Tenosynovial Giant Cell Tumor: Symptoms, Types, Causes and Treatment

Tenosynovial giant cell tumor (TGCT) is an intriguing and rare disease that impacts joints, tendon sheaths, and bursae, causing symptoms that can significantly disrupt daily life. Although benign, these tumors can be locally aggressive and challenging to treat, especially in diffuse forms. This article provides a comprehensive and human-centered overview of TGCT, drawing on the latest research to explore its symptoms, types, causes, and treatment options.

Symptoms of Tenosynovial Giant Cell Tumor

Tenosynovial giant cell tumor most commonly presents with symptoms related to joint and tendon involvement. These symptoms can subtly worsen over time, often being mistaken for other joint problems until more advanced. Recognizing the hallmark symptoms is crucial for early diagnosis and optimal management.

Symptom	Description	Frequency/Impact	Source(s)
Pain	Aching or sharp discomfort in joint	Very common, 82%	1
Swelling	Localized or diffuse swelling	Very common, 86%	1
Stiffness	Reduced ease of joint movement	Common, 73%	1
Reduced ROM	Limitation in normal joint movement	Common, 64%	1
Instability	Joint feels unstable or gives way	Common, 64%	1
Functional Loss	Difficulty with daily activities	Variable, often present	1, 3

Table 1: Key Symptoms

Common Presenting Symptoms

TGCT typically causes joint pain, swelling, and stiffness. These symptoms are often chronic and can be mistaken for other joint diseases like osteoarthritis or rheumatoid arthritis. The pain is usually persistent, sometimes worsening with activity. Swelling may be the first noticeable sign, especially in larger joints such as the knee or hip, and is often visible to both patients and clinicians. Stiffness is also frequently reported and tends to be worse in the morning or after periods of inactivity, impacting daily mobility 1.

Impact on Physical Function

As TGCT progresses, it can cause a reduced range of motion (ROM) and even joint instability. Patients may notice that their joint feels weak or "gives way," particularly during activities that put stress on the affected area. This can lead to functional limitations—difficulty with walking, grasping objects, or other routine tasks—depending on the joint involved 1 3.

Patient Experiences and Quality of Life

The combination of pain, swelling, and reduced function can significantly diminish quality of life. Many patients report difficulty in performing their usual activities, leading to frustration and emotional distress. In diffuse-type TGCT, these symptoms tend to be more severe and persistent, often requiring repeated interventions 3. Importantly, early recognition and treatment can help preserve joint function and prevent long-term disability.

Types of Tenosynovial Giant Cell Tumor

TGCT is not a single disease entity but encompasses several distinct subtypes, each with unique clinical features, prognosis, and management strategies. Understanding the differences is key for effective diagnosis and treatment planning.

Type	Common Location	Clinical Behavior	Sources
Localized	Fingers, hands	Indolent, less aggressive	2, 4, 5
Diffuse	Knees, large joints	Aggressive, recurrent	2, 3, 4, 5

Table 2: TGCT Types at a Glance

Localized TGCT

• Definition: Localized TGCT, previously known as "giant cell tumor of tendon sheath," is the most frequent form, especially in the fingers and hands.
• Clinical Course: These tumors tend to be well-circumscribed, slow-growing, and less likely to recur after surgical removal.
• Symptoms: Patients typically present with a painless or mildly painful mass on a finger or hand, which may cause stiffness or mild discomfort but rarely significant joint dysfunction 2 4 5.

Diffuse TGCT

• Definition: Diffuse-type TGCT, also called "pigmented villonodular synovitis" (PVNS), more commonly affects large joints such as the knee or hip.
• Clinical Course: This form is characterized by aggressive growth, widespread involvement of the joint lining, and a much higher tendency to recur after surgery.
• Symptoms: Patients often experience pronounced swelling, pain, and loss of joint function. The tumor can cause significant joint destruction over time, potentially leading to osteoarthritis and repeated surgical interventions 2 3 4 5.

Comparison and Distinguishing Features

• Recurrence: Diffuse TGCT has a recurrence rate over twice as high as localized types (up to 44% within 3 years for diffuse type) 2 3.
• Location: Localized forms predominate in the hands and feet, while diffuse types are most often found in larger joints, especially the knee 2 4.
• Aggressiveness: Diffuse TGCT is more likely to cause joint erosion and disability due to its extensive infiltration 3.

Causes of Tenosynovial Giant Cell Tumor

The underlying causes of TGCT have been the subject of much research. Once thought to be primarily inflammatory, TGCT is now recognized as a unique entity with both neoplastic (tumor-like) and inflammatory features.

Cause	Mechanism	Key Feature	Source(s)
CSF1 Overexpression	Genetic rearrangement in tumor cells	Attracts macrophages	5, 7, 8, 10, 12
Monoclonality	Some neoplastic cells are clonal	Tumor-like behavior	5, 8
Inflammation	Cytokine-driven synovial proliferation	Resembles arthritis	8

Table 3: TGCT Causes and Mechanisms

Genetic and Molecular Mechanisms

The central driver of TGCT is the overproduction of colony-stimulating factor 1 (CSF1) by a small subset of tumor cells. This is usually due to a specific genetic rearrangement leading to aberrant CSF1 expression 5 7 10 12. The high levels of CSF1 act as a chemical signal that attracts a large number of macrophages to the tumor site. These macrophages, although not themselves neoplastic, make up the bulk of the tumor mass and contribute to its growth and local aggressiveness 10 12.

