Since malignant peripheral nerve sheath tumor (MPNST) often develops in preexisting plexiform neurofibroma (PN) in the context of neurofibromatosis type 1 (NF1), the identification of the turning points is challenging. The final decision regarding the nebulous middle ground links to distinctly different malignant potential and survival. Recently, consensus recommendations proposed by Lucas et al. have made significant progress in addressing this issue,1 with the efforts to integrate the molecular biological advancements in the field of NF1 over the past decade with pathology.
In addition to addressing the molecular features of NF1-related peripheral nerve sheath tumor, the consensus recommended reclassifying the previously termed “Low-grade MPNST” as “atypical neurofibromatous neoplasms of uncertain biologic potential (ANNUBP) with increased proliferation.” This recommendation stems from the anecdotal experiences of oncologists and surgeons who have observed the administration of overly aggressive sarcoma-type therapies to low-grade MPNST patients due to the use of the term “malignant,” when marginal resection may be more appropriate. We believe the initiative is a reasonable consideration for patients, however, we still have several concerns.
We carefully reviewed the 2 studies cited by the author to support this recommendation. One indicates that positive marginal resection for low-grade MPNST achieves a 100% disease-specific survival. However, this older paper differs from the new consensus in its histologic criteria: the mitotic index in the reference is < 5/10 high power fields (HPFs), compared to 3–9/10 HPFs in the consensus, suggesting a lower malignancy.2 Another study with consistent histologic criteria reports no recurrence of low-grade MPNST after surgery. However, this study involved negative surgical margins, and the authors emphasized that the benefits of gross-total resection outweighed the risk of neural injury.3 Since the specific outcomes of different surgical margins in ANNUBP with increased proliferation remains inadequately understood, we believe that more caution may be warranted when emphasizing their potential negative effects on surgical damage.
Second, the term “malignant” serves as a reminder of the progression, poor morphology, invasiveness, and metastatic potential associated with sarcomas. The rationale for renaming appears to focused primarily on morphology, while other indicators are somewhat overlooked. Although these indicators can be summarized as prognosis discussed in the consensus, each should be carefully considered, as neglecting any of them could lead to serious consequences, with distant metastasis—rare but severe—being a notable example (Figure 1). Previous studies offer limited insights into the link between histologic features and clinical outcomes,4 further consideration may be necessary before discarding “malignant.”
Figure 1.
A 68-year-old patient underwent 3 surgeries for low-grade malignant peripheral nerve sheath tumor (MPNST) located in the back and subsequent recurrences. The pathological report from the most recent surgery confirmed low-grade MPNST (A, B), with spindle tumor cells involving the surgical margins but without significant atypia. Twenty two months postoperatively, the patient presented with recurrent tumors in the back (C). Magnetic resonance imaging (MRI) identified newly developed irregular tumors in the right axilla, lumbar region, and bilateral thoracic vertebrae (D–F). Positron emission tomography–computed tomography (PET-CT) further identified multiple soft tissue tumors throughout the body, some exhibiting increased metabolic activity, with the highest maximun standardized uptake value (SUVmax) reaching 20.61 in the axilla (G). Given this patient’s multiple surgical interventions and the persistently unfavorable clinical outcomes, we advocate for a careful consideration of treatment approaches for different patients.
Third, there is limited superiority study on post-operative low-grade MPNST with various surgical approaches. And, in existing MPNST studies, both the World Health Organization (WHO) grading system from the 2017 consensus and the Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC) grading system have been widely applied.5,6 Attempts to establish a conversion between these 2 grading systems to provide unified evidence have yielded ambiguous results, which complicates the systematic determination of the optimal treatment strategy and the risk of metastasis. Furthermore, few of these studies clarify whether adjunctive treatments such as chemotherapy and radiotherapy were included, making it difficult to exclude the potential impact of other factors on prognosis.
In conclusion, we largely agree with the authors’ proposal to reclassify low-grade MPNST as ANNUBP with increased proliferation. However, higher-level evidence is required to support the clinical overlap for low-grade MPNST and ANNUBP, as well as the absence of “malignant.” Additionally, molecular studies, such as genomic and epigenomic analyses, should be conducted to better differentiate ANNUBP from ANNUBP with increased proliferation at the molecular level. These efforts should strictly adhere to the histologic criteria proposed by Lucas et al., and will ultimately aid in identifying malignancy and selecting appropriate surgical strategies for these patients in the gray zone.
Contributor Information
Xuan Yu, Neurofibromatosis Type 1 Center and Laboratory for Neurofibromatosis Type 1 Research, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Jingxuan Huang, Neurofibromatosis Type 1 Center and Laboratory for Neurofibromatosis Type 1 Research, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Zhichao Wang, Neurofibromatosis Type 1 Center and Laboratory for Neurofibromatosis Type 1 Research, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Funding
This work was supported by grants from National Natural Science Foundation of China (82472579; 82102344); Shanghai Plastic Surgery Research Center of Shanghai Priority Research Center (2023ZZ02023); Shanghai Clinical Research Center of Plastic and Reconstructive Surgery supported by Science and Technology Commission of Shanghai Municipality (grant no. 22MC1940300); the Project of Biobank from Shanghai Ninth People’s Hospital (YBKA202204); Shanghai Jiao Tong University School of Medicine, Cross disciplinary Research Fund of Shanghai Ninth People’s Hospital, Shanghai Jiao Tong university School of Medicine (JYJC202407).
Conflict of interest statement. None declared.
Ethics statement
Ethical approval for this case was obtained from the Ethics Committee of the center (SH9H-2019-T163-2), and informed consent was acquired from the patient and their legal guardians.
Author contributions
Conception: Zhichao Wang. Initial draft and case summary: Xuan Yu. Reviewing and editing: Jingxuan Huang, Xuan Yu, and Zhichao Wang.
References
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