Malignant peripheral nerve sheath tumour (MPNST)

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Cranial and paraspinal nerve tumours

General

• Not recommended terminology
• Malignant schwannoma
• Neurofibrosarcoma
• Neurogenic sarcoma

Definition

• Essential:
• Histopathologically consistent malignant spindle cell tumour in a patient with NF1 OR
• In a pre-existing neurofibroma
• OR
• Malignant spindle cell tumour associated with a peripheral nerve AND
• No more than focal/patchy S100/SOX10 expression AND
• No SS18::SSX (SSX1, SSX2, or SSX4) fusion gene present
• t(X;18)(p11;q11) translocation, resulting in SS18-SSX rearrangements → pathogonomic for Synovial sarcoma
• OR
• Malignant spindle cell tumour associated with a peripheral nerve AND
• Evidence of PRC2 inactivation (molecularly or via loss of H3 p.K28me3 [K27me3] immunostaining)
• OR
• Tumour with features of ANNUBP in a patient with NF1, but with a mitotic count of at least 1.5-4.5 mitoses/mm2 (3-9 mitoses/10 HPF of 0.51 mm in diameter and 0.20 mm2 in area)
• OR
• Unresolved lesion with the methylation profile of MPNST

• Desirable:
• Loss of H3 p.K28me3 (K27me3)
• Loss of neurofibromin expression

Number

• Rare
• 2-10% of all soft tissue sarcoma
• 1.46 cases per 1 million person-years;

• Between 20-50 yrs
• Mean age MPNSTs associated with NF1 is approximately a decade younger (28-36 years) than that of patients with sporadic cases

• Childhood and adolescent cases account for 10-20% of MPNSTs

• Greater risk in Black people and lower risk in Asian and Latino/a people than in White people;

• M:F ratio is roughly 1.2:1

CNS WHO grading

• No clinically validated and reproducible grading, non-validated grading

• Low grade (15%)
• Low-grade MPNSTs are well-differentiated tumours most often arising in transition from neurofibroma

• High-grade (85%): subtypes considered high grade
• Conventional monomorphous spindle cell MPNSTs,
• Highly pleomorphic MPNSTs, and
• MPNSTs with divergent differentiation (e.g. malignant triton tumour; glandular MPNST; and osteosarcomatous, chondrosarcomatous, and angiosarcomatous differentiation)

Aetiology

• 50% associated with NF1
• Typically arise from deep-seated plexiform neurofibromas or large intraneural neurofibromas
• Life time risk of MPNSTs in NF1 10%
• Known to be one of the most frequent causes of death in patients with NF1

• 40% of MPNSTs arise in patients without known predisposition

• 10% of MPNSTs are associated with previous radiation therapy

• Other rare examples due to development from
• Conventional schwannoma
• Ganglioneuroblastoma/ganglioneuroma
• Phaeochromocytoma

Cell of origin

• Derived from differentiated schwann cells and not directly from neural crest stem cells

Localization

• Large and medium > small nerves being affected
• Sciatic nerve is most frequently affected

• Common sites:
• Buttock and thigh
• Brachial plexus
• Paraspinal region

• Cranial nerve MPNSTs are rare, and more commonly arise from schwannomas than do MPNSTs located elsewhere

• Primary intracranial intraparenchymal MPNST is rare

Genetic

• NF1
• Plexiform neurofibromas OR localized intra neural neurofibromas (a sub population of schwann cells already carry biallelic inactivation of NF1) → atypical neurofibromatous neoplasm of uncertain biological potential (ANNUBP) (carries homozygous CDKN2A and/or CDKN2B deletions) → MPNST

