Giant-cell fibroblastoma

Last updated
Giant cell fibroblastoma
Specialty Pediatrics, Dermatology, Pathology
Symptoms Painless mass in the dermis
Usual onsetPediatric population
CausesThought to be the formation of a COL1A1-PDGFB fusion gene
TreatmentSurgical excision
Prognosis Good
FrequencyRare

Giant cell fibroblastoma (GCF) is a rare type of soft-tissue tumor marked by painless nodules in the dermis (the inner layer of the two main layers of tissue that make up the skin) and subcutaneous (beneath the skin) tissue. These tumors may come back after surgery, but they do not spread to other parts of the body. They occur mostly in boys. [1] GCF tumor tissues consist of bland spindle-shaped or stellate-shaped cells interspersed among multinucleated giant cells. [2]

Contents

GCF tumors are closely related to dermatofibrosarcoma protuberans (DFSP) and dermatofibrosarcoma protuberans, fibrosarcomatous (DFSP-FS) (also termed fibrosarcomatous dermatofibrosarcoma protuberans) tumors. [3] The World Health Organization (2020) classified these three tumors as different tumors in the category of fibroblastic and myofibroblastic tumors with GCF and DFSP sub-classified as benign but aggressive tumors and DFSP-FS subclassified as a rarely metastasizing tumor. [4] However, The three tumor types may contain areas that have a microscopic histopathological appearance similar to one of the other types. [5] Furthermore, following their surgical resection GCF tumors may recur as DFSP tumors and vice versa and DFSP tumors may recur as DFSP-FS tumors. CGF, DFSP, and DFSP-FS have been regarded as an increasingly aggressive spectrum of related tumors. [6]

Giant cell fibroblastoma tumors are typically treated by surgical resection but have a very high rate of recurrence at the sites of their resection, particularly in cases where all of the tumor has not been removed. Accordingly, wide, complete tumor resections are the recommended treatment for them. [6]

Presentation

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]

Pathology

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]

Chromosome and gene abnormalities

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]

Diagnosis

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]

Treatment and prognosis

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.

Related Research Articles

Dermatofibrosarcoma protuberans Medical condition

Dermatofibrosarcoma protuberans (DFSP) is a rare locally aggressive malignant cutaneous soft-tissue sarcoma. DFSP develops in the connective tissue cells in the middle layer of the skin (dermis). Estimates of the overall occurrence of DFSP in the United States are 0.8 to 4.5 cases per million persons per year. In the United States, DFSP accounts for between 1 and 6 percent of all soft tissue sarcomas and 18 percent of all cutaneous soft tissue sarcomas. In the Surveillance, Epidemiology and End Results (SEER) tumor registry from 1992 through 2004, DFSP was second only to Kaposi sarcoma.

Liposarcoma Medical condition

Liposarcomas are the most common subtype of soft tissue sarcomas, accounting for at least 20% of all sarcomas in adults. Soft tissue sarcomas are rare neoplasms with over 150 different histological subtypes or forms. Liposarcomas arise from the precursor lipoblasts of the adipocytes in adipose tissues. Adipose tissues are distributed throughout the body, including such sites as the deep and more superficial layers of subcutaneous tissues as well as in less surgically accessible sites like the retroperitoneum and visceral fat inside the abdominal cavity.

Fibrosarcoma Medical condition

Fibrosarcoma is a malignant mesenchymal tumour derived from fibrous connective tissue and characterized by the presence of immature proliferating fibroblasts or undifferentiated anaplastic spindle cells in a storiform pattern. Fibrosarcomas mainly arise in people between the ages of 25–79 It originates in fibrous tissues of the bone and invades long or flat bones such as the femur, tibia, and mandible. It also involves the periosteum and overlying muscle.

Nodular fasciitis Medical condition

Nodular fasciitis (NF) is a benign, soft tissue tumor composed of myofibroblasts that typically occurs in subcutaneous tissue, fascia, and/or muscles. The literature sometimes titles rare NF variants according to their tissue locations. The most frequently used and important of these are: cranial fasciitis and intravascular fasciitis. In 2020, the World Health Organization classified nodular fasciitis as in the category of benign fibroblastic/myofibroblastic tumors. NF is the most common of the benign fibroblastic proliferative tumors of soft tissue and exceeds in frequency any other tumor or tumor-like lesion in this group of tumors.

PDGFB

Platelet-derived growth factor subunit B is a protein that in humans is encoded by the PDGFB gene.

Congenital mesoblastic nephroma, while rare, is the most common kidney neoplasm diagnosed in the first three months of life and accounts for 3-5% of all childhood renal neoplasms. This neoplasm is generally non-aggressive and amenable to surgical removal. However, a readily identifiable subset of these kidney tumors has a more malignant potential and is capable of causing life-threatening metastases. Congenital mesoblastic nephroma was first named as such in 1967 but was recognized decades before this as fetal renal hamartoma or leiomyomatous renal hamartoma.

