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Neurofibroma

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Neoplasms, Nerve Tissue

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Syndrome

Neoplastic Syndromes, Hereditary

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Peripheral Nervous System Diseases

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Peripheral Nervous System Neoplasms

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Neoplasms, Fibrous Tissue

Neoplasms, Connective Tissue

Neoplasms, Connective and Soft Tissue

Sarcoma

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Neurofibromatosis Type 1

Malignant Peripheral Nerve Sheath Tumor

Soft Tissue Sarcoma

Magnetic resonance imaging of the entire body from skull base through distal thighs/knees without contrast material

Whole Body Magnetic Resonance Imaging

Shivani Ahlawat, PhD

Shivani Ahlawat, MD

The goal of this prospective observational study is to learn about the utility of imaging and clinical features in patients with Neurofibromatosis type 1 categorized as high risk for the development of malignant peripheral nerve sheath tumors.

The main objectives are:

* To evaluate the prevalence, multi-parametric imaging features of distinct nodular lesions ("DNLs") and natural history in people with NF1 with clinical and genetic features deemed "high-risk" for malignancy.
* To assess the relationship between individual clinical, genetic and imaging factors that have been suggested to be risk factors for malignant peripheral nerve sheath tumors (MPNST) and the confirmation of atypical neurofibromas (aNF)/ atypical neurofibromatous neoplasm of unknown biologic potential (ANNUBP) or MPNST on pathology.

In this research study, the participants will be asked to undergo whole body MRI, provide blood sample and clinical evaluation annually.

Patients with the autosomal dominant genetic tumor predisposition syndrome neurofibromatosis type 1 (NF1) have an increased risk of developing both benign and malignant neoplasms throughout life. The most common tumors are peripheral nerve sheath tumors (PNSTs) such as plexiform neurofibromas (pNFs). pNFs are multicellular primary tumors of the peripheral nerve that are histologically benign but often cause significant neurologic morbidity due to involvement of critical nerves. However, the greatest fear is the development of malignant peripheral nerve sheath tumors (MPNSTs). MPNST is an aggressive, treatment resistant sarcoma with a 5-year survival rate of only 15-50% and is the leading cause of death in NF1 patients, especially in those under 50 years of age. An estimated 50% of NF1 patients develop pNFs and the lifetime risk of developing MPNST is 8-13%. The only possible cure for MPNST is complete resection with wide negative margins. This is only feasible if the lesion can be clearly defined and removed without life-threatening morbidity. A major challenge to clearly differentiating between MPNSTs and pNFs is that the vast majority of MPNSTs arise within pNFs. This intimate association makes it hard to distinguish MPNST clinically, radiologically, and pathologically from surrounding benign tissue, thus leading to delayed diagnosis until after symptoms (such as severe pain and loss of neurologic function) have emerged and the chance for cure is greatly diminished or lost. A great deal of time, resource and worry from patients, the patients loved ones and medical providers is dedicated to detecting MPNSTs early at great expense and unclear benefit.

Existing clinical factors and imaging markers of MPNST do not accurately identify patients at risk of developing either MPNST or the patients precursor tumors. Retrospective studies from various centers have suggested several clinical factors associated with the development of MPNST including: number and volume of internal PNSTs, presence of subcutaneous neurofibromas, younger age, presence of pain, microdeletion of the NF1 gene, family and personal history of MPNST, and presence of atypical neurofibromas (aNF)/ANNUBPs. None of the imaging diagnostic tools studied in NF1 patients have been prospectively assessed to identify aNF/ANNUBP. Natural history studies and clinical trials using MRI have identified nodular target lesions within pre-existing pNFs on standard anatomic MRI as potential precursor lesions to MPNST that may represent aNF/ANNUBP. These lesions have been coined "distinct nodular lesions" (DNLs) and described as greater than 3 cm in largest diameter, well demarcated, distinct from the patients underlying tissue (i.e. the surrounding pNF), and lacking the target sign typical of benign pNFs (defined as a central hypointense region on T2-weighted images). In a recent retrospective review of 76 histologically confirmed aNFs, all aNFs fulfilled the criteria for DNLs on MRI and 50 of 56 aNFs with available 18F-2-fluoro-2-deoxy-D-glucose fluorodeoxyglucose positron emission testing computed tomography (18F-FDG PET/CT) demonstrated elevated maximum standardized uptake value (SUVmax) (\>3.5), supporting the hypothesis that DNLs may be the imaging correlate of pre-malignant tumors.

