Neurofibromatosis Type 1 Tumor Involving the Anterosuperior Mediastinum With a Rare c.147C>G Germline Mutation: A Case Report

ABSTRACT

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder that affects multiple organ systems, most commonly the skin, peripheral nerves, and skeletal system. However, involvement of the anterior mediastinum is rare and has been sporadically reported in the literature. Patients with NF1 have a markedly increased risk of developing malignant peripheral nerve sheath tumors (MPNSTs), which are associated with poor 5‐year survival outcomes; therefore, early diagnosis and timely intervention are essential to improving clinical outcomes. We report a case of a solitary neurofibroma located in the anterosuperior mediastinum of a 41‐year‐old male of Han ethnicity. The tumor was completely resected via uniportal video‐assisted thoracoscopic surgery (VATS). Immunohistochemical (IHC) analysis showed positivity for SOX10, S100, CD34, and vimentin, with a Ki‐67 proliferation index of < 1%. Genetic analysis of tumor tissue identified two heterozygous nonsense variants in the NF1 gene: c.147C>G (p.Tyr49Ter), a rare pathogenic variant, and c.1318C>T (p.Arg440Ter), a common pathogenic variant. Concurrently, next‐generation sequencing of the patient's son's blood sample revealed only the c.147C>G (p.Tyr49Ter) variant. No evidence of recurrence was observed during a 1‐year postoperative follow‐up. This case underscores the importance of a comprehensive, multidisciplinary approach in the evaluation of mediastinal masses to achieve an accurate diagnosis. Furthermore, it highlights the role of genetic testing in facilitating risk stratification and informing preventive strategies aimed at reducing the risk of progression from NF1 to MPNSTs.

Key Clinical Message

Diagnosing rare anterior mediastinal neurofibromas requires integrating histopathological and genetic findings. Identifying novel pathogenic NF1 germline mutations (e.g., c.147C>G) is crucial for accurate atypical mass diagnosis, enabling early familial screening, and guiding proactive malignant risk stratification.

1. Introduction

Neurofibromatosis type 1 (NF1), historically referred to as von Recklinghausen's disease, is a multisystem autosomal dominant genetic disorder with a global incidence of approximately 1 in 2500–3000 live births. NF1 is primarily characterized by neurocutaneous manifestations, including café‐au‐lait macules, Lisch nodules, and the development of multiple nervous system tumors. The molecular pathogenesis of NF1 involves loss‐of‐function mutations in the NF1 gene located on chromosome 17q11.2 [1]. This gene encodes neurofibromin, a key tumor suppressor that acts as a negative regulator of the Ras signaling pathway. Consequently, NF1 inactivation leads to hyperproliferation of neural crest–derived cells, resulting in the diverse clinical phenotypes observed in affected individuals [2]. In addition, patients with NF1 carry a substantially increased risk of developing MPNSTs, with epidemiological studies estimating a lifetime risk of approximately 8%–13% [3]. MPNSTs are aggressive soft‐tissue sarcomas of neural origin and represent a major cause of mortality among patients with NF1.

While mediastinal neurogenic tumors most commonly arise from the sympathetic chain or intercostal nerves in the posterior mediastinum, their occurrence in the anterior mediastinal compartment is atypical. Notably, mediastinal involvement in NF1 remains clinically rare, with no prior reports of tumors localized to the anterior mediastinum. Here, we present a case of a solitary NF1‐associated tumor in the anterosuperior mediastinum that was successfully managed using video‐assisted thoracoscopic surgery (VATS). Genetic analysis identified a rare NF1 variant (c.147C>G) in the tumor tissue, which was also detected in the patient's son, suggesting familial transmission. Given the hereditary nature and malignant potential of these tumors, accurate diagnosis and the implementation of appropriate preventive strategies are imperative.

2. Case Report

A 41‐year‐old male of Han ethnicity was admitted to the hospital after noticing a mass in the right upper mediastinum for the past two weeks. He was asymptomatic at presentation. No prior special treatment administered. Physical examination revealed multiple café‐au‐lait spots distributed over the chest, back, and shoulders, along with scattered superficial cutaneous nodules (Figure 1A). Lung auscultation revealed clear breath sounds bilaterally, without audible rales or wheezes. Family pedigree analysis showed that the patient's son inherited the c.147C>G mutation. Detailed clinical assessment of the patient's parents and two siblings revealed no café‐au‐lait spots, cutaneous nodules, or neurological deficits, and no history of neurofibromatosis‐related complications. Given that the patient's father died of liver cirrhosis without known cutaneous signs, it is highly probable that the patient's condition represents either a de novo germline mutation in his generation or an inherited trait from a parent with minimal clinical expression (variable expressivity). This highlights the clinical challenge where genetic testing is often more reliable than physical examination for screening asymptomatic family members.

