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Undifferentiated pleomorphic sarcoma

Undifferentiated pleomorphic sarcoma (UPS) is a rare, aggressive soft tissue sarcoma arising from primitive mesenchymal cells that lack specific differentiation, characterized by pleomorphic spindle cells with high mitotic activity and necrosis.^[1] Formerly known as malignant fibrous histiocytoma, it accounts for approximately 5-10% of adult soft tissue sarcomas, with an incidence of approximately 0.3 new cases per 100,000 people annually.^[1] This high-grade malignancy most commonly presents as a painless, enlarging mass in the deep soft tissues of the extremities, particularly the thighs, though it can also occur in the trunk, retroperitoneum, or rarely in bone.^[1] UPS predominantly affects individuals aged 50 to 70 years, with a slight male predominance, and is rare in children.^[2] Risk factors are limited and include prior radiation exposure or chronic tissue injury, though most cases occur sporadically without identifiable causes.^[1] Clinically, it often manifests as a slow-growing, painless lump, but larger tumors may cause pain, swelling, numbness, or functional impairment depending on the location; retroperitoneal tumors can lead to abdominal pain, weight loss, or constitutional symptoms like fever.^[3] Diagnosis typically involves imaging such as MRI or CT to assess tumor extent, followed by core needle biopsy with histopathological examination and immunohistochemistry to confirm the undifferentiated nature and rule out other sarcomas.^[4] Treatment for UPS centers on wide surgical resection with negative margins (R0 resection) to achieve local control, often combined with adjuvant or neoadjuvant radiation therapy, especially for high-grade, deep, or large (>5 cm) tumors.^[1] Chemotherapy, such as doxorubicin-based regimens, may be used for metastatic disease or unresectable cases, though its role in localized disease remains controversial.^[2] The prognosis is guarded, with a 5-year overall survival rate of approximately 60% and a 10-year rate of 48%, influenced adversely by tumor size, depth, grade, and presence of metastases, which most commonly occur in the lungs.^[4] Early detection and multidisciplinary management at specialized centers are critical for optimizing outcomes.^[2]

Overview and epidemiology

Definition and classification

Undifferentiated pleomorphic sarcoma (UPS) is an aggressive, high-grade soft tissue sarcoma arising from primitive mesenchymal cells and characterized by a proliferation of pleomorphic spindle and histiocyte-like cells that lack any specific line of differentiation.^[1] Previously known as malignant fibrous histiocytoma (MFH), this terminology implied a fibrohistiocytic origin that has been refuted by immunohistochemical and molecular studies, leading to its reclassification to emphasize the undifferentiated nature of the tumor.^[5] The term UPS was formally adopted in the 2013 World Health Organization (WHO) classification of tumours of soft tissue and bone, replacing MFH and its variants to reflect the absence of true histiocytic differentiation and the diagnosis being one of exclusion after ruling out other pleomorphic sarcomas.^[6] In the 2020 WHO update, UPS is positioned within the category of "undifferentiated and unclassified sarcomas" under tumours of uncertain differentiation, encompassing a heterogeneous group of high-grade sarcomas without definable lineage.^[5] It is designated with the International Classification of Diseases for Oncology (ICD-O) morphology code 8802/3.^[7] UPS subtypes are primarily the storiform-pleomorphic variant, which is the most common and features a storiform pattern of spindle cells with pleomorphism, and the giant cell variant, characterized by multinucleated giant cells; a rare inflammatory variant also exists but is less frequently recognized.^[7] Clinically, UPS typically presents as a rapidly growing, deep-seated mass in the extremities or retroperitoneum and demonstrates high metastatic potential, most often to the lungs.^[1]

Incidence and demographics

Undifferentiated pleomorphic sarcoma (UPS) accounts for approximately 4-10% of all adult soft tissue sarcomas, representing a notable but relatively uncommon subtype among these malignancies.^[1] In the United States, it is estimated to affect 650-1,300 individuals annually, corresponding to an overall incidence of about 0.3-0.5 cases per 100,000 population.^[1] European data similarly report an annual incidence of 0.8-1 new case per 100,000 individuals.^[2] The disease predominantly impacts older adults, with a peak incidence between 50 and 70 years of age and a median diagnosis age of 60-70 years.^[1] It is rare in children and young adults, comprising less than 5% of cases in those under 50 years.^[1] There is a slight male predominance, with a male-to-female ratio of 1.2-1.5:1, as evidenced by cohort studies showing 54% male patients among diagnosed cases.^[8]^[2] No strong ethnic or racial predispositions have been identified for UPS, though reporting biases may contribute to slightly higher documented rates in Western populations with advanced diagnostic infrastructure.^[1] Incidence appears stable over recent decades, but improved histopathological classification has led to a decline in UPS diagnoses as some cases are reclassified to other sarcoma subtypes.^[1] Elevated rates are observed in cohorts with prior radiation exposure, aligning with known risk associations.^[1]

