Myxofibrosarcoma is a unique subtype of soft tissue sarcoma with a locally infiltrative behavior. High-quality MRI imaging is critical for preoperative planning. Wide surgical resection with a 2 cm soft tissue margin is the mainstay of treatment and can require complex vascular and plastic surgery reconstruction. Local recurrence is common, and a subset of patients with higher-grade lesions will develop distant metastases. Radiation may be beneficial in reducing local recurrence.
Key points
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Myxofibrosarcoma is a unique subtype of soft tissue sarcoma with a locally infiltrative behavior and a predilection for local recurrence.
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Histology reveals a highly myxoid neoplasm with a distinctly hypocellular appearance, although some lesions have more cellular areas and can be higher grade.
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Patients presenting with a diagnosis of myxofibrosarcoma should undergo high-quality T1- and T2-weighted MRI with pre- and postgadolinium imaging to accurately define the extent of the disease.
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Wide surgical resection with a 2 cm soft tissue margin encompassing the entire area of increased signal on T2-weighted MRI is required, which can require complex vascular and plastic surgery reconstruction.
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A subset of patients with higher-grade lesions will develop distant metastases.
Introduction: nature of the problem
Myxofibrosarcoma (MFS) is a unique subtype of soft tissue sarcoma often characterized by a diffusely infiltrative pattern. This represents approximately 5% of soft tissue sarcoma diagnoses ( Fig. 1 ). With the introduction of more stringent morphologic and immunohistochemical criteria in 2002 and reaffirmed in 2013, the World Health Organization (WHO) renamed the myxoid variant of malignant fibrous histiocytoma (MFH) with a predominant myxoid component (>50%) myxofibrosarcoma. Series of MFS and myxoid MFH studies describe these tumors as having a significant propensity for local recurrence, while exhibiting an overall better prognosis when compared with other complex karyotype sarcomas such as leiomyosarcoma. Given its relatively recent recognition as a distinct pathologic entity, the clinical behavior and outcomes for patients with MFS are uncertain, and there are no randomized trials to guide treatment protocols. Therefore, treatment decisions and understanding of this disease are based on case–control and retrospective studies.
Introduction: nature of the problem
Myxofibrosarcoma (MFS) is a unique subtype of soft tissue sarcoma often characterized by a diffusely infiltrative pattern. This represents approximately 5% of soft tissue sarcoma diagnoses ( Fig. 1 ). With the introduction of more stringent morphologic and immunohistochemical criteria in 2002 and reaffirmed in 2013, the World Health Organization (WHO) renamed the myxoid variant of malignant fibrous histiocytoma (MFH) with a predominant myxoid component (>50%) myxofibrosarcoma. Series of MFS and myxoid MFH studies describe these tumors as having a significant propensity for local recurrence, while exhibiting an overall better prognosis when compared with other complex karyotype sarcomas such as leiomyosarcoma. Given its relatively recent recognition as a distinct pathologic entity, the clinical behavior and outcomes for patients with MFS are uncertain, and there are no randomized trials to guide treatment protocols. Therefore, treatment decisions and understanding of this disease are based on case–control and retrospective studies.
Pathophysiology
Myxofibrosarcoma was first formally described in 1977. Diagnostic terminology has evolved over the years and thus merits some further discussion. In the original 1977 description in the journal Cancer , Enzinger and Weiss used the terminology “myxoid variant of malignant fibrous histiocytoma.” They noted that the myxoid variant of MFH had extensive, distinct myxoid features and exhibited less aggressive behavior than storiform or pleomorphic MFH. Use of the term myxofibrosarcoma extends back to at least 1951. However, it was only in the late 1970s that this terminology was applied to this specific entity. In the 1990s, MFH attracted attention as a potentially problematic and possibly nonspecific diagnostic category likely contaminated with multiple entities. Among the multiple histologic types of MFH, attempts were made to help better distinguish myxofibrosarcoma as a separate diagnostic category. Malignant fibrous histiocytoma (MFH) was renamed undifferentiated pleomorphic sarcoma (UPS) and was defined as a diagnosis of exclusion in both the 2002 and 2013 WHO Classification of Tumors of Soft Tissue and Bone. Given the use of modern methods including immunohistochemistry and molecular studies, UPS is now better defined and much less likely to be contaminated by mimics such as poorly differentiated carcinoma or spindle cell melanoma. Under the current WHO classification, the preferred diagnostic terminology for tumors formerly referred as myxoid malignant fibrous histocytoma is myxofibrosarcoma.
Not surprisingly, given the alterations in diagnostic terminology, the diagnostic criteria for myxofibrosarcoma have also evolved over the years. The original 1977 description detailed a grossly multilobular tumor with mucoid features on cut surface ( Fig. 2 ). Histology reveals a highly myxoid neoplasm with a distinctly hypocellular appearance ( Fig. 3 A). The myxoid areas are sparsely populated spindle cells or sometimes pleomorphic cells embedded in a matrix of the acid mucopolysaccharides ( Fig. 3 B, C). Due to the myxoid features, the vasculature is distinct. Areas of more diffuse cellularity are often present ( Fig. 3 D), and these areas often have conspicuous mitotic activity that is not usually a feature of the highly myxoid areas. Sometimes pseudo-lipoblasts (multivacuolated cells filled with mucin rather than lipid, see inset Fig. 3 E) are apparent in myxoid areas. It was recognized early on that areas of this myxofibrosarcoma may show much higher degrees of cellularity that were indistinguishable from malignant fibrous histiocytoma or what is now called undifferentiated pleomorphic sarcoma. The original 1997 article demonstrated that the degree of hypercellularity was related to the ultimate metastatic potential of these neoplasms. Rarely, myxofibrosarcoma can show epithelioid cellularity rather than spindle cells admixed within the myxoid areas or growing as a diffusely cellular proliferation ( Fig. 4 ). These epithelioid myxofibrosarcomas appear to behave more aggressively than their traditional spindle cell counterparts.
