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Tenosynovial giant cell tumor

Rare lesions with a tendency for local recurrence1,2

tenosynovial-giant-cell-tumor

Proton density weighted MRI of a patient with localized TGCT affecting the right knee. Note the well-circumscribed lesion in Hoffa’s fat pad.7 This image was used with permission from Mastboom et al.

Tenosynovial giant cell tumor (TGCT) is a group of rare tumors typically arising from the synovium of joints, bursae, and tendon sheaths. They are non-malignant neoplasms, which can be locally aggressive.1,2

TGCTs are rare, and the epidemiology has not been well-studied. Based on studies from 3 countries, the estimated incidence of TGCT is 11-50 cases per million person-years (Localized TGCT: ≈9-45 cases per million person-years; diffuse TGCT: ≈2-5 cases per million person-years). Based on a study done in the Netherlands, estimates were extrapolated to calculate worldwide incidence. The estimated worldwide incidence of TGCT is 43 cases per million person-years (4 cases per million person-years for diffuse TGCT and 39 cases per million person-years for localized TGCT).3

However, annual incidence rates alone may not provide the full picture. Because patients typically present relatively early in adulthood and can live with the disease for a long time, lifetime prevalence may be substantially greater.4-6

2 subtypes of TGCT

As the pathogenesis of these rare tumors has become better understood, medical terminology has also evolved2,8

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Sagittal proton density weighted turbo spin echo MRI of a patient with extensive diffuse TGCT. Note the extensive proliferative synovial process around both cruciate ligaments, dominating the anterior and posterior knee compartments, intra-articular and extra-articular. The suprapatellar pouch and Baker’s cyst show a blooming villonodular aspect with typical iron depositions.7 This image was used with permission from Mastboom et al.

Before localized and diffuse TGCT were known to share a common pathogenesis, the World Health Organization (WHO) classification considered diffuse giant cell tumor/pigmented villonodular synovitis (PVNS) as a separate entity from giant cell tumor of the tendon sheath (GCT-TS, which was listed as synonymous with TGCT).9,10

Currently, the WHO classification for TGCT encompasses 2 broad subtypes that differ clinically but share a common etiology: localized TGCT and diffuse TGCT.2

There is still wide variability in the terminology used to refer to TGCT in literature and clinical practice, with some terms considered synonymous (see table below). Ultimately, the localized or diffuse nature of the disease is a main determining factor of prognosis.2,8,11

TGCT nomenclature

WHO classification1,2,11

TGCT, localized type

TGCT, diffuse type

Other TGCT terminology found in literature1,2,11

Localized TGCT

GCT-TS

Localized nodular tenosynovitis

Nodular tenosynovitis

Localized PVNS

L-TGCT

Diffuse TGCT

PVNSa

Conventional PVNS

D-TGCT

 

aPVNS has been historically used as an overarching term to describe the disease.

Mechanism of disease

TGCT growth is characterized by overexpression of colony-stimulating factor-1 (CSF-1) and recruitment and accumulation of colony-stimulating factor-1 receptor (CSF-1R)–expressing cells in the synovium12,13

Neoplastic lesions

TGCT is a reactive and inflammatory neoplasm, although it was originally regarded as a nontumoral process.2,12,14

Molecular pathogenesis

The pathogenesis of TGCT is thought to derive from a small number of neoplastic cells arising from the lining of the synovium that overexpress a growth factor called CSF-1. In most patients, CSF-1 overexpression has been reported as a result of a genetic translocation.12,13

Tumor landscape

Tumors are typically composed of a small number of these neoplastic cells (2%-16%), along with a high number of CSF-1R–expressing myeloid-lineage cells, including monocytes and macrophages, recruited through CSF-1 signaling.2,12

How CSF-1 is thought to drive TGCT formation and progression

Autocrine stimulation:

CSF-1 may activate CSF-1R in cells within the tumor, resulting in the proliferation of neoplastic cells.12

pacrine_effect
Paracrine effect:

CSF-1 may recruit CSF-1R–expressing myeloid lineage cells that comprise the majority of the tumor mass.12

tgct_morbidity
TGCT morbidity:

CSF-1 overexpression may also contribute to the inflammation and osteochondral destruction seen in some cases.15

