Undifferentiated Pleomorphic Sarcoma

Undifferentiated pleomorphic sarcoma (UPS), previously known as malignant fibrous histiocytoma, is a high-grade sarcoma with no identifiable cell line of differentiation. This aggressive tumor arises in tissues of mesenchymal origin, affecting both bone and soft tissue. Undifferentiated pleomorphic sarcoma represents a heterogeneous group of tumors and is considered a diagnosis of exclusion.

Epidemiology

Soft tissue sarcomas as a group are rare, with approximately 3-4 cases per 100,000 individuals per year, comprising less than 1% of all malignancies. Within the category of soft tissue sarcomas, undifferentiated pleomorphic sarcoma accounts for about 15% of cases, resulting in an incidence of less than 1 per 100,000 individuals per year. Undifferentiated pleomorphic sarcoma predominantly occurs in older adults aged 55-80 years and affects both genders equally. This tumor can be found anywhere in the body but is most common in the lower extremities, upper extremities, and retroperitoneum. Notably, at least 25% of all radiation-induced soft-tissue sarcomas are undifferentiated pleomorphic sarcomas.

Clinical Features

Undifferentiated pleomorphic sarcoma often presents as a painless, enlarging mass. It may be palpable when superficial but harder to detect when located in deep tissues. Tumor size at presentation can vary widely, typically ranging from 5 to 15 cm in diameter. Undifferentiated pleomorphic sarcoma is usually identified by direct palpation or during imaging workup to evaluate associated swelling or asymmetry. Skin changes such as discoloration or ulceration are relatively uncommon, occurring mainly in advanced cases.

Diagnosis can be delayed due to the lack of pain and patients attributing the mass to swelling or bruising after minor trauma. The growth rate is variable but is rapid in most cases, with noticeable changes over weeks to months. Systemic symptoms such as fever, weight loss, or fatigue are rare but may occur in advanced stages.

Specific symptoms can vary based on location. For instance, retroperitoneal tumors may cause abdominal discomfort, changes in bowel habits, or urinary symptoms due to compression of surrounding structures. Lower extremity tumors can cause gait disturbances or vascular compression symptoms if large enough.

Radiologic Features

Initial evaluation often begins with plain radiographs, which may suggest a soft tissue mass and rarely bone erosion in advanced cases. Unlike synovial sarcoma and liposarcoma, undifferentiated pleomorphic sarcoma rarely shows intralesional calcifications on radiographs.

On ultrasound, undifferentiated pleomorphic sarcoma typically appears as a heterogeneous, hypoechoic mass with irregular margins and variable vascularity on Doppler imaging.

Magnetic resonance imaging is the modality of choice for local staging. On MRI (Figures 1 and 2), undifferentiated pleomorphic sarcoma presents as a large heterogeneous mass that is isointense to muscle on T1-weighted sequences, hyperintense on T2-weighted sequences, and enhances heterogeneously with gadolinium. Areas of necrosis or hemorrhage may be present, contributing to the heterogeneous appearance. The lesion tends to develop in the extremities, where it is often adjacent to neurovascular structures. MRI is crucial for surgical planning, providing detailed information about the tumor’s relationship to surrounding structures.

Figure 1: Post-contrast, fat-suppressed axial T1 of a large undifferentiated pleomorphic sarcoma of soft tissue in the anterior left thigh.

Figure 2: Post-contrast sagittal T1 MRI sequences of the anterior left thigh undifferentiated pleomorphic sarcoma seen in Figure 1.

On computed tomography, undifferentiated pleomorphic sarcoma typically appears as a heterogeneous soft tissue mass with areas of low attenuation representing necrosis or cystic degeneration.

Because undifferentiated pleomorphic sarcoma frequently leads to metastases, especially to the lungs, positron emission tomography (PET-CT) of the chest, abdomen, and pelvis may be performed prior to surgery to evaluate for metastatic disease. PET-CT has the added advantage of assessing metabolic activity, which can help differentiate viable tumor from necrosis and may aid in biopsy planning. Otherwise, a CT scan of the chest, abdomen and pelvis is also an acceptable test for disseminated disease.