Infantile digital fibromatosis (IDF), also termed inclusion body fibromatosis, Reye tumor, or Reye's tumor, usually occurs as a single, small, asymptomatic, nodule in the dermis on a finger or toe of infants and young children. IMF is a rare disorder with approximately 200 cases reported in the medical literature as of 2021. The World Health Organization, 2020, classified these nodules as a specific benign tumor type in the category of fibroblastic and myofibroblastic tumors. IDF was first described by the Australian pathologist, Douglas Reye, in 1965.

Fibrous hamartoma of infancy (FHI) is a rare, typically painless, benign tumor that develops in the subcutaneous tissues of the axilla, arms, external genitalia, or, less commonly, various other areas. It is diagnosed in children who are usually less than 2 years old or, in up to 20% of cases, develops in utero and is diagnosed in an infant at birth.

Infantile myofibromatosis (IMF) is a rare tumor found in 1 in 150,000 to 1 in 400,000 live births. It is nonetheless the most common tumor derived from fibrous connective tissue that occurs primarily in infants and young children. IMF tumors are benign in the sense that they do not metastasize to distant tissues although when occurring in the viscera, i.e. internal organs, carry guarded to poor prognoses and can be life-threatening, particularly in newborns and young infants.

Low-grade fibromyxoid sarcoma Medical condition

Low-grade fibromyxoid sarcoma (LGFMS) is a rare type of low-grade sarcoma first described by H. L. Evans in 1987. LGFMS are soft tissue tumors of the mesenchyme-derived connective tissues; on microscopic examination, they are found to be composed of spindle-shaped cells that resemble fibroblasts. These fibroblastic, spindle-shaped cells are neoplastic cells that in most cases of LGFMS express fusion genes, i.e. genes composed of parts of two different genes that form as a result of mutations. The World Health Organization (2020) classified LGFMS as a specific type of tumor in the category of malignant fibroblastic and myofibroblastic tumors.

Inflammatory myofibroblastic tumour Medical condition

Inflammatory myofibroblastic tumor (IMT) is a rare neoplasm of the mesodermal cells that form the connective tissues which support virtually all of the organs and tissues of the body. IMT was formerly termed inflammatory pseudotumor. Currently, however, inflammatory pseudotumor designates a large and heterogeneous group of soft tissue tumors that includes inflammatory myofibroblastic tumor, plasma cell granuloma, xanthomatous pseudotumor, solitary mast cell granuloma, inflammatory fibrosarcoma, pseudosarcomatous myofibroblastic proliferation, myofibroblastoma, inflammatory myofibrohistiocytic proliferation, and other tumors that develop from connective tissue cells. Inflammatory pseudotumour is a generic term applied to various neoplastic and non-neoplastic tissue lesions which share a common microscopic appearance consisting of spindle cells and a prominent presence of the white blood cells that populate chronic or, less commonly, acute inflamed tissues.

Mammary analogue secretory carcinoma (MASC) is a salivary gland neoplasm that shares a genetic mutation with certain types of breast cancer. MASCSG was first described by Skálová et al. in 2010. The authors of this report found a chromosome translocation in certain salivary gland tumors that was identical to the (12;15)(p13;q25) fusion gene mutation found previously in secretory carcinoma, a subtype of invasive ductal carcinoma of the breast.

Acral myxoinflammatory fibroblastic sarcoma (AMSF), also termed myxoinflammatory fibroblastic sarcoma (MSF), is a rare, low-grade, soft tissue tumor that the World Health Organization (2020) classified as in the category of rarely metastasizing fibroblastic and myofibroblastic tumors. It is a locally aggressive neoplasm that often recurs at the site of its surgical removal. However, it usually grows slowly and in only 1-2% of cases spreads to distant tissues.

Proliferative fasciitis and proliferative myositis (PF/PM) are rare benign soft tissue lesions that increase in size over several weeks and often regress over the ensuing 1–3 months. The lesions in PF/PM are typically obvious tumors or swellings. Historically, many studies had grouped the two descriptive forms of PF/PM as similar disorders with the exception that proliferative fasciitis occurs in subcutaneous tissues while proliferative myositis occurs in muscle tissues. In 2020, the World Health Organization agreed with this view and defined these lesions as virtually identical disorders termed proliferative fasciitis/proliferative myositis or proliferative fasciitis and proliferative myositis. The Organization also classified them as one of the various forms of the fibroblastic and myofibroblastic tumors.

Lipofibromatosis (LPF) is an extremely rare soft tissue tumor which was first clearly described in 2000 by Fetsch et al as a strictly pediatric, locally invasive, and often recurrent tumor. It is nonetheless a non-metastasizing, i.e. benign, tumor. While even the more recent literature has sometimes regarded LPF as a strictly childhood disorder, rare cases of LPF has been diagnosed in adults. The diagnosis of lipofibromatosis should not be automatically discarded because of an individual's age.

