Diagnostic tests for ES
Early diagnostic testing and timely diagnosis may lead to better patient outcomes1-6
Early diagnosis may improve patient outcomes,1-6 as advanced-stage, invasive, and metastatic ES may be associated with a poor prognosis.6-8
However, diagnosing ES may be clinically challenging due to its rarity, slow growth, and resemblance to benign conditions or other types of sarcoma, which may lead to delays in diagnosis or misdiagnosis.1,2,4-9
Non-sarcoma specialists rarely encounter ES, and clinical suspicion can be low2,5
Because ES is rare, it is seldom encountered by non-sarcoma specialists and the journey from symptom onset to diagnosis is complex;3,5-9 ES has an unpredictable course, and patients frequently present with advanced disease, including lymph node involvement or distant metastases.7,8
Due to its rarity, ES is seldom seen in clinical practice and is often misdiagnosed as a benign condition, leading to delays in definitive treatment.2,7,8
Seeking expert support and timely referral to a specialist multidisciplinary team (MDT) or a specialist sarcoma center is critical for early diagnosis and treatment.5,6,10-16
Healthcare professionals should remain highly vigilant to ensure timely and accurate diagnosis.2,6
Seeking expert support and timely referral to a specialist multidisciplinary team (MDT) or a specialist
sarcoma center is critical for early diagnosis and treatment
Testing of ES requires different evaluations:
Patients typically present with a firm, painless, slow-growing mass, most commonly on distal extremities (distal type) or alternatively, proximal limbs (proximal type), which may be accompanied by other nonspecific signs or symptoms.6-8,17,18
- A physical examination can help determine the approximate tumor size, its proximity to surrounding structures, signs of invasion, and any changes to the overlying skin.6
- A physical examination can help determine the approximate tumor size, its proximity to surrounding structures, signs of invasion, and any changes to the overlying skin.6
Imaging to visualize the extent of the lesion(s), stage local and distant spread, and guide biopsy.6,12-16
Imaging tests may include magnetic resonance imaging (MRI), computed tomography (CT), or a positron emission tomography (PET)-CT scan.6,12-16
An X-ray may be appropriate in selected cases.12
Imaging tests may include magnetic resonance imaging (MRI), computed tomography (CT), or a positron emission tomography (PET)-CT scan.6,12-16
An X-ray may be appropriate in selected cases.12
A tissue biopsy is essential for accurate diagnosis, providing the material for important histopathological and immunohistochemical (IHC) evaluations.6,7,12-16
Image-guided core needle biopsy is generally preferred; however, an excisional biopsy may be a more practical option in some cases.6,12,14-16
If clinical examination reveals suspicious lymph nodes, these should also be biopsied.6,7
A biopsy is required for IHC analysis of expression of INI1, a tumor suppressor protein encoded by the SMARCB1 gene and a key diagnostic marker for ES.6-8,12
Image-guided core needle biopsy is generally preferred; however, an excisional biopsy may be a more practical option in some cases.6,12,14-16
If clinical examination reveals suspicious lymph nodes, these should also be biopsied.6,7
A biopsy is required for IHC analysis of expression of INI1, a tumor suppressor protein encoded by the SMARCB1 gene and a key diagnostic marker for ES.6-8,12
Given its variable presentation and potential for misdiagnosis, a comprehensive histological evaluation, including morphology and immunohistochemical (IHC) profiling, is required for accurate identification of ES.2,6-8
Morphologic assessment of histologic sections remains the gold standard for diagnosis, and these should be reviewed by a pathologist specializing in soft tissue sarcomas.12
Since identification of the histopathologic type of sarcoma can be difficult, IHC and molecular genetic testing may also be used.12
- IHC analysis of expression of INI1, a tumor suppressor protein encoded by the SMARCB1 gene, serves as a crucial diagnostic marker for ES.6–8,12
- INI1 loss, in addition to the unique combination of histological/morphological characteristics, is highly specific to ES.6–8
- Although loss of INI1 expression is a hallmark of both distal-type and proximal-type ES, occurring in over 90% of cases,19 rare instances of INI1 positivity have been reported.20
- INI1 loss is also an important diagnostic feature of extrarenal rhabdoid tumors (ERT).12
- Molecular genetic testing has become an important additional diagnostic tool in challenging cases, as INI1 loss is defined by genetic alterations.7,8,12
Microscopic histology helps in differentiating between ES subtypes
ES subtypes are not strictly defined by their typical anatomical sites, as either can occur proximally and/or distally; as such, histological features, not tumor location, define the ES subtypes.6-8,17,18