Etiology and pathogenesis

Risk factors

Prior exposure to ionizing radiation is a well-established risk factor for UPS, accounting for a small but significant proportion of cases, estimated at less than 5% overall for soft tissue sarcomas including UPS.^[9]^[1] Therapeutic radiation for prior malignancies, such as breast cancer or lymphoma, carries this risk, with tumors typically developing in the irradiated field after a latency period of 5 to 20 years.^[10] Radiation-associated UPS often exhibits more aggressive behavior compared to sporadic cases.^[11] Certain genetic syndromes confer a rare increased risk for UPS, including Li-Fraumeni syndrome due to germline TP53 mutations and neurofibromatosis type 1 (NF1), though the vast majority of UPS cases are sporadic without identifiable hereditary factors.^[12]^[13] In Li-Fraumeni syndrome, affected individuals have a markedly elevated lifetime cancer risk, including sarcomas like UPS.^[14] Similarly, NF1 predisposes to various soft tissue sarcomas, including UPS, through loss of neurofibromin function.^[13] Chronic lymphedema, particularly post-surgical or post-radiation, has been associated with an increased risk of developing UPS in rare instances, akin to variants of Stewart-Treves syndrome beyond the classic angiosarcoma presentation.^[15]^[16] This association underscores the role of long-standing lymphatic impairment in promoting sarcomatous transformation in affected tissues. Occupational exposures show weak and inconsistent evidence as risk factors for UPS and other soft tissue sarcomas, with potential links to asbestos, phenoxyherbicides (such as those containing dioxin), and vinyl chloride, though these are not definitively causal and primarily implicate specific sarcoma subtypes like angiosarcoma.^[9]^[17] No clear viral or infectious etiologies have been established for UPS development.^[1]

Genetic and molecular features

Undifferentiated pleomorphic sarcoma (UPS) is characterized by profound genomic instability, manifesting as complex karyotypes with extensive chromosomal aneuploidy and structural rearrangements, including frequent gains in chromosomes 1, 3, 4, 6, 7, 8, 16, 17, and 20, as well as losses in chromosomes 2, 11, 12, 14, 18, 21, 22, and Y; notably, no recurrent translocations have been identified across cases.^[18] This heterogeneity underscores the absence of a defining genetic driver, distinguishing UPS from translocation-associated sarcomas and contributing to its aggressive biology through widespread copy number variations ranging from 2 to 168 per tumor.^[18] Deletions in tumor suppressor-rich regions, such as 13q (encompassing RB1), further amplify this instability, promoting unchecked cell proliferation.^[19] Key somatic mutations in UPS predominantly target cell cycle regulators and chromatin remodelers, with TP53 alterations occurring in approximately 69% of cases, often as missense mutations leading to loss of function and p53 overexpression that correlates with recurrence and metastasis.^[20] RB1 inactivation affects 31% of tumors, disrupting retinoblastoma pathway control and facilitating G1/S transition deregulation, while ATRX mutations are seen in 31-38% of cases, impairing telomere maintenance and homologous recombination.^[20] Subsets harbor PTEN deletions or NF1 inactivating variants, activating PI3K/AKT and RAS/MAPK signaling to enhance survival and invasion, though these occur at lower frequencies without defining the disease.^[20] Germline TP53 mutations, as in Li-Fraumeni syndrome, may predispose to UPS development in rare familial contexts.^[21] Tumor mutation burden (TMB) in UPS is generally low with a median of 4.3 mutations per megabase, but elevated TMB exceeding 5-10 mutations/Mb is observed in subsets (up to 10.9% of cases), correlating with higher neoantigen loads and potential responsiveness to immune checkpoint inhibitors.^[22] ^[23] This variability reflects the immune-high subgroup's distinct profile, where increased mutations drive antigenic diversity without recurrent hotspots.^[22] Epigenetic dysregulation in UPS involves aberrant DNA methylation patterns, such as hypermethylation of the p16INK4a promoter leading to cyclin-dependent kinase inhibition loss, and altered microRNA expression, including miR-152 downregulation that upregulates tyrosine kinase receptors to promote progression.^[18] Histone modifications, including mutations in H3 K36 or G34 in select cases, disrupt chromatin accessibility and may contribute to the dedifferentiated, pleomorphic phenotype by silencing differentiation genes.^[24] Methylation of genes like ITGA10 and PPP2R2B further perturbs AKT/mTOR signaling, reinforcing epigenetic contributions to oncogenesis.^[18] The pathogenesis of UPS follows a multistep model of accumulated genetic and epigenetic hits, beginning with initial chromosomal instability that evolves into a pleomorphic, mesenchymal-like state through sequential TP53/RB1/ATRX disruptions and pathway activations like PI3K and Hippo.^[18] In radiation-induced UPS, distinct molecular signatures emerge, including deleterious TP53 mutations and amplifications in KIT/PDGFRA, reflecting therapy-related genomic scars that accelerate this progression without canonical BRCA1/2 alterations but mimicking homologous recombination deficiency through heightened complexity.^[25]

