Surgical Management of Intrathoracic Triton Tumors: Insights into Emerging Molecular and Epigenetic Mechanisms with a Case Series of Three Patients

Abstract

Malignant Triton Tumors (MTTs) are rare, high-grade malignant peripheral nerve sheath tumors (MPNSTs) frequently associated with Type 1 Neurofibromatosis (NF1). NF1, an autosomal dominant disorder, predisposes approximately 10% of affected individuals to developing MPNSTs, with 50% of these tumors occurring in NF1 patients, while others arise sporadically or in association with radiation exposure. MTTs predominantly affect anatomical regions rich in large nerves, such as the limbs, spinal root, and cranial nerves. Mediastinal presentations are exceedingly rare, posing significant diagnostic and therapeutic challenges. Current treatment strategies include surgical resection, chemotherapy, radiotherapy, and lung-sparing procedures for metastatic disease. Molecular studies of MPNSTs have revealed that NF1 mutations lead to dysregulation of the RAS signalling pathway, while epigenetic alterations (e.g., SUZ12/EED mutations) further contribute to tumor progression. Dysregulated phylogenetically conserved pathways, including Wnt/beta-catenin and non-canonical SHH signalling, play a role in sarcoma progression and Schwann cell transformation. Recent advances in miRNA research highlight their involvement in tumor invasion and progression, with dysregulated miRNA expression and chromatin remodeling contributing to the pathogenesis of these neoplasms. However, the distinct molecular profiles for MTTs remain incompletely understood. Further investigation of the genetic and epigenetic landscape is essential for improving our understanding and identifying potential therapies. Herein, we present a single-center retrospective case series of three patients with an intrathoracic triton tumor treated at our University Hospital between 2000 and 2024, serving as a starting point for future insights into MPNST pathobiology.

1. Introduction

Malignant Triton Tumors (MTTs) are a high-grade malignant peripheral nerve sheath tumor (MPNST) characterized by skeletal muscle-like differentiation. MTTs arise along the course of a nerve, often in patients affected by Type 1 Neurofibromatosis (von Recklinghausen disease), and they are characterized by a dual population of Schwann-like cells and rhabdomyoblasts. They present a significant diagnostic challenge, as their histopathological features overlap with other high-grade sarcomas, including rhabdomyosarcomas and conventional MPNSTs. Immunohistochemistry and expert histopathological evaluation are essential for accurate diagnosis [1].

MTTs are generally localized along the course of nerves and plexuses, but rare sites of involvement, such as the brain, have also been reported [2]. Like other types of sarcomas, MTTs show aggressive clinical behavior. They usually present as a well-defined, fast-growing perineural mass, which may produce either painful or painless symptoms. Moreover, MTTs are usually associated with a poor prognosis [3].

The name MTT originates from the Triton salamander, an amphibian capable of regenerating tissues near a severed sciatic nerve. This phenomenon was first reported by Locatelli in 1925 [4]. The first formal description of this tumor was provided by Masson, who introduced the concept of MPNSTs [5]. Later, Woodruff [6] compared MPNSTs and the regenerative ability of the Triton salamander, ultimately coining the term MTT and establishing the fundamental diagnostic criteria distinguishing it within the broader group of Soft Tissue Sarcomas (STSs).

Due to its rarity and aggressive clinical course, a shared consensus on the optimal management of MTTs is still lacking and remains an urgent clinical need. Most data agree that radical surgical resection remains the cornerstone of treatment and offers the best chance of prolonged survival, particularly when complete excision with negative margins is achievable. This is primarily because MTTs tend to be resistant to conventional chemotherapy and radiotherapy, similar to other high-grade sarcomas. Chemotherapeutic regimens incorporating agents such as doxorubicin, ifosfamide, cyclophosphamide, and vincristine have been employed in unresectable or recurrent cases, though with variable and generally limited success. In particular, doxorubicin-based combinations are considered the standard first-line approach in soft tissue sarcomas, including MPNSTs, but their efficacy in MTTs remains poorly documented and mostly extrapolated from small case series and retrospective studies. Radiotherapy may be used in an adjuvant setting, especially in cases with close or positive margins, or in patients with inoperable tumors to achieve local control, although its benefit in overall survival is still uncertain [7]. In this work, we aim to highlight several pathological, molecular, and clinical features of MTTs, focusing on our case series.

