Tenosynovial giant cell tumor

Classification for TGCT encompasses two subtypes that can be divided according to site – within a joint (intra-articular) or outside of the joint (extra-articular) – and growth pattern (localized or diffuse) of the tumor(s).{{r|Fletcher|p=100|q=These tumors are usually divided according to their site (intra- or extra-articular) and growth pattern (localized or diffuse) which differ in their clinical features and biological behavior, but appear to share a common pathogenesis. This family of lesions includes the localized giant cell tumor of tendon sheath/Tenosynovial giant cell tumor, and the more diffuse and destructive variant called diffuse type giant cell tumor/pigmented villonodular synovitis. The localized type of giant cell tumor of the tendon sheath is a benign neoplasm composed of synovial-like mononuclear cells…}}{{r|Ravi|p=361|q=Tenosynovial giant cell tumors (TGCT) can be classified on the basis of their location and growth patterns as localized giant cell tumor of the tendon sheath (TGCT, localized type), and diffuse giant cell tumor of the tendon sheath (TGCT, diffuse type, or extra-articular pigmented villonodular synovitis (PVNS) with those involving the joint space known as PVNS.}} Localized and diffuse subsets of TGCT differ in their prognosis, clinical presentation, and biological behavior, but share a similar manner of disease development.{{r|Fletcher|p=100|q=These tumors are usually divided according to their site (intra- or extra-articular) and growth pattern (localized or diffuse) which differ in their clinical features and biological behavior, but appear to share a common pathogenesis.}}

File:Giant cell tumor of tendon sheath histopathology(1).jpg

Localized TGCT is sometimes referred to as localized pigmented villonodular synovitis (L-PVNS), giant cell tumor of the tendon sheath (GCT-TS), nodular tenosynovitis, localized nodular tenosynovitis, and L-TGCT.{{r|Lucas|p=1|q=Tenosynovial giant cell tumors, also known as pigmented villonodular synovitis, are benign soft tissue tumors that arise from the synovium of the joins, bursae, and tendon sheath. Diffuse type giant cell tumor is an extra articular form of pigmented villonodular synovitis… Localized types include giant cell tumors of the tendon sheath, and localized pigmented villonodular synovitis…}}{{r|Fletcher|p=100|q=(TGCT localized type): Synonyms: giant cell tumor of tendon sheath; nodular tenosynovitis}}

The localized form of TGCT is more common.{{r|Fletcher|p=100|q=The localized form is frequent and the most common subset of giant cell tumors.}}{{r|Rateb|p=245|q=Localize-type Tenosynovial GCTs are frequent, indolent, and arise from the synovium of the joint bursa or tissue. In contrast, the less frequent diffuse-type Tenosynovial GCTs are locally aggressive and commonly affect peri-articular soft tissue, but on rare occasion these lesions can be intramuscular.}} Localized TGCT tumors are typically 0.5 cm-4 cm),{{r|Fletcher|p=101|q=Grossly, most Tenosynovial giant cell tumors of localized type are small (0.5-4cm), although lesions of greater size may be found in large joints.}} develop over years,{{r|Fletcher|p=100|q=The tumors develop gradually over a long period and a preoperative duration of several years is often mentioned.}} are benign and non-destructive to the surrounding tissue, and may reoccur in the affected area.{{r|Fletcher|p=101|q=Tenovial giant cell tumor of localized type is a benign lesion with a capacity for local recurrence. While 4-30% of cases recur, these recurrences are usually non-destructive and are controlled by surgical re-excision.}} The most common symptom is painless swelling.{{r|Fletcher|p=101|q=The most common presenting symptom is that of a painless swelling.}} Localized TGCT most often occurs in fingers, but can also occur in other joints.

File:Pigmented villonodular synovitis high mag.jpg-laden macrophages (brown/red). H&E stain.]]

