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Epithelioid malignant peripheral nerve sheath tumor (EMPNST) is rare and differs from conventional malignant peripheral nerve sheath tumor by showing diffuse S-100 protein positivity, infrequent association with NF1, and occasional origin in a schwannoma. Loss of INI1 expression is seen in a subset of tumors. The purpose of this study was to furthe...
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This case study describes the cytological and histopathological findings of cutaneous masses in a bovine, including a peripheral nerve sheath tumor (PNST), vaccine-associated granulomatous inflammation, and eosinophilic inflammation due to parasitosis. A six-year-old undefined cow (SRD) presented with heterogeneous cutaneous lesions including multi...
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... However, the incidence and type of SMARCB1 LOF alterations vary depending on the histotype. For instance, loss of SMARCB1/INI1 protein expression is seen in 50% to 70% of epithelioid malignant peripheral nerve sheath tumors (MPNST; ref. 22), 50% of epithelioid schwannomas (8,23), 30% of soft tissue myoepithelial tumors (8), the majority of poorly differentiated chordomas (8), and almost all MRTs (21) and SMARCB1-decient sinonasal carcinoma (24) (7). Studies on recurrent genetic alterations (other than SMARCB1) among various SMARCB1-decient mesenchymal tumors are largely limited to case reports or small case series (8). ...
Epithelioid sarcoma (EpS) is an ultra-rare malignant soft-tissue cancer mostly affecting adolescents and young adults. EpS often exhibits an unfavorable clinical course with fatal outcome in ~50% of cases despite aggressive multimodal therapies combining surgery, chemotherapy, and irradiation. EpS is traditionally classified in a more common, less aggressive distal (classic) type, and a rarer aggressive proximal type. Both subtypes are characterized by a loss of nuclear INI1 expression, most often following homozygous deletion of its encoding gene SMARCB1 – a core subunit of the SWI/SNF chromatin remodeling complex. In 2020, the EZH2 inhibitor tazemetostat was the first targeted therapy approved for EpS, raising new hopes. Still, the vast majority of patients did not benefit from this drug or relapsed rapidly. Further, other recent therapeutic modalities, including immunotherapy, are only effective in a fraction of patients. Thus, novel strategies, specifically targeted to EpS, are urgently needed. To accelerate translational research on EpS and eventually boost the discovery and development of new diagnostic tools and therapeutic options, a vibrant translational research community has formed in past years and held two international EpS digital expert meetings in 2021 and 2023. This review summarizes our current understanding of EpS from the translational research perspective and points to innovative research directions to address the most pressing questions in the field, as defined by expert consensus and patient advocacy groups.
... Epithelioid malignant peripheral nerve sheath tumors (EMPNSTs) are a highly malignant and extremely rare variant of malignant peripheral nerve sheath tumors (MPNSTs), accounting for only 5% of all MPNST variants (1)(2)(3)(4). Primary EMPNSTs, particularly paravertebral dumbbell-shaped tumors, are rarely observed in the spine. ...
... In general, sarcomas arising from schwannomas often exhibit an epithelioid morphology, including epithelioid malignant peripheral schwannomas and epithelioid angiosarcomas, whereas most neurofibromas cause conventional spindle cell EMPNSTs (2,17). T1-weighted MRI of EMPNSTs shows a slightly hypointense signal, and an isointense or slightly high mixed signal can be observed on T2-weighted MRI. ...
Malignant peripheral nerve sheath tumors (MPNSTs) are commonly associated with poor prognosis and are primarily caused by germline mutations in the SMARCB1/INI-1 gene. However, these tumors are rarely found in the spine. This case report presents the case of a 3-year-old boy diagnosed with a lumbosacral dumbbell-shaped epithelioid MPNST, an extremely uncommon manifestation. Immunohistochemistry revealed the complete absence of the SMARCB1/INI-1 protein, and genetic testing identified a novel germline mutation in the SMARCB1/INI-1 gene in both the patient and his father, suggesting a “second-hit loss.” One year of follow-up after the tumor's radical resection revealed no suspected metastasis. This case report offers novel genetic research results regarding spinal dumbbell-shaped MPNSTs. Six studies, including 13 cases associated with spinal dumbbell MPNST, were included in the literature. The range of age of these patients varied from 2 to 71 years. Of the 12 known patients diagnosed with spinal dumbbell MPNST, only one received radiation therapy, while the rest underwent surgery. Two patients who underwent partial resection had metastases after surgery, while one of the five patients who underwent complete surgical resection alone had no distant metastases and a good prognosis, indicating that radical resection is more likely to be effective in inhibiting distant metastasis and improving the prognosis.
