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Abstract Background Metastatic epithelioid sarcoma (EPS) remains a largely unmet clinical need in children, adolescents and young adults despite the advent of EZH2 inhibitor tazemetostat. Methods In order to realise consistently effective drug therapies, a functional genomics approach was used to identify key signalling pathway vulnerabilities in a spectrum of EPS patient samples. EPS biopsies/surgical resections and cell lines were studied by next‐generation DNA exome and RNA deep sequencing, then EPS cell cultures were tested against a panel of chemical probes to discover signalling pathway targets with the most significant contributions to EPS tumour cell maintenance. Results Other biologically inspired functional interrogations of EPS cultures using gene knockdown or chemical probes demonstrated only limited to modest efficacy in vitro. However, our molecular studies uncovered distinguishing features (including retained dysfunctional SMARCB1 expression and elevated GLI3, FYN and CXCL12 expression) of distal, paediatric/young adult‐associated EPS versus proximal, adult‐associated EPS. Conclusions Overall results highlight the complexity of the disease and a limited chemical space for therapeutic advancement. However, subtle differences between the two EPS subtypes highlight the biological disparities between younger and older EPS patients and emphasise the need to approach the two subtypes as molecularly and clinically distinct diseases.

Background: Although biological resources are essential for basic and preclinical research in the oncological field, those of sarcoma are not sufficient for rapid development of the treatment. So far, some sarcoma cell lines have been established, however, the success rate was low and the established sarcoma types were frequently biased. Therefore, an efficient culture method is needed to determine the various types of sarcomas. Organoid culture is a 3-dimentional culture method that enables the recapitulation of the tumor microenvironment and the success rate reported is higher than the 2-dimentional culture. The purpose of this study was to report our newly established organoids from human epithelioid sarcoma using the air-liquid interface organoid culture method. Methods: We treated 2 patients with epithelioid sarcoma in our institute. The remaining sarcoma specimens after surgical resection were embedded in collagen type 1 gels according to the air-liquid interface organoid culture method. After serial passages, we xenografted the organoids to NOD-scid IL2Rgnull (NSG) mice. Using the developed tumors, we performed histological and genomic analyses to compare the similarities and differences with the original epithelioid sarcoma from the patient. Results: Organoids from the epithelioid sarcoma could be serially cultured and maintained in collagen type 1 gels for more than 3 passages. Developed orthotopic tumor xenografts were detected in the NSG mice. After the process was repeated severally, the patient derived organoid lines from the epithelioid sarcoma were established. The established organoids showed loss of integrase interactor 1 expression with polymerase chain reaction and immunohistochemical analyses. The xenografted organoids of the epithelioid sarcoma had histologically similar phenotypes with the original tumor and genetically resembled it to some degree. Conclusions: The present study demonstrated 2 novel established organoid models of epithelioid sarcoma, and our organoid models could be used to investigate the molecular pathogenesis and develop a novel treatment. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The pathology of poorly differentiated sinonasal malignancies has been the subject of extensive studies during the last decade, which resulted into significant developments in the definitions and histo-/pathogenetic classification of several entities included in the historical spectrum of "sinonasal undifferentiated carcinomas (SNUC)" and poorly differentiated unclassified carcinomas. In particular, genetic defects leading to inactivation of different protein subunits in the SWI/SNF chromatin remodeling complex have continuously emerged as the major (frequently the only) genetic player driving different types of sinonasal carcinomas. The latter display distinctive demographic, phenotypic and genotypic characteristics. To date, four different SWI/SNF-driven sinonasal tumor types have been recognized: SMARCB1(INI1)-deficient carcinoma (showing frequently non-descript basaloid, and less frequently eosinophilic, oncocytoid or rhabdoid undifferentiated morphology), SMARCB1-deficient adenocarcinomas (showing variable gland formation or yolk sac-like morphology), SMARCA4-deficient carcinoma (lacking any differentiation markers and variably overlapping with large cell neuroendocrine carcinoma and SNUC), and lastly, SMARCA4-deficient sinonasal teratocarcinosarcoma. These different tumor types display highly variable immunophenotypes with SMARCB1-deficient carcinomas showing variable squamous immunophenotype, while their SMARCA4-related counterparts lack such features altogether. While sharing same genetic defect, convincing evidence is still lacking that SMARCA4-deficient carcinoma and SMARCA4-deficient teratocracinosarcoma might belong to the spectrum of same entity. Available molecular studies revealed no additional drivers in these entities, confirming the central role of SWI/SNF deficiency as the sole driver genetic event in these aggressive malignancies. Notably, all studied cases lacked oncogenic IDH2 mutations characteristic of genuine SNUC. Identification and precise classification of these entities and separating them from SNUC, NUT carcinoma and other poorly differentiated neoplasms of epithelial melanocytic, hematolymphoid or mesenchymal origin is mandatory for appropriate prognostication and tailored therapies. Moreover, drugs targeting the SWI/SNF vulnerabilities are emerging in clinical trials. [ABSTRACT FROM AUTHOR]

