Five cases report and literature review of malignant peripheral nerve sheath tumor

Abstract

Rationale

Malignant Peripheral Nerve Sheath Tumor (MPNST) is an aggressive soft tissue sarcoma with limited therapeutic options and a poor prognosis. Its occurrence is closely related to genetic factors, and it is associated with Neurofibromatosis type I (NF1) in about 50% of cases. The overall incidence ranges from 3% to 10%, and it has been on the rise in recent years.

Methods

Retrospectively analyze the age of onset, tumor site, tumor size, metastasis, treatment plan, and prognosis of MPNST patients admitted to The First Affiliated Hospital of Henan Medical University from January 2018 to January 2022.

Results

In the past 5 years, 5 patients with MPNST aged 20–64 years were admitted to our center, including 2 males and 3 females. As of our writing of this manuscript: Of the 4 patients who underwent surgery, Case 1 patient died due to severe complications with overall survival of 11 months, Cases 2 and 4 patients are still alive with overall survival of 68 and 42 months, respectively, Case 5 patient with combined NF1 with overall survival of 18 months, and the patient in Case 3 patient was found to be inoperable due to the evaluation of condition at the time of discovery, but survived after systemic treatment with an overall survival of 45 months. All surviving patients continue to be followed up.

Conclusion

We described the clinical features, treatment, and clinical outcomes of 5 cases of MPNST, including one case of MPNST with NF1 gene mutation. This provides valuable clinical experience for the treatment of this rare tumor.

Introduction

Malignant peripheral nerve sheath tumor (MPNST) is a rare malignant tumor that originates from the peripheral nerve or shows different differentiation of the nerve sheath, accounting for about 2–10% of all soft tissue sarcomas and less than 1% of all malignancies [1]. The overall prognosis of MPNST is poor, with 5-year and 10-year survival rates of 34%-52% and 23%-34%, local recurrence rates of 40%-65%, and distant metastasis rates of 40%-68% [2]. NF1 is a negative regulatory factor that regulates cell proliferation and signal transduction, mainly negatively regulating the Ras/MAPK signaling pathway. Notably, approximately more than 1/3 of MPNST patients have combined NF1, and relevant data show that this group has the worst prognosis, and that the 5-year survival rate is significantly lower than that of patients with other malignant peripheral neurinoma [3]. Although total surgical resection is the mainstay of treatment for MPNST, the large size of the tumor, early metastasis, and proximity to nerves impose limitations on surgical resection, which results in a poor prognosis for patients who cannot be extensively resected intraoperatively. Although chemotherapy and radiotherapy are available for unresected and high-risk MPNST, the overall treatment options are limited [4–7], and there are no FDA-approved drugs for MPNST, which poses a great threat to the patient’s life and quality of life. In this paper, we retrospectively analyzed the treatment of five cases of MPNST in our center, which provided clinical experience for this disease.

Result

This study included 5 patients with MPNST (2 males, 3 females). The age range at onset was 20 to 64 years, and the tumor size ranged from 11 to 50 mm. All patients underwent lesion biopsy, confirming MPNST diagnosis. Immunohistochemical (IHC) analysis demonstrated positive reactions for the central nervous system-specific protein (S-100) and the sex-determining Y-chromosome framework protein 10 (SOX-10) in all patients (Table 1). Hematoxylin-eosin (HE) staining images from patients revealed that in NF1-associated MPNST (Figure E), neurofibromatous components typically exhibited spindle cells arranged in wavy or whorled patterns, sparse mucinous stroma, high cellular density, marked nuclear atypia, and pleomorphic/giant cells within the background. In contrast, these features were absent in the remaining NF1-negative MPNST cases (Figures A, B, C, and D) (Fig. 1). Imaging evaluation revealed varied lesion locations across patients, predominantly involving deep soft tissues of the trunk and extremities, particularly concentrated in nerve trunk regions of the upper and lower limbs. Two patients presented with pain symptoms, while three exhibited painless masses (Table 2).

Table 1.

Pathology of 5 patients

Patient	S-100	P53	Ki-67	EMA	Leu-7	SOX-10	Vimentin	CD34	Bc1-2	GFAP	SMA
Case 1	+	+	+, 20%	-	-	+	/	-	-	-	/
Case 2	+	-	+, 30%	+	/	+	+	+	-	/	-
Case 3	+	+	+, 25%	-	-	+	+	-	/	-	-
Case 4	+	-	+, 50%	/	-	+	+	+	/	/	-
Case 5	+	-	+, 50%	-	+	+	+	-	+	-	-

Fig. 1.

