Case Of Malignant Peripheral Nerve Sheath Tumor Research Articles

Malignant Tumor of the Sheaths and Peripheral Nerves: A Case Report

Malignant Peripheral Nerve Sheath Tumors (MPNST) are a rare anatomopathological subtype of soft tissue sarcoma. We report a case of MPNST in a patient without a history of neurofibromatosis. He presented with a progressively developing ulcerobourgennate lesion on the left buttock. Histopathological analysis of a biopsy of the mass confirmed MPNST. These are rare tumors that can occur in patients without any particular history and are difficult to manage at an advanced stage.

Clinical and cytohistomorphological evaluation of peripheral nerve sheath tumours with special reference to immunohistochemical diversity in a tertiary care hospital

Peripheral Nerve Sheath Tumours (PNST), though have a frequent prevalence, are diagnostically challenging. There is a wide spectrum of lesions ranging from benign entities like neurofibroma, Schwannoma, perineurioma to malignant entities like malignant peripheral nerve sheath tumours (MPNST), malignant granular cell tumour and malignant perineurioma. Since there is an overlap with other spindle and round cell tumours, IHC and molecular studies are needed to provide a clear distinction between different tumour types. It was a 5 years observational study (3 years retrospective and 2 years prospective) conducted in the Department of Pathology, JNMCH, AMU from 2015-2020. . History and relevant clinical findings were retrieved from the archives of both the Histopathology and Cytopathology Lab. Imprints as well as FNA smears were included from Cytopathology Lab and biopsies and resection specimen from Histopathology Lab. Immunohistochemistry was applied wherever necessary. A total of 82 cases were diagnosed over a 5 year period out of which 70 were benign and 12 malignant. Male preponderance was seen. Benign tumours comprised mostly of Neurofibroma and Schwannoma and there were 12 cases of MPNST. Correlation was established between Cytopathological and Histopathological findings and IHC, mostly S100 proved useful in differentiating it from other malignant spindle cell tumours. The differential diagnoses of these tumours has always posed a problem given their monotonous appearance and clinical overlap. This study, therefore, aims to analyse the diverse morphological features of Peripheral Nerve Sheath Tumours in the light of cytopathological and histopathological findings and immunohistochemistry.

Huge Malignant Peripheral Nerve Sheath Tumors Originating In Neurofibromatosis Type 1

Malignant peripheral nerve sheath tumors (MPNST) are malignant soft tissue neoplasms which account for 2% of all soft tissue sarcomas. These tumors are associated with poor prognosis, propensity to metastasize and high recurrence rates. About half of the MPNST arise from pre-existing neurofibroma and are associated with Neurofibromatosis type I (NF1), 10% are radiotherapy induced others are sporadic. Pathogenesis of MPNST is not fully understood yet. MPNST are common in extremities followed by trunk but are less common in head and neck area. MPNST show limited sensitivity to radiotherapy and chemotherapy and wide surgical resection is mainstay of treatment. We present a series of 3 cases of MPNST of head and neck region originating in patients having NF1.