The investigators hypothesize that NF1 patients with aNF/ANNUBP represent a subset of individuals who have not developed cancer yet but who are at high risk of developing a malignancy, possibly in the short term. the investigators further hypothesize that a subset of DNLs are imaging correlates of aNF/ANNUBP that can be characterized with advanced imaging techniques such as Diffusion weighted imaging (DWI) and 18F-FDG PET/CT. Imaging identification of ANNUBPs and characterization of DNLs will enable early diagnosis and management of lesions destined to become malignant, thereby potentially dramatically improving outcomes for People with NF1 at highest risk for development of MPNST.

Defining the prevalence of DNL in a population clinically to be at high-risk for future development of malignancy, the behavior of DNLs over time and the multi-parametric imaging features of DNLs will allow the generation of imaging markers to: (1) identify the specific lesions at highest risk for malignancy in a sea of lesions, (2) understand the biologic significance of these lesions and, (3) create the data about the optimal imaging marker for these lesions to inform evidence based guidelines for imaging in people with NF1.

2. Objectives (include all primary and secondary objectives):

* To evaluate the prevalence, multi-parametric imaging features of distinct nodular lesions "DNLs" and natural history in people with NF1 with clinical and genetic features deemed "high-risk" for malignancy.
* To assess the relationship between individual clinical, genetic and imaging factors that have been suggested to be risk factors for MPNST and the confirmation of aNF/ANNUBP or MPNST on pathology.

Multi-parametric Biomarker Development to Predict Malignant Conversion in Patients With Neurofibromatosis Type 1

Prevalence of distinct nodular lesions in people with NF1 associated pNF and clinical or genetic factors that are hypothesized to be "high risk" for MPNST

The imaging characteristics of DNL over time

Incidence of new DNLs over time (in both people who do and do not have DNL on initial imaging)

The imaging characteristics of pNF (independent of DNL) over time in people hypothesized to be "high risk" for MPNST

Frequency of biopsy in people with and without DNL.

Johns Hopkins University

Neurofibroma, Plexiform

Whole Body MRI along with standard of care regional MRI and blood draw at enrollment followed by Whole Body MRI along with standard of care regional MRI and blood draw after 4-6 months.

WBMRI with axial and coronal STIR (short inversion time inversion recovery) images + DWI (diffuse weighted imaging) will be performed and compared to regional MRI to assess value of this diagnostic test for the identification of suspicious looking lesions (i.e. diffuse nodular lesions or atypical plexiform neurofibroma)

Whole Body MRI

Miriam Bornhorst, MD

This study is being conducted to determine if Whole Body MRI (WBMRI) can be used to identify Atypical Neurofibromas (ANF) in Neurofibromatosis Type 1 (NF1) patients with high tumor burden. Each enrolled participant will have two (2) WBMRIs without sedation during the study period. Eligible participants must be Male or Female between the ages of 8-30 with diagnosed NF1; with one or more PN greater than 3cm in diameter and willing to comply with study procedures.

This is a study to determine the feasibility of using Whole Body MRI (WBMRI) to detect Atypical Plexiform Neurofibromas (ANF) among Neurofibromatosis Type 1 (NF1) patients who are at highest risk for developing these tumors. In order to do this, the investigators will prospectively obtain WBMRI scans on patients with high plexiform tumor burden (which investigators will define as \>=1 plexiform neurofibroma (PN) that is \>3cm in diameter on MRI) at the same time as their regularly scheduled MRI to allow for radiographic comparison of the identified PNs. In this study, the investigators will plan to establish a method that effectively characterizes PNs in terms of their volume, radiographic appearance on WBMRI and association with clinical characteristics.

As an exploratory aim, the investigators plan to collect blood samples from each patient at the same time as the MRI to determine the feasibility of isolating cfDNA (circulating free DNA) from plasma of patients with high plexiform tumor burden.

Whole Body MRI to Identify Atypical Neurofibromas in Patients With NF1

Whole Body MRI to Identify Atypical Neurofibromas in Patients With NF1 and High Plexiform Neurofibroma Tumor Burden

Level of cfDNA in plasma of participants with ANF compared to participants without ANF

Number of NF1 participants with high tumor burden who have ANF on WBMRI

Number of patients with high PN tumor burden who have clinical symptoms

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Multi-parametric Biomarker Development to Predict Malignant Conversion in Patients With Neurofibromatosis Type 1	NCT05677594	Neurofibromatos... Malignant Perip... Atypical Neurof...	Whole Body Magn...	6 Years -	Johns Hopkins University
Whole Body MRI to Identify Atypical Neurofibromas in Patients With NF1	NCT03820778	Neurofibromatos... Neurofibroma Atypical Neurof... Atypical Neurof... Plexiform Neuro... Von Recklinghau...	Whole Body MRI	8 Years - 30 Years	Children's National Research Institute

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