Diffuse TGCT is sometimes referred to as pigmented villonodular synovitis (PVNS), conventional PVNS, and D-TGCT.{{r|Lucas|p=1|q=…whereas diffuse types encompass conventional pigmented villonodular synovitis, and diffuse-type giant cell tumor.}}{{r|Ravi|p=361|q=...diffuse giant cell tumor of the tendon sheath (TGCT, diffuse type, or extra-articular pigmented villonodular synovitis (PVNS)) with those involving the joint space known as PVNS.}}{{r|Mastboom|p=1|q=...the diffuse-type (Diffuse-type Giant Cell Tumour (Dt-GCT), previously named Pigmented Villonodular Synovitis (PVNS))…}}{{r|Fletcher|p=102|q=Synonyms: diffuse-type giant cell tumor, pigmented villonodular synovitis, pigmented villonodular tenosynovitis}}

Diffuse TGCT occurs less frequently and is locally aggressive (in some cases, tumors may infiltrate surrounding soft tissue).{{r|Rateb|p=245|q=Despite the rarity of intramuscular diffuse GCTs, it is important to know that they infiltrate surrounding the soft tissue and have a high recurrence rate.}}{{r|Lucas|p=1|q=In contrast, the less frequent diffuse type Tenosynovial GCTs are locally aggressive and commonly affect periarticular soft tissue, but on rare occasion these lesions can be intramuscular…. Localized versus diffuse forms of Tenosynovial GCTs may cause different clinical symptoms.}}{{r|Fletcher|p=102|q=Tenosynovial giant cell tumor of diffuse type is a locally aggressive neoplasm…which may be intra-articular or extra articular}}{{cite journal | vauthors = Mastboom MJ, Verspoor FG, Gelderblom H, van de Sande MA | title = Limb Amputation after Multiple Treatments of Tenosynovial Giant Cell Tumour: Series of 4 Dutch Cases | journal = Case Reports in Orthopedics | volume = 2017 | pages = 7402570 | year = 2017 | pmid = 28744388 | pmc = 5506462 | doi = 10.1155/2017/7402570 | doi-access = free }}{{r|Mastboom|p=1|q=Diffuse-type is considered locally aggressive.}} It most commonly affects people under 40 years old, though the age of occurrence varies.{{r|Fletcher|p=102|q=The age of patients varies widely, but most lesions affect young adults aged <40 years}} Diffuse TGCT may occur inside a joint (intra-articular) or outside of a joint (extra-articular). Intra-articular tumors typically occur in the knee (approximately 75% of cases) and hip (approximately 15% of cases).{{r|Fletcher|p=102|q=Intra-articular lesions affect predominantly the knee (75% of cases), followed by the hip (15%), ankle, elbow, and shoulder… Extra-articular tumors most commonly involve the knee region, thigh and foot.}} Extra-articular tumors are usually found in the knee, thigh, and foot.{{r|Fletcher|p=101|q=Extra-articular tumors most commonly involve the knee region, thigh and foot. Uncommon locations include the finger, wrist, groin, elbow, and toe.}} Symptoms include swelling, pain, sensitivity, and/or limited range of motion.{{r|Fletcher|p=102|q=Patients complain of pain, tenderness, swelling or limitation of motion…. The symptoms are usually of relatively long duration (often several years).}} The rate of reoccurrence is estimated to be 18-46% for intra-articular tumors and 33-50% for extra-articular tumors.{{r|Fletcher|p=103|q=The recurrence rate has been estimated at 18-46% for intra-articular lesions and 30-55% for extra-articular tumours.}}{{r|Mastboom|p=1|q=Unfortunately, recurrences often occur (up to 92%), necessitating reoperations and adjuvant treatments.}}

Diffuse TGCT is locally aggressive and can spread to surrounding tissues, causing bone erosion and tissue damage. If not treated early, it can spread to areas outside the joint, extra-articular, and potentially cause permanent loss of range as well as intense pain.{{cite web| title = Clinical Study| publisher = The Stone Clinic|url=http://www.stoneclinic.com/PVNS.htm| format = web journal| access-date = 2007-08-07 |archive-url=https://web.archive.org/web/20070701034540/http://www.stoneclinic.com/PVNS.htm |archive-date = 2007-07-01}}{{cite journal | vauthors = Jabalameli M, Jamshidi K, Radi M, Hadi H, Bagherifard A | title = Surgical outcomes of 26 patients with pigmented villonodular synovitis (PVNS) of the knee at a mean follow-up of 4 years: introducing a novel technique | journal = Medical Journal of the Islamic Republic of Iran | volume = 28 | pages = 123 | year = 2014 | pmid = 25679002 | pmc = 4313448 }}

