Malignant peripheral nerve sheath tumor (MPNST) is the sixth most common type of soft tissue sarcoma. Most MPNSTs arise in association with a peripheral nerve or preexisting neurofibroma. Neurofibromatosis type is the most important risk factor for MPNST. Tumor size and fludeoxyglucose F 18 avidity are among the most helpful parameters to distinguish MPNST from a benign peripheral nerve sheath tumor. The histopathologic diagnosis is predominantly a diagnosis of light microscopy. Immunohistochemical stains are most helpful to distinguish high-grade MPNST from its histologic mimics. Current surgical management of high-grade MPNST is similar to that of other high-grade soft tissue sarcomas.
Key points
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Malignant peripheral nerve sheath tumor (MPNST) is the sixth most common soft tissue sarcoma, often arises from a neurofibroma, and in half of cases occurs in a patient with neurofibromatosis type I.
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The most accurate radiographic evaluation of MPNST uses a combination of PET along with CT or MRI.
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The pathologic diagnoses of peripheral nerve sheath tumors with atypia represent a histologic continuum, and include neurofibroma with atypical features, low-grade MPNST, and high-grade MPNST.
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Management and prognosis significantly differ between low-grade MPNST and high-grade MPNST.
Introduction to malignant peripheral nerve sheath tumor
MPNST is the sixth most common type of soft-tissue sarcoma, accounting for approximately 5% to 10% of cases. Although its exact cellular origins remain unclear, most MPNSTs arise in association with a peripheral nerve and are hypothesized to be of neural crest origin. Approximately 50% of all MPNST cases arise sporadically, whereas the other 50% of cases are observed in patients with neurofibromatosis type 1 (NF1). NF1 (also termed von Recklinghausen disease) is an autosomal-dominant genetic disorder with high penetrance that is characterized by mutations in the Neurofibromin 1 gene, in which patients develop both superficial and deep neurofibromas, among other tumor types. Guidelines for the diagnosis of NF1 are summarized in Box 1 . NF1 patients carry an estimated 8% to 13% lifetime risk of developing MPNST, and 30% of NF1-associated MPNSTs progress from a deeply situated neurofibroma. The incidence of MPNST among NF1 patients is 1:3,500, in comparison to the incidence among the general population of 1:100,000. 6 NF1 patients are also predisposed to developing astrocytic brain tumors, pheochromocytoma, and myeloid leukemia, among a diverse array of other benign and malignant tumors. Another main risk factor for the development of MPNST is radiation exposure. An estimated 3% to 10% of all MPNST patients have a clinical history of prior radiation exposure. The latency period for radiation-associated MPNST is typically more than 15 years. The median age at diagnosis among sporadic MPNST patients is 41 years of age, whereas NF1-associated MPNST patients are generally younger (mean age of 28 years). Although infrequent, NF1-associated MPNSTs in childhood do occur. The incidence of sporadic MPNST is approximately equal among men and women, whereas NF1-associated MPNST is somewhat more common in men.
Two or more of the following signs or factors
Six or more café au lait macules
Two or more neurofibromas or one plexiform neurofibroma
Axillary or inguinal region freckling
Optic glioma
Two or more iris hamartomas (Lisch nodules)
First-degree relative with NF1
In general, the clinical presentation of MPNST is typical of a soft tissue sarcoma. MPNST presents as an enlarging mass for several months. The location is most commonly near nerve roots and bundles of the extremities and the pelvis, including the sciatic nerve, brachial plexus, and sacral plexus. Therefore, a majority of MPNST occur in the proximal portions of the upper and lower extremities. Symptoms include pain, paresthesia, and neurologic deficits. New-onset pain in an existing neurofibroma, especially in an NF1 patient, should prompt evaluation for MPNST. Currently, the clinical standard of care for localized high-grade MPNST is surgical resection and adjuvant radiation. An estimated 40% to 65% of MPNST patients experience local recurrence and 30% to 60% develop metastasis, with the most common site primarily located in the lungs. Although chemotherapy is administered to systemically manage metastatic MPNST, survival rates remain low. In general, a diagnosis of MPNST carries a poor prognosis. For all patients with high-grade MPNST, overall 5-year survival rate ranges from 20% to 50% and a mortality rate of up to 75%. Although it was previously believed that patients with NF1-associated tumors have a worse prognosis, this has been disproved across multiple studies.