2. Materials and Methods

Cases Enrollment and Ethical Consent

This is a single-center, retrospective, short case series of patients who underwent surgical treatment for chest-located Malignant Triton Tumors at the University Hospital of Padova between 2000 and 2024 (

Table 1. Summary of the main characteristics of our case series.

Case	Age (Years)	Gender	Surgery	Chemotherapy	Radiotherapy	Outcome
Case 1	55	Male	Yes (radical)	Etoposide + Epirubicin	Yes	Alive, no recurrence
Case 2	56	Male	Yes (subtotal)	-	Yes	Deceased (18 months after surgery)
Case 3	56	Male	Yes (subtotal)	VAC protocol	Yes	Alive, local recurrence

Footnote. VAC protocol: Cyclophosphamide, Doxorubicin, and Vincristine.

). The inclusion criteria were as follows: (a) patients aged > 18 years old; (b) confirmed diagnosis of malignant nerve sheath tumor; (c) surgically resectable cases; (d) patients who provided consent to participate in our department’s scientific research.

Histological examination was performed on formalin-fixed (Diapath S.p.A., Martinengo, Italy), paraffin-embedded (FFPE) tissue sections stained with Hematoxylin and Eosin (H&E). The evaluation focused on cellular morphology, growth patterns, mitotic activity, and the presence of necrosis. Special attention was given to identifying features suggestive of Schwannian and rhabdomyoblastic differentiation. A panel of immunohistochemical stains was applied to further characterize the tumors. Routine markers included S100 protein and SOX10 for neural differentiation and desmin and myogenin for skeletal muscle differentiation. The Ki-67 proliferation index was assessed to estimate tumor cell proliferation. Additional IHC markers, such as CD34, EMA, and H3K27me3, were used to differentiate MTTs from histological mimics. To ensure diagnostic accuracy, each case underwent independent review by a soft tissue sarcoma expert pathologist. The evaluation included a detailed reassessment of histomorphological features and immunophenotypic findings to confirm the diagnosis.

This case series was conceptualized in accordance with the Declaration of Helsinki, and written informed consent was obtained from patients in order to increase the available literature on this rare type of cancer. Case reports are designed following the CARE guidelines for case report publication.

3. Case Series Presentation

3.1. Case 1

The first case that we present is a 55-year-old man with a Triton tumor in the left lower limb. Past medical history was deposed only for arterial hypertension. The patient was diagnosed with a Tritor tumor in 2022 and underwent a neoadjuvant treatment consisting of three cycles of chemotherapy with etoposide and epirubicin, followed by radiotherapy to the left leg (50.4 Gy/28 fractions). Following neoadjuvant therapy, the patient underwent left knee disarticulation in November 2023. Adjuvant chemotherapy (etoposide and epirubicin for four cycles) was administered, combined with radiotherapy to the hip stump. The patient then began regular radiological follow-up, which revealed a solitary pulmonary nodule in the middle lobe on a thoracic CT scan in January 2024. Initially, the patient was scheduled for a second major limb in August 2024. However, a follow-up CT scan showed a rapid increase in the lung nodule size, from 3.3 mm to 5 cm. Due to the progressive pulmonary involvement, the orthopedic procedure was postponed, and the case was discussed in a multidisciplinary tumor board. Given the significant growth of the lung nodule and the absence of other metastasis, the team opted for surgical exeresis of the lung nodule. A preoperative CT scan in November showed further progression, with the nodule reaching 9 cm (Figure 1).

On November 8th, the patient underwent a thoracoscopic middle pulmonary lobectomy. The final histological examination confirmed pulmonary metastasis from the known MTT. The post-operative course was uneventful. The chest drain was removed on postoperative day I, and the patient was discharged on postoperative day II. He is currently in a good general condition and is being evaluated for further treatment.

3.2. Case 2

The second case involves a 56-year-old man referred to our center for an invasive mass encasing the left pulmonary artery.

