Background

These rare soft-tissue tumors resembling giant cell tumor (GCT) of bone. Although early studies characterized benign tumors, there have been increasing reports of malignant tumors which have metastasized. The pathologist must distinguish this tumor from other tumors of the soft tissue which may contain giant cells.

OUTLINE

Epidemiology
Pathogenesis
Gross Appearance and Clinical Variants
Histopathological Features and Variants
Differential Diagnosis
Commonly Used Terms
Internet Links

EPIDEMIOLOGY	CHARACTERIZATION
SYNONYMS	Giant cell tumor of soft tissues Giant cell tumor of soft parts
INCIDENCE	Rare

 

PATHOGENESIS	CHARACTERIZATION
MICROPHTHALMIA-ASSOCIATED TRANSCRIPTION FACTOR EXPRESSION
Giant cell tumors: inquiry into immunohistochemical expression of CD117 (c-Kit), microphthalmia transcription factor, tartrate-resistant acid phosphatase, and HAM-56. Ramos RY, Haupt HM, Kanetsky PA, Donthineni-Rao R, Arenas-Elliott C, Lackman RD, Martin AM. Department of Pathology, Pennsylvania Hospital, Philadelphia 19107, USA.	Arch Pathol Lab Med. 2005 Mar;129(3):360-5. Abstract quote   CONTEXT: Osteoclast-like giant cells (GCs) in giant cell tumors (GCTs) are thought to derive from a monocyte-macrophage lineage. Microphthalmia transcription factor (MITF) is necessary for osteoclast gene expression and tartrate-resistant acid phosphatase (TRAP) activation; c-Kit plays a role in regulation of MITF. OBJECTIVE: To gain insight into the differentiation of GCTs of bone (GCTBs) and GCTs tendon sheath (GCTTSs) by investigating immunohistochemical staining for c-Kit, MITF, TRAP, and HAM-56 in the GCs and stroma. DESIGN: Immunoreactivity for CD117 (c-Kit), MITF, TRAP, and HAM-56 was studied in 35 GCTBs, 15 GCTTSs, and 5 foreign-body GC controls. RESULTS: Across tumors, MITF and TRAP but not c-Kit were generally expressed in GCs; TRAP was variably expressed in stromal cells. The MITF was expressed more consistently in stromal cells of GCTTSs than GCTBs (P < .001). The GCTBs showed more intense MITF stromal (P < .001) and TRAP GC staining (P = .04) than GCTTSs. HAM-56 staining by stromal cells was associated with MITF stromal staining (r2 = 0.6, P < .001). CONCLUSIONS: Results suggest that MITF and TRAP are expressed during osteoclast differentiation and that a proportion of mononuclear cells in GCTs express the macrophage marker HAM-56. Both GCTBs and GCTTSs show similar patterns of immunohistochemical expression.
Immunohistochemical evaluation of microphthalmia-associated transcription factor expression in giant cell lesions. Seethala RR, Goldblum JR, Hicks DG, Lehman M, Khurana JS, Pasha TL, Zhang PJ. 1University of Pennsylvania Medical Center, Philadelphia, PA, USA.	Mod Pathol. 2004 Dec;17(12):1491-6. Abstract quote Microphthalmia-associated transcription factor (Mitf), a member of the helix-loop-helix transcription factor subfamily, normally expressed in mononuclear and multinucleated osteoclasts, is involved in the terminal differentiation of osteoclasts. Dysfunction of osteoclast activity resulting from abnormal Mitf expression has been implicated in osteopetrosis. Numerous other giant cells of various types including osteoclast-like giant cells seen in various tumors, traditionally thought to be monocyte derived, are seen in a variety of bone and extraosseous lesions. Using a monoclonal antibody with a standard immunohistochemical technique on paraffin sections, we evaluated expression of Mitf in 89 various giant cell lesions including