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Epithelioid sarcoma affects three in 10 million people, usually teenagers and young adults. Tumours grow under the skin of the extremities or they can affect the trunk, head, or neck. It grows slowly, but can infiltrate surrounding tissues, later on, it frequently metastasis to lymph nodes. For advanced case, doxorubicin-based chemotherapy regimen is recommended. In January 2020, FDA approved the first-in-class, small molecule enhancer of zeste homolog 2 (EZH2) inhibitor, tazemetostat (Tazverik) to treat adults and paediatric patients aged 16 years and older with locally advanced or metastatic epithelioid sarcoma not suitable for complete resection. The recommended dosage is 800 mg twice daily until disease progression or unacceptable toxicity. The first-in-human study of tazemetostat was a phase 1 open-label multi-centered dose-escalation study. Tazemetostat is having an oral bioavailability of approximately 33%. Apparent volume of distribution at steady-state (Vss/F) is 1230 L (46%) with 88% bound to human plasma proteins. Metabolism takes place via CYP3A. 15% and 79% of radioactivity is excreted through urine and feces respectively. ≥20% of the adverse reactions and above was fatigue, pain, constipation, nausea, anorexia and vomiting. This article summarizes the history, chemistry, physical properties, mechanism of action, indications, and drug–drug interactions of tazemetostat and we also discuss briefly the results of various clinical trials.

Musculoskeletal tumors of the hand are a rare entity and are divided into skeletal and soft tissue tumors. Either category comprises benign and malignant or even intermediate tumors. Basic radiology allows an optimal resolution of bone and related soft tissue areas, ultrasound and more sophisticated radiologic tools such as scintigraphy, CT and MRI allow a more accurate evaluation of tumor extent. Enchondroma is the most common benign tumor affecting bone, whereas chondrosarcoma is the most commonly represented malignant neoplasm localized to hand bones. In the soft tissues, ganglions are the most common benign tumors and epithelioid sarcoma is the most frequently represented malignant tumor targeting hand soft tissues. The knowledge regarding diagnostic and therapeutic management of these tumors is often deriving from small case series, retrospective studies or even case reports. Evidences from prospective studies or controlled trials are limited and for this lack of clear and supported evidences, data from the medical literature on the topic are controversial, in terms of demographics, clinical presentation, diagnosis, prognosis and therapy. The correct recognition of the specific subtype and extension of the tumor through first line and second line radiology is essential for the surgeon, in order to effectively direct the therapeutic decisions.

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.

Epithelioid sarcoma is a rare soft-tissue tumor that occurs mainly in children and young adults. It typically presents as a subcutaneous or deep dermal mass in distal extremities. Due to its benign-appearing clinical presentation, infrequent occurrence, and histologic similarities with other pathologies, the diagnosis of epithelioid sarcoma in its early stages can be extremely difficult and can be easily confused with benign lesions such as warts or foreign body granuloma. In this paper, we report the case of a 12-year-old boy with a distal-type epithelioid sarcoma of the hand and wish to emphasize the difficulties of diagnosing this potentially lethal tumor both clinically and histologically.

Objectives: Aberrant expression of neuroendocrine markers has been reported in angiosarcomas and can occasionally result in diagnostic confusion. The aim of this study was to evaluate the expression of insulinoma-associated protein 1 (INSM1), a marker for neuroendocrine differentiation, in angiosarcomas as well as other sarcomas. Methods: Tissue microarrays, including angiosarcoma, Ewing sarcoma, desmoplastic small round cell tumor (DSRCT), clear cell sarcoma, synovial sarcoma, leiomyosarcoma, alveolar soft part sarcoma, epithelioid sarcoma, and undifferentiated pleomorphic sarcoma, were evaluated for expression of INSM1. The extent of immunoreactivity was graded according to the percentage of positive tumor cell nuclei (0, no staining; 1+, Results: INSM1 expression was found in a subset of angiosarcomas (n = 24/94, 26%; majority 5+, weak to moderate), as well as DSRCTs (n = 7/62, 11%; 2+, weak to strong) and rarely synovial sarcomas (n = 3/76, 4%; 2+, moderate to strong). No INSM1 expression was detected in the other sarcomas. Conclusions: Aberrant expression of INSM1 can be seen in a subset of angiosarcomas often with diffuse labeling. Other sarcomas that can rarely demonstrate small cell morphology and focal INSM1 expression include DSRCT and synovial sarcoma.

