Abstract
Introduction
Peripheral nerve sheath tumors are the most common tumor of the peripheral nerves. In general, surgery has a favorable outcome and is the treatment of choice. However, postoperative neurologic deficits are not uncommon, and predictors of outcome are poorly defined.
Objective
To evaluate clinical outcomes after surgical treatment of benign peripheral nerve sheath tumors and identify outcome predictors that may affect preoperative decision making and improve surgical outcomes.
Method
In this single center retrospective study, all patients surgically treated for a benign peripheral nerve sheath tumor between 2005 and 2020 were eligible for inclusion. Medical records and imaging data were reviewed. Studied outcomes were changes in neurological symptoms, pain, and tumor recurrence. Logistic regression was performed to identify possible outcome predictors.
Results
In total, 81 patients undergoing 85 separate surgeries for benign peripheral nerve sheath tumors were included. The most common preoperative symptoms were local pain (90%) followed by a noticeable mass (78%), radiating pain (72%), sensory deficit (18%), and motor deficit (16%). A postoperative improvement of symptoms was seen in 94% of those with pain, 48% of those with sensory deficits and 78% of those with motor deficits. However, 35% and 9% developed new postoperative sensory and motor deficits, respectively. Multivariable analysis showed complete tumor removal as a predictor of reduced pain (p = 0.033), and younger age and larger tumors were risk factors for persistent or increased sensory deficits (p = 0.002 and p = 0.005, respectively). There were no significant predictors of motor deficits. Neurocutaneous syndromes were associated with increased odds of tumor recurrence on univariable analysis (p = 0.008).
Conclusion
Surgery of benign peripheral nerve sheath tumors is a safe procedure with a favorable outcome in most cases. Younger age and larger tumors were risk factors for persistent or increased sensory deficits, while complete tumor removal was associated with reduced pain. Patients with neurocutaneous syndromes had a higher rate of tumor recurrence. To further evaluate outcome predictors, we recommend future studies to focus on longer follow-up periods to assess the natural course of postoperative neurological deficits.
Introduction
Peripheral nerve sheath tumors (PNST) are the most common tumors of the peripheral nerves [Citation1]. The annual incidence is 0.6 per 1,00,000 persons [Citation2]. These tumors are mostly benign, solitary and characterized by slow growth; however, malignant PNST occur [Citation1,Citation3,Citation4]. In cases of multiple PNSTs a neurocutaneous disorder such as neurofibromatosis type 1 (NF1), type 2 (NF2), or schwannomatosis is usually present [Citation5]. Solitary PNSTs usually occur sporadically but may develop secondary to radiation or trauma [Citation6,Citation7].
The most common types of PNSTs are Schwannoma and Neurofibroma. Both are composed of Schwann cells but while Schwannomas are well-encapsulated and arise from a single nerve fascicle, Neurofibromas have a more diffuse expansion pattern and may involve several nerve fascicles [Citation8]. PNSTs commonly present in adulthood between the third and sixth decade of life [Citation4,Citation9,Citation10]. There is no correlation to sex or race [Citation9]. They may arise from virtually any peripheral nerve but are most commonly found in the neck and extremities [Citation11].
Due to the abnormal proliferation of Schwann cells, tumor-associated symptoms are usually caused by nerve compression and include pain, sensory and motor deficits [Citation4,Citation11–13]. Depending on tumor size and localization they may also be asymptomatic or present as a noticeable mass [Citation9,Citation14].
Magnetic resonance imaging (MRI) is the gold standard for diagnosis, but ultrasound and computed tomography (CT) have also been used [Citation12,Citation13,Citation15,Citation16]. Fine needle biopsy and electrophysiological studies are used as supplementary diagnostic tools [Citation15].
