Case 6 -

Soft Tissue Giant Cell Tumor (of Low Malignant Potential) Steven D. Billings, M.D. Andrew L. Folpe, M.D.

Clinical History A 27 year-old woman presented with a firm subcutaneous nodule. A biopsy was obtained. Morphology The biopsy demonstrated a multinodular, intradermal proliferation, with a partial shell of woven bone. The individual tumor nodules were most notable for the presence of innumerable osteoclast-like multinucleated giant cell. Arrayed between these giant cells were a moderate number of mitotically active, normochromatic mononuclear cells. Pleomorphism and hyperchromatism were absent from both the multinucleated and mononuclear cells. The overall appearance was identical to that of a giant cell tumor of long bones. Diagnosis: Soft tissue giant cell tumor (of low malignant potential) Discussion Fibrohistiocytic tumors of soft tissue are classified into "benign", "intermediate malignancy", and "malignant" categories, based on their potential for local recurrence and distant metastases. The fibrohistiocytic tumors of intermediate malignancy include dermatofibrosarcoma protuberans, giant cell fibroblastoma, angiomatoid (malignant) fibrous histiocytoma, plexiform fibrous histiocytoma, and the newest member, soft tissue giant cell tumor (of low malignant potential). These tumors are all characterized by frequent local recurrences unless widely excised, but only rarely metastases to lymph nodes and lung. Fibrohistiocytic tumors of intermediate malignancy are of special interest to the dermatopathologist, as they typically present as dermal or subcutaneous masses, and because they may be confused with a variety of benign and fully malignant soft tissue neoplasms. This handout will review the clinicopathological features and differential diagnoses of soft tissue giant cell tumor and plexiform fibrohistiocytic tumor. Dermatofibrosarcoma protuberans is the subject of a separate lecture, and angiomatoid (malignant) fibrous histiocytoma is covered in the lecture on cellular fibrous histiocytoma. Soft tissue giant cell tumor (of low malignant potential) Background Soft tissue giant cell tumor was first described by Salm and Sissons in 1970, who noted a close resemblance between a subset of giant cell rich soft tissue tumors and giant cell tumors of bone. This seminal publication was unfortunately overshadowed by the nearly simultaneous publication of Guccion and Enzinger on malignant giant cell tumors of soft parts (giant cell-rich variant of malignant fibrous histiocytoma). Although the work of Guccion and Enzinger concentrated on the clearly malignant end of the histologic spectrum of soft tissue giant cell tumors, they did note that a subset of their cases displayed "less atypia and mitotic activity" and had an improved outcome. A detailed description of these cases was not however provided. Subsequently, owing to the emphasis placed on the high-grade malignant end of this histologic spectrum, the existence of low-grade soft tissue giant cell tumors was generally unappreciated. Little else was added to our understanding of soft tissue giant cell tumors between 1972 and 1993, although rare cases of probable soft tissue giant cell tumor were reported in the skin, as variants of atypical fibroxanthoma. In 1992, Nascimento published, in abstract form, 10 soft tissue giant cell lesions that he considered to be soft tissue equivalents of giant cell tumors of bone. Finally, in 1999 and 2000, 71 additional cases of soft tissue giant cell tumor were described in 3 essentially simultaneous publications by Folpe et al, O'Connell et al and Oliveira et al. Clinical and Histopathological Features Soft tissue giant cell tumor typically present as multinodular masses in the skin or subcutis of young to middle aged adults, although occasional cases may present as more deeply seated masses or in children. The tumors typically show involvement of the deep dermis and subcutis by a multinodular mass. The periphery of the nodules of soft tissue giant cell tumor often show a surrounding shell of metaplastic, woven bone. The individual tumor nodules consist of a mixture of osteoclastic giant cells, bland mononuclear cells, and short fascicles of bland spindled cells. Mitotic figures are usually easily identified, but atypical forms are not. Vascular involvement by the tumor is common and does not connote malignancy. A variety of other changes may be seen on occasion in soft tissue giant cell tumor, including spindled "fibrohistiocytic" proliferations of the type seen in giant cell tumors of bone, aneurysmal bone cyst-like changes including metaplastic bone and angiectatic spaces, and rarely cartilage. Necrosis, atypical mitotic figures and severe cytologic atypia are not seen in soft tissue giant cell tumor, and should prompt consideration of other diagnoses. Nothing is yet known about the etiology or genetics of soft tissue giant cell tumor. As indicated by their name, soft tissue giant cell tumor has significant capacity for local recurrences, but only metastasize in extremely rare instances. The locally recurring potential of these tumors is most likely related to the multinodular growth pattern, and wide excision should be curative in most cases. The behavior of superficially and deeply located soft tissue giant cell tumor appears to be similar. Differential Diagnosis The differential diagnosis of soft tissue giant cell