High-grade Malignant Peripheral Nerve Sheath Research Articles

Magnetic Resonance Imaging Features for Differentiating Low-Grade and High-Grade Malignant Peripheral Nerve Sheath Tumors.

This study aimed to assess the usefulness of magnetic resonance imaging (MRI) findings for differentiating low-grade and high-grade malignant peripheral nerve sheath tumors (MPNSTs). This study included 31 patients (onset age range, 19-83 years; mean onset age, 57 years; 9 men and 22 women) with 36 histopathologically proven MPNSTs (7 low-grade MPNSTs and 29 high-grade MPNSTs) who underwent preoperative MRI between December 2007 and October 2022. Quantitative and qualitative MRI findings were retrospectively evaluated and compared between the 2 subtypes. The maximum tumor diameter (106.1 ± 64.0 vs 54.9 ± 19.8 mm, P = 0.032) and tumor-to-muscle signal intensity ratio (SIR) of fat-suppressed gadolinium-enhanced T1-weighted images (2.69 ± 1.40 vs 1.62 ± 0.40, P = 0.005) were significantly higher in high-grade MPNSTs than in low-grade MPNSTs. The receiver operating characteristic analysis revealed that the tumor-to-muscle SIR of fat-suppressed gadolinium-enhanced T1-weighted images exhibited the highest area under the curve value (0.88), followed by the maximum tumor diameter (0.76). The sensitivity and specificity of the tumor-to-muscle SIR of fat-suppressed gadolinium-enhanced T1-weighted images for diagnosing high-grade MPNST at an optimal SIR threshold of greater than 1.73 were 90% and 83%, respectively. However, other MRI findings showed no significant differences between the 2 subtypes ( P = 0.16-1.00). Although the MRI findings of low-grade and high-grade MPNST overlapped considerably, the maximum tumor diameter and degree of contrast enhancement can be used to differentiate low-grade MPNST from high-grade MPNST.

Role of perioperative chemotherapy and radiotherapy for localized high-grade malignant peripheral nerve sheath tumor at the extremities and trunk wall: a population-based cohort study.

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

Abstract PR005: PRC2 inactivating mutations amplify cell death in response to DNMT1-targeted therapy through enhanced viral mimicry in malignant peripheral nerve sheath tumor

Abstract Polycomb Repressive Complex 2 (PRC2) establishes and maintains di- and tri-methylation at histone 3 at lysine 27 (H3K27me2/3) in the genome and plays oncogenic and tumor suppressor roles in context-dependent cancer pathogenesis. While there is clinical success of therapeutically targeting PRC2 core component, EZH2, in PRC2-dependent cancers (e.g., follicular lymphoma, epithelioid sarcoma), it remains an unmet therapeutic bottleneck in PRC2-inactivated cancer. Biallelic inactivating mutations in PRC2 core components are a hallmark feature of high-grade malignant peripheral nerve sheath tumor (MPNST), an aggressive subtype of sarcoma with poor prognosis and no effective targeted therapeutics. Using a custom RNAi-based drop out screen, we observed that PRC2-inactivation is synthetic lethal with DNA methyltransferase 1 (DNMT1) downregulation; we further observed that small molecule DNMT inhibitors (DNMTis) resulted in enhanced cytotoxicity and anti-tumor responses in PRC2-loss cancer context in vitro and in vivo. Mechanistically, DNMTi-mediated de-repression of retrotransposons (e.g., endogenous retroviral elements) and gene targets is partly restricted by PRC2, which potentially contributes to limited therapeutic activity in PRC2-wild-type (wt) cancer context. In contrast, DNMTi treatment synergizes with PRC2 inactivation and cooperatively amplifies the expression of retrotransposons, and subsequent viral mimicry response that promotes robust cell death in part through PKR-dependent double stranded-RNA (dsRNA) sensing. Collectively, our observations posit DNA methylation as a safeguard against anti-tumorigenic cell fate decisions in the context of PRC2-inactivation to promote cancer pathogenesis, identify DNMT1-targeted therapy as novel therapeutic strategy for PRC2-inactivated MPNST, and merit further preclinical and clinical investigation of this strategy in other PRC2-inactivated cancers. Citation Format: Ping Chi, Amish J. Patel, Sarah Warda, Jesper L.V. Maag, Rohan Misra, Miguel A. Miranda-Román, Mohini R. Pachai, Cindy J. Lee, Dan Li, Naitao Wang, Gabriella Bayshtok, Eve Fishinevich, Yinuo Meng, Elissa W.P. Wong, Juan Yan, Emily Giff, Jonathan Fletcher, Joseph M. Scandura, Richard Koche, Jacob L. Glass, Cristina R. Antonescu, Deyou Zheng, Yu Chen. PRC2 inactivating mutations amplify cell death in response to DNMT1-targeted therapy through enhanced viral mimicry in malignant peripheral nerve sheath tumor [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 PR005.