Both ES subtypes share certain consistent IHC characteristics6,21
Both distal and proximal ES typically show strong IHC expression of cytokeratin, epithelial membrane antigen (EMA), vimentin, and often CD34, with negative staining for INI1, S100, FL11, S100, desmin, and CD31.6,21
The absence of INI1 expression is a key diagnostic marker.6,21
Distal ES6,7,17 |
Proximal ES6,7,17 |
|---|---|
|
Nodular/lobular architecture |
Lacks granulomatous necrosis pattern |
|
Central necrosis surrounded by polygonal epithelioid cells with relatively abundant cytoplasm |
Cellular nodules with increased pleomorphism |
|
Granulomatous-like appearance under low power |
Prominent nuclear atypia |
|
Minimal nuclear atypia, few mitotic figures |
Signet-ring-like vacuolation possible |
|
Peripheral spindled/sarcomatous cells |
Rhabdoid morphology with prominent nucleoli |
|
Tumor may resemble angiomatoid, fibromatoid lesions |
May show overlapping features with metastatic carcinoma |
Some histological features may overlap between ES subtypes:6,21
- IHC biomarkers of tumor cells found in both subtypes:
- Positive for cytokeratin, epithelial membrane antigen, vimentin, and often CD346,21
- Negative for INI1, FLI1, S100, desmin, and CD316,21
Interpreting test results for diagnosis:
- IHC (especially INI1 staining) helps differentiate ES from conditions with a similar presentation.6-8
- Correlate findings with the clinical context and presentation for the most accurate diagnosis.6-8
- Consider molecular testing in challenging cases.12
Morphologic assessment of histologic sections remains the gold standard for diagnosis, and these should be reviewed by a pathologist specializing in soft tissue sarcomas.12
Since identification of the histopathologic type of sarcoma can be difficult, IHC and molecular genetic testing may also be used.12
- IHC analysis of expression of INI1, a tumor suppressor protein encoded by the SMARCB1 gene, serves as a crucial diagnostic marker for ES.6-8,12
- INI1 loss, in addition to the unique combination of histological/morphological characteristics, is highly specific to ES.6–8
- Although loss of INI1 expression is a hallmark of both distal-type and proximal-type ES, occurring in over 90% of cases,19 rare instances of INI1 positivity have been reported.20
- INI1 loss is also an important diagnostic feature of extrarenal rhabdoid tumors (ERT).12
- Molecular genetic testing has become an important additional diagnostic tool in challenging cases, as INI1 loss is defined by genetic alteration
Microscopic histology helps in differentiating between ES subtypes
ES subtypes are not strictly defined by their typical anatomical sites, as either can occur proximally and/or distally; as such, histological features, not tumor location, define the ES subtypes.6-8,17,18
Both ES subtypes share certain consistent IHC characteristics6,21
Both distal and proximal ES typically show strong IHC expression of cytokeratin, epithelial membrane antigen (EMA), vimentin, and often CD34, with negative staining for INI1, S100, FL11, S100, desmin, and CD31.6,21
The absence of INI1 expression is a key diagnostic marker.6,21
Interpreting test results for diagnosis:
- IHC (especially INI1 staining) helps differentiate ES from conditions with a similar presentation.6-8
- Correlate findings with the clinical context and presentation for the most accurate diagnosis.6-8
- Consider molecular testing in challenging cases.12
Test your ES diagnostic knowledge
Distal and proximal type ES are not strictly determined by anatomical location, as both types can occur in proximal and distal regions.6,7 Therefore, ES subtypes are defined by histological and morphological characteristics rather than tumor location.6,7,17,18
Distinguishing between distal and proximal ES:
A hypothetical diagnostic challenge
History of presenting symptoms: Slow growing mass on right wrist. Pain and numbness in the affected area, worsening over last 8 months.
Physical examination: Firm, tender 5x4 cm mass.
Imaging: X-ray shows soft tissue swelling without bone involvement; MRI reveals irregular subcutaneous mass on inner aspect of wrist.
Histology and morphological characteristics: The tumor exhibited a nodular/lobular architecture with central areas of necrosis, surrounded by polygonal epithelioid cells with moderate eosinophilic cytoplasm. Low-power microscopy revealed a pseudogranulomatous appearance. Nuclear atypia was minimal, and mitotic figures were not identified. The surrounding stroma was fibrotic, with no significant lymphovascular or perineural invasion observed.
Immunohistochemistry:Positive for cytokeratin, epithelial membrane antigen, vimentin, and CD347. Negative for INI1, S100, desmin, and CD317.
What do you think the diagnosis is in this hypothetical case study?