tumor is broad and includes both benign and malignant entities. Sarcomas that may be confused with soft tissue giant cell tumor include malignant giant cell tumors of soft parts (giant cell-rich variant of malignant fibrous histiocytoma), extraskeletal osteosarcoma, and various other osteoclast-rich malignancies. Occasionally, the distinction between soft tissue giant cell tumor and plexiform fibrohistiocytic tumor (see below) may be quite difficult. Malignant giant cell tumor of soft parts differs from soft tissue giant cell tumor by virtue of the presence of striking cytologic atypia in the mononuclear cell component. In general, the cells of malignant giant cell tumor of soft parts display clear cut features of malignancy, such as nuclear enlargement, high nuclear to cytoplasmic ratios, coarse chromatin, irregular nuclear contours and prominent nucleoli. Malignant giant cell tumor of soft parts also commonly show coagulative tumor necrosis and atypical mitotic figures, features impermissible in soft tissue giant cell tumor. Areas of more typical spindle cell pleomorphic sarcoma (malignant fibrous histiocytoma-like) are also usually present, but may be focal. Although occasional cases of malignant giant cell tumor of soft parts occur in the skin and subcutis, most are deeply seated, large masses, in contrast to soft tissue giant cell tumor. It should be remembered, however, that over 30% of soft tissue giant cell tumor may occur in locations deep to the muscular fascia. Extraskeletal osteosarcoma may on very rare occasions occur in the skin, and commonly shows the presence of osteoclasts. The presence of bone or osteoid production by the neoplastic cells in a malignant appearing, giant cell-rich tumor points towards a diagnosis of giant cell-rich extraskeletal osteosarcoma. There is certainly histologic overlap between giant cell-rich osteosarcoma and malignant giant cell tumor of soft parts with peripheral bone production, and in some cases this distinction may be quite arbitrary. Besides osteosarcoma, other sarcomas may contain abundant osteoclastic giant cells (e.g., leiomyosarcoma, epithelioid sarcoma), as may carcinomas and melanomas. Recognition of these entities depends on identification of more typical areas. Immunohistochemistry for such markers as smooth muscle actin, desmin, cytokeratin and S100 protein may also be of great value. With regards to benign tumors, soft tissue giant cell tumor may be mistaken for tenosynovial giant cell tumors or giant cell-rich forms of nodular fasciitis. In our experience, soft tissue giant cell tumor is most often mistaken for a mitotically active variant of tenosynovial giant cell tumor. Tenosynovial giant cell tumor differs from soft tissue giant cell tumor by virtue of its usual location near joint spaces or bursae, a generally uninodular rather than multinodular growth pattern, prominent stromal hyalinization, and by the generally more mixed population of small synoviocyte-like cells, siderophages, foamy histiocytes, and lymphocytes. Metaplastic bone production is not seen in tenosynovial giant cell tumor. Nodular fasciitis may show considerable numbers of osteoclastic giant cells, both in association with hemorrhage and in intravascular variants (intravascular fasciitis). Recognition of more typical areas of fasciitis, characterized by somewhat randomly arrayed bland myofibroblastic cells, commonly with associated microcystic change should allow this distinction in most cases. Intravascular fasciitis will also show the majority of the tumor to be within distended blood vessels, in contrast to soft tissue giant cell tumor, in which the bulk of the tumor is situated in the dermis Plexiform Fibrohistiocytic Tumor Clinical and Histopathological Features Plexiform fibrohistiocytic tumor is an unusual fibrohistiocytic tumor of intermediate malignancy that most commonly presents as a dermal or subcutaneous mass of the extremities in children or young adults. Any anatomic site may be involved, although location in the head is distinctly uncommon. Plexiform fibrohistiocytic tumor was originally described by Enzinger and Zhang in 1988, and including this original series of 65 cases fewer than 100 cases have been described. As befits its name, plexiform fibrohistiocytic tumor typically grows as a poorly circumscribed, plexiform proliferation of multiple small nodules, each composed of a distinctive admixture of rounded mononuclear cells and osteoclast-like giant cells. These nodules are in turn often surrounded by short fascicles of fibroblastic and/or myofibroblastic-appearing spindled cells, which mingle with the round cell nodules. The mononuclear cells typically resemble cytologically bland histiocytes, although rare pleomorphic variants occur. Mitotic activity is typically low. Immunohistochemically the spindled component may express smooth muscle actin in a myofibroblastic ("tram-track") pattern, and the rounded cells and osteoclasts are usually CD68 positive. In the original series of Enzinger and Zhang, approximately 40% of cases showed the classic bimorphic appearance, with another 40% consisting primarily of the histiocytic component, and 20% showing primarily a fibroblastic growth pattern. In consultation, we have seen several cases of distinctly plexiform, purely fibroblastic lesions of the skin, and believe these are most likely purely fibroblastic variants of