Uterine carcinosarcoma: the TAG systematic review

Uterine carcinosarcoma (UCS: uterine malignant mixed Müllerian tumor, uterine MMMT, uterine MMT) is an uncommon but aggressive malignancy. Given that UCS is metaplastic carcinoma, the stage system is according to the 2009 FIGO (Federation of International Gynecology and Obstetrics) staging system for endometrial cancer. In addition, UCS is included into the classification of mixed epithelial and mesenchymal tumors of the uterus, based on the current 2014 World Health Organization (WHO) classification. The diagnosis of UCS is made in the presence of high-grade malignant epithelial and mesenchymal components typically showing a sharp demarcation. The principal treatment in early and locally advanced UCS is a complete and comprehensive staging surgery, including total hysterectomy, bilateral salpingo-oophorectomy, and systematic lymphadenectomy. For advanced-stage UCS, en-bloc debulking surgery is also beneficial for the patients. Multi-agent chemotherapy with and without radiotherapy is often prescribed for patients with UCS, because it might be associated with a better progression-free survival and overall survival. This review summarizes and analyzed the updated information of this highly aggressive disease.

Endometrial cancer; Uterine carcinosarcoma; Uterine malignant mixed Müllerian tumor.

[1] McCluggage W.G.: “A practical approach to the diagnosis of mixed epithelial and mesenchymal tumors of the uterus”. Mod. Pathol., 2016, 29, S78.

[2] Horng H.C., Wen K.C., Wang P.H., Chen Y.J., Yen M.S., Ng H.T., et al.: “Uterine sarcoma part II-uterine endometrial stromal sarcoma: the TAG systematic review”. Taiwan J. Obstet. Gynecol., 2016, 55, 472.

[3] D’Angelo E., Prat J.: “Pathology of mixed Mullerian tumors”. Best. Pract. Res. Clin. Obstet. Gynecol., 2011, 25, 705.

[4] Tsui K.H., Lee F.K., Seow K.M., Chang W.C., Wang J.W., Chen S.U., et al.: “Conservative surgical treatment of adenomyosis to improve fertility: Controversial values, indications, complications, and pregnancy outcomes”. Taiwan. J. Obstet. Gynecol., 2015, 54, 635.

[5] Horng H.C., Chen C.H., Chen C.Y., Tsui K.H., Liu W.M., Wang P.H., et al.: “Uterine-sparing surgery for adenomyosis and/or adenomyoma”. Taiwan. J. Obstet. Gynecol., 2014, 53, 3.

[6] Tsui K.H., Lee W.L., Chen C.Y., Sheu B.C., Yen M.S., Chang T.C., et al.: “Medical treatment for adenomyosis and/or adenomyoma”. Taiwan. J. Obstet. Gynecol., 2014, 53, 459.

[7] Chen Y.J., Li Y.T., Huang B.S., Yen M.S., Sheu B.C., Chow S.N., et al.: “Medical treatment for heavy menstrual bleeding”. Taiwan. J. Obstet. Gynecol., 2015, 54, 483.

[8] Cantrell L.A., Blank S.V., Duska L.R.: “Uterine carcinosarcoma: A review of the literature”. Gynecol. Oncol., 2015, 137, 581.

[9] Wen K.C., Horng C.C., Wang P.H., Chen Y.J., Yen M.S., Ng H.T., et al.: “Uterine sarcoma part I-uterine leiomyosarcoma: the Topic Advisory Group (TAG) systematic review”. Taiwan J. Obstet. Gynecol. 2016, 55, 463.

[10] Prat J., Mbatani N.: “Uterine sarcomas”. Int. J. Gynecol. Obstet., 2015, 131, S105.

[11] Chao K.C., Wang P.H., Chang C.C., Lai C.R., Ng H.T.: “Establishment and characterization of a cell line, MT-213-VGH, isolated from a mixed müllerian tumor of the uterus”. Acta Cytol., 2001, 45, 683.

