3 Things You Should Know About Epithelioid Sarcoma

Learning Objectives

Upon successful completion of this activity, you should be better prepared to:

• Differentiate epithelioid sarcoma (ES) from other malignant and non-malignant lesions by identifying its clinical presentation, histopathologic markers, and molecular features

• Describe a multidisciplinary management approach for ES, integrating surgical oncology, pathology, radiation therapy, and medical oncology to optimize patient outcomes through coordinated care and individualized treatment planning

• Identify when to refer patients with ES to specialized academic centers and clinical trials to expand access to novel therapies and research opportunities

RELEASE DATE: March 1, 2026

EXPIRATION DATE: March 1, 2027

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Acknowledgement of Commercial Support

This activity is supported by an educational grant from Ipsen.

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This activity may or may not discuss investigational, unapproved, or off-label use of drugs. Learners are advised to consult prescribing information for any products discussed. The information provided in this activity is for accredited continuing education purposes only and is not meant to substitute for the independent clinical judgment of a health care professional relative to diagnostic, treatment, or management options for a specific patient’s medical condition. The opinions expressed in the content are solely those of the individual faculty members, and do not reflect those of PER^® or any company that provided commercial support for this activity.

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Soft tissue sarcomas (STSs) are a rare but heterogeneous group of tumors accounting for less than 1% of all cancers.¹ There were an estimated 13,520 new cases of STS and 5410 deaths due to the disease in the United States in 2025, with epithelioid sarcoma (ES) accounting for less than 1% of all STSs.^2-4 Although treatment for this rare STS subtype remains limited, the EZH2-targeting drug tazemetostat is approved and recommended specifically for ES.^5,6

1) ES can be difficult to diagnose and should be differentiated from other tumors by its clinical presentation and histological and molecular features.

ES, which is presumed to be of mesenchymal origin but also displays epithelial markers, can be difficult to diagnose, as it exhibits a wide immunophenotypic range.⁷ Virtually all ESs are cytokeratin and epithelial membrane antigen positive on immunohistochemistry, with most cases coexpressing vimentin and about 60% to 70% of cases expressing CD34. Loss of INI1 expression resulting in unopposed, constitutive activation of the EZH2 enzyme is a hallmark of ES.⁸ INI1 expression is lost through a deletion or point mutation of the tumor suppressor gene SMARCB1 in up to 50% of ES cases; however, in other cases, its expression may be lost epigenetically or via microRNA gene silencing.⁹

Most ESs arise in the extremities, presenting as a classical type in the distal extremities (Figure 1).^4,7,10 The proximal variant of the disease is characterized by larger cells, prominent nucleoli, and rhabdoid changes and is typically associated with a more aggressive clinical course.^4,10 The median age at diagnosis of ES is 35 years, with proximal disease occurring in older patients aged 20 to 65 years.⁷ In a Surveillance, Epidemiology, and End Results database analysis of 441 incident cases of ES between 1973 and 2005, about 50% of patients had localized disease, about 25% had regional spread, and about 25% had distant disease.¹¹

ESs have a variable presentation, further complicating and potentially delaying diagnosis. Some cases present as painless, slow-growing, firm nodules with superficial bleeding, necrosis, or ulceration.⁴ These tumors can also present with pain, for example, when in proximity to joints.¹² In addition to lymph nodes, ES most often metastasizes to the lungs, bone, and brain, and less commonly to the scalp, kidneys, musculoskeletal system, digestive tract, and liver.

2) Outcomes for patients with ES should be optimized through multidisciplinary management.

The diagnosis and treatment ofSTSs are highly nuanced and require collaboration between experienced pathologists, surgeons, and medical and radiation oncologists (Figure 2). Multidisciplinary management of STSs, including ES, is essential to improve patient outcomes.¹³ Clinicians are biased to recommend the treatment modality they specialize in providing, and patients with STSs who receive care through a multidisciplinary team are more likely to receive multiple therapeutic modalities.^14,15

Surgery with or without radiation therapy is the mainstay of treatment for localized ES, whereas the use of perioperative therapy remains controversial.⁶ A retrospective study of 98 patients with local or locally advanced ES reported on outcomes of management with resection, isolated limb perfusion, radiation, and chemotherapy.¹⁶ The median disease-free survival was 54.5 months, with a 5-year overall survival rate of 71%. Locally advanced disease, size greater than 5 cm, and R1 surgical margins were associated with a poor prognosis.

