Undifferentiated Pleomorphic Sarcoma: Symptoms, Types, Causes and Treatment

Undifferentiated Pleomorphic Sarcoma (UPS), formerly known as malignant fibrous histiocytoma, is a rare and aggressive cancer originating from the connective tissues. Despite comprising a small percentage of all cancers, UPS stands out for its rapid progression and complex clinical management. This article aims to provide a comprehensive overview of the symptoms, types, causes, and treatment options for UPS, drawing on the latest clinical and scientific research.

Symptoms of Undifferentiated Pleomorphic Sarcoma

Undifferentiated Pleomorphic Sarcoma often presents subtly, making early diagnosis a challenge. Recognizing the initial symptoms can be life-saving, as early intervention greatly improves outcomes.

Symptom	Description	Frequency/Context	Source(s)
Mass/Swelling	Rapidly enlarging lump	Extremities, trunk, skin	1 3 6
Pain	Localized discomfort	May be absent initially	1 3
Skin Changes	Ulceration, friability	Cutaneous UPS	6
Functional Impairment	Limited movement	Large/deep masses	1 3
Systemic Symptoms	Rare (fever, weight loss)	Advanced/metastatic cases	6
Cardiac Symptoms	Dyspnea, chest pain	Cardiac involvement	2

Table 1: Key Symptoms

Common Presentations

UPS typically appears as a rapidly growing, painless mass in the deep soft tissues—most frequently in the limbs or trunk. Some patients may notice discomfort or pain as the tumor enlarges and impinges on nerves or muscles. In rare cases, the tumor may arise in the skin, presenting as an ulcerated, friable nodule, or even in organs like the heart, causing symptoms such as shortness of breath or chest pain 1 2 3 6.

When to Seek Medical Attention

• Enlarging Masses: Any rapidly growing lump, especially in adults over 40, should prompt urgent medical evaluation.
• Functional Changes: Impaired limb movement or unexplained pain near a mass warrants imaging studies.
• Skin Lesions: Ulcerated, non-healing nodules should not be ignored, particularly in older adults 1 3 6.

Diagnostic Challenges

Due to its rarity, UPS is often mistaken for benign conditions (e.g., hematoma, cysts) or other malignancies, delaying diagnosis and treatment. Imaging (MRI, CT) and biopsy are essential for accurate identification 1 3 6.

Types of Undifferentiated Pleomorphic Sarcoma

UPS is a heterogeneous disease with several subtypes, each distinguished by location, histological features, and molecular characteristics.

Type	Location/Features	Distinction	Source(s)
Soft Tissue	Extremities, trunk, skin	Most common; deep masses	1 3 6 7
Bone (UPSb)	Primary bone involvement	Rare; resembles osteosarcoma	9 10
Cutaneous	Skin/subcutaneous tissue	Fast-growing nodules	6
Cardiac	Heart chambers	Extremely rare	2
Molecular Subtypes	Immune-high, Immune-low	Gene expression profiles	4

Table 2: Major Types of UPS

Soft Tissue UPS

This is the classic and most prevalent form, occurring mainly in the limbs or trunk. Tumors often invade deep muscle layers and can grow to substantial size before detection 1 3 7.

Bone UPS (UPSb)

UPSb is rarer and arises primarily in bone tissue. It can be difficult to differentiate from other bone sarcomas like osteosarcoma or dedifferentiated chondrosarcoma, requiring advanced genetic and molecular testing for confirmation 9 10.

Cutaneous UPS

Though uncommon, UPS can occur in the skin, presenting as rapidly enlarging, ulcerated, or friable nodules. This form is frequently seen in the elderly and may mimic other skin cancers 6.

Cardiac UPS

Extremely rare, cardiac UPS manifests as a mass within the heart, leading to symptoms such as shortness of breath, chest pain, and sometimes heart failure. Its diagnosis is often delayed due to the nonspecific cardiac symptoms 2.

Molecular Subtypes: Immune-high vs. Immune-low

Recent genetic profiling divides UPS into two main molecular groups:

• Immune-high: Tumors with strong immune cell infiltration; potentially more responsive to immunotherapies.
• Immune-low: Fewer immune cells; associated with increased chromosomal alterations and may respond better to targeted therapies like FGFR inhibitors 4.

Causes of Undifferentiated Pleomorphic Sarcoma

The exact causes of UPS remain elusive, but several risk factors and pathogenic mechanisms have been identified.

Cause/Risk Factor	Description	Notable Details	Source(s)
Age	Older adults (45–75+)	Most common age group	1 3 6 10
Radiation Exposure	Prior radiotherapy	Post-radiation sarcomas (0.5–5.5%)	10
Genetic Alterations	TP53, chromatin remodeling genes	Common in bone UPS	9
Bone Disorders	Paget’s disease, fibrous dysplasia	Predisposes to bone UPS	10
Unknown/Idiopathic	No clear predisposing factor	Most cases	1 3 5

Table 3: Causes and Risk Factors for UPS

Age and Demographics

UPS predominantly affects adults between the ages of 45 and 75, with slightly increased risk as age advances. Both men and women are susceptible 1 3 6 10.