Epithelioid sarcoma (ES) of the hand is a rare, aggressive cutaneous malignancy with high rates of recurrence, metastases and mortality. With an incidence rate of 0.4 cases/y per one million population, which compromise for approximately 1-1.4% of all soft tissue sarcoma, ES accounts for 10% of soft tissues sarcomas of the hand and foot. Its aggressiveness and propensity to spread and metastases without being noticed, makes it unique and potentially lethal. Missed or delayed diagnosis are often encountered as this tumor can mimic variety of different entities and due to the infrequent nature of this lesion, treatment options are still controversial. The authors provide systemic review of the current literature on epidemiology, etiology, pathogenesis, management and outcomes of this disease as well as a case presentation and a proposed treatment algorithm. The choice of treatment option depends on disease characteristics, staging at presentation, regional lymph node involvement, comorbidities and performance status of the patient. Emphasis on a multidisciplinary coordinated care is crucial as early diagnosis and treatment can decrease morbidity and mortality rates.

Summary Background Epithelioid sarcoma is a rare and aggressive soft-tissue sarcoma subtype. Over 90% of tumours have lost INI1 expression, leading to oncogenic dependence on the transcriptional repressor EZH2. In this study, we report the clinical activity and safety of tazemetostat, an oral selective EZH2 inhibitor, in patients with epithelioid sarcoma. Methods In this open-label, phase 2 basket study, patients were enrolled from 32 hospitals and clinics in Australia, Belgium, Canada, France, Germany, Italy, Taiwan, the USA, and the UK into seven cohorts of patients with different INI1-negative solid tumours or synovial sarcoma. Patients eligible for the epithelioid sarcoma cohort (cohort 5) were aged 16 years or older with histologically confirmed, locally advanced or metastatic epithelioid sarcoma; documented loss of INI1 expression by immunohistochemical analysis or biallelic SMARCB1 (the gene that encodes INI1) alterations, or both; and an Eastern Cooperative Oncology Group performance status score of 0–2. Patients received 800 mg tazemetostat orally twice per day in continuous 28-day cycles until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was investigator-assessed objective response rate measured according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary endpoints were duration of response, disease control rate at 32 weeks, progression-free survival, overall survival, and pharmacokinetic and pharmacodynamic analyses (primary results reported elsewhere). Time to response was also assessed as an exploratory endpoint. Activity and safety were assessed in the modified intention-to-treat population (ie, patients who received one or more doses of tazemetostat). This trial is registered with ClinicalTrials.gov , NCT02601950 , and is ongoing. Findings Between Dec 22, 2015, and July 7, 2017, 62 patients with epithelioid sarcoma were enrolled in the study and deemed eligible for inclusion in this cohort. All 62 patients were included in the modified intention-to-treat analysis. Nine (15% [95% CI 7–26]) of 62 patients had an objective response at data cutoff (Sept 17, 2018). At a median follow-up of 13·8 months (IQR 7·8–19·0), median duration of response was not reached (95% CI 9·2–not estimable). 16 (26% [95% CI 16–39]) patients had disease control at 32 weeks. Median time to response was 3·9 months (IQR 1·9–7·4). Median progression-free survival was 5·5 months (95% CI 3·4–5·9), and median overall survival was 19·0 months (11·0–not estimable). Grade 3 or worse treatment-related adverse events included anaemia (four [6%]) and weight loss (two [3%]). Treatment-related serious adverse events occurred in two patients (one seizure and one haemoptysis). There were no treatment-related deaths. Interpretation Tazemetostat was well tolerated and showed clinical activity in this cohort of patients with advanced epithelioid sarcoma characterised by loss of INI1/SMARCB1. Tazemetostat has the potential to improve outcomes in patients with advanced epithelioid sarcoma. A phase 1b/3 trial of tazemetostat plus doxorubicin in the front-line setting is currently underway ( NCT04204941 ). Funding Epizyme.

