NF1-Driven Rhabdomyosarcoma Phenotypes: A Comparative Clinical and Molecular Study of NF1-Mutant Rhabdomyosarcoma and NF1-Associated Malignant Triton Tumor.

PURPOSE: 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. CONCLUSION: 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.

Sporadic Malignant Triton Tumor of Shoulder: a Case Report.

Background: Malignant triton tumors (MTT) are subtype of malignant peripheral nerve sheath tumor (MPNST) which develop from Schwan cells of peripheral nerves or within neurofibromas, and shows rhabdomyoblastic differentiation. It is a rare soft tissue tumor with poor prognosis. Objective: We report a case of Malignant Triton Tumor (MTT) arising in the right shoulder in a 46 year old male patient presented to our Musculoskeletal Oncology Clinic at Royal Rehabilitation center at King Hussein Medical Center during June 2018. Case presentation: The patient was complaining of an 8 months long progressive right shoulder pain and swelling at the posterior lateral area of the shoulder. As accurate diagnosis is crucial in such case, investigations that included x-rays and magnetic resonance imaging (MRI) demonstrated an soft tissue tumor involving the right shoulder area leading to the differential diagnosis of aggressive soft tissue tumor which laid down the plan of an open incisional biopsy to be reported histopathological as a case of Malignant Triton Tumor which is a very rare and aggressive sarcoma originates from the peripheral nerve sheaths as it is subtype of malignant peripheral nerve sheath tumors after which excision of the entire tumor with safety margin was performed and referred for adjuvant chemotherapy. Conclusion: The treatment of choice is radical tumor excision with wide margins followed by chemotherapy and /or radiotherapy to improve the 5 years survival rates.

Malignant peripheral nerve sheath tumor (MPNST) and MPNST-like entities are defined by a specific DNA methylation profile in pediatric and juvenile population.

BACKGROUND: Malignant peripheral nerve sheath tumors (MPNSTs) account for 3-10% of pediatric sarcomas, 50% of which occur in neurofibromatosis type 1 (NF1). Sporadic MPNSTs diagnosis may be challenging due to the absence of specific markers, apart from immunohistochemical H3K27me3 loss. DNA methylation (DNAm) profiling is a useful tool for brain and mesenchymal neoplasms categorization, and MPNSTs exhibit a specific DNAm signature. An MPNST-like group has recently been recognized, including pediatric tumors with retained H3K27me3 mark and clinical/histological features not yet well explored. This study aims to characterize the DNAm profile of pediatric/juvenile MPNSTs/MPNST-like entities and its diagnostic/prognostic relevance. RESULTS: We studied 42 tumors from two groups. Group 1 included 32 tumors histologically diagnosed as atypical neurofibroma (ANF) (N = 5) or MPNST (N = 27); group 2 comprised 10 tumors classified as MPNST-like according to Heidelberg sarcoma classifier. We performed further immunohistochemical and molecular tests to reach an integrated diagnosis. In group 1, DNAm profiling was inconclusive for ANF; while, it confirmed the original diagnosis in 12/27 MPNSTs, all occurring in NF1 patients. Five/27 MPNSTs were classified as MPNST-like: Integrated diagnosis confirmed MPNST identity for 3 cases; while, the immunophenotype supported the change to high-grade undifferentiated spindle cell sarcoma in 2 samples. The remaining 10/27 MPNSTs variably classified as schwannoma, osteosarcoma, BCOR-altered sarcoma, rhabdomyosarcoma (RMS)-MYOD1 mutant, RMS-like, and embryonal RMS or did not match with any defined entity. Molecular analysis and histologic review confirmed the diagnoses of BCOR, RMS-MYOD1 mutant, DICER1-syndrome and ERMS. Group 2 samples included 5 high-grade undifferentiated sarcomas/MPNSTs and 5 low-grade mesenchymal neoplasms. Two high-grade and 4 low-grade lesions harbored tyrosine kinase (TRK) gene fusions. By HDBSCAN clustering analysis of the whole cohort we identified two clusters mainly distinguished by H3K27me3 epigenetic signature. Exploring the copy number variation, high-grade tumors showed frequent chromosomal aberrations and CDKN2A/B loss significantly impacted on survival in the MPNSTs cohort. CONCLUSION: DNAm profiling is a useful tool in diagnostic work-up of MPNSTs. Its application in a retrospective series collected during pre-molecular era contributed to classify morphologic mimics. The methylation group MPNST-like is a 'hybrid' category in pediatrics including high-grade and low-grade tumors mainly characterized by TRK alterations.