Correct
- Distal ES exhibits a nodular or lobular architecture with central necrosis surrounded by epithelioid cells containing eosinophilic cytoplasm and resembling a granulomatous lesion under low-power microscopy.6
Incorrect
- Proximal ES lacks the granulomatous pattern of necrosis.6
- It is characterized by cellular nodules with increased cytologic pleomorphism, nuclear atypia, and occasional signet-ring-like vacuolation.6
- A hallmark feature is rhabdoid morphology, often accompanied by prominent nucleoli.6
Differentiating ES
Differentiating ES from other conditions
Distinguishing ES from other differential diagnoses is essential to ensure accurate diagnosis and appropriate treatment.1,2,7,8
Accurately distinguishing ES from other morphologically similar tumors is critical for appropriate diagnosis, treatment, and prognosis.1,2,7,8
ES can mimic benign and malignant conditions, making misdiagnosis a risk that may delay appropriate management.6-8
The importance of distinguishing ES from differential diagnoses
Nodules Nodular growth patterns can mimic other conditions, for example, granulomas or reactive fibrous lesions6-8
Histopathology Mixed mesenchymal and epithelial differentiation can make ES resemble a range of reactive, benign, and malignant conditions6
Location ES can occur in areas commonly affected by other soft tissue tumors and carcinomas6,8
Accurately differentiating ES from other conditions is key to guiding appropriate treatment and improving outcomes.1,2,7,8
Benign/reactive conditions
- Granulomatous diseases.
- Nodular fasciitis.
- Fibrohistiocytic lesions.
- Fibromatosis.
- Tenosynovial giant cell tumors.
Malignant neoplasms
- Metastatic carcinoma.
- Melanoma.
- Synovial sarcoma.
- Vascular neoplasms (e.g., angiosarcoma).
- Spindle cell squamous cell carcinoma.
- Malignant peripheral nerve sheath tumor.
- Extrarenal rhabdoid tumor.
- Zegarra Buitron E, Vidal Panduro DA, Morales Luna D. Clinicopathological characteristics, treatment, and survival in patients diagnosed with proximal-type epithelioid sarcoma: a case report and systematic review. Cureus. 2022;14(12):e32962.
- Alexander L. Epithelioid sarcoma of upper extremity: diagnostic dilemma with therapeutic challenges. Cureus. 2021;13(3):e14156.
- Soomers V, Husson O, Young R, et al. The sarcoma diagnostic interval: a systematic review on length, contributing factors and patient outcomes. ESMO Open. 2020;5(1):e000592.
- Younger E, Husson O, Bennister L, et al. Age-related sarcoma patient experience: results from a national survey in England. BMC Cancer. 2018;18(1):991.
- Recommendations from the Epithelioid Sarcoma Collaborative: A white paper. Available at https://www.jons-online.com/issues/2021/september-2021-vol-12-no-9/3914-recommendations-from-the-epithelioid-sarcoma-collaborative-a-white-paper. Accessed February 2025.
- 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.
- Martin S, Clark SE, Gerrand C, et al. Patients' experiences of a sarcoma diagnosis: A process mapping exercise of diagnostic pathways. Cancers (Basel). 2023;15(15):3946.
- Weaver R, O'Connor M, Carey Smith R, et al. The complexity of diagnosing sarcoma in a timely manner: perspectives of health professionals, patients, and carers in Australia. BMC Health Serv Res. 2020;20(1):711.
- Shakya S, Banneyake EL, Cholekho S, et al. Soft tissue sarcoma: clinical recognition and approach to the loneliest cancer. Explor Musculoskeletal Dis. 2024;2:56-68.
- Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Soft Tissue Sarcoma V.1.2021. © National Comprehensive Cancer Network, Inc. 2024. All rights reserved. Accessed February 17, 2025. To view the most recent and complete version of the guideline, go to NCCN.org.
- von Mehren M, Kane JM III, Bui MM, et al. NCCN Guidelines insights: soft tissue sarcoma, version 1.2021. J Natl Compr Canc Netw. 2020;18(12):1604-1612.
- National Cancer Institute. Soft tissue sarcoma treatment (PDQ®) - health professional version. Available at https://www.cancer.gov/types/soft-tissue-sarcoma/hp/adult-soft-tissue-treatment-pdq. Accessed February 2025.
- Gronchi A, Miah AB, Dei Tos AP, et al. Soft tissue and visceral sarcomas: ESMO-EURACAN-GENTURIS Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2021;32(11):1348-1365.
- Hayes AJ, Nixon IF, Strauss DC, et al. UK guidelines for the management of soft tissue sarcomas. Br J Cancer. 2025;132(1):11-31.
- 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.
- 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(8):3042-3048.
- Hornick JL, Dal Cin P, Fletcher CD. Loss of INI1 expression is characteristic of both conventional and proximal-type epithelioid sarcoma. Am J Surg Pathol. 2009;33(4):542-550.
- Song L, Stashek KM, Benyounes A, et al. Epithelioid sarcoma with retained INI1 (SMARCB1) expression. Histopathology. 2021;78(3):464-466.
- PathologyOutlines.com. Epithelioid sarcoma. PathologyOutlines.com website. Available at https://www.pathologyoutlines.com/topic/softtissueepithelioidsarcoma.html. Accessed February 2025.