Undifferentiated Pleomorphic Sarcoma

Etiology

The etiology of UPS remains unclear. Most cases are sporadic without identifiable risk factors. UPS may be associated with radiation exposure, with resulting tumors characterized by aggressive clinical behavior. UPS may also arise in the setting of chronic tissue injury, eg, areas of prior trauma, surgical scars, or chronic inflammation, although these associations are not consistently observed. From a molecular standpoint, UPS does not have a characteristic driving mutation.[1][5][4]

Epidemiology

The incidence and prevalence of UPS are challenging to quantify due to historical misclassification (many tumors previously classified as UPS were likely other undifferentiated sarcomas) and the lack of specific tracking in national cancer registries (eg, the SEER database), where UPS is grouped within broader categories of high-grade or unclassified soft tissue sarcomas. Nevertheless, UPS is estimated to comprise approximately 5% to 10% of all adult soft tissue sarcomas, making it one of the most common high-grade sarcoma subtypes in this population. The estimated annual incidence of soft tissue sarcomas in the United States is roughly 13,000 cases, suggesting that approximately 650 to 1,300 of these may be UPS. Global incidence rates are likely similar, as no geographic or racial disparities have been reported.[6] 

UPS predominantly occurs in older adults, with peak incidence between the ages of 50 and 70, and is rare in pediatric populations. A slight male predominance has been observed, though sex differences in outcomes have not been established. Improved histopathologic classification and the adoption of advanced molecular diagnostics have led to a decline in UPS diagnoses, as many previously labeled cases have been reclassified into distinct, genetically defined sarcoma subtypes.[1]

Pathophysiology

UPS arises from primitive mesenchymal cells that have undergone genetic alterations leading to dysregulated cellular proliferation, loss of differentiation, and resistance to apoptosis. UPS tumors exhibit complex karyotypes and commonly harbor copy number alterations and mutations in tumor suppressor genes, eg, TP53, RB, and PTEN, along with disruptions in cell cycle regulators like CCNE1 and ATRX, the latter being involved in telomere maintenance and cellular senescence. These molecular changes drive genomic instability and unchecked proliferation. Unlike most sarcomas, however, UPS is not associated with a defining genetic mutation.[4]

Histopathology

Histopathologic evaluation is critical in establishing a definitive diagnosis of UPS. Core needle biopsy is the preferred technique for initial tissue sampling, preferably with image guidance that can help target the most abnormal appearing regions of the tumor. Biopsy sites should be along the eventual site of surgical incision. Fine needle aspiration and open incisional biopsies are seldom indicated. 

A thorough postoperative pathology report should include the anatomic location of the tumor, depth of invasion, maximal dimension, histologic grade, presence or absence of necrosis, margin status, vascular invasion, mitotic index, nature and extent of inflammatory infiltrate, and tumor-node-metastasis (TNM) staging according to established guidelines.[5][4]

Gross Histologic Examination

UPS typically presents as a large, poorly circumscribed, infiltrative soft tissue mass on gross examination. The cut surface often appears variegated, with areas of tan-white, gray, or fleshy tissue interspersed with zones of necrosis and hemorrhage. The tumor may demonstrate a lobulated appearance and extend into adjacent structures, including fascia, muscle, or subcutaneous fat. Regions of myxoid change, cystic degeneration, or fibrosis may also be present. Lesions are frequently firm to the touch due to a dense fibrous stroma, but softer areas of necrosis and hemorrhage can create heterogeneity. Tumor margins are usually irregular and indistinct, reflecting their locally aggressive nature and propensity for deep tissue invasion. In some cases, satellite nodules or multifocality may be noted, particularly in recurrent disease.[1]

Microscopic Examination

On light microscopy, UPS typically demonstrates markedly pleomorphic spindle cells arranged in storiform, fascicular, or sheet-like patterns within a fibrotic stroma, accompanied by a high mitotic index (see Image. Histologic Examination of Undifferentiated Pleomorphic Sarcoma). Tumor invasion may extend into the deep dermis, subcutis, fascia, and skeletal muscle (see Image. Tumor Invasion of Undifferentiated Pleomorphic Sarcoma). Deep-seated tumors are defined as those involving or penetrating beyond the superficial fascia. While the superficial versus deep designation primarily serves prognostic purposes, deep soft tissue invasion and the absence of solar elastosis are beneficial in distinguishing UPS from atypical fibroxanthoma.

