform, but not dermal, neurofibromas often undergo malignant progression to form malignant peripheral nerve sheath tumors (MPNSTs), the most common malignancy occurring in NF1 patients. In recent years, a number of genetically engineered mouse models have been created to investigate the molecular mechanisms driving the pathogenesis of these tumors. These models have been designed to address key questions including: (1) whether NF1 loss in the Schwann cell lineage is essential for tumorigenesis; (2) what cell type(s) in the Schwann cell lineage gives rise to dermal neurofibromas, plexiform neurofibromas and MPNSTs; (3) how the tumor microenvironment contributes to neoplasia; (4) what additional mutations contribute to neurofibroma-MPNST progression; (5) what role different neurofibromin-regulated Ras proteins play in this process and (6) how dysregulated growth factor signaling facilitates PNS tumorigenesis. In this review, we summarize the major findings from each of these models and their limitations as well as how discrepancies between these models may be reconciled. We also discuss how information gleaned from these models can be synthesized to into a comprehensive model of tumor formation in peripheral nervous system and consider several of the major questions that remain unanswered about this process.     

Plexiform-like neurofibromas develop in the mouse by intraneural xenograft of an NF1 tumor-derived Schwann cell line

Plexiform neurofibromas are peripheral nerve sheath tumors that arise frequently in neurofibromatosis type 1 (NF1) and have a risk of malignant progression. Past efforts to establish xenograft models for neurofibroma involved the implantation of tumor fragments or heterogeneous primary cultures, which rarely achieved significant tumor growth. We report a practical and reproducible animal model of plexiform-like neurofibroma by xenograft of an immortal human NF1 tumor-derived Schwann cell line into the peripheral nerve of scid mice. The S100 and p75 positive sNF94.3 cell line was shown to possess a normal karyotype and have apparent full-length neurofibromin by Western blot. These cells were shown to have a constitutional NF1 microdeletion and elevated Ras-GTP activity, however, suggesting loss of normal neurofibromin function. Localized intraneural injection of the cell line sNF94.3 produced consistent and slow growing tumors that infiltrated and disrupted the host nerve. The xenograft tumors resembled plexiform neurofibromas with a low rate of proliferation, abundant extracellular matrix (hypocellularity), basal laminae, high vascularity, and mast cell infiltration. The histologic features of the developed tumors were particularly consistent with those of human plexiform neurofibroma as well. Intraneural xenograft of sNF94.3 cells enables the precise initiation of intraneural, plexiform-like tumors and provides a highly reproducible model for the study of plexiform neurofibroma tumorigenesis. This model facilitates testing of potential therapeutic interventions, including angiogenesis inhibitors, in a relevant cellular environment.     

Recent advances in neurofibromatosis type 1

PURPOSE OF REVIEW: The past decade, since the identification of the neurofibromatosis type 1 (NF1) gene, has witnessed great advances in our understanding of the role of the NF1 gene in the molecular pathogenesis of NF1-associated clinical abnormalities. The purpose of this review is to highlight recent advances in defining the molecular etiology of nervous system tumors and learning disabilities. RECENT FINDINGS: Neurofibromas and optic pathway gliomas result from NF1 inactivation in Schwann cells and astrocytes, respectively, but other cellular factors contribute to tumorigenesis. In addition, malignant progression of plexiform neurofibromas to malignant peripheral nerve sheath tumors requires additional genetic changes, including increased expression of growth factor receptors, molecules that are involved in tumor invasion and metastasis, and inactivation of critical cell cycle regulators. In addition, specific types of NF1 gene mutation may be associated with an increased risk for malignancy in individuals with NF1. SUMMARY: Research over the past few years has resulted in a detailed understanding of the molecular genetics of benign and malignant tumors affecting individuals with NF1 as well as the development of refined small animal models for these tumors. In addition, clinical studies have begun to define specific subpopulations of patients at risk for cancer and have identified targeted therapies for NF1-associated tumors, based on basic science research advances.     

Dissecting the clinical phenotype associated with mosaic type-2 NF1 microdeletions

Patients with large deletions of the NF1 gene and its flanking regions (termed NF1 microdeletions) generally exhibit more severe clinical manifestations of neurofibromatosis type-1 (NF1). Here, we have investigated the clinical phenotype displayed by eight patients harbouring mosaic type-2 NF1 microdeletions. These patients did not exhibit facial dysmorphism, attention deficit hyperactivity disorder, delayed cognitive development and/or learning disabilities, cognitive impairment, congenital heart disease, hyperflexibility of joints, large hands and feet, muscular hypotonia or bone cysts. All these features have previously been reported to be disproportionately associated with germline (i.e. non-mosaic) type-1 NF1 microdeletions as compared with the general NF1 population. Plexiform neurofibromas were also less prevalent in patients with mosaic type-2 NF1 microdeletions as compared with patients carrying constitutional (germline) type-1 NF1 microdeletions. Five of the eight patients with mosaic type-2 deletions investigated here had 20-250 cutaneous neurofibromas, but only one of them exhibited a high load of cutaneous neurofibromas (N?>?1,000). By contrast, a previous study indicated a high burden of cutaneous neurofibromas (N?>?1,000) in 50?% of adult patients with germline type-1 NF1 deletions. Patients with germline type-1 NF1 microdeletions have been reported to have an increased lifetime risk of 16-26?% for a malignant peripheral nerve sheath tumour (MPNST). In this study, one of the eight investigated mosaic type-2 microdeletion patients developed an MPNST. We conclude that patients with mosaic type-2 NF1 microdeletions may also be at an increased risk of MPNSTs despite their generally milder disease manifestations as compared with germline type-1 NF1 microdeletions.     

