Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The authors provide an interesting and well designed study about the pain in tumors of the peripheral nerves.

The cohort is not very big but with proper statistical analysis is adequate.

I have some questions though:

You didnt include only nerve-tumors but tumors that were compressing the nerve. It would make sense to differentiate in the statistic this question, if the nerve compression was more painful than the nerve destruction due to the tumor or not and if the pain was different in any case.

Some nerves have a sensory function and some a motor function. You should distinguish those two categories as well.

Were patients with multiple tumors included? Which tumor did you use in your analysis in such cases? How about patients who have had chemotherapy or radiation therapy? Cancer patients? 

Comorbidities of the patients? Depression, but not only, would be relevant.

Did the pain correlate to the postoperative results? Did patients, for example, with more pain have after surgery even more temporarily or less?

In some parts you should let a native English speaker check the words/phrases you use. Otherwise its fine.

Author Response

Comment 1: Comments and Suggestions for Authors

The authors provide an interesting and well designed study about the pain in tumors of the peripheral nerves. The cohort is not very big but with proper statistical analysis is adequate. I have some questions though:

You didnt include only nerve-tumors but tumors that were compressing the nerve. It would make sense to differentiate in the statistic this question, if the nerve compression was more painful than the nerve destruction due to the tumor or not and if the pain was different in any case.

Response 1: We thank the reviewer for this important comment. We agree that the anatomical relationship between the lesion and the nerve is clinically relevant and may influence the pain phenotype. However, the present study was designed as a prospective, clinically oriented analysis. Therefore, all patients were included prospectively if there was a strong preoperative suspicion of a peripheral nerve tumor based on clinical presentation, imaging findings, and/or intraoperative findings. This reflects the real-world diagnostic situation, in which the final distinction between a true peripheral nerve sheath tumor and a nerve-adjacent tumor mimic is often only possible after histopathological confirmation.

For this reason, we considered it clinically meaningful to include not only histologically confirmed peripheral nerve sheath tumors but also lesions that closely mimicked nerve tumors because of their intimate anatomical relationship to a nerve. The primary aim of this interim analysis was to characterize pain in patients presenting with suspected peripheral nerve tumors, rather than to restrict the cohort to histologically confirmed lesions only. Accordingly, the dropout group was retained as a clinically relevant comparison cohort.

A further distinction between extrinsic nerve compression, displacement/stretching, and true intraneural infiltration or nerve destruction was not mandatory for the primary research question of this prospective interim analysis and could not be assigned with sufficient reliability in all cases based on the available documentation. Therefore, the current analysis was primarily based on histopathological groups and clinical presentation. We have clarified this point in the Methods Section.

Comment 2: Some nerves have a sensory function and some a motor function. You should distinguish those two categories as well.

Response 2: We agree that the functional profile of the affected nerve is relevant. In the current cohort, several nerves had mixed sensorimotor function, including the sciatic, peroneal, ulnar, brachial plexus, and lumbosacral plexus. Therefore, a strict binary classification into purely sensory versus purely motor nerves was not feasible for most cases. We have now clarified this in the Discussion.

Comment 3: Were patients with multiple tumors included? Which tumor did you use in your analysis in such cases? How about patients who have had chemotherapy or radiation therapy? Cancer patients?

Response 3: We thank you for this important comment. Patients with multiple tumors were included. In total, 11 of 91 patients had undergone resection of more than one tumor (12.1%); in 8 of 91 patients, information on previous multiple tumor resections was unknown or not documented (8.8%). Among these 11 patients, the tumors analyzed to date were schwannoma in 5 cases (45.5%), neurofibroma in 3 cases (27.3%), hybrid nerve sheath tumor in 2 cases (18.2%), and lipoma in 1 case (9.1%). Six of these 11 patients had undergone surgery for three tumors (54.5%), and two patients had undergone surgery for more than five tumors (18.2%). Seven of the 11 patients with multiple tumor resections had an associated tumor predisposition syndrome (Neurofibromatosis spectrum) (63.6%).

