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Journal of Clinical Oncology, Vol 26, No 10 (April 1), 2008: pp. 1757-1759 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.14.7330
Value of Cytogenetic Analysis in the Treatment of Dermatofibrosarcoma ProtuberansDepartment of Dermatology, Saint Louis Hospital, Assistance Publique Hôpitaux de Paris, Paris, France
Faculty of Medicine, Laboratory of Solid Tumors Genetics, Nice University Hospital, Nice, France
Department of Pathology, Saint Louis Hospital, Assistance Publique Hôpitaux de Paris; Université Denis Diderot Paris VII; INSERM U728, Paris, France
Department of Pathology, Saint Louis Hospital, Assistance Publique Hôpitaux de Paris, Paris, France
Department of Radiology, Assistance Publique Hôpitaux de Paris, Paris, France
Department of Plastic and Reconstructive Surgery, Assistance Publique Hôpitaux de Paris, Paris, France
Department of Nuclear Medicine, Assistance Publique Hôpitaux de Paris, Paris, France
Department of Oncology, Assistance Publique Hôpitaux de Paris, Paris, France
Department of Pharmacy, Assistance Publique Hôpitaux de Paris, Paris, France
Department of Dermatology, Saint Louis Hospital, Assistance Publique Hôpitaux de Paris, Paris, France
Center for Clinical Inestigations, Saint Louis Hospital, Assistance Publique Hôpitaux de Paris, Paris, France; Université Denis Diderot Paris VII, INSERM U716, Paris, France
Department of Pathology, Saint Louis Hospital, Assistance Publique Hôpitaux de Paris; Université Denis Diderot Paris VII; INSERM U728, Paris, France
Department of Dermatology, Saint Louis Hospital, Assistance Publique Hôpitaux de Paris; INSERM U716, Paris, France A 23-year-old female patient with a long history of relapsing dermatofibrosarcoma protuberans (DFSP) despite iterative surgery presented in April 2006 with rapidly relapsing tumor unresectable because of massive involvement of the hemifacial and periorbital region. The lesion presented as rapidly evolving, painful tumors more than 10 centimeters large, deeply infiltrating the fat and muscle (Fig 1). Histology confirmed the diagnosis of grade 3 fibrosarcoma arising on DFSP. Translocation t(17;22) was confirmed using caryotype showing a supernumerary ring chromosome (Fig 2, A), and fluorescent in situ hybridization (FISH) analysis on interphase cell nuclei showing the merged green-red signals corresponding to collagen 1A1 promoter (COL1A1)–platelet-derived growth factor-B (PDGF β) fusion gene (Fig 2, B), as previously described in Maire et al1 with no other cytogenetic abnormality. Loco-regional extension was demonstrated by magnetic resonance imaging and positron emission tomography scan before initiation of treatment that showed highly intensive fixation of [18F]fluorodeoxyglucose (18FDG) on tumor sites (Fig 3). Since tumors were unresectable, imatinib mesylate was started at 800 mg/d with good clinical tolerance except for grade 1 nausea and grade 3 creatine phosphokinase elevation with myositis, leading us to dose decrease to 600 and then 400 mg/d. Clinical improvement was seen as early as day 15 of treatment, and confirmed by a dramatic decrease of 18FDG fixation on positron emission tomography scan (Fig 3). The patient experienced a clinical complete response after 17 months of treatment (Fig 1), and treatment with imatinib was maintained, as surgery would be mutilating. Sequential biopsies at M2, M4, M7, and M10 showed progressive decrease in cellularity with onset of hyalinic fibrosis and peritumoral inflammatory cells. Apoptosis was assessed by in situ detection of fragmented DNA, using terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate-biotin nick-end labeling assay as described by Graviely et al2 and Zhao et al.3 Mean number of cells per field at 400x magnification before and after 7 months of imatinib mesylate (IM) was estimated to 0.14 (standard deviation [SD] 0.14) and 10.95 (SD 3.75), P = .0119.