giant cell tumor of bone (n26), giant cell tumor of tendon sheath/pigmented villonodular synovitis (n24), giant cell reparative granuloma (n3), aneurysmal bone cysts (n11), chondroblastomas (n7), foreign body giant cell reaction (n10), and sarcoidosis (n8). We also evaluated three cases of osteopetrosis and 27 various tissues without monocyte-derived giant cells (nine bone marrows, nine products of conception, seven lymph nodes with sinus histiocytosis, one granulation tissue and one thymus). Nuclear Mitf immunoreactivity was evaluated. Mitf was variably expressed in the monocyte-derived giant cells and/or the adjacent mononuclear cells/histiocytes in 23 (89%) giant cell tumors of the bone, 23 (96%) giant cell tumors of tendon sheath/pigmented villonodular synovitis, three (100%) giant cell reparative granuloma, eight (73%) aneurysmal bone cysts, five (71%) chondroblastomas, eight (80%) foreign-body giant cell reactions, and six (75%) sarcoidoses. No Mitf immunoreactivity was detected in cases of osteopetrosis and giant cells of nonmonocyte origin. Mitf immunoreactivity is rare in tissues with rich mononuclear cells/histiocytes but no monocyte derived giant cells. These findings support the notion that giant cells in giant cell lesions are likely derived from adjacent mononuclear cells and Mitf might play a role in the multinucleation process of such cells.
RANKL (RECEPTOR ACTIVATOR FOR NUCLEAR FACTOR kb LIGAND)
Phenotypic and molecular studies of giant-cell tumors of bone and soft tissue. Lau YS, Sabokbar A, Gibbons CL, Giele H, Athanasou N. Department of Pathology, University of Oxford, Nuffield Orthopaedic Centre, OX3 7LD Oxford, UK.	Hum Pathol. 2005 Sep;36(9):945-54. Abstract quote   Giant-cell tumor of bone (GCTB) and giant-cell tumor of soft tissue (GCTST) are tumors that contain a prominent osteoclastlike giant-cell component. The precise relationship between these morphologically similar tumors is unclear, and the cellular mechanism whereby giant cells accumulate within these and other locally aggressive tumors is uncertain. In this study, we have examined the cytochemical, functional, and molecular phenotype of the mononuclear and multinucleated components of GCTB and GCTST. Giant cells in GCTB and GCTST exhibited an osteoclast phenotype expressing tartrate-resistant acid phosphatase and vitronectin receptor and being capable of lacunar resorption. The mononuclear stromal cells derived from GCTB and GCTST exhibited an osteoblast phenotype, expressing alkaline phosphatase, and the receptor activator for nuclear factor kappaB ligand (RANKL), a factor that is essential for osteoclast formation. These cells also expressed osteoprotegerin (OPG), an inhibitor of osteoclastogenesis, and TRAIL, a receptor that binds OPG. Lacunar resorption by giant cells isolated from GCTB and GCTST was inhibited by OPG, zoledronate, and calcitonin. These findings indicate that the mononuclear and giant-cell components of GCTB and GCTST have similar phenotypic features and that the accumulation of osteoclasts in these giant-cell-rich tumors occurs by a RANKL-dependent process. RANKL expression by osteoblastlike mononuclear stromal cells in these tumors stimulates osteoclast formation and resorption; this would account for the osteolysis associated with these giant-cell-rich tumors. Inhibitors of osteoclast formation and activity are likely to be effective in controlling the osteolysis associated with GCTB and possibly other giant-cell-rich lesions.