Other Nerve Sheath Tumors of Brain and Spinal Cord.

The three main types of nerve sheath tumors are schwannomas, neurofibromas and perineuriomas. Multiple neurofibromas throughout the body are the hallmark of Neurofibromatosis type 1 (NF1). Spinal nerve sheath tumors are classified in the group of intradural extramedullary spinal cord tumors, in which they are the most common type (25-30%). Their incidence is 3-4 per 1 million people. Spinal schwannomas are encountered sporadically or in the context of Neurofibromatosis type 2, while neurofibromas are typical for patients with Neurofibromatosis type 1. Neurofibromas are composed predominantly of Schwann cells and fibroblasts, alongside which are also found axons, perineurial cells, mast cells and extracellular matrix. Most of the neurofibromas are asymptomatic. Any increase in the size of a neurofibroma or the presence of pain is an indicator of a possible malignant degeneration. Neurofibromas are treated surgically. Neurofibromas involve the whole nerve and cause its fusiform enlargement which makes it impossible to preserve the nerve's functions if complete tumor removal is performed. Hence, such tumors are initially observed. In case of progressive growth, the options are either resection of the tumor and immediate reconstruction with a peripheral nerve graft (e.g., nerve suralis interposition graft) or subtotal removal and follow-up. Malignant peripheral nerve sheath tumors (MPNST) are very rare tumors with incidence of around 1 per 1,000,000 people. MPNST account for 3-10% of all soft-tissue sarcomas. The most common initial symptom of MPNST is a painless mass. Any rapid increase in a subcutaneous mass or rapid onset of symptoms should raise the suspicion of a malignant tumor. In patients with diagnosed NF1, the recent rapid increase in a known lesion should raise the suspicion of malignant degeneration of the lesion and opt for active treatment. In the case of MPNST a wide surgical excision is advocated. The resectability depends greatly on the location of the tumors and varies from around 20% in paraspinal MPNST and reaches 95% in MPNST localized in the extremities. MPNST are a rare disease and should be managed by a multidisciplinary team of neurosurgeons, radiologists and oncologists.

Ovarian epithelioid malignant peripheral nerve sheath tumor with EWSR1-CREM fusion: A case report and literature review.

Epithelioid malignant peripheral nerve sheath tumor (EMPNST) is a rare soft tissue sarcoma. The authors report the first case of EMPNST arising in the ovary (OEMPNST). A 7-year-old child underwent left salpingo-oophorectomy due to tumor rupture and the pathology suggested a juvenile granulosa cell tumor (JGCT). Six cycles of bleomycin, etoposide, and carboplatin were administrated. A second surgery was applied due to relapse 4 months after the last cycle of chemotherapy, and the pathology revealed JGCT with extensive abdominopelvic seedings even after interinstitutional consultation in two hospitals. Next-generation sequencing demonstrated EWSR1 exon12-CREM exon6 fusion with neurofibromatosis-2 gene deletion, and no mutation was detected in either FOXL2 or DICER1. However, pathology consultation in two other hospitals suggested the diagnosis of OEMPNST, and additional immunohistochemical (IHC) staining revealed positive H3K27me3. Nonetheless, she was treated with nine courses of chemotherapy but experienced a second recurrence of extensive abdominal metastases approximately 3 months after ceasing chemotherapy. Neither elevated tumor makers nor abnormal sex hormones level was noted since the initial presentation. Repeated cytoreductive surgery was conducted and IHC staining showed expression of SOX10, S-100, INI-1, and α-inhibin in tumor tissue. A final diagnosis of OEMPNST with EWSR1-CREM fusion was established, indicating that the probability of OEMPNST could not be excluded when treatment for JGCT showed poor response. A comprehensive evaluation including biological characteristics, morphology, IHC staining, and molecular features is vital in the differential diagnosis between JGCT and OEMPNST.

Genomic Patterns of Malignant Peripheral Nerve Sheath Tumor (MPNST) Evolution Correlate with Clinical Outcome and Are Detectable in Cell-Free DNA.

