Tenosynovial Giant Cell Tumor: Case Report and Review:

A 24-year-old man presented with right knee pain with “popping and catching.” The pain began 4 years earlier following a twisting injury while playing basketball. Magnetic resonance imaging disclosed a torn medial meniscus and a 2.5-cm mass in the anterior joint space with low signal lines, likely representing hemosiderin (Figure 1). He underwent arthroscopic surgery with partial synovectomy. A nodular, encapsulated mass (Figure 2, A and B) was easily dissected and removed. Microscopically, it showed classic features of tenosynovial giant cell tumor (TSGCT) (Figure 3). Based upon these results a diagnosis of intra-articular localized TSGCT was rendered. The patient had not returned to visit his orthopedic surgeon in two years.

In this case, the tumor was well circumscribed and easily removed by simple excision. Aside from its intra-articular location, it otherwise had the morphologic attributes of a giant cell tumor of tendon sheath GCTTS. In particular, it was well circumscribed, multinodular, and encapsulated. However, unlike GCTTS, it involved the synovial surface of a large joint. This is an example of intra-articular, localized TSGCT, also known as localized pigmented villonodular synovitis (PVNS).¹  Unlike conventional PVNS, this type is indolent. Therefore, understanding this distinction has important clinical implications. Tenosynovial giant cell tumor consists of 4 clinicopathologic subtypes (Table).

Giant cell tumor of tendon sheath is the most common form of TSGCT. As the name implies, it arises from synovial-lined tendon sheaths. Giant cell tumor of tendon sheath occurs at any age, with peak incidence in the third to fourth decades. It usually presents as a painless, slowly growing mass. Three-fourths of these tumors occur in the digits, especially the fingers, usually on volar surfaces. It is the second most common soft tissue tumor of the hand, second only to ganglion. Grossly, it is well circumscribed and encapsulated and often has a bosselated or clefted outer surface (Figure 4). On cut section, it is lobulated and variegated with tan, red-brown, golden, and bright yellow areas. Its lobular architecture is defined by fibrous bands (Figure 5). The cell population is polymorphous (Figure 6) comprising large histiocytoid cells with abundant eosinophilic cytoplasm and eccentric vesicular nuclei, smaller mononuclear stromal cells with oval or reniform nuclei, osteoclast-like giant cells, and xanthoma cells. Mitotic figures can sometimes be very abundant. Large hemosiderin deposits, zones of fibrosis including areas resembling osteoid (Figure 7), sheets of xanthoma cells (Figure 8), and dyshesive cellular areas forming a pseudoalveolar pattern (Figure 9) are common findings. Some tumors are composed of a monotonous population of stromal cells with only rare giant cells (Figure 10). Giant cell tumor of tendon sheath is generally indolent and is successfully treated by simple excision. However, it recurs approximately 25% of the time.² 

Localized PVNS is morphologically identical to GCTTS. It presents as a circumscribed, sometimes pedunculated, intra-articular mass. The knee is the most common location. On imaging, it appears as a well-circumscribed tumor, and intraoperatively, it presents as a sessile, polypoid mass arising from the synovium. Simple excision is usually curative.¹ 

Pigmented villonodular synovitis is the prototypic form of diffuse TSGCT. The nomenclature has become complicated by introduction of the terms localized PVNS and diffuse-type giant cell tumor (GCT). The latter term encompasses both intra-articular and extra-articular tumors (see below). The term PVNS, however, is universally recognized across disciplines. Pigmented villonodular synovitis is rare, with an estimated annual incidence of 1.8 patients per million. It usually affects young adults (average age, 35 years) but has a wide age range and is slightly more common in women. It usually affects large joints, especially the knee,³  which accounts for 75% to 80% of cases. The hip is the second most common site (15%). Other less frequent sites include the ankle, elbow, temporal mandibular joint, and spine. It typically presents as a longstanding, painful mass with hemarthrosis, and it limits range of motion.

Imaging studies demonstrate an ill-defined, periarticular mass, often with associated cortical erosions and subchondral cysts (Figure 11). Magnetic resonance imaging shows low T1 and T2 signals, contrast enhancement, and signal voids secondary to hemosiderin, sometimes referred to as blooming. Grossly, most tumors exceed 5 cm, are red-brown or tan, and have a prominent villonodular growth pattern (Figure 12). The villi vary from thick to fine and delicate. Pigmented villonodular synovitis usually affects large areas of the synovial surface. Erosions into underlying cortex (Figure 13, A) and articular cartilage (Figure 13, B) are often present. Microscopically, PVNS comprises the same polymorphous cell population as other TSGCTs do; however, it is unencapsulated, has pronounced villonodular architecture (Figure 14), and often contains elongated synovial-line spaces (Figure 15). Pigmented villonodular synovitis is treated with wide, local excision and total synovectomy or arthroplasty; it has a high local recurrence rate, up to 50%, often with multiple recurrences.⁴ 

