Pathological and Immunohistochemical Features of Malignant Peripheral Nerve Sheath Tumor With Heterologous Rhabdomy Oblastic Differentiation (Malignant Triton Tumor) in the Context of the Malignant Peripheral Nerve Sheath Tumor Spectrum

Abstract

Malignant peripheral nerve sheath tumors (MPNST) are aggressive sarcomas arising from Schwann cells or neurofibromas, comprising ∼10% of soft tissue sarcomas. Found in 8% to 13% of neurofibromatosis type 1 patients, they typically show spindle cells expressing S100 and SOX10. Some display heterologous differentiation (bone, cartilage, vessels, or glands). When rhabdomyosarcomatous features are present, they are called malignant peripheral nerve heath tumor with heterologous rhabdomyoblastic differentiation (malignant triton tumors), which are more prone to recurrence, metastasis, and worse outcomes. Epithelial differentiation does not affect prognosis. Despite advances in understanding MPNST biology, many pathophysiological mechanisms remain unclear. This review highlights their histopathology, focusing on malignant triton tumor.

Keywords

malignant peripheral nerve sheath tumor malignant triton tumor malignant schwannoma immunohistochemistry

Introduction and Overview of Malignant Peripheral Nerve Sheath Tumors

Malignant peripheral nerve sheath tumors (MPNST) are rare and aggressive soft tissue sarcomas with a 5-year survival rate of 43%. They represent 3% to 10% of all soft tissue sarcomas and have an incidence of 1.46 per 1,000,000 people.^1,2 The term “malignant peripheral nerve sheath tumor” has replaced older terms such as malignant schwannoma, neurofibro sarcoma, and neurogenic sarcoma.

MPNST are thought to arise from peripheral nerve cells, including Schwann cells, fibroblasts, and perineurial cells.³ They may originate from mesenchymal stem cells committed to nerve sheath differentiation or from neurofibromatosis type 1 (NF1)-null Schwann cells that acquire mutations that drive MPNST progression.⁴ Moreover, neurofibromas may provide a “nurturing environment” for various cell populations within the tumor microenvironment, including stem cells, pericytes, fibroblasts, and endothelial cells, increasing susceptibility to tumorigenic progression into MPNST.⁴ In NF1-associated MPNST may arise from plexiform neurofibromas and progress to atypical neurofibromatous tumors of uncertain biological potential.⁵ However, these hypotheses remain under investigation, and the true cell of origin is still unknown.⁴

Approximately 50% of all MPNST occur in neurofibromatosis, especially NF1 (von Recklinghausen disease), underscoring the critical role of the NF1 gene in tumorigenesis.⁶ Patients with NF1 are at increased risk for soft tissue sarcomas, with MPNST being the most common malignancy. NF1, the most common genetic disorder affecting the human nervous system, is an autosomal-dominant condition caused by a loss-of-function mutation in the NF1 gene on chromosome 17q11.2. This gene encodes neurofibromin, a tumor suppressor that regulates Rat sarcoma (RAS) signaling and is linked to cell survival and proliferation.^4,5,7 NF1 is classified as a “RASopathy,” a group of developmental disorders caused by germline mutations that activate RAS/Mitogen-Activated Protein Kinase (MAPK) signaling.⁸ NF1 deficiency leads to RAS hyperactivation, disrupting pathways such as the RAS/MAPK/Extracellular Signal-Regulated Kinase and Phosphoinositide 3-Kinase/ATC serine/threonine kinase or Protein Kinase B(BPKB) (AKT)/mecanistic Target of Rapamycin (mTOR) pathways.^8,9 NF1 is characterized by multiple dermal or plexiform neurofibromas and can affect various organ systems. Pigmented lesions, such as café-au-lait spots and axillary/inguinal freckles (Crowe sign), as well as Lisch nodules, typically appear in early childhood or at birth. NF1 is also associated with bony dysplasias, optic nerve gliomas, high-grade astrocytic tumors, and pheochromocytomas.⁷ In NF1 patients, MPNST typically occur between the ages of 28 and 36 years and often arise from pre-existing intraneural or plexiform neurofibromas.⁵ Additionally, 10% of MPNST are linked to prior radiation exposure, whereas the rest are sporadic and usually present between the ages of 40 and 44.¹⁰ However, MPNST rarely develop in childhood.¹¹