Key characteristics and diagnostic considerations of each subtype

Characteristics of TGCT subtypes to look for as part of your differential diagnosis of localized and diffuse TGCT

Localized and diffuse TGCT have varying impacts on your patients.1,14 TGCT, like other soft tissue tumors, can be misdiagnosed, highlighting the importance of differential diagnosis.16,17

Because of the general presentation and insidious onset, delays in diagnosis may cause the disease to be diagnosed at a more advanced stage, when the tumor may involve surrounding bone, muscle, and tendon, particularly in diffuse TGCT. 11,18

Diagnosis of TGCT can be confirmed by MRI, determined preoperatively by biopsy, or occur during surgery.18,19

localized-TGCT LOCALIZED TGCT More common subtype2
diffuse-TGCT DIFFUSE TGCT Less common subtype2
Tumor Location
  • Mostly monoarticular and commonly seen in small joints2,20

  • The majority occur in the digits2,7

  • Can also occur in other joints such as the wrist, ankle, foot, knee, elbow, or hip joints2

  • Mostly monoarticular and commonly seen in large joints1,21

  • Most often occurs in the knee7,11,22

  • Can also occur in other joints such as the hip, ankle, elbow, and shoulder joints11

Lesion features
  • Nodular, well-circumscribed, at least partially encapsulated, and usually small2

  • Larger tumors can appear in larger joints2

  • May be intra-articular or extra-articular2,22

  • Rarely, localized lesions lead to degenerative changes to the adjacent joint, exert pressure causing erosion of nearby bone, or involve the skin2

  • Diffuse tumors are usually large (>5 cm) and have poorly defined borders11

  • May be associated with degenerative joint disease and cystic lesions in adjacent bone11

  • May be intra-articular or extra-articular1,11

  • Extra-articular tumors may impinge surrounding tendons and neurovascular structures, while intra-articular tumors can infiltrate joint spaces, disrupting tissue architecture1,21,23

Demographics
  • Typically seen between 30 and 50 years of age, although it can occur in patients of any age2

  • Has been reported to be 1.5 to 2 times more common in women than in men2,7

  • Tends to affect younger patients, although age can vary widely11

  • Most often seen in young adults <40 years of age11

  • Has been reported to be slightly more common in women than in men7

Symptoms
  • Most common presenting symptom is painless swelling2

  • Pain may develop, especially with tumor growth24

  • Tumors can interfere with joint function4

  • Common symptoms include pain, swelling, or limited joint motion; other symptoms such as locking and catching may occur3,5,11

  • Pain may be insidious, intermittent, or sustained3,5,11

  • Tumors can interfere with joint function11,25

Progression
  • Tumors can develop over a long period of time2

  • Patients may delay seeking medical treatment2,4

  • In one study,a average delay before consulting a physician was 25 months (range: 2 months-10 years) for TGCT of the finger/thumb and 19 months (range 3-48 months) for TGCT of the toe4

  • Tumor development can progress slowly11

  • Patients often delay seeking immediate medical consultation4,26

  • In one study,b average delay in diagnosis was 2.9 years (standard deviation: 3.7 years)22

Differential diagnosis can include many conditions such as:
  • Localized trauma/joint degeneration17

  • Ganglion cyst27

  • Xanthomas28

  • Hemangiomas28

  • GCT of the bone29

  • Meniscal tear or sports injuries30,31

  • Synovial proliferative disorders such as rheumatoid arthritis and synovial chondromatosis30,32,33

  • Fibromas34

  • Xanthomas34

  • Soft tissue sarcomas33,34

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Localized TGCT fast facts

This handy card conveys key facts about localized TGCT and can be used to support your discussions with your patients about their condition.

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Diffuse TGCT fast facts

This handy card conveys key facts about diffuse TGCT and can be used to support your discussions with your patients about their condition.

Footnotes

aAverage duration before consulting physician for patients with digit lesions in one retrospective analysis of 81 patients with TGCT.4

bAverage delay in diagnosis in patients with TGCT, most of which was diffuse, in a single-center retrospective study of 121 patients.22

References

1. Lucas DR. Tenosynovial giant cell tumor. Arch Pathol Lab Med. 2012;136(8):901-906. doi:10.5858/arpa.2012-0165-CR.

2. de Saint Aubain Somerhausen N, van de Rijn M. Tenosynovial giant cell tumour, localized type. In: Fletcher CDM, Bridge JA, Hogendoorn PCW, Mertens F, eds. WHO Classification of Tumours of Soft Tissue and Bone. Vol 5. 4th ed. Lyon, France: IARC Press; 2013:100-101.

