Subtitle: Recognise myxofibrosarcoma on H&E, grade it, choose the right IHC and molecular tests, and separate it from myxoid liposarcoma, low-grade fibromyxoid sarcoma, myxoma and myxoid dedifferentiated liposarcoma. Includes 10 interactive MCQs.

Author: PathologyMCQ Editorial Board

Category: Soft Tissue Pathology / WHO Bone and Soft Tissue Tumours

Last Updated: October 2026

Read Time: 10 minutes

At-a-Glance Diagnostic Summary

• Who and where: Elderly adults (peak 6th to 8th decades), limbs and limb girdles, about two-thirds dermal or subcutaneous.
• Key histology: Multinodular myxoid tumour with curvilinear vessels, perivascular condensation of atypical cells and vacuolated pseudolipoblasts.
• Behaviour: Infiltrative “tail” along fascia drives local recurrence; grade drives metastasis.
• Ancillary tests: No specific marker. Use IHC and molecular tests to exclude mimics; MDM2 is not amplified.

What Is Myxofibrosarcoma?

Myxofibrosarcoma is a malignant fibroblastic neoplasm with a variably myxoid stroma, nuclear pleomorphism and a distinctive curvilinear vasculature. It was previously called the myxoid variant of malignant fibrous histiocytoma. It is one of the most common sarcomas of the limbs in elderly patients, and its morphology spans a continuous spectrum from paucicellular, low-grade lesions to highly cellular, pleomorphic tumours that overlap with undifferentiated pleomorphic sarcoma.

Clinical Features and the Infiltrative Tail

• Age and sex: Elderly adults, slight male predominance; rare under 20 years.
• Site: Limbs (lower more than upper) and limb girdles. Retroperitoneal and visceral examples are rare, so a myxoid sarcoma at those sites should prompt MDM2 testing.
• Depth: About two-thirds are dermal or subcutaneous; the rest are deep, intramuscular or fascial.
• Presentation: Slowly enlarging, painless mass, often multinodular.
• Infiltrative “tail sign”: Thin tongues of tumour spread along fascial planes well beyond the main mass. This explains the high local recurrence rate and the need for wide excision with careful margin assessment.

Histopathology

Low power shows a multinodular tumour with incomplete fibrous septa and a myxoid matrix. The key is to look at the vessels and at the cells that hug them.

Key features

• Curvilinear vessels: Elongated, thin- to thick-walled vessels that curve through the myxoid stroma.
• Perivascular condensation: Tumour cells, and often the most atypical ones, cluster around these vessels.
• Atypical cells: Spindle and stellate cells with hyperchromatic, irregular nuclei; atypia is present even in low-grade tumours.
• Pseudolipoblasts: Vacuolated cells whose vacuoles contain acidic stromal mucin, not lipid. Do not mistake them for lipoblasts.
• Higher-grade areas: Solid sheets of pleomorphic cells, multinucleated giant cells, atypical mitoses and necrosis.

Grading and Behaviour

Myxofibrosarcoma is graded with the FNCLCC system. Within one tumour, cellularity and atypia often vary from area to area, so sample generously and grade on the worst area.

MyxofibrosarcomaA spectrum, not three boxes

Low grade

• Paucicellular, mostly myxoid
• Scattered atypical cells around curvilinear vessels
• Few mitoses, no necrosis
• Recurs locally, rarely metastasises

Intermediate grade

• More cellular, more atypia
• Solid areas start to appear
• Necrosis absent or focal
• Can metastasise

High grade

• Solid pleomorphic sheets, giant cells
• Brisk and atypical mitoses, necrosis
• Myxoid areas may be minor
• Highest metastatic risk (lung, bone)

Exam pearl: recurrences can come back at a higher grade, so the first excision matters most.

• Local recurrence: Common across all grades because of infiltrative growth; often quoted at 30–40% or higher with inadequate margins.
• Metastasis: Essentially limited to intermediate and high-grade tumours, mainly to lung and bone.
• Overlap with UPS: High-grade myxofibrosarcoma with only small myxoid foci merges with undifferentiated pleomorphic sarcoma; a meaningful myxoid component favours myxofibrosarcoma.

Immunohistochemistry and Molecular Genetics

There is no specific immunostain for myxofibrosarcoma. The diagnosis rests on morphology, and the panel is used to exclude mimics.

• Often positive (non-specific): CD34 (variable), focal SMA in myofibroblastic cells.
• Negative, and useful for exclusion: S100 and SOX10 (nerve sheath tumours), desmin and myogenin (myogenic tumours), MUC4 (low-grade fibromyxoid sarcoma), STAT6 (solitary fibrous tumour), cytokeratin (carcinoma).
• MDM2/CDK4: Not amplified. Amplification in a myxoid pleomorphic sarcoma means myxoid dedifferentiated liposarcoma, especially in the retroperitoneum.
• Genetics: Complex karyotype without a recurrent fusion; frequent alterations of TP53, RB1, CDKN2A/B and NF1. Fusion testing is used to exclude myxoid liposarcoma (DDIT3) and low-grade fibromyxoid sarcoma (FUS::CREB3L2), not to confirm myxofibrosarcoma.

Correction note: earlier versions of this article listed MDM2/CDK4 amplification as a feature of higher-grade myxofibrosarcoma. This is not correct; MDM2 amplification points to dedifferentiated liposarcoma.

Differential Diagnosis

WHO 6th Edition: What You Need to Know

Myxofibrosarcoma remains a malignant entity within the fibroblastic and myofibroblastic tumour group in the WHO 6th edition of soft tissue and bone tumours, and its diagnostic criteria are unchanged. Undifferentiated pleomorphic sarcoma now sits in the same group, which fits the morphological continuum between high-grade myxofibrosarcoma and UPS. The practical rule is the same as before: exclude specific mimics, especially MDM2-amplified dedifferentiated liposarcoma, before signing out either diagnosis.

Test Yourself: 10 MCQs

Exam Pearls

• Elderly + limb + subcutaneous + multinodular myxoid + curvilinear vessels = myxofibrosarcoma until proven otherwise.
• Pseudolipoblasts contain mucin, not fat. True lipoblasts with plexiform vessels in a younger patient mean myxoid liposarcoma (DDIT3).
• Retroperitoneal “myxofibrosarcoma”? Test MDM2 first.
• Grade predicts metastasis; infiltrative tail predicts recurrence.

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