- Case Report
- Open Access
Extraskeletal myxoid chondrosarcoma: tumor response to sunitinib
© Stacchiotti et al.; licensee BioMed Central Ltd. 2012
- Received: 17 August 2012
- Accepted: 30 September 2012
- Published: 11 October 2012
Extraskeletal myxoid chondrosarcoma (EMCS) is a rare soft tissue sarcoma of uncertain differentiation, characterized in most cases by a translocation that results in the fusion protein EWSR1-CHN (the latter even called NR4A3 or TEC). EMCS is marked by >40% incidence of metastases in spite of its indolent behaviour. It is generally resistant to conventional chemotherapy, and, to the best of our knowledge, no data have been reported to date about the activity of tirosin-kinase inhibitor (TKI) in this tumor. We report on two consecutive patients carrying an advanced EMCS treated with sunitinib.
Since July 2011, 2 patients with progressive pretreated metastatic EMCS (Patient1: woman, 58 years, PS1; Patient2: man, 63 years, PS1) have been treated with continuous SM 37.5 mg/day, on an individual use basis. Both patients are evaluable for response. In both cases diagnosis was confirmed by the presence of the typical EWSR1-CHN translocation.
Both patients are still on treatment (11 and 8 months). Patient 1 got a RECIST response after 4 months from starting sunitinib, together with a complete response by PET. An interval progression was observed after stopping sunitinib for toxicity (abscess around previous femoral fixation), but response was restored after restarting sunitinib. Patient 2 had an initial tumor disease stabilization detected by CT scan at 3 months. Sunitinib was increased to 50 mg/day, with evidence of a dimensional response 3 months later.
Sunitinib showed antitumor activity in 2 patients with advanced EMCS. Further studies are needed to confirm these preliminary results.
- Myxoid extraskeletal chondrosarcoma
- Sunitinib malate
- Targeted therapy
Extraskeletal myxoid chondrosarcoma (EMCS) is a rare soft-tissue sarcoma (STS) first described in 1972[1, 2]. EMCS is now considered a unique entity of uncertain differentiation (convincing evidence of a cartilaginous differentiation is lacking in most cases). Besides, EMCS can have a neuroendocrine differentiation[4–6].
It is market by a specific chromosomal translocation, t(9;22)(q22.3;q12.2), fusing CHN to EWSR1[7, 8]. Less frequently two different translocations, t(9;17)(q22.3;q12) and t(9;15)(q22.3;q21.3) are found, resulting in RBP56 CHN and TCF12 CHN fusion-genes, respectively[9, 10]. The fusion-proteins promote cellular growth and differentiation. Furthermore, the EWSR1-CHN fusion-protein may activate the PPARG nuclear receptor gene. Microscopically, EMCS can be subdivided into a conventional well-differentiated and a cellular high-grade EMCS, which is marked by epithelioid cells with prominent nucleoli, high mitotic rate and necrosis. Dedifferentiated ECMS were also described.
Most EMCS arise from the deep soft tissues of the extremities and limb girdles[15–20]. The natural history is usually characterized by an indolent behavior, but studies with a long median follow-up show a high-rate of late local and distant tumor recurrence despite a prolonged clinical course[16–21]. Metastases are reported in around 40% of cases, with a 58% overall survival rate at 15 years in the largest retrospective series.
Standard treatment of primary EMCS is complete surgical resection, followed by radiation in high-risk cases. Patients with advanced disease usually receive a medical treatment. Unfortunately, response rates to conventional chemotherapy are low[15, 21–24].
The identification of a CHN translocation partner ruled-out the diagnosis of myoepithelial carcinoma, raised by morphology and cytokeratin immunoreactivity, as well as an ossifying fibromixoid tumor, another ECMS mimic. Indeed, a subset of soft tissue myoepithelial carcinomas were recently reported to harbour EWSR1-POU5F1 chimera widening the growing family of EWSR1 gene-rearranged tumors and thus making the EWSR1 rearrangement test alone unable to discriminate.