FIGURE 1.

(A) Extensive distribution of café‐au‐lait spots on the head, neck, lower back, abdomen, and back. (B) Subcutaneous nodular abnormal signal located in the cervical region. (C) Cranial bone destruction located in the scalp vertex. (D) Soft tissue mass on top of the skull (vertex region).

Routine laboratory investigations, including complete blood count, erythrocyte sedimentation rate, hepatic and renal function tests, blood glucose, urinalysis, and stool analysis, were within normal limits. Chest computed tomography (CT) demonstrated a well‐defined, lobulated, low‐density mass measuring approximately 7 × 5 cm in the right upper mediastinum. The superior extent of the mass reached the thoracic inlet and root of the neck. The mass was adjacent to the right subclavian artery, right innominate vein, the proximal segment of the right phrenic nerve, and the cervical sympathetic plexus. The lesion demonstrated no significant enhancement on contrast‐enhanced imaging (Figure 2A–D). Cranial magnetic resonance imaging (MRI) revealed several punctate foci that were isointense on T1‐ and T2‐weighted sequences and hyperintense on T2‐FLAIR images in the periventricular white matter. Additionally, abnormal signal intensity was observed in the soft tissues of the scalp vertex, accompanied by adjacent bony erosion (Figure 1C,D). Multiple subcutaneous nodules were also identified in the cervical, thoracic, and lumbar regions (Figure 1B).

FIGURE 2.

(A–D) Chest CT scan reveals a lesion located in the right anterosuperior mediastinum, demonstrating a close relationship with adjacent vessels and showing the presence of tumor‐feeding vessels.

3. Surgical Procedure

Given the anatomical location of the lesion, a uniportal VATS approach was planned. The patient was placed in the left lateral decubitus position with the right side elevated at approximately 45°. A 5‐cm single utility incision was made in the right fourth intercostal space along the anterior axillary line. Intraoperative findings revealed a well‐circumscribed mass measuring approximately 7 cm, located beneath the mediastinal pleura in the anterosuperior compartment. After incising the mediastinal pleura, the lesion was meticulously dissected. The superior pole of the tumor extended to the thoracic inlet and lay in close proximity to the right brachiocephalic vein and right subclavian artery. Anteriorly, the superior pole was adjacent to the course of the right phrenic nerve as it entered the mediastinal pleura. Posteriorly, it was adjacent to the inferior portion of the cervical sympathetic chain and the segment of the vagus nerve entering the thoracic inlet. Medially, the tumor was related to the superior vena cava and the upper trachea. The tumor exhibited a bilobed (“dumbbell” or “hourglass”) configuration with expansive growth within the right anterosuperior mediastinum. Although the capsule was intact, the mass showed close adherence to surrounding structures. Most of the dissection was performed bluntly; however, areas of adhesion and fibrous bands required sharp dissection. Exposure of the superior pole was somewhat limited using the single‐port approach (Figure 3A). Using a combination of sharp and blunt dissection techniques, the tumor was carefully freed from its attachments, with particular attention paid to preserving the superior vena cava, thoracic duct tributaries, and the right phrenic nerve. The feeding vessels were ligated and divided, allowing complete en bloc resection of the tumor (Figure 3B).

FIGURE 3.

(A) Intraoperative view demonstrating the proximity of the tumor to adjacent structures. (B) Intraoperative dissection and isolation of the tumor mass. (C, D) The resected tumor specimen, measuring approximately 7.5 × 5 × 3 cm, exhibits a pale yellow color, firm consistency, and a characteristic bilobed (“dumbbell‐shaped”) configuration.

4. Pathological Findings

Gross examination revealed a resected specimen measuring 7.5 × 5 × 3 cm. The specimen was firm, tan‐yellow in color, and exhibited a characteristic bilobed (“dumbbell” or “hourglass”) morphology (Figure 3C,D). Microscopic examination revealed a proliferation of spindle‐ to oval‐shaped Schwann cells with elongated, tapered nuclei, fine chromatin, and inconspicuous nucleoli. The tumor cells were arranged in interlacing fascicles, whorls, and wave‐like patterns within a collagenous stroma (Figure 4A). IHC showed diffuse positivity of the tumor cells for S‐100 (Figure 4B), vimentin (Figure 4C), SOX10 (Figure 4D), and CD34 (Figure 4F), with a low Ki‐67 proliferation index of < 1% (Figure 4E). The tumor cells were negative for STAT6, desmin, smooth muscle actin (SMA), and epithelial membrane antigen (EMA). Special stains: Elastic staining was negative. Clinical diagnosis: neurofibromatosis.