Malignant peripheral nerve sheath tumor: a clinicopathological analysis

Objective: To investigate the clinicopathological, immunophenotypic, and genetic features of malignant peripheral nerve sheath tumor (MPNST). Methods: Twenty-three cases of MPNST were diagnosed at the Jiangsu Province Hospital (the First Affiliated Hospital of Nanjing Medical University), China, between January 2012 and December 2022 and thus included in the study. EnVision immunostaining and next-generation sequencing (NGS) were used to examine their immunophenotypical characteristics and genomic aberrations, respectively. Results: There were 10 males and 13 females, with an age range of 11 to 79 years (median 36 years), including 14 cases of neurofibromatosis type I-associated MPNST and 9 cases of sporadic MPNST. The tumors were located in extremities (7 cases), trunk (4 cases), neck and shoulder (3 cases), chest cavity (3 cases), paraspinal area (2 cases), abdominal cavity (2 cases), retroperitoneum (1 case), and pelvic cavity (1 case). Morphologically, the tumors were composed of dense spindle cells arranged in fascicles. Periphery neurofibroma-like pattern was found in 73.9% (17/23) of the cases. Under low magnification, alternating hypercellular and hypocellular areas resembled marbled appearance. Under high power, the tumor cell nuclei were irregular, presenting with oval, conical, comma-like, bullet-like or wavy contour. In 7 cases, the tumor cells demonstrated marked cytological pleomorphism and rare giant tumor cells. The mitotic figures were commonly not less than 3/10 HPF, and geographic necrosis was often noted. Immunohistochemically, tumor cells were positive for S-100 (14/23, 60.9%) and SOX10 (11/23, 47.8%). The loss of the CD34-positive fibroblastic network encountered in neurofibromas was observed in 14/17 of the MPNST cases. The loss of H3K27me3 expression was observed in 82.6% (19/23) of the cases. Moreover, SDHA and SDHB losses were presented in one case. NGS revealed that NF1 gene loss of function (germline or somatic) were found in all 5 cases tested. Furthermore, four cases accompanied with somatic mutations of SUZ12 gene and half of them had somatic mutations of TP53 gene, while one case with germline mutation in SDHA gene and somatic mutations in FAT1, BRAF, and KRAS genes. Available clinical follow-up was obtained in 19 cases and ranged from 1 to 67 months. Four patients died of the disease, all of whom had the clinical history of neurofibromatosis type Ⅰ. Conclusions: MPNST is difficult to be differentiated from a variety of spindle cell tumors due to its wide spectrum of histological morphology and complex genetic changes. H3K27me3 is a useful diagnostic marker, while the loss of CD34 positive fibroblastic network can also be a diagnostic feature of MPNST. NF1 gene inactivation mutations and complete loss of PRC2 activity are the common molecular diagnostic features, but other less commonly recurred genomic aberrations might also contribute to the MPNST pathogenesis.

Brain metastasis and intracranial leptomeningeal metastasis from malignant peripheral nerve sheath tumors: illustrative cases.

Malignant peripheral nerve sheath tumors (MPNSTs) are rare soft-tissue tumors. Intracranial metastasis from MPNSTs is quite rare. The authors report on a 73-year-old male whose MPNST metastasized to the brain and a 32-year-old male with leptomeningeal metastasis from MPNST and review 41 cases of MPNST that developed intracranial metastasis, as reported in the literature. Brain metastasis and leptomeningeal metastasis of MPNSTs show different clinical courses and require pathology-specific treatment.

A Case of Malignant Peripheral Nerve Sheath Tumour of the Kidney

Introduction: Malignant peripheral nerve sheath tumor (MPNST) of the kidney is an uncommon neoplasm. We present a rare case of MPNST successfully managed by surgical intervention. Case Presentation: A 23-year-old male patient presented with dull aching pain in the right flank associated with hematuria. On examination, an abdominal mass with firm consistency occupied the right lumbar quadrant with the fullness of the right renal angle. Contrast-enhanced computed tomography (CECT) showed heterogeneously hypoenhancing lobulated mass (9.2 × 6.4 × 7.6 cm) arising exophytically from the anterior cortex of the middle and lower poles of the right kidney with necrosis. It was compressing the pelvicalyceal system causing mild hydronephrosis. Kidney function tests revealed normal results. Urine cytology for malignant cells was negative. The patient underwent an open radical nephrectomy. Renal mass was adhered to ascending colon and duodenum and was abutting the liver. The histopathological report suggested malignant peripheral nerve sheath tumors with margins microscopically clear of tumor cells. S-100 and Vimentin were stained positively. The patient has been under regular follow-up (every three months) for the last year. Conclusions: If feasible, wide local excision is considered the preferred approach, as prognosis mainly depends on the completeness of surgical resection.

