Neurofibroma of Tongue - A Case Report

Nerve sheath tumors: evaluation with CT and MR imaging : Verstraete KL, Achten E, De Schepper A, et al. (Dienst Radiologie en Medische Beeldvorming, Universitair Ziekenhuis Gent, De Pintelaan 185, B-9000, Gent, Belgium). J Belge Radiol 1992;75:311–320

Angiosarcomatous differentiation represents the least common form of heterologous differentiation in malignant peripheral nerve sheath tumours (MPNST), and is seen most frequently in patients with neurofibromatosis type 1. More rarely, it has been reported in patients without stigmata of neurofibromatosis, or in benign nerve sheath tumours and peripheral nerves. This study was undertaken to confirm this rare association. Four cases of angiosarcoma arising in a peripheral nerve, in a long-standing schwannoma and in two MPNST are described. Immunohistochemical studies were performed on paraffin sections with the alkaline phosphatase-antialkaline phosphatase method. An intraneural high-grade epithelioid angiosarcoma arose in the left posterior tibial nerve of a 78-year-old man, a well to moderately differentiated angiosarcoma was seen in an ancient schwannoma of the lateral neck in a 73-year-old women, and an angiosarcoma of varying grades of differentiation developed in a recurrent MPNST in the thigh of 38-year-old man. In addition a high-grade MPNST in the axillary region of a 30-year-old man showed foci of heterologous high-grade angiosarcomatous differentiation. The neural and endothelial lines of differentiation were confirmed in each case by positive immunohistochemical staining for neural and endothelial markers, respectively. In all cases tested, the neural differentiated cells stained immunohistochemically positive for antibodies against vascular endothelial growth factor. This study confirms the rare association of angiosarcoma arising in peripheral nerves, as well as in benign and malignant peripheral nerve sheath tumours.

Aim: To assess the utility of MRI and PET/CT to differentiate benign versus malignant peripheral nerve sheath tumors (MPNST). Methods: We retrospectively identified 68 patients with histologically confirmed nerve sheath tumors. All of these patients had pretreatment magnetic resonance imaging (MRI) studies and 17 patients had pretreatment 18-fluorodeoxyglucose positron emission tomography (PET/CT). Age, history of neurofibromatosis, maximum size of the tumor, MR features, and maximum standardized uptake values (SUV) from PET/CT were obtained. We used Wilcoxon-Rank sum or Fisher's exact tests to compare benign versus malignant nerve sheath tumors. Results: There was no significant difference in the mean age of the patients with benign versus MPNST (P=0.85). Patients with NF1 had higher odds of MPNSTs (OR=26.7, P=2.6 x10-7). There was no difference in the mean size of the benign versus MPNSTs (P=0.44). Homogeneous enhancement of a lesion after intravenous contrast (OR=0.08, P=0.008) and the target sign (OR=0.0, P=0.041), were both associated with decreased odds of MPNST. Bone destruction seen on MRI (P=5.7x10-4) and an enlarged nerve (OR = 3.89, P=0.048) were associated with increased odds of MPNST. MPNSTs had significantly higher mean maximum SUV than benign nerve sheath tumors (P=0.0272). The previously published threshold maximum SUV of 3.5 had 100% sensitivity and 50% specificity to exclude MPNST as 50% (4/8) of the benign nerve sheath tumors had a maximum SUV >3.5. Conclusion: MRI and PET/CT are useful for differentiating benign from MPNST, but neither is specific. A maximum SUV of 3.5 is highly sensitive for identifying MPNST; however, tissue sampling is often necessary to confirm the diagnosis since using this threshold results in a large proportion of false positives. Citation Format: Ronnie Sebro, Paul Niziolek. Utility of MRI and PET/CT to differentiate benign versus malignant peripheral nerve sheath tumors (MPNST) [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr B17.

