Malignant Transformation of Plexiform Neurofibroma to MPNST while on MEK Inhibitor

AbstractPlexiform neurofibromas are congenital peripheral nerve sheath tumors characteristic of neurofibromatosis type 1 (NF1)—a frequent neurocutaneous disorder caused by mutations of the NF1 tumor suppressor gene. Since plexiform neurofibromas are a major cause of the burden of disease and may also progress to malignancy, many efforts have been undertaken to find a cure for these tumors. However, neither surgery nor medication has so far produced a breakthrough therapeutic success. Recently, a clinical phase I study reported significant shrinkage of plexiform neurofibromas following treatment with the MEK inhibitor selumetinib. Here, we report an 11-year-old NF1 patient with a large plexiform neurofibroma of the neck that had led to a sharp-angled kinking of the cervical spine and subsequent myelopathy. Although surgical stabilization of the cervical vertebral column was urgently recommended, the vertebral column was inaccessible due to extensive tumor growth. In this situation, treatment with the MEK inhibitor trametinib was initiated which resulted in a 22% reduction in tumor volume after 6 months of therapy and finally enabled surgery. These data show that MEK inhibitors may not lead to complete disappearance of NF1-associated plexiform neurofibromas but can be an essential step in a multimodal therapeutic approach for these tumors. The course of our patient suggests that MEK inhibitors are likely to play a significant role in providing a cure for one of the most devastating manifestations of NF1.

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Neurofibromatosis: Molecular Pathogenesis and Natural Compounds as Potential Treatments

Frontiers in Oncology ◽

10.3389/fonc.2021.698192 ◽

2021 ◽

Vol 11 ◽

Author(s):

Anusha Amaravathi ◽

Janet L. Oblinger ◽

D. Bradley Welling ◽

A. Douglas Kinghorn ◽

Long-Sheng Chang

Keyword(s):

Target Identification ◽

Plexiform Neurofibroma ◽

Tumor Biology ◽

Mek Inhibitor ◽

Natural Compounds ◽

Major Advance ◽

Primary Therapy ◽

Limited Success ◽

Fda Approval ◽

Genetics And Genomics

The neurofibromatosis syndromes, including NF1, NF2, and schwannomatosis, are tumor suppressor syndromes characterized by multiple nervous system tumors, particularly Schwann cell neoplasms. NF-related tumors are mainly treated by surgery, and some of them have been treated by but are refractory to conventional chemotherapy. Recent advances in molecular genetics and genomics alongside the development of multiple animal models have provided a better understanding of NF tumor biology and facilitated target identification and therapeutic evaluation. Many targeted therapies have been evaluated in preclinical models and patients with limited success. One major advance is the FDA approval of the MEK inhibitor selumetinib for the treatment of NF1-associated plexiform neurofibroma. Due to their anti-neoplastic, antioxidant, and anti-inflammatory properties, selected natural compounds could be useful as a primary therapy or as an adjuvant therapy prior to or following surgery and/or radiation for patients with tumor predisposition syndromes, as patients often take them as dietary supplements and for health enhancement purposes. Here we review the natural compounds that have been evaluated in NF models. Some have demonstrated potent anti-tumor effects and may become viable treatments in the future.

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Malignant transformation in a sciatic plexiform neurofibroma in Neurofibromatosis Type 1 - imaging features that aid diagnosis

Journal of Radiology Case Reports ◽

10.3941/jrcr.v14i12.4028 ◽

2020 ◽

Vol 14 (12) ◽

Author(s):

Dorinda Chee Yee Chew ◽

Daniel Bin Hang Zhao ◽

Kesavan Sittampalam ◽

S Krishna Kumar

Keyword(s):

Malignant Transformation ◽

Neurofibromatosis Type 1 ◽

Plexiform Neurofibroma ◽

Neurofibromatosis Type ◽

Imaging Features

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Concomitant Variants in NF1 , LZTR1 , and GNAZ Genes Probably Contribute to the Aggressiveness of Plexiform Neurofibroma and Warrant Treatment with MEK Inhibitor

Experimental Dermatology ◽

10.1111/exd.14514 ◽

2021 ◽

Author(s):

Eran Cohen‐Barak ◽

Hagit Toledano Alhadief ◽

Nada Danial‐Farran ◽

Ido Livneh ◽

Banan Mwassi ◽

...