Surgery is the treatment of choice for benign PNSTs [Citation17]. The goal of surgery is maximal tumor removal while keeping the nerve as intact as possible. This is usually performed via enucleation of the tumor under magnification (either by loupe or microscope) [Citation13,Citation14,Citation18,Citation19]. The most common indication for surgery is local or radiating pain [Citation8,Citation12,Citation14,Citation15]. The surgical results are usually favorable with most patients getting relief of pain and swelling [Citation11,Citation13,Citation14,Citation19]. However, sensory and motor deficits may persist after surgery. Among new postoperative deficits, sensory deficits are the most common [Citation8,Citation9,Citation11,Citation13,Citation14] but tend to resolve over time [Citation12,Citation14]. Other unfavorable outcomes include motor deficits, neuropathic pain and tumor recurrence [Citation8,Citation11,Citation14,Citation15].
Reported predictors of unfavorable outcome after surgery of PNSTs are previous biopsy, young age (below 50), large tumor size and tumors originating from small nerve branches [Citation8,Citation14,Citation20]. It has also been reported that older age and major motor nerve involvement are associated with a higher risk of complications [Citation21]. Since the number of studies examining outcome predictors is few and partly contradictory, we performed this study to evaluate our own data and compare it to previously published findings.
The aim of this single center retrospective cohort study was to evaluate clinical outcomes after surgery for benign PNSTs and identify outcome predictors that may affect surgical decision making.
Materials and method
The study hospital is a publicly funded and owned tertiary care center that serves a region of about 2.3 million inhabitants with neurosurgical care. Patients were identified in the surgical management software Orbit (Evry Healthcare Systems, Solna, Sweden). Medical records and the imaging data were retrospectively reviewed using the health record software TakeCare (CompuGroup Medical Sweden AB, Farsta, Sweden). The study was approved by the Regional and National Ethical Review Board (Dnr: 2016/1708-31/4). A retrospective study of all patients surgically treated between 2005 and 2020 was performed. An initial screening identified 103 patients who had undergone surgery for peripheral nerve lesions. Patients ≥18 years of age and histopathology showing any type of benign PNST were included. Patients with neurocutaneous disorders predisposing for multiple PNSTs, such as NF1 and schwannomatosis, were also included. However, patients with malignant PNST or with no follow up data were excluded.
The retrospective review included patient characteristics (age and sex), pre- and postoperative symptoms, tumor location, tumor size, surgical parameters (surgery time, extent of resection, and preservation of nerve), histopathology, follow-up time, complications, and tumor recurrence.
Tumor location was described by the body part and, when possible, the specific nerve. If not identifiable, the nerve was referred to as ‘other nerve’.
Size was measured on preoperative MRI but if not available, the measurements from the histology report were used instead. The size was expressed as volume in cm3, calculated with the formula (Length x Height x Width)/2.
The primary outcome measures were changes in symptoms (pain, sensory- and motor deficits) defined as improved, partially improved, persistent, or worsened, as well as tumor recurrence.
Surgical procedure
Prior to surgery, the patient was asked to indicate the tumor site which was marked by the surgeon using a permanent marker. All surgeries were performed under general anesthesia. After appropriate positioning to allow access to the tumor, ultrasound was used to verify the lesion site. After antiseptic skin preparation, sterile draping, and injection of local anesthetic, the skin was incised above the lesion. Dissection was performed to identify the tumor borders and the nerve. In most cases, a nerve preserving technique was used. Taking care to avoid nerve fibers, the tumor was incised along its long axis, i.e. the direction of the nerve. After stepwise incisions and dissection through the layers of the tumor capsule, the tumor was enucleated and removed from the nerve. The capsule, derived from the outer connective tissue layers of the nerve (epineurium) was then sutured, the anatomical layers repositioned, and the skin was closed using resorbable sutures. If the tumor infiltrated the nerve, only partial resection was performed. In a few cases, where the tumor was located distally on a small branch, the nerve was sacrificed.