The patient was treated with anthracycline-based chemotherapy. This was followed by a wide excision of the primary tumor en-bloc with a partial femur resection plus ipsilateral iliac LN dissection, and adjuvant radiotherapy on the tumor bed and on the right iliac region. A first multifocal intrabdominal/retroperitoneal relapse was detected in February 2008, and was treated with high-dose ifosfamide plus complete surgical resection. In December 2009, lung metastases appeared. A third-line chemotherapy with trabectedin was started, with progression. Lacking any conventional alternative, in June 2011 the patient started sunitinib 37.5 mg/day, on a continuous dosing regimen. Treatment was provided within a compassionate use program, with the approval of the Institutional Ethics Committee. At that time the disease involved the lungs, liver, abdomen, soft tissues, as confirmed by computed tomography scan (CT) and [18F]fluorodeoxyglucose–positron emission tomography scan (PET). No evidence of relapse to the primary tumor site was observed. Patient was asymptomatic, ECOG performance status (PS) = 1.
Following this experience another 67-years old consecutive patients, ECOG PS 1, affected by a EWSR1-CHN translocated progressive EMCS, metastatic to the lung and LN, pretreated with multiple lines of chemotherapy, started sunitinib in October 2011. After 3 months of treatment with sunitinib 37.5 mg/day a tumor disease stabilization was observed. At that point sunitinib was tentatively increased to 50 g/day, with a dimensional response by CT detectable after 3 months of therapy, 6 months from baseline.
Both patients are still on treatment and responsive, 11 and 8 months from baseline, respectively, without evidence of further major side effects.
We report on the tumor response to sunitinib in two consecutive patients with pretreated, progressive, metastatic extraskeletal myxoid chondrosarcoma, carrying the EWSR1-CHN translocation. In the first case the response was evident after only one month of treatment and marked by shrinkage of all lesions, on the face of a complete PET response. Decrease in tumor size was confirmed by further CT scans for 4 months after stopping treatment because of a therapy-related abscess. When disease progressed after 4 months from sunitinib discontinuation, response was restored by restarting treatment. At 9+ months of follow-up, tumor response was confirmed. In the second patient a dimensional response was evident at 6 months, after an initial tumor stabilization.
EMCS is a very rare STS, with low sensitivity to cytotoxic chemotherapy[15, 20–24]. The only responses to chemotherapy were reported by McGrory in 2 of 6 metastatic EMCS patients responsive to a multi-agents chemotherapy, and in one patient treated with anthracycline plus ifosfamide described by Han. No objective responses were observed in the MD Andersen series of 10 patients receiving doxorubicin and dacarbazine-based regimens, nor in the series of 21 patients treated with different regimens, mostly anthracycline-based, reported by Memorial Sloan Kettering and Royal Marsden. Finally, a response to interferon-α-2b was also described. To our knowledge, this is the first report on the activity of an antiangiogenic agent in EMCS.
Sunitinib is a multi-targeted tyrosine-kinase (RTK) inhibitor and antiangiogenic drug approved for the treatment of gastrointestinal stromal tumor (GIST) and renal cancer[28, 29]. Evidence of activity in selected STS subtypes other than GIST has been provided[30–34]. Responses are often non dimensional, with some exception as for alveolar soft part sarcoma (ASPS). Of interest, in these patients with ESMC we could observe a major dimensional response.
Unlike GIST, no specific genetic alterations associated with sensitivity to sunitinib have been identified in STS. As shown in ASPS, another STS bearing a translocation, the antitumor activity of sunitinib is unlikely to be directly linked to the fusion-protein. In the absence of selective targets and known mechanisms of action, sunitinib antiangiogenic activity as well as an effect on the autocrine-paracrine PDGFR/VEGFR activation-loop have been advocated as possible explanations for its antitumor activity. Even in EMCS the fusion-protein is unlikely to be related to sunitinib sensitivity. Unfortunately, due to absence of untreated frozen material, we could not assess the RTK activation profile.
The most common toxicities with sunitinib are hand-foot syndrome, rash, fatigue, hypertension, hypothyroidism and diarrhea. It is known that the sunitinib and other antiangiogenetic agents can interfere also with the normal vasculature formation and, possibly, with the T-cell mediated immunity[28, 35, 36]. This can lead to rare complications, such as abscess formation[37–39]. In our first patient, the abscess originated at a site where there was no evidence of disease and was probably related to the presence of the foreign material for the femoral fixation. For the differential diagnosis, CT is viewed as the most accurate exam. In our case the presence of clear clinical signs of infection, as fever, leukocytosis, calor and redness of the skin, were of much help to rule out an isolated disease progression. A conservative approach was enough to heal the abscess and a drainage could be avoided. However, CT findings may sometimes be insufficient for the diagnosis and a biopsy can be necessary to rule out a disease progression.