[12] Artioli G., Wabersich J., Ludwig K., Gardiman M.P., Borgata L., Garbin F.: “Rare uterine cancer: carcinosarcomas. Review from histology to treatment”. Critical. Rev. Oncol. Hematol., 2015, 94, 98.

[13] El-Nashar S.A., Mariani A.: “Uterine carcinosarcoma”. Clin. Obstet. Gynecol., 2011, 54, 292.

[14] Kalluri R., Weinberg R.A.: “The basics of epithelial–mesenchymal transition”. J. Clin. Invest., 2009, 119, 1420.

[15] Chen P., Yang C.C., Chen Y.J., Wang P.H.: “Tamoxifen-induced endometrial cancer”. Eur. J. Gynaecol. Oncol., 2003, 24, 135.

[16] Wang P.H., Chao H.T.: “A reconsideration of tamoxifen use for breast cancer”. Taiwan. J. Obstet. Gynecol., 2007, 46, 93.

[17] Lee W.L., Chao H.T., Cheng M.H., Wang P.H.: “Rationale for using raloxifene to prevent both osteoporosis and breast cancer in postmenopausal women”. Maturitas, 2008, 60, 92.

[18] Lee W.L., Cheng M.H., Chao H.T., Wang P.H.: “The role of selective estrogen receptor modulators on breast cancer: from tamoxifen to raloxifene”. Taiwan. J. Obstet. Gynecol., 2008, 47, 24.

[19] Lee W.L., Cheng M.H., Tarng D.C., Yang W.C., Lee F.K., Wang P.H.: “The benefits of estrogen or selective estrogen receptor modulator on kidney and its related disease-chronic kidney disease-mineral and bone disorders: osteoporosis”. J. Chin. Med. Assoc., 2013, 76, 365.

[20] Lee W.L., Lee F.K., Su W.H., Tsui K.H., Kuo C.D., Hsieh S.L., et al.: “Hormone therapy for younger patients with endometrial cancer”. Taiwan. J. Obstet. Gynecol., 2012, 51, 495.

[21] Lee W.L., Yen M.S., Chao K.C., Yuan C.C., Ng H.T., Chao H.T., et al.: “Hormone therapy for patients with advanced or recurrent endometrial cancer”. J. Chin. Med. Assoc., 2014, 77, 221.

[22] Wen K.C., Sung .PL., Wang P.H.: “Re: the revised 2009 FIGO staging system for endometrial cancer: should the 1988 FIGO stages IA and IB be altered?” Int. J. Gynecol. Cancer, 2012, 22, 178.

[23] McCluggage W.G., Colgan T., Duggan M., Hacker N.F., Mulvany N., Otis C., et al.: “Data set for reporting of endometrial carcinomas: recommendations from the International Collaboration on Cancer Reporting (ICCR) between United Kingdom, United States, Canada, and Australasia:”. Int. J. Gynecol. Pathol., 2013, 32, 45.

[24] Ferguson S.E., Tornos C., Hummer A., Barakat R.R., Soslow R.A.: “Prognostic features of surgical stage I uterine carcinosarcoma”. Am. J. Surg. Pathol., 2007, 31, 1653.

[25] Matsuo K., Takazawa Y., Ross M.S., Elishaev E., Podzielinski I., Yunokawa M., et al.: “Significance of histologic pattern of carcinoma and sarcoma components on survival outcomes of uterine carcinosarcoma”. Ann. Oncol., 2016, 27, 1257.

[26] Lee F.K., Yen M.S., Wang P.H.: “Is it safe to preserve the ovary of premenopausal women with supposed early-stage endometrial cancer”? Taiwan. J. Obstet. Gynecol., 2016, 55, 1.

[27] Li Y.T., Teng S.W.: “Surgery for endometrial cancer”. Taiwan. J. Obstet. Gynecol., 2016, 55, 152.

[28] Wang P.H., Horng H.C., Chen C.P.: “Is it safe to use minimally invasive surgery in the management of endometrial cancer”. Taiwan. J. Obstet. Gynecol., 2016, 55, 155.