Statistics
Medians and interquartile ranges (IQR) are used to describe continuous data while categorical data are presented using numbers and proportions. The Chi-squared, and when appropriate, the Fisher’s Exact tests were used to compare categorical data across groups, while the Mann-Whitney U test was used for the comparison of continuous data across binary groups. To identify relevant outcome predictors, a univariable logistic regression was used. Factors that showed a trend towards significance in the univariable analysis (p < 0.1) were then entered into a multivariable logistic regression to determine independent risk factors. Listwise deletion was used to handle missing data. Statistical significance was set to p < 0.05. All analyses were conducted using the statistical software program R (version 4.1.2).
Results
Patients
In total, 81 patients undergoing 85 surgeries for removal of 85 separate PNSTs were included. Most of the patients were female (52%), and the median age was 51 years (39–59). Six patients (7%) had a known diagnosis of NF1, and two (2%) a diagnosis of schwannomatosis. Most patients (91%) presented with only one tumor, while seven patients presented with multiple tumors (range: 2–6). The median follow-up time was 4 (2–8) months.
Tumors
Among the 85 tumors in this material, the average tumor volume was 2.4 cm3 (1.1–6.9).
The tumors manifested with symptoms including local pain (90%), a noticeable mass (78%), radiating pain (72%), sensory deficits (18%), and motor deficit (15%). The median time from symptom onset to diagnosis was 25 months (12–43), while the median time from diagnosis to surgery was 8 months (4–12). Complete tumor removal was achieved in 90% of the cases and nerve preservation was achieved in 89%. The median surgery time was 52 min (32–86.5). Histopathological diagnosis revealed 76 schwannomas (88%) and nine neurofibromas (12%) ().
Table 1. Characteristics of the 85 tumors.
Unfavorable outcomes
Perioperative complications, excluding postoperative neurologic deficits, occurred in two cases (2%) and consisted of one nosocomial pneumonia and one superficial surgical site infection. New sensory deficits occurred in 23 patients (35% of those who initially presented with no sensory deficits; ). These patients commonly experienced hypoesthesia (87%), followed by paresthesia (9%), or hyperesthesia (4%). New motor deficits occurred in 7 patients (9% of those who initially presented without any motor deficits; ). All patients with new postoperative motor deficits had tumors located in the upper extremities and brachial plexus. The severity of the motor deficits ranged from mild to pronounced weakness with overt muscle atrophy. Recurrence or regrowth occurred in 4 tumors (5%) within a median of 59 months (16.9–100.7). Repeat surgical treatment was offered in two of these cases while the other two were treated conservatively ().
Table 2. Change compared to preoperative symptoms at follow-up.
Regression analysis
Multivariable analysis showed that complete tumor removal was associated with significantly lower odds of persistent or worsened pain (OR: 0.1; 95% CI: 0.01–0.95; p = 0.033; ).
Table 3. Regression analysis for the prediction of persistent or increased pain after surgery.
Younger patients (OR: 0.91; 95%CI: 0.85–0.96; p = 0.002) and those with larger tumor volumes (OR: 1.09; 95%CI: 1.03–1,18; p = 0.005) showed significantly higher odds for persistent or worsened sensory deficits ().
Table 4. Regression analysis for the prediction of persistent or increased sensory deficits after surgery.
There were no significant predictors of unfavorable postoperative motor outcomes on univariable analysis ().
Table 5. Regression analysis for the prediction of persistent or increased motor deficits after surgery.
Univariable analysis showed that only patients with NF1 or schwannomatosis had statistically higher odds of tumor recurrence (OR: 13.7; 95%CI: 2.00–117; p = 0.008; ).
Table 6. Regression for the prediction of tumor recurrence .
Discussion
In this retrospective study we identified 85 surgeries performed on 81 patients with favorable outcome in terms of symptom relief in most of the cases. Pain was the predominant symptom, and a significant correlation between complete tumor removal and pain relief was seen. Patients of younger age and with a larger tumor volume had a higher risk of persistent or worsened sensory deficits after surgery.
