Giant cell tumor (GCT) of the soft tissue (GCT-ST) is a rare primary soft tissue tumor that is histologically similar to, but clinically and immunophenotypically distinct from, GCT of bone.1 The term is sometimes confused with GCT of the tendon sheath, tenosynovial GCT of tendon sheath, and even pigmented villonodular synovitis. However, GCT-ST is a completely distinct and unusual clinical entity that should not be confused with the other tumors listed above. The pathogenesis of GCT-ST is unclear; origin from undifferentiated mesenchymal cells has been proposed.2 Giant cell tumor of the soft tissue was originally reported as a benign tumor in 1972 by Salm and Sissons2; they considered that the tumor seemed to run a benign clinical course with no instances of metastasis. In 1972, Guccion and Enzinger3 described a series of 32 tumors rich in osteoclast-like giant cells, which they called malignant GCT-ST because they noticed an aggressive biologic behavior and malignant course in the majority of their patients. Currently, the malignant GCT-ST as described by Guccion and Enzinger3 is grouped under the heading of malignant fibrohistiocytic neoplasms and is called giant cell variant of malignant fibrous histiocytoma with a highly aggressive biologic behavior and an overall metastatic rate of 50%.3–5
In 1993, Nascimento6 considered GCT-ST a low-grade sarcoma. He reported 10 patients with GCT-ST that had histopathological features identical to those of GCT of bone. One of the 2 patients had a final histological diagnosis of a plexiform fibrohistiocytic tumor; both patients died of lung metastasis.6 In 1999, Folpe et al7 described a series of patients with GCT-ST with similar histopathological features but without cytologic atypia. With the observation of mitotic activity and vascular invasion in some GCT-ST in their series, and in the face of frequent local recurrences and metastatic potential, they reclassified GCT-ST as the benign end of the spectrum of malignant GCT of the soft tissues and proposed the term GCT-ST of low malignant potential and the term malignant GCT of soft parts or giant cell malignant fibrous histiocytoma for histologically high-grade lesions.7
In 2000, Oliveira et al8 studied the clinicopathological and immunohistochemical features of 22 neoplasms that were indistinguishable histologically from GCT of bone and analyzed the relationship between these neoplasms and the so-called giant cell variant of malignant fibrous histiocytoma, as previously described.3 They concluded that GCT-ST is clinically and histologically similar to GCT of bone; they found no histopathological features that could be associated with a more aggressive behavior of GCT-ST and recommended complete excision for a benign tumor course.8
In the World Health Organization's Classification of Tumors of Soft Tissue and Bone in 2002, GCT-ST is represented by 2 entities: the low-malignant end that is the GCT-ST (GCT-ST of low malignant potential) and the high-grade spectrum that is the undifferentiated pleomorphic sarcoma with giant cells (giant cell malignant fibrous histiocytoma or malignant giant cell tumor of soft parts).6,9 Currently, GCT-ST remains a confusing and difficult topic included in the group of so-called fibrohistiocytic tumors of intermediate (borderline) malignancy.10 Because of the rarity of GCT-ST, changes in nomenclature, and conflicting histological reports with respect to GCT-ST benign and malignant variants, the true incidence is not possible to be estimated; the current authors' literature search for the purpose of this study revealed fewer than 200 published cases in case reports and small series.
Giant cell tumor of the soft tissue mainly affects adults in the fifth decade of life, although it may affect patients at any age, ranging from 5 to 87 years.7,8,11 Both sexes are affected in an equal ratio, without any race predilection.7,8,11 Giant cell tumor of the soft tissue predominantly occurs in the superficial soft tissues of the extremities, although it may also occur in deep soft tissues. The thigh is the most common location; the trunk, head, and neck are less frequent, and the face, abdominal wall, hand and wrist, mediastinum, breast, retroperitoneum, and surgical scars are exceptional tumor locations.1,2,3,8,11–39
The most common symptom is a painless, slow-growing mass in a superficial location.8 Lesions are usually well-circumscribed, multinodular, subcutaneous with or without dermal involvement covered by normal skin, or with a fleshy red-brown surface.8,14,16,40,41 They are usually mobile without any firm connection to the underlying muscle, tendon, or bone. Their size ranges from 0.7 to 10 cm.1,7,8,41 The duration of symptoms before diagnosis ranges from 2 to 12 months (mean, 6 months),8 although long standing lesions up to 15 years have also been reported.2 Giant cell tumor of the soft tissue has been reported after long-term immunosuppressive therapy,25 in Paget disease of bone,42 and after trauma8 or radiation therapy.43 Unusually, patients with GCT-ST may experience oncogenic osteomalacia.44,45
Radiographs have no role for the diagnosis of GCT-ST. Radiographs show that the tumor does not show any mass-like opacity or bony involvement/erosion; rarely (<50% of the cases), radiographs may show peripheral calcification of the tumor.46,47 Computed tomography and magnetic resonance imaging (Figure 1) show a solid, heterogeneous, frequently hemorrhagic mass.16 Solid, small cystic regions are often present, and peripheral mineralization is frequent with gritty regions of mineralized bone also appearing at the periphery of the lesions.1,8,17,18,46,47 Fluid-fluid levels were also reported, probably related to prior hemorrhage or tumor necrosis.18
A 32-year-old man with a painless palpable mass at the right proximal thigh. The tumor was deep-seated and was noticed 4 months before. Coronal T1-weighted (A) and axial T2-weighted (B) magnetic resonance images showing a heterogeneous soft tissue mass with contrast enhancement.
