Tenosynovial giant cell tumor (TGCT) is a rare, aggressive, benign soft-tissue tumor that forms in the synovium, tendon sheaths, and bursae of the joints.1,2 Although generally not fatal, TGCT can cause significant pain and damage to the joints affected and reduce quality of life.
Classified by the World Health Organization as a type of “so-called fibrohistiocytic tumor,” TGCT has 2 distinct subtypes: TGCT localized to the digits or extremities (L-TGCT) and a diffuse form (D-TGCT) notable for lesions at multiple sites.3 The highly polymorphic appearance of TGCT originally led to the presumption that it was non-neoplastic, with an inflammatory etiology.4,5 Studies conducted in the early 2000s, however, implicated hyperexpression of colony-stimulating factor gene (CSF1) in its pathogenesis, despite its presence in a minority (2% to 16%) of TGCT cells.6,7 A history of trauma is reported in nearly one-half of cases, although the significance of trauma as a causative event is not well understood.7
Originally viewed as extremely rare, the incidence of TGCT was reported, in a study from a single county in the United States in 1980, as less than 2 cases of L-TGCT and less than 9 cases of D-TGCT for every 1 million people.3,4,8 A 2017 review from the Netherlands by Mastbloom and colleagues3 reported a 5-fold higher incidence of combined TGCT and a 2.6-fold higher rate of D-TGCT, along with a worldwide incidence for localized digits, localized extremities, and D-TGCT of 29, 10 and 4 cases, respectively, for every 1 million people. These data indicate that the disease occurs more frequently than previously reported. The limited studies available generally support a higher percentage of women with L-TGCT (in a 2:1 ratio) but an even distribution of women and men with D-TGCT.4,7 Although the condition is largely seen in adults older than 40 years, a retrospective review by the same group reported 57 cases in children younger than 18 years treated for TGCT in the Netherlands from 1995 to 2015.2,3
Differentiation of Subtypes
Localized TGCT was originally described as giant cell nodular or pigmented villonodular synovitis, a term that now better describes D-TGCT. Macroscopic examination generally reveals a small, often lobulated lesion measuring 0.5 to 4 cm in diameter with a well-circumscribed white or gray aspect with yellow or brown mottling.3 Lesions are defined as occurring in the digits distal to the larger metacarpal or metatarsal joints, with the fingers involved in 85% of cases.9 L-TGCT of the digits usually occurs in the tendon sheath, rather than in the synovial lining. Occasionally, L-TGCT is localized to larger joints and can originate from the synovial lining and bursa, as well as from the tendon sheaths.
Diffuse TGCT is a much more aggressive and problematic form of the disease, emanating from the synovial lining and causing more destruction to the affected region. Intra-articular projections from the affected membrane can be observed infiltrating further into the region.3 The knee is the most frequently affected joint, followed by the hip and spine.4 In some cases, the temporomandibular joint (TMJ) is also affected; there, the tumor can cause destruction of the jaw and intracranial involvement, impaired mouth opening, and hearing loss.9
Malignant TGCT is a malignant subtype of TGCT recently identified by the World Health Organization. The tumor is extremely rare, with fewer than 40 cases having been reported.5,10 Malignant TGCThas been determined to evolve either from a benign tumor that coexisted with a sarcoma (primary malignant TGCT) or as the result of a recurrence of a previously benign tumor (secondary malignant TGCT). In a limited study of 10 patients with malignant TGCT, Al-Ibraheemi and colleagues5 found large tumors that were “fleshy and poorly circumscribed with areas of hemorrhage and necrosis.” Histologic examination revealed findings typical of benign forms of TGCT, although the appearance of tumors varied from case to case. Three types of cell populations were observed in all cases, including small histiocytes, larger clusterin-positive mononuclear cells, and scattered desmin-positive mononuclear cells.
Symptoms of TGCT are highly variable and nonspecific, ranging from mild to seriously debilitating.