Patients present with a rapidly growing mass accompanied by neurological deficits (Figure 1). When a major nerve is involved, symptoms may include pain and paresthesia. However, these nonspecific symptoms make MPNST hard to distinguish from other nerve lesions.⁹ The tumor infiltrates insidiously, metastasizes through the bloodstream (rarely via lymphatics), and is often fatal.⁵ Poor prognosis is associated with larger tumors (5-10 cm), NF1 association, higher grade, trunk location, a mitotic index >6 per 10 high-power fields, and incomplete resection. Recurrence rates can reach 40%, with approximately two-thirds of patients having metastases to the lungs and bones. The 5-year survival rate is 20% to 50%.¹² Overall, the prognosis of MPNST is poor, with tumors in one extremity sites having worse outcomes than those in the extremities (43% vs 70%).^13,14 One study identified key factors for a poor prognosis: von Recklinghausen disease (P < .001), a tumor size >5 cm (P < .005), and incomplete resection (P < .01).^14,15

MPNST lack distinct gross characteristics; they may be attached to a nerve trunk, causing fusiform enlargement, and often extend along both the proximal and distal margins of the affected nerve. The sciatic nerve is the most frequently affected nerve (Figure 2). These tumors present as firm, white masses or soft, yellow masses, depending on the degree of necrosis, and may occasionally show myxoid changes or hemorrhage. The trunk and extremities are the most common locations, followed by the head and neck. Importantly, the presence of a nerve within a tumor does not confirm its origin, as many soft tissue sarcomas can infiltrate, encase nerves, and mimic MPNST.^15,16 Diagnosing MPNST presents significant challenges due to their histological and immunohistochemical variability, as well as the absence of standardized diagnostic histopathological criteria. A diagnosis typically requires correlation with clinical and imaging findings, including a history of NF1, along with the exclusion of morphologically similar neoplasms through immunohistochemistry and, in some patients, gene mutation analysis.⁹

Histologically, these tumors exhibit diverse architectural patterns and cellular morphologies, often showing a sharp transition from low- to high-grade malignancy (Figures 3 and 4). A single lesion may display spindle, epithelioid, pleomorphic, and small round cell patterns, along with hypercellular and hypocellular regions (the so-called “marbled appearance”), with hypercellular areas frequently showing perivascular accentuation. The spindle cells may be serpentine, with hyperchromatic, comma-shaped nuclei. Some neoplasms consist of sheets of highly anaplastic spindle, ovoid, and polygonal cells, which are typical of undifferentiated pleomorphic sarcomas. Common features include high mitotic activity, atypical mitoses, hemorrhage, and extensive necrosis, often resulting in viable tumor islands around blood vessels (perivascular cuffs) and geographic necrosis with pseudopalisading. Hemangiopericytoma-like blood vessels are also frequently observed. These histological features are nonspecific and cannot be used to definitively diagnose malignant peripheral nerve tumors but are helpful in differential diagnosis. While most malignant peripheral nerve tumors differentiate toward Schwann cells, a small subset shows perineurial cell differentiation, which is typically not associated with NF1.^17,18 Immunohistochemistry is discussed below.

Epithelioid malignant peripheral nerve sheath tumor is a rare variant of malignant peripheral nerve sheath tumor, accounting for less than 5% of all patients.³ It is composed of plump epithelioid cells with abundant eosinophilic cytoplasm, typically embedded in a prominent extracellular myxoid or hyalinized matrix, and often exhibits a lobulated growth pattern. As described further below, this variant is characterized by diffuse positivity for S100 and SOX10, along with frequent loss of SMARCB1 (INI1) expression by immunohistochemistry—observed in approximately 70% of patients. Unlike conventional malignant peripheral nerve sheath tumor, the epithelioid variant is only rarely associated with NF1. Although uncommon, it is the most frequent subtype of MPNST (MPNST) to arise from a pre-existing schwannoma, which itself shows SMARCB1 loss in approximately 40% of patients^12,19 (Table 1).

