Prenatal diagnosis for neurofibromatosis type 1 and the pitfalls of germline mosaics.

We report our 5-year experience in neurofibromatosis type 1 prenatal diagnosis (PND): 205 PNDs in 146 women (chorionic villus biopsies, 88% or amniocentesis, 12%). The NF1 variant was present in 85 (41%) and absent in 122 (59%) fetuses. Among 205 pregnancies (207 fetuses), 135 were carried to term (119 unaffected and 16 NF1 affected children), 69 pregnancy terminations (affected fetuses), 2 miscarriages, and 1 in utero death. The majority of PND requests came from parents with sporadic NF1. We describe two PNDs in women with mosaic NF1. In both families, direct PND showed the absence of the maternal NF1 variant in the fetus. However, microsatellite markers analysis showed that the risk haplotype had been transmitted. These rare cases of germline mosaicism illustrate the pitfall of indirect PND. Our study illustrates the crucial consequences of PND for medical and genetic counseling decisions. We also point to the challenges of germline mosaics.

Somatic Molecular Heterogeneity in Bilateral Macronodular Adrenocortical Disease (BMAD) Differs Among the Pathological Subgroups.

Bilateral macronodular adrenocortical disease (BMAD) is an uncommon cause of Cushing's syndrome leading to bilateral macronodules. Isolated BMAD has been classified into three molecular groups: patients with ARMC5 alteration, KDM1A alteration, and patients without known genetic cause. The aim of this study was to identify by NGS, in a cohort of 26 patients with BMAD, the somatic alterations acquired in different nodules after macrodissection from patients with germline ARMC5 or KDM1A alterations and to analyze potential somatic alterations in a panel of five other genes involved in adrenal pathology (GNAS, PDE8B, PDE11A, PRKAR1A, and PRKACA). Twenty-three patients (7 ARMC5, 3 KDM1A, and 13 BMAD with unknown genetic cause) were analyzable. Somatic ARMC5 or KDM1A events were exclusively observed in patients with germline ARMC5 and KDM1A alterations, respectively. Six out of 7 ARMC5 patients have a high heterogeneity in identified somatic events, whereas one ARMC5 and all KDM1A patients show a loss of heterozygosity (LOH) in all nodules. Except for passenger alterations of GNAS, no genetic alteration susceptible to causing the disease was detected in the BMAD with unknown genetic cause. Our study reinforces our knowledge of the somatic genetic heterogeneity of ARMC5 and the somatic homogeneity of KDM1A. It reveals the absence of purely somatic events in these two genes and provides a new tool for detecting KDM1A alterations by FISH 1p36/1q25.

Adrenal Cushing Syndrome: Diagnosis and Management in a 10-Year-Old Boy with Carney Complex.

INTRODUCTION: Adrenocorticotropic hormone (ACTH)-independent Cushing syndrome (CS) is very rare condition in children. Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of CS, which in most cases occurs in the context of Carney complex (CNC). CNC is a rare autosomal-dominantly inherited genetic syndrome, usually due to pathogenic variants of the PRKAR1A (regulatory subunit R1A of the protein kinase A) gene located at 17q22-24. The clinical picture is characterized by spotty skin pigmentation, cardiac, cutaneous, and mammary myxomas, melanocytic schwannomas, endocrinopathies, and tumours of the endocrine glands (mostly adrenal, pituitary, and thyroid). CASE PRESENTATION: A 10-year-old boy first came to our outpatient clinic due to severe obesity. During the first 3 months of follow-up, the height growth rate was normal, but the response to dietary-behavioural indications was poor in terms of weight loss. Later, 10 months after the last evaluation, there was evidence of significant worsening of obesity, growth failure (growth velocity 0.7 cm/year), arterial hypertension, and the occurrence of violaceous striae at the trunk and root of the limbs. Endocrinological causes of obesity associated with growth failure were investigated. The circadian rhythm of cortisol, ACTH, and cortisoluria were suggestive of ACTH-independent hypercortisolaemia. Iatrogenic causes were ruled out. Adrenal ultrasound and computer tomography scan were performed, which initially indicated the presence of a nodule or hyperplasia of the medial arm of the left adrenal gland. Conversely, magnetic resonance imaging showed a significant increase in the global dimensions of the adrenals with a bilateral micronodular appearance. In light of the association between ACTH-independent hypercortisolism and bilateral micronodular adrenal hyperplasia, a genetic investigation was performed, which found a pathogenic variant of the PRKAR1A gene. The patient was begun on treatment with metyrapone which was well tolerated over a 2-year period. The clinical picture has slightly improved, cortisoluria returned and remains within normal limits, but ACTH suppression persists. CONCLUSION: This is the first report on the clinical and biochemical effects of 2-year medical treatment with metyrapone of PPNAD-related hypercortisolaemia in a paediatric patient with CNC. Currently, there are no established protocols for the management of hypercortisolism in PPNAD and data are scarce, especially in the paediatric field. Medical therapies may play a role in reducing the need, at least initially, for patients to undergo bilateral adrenalectomy. However, further studies on larger case series are needed to clarify this aspect. In cases of CS due to PPNAD in which medical therapy was the initial approach, in the absence of clear clinical, auxological, and biochemical improvements, metyrapone may have to be discontinued in favour of another approach, including surgery.

