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Diffuse-Type Tenosynovial Giant Cell Tumors: Treatments and Progression

Diffuse-Type Tenosynovial Giant Cell Tumors: Treatments and Progression

Tenosynovial giant cell tumors (TGCT) – An Introduction

Tenosynovial giant cell tumors (TGCT) are rare, locally invasive lesions of synovial origin that involve joints, tendon sheaths, and bursae.  TGCT may be intra- or extra-articular and is classified by growth pattern and clinical presentation as localized-type tenosynovial giant cell tumors (L-TGCT) and diffuse-type tenosynovial giant cell tumors (dt-TGCT).

The benign form, L-TGCT, also known as giant cell tumor of the tendon sheath, is typically confined to the synovium or tendon sheath and mainly involves the digits and wrist. Excision is the standard treatment of choice. Subsequently, localized-type TGCT’s reported recurrence rate is only 0-6%.

Diffuse-type tenosynovial giant cell tumors, also known as pigmented villonodular synovitis, is characterized by metastasis and mainly involves the large joints: knee, hip, ankle, and elbow. The overall reported recurrence rates of diffuse-type TGCT following open synovectomy are 14% – 67% and after arthroscopic synovectomy 40% – 92%. D-TGCT has a high rate of recurrence (up to 50%), often on multiple occasions.

On histological examination, both forms are nearly indistinguishable, and they are diagnosed the same way. Typical symptoms include pain, stiffness, swelling, and limitation in range of motion. Because these early symptoms resemble conditions such as erosive arthritis, gout, and soft-tissue injuries, it can be misdiagnosed. Also, the slow growth rate of the lesions, especially in the case of dt-TGCT, delays the diagnosis for years.

Study Background

In diagnosing and surgical planning TGCT, magnetic resonance imaging (MRI) is indispensable. MR imaging reveals
a well-delineated lesion (localized-type) or articular, villous proliferation (diffuse-type). However,  TGCT’s treatment options are limited.  The current literature regarding treatments for and prognosis of Tenosynovial giant cell tumor is very less and the available data are mainly from small, retrospective studies. The present study explored the factors for therapy planning of giant cell tumor, especially the diffused-type tenosynovial giant cell tumor (dt-TGCT).

Materials and Methods

Approval

Protocol of this study, named TGCT Observational Platform Project (TOPP), was approved by the institutional review board or ethics board of the participating countries. Patients provided written informed consent for research review and analysis of medical records.

Study design and participants

This study was conducted at 12 tertiary sarcoma centers in 7 European countries, and 2 US sites from November 2016 to March 2019. TGCT patients were enrolled during a 2-year period with follow-up over 24 months. Patients 18 years or older, with a primary or recurrent dt-TGCT, were enrolled. TGCT was histologically confirmed and assessed as diffuse-type based on MRI or clinical presentation for the patients whose data was missing.

Demographics, TGCT-history, and current status, including radiological assessments and health resources used in the past 24 months, were collected at baseline. Baseline visits were at the outpatient clinic of either the orthopedic surgery or the oncology department. Baseline data on TGCT-related patient-reported outcomes (PRO) were collected and followed every year thereafter electronically.

The patient-reported outcome measurements (PROMs) consisted of the mean brief pain inventory (BPI), mean worst pain and stiffness numerical rating scale (NRS), the Patient-Reported Outcome Measurement Information System Physical Functioning (PROMIS-PF), and the EuroQoL 5D (EQ-5D.

All statistical analyses were performed using the Statistical Analysis System (SAS©) Version 9.4.

Results

A total of 166 patients with histopathologically proven tenosynovial giant cell tumor were enrolled in the TOPP registry. Briefly, the median age at diagnosis was 39 (range, 14.4–75.6; SD±14.42). The median time from diagnosis until TOPP entry point was 29.7 months (IQR, 9.5–80.0).

The majority of the patients were female (n=102; 61.4%), and the knee was the most commonly affected joint (n=112; 68.5%). Other affected locations were ankle (n=19; 11.4%), the hip (n=12; 7.2%), the shoulder (n=8; 4.8%), the foot (n=5, 3.0%), the elbow (n=3, 1.8%), the hand (n=3, 1.8%), and the temporomandibular joint (n=1; 0.6%). Of the participants, 57.2% (n=95) were primary diagnosed cases, and 42.8% (n=71) had at least one recurrence before baseline, occurring after primary tumor treatment.