TGCT tumors grow due to genetic overexpression of colony stimulating factor 1. This causes colony-stimulating factor-1 receptor (CSF1R) cells to accumulate in the joint tissue.{{cite journal | vauthors = West RB, Rubin BP, Miller MA, Subramanian S, Kaygusuz G, Montgomery K, Zhu S, Marinelli RJ, De Luca A, Downs-Kelly E, Goldblum JR, Corless CL, Brown PO, Gilks CB, Nielsen TO, Huntsman D, van de Rijn M | title = A landscape effect in tenosynovial giant-cell tumor from activation of CSF1 expression by a translocation in a minority of tumor cells | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 3 | pages = 690–695 | date = January 2006 | pmid = 16407111 | pmc = 1325107 | doi = 10.1073/pnas.0507321103 | quote = The CSF1 translocations result in overexpression of CSF1. In cases of TGCT and PVNS carrying this translocation, it is present in a minority of the intratumoral cells, leading to CSF1 expression only in these cells, whereas the majority of cells express CSF1R but not CSF1, suggesting a tumor-landscaping effect with aberrant CSF1 expression in the neoplastic cells, leading to the abnormal accumulation of nonneoplastic cells that form a tumorous mass. | doi-access = free | bibcode = 2006PNAS..103..690W }}{{cite journal | vauthors = Cupp JS, Miller MA, Montgomery KD, Nielsen TO, O'Connell JX, Huntsman D, van de Rijn M, Gilks CB, West RB | title = Translocation and expression of CSF1 in pigmented villonodular synovitis, tenosynovial giant cell tumor, rheumatoid arthritis and other reactive synovitides | journal = The American Journal of Surgical Pathology | volume = 31 | issue = 6 | pages = 970–976 | date = June 2007 | pmid = 17527089 | doi = 10.1097/PAS.0b013e31802b86f8 | quote = As the CSF1 translocation is postulated to play an important role in the biology of PVNS/TGCT, the consistent presence of CSF1 expression in translocation-negative cases implies that other mechanisms can lead to CSF1 up-regulation. | s2cid = 29544370 }}

