Myxofibrosarcoma: Symptoms, Types, Causes and Treatment

Myxofibrosarcoma (MFS) is one of the most common soft tissue sarcomas in adults, especially affecting older individuals. Known for its complex biology and high risk of local recurrence, understanding this tumor type is crucial for patients, families, and clinicians alike. This comprehensive overview will guide you through the symptoms, types, causes, and treatments of myxofibrosarcoma, using the latest research and clinical insights.

Symptoms of Myxofibrosarcoma

Myxofibrosarcoma can be a challenging disease to detect early due to its variable presentation. It typically develops as a slow-growing, painless mass, most often on the limbs, but can occur elsewhere. Because of its infiltrative nature, it may not be noticed until it becomes sizeable or causes complications.

Symptom	Description	Frequency/Pattern	Source(s)
Mass/Lump	Painless, enlarging soft tissue mass	Most common, extremities	1 5
Skin Changes	Redness, thinning, ulceration	Sometimes, superficial cases	1
Swelling	Localized to affected area	Variable	1 5
Pain	Usually absent, but may develop	If nerves/tissues compressed	1 5

Table 1: Key Symptoms

Common Presentations

The most frequent symptom is a painless, slow-growing lump or mass, typically located in the limbs—most often the lower extremities, followed by the upper extremities and trunk. In some cases, the tumor is found in the retroperitoneum, head, neck, or other rare sites 1 5.

Skin and Soft Tissue Changes

When myxofibrosarcoma is superficial, it may cause changes in the overlying skin, such as redness, thinning, or even ulceration if the tumor grows large enough. Swelling may be observed, particularly if the mass is deep-seated or impinges on surrounding tissues 1.

Pain and Functional Impairment

Pain is not a typical early symptom, as the tumor tends to grow slowly and does not immediately involve nerves. However, pain or functional impairment can arise if the tumor compresses nerves or becomes very large. In rare cases, patients may notice weakness or restricted movement in the affected limb 1 5.

Challenges in Diagnosis

Because the symptoms are often subtle and overlap with benign lesions, diagnosis can be delayed. Misdiagnosis with other soft tissue tumors is not uncommon, especially in high-grade lesions where typical myxoid stroma may be minimal 5. Fine-needle aspiration or biopsy with expert pathological review is essential for accurate diagnosis.

Types of Myxofibrosarcoma

Myxofibrosarcoma is a heterogeneous disease with several subtypes and histological grades, each with unique clinical features and prognoses. Understanding the types is important for guiding treatment and predicting outcomes.

Type/Grade	Characteristics	Prognosis/Behavior	Source(s)
Low-grade (G1)	Hypocellular, mainly myxoid, spindle cells	Locally aggressive, rarely metastasize	1 2 4
Intermediate (G2)	Increased cellularity, mild atypia	Metastatic risk increases	2 4
High-grade (G3)	Highly cellular, pleomorphic, necrosis	High metastatic potential	1 2 4 5
Superficial	Located in skin/subcutaneous tissue	Lower risk of metastasis	1
Deep-seated	Deep tissue involvement	Higher grade, metastatic risk	1

Table 2: Myxofibrosarcoma Types and Grades

Histological Grading

Myxofibrosarcoma is categorized into low, intermediate, and high grades based on cellularity, nuclear atypia, and presence of necrosis 1 2 4.

• Low-grade (G1): These tumors are hypocellular, composed mostly of spindle cells in a myxoid (mucoid) matrix with characteristic curvilinear blood vessels. They are primarily locally aggressive and rarely metastasize.
• Intermediate-grade (G2): As cellularity and atypia increase, so does the risk of metastasis.
• High-grade (G3): Highly cellular, pleomorphic, with frequent mitoses, multinucleated giant cells, and areas of necrosis. These are much more likely to metastasize and are associated with a poorer prognosis 1 2 4.

Tumor Location: Superficial vs. Deep

• Superficial Myxofibrosarcoma: Found in the dermis or subcutaneous tissues. These have a lower risk of metastasis but a high risk of local recurrence 1.
• Deep-seated Myxofibrosarcoma: Located in muscles or deeper tissues, these tumors are often larger, higher grade, and associated with a higher risk of metastasis and death 1.

Morphological Spectrum

Myxofibrosarcoma exhibits a range of appearances, from predominantly myxoid (mucous-like) to more solid or pleomorphic forms. This variability can lead to diagnostic confusion with other soft tissue sarcomas, such as undifferentiated pleomorphic sarcoma (UPS), especially in high-grade tumors where the myxoid component is less prominent 5 11.

Causes of Myxofibrosarcoma

The exact causes of myxofibrosarcoma remain poorly understood, but advances in molecular genetics have identified several risk factors and genetic changes associated with its development and progression.

Factor/Mechanism	Key Details/Genes Involved	Impact on Disease	Source(s)
Genetic Instability	Complex chromosomal aberrations	Drives tumor progression	2 3 4 7
Key Mutations	TP53, RB1, CDKN2A/B, ATRX, AXL	Affect cell cycle, growth	3 4 7 8
Epigenetic Changes	DNA methylation subtypes	Associated with outcomes	3
Tumor Microenvironment	Integrin-α10, TRIO, RICTOR	Promotes survival, metastasis	6

Table 3: Underlying Causes and Molecular Drivers

Genetic and Molecular Drivers

Recent studies show that myxofibrosarcoma is genetically complex, with no single, defining chromosomal abnormality 2 7. Instead, a combination of mutations and copy number changes drives tumor behavior:

• TP53: Mutated in over 50% of cases, affecting cell cycle control and genomic stability 3 4 7 8.
• RB1, CDKN2A/B: Frequently affected, these genes are pivotal in regulating cell proliferation 3 4 7 8.
• ATRX, HDLBP, AXL: Mutations and amplifications in these and other genes may also play a role, with AXL mutations (notably W451C) and amplifications being highly specific to MFS 8.
• Chromothripsis and BRCAness: Evidence of massive chromosomal rearrangements and DNA repair defects further highlights the genomic instability of these tumors 7.