BackgroundAlthough biological resources are essential for basic and preclinical research in the oncological field, those of sarcoma are not sufficient for rapid development of the treatment. So far, some sarcoma cell lines have been established, however, the success rate was low and the established sarcoma types were frequently biased. Therefore, an efficient culture method is needed to determine the various types of sarcomas. Organoid culture is a 3-dimentional culture method that enables the recapitulation of the tumor microenvironment and the success rate reported is higher than the 2-dimentional culture. The purpose of this study was to report our newly established organoids from human epithelioid sarcoma using the air-liquid interface organoid culture method.MethodsWe treated 2 patients with epithelioid sarcoma in our institute. The remaining sarcoma specimens after surgical resection were embedded in collagen type 1 gels according to the air-liquid interface organoid culture method. After serial passages, we xenografted the organoids to NOD-scid IL2Rgnull (NSG) mice. Using the developed tumors, we performed histological and genomic analyses to compare the similarities and differences with the original epithelioid sarcoma from the patient.ResultsOrganoids from the epithelioid sarcoma could be serially cultured and maintained in collagen type 1 gels for more than 3 passages. Developed orthotopic tumor xenografts were detected in the NSG mice. After the process was repeated severally, the patient derived organoid lines from the epithelioid sarcoma were established. The established organoids showed loss of integrase interactor 1 expression with polymerase chain reaction and immunohistochemical analyses. The xenografted organoids of the epithelioid sarcoma had histologically similar phenotypes with the original tumor and genetically resembled it to some degree.ConclusionsThe present study demonstrated 2 novel established organoid models of epithelioid sarcoma, and our organoid models could be used to investigate the molecular pathogenesis and develop a novel treatment.

Introduction; Epithelioid sarcoma is a malignant mesenchymal neoplasm with evidence of epithelial differentiation. All the cases reported in the solid organs are of "proximal type" occurring in adults. We report a primary epithelioid sarcoma arising in the adrenal gland of a young male. Case report: An 11-year-old male patient presented with right loin pain. Imaging revealed a 10.8 × 10.8 × 13.5 cm complex cystic mass with obscured right adrenal gland. Clinical and radiological studies did not reveal metastases. Histologic features were those of proximal type epithelioid sarcoma with extensive central necrosis. Immunohistochemistry showed strong positivity for pancytokeratin, vimentin, and CD34. Nuclear expression of SMARCB1 (INI-1) protein was lost. Conclusion: Proximal type of epithelioid sarcoma can arise from solid organs such as the adrenal. [ABSTRACT FROM AUTHOR]

Tumours of uncertain differentiation represent a markedly heterogeneous group of neoplasms that show no identifiable line of differentiation by currently available technologies, and do not resemble any specific normal cells or tissues. Continuing advances in molecular genetics have significantly aided to our understanding of these tumours, enabling refinements in classification and better insights into their biology, and furthering the development of ancillary immunohistochemical and molecular diagnostic tests and targeted therapies in the clinical setting. This review summarizes key genetic, morphologic and immunohistochemical features for a selection of cutaneous neoplasms of uncertain differentiation, with emphasis on new entities and developments in the diagnostic setting. [ABSTRACT FROM AUTHOR]

We present a case (41 years old pregnant female) with epithelioid sarcoma arising in the left external auditory canal. On immunohistochemistry, the tumor cell diffusely expressed cytokeratins and showed patchy expression of ERG and CD34. The neoplastic cells demonstrated uniform loss of INI1-expression. Epithelioid sarcoma arising in the external auditory canal is rare. Awareness that ES may rarely arise at unusual sites is of critical importance in order to apply a broad enough panel in the immunohistochemical study, so a misdiagnosis of carcinoma can be avoided. [ABSTRACT FROM AUTHOR]