The demographic data was similar to that of previous studies. A median age of 50 and an even distribution between male and female patients, matches the literature data [Citation13,Citation14,Citation19].
The tumor distribution was also in accordance with that of previous studies, with tumors in the upper extremity and brachial plexus being the most common [Citation4,Citation13,Citation15,Citation19].
Tumor size was presented as volume in cm3 (L × H × W)/2) to better describe the tumor shape (which is seldom spheric but rather oval). Sayed et al. [Citation22] used the same method of calculation and reported an average tumor volume just below 3 cm3 which is in line with our data.
Schwannomas were the most common tumor type in this material, representing 88% of the tumors. This is in line with most similar studies [Citation4,Citation9,Citation19] although Kim et al. showed a predominance for sporadic neurofibromas not associated with a neurocutaneous disorder (66%) [Citation6].
Pain was the most common preoperative symptom (90%) and significantly improved after surgery in 93% of cases. Levi et al. reported neuropathic pain syndromes in 5.7% of their patients [Citation8]
Patients with sensory deficits had the worst outcome in our material, with only 48% improvement of symptoms after surgery while 9% worsened. However, sensory deficit was seldom the main complaint of the patient or the main indication for surgery, most patients primarily complained of local or radiating pain.
Postoperatively, new sensory deficits occurred in as many as 34% of the patients. The reported incidence of postoperative sensory deficits varies considerably between studies, ranging from 9% to 30% [Citation8,Citation9,Citation20–22], with some studies disregarding this symptom completely [Citation15]. Granlund et al. [Citation14] propose, that this relates to how sensory deficits are reported in the different studies. For instance, transient sensory deficits are by some authors argued to be expected and not reported. We therefore decided to divide postoperative sensory deficits into the following categories: paresthesia, hyperesthesia, hypoesthesia and hypoesthesia in the peri-incisional areas (). Mild hypoesthesia within the cutaneous innervation of the affected nerve is arguably a consequence of the tumor itself and should not be expected to resolve with surgery. Similarly, hypoesthesia in the peri-incisional area was considered an expected and acceptable result after surgery. We believe that most postoperative sensory deficits are transient (as described in other studies [Citation12,Citation14,Citation20]). However, with a clinical follow up at 3 months after surgery, we could not verify this hypothesis.
Motor deficits were the least common presenting symptoms but had favorable outcomes after surgery, with seven out of nine patients (78%) experiencing complete or partial improvement. New postoperative motor deficits were identified in seven patients (9%), which is in line with previous studies [Citation15,Citation21]. All patients with postoperative motor deficits had tumors in the brachial plexus or upper extremities. The severity of the motor deficit ranged from mild to pronounced weakness with overt muscle atrophy.
In theory, neurofibromas may offer more of a surgical challenge than schwannomas because of their diffuse growth pattern in the nerve, usually involving several nerve fascicles. However, studies reporting less favorable outcomes for neurofibromas are few. Desai et al. [Citation15] could show a higher incidence of postoperative neuropathic pain in neurofibroma patients. In contrast, Levi et al. [Citation8] did not find any differences in outcomes, despite reporting that surgery for neurofibromas involved more extensive dissection of nerves. In this study, one patient with neurofibroma experienced reduced grip strength and hypothenar atrophy since one third of the nerve had to be transected. However, no statistical differences in outcome between schwannomas and neurofibromas could be detected.
Four patients (5%) in this study had a recurring tumor, all of them diagnosed with schwannomas. The incidence of tumor recurrence in the literature, ranges from 0% to 5% [Citation9,Citation13–15,Citation19]. As previously reported by Guha et al. a correlation between the presence of a neurocutaneous disorder and tumor recurrence was seen [Citation23]. This may explain the higher recurrence rate in this study where, unlike many other similar studies [Citation24], patients with neurocutaneous disorders were included.