Epithelioid sarcoma (ES) is a rare malignant mesenchymal neoplasm that accounts for less than one percent of all soft-tissue sarcomas. Only two cases of ES involving the adrenal gland were found after a literature review. We report a case of an 82-year-old female initially presenting with right flank pain who was subsequently found to have an incidental left adrenal mass on CT imaging. After appropriate diagnostic workup, the patient underwent surgical resection. A diagnosis of ES was made from the histopathological analysis. The characteristic findings of ES are epithelioid cells with rhabdoid morphology and moderate eosinophilic cytoplasm. Immunohistochemical findings are significant for positive staining for epithelial markers, cytokeratins, vimentin, and CD34, and loss of INI-1 stain. Due to the aggressive nature and limited data of ESs, the standard treatment continues to remain wide surgical excision.

Epithelioid Sarcomas is a rare aggressive subtype of soft tissue sarcomas that is most prevalent in young adult males. It is locally invasive and frequently metastasizes to regional lymph nodes and...

Epithelioid sarcoma, in the relapse-refractory setting, has limited expected survival. SMARCB1 inactivation, common in epithelioid sarcoma, causes loss of INI1 protein expression and overexpression of the cancer cell growth promoting methyltransferase enzyme, EZH2. We treated a 19-year-old male with stage IV SMARCB1 inactivated epithelioid sarcoma presenting with recurrent end stage (Eastern Cooperative Oncology Group Performance Status 4) rapidly progressing bulky disease with combination ipilimumab and nivolumab. He failed standard therapy and an EZH2 inhibitor (tazemetostat). He presented (May 13, 2019) with a large (16.1×18.6 cm) soft tissue back mass extending from T10 to L3. Complete clinical regression of the back mass occurred within 2 weeks (May 28, 2019) of cycle 1 of combined checkpoint inhibition therapy followed by a positron emission tomography-negative complete remission (October 11, 2019). After a second negative positron emission tomography/computed tomography scan (January 13, 2020), checkpoint inhibition therapy was discontinued. He has returned to normal activities with a normal physical examination and Eastern Cooperative Oncology Group Performance Status of 0 at his last visit (June 29, 2020). In conclusion, combined checkpoint inhibition therapy warrants further study in the salvage setting in patients with epithelioid and other INI1 protein-deficient sarcomas seemingly regardless of prior therapy, extent of disease, and performance status.

Introduction This case-series is aimed to describe the natural history of epithelioid sarcoma (ES) and to provide insights into the differential clinical behaviour of its two variants (“classic-type” and “proximal-type”). The value of a subtype-adapted grading system based on pathological features is explored. Methods Data from consecutive, primary, localised, INI1-deleted ES operated at three Italian sarcoma reference centres (1995–2015) were included. Centralised pathological review was performed. Classic-type ES was broken down into “high-grade” and “low-grade”, according to number of mitoses, evidence of necrosis and nuclear atypia. Five- and 10-year overall survival (OS) and crude cumulative incidence (CCI) of local recurrence (LR) and distant metastasis (DM) were estimated. Results Fifty-two patients were included. 5- and 10-year OS estimates were 70% and 47% in the whole series, 57% and 37% in patients with proximal-type ES, 77% and 54% in patients with classic-type ES (P = 0.02). In classic-type ES, 5- and 10-year OS was higher for low-grade (95% and 72%, respectively) than high-grade tumours (P = 0.002). 5- and 10-year CCI estimates for LR were 21% and 33% in the whole series. 5- and 10-year CCI estimates for DM were 35% and 39% in the whole series, both 28% in classic-type ES, 47% and 59% in proximal-type ES (P = 0.03). Conclusions Suffering from a proximal- or a classic-type is the stronger predictor of outcome in patients with localised ES, with proximal-type ES patients having lower survival due to a higher tendency toward metastatic spreading. However, the “high-grade” classic-type ES was associated with outcomes close to proximal-type ES.