Clinical presentation

Signs and symptoms

Undifferentiated pleomorphic sarcoma (UPS) typically presents as a painless, enlarging mass in the subcutaneous or deep soft tissues, often growing slowly at first but capable of rapid progression thereafter.^[1] This primary symptom is insidious, with many patients noticing the lump only after it has become palpable.^[3] The tumor most frequently arises in the extremities, accounting for 60-70% of cases, with the lower extremities affected more often than the upper ones, where it manifests as a firm, fixed mass.^[7] Retroperitoneal locations represent 15-20% of occurrences and may lead to abdominal distension or symptoms from organ compression, such as discomfort or functional impairment.^[26] Involvement of the head and neck is rare (1-3% of cases) but often symptomatic due to spatial constraints in these areas.^[27] Associated symptoms are generally limited, with local tenderness possible if the mass is large; advanced cases may include fatigue or weight loss, while early stages show no specific systemic manifestations.^[1] Physical examination reveals a non-mobile mass typically exceeding 5 cm, without skin changes or ecchymosis unless the lesion is superficial.^[1] In neglected instances, particularly superficial tumors, progression can result in ulceration or necrosis.^[3]

Associated paraneoplastic phenomena

Paraneoplastic phenomena in undifferentiated pleomorphic sarcoma (UPS) are uncommon but can manifest as systemic effects distinct from local tumor symptoms. The most frequently reported is neoplastic fever, observed in approximately 3.83% of UPS cases based on a retrospective analysis of 183 patients.^[28] This fever is typically low-grade and intermittent, often associated with intratumoral necrosis and extensive peritumoral edema visible on MRI, particularly in tumors located in the extremities or intermuscular spaces.^[28] The mechanism of neoplastic fever in UPS involves tumor-induced inflammatory responses, including the release of cytokines such as interleukin-6 (IL-6), IL-7, IL-8, granulocyte colony-stimulating factor (G-CSF), stem cell factor (SCF), and granulocyte-macrophage colony-stimulating factor (GM-CSF).^[29] Elevated serum IL-6 levels have been documented in a majority of sarcoma patients with this syndrome, contributing to the pyrexia through immune activation and tumor necrosis. It tends to occur in high-grade or locally advanced disease and may resolve following complete tumor resection, though recurrence can happen with metastatic progression.^[29] Clinically, this fever can mimic infectious processes, complicating diagnosis in cases of fever of unknown origin and necessitating exclusion of sepsis or other causes.^[28] Other paraneoplastic syndromes in UPS are rare. Hypoglycemia, mediated by tumor production of insulin-like growth factor-2 (IGF-2), has been reported in isolated cases, presenting as episodic low blood glucose levels unrelated to insulinoma.^[30] This occurs due to IGF-2's structural similarity to insulin, suppressing hepatic glucose production and enhancing peripheral uptake.^[31] These phenomena highlight the role of UPS in triggering remote immune dysregulation, more prevalent in metastatic settings.

Pathology

Histopathologic characteristics

Undifferentiated pleomorphic sarcoma (UPS) typically presents as a large, poorly circumscribed soft tissue mass measuring 5 to 20 cm in greatest dimension, with a firm, white-tan to grayish cut surface that often appears multinodular and variegated due to areas of hemorrhage and necrosis.^[1]^[32] The tumor exhibits infiltrative borders, reflecting its aggressive local growth pattern, and may show a lobulated architecture with dense fibrous stroma contributing to its firmness.^[1] Microscopically, UPS is characterized by a heterogeneous proliferation of markedly pleomorphic spindle cells, histiocyte-like cells, and multinucleated giant cells arranged in a storiform (whorled) or fascicular pattern, often interspersed with a variable amount of collagenous stroma.^[1]^[33] The cells display significant nuclear atypia, including hyperchromasia and irregular contours, with a high mitotic rate typically exceeding 10 mitoses per 10 high-power fields and frequent atypical mitotic figures.^[1]^[34] Geographic areas of necrosis are common, further underscoring the tumor's high-grade nature.^[1] According to the French Federation of Cancer Centers Sarcoma Group (FNCLCC) grading system, the majority of UPS cases (over 50%) are classified as high-grade (FNCLCC grade 3), reflecting their high cellularity, marked pleomorphism, and extensive necrosis.^[35]^[36] Myxoid change, characterized by stromal mucin deposition, occurs in about 20% of cases and may alter the tumor's texture without affecting overall grading.^[37] Histologic variants of UPS include the pure pleomorphic subtype, which is the most common and features prominent storiform architecture; the giant cell-rich variant, dominated by numerous multinucleated giant cells; and the inflammatory subtype, marked by a dense lymphocytic and neutrophilic infiltrate admixed with tumor cells.^[33]^[5] These variants share the core pleomorphic morphology but differ in cellular composition. Diagnosis based on morphology alone poses challenges, as UPS must be distinguished from carcinomas, melanomas, and other sarcomas such as leiomyosarcoma, which may exhibit overlapping pleomorphism and spindled architecture without specific differentiating features.^[1]^[33] Extensive sampling is often required to identify representative areas and exclude mimics.^[33]