Table 1.

A Comparative Analysis of Conventional, Epithelioid, and Triton MPNSTs Highlighting Key Molecular Features.

Tumor	S100 SOX10	Nestin	Keratin AE1/ AE3 EMA	CD56	Desmin SMA	MYOD1 Myogenin	BCL2	p16	PGP9.5	TLE1	H3K27me3	CD34	HMB45 MelanA MITF
Classic MPNST	+/−	++	-	+	-	-	+	+	+/−	−/+	Loss/+	++	-
Cellular schwannoma	+++	+++	-	-	-	-	-	++	+++	-	+++	+/−	-
Synovial sarcoma	−/+	-	+++	++	-	-	+++	-	++	+++	++	-	-
LMS	-	-	-	-	++	-	-	-	-	-	ND	-	-
DDLS	++	-	-	-	-	-	-	+++	-	-	ND	+/−	-
Spindle cells Melanoma	+++	+	-	-	-	-	-	-	-	-	ND	-	+++

Abbreviations: CDKN2A, cyclin-dependent kinase inhibitor 2A; EGFR, epidermal growth factor receptor; MMP13, matrix metallopeptidase 13; ND, no data available; NF1, neurofibromatosis type 1; PDGRFA, platelet-derived growth factor receptor alpha; PRC2, polycomb repressive complex 2; SMARCB1, SWI/SNF-related BAF chromatin remodeling complex subunit B1; SPP1, secreted phosphoprotein 1.

Approximately 15% of malignant peripheral nerve sheath exhibit heterologous differentiation, typically involving mesenchymal elements such as bone, cartilage, fat, benign striated muscle, nevus cells, and rarely, epithelial elements. Glandular differentiation (glandular malignant peripheral nerve sheath), with or without mucin production, is uncommon and often occurs in NF1 patients. Heterologous elements may form well-defined neoplasms, such as liposarcoma, angiosarcoma, osteosarcoma, chondrosarcoma, or malignant melanoma.^19,20 The coexistence of 2 heterologous components is extremely rare.²⁰ Occasionally, malignant peripheral nerve sheath display rhabdomyosarcomatous differentiation, a feature known as Malignant Peripheral Nerve Sheath Tumor with heterologous rhabdomyoblastic differentiation or malignant triton tumor.^10,20

Malignant Peripheral Nerve Sheath Tumor With Rhabdomyoblastic Differentiation (Malignant Triton Tumor)

MPNST with heterologous rhabdomyoblastic differentiation is a rare, highly aggressive malignant peripheral nerve sheath tumor subtype, distinguished by the presence of heterologous rhabdomyoblastic elements.^5,14

Claude L. Pierre Masson and Jean-François Martin were the first to describe rhabdomyosarcomatous differentiation in MPNST in a patient with neurofibromatosis. The sarcoma originated from a malignant neurofibroma in the left cervical nerve of a 23-year-old patient with von Recklinghausen disease.^20,21 They proposed that endoneurial cells in neuromas, influenced by motor nerve fibers, could differentiate into muscle tissue, a process they called “rhabdomyoma of nerve.”²² Masson and Martin supported their hypothesis, citing an experiment by Professor Piera Locatelli (1900-1975) from the University of Pavia, who induced the growth of supernumerary limbs, including bone and muscle, by implanting the cut end of the sciatic nerve into the soft tissues of tritons (small salamanders of the genus Triturus). This finding suggested that endoneurial cells in “neuromas” could differentiate into muscle tissue under the influence of motor nerve fibers.^22,23,24 However, Singer research revealed that limb and muscle regeneration in tritons does not rely on motor nerve innervation, and other studies reported that aneurogenic forelimbs in young salamanders can regenerate.^20,25 Masson later proposed the metaplasia theory, suggesting that neoplastic Schwann cells can transform into striated muscle elements.²⁶ This theory is supported by tumors with neoplastic muscle cells in neuroepithelial-derived tissues, such as medulloblastomas (medullomyoblastomas or teratoid tumors), and rhabdomyosarcoma in intraocular medulloepitheliomas.²⁷ A prevailing hypothesis for divergent mesenchymal differentiation involves the concept of “ectomesenchyme,” which proposes that mesenchymal differentiation may occur in neoplasms of both central and peripheral nerves.⁹ Heterogeneous components are often observed in tumors lacking S100 protein immunoreactivity or showing only focal reactivity, indicating that Schwann cells may not be the only contributors to these components.⁹