Abstract 3563: SWI/SNF-associated DPF1 is a unique transcriptional regulator of malignant peripheral nerve sheath tumors

Abstract Background: Malignant peripheral nerve sheath tumors (MPNST) are rare soft tissue sarcomas that are typically therapy resistant and associated with a poor prognosis. Genetic aberrations of the polycomb repressive complex 2 (PRC2) occur in up to 75% of MPNST cases. PRC2 functions antagonistically to SWI/SNF protein complexes, regulating expression of target loci in a dynamic relationship that is critical to normal cellular development and maintenance of cell identity. The consequences of PRC2 loss on chromatin state maintained by SWI/SNF in MPNST is unexplored. Therefore, this study used functional genomics to elucidate the role of SWI/SNF in MPNST. Methods: To define the transcriptional regulatory role of SWI/SNF complexes in MPNST, SWI/SNF components were targeted via a CRISPR knock-out (KO) screen combined with a single cell RNA sequencing (RNAseq) readout. Genes of interest highlighted by this screen were further investigated using bulk CRISPR RNAseq. Phenotypic effects of the expression of these genes were studied using loss-of-function assays coupled with colony formation assays. SWI/SNF complex heterogeneity was characterized using glycerol gradient sedimentation, co-immunoprecipitation (co-IP), and mass spectrometry experiments. Results: The investigation of SWI/SNF transcriptional regulation in MPNST highlighted the Double PHD Finger family proteins (DPF1,2,3) as regulating distinct downstream targets. Notably, DPF1 had a unique transcriptional profile compared to other SWI/SNF components. Bulk CRISPR KO RNAseq confirmed these findings and highlighted a specific set of DPF1 target genes including many long non-coding RNAs. The phenotypic role of DPF1 in MPNST was investigated using in vitro siRNA and CRISPR experiments, where DPF1 KO reduced proliferation and viability of MPNST cells in both 2D and 3D cell culture assays. Further, DPF1 was found contribute to anchorage independent cell growth of MPNST cells using soft agar assays. Glycerol gradient sedimentation assays demonstrated that DPF1 co-migrated with core components of a SWI/SNF complex known as canonical BAF (cBAF) and not the alternate GBAF and PBAF SWI/SNF complexes. These findings were further validated using co-immunoprecipitation assays where core the SWI/SNF ATPase, SMARCA4, pulled down DPF1, while components unique to the GBAF and PBAF complexes did not. An ATPase directed proteolysis targeting chimers (PROTAC) was used to therapeutically target cBAF in MPNST cells, reducing their growth and viability. Combination treatment with standard of care chemotherapy synergistically increased the efficacy of this drug. Conclusions: DPF1 was identified as a unique transcriptional regulator of MPNST cells and acts as a member of the cBAF SWI/SNF complex to play important phenotypic roles in this cancer type. Citation Format: Bega Murray, Xiyuan Zhang, Shahroze Abbas, Haiyan Lei, Hilda Jafarah, Jack F. Shern. SWI/SNF-associated DPF1 is a unique transcriptional regulator of malignant peripheral nerve sheath tumors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3563.

Paranasal Sinus Malignant Peripheral Nerve Sheath Tumour: A Rare Case Report.

Malignant Peripheral Nerve Sheath Tumour (MPNST) is a neoplastic lesion rarely reported in literature. In approximately 5% of cases it is associated with Neurofibromatosis type 1 syndrome. Pathognomic features of MPNST include slow growth rate, aggressive nature, nearly circumscribed, unencapsulated arising from non myelinated Schwann cells. In this case report we elaborate probable molecular pathogenesis, clinical features, histopathology (HPE) and radiological findings in a unique case of MPNST. A 52year old female patient presented with Right cheek swelling, Loss of sensations over right maxillary region, U/L nasal obstruction and watery nasal discharge, palatal buldge and intermittent pain over right maxillary region and generalised headache. Following Magnetic resonance imaging studies (MRI scan) of paranasal sinuses, Biopsy was taken from maxillary mass and palatal swelling. HPE report was suggestive of Spindle cell proliferation against myxoid stroma. Positron Emmision Tomography (PET-Scan) was done and Biopsy specimen was subjected for Immunohistochemistry staining (IHC). After confirmation of MPNST on IHC, patient was referred to skull base surgeon for complete excision of the tumour and reconstruction.