Abstract Background The evidence that albumin-bound paclitaxel (nab-paclitaxel) is safe and efficacious for the treatment of many types of malignant tumors is continuously increasing. However, the evidence and clinical data of nab-paclitaxel and gemcitabine in metastatic soft tissue sarcoma (STS) treatment are rare. Methods The clinical data of metastatic STS patients who received nab-paclitaxel/ gemcitabine chemotherapy between January 2019 and February 2020 were retrospectively analysed. All these patients were treated with nab-paclitaxel/ gemcitabine only after doxorubicin-based chemotherapy had failed. We evaluated the effectiveness and safety of nab-paclitaxel and gemcitabine in these patients. Results A total of 17 patients treated with nab-paclitaxel/ gemcitabine were enrolled in this study. One patient with angiosarcoma achieved complete response, 6 patients had partial response, 5 patients achieved stable disease, and 5 patients had progressive disease. The average diameter change in target lesion from baseline was − 19.06 ± 45.74%. And median progression free survival was 6 months (95% CI, 2–9 months). Grade 3 / 4 adverse events were not common, included neutropenia (17.6%), fatigue (11.8%), anemia (11.8%), leukopenia (11.8%), nausea (5.9%), peripheral neuropathy (5.9%), diarrhea (5.9%), and thrombocytopenia (5.9%). No treatment-related deaths occurred. Conclusion Nab-paclitaxel/ gemcitabine combination chemotherapy is comparatively effective in the treatment of STS, demonstrates low toxicity, and is worthy of further study.

A cranioplasty has a number of known associated complications including infection for non-biological implants and bone flap resorption where autologous grafts are used. In recent years, bioactive ceramic cranial implants have been developed as a new reconstructive option. The OssDsign cranial plate (OssDsign AB, Uppsala, Sweden) was first introduced in 2010 and consists of an interconnected mosaic of hydroxyapatite tiles mounted onto a 3D-printed titanium mesh. Each tile is composed of a monetite, beta-calcium pyrophosphate, beta-tricalcium phosphate and brushite compound designed to mimic the process of coupled bone formation once implanted.This case presents a patient's journey from diagnosis of an epithelioid sarcoma over the posterior scalp and its management in the following 7 years. Initial excision of the lesion was reconstructed with a tissue expander and local rotational flap. Recurrence of the disease 3 years later was treated with a course of radical radiotherapy. Persistent osteomyelitis over the next 3 years resulted in chronic ulceration and exposed bone in the treated area. As the first part of a 3-stage treatment plan, two separate tissue expanders became infected. The multidisciplinary team therefore chose to use a bespoke OssDsign cranial plate combined with a deep inferior epigastric perforator (DIEP) free flap to provide a definitive single operative solution. The advantages over other reconstruction options include that the plate can be removed should further excision be required, greater potential for long-term integration with surrounding tissues and the ability to be soaked in antibiotic to reduce the risk of infection.

Epithelioid sarcoma (ES) is a rare aggressive sarcoma that, unlike most soft-tissue sarcomas, shows a tendency toward local recurrence and lymph node metastasis. Novel antitumor agents are needed for ES patients. Forkhead box transcription factor 1 (FOXM1) is a member of the Forkhead transcription factor family and is associated with multiple oncogenic functions; FOXM1 is known to be overexpressed and correlated with pathogenesis in various malignancies. In this study, we immunohistochemically analyzed FOXM1 expression levels and their clinical, clinicopathologic, and prognostic significance in 38 ES specimens. In addition, to investigate potential correlations between FOXM1 downregulation and oncologic characteristics, we treated ES cell lines with thiostrepton, a naturally occurring antibiotic that inhibits both small interfering RNA (siRNA) and FOXM1. In the analyses using ES samples, all 38 specimens were diagnosed as positive for FOXM1 by immunohistochemistry. We separated specimens into high (n = 19) and low (n = 19) FOXM1-protein expression groups by staining index score, and into large (n = 12), small (n = 25), and unknown (n = 1) tumor-size groups using a cutoff of 5 cm maximum diameter. Although there were significantly more samples with high FOXM1 expression in the large tumor group (P = .013), there were no significant differences with respect to age (P = 1.00), sex (P = .51), primary site of origin (P = .74), histologic subtypes (P = 1.00), depth (P = .74), or survival rate (P = .288) between the high and low FOXM1-protein expression groups. In the in vitro experiments using ES cell lines, FOXM1 siRNA and thiostrepton successfully downregulated FOXM1 mRNA and protein expression. Furthermore, downregulation of FOXM1 inhibited cell proliferation, drug resistance against chemotherapeutic agents, migration, and invasion and caused cell cycle arrest in the ES cell lines. Finally, cDNA microarray analysis data showed that FOXM1 regulated cIAP2, which is one of the apoptosis inhibitors activated by the TNFα-mediated NF-κB pathway. In conclusion, the FOXM1 gene may be a promising therapeutic target for ES., (Copyright © 2024 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Epithelioid sarcoma (ES) is a rare soft tissue neoplasm with high recurrence rates. Wide surgical resection remains the only potential curative treatment. ES presents most commonly on the fingers, hands and forearm, making light-based cancer cell-targeted therapies such as near-infrared photoimmunotherapy (NIR-PIT) that is target-specific, but with limited penetration depth, suitable for ES treatment. We established that CD44 and EGFR were overexpressed in ES patient samples and in the VA-ES-BJ human ES cell line. NIR-PIT of VA-ES-BJ cells using antibody photosensitizer conjugates, prepared by conjugating a CD44 or EGFR monoclonal antibody to the photosensitizer IR700, confirmed that NIR-PIT with both conjugates resulted in cell death. Neither treatment with NIR light alone nor treatment with the conjugates but without NIR light were effective. CD44-IR700-PIT resulted in greater cell death than EGFR-IR700-PIT, consistent with the increased expression of CD44 by VA-ES-BJ cells. In tumors, EGFR-IR700 exhibited a higher tumor-to-normal ratio, as determined by in vivo fluorescence imaging, and a higher anti-tumor growth effect, compared to CD44-IR700. No antitumor effect of the EGFR antibody or the photosensitizer conjugate alone was observed in vivo. Our data support evaluating the use of EGFR-IR700-PIT in the management of ES for detecting and eliminating ES cells in surgical margins, and in the treatment of superficial recurrent tumors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

