Shreyaskumar R. Patel, MD: Let’s keep this patient centric. A patient is now presenting to one of you. What would be the appropriate clinical workup? Let me see if I can get back to Dr Abraham, and he can walk us through the clinical workup of a patient with tenosynovial giant cell tumor [TGCT] as they present to your clinic.

John A. Abraham, MD: I think the first thing to consider is the patient history. As I mentioned previously, there are a number of things that can present in a similar manner and many of them are much more common than TGCT. We take a good patient history, and I tend to look for those key phrases such as “My knee blows up,” or “I get swelling and I wasn’t doing anything. I was standing there and my knee blew up.” I keep referring to the knee because that’s the most common site that we see, but this can occur in any synovial joint. That is something that will always make my ears perk up.

There is the chronicity or recurrent nature of, “This happened three times last year, and then I remember it happened a few times the year before.” Things like that will make me think along the lines of TGCT. If I don’t hear those things and I don’t have that typical clinical picture, then I think it’s important to start asking about other things. Does this happen in many joints? Does any of this run in your family? These are things that may start pointing you toward something like rheumatoid arthritis. Have you been outside or been bitten by a tick? There are conditions like Lyme disease. You start looking through the differential diagnoses, and it’s important to distinguish between these.

Shreyaskumar R. Patel, MD: You’re making a very important point that in this era of PET [positron emission tomography] scans and next-generation sequencing, patient history and physical examination are still your best tools to get to the right diagnosis. I think it’s important that we emphasize that to our audience.

John A. Abraham, MD: Exactly. If I see 1 of the patients who ends up having TGCT, many times I will have a pretty good suspicion that could be what’s going on only on the basis of history and physical examination. I think that’s critical.

On physical examination, many times we’ll see signs of a swollen joint. There usually aren’t signs of an infected joint. There’s no diffuse erythema or anything like that, unless it’s very extensive disease with extraarticular component that is coming out through the joint. The typical things we see include a very swollen joint, hemarthrosis, or a knee full of fluid, which we would find later to be blood. Those are the things that will lead you on to further studies.

Shreyaskumar R. Patel, MD: For imaging, what do you order?

John A. Abraham, MD: Typically, we’ll start with an x-ray, and that’s good orthopedic medicine. It’s the cheapest option and there’s a lot of information. You may see an effusion on the x-ray. You can see the joint space being expanded. We can’t see soft tissue, so we don’t really know what’s causing that. TGCT, when it has that nodularity—not necessarily a nodular form, but nodularity even in the diffuse form—over time it tends to grind down the bone, so there are erosions in the bone that we can see on x-ray. Those are some of the things that make us think about the need for more extensive surgery such as joint replacements, and things like that. We do look for things such as erosions, which can indicate more severe disease.

Shreyaskumar R. Patel, MD: Is there a preferred cross-sectional imaging? How would you biopsy and establish tissue diagnosis?

John A. Abraham, MD: The preferred imaging modality is definitely an MRI [magnetic resonance imaging] scan. The MRI scan gives us a good look at the soft tissue. Synovitis can be seen very well on MRI scans. The T2 scan or fluid sensitive sequences can show fluid. We can see things like hemosiderin or blood products on T1 imaging. You can see things like blooming artifact. These are all things we look for on MRI. Even a combination of the patient history, the physical examination, and the imaging will give us a pretty good sense that this is what’s happening.

In the past, prior to knowing exactly what was causing TGCT or what the molecular details were, that alone would often be an indication for going forward to surgery. If you have a significant synovitis, we don’t think there is another medical cause like rheumatoid arthritis, and we see some bone destruction, that’s a problem that needs to be treated because we worry about the long-term effects of that. Usually, that situation will give severe pain and disability to the patient. In the past, it wasn’t really necessary to do a biopsy because you knew the patient needed surgery anyway. Now the landscape has changed a little bit because we are more informed, and we do know about the molecular basis. We can better distinguish between other diseases that cause massive synovitis like this.

The important thing is with the introduction of medical therapies for TGCT into the market, it becomes very important to know what we’re treating before we treat it with medical therapies. Along those lines, synovial biopsy was never appreciated to be something that worked well or could give a lot of information. We recently published a paper in Skeletal Radiology looking at the efficacy of synovial biopsy. We found we could get the information we needed from doing a synovial biopsy. These are typically needle biopsies, where a small piece of the synovium is removed. We send it to pathology specialists, and we can establish the differential diagnosis of things we are looking for. The pathologist will be looking for things such as hemosiderin-laden macrophages; this very villonodular appearance, where the villi of the synovium become thickened; and some typical signs that we can look for in PVNS [pigmented villonodular synovitis].

Shreyaskumar R. Patel, MD: We will come back to the molecular aspects of the diagnosis later. At this early stage in the patient’s journey, do you, as the orthopedic surgeon, order any molecular testing? Or is this an automatic thing that reference pathologists will do? How does it work in real life?

John A. Abraham, MD: I don’t necessarily order it initially for every patient. I won’t necessarily need it for every patient. With the combination of patient history, physical examination, imaging, and an experienced pathologist, the vast majority of times, we can make the diagnosis with that constellation of resources, at least to the point of being able to go on to surgical treatment. For cases of recurrence, if there is some question regarding the pathology or if the surgical excision specimen shows something different, we may start investigating the molecular diagnostics as well. It’s not something we routinely do.

Transcript Edited for ClaritySupported by an unrestricted educational grant from Daiichi Sankyo.