Predictors of outcome
Earlier reported predictors of poor outcome for PNSTs are previous biopsy, young age (below 50), large tumor size and tumors originating from small nerve branches [Citation8,Citation14,Citation20]. Hirai et al. [Citation21] reported that older age and major motor nerve involvement were associated with higher risk of complications.
In this study, complete tumor removal was associated with reduced pain. This may reflect the beneficial effect of removing pressure on adjacent nerve fascicles. Conversely, a surgeon may choose to perform only a partial resection when it is obvious that complete tumor removal is unattainable without severe nerve injury. Younger age and larger tumor volume were significant risk factors for persistent or worsened sensory deficits. On the one hand, larger tumors may compress nervous structures to a greater degree and require more extensive dissection when removed. On the other hand, small nerve branches may be too delicate to allow dissection and instead transected to allow complete tumor removal. Thus, the conflicting reports may all have merit. The increased risk of sensory deficits in younger individuals is however more challenging to explain, given the general expectation that younger people tend to have a higher potential for improvement. It would be interesting to see outcomes at longer follow-up (allowing the nerve to possibly heal over a longer period) which our data could not provide.
Strengths and limitations
In the context of peripheral nerve sheath tumors, this is a large consecutive, population-based, cohort study. However, its retrospective design limits the availability of variables. The medical records showed great variability in the quality of the clinical data, and in general the follow up period was short.
Importantly, we chose to include patients with multiple tumors as well as those with neurocutaneous disorders. We believe however that inclusion of these patients is important since they receive surgical treatment more often and the outcomes are rarely described.
Conclusion
Surgery of benign peripheral nerve sheath tumors is a safe procedure with a favorable outcome in most cases. Younger age and larger tumors were risk factors for persistent or increased sensory deficits, while complete tumor removal was associated with reduced pain. Patients with neurocutaneous syndromes had a higher rate of tumor recurrence. To further evaluate outcome predictors, we recommend future studies to focus on longer follow-up periods to assess the natural course of postoperative neurological deficits.
Disclosure statement
The authors report there are no competing interests to declare.
Data availability statement
Data is available from the corresponding author upon reasonable request.
Additional information
Funding
References
- Ariel IM. Tumors of the peripheral nervous system. CA Cancer J Clin. 1983;33(5):282–299. doi:10.3322/canjclin.33.5.282.
- Antinheimo J, Sankila R, Carpén O, et al. Population-based analysis of sporadic and type 2 neurofibromatosis-associated meningiomas and schwannomas. Neurology. 2000;54(1):71–76. doi: 10.1212/wnl.54.1.71.
- Ghaith AK, Johnson SE, El-Hajj VG, et al. Surgical management of malignant melanotic nerve sheath tumors: an institutional experience and systematic review of the literature. J Neurosurg Spine. 2023;40(1):28–37. doi: 10.3171/2023.8.SPINE23427.
- Ogose A, Hotta T, Morita T, et al. Tumors of peripheral nerves: correlation of symptoms, clinical signs, imaging features, and histologic diagnosis. Skeletal Radiol. 1999;28(4):183–188. doi: 10.1007/s002560050498.
- Tamura R. Current understanding of neurofibromatosis type 1, 2, and schwannomatosis. Int J Mol Sci. 2021;22(11):130–138.
- Kim DH, Murovic JA, Tiel RL, et al. A series of 397 peripheral neural sheath tumors: 30-year experience at Louisiana state university health sciences center. J Neurosurg. 2005;102(2):246–255. doi: 10.3171/jns.2005.102.2.0246.
- Yamanaka R, Hayano A. Radiation-Induced schwannomas and neurofibromas: a systematic review. World Neurosurg. 2017;104:713–722. doi: 10.1016/j.wneu.2017.05.066.
- Levi AD, Ross AL, Cuartas E, et al. The surgical management of symptomatic peripheral nerve sheath tumors. Neurosurgery. 2010;66(4):833–840. doi: 10.1227/01.NEU.0000367636.91555.70.