For the present prospective analysis, the PainDETECT questionnaire was completed only for the most recently operated tumor, which was defined as the index lesion. Previous tumor resections had occurred before the start of the prospective PainDETECT assessment and were therefore documented retrospectively from medical records. Consequently, no tumor-specific PainDETECT scores were available for previously resected lesions. In patients with multiple tumor resections, the mean PainDETECT overall score of the analyzed index lesion was 11.8, and the mean PainDETECT end score was 13.7. For future PNTR analyses, we plan to assess PainDETECT prospectively before each new tumor operation and separately for each tumor. This is particularly relevant in patients with syndrome-associated multiple tumors, as it may help identify which tumor types or locations are associated with higher pain burden.

Regarding previous medical history and oncological treatment, relevant data were available for 73 of 91 patients (80.2%). A history of malignancy was documented in 8 of 73 patients (11.0%), including optic glioma, malignant melanoma, prostate cancer, breast cancer, and testicular cancer. One patient had previously received chemotherapy with vincristine and carboplatin for optic glioma (1/73, 1.4%). Three patients with previous malignancy had not received adjuvant therapy (3/8, 37.5%). In several patients, the history of malignancy contributed to the decision for surgery, as metastasis could not be excluded preoperatively. Only one patient with previous malignancy received preoperative pain medication (1/8, 12.5%), consisting of ibuprofen, metamizole, pregabalin, and tilidine. Because of the small number and heterogeneity of previous malignancies and oncological treatments, no separate subgroup analysis was performed. We have clarified this in the manuscript.

Comment 4: Comorbidities of the patients? Depression, but not only, would be relevant.

Response 4: We agree that comorbidities are relevant for the interpretation of pain scores. Relevant comorbidity data were available for 73 of 91 patients (80.2%). Thirty-five of these 73 patients had no documented relevant comorbidity (47.9%), while no data were available for 18 of 91 patients (19.8%). Among the documented comorbidities, arterial hypertension requiring medical treatment was the most frequent comorbidity and was present in 14 of 73 patients (19.2%). Depression was documented in 4 of 73 patients (5.5%), type 2 diabetes mellitus requiring medical treatment in 3 of 73 patients (4.1%), and hypercholesterolemia in 3 of 73 patients (4.1%). A history of malignancy was documented in 8 of 73 patients (11.0%).

Preoperative pain medication data were available for 73 patients. No preoperative pain medication was required in 61 of 73 patients (83.6%). Twelve patients received preoperative pain medication (12/73, 16.4%). The medications included non-opioid analgesics such as ibuprofen and metamizole, opioid or opioid-like analgesics such as tapentadol, palexia, and tilidine, and medication typically used for neuropathic pain such as gabapentin, pregabalin, duloxetine, amitriptyline, and amineurin. Postoperatively, 63 of 73 patients received mainly ibuprofen and/or metamizole as needed for wound pain (86.3%). These medications were discontinued independently by the patients according to clinical need.

Because comorbidity and medication data were incomplete and heterogeneous, adjusted statistical analyses were not performed. However, we have added these data descriptively and expanded the Discussion to acknowledge their potential influence on PainDETECT and NRS scores.

Comment 5: Did the pain correlate to the postoperative results? Did patients, for example, with more pain have after surgery even more temporarily or less?

Response 5: We thank you for this clinically important question. Standardized follow-up data are still pending and were therefore not included in the present interim analysis. Based on our clinical experience, pain improved early after surgery in almost all patients, and additional postoperative medication was mainly used for wound-related pain rather than persistent tumor-associated pain.

The main aim of the present analysis was to challenge the common assumption that patients with peripheral nerve tumors, including benign tumors, do not experience relevant preoperative pain. Because of the limited patient number and incomplete standardized follow-up data, we did not perform a direct correlation analysis between preoperative pain scores and postoperative outcome. This will be addressed in future PNTR analyses once complete follow-up data are available.

In the present analysis, postoperative neurological deficits were not evaluated, as the primary focus was on preoperative pain symptomatology. However, in the overall cohort of the peripheral nerve tumor registry (n=613), preoperative pain appears to be more frequent in malignant tumors and is often accompanied by motor weakness and sensory deficits. These neurological deficits frequently persist after treatment. Corresponding data are not included in the present publication and will be analyzed separately.

