Abstract
Background/Aim: Plexiform neurofibromas are the hallmark of neurofibromatosis type 1, an autosomal dominantly inherited multisystem disorder. Spinal plexiform neurofibromas can particularly cause severe neurological symptoms. Treatment options are limited due to invasive growth, and targeted therapy with selumetinib is only approved for inoperable tumors in children. The aim of this report was to highlight that selumetinib therapy post-surgery provides an alternative strategy for spinal plexiform neurofibroma, providing both an immediate relief of the symptoms and long-term tumor management. Case Report: We describe a patient with neurofibromatosis type 1 and a large spinal plexiform neurofibroma causing severe neurological deficits. A drastic clinical improvement was achieved 6 months after neurosurgical spinal decompression and adjuvant selumetinib therapy. Conclusion: A combination of decompression surgery and selumetinib therapy provides a promising option for the management of spinal plexiform neurofibromas causing severe neurological deficits.
Neurofibromatosis type 1 (NF1) is an autosomal dominantly inherited disorder characterized by different clinical manifestations, such as café-au-lait macules, bilateral freckling, multiple neurofibromas, and plexiform neurofibromas (1, 2). Plexiform neurofibromas are particularly problematic because of their infiltrative nature and high risk of transforming into malignant peripheral nerve sheath tumors (3). Frequently, total resection is not possible without damaging the surrounding tissues and organs (3-5).
Spinal neurofibromas are especially problematic as they are often located in proximity to the spinal cord and can cause various serious neurological deficits, such as motor deficits, numbness, paresthesia or impairment of bladder and bowel control. Furthermore, compression of nerve structures by tumor growth causes chronic pain and therefore impacts patients’ quality of life (6-8). Nevertheless, in most cases, the tumors remain small and surgical treatment is not necessary. However, as soon as spinal cord compression is indicated, treatment has to be considered (9).
Recently, targeted therapies, such as inhibitors of mitogen-activated protein kinase kinase (MEK), have emerged as promising alternatives for managing inoperable plexiform neurofibromas (10) or as a pretreatment to reduce the tumor size for enabling surgery (11). Clinical trials have demonstrated that selumetinib, a selective MEK inhibitor, significantly reduces tumor growth and volume (10, 12). Previous studies also showed the effect of selumetinib on inoperable spinal neurofibromas by reducing spinal cord compression and associated neurological symptoms (13). Selumetinib has been specifically approved for the treatment of unresectable plexiform neurofibromas in children with NF1. For adults, a clinical trial is ongoing (KOMET: NCT04924608).
This study presents a case of a female patient with neurofibromatosis type 1 who received a combined therapy approach consisting of surgical spinal cord decompression and adjuvant selumetinib for her large spinal neurofibroma. We highlight the benefits of integrating both surgical and pharmacological treatment for plexiform neurofibromas as a multimodal strategy.
Case Report
In 2023, a 22-year-old female patient first came to the Neurofibromatosis Outpatient Clinic of the University Medical Center Hamburg-Eppendorf in Hamburg, Germany. She presented typical manifestations of neurofibromatosis type 1, including café-au-lait macules, bilateral freckling, cutaneous and subcutaneous neurofibromas, and a large palpable and visible plexiform neurofibroma in the area of the right shoulder.
Medical history. The patient was diagnosed with neurofibromatosis type 1 at the age of 3 years. The patient’s father was also affected by the disease. At the ages of 6 and 8 years, first surgical interventions were performed to partially remove the tumor at level C8 on the right side and then stabilize the cervical spine via dorsal spondylodesis from C4 to T4. Due to progressive paraparesis, she dropped out of school after acquiring her intermediate school-leaving certificate. The patient began vocational training, which had to be interrupted due to the progressive cervical spinal cord syndrome.
Physical findings before treatment. Neurological examination revealed spastic right- and leg-accentuated tetraparesis. The patient reported pronounced pain symptoms in her arms and was in a wheelchair due to impairment of leg motor function.
