• Genomics

Neurofibromatosis type 1 (NF1) is an autosomal dominant inherited tumour predisposition syndrome caused by pathogenic variants in the NF1 gene.1 The condition has a high de novo mutation rate with around 50%–60% of affected individuals being the first in their family. Birth incidence and prevalence range from 1 in 2–2700 and 1 in 4–4500, respectively.2 3 The condition can be diagnosed when at least two of eight major criteria are met including demonstration of a heterozygous pathogenic variant in NF1 and/or the presence of optic pathway glioma, a specific benign central nervous system tumour that occurs at high frequency in the condition.1 Additional major criteria include the presence of neurofibromas (NF), the benign nerve sheath tumours that provide the syndrome with its name and malignant peripheral nerve sheath tumours (MPNST), an aggressive soft tissue sarcoma subtype that accounts for a significant proportion of excess mortality associated with NF1.4–6

In the year 2000, there had not been a thorough epidemiological study to assess the likelihood of developing an MPNST in a patient with NF1. The literature available at the time consisted of either cross-sectional studies of NF1 patient populations that informed prevalence only, or series reported from specialised surgical centres where reported risk was inflated by referral bias towards patients more severely affected by NF1.7 8 Furthermore, while highly ascertained, local population-based studies can provide accurate estimates of risk, longitudinal follow-up is required as MPNST has a high mortality rate5 6 and thus low prevalence at any one time. The fact that only 2 of 138 (1.5%) of affected patients were identified in one such cross-sectional study led the authors to underestimate the risks of MPNST.7 Nonetheless, subsequent series that included longitudinal follow-up indicated a greater risk from MPNST in NF1 populations.9–11 A study of 1475 patients in North America found 34 new cases of MPNST over a 20-year period, equating to an annual risk of 1.3–6.8 per 1000 during the first to the fifth decades of life.9 Another North American study found that 353 of 3770 (9.4%) deaths were related to soft tissue neoplasms, the majority of which are likely to have been unclassified MPNST.12 However, in this study, only 1 in 8700 deaths were identified as associated with NF1 (much lower than the expected 1 in 2–2700 from birth incidence figures). This reflects how such studies that draw from death certification registries (where annotation of NF1 as a contributory factor to death is likely to be inconsistent) also underestimated risk from MPNST. Our own later work showed that many NF1 deaths did not have NF1 on the death certificates particularly when cause of death at the time was not believed to be related. For instance, with breast cancers, only 1 of 9 were coassociated with NF1 on the death certificate in our UK mortality study, with only 21 of 34 with MPNST.6 Previous studies also estimated that ~20%–50% of MPNST occurred in the context of NF1, where the risk of MPNST has an onset in childhood and increases rapidly to a peak in the third and fourth decades.9 13 14

Our study published in 20024 (table 1) used two main data sources to ascertain both MPNST and NF1. Our highly ascertained regional population was enhanced by a genetic family register set up in 1989 and the regional cancer registry, with both drawing from a regional general population of ~4.1 million at the time. MPNST with NF1 were identified from both populations over a period of 13 years (1984–1996). Overall, 21/60 (35%) diagnosed with MPNST in this time period were confirmed as having NF1, with NF1 patients being much younger than non-NF1 MPNST (median age 26 vs 62 years). 5-year survival in NF1 was notably worse than in non-NF1 MPNST (21%–95% CI 5%–37%) compared with 42% (95% CI 26%–58%) despite the younger age of NF1 patients younger. The annual incidence of MPNST in NF1 patients was assessed at 1.6 per 1000 and the lifetime risk of MPNST in NF1 at 8%–13%, which is around 2000 × that of the general population.4 14

The veracity of the estimates in our study was corroborated by a whole population epidemiological study of NF1 in Finland (population 5.5M).5 A total of 58 MPNST were observed from 1987 to 2012, indicating again a 2000-fold risk compared with the general population.5 Lifetime risk of MPNST was assessed at 15.8%. The standardised mortality ratio (SMR) for MPNST in NF1 was assessed at 2,300-fold.