Introduction to malignant peripheral nerve sheath tumor
MPNST is the sixth most common type of soft-tissue sarcoma, accounting for approximately 5% to 10% of cases. Although its exact cellular origins remain unclear, most MPNSTs arise in association with a peripheral nerve and are hypothesized to be of neural crest origin. Approximately 50% of all MPNST cases arise sporadically, whereas the other 50% of cases are observed in patients with neurofibromatosis type 1 (NF1). NF1 (also termed von Recklinghausen disease) is an autosomal-dominant genetic disorder with high penetrance that is characterized by mutations in the Neurofibromin 1 gene, in which patients develop both superficial and deep neurofibromas, among other tumor types. Guidelines for the diagnosis of NF1 are summarized in Box 1 . NF1 patients carry an estimated 8% to 13% lifetime risk of developing MPNST, and 30% of NF1-associated MPNSTs progress from a deeply situated neurofibroma. The incidence of MPNST among NF1 patients is 1:3,500, in comparison to the incidence among the general population of 1:100,000. 6 NF1 patients are also predisposed to developing astrocytic brain tumors, pheochromocytoma, and myeloid leukemia, among a diverse array of other benign and malignant tumors. Another main risk factor for the development of MPNST is radiation exposure. An estimated 3% to 10% of all MPNST patients have a clinical history of prior radiation exposure. The latency period for radiation-associated MPNST is typically more than 15 years. The median age at diagnosis among sporadic MPNST patients is 41 years of age, whereas NF1-associated MPNST patients are generally younger (mean age of 28 years). Although infrequent, NF1-associated MPNSTs in childhood do occur. The incidence of sporadic MPNST is approximately equal among men and women, whereas NF1-associated MPNST is somewhat more common in men.
Two or more of the following signs or factors
Six or more café au lait macules
Two or more neurofibromas or one plexiform neurofibroma
Axillary or inguinal region freckling
Optic glioma
Two or more iris hamartomas (Lisch nodules)
First-degree relative with NF1
In general, the clinical presentation of MPNST is typical of a soft tissue sarcoma. MPNST presents as an enlarging mass for several months. The location is most commonly near nerve roots and bundles of the extremities and the pelvis, including the sciatic nerve, brachial plexus, and sacral plexus. Therefore, a majority of MPNST occur in the proximal portions of the upper and lower extremities. Symptoms include pain, paresthesia, and neurologic deficits. New-onset pain in an existing neurofibroma, especially in an NF1 patient, should prompt evaluation for MPNST. Currently, the clinical standard of care for localized high-grade MPNST is surgical resection and adjuvant radiation. An estimated 40% to 65% of MPNST patients experience local recurrence and 30% to 60% develop metastasis, with the most common site primarily located in the lungs. Although chemotherapy is administered to systemically manage metastatic MPNST, survival rates remain low. In general, a diagnosis of MPNST carries a poor prognosis. For all patients with high-grade MPNST, overall 5-year survival rate ranges from 20% to 50% and a mortality rate of up to 75%. Although it was previously believed that patients with NF1-associated tumors have a worse prognosis, this has been disproved across multiple studies.
Molecular pathogenesis of malignant peripheral nerve sheath tumor
MPNSTs exhibit many different genetic aberrations that lead to the dysregulation of crucial signaling pathways that modulate cellular proliferation, growth, and apoptosis. Specifically, proteins that have been implicated in MPNST pathogenesis include neurofibromin 1, phosphatase and tensin homolog (PTEN), insulinlike growth factor 1 receptor (IGF1R), epidermal growth factor receptor (EGFR), and mitogen-activated protein kinases (MAPKs). As such, targeting these signal transduction pathways is an active area of research.