- Carvajal JA, Cuartas E, Qadir R, et al. Peripheral nerve sheath tumors of the foot and ankle. Foot Ankle Int. 2011;32(2):163–167. doi: 10.3113/FAI.2011.0163.
- Kransdorf MJ. Benign soft-tissue tumors in a large referral population: distribution of specific diagnoses by age, sex, and location. AJR Am J Roentgenol. 1995;164(2):395–402. doi: 10.2214/ajr.164.2.7839977.
- Gosk J, Gutkowska O, Mazurek P, et al. Peripheral nerve tumours: 30-Year experience in the surgical treatment. Neurosurg Rev. 2015;38(3):511–520; discussion 521. doi: 10.1007/s10143-015-0620-8.
- Albert P, Patel J, Badawy K, et al. Peripheral nerve schwannoma: a review of varying clinical presentations and imaging findings. J Foot Ankle Surg. 2017;56(3):632–637. doi: 10.1053/j.jfas.2016.12.003.
- Artico M, Cervoni L, Wierzbicki V, et al. Benign neural sheath tumours of major nerves: characteristics in 119 surgical cases. Acta Neurochir (Wien). 1997;139(12):1108–1116. doi: 10.1007/BF01410969.
- Granlund AS, Sørensen MS, Jensen CL, et al. Clinical outcome after surgery on schwannomas in the extremities. World J Orthop. 2021;12(10):760–767. doi: 10.5312/wjo.v12.i10.760.
- Desai KI. The surgical management of symptomatic benign peripheral nerve sheath tumors of the neck and extremities: an experience of 442 cases. Neurosurgery. 2017;81(4):568–580. doi: 10.1093/neuros/nyx076.
- Pilavaki M, Chourmouzi D, Kiziridou A, et al. Imaging of peripheral nerve sheath tumors with pathologic correlation: pictorial review. Eur J Radiol. 2004;52(3):229–239. doi: 10.1016/j.ejrad.2003.12.001.
- Gosk J, Zimmer K, Rutowski R. Peripheral nerve tumours–diagnostic and therapeutical basics. Folia Neuropathol. 2004;42(1):31–35.
- Gaba S, Mohsina S, John JR, et al. Clinical outcomes of surgical management of primary brachial plexus tumors. Indian J Plast Surg. 2021;54(2):124–129. doi: 10.1055/s-0041-1731252.
- Zipfel J, Al-Hariri M, Gugel I, et al. Surgical management of sporadic peripheral nerve schwannomas in adults: indications and outcome in a single center cohort. Cancers (Basel). 2021;13(5):1017. doi: 10.3390/cancers13051017.
- Siqueira MG, Socolovsky M, Martins RS, et al. Surgical treatment of typical peripheral schwannomas: the risk of new postoperative deficits. Acta Neurochir (Wien). 2013;155(9):1745–1749. doi: 10.1007/s00701-013-1818-6.
- Hirai T, Kobayashi H, Akiyama T, et al. Predictive factors for complications after surgical treatment for schwannomas of the extremities. BMC Musculoskelet Disord. 2019;20(1):166. doi: 10.1186/s12891-019-2538-8.
- El Sayed L, H Masmejean E, Lavollé A, et al. Clinical results after surgical resection of benign solitary schwannomas: a review of 150 cases. Orthop Traumatol Surg Res. 2022;108(4):103281. doi: 10.1016/j.otsr.2022.103281.
- Guha D, Davidson B, Nadi M, et al. Management of peripheral nerve sheath tumors: 17 years of experience at Toronto Western hospital. J Neurosurg. 2018;128(4):1226–1234. doi: 10.3171/2017.1.JNS162292.
- Singh A,Fletcher-Sandersjöö A,El-Hajj VG, et al. Long-term functional outcomes following surgical treatment of spinal schwannomas: A population-based cohort study. Cancers. 2024;16(3):519. doi: 10.3390/cancers16030519.