We experienced an extremely rare case of proximal epithelioid sarcoma (PES) of the vulva in a 77-year-old woman. After history taking and physical examination, the patient was tentatively diagnosed as having Bartholin’s cyst in the right labium. Based on histopathological and immunohistochemical (IHC) findings, however, a final diagnosis of PES of the vulva was made. After receiving CyberKnife treatment, the patient survived but with recurrent episodes and poor prognosis. In conclusion, our case indicates that patients with PES of the vulva should be appropriately managed with radiotherapy after a differential diagnosis based on histopathological and IHC findings.

Epigenetic processes are essential for normal development and the maintenance of tissue-specific gene expression in mammals. Changes in gene expression and malignant cellular transformation can result from disruption of epigenetic mechanisms, and global disruption in the epigenetic landscape is a key feature of cancer. The study of epigenetics in cancer has revealed that human cancer cells harbor both genetic alterations and epigenetic abnormalities that interplay at all stages of cancer development. Unlike genetic mutations, epigenetic aberrations are potentially reversible through epigenetic therapy, providing a therapeutically relevant treatment option. Histone methyltransferase inhibitors are emerging as an epigenetic therapy approach with great promise in the field of clinical oncology. The recent accelerated approval of the enhancer of zeste homolog 2 (EZH2; also known as histone-lysine N-methyltransferase EZH2) inhibitor tazemetostat for metastatic or locally advanced epithelioid sarcoma marks the first approval of such a compound for the treatment of cancer. Many other histone methyltransferase inhibitors are currently in development, some of which are being tested in clinical studies. This review focuses on histone methyltransferase inhibitors, highlighting their potential in the treatment of cancer. We also discuss the role for such epigenetic drugs in overcoming epigenetically driven drug resistance mechanisms, and their value in combination with other therapeutic approaches such as immunotherapy.

Introduction As a rare soft tissue malignancy, epithelioid sarcoma (EpS) is infrequently subjected to cytopathologic analysis. With the exception of a few series, the cytology literature regarding EpS is largely limited to single case reports. Our purpose was to evaluate our experience with EpS, and review the literature regarding its cytopathology. Materials and methods A search was made of our cytopathology and surgical pathology databases for cases diagnosed as EpS. Fine-needle aspiration biopsy smears and imprint smears were performed and examined using standard technique. Effusion samples were processed using liquid-based slides. Results Twenty cases of EpS were retrieved from 10 patients (M:F 1:1; mean age = 36 years). One patient had 5, 1 patient had 3, and 3 patients had 2 separate specimens. All patients had prior or subsequent tissue confirmation of EpS; all were of the classic/distal type. Seven were new patient cases, 7 were locally recurrent, and 6 were metastases. Sites included lower extremity (8 cases), upper extremity (4), trunk (4), serous effusion (2), scalp (1), and mediastinum (1). Specific cytologic diagnosis were EpS (13 cases), sarcoma not otherwise specified (5), and malignant neoplasm (2). All cases where cell-block SMARCB-1 staining was used were specifically recognized as EpS. Cytomorphology was composed primarily of epithelioid/plasmacytoid cells having eccentrically positioned nuclei, moderate cytoplasm, and variable nuclear pleomorphism. Conclusion The cytopathology of EpS is somewhat variable, morphologically non-specific, and mimics that of other neoplasms with epithelioid features. Ancillary immunostaining is necessary for a specific diagnosis in newly encountered patients.