Neoplastic and Inflammatory Features

TGCT is unique in that it exhibits characteristics of both a benign tumor and a chronic inflammatory condition:

• Neoplastic: Some synovial lining cells are clonal (arising from a single cell), and chromosomal translocations are present, supporting a tumor-like origin 5 7 8.
• Inflammatory: The disease also involves significant inflammation and synovial proliferation, similar to what is seen in rheumatoid arthritis, but typically affects only a single joint 8.

Pathophysiology in Brief

• CSF1/CSF1R Axis: The CSF1 produced by neoplastic cells binds to the CSF1 receptor (CSF1R) on macrophages and monocytes, promoting their survival, proliferation, and inflammatory activity.
• Result: The accumulation of these immune cells leads to the formation of the tumor, joint swelling, and eventually, tissue destruction 7 8 12.

Why Does TGCT Occur?

While the exact cause of the initiating genetic event is unknown, there is no strong evidence linking TGCT to environmental exposures, trauma, or inherited factors. It appears to be a sporadic event, with some predilection for women and adults aged 40–59 years 2.

Treatment of Tenosynovial Giant Cell Tumor

Management of TGCT is tailored to the type, location, and severity of the tumor, as well as patient factors. Treatment aims to relieve symptoms, preserve joint function, and prevent recurrence.

Treatment	Indication	Key Considerations	Source(s)
Surgery	First-line for most cases	Recurrence risk varies	3, 4, 10, 11, 12
Systemic Therapy	Advanced, unresectable, or recurrent	Pexidartinib (FDA-approved)	9, 12, 13
Radiation	Adjunct or alternative for recurrence	Used selectively	4, 11
Observation	Mild/early disease or high surgical risk	"Wait and see" approach	3

Table 4: TGCT Treatment Approaches

Surgery

• Localized TGCT: Surgical excision is highly effective, with recurrence rates of 8–20%. Marginal excision is typically curative, and repeat surgery can manage recurrences 2 4 10.
• Diffuse TGCT: Surgery is more challenging due to the tumor's infiltrative nature. Open or arthroscopic synovectomy aims to remove as much tumor as possible, but recurrence rates are much higher—ranging from 14% to 55% 3 4 10 11.
  • Multiple surgeries may be needed over a patient’s lifetime.
  • Risks include joint stiffness, infection, and functional loss.
• Key Points:
  • Complete resection is ideal but not always feasible in diffuse disease.
  • The knee is the most common site for surgery, especially in diffuse TGCT 2 3 4.

Systemic (Medical) Therapy

• CSF1R Inhibitors: Targeting the CSF1/CSF1R pathway has revolutionized management for patients who cannot undergo surgery or have persistent/recurrent disease.
  • Pexidartinib is the first FDA-approved oral therapy for adults with symptomatic TGCT not amenable to surgery, showing significant reduction in tumor size and improvement in pain, stiffness, and physical function 9 12 13.
  • Other agents (e.g., imatinib, nilotinib) are being investigated but are not yet standard care 10 11.
• Limitations and Side Effects:
  • Pexidartinib can cause liver toxicity and requires careful monitoring 9 13.
  • Not suitable for all patients; used when surgery is not possible or would cause unacceptable morbidity.

Radiation Therapy

• Application: Used as an adjunct to surgery or as a standalone treatment in some recurrent or unresectable cases.
• Effectiveness: Can reduce recurrence rates, but long-term risks and effectiveness are still under investigation 4 11.

Observation

• "Wait and See": In select cases with mild symptoms or when surgery carries high risk, observation may be appropriate. However, close monitoring is essential to detect progression 3.

Emerging and Future Therapies

• Ongoing Research: New targeted therapies and immunotherapies are under investigation, aiming to further improve outcomes and reduce recurrence 11 12.
• Multidisciplinary Care: Treatment planning should involve orthopedic surgeons, oncologists, radiologists, and rehabilitation specialists for best results.

Conclusion

Tenosynovial giant cell tumor is a rare but impactful disease, often masquerading as other joint problems but with unique features and management challenges. Here’s what you should remember:

• Symptoms: TGCT typically causes pain, swelling, stiffness, and reduced joint function; diffuse types are more aggressive and disabling.
• Types: Localized TGCT is common in the hands and tends to be indolent; diffuse TGCT affects large joints and is more aggressive.
• Causes: Driven by genetic rearrangements leading to CSF1 overproduction, attracting macrophages and causing tumor growth; features both neoplastic and inflammatory processes.
• Treatment: Surgical removal is first-line; diffuse types frequently recur. Pexidartinib is now available for advanced, inoperable cases, while radiation and observation are options in select situations.

In summary:

• TGCT is more common than once thought, but still rare.
• Early recognition and personalized treatment are key to preserving joint function.
• Advances in molecular therapy are offering new hope for patients, especially those with challenging diffuse disease.

By staying informed and working closely with a multidisciplinary care team, patients and clinicians can better navigate the evolving landscape of TGCT diagnosis and treatment.