Pathology

Undifferentiated pleomorphic sarcoma is a high-grade tumor characterized by its lack of a specific line of differentiation. Histologically, it lacks a definitive pattern but is notable for pleomorphic spindle cells with frequent, bizarre, multinucleate tumor giant cells. These cells often arrange in a cartwheel pattern around blood vessels, with marked cellular atypia and frequent mitoses (Figure 3). Tumor necrosis is often extensive.

Figure 3: H&E stain, undifferentiated pleomorphic sarcoma: High-grade sarcoma composed of pleomorphic spindle and polygonal cells showing no identifiable line of differentiation by histology, immunohistochemistry, or molecular studies. Necrosis, mitotic activity, and atypia are commonly seen. (Image courtesy of Drs. Amir Qorbani and Andrew Horvai.)

The diagnosis of undifferentiated pleomorphic sarcoma is one of exclusion. Extensive sampling and immunohistochemical studies are necessary to rule out other malignancies with specific lines of differentiation, such as dedifferentiated liposarcoma or leiomyosarcoma.

High-grade myxofibrosarcoma and undifferentiated pleomorphic sarcoma can be morphologically similar and are sometimes difficult to distinguish, particularly when the myxoid component is limited. A practical diagnostic criterion used by many soft tissue pathologists is that a pleomorphic sarcoma demonstrating 10% or more myxoid stroma is classified as high-grade myxofibrosarcoma, whereas tumors with minimal or absent myxoid change (<10%) are diagnosed as undifferentiated pleomorphic sarcoma.

Genetically, undifferentiated pleomorphic sarcoma is highly unstable with complex karyotypes. Cytogenetic abnormalities have been observed in nearly all chromosomes, with no consistent or characteristic alterations identified. Common findings include aneuploidy, chromosomal gains and losses, and structural rearrangements.

Differential Diagnosis

Other soft-tissue sarcomas, such as myxofibrosarcoma, dedifferentiated liposarcoma, among others
Hematoma

Disease Course: Treatment and Prognosis

Diagnosis should be confirmed by biopsy (needle or open). As mentioned above, staging studies, including PET-CT or CT of the chest, abdomen, and pelvis, should also be performed to delineate metastatic disease.

The primary treatment modality for localized undifferentiated pleomorphic sarcoma is wide surgical resection and external beam radiation. Radiation therapy can be administered either preoperatively or postoperatively. Preoperative radiation is usually given at a 50 Gy dose but carries an increased risk for surgical wound complications. Postoperative radiation is generally administered at a dose of 60-66 Gy to a larger field, leading to higher rates of soft-tissue fibrosis, arthrofibrosis (if a neighboring joint is included in the field), neuropathy, and lymphedema. There is no significant difference in local recurrence or survival between preoperative and postoperative radiation. Chemotherapy, which has an unproven survival benefit, is given preoperatively on a case-by-case basis, and is typically considered for younger patients, high-risk tumors, or patients with metastatic disease.

The 5-year metastasis-free survival rate for undifferentiated pleomorphic sarcoma found in the limbs or trunks of adults is approximately 80%. Local recurrence rates vary but are generally around 20% with combined modality treatment. Overall survival at 5 years ranges from 50-70%, depending on various prognostic factors. These factors include tumor size (with tumors larger than 5 cm associated with a worse prognosis), depth (deep tumors have a worse prognosis), margin status after resection, and the presence of metastatic disease at diagnosis.

Regular clinical examinations and imaging studies, usually MRI of the primary site and CT of the chest, are recommended. Typically, follow-up occurs every 3 months for the first 2 years, then every 6 months until 5 years, and annually thereafter. Despite aggressive multimodal treatment, undifferentiated pleomorphic sarcoma has a significant risk of both local recurrence and distant metastasis. Early detection and treatment of recurrences or metastases can sometimes lead to long-term survival, emphasizing the importance of early diagnosis and vigilant follow-up.

Key Test Points

MRI shows a heterogeneous soft-tissue mass in the extremities.
Histology shows pleomorphic cells with no specific immunohistochemical stains, except vimentin which identifies it as a mesenchymal tumor.
Treatment is wide resection and local radiation.