Epithelioid Sarcoma

Epithelioid sarcoma is a rare soft tissue sarcoma characterized by malignant cells that resemble the epithelium that lines the surfaces and cavities of the body, a so-called epithelioid cytomorphology. Epithelioid sarcoma typically affects young adults, particularly males, 20 to 40 years old. There are two subtypes: the conventional type, commonly found in hands, forearms, and lower legs, and the proximal-type variant, occurring in proximal extremities, trunk, and genital areas. This sarcoma presents with a nodular or multinodular growth pattern and follows an aggressive disease course with high rates of local recurrence and distant metastasis, particularly to lymph nodes and lungs. Wide surgical excision is the primary treatment, often supplemented with radiation and/or chemotherapy.

Epidemiology

Epithelioid sarcoma is very rare and accounts for less than 1% of soft tissue sarcomas. The incidence is less than 0.5 per million people. It is, however, the most common soft tissue sarcoma found in the forearm and hand. While epithelioid sarcoma can occur at any age, it tends to occur in young adults between 10 and 40 years of age with a median age of about 25 years. There is a slight male predominance with a ratio of 1.5 to 1. The conventional form is twice as common as the proximal type. The conventional form often presents in acral regions, with over 60% arising in the fingers and hand, followed by the distal lower extremity. Proximal epithelioid sarcoma is often seen in the deep soft tissue of proximal/truncal regions and tends to occur in older individuals.

Clinical Features

Epithelioid sarcoma can occur in either superficial or deep locations. Conventional epithelioid sarcoma most often presents as a slow-growing solitary mass or as multiple painless, superficial, firm nodules, which can result in non-healing skin ulcers. Because this tumor can crawl along fascial planes without the formation of a dominant mass, epithelioid sarcoma is often misdiagnosed as a non-malignant lesion and treated with repeated intralesional procedures before the correct diagnosis is established. In the extremities, growth can occur along fascial planes, tendons, and aponeuroses with long “tails” of tumor extension. Both conventional and proximal-type epithelioid sarcoma can occur in deep soft tissues and become larger and more infiltrative as they grow. In contrast to most soft tissue sarcomas, epithelioid sarcoma can metastasize to the lymph nodes, with rates exceeding 15% in some series.

Radiologic Features

Plain radiographs are an important step in the work-up of epithelioid sarcoma, as they can demonstrate bony erosions and, occasionally, calcifications within the soft tissue mass. An MRI with and without contrast is essential to assess the extent of the disease and for surgical planning, but it is not diagnostic as most soft tissue sarcomas look relatively similar on MRI. Epithelioid sarcoma is generally dark on T1-weighted images, bright on fat-suppressed T2-weighted images, and enhances on post-contrast images, similar to other soft tissue sarcomas (Figure 1A-C). A whole-body PET-CT scan is important for staging and can detect lymph node spread; however, a PET-CT scan is not sensitive for small-volume metastatic nodal disease. The role of sentinel lymph node biopsy in patients with localized disease after appropriate staging studies is unclear, and the decision regarding its indication should be made in a multi-disciplinary fashion on a case-by-case basis. A CT scan of the chest for staging is indicated if PET scanning is not obtained.

Figure 1A-C: Sagittal T1 (a), sagittal fat-suppressed T2 (b), and sagittal post-contrast fat-suppressed T2, (c) demonstrate epithelioid sarcoma of the anterior ankle, with uniform hypointensity on T1, hyperintensity on T2, and uniform internal contrast enhancement.

Pathology

In conventional epithelioid sarcoma, low-power histologic images show a nodular pattern of epithelioid and spindle cells with central degeneration that resembles granuloma formation, known as granulomatous necrosis. While epithelioid sarcoma is a tumor of mesenchymal origin (as are all sarcomas), it is a biphasic tumor containing cells that stain with both mesenchymal and epithelial markers (similar to synovial sarcoma and adamantinoma) with some of its cells having an epithelioid appearance (Figure 2), as the tumor’s name implies. As such, some epithelioid sarcoma cells stain positive for epithelial membrane antigen as well as mesenchymal markers such as CD34 and vimentin. (CD34 is positive in only approximately 50% of cases, making it a useful but imperfect marker.) High-power images of epithelioid sarcoma show plump spindle cells and large, ovoid epithelioid cells that lack the classic spindle shape of sarcoma cells and have eosinophilic cytoplasm. Mitotic activity tends to be low, and dystrophic calcifications can be seen in 20% of cases.