A tumor response to sunitinib was seen in two consecutive patients with EMCS. In one case the response was complicated by infection and was restored when treatment could be restarted after a while. Differential diagnosis of complicated tumor response versus tumor progression was crucial to continue with therapy in the first responding patient. Further prospective studies are needed to confirm these results and to better understand the molecular basis for the activity of sunitinib in this disease.
Written informed consent was obtained from the patients for publication of this Case Report and any accompanying legend. A copy of the written informed consents are available for review by the Editor-in-Chief of this journal.
- Enzinger M, Shiraki M: Extraskeletal myxoid chondrosarcoma: an analysis of 34 cases. Hum Pathol. 1972, 3: 421-435. 10.1016/S0046-8177(72)80042-XView ArticlePubMedGoogle Scholar
- Tumours of Soft tissue and Bone. Pathology and Genetics. World Health Organization Classification of Tumours. Edited by: Fletcher CDM, Unni KK, Mertens F. 2002, Lyon: IARC Press,Google Scholar
- Aigner T, Oliveira AM, Nascimento AG: Extraskeletal myxoid chondrosarcomas do not show a chondrocytic phenotype. Mod Pathol. 2004, 17: 214-221. 10.1038/modpathol.3800036View ArticlePubMedGoogle Scholar
- Panagopoulos I, Mertens F, Isaksson M: Molecular genetic characterization of the EWS/CHN and RBP56/CHN fusion genes in extraskeletal myxoid chondrosarcoma. Genes Chromosomes Cancer. 2002, 35: 340-352. 10.1002/gcc.10127View ArticlePubMedGoogle Scholar
- Subramanian S, West RB, Marinelli RJ: The gene expression profile of extraskeletal myxoid chondrosarcoma. J Pathol. 2005, 206: 433-444. 10.1002/path.1792View ArticlePubMedGoogle Scholar
- Goh YW, Spagnolo DV, Platten M: Extraskeletal myxoid chondrosarcoma: a light microscopic, immunohistochemical, ultrastructural and immuno-ultrastructural study indicating neuroendocrine differentiation. Histopathology. 2001, 39: 514-524. 10.1046/j.1365-2559.2001.01277.xView ArticlePubMedGoogle Scholar
- Hirabayashi Y, Ishida T, Yoshida MA: Translocation (9;22)(q22;q12). A recurrent chromosome abnormality in extraskeletal myxoid chondrosarcoma. Cancer Genet Cytogenet. 1995, 81: 33-37. 10.1016/0165-4608(94)00201-0View ArticlePubMedGoogle Scholar
- Stenman G, Andersson H, Mandahl N, Meis-Kindblom JM, Kindblom LG: Translocation t(9;22)(q22;q12) is a primary cytogenetic abnormality in extraskeletal myxoid chondrosarcoma. Int J Cancer. 1995, 62: 398-402. 10.1002/ijc.2910620407View ArticlePubMedGoogle Scholar
- Sjögren H, Meis-Kindblom J, Kindblom LG: Fusion of the EWS-related gene TAF2N to TEC in extraskeletal myxoid chondrosarcoma. Cancer Res. 1999, 59: 5064-5067.PubMedGoogle Scholar
- Sjögren H, Wedell B, Meis-Kindblom JM, Kindblom LG, Stenman G: Fusion of the NH2-terminal domain of the basic helix-loop-helix protein TCF12 to TEC in extraskeletal myxoid chondrosarcoma with translocation t(9;15)(q22;q21). Cancer Res. 2000 Dec 15;60(24):6832–5. Erratum in. Cancer Res. 2001, 61: 2339-Google Scholar
- Filion C, Labelle Y: The oncogenic fusion protein EWS/NOR-1 induces transformation of CFK2 chondrogenic cells. Exp Cell Res. 2004, 297: 585-592. 10.1016/j.yexcr.2004.03.040View ArticlePubMedGoogle Scholar
