BACKGROUND: Malignant peripheral nerve sheath tumours (MPNSTs) have high local recurrence (LR) rates. Literature varies on LR risk factors and treatment. This study aimed to elucidate treatment options and risk factors for first and second LRs (LR1 and LR2) in a large multicentre cohort.
METHODS: Surgically treated primary MPNSTs between 1988 and 2019 in the MONACO multicentre cohort were included. Cox regression analysed LR1 and LR2 risk factors and overall survival (OS) after LR1. Treatment of LR1 and LR2 was evaluated.
RESULTS: Among 507 patients, 28% developed LR1. Median follow-up was 66.9 months, and for survivors 111.1 months. Independent LR1 risk factors included high-grade tumours (HR 2.63; 95% c.i. 1.15 to 5.99), microscopically positive margins (HR 2.19; 95% c.i. 1.51 to 3.16) and large tumour size (HR 2.14; 95% c.i. 1.21 to 3.78). Perioperative radiotherapy (HR 0.62; 95% c.i. 0.43 to 0.89) reduced the risk. LR1 patients had poorer OS. Synchronous metastasis worsened OS (HR 1.79; 95% c.i. 1.02 to 3.14) post-LR1, while surgically treated LR was associated with better OS (HR 0.38; 95% c.i. 0.22 to 0.64) compared to non-surgical cases. Two-year survival after surgical treatment was 71% (95% c.i. 63 to 82%) versus 28% (95% c.i. 18 to 44%) for non-surgical LR1 patients. Most LR1 (75.4%) and LR2 (73.7%) patients received curative-intent treatment, often surgery alone (64.9% versus 47.4%). Radiotherapy combined with surgery was given to 11.3% of LR1 and 7.9% of LR2 patients.
CONCLUSIONS: Large, high-grade MPNSTs with R1 resections are at higher LR1 risk, potentially reduced by radiotherapy. Surgically treated recurrences may provide improved survival in highly selected cases.

OBJECTIVE: Alterations of the NF1 tumor suppressor gene is the second most frequent genetic event in embryonal rhabdomyosarcoma (ERMS), but its associations with clinicopathologic features, outcome, or coexisting molecular events are not well defined. Additionally, NF1 alterations, mostly in the setting of neurofibromatosis type I (NF1), drive the pathogenesis of most malignant peripheral nerve sheath tumor with divergent RMS differentiation (also known as malignant triton tumor [MTT]). Distinguishing between these entities can be challenging because of their pathologic overlap. This study aims to comprehensively analyze the clinicopathologic and molecular spectrum of NF1-mutant RMS compared with NF1-associated MTT for a better understanding of their pathogenesis.
METHODS: We investigated the clinicopathologic and molecular landscape of a cohort of 22 NF1-mutant RMS and a control group of 13 NF1-associated MTT. Cases were tested on a matched tumor-normal hybridization capture-based targeted DNA next-generation sequencing.
RESULTS: Among the RMS group, all except one were ERMS, with a median age of 17 years while for MTT the mean age was 39 years. Three MTTs were misdiagnosed as ERMS, having clinical impact in one. The most frequent coexisting alteration in ERMS was TP53 abnormality (36%), being mutually exclusive from NRAS mutations (14%). MTT showed coexisting CDKN2A/B and PRC2 complex alterations in 38% cases and loss of H3K27me3 expression. Patients with NF1-mutant RMS exhibited a 70% 5-year survival rate, in contrast to MTT with a 33% 5-year survival. All metastatic NF1-mutant ERMS were associated with TP53 alterations.
CONCLUSIONS: Patients with NF1-mutant ERMS lacking TP53 alterations may benefit from dose-reduction chemotherapy. On the basis of the diagnostic challenges and significant treatment and prognostic differences, molecular profiling of challenging tumors with rhabdomyoblastic differentiation is recommended.

The cytomorphology of MPNST in effusion specimens is rarely described. In this paper, the detailed cytopathological and immunohistochemical characteristics of metastatic MPNST has been described in pleural effusion. Patients\' medical history and the judicious utilization of ancillary studies contribute to ensure precise cytological diagnoses. The cytomorphology of malignant peripheral nerve sheath tumour (MPNST) in effusion specimens can be diagnostically challenging. The author presents detailed cytopathological and immunohistochemical characteristics of a case of metastatic MPNST in pleural effusion.