Epigenetic and Tumor Microenvironment Factors

Distinct DNA methylation profiles have been identified, clustering MFS into subtypes with different clinical outcomes and immune landscapes 3. Overexpression of integrin-α10 and its downstream effectors (TRIO, RICTOR) drives tumor progression and resistance to therapy, particularly in high-grade disease 6.

Tumor Progression and Recurrence

Myxofibrosarcoma often progresses from low- to higher-grade disease through the accumulation of genetic aberrations. Local recurrences tend to be of higher grade and exhibit more complex cytogenetic profiles than the primary tumor, supporting a multistep model of tumorigenesis 1 2 4 7.

Environmental and Other Factors

Unlike other cancers, there are no well-established environmental or lifestyle risk factors for myxofibrosarcoma. Most cases arise sporadically, primarily in older adults 1 2 5.

Treatment of Myxofibrosarcoma

Treatment strategies for myxofibrosarcoma are evolving, integrating surgery, radiation, chemotherapy, and emerging targeted therapies. Due to the high rate of local recurrence and the risk of metastasis, a multidisciplinary approach is essential.

Therapy	Role/Indication	Key Outcomes/Notes	Source(s)
Surgery	Mainstay for localized disease	Wide excision, R0 margin critical	1 10 11
Radiation Therapy	Adjuvant for local control	Reduces recurrence, improves survival	10
Chemotherapy	For advanced/metastatic/high-grade	Anthracyclines ± ifosfamide	9 11
Targeted Therapy	Clinical trials, select mutations	mTOR, RAC, AXL inhibition	4 6 8
Photodynamic Therapy	Experimental, adjunctive	Selective tumor cell killing	12

Table 4: Treatment Modalities

Surgery: The Mainstay

• Wide Surgical Excision: The primary treatment for localized MFS is wide excision (removal with a margin of healthy tissue). Achieving negative (R0) margins is critical to minimize recurrence 1 10 11.
• Margin Matters: Incomplete (R1) resection increases the risk of local relapse. Adjuvant radiation can partially mitigate this risk, but complete excision remains the goal 10.
• Limb-Sparing: Most tumors can be removed without amputation, though the infiltrative growth pattern of MFS often requires wider margins than other sarcomas 11.

Radiation Therapy

• Adjuvant Radiation: Postoperative (adjuvant) radiation therapy significantly reduces the risk of local recurrence, especially when margins are close or involved 10.
• Preoperative/Neoadjuvant Use: Radiation can also be given before surgery in select cases to shrink tumors and facilitate removal 10.

Chemotherapy

• Standard Regimens: For advanced, metastatic, or high-grade disease, chemotherapy with anthracyclines (e.g., epirubicin, doxorubicin) and ifosfamide is standard, though response rates are variable 9 11.
• Chemoresistance: Some tumors may be resistant, possibly related to molecular factors like TGF-β expression 9.
• Other Agents: Combinations such as gemcitabine and docetaxel are sometimes used in metastatic settings 11.

Emerging and Targeted Therapies

• Molecular Targeting: Advances in profiling have revealed actionable mutations and pathways, such as the integrin-α10/TRIO/RICTOR axis, mTOR, RAC, and AXL tyrosine kinase 4 6 8.
  • mTOR and RAC Inhibitors: Preclinical studies show promising effects of mTOR and RAC inhibitors, especially in high-risk disease 6.
  • AXL Inhibition: The discovery of AXL mutations/amplifications unique to MFS suggests potential for AXL-targeted therapies 8.
• Photodynamic Therapy: Novel approaches like 5-aminolevulinic acid (5-ALA) tumor paint and photodynamic therapy have shown selective killing of MFS cells in laboratory studies, offering future adjunctive strategies 12.

Multidisciplinary Approach and Follow-Up

• Team-Based Care: Optimal management involves surgeons, oncologists, pathologists, and radiation therapists.
• Surveillance: Due to high recurrence rates, long-term, scrupulous follow-up with imaging and clinical exams is essential 1 10.

Conclusion

Myxofibrosarcoma presents unique challenges due to its variable symptoms, complex pathology, and high risk of recurrence. Advances in molecular profiling are opening the door to more precise and personalized therapies.

Key takeaways:

• Myxofibrosarcoma most often presents as a painless, slow-growing mass in the limbs of older adults, with high rates of local recurrence 1 5 10.
• Types range from low-grade (locally aggressive) to high-grade (metastatic), with higher grade and deep-seated tumors posing greater risks 1 2 4 5.
• The disease is driven by complex genetic and epigenetic changes, including mutations in TP53, RB1, CDKN2A/B, and unique AXL aberrations 3 4 7 8.
• Standard treatment is wide surgical excision with negative margins, complemented by radiation; chemotherapy and targeted therapies play roles in advanced or high-grade cases 9 10 11.
• Novel targeted therapies and experimental approaches are in development, aiming to improve outcomes for patients with high-risk or recurrent disease 4 6 8 12.

By staying vigilant for symptoms, ensuring accurate diagnosis, and embracing advances in precision medicine, the outlook for patients with myxofibrosarcoma continues to improve.