Undifferentiated pleomorphic sarcoma

Undifferentiated pleomorphic sarcoma (UPS) is a high-grade malignant mesenchymal neoplasm that, by definition, shows no identifiable line of differentiation when analyzed by currently available technologies.[1][2] It is classified among tumors of uncertain differentiation in the 2020 WHO Classification of Tumours of Soft Tissue and Bone.[3][4] UPS may arise in soft tissue or, less commonly, as a primary intraosseous neoplasm.[5][6] In the oral and maxillofacial region, UPS is extremely rare, occurring in the jaws, sinonasal cavity, or oral soft tissues, where it typically presents as a rapidly enlarging destructive mass.[7][8] The etiology is largely unknown; prior radiation therapy is a recognized risk factor, and rare cases arise in pre-existing osseous conditions such as fibrous dysplasia, Paget disease, or bone infarcts.[9][10][11] Radiographically, jaw lesions characteristically produce aggressive osteolytic destruction without intrinsic mineralization.[12][13] Management centers on wide surgical resection with adjuvant radiation therapy.[3][7]

Current Classification

The 2020 WHO Classification of Tumours of Soft Tissue and Bone places UPS within the category of undifferentiated sarcomas under tumors of uncertain differentiation (ICD-O code 8802/3).[3][14] The WHO defines UPS as a pleomorphic high-grade sarcoma in which thorough sampling and judicious use of ancillary techniques fail to disclose a specific line of differentiation; it is explicitly a diagnosis of exclusion.[1][2]

Nomenclature Evolution

• Malignant fibrous histiocytoma (MFH) was the dominant term from the 1960s through the 1990s, when it was considered the most common adult soft tissue sarcoma. The 2002 WHO revision declassified MFH as a distinct entity and reclassified the storiform-pleomorphic, giant cell, and inflammatory subtypes under UPS, while the myxoid and angiomatoid subtypes were separated as distinct tumors.[2][15][16]
• The term MFH persists in older literature and some clinical databases but is now considered obsolete for diagnostic use.[2]
• Acceptable synonyms include undifferentiated high-grade pleomorphic sarcoma and pleomorphic undifferentiated sarcoma.[14][17]

• UPS accounts for no more than approximately 5% of adult soft tissue sarcomas under current diagnostic criteria, substantially lower than the historical MFH prevalence, which reflected overdiagnosis before modern immunohistochemistry and molecular techniques.[2]
• Peak incidence occurs in the sixth and seventh decades of life, with a median age at diagnosis near 60 years. A slight male predominance is reported for soft tissue UPS overall.[2][7][15][18]
• The extremities (particularly the lower limbs) are the most common sites, followed by the trunk and retroperitoneum; the head and neck region is uncommon.[2][15]
• In the oral and maxillofacial region, UPS is extremely rare. A systematic review of 687 oral and maxillofacial sarcomas found UPS in approximately 7% of cases, making it the fifth most common sarcoma at this site after osteosarcoma, rhabdomyosarcoma, chondrosarcoma, and synovial sarcoma. Among head and neck soft tissue sarcomas specifically, UPS was the most prevalent subtype in one large registry study.[19][20]
• Jaw involvement (mandible and maxilla) and the sinonasal cavity are the most frequently reported oral and maxillofacial sites. The mandible and maxilla are affected in roughly equal proportions in reported jaw series.[10][12]
• Radiation-induced UPS of the jaws is a recognized but rare entity, with fewer than 15 documented cases in the jawbone literature.[9][13]

Presentation and Symptoms

• The characteristic presentation is a rapidly progressive, enlarging mass that may be painful. In the jaws, swelling is the most common complaint, followed by pain, numbness, and trismus.[7][8][19]
• Soft tissue lesions of the oral cavity or gingiva may present as firm, nodular, reddish masses that may ulcerate, occasionally mimicking reactive or inflammatory conditions such as fibrous hyperplasia or chronic infection.[21][22]
• Intraosseous jaw lesions may present with jaw swelling, loosening of teeth, or pathologic fracture.[12]
• Sinonasal UPS may cause nasal obstruction, epistaxis, or facial asymmetry, and can extend into the orbit or cranial base.[10]

Tempo and Complications

• Growth is typically rapid, often over weeks to months, reflecting the high-grade biology. In one oral-maxillary series, the median overall survival was only 7.75 months, underscoring the aggressive clinical course when diagnosis is delayed.[7][8]
• Metastasis occurs hematogenously, most commonly to the lungs; regional lymph node metastasis is uncommon but reported. Approximately 5% of patients present with distant metastases at diagnosis.[2][17]

Red Flags

• Any rapidly enlarging deep-seated mass in the oral and maxillofacial region in an adult, particularly in the sixth or seventh decade, warrants urgent biopsy.
• A history of prior radiation therapy to the head and neck should raise suspicion for radiation-induced sarcoma.[9][13]

Location and Distribution

• Intraosseous UPS of the jaws affects the mandible and maxilla without strong site predilection. In the mandible, the body and molar region are commonly involved. Maxillary lesions may center in the alveolar process or extend into the maxillary sinus.[9][12][21][23]
• Soft tissue UPS of the oral cavity arises most often in the gingiva, buccal mucosa, or palate, and may secondarily invade underlying bone.[7][22]
• Sinonasal UPS most commonly originates in the maxillary sinus or nasal cavity.[10]