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Epithelioid sarcoma (ES) is a rare soft tissue sarcoma (STS), with limited therapies available for metastatic disease. Here, we describe a case of a 30-year-old male with ES of the left knee and underwent surgery and radiation therapy for the primary disease. After 2 years, he had local recurrence and underwent extensive resection surgery; however, adjuvant chemotherapies were delayed due to recurrent wound infection. Nine months after the second surgery, progressive disease was confirmed after detection of metastases to the lungs and inguinal lymph nodes. Amputation was performed for the local recurrence, followed by inguinal lymph nodes dissection. Pazopanib was transiently administered but discontinued as a result of wound dehiscence. The tumour specimens were detected with unexpected high level of PD-L1 expression and tumoural infiltrating lymphocytes. Subsequently, he received camrelizumab 2.0 mg/kg every 21 days for 18 cycles with rapid remission of the pulmonary metastases. This promising response to camrelizumab indicates that immunotherapies may be an alternative choice for patients with metastatic ES in lung based on analysing the tumour immune microenvironment. [ABSTRACT FROM AUTHOR]

Aims: Complete loss of SMARCB1/INI1 in soft‐tissue tumours such as malignant rhabdoid tumour, epithelioid sarcoma, myoepithelial tumour of soft tissue and extraskeletal myxoid chondrosarcoma is often associated with high‐grade malignancy and poor prognosis. The diagnosis is sometimes challenging, owing to histological similarities, so careful differential diagnosis is required. Therefore, soft‐tissue tumours with complete SMARCB1/INI1 loss could potentially include an unknown entity. Methods and results: We analysed 160 cases of SMARCB1/INI1‐deficient soft‐tissue tumour, and found 14 cases that were not classifiable into already existing categories and had common clinical and histological features. These involved two male and 12 female patients, ranging in age from 20 years to 61 years. The tumours were located in the the puboinguinal region (n = 13) and pelvic cavity (n = 1). Histologically, the tumours showed relatively uniform epithelioid to spindle‐shaped cells with myxoid stroma. All tumours showed immunoreactivity for brachyury, epithelial membrane antigen, and progesterone receptor, and 12 of 14 cases did so for oestrogen receptor. Variable positive staining for α‐smooth muscle actin, S100 and glial fibrillary acidic protein (GFAP) was seen. NR4A3 and EWSR1 gene rearrangements were not detected in 13 and 11 examined cases, respectively. Clinical follow‐up data for the 14 patients showed that 13 were alive without disease and one had been lost to follow‐up; four patients developed local recurrence and/or metastases. Conclusion: The designation 'myxoepithelioid tumour with choroid features' (METC) was proposed as a tumour with intermediate malignancy controllable with appropriate treatment, including the entity of myoepithelioma‐like tumour of the vulvar region. METC represents a novel and independent subset that is histologically, biologically and clinically distinct from already existing SMARCB1/INI1‐deficient soft‐tissue tumours. [ABSTRACT FROM AUTHOR]

Malignant scalp masses deserve much attention as they have the potential to destroy local structures, recur and metastasize to distant organs. Moreover, malignant scalp lesions are known to be more aggressive in behavior than their counterparts elsewhere in the body. Multimodality imaging is essential in narrowing the differential diagnoses of scalp masses, as well as in differentiating benign from malignant masses. Furthermore, imaging is important in (1) evaluating the extent of tumor invasion in the scalp, (2) staging the disease, (3) guiding surgical biopsy and/or resection of the tumor, (4) preoperative planning and post-treatment surveillance of scalp tumors. An interdisciplinary treatment approach is crucial for the management of scalp malignancies given their complex and aggressive nature. This review seeks to describe the unique clinical and imaging characteristics of various types of malignant scalp masses, as well as to review their current treatment strategies. • Malignant scalp tumors are notoriously more aggressive in behaviour than theircounterparts elsewhere. • Multimodality imaging is essential for treatment planning, assess tumor extent and guide surgery. • MRI is paramount to assess excision margins and postoperative surveillance. • Multidisciplinary treatment strategy needed for malignant scalp masses. [ABSTRACT FROM AUTHOR]

