ES epidemiology
ES is a rare and aggressive cancer
ES is a rare and aggressive soft tissue sarcoma with two subtypes: the distal (classical) type, which typically presents as a slow-growing mass in distal extremities (hands, forearms, or feet), and the proximal type, which is more aggressive and occurs in proximal limbs (pelvis, thighs, upper arms, or shoulders).1-5
ES makes up <1% of all soft tissue sarcomas1,3,4
It is twice as common in men as in women1-4
ES primarily affects young adult males aged 10 to 45;1 however, the age range spans from 4 to 90 years, with a median age of 271
ES is an aggressive tumor:1-4 While ~50% of cases are localized at diagnosis, ES has a high recurrence rate (15%-60%) and metastasizes to distant sites in 30%-50% of patients4
ES pathophysiology
ES pathophysiology is complex, with unique differences seen across subtypes
Genetic basis
The key genetic alteration in ES is inactivation of the SMARCB1 gene, which codes for the INI1 protein.4
This inactivation usually happens through homozygous deletions or mutations, resulting in loss of INI1 protein expression.6
Cellular mechanism
Loss of INI1 protein expression drives:
- Elevated expression of cell cycle regulatory proteins and disruption of the cell cycle.4
- Enhanced cell survival.4
- Ultimately, the development and progression of a tumor.4
ES tumor characteristics
An ES lesion is a slow-growing mass of epithelioid and spindle cells arranged in multiple nodules1,2,4,5
An ES tumor can arise in the dermis, subcutis, or deep fascia1,2,6
ES tumors may invade surrounding structures and may also cause ulceration due to their aggressive nature and proximity to the skin's surface1-3
Pathophysiological variation seen across ES subtypes
There are two ES subtypes – a more common, less aggressive distal (classical) type and a rarer, more aggressive proximal type.1-5,7
Each subtype has distinct clinical and pathophysiological features.1-5,7
Distal type
Tumor location: Subcutaneous or deep dermal mass in distal extremities,4 particularly fingers and hands1-5,7
Age of onset: Typically occurs in younger patients (20-40 years)2-4,7
Sex: Male-to-female ratio of 2:11,2,4
Presentation: A superficial, slow-growing solid nodule or cluster of nodules, which may become ulcerated.4,5 As the tumor invades, it compresses tendon sheaths and neurovascular bundles, causing pain, paresthesia, and restricted movement8
Behavior: Less aggressive, with lower recurrence and metastasis rates, leading to a better prognosis and lower mortality compared with proximal ES5,7
Growth pattern: Nodular or lobular structure, surrounded by polygonal epithelioid cells with abundant eosinophilic cytoplasm, creating a granuloma-like appearance.1,2,4,5,7 Central necrosis, hemorrhage, and cystic changes of nodules are common7
Proximal type
Tumor location: Proximal limbs, pelvis, perineum, and genital tract1-5,7
Age of onset: Can affect older patients (20-65 years)2-4,7
Sex: Male-to-female ratio of 1.6:14
Presentation: Commonly associated with hemorrhage and necrosis; as the tumor progresses, it may be associated with site-specific symptoms, including bleeding, pain, and organ dysfunction5,9
Behavior: More aggressive than distal ES, with a higher rate of recurrence and earlier metastasis4,5,7
Growth pattern: Cellular nodules with increased cytologic pleomorphism, nuclear atypia, and rhabdoid morphology, characterized by prominent nucleoli1,2,4,5,7
ES progression
ES progression is unpredictable
The ES disease course is unpredictable, with the potential for rapid progression, extensive lymph node or distant metastasis, and a high likelihood of local recurrence.1-4
Pattern of spread
ES is locally invasive and frequently metastasizes to regional lymph nodes and distant areas of the body.1-5 ES has a unique tendency to spread through the lymphatic system, distinguishing it from other sarcomas.1,3,4
Local invasion:
ES spreads along the fascia and muscles, often leading to multiple tumor sites.3
Localized lesion growth can damage surrounding tissues, nerves, blood vessels, and bones, leading to skin, soft tissue, and skeletal destruction. This can lead to a significantly wider area of involvement than is visible at presentation.1
At diagnosis, local spread may present as multiple nodules.1,3,5
Metastasis:
ES commonly metastasizes through subdermal lymph vessels and via the bloodstream.3,10
The most common sites of metastases are the lymph nodes, lungs, bones, brain, and skin.1,3,5
Metastasis to regional lymph nodes and distant sites affects up to 50% of patients.1,11,12
Proximal-type ES has a higher risk of early metastasis and worse outcomes compared with the distal type.4,5
Recurrence:
ES is characterized by a high rate of recurrence after initial treatment. This is due to its aggressive behavior, ability to infiltrate surrounding tissues, and potential for both local and distant spread.1-5
Recurrence rates of around 40%-60% have been reported.1,12
Recurrence usually happens within 1 to 2 years but can happen at any time after treatment, making long-term monitoring essential.1,5
Proximal-type ES has higher recurrence rates and worse outcomes than the distal type.3
Age at diagnosis
Local recurrence
Outcomes in ES may be negatively impacted by several clinical and pathological factors.1,3,5,11,14,15
Click the cards for a quick recap on important factors contributing to patient outcomes.
