Fact-checked by Grok 2 weeks ago

Malignant peripheral nerve sheath tumor

A malignant peripheral nerve sheath tumor (MPNST) is a rare, aggressive form of soft tissue sarcoma that originates from the Schwann cells or perineurial cells forming the protective sheath around peripheral nerves, often exhibiting neural differentiation and a high propensity for local invasion and distant metastasis.^[1]^[2] MPNSTs account for approximately 5-10% of all soft tissue sarcomas and have a lifetime incidence of about 0.001% in the general population, though the risk rises dramatically to 8-13% among individuals with neurofibromatosis type 1 (NF1), a hereditary genetic disorder caused by mutations in the NF1 tumor suppressor gene.^[3]^[2] Up to 50% of MPNST cases occur in patients with NF1, where they frequently arise from preexisting benign plexiform neurofibromas, while sporadic cases (without NF1) represent the remainder and may be linked to prior radiation exposure or other genetic alterations such as loss of NF1, TP53, or CDKN2A function.^[3]^[2] These tumors most commonly affect young to middle-aged adults, with a slight male predominance, and can develop in the extremities, trunk, head and neck, or retroperitoneum, often presenting as a rapidly enlarging, painful mass with associated neurological deficits like weakness or sensory changes due to nerve compression or infiltration.^[3]^[2] Diagnosis typically involves multimodal imaging, including MRI for detailed soft tissue evaluation and 18F-FDG PET/CT to assess metabolic activity and distinguish malignant transformation from benign lesions, followed by core biopsy for histopathological confirmation, which reveals spindle cell proliferation with S100 protein immunoreactivity in about 50-70% of cases; molecular testing often demonstrates biallelic inactivation or homozygous deletion of NF1.^[3]^[2] Treatment is primarily surgical, aiming for wide local excision with negative margins, though complete resection is challenging due to the tumor's infiltrative nature and proximity to vital neurovascular structures; adjuvant radiotherapy is commonly employed to reduce local recurrence, while chemotherapy (e.g., doxorubicin-based regimens) is reserved for metastatic disease or unresectable cases, with emerging targeted therapies like MEK inhibitors showing promise in NF1-associated MPNSTs.^[3]^[2] Despite advances, MPNSTs carry a poor prognosis, with 5-year overall survival rates ranging from 23-69% overall and varying by risk stratification: as high as 96% for low-risk tumors but dropping to 35% for high-risk cases involving large size (>10 cm), high-grade histology, or truncal location.^[3]^[2] Local recurrence occurs in 40-65% of cases, and distant metastasis, primarily to the lungs, develops in 30-60%, underscoring the need for multidisciplinary management at specialized sarcoma centers.^[3]^[2]

Overview

Definition and characteristics

A malignant peripheral nerve sheath tumor (MPNST) is a rare and aggressive form of soft tissue sarcoma that originates from Schwann cells or perineurial cells forming the nerve sheath, including those surrounding nerves that extend from the spinal cord to the rest of the body. These tumors often arise de novo or through malignant transformation of preexisting benign nerve sheath tumors such as neurofibromas. MPNSTs account for approximately 5-10% of all soft tissue sarcomas and have an estimated annual incidence of approximately 0.15 per 100,000 individuals in the general population.^[4]^[2]^[5]^[6] Histologically, MPNSTs are characterized by spindle-shaped cells arranged in fascicles with alternating areas of hypocellularity and hypercellularity, often exhibiting a marbled or whorled pattern under microscopic examination. These tumors typically display high mitotic activity, nuclear atypia, and geographic necrosis, classifying most as high-grade sarcomas, though low-grade variants exist. Immunohistochemical staining may show positivity for S100 protein or SOX10 in about 50% of cases, supporting nerve sheath differentiation, while heterologous elements such as rhabdomyoblastic or cartilaginous components occur in 10-15% of tumors and are associated with poorer outcomes.^[7]^[2] MPNSTs are locally invasive with a strong propensity for recurrence and distant metastasis, primarily to the lungs, and they most commonly arise in the deep soft tissues of the extremities, trunk, or pelvis, though they can occur anywhere along peripheral nerves. Up to 50% of cases are linked to neurofibromatosis type 1 (NF1), a genetic disorder that predisposes individuals to a 10% lifetime risk of developing these tumors, while prior radiation exposure increases the risk of secondary MPNSTs. The aggressive behavior and diagnostic challenges stem from their similarity to other spindle cell sarcomas, necessitating careful histopathological evaluation.^[4]^[5]^[2]