Figure 2: High power H&E stains of epithelioid sarcoma showing polygonal shaped epithelioid cells with irregular nuclei and abundant cytoplasm. (Image courtesy of Dr. Gord Zhu)

The proximal type of epithelioid sarcoma lacks the granulomatous pattern of necrosis and is characterized by a multinodular and sheet-like growth pattern; it can also demonstrate rhabdoid differentiation demonstrated by immunohistochemical stain positivity for muscle markers. Immunohistochemistry studies of both types are strongly positive for epithelial markers such as keratin and EMA as well as mesenchymal markers such as CD34 and vimentin. Approximately 90% of cases will show the loss of the INI-1 gene. INI-1, integrase interactor 1, is a tumor suppressor gene also known as SMARCB1. Loss of INI-1 expression is a characteristic finding in epithelioid sarcoma, indicating a disruption in chromatin remodeling and gene expression regulation.

Differential Diagnosis

Epithelioid sarcoma is often confused with benign tumors in the distal extremities such as giant cell tumor of the tendon sheath, nodular fasciitis, granulomatous disease, fibrohistiocytic lesions, and fibromatosis. The differential diagnosis of larger, deep-seated epithelioid sarcoma includes synovial sarcoma, melanoma, metastatic carcinoma, malignant peripheral nerve sheath tumors, and extrarenal rhabdoid tumor.

Disease Course: Treatment and Prognosis

The mainstay of treatment for epithelioid sarcoma is wide resection, often employing neoadjuvant or adjuvant radiation and occasionally chemotherapy. The stage at diagnosis, the site of disease, and the subtype of the tumor influence prognosis. The overall 5-year and 10-year survival rates for epithelioid sarcoma are approximately 70% and 50%, respectively. Metastases develop in 40 to 50% of patients, and the 5-year risk of local recurrence is 35% or more. In patients presenting with localized disease, negative-margin resection can be curative. The Children’s Oncology Group and the European Pediatric Soft Tissue Sarcoma Group found a poor prognosis associated with locoregional nodal involvement, invasive tumors, high grade, and positive margins at the time of surgery. The 5-year survival rate for patients with low-risk disease was more than 85%, compared to approximately 60% for intermediate-risk and 0% for high-risk disease, even with the use of neoadjuvant and adjuvant chemotherapy and radiation. Recurrences have been reported as late as 20 years after initial surgery; imaging annually for ongoing surveillance may be justified.

One large study using data collected by the National Cancer Institute reviewed the outcomes of over 400 patients with epithelioid sarcoma. The 5-year survival rate for patients with localized disease was 75%; for those with regional disease it was 49%; and there were no 5-year survivors for those who presented with metastatic disease. Interestingly, location was strongly associated with survival; patients with deep axial disease had an approximate 40% 5-year survival rate compared to 65% for those with superficial, axial tumors. Extremity epithelioid sarcomas fared better overall, with those in a superficial appendicular location having an approximately 80% 5-year survival compared to around 70% for those with deep, appendicular tumors.

The loss of INI-1 is currently being investigated as a therapeutic target. Tazemetostat, a potent and selective EZH2 inhibitor, has shown promising results in early-phase clinical trials for patients with metastatic disease

Key Test Topics

Epithelioid sarcoma is the most common soft tissue sarcoma found in the upper extremity and a majority of the conventional subtype occurs in the fingers and hands.
Unlike most soft tissue sarcomas, epithelioid sarcoma can metastasize to lymph nodes.
Regional and metastatic spread predicts a poor outcome.
90% of epithelioid sarcoma have loss of INI-1.
Epithelioid sarcoma is a biphasic tumor which shows positive staining with both mesenchymal and epithelial markers (similar to synovial sarcoma and adamantinoma).