This is the first reported longitudinal study with whole body MRI and three-dimensional volume measurement of internal PNs in an unselected group of NF1 patients. We see about 1200 individuals with NF1 each year at the NF Centre Hamburg, and patients are referred to us by physicians throughout Germany and through the German patient lay organization. We see a broad phenotypic spectrum; however, because of our recognized expertise, it is likely that more severe and complex cases are preferentially referred to our centre. Patients were asked consecutively to participate in the study between 2003 and 2008 regardless of gender, age, or clinical presentation, but only a fraction of these patients agreed to undergo WBMRI exam and gave written informed consent. The main reasons for patients or guardians to refuse participation were logistical problems, claustrophobia, the need for moderate sedation in children, and expected discomfort. It is possible that patients with a more severe course or, who were more concerned about the possibility of internal tumours were more likely to volunteer for the study.
Our results clearly show that the growth rate of PNs in NF1 patients is correlated with whole body total tumour volume and inversely correlated with age. The greater rate of growth in young children is consistent with clinical observations and with the results of two previous studies in NF1 patients
[7, 8]. Individuals with high whole body tumour volumes and young patients deserve close monitoring by clinical examination and whole body MRI. Because their tumours are more likely to grow, early surgical intervention may be considered
. Older patients and those with no internal tumours on initial MRI are less likely to develop neurological or other complications that are associated with large internal tumours or tumour growth. Further investigations are needed to see if more frequent monitoring of high-risk patients and less frequent monitoring of low-risk patients would improve care and over-all survival in NF1 patients.
Some of the patients included in our study had undergone surgery for removal or reduction of tumours in the past. Surgical reduction of tumours may have an influence on their growth
; this needs to be explored in future studies.
PNs that transform into MPNSTs often have growth rates that exceed those of most PNs. The only MPNST that arose during observation in this cohort (Patient 1890, tumour 3) showed a growth rate of 28% per year. The malignancy was diagnosed at 18.9 years of age after two years of follow up. The only NF1 patient, who developed an MPNST in our previous longitudinal study of internal tumours using local 2-dimensional MRI measurements was also the only adult in that study whose tumour exhibited rapid growth
. Since PNs usually grow slowly, if at all, in adulthood, adults with progressive tumours on serial MRI exams raise high suspicion for an MPNST and should undergo further diagnostic assessment by positron emission tomography or biopsy
Benign plexiform neurofibromas may grow rapidly in children and adolescents (Figure
3). Children and young adults with rapidly growing tumours or large total body tumour burden may be at especially high risk for developing an MPNST in the future, but longitudinal whole body MRI studies with longer follow up are needed to determine whether this is so. We note with some concern that whole body tumour burdens greater than 1000 mL are distinctly unusual in the patients we studied over 40 years of age.
Patients with no internal tumours on first MRI examination are unlikely to develop new PNs later. This is consistent with the observation that clinically apparent PNs rarely develop in NF1 patients after early childhood
[15, 16]. However, new PNs may develop, or at least first become apparent, later in life in people with NF1, who do have internal tumours, although this is not frequent. One previous longitudinal MRI study of NF1 patients reported the incidental detection of a new PN but could not draw any conclusions regarding the likelihood of new tumour formation
. MRI cannot determine when the molecular process of tumourigenesis began, and the rate of growth of tumours that are large enough to image does not necessarily have any relationship to their rate of growth earlier in tumour development. Therefore, we do not know if the molecular process that leads to formation of PNs always occurs before birth or if it can also take place later in life.
An important implication of our findings for therapeutic research in NF1 is that it may be best to design clinical trials for treatment of PNs to target pediatric patients, in whom either reduction of growth rate or regression of the tumour can be taken as outcome measures. For trials targeting adult patients, only tumour regression can be taken as an outcome measure because substantial growth of PNs is uncommon.
We found that 35.5% of the tumours in this study showed apparent decreases in volume during the period of observation without any medical or surgical intervention. The median decrease in the volume measurements for these tumours was 3.4% per year, with a range of 0.07% to 35.9% per year. It seems likely that many of these tumours did not actually change in size over the period of observation, and the difference observed represents measurement error
. In other instances, tumour shrinkage may have occurred as observed with clinical measurements during our practise. Further studies are needed to determine the magnitude of measurement variability in volumetric measurements of PNs obtained by MRI and the frequency and clinical implications of true tumour shrinkage, if it occurs. In any case, the possibility of apparent decrease in tumour size over time needs to be considered when evaluating therapeutic efficacy and treatment success in clinical trials.