Comment 6: In some parts you should let a native English speaker check the words/phrases you use. Otherwise its fine.

Response 6: The manuscript has been revised for English language, grammar, terminology, and clarity.

Reviewer 2 Report

Comments and Suggestions for Authors

The paper needs to be revised based on the following major comments: 

• 91 patients (61.5% male; mean age 49 years) from the Peripheral Nerve Tumor Registry (PNTR) at University Hospital Ulm and University Hospital Essen in Germany were examined for the study. Tools for Assessment: To determine the probability of neuropathic pain, researchers used the PainDETECT questionnaire (score 0–38). The Pittsburgh Sleep Quality Index (PSQI) and the EQ-5D-5L for quality of life were further instruments. Classification of Patients: Group 1: Neurofibromas and schwannomas are examples of benign peripheral nerve sheath tumors (PNSTs). Group 2: Malignant tumors, such as sarcomas and malignant peripheral nerve sheath tumors (MPNST). Group 3: Uncommon or uncommon tumor entities related to the nerves. Group 4: A comparison cohort of "dropout" lesions (non-PNST tissue that appeared to be tumors on imaging).
• Overall Scores: 21.9% of patients had scores ≥19, indicating likely neuropathic pain, while 51.6% of patients had low PainDETECT scores (≤12), suggesting nociceptive pain. Malignancy: With a mean score of 17 and higher Numerical Rating Scale (NRS) levels (mean 5.5) than benign groups, malignant tumors (Group 2) showed the greatest pain burden. Benign Tumors: These individuals demonstrated a considerable pain burden (mean score 11.9), defying the notion that benign tumors are frequently asymptomatic. Schwannomas scored lower than hybrid nerve sheath tumors and neurofibromas; however, this difference was not statistically significant. Typical Symptoms Electrifying/electric shock-like pain (75%) and pressure-related pain (77%) were the most common symptoms. In 86.8% of patients, the Tinel sign was positive.
• The absence of a relationship between the degree of discomfort and the physical features of the tumor was an important discovery: Size: Tumor size and Pain DETECT scores did not significantly correlate. Depth and Nerve: Whether a tumor was superficial or deep did not significantly change pain levels, nor did it correspond with the particular nerve that was impacted.
•  Even in benign PNTs, the interim findings indicate that pain is a significant contributor to morbidity. Individualized Management: Rather than depending on tumor size or histological type to predict pain, patient-centered assessments are necessary due to the variety of pain presentations. Surgical Intervention: Previous registry data shows that surgery frequently offers great relief; therefore, the results encourage prompt surgery for patients with significant pain, even in the absence of neurological impairments. Future Research: In order to monitor the durability of pain alleviation, the study will eventually incorporate postoperative follow-up data as well as a multicenter review.
• The following papers can be added to the current research:
• 1: Sughrue, M., Levine, J., & Barbaro, N. (2014). Pain as a symptom of peripheral nerve sheath tumors: clinical significance and future therapeutic directions. Journal of Brachial Plexus and Peripheral Nerve Injury, 03(01), e136–e140. https://doi.org/10.1186/1749-7221-3-6
• 2: Yosef, M., Bunimovich-Mendrazitsky, S., & Nave, Op. (2025). Multiscale Dynamics of MMC Chemotherapy in Bladder Cancer: The SPVF Approach. Mathematics, 13(24), 3974. https://doi.org/10.3390/math13243974

 

Comments on the Quality of English Language

The English could be improved to more clearly express the research.

Author Response

Comment 1: The paper needs to be revised based on the following major comments:

91 patients (61.5% male; mean age 49 years) from the Peripheral Nerve Tumor Registry (PNTR) at University Hospital Ulm and University Hospital Essen in Germany were examined for the study. Tools for Assessment: To determine the probability of neuropathic pain, researchers used the PainDETECT questionnaire (score 0–38). The Pittsburgh Sleep Quality Index (PSQI) and the EQ-5D-5L for quality of life were further instruments. Classification of Patients: Group 1: Neurofibromas and schwannomas are examples of benign peripheral nerve sheath tumors (PNSTs). Group 2: Malignant tumors, such as sarcomas and malignant peripheral nerve sheath tumors (MPNST). Group 3: Uncommon or uncommon tumor entities related to the nerves. Group 4: A comparison cohort of "dropout" lesions (non-PNST tissue that appeared to be tumors on imaging).