Malignant peripheral nerve sheath tumor (MPNST), an aggressive soft-tissue sarcoma, occurs in people with neurofibromatosis type 1 (NF1) and sporadically. Whole-genome and multiregional exome sequencing, transcriptomic, and methylation profiling of 95 tumor samples revealed the order of genomic events in tumor evolution. Following biallelic inactivation of NF1, loss of CDKN2A or TP53 with or without inactivation of polycomb repressive complex 2 (PRC2) leads to extensive somatic copy-number aberrations (SCNA). Distinct pathways of tumor evolution are associated with inactivation of PRC2 genes and H3K27 trimethylation (H3K27me3) status. Tumors with H3K27me3 loss evolve through extensive chromosomal losses followed by whole-genome doubling and chromosome 8 amplification, and show lower levels of immune cell infiltration. Retention of H3K27me3 leads to extensive genomic instability, but an immune cell-rich phenotype. Specific SCNAs detected in both tumor samples and cell-free DNA (cfDNA) act as a surrogate for H3K27me3 loss and immune infiltration, and predict prognosis. SIGNIFICANCE: MPNST is the most common cause of death and morbidity for individuals with NF1, a relatively common tumor predisposition syndrome. Our results suggest that somatic copy-number and methylation profiling of tumor or cfDNA could serve as a biomarker for early diagnosis and to stratify patients into prognostic and treatment-related subgroups. This article is highlighted in the In This Issue feature, p. 517.

No es GIST todo lo que parece / GIST is not all that it seems

We present a 41-year-old female who was admitted to our hospital with a history of 2-month epigastric pain and vomiting. Physical examination was normal. Upper gastrointestinal endoscopy showed a sessile submucosal tumor with central ulceration in the gastric body-antrum. Biopsies revealed a gastric mucosa without changes. Nevertheless, endoscopic ultrasound-guided biopsies showed interlacing bundles of spindle cells. The immunohistochemical study was negative for CD117 and smooth muscle actin and positive for S100 protein. A CT scan identified a heterogeneous mass in the stomach wall (AU)

PRAME expression in spindle cell melanoma, malignant peripheral nerve sheath tumour, and other cutaneous sarcomatoid neoplasms: a comparative analysis.

Diagnosis of spindle cell/sarcomatoid melanoma may be challenging due to frequent loss of expression of melanocytic marker(s) and histomorphologic resemblance to various mesenchymal tumours, particularly malignant peripheral nerve sheath tumour (MPNST). Overexpression of PReferentially expressed Antigen in MElanoma (PRAME) supports a diagnosis of melanoma when evaluating challenging melanocytic tumours. PRAME expression in MPNST and other cutaneous sarcomatoid neoplasms, however, has not been well characterised. We aimed to determine the utility of PRAME immunostain in distinguishing spindle cell melanoma from MPNST and other sarcomatoid mimics. PRAME expression was scored by extent (0 to 4+) and intensity (0 to 3) of staining. A strong positive correlation was observed between the extent and intensity scores (r = 0.84). An extent score of 4+, defined by staining in 76-100% of tumour cells, was seen in 56% (23/41) of spindle cell melanomas, 18% (7/38) of MPNSTs, 15% (4/27) of cutaneous sarcomatoid squamous cell carcinomas (SCCs), 33% (5/15) of poorly differentiated cutaneous angiosarcomas, 12% (4/33) of atypical fibroxanthomas (AFXs), 4% (1/25) of pleomorphic dermal sarcomas (PDSs), and none (0/16) of the high-grade cutaneous leiomyosarcomas. A significant difference was found between spindle cell melanoma and all other examined sarcomatoid neoplasms except angiosarcoma. While diffuse (and often strong) PRAME expression is more frequently observed in spindle cell melanoma than MPNST, sarcomatoid SCC, AFX, PDS, and high-grade leiomyosarcoma, its limited sensitivity and specificity caution against its use as a standalone diagnostic marker. PRAME may complement other epigenetic or lineage-specific markers and should only be used as part of an immunohistochemical panel when evaluating these sarcomatoid neoplasms.

PRC2-Inactivating Mutations in Cancer Enhance Cytotoxic Response to DNMT1-Targeted Therapy via Enhanced Viral Mimicry.