Efficacy and Safety of Immune Checkpoint Blockade in Patients With Li-Fraumeni Syndrome.

A case series evaluating efficacy and safety of immune checkpoint blockade in Li-Fraumeni syndrome.

A de novo germline pathogenic BRCA1 variant identified following an osteosarcoma pangenomic molecular analysis.

De novo germline pathogenic variants (gPV) of the BReast CAncer 1 (BRCA1) gene are very rare. Only a few have been described up to date, usually in patients with a history of ovarian or breast cancer. Here, we report the first case of an incidental de novo BRCA1 germline pathogenic variant which was identified within the framework of the Plan France Médecine Génomique (PFMG) 2025 French national tumor sequencing program. The proband was a 29-year-old man diagnosed with metastatic osteosarcoma. Tumor whole exome sequencing identified a BRCA1 c.3756_3759del p.(Ser1253Argfs*10) pathogenic variant without loss-of-heterozygosity. A low genomic instability score and the absence of single base substitution signatures of homologous recombination deficiency suggested that the BRCA1 variant was not driver in the osteosarcoma tumorigenesis. Germline whole genome sequencing asserted the germline nature of this variant, with a 36% allele frequency, suggesting a mosaicism caused by a post-zygotic mutational event. The proband's family (parents and siblings) were not carriers of this variant confirming the de novo occurrence. Tumor sequencing programs like the French PFMG 2025 have been implemented worldwide and may help identify new gPV, including de novo variants.

Correlation between large rearrangements and patient phenotypes in NF1 deletion syndrome: an update and review.

About 5-10% of neurofibromatosis type 1 (NF1) patients exhibit large genomic germline deletions that remove the NF1 gene and its flanking regions. The most frequent NF1 large deletion is 1.4 Mb, resulting from homologous recombination between two low copy repeats. This "type-1" deletion is associated with a severe clinical phenotype in NF1 patients, with several phenotypic manifestations including learning disability, a much earlier development of cutaneous neurofibromas, an increased tumour risk, and cardiovascular malformations. NF1 adjacent co-deleted genes could act as modifier loci for the specific clinical manifestations observed in deleted NF1 patients. Furthermore, other genetic modifiers (such as CNVs) not located at the NF1 locus could also modulate the phenotype observed in patients with large deletions. In this study, we analysed 22 NF1 deletion patients by genome-wide array-CGH with the aim (1) to correlate deletion length to observed phenotypic features and their severity in NF1 deletion syndrome, and (2) to identify whether the deletion phenotype could also be modulated by copy number variations elsewhere in the genome. We then review the role of co-deleted genes in the 1.4 Mb interval of type-1 deletions, and their possible implication in the main clinical features observed in this high-risk group of NF1 patients.

NF1 mutations as biomarker of response to immune checkpoint blockades for lung adenocarcinoma patients.

Little is known about immune checkpoint inhibitors (ICI) response of NF1-mutated lung adenocarcinomas. 341/4,181 (8.2%) TCGA lung adenocarcinomas samples have a somatic NF1 mutation. NF1-mutated tumors have higher TMB (p < 0.0001), higher expression of immune genes ("hot phenotype") and higher CD8 + T cell (p = 0.03) and macrophage (p = 0.02) infiltrations compared to NF1 wild-type tumors. NF1 mutation status appears as a candidate predictive biomarker for ICI response in lung adenocarcinoma patients.