A retrospective study involving 14 pet rabbits histopathologically diagnosed with malignant peripheral nerve sheath tumors (MPNSTs) was conducted. The age at diagnosis was 4-12 years, with a median age of 8.6 years. All rabbits had solid subcutaneous tumor masses in varied locations. Surgical excision of the tumors was performed in all cases. Recurrence was observed in 10 cases (71%), and postoperative metastasis to the lung was suspected in 4 cases (29%). The postoperative mean and median survival times were 11 months and 9 months, respectively. Hence, MPNSTs should be considered in the differential diagnosis for subcutaneous masses in rabbits and it is essential to inform the owners of the potentially high recurrence and metastasis rates.

OBJECTIVE: This study sought to investigate the role of radiotherapy (RT) in addition to surgery for oncological outcomes in patients with malignant peripheral nerve sheath tumors (MPNST).
METHODS: In this single-center, retrospective cohort study, histopathologically confirmed MPNST were analyzed. Local control (LC), overall survival (OS), and distant metastasis-free survival (DMFS) were assessed using the Kaplan-Meier estimator. Multivariable Cox regression analysis was performed to identify factors associated with LC, OS, and DMFS.
RESULTS: We included 57 patients with a median follow-up of 20.0 months. Most MPNSTs were located deeply (87.5%), were larger than 5 cm (55.8%), and had high-grade histology (78.7%). Seventeen patients received surgery only, and 25 patients received surgery and pre- or postoperative RT. Median LC, OS, and DMFS after surgery only were 8.7, 25.5, and 22.0 months; after surgery with RT, the median LC was not reached, while the median OS and DMFS were 111.5 and 69.9 months. Multivariable Cox regression of LC revealed a negative influence of patients presenting with local disease recurrence compared to patients presenting with an initial primary diagnosis of localized MPNST (hazard ratio: 8.86, p = 0.003).
CONCLUSIONS: The addition of RT to wide surgical excision appears to have a beneficial effect on LC. Local disease recurrence at presentation is an adverse prognostic factor for developing subsequent local recurrences. Future clinical and translational studies are warranted to identify molecular targets and find effective perioperative combination therapies with RT to improve patient outcomes.

Background. Spindle cell/sclerosing rhabdomyosarcoma is a rare neoplasm and has an aggressive clinical course. Because of its rarity, we performed a multi-institutional collaboration to comprehend the overarching clinical, histopathological, and immunohistochemical characteristics of a cohort of spindle cell/sclerosing rhabdomyosarcoma. Materials and Methods. Forty-five patients with spindle cell/sclerosing rhabdomyosarcoma were identified. Demographics, clinical, histopathological, and immunohistochemistry data were reviewed and recorded. Results. The patients\' age ranged from 1 to 85 years with a male to female ratio of 1.2:1. There were 15 children/adolescents and 30 adults. Eighteen (40%) tumors were located in the head and neck region. Twenty-four (53%) tumors displayed a bimorphic cellular arrangement with hypercellular areas having short, long, and sweeping fascicular and herringbone pattern, and hypocellular areas with stromal sclerosis and associated hyalinized and/or chondromyxoid matrix. Histomorphological differentials considered were leiomyosarcoma, malignant peripheral nerve sheath tumor, fibrosarcoma, nodular fasciitis, liposarcoma, synovial sarcoma, sarcomatoid carcinoma, solitary fibrous tumor, dermatofibrosarcoma protuberans, and schwannoma. Six tumors exhibited marked stromal sclerosis. The myogenic nature was confirmed by immunohistochemistry. Positivity for at least one skeletal muscle-associated marker (MyoD1 and/or myogenin) was observed. Conclusion. Spindle cell/sclerosing rhabdomyosarcoma diagnosis can be challenging as a number of malignant spindle cell neoplasm mimic this entity. Thus a correct diagnosis requires immunohistochemical work up with a broad panel of antibodies. In view of rarity of this neoplasm, further studies on a large cohort of patients with clinical follow-up data are needed for a better understanding of this tumor.

