High-Grade Undifferentiated Sarcomas of the Uterus: Diagnosis, Outcomes, and New Treatment Approaches
- 911 Downloads
High-grade undifferentiated sarcomas (HGUS) are rare malignancies accounting for 6 % of all uterine sarcomas and have a very poor outcome. Histological classification of HGUS is currently debated as a subgroup with uniform nucleoli, and frequently YWHAE–FAM22 transcript has been described, constituting a potential target for new therapies. In localized HGUS, surgery involving total hysterectomy and bilateral oophorectomy is recommended. Adjuvant radiotherapy has recently been suggested in a retrospective study to decrease local recurrence and improve survival versus observation in localized HGUS. In metastatic or recurrent disease, chemotherapy with doxorubicin with or without ifosfamide constitutes the standard of care. Gemcitabine plus docetaxel also seems to be an interesting alternative. Targeted therapies such as pazopanib are now available for soft tissue sarcomas and so could be proposed for uterine sarcoma patients after first- or second-line chemotherapy in the metastatic phase. Further investigations are needed to determine their indications and targets. A European Organisation for Research and Treatment of Cancer (EORTC) randomized trial testing maintenance therapy with cabozantinib after first-line chemotherapy in HGUS is ongoing.
KeywordsUndifferentiated endometrial sarcoma Endometrial stromal sarcoma High-grade endometrial sarcoma Uterine sarcoma Oncology
Compliance with Ethics Guidelines
Conflict of Interest
Charles-André Philip, Patricia Pautier, Florence Duffaud, and Isabelle Ray-Coquard declare that they have no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: • Of importance
- 2.Ducimetiere F, Lurkin A, Ranchere-Vince D, Decouvelaere AV, Peoc'h M, Istier L, et al. Incidence of sarcoma histotypes and molecular subtypes in a prospective epidemiological study with central pathology review and molecular testing. PLoS One. 2011;6(8):e20294. doi: 10.1371/journal.pone.0020294.PubMedCentralPubMedCrossRefGoogle Scholar
- 5.Malouf GG, Duclos J, Rey A, Duvillard P, Lazar V, Haie-Meder C, et al. Impact of adjuvant treatment modalities on the management of patients with stages I-II endometrial stromal sarcoma. Ann. Oncol. 2010;21(10):2002–6. doi: 10.1093/annonc/mdq064.
- 8.Hendrickson MR, Tavassoli FA, Kempson RL, et al. Mesenchymal tumours and related lesions. In: Tavassoli FA, Deville P, editors. World Health Organization classification of tumours. Pathology and genetics. Tumours of the breast and female genital organs. Lyon: IARC; 2003.Google Scholar
- 15.Lee CH, Marino-Enriquez A, Ou W, Zhu M, Ali RH, Chiang S, et al. The clinicopathologic features of YWHAE-FAM22 endometrial stromal sarcomas: a histologically high-grade and clinically aggressive tumor. Am J Surg Pathol. 2012;36(5):641–53. doi: 10.1097/PAS.0b013e31824a7b1a.PubMedCrossRefGoogle Scholar
- 18.Oliva E, Young RH, Amin MB, Clement PB. An immunohistochemical analysis of endometrial stromal and smooth muscle tumors of the uterus: a study of 54 cases emphasizing the importance of using a panel because of overlap in immunoreactivity for individual antibodies. Am J Surg Pathol. 2002;26(4):403–12.PubMedCrossRefGoogle Scholar
- 20.•Malouf GG, Lhomme C, Duvillard P, Morice P, Haie-Meder C, Pautier P. Prognostic factors and outcome of undifferentiated endometrial sarcoma treated by multimodal therapy. Int J Gynaecol Obstet. 2013;122(1):57–61. doi: 10.1016/j.ijgo.2013.01.025. A retrospective study on 30 patients with UES showing outcomes of this pathology. Adjuvant radiation was the only factor correlated with improved PFS.
- 25.Tamura R, Kashima K, Asatani M, Nishino K, Nishikawa N, Sekine M, et al. Preoperative ultrasound-guided needle biopsy of 63 uterine tumors having high signal intensity upon T2-weighted magnetic resonance imaging. Int J Gynecol Cancer. 2014;24(6):1042–7. doi: 10.1097/IGC.0000000000000189.PubMedCrossRefGoogle Scholar
- 27.•Tanner EJ, Garg K, Leitao Jr MM, Soslow RA, Hensley ML. High grade undifferentiated uterine sarcoma: surgery, treatment, and survival outcomes. Gynecol Oncol. 2012;127(1):27–31. doi: 10.1016/j.ygyno.2012.06.030. A retrospective study on 21 UES patients showing outocomes according to the stage of the disease and assessing docetaxel and gemcitabine in combination.
