Undifferentiated Pleomorphic Sarcoma

Staging is according to bone sarcoma protocols (see TNM staging of tumors of bone).

UPS of bone is highly aneuploid and shows complex chromosomal complements with numerous structural aberrations and marker chromosomes. These cytogenetic observations are confirmed by array hybridization studies, which reveal frequent losses of 8p, 9p, 10, 13q, and 18q and gains of 4q, 5p, 6p, 7p, 8q, 12p, 14q, 17q, 19p, 20q, 22q, and X. Homozygous deletions of CDKN2A, RB1, TP53, and ING1 are present in a subset of UPSs. Mutations in TP53 (~30%) and/or chromatin-remodeling genes (~40%) are most frequent. In general, the copy-number alterations in UPS of bone overlap with those identified in the same tumors originating in soft tissue. UPS of bone exhibits multiple somatic gene fusions, two of which, CLTC-VMP1 and FARP1-STK24, appear to be recurrent and were reported previously in multiple cancers. RNA sequencing expression data indicate that UPS has an expression profile distinct from that of its soft tissue counterpart and is characterized by activation of the FGF23 pathway.

The gross appearance of UPS is quite variable. The cut surface texture ranges from fibrous to soft. Areas of necrosis and hemorrhage are frequently present. The tumors exhibit a range of colors, including greyish-white, yellow, and brownish-tan. Cortical destruction and a soft tissue mass are commonly present.

The tumor is diffusely composed of spindle-shaped and epithelioid or polygonal cells with marked pleomorphism arranged in a haphazard, storiform, and fascicular growth pattern. Variable numbers of large, bizarre multinucleated giant cells and numerous typical and atypical mitotic figures are readily identified. The tumor cells are often embedded within a collagen-rich stroma, which may be hyalinized. A background population of scattered foamy histiocytes and inflammatory cells can be seen among the neoplastic cells. Importantly, the tumor lacks any evidence of malignant osteoid or cartilage, thus necessitating thorough sampling in order to rule out osteosarcoma and dedifferentiated chondrosarcoma. Trabeculae of reactive woven bone are occasionally present, particularly at the periphery or in the setting of a pathological fracture.

mmunohistochemistry is an essential part of the diagnosis because, by definition, UPS lacks an identifiable line of differentiation and is a diagnosis of exclusion. Caution is required when interpreting myogenic markers, because approximately 50% of UPSs of bone show focal positivity with a single myogenic marker. SMA positivity with an additional myogenic marker (desmin or h-caldesmon) supports leiomyosarcoma in an appropriate histological context. Desmin, myogenin, and MYOD1 aid in ruling out rhabdomyosarcoma. SATB2 immunoreactivity can be seen in UPS, a limiting factor when exploring the possibility of osteosarcoma. H3.3 p.Gly34Trp (G34W) expression is occasionally seen in bone sarcomas without associated giant cell tumor histology; these are usually sited in the epiphysis in young people, suggesting a relationship with a giant cell tumor. Therefore, there is a move to expand the definition of primary malignant giant cell tumor on the basis of an H3-3A (H3F3A) or H3-3B (H3F3B) p.Gly34 mutation. Focal cytokeratin positivity can be seen in UPS, but abundant expression should raise concern for metastatic sarcomatoid carcinoma. Several melanocytic markers are indicated in the setting of focal S100 expression in order to exclude melanoma.

The differential diagnosis is broad, including a variety of high-grade sarcomas, metastatic carcinoma, and metastatic melanoma. When features are similar to those of high-grade myxofibrosarcoma of soft tissue, some pathologists favor a diagnosis of high-grade myxofibrosarcoma of bone.

Not clinically relevant

Patients with UPS of bone are generally treated with chemotherapy and complete en bloc resection. Patients with localized disease and adequate therapy have a 5-year survival rate of 50–67%. Pulmonary metastases are common, occurring in approximately 35–50% of cases. Secondary UPS and metastatic disease are associated with a poorer prognosis. Incomplete expression of myogenic markers is not thought to affect the prognosis.

The absence of IDH1 or IDH2 mutations in UPS of bone can be used in the differential diagnosis with dedifferentiated chondrosarcoma. Similarly, the presence of an H3-3A (H3F3A) or H3-3B (H3F3B) p.Gly34 mutation may suggest a relationship with giant cell tumor of bone, and there is a move to expand the definition of primary malignant giant cell tumor of bone on the basis of an H3-3A (H3F3A) or H3-3B (H3F3B) p.Gly34 mutation.

Essential: bone tumor with compatible imaging; pleomorphic spindle-shaped and epithelioid cells in a storiform or fascicular growth pattern; no malignant cartilage or bone production by the tumor cells; no specific line of differentiation.

Desirable: atypical mitotic figures; necrosis.