Immunohistochemical Examination

The diagnosis of UPS is ultimately one of exclusion, requiring a comprehensive immunohistochemical (IHC) panel to rule out other morphologically similar entities, including cytokeratins to exclude sarcomatoid carcinoma, S100 and SOX10 for melanoma, smooth muscle actin and desmin for pleomorphic myogenic sarcomas. In cases of intra-abdominal or intrathoracic tumors, MDM2 and CDK4 staining assist in excluding dedifferentiated liposarcoma. Recent findings have shown overlapping expression of LN2, CD10, and ezrin in both UPS and atypical fibroxanthoma, challenging prior assumptions regarding the specificity of LN2 for UPS. In addition, IHC markers, eg, vimentin, p53, and Ki-67 may be expressed in UPS, though they lack diagnostic specificity.[1][4]

History and Physical

Clinical History

The clinical presentation of UPS is often insidious, with patients typically reporting a painless, enlarging soft tissue mass. This tumor most commonly arises in the deep soft tissues of the extremities, particularly the thigh, but can also be found in the trunk or, less commonly, the retroperitoneum. Symptoms may be absent for extended periods, with the lesion often discovered incidentally or once it attains a size sufficient to cause discomfort or functional impairment. Pain or neurological symptoms may occur due to mass effect or compression of adjacent neurovascular structures. Constitutional symptoms are rare unless metastatic disease is present.[5]

Physical Examination

On physical examination, UPS generally presents as a firm, nontender, and immobile mass located deep to the fascia. The overlying skin is usually intact without discoloration or ulceration. Lesions are often large at diagnosis, sometimes exceeding 5 cm in diameter, reflecting their deep location and indolent growth. Involvement of adjacent structures, such as nerves or vessels, may be suspected if associated limb weakness, paresthesia, or diminished pulses are present. Regional lymphadenopathy is uncommon as UPS typically metastasizes hematogenously, most frequently to the lungs. A thorough musculoskeletal and neurologic examination is essential to assess functional status and establish a baseline before intervention.[5]

Evaluation

The evaluation of UPS requires an interprofessional and systematic approach involving imaging, histologic confirmation, and metastatic staging, in accordance with guidelines from the National Comprehensive Cancer Network (NCCN), the European Society for Medical Oncology (ESMO), and other international sarcoma working groups.[5][7]

Laboratory Studies

Laboratory studies are not diagnostic but are often helpful in planning treatment. A complete blood count (CBC), renal and hepatic function panels, and coagulation profile are standard in preoperative evaluation. In rare instances, elevated lactate dehydrogenase (LDH) may suggest aggressive or metastatic disease, although this is not specific to UPS. Additional biomarkers or molecular profiling may be obtained for stratification in patients receiving systemic therapy or enrolled in clinical trials.

Radiographic Evaluation

Magnetic resonance imaging (MRI) of the primary tumor site is the imaging modality of choice for most soft tissue sarcomas. MRI provides detailed information on tumor size, location, compartmental involvement, and relationships with neurovascular bundles and bone. UPS typically demonstrates heterogeneous signal intensity on T2-weighted images and irregular enhancement on postcontrast sequences, often with central necrosis. Diffusion-weighted and subtraction imaging can assist in distinguishing viable tumor from hemorrhagic or necrotic areas. In addition, MRI can help identify the extent of perilesional edema and potential infiltration through fascial planes.[5]

Computed tomography (CT) is utilized for suspected retroperitoneal or truncal lesions. CT scans with contrast are useful initial studies. Moreover, given the relative ease of access to CT and its cheaper and more readily available nature, this modality is often the first imaging study pursued. All patients with high-grade soft tissue sarcomas, including UPS, require staging with a chest CT scan due to the high propensity for pulmonary metastases. This is a class I recommendation in the NCCN guidelines. Whole-body positron emission tomography (PET)/CT may be used selectively, particularly in cases where multifocal disease is suspected or for treatment response monitoring, though not routinely required.[5]

Biopsy

Histologic confirmation via core needle biopsy, performed under imaging guidance, is mandatory before definitive treatment. Biopsy should be performed in a manner that does not compromise future surgical margins. The diagnosis of UPS is one of exclusion, necessitating a comprehensive immunohistochemical workup to rule out other pleomorphic sarcoma subtypes, including dedifferentiated liposarcoma, leiomyosarcoma, malignant peripheral nerve sheath tumor, and solitary fibrous tumor (see Image. Undifferentiated Pleomorphic Sarcoma Biopsy). Immunostaining panels typically include desmin, SMA, S100, CD34, MDM2, CDK4, and nuclear STAT6 markers. Genomic profiling or fluorescence in situ hybridization (FISH) may be required to exclude specific translocation-associated sarcomas.[5][8]

Treatment / Management

Managing UPS involves an interprofessional team, including surgery, radiation, and chemotherapy clinicians. Due to the rarity of this condition and the significant gaps in the current understanding of UPS, enrolling all patients in clinical trials whenever possible should be considered.