The patient’s past medical history included arterial hypertension, diabetes mellitus, GERD, and two prior episodes of pneumonia treated with antibiotics.

In December 2018, the patient presented to the Emergency Department with left intrascapular thoracic pain, radiating anteriorly, and exacerbated by movement. A chest X-ray showed no abnormalities, prompting further evaluation with a chest CT scan, which revealed a 26 × 27 mm parenchymal thickening adherent to the pleura in the posterior segment of the left upper lobe. Due to the nonspecific nature of these findings, radiological follow-up was initiated. A subsequent CT scan in May 2019 demonstrated an increase in lesion size, with peri-hilar involvement, appearing closely adherent and poorly distinguishable from the left pulmonary artery and adjacent bronchial branches (Figure 2). A PET scan performed shortly after showed increased metabolic tracer uptake in the lesion (SUV max 3.6). Following multidisciplinary discussion, surgical resection of the lesion was planned in collaboration with a cardiac surgeon.

In July 2019, the patient underwent a left upper lobectomy with prosthetic reconstruction of the left pulmonary artery through median sternotomy. To ensure the oncological radicality at the level of the origin of the pulmonary artery, the procedure was performed with the aid of extracorporeal circulation (Figure 3). Post-operatively, the patient was monitored in the Intensive Care Unit ward for five days before being transferred to the general ward. The subsequent clinical course was uneventful, and the patient was discharged on the 20th postoperative day. Final histologic analyses confirmed a high-grade sarcomatous neoplasia, specifically a malignant peripheral nerve sheath tumor with heterologous rhabdomyosarcomatous differentiation, consistent with a malignant triton tumor.

After surgery, the patient underwent adjuvant radiotherapy, which was completed in January 2020. From March 2020, the patient began experiencing febrile episodes with spikes up to 39 °C. Due to the persistence of fever, he was admitted to the Infectious Disease Department, where sepsis caused by Mycoplasma pneumoniae and Streptococcus oralis was diagnosed. Targeted antibiotic therapy was initiated accordingly. A new PET/CT scan revealed moderate hypermetabolism (SUV max 3.3) localized at the pulmonary artery prosthesis, particularly along the medial and inferior aspects. Additionally, chest CT angiography demonstrated the presence of non-occlusive thrombotic defects within the left main pulmonary artery prosthesis (Figure 4). The case was re-evaluated in a multidisciplinary team discussion, and surgical intervention was recommended as the next course of action.

In October 2020, a re-sternotomy was performed as a tentative attempt to correct the thrombotic defects and restore vascular continuity. During the complex dissection of the main pulmonary artery, a purulent collection was identified, along with a pseudo-aneurysm of the proximal anastomosis, posterior to the prosthesis. Severe subversion of the pulmonary hilum structures, likely a consequence of radiation therapy, rendered vascular reconstruction unfeasible. Consequently, a left pneumonectomy was performed with extracorporeal circulation support via an anterolateral thoracotomy. The post-operative course was uneventful, and the patient was discharged two weeks after surgery. The disease remained stable for approximately 18 months before progressing, ultimately leading to the patient’s rapid passing.

3.3. Case 3

The third case involves a 56-year-old male who presented with pain and swelling in the right thigh. His medical history was notable for arterial hypertension and type II diabetes. A leg CT scan revealed a solid, expansive mass in the proximal third of the thigh. A surgical biopsy was performed, and histopathological examination confirmed a Triton tumor. The patient underwent neoadjuvant therapy, consisting of three cycles of chemotherapy followed by radiotherapy. Subsequently, the lesion was surgically resected along with the anteromedial portion of the thigh. The patient initiated regular radiological follow-up. A chest CT scan performed 6 months later revealed an 11 mm pulmonary nodule in the anterior segment of the right upper lobe, along with a centimetric lesion in the lingula. PET imaging confirmed metabolic activity in both lesions, and subsequent thoracic CT showed progressive enlargement of the nodules. The case was discussed in a multidisciplinary tumor board, and a surgical approach was recommended. A laser-guided excision of the right upper lobe lesion was performed via a posterolateral thoracotomy, followed one month later by a thoracoscopic wedge resection of the lingula nodule. The patient recovered uneventfully and resumed the radiological follow-up. However, a novel lingular nodularity developed one year later, prompting a repeated thoracoscopic lingulectomy (Figure 5). Since then, radiological follow-up has remained negative to date. After being discharged, histopathological examination confirmed both lesions as metastases from the previous triton tumor (Figure 6).