DFSP is a rare soft tissue sarcoma of intermediate malignant potential. Treatment relies on a wide, local excision with a negative margin and often with a need for reconstructive surgery. In more than 90% of cases, there is a translocation between chromosomes 17 and 22 that places PDGF β under the control of COL1A1, leading to an upregulation of PDGF-β expression and activation of the tyrosine kinase PDGFR β. Anecdotal reports on eight patients and more recently a neoadjuvant trial from our center4 demonstrate that IM, targeting PDGFR β, has a therapeutic value in DFSP.5 A minority of cases of DFSP have areas of fibrosarcoma (DFSP-FS) occasionally leading to distant metastases in cases of inadequate local disease control.6,7 More rarely, DFSP lesions contain areas of pleomorphic high-grade sarcoma (DFSP-PleoSarc, formerly known as malignant fibrous histiocytoma). Few cytogenetic data are available regarding high grade sarcomas arising on DFSP, showing the presence of the COL1A1-PDGF β fusion gene in 10 of 15 cases of DFSP-FS and three of three cases of DFSP-PleoSarc.8-11 Such findings led us to use IM as first-line therapy in a patient with unresectable high grade fibrosarcoma arising in DFSP. DFSP-FS, although rare, has been increasingly recognized as a form of tumor progression with a definite 10% to 15% risk of metastasis and a worse prognosis than classic DFSP. Occasionally, pleomorphic areas resembling pleomorphic sarcoma (malignant fibrous histiocytoma) are also seen.5,6 From a clinical point of view, transformation should be suspected in the event of rapid tumor enlargement that is sometimes painful. Histological examination shows a clear transition between areas of typical DFSP and areas of fibrosarcomatous components that include fascicular herringbone architecture, hypercellularity, increased mitotic rate, and necrosis.12 Apoptosis induction by imatinib could be detected in patient 1 but is probably underestimated due to late assessment. Fibrosis induced by imatinib treatment is intriguing owing to its presumed antifibrotic activity. Peripheral inflammatory infiltration enrichment during treatment could be due to stimulation of natural killer lymphocytes and dendritic cells by IM.13,14 Genomic gains of the COL1A1-PDGF β gene in DFSP-FS and previous experience of IM on DFSP encouraged us to treat our patient with IM as first-line therapy for the first time.5 Our patient experienced a dramatic response that was clinically and functionally evident as soon as the 15th day of therapy. Complete clinical response with minimal radiological and histological residual disease was achieved after 17 months of therapy in the first patient, leading us to maintain imatinib. Clinical tolerance was good except nausea grade 1 and increase creatine phosphokinase enzyme with clinical myositis leading us to decrease the dose to 600 and then 400 mg/d. We treated in December 2006 another 54-year-old woman with grade 3 fibrosarcoma arising on DFSP of the right flanc with unresectable tumor for which t(17;22) was also confirmed using caryotype and FISH analysis. IM was started at 800 mg/d with a dramatic partial response of more than 90% of the tumor after seven months of imatinib, allowing subsequent complete surgery. By contrast IM was inefficient in a 83-year-old female patient with past history of DFSP of the left leg, largely resected 2 years before, and suffering from grade 3 undifferentiated CD34-negative pleomorphic sarcoma with areas of DFSP. FISH analysis did not detect the COL1A1-PDGF β transcript (Fig 2C), while caryotyping analysis could not be performed because of necrosis. Conservative carcinologic surgery was impossible. The disease progressed after 1 month of treatment with imatinib 800 mg/d, therefore amputation was