Undifferentiated Pleomorphic Sarcoma (MFH)

Undifferentiated pleomorphic sarcoma (UPS) is a high-grade malignant mesenchymal tumour with no identifiable line of differentiation on light microscopy, immunohistochemistry or molecular testing. It is best understood as a default category rather than a single disease: what remains once every definable sarcoma and non-sarcoma has been excluded.

The old name. It was called malignant fibrous histiocytoma (MFH) in the belief that it arose from histiocytes. That origin was disproven, the cells are not histiocytic, and the WHO classification replaced the term with undifferentiated pleomorphic sarcoma. If you say "MFH" in a viva, add at once that it is now called UPS and explain why.

Why the name change matters. MFH was once the most common adult soft-tissue sarcoma diagnosis, but improved immunohistochemistry and molecular testing showed that a large proportion of these tumours were dedifferentiated liposarcoma, leiomyosarcoma, MPNST or other definable entities. Only the tumours truly without a line of differentiation are now called UPS. The label is therefore valid only after a thorough exclusion process, and finding a lineage (MDM2 amplification, for example) changes both the diagnosis and the prognosis.

Who and where. Most patients are over 50, with a peak in the 6th-7th decade and a slight male predominance. It is strongly age-associated, unlike the paediatric round-cell sarcomas, and even after reclassification it remains one of the most common adult soft-tissue sarcomas. It arises in the deep soft tissue of the extremities, especially the thigh, and also in the retroperitoneum and, less commonly, as a primary tumour of bone.

Prior radiotherapy. UPS is a recognised radiation-associated sarcoma, arising in a previous radiotherapy field after a latency of years.

Soft-tissue UPS and primary UPS of bone present, image and are treated differently:

Pathogenesis. UPS arises from primitive mesenchymal cells that fail to differentiate along any recognisable lineage. Cytogenetically it has a complex karyotype with multiple non-specific chromosomal gains and losses and no single recurrent translocation, in contrast to the recurrent gene fusions of synovial sarcoma (SS18-SSX) or Ewing sarcoma (EWSR1-FLI1). There is no diagnostic positive marker, so the diagnosis is reached by exclusion.

Microscopy. Marked nuclear pleomorphism with bizarre giant cells, frequent and often atypical mitoses, and necrosis, which is common in high-grade tumours. A storiform (cartwheel) arrangement of spindle cells is the classic pattern, but it is not specific. What the tumour lacks matters as much: no osteoid, no chondroid, no lipoblasts and no specific differentiation.

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Immunohistochemistry. The only positive stain is vimentin, a non-specific mesenchymal marker that is positive but unhelpful for typing. Every other stain in the panel is there to exclude something, and all must be negative:

• Cytokeratin / EMA - excludes sarcomatoid or metastatic carcinoma
• S100 / SOX10 - excludes melanoma and MPNST
• Desmin / SMA / h-caldesmon - excludes leiomyosarcoma and other smooth-muscle or myofibroblastic tumours
• Myogenin / MyoD1 - excludes rhabdomyosarcoma
• MDM2 / CDK4 not amplified - excludes dedifferentiated liposarcoma

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The old MFH variants. The tumours once grouped under MFH map onto modern entities as follows:

Soft-tissue UPS. The commonest presentation is a painless, progressively enlarging deep mass, most often in the thigh, then other extremity sites and the retroperitoneum. Because the tumour is deep and grows slowly at first, patients frequently present late with a large mass, frequently over 5 cm. Pain is often absent until the mass is large, and when present it is usually due to compression of adjacent structures rather than the tumour itself. Patients are usually systemically well, with weight loss only in advanced disease.

Primary UPS of bone. Progressive bony pain, which may be nocturnal, and a pathological fracture in a minority. The lesion is lytic, destructive and metaphyseal, commonly around the knee (distal femur, proximal tibia). Laboratory tests are usually non-specific, unlike those of Paget-associated tumours.

Examination. Measure the mass and record its site and its depth relative to fascia. It is firm, often fixed to deep structures, with mobility reduced when it lies deep to or is fixed to fascia, and tenderness is often minimal. Then examine the rest:

• Skin - usually intact; look for prior scars or radiotherapy tattoos, and venous prominence over large tumours
• Neurovascular - distal pulses, sensation and motor function
• Joint range - may be limited if the mass is juxta-articular; document baseline function for reconstruction planning
• Lymph nodes - usually not enlarged, but examine them, as nodal spread is possible
• Chest - keep a low threshold for CT chest

Histological confirmation is mandatory before definitive treatment. The biopsy is planned so that its track can be excised at the definitive operation, and is ideally performed by, or in coordination with, the treating sarcoma surgeon.