... They are characterized by a higher likelihood of invading surrounding structures and metastasizing [22,24]. They are often symptomatic and can cause arrhythmias, embolic events, chest pain, and compression symptoms [17,[20][21][22][24][25][26]29,35,[43][44][45][46]48,49,51,52,54,[60][61][62][63]72]. In this meta-analysis, more than 50% of the reported cases were malignant (29/53 cases) which denotes that the incidence of cardiac MPNST is more than that of benign cases. ...
... Malignant transformation to MPNST can occur on top of atypical plexiform neurofibroma10. Almost half of all MPNSTs arise in the context of NF1 syndrome [9,[72][73][74][75], while others occur sporadically or after radiation exposure [7,8]. The most frequent sites of MPNSTs are the extremities (45%), the trunk (34%), and head and neck region (19%) [9,76,77]. ...
... Outside these genetic syndromes, through our cases review, we found that few studies reported another association of cardiac schwannoma with other malignant tumors, such as lung cancer [48,64], renal cell carcinoma [19], ovarian cancer [26,41], breast cancer [51], colon cancer [39], parathyroid carcinoma [20], and lymphoma [72]. ...
Primary cardiac schwannoma (PCS) is a neurogenic tumor that arises from Schwann cells. Malignant schwannoma (MSh) is an aggressive cancer comprising 2% of all sarcomas. Information on the proper management of these tumors is limited. Four databases were searched for case reports/series of PCS. The primary outcome was overall survival (OS). Secondary outcomes included therapeutic strategies and the corresponding outcomes. Among 439 potentially eligible studies, 53 met the inclusion criteria. The patients included had 43.72 ± 17.76 years and 28.3% were males. Over 50% of patients had MSh, with 9.4% also demonstrating metastases. Schwannoma commonly occurs in the atria (66.0%). Left-sided PCS were more common than right-sided ones. Surgery was performed in almost 90% of the cases; chemotherapy and radiotherapy were used in 16.9% and 15.1% of cases, respectively. Compared to benign cases, MSh occurs at a younger age and is commonly located on the left side. OS of the entire cohort at 1 and 3 years were 60.7%, and 54.0%, respectively. Females and males OS were similar up to 2 years follow-up. Surgery was associated with higher OS (p < 0.01). Surgery is the primary treatment option for both benign and malignant cases and was the only factor associated with a relative improvement in survival.
... 17 In a cohort of 63 patients with EMPNST, all expressed the S-100 protein, and the majority (87%) showed strong and diffuse staining. 10 Loss of H3K27me3 can distinguish MPNST from histologic mimics that nearly 70% of MPNST negative express ...
... H3K27me3 and this phenomenon was more pronounced in NF-1associated and radiation-induced MPNST than sporadic disease. 11,19 Nonetheless, almost all of the cases of EMPNST retained (91.7% to 100%) H3K27me3, 11,19 and tumors were demonstrated in a multilobular growth pattern, with lobules and nests surrounded by myxoid and/or fibrous stroma, 10 13 Moreover, tumors with EWSR1-CREM fusion can express inhibin and cytokeratin (AE1/AE3) that is easily misdiagnosed as JGCT. 13 Indeed, our current case was misclassified as JGCT at initial presentation and first recurrence due to the age predisposition and high expression of α-inhibin as well as calretinin. ...
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.