performed. No significant apoptosis before and under treatment was seen using terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate-biotin nick-end labeling. Mean number of cells per field at 400x magnification before and after 1 month of IM was estimated to 0.74 (SD 0.17) and 0.88 (SD 0.34), P = .69. This therapeutic failure can be paralleled to the absence of COL1A1-PDGF β transcript detection in the tumor. To conclude, even if prognosis is poorer for patients presenting high grade sarcoma in DFSP (DFSP-FS and more rarely DFSP-PleoSarc) when compared to DFSP, two of our cases with the COL1Al-PDGF β transcript showed a dramatic and rapid response to imatinib mesylate. Our experience stresses the need for cytogenetic studies to predict clinical response to IM in the event of high grade sarcoma arising in DFSP. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
REFERENCES
1. Maire G, Fraitag S, Galmiche L, et al: A clinical, histologic, and molecular study of 9 cases of congenital dermatofibrosarcoma protuberans. Arch Dermatol 143:203-210, 2007 2. Gavrieli Y, Sherman Y, Ben-Sasson SA: Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J Cell Biol 119:493-501, 1992 3. Zhao WL, Daneshpouy ME, Mounier N, et al: Prognostic significance of bcl-xL gene expression and apoptotic cell counts in follicular lymphoma. Blood 103:695-697, 2004 4. Kérob D, Porcher R, Vérola O, et al: Imatinib mesylate (IM) as a pre-operative therapy in dermatofibrosarcoma: Results of a multicentric phase II study on 25 patients. J Clin Oncol 25:552s, 2007 (abstr 10032) 5. McArthur GA, Demetri GD, van Oosterom A, et al: Molecular and clinical analysis of locally advanced dermatofibrosarcoma protuberans treated with imatinib: Imatinib target exploration consortium study B225. J Clin Oncol 23:866-873, 2005 6. Goldblum JR, Reith JD, Weiss SW: Sarcomas arising in dermatofibrosarcoma protuberans: A reappraisal of biologic behaviour in eighteen cases treated by wide local excision with extended follow up. Am J Surg Pathol 24:1125-1130, 2000[CrossRef][Medline] 7. Abbott JJ, Oliveira AM, Nascimento AG: The prognostic significance of fibrosarcomatous transformation in dermatofibrosarcoma protuberans. Am J Surg Pathol 30:436-443, 2006[CrossRef][Medline] 8. Kiuru-Kuhlefelt S, El-Rifai W, Fanburg-Smith J, et al: Concomitant DNA copy number amplification at 17q and 22q in dermatofibrosarcoma protuberans. Cytogenet Cell Genet 92:192-195, 2001[CrossRef][Medline] 9. Wang J, Morimitsu Y, Okamoto S, et al: COL1A1-PDGFB fusion transcripts in fibrosarcoma areas of six dermatofibrosarcomas protuberans. J Mol Diagn 2:47-52, 2000 10. Abbott JJ, Erikson-Johnson M, Wang X, et al: Gains of COL1A1-PDGFB genomic copies occur in fibrosarcomatous transformation of dermatofibrosarcoma protuberans. Mod Pathol 19:1512-1518, 2006[Medline] 11. Szollosi Z, Scholtz B, Egervari K, et al: Transformed dermatofibrosarcoma protuberans: Real time polymerase chain reaction detection of COL1A1-PDGFB fusion transcripts in sarcomatous areas. J Clin Pathol 60:190-194, 2007 12. Mentzel T, Beham A, Katenkamp D, et al: Fibrosarcomatous (‘high-grade’) dermatofibrosarcoma protuberans: Clinicopathologic and immunohistochemical study of a series of 41 cases with emphasis on prognostic significance. Am J Surg Pathol 22:576-587, 1998[CrossRef][Medline] 13. Distler JH, Jungel A, Huber LC, et al: Imatinib mesylate reduces the proportion of extracellular matrix and prevents development of experimental dermal fibrosis. Arthritis Rheum 56:311-322, 2007[CrossRef][Medline] 14. Chaput N, Taieb J, Zitvogel L: Innate defence against tumor cells: The killer cells IKDC. Bull Cancer 93:449-451, 2006[Medline]
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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