[29] Nemani D., Mitra N., Guo M., Lin L.: “Assessing the effects of lymphadenectomy and radiation therapy in patients with uterine carcinosarcoma: A SEER analysis”. Gynecol. Oncol., 2008, 111, 82.

[30] Alagkiozidis I., Weedon J., Grossman A., Wang P., Mize B., Wilson K., et al.: “Extent of lymph node dissection and overall survival in patients with uterine carcinosarcoma, papillary serous and endometrioid adenocarcinoma: a retrospective cohort study”. Int. J. Surgery, 2015, 24, 9.

[31] Chen J.R., Chang T.C., Fu H.C., Lau H.Y., Chen I.H., Ke Y.M., et al.: “Outcomes of patients with surgically and pathologically stage IIIA-IV pure endometrioid-type endometrial cancer”. Medicine (Baltimore), 2016, 95, e3330.

[32] Silverberg S.G., Major F.J., Blessing J.A., Fetter B., Askin F.B., Liao S.Y., et al.: “Carcinosarcoma (malignant mixed mesodermal tumor) of the uterus. A Gynecologic Oncology Group pathologic study of 203 cases”. Int. J. Gynecol. Pathol., 1990, 9, 1.

[33] Scalici J., Laughlin B.B., Finan M.A., Wang B., Rocconi R.P.: “The trend towards minimally invasive surgery (MIS) for endometrial cancer: an ACS-NSQIP evaluation of surgical outcomes”. Gynecol. Oncol., 2015, 136, 512.

[34] Wang P.H., Yuan C.C., Lee W.L., Chin T.W.: “Laparoscopic surgery for early-stage endometrial cancers”. Gynecol. Oncol., 2008, 108, 456.

[35] Lee C.L., Huang K.G., Wu P.J., Lee P.S., Yen C.F.: “Long-term survival outcome of laparoscopic staging surgery for endometrial cancer in Taiwanese experience”. Taiwan. J. Obstet. Gynecol., 2014, 53, 57.

[36] Chiou H.Y., Chiu L.H., Chen C.H., Yen Y.K., Chang C.W., Liu W.M.: “Comparing robotic surgery with laparoscopy and laparotomy for endometrial cancer management: a cohort study”. Int. J. Surg., 2015, 13, 17.

[37] Chu L.H., Chang W.C., Sheu B.C.: “Comparison of the laparoscopic versus conventional open method for surgical staging of endometrial carcinoma”. Taiwan. J. Obstet. Gynecol., 2016, 55, 188.

[38] Walker J.L., Piedmonte M.R., Spirtos N.M., Eisenkop S.M., Schlaerth J.B., Mannel R.S., et al.: “Laparoscopy compared with laparotomy for comprehensive surgical staging of uterine cancer: Gynecologic Oncology Group Study LAP2”. J. Clin. Oncol., 2009, 27, 5331.

[39] Walker J.L., Piedmonte M.R., Spirtos N.M., Eisenkop S.M., Schlaerth J.B., Mannel R.S., et al.: “Recurrence and survival after random assignment to laparoscopy versus laparotomy for comprehensive surgical staging of uterine cancer: Gynecologic Oncology Group LAP2 Study”. J. Clin. Oncol., 2012, 30, 695.

[40] Wang P.H., Yen M.S., Yuan C.C., Chao K.C., Ng H.T., Lee W.L., et al.: “Port site metastasis after laparoscopic-assisted vaginal hysterectomy for endometrial cancer: possible mechanisms and prevention”. Gynecol. Oncol., 1997, 66, 151.

[41] Wang P.H., Yuan C.C., Lin G., Ng H.T., Chao H.T.: “Risk factors contributing to early occurrence of port site metastases of laparoscopic surgery for malignancy”. Gynecol. Oncol., 1999, 72, 38.

[42] Lai C.R., Yen M.S., Wang P.H.: “Neoplasms in the trocar site and peritoneal papillary serous cystadenocarcinoma”. Taiwan. J. Obstet. Gynecol., 2014, 53, 139.