Diagnostic pathway: Tenosynovial giant cell tumor

A median of 16.9 months (IQR, 4.0–44.0) elapsed from the onset of symptoms until diagnosis. In most cases, the MRIs requested closest to the baseline of TOPP were for postoperative follow-up (n=56; 40.0%). MRI results showed that 61.2% (n=90/147) of patients had both intra- and extra-articular diffuse-type Tenosynovial Giant Cell Tumor; with ligament involvement in 65.7% (n=88/134), and tendons and muscle involvement in 70.2% (n=99/141), indicating half of the patients (n=83) with severe dt-TGCT at baseline. Upon assessment, severe dt-TGCT was reported in the knee, ankle, hip, and other locations in 51.5% (n=51/99), 55.6% (n=5/9), 58.8% (n=10/17) and 77.2% (n=17/22) of the cases, respectively.

About 41.6% patients (n=69) were classified severe dt-TGCT even after treatment. Histological confirmation was primarily obtained after excisional biopsy (n=32; 41.6%), however several non-excisional biopsy techniques such as core needle biopsy, arthroscopic biopsy, or fine-needle aspiration were also performed on other patients. In 13% of the patients, TGCT diagnosis was based on surgical histology examination.

Treatments received before baseline of TOPP

Of the 166 patients of the study, 139 were under TGCT-related treatment, whereas 27 were treatment-naive. 95 patients were primary diagnosed ones, and 71 had at least one recurrence before baseline.

Of 57 patients who underwent surgical treatment at the time of initial diagnosis, 30 had been treated arthroscopically. At the time of relapse, 71 had a re-operation (49 open synovectomies; 33 arthroscopy; 5 prostheses). 52 patients received systemic treatment; in 39.4% this was indicated in recurrent cases and was still ongoing in 34.6% at baseline. 30 of 52 cases were for systemic therapies because of locally advanced TGCT, 9.8% as neoadjuvant, 7.8% for maintenance, and 7.8% for palliative therapy. 11 patients received systemic therapies as the first treatment for TGCT.

In most cases, imatinib or pexidartinib were administered as the latest treatment before baseline. Radiation therapy, comprising external beam radiotherapy and radiosynoviorthesis with 90Yttrium, was administered in 9% of patients. 53% of all cases had received prior and concomitant therapies for TGCT-related symptoms.

Treatment strategies at the time of TOPP study entry

Watchful waiting (n=81/166; 48.8%), surgery only (n=41/166; 24.7%), or targeted systemic therapy only (n=37/166; 22.3%) were employed.

A multimodality approach comprising a combination of surgery targeted systemic therapies and radiation therapy was used in 7/166 (4.2%) of cases.

A conservative monitoring approach at baseline was decided on for patients who received only surgery before baseline (n=47/81; 58.0%). MRIs were conducted as a regular postoperative follow-up (n=43/75; 57.3%). Since this group comprised the lowest percentage of severe cases, non-invasive interventions were common.

Patients indicated for surgery were most recently diagnosed with TGCT. A median of 6.7 months elapsed from TGCT diagnosis until baseline. About 65.9% (n=27) had a primary diagnosis, of which 39.0% (16/41) were therapy-naïve at baseline. MRIs closest to baseline were primarily indicated to diagnose TGCT (n=23; 57.5%).

21 patients indicated for targeted systemic therapies had already received multimodality treatment before baseline. None of them were therapy-naïve at baseline, and just 7 patients had only surgery before.

MRIs were predominantly obtained due to progressive complaints (n=13). The highest percentage of recurrent (n=18; 48.6%) and severe dt-TGCT (n=21; 56.8%) was observed in this group. These patients visited oncologists at a median of 12 times in the 24 months before baseline.

TGCT Patients indicated for systemic therapies had a median age of 48.0 years (range 20.0–73.0). Analgesics were most used by these patients (n=9) and mean worst stiffness and
pain NRS scores of 5.3 (SD±2.55) and 5.8 (SD±1.97), respectively, were reported.

