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Introduction

Malignant peripheral nerve sheath tumor (MPNST) is a rare, biologically aggressive subtype of soft tissue sarcomas (STS), accounting for 5–10% of all STS (1). It is a high-grade spindle-cell tumor originating from the peripheral nerve sheaths (2), with high malignancy and poor prognosis. A retrospective review from the Mayo Clinic Arizona by Stucky et al (3) indicated that high tumor grade and tumor size ≥50 mm predict undesirable disease-specific survival for MPNST. The incidence of MPNST is low, only 0.001% in the general population, with no gender predilection. Neurofibromatosis type 1 (NF1) is the most important risk factor, with ~10% of patients with NF1 developing MPNST during their lifetime (4). Furthermore, patients with prior radiation exposure also have a higher incidence of MPNST than the general population (5), and MPNST induced by radiation accounts for ~5% of all MPNSTs (6). MPNSTs can grow throughout the whole body, but most commonly occur in the extremities, the proximal parts of the trunk, as well as the head and neck (7). The occurrence of intrapulmonary MPNST is exceedingly minimal (8–12).

At present, there is still no standard treatment for MPNST. The existing treatment options are mostly based on the treatment of STS. Although surgery is the preferred treatment for MPNST, it's difficult to achieve extended or complete resection due to its high aggressiveness. The role of radiation, chemotherapy and targeted therapy for MPNST is still limited and uncertain (13). Programmed death 1 (PD-1)/programmed death-ligand 1 (PD-L1)-related immune checkpoint inhibitors (ICIs) as an emerging and promising cure have been proven to be effective for diversified cancer. However, due to the rarity of MPNST, there are few large-scale randomized controlled trials on the effectiveness of immunotherapy in MPNST.

The present study reported a case of intrapulmonary MPNST in an elderly man who received sintilimab and achieved a remarkable response. Compared with previous case reports of MPNST, this case has several particularities. First, it is worth noting that the primary location of MPNST in the lung is something of a rarity. Furthermore, this patient had no pulmonary symptoms but a large space-occupying lesion in the right upper lung lobe, which was found due to dizziness and lower limb fatigue by coincidence. Of note, single-agent immunotherapy was greatly effective in this patient with intrapulmonary MPNST who had not received any anti-tumor therapy in the past.

Case report

A 63-year-old man visited the Neurology Department of Zhongshan Hospital of Traditional Chinese Medicine (Zhongshan, China) in March 2023 with complaints of dizziness and weakness. The patient had no family history of NF1 and any other cancer. The patient had not received any radiotherapy. Computed tomography (CT) scans of the brain, chest and abdomen were ordered as parts of the examinations. Unexpectedly, the chest and abdominal CT examination showed a giant mass in the right upper lung lobe invading the adjacent chest wall and the third and fourth ribs, and its size was 91×70 mm. The primary consideration was malignancy. Multiple metastases were also found in both lungs, mediastinal lymph nodes, liver and bilateral iliac bone. A circular low-density mass with a size of 54×47 mm in liver segment 8, with blurred boundaries, was observed. No primary tumors were found in any other areas, so the large mass in the right upper lung lobe was considered to be the primary lesion. Various tumor markers were within the normal range. After being seen by an oncologist, the patient was referred to the Oncology Department of Zhongshan Hospital of Traditional Chinese Medicine (Zhongshan, China) and underwent a percutaneous lung puncture biopsy one week after the initial presentation. Examination of the histopathological image stained with hematoxylin and eosin according to a standard protocol indicated the following: The puncture tissue of the right lung mass showed a large amount of necrosis under the microscope, and the local cells were fusiform and oval (Fig. 1A-D). Tumor tissue was stained according to a standard immunohistochemical protocol (14). The final immunohistochemical results showed that the tumor stained positive for Vimentin (anti-Vimentin antibody: Cat. no. Kit-0019; MXB; pre-diluted) (data not shown), SOX10 (anti-SOX10 antibody: Cat. no. RMA-0726; MXB; pre-diluted) (data not shown), Ki-67 (20%) (anti-Ki67 antibody: Cat. no. RMA-0542; MXB; pre-diluted) (Fig. 1F), S-100 protein (anti-S-100 protein antibody: Cat. no. Kit-0007; MXB; pre-diluted) (Fig. 1G), histone H3 lysine 27 trimethylation (H3K27Me3) (anti-H3K27Me3 antibody: Cat. no. RMA-0843; MXB; pre-diluted) (Fig. 1H) and the tumor proportion score of PD-L1 (anti-PD-L1 antibody: Cat. no. HY-13421; DAKO; 1:50 dilution) was 60% (Fig. 1E). Taking into account these factors, this patient was finally diagnosed with primary intrapulmonary MPNST.