Epidemiology

Malignant peripheral nerve sheath tumors (MPNSTs) are rare soft tissue sarcomas, accounting for approximately 5-10% of all such malignancies.^[8] In the general population, the incidence is estimated at about 1 case per 100,000 individuals annually, though some analyses report lower rates around 1 per million, particularly for specific subtypes like intradural tumors.^[8]^[9] The age-standardized incidence has shown a gradual decline in recent decades, particularly among those aged 40 and older, based on large U.S. surveillance data from 1975 to 2019.^[10] Roughly 50% of MPNSTs arise in association with neurofibromatosis type 1 (NF1), a genetic disorder that dramatically elevates risk, with a lifetime incidence of 8-13% among NF1 patients compared to the general population.^[11]^[12] These tumors typically manifest in young to middle-aged adults, with a peak incidence between 20 and 50 years, though cases occur across all age groups, including children and the elderly.^[8]^[9] Sex distribution is approximately equal overall, with some studies noting a slight male predominance, especially in younger adults (e.g., ages 20-29).^[8]^[10] Racial disparities exist, with higher incidence rates observed among non-Hispanic Black individuals compared to non-Hispanic White or Asian/Pacific Islander populations in U.S. data.^[10]

Etiology and Pathogenesis

Risk factors

The primary risk factor for malignant peripheral nerve sheath tumor (MPNST) is neurofibromatosis type 1 (NF1), an autosomal dominant genetic disorder resulting from mutations in the NF1 gene on chromosome 17q11.2, which encodes the neurofibromin protein that regulates cell growth. Approximately 50% of MPNST cases occur in individuals with NF1, and conversely, 25% to 50% of patients diagnosed with MPNST have this condition.^[4] Individuals with NF1 face a lifetime risk of developing MPNST estimated at 8% to 13%, with tumors often arising from preexisting plexiform neurofibromas, which carry a transformation risk of up to 10%.^[13] In pediatric cohorts, NF1 is present in about 48% of MPNST cases and is independently associated with worse prognosis, with a hazard ratio of 2.2 for overall survival.^[13]^[4] Prior exposure to ionizing radiation is another established risk factor, accounting for roughly 10% of MPNST cases. These tumors typically develop 10 to 20 years after radiation therapy for unrelated cancers or other conditions, often in the radiation field.^[4]^[5] Environmental radiation exposure may also contribute, though less commonly documented.^[14] MPNSTs can arise de novo or through malignant transformation of benign peripheral nerve sheath tumors, such as neurofibromas or schwannomas, independent of NF1. In non-NF1 patients, sporadic genetic alterations, including loss of NF1 function or mutations in tumor suppressor genes like TP53, increase susceptibility, though these are not as strongly linked as hereditary syndromes.^[5] No other consistent environmental or lifestyle risk factors, such as smoking or chemical exposures, have been definitively established.^[4]

Genetics and molecular biology

Malignant peripheral nerve sheath tumors (MPNSTs) are strongly associated with neurofibromatosis type 1 (NF1), where biallelic inactivation of the NF1 tumor suppressor gene on chromosome 17q11.2 occurs in nearly all (approaching 100%) NF1-associated cases, driving uncontrolled RAS signaling and tumor initiation.^[15] This loss-of-function mutation, often through large deletions or intragenic mutations, is a hallmark event in NF1-associated MPNSTs, occurring in both germline and somatic contexts, and is less frequent (around 50%) in sporadic tumors.^[15] Seminal studies have established NF1 inactivation as the foundational genetic hit, with subsequent accumulation of alterations promoting malignant progression from benign neurofibromas. Additional recurrent genetic alterations include homozygous deletions or mutations in CDKN2A/B on chromosome 9p21, reported in 58%-81% of MPNSTs, which disrupt cell cycle regulation and are early events in atypical neurofibroma transformation.^[15] Inactivation of the Polycomb repressive complex 2 (PRC2) components, such as SUZ12 (34%-50%) and EED (up to 37.5%), leads to loss of histone H3 lysine 27 trimethylation (H3K27me3); the absence of H3K27me3 is observed in over 70% of MPNSTs and serves as a diagnostic hallmark.^[16] TP53 mutations or deletions affect 40%-75% of cases, correlating with aggressive behavior and poor survival, while other genes like PTEN, EGFR, and BRAF are variably altered, amplifying PI3K-AKT-mTOR and RAS-RAF-MAPK pathways.^[15] These changes collectively enhance genomic instability and oncogenic signaling. Multiplatform genomic analyses have revealed two molecular subgroups of MPNSTs: one (e.g., MPNST-G1) characterized by PRC2 mutations, complex copy number alterations (affecting ~17 chromosomes), hypermethylation, and Sonic Hedgehog (SHH) pathway activation, associated with worse progression-free survival; the other (MPNST-G2) features NF1 mutations, fewer alterations (~9 chromosomes), hypomethylation, and WNT pathway activation.^[17] Chromosomal abnormalities are prominent, including gains in 8q and 17q, losses in 9p21, and whole-genome doubling, with H3K27me3 loss tumors showing extensive loss of heterozygosity and chromothripsis.^[18] Evolutionary models indicate progression from NF1 inactivation to CDKN2A loss, followed by PRC2 or TP53 alterations, detectable in cell-free DNA for non-invasive monitoring and prognosis.^[18] Recent multiomic studies (as of 2025) have highlighted additional vulnerabilities, including activation of the pentose phosphate pathway (PPP) in NF1-associated MPNSTs and DLK1 expression distinguishing aggressive subsets, alongside new PRC2-regulated targets in Schwann cells.^[19]^[20]^[21]^[22] These molecular insights underscore potential therapeutic targets, such as MEK inhibitors for RAS pathway dysregulation and SMO inhibitors for SHH-activated subgroups.^[17]