 

CLINICAL VARIANTS	CHARACTERIZATION
BILIARY TREE, EXTRA-HEPATIC
Giant Cell Tumor of the Extrahepatic Biliary Tree: A Clinicopathologic Study of 4 Cases and Comparison With Anaplastic Spindle and Giant Cell Carcinoma With Osteoclast-Like Giant Cells. Albores-Saavedra J, Grider DJ, Wu J, Henson DE, Goodman ZD. *Department of Pathology, Louisiana State University Health Sciences Center, Shreveport, LA daggerDepartment of Hepatic and Gastrointestinal Pathology, Armed Forces Institute of Pathology, Washington, DC double daggerGeorge Washington University Cancer Institute, Washington, DC	Am J Surg Pathol. 2006 Apr;30(4):495-500. Abstract quote   We report four previously undescribed primary giant cell tumors of the extrahepatic biliary tree and morphologically compare them with 10 anaplastic spindle and giant cell carcinomas with osteoclast-like giant cells of the gallbladder. Two giant cell tumors were located in the distal common bile duct; one in the cystic duct and one in the gallbladder. The 3 patients with bile duct tumors were male, and the only patient with a gallbladder tumor was a female. The age of the patients ranged from 45 to 60 years with an average of 55 years. The patients with bile duct tumors presented with biliary obstruction, and the patient with a gallbladder tumor presented with symptoms of cholelithiasis and a gallbladder mass. Histologically, the tumors were similar to giant cell tumors of bone. They consisted of a mixture of mononuclear and multinucleated osteoclast-like giant cells. The mononuclear cells showed no atypical features, and their nuclei were similar to those of the multinucleated giant cells. CD163 immunoreactivity was restricted to the mononuclear cells, whereas CD68 and HAM 56 labeled only the multinucleated osteoclast-like giant cells. The mononuclear cells were EMA-positive but did not express cytokeratins. Follow-up showed that 3 patients were alive and disease-free 3.7 to 7 years after surgery. The anaplastic spindle and giant cell carcinomas contained a fewer number of osteoclast-like giant cells, and their mononuclear cells showed considerable variation in size and shape, marked cytologic atypia, and numerous mitotic figures. They were focally cytokeratin positive (AE1/AE3; CAM 5.2) and did not label with CD163, CD68, and HAM 56. The benign osteoclast-like giant cells showed immunoreactivity for CD68 and HAM 56 but were negative for CD163 and cytokeratins. Giant cell tumors of the extrahepatic biliary tree are benign true histiocytic neoplasms that should be distinguished from the highly lethal anaplastic spindle and giant cell carcinomas with osteoclast-like giant cells by detailed cytologic analysis and immunohistochemical stains for CD163, CD68, HAM 56, and cytokeratins.
MEDIASTINUM
Primary mediastinal giant cell tumors: A clinicopathologic and immunohistochemical study of two cases. Fu K, Moran CA, Suster S. University of Alabama at Birmingham, AL; The University of Texas, M.D. Anderson Cancer Center, Houston, TX; and the Ohio State University, Columbus, OH.	Ann Diagn Pathol 2002 Apr;6(2):100-5 Abstract quote Two cases of posterior mediastinal giant cell tumors are presented. The patients are a woman and a man, 31 and 18 years old, respectively. One of the patients had symptoms of paresthesias while the other was completely asymptomatic. Complete physical examination did not disclose evidence of tumor elsewhere. Neither patient had a previous history of malignancy. Surgical resection was performed. Histologically, both tumors were composed of a proliferation of osteoclast-like giant cells associated with a mononuclear cell population composed of oval and spindle cells. Mitotic activity and mild cellular atypia were present in the mononuclear cell component. No evidence of necrosis or hemorrhage could be demonstrated in either case. Immunohistochemically, both tumors showed strong positive reaction in the mononuclear component for antibodies against vimentin and CD68, while keratin, epithelial membrane antigen, CD45, S-100 protein, and desmin were negative. On clinical follow-up, both patients are alive and well without evidence of recurrence or metastasis 6 and 108 months after surgery. The present cases highlight the ubiquitous distribution of soft tissue giant cell tumors and the importance of considering these tumors in the differential diagnosis of posterior mediastinal neoplasms.
SKIN
Giant cell tumor of the skin: A morphologic and immunohistochemical study of five cases. Hoang MP, Rogers BB, Albores-Saavedra J. Department of Pathology, The University of Texas Southwestern Medical Center, Dallas; and Children's Medical Center, Dallas, TX.	Ann Diagn Pathol 2002 Oct;6(5):288-93 Abstract quote Giant cell tumor (GCT) of the skin is a rare entity that possesses similar gross and histologic features to GCT of bone. When located predominantly in the dermis GCT has been mistaken for benign fibrous histiocytoma and atypical fibroxanthoma. We report the clinical, morphologic, and immunohistochemical features of five cases of GCT of the skin. With one exception, all tumors are confined to the dermis. Patients' ages range from 6 to 78 years (median, 73 years) with a male to female ratio of 3:2. Gross and histologic features of the lesions are similar to those of GCT of bone (eg, brown fleshy tumor and a biphasic population of mononuclear cells admixed with osteoclast-like giant cells, respectively). The nuclei of the giant cells are similar to those of the mononuclear cells. A fascicular pattern with focal storiform arrangement of spindle neoplastic cells is noted in two cases. The osteoclast-like giant cells and some of the mononuclear cells are strongly positive for CD68, alpha-1-antitrypsin, and alpha-1-antichymotrypsin. Only the mononuclear cells express smooth muscle actin focally in one case. Both the osteoclast-like giant cells and the mononuclear cells are negative for cytokeratins (AE1/AE3 and CAM5.2) and S-100 protein in all cases. One patient developed lung metastases at presentation and local recurrence 4 months status post surgery. All patients are without evidence of disease 1 month to 12 years status post surgery. Cutaneous GCTs are low-grade sarcomas that can recur locally and infrequently metastasize. These tumors should be distinguished from a variety of cutaneous neoplasms that contain multinucleated giant cells.