• MPNST associated with NF1, sporadic MPNST, and radiation-induced MPNST share highly recurrent genetic inactivation in
• NF1
• Biallelic inactivation of NF1 is present in benign neurofibromas
• NF1 encodes for the important RasGAP neurofibromin, and its inactivation increases the levels of active RAS
• CDKN2A
• Atypical neurofibromas, which are presumed to be MPNST precursors, often show additional deletions in CDKN2A
• CDKN2A encodes for the important cell cycle regulators p16 and p14ARF, and deletion of the CDKN2A locus enables evasion from hyperactive RAS-induced senescence, promoting sustained proliferation
• PRC2 components SUZ12 and EED
• Tumour with loss of H3 p.K28me3 (K27me3)
• Deletion/mutation of SUZ12 or EED (both components of PRC2) → Loss of function of PRC2 → decreased levels of H3K27me3 (methylation) and increased levels of H3K27ac → amplifying the transcription of RAS target genes → EGER, PDGFRA, and MET
• Tumours with retained H3 p.K28me3 (K27me3)
• Are predominately paraspinal
• Show more frequent losses of 3q and gains of 5p

• Mutations of TP53 in 42% of MPNSTs,

• No cytogenetic differences have been noted between sporadic and NF1-associated

• Approximately half of all MPNSTs manifest in patients with NF1
• This association is particularly strong for malignant triton tumour and glandular MPNST

• Patients with NF1 and plexiform neurofibromas have the highest risk of developing MPNST

• Gain in distal 17q

• Loss of 13q14q21

Histopathology

Macroscopic

• Gross appearance of MPNST varies greatly.

• Sporadic tumours
• Fusiform, expansile masses or globular, entirely unencapsulated soft tissue tumours

• Familial tumour (NF1)
• Tumours arise in neurofibroma some as focal transformations, very little gross changes

• The vast majority of tumours are > 5 cm, and examples > 10 cm are common.

• Consistency ranges from soft to hard, and the cut surface is typically cream-coloured or grey.

Microscopic

• Many exhibit a herringbone (fibrosarcoma-like) or interwoven fasciculated pattern of cell growth

• Nuclei are typically elongated and wavy and (unlike those of smooth muscle) have tapered ends.

• Growth pattern
• Alternating loose and densely cellular areas (Marbling) or
• Diffuse

• Divergent differentiation
• Present in 15% of MPNSTs
• Of
• Mesenchymal
• Osseous
• Cartilaginous
• Rhabdomyosarcomatous (skeletal muscle)
• Aka Malignant triton tumour



• Epithelial elements
• Mucinous glands
• Islands of squamous differentiation

• Common perivascular hypercellularity and tumour aggregates appearing to herniate into vascular lumina

• A pseudocapsule of variable thickness is often present.

• 3/4 of these tumours have geographical necrosis and mitotic activity, often showing > 4 mitoses per high-power field (high-grade)

• Ki-67 index is > 20%

Immunohistochemistry reflects their neurogenic origin:

• Positive
• S100: positive in 50-70% -
• Low in high-grade MPNSTs
• p53 protein: positive in 75%
• EGFR: positive in 35%
• Amplification

• Negative
• CDKN2A (p16)
• Deletion
• SOX10
• Full-length neurofibromin is absent in
• 90% familial MPNSTs associated (NF1)
• 43% sporadic MPNSTs
• Loss of H3K27me3 expression
• Highly specific marker for MPNST,
• Only modestly more sensitive than S100 protein and SOX10,
• >90% of radiation-associated MPNST
• >60% of NF1-related MPNST
• 49-95% more variable within the sporadic MPNST

Clinical feature

• Most common presentation in the extremities is a progressively enlarging mass, with or without neurological symptoms.

• Spinal tumours often present with radicular pain

• Pain (41%) and weakness (26%) were the most common presenting symptoms.

Investigations

Imaging

• Imaging criteria are generally considered unreliable in differentiating from a more benign neurofibroma or schwannoma.

