Sclerosing Epithelioid Fibrosarcoma

Union for International Cancer Control (UICC) or American Joint Committee on Cancer (AJCC) staging is appropriate.

Sclerosing epithelioid fibrosarcoma usually displays a near-diploid karyotype with multiple chromosomal rearrangements. tumors consistently harbor translocations resulting in gene fusions, the most frequent (> 60%) of which is EWSR1-CREB3L1. In rare cases, EWSR1 is exchanged for FUS or PAX5 and/or CREB3L1 for CREB3L2, CREB3L3, or CREM. The most common of these variant fusion partners is FUS, which is involved in 10% of cases with pure sclerosing epithelioid fibrosarcoma morphology. Furthermore, most so-called hybrid sclerosing epithelioid fibrosarcomas/low-grade fibromyxoid sarcomas display a FUS-CREB3L2 chimera, identical to that seen in most low-grade fibromyxoid sarcomas. Sclerosing epithelioid fibrosarcoma and low-grade fibromyxoid sarcoma also have overlapping gene expression profiles, for example, with high expression of MUC4 and CD24 in both tumors. In contrast to low-grade fibromyxoid sarcoma, however, both pure and hybrid sclerosing epithelioid fibrosarcoma cases typically have complex genomic profiles, including deletions/copy-neutral loss of heterozygosity at chromosome arm 11p, loss of chromosome 22, and intragenic deletions of the DMD gene. No recurrent single-nucleotide variant has been detected. A small subset of sclerosing epithelioid fibrosarcomas do not have MUC4 expression or harbor any of the above fusion genes; little is known about the molecular pathogenesis of this group.

Sclerosing epithelioid fibrosarcoma is usually well circumscribed, is lobular or multilobulated, and involves deep musculature and fascia. Periosteal adherence is common, and there is occasionally erosion of underlying bone. The cut surface is firm and white. Areas of calcification may be present. Most tumors are < 10 cm, but occasional cases measure > 20 cm.

The margins of sclerosing epithelioid fibrosarcoma are typically infiltrative into muscle, fascia, or periosteum. A characteristic feature is a prominent hyalinized sclerotic collagenous stroma, within which relatively bland and monomorphic epithelioid cells are arranged in cords, nests, or occasionally sheets. Some tumors contain more cellular fascicular areas. Pseudoalveolar or acinar growth patterns are occasionally seen. Hypocellular areas with myxoid or fibrous stroma are common. The tumor cells usually have clear cytoplasm and inconspicuous nucleoli.
Unusual features include marked pleomorphism, necrosis, prominent mitotic activity, and haemangiopericytoma-like vessels. Calcifications or chondro-osseous differentiation may be seen. Areas of conventional low-grade fibromyxoid sarcoma may be present. Rarely, the sclerotic stroma is absent in large areas of the tumor in either sclerosing epithelioid fibrosarcoma or low-grade fibromyxoid sarcoma, making recognition difficult. Clues to the diagnosis in such cases include the relatively monomorphic appearance of the tumor cells and the presence of MUC4 expression in the absence of keratin expression, which would be unusual for carcinoma.
MUC4 expression is present in 80–90% of cases and is strong, diffuse, and cytoplasmic. Expression of EMA and SMA is present in approximately 40% of cases. Keratins are typically negative, which is helpful in the differential diagnosis with carcinoma.

Not clinically relevant

Sclerosing epithelioid fibrosarcoma pursues a more aggressive clinical course than the related low-grade fibromyxoid sarcoma, with recurrences (often multiple) in about 50% of cases. Metastases are common, occurring in 40–50% of cases to lung, pleura, bone, and brain. Poor prognostic features include large tumor size and proximal location. Whether sclerosing epithelioid fibrosarcoma that arises in the context of low-grade fibromyxoid sarcoma has the same prognosis has not yet been established.

Demonstration of EWSR1-CREB3L1 or other rearrangements can help confirm the diagnosis. For cases with characteristic morphology and MUC4 expression, additional molecular studies are not needed.

Essential: epithelioid cells arranged in cords, nests, or trabeculae and embedded in a dense sclerotic hyalinized stroma; diffuse strong MUC4 expression (in most cases); keratin-negative.

Desirable: EWSR1-CREB3L1 or other rearrangements (in selected cases).