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

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.

TMOD-06. MALIGNANT TRANSFORMATION OF PLEXIFORM NEUROFIBROMAS IN AN NF1 MUTANT MOUSE MODEL OF SPINAL IRRADIATION

Abstract PURPOSE Understanding the relationships between ionizing radiation (IR) and carcinogenesis, as well as other variables, including genetic background and sex, may minimize risks of transformation from benign to aggressive cancers while maintaining treatment efficacy. We aim to understand the relationship between IR, tumor microenvironments, and effect of sex on malignant transformation using a conditional knockout mouse model of Neurofibromatosis type 1 (NF1). METHODS Conditional knockout mouse models of plexiform neurofibromas (PeriCre+; Nf1fl/fl and PeriCre+; Nf1fl/-, n = 172) were treated with 0 Gy; 3 Gy x 5; 3 Gy x 10 of focal, fractionated spinal irradiation (SI) and aged until signs of illness. Histopathological analysis was performed on images from H&E-stained FFPE peripheral nerve tissues. RESULTS SI affected the survival of mice in a dose-dependent manner, with a significant decrease at 30Gy (median survival 254 and 218 days for 0 Gy and 30 Gy, p < 0.01, Log-rank test). Male mice had reduced overall survival at 15 and 30 Gy (median survival 368, 278 and 245 days for 0, 15 and 30Gy, p < 0.01, Log-rank test), but not in female mice, indicating sex-specific radiosensitivity. Differences in tumour microenvironments did not affect mouse survival after SI. Histopathological analysis is ongoing (43 out of 76 FFPE samples analyzed). Preliminary findings showed a total of 43 malignancies ranging from plexiform neurofibromas (PNs) to high-grade malignant peripheral nerve sheath tumours (MPNSTs). Increasing histologic aggressiveness was observed in higher SI doses, with high-grade MPNST (2.3%) exclusively found in mice irradiated at 30 Gy. CONCLUSION We present a novel mouse model to study malignant transformation in the context of NF1. Preliminary findings suggest increased malignant transformation at high doses of SI.

Elbow flexion reconstruction after arm-sparing excision for high-grade triton sarcoma: a case report

BackgroundSoft tissue sarcomas affecting the root of an upper extremity raise the question of limb amputation depending on their location, size, and malignancy. Malignant triton tumors are a rare subtype of neurofibrosarcomas that have been poorly reported in the literature. We report the case of a challenging reconstruction of the upper extremity using a pedicled latissimus dorsal flap.Case presentationA 25-year-old Occidental man was referred to our sarcoma unit for the management of a large, high-grade malignant peripheral nerve sheath tumor with no regional or distant extension and very fast progression. He was treated first by concomitant neoadjuvant radiotherapy and chemotherapy. Carcinologic excision was performed “en bloc” including the skin, the tumor, and the flexor muscles of our patient’s elbow. Coverage of the skin defect and elbow flexion restoration were achieved by using a homolateral pedicled musculocutaneous latissimus dorsi flap. Histological analysis showed an R0 resection. The reconstruction process recovered a complete bending of his elbow. He is still in remission at 26 months follow-up.ConclusionsA malignant triton tumor is a rare, aggressive, and high-grade sarcoma. It was successfully treated and this case report describes an effective treatment modality. Reconstructive surgery, allowing large, complete tumor removal, is indispensable after neoadjuvant chemotherapy and radiotherapy.