Overall Scores: 21.9% of patients had scores ≥19, indicating likely neuropathic pain, while 51.6% of patients had low PainDETECT scores (≤12), suggesting nociceptive pain. Malignancy: With a mean score of 17 and higher Numerical Rating Scale (NRS) levels (mean 5.5) than benign groups, malignant tumors (Group 2) showed the greatest pain burden. Benign Tumors: These individuals demonstrated a considerable pain burden (mean score 11.9), defying the notion that benign tumors are frequently asymptomatic. Schwannomas scored lower than hybrid nerve sheath tumors and neurofibromas; however, this difference was not statistically significant. Typical Symptoms Electrifying/electric shock-like pain (75%) and pressure-related pain (77%) were the most common symptoms. In 86.8% of patients, the Tinel sign was positive.

The absence of a relationship between the degree of discomfort and the physical features of the tumor was an important discovery: Size: Tumor size and Pain DETECT scores did not significantly correlate. Depth and Nerve: Whether a tumor was superficial or deep did not significantly change pain levels, nor did it correspond with the particular nerve that was impacted.

 Even in benign PNTs, the interim findings indicate that pain is a significant contributor to morbidity. Individualized Management: Rather than depending on tumor size or histological type to predict pain, patient-centered assessments are necessary due to the variety of pain presentations. Surgical Intervention: Previous registry data shows that surgery frequently offers great relief; therefore, the results encourage prompt surgery for patients with significant pain, even in the absence of neurological impairments. Future Research: In order to monitor the durability of pain alleviation, the study will eventually incorporate postoperative follow-up data as well as a multicenter review.

The following papers can be added to the current research:

1: Sughrue, M., Levine, J., & Barbaro, N. (2014). Pain as a symptom of peripheral nerve sheath tumors: clinical significance and future therapeutic directions. Journal of Brachial Plexus and Peripheral Nerve Injury, 03(01), e136–e140. https://doi.org/10.1186/1749-7221-3-6

2: Yosef, M., Bunimovich-Mendrazitsky, S., & Nave, Op. (2025). Multiscale Dynamics of MMC Chemotherapy in Bladder Cancer: The SPVF Approach. Mathematics, 13(24), 3974. https://doi.org/10.3390/math13243974

Response 1: We thank the reviewer for suggesting additional literature. The paper by Sughrue et al. is directly relevant to the clinical significance of pain in peripheral nerve sheath tumors and has already been included as a key reference in the manuscript. (Reference Nr. 1)

The second suggested article by Yosef et al. concerns multiscale dynamics of MMC chemotherapy in bladder cancer. After careful review, we considered this reference outside the scope of the present manuscript, which focuses on pain phenotyping in peripheral nerve tumors. Therefore, we did not include it.

Comment 2: The English could be improved to more clearly express the research.

Response 2: We thank the reviewer for this helpful comment. We agree that clearer, more consistent English improves the readability of the manuscript and better conveys the research question, methodology, and clinical relevance of our findings. Therefore, the manuscript has been carefully revised throughout by improving grammar, sentence structure, terminology, and overall flow.

In particular, we corrected inconsistent wording and terminology, reduced repetitive phrasing, and revised several sections to clarify the aims, results, and interpretation. The Abstract, Introduction, Methods, Results, Discussion, Limitations, and Conclusions were edited for clarity and consistency. We also improved the scientific phrasing to avoid overstatement and to better distinguish exploratory findings from definitive conclusions.

In addition, the figure legends were revised to provide clearer descriptions of the data shown, the analyzed subgroups, and the statistical interpretation. The figures themselves were also adjusted to improve readability, consistency, and presentation quality.

Reviewer 3 Report

Comments and Suggestions for Authors

The paper presents a prospective bicenter study evaluating pain in 91 patients with peripheral nerve tumors (PNTs) using the validated PainDETECT questionnaire. The study addresses a critical gap in structured pain characterization, particularly by challenging the assumption that benign tumors are often asymptomatic. The findings underscore the heterogeneity of pain phenotypes in this population and the need for individualized management.