In L-TGCT, there might be little pain from the tumor mass, but it might cause swelling and skin tension around the fingers or toes that limit functional movement or make it uncomfortable to wear shoes. The most common sites of L-TGCT are the digits (85% of cases); there, swelling and stiffness of the interphalangeal joints are more likely to be prominent on the palmar side than on the dorsal side.7 Other tumor locations include the wrist, foot, ankle, and knee, with rare involvement of the hip or elbow. The knee is also the most common site of intra-articular TGCT, which can be localized or diffuse.
In D-TGCT, 75% of cases involve the knee as well; the rest affect the hip, ankle, or shoulder as the main site.7 Even in diffuse cases, tumors are situated focally in a single region, with only the rare multifocal case reported, mainly in children.7 Pain is usually reported as a result of swelling of the joint that causes limited range of motion. When the knee is involved, there may be additional symptoms of blockage or instability. Most patients report slow evolution of symptoms, sometimes arising from physical trauma, although acute forms often related to torsion or necrosis have been reported.7 Progression from first recognition of symptoms to diagnosis is reported to take 10 months to 3 years.
Tenosynovial giant cell tumor is largely a diagnosis of exclusion. Clinical examination that reveals a soft, palpable mass of the soft tissue of the hand or foot might initially suggest L-TGCT, particularly when swelling is present, the skin is warm to the touch, or both.7 Biopsy and microscopic examination of a TGCT specimen shows heterogeneous morphology, including osteoclast-like giant cells, macrophages, mononuclear histiocytes, and larger stromal cells. Microscopically, localized and diffuse forms of TGCT appear identical.3
Standard imaging is important to identify less-detectable masses; the presence of symmetrical cysts in a nonweight-bearing region distal to a joint line contributes to a diagnosis. Magnetic resonance imaging (MRI) is an important tool for determining the subtype of TGCT: L-TGCT tumors appear discrete and well defined, whereas soft tissue masses with a villous growth pattern, extra-articular involvement, joint effusion, or a combination of those findings indicate D-TGCT.7,8
The differential diagnosis of TGCT includes many neoplastic and malignant tumors, including histiocytic sarcoma, melanoma, carcinoma, and hematopoietic neoplasms.5 It also includes other giant cell tumors of the bone and soft tissues. The most reliable tool for distinguishing these lesions from TGCT is MRI, which produces an intermediate to weak signal on T2-weighted images whereas ganglion cysts, hemangioma, nerve-sheath tumor, and synovial sarcoma of the foot are readily detected by their high T2-weighted signal.7,11
Still other types of lesions, particularly of the foot, have similarly intermediate signals, making it more difficult to distinguish fibromatosis, xanthomas, intermetatarsal neuroma, and various desmoid sarcomas from TGCT. These conditions require further evaluation of clinical findings, with careful attention to symptoms and location of the tumor. Subsequent imaging studies might be necessary, and biopsy is recommended whenever the diagnosis is in doubt.7
Differentiating TGCT as the Cause of a TMJ Disorder
Occasionally, a TGCT lesion is located in the jaw, where it can produce significant pain and dysmobility associated with a TMJ disorder. Chondroid metaplasia with calcification is often present in TGCT in this location.9 As the temporal bone is a common site of craniofacial chondroblastoma, it is both difficult and important to distinguish TGCT cells at this location from those of chondroblastoma, synovial chondromatosis, and chondrosarcoma.
Location Is Key to Diagnosis
There are many causes of soft-tissue tumor other than TGCT. Due to the heterogeneous morphology of TGCT, which can resemble other tumor types, location becomes an important consideration in making the diagnosis and determining subtype.