Carney complex predisposes to breast cancer: prospective study of 50 women.

OBJECTIVE: Carney complex (CNC) is a rare genetic syndrome, mostly due to germline loss-of-function pathogenic variants in PRKAR1A. Carney complex includes pigmented skin lesions, cardiac myxomas, primary pigmented nodular adrenocortical dysplasia, and various breast benign tumors. DESIGN: The present study was designed to describe the characteristics of breast lesions in CNC patients and their association with other manifestations of CNC and PRKAR1A genotype. METHODS: A 3-year follow-up multicenter French prospective study of CNC patients included 50 women who were analyzed for CNC manifestations and particularly breast lesions, with breast imaging, genotyping, and hormonal settings. RESULTS: Among the 38 women with breast imaging, 14 (39%) had breast lesions, half of them bilateral. Ten women (26%) presented with benign lesions and six with breast carcinomas (16%): one had ductal carcinoma in situ at 54, and five had invasive cancer before 50 years old, whom one with contralateral breast cancer during follow-up. The occurrence of breast cancer was more frequent in women with PRKAR1A pathogenic variant odds ratio = 6.34 (1.63-17.91) than in general population of same age. The mean age at breast cancer diagnosis was 44.7 years old: 17 years younger than in the general population. Breast cancer patients had good prognosis factors. All breast carcinomas occurred in individuals with familial CNC and PRKAR1A pathogenic variants. Loss of heterozygosity at the PRKAR1A locus in the 2 invasive breast carcinomas analyzed suggested a driver role of this tumor suppressor gene. CONCLUSIONS: As CNC could predispose to breast carcinoma, an adequate screening strategy and follow-up should be discussed in affected women. CLINICAL TRIAL REGISTRATION: ClinicalTrial.gov NCT00668291.

Beyond MEN1, When to Think About MEN4? Retrospective Study on 5600 Patients in the French Population and Literature Review.

CONTEXT: Germline CDKN1B variants predispose patients to multiple endocrine neoplasia type 4 (MEN4), a rare MEN1-like syndrome, with <100 reported cases since its discovery in 2006. Although CDKN1B mutations are frequently suggested to explain cases of genetically negative MEN1, the prevalence and phenotype of MEN4 patients is poorly known, and genetic counseling is unclear. OBJECTIVE: To evaluate the prevalence of MEN4 in MEN1-suspected patients and characterize the phenotype of MEN4 patients. DESIGN: Retrospective observational nationwide study. Narrative review of literature and variant class reassessment. PATIENTS: We included all adult patients with class 3/4/5 CDKN1B variants identified by the laboratories from the French Oncogenetic Network on Neuroendocrine Tumors network between 2015 and 2022 through germline genetic testing for MEN1 suspicion. After class reassessment, we compared the phenotype of symptomatic patients with class 4/5 CDKN1B variants (ie, with genetically confirmed MEN4 diagnosis) in our series and in literature with 66 matched MEN1 patients from the UMD-MEN1 database. RESULTS: From 5600 MEN1-suspected patients analyzed, 4 with class 4/5 CDKN1B variant were found (0.07%). They presented with multiple duodenal NET, primary hyperparathyroidism (PHPT) and adrenal nodule, isolated PHPT, PHPT, and pancreatic neuroendocrine tumor. We listed 29 patients with CDKN1B class 4/5 variants from the literature. Compared with matched MEN1 patients, MEN4 patients presented lower NET incidence and older age at PHPT diagnosis. CONCLUSION: The prevalence of MEN4 is low. PHPT and pituitary adenoma represent the main associated lesions, NETs are rare. Our results suggest a milder and later phenotype than in MEN1. Our observations will help to improve genetic counseling and management of MEN4 families.

Neurofibromatosis type 1 mosaicism in patients with constitutional mismatch repair deficiency.