A 33-year-old male presented with a one-centimetre lesion at the penoscrotal junction which was excised and revealed to be an epithelioid sarcoma (ES). A wide local excision of the lesion and subsequent neoadjuvant radiotherapy followed, with transposition of the patient's testicles laterally to protect fertility. At 3-year follow-up, the patient has no local or distant recurrence but does have a low sperm count. The patient has also had intermittent haematospermia since his treatment for which a cause has yet to be identified. This case highlights that ES of the penis can be managed successfully with surgical excision and local radiotherapy.

Epithelioid sarcoma (ES) is a rare soft tissue sarcoma (STS), with limited therapies available for metastatic disease. Here, we describe a case of a 30-year-old male with ES of the left knee and underwent surgery and radiation therapy for the primary disease. After 2 years, he had local recurrence and underwent extensive resection surgery; however, adjuvant chemotherapies were delayed due to recurrent wound infection. Nine months after the second surgery, progressive disease was confirmed after detection of metastases to the lungs and inguinal lymph nodes. Amputation was performed for the local recurrence, followed by inguinal lymph nodes dissection. Pazopanib was transiently administered but discontinued as a result of wound dehiscence. The tumour specimens were detected with unexpected high level of PD-L1 expression and tumoural infiltrating lymphocytes. Subsequently, he received camrelizumab 2.0 mg/kg every 21 days for 18 cycles with rapid remission of the pulmonary metastases. This promising response to camrelizumab indicates that immunotherapies may be an alternative choice for patients with metastatic ES in lung based on analysing the tumour immune microenvironment.

Epithelioid sarcoma (ES) is a rarely occurring malignant soft tissue tumor of uncertain histogenesis. It is most common among young males and commonly seen on the forearm, hand, and fingers. ES begins as a small lump or ulcer, and most were painless. ES has a high rate of recurrence and can spread to other parts of the body easily. Hence, physicians should take the necessary steps to ensure proper diagnosis and treatment. We present an interesting case of a 26-year-old male diagnosed with a proximal variant of ES of the shoulder.

Epithelioid sarcomas (ESs) of the vulva are extremely rare soft tissue tumors characterized by an aggressive clinical course and a poor prognosis. The proximal type of ES occurs in the trunk and external genital area and has higher recurrence and distant metastasis rates than the distal type, which is found in the upper and lower extremities. We describe a case of a vulvar ES in a 24-year-old patient who was referred from the department of plastic surgery with protruding mushroom-like lesions in multiple areas, including the lower abdomen, whole vulva, anus, and both inguinal lesions. A biopsy of the lesions confirmed a proximal-type ES. Computed tomography and magnetic resonance imaging revealed multiple metastatic lesions in several regions, including the perineum, vagina, and inguinal regions; nodal metastases in the left external iliac and right inguinal region; and distant metastases in the lungs, pleura of the left lung, bones, and soft tissue. The patient underwent active palliative radiotherapy, followed by chemotherapy, and showed a partial response to treatment. Nineteen months after the initial diagnosis, the patient expired due to cancer progression and pneumothorax.

Background: SMARCB1‐deficient malignancies can arise in various sites. We describe a novel primary SMARCB1‐deficient carcinoma of skin (SDCS) and characterize SMARCB1 mutations in non‐melanoma skin cancers (NMSC). Methods: Cases underwent immunophenotyping and targeted exome sequencing (MSK‐IMPACT) assay interrogating somatic mutations in 468 cancer‐related genes. The MSK‐IMPACT database from 2014 to 2020 encompassing 55, 000 cases was searched for NMSC with SMARCB1 mutations. Results: SDCS arose on the scalp of an 18‐year‐old woman showing homozygous SMARCB1 deletion with a LATS2 G963E variant. Another case arose on the temple of a 76‐year‐old man harboring a SMARCB1 W206* mutation associated with loss of heterozygosity (LOH), 59 concurrent mutations, and a UV mutation signature (UV‐MS). Both tumors exhibited INI1 loss, positive CK5/6, p40, p63, and claudin‐4 with negative CD34. Of 378 NMSC cases, including 370 carcinomas, 7 SMARCB1‐mutated tumors were identified: 3 squamous cell, 3 Merkel cell, and one basal cell carcinoma. Six showed UV‐MS. Five INI1‐interrogated cases retained protein expression suggesting they were SMARCB1‐proficient. Conclusions: SDCS can be clinically aggressive, harbor SMARCB1 homozygous deletions or truncating SMARCB1 mutations associated with LOH, and can occur with or without UV‐MS. Overall, SMARCB1 mutations in NMSC are rare with most being of undetermined significance and associated with retained INI1 and UV‐MS. [ABSTRACT FROM AUTHOR]