4. Discussion

Among all soft tissue sarcomas, MTTs represent an extremely rare, high-grade variant of malignant peripheral nerve sheath tumor, with an estimated incidence of one case per 100,000 individuals. A significant proportion of these cases occur in patients with Type 1 neurofibromatosis (NF1) [8]. Curiously, our cases all were out of criteria for NF1 diagnosis.

MTTs are complex clinicopathological entities that require differentiation from other nerve sheath-derived tumors, such as malignant granular cell tumors and plexiform neurofibromas. Type 1 Neurofibromatosis, an autosomal dominant genetic disorder, is characterized by café-au-lait macules and cutaneous neurofibromas, arising from small peripheral nerves. Approximately 10% of NF1 patients develop MPNST over their lifetime [8], and conversely, nearly 50% of MPNSTs occur in NF1 patients [9]. The remaining 50% of cases are either sporadic or associated with prior radiation therapy for other malignancies. MTTs may develop in various anatomical regions, particularly those containing medium or large nerves, such as the limbs, spinal roots, and cranial nerves. Although tumor location alone is not a definitive diagnostic marker, a rapidly growing, solid, infiltrative, well-defined mass along a peripheral nerve should raise suspicion for MTT. Intrathoracic involvement is extremely rare, with mediastinal localization being the most frequently reported primary chest presentation. In contrast, pulmonary involvement typically represents metastatic spread, as seen in our third case [10,11]. Confirming this origin is challenging, as deep mediastinal dissections—often necessary for tumor resection—frequently result in postoperative complications, including dysphonia, phrenic nerve dysfunction with diaphragmatic elevation, or gastroparesis.

The cases presented in this study highlight the diverse clinical presentations and treatment strategies for MTTs, emphasizing the complexity of their diagnosis and management.

In the first case, the patient underwent neoadjuvant chemoradiotherapy, followed by surgical resection of the primary tumor, and subsequently received adjuvant chemoradiotherapy. Given the aggressive nature of MTTs, close follow-up was essential, with serial chest CT scans scheduled to monitor the disease progression and detect changes in the middle lobe nodule. This case is particularly notable due to the rapid increase in size of the metastatic pulmonary nodule, indicating high tumor aggressiveness, as well as its morphological evolution, an additional hallmark of malignant behavior. Initially, an upper lobectomy was planned, but intraoperative findings revealed complete incorporation of the lesion within the middle lobe.

The second case reported a primary intrathoracic MTT, an extremely rare presentation. This rare case is particularly noteworthy due to the diagnostic challenges in obtaining a definite pathological classification, as well as the complexity of a two-staged surgical approach and the post-operative management, which was further complicated by infections. This case underscores the necessity of management in high-volume centers with expertise in great-vessel repair and complex oncological resections. Given the highly aggressive nature of MPNSTs, the risk of intraoperative complications is significant, and technically demanding procedures should always be considered when pursuing surgical radicality.

The third serves as a significant example of multiple lung-sparing resections for metastatic disease. Following primary tumor resection and close surveillance, the patient underwent bilateral sublobar pulmonary resections to preserve functional lung parenchyma. However, residual pathological tissue was suspected at the left upper lobe resection margins, necessitating a completion lingulectomy to achieve oncological radicality. The benefits of lung-sparing surgery must always be carefully balanced in terms of costs and benefits with oncological radicality. In this case, an initial limited resection allowed for a subsequent, more extensive “salvage” procedure when needed, highlighting the importance of a tailored surgical approach in metastatic disease management. This case reinforces the concept that aggressive surgical management of metastases should be evaluated on an individual basis and, when feasible, actively pursued as part of a multimodal therapeutic strategy.