FIGURE 4.

(A) Histopathology (H&E staining, × 200) reveals spindle or oval‐shaped Schwann cells with elongated, tapered nuclei, fine chromatin, and inconspicuous nucleoli, arranged in interlacing wavy or whorled patterns amidst collagen fibers. (B) IHC demonstrates strong nuclear expression of S‐100 protein (brown staining) in the spindle‐shaped Schwann cells (S100, × 200). (C) IHC shows diffuse cytoplasmic positivity for Vimentin (brown staining) (Vimentin, × 200). (D) IHC reveals positive nuclear staining for SOX10 (brown) in the spindle cells (SOX10, × 200). (E) IHC for Ki‐67 shows sparse and scattered positive staining (brown‐yellow nuclei), with a low proliferative index of less than 1% (Ki‐67, × 200). (F) IHC shows positive staining for CD34 (CD34, × 200).

5. Genetic Sequencing

Next‐generation sequencing (NGS) was performed on the patient's tumor tissue. Sequencing reads were aligned to the human reference genome (hg19) using BWA‐MEM, and single nucleotide variants (SNVs) and insertions/deletions (indels) were analyzed using the Sentieon pipeline. Variant annotation and pathogenicity assessment were performed by cross‐referencing databases, including ANNOVAR, ClinVar, InterVar, and COSMIC. Analysis of tumor tissue: NGS of the tumor specimen identified two heterozygous nonsense variants in the NF1 gene: a cytosine‐to‐guanine substitution at position 147 in exon 2 (c.147C>G, p.Tyr49Ter) with a variant allele frequency (VAF) of 46.6% (Figure 5A), and a cytosine‐to‐thymine substitution at position 1318 in exon 12 (c.1318C>T, p.Arg440Ter) with a VAF of 9.3% Figure 5 which are predicted to generate premature termination codons, resulting in loss of protein function. According to ACMG guidelines, both variants are classified as pathogenic. Familial genetic testing and validation: Given that the patient's 2‐year‐old son also exhibited clinical signs of NF1, NGS was performed on peripheral blood samples from the patient, his son, and his wife, followed by Sanger sequencing confirmation. Sanger sequencing confirmed that both the patient (Figure 6A) and his son (Figure 6B) carried the germline NF1 c.147C>G (p.Tyr49Ter) variant, whereas the c.1318C>T (p.Arg440Ter) variant was absent in their blood‐derived DNA. No pathogenic NF1 variants were detected in the wife's sample (Figure 6C).

FIGURE 5.

Analysis plot of the patient's genetic sequencing data.

FIGURE 6.

(A) Sanger sequencing validation result of the genetic testing performed on the patient's blood sample, confirming the presence of the c.147C>G mutation. (B) Sanger sequencing validation result of the genetic testing performed on the patient's son's blood sample, confirming the presence of the c.147C>G mutation. (C) Sanger sequencing validation result of the genetic testing performed on the patient's wife.

6. Postoperative Course and Follow‐Up

On postoperative day 1, the patient developed right‐sided ptosis, miosis, and facial anhidrosis, consistent with Horner syndrome. This was attributed to intraoperative traction, and possibly minor injury, to the inferior cervical sympathetic chain and stellate ganglion. The patient was treated with mecobalamin (0.5 mg orally, three times daily).

The symptoms gradually resolved over two months. Complete resolution of Horner syndrome was confirmed at the three‐month follow‐up, supporting the initial impression of neuropraxia caused by traction rather than sharp transection.

A follow‐up chest CT at one year postoperatively demonstrated satisfactory healing at the surgical site, with no evidence of residual or recurrent tumor (Figure 7). The patient remained in good clinical condition and reported no significant symptoms.

FIGURE 7.

One‐year postoperative follow‐up examination (compared with Figure 2), demonstrating complete tumor resection with no evidence of recurrence at the tumor bed.

