Myxofibrosarcoma landscape: diagnostic pitfalls, clinical management and future perspectives

Abstract

Myxofibrosarcoma (MFS) is a common entity of adult soft tissue sarcomas (STS) characterized by a predilection of the extremities and a high local recurrence rate. Originally classified as a myxoid variant of malignant fibrous histiocytoma, this musculoskeletal tumor has been recognized since 2002 as a distinct histotype showing a spectrum of malignant fibroblastic lesions with myxoid stroma, pleomorphism and curvilinear vessels. Currently, the molecular pathogenesis of MFS is still poorly understood and its genomic profile exhibits a complex karyotype with a number of aberrations including amplifications, deletions and loss of function. The diagnosis is challenging due to the unavailability of specific immunohistochemical markers and is based on the analysis of cytomorphologic features. The mainstay of treatment for localized disease is represented by surgical resection, with (neo)-adjuvant radio- and chemotherapy. In the metastatic setting, chemotherapy represents the backbone of treatments, however its role is still controversial and the outcome is very poor. Recent advent of genomic profiling, targeted therapies and larger enrollment of patients in translational and clinical studies, have improved the understanding of biological behavior and clinical outcome of such a disease. This review will provide an overview of current diagnostic pitfalls and clinical management of MFS. Finally, a look at future directions will be discussed.

Keywords: chemotherapy; musculoskeletal tumor; myxofibrosarcoma; soft tissue sarcoma; targeted therapy; translational models.

Graphical Abstract Legend

Schematic representation of the main available tools for myxofibrosarcoma (MFS) diagnosis, prognosis, treatment and translational research. MFS most commonly occurs in adults and presents as an intramuscular mass, typically located in limbs. Diagnosis mainly relies on histopathological analysis (IHC) and imaging (MRI), however in recent years also NGS proved helpful in detecting distinct molecular alterations. Prognosis has been shown to correlate with specific gene expression signatures, as well as with immune microenvironment markers and infiltrating cells. The cornerstone of treatment for localized disease is surgical resection, possibly in combination with radiotherapy, while in metastatic MFS the standard systemic treatment is based on anthracycline chemotherapy, targeted therapy such as TKIs and CDKIs or immunotherapy. In order to gain better insight on the still poorly understood pathogenesis and behaviour of MFS, several in vitro cell cultures and in vivo xenograft models have been established, representing promising tools for the improvement of MFS management.

Figure 1.

Representative histopathological images of low-grade (a,c) and high-grade (b,d) myxofibrosarcoma. H&E of typical MFS cases showing myxoid stroma, pleomorphic cells and curvilinear vessels. Upper panels show 10× magnification, lower panels represent 20× magnification. MFS, myxofibrosarcoma.

Figure 2.

MRI patterns of myxofibrosarcoma. (a) Sagittal T1-weighted MRI shows a highly intense mass signal typical of myxoid matrix in subcutaneous tissues in the right thigh. (b) Axial T1-weighted MRI shows tail-like margin (white arrow) at caudal extent of lesion. MRI, magnetic resonance imaging.