Glioblastoma in adults with neurofibromatosis type I: A report of two cases

Neurofibromatosis type I (NF1) is a familial tumor syndrome with an autosomal‐dominant inheritance. NF1‐associated tumors often include neurofibromas, malignant peripheral nerve sheath tumors and pilocytic astrocytomas of the optic nerve. The presentation of NF1 patients with glioblastoma is a rare occurrence, with only a handful of cases reported in the literature. We report two cases of glioblastomas occurring in adults with NF1 and briefly review the relevant literature.     

Schwann cell lines derived from malignant peripheral nerve sheath tumors respond abnormally to platelet-derived growth factor-BB

Neurofibromatosis type 1 (NF1) is a genetic disease caused by the loss of neurofibromin, which can lead to formation of highly invasive malignant peripheral nerve sheath tumors (MPNST). We characterized platelet-derived growth factor-beta (PDGF-beta) receptor expression levels and signal transduction pathways in NF1 MPNST cell lines and compared them with the expression of PDGF-beta receptors in normal human Schwann cells (nhSC). As examined by Western blotting, PDGF-beta receptor expression levels were similar in nhSC and NF1 MPNST cell lines. MAPK and Akt also were phosphorylated in both cell types to a similar degree in response to PDGF B chains (PDGF-BB). However, increased intracellular calcium (Ca2+) levels in response to PDGF-BB were observed only in the NF1 MPNST cell lines; nhSC did not show any increase in intracellular calcium when stimulated with PDGF-BB. The calcium response in NF1 MPNST cell lines was blocked with thapsigargin, suggesting that the PDGF-BB-stimulated increases in intracellular calcium originated in the internal compartment of the cell rather than reflecting influx of calcium from the extracellular compartment. Calmodulin kinase II (CAMKII) is phosphorylated in response to PDGF-BB in the NF1 MPNST cell lines, whereas no phosphorylation of CAMKII was observed in nhSCs. The decreased growth of NF1 MPNST cell lines after treatment with a CAMKII inhibitor is consistent with the view that aberrant activation of the calcium-signaling pathway by PDGF-BB contributes to the formation of MPNST in NF1 patients.     

利用基因芯片研究与胶质母细胞瘤侵袭性相关的基因

目的探讨利用基因表达谱芯片筛选人脑胶质母细胞瘤与侵袭性相关基因的表达及功能。方法用含13 939种人类基因的BioStarH140S型芯片,以成人脑及6例胶质母细胞瘤组织总RNA制备的探针杂交芯片;ScanArray4 000扫描芯片荧光信号,提取脑及胶质母细胞瘤组织差异基因,并进行生物信息分析及功能研究。结果表达谱芯片筛选出胶质母细胞瘤差异基因198条(1.42％),与细胞信号和传递蛋白、细胞骨架、代谢、蛋白翻译合成、细胞周期蛋白类、癌基因和抑癌基因等多类基因密切相关;与侵袭性相关的8条细胞骨架和细胞外基质基因表达谱相似,均在胶质母细胞瘤中显著上调,生物信息分析为α-连环素基因、钙粘附素1基因、层粘连蛋白、纤连蛋白1基因、基质金属蛋白酶2、Ⅲ型胶原基因、组织金属蛋白酶抑制1基因和血小板衍生生长因子受体A基因。结论表达谱芯片是高通量筛选胶质瘤相关基因的生物高新技术,侵袭性相关基因为判断胶质母细胞瘤患者的预后提供了分子生物学指标,有助于临床诊治。     

Diagnostic delay of NF1 in hemifacial hypertrophy due to plexiform neurofibromas

Benign tumors of the peripheral nerve sheath, termed neurofibromas, are the hallmark feature of neurofibromatosis type 1 (NF1). These tumors can result in hypertrophy of a limb or another anatomic region. Hemifacial hypertrophy due to an underlying neurofibroma is a typical manifestation of NF1 in young children although the overall frequency of facial involvement is low. We retrospectively studied all patients, which were referred to our outpatient clinic because of hemihypertrophy or swelling of the face for initially unknown reason with a final diagnosis of NF1. A total number of six patients were identified. Clinical and radiological characteristics of these patients were analyzed. In all patients, diagnosis of NF1 could be established based on the typical clinical criteria. However, despite other typical NF1-associated features (e.g. multiple café-au-lait spots) diagnosis of a plexiform neurofibroma as underlying cause for the hemifacial hypertrophy was significantly delayed in all patients. MRI scans were misinterpreted in all of the cases as lymphangioma because plexiform neurofibromas can resemble mesenchymal tumors or lymphangiomas. NF1 has to be considered in the differential diagnosis of hemifacial hypertrophy. A thorough clinical examination of affected patients should focus on typical disease-defining features. Early diagnosis of NF1 can prevent unnecessary treatment at least in some patients.     

