Tenosynovial Giant Cell Tumour (PVNS / GCT-TS)

Tenosynovial giant cell tumour (TGCT) is the most common synovial neoplasm. It is a true neoplasm driven by CSF1 overexpression, not an inflammatory or reactive process, and its localised and diffuse types behave very differently and must be distinguished. It bridges pathology (a translocation and haemosiderin-laden macrophages), imaging (the blooming artefact on MRI) and treatment (surgery versus targeted therapy), and pexidartinib, targeted therapy against the CSF1R pathway, has shifted how diffuse disease is treated.

Terminology. TGCT is the unified WHO term. It replaces giant cell tumour of tendon sheath (GCT-TS) for the localised type and pigmented villonodular synovitis (PVNS) for the diffuse type. Pathologists now regard "pigmented villonodular synovitis" as obsolete nomenclature, though clinicians still use it.

Who gets it. The incidence is approximately 10 per million person-years, with the diffuse type rarer at 1-2 per million. The peak is at 30-50 years, with a slight female predominance for the diffuse type.

• Localised type - the most common soft-tissue tumour of the hand after ganglion cyst, most common in the fingers, with the index and middle most frequent
• Diffuse type - the knee (approximately 80%), hip, ankle, shoulder and elbow

What it does. The diffuse type causes chronic, progressive pain and joint effusion, and recurrent haemarthrosis is the hallmark of diffuse intra-articular disease.

Left untreated. Prostaglandins and metalloproteinases cause bone erosion and joint damage, so untreated disease goes on to secondary osteoarthritis, with limited range of motion and mechanical symptoms along the way. After treatment, recurrence is the dominant clinical challenge in diffuse disease.

The driver. A chromosomal translocation, most commonly t(1;2)(p13;q35), fuses CSF1 to COL6A3 and places the CSF1 (colony-stimulating factor 1) gene under the control of the COL6A3 promoter, so CSF1 is overexpressed constitutively. The translocation is present in approximately 70% of cases; trisomy 5 and trisomy 7 are found in some cases instead.

A minority drives the majority. Only 2-15% of the cells carry the translocation. These neoplastic cells secrete abundant CSF1, which recruits CSF1R-expressing monocytes and macrophages by a paracrine ligand-receptor mechanism, and the recruited cells make up the vast majority of the tumour mass, often more than 90%. They differentiate into the multinucleated giant cells, haemosiderin-laden macrophages and foam cells that characterise the histology.

The drug target. Pexidartinib blocks the CSF1R tyrosine kinase and so halts the recruitment cascade. The paracrine recruitment model is the molecular rationale for pexidartinib and the other CSF1R inhibitors.

Histology. Three cell populations, in varying proportion with foam (xanthoma) cells, inflammatory cells and fibrosis:

1. Mononuclear stromal cells with round to oval nuclei, among which lie the neoplastic cells; immunohistochemistry separates them from the recruited histiocytes (see Investigations)
2. Osteoclast-like multinucleated giant cells, scattered, with 5-50 nuclei per cell
3. Haemosiderin-laden macrophages, dark brown pigment that is Prussian blue positive

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The WHO 2020 classification recognises localised and diffuse TGCT, and diffuse disease is further divided into intra-articular and extra-articular patterns. Imaging is critical for telling them apart and for planning the surgical approach.

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Localised TGCT (formerly giant cell tumour of tendon sheath). A well-circumscribed nodule attached to a tendon sheath, most frequently on the volar surface of the index and middle fingers, usually 1-3 cm across. Recurrence after excision is much lower than for the diffuse type.

Diffuse TGCT (formerly PVNS). An infiltrative neoplasm of large-joint synovium, with villous and nodular proliferation, brownish haemosiderin discolouration and high recurrence rates. It may be intra-articular, or extend outside the joint.

Extra-articular TGCT. Disease that extends beyond the joint capsule, or arises primarily in the bursae and tendon sheaths of large joints. It may extend into popliteal cysts, the calf or the thigh, requires wider excision, and is the most challenging subgroup for surgical clearance.