Radiation Exposure

A significant minority of cases occur as a complication of previous radiotherapy, typically emerging several years after treatment for other cancers (e.g., breast cancer). Radiation-induced UPS is well-documented in the chest wall and soft tissue 10.

Genetic and Molecular Factors

• TP53 Mutations: Frequently observed in UPS, particularly in bone, indicating a role for tumor-suppressor gene dysfunction 9.
• Chromatin Remodeling Gene Mutations: Alterations in genes such as H3F3A, ATRX, and DOT1L highlight the importance of epigenetic dysregulation in UPS pathogenesis 9.
• Gene Fusions: Novel gene fusions have been identified, though their clinical significance is still under study 9.

Pre-existing Bone Disorders

Chronic bone diseases like Paget’s disease, fibrous dysplasia, and non-ossifying fibroma can predispose individuals to bone UPS 10.

Idiopathic Origins

For most patients, no specific risk factor or underlying cause can be identified, reflecting the complexity and heterogeneity of UPS biology 1 3 5.

Treatment of Undifferentiated Pleomorphic Sarcoma

UPS is a challenging malignancy, but advances in surgical, medical, and radiation oncology have improved outcomes. Treatment is multidisciplinary, tailored to tumor location, size, and molecular characteristics.

Treatment	Approach/Method	Indication/Benefit	Source(s)
Surgery	Wide excision, limb-sparing	Mainstay for localized disease	1 3 6 7 11
Radiotherapy	Pre/post-operative/adjuvant	Reduces recurrence, improves survival	11 13
Chemotherapy	Anthracycline-based, gemcitabine/docetaxel	Advanced/metastatic UPS	7
Immunotherapy	Checkpoint inhibitors	Subset of patients, immune-high UPS	4 12
Targeted Therapy	FGFR inhibitors	Immune-low, molecular-selected cases	4 9
Multimodality	Combination of above	Elderly/complex cases	13

Table 4: Major Treatment Modalities for UPS

Surgery

Wide surgical excision with negative margins remains the cornerstone of UPS treatment. Limb-sparing approaches are preferred over amputation, even for large tumors, provided clear margins can be achieved. In cutaneous or superficial tumors, complete resection is generally curative if margins are negative 1 3 6 7 11.

• Negative Margins: Achieving clear (R0) margins is crucial, as positive margins (R1/R2) are linked to higher rates of recurrence and poorer survival 11.
• Margin Width: While the presence of a negative margin is important, the actual width may be less critical 11.

Radiotherapy

Adjuvant radiotherapy—either before or after surgery—significantly reduces the risk of local recurrence and can also improve overall survival, particularly in patients with close or positive margins 11 13. It is underused in elderly patients, despite its clear benefits 13.

Chemotherapy

For advanced or metastatic disease, systemic chemotherapy (usually anthracycline-based regimens or gemcitabine and docetaxel) may be employed. Its benefit in localized disease is less clear but may be considered for high-risk tumors 7.

Immunotherapy

Immune checkpoint inhibitors (e.g., nivolumab, ipilimumab) are showing promise in a subset of patients, especially those with "immune-high" UPS characterized by abundant immune cell infiltration 4 12. These therapies are sometimes combined with radiotherapy for improved results 12.

Targeted Therapy

For "immune-low" molecular subtypes, targeted therapies such as FGFR inhibitors are being explored and may offer benefit in select patients 4 9.

Multimodality and Personalized Care

Elderly patients and those with complex presentations benefit from multimodal treatment approaches, combining surgery, radiotherapy, and systemic therapies as appropriate. Multidisciplinary tumor boards optimize individualized treatment planning 13.

Surveillance and Follow-up

Given UPS’s high risk of recurrence and metastasis, ongoing surveillance with MRI or CT scans is essential after curative treatment. Regular follow-up enables early detection of recurrences or late metastatic disease 1 3.

Conclusion

Undifferentiated Pleomorphic Sarcoma is a rare but aggressive malignancy requiring prompt recognition and expert multidisciplinary care. Its presentation can vary widely, but rapid growth of a deep tissue mass—especially in older adults—should always raise suspicion. Advances in molecular profiling, immunotherapy, and targeted treatments are opening new avenues for personalized care.

Key Points:

• UPS usually presents as a rapidly enlarging, painless mass in the extremities, trunk, or, rarely, skin or internal organs.
• Major types include soft tissue, bone (UPSb), cutaneous, and rare cardiac forms; new molecular subtypes are defined by immune infiltration.
• Risk factors include age, prior radiation therapy, pre-existing bone disorders, and specific genetic mutations, though most cases are idiopathic.
• Treatment is multidisciplinary: surgery (with negative margins) is central, radiotherapy reduces recurrence, and systemic therapies (including immunotherapy and targeted agents) are increasingly important for advanced or molecularly defined cases.
• Vigilant surveillance is crucial due to high recurrence and metastasis risks.

Early diagnosis and tailored therapy—guided by the latest molecular insights—offer the best chance for successful treatment and improved patient outcomes.