... MPNSTs, which are frequently associated with either heritable or sporadic mutations in NF1, can result from prior radiation treatment and are malignant tumors with Schwann cell or perineural cell differentiation [3,165]. LOF of SWI/SNF proteins and/or significant alterations in their expression have been observed in both schwannomas and MPNST [62][63][64][65]161,167]. ...
... Patients with NF1-MPNST and aberrant expression of ATRX had a significantly decreased survival rate, and the authors suggest it could be used as a prognostic marker in this cancer [65]. In the epithelioid histopathologic subtype of MPNST, a rare tumor with diffuse S-100 positivity, infrequent association with NF1, and occasional malignant transformation from schwannoma, mutations in SMARCB1 have also been observed in two-thirds of patients evaluated (n = 63) [62]. In another study, loss of SMARCB1 expression was established by immunohistochemistry in 70% of patients; further, some cases of epithelioid MPNST (EMPNST) arose from pre-existing epithelioid schwannoma (ESCW), which also had a loss of SMARCB1 expression in 40% of cases [63]. ...
Simple Summary
In this review, the authors re-evaluate the fifth edition of the World Health Organization Classification of Central Nervous System tumors in light of recent advances in epigenetic tools and evidence of the critical nature of endogenous retroviruses in tumorigenesis. The data systematically presented herein demonstrates that tumors with histopathologic heterogeneity and dichotomous clinical behaviors more often harbor chromatin remodeling defects and/or associated aberrant endogenous retrovirus expression. The authors believe these observations warrant further investigation as they could potentially lead to a deeper understanding of tumor biology and more translationally relevant tumor stratification.
Abstract
Originally approved in 1979, a specific grading classification for central nervous system (CNS) tumors was devised by the World Health Organization (WHO) in an effort to guide cancer treatment and better understand prognosis. These “blue books” have since undergone several iterations based on tumor location, advancements in histopathology, and most recently, diagnostic molecular pathology in its fifth edition. As new research methods have evolved to elucidate complex molecular mechanisms of tumorigenesis, a need to update and integrate these findings into the WHO grading scheme has become apparent. Epigenetic tools represent an area of burgeoning interest that encompasses all non-Mendelian inherited genetic features affecting gene expression, including but not limited to chromatin remodeling complexes, DNA methylation, and histone regulating enzymes. The SWItch/Sucrose non-fermenting (SWI/SNF) chromatin remodeling complex is the largest mammalian family of chromatin remodeling proteins and is estimated to be altered in 20–25% of all human malignancies; however, the ways in which it contributes to tumorigenesis are not fully understood. We recently discovered that CNS tumors with SWI/SNF mutations have revealed an oncogenic role for endogenous retroviruses (ERVs), remnants of exogenous retroviruses that integrated into the germline and are inherited like Mendelian genes, several of which retain open reading frames for proteins whose expression putatively contributes to tumor formation. Herein, we analyzed the latest WHO classification scheme for all CNS tumors with documented SWI/SNF mutations and/or aberrant ERV expression, and we summarize this information to highlight potential research opportunities that could be integrated into the grading scheme to better delineate diagnostic criteria and therapeutic targets.
... Epithelioid malignant peripheral nerve sheath tumor, accounting for less than 5% of malignant peripheral nerve sheath tumor (MPNST), differs from conventional MPNST by the strong and diffuse expression of S-100 protein and SOX10, a rare association with type 1 neurofibromatosis, occasional origin in a schwannoma, and loss of expression of SMARCB1 following homozygous deletion, nonsense, frameshift, or splice site mutations in up to 75% of cases [50,51]. ...
Mutations in subunits of the SWItch Sucrose Non-Fermentable (SWI/SNF) complex occur in 20% of all human tumors. Among these, the core subunit SMARCB1 is the most frequently mutated, and SMARCB1 loss represents a founder driver event in several malignancies, such as malignant rhabdoid tumors (MRT), epithelioid sarcoma, poorly differentiated chordoma, and renal medullary carcinoma (RMC). Intriguingly, SMARCB1-deficient pediatric MRT and RMC have recently been reported to be immunogenic, despite their very simple genome and low tumor mutational burden. Responses to immune checkpoint inhibitors have further been reported in some SMARCB1-deficient diseases. Here, we will review the preclinical data and clinical data that suggest that immunotherapy, including immune checkpoint inhibitors, may represent a promising therapeutic strategy for SMARCB1-defective tumors. We notably discuss the heterogeneity that exists among the spectrum of malignancies driven by SMARCB1-loss, and highlight challenges that are at stake for developing a personalized immunotherapy for these tumors, notably using molecular profiling of the tumor and of its microenvironment.