Treatment of TGCT includes open or arthroscopic surgery, radiosynovectomy, external-beam radiotherapy, cryosurgery, immunotherapy, and amputation. Surgical excision is the most common approach when the primary lesion is distinct, such as in the knee (which accounts for 75% of cases of D-TGCT) and in most cases involving the fingers.3 However, all these treatments are associated with a high rate of recurrence: Arthroscopic surgery has a 40% recurrence rate, and surgical excision has a 14% recurrence rate. Lifetime risk of recurrence of L-TGCT is 15% compared with a rate as high as 55% among patients treated for D-TGCT.4
Because TGCT is a rare disease that is largely benign, it has not been well studied. Most epidemiologic data are retrospective and incomplete; only through extensive reviews by investigational groups from the Netherlands could worldwide incidence be estimated.3,4 The literature has explored clinical presentations that are highly nonspecific and require nuanced evaluation of symptoms, imaging studies, and, in many cases, biopsy to confirm TGCT and determine subtype. The differential diagnosis can be challenging.
Although TGCT malignancies are extremely rare, all forms of the disease are likely to cause discomfort and limit range of movement in the affected joint. Accurate diagnosis is important to determining the most effective treatment strategy for the individual patient.
- Bernthal NM, Spierenburg G, Healey JH, et al. The diffuse-type tenosynovial giant cell tumor (dt-TGCT) patient journey: a prospective multicenter study. Orphanet J Rare Dis. 2021;16(1):191. doi:10.1186/s13023-021-01820-6
- Mastboom MJL, Verspoor FGM, Uittenbogaard D, et al. Tenosynovial giant cell tumors in children: a similar entity compared with adults. Clin Orthop Relat Res. 2018;476(9):1803-1812. doi:10.1007/s11999.0000000000000102
- Mastboom MJL, Verspoor FGM, Verschoor AJ, et al; TGCT Study Group. Higher incidence rates than previously known in tenosynovial giant cell tumors. Acta Orthop. 2017;88(6):688-694. doi: 10.1080/17453674.2017.1361126
- Ehrenstein V, Andersen SL, Qazi I, et al. Tenosynovial giant cell tumor: incidence, prevalence, patient characteristics, and recurrence. A registry-based cohort study in Denmark. J Rheumatol. 2017;44(10):1476-1483. doi:10.3899/jrheum.160816
- Al-Ibraheemi A, Ahrens WA, Fritchie K, et al. Malignant tenosynovial giant cell tumor: the true “synovial sarcoma?” A clinicopathologic, immunohistochemical, and molecular cytogenetic study of 10 cases, supporting origin from synoviocytes. Mod Pathol. 2019;32(2):242-251. doi: 10.1038/s41379-018-0129-0
- West RB, Rubin BP, Miller MA, et al. A landscape effect in tenosynovial giant-cell tumor from activation of CSF1 expression by a translocation in a minority of tumor cells. Proc Natl Acad Sci U S A. 2006;103(3):690-695. doi:10.1073/pnas.0507321103
- Gouin F, Noailles T. Localized and diffuse forms of tenosynovial giant cell tumor (formerly giant cell tumor of the tendon sheath and pigmented villonodular synovitis). Orthop Traumatol Surg Res. 2017;103(1S):S91-S97. doi:10.1016/j.otsr.2016.11.002
- Myers BW, Masi AT. Pigmented villonodular synovitis and tenosynovitis: a clinical epidemiologic study of 166 cases and literature review. Medicine (Baltimore). 1980;59(3):223-238.
- Lee J-C, Huang H-Y. Soft tissue special issue: giant cell-rich lesions of the head and neck region. Head Neck Pathol. 2020;14(1):97-108. doi:10.1007/s12105-019-01086-2
- de Saint Aubain Somerhausen NS, van de Rijn M. Tenosynovial giant cell tumour. In: WHO Classification of Tumours Editorial Board, eds. WHO Classification of Tumours of Soft-Tissue and Bone. Vol 3. 5th ed. IARC Press; 2020:133-136.
- Ding Y, Griffin JE, Raghavan M, Xu H, Henderson-Jackson E, Bui MM. Tenosynovial giant cell tumors lacking giant cells: report of diagnostic pitfalls. Ann Clin Lab Sci. 2014;44(2):222-227.
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Reviewed September 2021