The establishment of the multicentric Peripheral Nerve Tumor Registry (PNTR) in 2015 in Germany allows for the systematic analysis of patients with benign, malignant, and other rare tumor entities associated with the peripheral nerves. So far, no multicentric data on peripheral nerve tumors exist in Europe. The PNTR was divided into a retrospective (2015–2016) and prospective (since 2017) study arm. Patient characteristics (age, sex) as well as disease (affected nerve, tumor location, histopathology), surgical treatment (type of treatment, pre- and postoperative symptoms), radiological imaging, diagnosis of neurofibromatosis (NF), data on health-related quality of life (HRQoL), return to work, and long-term follow-up data were analyzed. The long-term goal is to create uniform treatment recommendations (10).

This substudy of the PNTR contains a partially retrospective and prospective analysis of HRQoL in 171 patients with benign, malignant, and rare peripheral nerve tumors that were surgically treated in either the Department for Neurosurgery in Günzburg, University Hospital Ulm; the Department for Neurosurgery in Berlin, Charité University Hospital; or the Department for Neurosurgery in Essen, University Hospital, which were treated between January 2015 and January 2023. All patients gave written permission. This study was approved by our local ethics committees in Ulm (Nr. 249/17) and Berlin (EA4/058/17) and is registered with the German Trials Registry (www.drks.de) (10).

All patients who were diagnosed with a tumor in association with a peripheral nerve and surgically treated in one of the high-volume recruiting study centers were enrolled.

The assessment of HRQoL was conducted by the standardized preference-based questionnaire Euro-Qol-5D-5L (EQ-5D-5L) and Euro-Qol visual analog scale (EQ-VAS), which were developed by the EuroQol Group in 2005 (11). The EQ-5D-5L is a generic instrument for describing and evaluating health status by interrogating questions related to five dimensions: mobility (MO), self-care (SC), usual activities (UA), pain/discomfort (PD), and anxiety/depression (AD). Each dimension has five response levels ( Table 1 ). The questionnaire is designed for self-completion, has been widely tested in different populations and patient samples, and is routinely used in clinical research (12).

An index value was calculated based upon the EQ-5D-5L, which reflects the quality of the health status according to the preferences of the general population of a country, in this case, Germany (0: worst possible state of health, 1: best possible state of health). Therefore, the EQ-5D-5L-Crosswalk-Index-Value-Calculator from the research by van Hout et al. was used (13). The EQ-VAS ranges from 0% (worst possible health status) to 100% (best imaginable health status) (11, 12).

Data were collected via face-to-face interviews during follow-up examinations or telephone interviews or completed at home and sent postally.

All in all, the PNTR contains to date 267 patients; for this substudy, the response rate was 64% (n = 171). In summary, the surveys were assessed at a mean of 36.9 months (SD 23 months) after surgery.

Detailed patient characteristics, including age and sex, as well as histopathological diagnosis, type of surgical treatment, neurological symptoms, pain, and imaging-specific data, were analyzed. Surgical therapy was performed according to established principles (14).

Dataset analysis was performed using SPSS 27.0 (SPSS, Inc., Chicago, IL, USA). Metric data were described using median, mean, and standard deviation; categorical data were characterized by frequency and valid percent. Mann–Whitney U, Wilcoxon, Fisher exact, McNemar, and chi-square tests were used for the analysis. The correlation was calculated using Pearson correlation. A level of significance was defined as p <0.05.

A total of 171 surgically treated patients at three high-volume centers were included in this study. Forty-five percent of patients were women (n = 77), and 55% were men (n = 94), with a mean patient age of 48.1 years (SD 13.4). Patients were surgically treated by complete tumor resection in 88.9%, by biopsy in 7%, and by partial tumor removal in 4.1%. A neurofibromatosis spectrum disease was scientifically proven in 15 patients (8.7%). The demographic and clinical characteristics of the patients are presented in Table 2 .

PNSTs were most often located in the brachialis plexus region in 16.4% (n = 28), in the median nerve in 15.8% (n = 27), and in the ulnar nerve in 12.3% (n = 21), respectively. The upper and lower extremities were the location of 96 (56.1%) and 75 (43.9%) tumors. Table 3 shows the distribution of the 171 peripheral nerve tumors according to their location.

Most of the 171 surgically treated PNSTs were benign (86.5%) and included schwannoma (n = 121) and neurofibroma (n = 27). Other histopathological diagnoses were perineurioma (n = 6), hybrid nerve sheath tumors (schwannoma/neurofibroma and schwannoma/perineurioma, n = 4), and lymphangioma (n = 2). Malignant tumors included malignant peripheral nerve sheath tumors (MPNSTs) (n = 5). Rarities were singularly represented such as cavernous hemangioma, desmoid tumor, metastasis of breast cancer, amyloidoma, plasmacellular myeloma, and B-cell lymphoma Table 4 .