Physical functioning was limited and showed a median PROMIS-PF score of 39.98. The lowest QoL scores were reported (EQ-5D index score = 0.74; visual analog scale (VAS) score = 70.0). At baseline, 33 TGCT patients (89.2%) had a current systemic therapy, of which 18 (54.5%) were started before.

All current systemic therapies consisted of TKIs (imatinib n=14; 42.4%; pexidartinib n=19; 57.6%).

Only 11 patients did not report any TGCT-related complaints at baseline. Patients indicated for treatment reported TGCT-related symptoms (e.g., pain, stiffness, swelling, and limited range of motion) more frequently compared to those with the watchful waiting groups. Both patient groups indicated for surgery and systemic therapies reported higher pain severity and interference scores compared to patients indicated for watchful waiting. Also, both treatment groups reported lower PROMISPF scores (39.54 and 39.98, respectively), EQ-5D index scores (0.80 and 0.74, respectively), and EQ-5D VAS scores (69.0 and 70.0, respectively).

Health economics related to the TOPP cohort

  • About 23.9% of patients (n=33) required at least 5 visits from disease onset, before TGCT diagnosis.
  • 55.9% (n=76) opted to consult a specialist 5 times or more in the 24 months before baseline.
  • 25.5% (n=36) had 10+ physical therapy sessions in the 24 months before baseline.
  • Hospitalization and rehabilitation were required in 91.0% (151/166) and 18.6% (26/140), respectively, with a median of 3.0 (range, 1.0–184.0) and 15.0 (range, 1.0–120.0) days, respectively.
  • 9.9% (n=15) were hospitalized 5 or more times.
  • 56.9% (n=66) missed work due to TGCT in the 2 years before baseline, with a median of 25.0 days (range, 1.0–75.0).
  • Of the 146 patients who were employed, 17 (11.6%) were forced to change their employment status or choose early retirement due to poor health. Domestic help was inevitable in 26 cases (16.0%).

Discussion

This study confirmed that Diffuse-type Giant Cell Tumor (dt-GCT) affects the younger, working population and is more predominant in women. The time between the onset of symptoms until the diagnosis is averaged more than a year, and patients had numerous consultations with specialists in this time interval. Though MRI was the gold standard to diagnose TGCT type and diagnosis, histological examination was also used for definitive diagnosis. In 10 patients TGCT was diagnosed after surgery for an initial suspicion of cancer.

The primary care for TGCT is arthroscopy. However, it imposes greater risk for recurrence, especially in diffuse-type tenosynovial giant cell tumors, due to metastasis. Similarly, synovectomy also has a high recurrence rate. Multimodality treatments done to reduce the recurrence rate in dt-TGCT have shown varied outcomes. A few studies reported promising results in reducing debilitating symptoms and tumor volume when treated with CSF1R inhibitors including TKIs, especially pexidartinib.

In agreement with the previous studies, this study also confirms that surgery remains the mainstay treatment for tenosynovial giant cell tumors. The researchers hypothesized that open surgery can help access the tumor thoroughly, possibly resulting in the complete removal of the abnormal tissue.

About one-third of the patients received TKIs such as pexidartinib (in a research setting) and imatinib (off-label). This was mostly due to a selection bias since sarcoma centers participating in TOPP were also involved in clinical studies.

TKIs were used majorly in locally advanced refractory cases; that means it is the last resort for patients who are not amenable to surgery. A well-planned multidisciplinary approach is therefore needed considering the recurrence rate, post-surgical complications, and side effects in patients with tenosynovial giant cell tumor.

At the baseline of TOPP, wait-and-see policy patients reported fewer TGCT-related symptoms, less frequent use of painkillers and higher QoL. This indicates that lack of symptoms may be the deciding factor for choosing a treatment approach. In two years before baseline, one-fourth of the TGCT patients had multiple physical therapies, and there were frequent medical consultations by more than 50% of the patients. Furthermore, TGCT related symptoms often caused work absence, changing from full-time to part-time employment, and early retirement.

Conclusion

This multicenter, prospective study confirms that diffuse-type Tenosynovial giant cell tumor (dt-TGCT) can highly impact patient’s quality of life. Therefore, developing multidisciplinary guidelines for the treatment of primary and refractory cases is of the utmost importance.

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