... EMPNST is a rare sarcoma and is considered a variant of MPNST with histopathologic differences as listed in Table 1 [2][3][4]7]. EMPNST has an equal sex distribution and presents most commonly in the third or fourth decade of life with a broad age range from 6 to 80 years old. ...
... Malignant rhabdoid tumor typically shows patchy S100 positivity, whereas EMPNST possesses strong and diffusely positive S100 expression [2,8,18]. Age and cytokeratin expression may also be helpful to differentiate malignant rhabdoid tumor from EMPNST as the former usually occurs in children less than or equal to 3 years of age and marks with cytokeratin while EMPNST typically present in the third or fourth decade and are cytokeratin negative [7,8,19]. Cytogenetics and mutational analysis may not be helpful to differentiate these two entities as both have inactivating mutations of SMARCB1/ INI1 and chromosomal aberrations of 22q [10,[20][21][22]. ...
Malignant peripheral nerve sheath tumor (MPNST) is a rare aggressive type of sarcoma. The epithelioid variant of MPNST has a distinctive morphology and immunophenotype, which can be a diagnostic challenge when it arises in an unusual location. Awareness of these morphologic entities is essential to make an accurate diagnosis. Here, we report a case of epithelioid MPNST involving the liver. The tumor displayed rhabdoid morphology and an unusual immunophenotype. The report also discusses histopathologic features, molecular alterations, and the differential diagnoses of this rare entity.
... However, in contrast to CMTCT they also display immunoreaction for (myo)epithelial markers such as EMA, low-molecular weight cytokeratins, calponin, and p63 and a subset of them harbors EWSR1 rearrangements [41]. Epithelioid schwannoma and epithelioid malignant peripheral nerve sheath tumor (MPNST) lie in the differential as well, but they are consistently negative for melanocytic markers including MITF, and a subset of them shows loss of INI1 expression [42,43]. ...
“Cutaneous melanocytic tumor with CRTC1::TRIM11 fusion” (CMTCT) is a recently described entity belonging to the family of superficial tumors displaying melanocytic differentiation. Thirteen cases have been reported so far, on the head and neck, extremities, and trunk of adults of all ages (12 cases) and one in an 11-year-old child. Histopathologically, it is a nodular or multilobulated tumor composed of spindle and epithelioid cells arranged in nests, fascicles, or bundles that are surrounded by thin collagenous septa. By immunohistochemistry, the tumor shows variable immunoreactivity for S100-protein, SOX10, and MITF, as well as specific melanocytic markers such as MelanA and HMB-45. The neoplasm’s biologic behavior remains uncertain since the reported cases are limited and the follow-up is short (median 12 months). However, local recurrence and synchronous distant metastasis after 13 years of initial resection has been described in one case. Herein, we present a comprehensive literature review of CMTCT hoping to raise awareness among the dermatopathologists of this potentially novel entity.
... The MPNST specimens included 89 primary, 30 recurrent, and 11 metastatic tumors. Among these samples, 15 cases revealing epithelioid differentiation were excluded because their type of tumor disclosed different biological backgrounds, such as diffuse positivity of S-100 protein, preservation of H3K27me3 immunoreactivity, and loss of SMARCB1/INI1 expression, as previously reported [19,20]. In the present study, 84 MPNSTs were used, with each sample being prepared from a different patient. ...