TGCT can be diagnosed by magnetic resonance imaging (MRI), by biopsy, or during surgery.{{cite journal | vauthors = Akinci O, Akalin Y, İncesu M, Eren A | title = Long-term results of surgical treatment of pigmented villonodular synovitis of the knee | journal = Acta Orthopaedica et Traumatologica Turcica | volume = 45 | issue = 3 | pages = 149–155 | year = 2011 | pmid = 21765227 | doi = 10.3944/AOTT.2011.2442 | doi-access = free }}{{cite journal | vauthors = Verspoor FG, Zee AA, Hannink G, van der Geest IC, Veth RP, Schreuder HW | title = Long-term follow-up results of primary and recurrent pigmented villonodular synovitis | journal = Rheumatology | volume = 53 | issue = 11 | pages = 2063–2070 | date = November 2014 | pmid = 24917565 | doi = 10.1093/rheumatology/keu230 | doi-access = free }} The disorder is difficult to identify and is often not diagnosed for years due to nonspecific symptoms or a general paucity of symptoms.{{cite journal | vauthors = Frassica FJ, Bhimani MA, McCarthy EF, Wenz J | title = Pigmented villonodular synovitis of the hip and knee | journal = American Family Physician | volume = 60 | issue = 5 | pages = 1404–10; discussion 1415 | date = October 1999 | pmid = 10524485 | url = http://www.aafp.org/afp/991001ap/1404.html | access-date = 2020-08-06 | url-status = dead | archive-url = https://web.archive.org/web/20110606011227/http://www.aafp.org/afp/991001ap/1404.html | archive-date = 2011-06-06 }} TGCT cases are often misdiagnosed as osteoarthritis,{{cite journal | vauthors = Lei P, Sun R, Liu H, Zhu J, Wen T, Hu Y | title = Prognosis of Advanced Tenosynovial Giant Cell Tumor of the Knee Diagnosed During Total Knee Arthroplasty | journal = The Journal of Arthroplasty | volume = 32 | issue = 6 | pages = 1850–1855 | date = June 2017 | pmid = 28161138 | doi = 10.1016/j.arth.2016.12.053 }} localized trauma,{{cite journal | vauthors = Illian C, Kortmann HR, Künstler HO, Poll LW, Schofer M | title = Tenosynovial giant cell tumors as accidental findings after episodes of distortion of the ankle: two case reports | journal = Journal of Medical Case Reports | volume = 3 | pages = 9331 | date = December 2009 | pmid = 20062758 | pmc = 2803852 | doi = 10.1186/1752-1947-3-9331 | doi-access = free }} sports injuries,{{cite journal | vauthors = Hegedus EJ, Theresa K | title = Postoperative management of pigmented villonodular synovitis in a single subject | journal = The Journal of Orthopaedic and Sports Physical Therapy | volume = 38 | issue = 12 | pages = 790–797 | date = December 2008 | pmid = 19047769 | doi = 10.2519/jospt.2008.2934 }}{{cite journal | vauthors = Krych A, Odland A, Rose P, Dahm D, Levy B, Wenger D, Stuart M, Sim F | title = Oncologic conditions that simulate common sports injuries | journal = The Journal of the American Academy of Orthopaedic Surgeons | volume = 22 | issue = 4 | pages = 223–234 | date = April 2014 | pmid = 24668352 | doi = 10.5435/JAAOS-22-04-223 | s2cid = 37108679 }} xanthomas,{{cite journal | vauthors = Adams EL, Yoder EM, Kasdan ML | title = Giant cell tumor of the tendon sheath: experience with 65 cases | journal = ePlasty | volume = 12 | pages = e50 | year = 2012 | pmid = 23185646 | pmc = 3499005 }} or other conditions.{{cite journal | vauthors = Lee YJ, Kang Y, Jung J, Kim S, Kim CH | title = Intramuscular Tenosynovial Giant Cell Tumor, Diffuse-Type | journal = Journal of Pathology and Translational Medicine | volume = 50 | issue = 4 | pages = 306–308 | date = July 2016 | pmid = 26755356 | pmc = 4963964 | doi = 10.4132/jptm.2015.11.15 }} One study of 122 diffuse TGCT patients found that the average delay in diagnosis was 2.9 years.{{cite journal | vauthors = Ottaviani S, Ayral X, Dougados M, Gossec L | title = Pigmented villonodular synovitis: a retrospective single-center study of 122 cases and review of the literature | journal = Seminars in Arthritis and Rheumatism | volume = 40 | issue = 6 | pages = 539–546 | date = June 2011 | pmid = 20884045 | doi = 10.1016/j.semarthrit.2010.07.005 }}

To identify or monitor using MRI, the minimum techniques required include T1 weighted images, T2 weighted images, and a fluid sensitive sequence.{{cite journal | vauthors = Stacchiotti S, Dürr HR, Schaefer IM, Woertler K, Haas R, Trama A, Caraceni A, Bajpai J, Baldi GG, Bernthal N, Blay JY, Boye K, Broto JM, Chen WT, Dei Tos PA, Desai J, Emhofer S, Eriksson M, Gronchi A, Gelderblom H, Hardes J, Hartmann W, Healey J, Italiano A, Jones RL, Kawai A, Leithner A, Loong H, Mascard E, Morosi C, Otten N, Palmerini E, Patel SR, Reichardt P, Rubin B, Rutkowski P, Sangalli C, Schuster K, Seddon BM, Shkodra M, Staals EL, Tap W, van de Rijn M, van Langevelde K, Vanhoenacker FM, Wagner A, Wiltink L, Stern S, Van de Sande VM, Bauer S | title = Best clinical management of tenosynovial giant cell tumour (TGCT): A consensus paper from the community of experts | journal = Cancer Treatment Reviews | volume = 112 | pages = 102491 | date = January 2023 | pmid = 36502615 | doi = 10.1016/j.ctrv.2022.102491 | hdl-access = free | hdl = 10067/1923310151162165141 }}

Patients affected by TGCT should be managed within expert centers or reference networks, by a dedicated, experienced sarcoma multidisciplinary treatment team, including a pathologist, radiologist, orthopaedic surgeon, pain specialist, surgical, radiation and medical oncologists. Patients initially treated at cancer centers have lower recurrence rates than those initially treated by community centers.