Differential diagnosis between constitutional mismatch repair deficiency (CMMRD) and neurofibromatosis type 1 (NF1) is crucial as treatment and surveillance differ. We report the case of a girl with a clinical diagnosis of sporadic NF1 who developed a glioblastoma. Immunohistochemistry for MMR proteins identified PMS2 loss in tumour and normal cells and WES showed the tumour had an ultra-hypermutated phenotype, supporting the diagnosis of CMMRD. Germline analyses identified two variants (one pathogenic variant and one classified as variant(s) of unknown significance) in the PMS2 gene and subsequent functional assays on blood lymphocytes confirmed the diagnosis of CMMRD. The large plexiform neurofibroma of the thigh and the freckling were however more compatible with NF1. Indeed, a NF1 PV (variant allele frequencies of 20%, 3% and 9% and in blood, skin and saliva samples, respectively) was identified confirming a mosaicism for NF1. Retrospective analysis of a French cohort identified NF1 mosaicism in blood DNA in 2 out of 22 patients with CMMRD, underlining the existence of early postzygotic PV of NF1 gene in patients with CMMRD whose tumours have been frequently reported to exhibit somatic NF1 mutations. It highlights the potential role of this pathway in the pathogenesis of CMMRD-associated gliomas and argues in favour of testing MEK inhibitors in this context.

Droplet Digital PCR for Fast and Accurate Characterization of NF1 Locus Deletions: Confirmation of the Predominant Maternal Origin of Type-1 Deletions.

Neurofibromatosis type-1 is a genetic disorder caused by loss-of-function variants in the tumor-suppressor NF1. Approximately 4% to 11% of neurofibromatosis type-1 patients have a NF1 locus complete deletion resulting from nonallelic homologous recombination between low copy repeats. Codeleted genes probably account for the more severe phenotype observed in NF1-deleted patients. This genotype-phenotype correlation highlights the need for a detailed molecular description. A droplet digital PCR (ddPCR) set along the NF1 locus was designed to delimitate the three recurrent NF1 deletion breakpoints. The ddPCR was tested in 121 samples from nonrelated NF1-deleted patients. Classification based on ddPCR versus multiplex ligation-dependent probe amplification (MLPA) was compared. In addition, microsatellites were analyzed to identify parental origin of deletions. ddPCR identified 77 type-1 (64%), 20 type-2 (16%), 7 type-3 (6%), and 17 atypical deletions (14%). The results were comparable with MLPA, except for three atypical deletions misclassified as type-2 using MLPA, for which the SUZ12 gene was not deleted. A significant maternal bias (25 of 30) in the origin of deletions was identified. This study proposes a fast and efficient ddPCR quantification to allow fine NF1 deletion classification. It indicates that ddPCR can be implemented easily into routine diagnosis to complement the techniques dedicated to NF1 point variant identification. This new tool may help unravel the genetic basis conditioning phenotypic variability in NF1-deleted patients and offer tailored genetic counseling.

Identification of potential common genetic modifiers of neurofibromas: a genome-wide association study in 1333 patients with neurofibromatosis type 1.

BACKGROUND: Neurofibromatosis type 1 (NF1) is characterized by the highly variable and unpredictable development of benign peripheral nerve sheath tumours: cutaneous (cNFs), subcutaneous (scNFs) and plexiform (pNFs) neurofibromas. OBJECTIVES: To identify neurofibroma modifier genes, in order to develop a database of patients with NF1. METHODS: All patients were phenotypically evaluated by a medical practitioner using a standardized questionnaire and the causal NF1 variant identified. We enrolled 1333 patients with NF1 who were genotyped for > 7 million common variants. RESULTS: A genome-wide association case-only study identified a significant association with 9q21.33 in the pNF phenotype in the discovery cohort. Twelve, three and four regions suggestive of association at the P ≤ 1 × 10-6 threshold were identified for pNFs, cNFs and scNFs, respectively. Evidence of replication was observed for 4, 2 and 6 loci, including 168 candidate modifier protein-coding genes. Among the candidate modifier genes, some were implicated in the RAS-mitogen-activated protein kinase pathway, cell-cycle control and myelination. Using an original CRISPR/Cas9-based functional assay, we confirmed GAS1 and SPRED2 as pNF and scNF candidate modifiers, as their inactivation specifically affected NF1-mutant Schwann cell growth. CONCLUSIONS: Our study may shed new light on the pathogenesis of NF1-associated neurofibromas and will, hopefully, contribute to the development of personalized care for patients with this deleterious and life-threatening condition.

NF1 alterations in cancers: therapeutic implications in precision medicine.