Clinical Features

Signs and symptoms

Malignant peripheral nerve sheath tumors (MPNSTs) most commonly present as a rapidly enlarging, palpable soft-tissue mass, often greater than 5 cm in size at diagnosis.^[23] These tumors frequently arise in the extremities, trunk, or pelvis, and the mass may initially be painless but can become tender as it grows.^[5] In patients with neurofibromatosis type 1 (NF1), which accounts for about 50% of cases, the tumor often develops from a preexisting plexiform neurofibroma, leading to sudden enlargement or new symptoms in an established lesion.^[23] Pain is a prominent symptom, reported in the majority of patients, and may be constant, worsening, or radicular in nature due to nerve compression or infiltration.^[2] Neurological deficits are common and include weakness, paresthesias (such as tingling or numbness), hypoesthesia (reduced sensation), or dysesthesia (abnormal sensations like burning) in the affected area, reflecting the tumor's origin from peripheral nerves.^[4]^[2] These symptoms typically progress quickly as the tumor invades nearby tissues or nerve plexuses, potentially causing motor impairment or loss of function in the involved limb.^[5] Early-stage tumors may be asymptomatic, particularly if deep-seated, allowing them to go unnoticed until they reach a significant size or cause mass effect.^[24] In NF1-associated cases, any new or persistent pain in a known neurofibroma is a red flag for malignant transformation and warrants prompt evaluation.^[23] Systemic symptoms like weight loss or fever are rare unless metastasis has occurred, most commonly to the lungs.^[3]

Associated conditions

Malignant peripheral nerve sheath tumors (MPNSTs) are strongly associated with neurofibromatosis type 1 (NF1), an autosomal dominant genetic disorder caused by mutations in the NF1 gene on chromosome 17, which encodes the protein neurofibromin. Approximately 50% of MPNST cases occur in individuals with NF1, a condition that affects about 1 in 3,000 live births.^[23] In NF1 patients, the lifetime risk of developing an MPNST is 8% to 13%, with tumors often arising from malignant transformation of preexisting benign plexiform neurofibromas, which are pathognomonic for the syndrome.^[3]^[23] This association underscores the role of NF1 loss in tumorigenesis, leading to hyperactivation of the RAS-MAPK signaling pathway and increased cellular proliferation.^[23] Beyond NF1, MPNSTs can rarely arise in the context of other hereditary syndromes, though these links are less established and occur at much lower frequencies. For instance, isolated case reports document MPNST development in schwannomatosis, a condition characterized by multiple schwannomas due to germline mutations in SMARCB1 or LZTR1 genes; however, the incidence of malignant transformation in schwannomatosis-associated tumors is extremely rare compared to NF1.^[25] Similarly, a potential but unconfirmed association exists with Li-Fraumeni syndrome, driven by germline TP53 mutations, where MPNSTs may represent one of the diverse sarcomas in this high-cancer-risk disorder, though establishing a direct causal link remains challenging due to the syndrome's broad tumor spectrum.^[26] Prior radiation exposure is another notable association, accounting for about 10% of MPNST cases, often following therapeutic irradiation for conditions like breast cancer or lymphoma, with tumors typically emerging 5 to 20 years post-exposure.^[23] These radiation-induced MPNSTs tend to have poorer prognoses and distinct molecular profiles compared to NF1-associated or sporadic forms.^[23] Overall, while NF1 dominates the syndromic associations, screening for MPNST is particularly emphasized in at-risk populations with these conditions to facilitate early detection.^[3]