While surgical resection remains the cornerstone of treatment for MTTs and MPNSTs, recent advances in the literature have provided valuable new insights into their molecular mechanisms and potential therapeutic targets, paving the way for future personalized treatment approaches.

4.1. Molecular Scenario in MPNSTs and Recent Advances in Epigenome Investigations

The mechanisms underlying the development and progression of MPNSTs, including MTTs, remain incompletely understood. As MPNSTs are classified within the broader category of STSs, some molecular characteristics have been identified across these tumor types.

One of the earliest reports investigating molecular alterations in MTTs, published in 1999 [10], reported impaired p53 expression, contributing to a higher risk of genetic instability. This finding aligns with the well-established role of p53 as a tumor suppressor gene, frequently inactivated in several soft tissue neoplasms [12]. In fact, Nassif et al. identified p53 mutations as one of the six most commonly altered genes in sarcomas, along with RB1, CDKN2A, PTEN, CDK4, and MDM2. Notably, while p53 mutations (but not deletions) were associated with worse disease-free survival in STSs, their germline mutation remains rare [13].

4.2. Genetic Alterations in NF1-Associated and Sporadic MPNSTs

It is well established that approximately 50% of MPNSTs arise in patients with NF1, often evolving from preexisting neurofibromas through malignant transformation [14]. NF1-MPNSTs exhibit abnormal RAS pathway activation, with downstream signaling converging on the Akt/mTOR and MAPK pathways [15].

The loss of heterozygosity (LOH) at the NF1 locus is a hallmark not only in MPNSTs but also in premalignant neurofibromas [16]. The stepwise genetic progression of NF1-associated MPNSTs follows a characteristic sequence: (a) Biallelic NF1 inactivation (double-hit mutation); (b) CDKN2A loss of heterozygosity (LOH); and (c) SUZ12 or EED mutations (third hit), leading to hyperactive RAS signaling and epigenetic dysregulation [17]. In preclinical models, mice with concurrent NF1 and p53 germline mutations have been shown to develop MPNSTs, reinforcing the interplay between these two tumor suppressor pathways [18]. However, p53 germline mutations are rare, and when present, they predispose to a broad spectrum of early-onset malignancies, not limited to sarcomas [19]. Moreover, nearly 50% of MPNSTs arise in NF1 wild-type individuals, suggesting distinct molecular mechanisms driving sporadic MPNSTs, which are generally classified separately from NF1-associated cases [20].

4.3. Genomic Instability and Wnt/β-Catenin Dysregulation

MPNSTs exhibit complex and nonspecific karyotypic alterations, with a low somatic mutational burden, similar to other soft tissue sarcomas [20]. According to The Cancer Genome Atlas (TCGA), MPNSTs and sarcomas are primarily characterized by copy number variations (CNVs) rather than single-nucleotide mutations [21,22]. A key molecular pathway implicated in MPNST pathogenesis is Wnt/β-catenin signaling, which is essential for embryogenesis, tissue differentiation, and mesenchymal stem cell maintenance [23]. Aberrant Wnt activation has been linked to mesenchymal transformation and sarcomagenesis [24,25,26].

The Wnt/β-catenin pathway operates through two major branches: (a) canonical signal and (b) non-canonical signals (NCs).

The canonical signaling is mediated by the Frizzled receptors (FZD), leading to β-catenin accumulation and nuclear translocation, where it functions as a transcriptional regulator. In the NC-PCP pathway, Wnt interacts with FZD activating Dishevelled (Dvl), which subsequently stimulates RHOA signaling (Ras homolog gene family member A). Wnt-FZD interaction triggers calcineurin activation and Nuclear Factor of Activated T-Cells (NFAT) signaling. Dysregulation of Wnt signaling is implicated in MPNSTs, but nuclear β-catenin expression is typically absent, suggesting that oncogenic activation occurs upstream [27,28].

4.4. Non-Canonical Sonic Hedgehog (SHH) Signaling and Epigenetic Modifications

Recent studies suggest that non-coding RNAs (ncRNAs) and chromatin remodeling mechanisms play a role in Schwann cell transformation and MPNST progression. One key pathway is the non-canonical Sonic Hedgehog (NC-SHH) signaling pathway, which differs from the canonical Smoothened (Smo)-dependent pathway. In the NC-SHH pathway, oncogenic activation occurs via direct transcriptional regulation by ncRNAs and other epigenetic factors, bypassing Smo activation [29].