Imaging. A positron-emission tomography/computed tomography (CT) scan in June 2023 showed an inhomogeneous cervicothoracic mass with displacing growth and tumorous invasion of the spinal canal. The mass showed multifocal metabolic activity, in part strongly increased, especially paravertebral at the level of T1 to T3 on the left. These parts also showed marked enhancement after administration of contrast agent (Figure 1). Morphologically, an atypical neurofibromatous neoplasm with uncertain biological potential with potential malignant transition was conceivable but was not confirmed after histopathological examination. Magnetic resonance imaging of the whole spine in July 2023 revealed a confluent circumferential tumor burden with a punctum maximum caudally cervical, as well as in the upper mediastinum, and the upper thoracic aperture on both sides. The lesions extended caudally to the level of T8 in the paravertebral back muscles. Cranially, the spinal canal was dilated to approximately 2.2 cm. At the level of C7/T1, large areas of tumor were visible in the epidural spinal canal, with consequent compression of the spinal cord, but without a definite signal of radiographic myelopathy (Figure 2).
Contrast-enhanced computed tomography (CT) in sagital (A) and axial (B) orientation, and axial fusion image (C) of [18F]-fluorodeoxyglucose positron-emission tomography/CT of the patient showing a large inhomogeneous cervicothoracic mass (closed arrows) with displacing growth and tumorous invasion of the spinal canal (arrowheads). Parts of the mass displayed inhomogeneous contrast uptake and increased metabolic activity (open arrows).
Spinal magnetic resonance imaging with T2-weighted sequences in sagital (A) and axial (B) orientation, and a T1-weighted fat-suppressed contrast-enhanced sequence in axial orientation (C). Imaging showed a large, inhomogeneous, mostly T2 hyperintense cervicothoracic mass (closed arrows) with displacing growth and tumorous invasion of the spinal canal and consequent compression of the spinal cord (arrowheads). Parts of the mass displayed inhomogeneous contrast uptake (open arrows). Note the dilation of the spinal canal (asterisk) cranially of the large mass.
Partial surgical resection. Due to instability and deformation of the cervicothoracic junction, a microsurgical dorsal decompression procedure was performed in July 2023 to prevent long-term damage of the spinal cord. In addition, a paravertebral biopsy of the positive findings in the positron-emission tomography/CT was performed, excluding malignant peripheral nerve sheath tumor. The long-distance epidural decompression was carried out via a microsurgical re-laminectomy from C6 to T3 under continuous neuromonitoring.
CT-guided biopsy. In August 2023, another CT-guided biopsy of four tumor lesions with increased metabolic activity exhibited no evidence of malignancy histologically. Neuropathological diagnosis revealed plexiform neurofibromas in all but one lesion. One lesion on the extensor side of the upper arm was compatible with an atypical neurofibromatous neoplasm with uncertain biological potential.
Physical findings after surgery. The patient was treated in a rehabilitation clinic after surgery. Neurological examination revealed spastic right-accentuated paraparesis. The patient had to use a walking frame for longer distances but was able to walk a few steps independently. The chronic pain symptoms persisted.
Adjuvant therapy. Two months after successful decompression of the spinal cord, off-label drug therapy with selumetinib at a dose of 45 mg twice daily was started in October 2023. Due to side-effects, such as skin rash and hair loss, the dose was reduced 1 month later to 35 mg in the morning and 30 mg in the evening.
Combined therapy outcome. Clinical follow-up was carried out 2 months after the start of treatment with selumetinib, 4 months after surgery. The patient already reported a slight improvement in mobility at home. Neurologically, the spastic tetraparesis was regressive and walking a few steps was possible. The chronic pain symptoms had improved slightly. Six months after the first clinical follow-up, another follow-up showed a drastic improvement in mobility. The patient was then able to walk longer distances without walking aids; a wheelchair was no longer needed at all. Chronic neuropathic pain symptoms had improved considerably, and the patient was also able to resume vocational training. Whole-body magnetic resonance imaging in April 2024 revealed no relevant progression of spinal neurofibromas, but a large mass still remains, with persistent invasion of the spinal canal and consequent compression of the spinal cord (Figure 3). Selumetinib therapy was ongoing at the same dose.