- Filion C, Motoi T, Olshen AB: The EWSR1/NR4A3 fusion protein of extraskeletal myxoid chondrosarcoma activates the PPARG nuclear receptor gene. J Pathol. 2009, 217: 83-93. 10.1002/path.2445PubMed CentralView ArticlePubMedGoogle Scholar
- Lucas DR, Fletcher CD, Adsay NV: High-grade extraskeletal myxoid chondrosarcoma: a high-grade epithelioid malignancy. Histopathology. 1999, 35: 201-208. 10.1046/j.1365-2559.1999.00735.xView ArticlePubMedGoogle Scholar
- Antonescu CR, Argani P, Erlandson RA, Healey JH: Skeletal and extraskeletal myxoid chondrosarcoma: a comparative clinicopathologic, ultrastructural, and molecular study. Cancer. 1998, 83: 1504-1521. 10.1002/(SICI)1097-0142(19981015)83:8<1504::AID-CNCR5>3.0.CO;2-BView ArticlePubMedGoogle Scholar
- Saleh G, Evans HL, Ro JY: Extraskeletal myxoid chondrosarcoma. A clinicopathologic study of ten patients with long-term follow-up. Cancer. 1992, 70: 2827-2830. 10.1002/1097-0142(19921215)70:12<2827::AID-CNCR2820701217>3.0.CO;2-VView ArticlePubMedGoogle Scholar
- Meis-Kindblom JM, Bergh P, Gunterberg B, Kindblom LG: Extraskeletal myxoid chondrosarcoma: a reappraisal of its morphologic spectrum and prognostic factors based on 117 cases. Am J Surg Pathol. 1999, 23: 636-650. 10.1097/00000478-199906000-00002View ArticlePubMedGoogle Scholar
- Ogura K, Fujiwara T, Beppu Y: Extraskeletal myxoid chondrosarcoma: a review of 23 patients treated at a single referral center with long-term follow-up. Arch Ortop Thauma Surg. 2012, 132: 1379-1386. 10.1007/s00402-012-1557-9.View ArticleGoogle Scholar
- Okamoto S, Hisaoka M, Ishida T: Extraskeletal myxoid chondrosarcoma: a clinicopathologic, immunohistochemical, and molecular analysis of 18 cases. Hum Pathol. 2001, 32: 1116-1124. 10.1053/hupa.2001.28226View ArticlePubMedGoogle Scholar
- Oliveira AM, Sebo TJ, McGrory JE: Extraskeletal myxoid chondrosarcoma: a clinicopathologic, immunohistochemical, and ploidy analysis of 23 cases. Mod Pathol. 2000, 13: 900-908. 10.1038/modpathol.3880161View ArticlePubMedGoogle Scholar
- Drilon AD, Popat S, Bhuchar G: Extraskeletal Myxoid Chondrosarcoma: A Retrospective Review From 2 Referral Centers Emphasizing Long-term Outcomes With Surgery and Chemotherapy. Cancer. 2008, 113: 3364-3371. 10.1002/cncr.23978PubMed CentralView ArticlePubMedGoogle Scholar
- McGrory JE, Rock MG, Nascimento AG: Extraskeletal myxoid chondrosarcoma. Clin Orthop Relat Res. 2001, 382: 185-190.View ArticlePubMedGoogle Scholar
- Kawaguchi S, Wada T, Nagoya S: Extraskeletal myxoid chondrosarcoma: a multi-institutional study of 42 cases in Japan. Cancer. 2003, 97: 1285-1292. 10.1002/cncr.11162View ArticlePubMedGoogle Scholar
- Patel SR, Burgess MA, Papadopoulos NE: Extraskeletal myxoid chondrosarcoma. Long-term experience with chemotherapy. Am J Clin Oncol. 1995, 18: 161-163. 10.1097/00000421-199504000-00014View ArticlePubMedGoogle Scholar
- Han K, Sun YJ, Shen Z: Extraskeletal myxoid chondrosarcoma: a case report of complete remission by chemotherapy and review of the literature. BMJ Case Rep. 2010, pii (bcr07): 2009-2128.Google Scholar
- Hornick JL, Fletcher CD: Myoepithelial tumors of soft tissue: a clinicopathologic and immunohistochemical study of 101 cases with evaluation of prognostic parameters. Am J Surg Pathol. 2003, 27: 1183-1196. 10.1097/00000478-200309000-00001View ArticlePubMedGoogle Scholar