A higher lifetime risk of MPNST has now been associated with certain NF1 germline genotypes (eg, missense variants that involve codons 844–848; microdeletions that involve the adjacent SUZ12 gene), a high internal burden of plexiform neurofibroma and/or previous premalignant changes within such previous exposure to radiotherapy and a family history of MPNST in a relative with NF1.14–19 Survival outcomes have also been confirmed to be worse in NF1-related MPNST (5-year survival rates 16%–26%) compared with sporadic cases (42%–55%), although a focus on more recent series suggests this difference may be less than previously suspected.20 Indeed, our own more recent assessment showed improved survival, especially in NF1 women with MPNST.21 Updated histological classification, earlier diagnosis and improved surgical techniques may have contributed to a narrowing over time of prognostic differences between NF1-associated and sporadic MPNST. Regardless, MPNST remains a leading cause of excess and early mortality in NF1. This is also borne out by our later study of mortality in NF1.6 In total, 34/131 (26%) deaths identified in NF1 patients were due to MPNST, with 25 of 34 (62.5%) deaths occurring before age 40 years.6 Another mortality study in France also found a high proportion of deaths due to MPNST.22 The cause of death was available for 58/67 (87%) patients with MPNST the main cause of death (60%). MPNST is, therefore, still the leading cause of early death in NF1. Indeed, the already extremely high OR of 2000-fold for MPNST in NF14 5 may be an underestimate as the comparison is with population rates, which include NF1-related MPNST. In reality, as one-third of population MPNSTs will have NF1, the OR will be nearer 3000-fold. Equally this will be true for the SMR for MPNST.

While histological diagnosis of non-NF1 MPNST can be challenging, the appearance of overt malignant features within a precursor plexiform neurofibroma makes diagnosis of NF1-associated MPNST fairly straightforward. More difficult can be the distinction between neurofibroma with premalignant changes or low-grade malignancy. The spectrum from entirely benign to highly malignant nerve sheath tumours has been subjected to updated consensus diagnostic criteria.23

Genomic study of preclinical models and clinical tumour samples from malignant and premalignant nerve sheath tumours has improved the characterisation of the molecular alterations associated with the progression from benign neurofibroma or plexiform neurofibroma to MPNST. Heterozygous inactivation of the remaining wild type NF1 to the homozygous state is seen as an early initiating event that is sufficient for the formation of benign plexiform or cutaneous neurofibromas but does not lead to malignancy in the absence of other genetic alterations.24 ‘Second hit’ alterations of NF1 can include intragenic loss-of-function point mutation or loss of heterozygosity through partial or complete chromosomal deletion. Successful curative treatment of MPNST is mainly reliant on a complete surgical resection before metastasis. Failure to completely remove a high-grade MPNST leaves a very poor prognosis as tumours typically exhibit limited sensitivity to radiotherapy and chemotherapies. This means early diagnosis is essential.16 Recent European guidelines for surveillance recommend the following: clinical assessment for MPNST should consist of assessing the following:

• Tumour growth: a rapid increase in the size or a change in growth rate or of an existing plexiform neurofibroma.

• Pain: new and persistent, nocturnal, substantial pain/pain that is difficult to control.

• New motor deficit, sensory deficit associated with any neurofibroma or peripheral nerve. This includes bladder function, bowel disturbance, swallowing problems and breathing difficulty.

• Tumour consistency: development of hard nodule in a previously soft plexiform neurofibroma.

People with NF1 and any of the above should be investigated for MPNST using the following approach. Urgent regional MRI is the usual initial investigation. Discussion in an appropriate MDT can determine whether 18FDG PET MRI (preferred) or 18FDG PET CT (if 18FDG PET MRI is not available) may contribute to assessment of the lesion. Where this is undertaken, visual and semiquantitative assessments with a cut-off standardised uptake value are made. The role of PET-based imaging is evolving, and the lower radiation dose of PET-MRI may be easier to justify, though the impact of such investigations on effectiveness of management is not fully clear. Biopsy of any suspicious area can be considered, though if a concerning tumour can be resected in its entirety as a single procedure, this may be preferred. Such decisions should be taken at the discretion of a (sarcoma) multidisciplinary team. Tumours can be heterogeneous, with the potential for false-negative results by failing to sample malignant regions. Prognostication and management is complicated by the existence of an intermediate pathology between benign neurofibroma and MPNST called Atypical Neurofibromatous Neoplasms with Uncertain Biologic Potential (ANNUBP), thought to represent precursor lesions for MPNST with a relatively high chance of transformation.

Before publication of our article in 2002, the field of MPNST and NF1 was somewhat confused, with articles suggesting a high risk, but other epidemiological studies and recommendations suggesting risk was much lower.7 The publication of our article4 and subsequent ratification of lifetime risks between 8% and 15.8% for MPNST in an NF1 patient5 have sharpened minds as to the importance of early diagnosis in view of the very poor survival.4 5 There are signs that greater awareness may be improving outcomes more recently,16 21 especially in women who are more likely to present with early symptoms.21 The importance of the article4 is demonstrated by over 1000 citations with still as many as 81 citations in 2023 (https://scholar.google.co.uk/scholar?oi=bibs&hl=en&authuser=1&cites=9832122694704840119,18434583464576637190&as_sdt=5&as_ylo=2023&as_yhi=2023).