Tumor size
Tumors >5 cm are associated with increased risk of recurrence and metastasis and a poorer prognosis11
Tumor stage
Advanced stage ES substantially decreases survival15
Tumor depth
Deep-seated tumors can be more challenging to resect and are associated with a poorer prognosis15
Tumor Location
Tumors in deep or proximal locations are associated with increased risk of metastasis and are linked to poor outcomes15
metastasis
The presence of metastases at diagnosis adversely impacts survival15
Patient Age
ES diagnosed in older adults behaves more aggressively, and is associated with a poorer prognosis15
Recurrence
Recurrence indicates aggressive disease and is associated with worse outcomes11
- Needs T, Fillman EP. Epithelioid sarcoma. Updated July 2, 2024. Available at https://www.ncbi.nlm.nih.gov/books/NBK532911/. Accessed February 2025.
- Czarnecka AM, Sobczuk P, Kostrzanowski M, et al. Epithelioid sarcoma – from genetics to clinical practice. Cancers. 2020;12:2112.
- Czarnecka AM. Epithelioid sarcoma. NOWOTWORY J Oncol. 2023;73:154-161.
- Del Savio E, Maestro R. Beyond SMARCB1 Loss: Recent insights into the pathobiology of epithelioid sarcoma. Cells. 2022;11(17):2626.
- Krotewicz M, Czarnecka AM, Błoński P, et al. Distal and proximal epithelioid sarcoma - differences in diagnosis and similarities in treatment. Oncol Clin Pract. 2024;99119.
- Dermawan JK, Singer S, Tap WD, et al. The genetic landscape of SMARCB1 alterations in SMARCB1-deficient spectrum of mesenchymal neoplasms. Mod Pathol. 2022;35:1900-1909.
- Li Y, Cao G, Tao X, et al. Clinicopathologic features of epithelioid sarcoma: Report of seventeen cases and review of literature. Int J Clin Exp Pathol. 2019;12:3042-3048.
- Alexander L. Epithelioid sarcoma of upper extremity: Diagnostic dilemma with therapeutic challenges. Cureus. 2021;13(3):e14156.
- Ahmad Z, Stanazai Q, Wright S, et al. Primary pleural epithelioid sarcoma of the proximal type: a diagnostic and therapeutic challenge. Transl Lung Cancer Res. 2019;8(5):700-705.
- Sobanko JF, Meijer L, Nigra TP. Epithelioid sarcoma: a review and update. J Clin Aesthet Dermatol. 2009;2:49-54.
- de Visscher SA, van Ginkel RJ, Wobbes T, et al. Epithelioid sarcoma: Still an only surgically curable disease. Cancer. 2006;107(3):606-612.
- Halling AC, Wollan PC, Pritchard DJ, et al. Epithelioid sarcoma: a clinicopathologic review of 55 cases. Mayo Clin Proc. 1996;71(7):636-642.
- Grunewald TGP, Postel-Vinay S, Nakayama RT, et al. Translational aspects of epithelioid sarcoma – current consensus. Clin Cancer Res. 2024;30(6):1079-1092.
- Zhang S, Jing C, Liu H, et al. Epithelioid sarcoma: A single-institutional retrospective cohort study of 36 cases. J Orthop Surg. 2021;29(3):1-10.
- Jawad MU, Extein J, Min ES, et al. Prognostic factors for survival in patients with epithelioid sarcoma: 441 cases from the SEER database. Clin Orthop Relat Res. 2009;467(11):2939-2948.