Periphery and Shape

• Intraosseous lesions characteristically display ill-defined, irregular margins without a sclerotic border, consistent with aggressive biologic behavior. On panoramic radiographs, the margins are ragged and poorly demarcated from surrounding normal bone.[12][13]
• Soft tissue masses arising adjacent to bone typically show irregular, infiltrative borders on cross-sectional imaging.[10][24]
• Well-defined margins are rare and reported only occasionally.[10]

Internal Architecture

• The hallmark is a purely radiolucent (osteolytic) lesion without intrinsic mineralization. Unlike osteosarcoma, UPS does not produce osteoid or chondroid matrix, so no internal calcification or ossification is expected.[12][25]
• The pattern of bone destruction is characteristically aggressive: moth-eaten or permeative osteolysis is common, while geographic destruction with ill-defined margins may also occur.[13][26][27]
• Periosteal reaction is uncommon in jaw UPS; when present, it is typically interrupted or absent rather than organized, reflecting the tumor's rapid, destructive growth. Codman triangle formation is occasionally seen in osseous lesions.[13][25][27]

Effects on Teeth and Adjacent Structures

• Displacement and loosening of teeth are common when the lesion involves the alveolar process.[12]
• Root resorption may occur but is not a prominent or consistent feature.
• The inferior alveolar canal may be destroyed or obscured by the lesion in mandibular cases.

Extent and Cortical Involvement

• Cortical destruction with soft tissue extension is characteristic and present in the majority of reported jaw cases. Buccal and lingual cortical plates are frequently breached.[10][12]
• Maxillary lesions commonly extend into the maxillary sinus, nasal cavity, orbit, or infratemporal fossa.[10][21]
• Mandibular lesions may extend into the floor of mouth, masticator space, or along the inferior alveolar nerve canal.
• CBCT demonstrates cortical perforation and the three-dimensional extent of bone destruction more reliably than panoramic radiography, particularly for detecting early cortical breach and for surgical planning.[28]

Growth Pattern

• The growth pattern is infiltrative and aggressive, with rapid expansion and destruction of surrounding structures. A pseudocapsule may form in soft tissue lesions but does not indicate containment, as microscopic tumor infiltration beyond the pseudocapsule is typical.[10][24][29]

Variants and Special Patterns

• Radiation-induced UPS of the jaws presents radiographically as a poorly defined radiolucent lesion without periosteal or endosteal reaction, arising within a previously irradiated field; the background bone may show changes of osteoradionecrosis or chronic osteomyelitis.[9][13]
• UPS arising in pre-existing fibrous dysplasia of the jaw has been reported; the development of a new aggressive lytic focus within ground-glass bone should raise concern for malignant transformation.[10]

Medical CT

• Contrast-enhanced CT demonstrates a heterogeneously enhancing soft tissue mass with bone destruction. Attenuation values are nonspecific, typically iso- to slightly hyperdense relative to muscle. CT is superior for delineating cortical bone destruction and detecting subtle matrix mineralization (which should be absent in UPS).[10][30][31]
• CT of the chest is essential for staging, given the propensity for pulmonary metastasis.[3]

MRI

• MRI is the preferred modality for evaluating soft tissue extent, marrow involvement, perineural spread, and skull base invasion in head and neck UPS.[3][30]
• Signal characteristics are nonspecific: lesions are typically isointense to slightly hyperintense to muscle on T1-weighted images and heterogeneously hyperintense on T2-weighted images, with areas of necrosis and hemorrhage contributing to signal heterogeneity. Notably, some osseous UPS lesions display unusually low to intermediate T2 signal intensity relative to their aggressive radiographic appearance.[26][27][32]
• Gadolinium-enhanced sequences show heterogeneous enhancement, often with peripheral or nodular patterns and central non-enhancing areas corresponding to necrosis.[24][27]
• MRI is also preferred for postoperative surveillance to detect local recurrence.[3]

FDG-PET/CT

• FDG-PET/CT may be considered for staging, prognostication, grading, and assessing response to neoadjuvant chemotherapy in soft tissue sarcomas, including UPS.[3]

The imaging appearance of UPS in the jaws is nonspecific, consisting of aggressive osteolytic destruction without matrix production. The differential centers on other malignant lesions that produce similar aggressive radiolucencies in the jaws of adults.