H3K27 trimethylation loss in malignant peripheral nerve sheath tumor: a systematic review and meta-analysis with diagnostic implications.

Multiple studies have reported the loss of trimethylation at lysine (K) 27 on histone 3 (H3K27me3) in high-grade malignant peripheral nerve sheath tumors (MPNSTs). However, the diagnostic potential of this finding in MPNSTs remains yet to be fully substantiated. Correspondingly, our aim was to pool systematically-identified metadata in the literature and substantiate the incidence of H3K27me3 loss in this setting. Searches of 7 electronic databases from inception to May 2019 were conducted following PRISMA guidelines. Articles were screened against pre-specified criteria. The incidence of loss was then pooled by random-effects meta-analysis of proportions. Nine pertinent studies described a total of 823 high-grade MPNST samples. When pooled, incidence (sensitivity) of complete H3K27me3 loss was estimated to be 53% (95% CI 42-64%). For MPNST subtypes, estimated incidences of complete loss in NF1 subtype was 52% (95% CI 41-62), in sporadic subtype was 53% (95% CI 36-70%), in the epithelioid subtype was 0% (95% CI 0-7%), and radiation-associated subtype was 98% (95% CI 86-100%). Finally, incidence of incomplete loss (specificity) in 1231 MPNST-mimic samples was estimated to be 96% (95% CI 90-99%). Certainty of these outcomes ranged from very low to high. The incidence of complete H3K27me3 loss is substantial in high-grade MPNSTs and is low in MPNST-mimics. Greater cohort study and biological investigation will validate the certainty of these findings as well as elucidate their true molecular and clinical significances.

Clinical Outcome and Prognostic Factors of Malignant Spinal Dumbbell Tumors.

Introduction To investigate the clinical outcome and prognostic factors of malignant spinal dumbbell tumors (m-SDTs). Methods We retrospectively reviewed the clinical outcome of 22 consecutive cases of m-SDTs and analyzed the prognostic factors associated with worse outcome. Results Nineteen of the 22 cases were managed with surgery (86%), and gross total resection (GTR) was achieved in four cases (21%). The duration of overall survival (OS) ranged from 3 to 140 months, with a median survival time of 15.3 months. The 5 year OS rate was 55.6%. In multivariate analysis, histological subtype (high-grade malignant peripheral nerve sheath tumor) (hazard ratio [HR] 14.9, p = 0.0191), GTR (HR 0.07, p = 0.0343), and presence of local recurrences (HR 11.2, p = 0.0479) were significant and independent predictors of OS. Conclusions On the basis of clinical data, we propose that GTR and prevention of local recurrence may improve the clinical outcome of m-SDTs.

Methylation-based classification of benign and malignant peripheral nerve sheath tumors

