Low-Grade Fibromyxoid Sarcoma

American Joint Committee on Cancer (AJCC) eighth-edition staging is appropriate.

The cytogenetic hallmark of low-grade fibromyxoid sarcoma is the t(7;16)(q33;p11), which is present, often as the sole change, in two thirds of cases. Another 25% show supernumerary ring chromosomes. Both aberrations result in fusion of the 5′ part of the FUS gene in 16p11 with the 3′ part of CREB3L2 in 7q33; a chimeric FUS-CREB3L2 transcript is seen in > 90% of cases. Rare cases have one of the fusion variants FUS-CREB3L1 or EWSR1-CREB3L1. Apart from recurrent microdeletions in association with the t(7;16) chromosomal breakpoints and gain of 7q in cases with ring chromosomes, no recurrent genomic imbalances or single-nucleotide variants have been found in low-grade fibromyxoid sarcoma. The chimeric FUS-CREB3L2 protein functions as an aberrant transcription factor, causing deregulated expression of CREB3L2 target genes. Many of these target genes, such as CD24 and MUC4, are shared with sclerosing epithelioid fibrosarcoma, with which low-grade fibromyxoid sarcoma overlaps with regard to underlying gene fusions but differs with regard to additional genomic imbalances.

Grossly, low-grade fibromyxoid sarcomas are well-circumscribed, fibrous, and often focally mucoid. tumor size ranges from 1 to > 20 cm in greatest dimension.

Low-grade fibromyxoid sarcoma is composed of collagenous hypocellular areas and more-cellular myxoid nodules. An abrupt transition between these two areas is typical. The tumor cells are bland, spindled, and sometimes plump, and they grow in short fascicles or in a whorling pattern. Mitotic activity is generally inconspicuous. Arcades of small vessels and arteriole-sized vessels with perivascular sclerosis are seen. Occasionally, the vessels have a haemangiopericytoma-like pattern. Approximately 30% of cases contain collagen rosettes – a central core of hyalinized collagen surrounded by a cuff of epithelioid tumor cells. In some cases, areas of sclerosing epithelioid fibrosarcoma are present, reflecting the overlap between these two entities. Unusual features (< 10% of cases) include the presence of focal pleomorphism or nuclear atypia, hypercellularity, epithelioid or round cell features, and heterotopic ossification. By immunohistochemistry, tumor cells show strong, diffuse cytoplasmic expression of MUC4, an epithelial glycoprotein, in approximately 99% of cases. MUC4 is highly sensitive and specific for low-grade fibromyxoid sarcoma and sclerosing epithelioid fibrosarcoma among fibroblastic and neural tumors. Expression of EMA is present in 80% of cases and focal expression of SMA in approximately 30%.

Not clinically relevant

Although low-grade fibromyxoid sarcoma shows low rates of recurrence and metastasis in the first 5 years after excision of the primary tumor (10% and 5%, respectively), rates are much higher with long-term follow-up. A large study with long follow-up showed recurrences, metastases, and death from disease in 64%, 45%, and 42% of patients, respectively. Metastases occurred as long as 45 years after primary excision (median: 5 years), and the median interval to tumor-related death was 15 years. The most common metastatic sites are lung and pleura. Histological features generally do not correlate with clinical behavior, although tumors with areas of sclerosing epithelioid fibrosarcoma or round cell morphology tend to pursue a more aggressive clinical course, similar to that expected for sclerosing epithelioid fibrosarcoma.

If MUC4 is negative or not available to confirm the diagnosis, identification of FUS-CREB3L2 (or other rare variants) offers molecular genetic support for the diagnosis.

Essential: alternating fibrous and myxoid areas; bland spindle cells in a whorled or short fascicular growth pattern; diffuse strong MUC4 expression (in nearly all cases).

Desirable: FUS gene rearrangement (in selected cases).