Epithelioid sarcoma is a rare highly aggressive soft tissue sarcoma with a high incidence of local recurrence and metastasis. It is a tumor of uncertain histogenesis & poses a diagnostic difficulty as it is often misdiagnosed as other benign or malignant condition. We present the case of 49-year-old male presenting with chief complaints of pain and gradually progressive swelling on right 3rd toe since 3 months. Based on clinicoradiological evaluation suggestive of malignancy, an amputation of toe was done. Histopathological & Immunohistochemical findings suggestive of Epithelioid sarcoma. The patient was referred to the oncology centre for further management where he was advised wide excision followed by radiotherapy. No regional or distant metastasis was found.

Tazemetostat (Tazverik™), a first-in-class, small molecule enhancer of zeste homolog 2 (EZH2) inhibitor, received accelerated approval in January 2020 in the USA for the treatment of adults and adolescents aged ≥ 16 years with locally advanced or metastatic epithelioid sarcoma not eligible for complete resection. Developed by Epizyme, in collaboration with Eisai, it is the first therapy to be approved specifically for the treatment of epithelioid sarcoma in the USA. The recommended dosage regimen is 800 mg twice daily, administered orally with or without food, until disease progression or unacceptable toxicity. Tazemetostat is also undergoing clinical development in various countries worldwide for use in several other tumour types, including diffuse large B-cell lymphoma and mesothelioma, with the US FDA accepting a New Drug Application and granting priority review for its use in the treatment of follicular lymphoma. This article summarizes the milestones in the development of tazemetostat leading to this first approval for the treatment of adults and adolescents aged ≥ 16 years with locally advanced or metastatic epithelioid sarcoma not eligible for complete resection.

Highlights • It is difficult to diagnose cellular variants of Sclerosing epithelioid sarcoma by fine needle aspiration. • If dense areas of tumor cells are collected by FNA, multiple myeloma and myoepithelioma can be different diagnosis. • MUC4 is a very useful immunological marker for diagnosis of Sclerosing epithelioid sarcoma., Introduction Sclerosing epithelioid sarcoma (SEF) is a rare fibroblastic sarcoma. It is classically composed of cords of epithelioid cells embedded in a hyalinized stroma; however, cases of cellular variants also exist. A cellular variants of SEF can mimic Plasmacytoma/Myeloma (PM) and myoepithelioma. Hence, accurate diagnosis of SEF is important for cytologists and pathologists. Presentation of case We present the case of a 75-year-old female patient diagnosed with a cellular variant of SEF occurring in the erector spinal muscle. Immunostaining of MUC4 and fluorescence in situ hybridization of EWSR1 (break-apart signal) were used for diagnosis. Conclusion The cellular variants of SEF presented diagnostic difficulties in fine needle aspiration. Moreover, it could not be distinguished from PM.

Background Soft-tissue sarcomas (STS) are rare in hand and foot. In this paper we present a case of reconstruction of Achilles tendon defect with peroneus brevis transfer reinforced with medial gastrocnemius fascia and plantaris tendon after excision of a local recurrence of epithelioid sarcoma. Case presentation Fifty-five years-old female. MRI showed a lump of 5 × 2,5 × 2 cm into Achille’s tendon with invasion of the anterior fat tissue but no invasion of the surrounding bones. The patient underwent excision of the tumour and reconstruction of the tendinous defect with peroneus brevis transfer. Surgical technique has been widely described. Discussion and conclusions Epithelioid sarcoma arising from the Achilles tendon is an extremely rare malignant tumour in an atypical site and may easily be confused with other soft tissue masses. It presents a technical challenge because of the large tendon defect remaining following wide resection. Reconstruction with peroneus brevis transfer, reinforced with medial gastrocnemius fascia and plantaris tendon, restore appropriate structural continuity and resistance. Functional results are satisfactory.