INTRODUCTION: NF1 is a tumor suppressor gene encoding neurofibromin, an inhibitor of the RAS/MAPK and PI3K-AKT-mTOR signaling pathways. NF1 germline pathogenic variants cause the tumor predisposition syndrome neurofibromatosis type 1. Targeted therapies (MEK inhibitors) have been approved for benign nerve sheath tumors in neurofibromatosis type 1 patients. NF1 somatic alterations are present in ~5% of all human sporadic cancers. In melanomas, acute myeloid leukemias and lung adenocarcinomas, the NF1 somatic alteration frequency is higher (~15%). However, to date, the therapeutic impact of NF1 somatic alterations is poorly investigated. AREAS COVERED: This review presents a comprehensive overview of targeted therapies and immunotherapies currently developed and evaluated in vitro and in vivo for NF1-altered cancer treatment. A PubMed database literature review was performed to select relevant original articles. Active clinical trials were researched in ClinicalTrials.gov database in August 2022. TCGA and HGMD® databases were consulted. EXPERT OPINION: This review highlights the need to better understand the molecular mechanisms of NF1-altered tumors and the development of innovative strategies to effectively target NF1-loss in human cancers. One of the current major challenges in cancer management is the targeting of tumor suppressor genes such as NF1 gene. Currently, most studies are focusing on inhibitors of the RAS/MAPK and PI3K-AKT-mTOR pathways and immunotherapies.

Clinical and genetic definition of serum bilirubin levels for the diagnosis of Gilbert syndrome and hypobilirubinemia.

BACKGROUND AND AIMS: Gilbert syndrome (GS) is genotypically predetermined by UGT1A1*28 homozygosity in Europeans and is phenotypically defined by hyperbilirubinemia using total bilirubin (TB) cutoff ≥1mg/dL (17 µmol/L). The prevalence of illnesses associated with GS and hypobilirubinemia has never been studied prospectively. As TB varies with UGT1A1*28 genotyping, sex, and age, we propose stratified definitions of TB reference intervals and report the prevalence of illnesses and adjusted 15 years survival. METHODS: UK Biobank with apparently healthy liver participants (middle-aged, n=138,125) were analyzed after the exclusion of of nonhealthy individuals. The stratified TB was classified as GS when TB >90th centile; <10th centile indicated hypobilirubinemia, and between the 10th and 90th centile was normobilirubinemia. We compared the prevalence and survival rates of 54 illnesses using odds ratio (OR), logistic regression, and Cox models adjusted for confounders, and causality by Mendelian randomizations. RESULTS: In women, we identified 10% (7,741/76,809) of GS versus 3.7% (2,819/76,809) using the historical cutoff of ≥1 mg/dL (P<0.0001). When GS and hypobilirubinemia participants were compared with normobilirubinemia, after adjustment and Mendelian randomizations, only cholelithiasis prevalence was significantly higher (OR=1.50; 95% CI [1.3-1.7], P=0.001) in men with GS compared with normobilirubinemia and in causal association with bilirubin (P=0.04). No adjusted survival was significantly associated with GS or hypobilirubinemia. CONCLUSIONS: In middle-aged Europeans, the stratified TB demonstrates a careless GS underestimation in women when using the standard unisex 1 mg/dL cutoff. The prevalence of illnesses is different in GS and hypobilirubinemia as well as survivals before adjusting for confounding factors. With the exception of cholelithiasis in men, these differences were no more significant after adjustment and Mendelian randomization.

Biology and Management of High-Grade Chondrosarcoma: An Update on Targets and Treatment Options.

This review provides an overview of histopathology, clinical presentation, molecular pathways, and potential new systemic treatments of high-grade chondrosarcomas (CS), including grade 2−3 conventional, dedifferentiated, and mesenchymal CS. The diagnosis of CS combines radiological and histological data in conjunction with patient clinical presentations. Conventional CS is the most frequent subtype of CS (85%) and represents about 25% of primary bone tumors in adults; they can be categorized according to their bone location into central, peripheral, and periosteal chondrosarcomas. Central and peripheral CS differ at the molecular level with either IDH1/2 mutations or EXT1/2 mutations, respectively. CDKN2A/B deletions are also frequent in conventional CS, as well as COL2A1 mutations. Dedifferentiated CS develops when low-grade conventional CS transforms into a high-grade sarcoma and most frequently exhibits features of osteosarcoma, fibrosarcoma, or undifferentiated pleomorphic sarcoma. Their molecular characteristics are similar to conventional CS. Mesenchymal CS is a totally different pathological entity exhibiting recurrent translocations. Their clinical presentation and management are different too. The standard treatment of CSs is wide en-bloc resection. CS are relatively radiotherapy resistant; therefore, doses >60 Gy are needed in an attempt to achieve local control in unresectable tumors. Chemotherapy is possibly effective in mesenchymal chondrosarcoma and is of uncertain value in dedifferentiated chondrosarcoma. Due to resistance to standard anticancer agents, the prognosis is poor in patients with metastatic or unresectable chondrosarcomas. Recently, the refined characterization of the molecular profile, as well as the development of new treatments, allow new therapeutic options for these rare tumors. The efficiency of IDH1 inhibitors in other malignancies suggests that these inhibitors will be part of IDH1/2 mutated conventional CS management soon. Other treatment approaches, such as PIK3-AKT-mTOR inhibitors, cell cycle inhibitors, and epigenetic or immune modulators based on improving our understanding of CS molecular biology, are emerging.