- Antonescu CR, Zhang L, Chang NE: EWSR1-POU5F1 fusion in soft tissue myoepithelial tumors. A molecular analysis of sixty-six cases, including soft tissue, bone, and visceral lesions, showing common involvement of the EWSR1 gene. Genes Chromosomes Cancer. 2010, 49: 1114-1124. 10.1002/gcc.20819PubMed CentralView ArticlePubMedGoogle Scholar
- Rubinger M, Plenderleithi IH, Lertzman M: Metastatic extraskeletal myxoid chondrosarcoma. Successful therapy with interferon alfa-2b. Chest. 1995, 108: 281-282. 10.1378/chest.108.1.281View ArticlePubMedGoogle Scholar
- Demetri GD, Van Oosterom AT, Garrett CR: Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet. 2006, 368: 1329-1338. 10.1016/S0140-6736(06)69446-4View ArticlePubMedGoogle Scholar
- Motzer RJ, Rini BI, Bukowski RM: Sunitinib in patients with metastatic renal cell carcinoma. JAMA. 2006, 295: 2516-2524. 10.1001/jama.295.21.2516View ArticlePubMedGoogle Scholar
- Stacchiotti S, Tamborini E, Marrari A, Brich S, Rota SA, Orsenigo M, Crippa F, Morosi C, Gronchi A, Pierotti MA, Casali PG, Pilotti S: Response to Sunitinib Malate in Advanced Alveolar Soft Part Sarcoma (ASPS). Clin Cancer Res. 2009, 15: 1096-1104. 10.1158/1078-0432.CCR-08-2050View ArticlePubMedGoogle Scholar
- Stacchiotti S, Negri T, Libertini M: Sunitinib in solitary fibrous tumor. Ann Oncol. 2012, in press,Google Scholar
- George S, Merriam P, Maki RG: Multicenter phase II trial of sunitinib in the treatment of non-gastrointestinal stromal tumor sarcomas. J Clin Oncol. 2009, 27: 3154-3160. 10.1200/JCO.2008.20.9890PubMed CentralView ArticlePubMedGoogle Scholar
- Domont J, Massard C, Lassau N: Hemangiopericytoma and antiangiogenic therapy: clinical benefit of antiangiogenic therapy (sorafenib and sunitinib) in relapsed Malignant Haemangioperyctoma/Solitary Fibrous Tumour. Invest New Drugs. 2010, 28: 199-202. 10.1007/s10637-009-9249-1View ArticlePubMedGoogle Scholar
- Stacchiotti S, Grosso F, Negri T, Palassini E, Morosi C, Pilotti S, Gronchi A, Casali PG: Tumor response to sunitinib malate observed in clear cell sarcoma. Ann Oncol. 2010, 21: 1130-1131. 10.1093/annonc/mdp611View ArticlePubMedGoogle Scholar
- Desai J, Yassa L, Marqusee E: Hypothyroidism after sunitinib treatment for patients with gastrointestinal stromal tumors. Ann Intern Med. 2006, 145: 660-664.View ArticlePubMedGoogle Scholar
- Motzer RJ, Hutson TE, Olsen MR: Randomized Phase II Trial of sunitinib on an intermittent versus continuous dosing schedule as first-line therapy for advanced renal cell carcinoma. J Clin Oncol. 2012, 12: 1371-1377.View ArticleGoogle Scholar
- Michalaki V, Arkadopoulos N, Kondi-Pafiti A: Abscess formation mimicking disease progression, in a patient with metastatic renal cell carcinoma during sunitinib treatment. World J Surg Oncol. 2010, 8: 45- 10.1186/1477-7819-8-45PubMed CentralView ArticlePubMedGoogle Scholar
- Dembry LM: Renal and perirenal abscesses. Curr Treat Options Infect Dis. 2002, 4: 21-30.Google Scholar
- Geeting GK, Shaikh N: Renal abscess. J Emerg Med. 2006, 31: 99-100. 10.1016/j.jemermed.2005.08.015View ArticlePubMedGoogle Scholar
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