7. Discussion

NF1 can affect the skin, deep tissues, and visceral organs. Approximately half of NF1 cases are familial, while the remainder arise from de novo mutations [4]. The pathogenesis is driven by mutations in the NF1 gene, a tumor suppressor located on chromosome 17q11.2 that encodes neurofibromin. Neurofibromin is predominantly expressed in neurons and astrocytes of the central nervous system, as well as in Schwann cells of the peripheral nervous system [5], and functions as a negative regulator of the RAS‐MAPK signaling pathway.

Neurofibromin has a complex domain architecture, including N‐terminal HEAT/ARM repeats, a central GTPase‐activating protein (GAP)‐related domain (GRD), a Sec14‐PH domain, a central dimerization module (CDM), and a C‐terminal domain. The GRD represents the key functional region, responsible for neurofibromin's RAS‐GTPase activating activity [6]. Under physiological conditions, neurofibromin stimulates RAS GTPase activity through its GRD, catalyzing the hydrolysis of active GTP‐bound RAS to the inactive GDP‐bound form, thereby terminating RAS‐mediated signaling [6]. Consequently, loss of neurofibromin function elevates RAS‐GTP levels, resulting in constitutive activation of the downstream MAPK cascade, including the RAF–MEK–ERK pathway [7]. This aberrant signaling promotes hyperproliferation of neural crest‐derived cells, ultimately driving tumorigenesis.

In the present case, both identified mutations generate premature termination codons and are predicted to result in complete loss of neurofibromin function. The p.Tyr49Ter mutation, located in the N‐terminal region, introduces translational termination at tyrosine 49, producing a severely truncated protein of only 48 amino acids. Because all major functional domains—including the critical GAP‐related domain (GRD)—are situated downstream of this site, the mutation abolishes neurofibromin's RAS‐GTPase regulatory function. Similarly, the p.Arg440Ter mutation in exon 12 causes termination at arginine 440, upstream of the GRD, resulting in a truncated protein that lacks the entire GRD and all C‐terminal domains. Consequently, both variants disrupt neurofibromin‐mediated negative regulation of the RAS/MAPK pathway, promoting unregulated cell proliferation characteristic of neurofibroma formation.

Next‐generation sequencing of the tumor tissue confirmed the presence of these heterozygous nonsense variants: c.147C>G (p.Tyr49Ter) in exon 2 with a variant allele frequency (VAF) of 46.6% (Figure 5A), and c.1318C>T (p.Arg440Ter) in exon 12 with a VAF of 9.3% (Figure 5B). Both mutations are classified as pathogenic according to ACMG guidelines. The c.147C>G variant is rare, with only sporadic reports in NF1 cases [8, 9] and, to our knowledge, has not been previously described in a mediastinal neurofibroma, this is the first report of the c.147C>G mutation in the context of an anterior mediastinal neurofibroma. In contrast, the c.1318C>T variant is a relatively common pathogenic mutation reported in individuals with NF1 [9, 10]. These findings highlight the potential for both novel and recurrent NF1 mutations to contribute to tumor development in atypical anatomical locations.

Genetic testing of the patient's son confirmed inheritance of the paternal NF1 germline mutation c.147C>G (p.Tyr49Ter), whereas the c.1318C>T variant was not detected. These findings establish c.147C>G as the familial pathogenic mutation. In the patient's tumor, the coexistence of two pathogenic mutations—the germline c.147C>G and the likely somatic c.1318C>T—supports Knudson's “two‐hit” hypothesis for tumor suppressor genes [11]. Literature review of the c.147C>G (p.Tyr49Ter) variant (rs1597626026) identified only two previous reports [8, 9]. Moreover, this case constitutes the first documented instance of NF1 involving the anterior mediastinum.

The diagnostic criteria for NF1 were first established by the National Institutes of Health (NIH) in 1987 [12] and updated in 2021 [13]. According to the updated guidelines, a diagnosis can be made in individuals with an affected parent and at least one additional diagnostic criterion. In the present case, the patient exhibited classic cutaneous features, including café‐au‐lait macules. Imaging studies demonstrated characteristic findings, including a soft tissue mass with adjacent calvarial erosion, punctate periventricular white matter lesions (isointense on T1‐weighted and hyperintense on T2‐FLAIR sequences), and multiple subcutaneous nodules across the cervical, thoracic, and lumbar regions. These clinical and radiological features are consistent with a diagnosis of NF1. Consequently, the mediastinal mass was interpreted within the spectrum of NF1‐associated manifestations during the diagnostic workup, prompting a comprehensive multidisciplinary evaluation.