Contribution of whole genome sequencing in the molecular diagnosis of mosaic partial deletion of the NF1 gene in neurofibromatosis type 1.

Neurofibromatosis type 1 (NF1) is an autosomal dominant disease with complete penetrance but highly variable expressivity. In most patients, Next Generation Sequencing (NGS) technologies allow the identification of a loss-of-function pathogenic variant in the NF1 gene, a negative regulator of the RAS-MAPK pathway. We describe the 5-year diagnosis wandering of a patient with a clear NF1 clinical diagnosis, but no molecular diagnosis using standard molecular technologies. The patient presented with a typical NF1 phenotype but NF1 targeted NGS, NF1 transcript analysis, MLPA, and array comparative genomic hybridization failed to reveal a genetic aberration. After 5 years of unsuccessful investigations, trio WGS finally identified a de novo mosaic (VAF ~ 14%) 24.6 kb germline deletion encompassing the promoter and first exon of NF1. This case report illustrates the relevance of WGS to detect structural variants including copy number variants that would be missed by alternative approaches. The identification of the causal pathogenic variant allowed a tailored genetic counseling with a targeted non-invasive prenatal diagnosis by detecting the deletion in plasmatic cell-free DNA from the proband's pregnant partner. This report clearly highlights the need to make WGS a clinically accessible test, offering a tremendous opportunity to identify a molecular diagnosis for otherwise unsolved cases.

VEGF and VEGFR family members are expressed by neoplastic cells of NF1-associated tumors and may play an oncogenic role in malignant peripheral nerve sheath tumor growth through an autocrine loop.

Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder. The role of angiogenesis and VEGF pathway in the pathogenesis of neurofibromas and malignant peripheral nerve sheath tumors (MPNSTs) remains poorly understood. We assessed the expression of VEGF and VEGFR family members in cohorts of plexiform neurofibromas (pNF), MPNSTs and MPNST cell lines at transcript [pNF, n = 49; MPNST, n = 34] and protein levels [pNF, n = 21; MPNST, n = 9]. VEGF and VEGFR members were variably expressed in cell lines. VEGFA (p = 3.10-5), VEGFR1 (p = 0.08), and VEGFR2 (p = 2.10-4) mRNAs were overexpressed in MPNSTs in comparison with pNFs. Both VEGFA and VEGFR1 proteins were expressed by spindle tumor cells of pNFs and MPNSTs. VEGFA was expressed more in MPNSTs than in pNFs (p = 9.10-6) and a trend for VEGFR1 overexpression was observed (p = 0.06). VEGFR2 was not found at the protein level. The microvascular density was significantly reduced in MPNSTs as compared to pNFs (p = 0.0025), with no differences regarding the expression of the activated phosphorylated forms of ERK (P-ERK [p = 0.63]) and AKT (P-AKT [p = 0.41]) in endothelial cells, suggesting that VEGF-dependant angiogenesis may not be critical for MPNST oncogenesis. Altogether, these results indicate that the VEGF-VEGFR pathway may play a role in the development of pNFs and MPNSTs, independently of angiogenesis. Whether or not it drives an oncogenic autocrine/paracrine loop in neoplastic cells, participating in an increased activation of signaling pathways downstream of tyrosine kinase receptors, including VEGFRs, is a tempting hypothesis. Nevertheless, the specific targeting of angiogenesis in MPNSTs may not be sufficient to slow down tumor growth.