1.Check the formatting of Reference 31 and 32. In the bibliography, some DOIs are listed with "doi:" while others are just the URL. Ensure they follow the MDPI Cancers house style consistently throughout.

2. Ensure all abbreviations are defined at first mention in the main text, even if they were already defined in the abstract (e.g., "NRS" for Numerical Rating Scale).

3. In the Discussion, clearly state the expected timeline or the remaining patient count needed to transition from this "interim" report to the "final" analysis of the PNTR study.

4. It would be helpful to briefly mention if the anatomical location (e.g., upper limb vs. lower limb) had any impact on the "pain quality" (burning vs. pressure), even if the correlation was weak. This adds a layer of clinical utility.

5. Pain scores (NRS and PainDETECT) are highly sensitive to treatment. A patient with a "low" score might simply be well-managed pharmacologically, whereas a patient with a "high" score might be untreated.If the data is available in the registry, it must be included. If not, the Discussion must more vigorously address how this "confounder" impacts the classification of tumors as "painful" or "painless."

6. The authors should explicitly state that the comparison between Group 1 (Schwannomas) and Groups 2/3/4 is exploratory. Avoid using p-values to imply definitive clinical differences where the n is insufficient to represent the biological variety of those rare tumors.

7. The "Dropout Group" (Group 4) is used as a control, but it consists of lesions that clinically mimicked nerve tumors. This group actually showed surprisingly high pain scores (Mean 12.3).This finding is a "hidden gem" in the data. The authors should expand the Discussion to explain why these mimics (like ganglion cysts or localized fibrosis) are causing pain levels comparable to benign tumors. This is crucial for differential diagnosis in clinical practice.

8.The authors should clarify if the high scores in benign tumors are truly neuropathic (nerve fiber dysfunction) or if the questionnaire might be picking up deep somatic pain. This distinction is vital for determining whether these patients should be treated with nerve-pain agents or standard NSAIDs.

Comments on the Quality of English Language

Language should be polished throughout the manuscript

Author Response

Comment 1: The paper presents a prospective bicenter study evaluating pain in 91 patients with peripheral nerve tumors (PNTs) using the validated PainDETECT questionnaire. The study addresses a critical gap in structured pain characterization, particularly by challenging the assumption that benign tumors are often asymptomatic. The findings underscore the heterogeneity of pain phenotypes in this population and the need for individualized management.

1.Check the formatting of Reference 31 and 32. In the bibliography, some DOIs are listed with "doi:" while others are just the URL. Ensure they follow the MDPI Cancers house style consistently throughout.

Response 1: We thank the reviewer for noting this. We have checked and standardized the reference formatting according to the journal style.

Comment 2. Ensure all abbreviations are defined at first mention in the main text, even if they were already defined in the abstract (e.g., "NRS" for Numerical Rating Scale).

Response 2: We agree. We revised the manuscript to define all abbreviations at first mention in the main text, including peripheral nerve tumors, Peripheral Nerve Tumor Registry, malignant peripheral nerve sheath tumors, Numerical Rating Scale, Euro-QoL-5D-5L, Euro-QoL visual analog scale, Pittsburgh Sleep Quality Index, and magnetic resonance imaging.

Comment 3: In the Discussion, clearly state the expected timeline or the remaining patient count needed to transition from this "interim" report to the "final" analysis of the PNTR study.

Response 3: We thank the reviewer for this helpful comment. We have now clarified in the Discussion that the transition from the present interim analysis to the final PNTR analysis is planned once at least 200 patients with histologically confirmed peripheral nerve tumors have been included, excluding the drop-out cohort, and complete follow-up data are available. At present, complete follow-up data are available only from the Günzburg center, comprising 50 patients. As recruitment and complete follow-up documentation from the other participating centers are still pending, the exact timeline will depend on the future recruitment rate across centers and therefore cannot currently be stated with sufficient reliability. We also added that follow-up data collection remains challenging, as patients who recover well frequently cancel scheduled follow-up visits. If it becomes apparent that patients will not return for in-person follow-up, structured telephone interviews are planned to minimize missing follow-up data.