Mediastinal involvement in neurofibromatosis is often incidentally detected as a mediastinal mass during routine examinations and is typically asymptomatic. However, some patients may present with dyspnea or restrictive respiratory dysfunction due to mass effect [14]. Involvement of the phrenic or recurrent laryngeal nerves can result in respiratory muscle paralysis or vocal cord palsy, respectively [15]. Although the patient in this report was asymptomatic, the tumor's close proximity to critical structures—including the brachiocephalic vein, subclavian artery, recurrent laryngeal nerve, and phrenic nerve—necessitated surgical intervention to prevent potential invasion and neurological compromise.

Given the tumor's adjacency to the inferior portion of the cervical sympathetic plexus near the stellate ganglion and the somewhat limited superior exposure afforded by the uniportal fourth intercostal approach, the patient developed Horner syndrome on the first postoperative day. The symptoms resolved completely after several months of neurotrophic therapy, highlighting the intimate anatomical relationship between the tumor and the sympathetic plexus. This experience underscores several key considerations in managing anterior mediastinal neurofibromas, which frequently originate from adjacent major nerve trunks or their branches: (1) comprehensive preoperative imaging is essential to delineate the tumor's relationship to potential nerves of origin; (2) surgical incision should be individualized to optimize exposure while maintaining a minimally invasive approach; and (3) meticulous dissection is required to avoid injury to major vessels in the anterosuperior mediastinum and to preserve involved nerve trunks or critical branches, which is vital for maintaining long‐term function and quality of life.

Surgical resection remains the primary therapeutic modality for mediastinal neurofibromas. In addition, MEK inhibitors, such as selumetinib, have emerged as first‐line systemic treatment for inoperable, symptomatic plexiform neurofibromas in NF1 by inhibiting the constitutively active RAS‐MAPK signaling pathway, thereby exerting antitumor effects [16]. Other targeted agents—including mTOR inhibitors (e.g., sirolimus), c‐KIT inhibitors (e.g., imatinib), and multikinase inhibitors (e.g., nilotinib)—have also been investigated, primarily to block pathways such as mTOR and suppress tumor cell proliferation and angiogenesis [17]. Preclinical and clinical evidence suggests that combining a MEK inhibitor with an mTOR inhibitor can produce synergistic antitumor effects in NF1‐deficient tumor cells [18], while combination with a VEGFR inhibitor may enhance efficacy through more potent antiangiogenic activity [19].

This case highlights the critical role of a multidisciplinary approach in managing complex NF1‐associated tumors. Preoperative collaboration between radiology and thoracic surgery enabled precise assessment of the tumor's proximity to the right subclavian artery and phrenic nerve, facilitating the selection of an optimal uniportal VATS strategy. Integration of next‐generation sequencing data through genetic counseling and molecular pathology not only confirmed the diagnosis but also allowed for accurate counseling regarding recurrence and inheritance risk. Furthermore, the timely recognition and management of Horner syndrome by the neurology and surgical teams, including neurotrophic therapy, resulted in complete resolution, emphasizing that an MDT approach extends beyond surgical planning to encompass long‐term monitoring and management of treatment‐related complications. Collectively, these findings underscore the necessity of coordinated multidisciplinary care in optimizing both short‐ and long‐term outcomes for NF1 patients.

8. Conclusion

We present a rare anterosuperior mediastinal solitary neurofibroma successfully resected by uniportal VATS without recurrence. Benign histologic features together with identification of NF1 nonsense variants confirmed the genetic basis and suggested a potential hereditary component, indicating that accurate characterization of mediastinal neurogenic tumors requires integration of clinical, pathological, and molecular findings rather than imaging alone. Genetic testing further enables diagnostic confirmation, risk stratification, and family counseling, particularly for assessing the risk of malignant peripheral nerve sheath tumors. Overall, a multidisciplinary strategy combined with minimally invasive surgery may optimize management and facilitate early preventive intervention in NF1‐associated mediastinal disease.

Author Contributions

Yuhao Qi: writing – review and editing, writing – original draft. Zhaokun Sun: writing – review and editing, resources. Jianhua Du: resources, writing – review and editing. Jun Li: funding acquisition, methodology, supervision, writing – review and editing. Shenghai Wang: writing – review and editing, resources.

Funding

The authors have nothing to report.

Ethics Statement

Ethical review and formal approval were waived by Ethics Committee of Shandong Provincial Hospital Affiliated to Shandong First Medical University since this is a case report.

Consent

Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor‐in‐Chief of this journal.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.