Immunohistochemical profile and differential diagnosis

Undifferentiated pleomorphic sarcoma (UPS) exhibits a nonspecific immunohistochemical (IHC) profile, with vimentin expression observed universally in tumor cells, reflecting its mesenchymal origin.^[1] Focal positivity for smooth muscle actin (SMA) or desmin is seen in approximately 20-30% of cases, potentially indicating minor myofibroblastic or myogenic differentiation, while these markers are typically negative or only focally expressed in the pleomorphic cells identified on histopathology.^[7]^[38] The proliferation index, assessed by Ki-67, is markedly elevated, often exceeding 50% and indicating high-grade malignancy.^[1] UPS is negative for lineage-specific markers such as S100 (to exclude melanoma or neural tumors), cytokeratins and pancytokeratin (to rule out sarcomatoid carcinoma or metastatic carcinoma), and CD34 (to differentiate from solitary fibrous tumor or dermatofibrosarcoma protuberans).^[7]^[1] Diagnosis relies on exclusion, requiring a comprehensive IHC panel to negate specific differentiations, including ALK (for inflammatory myofibroblastic tumor) and DOG1 (for gastrointestinal stromal tumor).^[7] TP53 IHC positivity may serve as a surrogate for underlying genetic alterations commonly seen in UPS.^[1] Key differential diagnoses include leiomyosarcoma, which shows diffuse desmin and SMA positivity; dedifferentiated liposarcoma, characterized by MDM2 and CDK4 amplification with corresponding IHC overexpression; rhabdomyosarcoma, marked by myogenin or MyoD1 expression; and metastatic carcinoma, confirmed by pancytokeratin positivity.^[38]^[7] In ambiguous cases, electron microscopy is rarely employed to detect ultrastructural features suggestive of specific differentiation, such as smooth or skeletal muscle elements, while next-generation sequencing can identify mutations or fusions to confirm the diagnosis.^[7] Diagnostic pitfalls arise from tumor heterogeneity, which may result in sampling errors during biopsy, leading to inconclusive IHC results; re-biopsy is recommended in such scenarios to ensure representative tissue sampling.^[1]

Diagnosis and staging

Imaging techniques

Ultrasound serves as an initial screening tool for superficial undifferentiated pleomorphic sarcoma (UPS) lesions, particularly in extremities where a palpable mass is present. It typically reveals a heterogeneous, hypoechoic mass with areas of increased echogenicity corresponding to cellular regions and hypoechoic zones indicating necrosis or cystic change. Doppler imaging may demonstrate hypervascularity within the lesion or invasion of adjacent vascular structures, aiding in preliminary assessment of local extent.^[39]^[30] Magnetic resonance imaging (MRI) is the gold standard for evaluating the local extent of UPS, providing detailed assessment of tumor size, location, compartmental involvement, and invasion of muscle, fascia, or neurovascular structures. On T1-weighted sequences, UPS appears iso- to hypointense relative to muscle, with heterogeneity if hemorrhage, necrosis, or myxoid components are present. T2-weighted images show hyperintense signal overall, often heterogeneous due to necrosis or fibrosis, while post-contrast enhancement is irregular and prominent in viable solid components, highlighting perilesional edema or fascial infiltration.^[1]^[40]^[30] Computed tomography (CT) is particularly useful for staging UPS in retroperitoneal or truncal locations and for detecting distant metastases, especially in the lungs, where it is recommended as a baseline study. UPS lesions on CT exhibit soft-tissue density similar to muscle, with heterogeneous areas of lower attenuation from necrosis, hemorrhage, or myxoid degeneration; contrast enhancement occurs in viable tumor portions, while calcifications are rare, seen in approximately 15-20% of cases. For pulmonary staging, non-contrast chest CT identifies nodules, given the high risk of lung metastases in UPS.^[1]^[40]^[30] Positron emission tomography-computed tomography (PET-CT) using 18F-fluorodeoxyglucose (FDG) demonstrates high avidity in UPS, with standardized uptake values (SUV) often exceeding 5 and reaching up to 12-14 in high-grade lesions, facilitating detection of occult metastases in lymph nodes or bones beyond conventional imaging capabilities. It is selectively employed for suspected multifocal disease or to monitor treatment response, where a greater than 40% decline in SUVmax post-therapy indicates favorable necrosis and predicts better outcomes. However, dedicated chest CT remains superior for pulmonary metastases.^[41] Despite these modalities, UPS lacks pathognomonic radiologic features, presenting nonspecific heterogeneous appearances that overlap with other soft-tissue sarcomas, necessitating biopsy for definitive diagnosis.^[1]^[40]

