Giant-cell fibroblastoma

As found in one study of 86 individuals, GCF commonly present as single tumors in children less than 10 years old (62% of cases), 10-40 year old individuals (26% of cases), and adults greater that 40 years (12% of cases) (overall median age: 6 years).[6] There is a strong predominance of males in the reported cases of GCF.[3][7] The tumors are slow-growing, painless, often protuberant, multinodular or polyp-like dermal and subcutaneous tumors masses or plaques (i.e. a lesion that is greater in its diameter than in its depth) that commonly occur on the trunk, upper parts of the arms or legs, or, rarely, the head and neck areas.[3]

As defined by microscopic histopathology analyses, GCF tumors consist of a few spindle- and/or stellate-shaped cells in a sclerotic (i.e. collagen fiber-rich) background[8] with distinctive dilated blood vessel-like spaces lined by floret-shaped (i.e. small flower-shaped) multinuclear giant cells.[3] The giant cells vary in size and shape with their nuclei often lined-up in wreath-like or lobular formations.[2] The tumors may infiltrate into and through nearby subcutaneous fat tissue,[2] commonly have intralesional hemorrhages and distinctive perivascular onionskin-like lymphocytes,[6] and occasionally contain nodules of smooth muscle-like cells. Some GCF tumors have hybrid characteristics with areas resembling DFSP (e.g. immature-appearing[7] spindle- and/or stellate-shaped cells with abnormally dark nuclei arranged in a monotonous cartwheel or whorled pattern[6]). These hybrid lesions typical have pure GCF-like areas, pure DFSP-like areas, and mixed areas with a gradual or abrupt transition from one to the other.[7] Surgically removed GCF may recur as a DFSP (and vice versa).[2][6] (DFSP-FS tumors consist of rapidly growing bundles of spindle- and/or stellate-shaped cells with vesicle-containing, abnormally shaped nuclei.[2])

Immunohistochemistry analyses indicate that the tumor cells in GCF express CD34 and vimentin proteins but not epithelial membrane antigen (also termed MUC1),[7] ACTA2 (also termed α-SMA), desmin, HMB-45, keratin, S100,[6] or MLANA (also termed Melan-A) proteins.[5]

Cases of GCF consistently contain tumor cells that express a COL1A1-PDGFB fusion gene, i.e. a hybrid gene formed by a chromosomal translocation which mergers two previously independent genes. The COL1A1 gene, which directs production of collagen, type I, alpha 1 protein, is normally located in band 21.33 on the long (or "q") arm of chromosome 17.[9] The PDGFB gene, which directs production of platelet-derived growth factor subunit B (PDGFβ), is normally located in band 13.1 on the q arm of chromosome 22. This translocation is typically balanced, i.e. involving an even exchange of material with no genetic information gained or lost and, ideally, resulting in the formation of a fusion gene which directs production of a fully functional protein. DFSP tumors cells also express a COL1A1-PDGFB fusion gene, but this fusion gene typically results from the formation of small supernumerary ring chromosome, i.e. an extra ring-shaped chromosome that contains a merger between the COL1A1 and PDGFB genes. Hybrid GCF-DFSP tumors typically have more copies of the COL1A1-PDGFB fusion gene in DFSP areas compared to GCF areas and GCF tumors progressing to hybrid GCF-DFSP, GCF progressing to DFSP, and DFSP progressing to DFSP-FS tumors tend to show step-wise increases in the total numbers of these fusion genes that they express.[3]

Either form of the COL1A1-PDGFB fusion gene leads to the overexpression of fully active PDGFβ proteins and thereby the continuous activation of the their target, the PDGF receptor β, along with this receptor's protein-tyrosine kinase activity. The continuously active protein-tyrosine kinase stimulates mitogen-activated protein kinase, PI3K/AKT/mTOR, and other cell signaling pathways which promote the growth, proliferation, and abnormally prolonged survival of their parent cells. It is suggested that these events underlie the development and progression of GCF, GCF-DFSP, DFSP, and DFSP-FS tumors.[8]

The diagnosis of GCF depends on its presentation as a dermal tumor that has a characteristic histology consisting of spindle- and/or stellate-shaped CD34 protein-expressing cells, distinctive dilated blood vessel-like spaces lined by floret-shaped multinuclear giant cells, and/or distinctive perivascular onionskin-like lymphocytes and/or intralesional hemorrhages[6] in a collagen fiber-rich background.[6][7] Presence of tumor cells containing a COL1A1-PDGFB fusion gene, particularly if it is due to a chromosomal translocation rather than an extra supernumerary chromosome, strongly supports the diagnosis of GCF.[3][7] GSF may have areas with the pathologic and chromosomal findings of DFSP. GCF and these "hybrid" tumors, when surgically resected, often recur and may recur as DFSP tumors.[5]

Surgical excision with wide surgical margins to ensure the removal of all tumor tissue is the treatment of choice for GCF tumors[3] and their hybrid forms.[5] However, these tumors, particularly in cases that left tumor tissue behind, have had recurrence rates as high as 50% of all cases.[3][6] The mean time of recurrence after resection was 6.8 years in one large study.[6] Recurrent tumors have been treated by a second surgical excision making sure that all tumor tissue is removed.[7]

Tyrosine kinase inhibitor drugs such as imatinib, sunitinib, and sorafenib have had modest success it treating DFSP tumors located in sites where these tumors are surgical inoperable primary tumors or locally inoperable recurrent tumors or where surgical removal would be disfiguring.[8][10][11] Some studies have suggested that these inhibitors might be useful for treating similarly inoperable or disfiguring GCF tumors[3][6] but no formal studies on the use of tyrosine kinase inhibitors in GCF have been as yet reported.

• Giant cell fibroblastoma entry in the public domain NCI Dictionary of Cancer Terms

 This article incorporates public domain material from Dictionary of Cancer Terms. U.S. National Cancer Institute.