The highest-risk diagnostic pitfall is misidentifying a sarcomatoid carcinoma or undifferentiated carcinoma as UPS, or vice versa, because management differs fundamentally. A comprehensive immunohistochemical panel including cytokeratins, S100, desmin, and melanocytic markers is essential before accepting a diagnosis of UPS.[34][35]

Microscopic Features

• UPS is characterized by marked nuclear pleomorphism with bizarre multinucleated giant cells admixed with spindle-shaped cells and rounded histiocyte-like cells arranged in a haphazard or storiform growth pattern.[2][7]
• Mitotic activity is brisk, including atypical mitoses. Necrosis is common and contributes to high-grade designation.[2]
• A variable number of foamy histiocytes (xanthoma cells) and stromal chronic inflammatory cells may be present.[2][7]

Immunohistochemistry

• UPS typically expresses only vimentin; this "vimentin-only" phenotype is characteristic but not specific.[2][7]
• Focal smooth muscle actin (SMA) positivity may occur in scattered cells reflecting myofibroblastic differentiation and should not be interpreted as evidence of leiomyosarcomatous lineage.[2][36]
• The diagnosis requires negativity for lineage-specific markers: cytokeratins (to exclude carcinoma), S100 protein (to exclude melanoma and nerve sheath tumors), desmin and myogenin (to exclude rhabdomyosarcoma), h-caldesmon (to exclude leiomyosarcoma), and CD34.[21][34][36]
• CD68 and lysozyme (histiocytic markers) are not diagnostically useful and do not support a histiocytic origin.[7]
• MDM2 and CDK4 immunohistochemistry or FISH should be performed to exclude dedifferentiated liposarcoma, which can morphologically mimic UPS but carries a different prognosis and may be amenable to targeted therapy.[1][36]

Radiologic-Pathologic Correlation

The purely osteolytic, non-matrix-producing radiographic appearance correlates with the absence of osteoid, chondroid, or other differentiated matrix at the histologic level, distinguishing UPS from osteosarcoma and chondrosarcoma.[6][25]

Molecular Features

• UPS lacks recurrent, diagnostically defining molecular alterations, which is consistent with its status as a genomically complex sarcoma and a diagnosis of exclusion.[1][37]
• Molecular testing (including next-generation sequencing) is primarily useful to exclude other entities with specific genetic signatures (e.g., MDM2 amplification in dedifferentiated liposarcoma, SS18 rearrangement in synovial sarcoma) rather than to confirm UPS.[1][37]

Workup and Referral

• All patients with suspected UPS should be evaluated by a multidisciplinary team with sarcoma expertise before initiation of therapy.[3][37]
• Imaging of the primary site (MRI preferred for head and neck) and chest CT for pulmonary staging are essential components of the initial workup.[3]
• Biopsy should be carefully planned along the anticipated surgical resection axis; core needle biopsy is preferred, with incisional biopsy reserved for cases requiring more tissue.[3]

Definitive Treatment

• Wide surgical resection with oncologically appropriate (negative) margins is the cornerstone of treatment. In the jaws, this typically requires segmental mandibulectomy or maxillectomy with adequate bony and soft tissue margins.[3][7][38]
• Achieving negative margins (R0 resection) is a critical independent predictor of both overall survival and recurrence-free survival.[20][38][39]
• Adjuvant radiation therapy is recommended for high-grade lesions and is associated with improved local control and overall survival. Neoadjuvant radiation is a category 1 recommendation for resectable stage II–III extremity/head and neck soft tissue sarcomas per NCCN guidelines.[3][7][20][38]
• Neoadjuvant pembrolizumab with radiation therapy followed by adjuvant pembrolizumab is now included as a preferred neoadjuvant/adjuvant option for UPS-related sarcomas in the NCCN guidelines.[3]
• Anthracycline-based chemotherapy (e.g., doxorubicin/ifosfamide) may be considered in the neoadjuvant or adjuvant setting for high-risk disease, though chemotherapy offers limited additional benefit in UPS compared with surgery and radiation.[3][7]

Recurrence and Prognosis

• UPS carries a high propensity for both local recurrence and distant metastasis. Reported local recurrence rates exceed 30%, and metastatic rates approach 30–40%.[7][15][16]
• Five-year overall survival for UPS across all sites is approximately 50–60%. Head and neck UPS carries a poorer prognosis than extremity disease, with an average survival of 18 months in one SEER analysis.[7][18][38]
• Oral and maxillofacial UPS has a particularly aggressive course; one series reported a median overall survival of only 7.75 months.[8]
• Adverse prognostic factors include older age, tumor size ≥5 cm, positive surgical margins, high tumor grade, and presence of metastatic disease at diagnosis.[20][38]

Surveillance

• Follow-up includes history and physical examination every 3–6 months for 5 years, then annually, with periodic imaging of the primary site (MRI preferred) and chest imaging for metastatic surveillance.[3]

Radiation-Induced UPS

• UPS arising in a previously irradiated field is a recognized entity, typically developing years to decades after radiation therapy for head and neck malignancies such as nasopharyngeal carcinoma or lymphoma. The diagnosis requires a latency period (generally ≥3 years), location within the prior radiation field, and histologic confirmation of sarcoma distinct from the original malignancy.[9][13]
• Radiation-induced sarcomas of the jaws carry a particularly poor prognosis, with most patients succumbing to disease despite aggressive multimodality treatment.[12][13]

Pre-existing Osseous Conditions

• Rare cases of UPS have been reported arising in the setting of fibrous dysplasia, Paget disease, or chronic osteomyelitis of the jaws. Development of new pain, rapid growth, or a new lytic focus within a known benign osseous condition should prompt urgent re-evaluation and biopsy.[9][10]