Although the hypocellular myxoid component of myxofibrosarcoma is relatively easy to recognize, there has been debate in the field over how much of the neoplasm must be comprised of this hypocellular myxoid component in order to diagnose this entity. Opinions vary widely, with requirements of as much as 75% to as little as 5% hypercellular myxoid content. Furthermore, myxofibrosarcoma can progress to a completely cellular neoplasm devoid of a myxoid component that is indistinguishable from UPS (see Fig. 3 D). There is a tendency for myxofibrosarcomas to become more cellular over time and with local recurrence, suggesting this is a form of tumor progression in at least some cases. Neoplasms composed mainly of the hypocellular myxoid component tend to show local recurrence rather than distant metastasis. A recent paper by Singer and colleagues indicates that even a minimal hypocellular myxoid component of at least 5% confers a better prognosis for myxofibrosarcoma relative to undifferentiated pleomorphic sarcoma lacking this myxoid component. They thus suggest defining myxofibrosarcoma as having at least a 5% hypocellular myxoid component, while anything with less than 5% myxoid is best considered as undifferentiated pleomorphic sarcoma. Given the virtually complete morphologic overlap of the hypercellular and generally nonmyxoid portions of myxofibrosarcoma with undifferentiated pleomorphic sarcoma, distinguishing these 2 entities can be challenging when only a minimal myxoid component is present. At the authors’ institution, a cut-off of roughly 20% characteristic myxoid component is used for the diagnosis of myxofibrosarcoma.
Myxofibrosarcoma can be graded under the FNCLCC (Fédération Nationale des Centres de Lutte Contre le Cancer) system. Hypocellular cases tend have low mitotic activity and no necrosis and are thus considered low-grade when the entire lesion is composed of this characteristic component. Areas of increased cellularity with mitotic activity result in designation of a higher grade. Many of these neoplasms turn out to be intermediate- rather than high-grade, as the tumor differentiation score for myxofibrosarcoma is 2, in contrast to undifferentiated pleomorphic sarcoma, which is assigned a differentiation score of 3. Thus, myxofibrosarcoma must exhibit both high mitotic rate and necrosis to achieve a designation of high-grade under the FNCLCC system. However, many institutions and the American Joint Committee on Cancer (AJCC), group intermediate- and high-grade tumors into 1 category for purposes of staging given that intermediate sarcomas have some potential for distant metastasis. Given the challenges and debate in the literature regarding the diagnostic criteria and grading, management approaches vary for the more cellular and higher-grade myxofibrosarcomas.
Cytogenetics and molecular findings
Most cases of MFS demonstrate a highly complex karyotype, often with tripoid or tetrapoid alterations. Willems and colleagues demonstrated that most cases have complex cytogenetic anomalies, and such alterations were observed in tumors of all grades. Furthermore, this group observed that the tumors that locally recurred had more complex cytogenetic aberrations when compared with those that did not recur. Based on this observation, the authors proposed the concept of MFS progression as a multistep genetic process that is lead by genetic instability. MFS is among the sarcoma subtypes currently being characterized by The Cancer Genome Atlas (TCGA) for sarcoma, and this collaborative project should provide additional insights into the relatively uncharacterized genomic landscape of this tumor.
Clinical presentation/examination
MFS usually affects older patients ( Table 1 ). Although the age range is broad, most patients are in their fifth to seventh decades of life, and men are affected slightly more often than women. The most common sites of presentation are the extremities (77%), with a predilection for the lower extremities ( Fig. 5 A). MFS tumors can also be located on the trunk (12%) and head and neck region (3%), but to a lesser extent. MFS is uncommon in the abdominal cavity and retroperitoneum. It has been reported in the skin, breast, heart, and paratesticular region.
| Features | Low-Grade Myxofibrosarcoma |
|---|---|
| Peak age | Elderly |
| Depth | Subcutaneous tissue |
| Stroma | Usually uniformly myxoid |
| Atypia | Present |
The tumor most commonly arises as a slowly enlarging, painless mass. It may present as a predominantly deep or subcutaneous multinodular growth ( Fig. 5 B). Mentzel and colleagues classified MFS into 2 groups: superficial (dermal/subcutaneous) and deep (intramuscular/mainly subfascial). The superficial group tends to infiltrate through the fascia, whereas the deep lesions tend to form a single discrete mass. The superficial lesions may involve the dermal layer and present as a cutaneous lesion as well. Deep-seated lesions tend to be less nodular and can demonstrate an infiltrative growth pattern. Usually, they are larger than their superficial counterparts.
Diagnostic procedures
One of the major challenges of myxofibrosarcoma is to define the boundaries of the tumor. As with other soft tissue sarcomas of the extremity, MRI is the diagnostic modality of choice. MFS has low attenuation on computed tomography (CT) and shows low-to-intermediate signal on T1-weighted MRI ( Fig. 6 A). The solid and myxomatous components both show high signal on T2-weighted MRI, with the myxoid component showing higher signal intensity similar to that of fluid ( Figs. 6 B–D). Nodular and peripheral enhancement is often seen in the solid components.
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