The prevailing preoperative symptom was pain, including stress and rest pain in 140 patients (82%), rest pain in 60 patients (35%), and stress pain, including a positive Tinel sign in 125 patients (73%). In the follow-up examination, which was in the mean 36.9 months after surgery, patients benefited significantly from surgery, reporting overall pain release (p < 0.001). Only 55 patients (32%) reported pain postoperatively (stress and rest pain altogether) Figure 1 .

Preoperative motor deficits occurred in 18.7% (n = 32), which increased postoperatively to 23.4% (n = 40) but decreased in the follow-up examination to 18% (n = 31) Figure 2 . In 7 of these 32 patients (21.8%), motor deficits occurred after a previous surgery or biopsy at an unspecialized center.

In the total cohort of 171 patients, 13 patients (7.6%) underwent previous surgery, including biopsies at an unspecialized center. In 7 of 13 patients (53.8%) and in 11 of 13 patients (84.6%), motor deficits and sensory deficits respectively occurred after previous surgery or biopsy at an unspecialized center. Out of 158 patients who had no previous biopsy, 28 patients presented preoperative motor deficits, while 27 cases exhibited deficits. Among the 158 cases, 7 patients (4%) experienced new motor deficits after undergoing surgery at a specialized center.

A significant correlation (p < 0.001, r = 0.744) was found between patients with preoperative motor deficits (n = 32) and patients with permanent motor deficits (n = 24).

The same trend is seen in sensory deficits. Preoperative sensory deficits occurred in 38.6% (n = 66), which increased postoperatively to 52.6% (n = 90) but then decreased in the follow-up examination to 38% (n = 65). In 11 of these 66 patients (16.6%), sensory deficits occurred after a previous surgery or biopsy at an unspecialized center. We found a weak correlation between the preoperative and postoperative permanent sensory deficit (p < 0.001, r = 0.443).

The median health index value of the entire cohort was 0.887 (n = 167) preoperatively and improved postoperatively to 0.910 (n = 166, p < 0.001). The median EQ-VAS score was 75% (n = 167) preoperatively and enhanced to 85% (n = 166, p < 0.001) postoperatively ( Table 5 ).

EQ-5D-5L levels were dichotomized into “no limitations” (i.e., level 1) and “with limitations” (i.e., levels 2 to 5). The results are shown in Table 1 .

Preoperatively, 12.3% of the patients reached the highest index value score of 1.0 in the EQ-5D-5L and improved postoperatively to 33.3%. In the Euro-Qol visual analog scale (EQ-VAS score), patients rated their overall health preoperatively with a median of 75%, which improved to 85% postoperatively.

Health index values and EQ-VAS scores were compared between different subgroups (histopathological diagnosis, age, and gender). According to histopathological features, three subgroups were defined. Group 1 included benign nerve sheath tumors (schwannoma and neurofibroma), with a total of 148 patients. Group 2 included malignant tumors, including MPNST, metastasis of breast cancer, plasmacellular myeloma, and B-cell lymphoma, with a total of eight patients. In group 3, rare histopathological diagnoses were summarized, including perineurioma, hybrid nerve sheath tumors, and lymphangioma, and represented diagnoses with a total number of 15 patients.

Because of the small number of patients in groups 2 and 3, no levels of significance were calculated.

In Table 1 , all pre- and postoperative EQ-5D-5L dimension levels are compared regarding the distribution in subgroups after histopathological patterns.

In the overall cohort, after surgery, the number of patients with no limitations significantly increased in the dimension’s mobility, usual activities, pain, and anxiety/depression ( Table 1 ). Additionally, the EQ-5D-%L index scores and the EQ-VAS scores improved postoperatively significantly (p < 0.001) in the overall cohort ( Table 1 ).

In the further analysis of our data regarding upper and lower extremities, we did not find any significant differences in the median health index values preoperatively (upper extremity 0.887, lower extremity 0.828) and postoperatively (upper and lower extremity 0.910) and in the median EQ-VAS scores preoperatively (upper extremity 80%, lower extremity 75%) and postoperatively (85%).

The mean EQ-5D-5L index score of the German general adult population was stated to be 0.88 (SD 0.18), and the overall EQ-VAS score was 71.59 (SD 21.36). Higher education, full-time work, and private health insurance were associated with a higher EQ-5D-5L index score. Female gender and higher age were associated with a lower EQ-5D-5L index score (12).

