Prognostic factors in neurofibromatosis type 1 (NF1)‐associated malignant peripheral nerve sheath tumors: Clinical implications beyond NF1 status

The article by Aubrey et al.1 regarding significantly worse outcomes after definitive treatment among patients who have neurofibromatosis type 1 (NF1)-associated malignant peripheral nerve sheath tumors (MPNSTs) contains important evidence regarding differences in the clinical outcomes in NF1-associated versus sporadic MPNSTs. Although research has demonstrated that NF1 status is an independent, negative prognostic factor of overall survival, I do think that various other dimensions should be explored in further research to maximize the stratification of patients and the planning of treatment. The finding of the study that patients who have NF1-associated MPNSTs have much larger tumors (8.4 vs. 6.0 cm; p < .001) located in less surgically accessible sites (trunk/head/neck sites) is important in terms of early detection and screening. The authors assume that the cause of this finding could be a delayed diagnosis of malignancy in the environment of benign neurofibromas.1 Nonetheless, the possibility of using molecular surveillance or imaging technologies to identify early malignant transformation in plexiform neurofibromas should also be investigated. Future research using more advanced imaging and molecular markers may provide the opportunity to detect transformation earlier, which, in turn, may result in better survival and surgical margins. Moreover, the rate of positive resection margins among patients with NF1-related MPNSTs (37.2% vs. 14.9% among those without NF1; p = .006) should be specifically discussed. Although this disparity can be explained by anatomic factors in trunk and head/neck regions, the article does not cover the possibility that there may be neoadjuvant therapeutic interventions that would enhance resectability. New developments in neoadjuvant systemic therapy and radiation for soft tissue sarcomas indicate that preoperative therapy may help allow more adequate negative-margin resections in difficult anatomic regions. Future comparative trials assessing neoadjuvant therapies in NF1-related MPNSTs may have the potential to change the treatment patterns. The finding that the only independent predictor of distant metastasis in patients who had resectable, NF1-related MPNSTs was tumor size (whereas NF1 status no longer had statistical significance; p = .087) indicates that tumor biology, and not NF1 status itself, is the determinant of metastatic propensity.1 The implication of this difference is far reaching. Genome-wide studies of the genomic difference between NF1-associated MPNSTs with high metastatic potential and those with sluggish behavior may help identify therapeutically targetable pathways. With the genomic abnormalities recorded in CDKN2A, TP53, and other driver genes, genomic profiling of tumors may add value to risk stratification over and above clinical aspects. The 2-year overall survival of patients who have NF1-related MPNSTs is also considerably worse (48 vs. 79 months in those without NF1; p < .001), which calls into doubt the intensification of treatment and the optimization of multimodal therapy.1 The researchers indicate that 68.1% of patients received radiotherapy, 14.5% received chemotherapy, and chemotherapy had an opposite, negative impact on overall survival. Nevertheless, this is probably a treatment selection bias in favor of more advanced disease. Future research also should prospectively determine whether future multimodal interventions, such as new systemic agents (pazopanib, immunotherapy, targeted therapies), can enhance the process, especially in patients who have NF1-related tumors with high-risk factors. The quality-of-life and psychological effects experienced by patients with positive NF1 status as a result of being diagnosed with MPNST also should be considered. These patients have a higher likelihood of a poor prognosis because the 2-year cumulative incidence of distant metastasis is 39% versus 17% in those with non-NF1–related MPNSTs.1 Future research that involves the use of quality-of-life measures, psychosocial interventions, and genetic counseling measures would offer comprehensive support and make informed treatment decisions. Finally, the molecular hypothesis put forward by the authors, which assumes that the timing and order of genomic changes, and not the changes themselves, could explain the aggressiveness of NF1-related MPNSTs, is a hypothesis that should be longitudinally examined. Cell-free DNA analyses and serial tumor sampling may shed light on the evolutionary process of NF1-related MPNSTs and indicate potential intervention periods before the development of metastatic spread. In conclusion, although Aubrey and colleagues have presented useful evidence that NF1-related MPNSTs have a much more unfavorable prognosis, the underlying mechanisms of these variations go beyond NF1 status in itself. Future studies that include early detection methods, tumor genomic mapping, best neoadjuvant therapy, and prospective multimodal treatments would benefit the care provided to such a complicated group of patients. Such studies eventually could have positive effects on the survival and quality of life of patients with NF1-related MPNSTs. The author declares no conflicts of interest.