3. Mastboom MJL, Verspoor FGM, Verschoor AJ, et al. Higher incidence rates than previously known in tenosynovial giant cell tumors. Acta Orthop. 2017;88(6):688-694. doi: 10.1080/17453674.2017.1361126.

4. Rao AS, Vigorita VJ. Pigmented villonodular synovitis (giant-cell tumor of the tendon sheath and synovial membrane): a review of eighty-one cases. J Bone Joint Surg Am. 1984;66(1):76-94.

5. Gelhorn HL, Tong S, McQuarrie K, et al. Patient-reported symptoms of tenosynovial giant cell tumors. Clin Ther. 2016;38(4):778-793. doi:10.1016/j.clinthera.2016.03.008.

6. Thomas DM. The growing problem of benign connective tissue tumours. Lancet Oncol. 2015;16(8):879-880. doi:10.1016/S1470-2045(15)00147-3.

7. Mastboom MJL, Verspoor FGM, Verschoor AJV, et al; TGCT study group. Higher incidence rates than previously known in tenosynovial giant cell tumors: a nationwide study in The Netherlands [published online August 8, 2017]. Acta Orthop. doi:10.1080/17453674.2017.1361126.

8. van der Heijden L, Gibbons CLMH, Hassan AB, et al. A multidisciplinary approach to giant cell tumors of tendon sheath and synovium: a critical appraisal of literature and treatment proposal. J Surg Oncol. 2013;107(4):433-435. doi:10.1002/jso.23220.

9. de Saint Aubain Somerhausen N, Dal Cin P. Giant cell tumor of tendon sheath. In: Fletcher CDM, Unni KK, Mertens F, eds. World Health Organization Classification of tumours. Pathology and Genetics of Tumours of Soft Tissue and Bone. Lyon, France: IARC Press; 2002:110–111.

10. de Saint Aubain Somerhausen N, Dal Cin P. Diffuse-type giant cell tumour. In: Fletcher CDM, Unni KK, Mertens F, eds. World Health Organization Classification of tumours. Pathology and Genetics of Tumours of Soft Tissue and Bone. Lyon, France: IARC Press; 2002:112–114.

11. de Saint Aubain Somerhausen N, van de Rijn M. Tenosynovial giant cell tumour, diffuse type. In: Fletcher CDM, Bridge JA, Hogendoorn PCW, Mertens F, eds. WHO Classification of Tumours of Soft Tissue and Bone. Vol 5. 4th ed. Lyon, France: IARC Press; 2013:102-103.

12. 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.

13. Cupp JS, Miller MA, Montgomery KD, et al. Translocation and expression of CSF1 in pigmented villonodular synovitis, tenosynovial giant cell tumor, rheumatoid arthritis and other reactive synovitides. Am J Surg Pathol. 2007;31(6):970-976.

14. 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.

15. Ota T, Urakawa H, Kozawa E, et al. Expression of colony-stimulating factor 1 is associated with occurrence of osteochondral change in pigmented villonodular synovitis. Tumor Biol. 2015;36(7):5361-5367. doi:10.1007/s13277-015-3197-5.

16. Bisbinas I, De Silva U, Grimer RJ. Pigmented villonodular synovitis of the foot and ankle: a 12-year experience from a tertiary orthopedic Oncology Unit. J Foot Ankle Surg. 2004;43(6):407-411. doi:10.1053/j.jfas.2004.09.002.

17. Illian C, Kortmann H-R, Künstler HO, Poll LW, Schofer M. Tenosynovial giant cell tumors as accidental findings after episodes of distortion of the ankle: two case reports. J Med Case Rep. 2009;3:9331. doi:10.1186/1752-1947-3-9331.

18. Akinci O, Akalin Y, Incesu M, Eren A. Long-term results of surgical treatment of pigmented villonodular synovitis of the knee. Acta Orthop Traumatol Turc. 2011;45(3):149-155. doi:10.3944/AOTT.2011.2442.