Diagnosis

Imaging and clinical evaluation

Clinical evaluation of malignant peripheral nerve sheath tumors (MPNSTs) typically begins with assessment of symptoms that may indicate malignant transformation, particularly in patients with neurofibromatosis type 1 (NF1), where approximately 50% of MPNSTs arise. Common presenting features include a rapidly enlarging, painful soft-tissue mass, often accompanied by new-onset neurological deficits such as hypoesthesia, dysesthesia, or motor weakness due to nerve compression or invasion. In sporadic cases without NF1, patients may report localized pain or a palpable lump, with tumors frequently located along the sciatic nerve, brachial plexus, or sacral plexus. Suspicion is heightened in NF1 patients with plexiform neurofibromas showing sudden growth or symptom changes, prompting multidisciplinary evaluation involving neurologists, oncologists, and surgeons to correlate clinical findings with imaging and biopsy results.^[27] Magnetic resonance imaging (MRI) serves as the cornerstone for initial imaging evaluation, offering superior soft-tissue contrast to delineate tumor extent, margins, and relationship to surrounding nerves and structures. On T2-weighted sequences, MPNSTs typically appear heterogeneous with hyperintense areas indicating cystic changes, necrosis, or hemorrhage, contrasting with the more uniform "target sign" (central hypointensity surrounded by peripheral hyperintensity) seen in benign neurofibromas. Key malignant features include irregular or infiltrative margins, peritumoral edema (described as a "feathery" appearance), and nodular or peripheral enhancement on post-gadolinium T1-weighted images. Diffusion-weighted imaging (DWI) enhances diagnostic accuracy, with lower apparent diffusion coefficient (ADC) values (sensitivity 88%, specificity 94%) reflecting increased cellularity in MPNSTs compared to benign lesions. A meta-analysis of 616 patients reported MRI sensitivity of 68% and specificity of 93% for distinguishing MPNSTs from benign peripheral nerve sheath tumors (PNSTs).^[28]^[27]^[28] Computed tomography (CT) is adjunctive, particularly for assessing bony involvement or calcification, though it lacks specificity for soft-tissue characterization. MPNSTs may appear as ill-defined masses with possible erosion of adjacent bone, but CT is less sensitive than MRI for nerve sheath origin. Positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) is valuable for metabolic assessment and detecting multifocal disease, especially in NF1 patients; MPNSTs exhibit significantly higher maximum standardized uptake values (SUVmax, typically 3-21, mean ~14.4) than benign PNSTs (mean ~4.9), with SUV exceeding 1.5 times hepatic uptake strongly suggesting malignancy (sensitivity >90%, specificity >70%). Combined PET/MRI further improves accuracy for preoperative planning and surveillance. Ultrasound, while operator-dependent, can initially evaluate superficial lesions, revealing heterogeneous echotexture, irregular margins, and increased vascularity in MPNSTs versus homogeneous features in benign tumors >5 cm in size. Definitive diagnosis requires histopathological confirmation, as imaging alone cannot reliably exclude malignancy.^[28]^[27]^[28]

Histopathology and classification

Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive sarcomas arising from the peripheral nerve sheath, characterized by a heterogeneous microscopic appearance that often includes alternating hypercellular and hypocellular areas, giving a marbled pattern on low-power examination.^[7] The tumor typically consists of spindle cells arranged in sweeping fascicles with wavy, buckled, or hyperchromatic nuclei, resembling fibrosarcoma, though areas of myxoid stroma, geographic necrosis, and perivascular accentuation are common.^[7] Mitotic activity varies, but high-grade lesions show frequent mitoses (often ≥10 per 10 high-power fields) and nuclear pleomorphism, while low-grade forms exhibit milder atypia and fewer mitoses.^[7] Heterologous elements, such as rhabdomyoblastic (malignant Triton tumor), chondrosarcomatous, or osteosarcomatous differentiation, occur in approximately 10-15% of cases, complicating diagnosis.^[7] Diagnosis relies on histopathological examination combined with clinical context, as no single biomarker is entirely specific; tumors often arise de novo or from preexisting neurofibromas, particularly in neurofibromatosis type 1 (NF1) patients.^[29] Key diagnostic criteria include origin from a nerve or preexisting benign nerve sheath tumor, spindle cell morphology with nerve sheath features, and exclusion of mimics like fibrosarcoma, leiomyosarcoma, or melanoma via immunohistochemistry.^[7] Immunohistochemically, about 50% of MPNSTs express S100 protein (often focal) and SOX10, supporting neural differentiation, but they are typically negative for EMA, cytokeratins, desmin, smooth muscle actin, and other markers like MUC4 (to rule out synovial sarcoma).^[7] Molecular testing may reveal loss of H3K27me3 expression in up to 90% of NF1-associated cases, aiding distinction from other sarcomas.^[29] In the 2020 World Health Organization (WHO) classification of soft tissue tumors, MPNSTs are categorized under peripheral nerve sheath tumors as malignant neoplasms (ICD-O code 9540/3), with epithelioid variants designated as 9542/3.^[30] The classification recognizes subtypes including epithelioid MPNST, melanotic MPNST (formerly melanotic schwannoma, reclassified due to malignant potential), and those with rhabdomyoblastic differentiation.^[31] Grading follows the French Federation of Cancer Centers Sarcoma Group (FNCLCC) system, assessing tumor differentiation, mitotic count, and necrosis to assign grades 1-3, where grade 1 (low) features well-differentiated morphology with <10% necrosis and low mitotic rate, and grade 3 (high) shows poor differentiation, ≥10 mitoses per 10 high-power fields, and >50% necrosis—prognostic implications are significant, with higher grades correlating to worse outcomes.^[29] Atypical neurofibromatous tumors of uncertain biologic potential (ANNUBP) represent an intermediate category with borderline features like cytologic atypia and low mitotic activity, not fully meeting MPNST criteria.^[7]

