Obligatory—This is not medical advice
Unfortunately, in the sarcoma world, there are many instances in which we cannot provide a clear answer for where a cancer came from, how long it’s been present, or how it might behave. Undifferentiated pleomorphic sarcoma (UPS) is an example of a condition of uncertain origin. Historically, this group of cancers was categorized as malignant fibrous histiocytoma (MFH), but as the field evolved, pathologists gained new insights into subtypes of sarcoma, and so this general term became more refined. It was ultimately determined that rather than originating from histiocytes, these cancers instead came from mesenchymal cells.1 With time, and understanding, UPS became the more common term used for a diagnosis of exclusion—meaning that other conditions are ruled out first.
Definition of Undifferentiated Pleomorphic Sarcoma
Let’s talk about the words that compose the name Undifferentiated Pleomorphic Sarcoma.
Undifferentiated: there is not a line of cellular differentiation. For example, there is not visible production of fat (lipogenic origin), bone (osteogenic origin), or muscle (myogenic).
Pleomorphic: variable, or with multiple distinct appearances. Pathologists use this word to indicate that things are not consistent across multiple fields of view in the specimen
Sarcoma: of mesenchymal origin, or not epithelial
Sometimes a picture can help solidify our understanding. See the example below which reveals just how indistinguishable portions of a pleomorphic sarcoma can be. It lacks identifiable immunohistochemistry characteristics that allows pathologists to give it a clear name. Cells are irregular and do not show that they are adhering to a particular pattern. This, by its nature, makes it a higher grade entity in general .
This can be distinguished from other sarcomas that may be pleomorphic, but still with some elements that show a story of differentiation, such as pleomorphic liposarcoma.
Within this view, for instance, we see fat cells, perhaps alluding to a lipoblast progenitor of this particular cancer. Also, keep in mind, if a biopsy diagnosis pleomorphic sarcoma, there is only a limited view of what is in the specimen (eg what was present where the biopsy needle traveled). Frequently, in sarcoma, there are regions within a tumor of more or less differentiation.
Epidemiology
The above figure shows the relative frequencies of various types of soft-tissue sarcomas in adults. It’s important to keep in mind that UPS may also occur in bone, but that is much more rare.2 It is approximately 11% of cases. This amounts to approximately 1500 cases annually.3 Given it is difficult to disentangle UPS based on SEER data, usually this is a diagnosis of older adults (see figure).
Treatment
For patients with localized disease, treatment involves multidisciplinary discussion about the risks/benefits of perioperative treatment. If resection is feasible, that should be pursued with curative intention. Other treatments may be offered if they fit with the goals of patients and would improve quality and duration of life. See prior reviews of general therapy for localized soft tissue sarcoma and outcomes by grade.4
For patients with advanced or metastatic disease, first line therapy is somewhat controversial. Here, again, we rely on what we know about sequential vs combined active treatment in this setting. The reference, as before, is Judson et al. Lancet. 2014.
Depending upon performance status, they may be offered this regimen, or an alternative such as gemcitabine/docetaxel5, or liposomal doxorubicin.6 Keep in mind, UPS had not been separated from other subtypes of soft tissue sarcoma, and so the exact answer of what is best, and when, is not well delineated specifically for this subtype. As a result, there is theoretically equipoise with any regimen that has been tested in this area.
After the first line
What is particularly exciting within the treatment of pleomorphic sarcoma, however, is the potential of immunotherapy. It should readily be considered in second line and beyond. This was shown in SARC028, a single arm, open label Phase 2 trial of pembrolizumab for patients with sarcoma.7 There was a very small number of patients enrolled on trial. Amongst that small fraction with a diagnosis of UPS, which was 10 patients, 4 of those patients had partial responses. This had led to a preliminary NCCN recommendation for consideration of administration of pembrolizumab for patients with UPS.8 Clearly, further qualification of the efficacy of pembrolizumab alone is needed for patients with UPS and soft tissue sarcoma, and additional study is under way.
At present, there are also many studies that are recruiting patients with a diagnosis of UPS with new mechanisms of action not previously studied in sarcoma. One such example is an antibody-drug conjugate targeted at the AXL protein.910 Preliminary, Phase I data indicated a few responses amongst patients with high levels of AXL membrane expression. See CTOS 2021 poster spider plot below. This trial continues to recruit patients into multiple arms for study of efficacy.
Other clinical trials, also continue to focus on the role of alteration of the immune microenvironment, including utilization of advanced local therapeutic techniques such as HIFU. 11 While I have named a distinct few, it's important to note that there are many ongoing in this space.
Conclusions
Undifferentiated pleomorphic sarcoma is a common subgroup that accounts for approximately 11% of new diagnoses of soft tissue sarcoma. It is a diagnosis of exclusion. Treatment for patients with local disease is best performed in a center of excellence by a multidisciplinary team. Systemic therapy for advanced disease relies generally on chemotherapy in the early lines. Immunotherapy may be considered in the later lines of treatment, but further trials are needed in this space. Ongoing study of immunotherapy, as well as other agents, will help better delineate the best treatments for patients with UPS and other sarcomas.
https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70063-4/fulltext
https://pubmed.ncbi.nlm.nih.gov/28882536/
https://pubmed.ncbi.nlm.nih.gov/28988646/
nccn.org
Full disclosure, I am an investigator on this trial
https://clinicaltrials.gov/ct2/show/NCT04123535?cond=undifferentiated+pleomorphic+sarcoma&draw=2&rank=1