Figure 1. Histopathological and immunohistochemical results of malignant peripheral nerve sheath tumor in the right upper lung lobe. (A) Microscopic examination of the primary tumor in the right lung showed tumour cells that were comma-shaped, curved and short spindle-shaped, with some translucent cytoplasm. (B) The tumor cells were arranged in bundles and nuclear mitosis is visible in the pathological image. (C) Map-like necrosis of tumor cells was observed. (D) Certain tumor cells had obvious atypia and invaded the vascular wall (hematoxylin and eosin staining; magnification, ×200). (E) ~60% of tumor cells expressed PD-L1 at their cell membrane (original magnification, ×100). (F) Ki-67 was positive in 20% of tumor cells. (G) Positive staining for S-100 protein. (H) Positive staining for histone H3 lysine 27 trimethylation (original magnification, ×200). PD-L1, programmed death-ligand 1.

After the diagnosis, the patient refused to undergo surgery or chemotherapy. Considering that PD-L1 expression in 60% of tumor cells, it was decided to use pembrolizumab for treatment after reviewing relevant case reports. However, the patient refused to use pembrolizumab due to its high cost, and the more affordable sintilimab was started at a dose of 200 mg every 21 days in late April 2023. Initially, no immunotherapy-related adverse reactions (irAEs) occurred. After receiving the second course of sintilimab in late May 2023, the patient developed symptoms of generalized skin itching. Due to the irAEs, the patient did not proceed with the next course as scheduled. After symptomatic treatment, the patient stabilized and received the third course in August 2023. One week later, the patient developed symptoms of itching again and generalized erythema appeared. After treatment with antihistamines and glucocorticoids, the erythema gradually subsided. The patient was then treated with three further courses of sintilimab in October 2023, November 2023 and January 2024 without any grade 3 or higher irAEs. Sintilimab immunotherapy was scheduled to continue thereafter.

Throughout the immunotherapy period, the patient received a CT scan nearly every three months and each imaging review showed a significant clinical response. Specifically, the chest CT scan from July 2023 (i.e. after having received two courses of sintilimab) showed that the tumor in the right upper lung lobe and multiple metastases were significantly smaller than before. In October 2023 (i.e. after having received three courses of sintilimab), the patient's CT scan exhibited another regression of the tumor in the right upper lung lobe (40×30 mm). The latest chest CT scan in January 2024 (i.e. after having received five courses of sintilimab) revealed the tumor in the right upper lung lobe to be 34×24 mm and the mass in the right hepatic lobe had a diameter of 18 mm. A combination of CT images from all phases suggested marked partial remission of all measurable primary and metastatic lesions. CT manifestations of each metastatic lesion before and after immunotherapy are displayed in Fig. 2. The timeline of the complete treatment process and imaging of each stage are provided in Fig. 3. The long-term efficacy of sintilimab is still being observed in the patient by performing CT examinations every three months.

Figure 2. CT images of each metastatic lesion before and after sintilimab therapy. (A) Metastases in the right lung. (B) Metastases in the left lung. (C) Metastases in the right lower paratracheal lymph node. (D) Metastases in the right lower paratracheal lymph node. (E) Metastases in the liver. (F) Enlarged lymph nodes in the hepatogastric space. (G) Enlarged retroperitoneal lymph nodes. The red arrows indicate the specific location of each metastatic lesion in the CT images. CT, computed tomography.

