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Precision Diagnosis and Disease Biology of TGCT—Establishing the Rationale for CSF1R Targeting
CME/CE Information

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1 2 3
Course Completed
Activity Information

Physician Assistants/Physician Associates: 0.50 AAPA Category 1 CME credit

Pharmacists: 0.50 contact hour (0.05 CEUs)

ABIM MOC: maximum of 0.50 Medical Knowledge MOC point

Physicians: maximum of 0.50 AMA PRA Category 1 Credit™

Nurse Practitioners/Nurses: 0.50 Nursing contact hour

Released: August 07, 2026

Expiration: February 06, 2027

Emanuela Palmerini
Emanuela Palmerini, MD, PhD

This transcript was automatically generated from the video recording and may contain inaccuracies, including errors or typographical mistakes.

 

Tenosynovial Giant Cell Tumor: Evolving Standards in Diagnosis, Systemic Therapy, and Multidisciplinary Care

 

[00:00:12]

 

Microlearning Module 1: Precision Diagnosis and Disease Biology of TGCT – Establishing the Rationale for CSF1R Targeting

 

Dr. Emanuela Palmerini (Miami Miller School of Medicine): Good morning. I am Dr. Emanuela Palmerini, a medical oncologist and professor of medicine at the University of Miami.

 

Today, we will discuss a microlearning module focused on precision diagnosis and the disease biology of tenosynovial giant cell tumor (TGCT). The objective of this session is to establish the rationale for colony-stimulating factor 1 receptor (CSF1R) targeting.

 

[00:00:50]

 

Tenosynovial Giant Cell Tumors (TGCTs): Overview

 

Tenosynovial giant cell tumor is a rare neoplasm that is benign but locally aggressive. It arises directly from the synovium, and does not have metastatic, so it is benign, but the local growth may be severely functionally disabling for the patient. Most patients present with local symptoms, which include joint swelling, pain, and stiffness. Basically, they cannot run a normal life, and activities like doing stairs or playing soccer with their kids often becomes impossible.

 

For example, when it is localized in the knee, which is the most common site, but other sites like fingers or ankles can be affected. Usually the disease is monoarticular and presents with recurrent effusions. So there are holidays between the worse period when they are very symptomatic, and the duration of the symptoms is related to this cross-talk between the inflammatory component and the tumor component, which we will discuss during this presentation. For all these reasons and the important impact on quality of life, the early recognition of this diagnosis is really paramount, and the early referral might eventually impact of the outcome of the disease, making the treatment easier and more successful.

 

[00:03:20]

 

TGCT: Two Diffuse Subtypes

 

We recognize two very different subtypes, which are composed of the same subtype of malignant cells. Histologically, under the microscope, these forms cannot be distinguished, but they are extremely different in terms of growth patterns, burden, and eventual treatment pathways.

 

The localized, as you can see in the upper right, is very well-circumscribed. That means that usually it is associated with fewer symptoms and can be successfully treated by surgery only, and often the surgery is curative. Not in all of the cases. Unfortunately, we see patients with a local occurrence of relapsing, but the rate of relapse is not exceeding 10-15%. In these cases, early referral is important so that the surgery is even easier.

 

The diffuse pattern is another story. As you can see on the right, the synovial is all involved. The synovium can be considered like a coat all around the bone, and this coat in patients with diffuse TGCT is like a tumor growing in every direction. We call it finger-like diffusion to exemplify that the growth is really irregular in the knee and the synovium. This always makes the surgery intralesional, and the recurrence rate very high, at 50%. These patients live with extensive pain and stiffness, and importantly, functional limitations. These patients presents a challenging treatment because it is a chronic condition.

 

[00:06:34]

 

Diffuse TGCT Can Behave Like a Chronic Joint Disease

 

TGCT in the diffuse form is chronic in the sense that symptoms persist even after local interventions because the surgery, as discussed, might immediately reduce the tumor burden, but to actually eradicate this kind of infiltrative disease, you would need aggressive surgery like an amputation.

 

I always discuss this kind of case with my colleagues, even patients undergoing prosthesis removal of the knee, for example, which one would consider an aggressive treatment for a benign lesion; they still may have a relapse. I saw this patient relapse eight times for diffuse knee TGCT, and the last surgery was a total knee prosthesis, but when I saw her, the knee was all swollen because the disease grew back all around the prosthesis. Basically, it is a chronic disease, which is a very long-term mobility.