Epithelioid sarcoma (EpS) is a rare malignant neoplasm that accounts for < 1% of adult soft tissue sarcomas. Primary EpS of the bone is extremely rare and only a few cases have been reported to date. We report a case of primary distal-type EpS of the lumbar vertebra. A 30-year-old man without any history of malignant tumors had complained of lumbago for 3 months before visiting the hospital. Magnetic resonance imaging (MRI) of the lumbar spine showed a high signal intensity on the fat-suppressed T2-weighted image (WI) and a low signal on the T1WI at the L1 vertebral body. The tumor protruded toward the anterior components. Systemic radiological examination revealed no other lesion. A biopsy revealed a primary malignant tumor with epithelioid features. After chemotherapy, total en bloc spondylectomy was performed. Macroscopically, the tumor replaced the entire L1 with necrosis. Histologically, the tumor showed nodules of epithelioid cells that were strongly positive for epithelial markers, but a lack of INI1 expression. Central necrosis in the tumor nodule was also observed. This tumor showed loss of heterozygosity at the SMARCB1 locus but without the SMARCB1 mutation. The result of Foundation One ®CDx showed no actionable mutations. Seven months after surgery, a subcutaneous metastasis to the left cheek and bilateral lung metastasis with pleural dissemination were observed on radiological examination. A final diagnosis of distal-type EpS was made based on these findings. The patient died of the disease 8 months after surgery. [ABSTRACT FROM AUTHOR]

Background: Epithelioid sarcomas and rhabdoid tumors are rare, aggressive malignancies with poor prognosis. Both are characterized by INI1 alterations and deregulation of growth factor receptors albeit their interaction has not been elucidated.Methods: In this study, we investigated the activity of a panel of epigenetic modulators and receptor tyrosine kinase inhibitors in vitro on respective cell lines as well as on primary patient-derived epithelioid sarcoma cells, and in vivo on xenografted mice. Focusing on histone deacetylase (HDAC) inhibitors, we studied the mechanism of action of this class of agents, its effect on growth factor receptor regulation, and changes in epithelial-to-mesenchymal transition by using cell- and RT-qPCR-based assays.Results: Pan-HDAC inhibitor panobinostat exhibited potent anti-proliferative activity at low nanomolar concentrations in A204 rhabdoid tumor, and VAESBJ/GRU1 epithelioid sarcoma cell lines, strongly induced apoptosis, and resulted in significant tumor growth inhibition in VAESBJ xenografts. It differentially regulated EGFR, FGFR1 and FGFR2, leading to downregulation of EGFR in epithelioid sarcoma and to mesenchymal-to-epithelial transition whereas in rhabdoid tumor cells, EGFR was strongly upregulated and reinforced the mesenchymal phenotype. All three cell lines were rendered more susceptible towards combination with EGFF inhibitor erlotinib, further enhancing apoptosis.Conclusions: HDAC inhibitors exhibit significant anticancer activity due to their multifaceted actions on cytotoxicity, differentiation and drug sensitization. Our data suggest that the tailored, tissue-specific combination of HDAC inhibitors with therapeutics which target cellular salvage mechanisms might increase their therapeutic relevance. [ABSTRACT FROM AUTHOR]

Background: Epithelioid sarcoma most frequently occurs in the dermal or subcutaneous area of the distal extremities. To date, there have been three cases of primary pulmonary epithelioid sarcoma reported. We report a case of epithelioid sarcoma that is considered a primary lung tumor. Case presentation: A 65-year-old asymptomatic Asian male patient underwent chest radiography during a routine health examination, and an abnormal mass was detected. His past medical history was unremarkable. He smoked 40 cigarettes every day and had slightly obstructive impairment on spirometry. He worked as an employee of a company and had no history of asbestos exposure. He underwent partial resection of the right lung by thoracoscopy. A histological examination of the tumor revealed a cellular nodule of epithelioid and spindle-shaped cells. Some of the tumor cells displayed rhabdoid features and reticular arrangement in a myxomatous stroma. Immunohistochemically, the tumor cells were positive for vimentin, smooth muscle actin (SMA), CD34, and epithelial membrane antigen (EMA); loss of the BAF47/INI1 protein in the tumor cells was also confirmed. A diagnosis of epithelioid sarcoma was established. Careful screening by whole-body positron emission tomography for another primary lesion after surgery did not detect any possible lesion. He had no cutaneous disease. Conclusion: To our knowledge, this is the fourth case of a proximal-type epithelioid sarcoma considered as a primary lung tumor. [ABSTRACT FROM AUTHOR]