Polycomb repressive complex 2 (PRC2) has oncogenic and tumor-suppressive roles in cancer. There is clinical success of targeting this complex in PRC2-dependent cancers, but an unmet therapeutic need exists in PRC2-loss cancer. PRC2-inactivating mutations are a hallmark feature of high-grade malignant peripheral nerve sheath tumor (MPNST), an aggressive sarcoma with poor prognosis and no effective targeted therapy. Through RNAi screening in MPNST, we found that PRC2 inactivation increases sensitivity to genetic or small-molecule inhibition of DNA methyltransferase 1 (DNMT1), which results in enhanced cytotoxicity and antitumor response. Mechanistically, PRC2 inactivation amplifies DNMT inhibitor-mediated expression of retrotransposons, subsequent viral mimicry response, and robust cell death in part through a protein kinase R (PKR)-dependent double-stranded RNA sensor. Collectively, our observations posit DNA methylation as a safeguard against antitumorigenic cell-fate decisions in PRC2-loss cancer to promote cancer pathogenesis, which can be therapeutically exploited by DNMT1-targeted therapy. SIGNIFICANCE: PRC2 inactivation drives oncogenesis in various cancers, but therapeutically targeting PRC2 loss has remained challenging. Here we show that PRC2-inactivating mutations set up a tumor context-specific liability for therapeutic intervention via DNMT1 inhibitors, which leads to innate immune signaling mediated by sensing of derepressed retrotransposons and accompanied by enhanced cytotoxicity. See related commentary by Guil and Esteller, p. 2020. This article is highlighted in the In This Issue feature, p. 2007.

Sporadic malignant peripheral nerve sheath tumour (MPNST) in a 3-year-old girl: A diagnostic challenge.

INTRODUCTION: Malignant peripheral nerve sheath tumour (MPNST) is an uncommon malignant neoplasm of childhood with unfavourable prognosis. Only a limited number of cases have been reported in children less than 12 years of age, and approximately one-half arise from a benign peripheral nerve sheath tumour, especially in the background of neurofibromatosis type 1 (NF1). Primary MPNST in children is even rarer. CASE REPORT: A 3-year-old Malay girl presented with painful right axillary swelling for six months, initially treated as axillary lymphadenitis and she defaulted follow up. She came back four months later with enlargement of the swelling. The previous biopsy was reported as Schwannoma, which correlates with a benign peripheral nerve sheath tumour's MRI findings. The final diagnosis after debulking surgery was consistent with MPNST. She succumbed to death 20 months after her initial diagnosis of advanced MPNST and lung metastasis. PATHOLOGICAL FINDINGS: Grossly, a huge partly circumscribed soft tissue mass was noted arising from a nerve with a solid greyish yellowish myxoid cut surface. Spindle-shaped cells arranged in a herringbone pattern alternated with areas of myxoid hypocellular areas exhibited marked pleomorphism, brisk mitosis, and extensive necrosis are seen microscopically. Immunohistochemistry shows patchy S100 protein staining with loss of expression of H3K27me3. CONCLUSION: Although MPNST is rare in the paediatric age group, the diagnosis should be considered in children without NF1 with a rapidly evolving and painful mass in the peripheral nerve distribution. In this case, the diagnosis was delayed and made after surgery. Due to its morphologic heterogeneity and lack of specific immunohistochemical markers, MPNST remains a diagnostic challenge.

Assessment of H3K27me3 immunohistochemistry and combination of NF1 and p16 deletions by fluorescence in situ hybridization in the differential diagnosis of malignant peripheral nerve sheath tumor and its histological mimics.

