What Is the Malignancy Risk in Neurofibromatosis Type 1?
Authors: D. Gareth R. Evans
Journal: Journal of Clinical Oncology (2016)

Neurofibromatoses consist of at least three autosomaldominant tumor predisposition syndromes, which are characterized by the development of predominantly benign nerve sheath tumors. Neurofibromas are the characteristic tumor in neurofibromatosis type 1 (NF1), whereas schwannomas are the major tumor type in neurofibromatosis type 2 (NF2) and schwannomatosis. NF1, by far, is the most common type of neurofibromatosis and it affects approximately 1 in 2,500 births. Before the National Institutes of Health Consensus conference in 1987, many studies contained collective samples of both NF1 and NF2 that were not distinguished from each other. Multiple studies have shown substantial risk of nervous system malignancy, with indisputable excess risk of gliomas and malignant peripheral nerve sheath tumor (MPNST), both of which result in excess risk of mortality. Most studies that have addressed the risk of malignancy and early death have been either cohort studies or death certification studies. Both types of studies have shown an approximately 8to 15-year decrease in life expectancy in patients with NF1, mainly as a result of malignancy. This, to a great extent, is driven by the substantial risk of developing and dying from an MPNST, with lifetime risks of between 8% and 13% and little more than 20% to 25% of patients surviving the malignancy. Both types of studies, however, have the potential for bias from underascertainment, especially of mildly affected individuals. Most cohort studies do not reach anything close to the population frequency for their regional area or country. Sorensen et al observed a nationwide cohort of 212 patients with NF1 in Denmark, whereas Zoller et al conducted a 12-year follow-up study of 70 adult patients with NF1 from Goteborg, Sweden. Walker et al observed 448 patients with NF1 from the United Kingdom, and Airewele et al studied138 white patients with NF1 from Texas. These studies found a standard incidence ratio (SIR) of 2.7-fold to four-fold for malignancy in NF1 but were largely based on adult incidence alone. In contrast, St03, the Finnish study by Uusitalo et al that accompanies this editorial, found a five-fold SIR despite being a whole population study with extremely high levels of ascertainment. Nonetheless, this is driven by extremely high SIRs: 63-fold for childhood cancer (age 0 to 14 years; 47 cancers) and 27-fold for young adults (age 15 to 29 years; 47 cancers). It is therefore likely that previous studies reflect a reasonable estimate of the SIR for adult malignancy in NF1 given the 3.26-fold SIR for patients with NF1 who are age $ 30 years (150 cancers observed; 46 expected) in the article by Uusitalo et al. The authors sensibly divided malignancy risk into characteristic tumors (MPNST and gliomas), NF1-related cancers, including breast cancer, and a third group with no clear association. The first group accounted for 63% of cancers in the cohort, with an SIR for MPNSTof 2,056 (58 confirmed cases). The lifetime risk of MPNST was estimated to be as high as 15.8%—higher than the upper end of the previous estimate of 13%. CNS malignancy also had an extremely high SIR (SIR, 186) in childhood, which was most marked for females. The link between NF1 and breast cancer that has been suggested in previous cohort studies is now beyond doubt, with 31 observed cases in the current report compared with 10.2 expected (SIR, 3.02; P , .001). As in previous studies, this is driven by a much higher SIR at younger ages (11.1-fold at age, 40 years), and strategies to screen younger women with NF1, such as breast magnetic resonance imaging, must be considered, especially in light of the even higher standard mortality ratio (SMR; 5.2). The study by Uusitalo et al also reported significant excess risk of other know NF1-related tumors, including GI stromal tumors (SIR, 34.2), malignant fibrous histiocytomas (SIR, 51.2), pheochromocytomas (SIR, 74.3), and rhabdomyosarcoma (SIR, 45.3). However, juvenile myelomonocytic leukemia was not observed in St03, although this remains a specific risk with NF1, with a lifetime risk of approximately . 1 in 1,000. The authors propose that thyroid cancer should be recognized as a new NF1 association; however, this is based on a nonsignificant SIR of 2.7 from three cases, with this tumor type only reaching significance for mortality (SMR, 30.2; P , .001). Additional evidence is required before thyroid cancer can be considered to be related to NF1 as the increased mortality may be a result of failure of patients with NF1 to report yet another subcutaneous swelling. Uusitalo et al also report an SMR for cancer of 6.49 (95%CI, 5.32 to 7.85) that is greatest in young adulthood between age 15 and 30 years. All cohort studies have found an excess mortality risk from cancer. Evans et al reported 130 deaths in a cohort of 1,186 patients with NF1. The most notable result was that of death attributable to MPNST. MPNST was reported as cause of death significantly more than expected for both men and women with NF1 (men: SMR, 3,819.6; 95%CI, 1,971.4 to 6,672.5; women: SMR, 7,788.2; 95% CI, 4,355.7 to 12,846.2) compared with an