plexiform fibrohistiocytic tumor. One such case has been reported by Salamanca et al. Plexiform fibrohistiocytic tumor recurs in between 12 and 40% of cases, but have a very low risk of metastatic disease. Lymph node metastases have been reported in 2 cases, and 3 patients have suffered pulmonary metastases. There do not appear to be any histologic features that predict which plexiform fibrohistiocytic tumor will metastasize. Genetics Although cytogenetic abnormalities have been reported in two cases of plexiform fibrohistiocytic tumor, a recurring genetic event has not been found. Differential Diagnosis Owing to its generally distinctive histologic appearance, the differential diagnosis of plexiform fibrohistiocytic tumor is more restricted than that of soft tissue giant cell tumor, and includes soft tissue giant cell tumor, granulomatous inflammation, cellular neurothekeoma, fibromatosis, and fibrous hamartoma of infancy. The nodules of rounded cells and osteoclasts seen in plexiform fibrohistiocytic tumor are essentially indistinguishable from the tumor nodules of soft tissue giant cell tumor, and in cases lacking a prominent spindled component this distinction may be difficult. Features that should suggest plexiform fibrohistiocytic tumor include younger patient age and a plexiform growth pattern with minute nodules (as opposed to the coarser multinodular pattern of soft tissue giant cell tumor). The presence of metaplastic bone, aneurysmal bone cyst like changes and fibrohistiocytic zones should suggest soft tissue giant cell tumor (see below). Careful attention should be paid to the presence or absence of a subtle fibroblastic spindled component. The presence of nodules of histiocyte-like mononuclear cells with admixed giant cells may suggest the possibility of a granulomatous process. However, close inspection will reveal the nodules in plexiform fibrohistiocytic tumor to contain osteoclast-like, rather than Langerhans-type giant cells. Central necrosis is not a feature of the histiocytic and giant cell-rich nodules of plexiform fibrohistiocytic tumor. Cases of plexiform fibrohistiocytic tumor with relative predominance of the fibroblastic component, and only rare (or even absent) fibrohistiocytic nodules are occasionally confused with fibromatoses. Indeed, at high power magnification, the spindled (myo) fibroblastic areas of plexiform fibrohistiocytic tumor are very similar to fibromatosis. However, fibromatosis typically does not grow in a plexiform fashion, is usually deeply seated rather than cutaneous, and shows longer, sweeping fascicles with characteristic thin-walled dilated blood vessels. Cellular neurothekeoma is a rare cutaneous neoplasm of putative nerve sheath origin. Like plexiform fibrohistiocytic tumor, cellular neurothekeoma grows in a distinctly nodular fashion, with small nests of generally bland epithelioid cells, separated by thin fibrous septae. This multinodular growth pattern may closely mimic examples of plexiform fibrohistiocytic tumor that lack a prominent fibroblastic component. However, unlike plexiform fibrohistiocytic tumor, cellular neurothekeomas lack osteoclast-like giant cells, and in most cases will show at least focal areas of more typical neurothekeoma, characterized by abundant myxoid matrix and more spindled cells. Although typical myxoid neurothekeomas commonly express S100 protein, this marker is of far less value in the diagnosis of cellular neurothekeoma, which is usually S100 protein-negative. Finally, fibrous hamartomas of infancy may display a somewhat plexiform growth pattern, reminiscent of plexiform fibrohistiocytic tumor. Recognition of the typical triphasic histology of fibrous hamartoma, with fibroblastic fascicles, fat, and most importantly nodules and whorls of primitive mesenchymal tissue is critical for this distinction. Fibrous hamartoma also typically occurs in much younger patients than does plexiform fibrohistiocytic tumor, and lacks fibrohistiocytic nodules and osteoclast-like giant cells. Selected References Salm R, Sissons HA. Giant-cell tumours of soft tissues. Journal of Pathology 1972;107(1):27-39. Guccion JG, Enzinger FM. Malignant giant cell tumor of soft parts. An analysis of 32 cases. Cancer 1972;29(6):1518-29. Folpe AL, Morris RJ, Weiss SW. Soft tissue giant cell tumor of low malignant potential: a proposal for the reclassification of malignant giant cell tumor of soft parts. Mod Pathol 1999;12(9):894-902. O'Connell JX, Wehrli BM, Nielsen GP, Rosenberg AE. Giant cell tumors of soft tissue: a clinicopathologic study of 18 benign and malignant tumors. Am J Surg Pathol 2000;24(3):386-95. Oliveira AM, Dei Tos AP, Fletcher CD, Nascimento AG. Primary giant cell tumor of soft tissues: a study of 22 cases. Am J Surg Pathol 2000;24(2):248-56 Enzinger FM, Zhang RY. Plexiform fibrohistiocytic tumor presenting in children and young adults. An analysis of 65 cases. American Journal of Surgical Pathology 1988;12(11):818-26. Remstein ED, Arndt CA, Nascimento AG. Plexiform fibrohistiocytic tumor: clinicopathologic analysis of 22 cases. Am J Surg Pathol 1999;23(6):662-70. Salomao DR, Nascimento AG. Plexiform fibrohistiocytic tumor with systemic metastases: a case report. Am J Surg Pathol 1997;21(4):469-76 . Billings SD, Folpe AL. Cutaneous and subcutaneous fibrohistiocytic tumors of intermediate malignancy: an update. Am J Dermatopathol. 2004;26:141-55.