Although Masson authored 2 articles on the subject, he never coined the term “triton tumor.” Dr James M. Woodruff and colleagues introduced the term “malignant triton tumor” in their 1973 publication in Cancer.²⁰

Woodruff explained that in 1968, Dr William Millett sent a slide of what is now called “malignant triton tumor” to Dr Frank W. Foote, Jr. at Memorial Sloan-Kettering Cancer Center. Familiar with Masson work, Dr Foote referred Millett to Masson articles, leading Millett to adopt the term “triton tumor.”²⁰ These tumors are known as MPNST with rhabdomyoblastic differentiation or “malignant Triton tumors.”¹⁹

On average, malignant triton tumors occur approximately a decade later than MPNST (50 vs 40 years), are larger (12 vs 8 cm), and metastasize more rapidly, resulting in a worse prognosis.^14,15 Malignant triton tumors aggressiveness is linked to high-grade (grade III) nuclear features and an elevated Ki67 proliferation index. The 5-year survival rate for malignant triton tumors is 5% to 15%, whereas it is 50% to 60% for MPNST.¹⁰

Malignant triton tumors lack specific gross and histological features beyond those of conventional MPNST, with the presence of rhabdomyoblasts being its defining characteristic¹⁹ (Figure 5A). Rhabdomyoblasts have an eosinophilic cytoplasm, eccentrically placed nuclei, and may exhibit striations (Figure 5B and C).⁵ Woodruff proposed 3 criteria for diagnosing malignant triton tumors: (1) a tumor with peripheral nerve involvement in an NF1 patients, (2) a predominance of Schwann cells, and (3) the presence of rhabdomyoblasts.^10,20 Patients with rhabdomyosarcomatous and glandular differentiation have been reported, but they remain exceedingly rare.¹² MPNST may occasionally exhibit complete heterologous rhabdomyoblastic differentiation without histological evidence of residual conventional MPNST closely resembling spindle cell rhabdomyosarcoma.²⁸

Conventional treatment involves radical excision followed by high-dose radiotherapy, as these tumors have a limited response to chemotherapy.²⁹ Radiotherapy helps manage local disease and reduce recurrences but has a minimal impact on long-term survival. Chemotherapy is generally ineffective, although some studies suggest potential benefits for high-grade or unresectable tumors in children.³⁰ Currently, no targeted therapies are effective for treating MPNST, but the mTOR pathway is a potential target. Preclinical studies suggest that rapamycin, alone or with AKT inhibitors, may offer promising results.²⁹

Immunohistochemistry

MPNST are among the most challenging tumors to diagnose due to the absence of specific histopathological criteria, the wide range of histological features, and the lack of reliable immunohistochemical markers (Figures 6 and 7).¹⁹ As a result, no definitive set of diagnostic markers exists, making it difficult to differentiate MPNST from other soft tissue sarcomas, which often requires a process of exclusion.³¹