Malignant peripheral nerve sheath tumor (MPNST) is a very aggressive peripheral nerve sheath-derived sarcoma, which is one of the most difficult tumors to diagnose due to its wide spectrum of histological findings and lack of specific immunohistochemical markers. Recently, it has been reported that losses of expression of H3K27me3 and H3K27me2 caused by PRC2 dysfunction may be useful diagnostic markers for MPNST, but there is no consensus on their clinicopathological significance. Here, we investigated the relationship between loss of H3K27 methylation and various parameters and clarified the clinicopathological significance of such loss. We analyzed the clinicopathological and immunohistochemical features in 84 MPNST cases. Complete losses of H3K27me3 and H3K27me2 were observed in 37 (44%) and 29 (35%) cases, respectively. Losses of H3K27me3 and H3K27me2 were significantly correlated with myogenic immunopositivity (H3K27me3 vs. desmin, P = 0.0051; H3K27me3 vs. myogenin, P = 0.0009; H3K27me2 vs. myogenin, P = 0.042). Meanwhile, there were significant correlations between preservation of immunohistochemical neurogenic markers and intact H3K27me3 and H3K27me2 (H3K27me3 vs. S-100 protein, P = 0.0019; H3K27me3 vs. SOX10, P = 0.014; H3K27me2 vs. S-100 protein, P = 0.0011; H3K27me2 vs. SOX10, P = 0.0087). In multivariate analysis, local recurrence, distant metastasis, high FNCLCC grade, and loss of SOX10 expression were independent prognostic factors for overall survival. H3K27me3 and H3K27me2 expression was retained in all 26 cases of rhabdomyosarcoma non-alveolar subtype. In conclusion, we suggest that H3K27me3 and H3K27me2 immunonegativity is useful but not definitive for diagnosing MPNST. Complete loss of H3K27 methylation may be involved in aggressive transdifferentiation from neural differentiation to skeletal muscle differentiation in MPNST.
... In contrast, the heterogeneous enhancement can be caused by cyst formation or necrosis [11]. Malignant peripheral epithelioid schwannomas are usually observed as isointense on the T1weighted MRI image and hyperintense on the T2-weighted image with well-de ned margins and strong contrast enhancement and polycystic changes are present within the lesions [12,13]. The radiographic ndings of intraspinal PNET are usually lack of speci city, and radiographic diagnosis may often indicate astrocytoma, ependeoma or schwannoma. ...
Background: Pediatric intraspinal space-occupying lesions are relatively uncommon. However, these lesions can result in neurological disabilities due to misdiagnosis and delayed treatment. The main goal of the present study is to evaluate the clinical and radiological features and treatment options of pediatric intraspinal space-occupying lesions in order to improve the clinical recognition and management.
Methods: Clinical data of 27 children with intraspinal space-occupying lesions who underwent surgery treatment in a tertiary-care hospital between 2010 and 2018 were retrospectively reviewed and analyzed.
Results: Of these 27 patients, 14 (51.85%) were girls and 13 (48.15%) were boys. The most common age group affected was 10~14 years (62.96%, 9 girls and 8 boys in this age group). The mean age was 10.11 years old. Pain and weakness were the most common clinical symptoms. Preoperative magnetic resonance imaging (MRI) identified intramedullary (10 cases, 37.04%), intradural extramedullary (10 cases, 37.04%) and extradural (7 cases, 25.92%) lesions, respectively. The majority of the lesions were intraspinal tumors (23 cases, 85.19%). The histological diagnosis of tumors included embryonic residual tumors (6 cases, 22.22%), ependymoma (5 cases, 18.52%), primitive neuroectodermal tumors (PNET) (3 cases, 11.11%), schwannomas (2 cases, 7.4%), ganglioneuroma (1 case, 3.7%), Ewing’s sarc (1 case, 3.7%), B-cell non Hodgkin lymphoma (1 case, 3.7%), Hodgkin lymphoma (1 case, 3.7%), chondrosarcoma (1 case, 3.7%), ganglioglioma (1 case, 3.7%), and glioma (1 case, 3.7%).
Conclusions: The incidence of pediatric intraspinal space-occupying lesions is low, and the clinical manifestation is lack of specificity. The prognosis for children with malignant tumors is poor and surgical resection is still the primary treatment option.