Abstract Background Epithelioid sarcoma (ES) is a rare malignant soft tissue tumor, commonly occurring in distal extremities, such as fingers, hands and wrists. For oncologists and surgeons, a female patient with enlarged axillary lymph node on one side only is easily diagnosed with an occult breast carcinoma rather than ES. Besides, whole breast metastasis of ES has not been reported yet. Case presentation A 47-year-old Chinese woman came to the outpatient clinic of First Affiliated Hospital of Zhejiang University (FAHZU) with a complaint of an asymptomatic right axillary mass for 3 months. Then she received surgical resection of the right axillary lymph nodes and right supraclavicular lymph nodes. According to the clinical tumor site and routine immunohistochemistry (IHC), suspicion of metastatic epithelial sarcoma and metastatic breast cancer could not be ruled out. Subsequently, with more detailed medical history review and physical examination, a mass on the right forearm was found, which was considered as the primary lesion. Further IHC and Molecular Genetics revealed that all the neoplastic cells exhibited loss of INI1 protein and were negative for ERG gene rearrangement yet positive for epithelial membrane antigen (EMA), cytokeratin (CK) 8, CK19, Vimentin, CD34. The final diagnosis was ES. She received postoperative chemotherapy, without radiotherapy. Unexpectedly, an ipsilateral breast metastasis was developed at ten months after surgery. Regrettably, there was no positive result of the metastatic breast sample, based on a genome sequencing by a 381-cancer-gene panel in a lab. Therefore, she went through another round of chemotherapy and took Apatinib for maintenance treatment. During the last follow-up (26 months after diagnosis), the disease was under control. Conclusion This rare but interesting case enables breast surgeons and pathologists to accumulate more experience of differential diagnosis of axillary mass for personalized treatment in clinical practice. Meanwhile, ipsilateral breast metastasis of ES we reported in the case urges that clinicians attach greater importance to the tumor metastasis mechanism.

Epithelioid sarcoma (ES) is a very rare and aggressive mesenchymal tumor of unclear origin and uncertain lineage characterized by a prevalent epithelioid morphology. The only recurrent genetic alteration reported in ES as yet is the functional inactivation of SMARCB1 (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1), a key component of the SWI/SNF (SWItch/Sucrose Non-Fermentable) chromatin remodeling complexes. How SMARCB1 deficiency dictates the clinicopathological characteristics of ES and what other molecular defects concur to its malignant progression is still poorly understood. This review summarizes the recent findings about ES pathobiology, including defects in chromatin remodeling and other signaling pathways and their role as therapeutic vulnerabilities.

Epithelioid sarcoma (ES) is a rare soft tissue sarcoma with an incidence of 0.05 per 100,000 population in the USA. It is characterized by multiple local recurrences and regional lymph nodes form the commonest site of metastases. The function of Integrase Inhibitor 1 (INI1) protein is lost in more than 90% of cases, which was the basis for the introduction of tazemetostat into the therapeutic armamentarium for management of advanced ES. The efficacy and manageable toxicity profile of tazemetostat have been demonstrated recently, leading to its accelerated approval for treatment of advanced ES. We report one of the first real-world cases of relapsed, metastatic ES treated with tazemetostat. The patient attained partial response with the therapy and is tolerating the drug well without serious toxicities.

Epithelioid sarcoma (ES) was first described by Enzinger in 1970. It is a rare variant of soft tissue sarcoma with a 5-year overall survival (OS) rate of 50%. Here, we reported a case of epithelioid sarcoma in the parapharyngeal space of an adult, resulting in a favorable prognosis after chemotherapy and radiation therapy. A 34-year-old female who complained of pharynx pain and discomfort was suspected of having a tumor in the right parapharyngeal space by CT scan. Excision biopsy suggested epithelioid sarcoma. Clinical and radiological studies did not reveal tumor distant metastasis in the patient. After excisional biopsy, the patient underwent chemotherapy and external beam radiation treatment. She has remained alive for 2 years and 7 months without recurrence since her last treatment. In this paper, we also provide a detailed review of the role of radiotherapy in the treatment of epithelioid sarcoma in previously reported cases. [ABSTRACT FROM AUTHOR]