Biopsy and confirmatory tests

Diagnosis of undifferentiated pleomorphic sarcoma (UPS) requires tissue acquisition through biopsy, with core needle biopsy (CNB) performed under imaging guidance being the preferred initial method due to its minimally invasive nature, high diagnostic accuracy, and low complication rate.^[1] CNB allows for sufficient material to perform histologic evaluation and ancillary studies while minimizing contamination of surrounding tissues. For large or heterogeneous masses where CNB may yield nondiagnostic samples, an incisional biopsy is recommended to obtain representative tissue from the most suspicious area.^[11] Excisional biopsy should be avoided if preoperative staging suggests potential multifocality or metastasis, as it may complicate subsequent wide-margin resection planning.^[42] Adequate sampling is essential, typically involving multiple core samples (at least 3-5) from different regions of the lesion to account for intratumoral heterogeneity and ensure materials for immunohistochemistry (IHC), cytogenetics, and molecular analysis. Fresh frozen tissue should be preserved when possible for next-generation sequencing (NGS) if advanced testing is anticipated.^[43] Confirmatory diagnosis relies on histopathologic examination showing high-grade pleomorphic spindle and epithelioid cells in a storiform pattern, without evidence of specific differentiation, as defined by World Health Organization (WHO) criteria for soft tissue tumors. IHC is crucial for ruling out other sarcomas or carcinomas, typically showing vimentin positivity but negativity for markers of muscle (desmin, myogenin), vascular (CD31, CD34), or epithelial (cytokeratins) differentiation; no specific IHC profile exists for UPS, making it a diagnosis of exclusion. Cytogenetic analysis often reveals complex karyotypes with numerical and structural abnormalities, supporting the undifferentiated nature. In research or select clinical settings, NGS may identify recurrent alterations such as TP53 and RB1 mutations, which occur in over 60% of cases and aid in confirming the diagnosis when histology is ambiguous.^[1]^[44]^[45] Biopsy-related complications are rare but include hemorrhage, infection, and tumor seeding along the needle tract, with the latter reported in less than 1% of cases for CNB and slightly higher for incisional approaches; meticulous technique and tract excision during definitive surgery mitigate this risk. Adequate sampling is critical for accurate tumor grading, as undersampling can lead to underestimation of malignancy.^[46]^[47] Final diagnosis of UPS necessitates multidisciplinary review involving pathologists, oncologists, and surgeons to integrate biopsy findings with clinical and imaging data, ensuring exclusion of mimics and guiding management.^[38]