Neurofibromin 1
Mutations in the neurofibromin 1 tumor suppressor gene responsible for NF1 have been examined in research into the molecular pathogenesis of MPNST. In 1 study, Cichowski and Jacks found that the neurofibromin 1 gene is closely linked to the tumor suppressor gene p53 on chromosome 11 in mice. Specifically, mice carrying null mutations of both genes developed MPNST at high frequencies, indicating that concomitant loss of these tumor suppressors enables tumor cells to avoid growth arrest and apoptosis.
Phosphatase and Tensin Homolog
The tumor suppressor PTEN is a central negative regulator of the PI3K/AKT/mTOR signaling cascade, which controls cell growth, proliferation, and survival. PTEN is the most commonly altered component of the PI3K pathway in human malignancies, including MPNST. Specifically, the reduction or deletion of PTEN is associated with the malignant transformation of neurofibroma to MPNST in humans and animal models.
For example, Keng and colleagues created transgenic mice lacking both the Pten and Nf1 in Schwann cells and their precursors to elucidate the role of these 2 tumor suppressor genes in vivo. When coupled with Nf1 loss, both the decrease and loss of Pten resulted in MPNST development from neurofibromas and seemed to accelerate the progression from low-grade to high-grade MPNST. Additionally, genetic analysis of human MPNST exhibited down-regulation of PTEN expression, suggesting that PTEN -regulated pathways play key roles as tumor suppressors to inhibit the progression of benign neurofibroma to MPNST.
Likewise, Gregorian and colleagues found that concomitant activation of the K-ras oncogene along with single allelic deletion of Pten led to 100% development of NF1 lesions and subsequent progression to MPNST in mice. In the same study, they observed loss of PTEN expression in human NF1-associated MPNST lesions, because less than 20% of the tumor cells were PTEN positive.
In a similar study, Bradtmoller and colleagues discovered significantly reduced PTEN expression in human MPNST samples (5%) compared with benign neurofibromas (30%). Furthermore, a significantly higher methylation frequency in MPNST was observed compared with benign peripheral nerve sheath tumor (PNST), including neurofibroma. These findings indicated that the methylation of CpG island 3’ as one mechanism that down-regulates PTEN in MPNST.
In summary, deletion of the tumor suppressor PTEN in the cell-cycle regulatory PI3K/AKT/mTOR pathway plays a critical role in the malignant transformation of neurofibroma to MPNST. For a more detailed review on the role of PTEN in neoplastic growth, please refer to the article by Chow and Baker.
Insulinlike Growth Factor 1 Receptor and Epidermal Growth Factor Receptor
Genetic alterations of the IGF1R pathway have been correlated to MPNST progression. For example, Yang and colleagues observed IGF1R amplification and increased IGF1R protein expression, respectively, in 24% and 82% of human MPNST samples. Higher IGF1R protein expression correlated with worse tumor-free survival and increased risk of tumor progression. Moreover, activation of IGF1R induces MPNST cell proliferation, migration, and invasion via up-regulation of the PI3K/AKT/mTOR pathway. Specifically, inhibition of IGF1R in ST88 to 14 MPNST cells via small interfering RNA or the IGF1R inhibitor MK-0646 significantly decreased cell proliferation, invasion, and migration due to attenuation of the PI3K/AKT/mTOR pathway.
Likewise, up-regulation of EGFR has also been implicated in the progression of MPNST. DeClue and colleagues found significantly increased EGFR expression in the Schwann cells of MPNST compared with benign neurofibromas. Additionally, proliferation of cultured primary cells from human MPNST was inhibited by the EGFR antagonists mAb225, A-25, and AG-1478.