Objectives: Epithelioid sarcoma (ES) rarely arises in the nerve. To increase our understanding of this unusual tumor originating in the nerve, we describe the features of three cases and review the literature.Methods: Clinical data, imaging, pathology, treatment, and follow-up are detailed. A systematic literature review was conducted.Results: Two patients were male and one female; the median age was 24 years. The patients had neurologic symptoms, and the tumors arose in large nerves and ranged from 2.4 to 5.8 cm. The tumors were avid on positron emission tomography-computed tomography and showed increased signal intensity on T2-weighted magnetic resonance imaging. Centered in the nerve, the tumors grew with an infiltrative pattern and encased the nerve fascicles. All were treated with wide resection, and adjuvant treatment included combinations of chemotherapy and radiation. One recurred, and the limb was amputated. Metastases were documented to lymph nodes, lung, pleura, and skin. One patient died of disease after 54 months. Literature review including our cases showed that tumors stained with pancytokeratin (9/9), EMA (4/4), and CD34 (7/7); there was loss of INI1 in all six cases tested.Conclusions: ES rarely arises in the peripheral nerve, and its infiltrative nature often requires morbid surgery. The differential includes a variety of benign and malignant epithelioid neoplasms. [ABSTRACT FROM AUTHOR]

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Introduction: Epithelioid sarcoma is a rare soft tissue malignancy that usually presents in the distal extremities along fascial planes, aponeuroses or tendon sheaths. Very rarely, it presents as a primary or metastatic lesion of the head neck. Methods: Chart review and comprehensive literature review using PubMed and Google Scholar. Results: A 17-year-old non-smoker was referred for evaluation of an ulcerative lesion of the right anterior-lateral tongue, progressing over several months. Incisional biopsy was concerning for squamous cell carcinoma. He underwent partial glossectomy and bilateral selective neck dissections, with reconstruction using a radial forearm free flap. Final pathology was consistent with epithelioid sarcoma, proximal type, demonstrating perineural invasion and close margins. Post-operative PET scan showed no persistent nor metastatic disease. He underwent post-operative radiation therapy to a total dose of 56 Gy to the primary site. Conclusion: Epithelioid sarcoma is a rare malignancy usually presenting in the extremities of young adults, which uncommonly presents in the head and neck as a primary or metastatic lesion. The infrequency of these lesions has prevented development of evidence-based treatment recommendations. As with most sarcomas, surgery is the mainstay of therapy for epithelioid sarcoma, while radiation has been used in an adjunctive role. Although a rare lesion, epithelioid sarcoma should be considered in the differential diagnosis for atypical epithelioid lesions of the tongue and oral cavity when patient demographics, gross lesion characteristics, or histopathology are not entirely consistent with more common lesions, such as squamous cell carcinoma. [ABSTRACT FROM AUTHOR]

Epithelioid sarcoma (ES) is an aggressive ultra-rare soft-tissue sarcoma marked by SMARCB1/INI1 deficiency. SMARCB1/INI1 deficiency leads to elevated expression of EZH2, a component of polycomb repressive complex 2, which mediates gene silencing by catalyzing H3K27me3. Tazemetostat is an oral, SAM-competitive inhibitor of EZH2, whose blockade prevents the methylation of histone H3K27, thus decreasing the growth of EZH2 mutated or over-expressing cancer cells. Tazemetostat has been approved for the treatment of patients aged 16 years and older with metastatic or advanced ES not eligible for complete resection, based on the positive results of a single-arm Phase II basket study. Tazemetostat though represents a new treatment option for ES patients, although clinical/molecular predictors of response are still to be identified. The combination of tazemetostat with other drugs like doxorubicin and immunotherapeutic agents is currently under investigation in ES patients. [ABSTRACT FROM AUTHOR]

Rhabdoid tumor predisposition syndrome (RTPS) is defined as the presence of a SMARCB1 or SMARCA4 genetic aberration in a patient with malignant rhabdoid tumor. Patients with RTPS are more likely to present with synchronous or metachronous rhabdoid tumors. Based on the current state of rhabdoid tumor taxonomy, these diagnoses are based largely on patient demographics, anatomic location of disease, and immunohistochemistry, despite their nearly identical histologic and immunohistochemical profiles. Thus, the true distinction between such tumors remains a diagnostic challenge. Central nervous system atypical teratoid/rhabdoid tumor (AT/RT) is a rare, aggressive, primarily pediatric malignancy with variable histologic features and a well documented association with loss of SMARCB1 expression. Epithelioid sarcoma (ES) is a rare soft tissue tumor arising in patients of all ages and characteristically staining for both mesenchymal and epithelial immunohistochemical markers while usually demonstrating loss of SMARCB1 expression. To our knowledge we herein present the first documented case of a patient with RTPS who presented with metachronous AT/RT and ES. [ABSTRACT FROM AUTHOR]