Macroscopically, GCT-ST is usually small (mean maximum diameter, 0.5–5 cm) but may grow at any size (usually <10 cm).8–11,13,16,17 The tumor is usually located at the dermis or subcutis with 30% being deep-seated. Lesions are well-circumscribed, nodular, fleshy, red-brown-gray, and gritty at the periphery of lesions due to calcification (Figure 2). Microscopically, most GCT-ST show a multinodular architecture with the nodules ranging in size from microscopic dimensions to 15 mm.8 The cellular nodules are separated by fibroconnective tissue septa and are composed of a mixture of round to oval (some fibroblast-like) mononuclear stromal cells and osteoclast-like multinucleated giant cells, with both cell types immersed in a richly vascularized stroma.11 A peripheral shell of metaplastic woven bone formation is often detected in 40% to 50% of these lesions, raising the possibility of an extraskeletal variant of osteosarcoma.1,8,11,45 Mitotic activity ranging from 1 to 30 figures per 10 high-power fields is generally present in all cases of GCTST; however, atypia, pleomorphism, and tumoral giant cells are absent, and necrosis is rare (Figure 3). Giant cell tumor of the soft tissue shows immunoreactivity for vimentin, CD68, and smooth muscle actin. CD68 strongly marks the multinucleated giant cells, whereas mononuclear cells show focal staining only.7,8,11,19 Alkaline phosphatase, osteoprotegerin, RANKL, TRAIL, and TRAP stain positive for GCT-ST.48
An 80-year-old man with a painless palpable mass at the left shoulder. The tumor was located subcutaneously and was noticed 12 months before. Marginal excision was done. Macroscopically, the tumor is well-circumscribed with a beige cut surface, including partially yellow and hemorrhage area (A). Microscopically, the lesion is composed of a mixture of osteoclast-like giant cells and mononuclear cells; fibrous septa are observed, and fibrous fat tissue and striated muscle tissue, including a small bone tissue, are present at the periphery (hematoxylin and eosin, original magnification ×40) (B). Mitotic figures are less than 1 per 10 high-power fields (hematoxylin and eosin, original magnification ×400). Histological findings were consistent with giant cell tumor of the soft tissue (C).
Histological sections show a multinodular growth pattern of multinucleated osteoclast-like giant cells distributed evenly among mononuclear cells within a vascular stroma (hematoxylin and eosin, original magnification ×100) (A). The nodules are surrounded by dense fibrous tissue containing small blood vessels (hematoxylin and eosin, original magnification ×200) (B). The tumor is constituted by osteoclast-like giant cells evenly distributed among mononuclear cells associated to hemosiderin deposits; mitotic figures are rare (<1 per 10 high-power fields); morphologically, the nuclei of the mononuclear cells are similar to those of the giant cells, namely round to oval with vesicular chromatin and small nucleoli (hematoxylin and eosin, original magnification ×400). Histological findings were consistent with giant cell tumor of the soft tissue (C).
