Myxofibrosarcoma

The Union for International Cancer Control (UICC) or American Joint Committee on Cancer (AJCC) TNM system is applicable.

Karyotypes are highly complex, with intratumoral heterogeneity and chromosome numbers in the triploid or tetraploid range in most cases, including even grade 1 neoplasms. Progression in grade is accompanied by an increase in cytogenetic aberrations. Local recurrences may show more complex cytogenetic aberrations than the primary neoplasms, suggesting tumor progression.
Recent integrated genomic studies indicate a predominance of somatic copy-number alterations in myxofibrosarcoma, with comparatively lower mutation burdens than many other pleomorphic sarcoma types. These include frequent gains of chromosome 5p, where several oncogenes (TRIO, RICTOR, SKP2, and AMACR) are variably coamplified and potentially associated with increased grade. Occurring almost mutually exclusively, genetic aberrations in p53 signaling and the cell-cycle G1/S checkpoint collectively play a central pathogenetic role in half of myxofibrosarcomas; TP53 (46%; most frequently mutated), RB1 (18%), and CDKN2A/CDKN2B (16%) tumor suppressor gene mutations are more common than CDK6, CCND1, and MDM2 amplifications. Components of driver regulomic pathways also harbor recurrently altered targets, such as missense mutation and amplification of NTRK1 and loss-of-function mutations and homozygous deletion of NF1 in the RTK/RAS/MAPK pathway and amplification of VGLL3 in the Hippo pathway, as well as amplifications of TRIO and RICTOR that activate the RAC/PAK and AKT/mTOR pathways, respectively.

Superficially located neoplasms typically consist of multiple, variably gelatinous or firmer nodules, whereas deep-seated neoplasms often form a single mass with an infiltrative margin. In high-grade lesions, areas of tumor necrosis are often found.

Myxofibrosarcoma shows a broad spectrum of cellularity, pleomorphism, and proliferative activity; however, all cases share distinct morphological features, particularly multinodular growth with incomplete fibrous septa and myxoid stroma. Subcutaneous examples commonly have very infiltrative margins, often extending beyond what is detected clinically. The low-grade end of the morphological spectrum is characterized by hypocellular neoplasms composed of only a few, non-cohesive, plump spindled or stellate tumor cells with ill-defined, slightly eosinophilic cytoplasm and atypical, enlarged, hyperchromatic nuclei. Mitotic figures are infrequent in low-grade lesions. A characteristic finding is the presence of prominent elongated, curvilinear, thin-walled blood vessels with a perivascular condensation of tumor cells and/or inflammatory cells (mainly lymphocytes and plasma cells). Frequently, so-called pseudolipoblasts containing cytoplasmic mucin are noted in the form of vacuolated neoplastic fibroblastic cells. In contrast, high-grade neoplasms are composed partly of solid sheets and cellular fascicles of spindled and pleomorphic tumor cells with numerous, often atypical mitoses, areas of hemorrhage, and necrosis. In many cases, bizarre, multinucleated giant cells with abundant eosinophilic cytoplasm (resembling myoid cells) and irregularly shaped nuclei are noted. However, high-grade lesions also focally show features of a lower-grade neoplasm, with a prominent myxoid matrix and numerous elongated capillaries. The intermediate-grade lesions are more cellular and pleomorphic relative to purely low-grade neoplasms, but they lack well-developed solid areas, pronounced cellular pleomorphism, and necrosis.
The rare epithelioid subtype of myxofibrosarcoma is composed predominantly of atypical epithelioid tumor cells with abundant eosinophilic cytoplasm and round vesicular nuclei arranged in small cohesive clusters in the myxoid areas or forming sheets in the hypercellular areas, mimicking metastatic carcinoma or melanoma. By immunohistochemistry, focal SMA and/or CD34 reactivity is occasionally seen in myxofibrosarcoma, whereas desmin and S100 are negative.

Not clinically relevant

Local, often repeated recurrences, unrelated to histological grade, occur in 30–40% of cases, usually as a result of inadequate surgery, sometimes even in experienced hands. Metastases and tumor-related mortality are closely related to tumor grade. The overall 5-year mortality rate is 30–35%. Although none of the low-grade neoplasms metastasize, high-grade tumors develop metastases in 20–35% of cases. In addition to pulmonary and osseous metastases, lymph node metastases are sometimes seen. Local recurrence within 12 months increases tumor-associated mortality. Given the propensity for relentless local recurrence associated with highly infiltrative growth, aggressive surgery combined with radiotherapy is advised for myxofibrosarcoma in order to achieve improved local control, which may translate into survival benefits. Compared with other high-grade pleomorphic sarcomas of somatic soft tissue, intermediate-grade and high-grade myxofibrosarcomas have a lower metastatic rate. tumor size, morphological grade (inversely related to the percentage of the myxoid component), and surgical margins are significant predictors of survival. The epithelioid subtype of myxofibrosarcoma behaves more aggressively, with an increased risk of metastasis (> 50%).

Not clinically relevant

Essential: multinodular architecture with infiltrative margins; myxoid stroma; variably prominent pleomorphic cells; distinctive curvilinear vessels; hypercellular areas in higher-grade tumors.