Regional recurrence of malignant peripheral nerve sheath tumor in upper extremity – a rare case report

Introduction: Malignant Peripheral Nerve Sheath Tumor (MPNST) are aggressive soft tissue sarcoma (STS), originally arising from neural cell components. MPNST had a relatively high local recurrence rate of 22% and a disease survival rate of 45 - 60%. In this study, we would like to report a rare case of recurrent MPNST affecting the upper arm region, with a history of previously resected MPNST at the patient's ipsilateral elbow. Case Presentation: A 38-years old male patient complained of an enlarging mass in his left anterior axilla Patient had a history of left elbow mass 2 years before and had resected twice. Eight months afterward, a new tumor grew from his left axilla. From the physical examination, the mass was fixated and firm with an oval shape, size 8 x 6 cm. From chest CT scan examination, it appeared a soft tissue mass surrounded with stranding fat had infiltrated his left teres major muscle. The mass was removed successfully and the pathology result revealed a grade 2 MPNST. Post-operative radiotherapy was then scheduled. Among many STS, MPNSTs are notorious for having a high recurrence rate. NF1 mutation, tumors deeper than fascia, large tumors, high-grade tumors, and tumors arising from the trunk, head, and neck are related to poor prognosis in MPNST. Surgeons' inadequate knowledge, unplanned resections, and their dependency on radiotherapy are other iatrogenic factors for recurrences. Conclusion: MPNST has high recurrent risk, especially in high-grade tumors, large or deep tumors, surgery with positive resection margins, and NF1 mutations. The primary option for treatment is surgery and radiation therapy.

Jejunal Malignant Peripheral Nerve Sheath Tumor with Preoperative Suspicion of Gastrointestinal Stromal Tumor: Report of a Korean Case and Literature Review

Background: Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are defined as malignant tumors arising from a peripheral nerve or displaying nerve sheath differentiation. We report the first Korean case of MPNST of the ileum. Case Presentation: A 33-year-old female without family history of neurofibromatosis type I complained of lower abdominal pain. An abdomen computed tomography and enhanced magnetic resonance imaging of the pelvis confirmed a 5.6 cm heterogenous lobulated lesion in the ileum. Laparoscopic exploration revealed severe adhesion of the main ileal mass to the sigmoid colon. Laparoscopic adhesiolysis and segmental resection with anastomosis of the ileum was performed. On gross examination, the resected specimen was 6.5 cm and the tumor was located 10 cm proximal and 15 cm distal from the resection margins. In microscopic examination, the nucleus of the tumor cells was oval to elongated shape, showing moderate pleomorphism. Immunohistochemical staining showed that the main tumor cells were positive for S100 and about 10% of the tumor cells were positive for Ki-67. During the 12-month follow-up period, she presented no symptoms and the abdomen CT scans showed no evidence of distant metastasis in the thorax or abdominal recurrence. Conclusion: We report a rare case of a young female with a MPNST of jejunum, suspected of having GIST before surgery and an extensive review of the literature for MPNST in intestinal tract.

MEK Inhibition Synergizes with TYK2 Inhibitors in NF1-Associated Malignant Peripheral Nerve Sheath Tumors.

Malignant peripheral nerve sheath tumors (MPNST) are aggressive sarcomas with limited treatment options and poor survival rates. About half of MPNST cases are associated with the neurofibromatosis type 1 (NF1) cancer predisposition syndrome. Overexpression of TYK2 occurs in the majority of MPNST, implicating TYK2 as a therapeutic target. The effects of pharmacologic TYK2 inhibition on MPNST cell proliferation and survival were examined using IncuCyte live cell assays in vitro, and downstream actions were analyzed using RNA-sequencing (RNA-seq), qPCR arrays, and validation of protein changes with the WES automated Western system. Inhibition of TYK2 alone and in combination with MEK inhibition was evaluated in vivo using both murine and human MPNST cell lines, as well as MPNST PDX. Pharmacologic inhibition of TYK2 dose-dependently decreased proliferation and induced apoptosis over time. RNA-seq pathway analysis on TYK2 inhibitor-treated MPNST demonstrated decreased expression of cell cycle, mitotic, and glycolysis pathways. TYK2 inhibition resulted in upregulation of the MEK/ERK pathway gene expression, by both RNA-seq and qPCR array, as well as increased pERK1/2 levels by the WES Western system. The compensatory response was tested with dual treatment with TYK2 and MEK inhibitors, which synergistically decreased proliferation and increased apoptosis in vitro. Finally, combination therapy was shown to inhibit growth of MPNST in multiple in vivo models. These data provide the preclinical rationale for the development of a phase I clinical trial of deucravacitinib and mirdametinib in NF1-assosciated MPNST.