The vast majority of peripheral nerve sheath tumors derive from the Schwann cell lineage and comprise diverse histological entities ranging from benign schwannomas and neurofibromas to high-grade malignant peripheral nerve sheath tumors (MPNST), each with several variants. There is increasing evidence for methylation profiling being able to delineate biologically relevant tumor groups even within the same cellular lineage. Therefore, we used DNA methylation arrays for methylome- and chromosomal profile-based characterization of 171 peripheral nerve sheath tumors. We analyzed 28 conventional high-grade MPNST, three malignant Triton tumors, six low-grade MPNST, four epithelioid MPNST, 33 neurofibromas (15 dermal, 8 intraneural, 10 plexiform), six atypical neurofibromas, 43 schwannomas (including 5 NF2 and 5 schwannomatosis associated cases), 11 cellular schwannomas, 10 melanotic schwannomas, 7 neurofibroma/schwannoma hybrid tumors, 10 nerve sheath myxomas and 10 ganglioneuromas. Schwannomas formed different epigenomic subgroups including a vestibular schwannoma subgroup. Cellular schwannomas were not distinct from conventional schwannomas. Nerve sheath myxomas and neurofibroma/schwannoma hybrid tumors were most similar to schwannomas. Dermal, intraneural and plexiform neurofibromas as well as ganglioneuromas all showed distinct methylation profiles. Atypical neurofibromas and low-grade MPNST were indistinguishable with a common methylation profile and frequent losses of CDKN2A. Epigenomic analysis finds two groups of conventional high-grade MPNST sharing a frequent loss of neurofibromin. The larger of the two groups shows an additional loss of trimethylation of histone H3 at lysine 27 (H3K27me3). The smaller one retains H3K27me3 and is found in spinal locations. Sporadic MPNST with retained neurofibromin expression did not form an epigenetic group and most cases could be reclassified as cellular schwannomas or soft tissue sarcomas. Widespread immunohistochemical loss of H3K27me3 was exclusively seen in MPNST of the main methylation cluster, which defines it as an additional useful marker for the differentiation of cellular schwannoma and MPNST.

Malignant Triton Tumors in Sisters with Clinical Neurofibromatosis Type 1.

Malignant triton tumors (MTTs) are rare and aggressive sarcomas categorized as a subgroup of malignant peripheral nerve sheath tumors (MPNSTs). MTTs arise from Schwann cells of peripheral nerves or existing neurofibromas and have elements of rhabdomyoblastic differentiation. We report the occurrence of MTTs in two sisters. The first patient is a 36-year-old female who presented with left sided chest wall swelling. She also had clinical features consistent with neurofibromatosis type 1 (NF-1). Debulking of the mass showed high-grade malignant peripheral nerve sheath tumor with skeletal muscle differentiation (MTT). The patient was treated with ifosfamide and adriamycin along with radiation. Four years after treatment, she still has no evidence of disease recurrence. Her sister subsequently presented to us at the age of 42 with left sided lateral chest wall pain. Imaging showed a multicompartmental retroperitoneal cystic mass with left psoas involvement. The tumor was resected and, similarly to her sister, it showed high-grade malignant peripheral nerve sheath tumor with rhabdomyoblastic differentiation (MTT). The patient was started on chemotherapy and radiation as described above.

Giant sporadic high-grade malignant peripheral nerve sheath tumor: A case report with review of literature

Malignant peripheral nerve sheath tumors (MPNSTs) are uncommon spindle cell sarcomas originating from the pleuripotent cells of neural crest or Schwann cells. Head and neck region, the extremities and peripheral nerve trunk roots are its common locations. Sporadic type is a rare variant than the neurofibromatosis-1 associated type of MPNST. This study presents a case of giant, sporadic, and high-grade MPNST of right shoulder in a 48-year-old female.

SARC006: Phase II trial of chemotherapy in sporadic and neurofibromatosis type 1 (NF1)-associated high-grade malignant peripheral nerve sheath tumors (MPNSTs).

