How should adult patients with neurofibromatosis 1 be managed?

Among familial tumor syndromes, neurofibromatosis 1 (NF-1) is the most prevalent, affecting about 1 in 3000 births. The disorder leads to a microdeletion in the gene coding for neurofibromin, which is a negative regulator of the Ras oncogene signal transduction pathway. The gene is situated on 17q11.2, and mutation is transmitted as an autosomal dominant trait. However, half of affected individuals are spontaneous mutations.

The clinical presentation is highly variable, affecting many tissues, giving rise mostly to peripheral nervous system tumors, musculoskeletal disorders, mental and behavioral disorders, characteristic skin manifestations (cutaneous neurofibromas, café au lait spots), and Lisch nodules in the ocular iris that guide diagnosis. The majority of patients show mild (60%) or moderate (20%) symptoms, whereas up to 20% of affected persons suffer severe symptoms with impact on their quality of life or even life-threatening complications. The eponymous anomaly is the formation of tumors in the peripheral nervous system (eg, neurofibromas derived from Schwann cells that can arise in all parts of the body).¹

Whereas cutaneous and diffuse neurofibromas rarely undergo malignant transformation, noncutaneous neurofibromas, especially intraneural and/or plexiform neurofibromas, bear the potential to progress to malignancy, leading to atypical neurofibromas (ANFs) with increased cellularity and atypia and further to malignant peripheral nerve sheath tumors (MPNSTs), a difficult-to-treat neoplasm with grim prognosis. A recent consensus paper emphasized the need for further research on ANF, categorizing new subsets that the authors named “neurofibroma with cytological atypia or hypercellularity” in contrast to “atypical neurofibromatous tumor of uncertain biologic potential (ANNUBP)”—the latter, however, being defined by at least 2 of 4 features: cytologic atypia, loss of neurofibroma architecture, hypercellularity, mitotic index >1/50 high-power fields (HPFs) and <3/10 HPFs.² Follow-up MRI of plexiform neurofibromas has been recommended for the detection of intralesional nodules that are morphologically different from the surrounding neurofibromas and for the assessment of significant growth in MR volumetry.³ In fluorodeoxyglucose (FDG) PET, those nodules are typically PET avid compared with the low avidity of plexiform neurofibromas.⁴ Indeterminate lesions should undergo histologic correlation. However, systematic studies showing which patient subset and which imaging characteristics definitively represent precursors for malignancy are still lacking.

Very limited data are available on how to monitor, how to treat, and finally how to detect the transition from ANF to MPNST, as the malignant end of this spectrum of neoplastic transformation. It is the current understanding that ANF can be treated with curative intent compared with MPNST, which is associated with a very high relapse rate. Furthermore, as soon as it becomes metastatic or inoperable due to locally advanced disease, MPNST is one of the histologic subentities in soft-tissue sarcoma regarded as being rather chemorefractory. Several drugs tested showed limited activity in this histology. In this context, our subjective proposal would be to advise for monitoring with MRI as the preferred methodology and resection of ANF as soon as it is described and as long as the scope and morbidity of respective surgery can be justified. Diagnosis, monitoring, and treatment of NF-1 patients should be carried out in high-volume centers with shared decision making by multidisciplinary tumor boards.

A cohort study involving 1895 NF-1 patients from France followed up for a median of 6.8 years showed that with 60%, MPNST was the most prevalent cause of death in NF-1 patients aged 10 to 40 years,⁵ whereas the occurrence of MPNST in the general population is around 0.001%.⁶ In 2011, Beert et al reported that in NF-1, ANFs are precursor lesions to MPNST by acquiring a cyclin-dependent kinase inhibitor 2A/B deletion at 9p21 as the first step in the progression toward MPNST,⁷ evocative of the “adenoma-carcinoma sequence” in colorectal tumors by Fearon and Vogelstein.⁸

In this issue of the journal, Higham et al report the natural history of 63 NF-1 patients with 76 pathologically confirmed ANFs followed at three institutions: the National Cancer Institute in Bethesda, Maryland, USA; the Catholic University in Leuven, Belgium; and Guy’s and St Thomas’ NHS Foundation Trust in London, UK. This study reports clinical data including location, palpability, and painfulness linked to imaging data including MRI with volumetric analysis and FDG-PET imaging related to clinical outcome.⁹ This paper delivers useful information about NF-1 patients with ANFs and illustrates the actual follow-up and treatment policies at different centers, although open questions remain. As a third of the patients described in this paper developed MPNST, it clearly demonstrates the need for offering these patients a continuous framework of surveillance, comparable to the follow-up programs used for patients with BRCA1 and BRCA2 mutations; however, it seems a consensus for the management of adult neurofibromatosis patients has not yet been formulated. Taking into account the exemplary British guidelines by Ferner et al addressing mainly children and the new insights gained since their publication in 2006,¹⁰ as well as the most recent contribution in this issue of Neuro-Oncology, NF-1—as the most frequent familial tumor syndrome—could serve as a model for a shared initiative to pool data necessary for developing guidelines. Such guidelines could contribute to surveillance by defining the intervals of clinical follow-up, imaging frequency and modalities, and targeting characterization of ANFs to be removed to avoid postsurgical deficits and prevent emergence of MPNST. Moreover, recommendations for surgical methods to be used and for pathological and genetic workup of tissue would be valuable parts of such future guidelines. The contributions of these authors are likely to make a substantial impact on clinical practice for patients with NF-1.