 

HISTOLOGICAL TYPES	CHARACTERIZATION
General
Giant Cell Tumors of Soft Tissue A Clinicopathologic Study of 18 Benign and Malignant Tumors John X. O'Connell, M.B., F.R.C.P.C.; Bret M. Wehrli, M.D.; Gunnlaugur P. Nielsen, M.D.; Andrew E. Rosenberg, M.D. From the Department of Pathology (J.X.O., B.M.W.), Vancouver General Hospital, Vancouver, BC; and the Department of Pathology (G.P.N., A.E.R.), Massachusetts General Hospital, Boston, MA, U.S.A.	Am J Surg Pathol 2000;24:386-395 Abstract quote Primary giant cell tumors (GCTs) of soft tissue resembling osseous GCTs are uncommon but distinct entities. Malignant GCTs of soft tissue have been designated giant cell malignant fibrous histiocytomas; however, there is scant data regarding benign GCTs of soft tissue. Eleven benign and seven malignant GCTs of soft tissue were identified from the authors' consultation files and the surgical pathology files of the Vancouver General Hospital and Massachusetts General Hospital. The tumors occurred in adults (eight men, 10 women; age range, 25–89 years; mean age, 54 years) in the extremities (n = 14) and in the trunk, abdomen, and pelvis (n = 4). In each patient the skeleton was normal and there was no history of prior osseous GCT. Tumors ranged in size from 0.8 to 9.0 cm. Eleven occurred in the superficial soft tissue and seven occurred in deep soft tissue. Grossly they were circumscribed and frequently hemorrhagic. Cystic change was present in seven tumors. Nine tumors were partially surrounded by a shell of reactive bone. In all tumors, multinucleated osteoclast-like giant cells were distributed uniformly and evenly among mononuclear cells. The histologically benign GCTs of soft tissue were identical to typical osseous GCTs. The mononuclear cells in these tumors lacked nuclear atypia or pleomorphism, and the mitotic rate within this population was low (mean, three mitoses per 10 high-power fields [HPF]). In the malignant GCTs of soft tissue, the mononuclear cells exhibited anisocytosis, nuclear atypia, pleomorphism, and readily detectable mitoses including atypical forms (mean, 25 mitoses per 10 HPF). None of the benign or malignant tumors exhibited neoplastic bone production. The benign and malignant GCTs of soft tissue demonstrated a similar immunohistochemical staining profile to GCT of bone (12 tumors examined), exhibiting strong positive staining for CD68 within multinucleated osteoclastlike cells, and focal staining of mononuclear cells for CD68, Ham 56, and smooth muscle actin. All tumors were treated by surgical resection. Follow-up information is available for 15 patients (range, 0–108 months). No benign tumor has recurred or metastasized. Of the four patients with malignant tumors for whom follow-up information is available, one died of metastatic disease at 13 months and one developed a local recurrence at 84 months but is alive, apparently free of disease after additional excisional surgery. Primary GCTs of soft tissue are distinctive neoplasms that, like osseous GCTs, exhibit a wide clinicopathologic spectrum. These neoplasms should be distinguished from other giant cell-rich soft-tissue tumors with which they may be confused.
Diffuse-Type Giant Cell Tumor Clinicopathologic and Immunohistochemical Analysis of 50 Cases With Extraarticular Disease Nicolas de Saint Aubain Somerhausen, M.D.; Christopher D. M. Fletcher, M.D., F.R.C.Path. From the Departments of Pathology, Brigham & Women's Hospital and Harvard Medical School, Boston, Massachusetts, U.S.A. (C.D.M.F.); and Institut Jules Bordet, Université Libre de Bruxelles, Bruxelles, Belgium (N.dS.A.S).	