BACKGROUND: A definitive diagnosis of malignant peripheral nerve sheath tumor (MPNST) is challenging, especially in cases without neurofibromatosis 1 (NF1), because MPNST lacks specific markers on immunohistochemistry (IHC). METHODS: We performed IHC for histone 3 trimethylated on lysine 27 (H3K27me3) and evaluated the percentage of cells with H3K27me3 loss using measured values at 10% intervals, categorized as complete loss (100% of tumor cells lost staining), partial loss (10% to 90% of tumor cells lost staining), and intact (no tumor cells lost staining). We conducted fluorescence in situ hybridization (FISH) for NF1 and p16 deletions comparing 55 MPNSTs and 35 non-MPNSTs, consisting of 9 synovial sarcomas (SSs), 8 leiomyosarcomas (LMSs), 10 myxofibrosarcomas (MFSs), and 8 undifferentiated pleomorphic sarcomas (UPSs). We assessed the percentage of cells with homozygous and heterozygous deletions and defined "deletion" if the percentage of either the NF1 or p16 deletion signals was greater than 50% of tumor cells. RESULTS: Among the 55 MPNSTs, 23 (42%) showed complete H3K27me3 loss and 32 (58%) exhibited partial loss or intact. One each of the 9 SSs (11%), 8 LMSs (12%), and 8 UPSs (12%) showed complete H3K27me3 loss and many non-MPNSTs exhibited intact or partial H3K27me3 loss. Among the 55 MPNSTs, 33 (60%) and 44 (80%) showed NF1 or p16 deletion, respectively. Co-deletion of NF1 and p16 was observed in 29 (53%) MPNSTs. Among the 23 MPNTSs showing H3K27me3 complete loss, 18 (78%) and 20 (87%) exhibited NF1 or p16 deletion, respectively. Among the 32 MPNSTs with H3K27me3 partial loss or intact, 15 (47%) and 24 (75%) exhibited NF1 or p16 deletion, respectively. The frequency of NF1 and/or p16 deletion tended to be lower in non-MPNSTs than in MPNSTs. Approximately 90% of MPNSTs included cases with H3K27me3 complete loss and cases showing H3K27me3 partial loss or intact with NF1 and/or p16 deletion. Approximately 50% of MPNSTs showed co-deletion of NF1 and p16 regardless of H3K27me3 loss. CONCLUSIONS: FISH for NF1 and p16 deletions, frequently observed in high-grade MPNSTs, might be a useful ancillary diagnostic tool for differentiating MPNST from other mimicking spindle cell and pleomorphic sarcomas.

Cell-free DNA ultra-low-pass whole genome sequencing to distinguish malignant peripheral nerve sheath tumor (MPNST) from its benign precursor lesion: A cross-sectional study.

BACKGROUND: The leading cause of mortality for patients with the neurofibromatosis type 1 (NF1) cancer predisposition syndrome is the development of malignant peripheral nerve sheath tumor (MPNST), an aggressive soft tissue sarcoma. In the setting of NF1, this cancer type frequently arises from within its common and benign precursor, plexiform neurofibroma (PN). Transformation from PN to MPNST is challenging to diagnose due to difficulties in distinguishing cross-sectional imaging results and intralesional heterogeneity resulting in biopsy sampling errors. METHODS AND FINDINGS: This multi-institutional study from the National Cancer Institute and Washington University in St. Louis used fragment size analysis and ultra-low-pass whole genome sequencing (ULP-WGS) of plasma cell-free DNA (cfDNA) to distinguish between MPNST and PN in patients with NF1. Following in silico enrichment for short cfDNA fragments and copy number analysis to estimate the fraction of plasma cfDNA originating from tumor (tumor fraction), we developed a noninvasive classifier that differentiates MPNST from PN with 86% pretreatment accuracy (91% specificity, 75% sensitivity) and 89% accuracy on serial analysis (91% specificity, 83% sensitivity). Healthy controls without NF1 (participants = 16, plasma samples = 16), PN (participants = 23, plasma samples = 23), and MPNST (participants = 14, plasma samples = 46) cohorts showed significant differences in tumor fraction in plasma (P = 0.001) as well as cfDNA fragment length (P < 0.001) with MPNST samples harboring shorter fragments and being enriched for tumor-derived cfDNA relative to PN and healthy controls. No other covariates were significant on multivariate logistic regression. Mutational analysis demonstrated focal NF1 copy number loss in PN and MPNST patient plasma but not in healthy controls. Greater genomic instability including alterations associated with malignant transformation (focal copy number gains in chromosome arms 1q, 7p, 8q, 9q, and 17q; focal copy number losses in SUZ12, SMARCA2, CDKN2A/B, and chromosome arms 6p and 9p) was more prominently observed in MPNST plasma. Furthermore, the sum of longest tumor diameters (SLD) visualized by cross-sectional imaging correlated significantly with paired tumor fractions in plasma from MPNST patients (r = 0.39, P = 0.024). On serial analysis, tumor fraction levels in plasma dynamically correlated with treatment response to therapy and minimal residual disease (MRD) detection before relapse. Study limitations include a modest MPNST sample size despite accrual from 2 major referral centers for this rare malignancy, and lack of uniform treatment and imaging protocols representing a real-world cohort. CONCLUSIONS: Tumor fraction levels derived from cfDNA fragment size and copy number alteration analysis of plasma cfDNA using ULP-WGS significantly correlated with MPNST tumor burden, accurately distinguished MPNST from its benign PN precursor, and dynamically correlated with treatment response. In the future, our findings could form the basis for improved early cancer detection and monitoring in high-risk cancer-predisposed populations.