Comment 4. It would be helpful to briefly mention if the anatomical location (e.g., upper limb vs. lower limb) had any impact on the "pain quality" (burning vs. pressure), even if the correlation was weak. This adds a layer of clinical utility.

Response 4: We agree that this would add clinical value. In the present interim cohort, anatomical location did not show a statistically significant association with overall PainDETECT scores. An addition to the discussion section was made: Although lower-extremity lesions showed a slightly higher proportion of patients within the neuropathic PainDETECT range, no robust association between anatomical location and specific pain quality was identified in this interim cohort.

Comment 5. Pain scores (NRS and PainDETECT) are highly sensitive to treatment. A patient with a "low" score might simply be well-managed pharmacologically, whereas a patient with a "high" score might be untreated.If the data is available in the registry, it must be included. If not, the Discussion must more vigorously address how this "confounder" impacts the classification of tumors as "painful" or "painless."

Response 5: We fully agree. Analgesic and neuropathic pain medication can substantially influence NRS and PainDETECT scores. Data on Mediaction, Comorbidities and Previous medical History has been added in the result and Discussion.

Comment 6. The authors should explicitly state that the comparison between Group 1 (Schwannomas) and Groups 2/3/4 is exploratory. Avoid using p-values to imply definitive clinical differences where the n is insufficient to represent the biological variety of those rare tumors.

Response 6: We agree. The small number of patients in Groups 2, 3, and 4 limits statistical power and precludes definitive conclusions about biological differences among rare entities. We have revised the Methods section to clarify:

Given the limited sample size and biological heterogeneity of several histopathological subgroups, particularly Groups 2–4, all subgroup comparisons should be interpreted as exploratory and hypothesis-generating.

Comment 7: The "Dropout Group" (Group 4) is used as a control, but it consists of lesions that clinically mimicked nerve tumors. This group actually showed surprisingly high pain scores (Mean 12.3). This finding is a "hidden gem" in the data. The authors should expand the Discussion to explain why these mimics (like ganglion cysts or localized fibrosis) are causing pain levels comparable to benign tumors. This is crucial for differential diagnosis in clinical practice.

Response 7:We thank the reviewer for this insightful comment. We agree that the dropout group is clinically important because these lesions mimicked peripheral nerve tumors and were associated with relevant pain. We clarified this in the Discussion.

However, we note that in the current manuscript, Group 4 had a mean PainDETECT score of 9.1, not 12.3. The value 12.3 corresponds to the mean score of deep lesions in Table 1. Nevertheless, the dropout group included individual lesions with high scores, especially angioleiomyoma and glomus tumor, supporting the reviewer’s point that non-PNST mimics may produce clinically relevant pain.

An addition to the discussion was made.

Comment 8: The authors should clarify if the high scores in benign tumors are truly neuropathic (nerve fiber dysfunction) or if the questionnaire might be picking up deep somatic pain. This distinction is vital for determining whether these patients should be treated with nerve-pain agents or standard NSAIDs.

Response 8: We thank the reviewer for this important comment. We agree that high PainDETECT scores should not automatically be interpreted as proof of true neuropathic pain caused by nerve fiber dysfunction. The PainDETECT questionnaire was primarily selected because it is an established, standardized, and easy-to-use instrument that captures a broad range of pain qualities and can be applied reliably in routine clinical practice. However, in the context of peripheral nerve tumors, high scores may also reflect deep somatic pain or local mechanical irritation rather than purely neuropathic pain.

We have therefore clarified in the Discussion that PainDETECT scores should be interpreted as an indicator of neuropathic-like pain qualities, not as a definitive diagnosis of neuropathic pain. Treatment decisions should not be based on the questionnaire alone, but should also consider clinical examination, imaging findings, tumor–nerve relationship, and individual symptom patterns.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Well done!

Author Response

Thank you, we uploaded the revised Version with only a minor correction in the methods part.

Reviewer 2 Report

Comments and Suggestions for Authors

I can confirm the the authors revised the paper based on the major comments

Comments on the Quality of English Language

The English could be improved to more clearly express the research.

Author Response

Thank you, we uploaded the revised Version with only a minor correction in the methods part.