Neurofibromatosis type 1 (NF1) is associated with the development of benign (BPNST) and malignant (MPNST) peripheral nerve sheath tumors. Recently described atypical neurofibromas (ANF) are considered pre-malignant precursor lesions to MPNSTs. Previous studies indicate that diffusion-weighted magnetic resonance imaging (DW-MRI) can reliably discriminate MPNSTs from BPNSTs. We therefore investigated the diagnostic accuracy of DW-MRI for the discrimination of benign, atypical, and malignant peripheral nerve sheath tumors. In this prospective explorative single-center phase II diagnostic study, 44 NF1 patients (23 male; 30.1 ± 11.8 years) underwent DW-MRI (b-values 0-800s/mm²) at 3T. Two radiologists independently assessed mean and minimum apparent diffusion coefficients (ADCmean/min) in areas of largest tumor diameters and ADCdark in areas of lowest signal intensity by manual contouring of the tumor margins of 60 BPNSTs, 13 ANFs, and 21 MPNSTs. Follow-up of ≥ 24 months (BPNSTs) or histopathological evaluation (ANFs + MPNSTs) served as diagnostic reference standard. Diagnostic ADC-based cut-off values for discrimination of the three tumor groups were chosen to yield the highest possible specificity while maintaining a clinically acceptable sensitivity. ADC values of pre-malignant ANFs clustered between BPNSTs and MPNSTs. Best BPNST vs. ANF + MPNST discrimination was obtained using ADCdark at a cut-off value of 1.6 × 10-3 mm2/s (85.3% sensitivity, 93.3% specificity), corresponding to an AUC of 94.3% (95% confidence interval: 85.2-98.0). Regarding BPNST + ANF vs. MPNST, best discrimination was obtained using an ADCdark cut-off value of 1.4 × 10-3 mm2/s (83.3% sensitivity, 94.5% specificity). DW-MRI using ADCdark allows specific and noninvasive discrimination of benign, atypical, and malignant nerve sheath tumors in NF1.

Benign tumors of the nerve sheath are of 2 types: schwannoma and neurofibroma. Neurofibromas are most commonly found with neurofibromatosis type 1 and characterized by incorporation of the nerve fibers within their matrix. Both benign and malignant tumors can affect the facial nerve. These tumors can be intrinsic or extrinsic; in other words, it can originate from the facial nerve itself or from a contiguous structure or a metastatic disease. Actually, extrinsic tumors are far more common than intrinsic tumors. Intraparotid location of benign tumors of the facial nerve sheath is considered a rare event compared with intratemporal location.