The unplanned excision. An unplanned excision of an unsuspected sarcoma, the "whoops procedure", contaminates the surgical field, leaves microscopic disease and converts a straightforward wide excision into a re-excision of a larger volume of tissue, frequently requiring adjuvant radiotherapy and worsening function. The correct sequence is image, then biopsy through a planned track, then resect; never excise a deep or large soft-tissue mass without a diagnosis.

The differential of a high-grade pleomorphic sarcoma is the exclusion list, each entity separated by its immunoprofile or molecular test:

Dedifferentiated liposarcoma. The most important mimic, and the single most important exclusion. It is biologically distinct and carries a different prognosis, yet it can look identical to UPS, and the distinction is frequently impossible on morphology alone. Test for MDM2 and CDK4, by FISH for amplification or immunohistochemistry for overexpression: amplification indicates dedifferentiated liposarcoma, a negative result supports UPS. This matters most for retroperitoneal pleomorphic tumours, where dedifferentiated liposarcoma is common.

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Prognosis. High histological grade is the dominant driver of metastasis and death, and positive or close margins drive local recurrence. The adverse factors:

• High grade, with necrosis and a high mitotic count
• Size over 5 cm, a key AJCC and prognostic factor, and especially over 10 cm
• Deep rather than superficial location
• Positive or close margins
• Retroperitoneal or axial site, where wide margins are hard to achieve
• Older age, and metastatic disease

The favourable profile is the mirror image: lower grade within the high-grade category, under 5 cm, superficial, wide negative margins, an extremity site and no metastases at presentation.

Surveillance. High-grade UPS recurs and metastasises mainly in the first 2-3 years, so surveillance is most intensive early: clinical review with imaging of the primary site and CT chest every few months for the first 2-3 years, then less frequently out to 5-10 years. Chest surveillance is essential because of the lung's dominance as a metastatic site, and the intensity is tailored to grade, size and margin status.

Is UPS a single entity? As immunohistochemistry and molecular testing improve, more "UPS" is reclassified to definable entities (dedifferentiated liposarcoma, leiomyosarcoma, MPNST). Whether a true lineage-negative UPS is a distinct biological disease or simply the current limit of our diagnostic tools is debated.

Radiotherapy timing and survival. On survival the randomised trial is slightly more interesting than "no difference": overall survival was marginally better with preoperative treatment (p=0.0481). That is a borderline result on a secondary endpoint at a median 3.3 years, not a reason to choose preoperative treatment by itself, but not nothing either, and plausibly related to the lower dose and smaller field. The right choice is individualised, not settled.

Adjuvant chemotherapy in soft-tissue UPS. The survival benefit for localised soft-tissue UPS is modest and contested. It is generally reserved for large, deep, high-grade tumours and trial settings, unlike bone UPS, where osteosarcoma-type chemotherapy is standard.

Immunotherapy. UPS is relatively immune-responsive among sarcomas, but checkpoint inhibition is not yet standard of care and patient selection is unresolved.

Global Epidemiology

Undifferentiated pleomorphic sarcoma is one of the most common adult soft-tissue sarcomas worldwide, even after the reclassification of many former MFH cases. It is strongly age-associated, peaking in the 6th-7th decade, with the deep soft tissue of the thigh the commonest site. Primary UPS of bone is rare, falling within the group of rare primary malignant bone sarcomas (RPMBS) that together make up 5-10% of high-grade bone tumours (EURO-B.O.S.S.).

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Registries and Evidence Networks

• Cooperative trial groups (EURO-B.O.S.S., COSS, EORTC and SARC networks) pool these relatively uncommon tumours to generate the prospective evidence base for chemotherapy and radiotherapy.
• Population registries such as SEER provide large-scale incidence, metastasis and survival data that complement single-centre series for a tumour distributed across many institutions.
• There is no implant-survivorship registry endpoint specific to UPS; reconstruction outcomes are extrapolated from general limb-salvage endoprosthesis and allograft data.

High- versus Limited-Resource Practice