Giant cell tumor of the soft tissue is immunophenotypically and genetically distinct from any giant cell–rich neoplasm of bone and soft tissue.1,49 Giant cell tumor of bone shows consistent genetic abnormalities, including a driver mutation in the histone gene H3F3A; this mutation appears to be highly specific for GCT, as it has been detected in only a few cases of giant cell–rich sarcomas.50 In other studies, no H3F3 mutations or similar immunophenotypic markers were detected in GCT-ST compared to bone counterpart, indicating that GCT-ST should be considered genetically distinct.1,49
Differential diagnosis is broad and should include benign and malignant entities.15,16,19,51,52 Benign entities to be included in the differential diagnosis include soft tissue mesenchymal tumors that are rich in giant cells, such as GCT of the tendon sheath, cellular dermatofibroma with osteoclast-like giant cells, ossifying dermatofibroma with osteoclast-like giant cells, reparative giant cell granuloma, brown tumor of hyperparathyroidism extending to soft tissues, giant cell–rich forms of nodular fasciitis,40 and echinococcosis.18
Giant cell tumor of the tendon sheath is generally located near joint spaces or bursae but may also occur in extra-articular soft tissues. In comparison with GCTST, GCT of the tendon sheath shows a uninodular architecture, prominent stromal hyalinization and a more mixed population of osteoclastic giant cells, small synoviocyte-like cells, siderophages, foamy histiocytes, and lymphocytes; metaplastic bone formation is characteristically absent.7,40 Nodular fasciitis with osteoclast-like giant cells are composed of immature fibroblasts in sheets and irregular bundles; giant cells surround areas of hemorrhage and myxoid degeneration.19,40 A possible soft tissue extension or recurrence of a primary GCT of bone can be documented by a careful radiographic workup and a focused clinical history in any patient with GCT-ST.8
Malignant entities to be included in the differential diagnosis include giant cell malignant fibrous histiocytoma, osteoclast-like giant cell-rich leiomyosarcoma, epithelioid sarcoma with giant cells, atypical fibroxanthoma with osteoclast-like giant cells, plexiform fibrohistiocytic tumor, and extraskeletal osteosarcoma. Malignant tumors are usually large, deep-seated lesions with obvious cellular atypia. In contrast, GCT-ST is frequently superficial and devoid of significant pleomorphism and atypical mitosis.3,4,11,14,19,20,40 In general, differentiation is purely histological.8
The treatment of GCT-ST remains controversial because of the small number of reported cases and the lack of consensus regarding its clinical behavior. Excision margins are also unclear; although GCT-ST has a favorable natural history, it often persists unless it is excised with adequate surgical margins. Some patients are cured by a simple surgical excision, whereas other patients experience local recurrences and metastases.8,13,15 Incomplete surgical excision due to an infiltrative growth pattern that can involve deep delicate anatomical structures, such as the neurovascular bundles, is usually followed by local recurrence.7,8,21 Given the benign biology, adjuvant radiation therapy for GCT-ST remains controversial; however, radiation therapy may be considered when the proximity of critical structures prevents microscopically negative surgical margins.8,22,23
Biological behavior of GCT-ST is unpredictable. Although the tumor has a biologically benign behavior, the infiltrative growth pattern can involve deep, delicate anatomical structures, such as the neurovascular bundles, making complete surgical excision difficult and the outcome complicated by local recurrences and distant metastases.3,8,11,15,16,38 Giant cell tumor of the soft tissue has shown a lower mean local recurrence rate (6.2%) compared to GCT of bone (25% in long bones and approximately 50% in the axial skeleton); the higher local recurrence rate in the bone tumors can be explained by a much better accessibility of the soft tissues in general, which facilitates complete excision of the tumors.8,21 However, deep-seated, infiltrative GCT-ST may preclude microscopically negative resection margins and increase the risk for local recurrence.7,8,21
Giant cell tumor of the soft tissue has a higher metastatic and death rate (6.2%) compared to GCT of bone.8 However, large studies are missing to draw important conclusions for the biologic behavior and outcome of the patients with these tumors, and in published studies reporting metastases in patients with GCT-ST, the metastatic disease was not histologically documented and a second cancer was not excluded.9 Metastases related to GCT-ST are most commonly in the lungs.8,13,15 At a follow-up ranging from 6 to 108 months, a 10% to 45% local recurrence rate2,7,8,16,19,24 and up to 6.2% metastasis rate have been reported.8,16,21,25,28,53,54 No clinicopathological predictors of metastatic behavior have been reported for GCT-ST.7,8,11
Giant cell tumor of the soft tissue is a rare soft tissue tumor with a low malignant potential that should be considered in the differential diagnosis of giant cell–rich soft tissue neoplasms. It is a completely distinct and unusual clinical entity that should not be confused with any giant cell rich tumor of bone or soft tissue. Even if GCT-ST is completely excised with microscopically negative surgical margins, close clinical follow-up is recommended because local recurrences and distant metastases are possible in the first years after diagnosis and treatment.
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