Figure 3. Timeline of the complete treatment process and CT films. The upper CT image is the lung window and the lower CT image is the mediastinal window. The scale on the timeline is in years/months and cycles of sintilimab treatment are indicated with red arrows. CT, computed tomography.

Discussion

MPNST is an uncommon and growth-delayed tumor with high occultation. Its clinical manifestations have no specificity, and accordingly, early diagnosis of this disease is difficult. Some patients may experience rapidly increasing masses. They may also have corresponding motor and paresthesia neurological symptoms, which are often caused by advanced tumor compression of the nerve (15). However, certain patients may be asymptomatic.

MPNST may occur throughout the whole body, with the extremities and trunk as the most common sites, followed by deep soft tissues, retroperitoneum and mediastinum. However, it is rarely observed in the lung. Certain patients with intrapulmonary MPNST may present with chest pain, cough, hemoptysis and dyspnea because of compression of the intercostal nerve or trachea (7). However, the patient of the current study did not present with any pulmonary symptoms and was diagnosed with intrapulmonary MPNST when the tumor had already reached a considerable size. Before this case, there were already seven reported cases of pulmonary MPNST (8–12). Details of these cases are presented in Table I. The surgical treatment of intrapulmonary MPNST has been highlighted in previous cases, whereas this article is the first to report remarkable efficacy of sintilimab in the treatment of this rare malignancy. This is undoubtedly a reflection of the innovativeness of immunotherapy in treating this disease.

Table I. List of case reports of pulmonary malignant peripheral nerve sheath tumor.

Table I.

List of case reports of pulmonary malignant peripheral nerve sheath tumor.

Age, years/sex	Self-reported symptom	Position of metastasis tumor	Treatment	Adverse reactions	Outcome	(Refs.)
68/male	Visual disturbances, confusion	Liver, brain and	Imatinib 400 mg per day	General weakness preventing	•After five months of treatment,	(8)
	and headaches, multiple	vertebral body	in combination with	from walking and disturbance	the patient's neurological
	cutaneous neurofibromas all	of D3	cerebral radiotherapy	of consciousness one-and-half	symptoms improved and the
	over the body with the classic			months after the start of	tumor partially receded.
	light brown spots			treatment	•After 7 months of treatment,
					symptoms worsened and
					treatment was discontinued.
					The patient is now lost to
					follow-up
69/female	Recurring intensive hemoptysis	Lymph nodes of	•Upper left-sided	Postoperative worsening of	Died about two months after	(9)
	episodes, shortness of breath on	the chest and the	lobectomy	pain in the left half of the	surgery
	exertion, cough, retrosternal	lower lobe of the	•Radiotherapy	chest, shortness of breath
	pain and subfebrile temperature	left lung		and mucous cough
66/male	Dyspnea	No	Extrapleural right	•Postoperative delirium	Died 22 days after surgery	(10)
			pneumonectomy	•Fungal pneumonia
67/male	Dizziness, neck pain, nausea	Brain	•Craniotomy with the	No	Alive without any signs of	(10)
	and vomiting		removal of the tumor		recurrent disease with a
			and postoperative		follow-up of 4 months
			cranial radiotherapy
			•Video-assisted
			thoracoscopic surgery
			left upper lobectomy
			with mediastinal
			lymphadenectomy
42/female	Mild dyspnea	No	•Right upper lobectomy	No	Alive without tumor free with a	(10)
			and mediastinal lymph		follow-up of 55 months
			node dissection
			•Video-assisted thoraco-
			scopic surgery for the
			presence of a second
			tumor in the lingula
			portion of the left
			upper lobe
82/male	Chest pain	No	Left lower lobectomy	No	Alive without signs of	(11)
					recurrence with a follow-up
					of 2 years
33/female	Right chest pain	No	Debulking wedge	No	Alive without any recurrence	(12)
			resection
63/male	Dizziness and weakness in both	Mediastinal	Sintilimab 200 mg	Immune dermatitis	Marked partial remission	Curr-
	lower limbs	lymph nodes,	intravenously every		(sintilimab will continue to be	ent
		liver and	21 days for 6 cycles		used)	study
		bilateral iliac	(due to personal
		bone	reasons, treatment was not performed on the scheduled date)