Malignant Peripheral Nerve Sheath Tumor of Tongue: A Rare Tumor of Oral Cavity

Malignant peripheral nerve sheath tumor (MPNST) is a rare tumor of oral cavity. Tongue is an extremely rare site for MPNST. We present a rare case of MPNST of tongue in a 34-year-old male. Presentation remains same as carcinoma of tongue but histopathology and immunohistochemistry help to establish the diagnosis. Biopsy of lesion was suggestive of malignant spindle cell neoplasm. On immunohistochemical examination, tumor cells were immunopositive for vimentin and S100 and SMA. Patient underwent surgery followed by adjuvant radiotherapy in order to reduce the risk of recurrence.

Abstract B011: Single cell CRISPR screen of malignant peripheral nerve sheath tumors identifies SWI/SNF genes of regulatory importance

Abstract Background: Malignant peripheral nerve sheath tumors (MPNST) are rare and aggressive soft tissue sarcomas of the peripheral nervous system which are associated with a poor prognosis. Recurrent genetic mutations of the polycomb repressive complex 2 (PRC2) have been identified in up to 75% of MPNST cases. PRC2 is involved in an intricate epigenetic regulatory network in mammalian cells, where it is known to function antagonistically to the SWI/SNF protein complexes which are commonly associated with active transcription. The regulatory relationship between these complexes is critical to normal cell development and maintenance of cellular identity. However, little is known about how PRC2 aberrations affect this regulatory balance in MPNST. Therefore, this study aims to investigate the role of SWI/SNF in MPNST. Methods: A CRISPR knock-out (KO) screen combined with single cell RNA sequencing (RNAseq) was used to target 44 components of SWI/SNF complexes. The transcriptional regulatory effects of resulting genes of interest were further investigated via bulk CRISPR RNAseq experiments, while phenotypic effects were studied using loss-of-function assays coupled with colony formation assays. The dynamic complex formation was further deciphered using glycerol gradient sedimentation and co-immunoprecipitation (co-IP) assays. Results: Double PHD Fingers 1 gene, DPF1, was identified as a unique transcriptional regulator of MPNST via the single cell CRISPR KO screen. These findings were confirmed using a bulk RNAseq screen, where gene set enrichment analysis suggested DPF1 KO has an inhibitory effect on MPNST cell cycle and proliferation through enrichment of genes involved in the P53 pathway (FDR<0.0001) and the apoptotic pathway (FDR<0.0001). This hypothesis was validated using siRNA and CRISPR KO studies in MPNST cell lines, where DPF1 KO led to reduced proliferation and viability of these cells in both 2D and 3D cell culture assays. Soft agar assays were then used to highlight a role of DPF1 to in anchorage independent cell growth of MPNST cells. We then used glycerol gradient sedimentation assays to confirm DPF1 function as a member of the SWI/SNF complexes in MPNST, where DPF1 was observed to co-migrate with SMARCA4, a core ATPase commonly associated with the BAF complex of the SWI/SNF family. This assay was also used to eliminate DPF1 as a member of the GBAF and PBAF SWI/SNF complexes in MPNST, as we identified distinct sedimentation of DPF1 and proteins unique to these complexes. These findings were further validated using co-immunoprecipitation assays, where SMARCA4 had the ability to pull down DPF1, while components of the GBAF and PBAF complexes did not. Conclusions: DPF1 has been identified as a unique regulator of MPNST cells and acts as a member of the BAF SWI/SNF complex. Citation Format: Bega Murray, Xiyuan Zhang, Shahroze Abbas, Haiyan Lei, Hilda Jafarah, Michael C. Kelly, Jack F. Shern. Single cell CRISPR screen of malignant peripheral nerve sheath tumors identifies SWI/SNF genes of regulatory importance. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr B011.