Staging systems

The staging of undifferentiated pleomorphic sarcoma (UPS), a high-grade soft tissue sarcoma, primarily follows the American Joint Committee on Cancer (AJCC) TNM system as outlined in the 8th edition (2017), which remains the standard as of 2025 with no major revisions for soft tissue sarcomas in subsequent updates.^[48]^[49] The TNM classification assesses tumor size and extent (T), regional lymph node involvement (N), and distant metastasis (M). For UPS in the extremities or trunk—the most common sites—the T category is defined solely by tumor size: T1 for tumors ≤5 cm in greatest dimension, T2 for >5 cm but ≤10 cm, T3 for >10 cm but ≤15 cm, and T4 for >15 cm; there is no distinction for depth in the T category itself, though superficial (above fascia) versus deep (below fascia) location influences stage grouping for smaller tumors.^[48]^[50] Regional lymph node metastasis (N1) is rare in UPS, occurring in fewer than 5% of cases, while N0 indicates no involvement; distant metastasis (M1, typically to lungs) defines stage IV disease regardless of other factors.^[1]^[51] Histologic grade is integrated into the AJCC staging via the Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC) system, which scores tumors on a 0-3 scale for differentiation (UPS typically scores 3 due to pleomorphic, undifferentiated cells), mitotic count (≥10 mitoses per 10 high-power fields scores 3), and necrosis (≥50% scores 3), yielding a total score stratified as G1 (low, 2-3 points), G2 (intermediate, 4-5 points), or G3 (high, 6-8 points).^[52]^[53] As UPS is almost invariably G3, it shifts most localized cases to higher stages: stage groups I-II apply to low-grade tumors (T1/T2 N0 M0 G1/G2), while stage III encompasses T3/T4 N0 M0 any G or any T N0 M0 G3; stage IV includes any M1 or N1.^[48]^[50] Approximately 90% of UPS cases are diagnosed at localized stages (I-III), with about 10% presenting with metastasis.^[1] Site-specific modifications in the AJCC system account for anatomic differences affecting prognosis and management. For extremity or trunk UPS, staging emphasizes resectability, with deep-seated tumors >5 cm (T2b) conferring higher risk than superficial ones.^[51] Retroperitoneal UPS follows a distinct algorithm without grade incorporation, as nearly all are high-grade; stages are based on size alone (stage I: T1 N0 M0; stage II: T2 N0 M0; stage III: T3/T4 N0 M0), reflecting worse outcomes due to delayed diagnosis and incomplete resection, with 5-year survival rates 20-30% lower than extremity sites.^[48]^[54] Head and neck UPS is staged separately with smaller size cutoffs (T1: ≤2 cm; T2: >2-4 cm; T3: >4 cm; T4: invasion of critical structures like neurovascular or skeletal components), classifying it as high-risk due to functional morbidity and lower resectability.^[48]^[50] Prognostic staging for UPS incorporates additional factors beyond TNM, such as tumor size >5 cm (doubling recurrence risk), deep location (associated with 1.5-2-fold higher metastasis rates), and surgical margins (positive margins increase local recurrence by 2-3 times).^[1]^[55] These elements refine risk stratification, guiding adjuvant therapy decisions.^[56] The 2025 National Comprehensive Cancer Network (NCCN) guidelines continue to endorse the AJCC 8th edition but emphasize emerging molecular risk modifiers in clinical trials, particularly low tumor mutational burden (TMB) in UPS, though some cases may respond to immunotherapy due to high T-cell infiltration, which may inform intensified systemic therapy in select subsets.^[57]

Management

Surgical interventions

Surgical intervention remains the cornerstone of treatment for localized undifferentiated pleomorphic sarcoma (UPS), aiming for complete tumor resection with negative margins to minimize local recurrence.^[1] Wide local excision is the standard approach for resectable disease, typically involving margins of 2-5 cm of normal tissue or the inclusion of a fascial barrier to achieve R0 resection.^[31] This limb-sparing technique is feasible in approximately 90% of extremity cases, preserving function while removing the tumor en bloc.^[58] Amputation is reserved for cases where wide excision is not possible due to extensive neurovascular involvement or recurrent disease, occurring in fewer than 10% of extremity presentations; advances in prosthetic technology have improved post-amputation quality of life.^[59] For retroperitoneal UPS, surgery requires en-bloc resection often including adjacent organs such as kidney, colon, or vessels due to the tumor's infiltrative growth, though this carries a high morbidity rate of 20-30% from complications like bleeding or organ dysfunction.^[60] Neoadjuvant planning incorporates advanced preoperative imaging, such as MRI or PET-CT, to define tumor extent and resectability, guiding surgical strategy.^[1] Intraoperative frozen section analysis is routinely used to confirm margin status and adjust resection as needed during the procedure.^[11] Following resection, reconstructive techniques address resultant defects, employing local or free flaps, skin grafts, or vascularized tissue transfers to restore form and function; these are performed in multidisciplinary collaboration with plastic surgeons to optimize outcomes.^[61]