A, B, C, and D show HE (blood smear-eosin stain) staining of four patients with MPNST without NF1, while Figure E shows HE staining of a patient with MPNST with NF1 (magnification of pathologic sections in Figures A, B, D, and E: 10 × 10; magnification in Figure C: 5 × 10)

Table 2.

Clinical information of 5 patients

Patient	Sex (M/F)	Age(Years)	Site of disease	Symptoms	Tumor diameter(mm)	Stage
Case 1	M	64	Left C6-7 nerve root	Pain and limited movement in the left upper limb	22.4 × 21.2 × 17.7	Limited-stage
Case 2	F	35	Skin of right lower limb	Skin ulcer with intermittent localized pain	17.0 × 15.8 × 11.0	Limited-stage
Case 3	F	20	Multiple bone metastases and lumbar 5 left nerve root invasion	lumbago	28 × 22 × 20	Stage IV
Case 4	F	52	Parotid gland	Localized swelling and pain	21.3 × 19.4 × 18.9	Limited-stage
Case 5	M	25	Lumbar skin	Localized pain	80 × 70 × 50	Limited-stage

The limited stage of MPNST is defined as a tumor that has not invaded beyond the primary anatomical region and shows no evidence of metastasis (T1–2, N0, M0)

In case 1, the patient’s first primary tumor was nasopharyngeal carcinoma, which did not recur after radical surgery and was periodically reviewed for complete remission (CR), and then the patient developed MPNST as a new second primary tumor, which was located in the left C6-7 nerve root, and it did not recur after surgical complete resection; however, due to immunocompromise, the patient eventually died of respiratory failure due to infection with a novel coronavirus pneumonia with a survival time of 11 months. In case 2, the patient’s lesion was located in the skin of the right lower extremity. 2 years after surgical excision, the lesion recurred locally and survived another surgical excision to the present day, with a current total survival time of more than 68 months. In case 3, the patient’s lesion was located in the lumbar spine, which was inoperable due to metastasis at the time of diagnosis, and received 11 cycles of systemic therapy with “sintilimab + anlotinib” with an stable disease (SD) rating, and developed persistent pain at the 5th lumbar vertebrae and slight numbness of the left lower extremity 1 year ago, and palliative radiotherapy was given to the T8 vertebral body in conjunction with the guidelines, with the current overall survival time of over 45 months or more. The patient in case 4 had a parotid gland site and survived surgical complete resection, with no recurrence on regular follow-ups, and is now surviving for a total of more than 42 months. In case 5, NF1 appeared in the lumbar region 20 years before the onset of the disease, and clinical cure was achieved after surgical resection. Four years ago, a painless skin mass in the lumbar region was found, with a size of about 35 mm × 20 mm × 15 mm, which was not treated at that time, and then the mass rapidly enlarged to 80 mm × 70 mm × 50 mm, and adjuvant radiotherapy was carried out after complete resection, and regular out-of-hospital review was performed to evaluate the SD. After 2 years, the patient’s review images showed progressive disease (PD) with local recurrence and lung metastasis, and the patient then received a first-line treatment regimen of “anlotinib + epirubicin” for 2 cycles. Two cycles later, the review showed enlargement of lung metastasis and chest pain, and he was replaced with “anlotinib + sintilimab”second-line regimen for 5 cycles, and palliative radiotherapy was also performed on the lung metastases to treat the symptoms of chest pain. Unfortunately, however, after 6 months, the patient passed away due to tumor overload with an overall survival of 18 months (Fig. 2) (Table 3).

Fig. 2.

Figures A, B, C, D, and E show the preoperative images of cases 1, 2, 3, 4, and 5, respectively. Among these, Figure D is a CT image, while the remaining figures (A, B, C, and E) are MRI images.

Table 3.

Treatment and prognosis of 5 patients

Patient	Radiotherapy dose	Systemic therapy	Evaluation of the efficacy of treatment	Relapse and metastasis	Backline treatment	Clinical outcome	Comorbidities	Survival (months)
Case 1	-	-	CR	-	-	Death/respiratory failure	Nasopharyngeal carcinoma/CR	11
Case 2	-	-	PD	-	Surgery	Survive	-	68+
Case 3	-	Sintilimab + Anlotinib for 11 cycles	SD	-	T8 vertebral palliative radiotherapy	Survive	Chickenpox/cure	45+
Case 4	-	-	CR	-	-	Survive	-	42+
Case 5	50 Gy/25F	-	PD	Lung	First line: 2 cycles of anlotinib + epirubicin Radiotherapy for lung metastases 45 Gy/15F Second-line: 5 cycles of anlotinib + sintilimab	Death/tumor load	NF1/cure	18