Mitogen-Activated Protein Kinase
MAPK has also been found overexpressed in MPNST. This signaling cascade, which includes rapidly accelerated fibrosarcoma (RAF), extracellular signal-regulated kinase (ERK), and MAPK/ERK kinase [MEK]), is responsible for cell-cycle progression from the G1 phase to the S phase. Thus, dysregulation of the MAPK pathway leads to uncontrolled growth in cancer. For example, Zou and colleagues observed that 91% of MPNST samples stained positive for phosphorylated MEK compared with only 21% of benign neurofibromas. See Table 1 for a brief summary of main molecular pathways dysregulated in MPNST.
| Molecular Pathway | Normal Role | Change in Malignant Peripheral Nerve Sheath Tumor |
|---|---|---|
| NF1 | Tumor suppressor | Down-regulation |
| PTEN | Tumor suppressor Negative regulator of PI3K/AKT/mTOR signaling cascade | Down-regulation |
| IGF1R | Positive regulator of PI3K/AKT/mTOR signaling cascade | Up-regulation |
| EGFR | Positive regulator of PI3K/AKT/mTOR signaling cascade | Up-regulation |
| MAPK | Phosphorylation of RAF/MEK/ERK signaling cascade | Up-regulation |
Radiographic diagnosis of malignant peripheral nerve sheath tumor
The detection of MPNST and its differentiation from benign neurofibromas remains a clinical challenge, because the symptomology of these 2 conditions, including tumor size, pain, and neurologic deficits, exhibits considerable overlap. Currently, the imaging modalities that are used to evaluate and diagnose MPNST include CT, MRI, and PET. Each is discussed.
Both CT and MRI are used to define the anatomic tumor size and local invasiveness of PNST. For example, Benz and colleagues used CT imaging and observed that MPNSTs are larger than their benign counterparts. Specifically, the mean tumor size for malignant and benign PSNT were 7.4 cm ± 4.1 cm and mean 4.8 cm ± 2.7 cm, respectively. Due to the clear overlap between the size ranges of benign and malignant PNST, however, CT-based evaluation of tumor size is limited when used as the sole imaging modality to diagnose MPNST.
Several studies have established diagnostic criteria for distinguishing benign PNST and MPNST using MRI ( Table 2 ). Mautner and colleagues, however, evaluated the efficacy of MRI in the diagnosis of MPNST and concluded that MRI when used alone can likewise not reliably distinguish between malignant and benign PNST, especially when tumors are inhomogeneous. Overall, the central limitation of both CT and MRI is that they cannot effectively confirm malignant transformation of lesions.
| Parameter | Malignant Peripheral Nerve Sheath Tumor | Benign Peripheral Nerve Sheath Tumor |
|---|---|---|
| Tumor size (mm) | 74–100 | 43–69 |
| Intratumoral lobulation (%) | 50–63 | 12–17 |
| Intratumoral heterogeneity (%) | 51–90 | 30–52 |
| Irregular or peripheral contrast enhancement (%) | 34–75 | 5–33 |
| Intratumoral cystic changes (%) | 21–39 | 10–17 |
| Peritumoral edema (%) | 29–66 | 0–23 |
To improve on anatomic imaging, various studies have used quantitative fludeoxyglucose F 18 (FDG) PET imaging to distinguish between benign PNST and MPNST based on a tumor’s metabolic activity. In these studies, the maximum standardized uptake value (SUVmax) is used to measure tumor glucose utilization; in summary, lower tumor FDG uptake is correlated with benign peripheral nerve sheath tumors, whereas higher tumor FDG uptake is correlated with MPNST.
Benz and colleagues determined that the mean SUVmax for MPNSTs (12.0 g/mL ± 7.1 g/mL) was significantly higher than that of benign peripheral nerve sheath tumors (3.4 g/mL ± 1.8 g/mL). In addition, they determined that the optimum threshold for separating MPNSTs from their benign counterparts was an SUVmax of 6.1 g/mL, with sensitivity and specificity of 94% and 91%, respectively. In a similarly conducted study, Ferner and colleagues determined that lesions in NF1 patients with an SUVmax of 3.5 g/mL should be resected to prevent progression towards MPNST, with sensitivity and specificity of 89% and 95%, respectively.
In summary, the definitive radiographic distinction of benign PNST and MPNST is a challenge. Currently, quantitative FDG-PET imaging used in conjunction with CT or MRI offers the best ability to distinguish benign PNST from MPNST. The authors think that these data should be combined with the clinical assessment of patients to identify patients undergoing and who have undergone malignant transformation. Radiographic imaging and clinical features of PNST/MPNST have not supplanted histopathologic examination as the gold standard for the diagnosis of MPNST.