10522 Background: MPNSTs occur in 10% of the NF1 population, and retrospective, pooled analyses have reported worse chemotherapy response for NF1 (9-18%) compared to sporadic MPNSTs (39-55%). Methods: We prospectively evaluated the objective response (OR) rate, [complete responses (CR) and partial responses (PR) WHO criteria] of children and adults with high-grade, unresectable or metastatic chemotherapy naive NF1 associated versus sporadic MPNST after 2 cycles of ifosfamide and doxorubicin (IA) followed by 2 cycles of ifosfamide and etoposide (IE) as primary endpoint. This was followed by surgery and/or radiation for local control and up to 2 more cycles of IA and IE each. Pathology was centrally confirmed. A Simon optimal two-stage design was used with a target response rate of 40% and 17 patients per stratum in the first stage. With 4+/17 ORs, enrollment was to be expanded to 37 patients per stratum, and 11+/37 ORs would be potentially consistent with a 40% OR rate. Results: Both initial stages met criteria for enrollment expansion with 4/17 PRs in NF1 and 4/12 PRs in sporadic MPNSTs, but only 1 additional PR was observed in the expanded NF1 stratum. Of the 9 PRs, 5 were first observed after 2 cycles IA, and additional 4 after 2 cycles IE. Enrollment was slower than expected and the trial was closed before full accrual. Conclusions: While the primary trial objective was not reached due to slow enrollment, with only 5/29 ORs in the NF1 stratum the desired OR rate of 11+/37 would have unlikely been met even if accrual had been completed. We observed a lower OR rate in NF1 compared to sporadic MPNSTs similar to retrospective literature reports. However, our trial was not powered to detect a difference in response rates between the two strata. In addition to PRs after both IA and IE, disease stabilization was achieved in most patients. Novel strategies including the evaluation of targeted agents in combination with chemotherapy should be considered. Clinical trial information: NCT00304083. [Table: see text]

DNA copy number changes in high-grade malignant peripheral nerve sheath tumors by array CGH

BackgroundMalignant peripheral nerve sheath tumors (MPNSTs) are rare and highly aggressive soft tissue tumors showing complex chromosomal aberrations. In order to identify recurrent chromosomal regions of gain and loss, and thereby novel gene targets of potential importance for MPNST development and/or progression, we have analyzed DNA copy number changes in seven high-grade MPNSTs using microarray-based comparative genomic hybridization (array CGH).ResultsConsiderable more gains than losses were observed, and the most frequent minimal recurrent regions of gain included 1q24.1-q24.2, 1q24.3-q25.1, 8p23.1-p12, 9q34.11-q34.13 and 17q23.2-q25.3, all gained in five of seven samples. The 17q23.2-q25.3 region was gained in all five patients with poor outcome and not in the two patients with disease-free survival. cDNA microarray analysis and quantitative real-time reverse transcription PCR were used to investigate expression of genes located within these regions. The gene lysyl oxidase-like 2 (LOXL2) was identified as a candidate target for the 8p23.1-p12 gain. Within 17q, the genes topoisomerase II-α (TOP2A), ets variant gene 4 (E1A enhancer binding protein, E1AF) (ETV4) and baculoviral IAP repeat-containing 5 (survivin) (BIRC5) showed increased expression in all samples compared to two benign tumors. Increased expression of these genes has previously been associated with poor survival in other malignancies, and for TOP2A, in MPNSTs as well. In addition, we have analyzed the expression of five micro RNAs located within the 17q23.2-q25.3 region, but none of them showed high expression levels compared to the benign tumors.ConclusionOur study shows the potential of using DNA copy number changes obtained by array CGH to predict the prognosis of MPNST patients. Although no clear correlations between the expression level and patient outcome were observed, the genes TOP2A, ETV4 and BIRC5 are interesting candidate targets for the 17q gain associated with poor survival.

Cellular Neurofibroma with Atypia Mimics Sarcoma: Report of a Case with Immunohistochemical Staining Pattern Analysis and Literature Review

A case of two sporadic cellular neurofibromas with atypia and one widespread hyalinization neurofibroma of the lumbar spine in a 51-year-old man without evidence of neurofibromatosis-1 is reported. Cellular neurofibroma with atypia is an unusual variant. The definite criteria for low-grade and high-grade malignant peripheral nerve sheath tumors as well as cellular neurofibroma are not well defined in the literature. The clinical significance of atypical cellular neurofibroma has rarely been systematically studied. To our knowledge, the concomitance of cellular architecture and cytologic atypia is rarely documented, and this is a rare report of atypical cellular neurofibroma. The recognition of this entity is of great importance to both pathologists and clinicians because atypical cellular neurofibroma is clever at masquerading both histologically and cytologically as a sarcoma; therefore, a precise diagnosis of this variant is essential because of the differences in treatment and clinical behavior between benignancy and malignancy. We also examined the immunohistochemical characteristics of CD34 positive cells and focal high expression of p53 up to 73% encountered in our case. To our knowledge, seldom have series or case reports elucidated this phenomenon.