BACKGROUND: Primary tumor resection is the mainstay of treatment for malignant peripheral nerve sheath tumors. However, the efficacy of perioperative chemotherapy and radiotherapy for malignant peripheral nerve sheath tumors has not been elucidated.
METHODS: This retrospective analysis based on a Japanese registry included patients with localized malignant peripheral nerve sheath tumors arising at the extremities and trunk wall. Disease-specific overall survival and local recurrence-free survival were estimated using the Kaplan-Meier method. A Cox regression model was used to identify prognostic factors. Characteristics of groups with or without chemotherapy were adjusted using propensity score matching.
RESULTS: In total, 291 patients were included. The 5-year disease-specific overall survival rate was 70.6%. Multivariate analysis of disease-specific overall survival revealed that deep-seated tumors were a poor prognostic factor, but perioperative chemotherapy was not associated with disease-specific overall survival (hazard ratio, 0.81; 95% confidence interval, 0.45-1.43, P = 0.46). Local recurrence was observed in 55 patients (19.0%), and surgical margins (R1 and R2) were significant risk factors. Overall, perioperative chemotherapy did not prolong disease-specific overall survival (5-year disease-specific overall survival: 74.1% vs. 69.3%, P = 0.75) and had limited efficacy in the group with tumor size ≥ 5 cm, although the difference was not statistically significant (5-year disease-specific overall survival: 77.2% vs. 68.6%, respectively, P = 0.13). After adjustment by propensity score matching, perioperative chemotherapy significantly prolonged disease-specific overall survival (5-year disease-specific overall survival: 74.9% vs. 57.1%, P = 0.03), but this effect was not observed in local recurrence-free survival. In all patients, perioperative radiotherapy did not correlate with local recurrence-free survival (hazard ratio, 1.43; 95% confidence interval 0.78-2.62, P = 0.25).
CONCLUSIONS: Perioperative chemotherapy had limited efficacy for disease-specific overall survival in patients with localized malignant peripheral nerve sheath tumors.

Malignant peripheral nerve sheath tumors (MPNST) are aggressive neoplasms, arising either sporadically, in the setting of neurofibromatosis type I (NF1) or post radiation. Most MPNST occur in adults and their pathogenesis is driven by the loss of function mutations in the PRC2 complex, regardless of their clinical presentation. In contrast, pediatric MPNST are rare and their pathogenesis has not been elucidated. In this study, we investigate a large cohort of 64 MPNSTs arising in children and young adults (younger than the age of 20 years) to better define their clinicopathologic and molecular features. Sixteen (25%) cases were investigated by MSK-IMPACT, a targeted NGS panel of 505 cancer genes. Most patients (80%) were aged 11-20 years. A history of NF1 was established in half of the cases. Mean tumor size was 8.5 cm. The most common locations included the extremities (34%) and abdomen/pelvis (27%). Histologically, 89% of high-grade MPNST showed conventional features, while the remaining three cases showed a predominant epithelioid phenotype. Heterologous differentiation occurred in 25% of high grade cases, with half showing rhabdomyoblastic differentiation. Tumors arose in a background of a plexiform neurofibroma (16%), neurofibroma (13%), and schwannoma in two cases (3%). Immunohistochemically, H3K27me3 expression was lost in 82% of conventional high-grade MPNST analyzed, while loss of SMARCB1 expression was seen in one epithelioid MPNST. Genomically, all cases showed more than one genetic abnormality, with 53% showing mutations in EED / SUZ12 genes, and 47% of cases harboring alterations in NF1 and CDKN2A/CDKN2B genes. At the last follow-up, 30% patients died of disease, 28% were alive with disease and 42% had no evidence of disease. NF1 status did not correlate with overall survival. In conclusion, half of pediatric and young adult MPNST were NF1-related and showed loss of function alterations in PRC2 complex, NF1, and CDKN2A, similar to the adult counterpart. Thus, H3K27me3 loss of expression may be used in the diagnosis of high grade MPNSTs in children. Moreover, a small subset of pediatric MPNST have an epithelioid morphology with different pathogenesis.