Management

Surgical treatment

Surgical treatment remains the cornerstone of management for localized malignant peripheral nerve sheath tumors (MPNSTs), aiming for complete resection to achieve local control and potential cure.^[32] The primary goal is to perform a wide local excision with negative margins (R0 resection), typically involving removal of the tumor along with a 1-2 cm cuff of surrounding normal tissue to minimize the risk of local recurrence.^[33] This approach is particularly challenging due to the tumors' origin along peripheral nerves, often requiring nerve sacrifice and reconstruction, especially in patients with neurofibromatosis type 1 (NF1), where MPNSTs arise from plexiform neurofibromas in up to 50% of cases.^[34] Multidisciplinary evaluation at specialized sarcoma centers is essential to balance oncologic efficacy with functional preservation, incorporating input from neurosurgeons, orthopedic surgeons, and plastic surgeons.^[34] For resectable tumors, limb-sparing surgery is preferred over amputation when feasible, preserving function while achieving adequate margins; amputation is reserved for cases where vital structures are extensively involved or prior resections have failed.^[35] Gross total resection is achieved in approximately 73% of cases across large cohorts, correlating with improved survival compared to subtotal resections.^[32] Positive margins (R1 or R2) significantly elevate local recurrence rates, with meta-analyses reporting a 2.4-fold increased risk, underscoring the need for preoperative imaging and planning to optimize surgical outcomes.^[32] In NF1-associated MPNSTs, which comprise 40-50% of cases and often present at larger sizes (>5 cm), achieving R0 resection is more difficult, yet it remains the only potentially curative modality. NF1-associated cases are linked to worse outcomes compared to sporadic MPNSTs.^[34]^[36] Postoperative complications include wound infections, nerve deficits, and functional impairments, occurring in up to 30% of patients, with higher rates in extremity tumors requiring extensive reconstruction.^[32] Despite optimal surgery, 5-year overall survival following resection is around 47%, influenced by tumor grade, size, and NF1 status.^[32] Adjuvant therapies are often integrated based on margin status and risk factors, but surgery alone provides the best chance for long-term control in low-burden disease.^[3] For metastatic or unresectable MPNSTs, palliative debulking may alleviate symptoms, though it does not alter overall prognosis.^[33]

Adjuvant therapies

Adjuvant therapies for malignant peripheral nerve sheath tumors (MPNSTs) are employed following surgical resection to improve local control and address microscopic disease, particularly in high-risk cases such as those with large tumors (>5 cm), high-grade histology, or incomplete margins. Radiation therapy is the most commonly recommended adjuvant modality, typically delivered at doses of 50-60 Gy to the tumor bed, which has been shown to reduce local recurrence rates without conferring a clear survival advantage. In a retrospective analysis of 120 patients with sporadic MPNSTs, adjuvant radiation was associated with improved local control (5-year local recurrence-free survival of 70% versus 46% without radiation), though overall survival remained similar between groups. For NF1-associated MPNSTs, radiation use is more cautious due to risks of secondary malignancies and growth impairment in pediatric patients, but it remains indicated for high-risk features.^[37] Chemotherapy as an adjuvant treatment is controversial and generally not supported by strong evidence for routine use in localized MPNSTs, given their relative chemoresistance and the lack of impact on survival or recurrence in multiple studies. Standard regimens, such as doxorubicin combined with ifosfamide, yield response rates of approximately 20-30% in advanced disease but show no significant benefit in the adjuvant setting; a phase II trial (SARC006) reported a median progression-free survival of only 3.6 months with this combination in chemotherapy-naïve patients. However, select regimens like epirubicin plus ifosfamide have demonstrated modest improvements in post-local therapy survival (median 75 months versus 45 months without), prompting consideration in cases with adverse prognostic factors. The Children's Oncology Group ARST0332 trial in pediatric patients incorporated adjuvant chemotherapy with ifosfamide and doxorubicin alongside radiation for intermediate- and high-risk MPNSTs, achieving 5-year event-free survival rates of 65% and 21%, respectively, though these outcomes reflect multimodality approaches rather than chemotherapy alone.^[37]^[2] Emerging targeted therapies, such as MEK inhibitors (e.g., selumetinib), are under investigation for NF1-associated MPNSTs due to the role of RAS pathway dysregulation, but their adjuvant application remains experimental and is not standard. As of 2025, additional investigational approaches include PRMT5 inhibitors, which show promise in preclinical and early clinical studies for MTAP-deficient MPNSTs, and combination therapies like pexidartinib (a CSF1R inhibitor) plus sirolimus (an mTOR inhibitor), demonstrating clinical benefit in unresectable cases. Overall, decisions for adjuvant therapies should be individualized, guided by multidisciplinary tumor boards, with emphasis on balancing efficacy against potential toxicities like neuropathy exacerbation or secondary cancers.^[37]^[38]^[39]