Differential Diagnosis

The most common differential diagnoses of UPS are other types of soft tissue sarcomas, which must be distinguished by clinical history, physical examination, and immunohistochemistry markers, including atypical fibroxanthoma, liposarcoma, leiomyosarcoma, angiosarcoma, fibrosarcoma, myxofibrosarcoma, dermatofibrosarcoma protuberans, osteosarcoma, and malignant peripheral nerve sheath tumor.[9][10] Metastases, desmoplastic melanoma, and spindle-cell squamous cell carcinoma may also resemble UPS clinical or histopathological morphology.[11]

Surgical Oncology

Surgical resection is the mainstay for curative intent treatment for UPS. The primary goal is an en-bloc resection with negative microscopic margins (R0 resection), as local recurrence is significantly associated with positive margins. When feasible, wide local excision with a goal of at least 1 cm margins or the inclusion of an anatomic barrier (eg, fascia) is highly recommended.[12] For extremity or trunk-based tumors, limb-sparing surgery should be the standard of care, with amputation reserved for cases where critical neurovascular structures are extensively involved, and reconstruction is not feasible. In the retroperitoneum, complete gross resection, including adjacent organs, may be necessary given the infiltrative nature of high-grade sarcomas in that location. Close coordination with plastic and reconstructive surgery may be required for closure or functional preservation.[5][7]

Radiation Oncology

Adjuvant or neoadjuvant radiation therapy is frequently utilized in the management of UPS, particularly for high-grade tumors or those with close or positive margins. According to randomized data, including the landmark Yang study and subsequent trials, radiation reduces the risk of local recurrence but has not demonstrated a survival benefit.[13] Preoperative radiation (typically 50 Gy) is often preferred for extremity sarcomas, as it allows for a smaller radiation field and better tissue oxygenation.

However, radiation therapy carries a higher risk of postoperative wound complications. Postoperative radiation (generally 60–66 Gy) is indicated when margins are close or positive or when tumors are unexpectedly upstaged. In the retroperitoneum, preoperative radiation is more controversial. Adjuvant or neoadjuvant radiation is typically reserved for selected cases, as shown by the STRASS trial, which did not demonstrate a clear benefit in all comers but suggested a possible role in liposarcoma. For UPS, individualized assessment of recurrence risk and expected morbidity is essential in guiding radiotherapy use.[14][5][7]

Medical Oncology

Systemic therapy plays a role in resectable and metastatic UPS.[5][7]

Adjuvant Chemotherapy

For high-risk localized tumors (generally >5 to 10 cm, deep, and high grade), adjuvant chemotherapy with doxorubicin and ifosfamide may be indicated. The survival benefit remains modest and must be weighed against the significant toxicity.[15]

Neoadjuvant and Perioperative Chemotherapy

Recent meta-analyses and trials, eg, EORTC-STBSG 62931 and ISG-STS 1001, suggest that selected patients, particularly those with poor prognostic features as determined by nomograms (eg, Sarculator), may derive a survival advantage from perioperative chemotherapy.[16][17]

Metastatic Disease

In the metastatic or unresectable setting, doxorubicin remains the first-line agent, alone or in combination with ifosfamide. Other regimens may be used as second-line therapy, such as gemcitabine-docetaxel or gemcitabine-dacarbazine. Targeted therapies, including pazopanib, a multikinase inhibitor, have shown modest efficacy and are approved for pretreated soft tissue sarcomas. Immunotherapy with PD-1 inhibitors, particularly pembrolizumab and nivolumab (alone or in combination with ipilimumab), has demonstrated meaningful response rates in UPS, distinguishing it as one of the more immune-responsive sarcoma subtypes. Clinical trials should be considered for patients with advanced or recurrent disease, especially at high-volume sarcoma centers.[18][19]

Staging

Trunk and extremities UPS is staged according to the TNM and histologic grade (G) (see Table 1. Tumor, Node, Metastasis, and Grade Criteria).[20][21] G is defined by the differentiation, mitotic count, and necrosis extension of the tumor, as stated by the French Federation of Cancer Centers Sarcoma Group (FNCLCC) (see Table 2. Histologic Grade). After TNM and G evaluation, the disease is classified into stages I to IV for therapeutic purposes (see Table 3. Tumor Staging).