The localised lesion. Months to years of slow growth of a firm, non-tender nodule on the volar surface of a digit. It is usually painless or minimally painful, occasionally causes mild discomfort on flexion, may cause clicking or limited flexion if large, and rarely compresses a nerve. Ask about previous excisions, because the nodule may be a recurrence.

Examining the nodule. It is firm, fixed to deep tissues and does not transilluminate, and the skin is freely mobile over it. The key clinical distinction is from a ganglion cyst, which transilluminates and is fluctuant, and from a foreign-body granuloma, which follows a penetrating injury.

The diffuse lesion. An insidious onset over months to years of progressive, aching joint pain, recurrent effusions and limited range of motion, with mechanical symptoms of locking, catching and giving way. Aspiration gives brownish or blood-stained fluid, negative for crystals and organisms. Ask about previous synovectomy, since recurrence is common.

Radiographs. AP and lateral views of the affected joint, with dedicated views for digits. The localised type usually gives a normal film, but may show a soft-tissue density or pressure remodelling of the adjacent bone.

The diffuse type on the film. Diffuse disease shows periarticular soft-tissue swelling and lucency, subchondral cysts and bone erosions with sclerotic margins, with the joint space preserved early and narrowing late in advanced disease. Look for the absence of calcification, which distinguishes TGCT from synovial chondromatosis and synovial sarcoma.

MRI is the gold standard and the essential investigation, with T1, T2, fat-saturated T2, proton density and gradient-echo (GRE) sequences.

The signal. The thickened, nodular synovial proliferation shows on all sequences, and the hallmark is low signal on both T1 and T2, from haemosiderin deposited in the proliferative synovium: haemosiderin-laden fibrous synovium is low on T1, and haemosiderin and fibrosis make it dark on T2, which distinguishes it from most synovial tumours. The dominant haemosiderin effect is T2* susceptibility, not T1 shortening.

The blooming artefact. On GRE sequences the magnetic susceptibility of haemosiderin produces dramatic signal loss that makes the deposits look larger and darker than on spin-echo sequences. This blooming is virtually pathognomonic for TGCT, although haemophiliac arthropathy shows it too. Amyloid arthropathy and gouty tophi also produce a low-T2 synovial mass, but they do not bloom.

Reading the scan. A localised lesion is a well-circumscribed nodule adjacent to the tendon sheath, low on T2, with homogeneous enhancement. Diffuse disease is extensive, infiltrative, villonodular synovial thickening, low on T2 with blooming, with a joint effusion and bone erosions. Before surgery, stage the extent: the anterior and posterior compartments, extra-articular extension and popliteal involvement.

Biopsy is kept for the case that does not fit, by core needle under imaging guidance or arthroscopically. Histology is required before systemic therapy, to confirm the diagnosis and exclude synovial sarcoma. Indications:

• Atypical presentation
• Rapid growth
• Concern for sarcoma
• Before starting pexidartinib

The principle. Localised TGCT is treated by marginal excision and has a low recurrence rate. Diffuse TGCT needs a complete synovectomy and has a high one, 20-50%.

Where pexidartinib fits. Pexidartinib is for symptomatic diffuse TGCT where surgery is not feasible or has failed, reserved for diffuse disease in which the risk-benefit ratio of further surgery is unfavourable. It is not indicated for localised TGCT, where surgery is curative with low recurrence.

Recurrence, with its rates by type and approach, is set out under Management and Outcomes. The other complications:

Prognostic factors. The best prognosis goes with the localised type, a first-time excision, complete margins and a digit location. A poor prognosis goes with the diffuse type, extra-articular extension, multiple prior recurrences, and a hip or ankle location, which is harder to access for complete synovectomy.

Local, not distant. Conventional TGCT does not metastasise; it is a locally aggressive neoplasm. Its morbidity comes from local destruction, functional impairment and the morbidity of repeated surgical interventions.