• However, general rules favouring an MPNST include:
• The larger the lesion, the more likely for it to be malignant
• Irregular borders (although most MPNSTs can have well-defined margins)
• Rapid growth in interval imaging

• MRI
• T1
• Usually isointense to muscle
• A heterogeneous signal on T1 (if present) may useful in differentiating from a neurofibroma
• T2
• Can have low signal due to high collagen content
Images





 


 

• FDG-PET is a most efficient imaging tool for the detection of MPNSTs in patients with NF1
• An SUVmax (maximum standardized uptake value) ratio greater than 1.5 provides a 98.8% negative predictive value, and a 61.5% positive predictive value.
• In view of the false positives rate, it is not specific enough to make an NF1 related MPNST diagnosis

EMG studies and NCS

• May assist in
• Localisation
• Detect subclinical deficits
• Document baseline function for future comparison

Variants

Epithelioid malignant peripheral nerve sheath tumour

• Characterized by a predominance of large epithelioid cells

• Are more common in superficial sites and in contrast to conventional MPNSTs,

• < 5% of MPNSTs are either partially or purely epithelioid

• No association with NF1

• The great majority of MPNST arising within pre- existing schwannomas are of epithelioid type

• Both superficial (above the fascia) and deep-seated examples have been reported.

• Risks of recurrence, metastasis, and disease-related death seem to be lower than those associated with conventional MPNST

• Immunophenotype
• Diffuse S100 protein expression is common
• SMARCB1 (INI1) is lost in 50% of cases

• Pathogenesis of epithelioid MPNST is distinct from that of conventional MPNST
• Epithelioid MPNSTs
• Are not associated with NF1
• Do not harbour most of the genetic alterations present in conventional MPNST;
• Retain H3 p.K28me3 (K27me3)
• Are driven by genetic inactivation of SMARCB1 in the vast majority of cases
• Recurrent chromosomal alterations include
• Loss of 22q,
• Deletion of 9p including CDKN2A and/or CDKN2B,
• Gain of 2q

 

MPNST with perineurial differentiation (malignant perineurioma)

• Rare MPNSTs show histological and ultrastructural features of perineurial differentiation.

• Like benign perineuriomas, these tumours are EMA-positive and S100-negative, but show hypercellularity, nuclear atypia, and increased mitotic activity.

• Perineurial MPNSTs have the potential to metastasize, but appear to be less aggressive than conventional MPNSTs

• Molecular data on perineurial MPNST are lacking;The pathogenesis of perineurial MPNST is currently unknown (WHO 2021).

Malignant peripheral nerve sheath tumour with divergent differentiation

• 2 types
• Malignant triton tumour
• MPNSTs showing rhabdomyosarcomatous differentiation
• 60% have NF1.
• Glandular malignant peripheral nerve sheath tumour
• A variant containing glandular epithelium that resembles that of intestine.
• Neuroendocrine differentiation is frequently seen, whereas squamous epithelium is far less often encountered.
• 75% have NF1

• Have similar microscopic features to ordinary MPNST suggest a close relationship between high-grade MPNST with divergent differentiation and conventional high-grade MPNST

• Immunophenotype
• Express differentiation markers
• Desmin in malignant triton tumour or
• Keratin, carcinoembryonic antigen, and neuroendocrine markers in glandular MPNST

Management

Surgical Treatment

• Goal of Resection: Postsurgical outcomes largely depend on achieving complete tumor resection with negative margins. This is critical for improving prognosis and minimizing the risk of recurrence.

• Classification of Resection: The extent of resection is classified based on postoperative imaging and intraoperative reports as:
• Biopsy (Bx)
• Partial Resection (PR) or Subtotal Resection (STR)
• Gross-Total Resection (GTR)

• Prognostic Impact of GTR: Achieving GTR is a key prognostic factor associated with significantly improved survival.
• GTR improved Overall Survival (OS) from a median of 9 months (in the non-GTR group) to 48 months.
• GTR prolonged Progression-Free Survival (PFS) from 5 months to 36 months.
• GTR is identified as a favorable criterion in the preliminary risk stratification tool for better outcomes.

• Frequency of GTR: In the reviewed cohort, 44.4% of patients (16 of 36 cases where operation status was recorded) underwent GTR.

Radiotherapy Treatment

• Adjuvant Radiotherapy Outcomes:
• Postoperative treatment with radiation therapy was recorded in the systematic review.
• In the meta-analysis, no statistically significant differences in outcomes were noted with adjuvant radiation therapy.
• However, adjuvant RT did show a trend toward improved outcomes. For instance, patients who received postoperative RT (11 cases) had a median OS of 17 months compared to 7 months for those who did not (17 cases).