Treatment of advanced ES with anthracycline- or gemcitabine-based chemotherapy can be considered based on retrospective studies of small numbers of patients.^17,18 Investigators of an observational study collected data on patients with advanced ES from 17 sarcoma centers in Europe, the United States, and Japan.¹⁹ This multi-institutional case series study reported outcomes for patients who received anthracycline-based chemotherapy (n = 85), gemcitabine-based chemotherapy (n = 41), or pazopanib (n = 18) between 1990 and 2016. Although the retrospective design and small number of participants for this study preclude formal statistical comparisons, the chemotherapy regimens had higher objective response rates (ORRs; 22% and 27% for anthracycline and gemcitabine regimens, respectively) and median progression-free survival (PFS; 6 and 4 months for anthracycline and gemcitabine regimens, respectively) compared with pazopanib (ORR, 0%; PFS, 3 months). A multicenter, US-based retrospective real-world study of 74 patients receiving systemic therapy for advanced ES, including anthracycline-based (54.1%) and gemcitabine-based (24.3%) regimens, reported limited response with available regimens.²⁰ For example, first-line therapies were associated with an ORR of just 14.9% with a disease control rate of 20.3%, a median duration of response of 14.5 weeks, and a median overall survival of 66.3 weeks.

3) ES are rare tumors, and clinical trial enrollment should be considered for all patients with this disease to investigate and expand access to novel therapies.

Inactivation of SMARCB1 with loss of INI1 confers oncogenic dependency on EZH2 (Figure 3).^21,22 INI1 expression is absent in more than 90% of conventional, proximal, and hybrid ESs.²³ A cohort of a phase 2 basket study (NCT02601950) of tazemetostat evaluated the efficacy and safety of this oral selective EZH2 inhibitor for 62 patients with advanced ES, including 44% of patients with proximal disease and 61% with at least 1 prior systemic anticancer therapy.²⁴ Enrolled patients had disease that was negative for INI1 expression and/or had a biallelic SMARCB1 alteration. Nine patients (15%) had an objective response at data cutoff, and 16 patients (26%) had disease control at 32 weeks. Grade 3 or worse treatment-related adverse events included anemia (6%) and weight loss (3%), and 2 patients developed treatment-related serious adverse events (seizure and hemoptysis). In 2020, the FDA granted accelerated approval for tazemetostat for patients 16 years and older with metastatic or locally advanced ES not eligible for complete resection.⁵

Tazemetostat remains the only (category 2A) recommended treatment specifically for ES, and clinical trial enrollment should be considered for all patients with this rare, understudied disease.⁶ Trials evaluating combination frontline therapies for ES are ongoing, including a study of tazemetostat in combination with doxorubicin (NCT04204941).²⁵

Key References

3. Thway K, Jones RL, Noujaim J, Fisher C. Epithelioid sarcoma: diagnostic features and genetics. Adv Anat Pathol. 2016;23(1):41-49. doi:10.1097/pap.0000000000000102

19. Frezza AM, Jones RL, Lo Vullo S, et al. Anthracycline, gemcitabine, and pazopanib in epithelioid sarcoma: a multi-institutional case series. JAMA Oncol. 2018;4(9):e180219. doi:10.1001/jamaoncol.2018.0219

24. Gounder M, Schöffski P, Jones RL, et al. Tazemetostat in advanced epithelioid sarcoma with loss of INI1/SMARCB1: an international, open-label, phase 2 basket study. Lancet Oncol. 2020;21(11):1423-1432. doi:10.1016/s1470-2045(20)30451-4

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CME POSTTEST QUESTIONS

1) Which of the following is the molecular hallmark of epithelioid sarcoma?

A. Alteration of INI1 and increase in SMARCB1 expression

B. Deletion of SMARCB1 and loss of INI1 expression

C. Fusion of SMARCB1 and INI1

D. Mutation of SMARCB1 and increase in INI1 expression

2) SA is a 24-year-old man who presents with a history of a slowly enlarging mass on the medial aspect of his forearm near the wrist, which gradually increased in size and became uncomfortable. MRI of the region demonstrates a well-defined soft tissue nodule within the subcutaneous tissues, measuring up to 4.4 cm. Biopsy confirms a diagnosis of epithelioid sarcoma. A PET scan reveals an 18F-fludeoxyglucose (FDG)-avid mass at the primary site and ipsilateral, mildly hypermetabolic, minimally enlarged axillary lymph nodes measuring up to 1.4 cm; no evidence of distant metastasis is identified. Results of routine laboratory investigations are within normal limits. What is the next step in the management of SA’s condition?

A. Repeat imaging in 6 to 8 weeks to assess the disease’s progression.

B. Resect the primary tumor with axillary lymph node biopsy and/or dissection.

C. Order an MRI of the brain.

D. Initiate palliative chemotherapy.

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