MPNST typically show patchy S100 protein positivity (nuclear and cytoplasmic) in 50% to 90% of patients, depending on Schwannian differentiation. Higher-grade tumors are less likely to express S100^19,32 (Figure 5). Zou et al reported that a lack of S100 expression is correlated with a 5-fold increased risk of distant metastasis.²⁹ Diffuse S100 expression is unusual in MPNSTs, except in tumors with epithelioid cells, and should raise suspicion for other diagnoses, such as neurofibroma, cellular schwannoma, or malignant melanoma. Nuclear expression of SOX10, a neural crest transcription factor crucial for Schwann cell and melanocyte development, is found in most melanomas and in up to 50% of MPNST. SOX10 is more sensitive than other neural markers for diagnosing MPNST and is not typically detected in non-Schwannian, nonmelanocytic tumors, indicating it has greater specificity for neural crest-derived tumors than the S100 protein has.³² Other markers of neural/nerve sheath differentiation, such as PGP9.5, CD271 (NGFR/p75), neurofibromin, glial fibrillary acidic protein (GFAP), and GAP43, have low sensitivity and specificity for MPNST, with some, such as neuron-specific enolase, being nonspecific. When SOX10 and S100 are negative, the diagnosis depends on the tumor association with a neurofibroma or large nerve, tumor size, adequate inclusion of neoplastic tissue, and examination of multiple sections to exclude other lesions in the differential diagnosis. Nestin, an intermediate filament protein strongly expressed in the MPNST cytoplasm, has been suggested to be more sensitive for diagnosing MPNST than other neural markers are.³³ A positive nestin stain, combined with markers such as S100, SOX10, CD56, and PGP9.5, could be valuable for diagnosis.³³

Additional, nonspecific immunohistochemical markers, such as vimentin, CD10, BCL2, CD57, and CD99, have been used. GLUT1, D240, neurofilament protein, and CD34 are often positive in MPNST but lack specificity, as they can also be found in other sarcomas.^5,32 MPNST may express epithelial markers such as AE1/AE3 and EMA, especially in epithelioid and glandular formations, but usually do not express keratin 7 or 19, helping distinguish them from monophasic synovial sarcoma.¹³ Ki67 is an important prognostic marker; a labeling index greater than 25% correlates with reduced survival.^9,34 Levels of 2% to 5% are typical in neurofibromas, whereas levels over 10% may suggest MPNST.^9,34

Differentiating synovial sarcomas from MPNST can be histologically challenging. TLE1 (transducin-like enhancer of split 1), a transcriptional corepressor involved in embryogenesis and hematopoiesis, is a sensitive and specific marker for synovial sarcoma; it shows strong, diffuse nuclear expression in nearly all synovial sarcomas, with TLE1 negativity strongly suggesting the absence of synovial sarcoma. However, TLE1 may also be weakly and focally positive in up to 30% of MPNST.³⁵ Synovial sarcoma is characterized by specific t(X;18) translocations in which SSX1, SSX2, or SSX4 are fused with SS18. The detection of SYT::SSX fusion transcripts, which are absent in MPNST, is diagnostically helpful for the treatment of synovial sarcoma.

HMGA1 and HMGA2 (high-mobility group AT-hook 1 and 2) have been tested for their ability to differentiate MPNST from synovial sarcomas.³⁶ These proteins are part of the HMGA family of architectural transcription factors, which regulate chromosomal organization and transcription.³⁶ MPNST show moderate to strong nuclear staining for both HMGA1 and HMGA2.^19,36 HMGA2 expression is specific to MPNST and absent in synovial sarcomas, making HMGA2 immunohistochemistry a useful marker for distinguishing between the two.

Recent genetic alterations in core components of the polycomb repressive complex 2 (PRC2), specifically EED and SUZ12, led to the global loss of the histone marker H3K27me3, driving malignancy and offering a promising diagnostic tool for MPNST.^37,38 The frequency of heterologous differentiation in MPNSTs may be partially linked to recurrent loss-of-function mutations in PRC2 components, EED or SUZ12.³⁹ Complete loss of H3K27me3, as detected via immunohistochemical staining, is observed in up to 80% of MPNSTs and serves as a marker for EED or SUZ12 alterations and PRC2 dysfunction.^39,40 Ito et al reported that losses of H3K27me3 and H3K27me2 significantly correlated with myogenic (desmin) immunopositivity in patients of malignant triton tumor.⁴¹ Although loss of H3K27me3 is observed in up to 50% of MPNSTs, some patients may retain intact staining. The specificity of the complete loss of H3K27me3 as a distinguishing marker for MPNSTs has been controversial. Subsets of malignant melanoma, extraskeletal osteosarcoma, and dedifferentiated liposarcoma also exhibit complete loss of H3K27me3.⁴¹ H3K27me3 detection is especially useful in postradiation settings and high-grade lesions, where staining loss occurs in 90% of patients.²