Surgery has been the most common form of treatment for both localized{{r|Fletcher|p=101|q=Tenovial giant cell tumor of localized type is a benign lesion with a capacity for local recurrence. While 4-30% of cases recur, these recurrences are usually non-destructive and are controlled by surgical re-excision.}}{{r|Ravi|p=361|q=Currently, surgery remains the treatment of choice for patients with TGCT/PVNS. Localized TGCT/PVNS is managed by marginal excision.}} and diffuse TGCT.{{r|Fletcher|p=103|q=Therefore, Tenosynovial giant cell tumors of diffuse type should be regarded as locally non-aggressive but non-metastasizing neoplasms and wide excision is the treatment of choice}}{{r|Ravi|p=361|q=Currently, surgery remains the treatment of choice for patients with TGCT/PVNS.}}{{r|Mastboom|p=1|q=Surgical resection is the most commonly performed treatment.}} After surgery, patients may receive physical therapy in order to help rehabilitate affected joints. However, recurrence of TGCT after surgery is common, with a higher rate of recurrence for diffuse TGCT than for localized TGCT.{{r|Ravi|p=361|q=Localized TGCT/PVNS is managed by marginal excision. Recurrences occur in 8-20% of patients and are easily managed by re-excision. Diffuse TGCT/PVNS tends to recur more often (33-50%) and has a much more aggressive clinical course.}} In cases of recurrent or resistant disease, multiple surgeries, total joint arthroplasties, or amputation may be required.{{r|Mastboom|p=1|q=Recurrent or resistant disease frequently necessitates multiple mutilating surgeries and ends occasionally inevitably in total joint arthroplasties… Unfortunately, recurrences often occur (up to 92%), necessitating reoperations and adjuvant treatments. Once all treatments fail or if severe complications occur, limb amputation may become unavoidable.}}

A multidisciplinary approach, supplementing surgery or other treatments, can also improve outcomes in cases of recurrent TGCT.{{cite journal | vauthors = van der Heijden L, Gibbons CL, Dijkstra PD, Kroep JR, van Rijswijk CS, Nout RA, Bradley KM, Athanasou NA, Hogendoorn PC, van de Sande MA | title = The management of diffuse-type giant cell tumour (pigmented villonodular synovitis) and giant cell tumour of tendon sheath (nodular tenosynovitis) | journal = The Journal of Bone and Joint Surgery. British Volume | volume = 94 | issue = 7 | pages = 882–888 | date = July 2012 | pmid = 22733940 | doi = 10.1302/0301-620X.94B7.28927 }} In the late 2010s, treatment with CSF1R inhibitors emerged as an option{{cite journal | vauthors = Cannarile MA, Weisser M, Jacob W, Jegg AM, Ries CH, Rüttinger D | title = Colony-stimulating factor 1 receptor (CSF1R) inhibitors in cancer therapy | journal = Journal for Immunotherapy of Cancer | volume = 5 | issue = 1 | pages = 53 | date = July 2017 | pmid = 28716061 | pmc = 5514481 | doi = 10.1186/s40425-017-0257-y | quote = The tumor-permissive and immunosuppressive characteristics of tumor-associated macrophages (TAM) have fueled interest in therapeutically targeting these cells. In this context, the colony-stimulating factor 1 (CSF1)/colony-stimulating factor 1 receptor (CSF1R) axis has gained the most attention, and various approaches targeting either the ligands or the receptor are currently in clinical development. | doi-access = free }} that may help improve functionality for patients with recurrent TGCT or TGCT that is not easily managed by surgery.{{r|Ravi|p=361|q=For patients with unresectable disease or multiple recurrences, systemic therapy using CSF1R inhibitors may help delay or avoid surgical procedures and improve functional outcomes.}}An oral CSF-1R inhibitor pexidartinib is approved in the US and only available through a Risk Evaluation and Mitigation Strategy (REMS) Program,{{cite journal | url=https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pexidartinib-tenosynovial-giant-cell-tumor | title=FDA approves pexidartinib for tenosynovial giant cell tumor | journal=FDA | date=20 December 2019 }} and two other oral CSF-1R inhibitors, pimicotinib and vimseltinib are being developed in phase 3 trials.{{cite journal | url=https://clinicaltrials.gov/study/NCT05804045?intr=absk021&rank=2 | title=CTG Labs | journal = ClinicalTrials.gov | date=28 August 2024 | publisher = U.S. National Center for Biotechnology Information (NCBI) }}{{cite journal | url=https://clinicaltrials.gov/study/NCT05059262?intr=vimseltinib&rank=1 | title=CTG Labs | journal = ClinicalTrials.gov | date=8 August 2024 | publisher = U.S. National Center for Biotechnology Information (NCBI) }}