In our cohort, the median health index values were identical for the male and female genders (0.887 T¹, 0.910 T²). Women reported a lower score (72.5%) than men (80%) only in the preoperative median EQ-VAS score. Postoperatively, the median EQ-VAS score increased in both genders to 85%. In our cohort, it can therefore be concluded that there was no gender difference in life quality.

In terms of age relevance for HRQoL, we could not find significant differences in our cohort. With a median age of 48 years, our cohort was slightly younger than the cohort described by Grochtdreis et al. with a median age of 51 years (12). Younger age according to their data was associated with better life quality. This correlation could not be found in our dataset of PNT patients.

Overall, patients in our cohort had a higher median index score postoperatively than in the German general adult population (0.91 vs. 0.88). Reduced pain and symptom control could be a possible explanation.

Among the five different dimensions that were analyzed in our cohort, the fewest restrictions were in the dimension of self-care. Nearly all patients can fend for themselves. Disabilities in patients with PNT—excluding NF patients—are mostly limited to one extremity.

Our data show overall that patients improved postoperatively in HRQoL. A non-negligible percentage of motor and sensory deficits occurred after previous surgeries or needle biopsies in non-specific centers; those deficits are frequently permanent. The harm that can be caused due to surgical treatment in non-specialized centers has been shown in a recent study and supports our results (4). Overall, the key observation is that patients who presented deficits prior to surgery are more prone to experiencing permanent deficits. Because neurological deficits determine life quality, especially in the domain of mobility, self-care, and usual activities, these previous surgeries can negatively influence HRQoL. Furthermore, due to their rarity, patients often experience a long diagnostic process in the future with the potential of misdiagnosis and severe consequences (44.7%) (4).

Our study shows that preexisting neurological deficits, including pain, are risk factors for permanent deficits. This additionally supports the recommendation to perform surgery at a specialized center to prevent function and consecutively impaired life quality.

In our dataset, most restrictions occurred in the dimension of pain. In 76%, preoperative limitations (slight–extreme problems) occurred, which significantly improved postoperatively to 54.8% (p < 0.001). These results are mirrored in the preoperative collected data of symptoms; pain (rest and stress pain) was reported in 82% and improved postoperatively to 32%. All in all, surgery led to improved symptom control in the dimension of pain. Pain was not only the leading symptom in patients with malignant or rare PNTs but also in patients with benign PNTs like schwannoma and neurofibroma with no other neurological deficits, which is in concordance with previous studies (2, 15). For this reason, we recommend early surgery at a specialized center for symptom control and for returning to everyday life and work quickly.

Compared with patients with benign PNT, patients with malignant peripheral nerve tumors undoubtedly have a worse life quality ( Table 1 ), which is, on the one hand, related to the physio- and psychological burden of the disease itself and, on the other hand, influenced by the more radical surgical treatment followed by neurological deficits and the duration of the disease. Due to the small number of patients with malignant PNT, generalized recommendations are not possible; however, due to limited life expectancy, it is even more critical to counterbalance the radicality of treatment and the QoL. Different concepts regarding the priority of neurological function preservation in contrast to surgical radicality are currently applied and must be discussed with the patient before surgery (16). Interestingly, patients in the group with rare entities had comparable pre- and postoperative index scores to the group with benign PNT (T¹ 0.818, T² 0.911).

The effect that the degree of HRQoL improvement varies according to preoperative neurological symptoms is not only shown in our data but also by Haider et al., who report this effect in patients with intracranial meningiomas (17).

As diagnosis and treatment modalities have improved over time, early return to work and life quality are necessary outcome measurements in patients with PNT. Additional work and employment are essential factors in life quality, ranked right after family and partnership (18). It becomes clear that PNT concerns, in particular, the working population with a mean age of 48.1 years. With pain as the leading symptom and knowing the obstacles and the effort that occur in patients with chronic pain returning to work, including managing symptom control, work relationships, and making workspace adjustments (19), the highest goal should be treating pain immediately at the initial diagnosis. The more neurological deficits occur pre- or postoperatively, the more likely it may be that patients will not return to work as fast as patients without deficits. However, a specific analysis of return to work in patients with PNT needs to be improved. Our data show that resection at a specialist high-volume center is safe and improves symptoms and life quality after surgery.

The strength of this study is the large cohort of patients with clearly peripheral nerve tumors; intraspinal schwannoma was not included. A second strength is the multicentric study design.

The limitations are that the results are from a retrospective analysis. The number of patients with malignant PNT and neurofibromatosis was proportionally small.