The “+” sign in the table indicates that the process is still ongoing

Discussion

MPNST is a rare malignant tumor originating from peripheral nerves or displaying nerve sheath differentiation, which is prevalent in the trunk of the limbs and neck and is usually characterized by a painless mass as the first symptom, which is often accompanied by pain when the tumor invades the nerves or metastasizes, or may be characterized by localized pain as the first symptom [8]. According to statistics, the median age of onset of MPNST is 37 years old, and about 1/3 of patients are combined with NF1, and the presence of NF1 often suggests a poor prognosis, which will greatly increase the surgical recurrence and metastasis rates, while the most common site of metastasis is the lung, and the others are tissues and organs, such as the liver, bone, and the brain [9]. In addition, the maximum diameter of the tumor >5 cm and the extent of surgical resection are now considered to be the direct factors affecting the five-year survival rate of patients, and postoperative adjuvant radiotherapy does not affect the overall survival rate, although it may increase the tumor-free survival rate [10]. In this report, we collected one patient with MPNST secondary to NF1 who had an overall survival of only 18 months. In contrast, except for the first patient who died of complications of respiratory failure, the three patients with MPNST not secondary to NF1 and with tumors less than 5 cm in length had significantly higher overall survival of at least 42–68 months.

Given the limitations of MPNST treatment, proteomics and genomics are receiving more and more attention in MPNST research to open up new fields in finding therapeutic targets, developing novel drugs, and judging prognosis. Currently, it has been found that the development of MPNST is mainly related to signaling pathways such as p53, RB1, PI3K-Akt-mTOR, RAS-ERK, and Wnt. Histological studies have shown that tumors originating from neuronal or Schwann cells often express S-100, GFAP, CD 57, and myelin basic protein [11]. Comparative analysis with this revealed the presence of several specific molecular markers in MPNST, such as SOX10 and adrenomedullin [11, 12]. Regarding the molecular markers that determine the prognosis of MPNST patients, many studies have shown S-100 protein negativity [11] and hyaluronic acid positivity [13]. MDM2 and P53 protein positivity [14], inactivation of P14, P15, and P16 proteins [15], HIF-1α protein positivity [16], high expression of ENG [17], and high expression of RRM2 [18] suggests a poor prognosis, whereas high expression of FGFR-1 protein [19] and low expression of PTEN protein [20] suggested a better prognosis. In our case, 5 patients were positive for SOX10 protein, with a 100% positive rate. 3 cases had a strong positive expression of S-100 protein, and 2 cases had a weak positive expression, suggesting a better prognosis; however, due to the combination of severe complications, oversized tumors, and secondary to NF1, the prognosis of 2 of these cases was significantly poorer.

Overall, the therapeutic means for MPNST are still very limited. Although proteomic and genomic targets for MPNST are under constant research, there is no application of targeted drugs for MPNST in clinical work, and traditional radiotherapy and chemotherapy have not achieved significant results. We hope that this report will provide some therapeutic experiences and insights for the treatment of MPNST, to help more MPNST patients.

Conclusion

In conclusion, we share the detailed treatment history, pathology, and outcome of five MPNST patients, and we also discuss the correlation between pathological findings and prognosis at the molecular level for patients with MPNST, emphasizing the need for more targeted and aggressive therapeutic strategies to improve the prognosis of patients with MPNST. Of course, our report has the limitation of a small sample size, and larger samples are needed to conduct studies to improve the survival and quality of life of all MPNST patients.

Author contributions

The first draft of the manuscript was written by X. W. and Y. Z., who were co-first authors. Data curation was performed by X. L. Formal analysis was performed by Q. Z. and Q. Y.; writing – review and editing was performed by M. Z.and P. L. All authors reviewed the manuscript.

Funding

This manuscript received no external funding.

Data availability

The original contributions presented in the study are included in the article Material, further inquiries can be directed to the corresponding authors.

Declarations

Ethics approval and consent to participate

This study is a retrospective multi-case analysis based on clinically acquired data. Only case data were analyzed and summarized.” Exempted by the Ethics Committee of The First Affiliated Hospital of Henan Medical University, this study did not involve human or animal experiments requiring ethical review. Written informed consent was obtained from patients permitting the publication of this case report and related imaging materials. All research subjects signed written informed consent forms prior to inclusion in the study.

Patient perspective

Written informed consent from the patient for the use of figure and publication of their case details has been obtained by the authors.

Competing interests

The authors declare no competing interests.