Somatic mutations in cyclin-dependent kinase inhibitor 2A (CDKN2A) are common in many cancers, making it the second most frequently inactivated gene after p53. CDKN2A, located on chromosome 9p21.3, is widely expressed in various tissues. This gene encodes 2 tumor suppressor proteins that regulate the cell cycle. First, p16 inhibits cyclin-dependent kinases 4 and 6 (CDK4 and CDK6), activating the retinoblastoma (Rb) family of proteins, which prevents the transition from the G1 phase to the S phase. Second, p14ARF activates the p53 tumor suppressor. Loss of CDKN2A is a frequent alteration in atypical neurofibromatous tumors of uncertain biological potential and MPNST, unrelated to NF1-associated or sporadic causes.⁴² CDKN2A mutation is considered an early event in MPNSTs, with complete loss of the p16 protein commonly observed. However, the loss of p16 does not necessarily indicate malignancy.⁴²

The expression of INI1 protein (integrase interactor 1), which is ubiquitously expressed in the nuclei of most cells, is lost in 50% of epithelioid MPNST. Notably, INI1 is also expressed in 90% of epithelioid sarcomas and in all malignant extrarenal rhabdoid tumors.⁴³ The INI1/SMARCB1 gene, located at chromosomal band 22q11.2, encodes a component of the SWI/SNF chromatin remodeling complex, which serves as a negative regulator of the cell cycle and functions as a tumor suppressor gene.⁴⁴

CDX2 expression has been observed in MPNST, even in the absence of morphological evidence of epithelial differentiation. Odeyemi et al reported that 14 out of 32 MPNSTs (44%) presented CDX2 immunoreactivity, ranging from weak to strong, in 2% to 95% of neoplastic spindle cells.⁴⁵ This expression is closely associated with PRC2 inactivation, as evidenced by the diffuse loss of trimethylated histone H3K27. The presence of CDX2 in MPNST may suggest sarcomatoid carcinoma of the gastrointestinal tract; however, MPNST are typically negative for keratin AE1/AE3 or show only focal, weak expresion, whereas sarcomatoid carcinoma typically presents stronger and more diffuse keratin staining. Additionally, the presence of S100 protein and SOX10 expression, even if focal, suggests Schwann cell differentiation, supporting the diagnosis of malignant peripheral nerve sheath tumor over sarcomatoid gastrointestinal carcinoma.⁴⁵

It has been proposed that CDX2 expression may aid in diagnosing MPNST when faced with a spindle cell sarcoma of the intestine, as anti-CDX2 immunoreactivity has not been observed in previously studied soft tissue tumors. However, further studies are needed to confirm these findings.⁴⁵ In MPNST with rhabdomyoblastic differentiation, while desmin is the most sensitive marker for myogenic differentiation, its lower specificity requires the use of more specific markers, such as the muscle-specific basic helix-loop-helix (bHLH) transcription factor “myogenin” or MYOD1—myogenic differentiation 1—to confirm this differentiation (Figure 8). Therefore, the expression of myogenin or MTORMYOD1 is crucial for diagnosing MTT.^5,14

Differential Diagnosis

Several sarcomas should be considered in the differential diagnosis, including synovial sarcoma, rhabdomyosarcoma, leiomyosarcoma, dedifferentiated liposarcoma, and dermatofibrosarcoma protuberans (Table 2).¹⁵

Table 2.

Differential Diagnosis of Malignant Peripheral Nerve Sheath Tumor Using Immunohistochemistry.