Extensive glandular and neuroendocrine differentiation of a malignant peripheral nerve sheath tumor in a neurofibromatosis-1 patient

The histologic diagnosis of a malignant peripheral nerve sheath tumor (MPNST) is complex with no defining biomarkers or generally accepted diagnostic criteria, but based on whether it is identified arising from a peripheral nerve, arising from a benign nerve sheath tumor, in the setting of neurofibroma or when its constellation of features suggest a Schwann-cell differentiation [1- 3]. Further complicating the histologic diagnosis is the small subset of these tumors with divergent differentiation demonstrating various heterologous elements [4]. Divergent differentiation presenting in a glandular form in MPNST is particularly rare, though has been described, usually in context of Neurofibromatosis I (NF1) patients, as discrete localized areas occasionally associated with neuroendocrine features [3,5,6]. Being aware of the possible extent of variable histologic features is critical for diagnosis, particularly if only a needle core biopsy is provided. We present a case of MPNST arising in a 20-year-old woman with NF1 found to have an unusual extensive glandular and neuroendocrine divergent differentiation comprising more the 75% of the tumor, arising from a plexiform neurofibroma. The patient had a prior MPNST resected without evidence of divergent differentiation, and then a subsequent metastasis to the base of the skull with similar glandular histology following our presenting case. To our knowledge, such extensive glandular and neuroendocrine differentiation has not been previously described in these tumors.

Abstract A008: Mechanisms of immune escape in NF1-associated peripheral nerve sheath tumors

Abstract Background: Neurofibromatosis type 1 (NF1) is a neurogenetic condition characterized by neurocognitive symptoms, cutaneous findings, and a predisposition for benign and malignant tumors including peripheral nerve sheath tumors (PNST). About half of patients with NF1 develop plexiform neurofibromas (pNF), non-malignant tumors that often grow rapidly during childhood and can cause significant deformity, disruption of function, and pain. Some lesions, denoted atypical neurofibromatous neoplasms of uncertain biologic potential (ANNUBP), exhibit atypia, loss of neurofibroma architecture, high cellularity and mitotic activity, as an immediate precursor to malignant transformation. For people with NF1 there is a 10-15% overall lifetime risk of developing the aggressive soft tissue sarcoma malignant peripheral nerve sheath tumors (MPNST). Despite many clinical trials of chemotherapy and targeted agents, there has been little advancement in treatment outcomes and overall patient survival remains poor; therefore, new therapeutic approaches are needed. PNST are made up of transformed Schwann cell precursors, which do not grow and survive in isolation but rather interact with infiltrating immune cells. A deeper understanding of the relationship between the pre-existing immunity and the tumor microenvironment (TME) will help unveil potential for new combinations and adjuvant therapies for patients with PNST. Methods: We have developed a unique Johns Hopkins biospecimen repository of human NF1-associated PNST specimens. We use quantitative and spatial resolution of the geography and nature of tumor infiltrating immune cells in human PNST and have determined the interactions of T cells, myeloid cells, and immunoregulatory molecules, using a combination of multiplex chromogenic, high-dimensional flow cytometry and gene expression profiling studies. We have also analyzed existing transcriptomic datasets from 21 pNF and 34 MPNST cases. Results: RNA sequence analysis revealed an accumulation of immunosuppressive Th2 cells and tumor infiltrating myeloid cells (TIM) in the TME of PNST, which we postulate generates an anti-inflammatory response against tumors. Immunophenotyping of 17 pNF, 8 ANNUBP, and 15 MPNST human specimens confirmed the higher presence of infiltrating myeloid compared to lymphoid cells, with a predominance of CD163+ myeloid cells (TIM) during progression to malignancy. We also detected a significant increase in regulatory T cells and cytotoxic CD8+ T cells in MPNST vs ANNUBP vs pNF and near absence of CD19+ B cells in all tumor types. Multiparameter flow cytometry of single cells suspensions are being studied to further investigate the association of myeloid inflammation leading to the immune evasion of PNST. Conclusions: An immunosuppressive microenvironment characterizes PNST during the process of malignant transformation, generating an immune-excluded phenotype. Leveraging the immune contexture and the mechanisms of immune modulation in PNST will inform interventions to stimulate anti-tumor immunity in this dire disease. Citation Format: Lindy Zhang, Kai Pollard, Ana Calizo, Alexandre Maalouf, Aditya Suru, Jiawan Wang, Jineeta Banerjee, Christine A. Pratilas, Nicolas J. Llosa. Mechanisms of immune escape in NF1-associated peripheral nerve sheath tumors [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr A008.

