Malignant Fibrous Histiocytoma (UPS): Undifferentiated Pleomorphic Sarcoma — Overview, Diagnosis & Treatment Options | MyMedicPlus

Malignant fibrous histiocytoma (MFH), now reclassified as undifferentiated pleomorphic sarcoma (UPS), was historically the most commonly diagnosed soft tissue sarcoma in adults. Under WHO 2013 and 2020 classifications, MFH is no longer recognized as a distinct entity; the diagnosis is now UPS, a high-grade sarcoma showing no line of differentiation by immunohistochemistry or molecular analysis. UPS represents approximately 20% of all soft tissue sarcomas and predominantly occurs in adults aged 50-70 years, most commonly in the extremities.

Most UPS cases are sporadic without identifiable cause. Prior therapeutic radiation to any anatomical site is a recognized risk factor for radiation-induced UPS, with a latency period of 5-30 years. Li-Fraumeni syndrome (TP53 germline mutation), NF1, and retinoblastoma syndrome increase sarcoma risk including UPS. Complex genomic instability (numerous chromosomal gains and losses without recurrent translocations) is the hallmark of UPS. TP53 mutations are found in approximately 30-40% of UPS. CDKN2A homozygous deletion and RB1 loss are common. No established environmental or dietary risk factors exist for sporadic UPS.

UPS typically presents as a deep-seated, painless or minimally painful enlarging soft tissue mass in the extremity or retroperitoneum. Extremity UPS often crosses fascial planes and may involve adjacent neurovascular structures with time. Retroperitoneal UPS may grow to large sizes (greater than 10 cm) before causing symptoms: abdominal pain, nausea, early satiety, or compression of adjacent organs. Constitutional symptoms (weight loss, fatigue) suggest advanced disease. Pathological fracture may be a presenting feature when UPS arises adjacent to bone.

MRI with gadolinium is the preferred imaging for local staging, delineating tumor compartmentalization and neurovascular proximity. CT of chest, abdomen, and pelvis evaluates for pulmonary and hepatic metastases. Core needle biopsy in the planned resection plane is the diagnostic standard; surgical excisional biopsy risks compromising subsequent R0 resection. Histology shows a highly pleomorphic spindle and epithelioid cell tumor with no identifiable differentiation by immunohistochemistry (negative for actin, desmin, S100, CD34, MDM2, SOX10, MUC4). FNCLCC grading (grade 2 or 3 in UPS) and AJCC 8th edition TNM staging guide management.

Wide excision with negative margins (R0) is the cornerstone of curative treatment. Extremity UPS: limb-preserving surgery with pre-operative (50Gy) or post-operative (60-66Gy) radiation for high-grade tumors greater than 5 cm; amputation reserved for unresectable cases. Retroperitoneal UPS: aggressive resection of contiguous organs to achieve R0 margins if feasible. Adjuvant doxorubicin-based chemotherapy for high-risk UPS is used based on institutional practice. Metastatic UPS: doxorubicin monotherapy or doxorubicin plus ifosfamide; gemcitabine plus docetaxel; trabectedin; eribulin; pazopanib. Immunotherapy (pembrolizumab) shows modest activity in selected patients.

Five-year overall survival for localized extremity UPS is approximately 50-60%; retroperitoneal UPS approximately 30-40% due to challenges achieving R0 resection. FNCLCC grade is the most important prognostic factor; all UPS are grade 2-3 (high-grade). Tumor size greater than 5 cm, depth (deep vs superficial), retroperitoneal location, and positive surgical margins are adverse prognostic factors. Approximately 40-50% of patients with localized high-grade UPS develop distant metastases, predominantly to the lungs, within 2-3 years. Median OS for metastatic UPS is approximately 12-16 months.

No prevention strategies exist for sporadic UPS. Avoidance of unnecessary therapeutic radiation minimizes radiation-induced sarcoma risk. Patients with hereditary predisposing syndromes (Li-Fraumeni syndrome, NF1, retinoblastoma) should undergo annual whole-body MRI surveillance starting in childhood or early adulthood. Unexplained soft tissue masses greater than 5 cm, or deep to fascia regardless of size, or rapidly enlarging masses, should be urgently referred to a specialist sarcoma center for evaluation and biopsy planning rather than excision in a non-specialist setting.