- 30.Bartosch C, Exposito MI, Lopes JM. Low-grade endometrial stromal sarcoma and undifferentiated endometrial sarcoma: a comparative analysis emphasizing the importance of distinguishing between these two groups. Int J Surg Pathol. 2010;18(4):286–91. doi: 10.1177/1066896909337600.PubMedCrossRefGoogle Scholar
- 35.Sciallis AP, Bedroske PP, Schoolmeester JK, Sukov WR, Keeney GL, Hodge JC, et al. High-grade endometrial stromal sarcomas: a clinicopathologic study of a group of tumors with heterogenous morphologic and genetic features. Am J Surg Pathol. 2014. doi: 10.1097/PAS.0000000000000256.PubMedGoogle Scholar
- 40.Reed NS, Mangioni C, Malmstrom H, Scarfone G, Poveda A, Pecorelli S, et al. Phase III randomised study to evaluate the role of adjuvant pelvic radiotherapy in the treatment of uterine sarcomas stages I and II: an European Organisation for Research and Treatment of Cancer Gynaecological Cancer Group study (protocol 55874). Eur J Cancer. 2008;44(6):808–18. doi: 10.1016/j.ejca.2008.01.019.PubMedCrossRefGoogle Scholar
- 41.•Pautier P, Floquet A, Gladieff L, Bompas E, Ray-Coquard I, Piperno-Neumann S, et al. A randomized clinical trial of adjuvant chemotherapy with doxorubicin, ifosfamide, and cisplatin followed by radiotherapy versus radiotherapy alone in patients with localized uterine sarcomas (SARCGYN study). A study of the French Sarcoma Group. Ann Oncol. 2013;24(4):1099–104. doi: 10.1093/annonc/mds545. One of the few prospective study in uterine sarcoma showing the benifit of doxorubicin based adjuvant chemotherapy combined with adjuvant pelvic radiation.
- 45.Muss HB, Bundy B, DiSaia PJ, Homesley HD, Fowler Jr WC, Creasman W, et al. Treatment of recurrent or advanced uterine sarcoma. A randomized trial of doxorubicin versus doxorubicin and cyclophosphamide (a phase III trial of the Gynecologic Oncology Group). Cancer. 1985;55(8):1648–53.PubMedCrossRefGoogle Scholar
- 47.•Hensley ML, Blessing JA, Mannel R, Rose PG. Fixed-dose rate gemcitabine plus docetaxel as first-line therapy for metastatic uterine leiomyosarcoma: a Gynecologic Oncology Group phase II trial. Gynecol Oncol. 2008;109(3):329–34. doi: 10.1016/j.ygyno.2008.03.010. A prospective study on metastatic LMS showing the interest of gemcitabine plus docetaxel in first line chemotherapy.
- 48.•Sutton G, Blessing JA, Malfetano JH. Ifosfamide and doxorubicin in the treatment of advanced leiomyosarcomas of the uterus: a Gynecologic Oncology Group study. Gynecol Oncol. 1996;62(2):226–9. doi: 10.1006/gyno.1996.0220. A prospective study on advanced LMS showing the interest of doxorubicine plus or less ifosfamide in first line chemotherapy.
- 52.Mitsuhashi T, Nakayama M, Sakurai S, Fujimura M, Shimizu Y, Ban S, et al. KIT-negative undifferentiated endometrial sarcoma with the amplified epidermal growth factor receptor gene showing a temporary response to imatinib mesylate. Ann Diagn Pathol. 2007;11(1):49–54. doi: 10.1016/j.anndiagpath.2006.03.012.PubMedCrossRefGoogle Scholar
- 54.Ray-Coquard I, Sleijfer S, Litière S, Blay J-Y, Le Cesne A, Van der Graaf WT. Pazopanib in uterine sarcoma (UtS): review of two European Organisation for Research and Treatment of Cancer (EORTC) and GSK clinical trials 62043 and 62072 on pazopanib for soft tissue sarcoma (STS). J Clin Oncol. 2014;32(15 Suppl):10579.Google Scholar
- 55.Hensley ML, Miller A, O’Malley DM, Mannel RS, Behbakht K, Bakkum-Gamez JN, et al. A randomized phase III trial of gemcitabine + docetaxel + bevacizumab or placebo as first-line treatment for metastatic uterine leiomyosarcoma (uLMS): a Gynecologic Oncology Group study. Gynecol Oncol. 2014;133(Supp 1):3. doi: 10.1016/j.ygyno.2014.03.022.CrossRefGoogle Scholar