Prognosis and Outcomes

Survival rates

The prognosis for malignant peripheral nerve sheath tumors (MPNSTs) is generally poor, with 5-year overall survival (OS) rates varying widely across studies, typically ranging from 23% to 69%.^[3] A 2020 systematic review and meta-analysis of 22 studies involving 6,742 patients reported a pooled 5-year OS rate of 49% (95% CI: 45–53%).^[40] Similarly, a 2024 meta-analysis confirmed 5-year survival rates between 16% and 62%, emphasizing the aggressive nature of the disease.^[41] A 2025 meta-analysis of surgical outcomes from 16 studies and 4,265 patients reported a pooled 5-year OS of 47% (95% CI: 35–58%).^[42] Survival outcomes differ significantly between NF1-associated and sporadic MPNSTs, with NF1-associated cases showing worse prognosis. In the 2020 meta-analysis, NF1 status was associated with a hazard ratio (HR) of 1.56 (95% CI: 1.35–1.79) for poorer OS compared to sporadic tumors.^[40] The 2024 meta-analysis of 59 studies (3,602 patients) further quantified this disparity, reporting an HR of 1.63 (95% CI: 1.45–1.84) for all-cause mortality and 1.52 (95% CI: 1.24–1.88) for disease-specific mortality in NF1-associated MPNSTs.^[41] The 2025 meta-analysis reported 5-year OS of 50% (95% CI: 31–68%) for NF1-associated cases.^[42] Event-free survival (EFS) rates are also low, with the 2020 meta-analysis pooling data from 8 studies (1,243 patients) to estimate a 5-year EFS of 37% (95% CI: 32–43%).^[40] Median overall survival has been reported as 55 months in a retrospective series of 65 patients, with a 5-year OS of 49%.^[43] For completely resected tumors, 3- and 5-year tumor-free survival rates were 40% and 34%, respectively, in a study of 159 cases.^[44] These figures underscore the challenges in achieving long-term remission, particularly in advanced or metastatic disease.

Factors affecting prognosis

The prognosis of malignant peripheral nerve sheath tumors (MPNSTs) is generally poor, with five-year overall survival rates ranging from 23% to 69% across studies and influenced by multiple clinical, pathological, and molecular factors.^[3] Among these, association with neurofibromatosis type 1 (NF1) is a significant adverse predictor; NF1-related MPNSTs exhibit higher mortality risks, with meta-analyses reporting a 63% increased hazard ratio for overall survival (HR 1.63, 95% CI 1.45–1.84) and a 52% increased hazard for disease-specific survival (HR 1.52, 95% CI 1.24–1.88) compared to sporadic cases.^[41] This disparity persists in multivariate analyses, independent of study quality or publication year, though some institutional series show no significant survival difference after adjusting for tumor size.^[41]^[45] Tumor characteristics play a central role in outcomes, particularly size and location. Tumors exceeding 5 cm in diameter are linked to reduced disease-specific and overall survival, with larger lesions complicating complete resection and increasing recurrence risk.^[46] Deep-seated or retroperitoneal tumors confer worse prognosis than superficial or extremity-based ones, with median survival for retroperitoneal MPNSTs at approximately 1.1 years versus 6.0 years for non-retroperitoneal sites (p < 0.05).^[47] Axial or trunk locations similarly predict poorer survival compared to extremities.^[48] Surgical resectability and margin status are critical determinants of long-term survival. Achievement of R0 (negative) margins yields the best outcomes, with 10-year overall survival rates up to 65%, while R2 (grossly positive) resections are associated with markedly inferior survival (HR 2.61, p = 0.043) and median survival under 1 year.^[48]^[47] No significant survival benefit is observed between R0 and R1 (microscopically positive) margins in some cohorts.^[47] Patient demographics and comorbidities also modulate prognosis. Older age at diagnosis (over 60 years) correlates with reduced median survival (4.5 years versus 14.5 years for those under 60; p < 0.05), reflecting higher comorbidity burdens such as those captured by the Charlson-Deyo score.^[47] The presence of metastases at presentation is the strongest negative factor, drastically lowering five-year overall survival to 22% from 55% in localized disease (p < 0.001).^[48] Pathological grade and molecular features further refine risk stratification. High-grade tumors, per the French Federation of Cancer Centers Sarcoma Group (FNCLCC) system, predict worse survival and higher metastasis rates, while 10–15% of MPNSTs classified as low-grade have relatively better outcomes.^[46] Loss of histone H3K27 trimethylation (H3K27me3), observed in up to 50% of cases, is associated with inferior survival and may serve as a biomarker for aggressive disease.^[46] Adjuvant therapies like radiotherapy and chemotherapy show limited impact on survival in multivariate models, underscoring the dominance of these inherent factors.^[47]