Histopathologic diagnosis of malignant peripheral nerve sheath tumor
The diagnosis of MPNST may be suspected prior to biopsy, based on a variety of factors, including known diagnosis of NF1, changes in the tempo of clinical symptoms, relationship to a peripheral nerve, relationship to preexisting neurofibroma, or imaging characteristics, including rapidly growing tumors and highly FDG-avid lesions. The typical histology of MPNST is that of a proliferation of spindle cells showing a fascicular growth pattern, often with a branching hemangiopericytoma-like vascular pattern, as well as alternating hypercellular and hypocellular areas. The histologic appearance of MPNST may vary significantly — from tumors appearing similar to neurofibroma ranging to those more resembling a fibrosarcoma. From a biological perspective, this variation in appearance may reflect different elements within the native peripheral nerve sheath, including Schwann cells, perineural cells, and fibroblasts. Given this spectrum of findings and the lack of definitive markers for MPNST, it is important to recognize that there is still a lack of widely accepted diagnostic criteria for MPNST.
Typical cytologic features of MPNST include nuclei that are wavy, buckled or comma-shaped. Other less common histologic features of MPNST that may be present include epithelioid or pleomorphic cytomorphology, heterologous elements, glandular differentiation, and melanin pigment. Heterologous elements are more common in MPNST compared with other tumor types and most commonly include mature islands of cartilage and bone (seen in up to 15% of MPNST). Glandular differentiation is rare and most commonly brings up the diagnostic alternative of biphasic synovial sarcoma. Epithelioid MPNST constitutes less than 5% of MPNST and is distinctive for diffuse S100 immunoreactivity in a majority of tumors as well as loss of INI1 in approximately half of cases. A more comprehensive discussion of the histopathologic variation with MPNST can be found within the following reference.
Immunohistochemistry (IHC) is of some help in the diagnosis of MPSNT, including the exclusion of competing diagnostic possibilities. All IHC markers, however, have limited sensitivity or specificity, so a single diagnostic marker for MPNST is not currently available. S100 protein expression is the most commonly used in the evaluation of MPNST. When present (estimated at anywhere from 50% to 90% frequency ), S100 immunostaining is usually focal. Diffuse S100 expression is more consistent with a cellular schwannoma, melanoma, or clear cell sarcoma. The exception to this is epithelioid MPNST, which often shows diffuse S100 immunostaining. SOX10 may show improved sensitivity and specificity over S100 protein for MPNST. Melanocytic markers are negative, whereas keratins may be positive (either in epithelioid MPNST or glandular MPNST). TLE1 expression is usually focal and weak in MPNST, rather than strong and diffuse, as seen in synovial sarcoma.
Two diagnostic dilemmas that may face pathologists when considering the diagnosis of MPNST are discussed briefly. The first is distinguishing low-grade MPNST from neurofibroma and neurofibroma with atypical features. When neural differentiation is clearly identified, the next step is histopathologic subcategorization. The differentiation of atypical neurofibroma from low-grade MPNST is challenging and not entirely agreed on by experts in the field, because these lesions likely represent a histologic continuum. For example, some investigators maintain that both hypercellularity and nuclear atypia, with or without mitoses, are consistent with low-grade MPNST. Other experts add that if mitotic activity is not present, low-grade MPNST may be diagnosed if the cellularity and atypia are marked and the architectural pattern is fascicular. Other experts accept any mitotic activity in a cellular or atypical neurofibroma, particularly in a patient with NF1, as evidence for malignant transformation. In contrast, the current World Health Organization classification maintains that “hypercellularity of otherwise unremarkable neurofibroma cells, atypical tumour cells with hyperchromatic smudgy nuclei, or mitotic activity, alone or together, do not indicate malignant change.” This debate over the hematoxylin-eosin diagnosis is compounded by the fact that current molecular or immunohistochemical assays do not distinguish between these diagnostic categories. Current guidelines that the authors use in practice for the light microscopic diagnosis of neurofibroma are shown in Box 2 , adapted from Goldblum and colleagues.
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