Delayed rectifier K currents in NF1 Schwann cells. Pharmacological block inhibits proliferation

K+(K) currents are related to the proliferation of many cell types and have a relationship to second messenger pathways implicated in regulation of the cell cycle in development and certain disease states. We examined the role of K currents in Schwann cells (SC) cultured from tumors that arise in the human disease neurofibromatosis type 1 (NF1). Comparisons were made between whole cell voltage clamp recordings from normal human SC cultures and from neurofibroma cultures and malignant peripheral nerve sheath tumor (MPNST) cell lines. The outward K currents of normal and tumor cells could be divided into three types based on pharmacology and macroscopic inactivation: (1) "A type" current blocked by 4-aminopyridine, (2) delayed rectifier (DR) current blocked by tetraethylammonium, and (3) biphasic current consisting of a combination of these two current types. The DR K current was present in MPNST- and neurofibroma-derived SC, but not in quiescent, nondividing, normal SC. DR currents were largest in MPNST-derived SC (50 pA/pF vs. 2.1-4.9 pA/pF in dividing and quiescent normal SC). Normal SC cultures had significantly more cells with A type current than cultures of MPNST and the plexiform neurofibroma. Conversely, MPNST and plexiform neurofibroma cultures had significantly more SC with DR current than did normal cultures, and these DR currents were significantly larger. In addition, the plexiform neurofibroma culture had significantly more cells with DR current than the dermal neurofibroma culture. K currents in SC from normal NF1 SC cultures had current abundances similar to GGF-exposed normal SC and the plexiform neurofibroma. We have established a link between DR K current blockade via TEA analogs and inhibition of proliferation of NF1 SC in vitro. In addition, a farnysyl transferase inhibitor (FTI), a blocker of Ras activation, blocked cell proliferation without blocking K currents in all cultures except a plexiform neurofibroma, suggesting that regulation of proliferation in neoplastic and normal SC in vitro is complex.     

Brachial plexopathy due to malignant peripheral nerve sheath tumor in neurofibromatosis type 1: case report and subject review

Neurofibromatosis type 1 (NF1) is a common tumor predisposition syndrome affecting approximately 1 in 4,000 persons. It is an autosomal-dominant disorder with half of the cases resulting from spontaneous mutations. This genetic defect leads to the formation of benign tumors or neurofibromas of the peripheral nervous system. Dermal neurofibromas may cause local discomfort and itching but are rarely associated with neurological deficit and do not undergo malignant change. The more extensive plexiform neurofibromas produce neurological complications in 27%-43% of patients with NF1 and may undergo malignant degeneration in 5% of cases. Patients with NF1 who develop pain or new neurological symptoms should have a rapid and thorough assessment for malignancy. In this report, we illustrate this point by presenting a patient who developed acute shoulder pain and weakness due to malignant degeneration of a plexiform neurofibroma involving the left brachial plexus, and review the literature on this subject.     

Molecular mechanisms promoting the pathogenesis of Schwann cell neoplasms

Neurofibromas, schwannomas and malignant peripheral nerve sheath tumors (MPNSTs) all arise from the Schwann cell lineage. Despite their common origin, these tumor types have distinct pathologies and clinical behaviors; a growing body of evidence indicates that they also arise via distinct pathogenic mechanisms. Identification of the genes that are mutated in genetic diseases characterized by the development of either neurofibromas and MPNSTs [neurofibromatosis type 1 (NF1)] or schwannomas [neurofibromatosis type 2 (NF2), schwannomatosis and Carney complex type 1] has greatly advanced our understanding of these mechanisms. The development of genetically engineered mice with ablation of NF1, NF2, SMARCB1/INI1 or PRKAR1A has confirmed the key role these genes play in peripheral nerve sheath tumorigenesis. Establishing the functions of the NF1, NF2, SMARCB1/INI1 and PRKAR1A gene products has led to the identification of key cytoplasmic signaling pathways promoting Schwann cell neoplasia and identified new therapeutic targets. Analyses of human neoplasms and genetically engineered mouse models have established that interactions with other tumor suppressors such as TP53 and CDKN2A promote neurofibroma-MPNST progression and indicate that intratumoral interactions between neoplastic and non-neoplastic cell types play an essential role in peripheral nerve sheath tumorigenesis. Recent advances have also provided new insights into the identity of the neural crest-derived populations that give rise to different types of peripheral nerve sheath tumors. Based on these findings, we now have an initial outline of the molecular mechanisms driving the pathogenesis of neurofibromas, MPNSTs and schwannomas. However, this improved understanding in turn raises a host of intriguing new questions.