To our knowledge, this is the largest study to demonstrate the ability of FDG PET imaging to differentiate neurofibromas and schwannomas from malignant PNSTs. The current findings have several important clinical implications. First, noninvasive tools for detecting malignancy are critical, because patients with neurofibromatosis type 1 carry a 10% lifetime risk of developing MPNST,3
typically have multiple simultaneous PNSTs, and usually develop synchronous MPNSTs and benign PNSTs. This malignant degeneration cannot be reliably detected using clinical symptoms, anatomical imaging, or, because of sampling errors, even biopsy. Because of these limitations, malignant degeneration is often identified late in the course of the disease, compromising the potential for cure.
Currently, anatomical imaging (CT or MRI) is the standard technique for diagnosing and surveying PNSTs. In this study, ROC analysis revealed that CT was significantly less accurate than FDG PET for characterizing tumors as malignant or benign ().
Our results in this large patient population support prior observations that PET can differentiate benign PNSTs from MPNSTs in neurofibromatosis type 1 patients.19–23
In the largest study,20
FDG PET diagnosed neurofibromatosis type 1-associated MPNST with a sensitivity of 89% and a specificity of 95%. This is consistent with our observations in both sporadic and neurofibromatosis type 1-associated PNSTs.
FDG PET accurately identified a MPNST arising from a benign PNST in 1 of the neurofibromatosis type 1 patients (). This patient had several PNSTs, including 1 in the right distal thigh that, similar to this patient’s other PNSTs, had shown slight growth over time. Given the large size of this lesion, biopsy was recommended and showed only a benign neurofibroma. However, PET showed a heterogeneous tumor with a large area of markedly increased FDG uptake (SUVmax = 14.9 g/mL), with much lower uptake elsewhere in the tumor and in a PNST in the contralateral thigh. The resected right distal thigh mass demonstrated a high-grade MPNST arising from a benign neurofibroma (). Thus, in this patient, FDG PET accurately identified both components—the benign neurofibroma and the MPNST—within this single tumor. This case illustrates the potential contribution of PET imaging for optimal clinical management of patients with PNSTs.
Figure 3 (A) A positron emission tomography/computed tomography study in a patient with neurofibromatosis (NF) type 1-associated malignant peripheral nerve sheath tumor (MPNST) is depicted. The MPNST is located in the right distal thigh (maximum standard uptake (more ...)
Pretreatment classification of PNSTs dictates subsequent clinical interventions. Benign PNST patients can be followed with serial imaging or undergo nerve-sparing/function-sparing surgery. In contrast, patients with MPNST, an aggressive soft tissue sarcoma with a 5-year disease-specific mortality of up to 75%,6
require radical surgical resection, radiation therapy, and often chemotherapy.24,25
Our results indicate that PET imaging can differentiate benign PNSTs from MPNSTs with high sensitivity and specificity. Furthermore, PET imaging can assist in guiding targeted needle core biopsies of PNSTs, as in the above case. Finally, because of the high sensitivity and specificity, PET imaging may provide critical information in tumors that are not amenable to biopsy.
FDG uptake varied considerably among patients with MPNSTs. The current study did not attempt to elucidate the reasons for this variability. However, the substantial variability might in part be explained by differences in hypoxia-inducible factor-1α expression, as shown previously in soft tissue sarcomas.26
Currently, the diagnosis of MPNST is made pathologically. Unfortunately, even in experienced hands, targeted needle core biopsies are often technically not feasible or falsely negative because of the often heterogeneous nature of these tumors, which frequently exhibit large areas of necrosis. Furthermore, in many patients with neurofibromatosis type 1, benign and malignant lesions coexist, and therefore the appropriate target tissue for biopsy frequently is unknown. In addition, clinical symptoms such as rapid increase in tumor size, neurological deficits, and pain, although suspicious, are not specific formalignancy.
Interestingly, the difference between malignant PNSTs and benign schwannomas was less prominent ( and ). This was largely because of the finding that 3 of the 14 patients with schwannoma exhibited SUVs >5 g/mL. A substantial variability in FDG uptake by schwannoma has been reported previously.27–29
In contrast to a previous report,30
studies by our group did not find significant differences in proliferative rate (measured by maximal mitoses per 10 HPFs, Ki-67 rate, skp2 rate), apoptotic rate (measured by TUNEL staining), expression of markers of glucose utilization (glucose-transport protein 1 and hexokinase II), or degree of intratumoral lymphocytes between the PET-positive and PET-negative benign PNST cases in this study (data not shown) that could explain the differences in FDG uptake as shown in . However, different factors such as the expression level of hypoxia-inducible factor-1α, not measured in these samples, might have contributed to different glucose metabolic phenotypes by FDG PET imaging.31
Thus, although the mechanism for increased PET activity in schwannomas remains unclear, it is evident from this and prior studies that schwannomas are less reliably discriminated from MPNST by FDG PET imaging.
Figure 4 (A) A schwannoma with high F18-fluorodeoxyglucose (FDG) uptake located in the pelvis is depicted. (B) By comparison, a patient with a schwannoma located in the right retroperitoneum with low FDG uptake is shown. This illustrates the wide range of maximum (more ...)
The role of metabolic imaging is rapidly evolving. We currently use FDG PET/CT in patients with suspected malignant PNST, particularly before surgery or biopsy. For surveillance, we perform FDG PET/CT scans every 6 months for the first 2 years and annually thereafter, if the clinical status is unchanged. Rarely do we use MRI. In addition, we have found that FDG PET can accurately monitor response to therapy in MPNST.32,33
Limitations of this study include that all but 1 of the patients with MPNST (intermediate grade; SUVmax: 8.3 g/mL) had high-grade tumors. Thus, it remains unclear whether FDG PET can reliably discriminate intermediate- and/or low-grade MPNST from benign tumors.
In summary, our study demonstrated that FDG PET can reliably discriminate MPNST from benign PNST and confirmed that size criteria, by CT imaging, cannot make this distinction. ROC curve analysis revealed that an SUVmax threshold of 6.1 g/mL differentiated malignant from benign PNST with a sensitivity and specificity of 94% and 91%, respectively. Lowering this threshold to 4.5 g/mL would have increased the sensitivity to 100% but reduced the specificity to 83%. Conversely, raising the threshold to 8.5 g/mL increased the specificity to 100% but reduced the sensitivity to 65%. These thresholds need to be applied prospectively in future PNST studies to determine the best thresholds and the true diagnostic accuracy of FDG PET. FDG PET imaging can play a critical role and should be considered in the treatment planning of patients with PNSTs.