Characterization of PD-1/PD-L1 immune checkpoint expression in soft tissue sarcomas.

Inhibitors of the programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) immune checkpoint system are used for treating various malignancies. However, evidence on their use in soft tissue sarcomas (STS) is limited. This study aimed to retrospectively investigate the relationship between the expression of PD-1/PD-L1 and related antigens in STS, and their association with clinical characteristics. Immunostaining for CD4, CD8, PD-1, PD-L1, IL-2, and IFN-γ was performed using pathological specimens harvested at the time of biopsy from 10 patients with undifferentiated pleomorphic sarcoma (UPS), nine with myxofibrosarcoma (MFS), and three with malignant peripheral nerve sheath tumor (MPNST) who were treated at our hospital. Subsequently, the positive immunostaining cell rates were calculated. We also examined the correlation between each immune positive cell rate and age, tissue grade, size, and maximum standardized uptake (SUV-max) values. The 3-year event-free survival (EFS) and overall survival (OS) rates were compared between the positive and negative groups (positive rate >10%; negative <10%) for various immune stains. The positive rates were also compared between the presence and absence of events groups. There was positive staining for the immune checkpoint molecules in every STS type except for PD-1 in MPNST. CD4, CD8, and PD-1 stained lymphocytes in close proximity to the tumor in adjacent tissue sections. A positive correlation was observed between the positive cell rates of each immune component including inflammatory cytokines such as IL-2 and IFN-γ. Additionally, the clinical features positively correlated with the positive PD-1/PD-L1 expression rates. No significant differences in the 3-EFS and OS rates was observed between the PD-1/PD-L1 positive and negative groups. Our results suggest that an inducible immune checkpoint mechanism may be involved in UPS, MFS, and MPNST.

[Malignant Triton tumour: A case report]. / Tumeur Triton maligne : à propos d'un cas.

Malignant Triton tumour (MTT) is a subtype of malignant peripheral nerve sheaths tumour (MPNST) with exclusive heterologous rhabdomyosarcomatous contingent. MTT is rare and of poor prognosis. This entity illustrates the great heterogeneity of MPNST, the diagnosis of which is difficult in the absence of a specific marker, especially in sporadic forms. Although MTT preferentially develop in patients with type 1 neurofibromatosis, sporadic cases may occur. We herein present a case of MTT of the left arm, occurring in a 74-year-old patient, without clinical context of NF1. The fast-growing tumour reached 9.2cm of greater dimension at the time of surgical excision. Histology showed a spindle cell sarcoma with rhabdoid cell areas expressing myogenin. In the absence of neural crest markers expression, the diagnosis of MPNST was based on a significant loss of expression of the histone 3 tri-methylated lysine 27, a classical although not specific epigenetic mark for this sarcoma group, and on the identification of the heterologous rhabdomyosarcomatous contingent, previously described in the context of MTT.

Loss of H3K27me3 occurs in a large subset of embryonal rhabdomyosarcomas: Immunohistochemical and molecular analysis of 25 cases.

