Ten-Year Follow-up of Internal Neurofibroma Growth Behavior in Adult Patients With Neurofibromatosis Type 1 Using Whole-Body MRI.

BACKGROUND AND OBJECTIVES: Internal neurofibromas, including plexiform neurofibromas (PNF), can cause significant morbidity in patients with neurofibromatosis type 1 (NF1). PNF growth is most pronounced in children and young adults, with more rapid growth thought to occur in a subset of PNF termed distinct nodular lesions (DNL). Growth behavior of internal neurofibromas and DNL in older adults is not well documented; yet knowledge thereof is important for patient risk stratification and clinical trial design. The primary objective of this study was to evaluate the long-term growth behavior of internal neurofibromas in adults with NF1. Secondary objectives were to correlate tumor growth behavior with patient-specific, tumor-specific, and patient-reported variables. METHODS: In this prospective cohort study, internal neurofibromas were identified on coronal short TI inversion recovery sequences on baseline and follow-up whole-body MRIs (WBMRIs). Tumor growth and shrinkage were defined as a volume change ≥20%. The association between tumor growth and patient-specific (baseline age, sex, and genotype), tumor-specific (morphology, location, DNL presence on baseline WBMRI, and maximum standardized uptake value on baseline PET imaging), and patient-reported variables (endogenous and exogenous hormone exposure, pain intensity, and quality of life) was assessed using the Spearman correlation coefficient and Kruskal-Wallis test. RESULTS: Of 106 patients with a baseline WBMRI obtained as part of a previous research study, 44 had a follow-up WBMRI. Three additional patients with WBMRIs acquired for clinical care were included, generating 47 adults for this study. The median age during baseline WBMRI was 42 years (range 18-70). The median time between WBMRIs was 10.4 years. Among 324 internal neurofibromas, 62.8% (56% of PNF and 62.1% of DNL) shrank spontaneously without treatment and 17.1% (17.9% of PNF and 13.8% of DNL) grew. Growth patterns were heterogeneous within participants. Patient-specific, tumor-specific, and patient-reported variables (including endogenous and exogenous hormone exposure) were not strong predictors of tumor growth. DISCUSSION: Internal neurofibroma growth behavior in older adults differs fundamentally from that in children and young adults, with most tumors, including DNL, demonstrating spontaneous shrinkage. Better growth models are needed to understand factors that influence tumor growth. These results will inform clinical trial design for internal neurofibromas.

Validating Techniques for Measurement of Cutaneous Neurofibromas: Recommendations for Clinical Trials.

OBJECTIVE: To assess the reliability and variability of digital calipers, 3D photography, and high-frequency ultrasound (HFUS) for measurement of cutaneous neurofibromas (cNF) in patients with neurofibromatosis type 1 (NF1). BACKGROUND: cNF affect virtually all patients with NF1 and are a major source of morbidity. Reliable techniques for measuring cNF are needed to develop therapies for these tumors. METHODS: Adults with NF1 were recruited. For each participant, 6 cNF were assessed independently by 3 different examiners at 5 different time points using digital calipers, 3D photography, and HFUS. The intraclass correlation coefficient (ICC) was used to assess intrarater and interrater reliability of linear and volumetric measurements for each technique, with ICC values >0.90 defined as excellent reliability. The coefficient of variation (CV) was used to estimate the minimal detectable difference (MDD) for each technique. RESULTS: Fifty-seven cNF across 10 participants were evaluated. The ICC for image acquisition and measurement was >0.97 within and across examiners for HFUS and 3D photography. ICC for digital calipers was 0.62-0.88. CV varied by measurement tool, linear vs volumetric measurement, and tumor size. CONCLUSIONS: HFUS and 3D photography demonstrate excellent reliability whereas digital calipers have good to excellent reliability in measuring cNF. The MDD for each technique was used to create tables of proposed thresholds for investigators to use as guides for clinical trials focused on cNF size. These criteria should be updated as the performance of these end points is evaluated.