Follow-up whole-body magnetic resonance imaging with T2-weighted (A) and fat-suppressed contrast-enhanced T1-weighted (B) sequences in axial orientation. The imaging showed a large mass remaining, with persistent invasion of the spinal canal and consequent compression of the spinal cord (arrowheads).
Consent. Written informed consent was obtained from the patient for publication of this Case Report. The study was carried out in compliance with the Helsinki Declaration and in accordance with the ethical requirements for case reports of the Ethical Board Hamburg.
Discussion
Symptomatic spinal neurofibroma often leads to severe pain and neurological deficits, and affects quality of life significantly (7, 8, 14). Surgical treatment is challenging due to tumor location and configuration. Repeated operations are associated with risks, complications, and long recovery times. The management of plexiform neurofibromas has traditionally relied on surgery, as these tumors are not responsive to radiation and show limited benefit from chemotherapy, although novel approaches such as MEK inhibitors (e.g. selumetinib) are showing promise in clinical trials (15). Therefore, targeted therapy such as selumetinib represents a recent paradigm shift in management of plexiform neurofibroma, although only approved for inoperable tumors (15, 16).
We present a case treated with a combination of surgical treatment and selumetinib for the management of a spinal neurofibroma causing severe neurological deficit and chronic pain. Microsurgical decompression was performed first in order to achieve immediate relief of the spinal cord and avoid long-term damage. Adjuvant selumetinib therapy was used for long-term management.
A previous study already showed the benefit of selumetinib for management of spinal neurofibromas, leading to tumor shrinkage and clinical improvement (13). In that study, only patients with inoperable tumors were included to investigate the effect of selumetinib as monotherapy. Another study discussed the neoadjuvant use of the MEK inhibitor trametinib to enable surgical therapy of a formerly inoperable tumor (11). A combined surgical and selumetinib approach had not been investigated so far.
The integration of selumetinib therapy post-surgery represents an alternative strategy that provides both immediate relief of the symptoms and long-term tumor management. In this case, combined therapy resulted in substantial improvement in neurological function and quality of life, although follow-up magnetic resonance imaging still showed relevant spinal cord compression. As plexiform neurofibromas are rarely fully resectable in patients with NF1 (15), an adjuvant result-conserving treatment is of high value in this population. Furthermore, this case highlights the importance of interdisciplinary collaboration among medical specialists, including surgeons, oncologists and neurologists, in optimizing care for individuals with complex conditions such as NF1 with spinal neurofibroma. Prospective studies in larger cohorts will be necessary to more objectively evaluate a combined therapy approach and clinical improvement in patients with spinal neurofibroma.
Conclusion
Combining surgical therapy with targeted pharmacological therapy using selumetinib provides a beneficial option for managing spinal plexiform neurofibromas causing severe neurological deficits.
Acknowledgements
We thank our patient for participating in this study. The Authors would like to thank Susan Eick, who is a native English speaker, for critical reading of the manuscript.
Footnotes
Authors’ Contributions
Tabea I. Hartung: Conceptualization, project administration, writing – original draft, writing – review and editing. Lan Kluwe: Writing – review and editing. Florian Brembach: Writing – review and editing. Lennart Well: Visualization, writing – review and editing. Catena Kresbach: Writing – review and editing. Reinhard E. Friedrich: Writing – review and editing. Malte Mohme: Conceptualization, treatment of the patient, writing – review and editing. Said C. Farschtschi: Conceptualization, treatment of the patient, writing – review and editing.
Conflicts of Interest
SF has received speaker honoraria from Astra Zeneca and Alexion and compensation from Alexion for advice or lecturing not related to this study. LW has received speaker honoraria from Alexion not related to this study.
- Received October 22, 2024.
- Revision received November 9, 2024.
- Accepted November 11, 2024.
- Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