References

[1]
Definition of malignant peripheral nerve sheath tumor
A type of soft tissue sarcoma that develops in cells that form a protective sheath (covering) around peripheral nerves.
[2]
Malignant Peripheral Nerve Sheath Tumors—A Comprehensive ...
Jan 1, 2022 · Malignant peripheral nerve sheath tumors (MPNSTs) are malignant, locally aggressive soft tissue sarcomas (STS) with nerve sheath differentiation ...3. Mpnst Pathophysiology · 4.2. Radiology · 4.3. Histopathology
[3]
Malignant Peripheral Nerve Sheath Tumor - National Cancer Institute
Jul 22, 2020 · Malignant Peripheral Nerve Sheath Tumor, or MPNST, is a cancer of the cells that form the sheath that covers and protects peripheral nerves.
[4]
Malignant Peripheral Nerve Sheath Tumor (MPNST) - Cleveland Clinic
Jul 31, 2024 · A malignant peripheral nerve sheath tumor (MPNST) is a very rare type of soft tissue sarcoma. In MPNST, there are malignant (cancerous) tumors ...
[5]
Malignant peripheral nerve sheath tumors - Symptoms and causes
Jul 31, 2024 · Malignant peripheral nerve sheath tumors are rare cancers that start in the lining of the nerves. These cancers happen in the nerves that ...
[6]
Malignant peripheral nerve sheath tumor (MPNST)
Sep 19, 2023 · Malignant neoplasm arising from peripheral nerve; May arise from a preexisting nerve sheath tumor in neurofibromatosis type 1 (NF1) or in ...
[7]
Malignant peripheral nerve sheath tumor - Orphanet
Incidence of MPNST in the general population has been reported to be 1/100,000. MPNSTs account for about 5 to 10% of all soft tissue sarcomas. The sex ratio is ...
[8]
Epidemiology, Characteristic, and Prognostic Factors of ... - Frontiers
Jul 7, 2022 · MPNSTs are highly aggressive and locally invasive rare malignancies with an incidence of 0.0001% in the general population and 3%–5% in patients ...Abstract · Introduction · Materials and Methods · Discussion
[9]
Epidemiologic and survival analysis of malignant peripheral nerve ...
Malignant peripheral nerve sheath tumor (MPNST) is an aggressive soft-tissue sarcoma that originates from Schwann cells or pluripotent cells of the neural crest ...
[10]
Superficial malignant peripheral nerve sheath tumor from recurrent ...
Dec 20, 2018 · Fifty percent of patients with MPNST have neurofibromatosis type 1 (NF1). NF-associated MPNST occurs more often at younger ages than ...Missing: proportion | Show results with:proportion
[11]
Neurofibromatosis type I-associated malignant peripheral nerve ...
In NF1 patients, the lifetime risk of MPNST is 8% to 13% [4]. The recovery from NF1-associated MPNST is worse than the sporadic or radiation-related form [5].
[12]
Risk factors in pediatric Malignant Peripheral Nerve Sheath Tumors ...
Patients harboring the NF1 gene pathogenic variant have a lifelong risk of presenting MPNST at a rate of 8–13%, often after transformation of existing plexiform ...Risk Factors In Pediatric... · 3. Results · 3.6. Factors Associated With...
[13]
Malignant Peripheral Nerve Sheath Tumor - Aurora Health Care
Previous radiation exposure, from treatment or from the environment, also increases the risk of developing these tumors. However, some cases occur randomly ...
[14]
Genetics of human malignant peripheral nerve sheath tumors - PMC
Here we review the genetic discoveries and their implications in understanding MPNST biology. ... Malignant peripheral nerve sheath tumor: molecular ...
[15]
https://pmc.ncbi.nlm.nih.gov/articles/PMC7317054/
[16]
Multiplatform molecular profiling uncovers two subgroups of ... - Nature
May 10, 2023 · Malignant peripheral nerve sheath tumor (MPNST) is a highly aggressive sarcoma, and a lethal neurofibromatosis type 1-related malignancy, with ...
[17]
Genomic Patterns of Malignant Peripheral Nerve Sheath Tumor ...
Genomic patterns of malignant peripheral nerve sheath tumor (MPNST) evolution correlate with clinical outcome and are detectable in cell-free DNA.Abstract · INTRODUCTION · RESULTS · METHODS
[18]
Malignant Peripheral Nerve Sheath Tumors - PMC - PubMed Central
Malignant peripheral nerve sheath tumors (MPNST) are uncommon, biologically aggressive soft tissue sarcomas of neural origin that pose tremendous challenges to ...Epidemiology, Etiology, And... · Clinical Presentation And... · Treatment
[19]
Malignant Peripheral Nerve Sheath Tumor - Penn Medicine