Keyword(s):

Plexiform Neurofibroma ◽

Mek Inhibitor

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Isolated Plexiform Neurofibroma of the Tongue

Journal of Laboratory Physicians ◽

10.4103/0974-2727.119867 ◽

2013 ◽

Vol 5 (02) ◽

pp. 127-129 ◽

Cited By ~ 5

Author(s):

Abhishek Sharma ◽

Parama Sengupta ◽

Anjan KR Das

Keyword(s):

Malignant Transformation ◽

Rare Case ◽

Benign Tumor ◽

Clinical Presentation ◽

Plexiform Neurofibroma ◽

Common Variant ◽

Benign Tumors ◽

Plexiform Neurofibromas ◽

Neural Origin ◽

Rare Benign Tumor

ABSTRACTNeurofibromas (NF) are benign tumors of neural origin, of which roughly 90% appear as solitary lesions. They are classified into cutaneous, subcutaneous, and plexiform subtypes. Plexiform neurofibromas are the least common variant and usually are pathognomonic for NF I. Here, we present a very rare case of isolated plexiform neurofibroma with a painless enlarging mass of the tongue of an 11-year-old girl. This rare benign tumor has the potential for malignant transformation, and the diagnosis was difficult owing to the patient's age and to the insidious clinical presentation. The present case is a diffuse isolated plexiform neurofibroma of the tongue that was not associated with neurofibromatosis that was treated with intraoral surgery.

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Impact of MEK inhibitor therapy on neurocognition in neurofibromatosis type 1

10.1101/2020.12.18.20248334 ◽

2020 ◽

Author(s):

Karin S. Walsh ◽

Pamela L. Wolters ◽

Brigitte C. Widemann ◽

Allison A. del Castillo ◽

Maegan D. Sady ◽

...

Keyword(s):

Visual Learning ◽

Plexiform Neurofibroma ◽

Unmet Need ◽

Mek Inhibitor ◽

Cognitive Intervention ◽

Reliable Change Index ◽

Future Research ◽

Group Level ◽

Chi Square ◽

Patients Âgés

AbstractObjectiveNF1-associated cognitive impairments carry significant life-long morbidity. The lack of targeted biologic treatments remains a significant unmet need. We examine changes in cognition in patients with NF1 in the first 48 weeks of MEK inhibitor (MEKi) treatment.Methods59 NF1 patients ages 5-27 on a MEKi clinical trial treating plexiform neurofibroma underwent pre-treatment and follow-up cognitive assessments over 48-weeks of treatment. Performance tasks (Cogstate) and observer-reported functioning (BRIEF) were primary outcomes. Group-level (paired t-tests) and individual-level analyses (reliable change index; RCI) were used.ResultsAnalysis showed statistically significant improvements on BRIEF compared to baseline (24-week BRI: t(58)=3.03, p=.004, d=0.24; 48-week MCI: t(39)=2.70, p=.01, d=0.27). RCI indicated more patients had clinically significant improvement at 48-weeks than expected by chance (Chi Square=11.95, p=.001, OR=6.3). Group-level analyses indicated stable performance on Cogstate (p>.05). RCI statistics showed high proportions of improved working memory (24-weeks Chi Square=8.36, p=.004, OR=4.6 and 48-weeks Chi Square=9.34, p=.004, OR=5.3) but not visual learning/memory. Patients with baseline impairments on BRIEF were more likely to show significant improvement than non-impaired patients (24-weeks 46% v. 8%; Chi Square=9.54, p=.008, OR=9.22; 48-weeks 63% v. 16%; Chi Square=7.50, p=.02, OR=9.0).InterpretationOur data shows no evidence of neurotoxicity in 48-weeks of treatment with a MEKi and a potential clinical signal supporting future research of MEKi as a cognitive intervention.

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Extensive Pelvic Plexiform Neurofibroma Presenting As Clitoromegaly in a 3-Year-Old Female: Presentation and Management with MEK Inhibitor

Journal of Pediatric Genetics ◽

10.1055/s-0040-1715638 ◽

2020 ◽

Author(s):

Richelle C. Waldner ◽

Marta Rojas-Vasquez ◽

Peter D. Metcalfe ◽

Andrea M. Haqq

Keyword(s):

Kinase Inhibitor ◽

Bladder Wall ◽

Plexiform Neurofibroma ◽

Pelvic Mass ◽

External Genitalia ◽

Neurofibromatosis Type ◽

Mek Inhibitor ◽

Mitogen Activated Protein Kinase ◽

Type I ◽

Mitogen Activated Protein

AbstractPlexiform neurofibroma (PN) involvement of the external genitalia in patients with neurofibromatosis type I (NF1) is a rare cause of nonhormonal clitoromegaly. We present a 3-year-old female with known NF1 who presented with clitoromegaly. She was identified with an extensive pelvic mass involving the bladder wall, perineum, labia, clitoris, rectum, and sacral foramina. A partial cystectomy was performed, and histopathology was consistent with PN. She has been initiated on a mitogen activated protein kinase enzyme kinase inhibitor, trametinib, which has been effective in achieving partial radiographic response of the bladder mass over 5 months. Additionally, she has experienced clinical response to trematinib with resolution of urinary urgency and frequency since initiating treatment.

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