Malignant peripheral nerve sheath tumour of median nerve - an unusual presentation: a case report

Malignant peripheral nerve sheath tumours (MPNST) are rare tumours, which usually occur in patients with multiple neurofibromatosis. They are common in the head and neck and trunk and only a few cases have been reported in the hand. Many of these occur in patients with von Recklinghausen’s disease and rarely as a malignant transformation of benign schwannomas. When they appear in the hand they often present with various symptoms. We encountered a patient who presented with a longstanding asymptomatic swelling of the palm. On excision the histopathology showed a high-grade malignant peripheral nerve sheath tumour, which led us to speculate that a malignant transformation had occurred in a pre-existing benign swelling. This is reported for its unusual presentation, which, to our knowledge, has never been described previously.

Angiosarcoma With Malignant Peripheral Nerve Sheath Tumour Developing in a Patient With Klippel–Trénaunay–Weber Syndrome

Purpose: We discuss the coexistence of Klippel–Trénaunay–Weber syndrome with various malignancies, the possible histogenetic pathways and therapeutic implications. Patient: We report on a 46-year-old man presenting with increasing pain and swelling of his right lower leg after fracturing his fibula. Since birth he was known as having the uncommon syndrome of Klippel–Trénaunay–Weber of his right lower leg. Methods: Our patient underwent an above-knee amputation for biopsy-proven malignant vascular tumour, first thought to be a composite hemangio-endothelioma and/or angiosarcoma with lung metastases. Results: In the amputated extremity, a vascular malformation was found with tumour showing various components with foci of angiosarcoma adjacent to diffuse neurofibroma and areas with high-grade malignant peripheral nerve sheath tumour. Amputation and palliative chemotherapy were indicated, but he died of pulmonary and cerebral metastases 2 months postoperatively. Discussion: This case describes an angiosarcoma with malignant peripheral nerve sheath tumour developing in a patient with Klippel–Trénaunay–Weber syndrome. A case never described before in literature and probably, as in our case, difficult to diagnose at first biopsy.

Poorly differentiated synovial sarcoma: immunohistochemical distinction from primitive neuroectodermal tumors and high-grade malignant peripheral nerve sheath tumors.

Synovial sarcoma is a relatively common sarcoma in adults, which in its classic bimorphic form infrequently poses a diagnostic problem. Monomorphic spindled variants, as well as the less common poorly differentiated variants, may be confused with other soft-tissue sarcomas; the poorly differentiated variant (PDSS), in particular, may be histologically indistinguishable from other small, blue, round cell tumors, including primitive neuroectodermal tumors (PNETs). Detection of the synovial sarcoma-associated t(X;18) by either cytogenetic or molecular genetic approaches may be necessary to confirm the diagnosis of synovial sarcoma in difficult cases. We evaluated 10 cases of PDSS from eight patients using a panel of antibodies (including those to intermediate filament proteins, nerve-sheath associated markers, and neuronal and neuroectodermal associated markers) in order to better establish the immunophenotype of this tumor and to help distinguish it from the tumors with which it may be confused, particularly PNETs and high-grade malignant peripheral nerve sheath tumors (MPNSTs). Our results showed PDSS to have significant immunophenotypic overlap with both PNETs and MPNSTs. In most instances these three entities may be differentiated by a panel of antibodies that should include those to both low and high molecular weight cytokeratins, epithelial membrane antigen, type IV collagen, CD99, CD56, and S-100 protein. Our results also suggest that synovial sarcoma may be a tumor showing combined neuroectodermal and nerve sheath differentiation--perhaps because of translocation-associated expression of specific proteins--rather than a carcinosarcoma of soft tissues or a tumor of specialized arthrogenous mesenchyme.