Table 1. Tumor, Node, Metastasis, and Grade Criteria

Table 2. Histologic Grade

 Table 3. Tumor Staging

Staging of head, neck, abdominal, thoracic, and retroperitoneum tumors can be consulted in the American Joint Committee on Cancer Staging (AJCC) Manual Eighth Edition, 2017.[20]

Prognosis

Early disease recognition and an adequate treatment strategy are the most critical interventions to improve overall prognosis. In a current retrospective study of 319 patients from 3 tertiary care centers, recurrences and metastases occurred in 14.1% and 7.8% of the cases, respectively.[22] The recurrence risk was significantly increased with preoperative tumors >5 cm, invasion beyond the subcutaneous fat, and advanced AJCC staging. Besides these, metastasis risk was also significantly increased in 2 to 5 cm tumors and those with lymphatic or vascular invasion. However, an essential limitation of this work is that atypical fibroxanthoma diagnoses were pooled together with UPS. In a UPS-specific report, posttreatment local recurrence (15%) was statistically associated with advanced age and inadequate surgical margins, whilst posttreatment metastatic disease (37.6%) was significantly relevant in tumors ≥5 cm.[23] 

The overall survival rates for the 5-year and 10-year periods were 60% and 48%, respectively. Interestingly, in another publication, the 5-year disease-specific survival and recurrence rates were significantly worse in radiation-associated UPS than sporadic UPS, suggesting distinct mutational profiles might exist for the disease.[24]

Follow-up visits are essential to detect local recurrences or metastasis. Physical examination of stage I tumors should be performed at 3- to 6-month intervals for the first 2 years and then annually.[20] Imaging studies are not generally indicated unless prompted by clinical signs and symptoms. Stage II to IV disease must be followed every 2 to 6 months for 2 to 3 years, then every 6 months for 2 years, and annually thereafter. Postoperative MRI with and without contrast or contrast CT are recommended for primary tumor site assessment. Subsequent imaging of the affected and distant areas may be warranted based on the individual risk of recurrence.

Complications

Undifferentiated Pleomorphic Sarcoma Complications

UPS is a high-grade soft tissue malignancy associated with various complications that can arise from the tumor itself, its local and systemic effects, and the treatment modalities used. 

Local complications primarily result from the tumor's aggressive and infiltrative behavior. Large or deeply situated tumors can compress or invade adjacent neurovascular structures, leading to pain, sensory deficits, or motor dysfunction. In the extremities, such involvement may result in impaired limb function or even necessitate amputation in cases where critical structures cannot be preserved during resection. In retroperitoneal locations, UPS may compress or infiltrate vital organs, leading to bowel obstruction, hydronephrosis, or vascular compromise.

UPS has a high propensity for hematogenous metastasis, most commonly to the lungs. Pulmonary metastases may be asymptomatic or present with cough, hemoptysis, pleuritic pain, or dyspnea. Less commonly, liver, bone, or brain metastases may occur, contributing to systemic symptoms and organ-specific dysfunction. High-grade tumors are also at risk for early recurrence, particularly if resection margins are inadequate.

Treatment-Related Complications

Treatment-related complications are also significant. Surgical resection, especially when involving large or anatomically complex tumors, can lead to wound healing problems, seroma or hematoma formation, infection, and long-term functional impairment. In the case of preoperative or postoperative radiation therapy, patients may experience fibrosis, joint stiffness, lymphedema, delayed wound healing, and secondary radiation-induced malignancies. Chemotherapy-related toxicity includes myelosuppression, cardiotoxicity (particularly with doxorubicin), nephrotoxicity, and fatigue, all of which may limit treatment intensity or duration.

Finally, psychosocial distress, decreased quality of life, and physical disability are essential but sometimes underrecognized complications, particularly in patients requiring extensive surgeries or facing recurrent or metastatic disease. As such, early engagement of rehabilitation, pain management, psychosocial support, and survivorship care is essential to comprehensive management.[1][5][7]