UPS is a
diagnosis of exclusion (a diagnosis reached by the
process of elimination) because the histopathology of this disorder's tumors is non-specific. UPS tumor cells are undifferentiated (i.e. do not resemble any particular cell type) and pleomorphic (i.e. highly variable in size, shape, and/or color) when examined microscopically. Therefore, the diagnosis of UPS is commonly based on detecting a specific set of proteins that are expressed by UPS tumor cells but not by the cells of other undifferentiated and pleomorphic tumors or
visa versa (see Diagnosis section). Tumor cells that strongly expressed PD-L1 also expressed
CMTM6 protein (i.e. CKLF like MARVEL transmembrane domain containing 6 protein). Strong PD‑L1 expression proved to be a poor, while expression of IDO‑1 proved to be a favorable, prognostic factor for disease outcomes. In a later study that examined 83 individuals, 72.8% had UPS tumor cells that expressed PD-L1 with 53%, 35%, and 12% of these cases showing weak, intermediate, and strong PD-L1 expression, respectively. Other abnormalities found in some or isolated cases of UPS include:
1) Amplification of the
Hippo signaling pathway, an intracellular
cell signaling pathway that regulates cell proliferation and cell death; this amplification is associated with the overexpression of two proteins,
vestigial-like family member 3 protein, a product of the
VGLL3 gene, and
YAP1, i.e. yes-associated protein 1, a product of the
YAP1 gene, in the Hippo signaling pathway;
2) Abnormal activation of
notch signaling pathways (this activation has been shown to promote the growth and survival of various types of cancer cells; and
3) Overexpression of
DKK1, i.e. Dickkopf-related protein 1 (elevated in the tumor cells of various cancer types). UPS tumors also show gene and chromosome abnormalities that further studies may find contribute to the development and/or progression of UPS. These abnormalities, which have not yet been reported to be helpful in diagnosing UPS, include the following.
1) Deletion and/or inactivation or the
RB1 gene that encodes (i.e. is responsible for production of) the retinoblastoma protein that functions as a
tumor suppressor protein;
2) deletions and/or mutations in the
TP53 gene that encodes tumor protein P53 (a protein which regulates cell proliferation and cell death);
3) mutations in the
ATRX gene that encodes transcriptional regulator ATRX protein which contributes to regulating the expression of various genes;
4) mutations in the
KMT2C gene which encodes lysine N-methyltransferase 2C protein (the
KMT2C gene is mutated in various cancer types);
5) amplification of the
IL7R gene which encodes Interleukin-7 receptor-α protein (mutations in the
IL7R gene are commonly found in
acute lymphoblastic leukemia) and
6) expression of a
fusion gene (i.e. a hybrid gene formed from two previously independent genes as a result of a mutation) that merges
TRIO with other genes and is often found in other sarcoma subtypes.) ==Diagnosis==