Prevalence and detection of actionable BRAF V600 and NRAS Q61 mutations in malignant peripheral nerve sheath tumor by droplet digital PCR

Malignant peripheral nerve sheath tumors ( MPNSTs) are aggressive tumors with poor prognosis that do not typically respond well to standard chemotherapy. Recently, point mutations involving BRAF V600E have been demonstrated in a subset of MPNST, offering the possibility of targeted treatment. However, the reported prevalence of these alterations is variable. Mutations involving NRAS, which is also involved in the MAPK/ERK pathway and amenable to targeted inhibitors, have not been well characterized in MPNST. In this study, we validated droplet digital polymerase chain reactionfor the detection of BRAF V600E and NRAS Q61 mutations and evaluate the prevalence of BRAF V600E and NRAS Q61 mutations in 79 cases of MPNST, including 45 sporadic, 27 NF-1 associated, and 7 radiation-associated tumors. We detected actionable BRAF or NRAS mutations in 3 of 44sporadic MPNSTs (6.8%), including 2 BRAFV600 and 1 NRAS Q61 mutations, as well as 1 NRAS Q61 mutation in a tumor that was ultimately considered to represent melanoma. These 3 cases with positive mutations were exclusively in sporadic, high-grade MPNST (FNCLCC grade 3 of 3), with a prevalence of 11.5% in this group (3.8% NRAS Q61 mutations and 7.7% BRAF V600 mutations). None of the tumors associated with NF-1 or prior radiation had detectable mutations in the genes tested. Overall, the prevalence of these alterations offers the possibility of targeted therapy in this aggressive type of sarcoma and suggests the potential benefit of routine clinical testing.

Abstract LB060: Single-cell CRISPR screen of malignant peripheral nerve sheath tumors (MPNST)

Abstract Background: Malignant peripheral nerve sheath tumors (MPNST) are aggressive sarcomas of the peripheral nervous system. Loss of function of the polycomb repressive complex 2 (PRC2) have been identified in up to 80% of MPNST cases, via recurrent genetic mutations in the core components, EED and/or SUZ12. However, the transcriptional mis-regulation incurred by the loss of transcriptional repression in MPNST, through loss of H3K27me3, has yet to be fully deciphered. We hypothesize that PRC2 loss leads to transcriptional regulatory imbalance between key epigenetic regulating complexes in this malignancy, which may contribute to the oncogenesis of this disease. Therefore, this project aims to elucidate the role of the SWI/SNF chromatin remodeling complexes in MPNST, epigenetic regulators known to act antagonistically to PRC2. Method: This project uses a CRISPR knock out screen combined with a single cell RNA sequencing readout to target 44 known components of the SWI/SNF complexes. This technology enables large scale phenotypic assays, which we leverage to decipher the complicated epigenetic regulatory network within these lesions. Resulting genes of interest were further studied via loss-of-function assays coupled with colony formation assay and chromatin immunoprecipitation DNA sequencing (ChIP-seq) experiments. Results: This CRISPR screen highlighted core SWI/SNF components, SMARCA4 and SMARCE1, as genes of interest in MPNST. Knockdown of these genes in MPNST cell lines reduced proliferation, indicating a role for these genes in MPNST growth and viability. Further, investigations via soft agar assay found both SMARCA4 and SMARCE1 knock out to decrease the tumorigenic potential of MPNST cells. The potential dependency of SMARCA4 function in MPNST cells on PRC2 mutation was investigated using a doxycycline-inducible PRC2-restoration MPNST cell line model. ChIP-seq results suggest that loss of PRC2 does not substantially affect the binding of SMARCA4-containing SWI/SNF complexes across the genome. DPF1, a member of the neuronal-specific SWI/SNF chromatin remodeling complex, was further highlighted as a unique regulator of MPNST transcription via the CRISPR single-cell screen. CRISPR knockdown of this gene in MPNST cell lines has been found to decrease proliferation, while soft agar assay experiments highlighted that DPF1 loss reduces cell tumorigenicity. The unique dependency of this gene observed in MPNST but not in any other cancer subtypes highlights the potential of DPF1 to be a novel and unique therapeutic target in MPNST. Conclusion: Thus far, our studies have shown that members of the SWI/SNF complex play key roles in the MPNST cell proliferation and tumorigenicity. The function of these complexes in MPNST, however, may be independent of the transcriptional imbalance caused by PRC2 mutation. Citation Format: Béga Murray, Xiyuan Zhang, Shahroze Abbas, Hilda Jafarah, Jack F. Shern. Single-cell CRISPR screen of malignant peripheral nerve sheath tumors (MPNST) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB060.