BACKGROUND: Loss-of-function mutations in EED and SUZ12, core components of the polycomb repressive complex 2 (PRC2), occur in >90% of sporadic and radiation-associated malignant peripheral nerve sheath tumors (MPNST) and in roughly 70% of NF1-related tumors. PRC2 inactivation results in loss of H3K27me3 expression and aberrant downstream transcription. H3K27me3 expression is lost in 40-90% of spindle cell MPNST but is not specific. A single study has suggested that dimethylated H3K27 (H3K27me2) is a more specific marker of MPNST.
METHODS: We compared the expression of H3K27me3 and H3K27me2 by immunohistochemistry in a series of MPNST (n = 26), neurofibroma (n = 11), conventional dermatofibrosarcoma protuberans (n = 8), fibrosarcomatous dermatofibrosarcoma protuberans (n = 7), spindle cell rhabdomyosarcoma (n = 6), high-risk solitary fibrous tumor (n = 9), dedifferentiated chondrosarcoma (n = 7), synovial sarcoma (n = 9), diffuse midline glioma, H3K27-altered (n = 13), conventional diffuse astrocytoma (n = 2), conventional cutaneous melanoma (n = 8), uveal melanoma (n = 8), cellular blue nevus (n = 17) and melanoma arising in blue nevus (n = 6).
RESULTS: H3K27me3 and H3K27me2 expression patterns were concordant in 115/137 (84%) with 85 cases (62%) expressing both markers and 30 cases (22%) showing loss of both. Discordant results were seen in 22 cases (H3K27me3 loss with retained H3K27me2, 10 cases (7%); H3K27me3 expression with H3K27me2 loss, 12 cases (9%)). H3K27me2 loss was not specific for MPNST and was also seen in certain other tumors, in particular those in the \"blue nevus family\".
CONCLUSIONS: We conclude that H3K27me2 loss is not specific for MPNST, and like H3K27me3, should be used in the appropriate clinicopathologic, immunohistochemical and molecular genetic context. Loss of H3K27me2 with retained H3K27me3 is a common feature of \"blue nevus family\" melanocytic tumors known to harbor GNAQ/GNA11 mutations.

OBJECTIVE: The aim of the present investigation was to characterize the growth pattern and antigen profile of peripheral nerve sheath tumors (PNST) in a large series of tumors obtained from patients with Neurofibromatosis type 1 (NF1) focusing on morphological characteristics of diffuse plexiform neurofibroma (DPNF).
METHODS: Tissue micro-array (TMA) analysis was applied to study 520 formalin-fixed, paraffin-embedded human PNST of 385 patients with confirmed NF1 diagnosis. PNST originated from all areas of the body and were classified as cutaneous neurofibroma (CNF, n=114), diffuse neurofibroma (DNF, n=109), DPNF (n=108), plexiform neurofibroma (PNF, n=110), and malignant peripheral nerve sheath tumor (MPNST, n=22). Histomorphology and antigen expression patterns of the tumors were determined [S100, epithelial membrane antigen (EMA), CD90, mast cell tryptase, and neurofilament].
RESULTS: Benign PNST showed significantly more S100-positive tumor cells than MPNST (p<0.001). EMA expression was most pronounced in perineurium of DPNF. The number of mast cells in CNF, DNF and DPNF was significantly higher compared to PNF and MPNST (p<0.001 for both comparisons, Mann-Whitney U-test).
CONCLUSIONS: DPNF show some distinct cellular characteristics. A high number of EMA positive cells possibly indicates the dissemination of perineural cells to the surrounding tissue. Concerning mast cell density, DPNF resemble DNF and CNS rather than PNF. Close contact of tumor cells in DPNF, DNF and CNF with the immune system is a prerequisite for permanent immunological reactions in contrast to PNF in which tumor cells are partitioned from the immune system by the perineurium and blood-nerve barrier of blood vessels. It is assumed that these morphological distinctions may reflect in part the biological differences between the entities. While PNF is a known precancerous stage in NF1 patients, DPNF are not rated as such. Furthermore, the morphologic differences between benign nerve sheath tumors may be important for the efficacy of drugs to access tumor cells.