3108 Background: NF1 is an autosomal-dominant genetic disease that can manifest as neurofibromas, including cutaneous neurofibromas (cNFs) affecting almost all NF1 patients (pts), and plexiform neurofibromas (PNs, up to 50%), which are benign nerve sheath tumors. However, PNs can cause substantial pain, disfigurement and impairment in pts and are at risk of transforming into malignant peripheral nerve sheath tumors (MPNSTs). Currently, there is no medical cure for adult pts with NF1-related PN (NF1-PN), and fewer options for adult pts with cNFs. TQ-B3234 is a highly selective MEK1/2 inhibitor. A phase 1 dose-escalation and dose-expansion trial (NCT05107037) evaluated the safety and efficacy of TQ-B3234 in adult pts with inoperable NF1-PN, MPNSTs or cNFs. Methods: Eligible adult pts with inoperable NF1-PN, MPNSTs or cNFs were included in the dose-escalation phase using a 3+3 design, while only NF1-PN pts proceeded to the dose-expansion phase. TQ-B3234 was administered as a capsule, with doses ranging from 5 mg to 100 mg, once daily in 28-day cycles during the dose-escalation phase. A dose of 50mg was chosen for the dose-expansion phase. The primary endpoints were safety and objective response rate (ORR). ORR was assessed by investigators using REiNS for NF1- PN pts, RECIST 1.1 for MPNSTs pts, and paper frames for the cNF population. Results: As of September 30, 2024, 40 adult pts (31 pts of PNs, 7 pts of cNFs, and 2 MPNSTs) were enrolled. The distribution of doses was as follows: 4 pts at 5 mg, 1 at 10 mg, 3 at 15 mg, 24 at 50 mg, 5 at 70 mg, and 3 at 100 mg. One patient, a cNF case, experienced dose-limiting toxicity (DLT), in the form of G3 diarrhea (16.7%) at the 100 mg dose during the dose-escalation phase. After a median follow-up of 12 months, treatment-emergent adverse events (TEAEs) were observed in 39 pts (97.5%), with the majority were grade 1 or 2. Grade 3 TEAEs were reported in 17.5% of pts; the principal reasons for dose reductions (15.0%) TEAEs included rash acneiform (5.0%), diarrhea (2.5%), and edema (2.5%). No death occurred during the study. Among the 30 pts with NF1-PN who had at least one tumor assessment, 29 pts (96.7%) experienced tumor size reduction, and 11 (36.7%) achieved partial response (PR) based on REiNS criteria. The largest reduction in tumor size was 37.7%. For the 6 cNF pts who had at least one tumor assessment using paper frames, all 6 pts (100%) experienced reduced tumor size, with the largest reduction being 85.2%. Conclusions: TQ-B3234 demonstrated manageable safety and a significant ORR in adult NF1- PN pts. These results support the potential of TQ-B3234 to become a new treatment option for NF1- PN pts. Additionally, TQ-B3234 showed deep and durable volume reduction in adult cNF pts, as assessed by paper frames. This method could serve as a valuable tool in clinical research for achieving accurate quantitative phenotype for NF1. Clinical trial information: NCT05107037 .

Multiple Ipsilateral Lower Extremity Masses in a 46-year-old Man

Malignant peripheral nerve sheath tumours (MPNST) are aggressive sarcomas that develop in about 10% of patients with the genetic disease neurofibromatosis type 1 (NF1). Molecular alterations contributing to MPNST formation have only partially been resolved. Here we examined the role of Pten, a key regulator of the Pi3k/Akt/mTOR pathway, in human MPNST and benign neurofibromas. Immunohistochemistry showed that Pten expression was significantly lower in MPNST (n = 16) than in neurofibromas (n = 16) and normal nervous tissue. To elucidate potential mechanisms for Pten down-regulation or Akt/mTOR activation in MPNST we performed further experiments. Mutation analysis revealed absence of somatic mutations in PTEN (n = 31) and PIK3CA (n = 38). However, we found frequent PTEN promotor methylation in primary MPNST (11/26) and MPNST cell lines (7/8) but not in benign nerve sheath tumours. PTEN methylation was significantly associated with early metastasis. Moreover, we detected an inverse correlation of Pten-regulating miR-21 and Pten protein levels in MPNST cell lines. The examination of NF1−/− and NF1+/+Schwann cells and fibroblasts showed that Pten expression is not regulated by NF1. To determine the significance of Pten status for treatment with the mTOR inhibitor rapamycin we treated 5 MPNST cell lines with rapamycin. All cell lines were sensitive to rapamycin without a significant correlation to Pten levels. When rapamycin was combined with simvastatin a synergistic anti-proliferative effect was achieved. Taken together we show frequent loss/reduction of Pten expression in MPNST and provide evidence for the involvement of multiple Pten regulating mechanisms.

Understanding the biological pathways critical for common neurofibromatosis type 1 (NF1) peripheral nerve tumours is essential, as there is a lack of tumour biomarkers, prognostic factors and therapeutics. We used gene expression profiling to define transcriptional changes between primary normal Schwann cells (n = 10), NF1-derived primary benign neurofibroma Schwann cells (NFSCs) (n = 22), malignant peripheral nerve sheath tumour (MPNST) cell lines (n = 13), benign neurofibromas (NF) (n = 26) and MPNST (n = 6). Dermal and plexiform NFs were indistinguishable. A prominent theme in the analysis was aberrant differentiation. NFs repressed gene programs normally active in Schwann cell precursors and immature Schwann cells. MPNST signatures strongly differed; genes up-regulated in sarcomas were significantly enriched for genes activated in neural crest cells. We validated the differential expression of 82 genes including the neural crest transcription factor SOX9 and SOX9 predicted targets. SOX9 immunoreactivity was robust in NF and MPSNT tissue sections and targeting SOX9 – strongly expressed in NF1-related tumours – caused MPNST cell death. SOX9 is a biomarker of NF and MPNST, and possibly a therapeutic target in NF1.