Adjuvant and neoadjuvant therapies

Adjuvant radiation therapy is recommended for patients with undifferentiated pleomorphic sarcoma (UPS) exhibiting high-risk features, such as tumors larger than 5 cm or those with close surgical margins, to reduce the risk of local recurrence following surgical resection.^[62] External beam radiation is typically delivered postoperatively at a total dose of 50-60 Gy in 1.8-2 Gy fractions over 5-6 weeks, which has been associated with a relative reduction in local recurrence risk by approximately 50-60% compared to surgery alone.^[63]^[64] This approach improves overall survival in resected UPS cases, particularly when combined with limb-sparing surgery.^[62] Neoadjuvant radiation therapy is employed preoperatively for borderline resectable UPS to facilitate surgical resection and minimize the volume of irradiated tissue.^[65] A standard preoperative dose of 50 Gy in 25 fractions is commonly used, often with intensity-modulated radiation therapy (IMRT) to spare surrounding normal tissues and reduce toxicity.^[63]^[66] This modality achieves comparable local control to postoperative radiation while potentially lowering late fibrosis rates.^[67] Chemotherapy with the doxorubicin and ifosfamide (AI) regimen is utilized in the neoadjuvant setting for large UPS tumors exceeding 10 cm to shrink the tumor and improve resectability, as well as adjuvantly for high-grade disease to address micrometastatic spread.^[68]^[69] The AI combination yields objective response rates of 20-40% in UPS and other high-risk soft tissue sarcomas, facilitating R0 resection in select cases.^[70]^[71] Combined chemoradiation approaches are applied for extremity UPS to enhance local control, particularly in high-grade tumors, with neoadjuvant AI followed by radiation showing feasibility in multimodal protocols.^[72] The EORTC 62931 trial supports perioperative AI as a standard for high-grade soft tissue sarcomas, including UPS, demonstrating improved disease-free survival without excessive toxicity.^[73] Common side effects of these therapies include wound complications, occurring in 20-35% of cases with radiation—higher with preoperative timing due to impaired healing—and cardiotoxicity from anthracyclines in the AI regimen, affecting up to 6% of patients with cumulative doses exceeding 300 mg/m².^[64]^[74]^[75] Monitoring with echocardiography is recommended to mitigate long-term cardiac risks.^[76]

Emerging treatments

Immunotherapy has emerged as a key investigational approach for advanced and metastatic undifferentiated pleomorphic sarcoma (UPS), particularly with PD-1 inhibitors like pembrolizumab. In the phase II SARC028 trial, pembrolizumab monotherapy yielded an objective response rate of 23% among 40 patients with advanced UPS, with a median progression-free survival of 3 months and overall survival of 12 months.^[77] This activity is partly linked to elevated tumor mutational burden (TMB) in responsive UPS cases, where TMB exceeding 5 mutations per megabase correlated with better outcomes, as seen in subset analyses from SARC028 and the KEYNOTE-158 study showing 29% response in TMB-high sarcomas.^[78] The U.S. Food and Drug Administration has granted tissue-agnostic approval for pembrolizumab in microsatellite instability-high (MSI-H) solid tumors, applicable to the small subset of UPS exhibiting this feature.^[79] Combination strategies are enhancing immunotherapy efficacy in UPS. The phase III SU2C-SARC032 trial demonstrated that adding perioperative pembrolizumab to preoperative radiotherapy and surgery improved 2-year disease-free survival to 67% in stage III extremity UPS, compared to 52% with radiotherapy and surgery alone (hazard ratio 0.61; 90% CI 0.39–0.96).^[80] Other combinations, such as nivolumab plus ipilimumab, achieved a 16.6% response rate in UPS, while pembrolizumab with doxorubicin showed 36.7% responses in limited UPS cohorts.^[81] Targeted therapies remain investigational for UPS, with limited but promising data from combinations like pembrolizumab plus lenvatinib yielding a 20% objective response rate in a small cohort of 5 UPS patients.^[81] mTOR inhibitors such as everolimus are under exploration for UPS cases with PI3K pathway alterations, though specific efficacy in sarcoma subtypes is still emerging from broader pathway-targeted studies.^[82] Ongoing clinical trials are advancing novel modalities for UPS. Phase I studies of chimeric antigen receptor (CAR)-T cell therapies targeting sarcoma antigens like HER2 have shown safety and preliminary antitumor activity in advanced sarcomas.^[83] A phase III trial (NCT06422806) is evaluating pembrolizumab combined with doxorubicin versus doxorubicin alone in advanced UPS and related sarcomas.^[81] Gene therapy approaches are in preclinical stages for UPS. CRISPR/Cas9-based editing to restore wild-type TP53 function has demonstrated potential in suppressing growth of p53-deficient tumor cells, including sarcoma models, by repairing mutant TP53 alleles.^[84] Oncolytic viruses, such as OH2, have induced antitumor immune responses and shown activity in advanced sarcomas through selective tumor lysis and microenvironment remodeling.^[85] Future directions emphasize biomarker-driven selection to optimize immunotherapy in UPS. High TMB (>10 mutations per megabase) and presence of tertiary lymphoid structures guide patient stratification for immune checkpoint inhibitors, with 2025 reviews recommending their use in unresectable disease harboring these features to improve response rates.^[81]

Prognosis and follow-up

Survival rates and outcomes

Undifferentiated pleomorphic sarcoma (UPS) exhibits variable survival outcomes depending on disease extent at diagnosis. The overall 5-year overall survival (OS) rate across all stages is approximately 50-60%. For localized disease confined to the extremities, 5-year OS improves to 70-80%, reflecting the benefits of early detection and localized treatment. In contrast, patients presenting with metastatic disease at diagnosis face a 5-year OS rate of less than 30%. Historical data indicate improvements in survival attributed to refined surgical margins and adjuvant therapies. Long-term 10-year OS stands at approximately 40%. For patients with metastatic UPS, median OS is 12-18 months, though isolated pulmonary metastases confer better prognosis than multi-organ involvement. Recent analyses from the Surveillance, Epidemiology, and End Results (SEER) database report a 5-year OS of 55.6%, positively influenced by multimodal therapeutic strategies.^[55]