Malignant spindle cell tumor of the anal canal, what are the differential diagnoses?

Malignant peripheral nerve sheath tumor (MPNST) is an uncommon tumor. Here, we report a case of rectal MPNST. The patient was a 75 year old man with symptoms and signs of a mass protruded from anus. There was no evidence of neurofibromatosis type 1 in him or his family. Primary diagnosis was hemorrhoid. Biopsy was taken. The microscopic examination revealed spindle cells with large and hyperchromatic nuclei. Mitotic figures were numerous. Routine and ancillary techniques confirmed the diagnosis of MPNST. MPNST should be distinguished from more common lesions encountered at this anatomic site such as hemorrhoid, malignant melanoma, sarcomatoid carcinoma, and gastrointestinal stromal tumor.

Malignant peripheral nerve sheath tumor of temporoparietal region of brain mimicking as glioma: A rare case report

Malignant peripheral nerve sheath tumor (MPNST) is exceedingly rare to occur intracerebrally. The incidence of this subtype is 0.001%. Their typical origin is from peripheral nerves of the limbs, trunk, and lumbar and brachial plexuses. It carries a poor prognosis despite aggressive management due to high chances of local recurrence. We present a case of MPNST occurring intracerebrally in a 60-year-old male patient. Imaging showed a 63 × 74 × 46 mm mass lesion in the left temporoparietal region with mass effect. The patient underwent left temporoparietal craniotomy with maximum gross dissection of the tumor. Histopathology was suggestive of spindle cell neoplasm. On immunohistochemistry, cells were positive for S-100 and SOX-10, which are consistent with the diagnosis of MPNST. The post-operative contrast-enhanced magnetic resonance imaging brain showed gross residual disease. Post-operative radiotherapy was given of intensity-modulated radiation therapy and chemotherapy of doxorubicin and ifosfamide.

A Clinicopathological Study of Malignant Peripheral Nerve Sheath Tumors- At a Tertiary Care Center

Aim: To study the clinicopathological profile in Malignant Peripheral Nerve Sheath Tumors (MPNST).
 Study Design: A retrospective descriptive study.
 Place and Duration of Study: Department of Pathology, Saveetha medical college and hospital, Chennai, between June 2016 and May 2021.
 Methodology: A complete enumerative sampling of all the MPNSTs received at Saveetha Medical College and Hospital over a five-year period was done which included 9 cases (4 men, 5women; age range (19-66 years). The details were obtained from the records in the Department of Pathology. The demographic parameters, clinical and histomorphological data were tabulated and analysed.
 Results: Nine cases of MPNSTs were received in our hospital during the study period. In our study a female preponderance was noted, with late thirties being the median age of presentation. Extremities and trunk were the most common sites. Two rare lesions involving the pancreas and mesentery were reported. 4 cases had underlying Neurofibromatosis (NF1). The average tumour size was 8.8cm, with majority having a tumour size >5cm. Histomorphologically most cases showed hypo and hypercellular areas composed of spindle cells with wavy nuclei arranged in interlacing fascicles with increased mitotic activity and tumour necrosis. Two cases showed epithelioid differentiation and three had heterologous elements in the form of glandular differentiation or rhabdomyoblastic differentiation.
 Conclusion: MPNSTs are very rare tumours accounting for 6% of soft tissue sarcomas and have a very aggressive course. Details of the clinical presentation and careful histomorphological typing of these tumours are essential for identifying and treating them.