Editorial: Understanding the Nature of Attention Problems in Neurofibromatosis Type 1: Clinical and Research Implications.

What Is the Malignancy Risk in Neurofibromatosis Type 1?

Neurofibromas and schwannomas are benign tumours of the peripheral nerve sheath. They are encountered within a wide range of medical specialities and may occur as isolated sporadic lesions or as a key feature of genetic disorders including schwannomatosis, neurofibromatosis type 1 (NF1) and neurofibromatosis type 2 (NF2). Approximately half of cases of NF1 and NF2 are the result of autosomal dominant inheritance of a germline mutation from an affected parent, whilst the remainder are caused by de novo mutations. NF1 is caused by mutations in the NF1 gene on chromosome 17q11.2, and NF2 is caused by mutation of the NF2 gene at locus 22q12.2. Despite considerable phenotypic overlap with NF2, schwannomatosis has been shown to a distinct entity with pathological variants in SMARCB1 and LZTR1 genes. NF1 is the most common of the three conditions, with a frequency of 1 in 2500–3000 live births, whereas NF2 and schwannomatosis are considerably less common. Each of these disorders has a distinct clinical profile. NF1 is predominantly neurocutaneous, characterised by neurofibromas, with concomitant eye and bone manifestations. NF2 is a central disorder, with tumours occurring in cranial and spinal nerves, most commonly bilateral vestibular schwannomas. The characteristic presentation of schwannomatosis is with chronic pain associated with cutaneous and central schwannomas, but without the other features of NF1 or NF2. The nature of these disorders results in overlap in care between neurology, dermatology and genetics and current management is largely symptomatic and surgical, with effective disease modifying treatments remaining elusive. In this month’s journal club we review two articles relating to these conditions: a study providing insights into the epidemiology of schwannomatosis and NF2, and a phase 1 study examining the use of a selective inhibitor of mitogen-activated protein kinase (MAPK).

Neurofibromatosis type 1 (NF1) is a neurogenetic disorder. Individuals with NF1 may develop a variety of benign and malignant tumors of which peripheral nerve sheath tumors represent the most frequent entity. Plexiform neurofibromas may demonstrate a locally destructive growth pattern, may cause severe symptoms and may undergo malignant transformation into malignant peripheral nerve sheath tumors (MPNSTs). Whole-body magnetic resonance imaging (MRI) represents the reference standard for detection of soft tissue tumors in NF1. It allows for identification of individuals with plexiform neurofibromas, for assessment of local tumor extent, and for evaluation of whole-body tumor burden on T2-weighted imaging. Multiparametric MRI may provide a comprehensive characterization of different tissue properties of peripheral nerve sheath tumors, and may identify parameters associated with malignant transformation. Due to the absence of any radiation exposure, whole-body MRI may be used for serial follow-up of individuals with plexiform neurofibromas. (18)F-fluorodeoxyglucose positron-emission-tomography (FDG PET/CT) allows a highly sensitive and specific detection of MPNST, and should be used in case of potential malignant transformation of a peripheral nerve sheath tumor. PET/CT provides a sensitive whole-body tumor staging. The use of contrast-enhanced CT for diagnosis of peripheral nerve sheath tumors is limited to special indications. To obtain the most precise readings, optimized examination protocols and dedicated radiologists and nuclear medicine physicians familiar with the complex and variable morphologies of peripheral nerve sheath tumors are required. Individuals with NF1 may develop benign and malignant nerve sheath tumors. Whole-body MRI is the reference standard to identify nerve sheath tumors in NF1. MRI provides a comprehensive characterization of the growth pattern, growth dynamics and extent of nerve sheath tumors. (18)F-FDG PET/CT provides a sensitivity of 100% and a specificity of 77-95% for detection of malignant transformation.