Prognostic factors

Several tumor-related characteristics significantly influence the prognosis of undifferentiated pleomorphic sarcoma (UPS). Tumors larger than 5 cm are associated with poorer overall survival (OS), reflecting higher risks of metastasis and recurrence compared to smaller lesions.^[86] As a high-grade malignancy, UPS has aggressive biology and propensity for distant spread.^[86] Deep-seated tumors, located beneath the superficial fascia, worsen prognosis, as they are more challenging to resect completely and are linked to higher recurrence rates.^[86] Additionally, tumor necrosis is an adverse histologic feature indicating aggressive disease and is incorporated into grading systems like FNCLCC to predict worse survival.^[1] Patient-specific factors also play a critical role in UPS outcomes. Advanced age greater than 60 years is linked to an HR of approximately 1.5 to 2.4 for reduced OS, attributable to decreased physiologic reserve and higher comorbidity burden that complicates treatment tolerance. Comorbidities, such as cardiovascular disease or immunosuppression, further impair recovery and increase mortality risk by limiting eligibility for aggressive multimodal therapy. Male sex is associated with slightly worse prognosis in some cohorts, potentially due to differences in tumor biology or treatment response, though this effect is modest and not universally observed.^[56]^[31]^[87] Treatment-related variables are key modifiable prognostic elements. Positive surgical margins after resection elevate the local recurrence rate to around 40%, substantially increasing the risk of disease progression compared to negative margins. Omission of adjuvant therapy, particularly radiotherapy, heightens the risk of local recurrence and distant metastasis, with studies showing improved OS in high-risk cases (e.g., tumors ≥5 cm) treated with adjuvant chemotherapy or radiation.^[88]^[89] Molecular alterations provide additional prognostic insights, though their clinical integration remains evolving. Co-mutations in TP53 and RB1 are linked to poorer OS, as these tumor suppressor gene losses promote genomic instability and resistance to therapy in pleomorphic sarcomas. Paradoxically, high tumor mutational burden (TMB) in UPS correlates with better responses to immunotherapy, despite overall low TMB in this sarcoma subtype, potentially guiding patient selection for immune checkpoint inhibitors.^[90]^[91] Prognosis varies markedly by anatomic site, independent of other factors. Retroperitoneal UPS carries a 5-year OS of approximately 30%, owing to diagnostic delays, incomplete resection, and higher metastatic potential. In contrast, extremity lesions achieve a 5-year OS of about 70%, benefiting from more feasible wide excisions. Head and neck sites yield intermediate outcomes, with 5-year OS around 48-50%, influenced by anatomic constraints on surgery and radiation.^[11]^[11]^[92]

Surveillance strategies

Surveillance strategies for undifferentiated pleomorphic sarcoma (UPS) focus on early detection of recurrence through structured post-treatment monitoring, tailored to the tumor's high risk of local and distant spread. The National Comprehensive Cancer Network (NCCN) guidelines for soft tissue sarcoma, version 2025, recommend a risk-stratified approach, with more intensive follow-up for high-grade tumors like UPS based on factors such as stage, size, and margins.^[93]^[94] Routine clinical evaluation includes history and physical examination every 3 to 6 months for the first 2 years after treatment, followed by every 6 to 12 months up to year 5, and annually thereafter, as most recurrences occur within the initial 2 to 3 years.^[94]^[95] Cross-sectional imaging of the primary site with MRI or CT may be considered based on risk factors, typically every 6 to 12 months during years 1 and 2, then less frequently beyond year 2, to monitor for local recurrence, which affects 20% to 30% of patients and typically manifests within 2 years.^[94]^[56] Chest CT is performed every 3 to 6 months for the first 2 to 3 years to screen for pulmonary metastases, given that distant recurrence occurs in approximately 40% of cases, with the lungs accounting for about 80% of metastatic sites.^[94]^[1]^[35] Laboratory tests, including routine tumor markers, are not recommended due to the lack of specific biomarkers for UPS.^[93] Positron emission tomography-computed tomography (PET-CT) may be used selectively for equivocal findings on standard imaging or in high-risk patients to assess metabolic activity and guide biopsy.^[57] Patient education is emphasized, including instructions on self-examination for local symptoms such as lumps or pain, to facilitate prompt reporting of potential recurrence.^[93]

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