 

[00:08:20]

 

Diagnostic Workup Begins With Pattern Recognition

 

When to suspect TGCT and when to start our workup in order to avoid any delay in referral? There are some symptoms that we can recognize. For example, swelling in the joint is very typical. It might not be so specific, but recurrent swelling should always be taken in serious consideration. And then all those other symptoms I discussed, pain, stiffness, and decreased range of motion that are not related to a recent injury and are, again, recurring. And the persistence of the symptom, I think, is the most typical feature of this, that we should drive the suspicion and initial workup for TGCT.

 

Of course, there are several conditions that can cause these symptoms, like, for example:

 

  • Inflammatory arthritis and other types of synovitis, so different from TGCT;
  • Of course, in the beginning, injury may have very similar presentation;
  • Other bleeding disorder or hemarthrosis because they call local inflammation;
  • Any other malignant synovial lesions. Those are the most important to take into account.

 

For this reason, I believe that biopsy of this tumor is important.

 

[00:10:46]

 

MRI is Central to Diagnosis and Disease Mapping

 

The main diagnostic tool is magnetic resonance (MRI). Actually, most of the surgeons would sometimes operate on suspect TGCT patients without even confirmatory biopsy because the MRI it is a super typical feature and is the preferred modality, which led us to understand the synovial disease involvement, how the tendon sheaths are also affected, and also distinguishing between localized and diffuse pattern.

 

Where do we sometimes associate CT? CT is most accurate in discriminating the osseous erosions, and this is something very frequent in patients with TGCT. The reason is that the chronic inflammation causes secondary osteoarthritis. A large retrospective study including more than 1,000 patients, we were able to see that the prosthesis was employed in more than 10% of patients, underscoring how the bone is definitely part of this inflammatory process and chronic exposure to this inflammation.

 

Also, a CT scan is sometimes helpful to guide biopsy, but is less informative on the intra-articular extent of the disease.

 

Something I would also like to point out in this module is that the accuracy of the report, which is helpful for the oncologist and the orthopedic surgeon so that they should also be aware, to describe in the report the subtype, diffuse vs. localized, and the compartment involved, the extra-articular extension, and bone erosion. This, together with the relationship with surgical planes, would help in informing the discussion and pointing out the different treatment options to the patient, having all that information ready at hand.

 

[00:13:54]

 

Radiologic Features that Should Prompt TGCT Referral

 

Radiology is something very specific that should guide the referral because of increased TGCT diagnosis.

 

First, the presence of a mass or nodular distinct proliferation. That is less typical of inflammatory synovial but more typical of a tumor. Then the infiltrative thickening, as we saw in the MRI earlier, which is very diffuse in several compartments of the knee. And then something that l learned when I was in Tokyo, and a prominent orthopedic surgeon from New York told me that you do not need contrast media to recognize TGCT because it is black on T1 and T2. This is super specific, in that it is low signal intensity. This is linked to the pathogenesis of the disease, and we will see in the histology discussion. This disease is hemosiderin-deposit, so there is this echo gradient that is very typical, and the disease is low signal in both T1 and T2, so we can easily recognize it, as in the picture we saw.

 

Also the effusion, sometimes we see a huge, large, whitish imaging. That is the water. The water is most of the sequences, is whitish, and it is very typical of inflammatory TGCT imaging, and as discussed, 10-20% of patients, bone erosion might be a consequence of long exposure, and also, of course, age plays a role. In this case, we should know that TGCT mainly affects patients in their 30s, but any age is potentially affected.

 

It is important to refer the diffuse type. But also, patients with localized TGCT should also be referred to a specialized center with expertise in soft tissue sarcoma treatment.

 

[00:17:38]

 

Pathology Confirms the Diagnosis and Explains Imaging

 

The pathology is really fascinating. There are several populations that are present and help a lot in distinguishing this disease from other conditions. Of course, as we know from the name, multinucleated giant cell, that is related to tenosynovial giant cell tumor because we can observe these cells that are large and contain up to 100 nuclei.

 

Then there are the inflammatory cells, macrophages, which are often foamy macrophages. Under the microscope, they look a little bit bubbly and whitish. Then there are other inflammatory cells, which are monocytes, which are very important in the pathogenic vicious cycles in between the tumor and inflammatory cells because they have the receptors. Lastly, the typical hemosiderin-containing siderocytes, so reddish under the microscope.

 

With all these features under the microscope together with the clinical presentation, and of course, the MRI feature we already discussed, we have the confirmation of the diagnosis, which is paramount.