There is insufficient and contradictory evidence on radiation therapy, in the form of radiosynoviorthesis (yttrium injections) or external beam, before or after surgery and thus no recommendation for its use in TGCT can be made.

For asymptomatic patients, active surveillance is the preferred method.{{cite journal | vauthors = Spierenburg G, Staals EL, Palmerini E, Randall RL, Thorpe SW, Wunder JS, Ferguson PC, Verspoor FG, Houdek MT, Bernthal NM, Schreuder BH, Gelderblom H, van de Sande MA, van der Heijden L | title = Active surveillance of diffuse-type tenosynovial giant cell tumors: A retrospective, multicenter cohort study | journal = European Journal of Surgical Oncology | volume = 50 | issue = 2 | pages = 107953 | date = February 2024 | pmid = 38215550 | doi = 10.1016/j.ejso.2024.107953 | hdl-access = free | doi-access = free | hdl = 1887/3748215 }} Active surveillance includes monitoring with MRI in intervals (e.g., every 6 months) to ensure the delay in treatment does not pose a potential harm. This should be carefully weighed against the potential for over treatment.

Vimseltinib (Romvimza) was approved for medical use in the United States in February 2025.{{cite web | title=FDA approves vimseltinib for symptomatic tenosynovial giant cell tumor | website=U.S. Food and Drug Administration (FDA) | date=14 February 2025 | url=https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-vimseltinib-symptomatic-tenosynovial-giant-cell-tumor | access-date=16 February 2025}} {{PD-notice}}

A study conducted in the Netherlands estimated that the worldwide incidence of TGCT is 43 cases per million person-years. The majority – 39 cases per million person-years – were estimated to be localized TGCT; the remaining 4 cases per million person-years were estimated to be diffuse TGCT.{{cite journal | vauthors = Mastboom MJ, Verspoor FG, Verschoor AJ, Uittenbogaard D, Nemeth B, Mastboom WJ, Bovée JV, Dijkstra PD, Schreuder HW, Gelderblom H, Van de Sande MA | title = Higher incidence rates than previously known in tenosynovial giant cell tumors | journal = Acta Orthopaedica | volume = 88 | issue = 6 | pages = 688–694 | date = December 2017 | pmid = 28787222 | pmc = 5694816 | doi = 10.1080/17453674.2017.1361126 | collaboration = TGCT study group }} TGCT can occur in patients of any age, but people with localized TGCT are typically between 30 and 50 years old,{{r|Fletcher|pp=100–101}} while diffuse TGCT tends to affect people under the age of 40.{{r|Fletcher|pp=102–103}}

• Fibroma of tendon sheath
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| NORD = Tenosynovial Giant Cell Tumor

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{{Diseases of the musculoskeletal system and connective tissue}}

{{Soft tissue disorders}}

Category:Dermal and subcutaneous growths

Category:Ailments of unknown cause

Category:Musculoskeletal disorders

Category:Rare diseases