The diagnosis of MPNST is one of the most difficult and elusive among STS. Its clinical manifestations, imaging features and histologic features are nonspecific, and thus, the clinical diagnosis relies on immunohistochemistry (15,16). The most studied immunohistochemical marker is S-100 protein. S-100 is usually weakly or patchily present in MPNST cases. S-100 expression may be present in 50–60% of MPNST tumor cells. Strong diffuse staining for S-100 nearly excludes a diagnosis of MPNST, except for epithelioid MPNST (17). At times, positive expression of SOX10, Ki-67, cytokeratin and glial fibrillary acidic protein may be found in MPNST tumor cells, but the diagnostic value of these immunohistochemical markers is limited (17–20). H3K27me3 is a new immunohistochemical marker for MPNST, which has better sensitivity and specificity than S-100. Approximately 80% of high-grade MPNSTs, 60% of intermediate-grade MPNSTs and 30% of low-grade MPNSTs showed loss of H3K27me3 expression (21). Several studies have assessed H3K27me3 in MPNST by immunohistochemistry and found that a subset of MPNST retained H3K27me3 expression (22–24). H3K27me3 loss is frequent in radiotherapy-related, NF1-related and sporadic MPNST, but it is less sensitive in low-grade and intermediate-grade tumors. Therefore, H3K27me3 loss, although more specific, is not a fully sensitive immunohistochemical marker.

At present, surgery remains the preferred treatment for MPNST. However, not all patients with MPNST can be treated with surgery (25). Whether MPNST can be resected or not mainly depends on the size of the tumor, the growth site of the tumor and the scope of nerve invasion of the tumor. Extensive local resection is more effective for MPNST involving distal extremities (26). However, for MPNST in the head, neck, chest and abdomen, it is difficult to achieve exact extensive resection because of tumors' proximity to vital organs, blood vessels and nerves. The local recurrence rate of MPNST following gross total resection is as high as 32–65% due to the limitations in the extent of resection and high aggressiveness of the tumor (13).

Radiotherapy is often used in conjunction with surgery to improve the local control rate of MPNST, but only has a minor effect on long-term survival and increases the risk of radiation-induced sarcoma (15,26). Chemotherapy regimens for MPNST are mostly based on STS. At present, the main first-line chemotherapeutic agents are doxorubicin and ifosfamide. When these two agents were used in combination to treat STS, the Response Evaluation Criteria in Solid Tumors (RECIST) response rate was ~25%; however, the RECIST response rate for MPNST was only 21% (27). Gemcitabine, docetaxel and etoposide can be used as second-line chemotherapeutic agents, but their efficacy is not optimal. There is insufficient data on the roles of radiotherapy and chemotherapy in MPNST management, and their roles remain controversial and uncertain. At present, radiotherapy and chemotherapy are still the main palliative treatments routinely used to alleviate local symptoms, due to the limited treatment options for MPNST.

With the deepening of the understanding of MPNST pathogenesis, certain clinical trials using targeted therapy blocking known signaling pathways that drive MPNST pathogenesis are underway (e.g. NCT05107037 and NCT02584647) or completed (e.g. NCT01661283 and NCT02008877). However, so far, existing research showed that the efficacy of targeted therapy for MPNST is also unsatisfactory (13).

