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.
- 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.