19.Verspoor FGM, Zee AAG, Hannink G, van der Geest ICM, Veth RPH, Schreuder HWB. Long-term follow-up results of primary and recurrent pigmented villonodular synovitis. Rheumatology (Oxford). 2014;53(11):2063-2070. doi:10.1093/rheumatology/keu230.

20. Brahmi M, Vinceneux A, Cassier PA. Current systemic treatment options for tenosynovial giant cell tumor/pigmented villonodular synovitis: targeting the CSF1/CSF1R axis. Curr Treat Options Oncol. 2016;17(2):10. doi:10.1007/s11864-015-0385-x.

21. Ravi V, Wang W-L, Lewis VO. Treatment of tenosynovial giant cell tumor and pigmented villonodular synovitis. Curr Opin Oncol. 2011;23(4):361-366. doi:10.1097/CCO.0b013e328347e1e3.

22.Ottaviani S, Ayral X, Dougados M, Gossec L. Pigmented villonodular synovitis: a retrospective single-center study of 122 cases and review of the literature. Semin Arthritis Rheum. 2011;40(6):539-546. doi:10.1016/j.semarthrit.2010.07.005.

23. Asano N, Yoshida A, Kobayashi E, Yamaguchi T, Kawai A. Multiple metastases from histologically benign intraarticular diffuse-type tenosynovial giant cell tumor: a case report. Hum Pathol. 2014;45(11):2355-2358. doi:10.1016/j.humpath.2014.06.025.

24. Hsu CS, Hentz VR, Yao J. Tumours of the hand. Lancet Oncol. 2007;8(2):157-166.

25. Verspoor FGM, van der Geest ICM, Vegt E, Veth RPH, van der Graaf WT, Schreuder HWB. Pigmented villonodular synovitis: current concepts about diagnosis and management. Future Oncol. 2013;9(10):1515-1531. doi:10.2217/FON.13.124.

26. Shoji T, Yasunaga Y, Yamasaki T, et al. Transtrochanteric rotational osteotomy combined with intra-articular procedures for pigmented villonodular synovitis of the hip. J Orthop Sci. 2015;20(5):943-950. doi:10.1007/s00776-014-0563-x.

27. Zhang Y, Huang J, Ma X, Wang X, Zhang C, Chen L. Giant cell tumor of the tendon sheath in the foot and ankle: case series and review of the literature. J Foot Ankle Surg. 2013;52(1):24-27. doi:10.1053/j.jfas.2012.09.008.

28. Adams EL, Yoder EM, Kasdan ML. Giant cell tumor of the tendon sheath: experience with 65 cases. Eplasty. 2012;12:e50.

29. Cho JM, Chang JH, Kim SH, Lee KS. Pediatric giant cell tumor of the tendon sheath of the craniocervical junction involving the occipital condyle. Childs Nerv Syst. 2016;32(1):175-179. doi:10.1007/s00381-015-2820-5.

30. Hegedus EJ, Theresa K. Postoperative management of pigmented villonodular synovitis in a single subject. J Orthop Sports Phys Ther. 2008;38(12):790-797. doi:10.2519/jospt.2008.2934.

31.Krych A, Odland A, Rose P, et al. Oncologic conditions that simulate common sports injuries. J Am Acad Orthop Surg. 2014;22(4):223-234. doi:10.5435/JAAOS-22-04-223.

32. Abdullah A, Abdullah S, Haflah NHM, Ibrahim S. Giant cell tumor of the tendon sheath in the knee of an 11-year-old girl. J Chin Med Assoc. 2010;73(1):47-51.

33. Bredell M, Schucknecht B, Bode-Lesniewska B. Tenosynovial, diffuse type giant cell tumor of the temporomandibular joint, diagnosis and management of a rare tumor. J Clin Med Res. 2015;7(4):262-266. doi:10.14740/jocmr1872w.

34.Lee YJ, Kang Y, Jung J, Kim S, Kim CH. Intramuscular tenosynovial giant cell tumor, diffuse-type. J Pathol Transl Med. 2016;50(4):306-308. doi:10.4132/jptm.2015.11.15.

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