Plexiform neurofibroma is a multi-nodular and diffuse benign peripheral nerve sheath tumor and is usually associated with neurofibromatosis type 1. Plexiform neurofibroma of the brachial plexus is rare. Plexiform neurofibroma of the whole upper limb, presenting with multiple nodular tumor masses from cervical nerve roots along the course of the brachial plexus and at the termination of the peripheral nerves is especially rare. Here we report two cases of pan-limb plexiform neurofibroma with similarity in symptoms and signs: diffuse nerve tumor masses, cutaneous pigmentation (cafe-au-lait spots) and severe neurological deficits of the upper limb. Case 1, a 28-years-old lady with Von Recklinghausen's disease presented with diffuse swelling and weakness of the left upper limb. Case 2, a 3-years- old boy, presented with multiple masses over the right neck with dropped shoulder and progressive inability to flex his elbow over the duration of one year. Both of them received cervical spine surgery for cord decompression and peripheral nerve surgeries for the limb tumor growth. They both had multiple nerve tumors resection and received palliative reconstruction: by tendon transfer and nerve transfer. Based on the clinical and intraoperative findings of these two cases, we made our hypothesis in tumor genesis and progression. ”Neighboring transmission” in such ”pan-limb” plexiform neurofibroma is proposed. Although it is rare, once it develops, it often results in severe neurological deficits and is a big challenge to the surgeon for both tumor resection and reconstruction. Early radical excision to prevent pathological neurogenic tumor spreading is probably one of the best choices of treatment. Late reconstruction by tendon, muscle, or nerve transfer, similar to the treatment of brachial plexus injuries is then supplemented.

The aim of the present investigation was to characterize the growth pattern and antigen profile of peripheral nerve sheath tumors (PNST) in a large series of tumors obtained from patients with Neurofibromatosis type 1 (NF1) focusing on morphological characteristics of diffuse plexiform neurofibroma (DPNF). Tissue micro-array (TMA) analysis was applied to study 520 formalin-fixed, paraffin-embedded human PNST of 385 patients with confirmed NF1 diagnosis. PNST originated from all areas of the body and were classified as cutaneous neurofibroma (CNF, n=114), diffuse neurofibroma (DNF, n=109), DPNF (n=108), plexiform neurofibroma (PNF, n=110), and malignant peripheral nerve sheath tumor (MPNST, n=22). Histomorphology and antigen expression patterns of the tumors were determined [S100, epithelial membrane antigen (EMA), CD90, mast cell tryptase, and neurofilament]. Benign PNST showed significantly more S100-positive tumor cells than MPNST (p<0.001). EMA expression was most pronounced in perineurium of DPNF. The number of mast cells in CNF, DNF and DPNF was significantly higher compared to PNF and MPNST (p<0.001 for both comparisons, Mann-Whitney U-test). DPNF show some distinct cellular characteristics. A high number of EMA positive cells possibly indicates the dissemination of perineural cells to the surrounding tissue. Concerning mast cell density, DPNF resemble DNF and CNS rather than PNF. Close contact of tumor cells in DPNF, DNF and CNF with the immune system is a prerequisite for permanent immunological reactions in contrast to PNF in which tumor cells are partitioned from the immune system by the perineurium and blood-nerve barrier of blood vessels. It is assumed that these morphological distinctions may reflect in part the biological differences between the entities. While PNF is a known precancerous stage in NF1 patients, DPNF are not rated as such. Furthermore, the morphologic differences between benign nerve sheath tumors may be important for the efficacy of drugs to access tumor cells.