Mesenchymal Chondrosarcoma Is a Rare Sarcoma Subtype With Challenging Diagnosis

R. Lor Randall, MD, FACS

Primary mesenchymal chondrosarcoma accounts for less than 10% of all chondrosarcoma diagnoses, according to R. Lor Randall, MD, FACS.

They are the most common form of primary bone cancer we see in adults, but they're much less common in children. The disease has not been studied in a clinical trial, and most data on the diagnosis, treatment, and management stem primarily from individual case reports. As such, securing a firm diagnosis can present a challenge, Randall said.

“What is interesting is that mesenchymal chondrosarcomas are rare enough that they are not diagnosed readily by pathologists who don't see them very often. If a given oncologist, whether they be surgical or medical, is seeing 1 of these patients and gets a biopsy, it is likely that this specimen will need to go to a major tumor center that has a high-volume pathologist to nail the diagnosis,” Randall explained. He is the David Linn Endowed chair for Orthopedic Surgery, the chair of the Department of Orthopedic Surgery, and a professor at UC Davis Comprehensive Cancer Center in Sacramento, California.

In an interview with OncLive^®, Randall discussed the presentation and diagnosis of mesenchymal chondrosarcomas, the role of HEY1-NCoA2 gene fusions in the disease, and potential treatment options for this rare subgroup of patients.

OncLive: How does this malignancy typically present?

Randall: These mesenchymal chondrosarcomas are interesting [as] they will sometimes present as extraskeletal in soft tissue. They're rare enough that even major cancer centers and sarcoma programs don't see them very often. I recently consulted for one [patient] and then was also asked to review a paper on [another patient]. I've talked to a couple other colleagues who have seen some [cases of mesenchymal chondrosarcoma] recently, and so that is to say that there has been this punctuated equilibrium of mesenchymal chondrosarcoma that some people are seeing. [Now] is a good opportunity to raise awareness and talk about potential therapeutic avenues for medical oncologists if they were ever to see mesenchymal chondrosarcoma.

Chondrosarcoma is usually seen in older patients, but mesenchymal chondrosarcoma tends to arise in younger people in the first few generations of life—not children, per se, but young adults. [Mesenchymal chondrosarcomas] have a relatively high predilection for showing up in a multifocal manner, meaning they will show up as a primary [tumor], but then a PET CT or staging study will show that [patients] have other sites of disease, which is more aggressive than most chondrosarcomas. There are dedifferentiated chondrosarcomas that can present with metastases, but most of the time, chondrosarcoma will present it as isolated disease.

Mesenchymal chondrosarcoma tends to have multifocal disease or probably metastatic disease. I qualify it that way because there are just not a lot of data on these tumors.

What advice would you give for those presented with a patient with mesenchymal chondrosarcoma?

Point number 1 for medical oncologists would be, if they are taking care of a patient with mesenchymal chondrosarcoma, please be aggressive in doing staging studies to look for noncontiguous disease. Point number 2 is for isolated disease, it's usually treated with surgical resection, so having an orthopedic or a similar type of oncologist available to manage the primaries is of utmost importance.

What treatment options are available?

There is a [gene] fusion that has been described in literature as HEY1-NCoA2.2 [This gene fusion] is able to be detected in most laboratories now and will nail down the diagnosis. That type of molecular profiling is necessary to affirm this tumor and make sure that oncologists are dealing with [mesenchymal chondrosarcoma].

What then makes [HEY1-NCoA2] clinically interesting is that this does seem to be involved with PDGFR signaling. So, there may be a role for imatinib [Gleevec] in treating these patients. Historically, conventional chemotherapy has not been efficacious in the mesenchymal chondrosarcoma. Cytotoxic chemotherapy that we give for soft tissue sarcomas does not make a dent on advanced mesenchymal chondrosarcoma.

However, imatinib, which is commercially available in the generic form now, is readily available. It is a salient point for the medical oncologist know that imatinib is a good line of therapy. Although there are no trials or proven efficacy, this gene product does involve the PDGFR pathway. So imatinib may help some of these patients in their disease.

When it is not possible to access highly specialized centers to accurately diagnose mesenchymal chondrosarcoma, what does the disease typically mimic? What should providers be aware of?

If [mesenchymal chondrosarcoma] is in the bone, it will often present as pain. I recently reviewed a case report involving the lumbar spine, which is unusual. The disease is usually in the appendicular skeleton if it's in the bone. However, [the case report I reviewed] was in a 47-year-old, which is a bit old for mesenchymal chondrosarcoma. [Mesenchymal chondrosarcoma] will usually be present with pain. You can obtain a radiograph, which will show some of the [structure] of the bone, which will then lead to an MRI.

[Mesenchymal chondrosarcoma] can also present it as a soft tissue mass. I recently consulted on a patient from outside of the United States with mesenchymal chondrosarcoma who wanted a second opinion. They presented with a large shoulder mass, and otherwise they were a healthy, 20-something-year-old patient who was very athletic that noticed this mass that was growing, and they got a biopsy. They got the molecular tests to confirm the diagnosis, and the patient is undergoing resection now. However, it usually presents as a mass or pain in the bone.

Although imatinib could potentially be effective in these patients, this would be off-label use and this is an aggressive disease, so how should oncologists approach this?

Welcome to sarcoma care. Much of what we do is sort of off label for some of these very rare tumors where we have some sort of signal that a particular TKI might have efficacy, but these patients are facing imminent demise. [Therefore], we go off label [frequently].

Are there any anecdotal case reports or additional research that you wanted to shine light on?

The HEY1-NCoA2 fusion product is fascinating. They've built some preclinical models of the mesenchymal chondrosarcoma using it. While it's rare, there is some great, fundamental biology that has real clinical applications in terms of how we can treat these few and far between patients.

Given the rarity of mesenchymal chondrosarcoma, are further translational studies into the biology of the disease possible? How would that be done?

Now that we have preclinical models, we can screen particular drugs with them. There will still be basket trials, because you just won't be able to accrue a large enough number of patients to be able to have a specific [trial] for mesenchymal chondrosarcoma. However, if you can show it in a preclinical model, then I believe there is an argument to be made to expand indications for using a certain drug in these patients. Obviously, the FDA would have to weigh in on that.

References

1. Theriault RV, Jawad MU, Randall RL. Brief overview of primary mesenchymal chondrosarcoma and discussion of a case report. Transl Cancer Res. 2022;11(12):4235-4236. doi:10.21037/tcr-22-2284
2. Tepes PS, Segovia D, Jevtic S, et al. Patient-derived xenografts and in vitro model show rationale for imatinib mesylate repurposing in HEY1-NCoA2-driven mesenchymal chondrosarcoma. Lab Invest. 2022;102(9):1038-1049. doi:10.1038/s41374-021-00704-4