Association of plexiform neurofibroma volume changes and development of clinical morbidities in neurofibromatosis 1

Abstract

Background: Plexiform neurofibromas (PN) in neurofibromatosis 1 (NF1) can cause substantial morbidities. Clinical trials targeting PN have recently described decreases in PN volumes. However, no previous study has assessed the association between changes in PN volumes and PN-related morbidities. Our objective was to assess if increasing PN volume in NF1 is associated with increasing PN-related morbidity.

Methods: This is a retrospective review of patients enrolled on the NCI NF1 natural history study with ≥7 years of data available. Morbidities including pain, motor dysfunction, vision loss, and PN-related surgery were assessed at time of baseline PN MRI with volumetric analysis and time of MRI with maximum PN volume.

Results: Forty-one patients (median age at baseline 8 y) with 57 PN were included. At baseline, 40 PN had at least 1 PN-associated morbidity. During the observation period, 27 PN required increasing pain medication, and these PN grew faster per year (median difference 8.3%; 95% CI: 2.4, 13.8%) than those PN which did not. PN resulting in motor impairment at baseline (n = 11) had larger volumes compared with those that did not (median difference 461 mL; 95% CI: 66.9, 820).

Conclusions: Many NF1 PN were associated with clinically significant morbidity at baseline, highlighting the need for longitudinal morbidity evaluations starting at an early age to capture changes in PN-associated morbidities. Prospective evaluation of standardized patient reported and functional outcomes in clinical trials are ongoing and may allow further characterization of the association of PN volume increase or decrease and clinical changes.

Fig. 1.

PN-related morbidities and surgeries at baseline and maximum assessment. The number of PN with each type of PN-related morbidity at baseline and maximum volume assessments.

Fig. 2.

Example of worsening PN related morbidity over time. This patient has a PN of the cervical spine which grew 235% in the 10.5 years between the baseline and maximum volumetric assessments (A). At his baseline assessment, he already had mild limitation in his neck range of motion and had required 2 debulking procedures. Between his baseline and maximum assessments, he required 3 more surgeries, as well as developing worsening disfigurement (B), increased pain requiring the addition of multiple pain medications, speech and swallowing difficulties, intermittent bowel incontinence, and increasing limitation in his neck and shoulder range of motion (C). The decrease in tumor volume at age 5 was the result of a debulking procedure.

Fig. 3

Pain morbidity at baseline and maximum assessments. Pain medication was used as a surrogate marker for PN related pain at both timepoints. There was an increase in the amount of scheduled and PRN (as needed) pain medications used at maximum assessment (A, solid bars) compared with baseline (A, striped bars). Similarly, the use of opioid, neuropathic and over-the-counter (OTC) pain medications all increased between the baseline and maximum assessments (B).