Feature	Conventional MPNST Most common form (∼80% of tumors).	Epithelioid MPNST Rare subtype (∼5% of tumors)	Malignant Peripheral Nerve Sheath Tumor with Heterologous Rhabdomyoblastic Differentiation (Malignant Triton Tumor)
NF1 gene loss/mutation	Common (especially in NF1 patients)	Rare (less common than in conventional MPNST)	Very common
PRC2 loss (H3K27me3 loss)	Common	Rare (usually retained, unlike in conventional MPNST)	Common
SMARCB1 (INI1) loss	Rare	Defining feature	Rare
S100 expression	Typically focal or negative (unlike in benign schwannomas)	Strongly and diffusely positive (unlike conventional MPNST)	Usually negative or focally positive
SOX10 expression	Often positive	Often positive	Usually negative or focally positive
Desmin, Myogenin MYOD1	Absent	Absent	Strongly positive in rhabdomyoblastic areas

Abbreviations: cyto, cytoplasmic staining; DDLS, dedifferentiated liposarcoma; EMA, epithelial membrane antigen; LMS, leiomyosarcoma; mem, membrane staining; MPNST, malignant peripheral nerve sheath Tumor; ND, no data available; SMA, smooth muscle actin.

Cellular schwannoma as described by Woodruff, is likely one of the most important differential diagnoses to consider.⁴⁶ Typically, it is solitary and well-circumscribed and can occasionally present as multinodular or plexiform. These tumors are commonly found in deep locations, such as the posterior mediastinum, retroperitoneum, and pelvis. Cellular schwannoma is a hypercellular schwannoma variant, primarily consisting of Antoni A areas with interlacing fascicles of spindle cells showing moderate nuclear atypia and mitotic activity (<4 mitoses/10 HPF), without Verocay bodies. Subcapsular lymphocytes and hypocellular Antoni B areas (less than 10%) may be present, and small areas of necrosis can raise concerns for MPNST. The features supporting cellular schwannoma include a well-circumscribed tumor, high cellularity with low mitotic activity, perivascular hyalinization, and focal Antoni B areas. In contrast to MPNST, cellular schwannomas show strong diffuse S100 immunoreactivity. Ki67 labeling is limited to hotspots with an index below 20%, and p16 and H3K27me3 expression is retained. Cellular schwannomas have benign biological behavior, with rare recurrences after complete excision and no reported metastases.⁴⁷

Conclusion

According to the WHO, the key diagnostic criteria for MPNST include origin from a nerve, a pre-existing nerve sheath tumor, or occurrence in patients with NF1. Tumors typically exhibit spindle cell growth with geographic necrosis and mild nuclear pleomorphism. In sporadic tumors, the diagnosis is supported by Schwann cell differentiation (S100/SOX10 positivity) and/or loss of H3K27me3 expression. The presence of heterologous elements in a sarcoma may also suggest an MPNST. Epithelioid MPNST, which arise outside the NF1 context, often display diffuse S100 and SOX10 positivity along with loss of SMARCB1 expression.

MPNST generally have a poor prognosis unless they are small, localized, and resectable, with a 5-year survival rate of 50% to 60% and a median survival of 6 years.⁴⁸ Compared with sporadic MPNST, NF1 mutations are associated with worse outcomes.⁴⁹ Since half of MPNST occur in NF1 patients, understanding the progression from NF1 lesions to MPNST is crucial for new therapies. Age over 60 years and tumors larger than 5 cm are independent poor survival predictors (50). R0 (no residual tumor) and R1 (microscopic residual tumor) resections offer better outcomes than R2 (macroscopic residual tumor) does. The effectiveness of radiotherapy and chemotherapy is debated, and the incidence of recurrence remains high (40%-65%).^6,9 MPNST with rhabdomyoblastic differentiation are challenging to manage, with surgical resection being the primary treatment, often combined with adjuvant radiotherapy. Chemotherapy may be considered, but its effectiveness is unclear. The impact of different therapies for MPNST is still being investigated.

This narrative literature review was conducted considering the general recommendations of the PRISMA 2020 statement, with the aim of ensuring a clear and transparent presentation of the available evidence.

Footnotes

ORCID iDs

Luis Felipe Arias-Ruiz

Carlos Ortiz-Hidalgo

Ethics Approval Statements

This retrospective study used de-identified patient data, and informed consent was not required. The data will not be shared with third parties.

Consent to Participate

Not applicable.

Consent for Publication

Not applicable.

Authors’ Contributions

Both authors contributed to the conceptualization, methodology, as well as the writing—original draft.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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