Two different types of MPNSTs have been proposed: the first one (G1) is characterized by high CpG island methylation, chromatin remodeling defects, and aggressive progression with poorer survival [30]. The second one (G2) is associated with APC inactivation, high recurrence rates, but longer recurrence-free survival (RFS) than G1 tumors [31]. It remains unclear whether MTTs predominantly fall within the G1 or G2 subgroup, and further investigation is required to delineate their molecular profile.

4.5. miRNA Dysregulation and Epigenetic Aberrations

Emerging evidence highlights miRNA dysregulation as a critical factor in MPNST progression. A study by Amirnasr et al. demonstrated that distinct miRNA expression patterns differentiate sporadically from NF1-associated MPNSTs [32]. This study demonstrated that the presence of dysfunctional NF1-MPNSTs has been directly linked to the progression of cancer (miRNA-143, -145, and -135b). Indeed, the inhibition of microRNAs 135b and 889 led to a substantial reduction in the invasive behavior of cell cultures. It is noteworthy that these two miRNAs interfere with the Wnt/beta-catenin pathway, thereby confirming that non-canonical signalling modulation is impaired in these neoplasms.

Further, Polycomb Repressive Complex 2 (PRC2) inactivation, commonly seen in MPNSTs, leads to widespread epigenetic dysregulation, including aberrant miRNA expression. Loss of PRC2 function results in reactivation of normally silenced genetic elements, contributing to tumor progression via non-coding RNA activation [33,34].

4.6. Target Therapies, Pre-Clinical Experiments, and Future Directions

Recently, a few papers have discussed the introduction of a targeted therapy to manage the progression of MPNSTs. In fact, as previously discussed, some molecular pathways became dysregulated in these tumors, in particular, RAS and mTOR. As an example, Gonzalez-Munoz summarized that Tyrosine-Kinase Inhibitors targeting the RAS/MEK/ERK pathway and anti-angiogenetic drugs were tested in MPNSTs with limited results in recurrent and/or metastatic settings. Instead of a single therapy, a combined approach was reported to produce better outcomes [35]. In preclinical studies, JAK2 inhibitors showed a delayed tumor growth in MPNSTs targeting the JAK2-STAT3 interaction [7], but a clear advantage was lacking. Otherwise, PI3K/Akt/mTOR regulatory pathways were successfully targeted by a chaperone protein (Hsp90) inhibitor combined with Sirolimus (mTOR inhibitor), demonstrating a synergic action against MPNST [36]. The new panorama of immunotherapy, which is opening new promising frontiers in oncology, was also tested in MPNSTs, and, as a consequence, a moderate-to-high expression of PD-L1 is reported. Results are encouraging, but they will be conclusive only in the near future. Future directions will explore further molecular landscapes. For example, a recent phase 2 study with the MDM2/p53 inhibitor combined with pembrolizumab showed a satisfactory disease control rate in progressed MPNSTs, suggesting that pathways not yet completely investigated will hopefully provide interesting results in the future [37]. Future directions will investigate oncolytic virus vaccine therapies due to the promising results of in vivo studies [38]. In summary, several novelties are growing as promising treatment options with our deeper comprehension of genetic and epigenetic mechanisms. Surgical resection remains the main goal, but unresectable cases are showing more and more treatment tools, unthinkable only a few years ago.

5. Conclusions

While genetic alterations—particularly in NF1, CDKN2A, SUZ12, and EED—are well characterized in NF1-associated MPNSTs, sporadic cases appear to be driven by epigenetic dysregulation and alternative oncogenic pathways.

Chromatin remodeling, miRNA dysfunction, and phylogenetically conserved signaling pathways such as Wnt/β-catenin and SHH are emerging as key contributors to MPNST progression. Future studies should aim to clarify whether MTTs preferentially align with the NC-SHH-driven (G1) or Wnt/β-catenin-driven (G2) MPNST subclass, which may have implications for targeted therapy development.