PD-1 and PD-L1 can limit the killing effect of T cells on tumors and help avoid autoimmunity (28). Therefore, blocking PD-1/PD-L1 is an important method of tumor immunotherapy. PD-1/PD-L1-related ICIs are ideal tumor immunotherapy agents. Furthermore, PD-L1 expression by tumor cells has been identified as a predictive immunotherapy biomarker for the response to PD-1/PD-L1-related ICIs (29). Although vast information about the use of PD-1/PD-L1-related ICIs in treating common cancer has been published, limited data on the use of immunotherapy in MPNST and the expression of PD-L1 in MPNST are available. A study by Wang et al (30) described PD-1/PD-L1 axis-mediated immune escape mechanisms and revealed that PD-L1 is expressed in NF1- and NF2-associated tumors. A study by Farschtschi et al (31) showed that NF1 patients with MPNST had higher serum levels of PD-L1 compared with NF1 patients without MPNST and indicated that PD-L1 is upregulated in patients with MPNST. Another study by Liu et al (32) also proved PD-L1 expression in MPNST. Furthermore, prior to this case, there were four reports of patients with MPNST achieving significant remission after immunotherapy (33–36). Details of these cases are provided in Table II. Of these cases, three involved treatment with pembrolizumab, one after two courses combination of epirubicin, ifosfamide and mesna (33), one in combination with procarbazide (34), and one after surgical resection and radiation therapy (35). Furthermore, one case involved treatment with nivolumab plus radiation (36). Overall, significant remission was consistently seen in all five PD-L1-positive patients with MPNST treated with immunotherapy. These clinical studies and case reports supported the possibility of immunotherapy for MPNST and suggested immunotherapy as a promising treatment for MPNST that needs further exploration, particularly those ICIs aimed at inhibiting the PD-1/PD-L1 signaling axis.

Table II. List of case reports of malignant peripheral nerve sheath tumor treated with immunotherapy.

Table II.

List of case reports of malignant peripheral nerve sheath tumor treated with immunotherapy.

Age, years/sex	Location of primary tumor	Position of metastasis tumor	Previous treatment	Genetic change	PD-L1 expression (assay)	Immunotherapy	Outcome	(Refs.)
60/male	Primary	Left lower lobe,	•Left thoracotomy	Pathogenic	PD-L1 2+ 70%	•Pembrolizumab	Complete	(33)
	paravertebral	liver, peritoneum,	with resection of	mutations in	(IHC)	200 mg intra-	remission
	tumor at T7-T8	bone	the chest wall	ARID1A,		venously every
			tumor	CDKN2A,		21 days for
			•Two courses	KMT2A, NF1,		2 cycles
			combination of	and TP53		•Pembrolizumab
			epirubicin, ifos-			400 mg intra-
			famide and mesna			venously every
						21 days for
						4 cycles
48/male	Retroperitoneum	Mesentery	•Surgery	Not	PD-L1 90% (TPS)	Six courses of	Complete	(34)
			•Six courses of	available		pembrolizumab	response
			combination of			(200 mg
			doxorubicin and			intravenously
			ifosfamide			every 21 days)
			•Imatinib 400 mg			combined with
			per day			procarbazine
			•Six courses of			hydrochloride
			Eribulin			(50 mg/m2 twice
						a day)
22/male	Head and neck	Lung and pelvic	•Total gross	CDK6	PD-L1 2+ 5%	Pembrolizumab	Complete	(35)
	of femur	lymph node	resection with	amplification	(IHC)	200 mg	metabolic
			endoprosthesis			intravenously	response
			placement			every 21 days
			•Postoperative			for 21 cycles
			radiotherapy
45/male	Left calf	Lung and pleura	•Surgery	MED12, TP53,	PD-L1 100%	•Nivolumab	Complete	(36)
	(peroneal nerve)		•Five courses of	NF1, PLCG1	(IHC)	3 mg/kg	response
			doxorubicin	and EP300		intravenously
			chemotherapy	CD274/PD-L1		every 2 weeks
			•Two courses of	amplification		for 18 months
			ifosfamide			•Radiotherapy to
						the bilateral
						anterior pleural
						metastases
63/male	The right upper	Mediastinum,	No	Not available	PD-L1 60% (TPS)	Sintilimab	Marked	Current
	lung lobe	liver and bilateral				200 mg intra-	partial	case
		iliac bone				venously every	remission
						21 days for	(sintili-
						6 cycles (due to	mab will
						personal reasons,	be conti-
						treatment was	nued)
						not performed
						on the scheduled
						date)

[i] IHC, immunohistochemistry; TPS, tumor proportion score; PD-L1, programmed death-ligand 1; T, thoracic vertebra; ARID1A, AT rich interaction domain 1A; CDKN2A, cyclin-dependent kinase inhibitor 2A; KMT2A, lysine methyltransferase 2A; NF1, neurofibromatosis type 1; TP53, tumor protein 53; CDK6, cyclin-dependent kinase 6; MED12, mediator complex subunit 12; PLCG1, phospholipase C-g1; EP300, E1A-binding protein P300; CD274, cluster of differentiation 274.