Diffuse-type GCT is defined by invasive, extra-articular disease (Figure 16), regardless of whether the GCT arose from a joint or soft tissue. In fact, most cases are believed to represent extra-articular extensions of primary intra-articular disease.^5,6  Because of its diffusely invasive growth, however, it is often impossible to define the origin. Diffuse-type GCT has a similar age distribution, location, and symptoms as PVNS does. The most common sites are the knee, ankle, wrist, and foot. Diffuse-type GCTs form large, firm to spongelike, often clefted masses. Microscopically, they are identical to other forms of TSGCT in its cell population. However, unlike localized TSGCT, diffuse type GCT widely infiltrates and entraps adjacent soft tissue (Figure 17) and frequently erodes bone. Pseudoalveolar spaces and cellular areas devoid of giant cells are often present. Diffuse-type GCT is locally aggressive and recurs in 33% to 50% of cases, often with multiple recurrences.^5,6  Very rarely, a histologically benign, diffuse-type GCT metastasizes, usually following multiple recurrences.^5,6 

Malignant TSGCT is very rare. The standard definitional criteria are the presence of a frankly malignant tumor coexisting with benign TSGCT or recurrence of a previously treated TSGCT in the form of a malignant neoplasm.⁶  Many malignant TSGCTs are radiation-associated tumors, which occur many years after radiotherapy for uncontrolled PVNS. They often comprise large, polygonal cells with granular, eosinophilic cytoplasm. Trisomies 7 and 5 have been detected.⁷ 

The pathology of TSGCT was first described by Henry Jaffe in 1941 as pigmented villonodular synovitis, bursitis, and tenosynovitis.⁸  As this nomenclature indicates, TSGCT was believed to be a reactive, nonneoplastic condition. This conclusion was supported by failure to detect clonality utilizing a polymerase chain reaction based assay for methylation of the X-linked human androgen receptor gene.⁹  Cytogenetic studies, however, suggested otherwise. For example, simple structural and numeric aberrations, as well as a variety of balanced chromosomal aberrations, have been discovered. In particular, clonal structural aberrations affecting the 1p11 to 1p13 region,¹⁰  and trisomies¹¹  of chromosomes 5 and 7 were commonly found. Using fluorescent in situ hybridization probes, Nilsson et al¹⁰  detected recurrent breakpoints localized to 1p13, often partnered with 2q35. Based on these results, they suggested activation of a growth promoting gene through balanced translocation as the pathogenic mechanism. However, because similar translocations had been found in hemorrhagic and rheumatoid synovitis, there were still doubts about a neoplastic origin, especially in the face of the lack of clonality detected by the X-linked human androgen receptor gene assay.⁹ 

Macrophage colony stimulating factor (CSF1) is a secreted cytokine/hematopoietic growth factor that plays an essential role in the proliferation, differentiation, and survival of monocytes, macrophages, and related cells. It is localized to the 1p13 breakpoint and appears to have a major oncogenic role in TSGCT.¹²  Using a variety of molecular techniques, investigators from Stanford University¹²  detected high levels of receptor (CSFR1) expression in most of the cells in TSGCT. By contrast, high ligand (CSF1) expression was limited to a small population of mononuclear stromal cells, which also harbored CSF1 translocations. In some cases, CSF1 was fused to COL6A3 (2q35). From these results, they concluded that TSGCT was indeed a neoplasm. However, the neoplastic cells constitute a minor component within the tumor, accounting for only 2% to 16% of the cells. Most cells are nonneoplastic, inflammatory cells recruited and activated by CSF1 produced by the neoplastic cells, a phenomenon they called tumor landscaping. In addition, because the neoplastic cells also had strong CSF1 expression, they postulated that the neoplastic cells are driven by an autocrine mechanism. Finally, because the neoplastic cells are so sparse, they probably eluded detection in the X-linked human androgen receptor gene clonality assay. These same researchers¹³  subsequently identified a subset of tumors with high CSF1 expression but the absence of the 1p13 translocation, suggesting an alternate mechanism in some tumors.

In summary, TSGCT can be roughly divided into localized and diffuse types, with diffuse types being much more aggressive. Based on cytogenetic and molecular findings, most tumors appear to be clonal, neoplastic proliferations driven by CSF1 production of the neoplastic cells, which account for only a small percentage of the cell population in TSGCT. Finally, CSFR1, which is highly expressed in TSGCT, is a group III receptor tyrosine kinase that shows structural homology with KIT. Thus, in theory, TSGCT could be inhibited by a tyrosine kinase receptor inhibitor, such as imatinib (Gleevec, Novartis, Basel, Switzerland). In fact, imatinib therapy has indeed shown early success in the treatment of relapsing PVNS.¹⁴