Undifferentiated Sarcoma

The American Joint Committee on Cancer (AJCC) or Union for International Cancer Control (UICC) TNM system may be used.

Undifferentiated pleomorphic sarcomas (UPSs) typically display extensive genomic rearrangements. Cytogenetic data from over 100 cases have revealed complex karyotypes with chromosome numbers ranging from near-haploid to hyperoctaploid. The extensive reshuffling of chromosomal material indicated by tumor karyotypes is corroborated by array-based genomic studies, showing structural rearrangements and copy-number shifts involving most if not all chromosomes, as well as by massively parallel sequencing studies. UPSs demonstrate substantial copy-number heterogeneity compared with other sarcoma subtypes and do not form distinct methylation subgroups. Whole-genome sequencing has revealed that punctuated evolutionary events such as whole-genome duplications and chromothripsis accompanied by telomere dysfunction underpin the genomic complexity of UPS. The aberrations in telomere biology are achieved either through activation of telomerase through deregulation of TERT or through the alternative lengthening of telomeres pathway. There are no tumor-specific amplicons, but some 10–15% of cases show amplification of VGLL3 or YAP1, and 10% have amplification of CCNE1. Targets of frequent deletions and disruptive rearrangements include CDKN2A and CDKN2B in 9p, PTEN in 10q, RB1 in 13q, and TP53 in 17p, each affected in 10–20% of cases. RB1 and TP53, as well as ATRX, are among the few genes that recurrently show pathogenetic variants at the nucleotide level. At the transcriptomic level, UPS cannot be distinguished from high-grade myxofibrosarcoma, and it is possible that these two entities may lie on a spectrum of differentiation. A small subset of UPSs with low mitotic counts show gene fusions involving the PRDM10 gene, with either MED12 or CITED2 as the 5′ partner. Otherwise, driver gene fusions have not been found in UPS.

USTSs are a heterogeneous group and thus have no distinctive macroscopic features, other than the frequent presence of necrosis and hemorrhage.

USTSs may be broadly divided into pleomorphic, spindle cell, round cell, and epithelioid subsets, but none have specific defining features other than their lack of an identifiable line of differentiation. Pleomorphic USTSs, which represent the largest group, closely resemble other specific types of pleomorphic sarcomas and are often patternless, with frequent bizarre multinucleated tumor giant cells. Spindle cell USTSs most often show a fascicular architecture with variably amphophilic or palely eosinophilic cytoplasm and tapering nuclei. Round cell USTSs consist of relatively uniform rounded or ovoid cells with a high N:C ratio, and they most often closely resemble other specific types of round cell sarcomas, especially Ewing sarcoma. However, many cases can now probably be more precisely classified within specific molecular subsets, such as CIC-rearranged and BCOR-rearranged sarcomas, as well as within the group of round cell sarcomas associated with EWSR1 fusions involving partners unrelated to the ETS family of genes. USTSs with epithelioid morphology have been little studied as yet, but they are probably not rare. Morphologically, these lesions closely resemble metastatic carcinoma or melanoma, but they generally lack nesting and have amphophilic or palely eosinophilic cytoplasm and large vesicular nuclei. Some appear to show SMARCA4 inactivation. Importantly, genomic profiling may reveal that some seemingly undifferentiated sarcomas can be classified more specifically.

Not clinically relevant

Because of the lack of substantive studies, data are limited. The majority of USTSs are morphologically high-grade. Among pleomorphic sarcomas in adults, those that are undifferentiated and arise in the limbs or trunk have a reported 5-year metastasis-free survival rate of 83%. USTS with epithelioid morphology seems to be more aggressive. In children, reported survival rates for USTS, whether of round cell or spindle cell/pleomorphic type, are 70–75%.

Undifferentiated pleomorphic and epithelioid sarcomas are characterized by complex genetic aberrations not suitable for diagnostic purposes. However, molecular genetics plays a major role in excluding specific molecular entities, particularly when dealing with undifferentiated round cell sarcomas. UPS must be separated from dedifferentiated liposarcoma, a lesion characterized molecularly by MDM2 and CDK4 gene amplification.

Essential: spindle, pleomorphic, epithelioid, and round cell (most often high-grade) morphology; absence of any morphological or immunohistochemical feature of specific differentiation; demonstrated absence of distinctive molecular aberration.