Unlike the other four case reports, the patient with high PD-L1 expression in the present case had not received any prior anti-tumor therapy. The patient was treated with single-agent sintilimab without combining it with surgery, chemotherapy, radiotherapy or targeted therapy. For economic reasons, the patient chose the more affordable sintilimab instead of pembrolizumab. Sintilimab has been included in Chinese medical insurance in 2022, so it is more affordable than pembrolizumab, and the financial burden of patients is relatively small. Although previous case reports have reported on the use of pembrolizumab or nivolumab combined with chemotherapy or radiotherapy for MPNST, the efficacy of sintilimab alone was also excellent in this case. Pembrolizumab, nivolumab and sintilimab are humanized monoclonal IgG4 antibodies against PD-1. They can bind to PD-1 to block the connection of PD-1 with its ligands and impede inhibitory signals in T cells. While data from large-scale randomized clinical trials on the efficacy and safety immunotherapy for MPNST are scarce, several clinical trials on immunotherapy for MPNST are currently recruiting. Updated results of a phase II trial (NCT03611868) showed that alrizomadlin combined with pembrolizumab was well tolerated and demonstrated preliminary anti-tumor activity in an MPNST cohort with a 40% clinical benefit rate (37). A phase ІІ clinical trial (NCT02691026) is underway on the efficacy of pembrolizumab in patients with MPNST. There are also two ongoing clinical trials (NCT02834013 and NCT04465643) on the efficacy of nivolumab plus ipilimumab for MPNST (38,39). However, no clinical trial has been conducted on the efficacy and safety of sintilimab for MPNST, and it is necessary to perform this in the future.

The present study reported for the first time that sintilimab single-agent immunotherapy achieved a remarkable response of intrapulmonary MPNST. From this and previous cases, it may be speculated that single-agent immunotherapy may be a good choice of first-line treatment for MPNST in patients with high PD-L1 expression or in patients with an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 3–4 who cannot tolerate high-intensity chemotherapy. Immunotherapy in combination with chemotherapy may be a viable treatment option for MPNST in patients with low PD-L1 expression or in patients with an ECOG PS of 0–2. Rational combination of immunotherapy regimens may yield significant results. Additional prospective trials are still needed to confirm these preliminary results.

In conclusion, the case reported in the present study illustrates that PD-1/PD-L1-related ICIs may be an effective therapeutic method for patients with primary intrapulmonary MPNST with positive PD-L1 expression. Particularly for patients with high PD-L1 expression, a remarkable response may be achieved by using PD-1/PD-L1-related ICIs as first-line treatment. We are confident about the outlook of immunotherapy for MPNST and expect that the outcome of the ongoing clinical trials will contribute to the design of personalized immunotherapy.

Acknowledgements

Not applicable.

Funding

Funding: No funding was received.

Availability of data and materials

The data generated in the present study are included in the figures and/or tables of this article.

Authors' contributions

Manuscript writing, literature search and acquisition of data: YQC. Treatment and observation of the patient, study conception and design: TC. Manuscript drafting, aggregation of materials and analysis of data: WSZ, LZL and CTF. Manuscript revision, manuscript reviewing for intellectual content and interpretation of data: HTZ. All authors have read and approved the final manuscript. HTZ and YQC have confirm the authenticity of all the raw data.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Written informed consent was obtained from the patient to publish this report and any associated accompanying images.

Competing interests

The authors declare that they have no competing interests.

Glossary

Abbreviations

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References