A malignant peripheral nerve sheath tumor is a rare, aggressive soft tissue sarcoma that develops in protective coverings called sheaths surrounding certain ...
[20]
Malignant Peripheral Nerve Sheath Tumor Arising in ... - PubMed
Many cases of MPNST usually developed from neurofibromatosis type 1. However, the incidence of MPNST arising from schwannomatosis was extremely rare.
[21]
Malignant peripheral nerve sheath tumours in inherited disease - PMC
Oct 4, 2012 · MPNST is associated with schwannomatosis and TP53 mutations and is confirmed at high frequency in NF1. It appears to be only increased in NF2 ...
[22]
https://academic.oup.com/noa/article/6/1/vdae188/7888919
[23]
https://pmc.ncbi.nlm.nih.gov/articles/PMC3926794/
[24]
Histopathologic findings in malignant peripheral nerve sheath tumor ...
Oct 1, 2020 · Malignant peripheral nerve sheath tumor (MPNST) is an aggressive and rare neoplasm involving peripheral nerves and extraneural soft tissues.
[25]
WHO classification - Soft tissue - Pathology Outlines
Dec 30, 2024 · WHO classification · Malignant peripheral nerve sheath tumor, NOS9540/3. Malignant peripheral nerve sheath tumor, epithelioid9542/3 · Melanotic ...
[26]
The 2020 WHO Classification of Soft Tissue Tumours
The recent publication of the new WHO classification of Soft Tissue Tumours and Bone represents a major step toward improved standardization of diagnosis.
[27]
An Assessment of Surgical Outcomes in Malignant Peripheral Nerve ...
Jun 15, 2025 · An assessment of surgical outcomes in malignant peripheral nerve sheath tumors: a systematic review and meta-analysis of surgical interventions.
[28]
Soft Tissue Sarcoma - Guidelines Detail - NCCN
Guidelines Firewall Policy Treatment by Cancer Type Detection, Prevention, and ... - Malignant peripheral nerve sheath tumor. - Malignant Perivascular ...Missing: surgical | Show results with:surgical
[29]
Contemporary Approach to Neurofibromatosis Type 1–Associated ...
May 6, 2024 · Most malignant peripheral nerve sheath tumors (MPNSTs) are clinically aggressive high-grade sarcomas, arising in individuals with neurofibromatosis type 1 (NF1 ...
[30]
[PDF] NCCN Guidelines for Patients: Soft Tissue Sarcoma
Surgery is the main treatment for sarcoma that has not spread. The method and extent of surgery for sarcoma depend on the tumor's location and size, and whether ...
[31]
Malignant Peripheral Nerve Sheath Tumors - PubMed Central - NIH
Malignant peripheral nerve sheath tumor (MPNST) is an aggressive soft tissue sarcoma with limited therapeutic options and a poor prognosis.2. Etiology And Risk Factors · 4. Diagnosis · 5. Treatment
[32]
Prognosis and risk factors for malignant peripheral nerve sheath tumor
The significant prognostic factors for survival were NF1 status, tumor size, depth, location, malignant grade, margin status, chemotherapy, and radiotherapy.
[33]
Survival outcomes of malignant peripheral nerve sheath tumors ...
Jan 9, 2024 · The prognosis for MPNST is poor and has remained abysmal in the last few decades with 5-year survival rates ranging between 16 and 62% [6, 7].
[34]
Diagnosis, Treatment and Survival of 65 Patients with Malignant ...
The overall median survival rate was 55 months (Figure 1). The 5-year overall survival was 49%. Of the patients with T1 tumors 60% were still alive five years ...
[35]
a retrospective study of 159 cases from 1999 to 2016 - Oncotarget
Dec 1, 2017 · 3- and 5-year tumor-free survival rates for 140 completely resected patients were 40.0% and 34.0%, respectively. Multivariate analysis showed ...
[36]
Malignant Peripheral Nerve Sheath Tumors: Latest Concepts ... - MDPI
Malignant peripheral nerve sheath tumor (MPNST) is an aggressive soft tissue sarcoma with limited therapeutic options and a poor prognosis.<|control11|><|separator|>
[37]
Malignant peripheral nerve sheath tumors: prognostic factors and ...
The disease-specific mortality rate was 43% at 10 years, with a continuously disease-free survival rate of no greater than 40%. Presentation with either primary ...
[38]
https://aacrjournals.org/clincancerres/article/31/22/4620/767059/PRMT5-Inhibition-Hits-a-Nerve-Sheath-Tumor-A
[39]
Outcomes of Treatment for Malignant Peripheral Nerve Sheath Tumors
Dec 1, 2016 · These tumors account for 5%-10% of all soft tissue tumors, but their occurrence is rare in the general population with an estimated annual ...