Loss of histone 3 lysine 27 trimethylation (H3K27me3) has been described as a diagnostic marker for malignant peripheral nerve sheath tumor (MPNST), also discriminating MPNST with rhabdomyoblastic differentiation (malignant Triton tumor) from rhabdomyosarcoma (RMS). We studied the immunohistochemical expression of H3K27me3 in embryonal RMSs (ERMSs), performed methylation profiling in order to support the diagnosis and RNA-sequencing for comparison of the transcriptome of H3K27me3-positive and -negative cases. Of the 25 ERMS patients, 17 were males and 8 were females with an age range from 1 to 67 years (median, 6 years). None were known with neurofibromatosis type 1. One patient had Li-Fraumeni syndrome. Tumor localization included paratesticular (n = 9), genitourinary (n = 6), head/neck (n = 5), retroperitoneal (n = 4) and lower arm (n = 1). Five MPNSTs served as reference group. All ERMS had classical features including a variable spindle cell component. Immunohistochemical loss (partial or complete) of H3K27me3 was detected in 18/25 cases (72%). Based on methylation profiling, 22/22 cases were classified as ERMS. Using RNA sequencing, the ERMS group (n = 14) had a distinct gene expression profile in contrast to MPNSTs, confirming that the H3K27me3 negative ERMS cases do not represent malignant Triton tumors. When comparing H3K27me3-negative and -positive ERMSs, gene set enrichment analysis revealed differential expression of genes related to histone acetylation and normal muscle function with H3K27me3 negative ERMSs being associated with acetylation. Conclusion: Loss of H3K27me3 frequently occurs in ERMSs and correlates with H3K27 acetylation. H3K27me3 is not a suitable marker to differentiate ERMS (with spindle cell features) from malignant Triton tumor.

Intracranial metastasis from a malignant peripheral nerve sheath tumor in a patient with neurofibromatosis type 1: A case study and literature review.

INTRODUCTION: Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are a rare type of soft tissue sarcoma. While these tumors often metastasize, intracranial metastases of MPNSTs have only been rarely noted. METHODS: Using Pubmed, Google Scholar, and Science Direct we conducted a systematic review of the literature to identify all reported cases of MPNSTs with metastases to the brain since the inception of these databases through January 2020. Data were extracted and data analysis was completed using python statistical packages. RESULTS: Only 26 cases (including present study) of MPNSTs resulting in intracranial metastases have been reported in the literature. Eight of these 26 cases occurred in patients who were previously diagnosed with Neurofibromatosis Type 1 (NF1). Additionally, one patient had been previously diagnosed with Neurofibromatosis Type 2 (NF2). The average reported time from diagnosis of a MPNST to the time of diagnosis with intracranial metastasis was 36 months, with a median time of 14 months. The average reported survival time for patients after being diagnosed with intracranial metastasis was 5.9 months. The cases that utilized a combination of therapeutic intervention including surgical resection, radiotherapy and chemotherapy saw the greatest improvement of survival times. CONCLUSION: MPNSTs with brain metastases are extremely rare and have a poor prognosis with a 6 months median survival after metastasis. While combination therapy is indicated, further studies on treatment are needed to determine survival benefits. Early and effective initial diagnosis of MPNST before brain metastases occurs is likely to give the best chance of increased overall survival.

Spinal Malignant Peripheral Nerve Sheath Tumours in Nigerians.

BACKGROUND: Spinal Malignant peripheral nerve sheath tumours (MPNSTs) are very rare aggressive tumours with poor prognosis. Little is known about these tumours in sub-saharan Africa. OBJECTIVES: This study aims to evaluate the clinical profile and outcome of management of these tumours in a resource limited country. METHODS: We retrospectively analysed data from the records of patients who had surgery for spinal MPNSTs at our center between January 2004 and December 2018. RESULTS: There were four patients in this study (M:F= 1:1). The ages ranged from 27-53 years with a mean of 43.25 ± 11.84 years. The tumour was located in the thoracic region in 2 of the patients (50%), the lumbar region in one (25%) and thoracolumbar in the 4th patient. Three patients (75%) presented with back pain while limb weakness, sensory deficit and sphincteric dysfunction were present in all patients at presentation. The duration of symptoms were 2 months in 2 patients (50%) and 3 months in the other 2. None of the patients had neurofibromatosis. Gross total tumour excision was achieved in 2 patients (50%) and subtotal resection in the other 2. The tumours were high grade in three patients (75%) and low grade in one. Two patients had adjuvant radiotherapy. Two of the patients were dead within 6 months of the diagnosis, another one within 18 months while one patient is still alive 3 years after. CONCLUSIONS: MPNSTs are very rare in our practice. Most of the tumours were high grade tumours and ran an aggressive course.

Phase II clinical trial of pazopanib for patients with unresectable or metastatic malignant peripheral nerve sheath tumors.