Am J Surg Pathol 2000;24:479-492 Abstract quote The clinical and pathologic features of 50 cases of diffuse-type tenosynovial giant cell tumor (D-TGCT), also known as extraarticular pigmented villonodular tenosynovitis (PVNTS), are presented. Patients' ages ranged from 4 to 76 years (median, 41 yrs), with a slight female predominance (28 women, 22 men). By definition, all lesions presented as predominant soft tissue masses, with or without an associated articular component. Tumor sites included the wrist (9 cases), knee (8 cases), thigh and foot (6 cases each), finger (5 cases), ankle (3 cases), hand, elbow, toes, buttock, paravertebral region (2 cases each), lower leg, sacrococcygeal area, and retroperitoneum; 27 cases were described as entirely extraarticular. Tumors showed infiltrative margins and, in most cases, a sheet-like growth pattern. Striking variation in the number of osteoclast-like giant cells, foamy cells, amount of hemosiderin, and in the degree of stromal hyalinization were responsible for a wide morphologic spectrum. In addition to the predominant histiocyte-like cells, we identified in most cases a subpopulation of large dendritic, desmin-positive cells showing characteristic, but potentially misleading, cytologic features, including abundant eosinophilic cytoplasm, large vesicular nuclei, paranuclear eosinophilic inclusions, and occasional nuclear inclusions. Follow-up information was available for 24 patients, with a duration ranging from 6 months to 30 years (mean, 55 mos). Local recurrence occurred in eight cases (33%), between 4 months and 6 months after surgery (median, 15 mos) and was repeated in five cases; recurrence did not appear to correlate with morphologic parameters. Six cases showed atypical histologic features and four of these contained areas of sarcomatous change. Among the latter, one of three cases with available follow up developed pulmonary metastases and died after 35 months. In addition, one histologically benign lesion gave rise, after two local recurrences, to inguinal and iliac lymph node metastases. Despite this exceedingly uncommon event, we think most cases of D-TGCT are best regarded as benign but locally aggressive neoplasms with significant recurrent potential and should be treated, when possible, by wide excision. Atypical features such as increased mitotic activity, necrosis, spindling of the mononucleate cells, and cytologic atypia are not indicative of malignancy when present individually. This study also confirms the existence of malignant tenosynovial giant cell tumors, some of which are characterized by aggressive behavior.
Primary giant cell tumor of soft tissue Valerie A. Holst and Rosalie Elenitsas Division of Dermatopathology, Department of Dermatology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA	Journal of Cutaneous Pathology 2001;28 (9), 492-495 Abstract quote Background: Primary giant cell tumor of soft tissue, also known as soft tissue giant cell tumor of low malignant potential, is a rare soft tissue tumor located in both superficial and deep soft tissue. Histologically, these lesions bear a close resemblance to their bony counterparts, giant cell tumor of bone, with round to spindle-shaped cells intimately admixed with uniformly scattered osteoclast-like multinucleated giant cells. In 1989 in the dermatology literature, two malignant giant cell tumors of soft parts were described that filled the dermis and extended into the subcutaneous tissue. Methods: The authors report the rare occurrence of a giant cell tumor of soft tissue occurring primarily in the dermis that lacks overtly malignant features and clinically was thought to be an epidermal inclusion cyst. Results: Light microscopy revealed a non-encapsulated cellular dermal tumor containing numerous osteoclast-like giant cells. Cytologic atypia was minimal and the mitotic count averaged 2–3/10 HPF. The histologic differential diagnosis is also discussed. Conclusion: Giant cell tumor of soft tissue is a rare neoplasm of the skin, however, recognition of this tumor is important due to its behavior as a low-grade malignancy.

 

DIFFERENTIAL DIAGNOSIS	KEY DIFFERENTIATING FEATURES
Malignant fibrous histiocytoma with giant cells
Plexiform fibrohistiocytic tumors
Giant cell tumor of tendon sheath

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