 

I will discuss a patient from Sardinia that had very tiny localized-looking TGCT of the knee. She was an expert basketball player, and we were planning the surgery because that is inappropriate, but the biopsy that was performed after two weeks showed a diagnosis of synovial sarcoma, which is another very aggressive malignant disease and which may require a combination of radiation therapy, chemotherapy and surgery. It is paramount to incorporate all these features in the final diagnostic pathway.

 

[00:20:30]

 

TGCT Management Requires Multidisciplinary Coordination

 

That is why it is very important to coordinate all the specialists that are required to get to the right diagnosis. Of course, the orthopedic oncology surgeon, sometimes the radiologist, pathologist, and medical oncologist, and later on the patient journey, of course, the pharmacy and rehabilitation are seen.

 

It is important to underscore that tenosynovial giant cell tumor is a benign condition with chronic consequences in the life of our patients, which requires a very carefully coordinated team in order to achieve the goal of a cure if we can, but we cannot always, and control of the symptoms in the best possible way for our patients.

 

[00:21:50]

 

Surgery is Important but Diffuse Disease Creates Limits

 

The reason you need this large team is that in the past, we relied mainly on the surgeon, which, do not get me wrong, is still the main actor and most important referral after the diagnosis of TGCT. But the problem is that especially in the diffuse type, that surgery is always intralesional, so the relapse rate is more than 50%, so one out of two patients will recur. We know that once you recur, you are probably going to recur more. It is really high.

 

A multidisciplinary discussion of every case, sharing with the patient the objective of the treatment, of course, related to the extent of the disease and also the morbidity of the treatment and the possibility to preserve joint function, I think, is important so that the patient goals are clearly stated and the patient is well-informed and part of the therapeutic decision and treatment path, which again I want to underscore is something that is going to be a chronic feature of the patient's life.

 

[00:23:52]

 

Biology Behind TGCT: CSF1 Overexpression

 

The last part of this now relates to discussing something that I really like and is a fascinating discovery. The first paper, which underscores this tumor has a genetic origin, dates back to 1994, when the translocation was discovered. The reason is a specific translocation that causes CSF1 overexpression.

 

As you can see in the cartoon, we have the tumor cells and then the inflammatory cells. The tumor cells have a receptor on CSF1, and the link between CSF1 with tumor cells and also the cells of stroma monocytes, a macrophage, creates these destructive, vicious cycles which brings not only tumor cells but a lot of inflammatory cells into the lesion. That is responsible for all the swelling and the large effusion, which eventually causes patient symptomatic burden. The mass which we observe is eventually composed in large by inflammatory and tumor cells.

 

[00:25:56]

 

CSF1/CSF1R Biology Provides the Therapeutic Rationale

 

This CSF1/CSF1R axis provides an important rationale for treatment. In fact, several drugs have been developed that are able to direct the treatment not only on the tumor, but on the cross-talk between the macrophage on the one side and tumor cells. The class is CSF1R inhibitors. There are several of them with different features, and they are really effective. We will discuss in the next module, but they are effective because there is a strong biology in this disease, as pointed out by the first work by West in 2006. It is a very recent history, which I think already revolutionized the management of this disease.

 

[00:27:26]

 

Key Takeaways

 

The key takeaways from this learning module are:

 

  • TGCT is a benign condition but locally malignant because the symptom, especially in patients that are very young, 30-40 years old, which should be exercising, working, and with their family, they are socially disrupted, so it is a very important condition.
  • There are two forms, localized and diffuse, which are very distinct in symptom burden and treatment. Localized can be cured by surgery in most of the cases, while for the diffuse cases it is almost never possible, so it is a chronic condition.
  • We discussed the importance of diagnosis, which requires collaboration between radiology with MRI being the cornerstone of diagnosis without contrast media is fine.
  • Pathology is always important to confirm the diagnosis. It is a very easy diagnosis, and we discussed the different inflammatory populations, which have a pathology in the lab, and of course, the very characteristic hemosiderin deposits.
  • Lastly, the discovery, which is not recent, the first paper was in 1994, but then an important paper by West in 2006 underscoring the issues of cross-talk between tumor and inflammatory cells linked to the CSF1 receptor and CSF1 which is overexpressed by the stroma cells and is responsible for all the symptomatic burden, increasing the swelling and eventually the size of the lesion because it creates a lot of inflammatory cells in the vicinity of the tumor cells.

 

I really thank you for being here today and for your attention. I look forward to discussing in the podcast with my colleague in the next meeting. Thank you.

 

[END OF TRANSCRIPT]