Malignant peripheral nerve sheath tumor (MPNST) often does not respond well to chemotherapy and develops against a background of NF1. The purpose of our study was to examine the efficacy of pazopanib against MPNST. Our study was designed as a physician-initiated phase II clinical trial in patients with advanced MPNST. Patients were registered from 11 large hospitals. The primary endpoint was set to clarify the clinical benefit rate (CBR) at 12 weeks according to response evaluation criteria in solid tumors (RECIST). Progression-free survival (PFS), overall survival (OS) and the CBR based on modified Choi evaluation at week 12 were set as secondary endpoints along with treatment-related safety. The study enrolled 12 patients. Median age was 49 years. Seven had Grade 2 and five Grade 3 according to the FNCLCC evaluation. Median follow-up period was 10.6 months. CBR at 12 weeks was both 50.0% (RECIST and Choi). The median PFS was 5.4 months for both RECIST and Choi, and the median OS was 10.6 months. Of special interest, the median PFS was 2.9 months for patients with FNCLCC Grade 2 and 10.2 months for Grade 3 (both RECIST and Choi). Grade 4 adverse events of neutropenia and lipase elevation were noted in one patient each. The results of this pazopanib therapy were generally better than those of any of the other single molecular targeted therapies reported previously. Although accumulation of more cases remains necessary, we conclude pazopanib treatment for MPNST to be a safe and promising treatment after doxorubicin-based chemotherapy.

A Case of Inv(1)(q23q31) TPR-NTRK1 Fusion-Positive Spindle Cell Neoplasm in an Infant-Uncovered by Next-Generation Sequencing: Diagnostic Challenge, Review, and Therapeutic Implications.

Lately, NTRK-positive mesenchymal tumors are being increasingly identified, mostly in pediatric patients, in view of associated treatment implications, especially in recurrent and unresectable tumors. A 1-year-old male child presented with a rapidly growing tumor mass in his cervical region of 2 months duration. Radiologic imaging disclosed a tumor measuring 11 cm in size, almost filing his right neck spaces. Review of biopsy sections revealed a cellular tumor comprising spindle cells arranged in sheets and fascicles with interspersed collagenous strands and areas of adipocytic, myxoid, and hyaline degeneration. Immunohistochemically, tumor cells were diffusely positive for CD34 and S100 protein. Subsequently, on testing the tumor for a solid tumor gene panel by next-generation sequencing, it was found to be positive for inv(1)(q23q31) TPR-NTRK1 fusion. Furthermore, tumor cells displayed NTRK1 gene rearrangement by fluorescence in situ hybridization technique. The patient was offered chemotherapy; however, he had a rapid local progression, leading to respiratory obstruction; he then succumbed to the disease. The present case underpins the value of next-generation sequencing as a useful technique for uncovering NTRK-fusion-positive mesenchymal tumors. Review of similar cases, diagnostic challenge, and treatment implications in such cases are discussed.

Radiation-associated sarcomas other than malignant peripheral nerve sheath tumours demonstrate loss of histone H3K27 trimethylation†.

BACKGROUND AND AIMS: Complete loss of histone H3 lysine 27 trimethylation (H3K27me3) has recently emerged as a biomarker for malignant peripheral nerve sheath tumours (MPNST). Loss of H3K27me3 staining has also been reported in post-radiation MPNST; however, it has not been evaluated in a large series of radiation-associated sarcomas of different histological subtypes. The aim of this study was to assess H3K27me3 labelling by immunohistochemistry in radiation-associated sarcomas and to determine the prevalence of H3K27me3 loss in these tumours. METHODS AND RESULTS: Radiation-associated sarcomas (n = 119) from two tertiary care referral centres were evaluated for loss of H3K27me3, defined as complete loss of staining within tumour cells in the presence of a positive internal control. Twenty-three cases (19%) showed H3K27me3 loss, including nine of 10 (90%) MPNST, seven of 77 (9%) undifferentiated spindle cell/pleomorphic sarcomas, five of 25 (20%) angiosarcomas, one of five (20%) leiomyosarcomas and one of two (50%) osteosarcomas. CONCLUSIONS: Complete H3K27me3 loss was present in 19% of radiation-associated sarcomas in our series. Our findings demonstrate that loss of H3K27me3 is not specific for radiation-associated MPNST and may also occur in other histological subtypes of RAS, including radiation-associated undifferentiated spindle cell/pleomorphic sarcoma, angiosarcoma, leiomyosarcoma and osteosarcoma.