• Neuro Phakomatosis and Risk of Prior Radiation Exposure:
• Radiation therapy is often avoided in NF2 patients due to the increased risk of secondary malignancies, including MPNSTs.
• Prior reports suggest RT can play a role in the malignant transformation of benign nerve sheath tumors.
• MPNSTs can arise in NF2 patients, especially those who have undergone radiotherapy.
• Having NF2 in the setting of prior radiation therapy is associated with decreased survival and increased progression. This factor places patients in the High-Risk category of the stratification tool.
• Only 37.9% of MPNST cases reviewed (n=29) occurred in a patient with a history of radiotherapy.
• Seven cases of NF2-associated vestibular schwannomas (VSs) were noted to have transformed following stereotactic radiosurgery (SRS).
• Limitations of RT:
• Based on experience with MPNST in NF1, challenges in achieving negative surgical margins in anatomically complex locations (e.g., spine and brachial plexus) can limit the overall effectiveness of RT, contributing to higher rates of recurrence and metastasis.

Chemotherapy Treatment

• 33.3% of patients received adjuvant chemotherapy.

• Porche 2025: Analysis comparing postoperative chemotherapy use (7 cases) versus no use (15 cases) showed no statistically significant difference in OS (p=0.575) or PFS (p=0.339).

Targeted therapies

• NF2-associated MPNSTs:
• Targets include inhibitors of the mTOR pathway and PLK1.
• Targeted therapies such as selumetinib, an MEK inhibitor used for NF1-associated tumors, are being investigated for use in NF2-associated tumors.
• BET inhibitors, targeting BRD4, are also being explored as a novel treatment option, though their efficacy in treating MPNSTs specifically remains limited.

• SMARCB1-related MPNSTs:
• Trials are being done on: EZH2 inhibitors, histone deacetylase inhibitors (HDACi), CDK4 inhibitors, aurora-A-kinase inhibitors, DNA methyltransferase inhibitors, and immunotherapy

Differential diagnosis

• Until proven otherwise, malignant spindle cell tumours in patients with NF1 should be considered to be MPNSTs

• Synovial sarcomas
• Common soft tissue sarcomas but can also occur as distinct rare primary tumours of nerve.
• Synovial sarcomas show considerable morphological and immunohistochemical overlap with tumours of the cranial and paraspinal nerves
• But unlike MPNSTs, they carry an SS18-SSX2o\ SS18SSX1 fusion gene

• Malignant melanoma
• MPNSTs do not staining for HMB45 and melan-A,
• MPNSTs is originate from a peripheral nerve or a benign nerve sheath tumour

• Cellular schwannoma
• Diffuse loss of SOX10 occurs in 75% of MPNSTs, but SOX10 is retained in cellular schwannomas
• Patchy expression of CDKN2A (p16) in cellular schwannoma but is loss in MPNST

Outcome and prognosis

• High metastatic potential
• 20-25% of patients develop metastases, most commonly to the lungs
• Spread:
• Often infiltrate adjacent soft tissues
• May spread along intraneural and haematogenous routes

• Porche 2025

• Poor prognosis
• MPNSTs (except those with perineurial differentiation) are highly aggressive tumours with a poor prognosis
• The mortality rate was 72.9%
• Poor prognostic factor
• Truncal location
• Tumour size > 5 cm
• Local recurrence
• High-grade designation
• Presence NF1 mutation
• Significantly worse outcomes for MPNST arising in the setting of NF1 compared to sporadic tumours
• Poorer responses to cytotoxic chemotherapy
• 5- year survival up to 50% worse
• Surgical margin status
• Local recurrence
• Heterologous rhabdomyoblastic differentiation.
• Chr changes
• Gains at 16p
• Losses from 10q or Xq
• CDK4 amplifications
• Nuclear p53 expression
• AKT activation
• TOR pathway activation
• MET activation
• 5- year OS
• NF1 associated MPNST: 35%
• Radiation induced MPNST: 23.5%
• MPNST Sporadic: 65%

• Epithelioid and perineurial MPNST have a less aggressive course