Epithelioid Sarcoma

Epithelioid sarcoma is a rare malignant soft tissue tumour of uncertain differentiation, best known as the most common soft tissue sarcoma of the hand and distal forearm in young adults and as a notorious mimic of benign disease. The World Health Organization now classifies it among the INI1 (SMARCB1)-deficient tumours, reflecting the loss of nuclear INI1 expression seen in the large majority of cases.

Who gets it. It accounts for under 1% of all soft tissue sarcomas, with a male predominance in most series. The distal (classic) type typically presents at 20-40 years; the proximal type tends to occur in older patients.

Where it arises. Site tracks the variant, and the lesion is frequently superficial.

• Distal upper limb - hand, fingers and forearm, the classic type
• Distal lower limb - foot, ankle and lower leg
• Proximal and axial sites - pelvis, perineum, genitalia and buttock, the proximal type
• Often dermal or subcutaneous, tracking along fascia and tendon

The delay is the clinical problem. Because it grows slowly and looks unremarkable, patients are repeatedly treated for benign disease for months to years - a granuloma, a chronic abscess, a wart, a Dupuytren nodule or a non-healing ulcer. Any persistent, firm or ulcerating lesion of the distal limb in a young adult must be biopsied rather than observed.

Two variants, not one tumour. Guillou and colleagues defined the proximal-type variant as a distinctive, more aggressive neoplasm showing rhabdoid features, in contrast with the conventional distal type. The pair differ in age, site, architecture and behaviour.

A tumour with an epithelial face. Epithelioid sarcoma is of uncertain differentiation but shows partial epithelial differentiation, co-expressing keratins with the mesenchymal marker vimentin. The morphology carries the same duality, epithelioid cells with a spindled component alongside them.

The defining event. Loss of function of SMARCB1 (INI1), a core subunit of the SWI/SNF chromatin-remodelling complex that normally acts as a tumour suppressor. SMARCB1 - also called INI1, SNF5 or BAF47 - is encoded at 22q11.2, and biallelic inactivation leaves no nuclear protein to stain: loss of nuclear INI1 on immunohistochemistry is demonstrable in over 90% of cases.

Why the loss is targetable. SMARCB1 loss removes the normal antagonism of EZH2, a transcriptional repressor, and the tumour becomes oncogenically dependent on it. That dependence is the rationale for the EZH2 inhibitor tazemetostat. A minority of cases retain INI1, and in those other SWI/SNF subunits may be abnormal.

Distal type: the granuloma trap. Nodules of tumour cells with central necrosis are the classic architecture, and at low power they resemble a necrotising granuloma such as a rheumatoid nodule or an infection. The cells track along fascia, tendon sheaths and dermis, and that slow infiltrative spread is what makes recurrence so common.

• A mixture of epithelioid and spindle cells, with transition between the two forms; the peripheral spindle-cell component can be conspicuous
• Eosinophilic cytoplasm, with relatively bland to moderate atypia
• Mitoses present, but they may be inconspicuous

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Proximal type: sheets of rhabdoid cells. Deeper and larger multinodular masses of large cells with frequent necrosis, in which the granuloma-like pattern is usually absent. The cells are rhabdoid - eccentric nuclei with inclusion-like cytoplasm - with marked nuclear atypia, prominent nucleoli, and higher grade and mitotic activity, which is where the morphological overlap with malignant rhabdoid tumour comes from.

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The immunoprofile. One stain is read for loss; the rest are read for expression.

Keratin and EMA positivity with CD34 positivity and INI1 loss together is highly characteristic, because true carcinomas are almost always CD34 negative. CD34 is variably expressed, though, so a negative result does not exclude epithelioid sarcoma; keratin expression plus INI1 loss and compatible morphology carries more weight.

The differential. The entities that overlap morphologically are separated by the immunopanel and by the clinical setting.

The typical story. The commonest presentation is a firm, painless nodule in skin or subcutis, usually in the hand, fingers or forearm of a young adult, enlarging slowly and sometimes with satellite nodules around it. A non-healing ulcer over such a nodule is the classic picture and the most misleading one.

What should raise suspicion. The history is usually longer than the lesion looks.

• Symptoms for months to years before diagnosis
• A lesion already "treated" as a wart, an abscess, a granuloma or Dupuytren disease
• Recurrence after a presumed benign excision
• Palpable regional lymph nodes

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Examination of the lesion. Inspect for nodules, ulceration, the scar of a previous excision, and satellite lesions running along lymphatics or fascia; the site itself is a clue, since a distal limb lesion favours the classic type. Palpate for consistency - firm to hard, and fixed to deep tissue where it is infiltrative, with mild tenderness at most - and for the relationship to tendons and neurovascular structures.

Then examine the nodes, every time. Palpate the draining basin, epitrochlear, axillary or inguinal, because nodal metastasis is a recognised pattern in this tumour, and document any palpable node so it can be staged and biopsied. Finish with neurovascular status distal to the mass and with joint movement and hand function, which is the baseline against which any reconstruction is planned.

Core needle biopsy at, or after discussion with, a specialist sarcoma centre is the standard. Plan the tract so that it can be excised en bloc at definitive surgery; the biopsy is part of the operation.

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Grading and staging use the same framework as any extremity or trunk soft tissue sarcoma, read with this tumour's habits in mind.

Treatment by scenario. Wide local excision with negative margins is the priority in every row of the table below. Biopsy-proven nodal disease adds a therapeutic node dissection at a sarcoma centre, and systemic therapy belongs to unresectable, metastatic or relapsed disease.

Plan the resection from the MRI, en bloc. The infiltrative, multinodular pattern demands it rather than shelling out the visible mass.

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Where radiotherapy fits. It is considered for close or positive margins, for large or recurrent tumours, and in anatomically constrained sites, and it can be delivered stereotactically to oligometastases. It does not replace adequate surgery when a clear margin is achievable.

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Systemic therapy and the EZH2 target. The dependence of INI1-deficient epithelioid sarcoma on EZH2 has been translated into a licensed targeted therapy. The EZH2 inhibitor tazemetostat was studied in a phase 2 basket of 62 patients with advanced INI1-negative disease: the objective response rate was 15% and median progression-free survival 5.5 months, but the responses that occurred were durable (median duration not reached) and the drug was well tolerated, which is what drove regulatory approval for advanced disease not amenable to complete resection. Say it plainly: tazemetostat is a well-tolerated disease-control drug with a low response rate, not a tumour-shrinking one - and conventional anthracycline-based chemotherapy is in the same position, so the choice in the palliative setting is genuinely open.

Failure comes by the same three routes as spread, with time added: relapse can arrive years after treatment.

Unusual metastatic sites do occur, and are pursued with symptom-directed cross-sectional imaging.

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The factors that predict outcome fall into three groups: what the tumour is (variant, grade, the presence of rhabdoid cells), where it sits (superficial and small against deep and large), and what has happened to it (the margin achieved, the nodes, distant disease).

One reconciliation is worth noticing. The multi-institutional series of 44 patients in the evidence base found that the proximal subtype only trended towards a worse outcome and the difference did not reach significance, while nodal and distant metastasis were independent predictors. The variant colours the prognosis; the metastatic status settles it.

Global Epidemiology

Side-by-Side Principles from Major Sarcoma Frameworks

High- vs Limited-Resource Practice Variation