Fibroblastic and myofibroblastic tumors (FMTs) develop from the mesenchymal stem cells which differentiate into fibroblasts and/or the myocytes/myoblasts that differentiate into muscle cells. FMTs are a heterogeneous group of soft tissue neoplasms. The World Health Organization (2020) defined tumors as being FMTs based on their morphology and, more importantly, newly discovered abnormalities in the expression levels of key gene products made by these tumors' neoplastic cells. Histopathologically, FMTs consist of neoplastic connective tissue cells which have differented into cells that have microscopic appearances resembling fibroblasts and/or myofibroblasts. The fibroblastic cells are characterized as spindle-shaped cells with inconspicuous nucleoli that express vimentin, an intracellular protein typically found in mesenchymal cells, and CD34, a cell surface membrane glycoprotein. Myofibroblastic cells are plumper with more abundant cytoplasm and more prominent nucleoli; they express smooth muscle marker proteins such as smooth muscle actins, desmin, and caldesmon. The World Health organization further classified FMTs into four tumor forms based on their varying levels of aggressiveness: benign, intermediate, intermediate, and malignant.

Lipofibromatosis-like neural tumor (LPF-NT) is an extremely rare soft tissue tumor first described by Agaram et al in 2016. As of mid-2021, at least 39 cases of LPF-NT have been reported in the literature. LPF-NT tumors have several features that resemble lipofibromatosis (LPF) tumors, malignant peripheral nerve sheath tumors, spindle cell sarcomas, low-grade neural tumors, peripheral nerve sheath tumors, and other less clearly defined tumors; Prior to the Agaram at al report, LPF-NTs were likely diagnosed as variants or atypical forms of these tumors. The analyses of Agaram at al and subsequent studies uncovered critical differences between LPF-NT and the other tumor forms which suggest that it is a distinct tumor entity differing not only from lipofibromatosis but also the other tumor forms.

Cellular angiofibroma (CAF) is a rare, benign tumor of superficial soft tissues that was first described by M. R. Nucci et al. in 1997. These tumors occur predominantly in the distal parts of the female and male reproductive systems, i.e. in the vulva-vaginal and inguinal-scrotal areas, respectively, or, less commonly, in various other superficial soft tissue areas throughout the body. CAF tumors develop exclusively in adults who typically are more than 30 years old.

Angiofibroma of soft tissue (AFST), also termed angiofibroma, not otherwise specified, is a recently recognized and rare disorder that was classified in the category of benign fibroblastic and myofibroblastic tumors by the World Health Organization in 2020. An AFST tumor is a neoplasm that was first described by A. Mariño-Enríquez and C.D. Fletcher in 2012.

Dermatofibrosarcoma protuberans, fibrosarcomatous (DFSP-FS), also termed fibrosarcomatous dermatofibrosarcoma protuberans, is a rare type of tumor located in the dermis. DFSP-FS tumors have been viewed as: 1) a more aggressive form of the dermatofibrosarcoma protuberans (DFSP) tumors because they have areas that resemble and tend to behave like malignant fibrosarcomas or 2) as a distinctly different tumor than DFSP. DFSP-FS tumors are related to DFSP. For example, surgically removed DFSP tumors often recur with newly developed fibrobosarcoma-like areas. Nonetheless, the World Health Organization (WHO), 2020, classified DFSP and DFSP-FS as different tumors with DFSP being in the category of benign and DFSP-FS in the category of rarely metastasizing fibroblastic and myofibroblastic tumors. This article follows the WHO classification: the 5-15% of DFSP tumors that have any areas of fibrosarcomatous microscopic histopathology are here considered DFSP-FS rather than DFSP tumors.

References

  1. ↑ Cerio, R. (2012). Dermatopathology. Springer Science & Business Media. ISBN   9783642595523 . Retrieved 13 November 2017.
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  6. 1 2 3 4 5 6 7 8 9 10 11 12 Jha P, Moosavi C, Fanburg-Smith JC (April 2007). "Giant cell fibroblastoma: an update and addition of 86 new cases from the Armed Forces Institute of Pathology, in honor of Dr. Franz M. Enzinger". Annals of Diagnostic Pathology. 11 (2): 81–8. doi:10.1016/j.anndiagpath.2006.12.010. PMID   17349565.
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  8. 1 2 3 Hao X, Billings SD, Wu F, Stultz TW, Procop GW, Mirkin G, Vidimos AT (June 2020). "Dermatofibrosarcoma Protuberans: Update on the Diagnosis and Treatment". Journal of Clinical Medicine. 9 (6): 1752. doi: 10.3390/jcm9061752 . PMC   7355835 . PMID   32516921.
  9. ↑ "COL1A1 collagen type I alpha 1 chain [Homo sapiens (Human)] - Gene - NCBI".
  10. ↑ Thway K, Noujaim J, Jones RL, Fisher C (December 2016). "Dermatofibrosarcoma protuberans: pathology, genetics, and potential therapeutic strategies". Annals of Diagnostic Pathology. 25: 64–71. doi:10.1016/j.anndiagpath.2016.09.013. PMID   27806849.
  11. ↑ Saiag P, Grob JJ, Lebbe C, Malvehy J, del Marmol V, Pehamberger H, Peris K, Stratigos A, Middelton M, Basholt L, Testori A, Garbe C (November 2015). "Diagnosis and treatment of dermatofibrosarcoma protuberans. European consensus-based interdisciplinary guideline". European Journal of Cancer. 51 (17): 2604–8. doi:10.1016/j.ejca.2015.06.108. PMID   26189684.

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