[43] Lee W.L., Chang W.H., Wang K.C., Guo C.Y., Chou Y.J., Huang N., et al.: “The risk of epithelial ovarian cancer of women with endometriosis may be varied greatly if diagnostic criteria are different: a nationwide population-based cohort study”. Medicine (Baltimore), 2015, 94, e1633.

[44] Horng H.C., Teng S.W., Huang B.S., Sun H.D., Yen M.S., Wang P.H., et al.: “Primary fallopian tube cancer: domestic data and up-to-date review”. Taiwan. J. Obstet. Gynecol., 2014, 53, 287.

[45] Chang W.H., Wang K.C., Lee W.L., Huang N., Chou Y.J., Feng R.C., et al.: “Endometriosis and the subsequent risk of epithelial ovarian cancer”. Taiwan. J. Obstet. Gynecol., 2014, 53, 530.

[46] Wang K.C., Chang W.H., Lee W.L., Huang N., Huang H.Y., Yen M.S., et al.: “An increased risk of epithelial ovarian cancer in Taiwanese women with a new surgico-pathological diagnosis of endometriosis”. BMC Cancer, 2014, 14, 831.

[47] Wu H.H., Wang P.H., Yeh Y.J., Chen Y.J., Yen M.S., Huang R.L., et al.: “Serum cytokeratin-19 fragment (Cyfra 21-1) is a prognostic indicator for epithelial ovarian cancer”. Taiwan. J. Obstet. Gynecol., 2014, 53, 30.

[48] Wen K.C., Sung P.L., Yen M.S., Chuang C.M., Liou W.S., Wang P.H.: “MicroRNAs regulate several functions of normal tissue and malignancies”. Taiwan. J. Obstet. Gynecol., 2013, 52, 465.

[49] Tanner E.J., Leitao M.M. Jr., Garg K., Chi D.S., Sonoda Y., Gardner G.J., et al.: “The role of cytoreductive surgery for newly diagnosed advanced-stage uterine carcinosarcoma”. Gynecol. Oncol., 2011, 123, 548.

[50] Harano K., Hirakawa A., Yunokawa M., Nakamura T., Satoh T., Nishikawa T., et al.: “Optimal cytoreductive surgery in patients with advanced uterine carcinosarcoma: A multi-institutional retrospective study from the Japanese gynecologic oncology group”. Gynecol. Oncol., 2016, 141, 447.

[51] Manzerova J., Sison C.P., Gupta D., Holcomb K., Caputo T.A., Parashar B., et al.: “Adjuvant radiation therapy in uterine carcinosarcoma: A population-based analysis of patient demographic and clinical characteristics, patterns of care and outcomes”. Gynecol. Oncol., 2016, 141, 225.

[52] Brooks S.E., Zhan M., Cote T., Baquet C.R.: “Surveillance, epidemiology, and end results analysis of 2677 cases of uterine sarcoma 1989-1999”. Gynecol. Oncol., 2004, 93, 204.

[53] Wright J.D., Seshan V.E., Shah M., Schiff P.B., Burke W.M., Cohen C.J., et al.: “The role of radiation in improving survival for earlystage carcinosarcoma and leiomyosarcoma”. Am. J. Obstet. Gynecol., 2008, 199, 536.e1.

[54] Guttmann D.M., Li H., Sevak P., Grover S., Jacobson G., Feldman A., et al.: “The impact of adjuvant therapy on survival and recurrence patterns in women with early-stage uterine carcinosarcoma: a multi-institutional study”. Int. J. Gynecol. Cancer, 2016, 26, 141.

[55] Omura G.A., Blessing J.A., Major F., Lifshitz S., Ehrlich C.E., Mangan C., et al.: “A randomized clinical trial of adjuvant adriamycin in uterine sarcomas: A Gynecologic Oncology Group Study”. J. Clin. Oncol., 1985, 3, 1240.

[56] Wolfson A.H., Brady M.F., Rocereto T., Mannel R.S., Lee Y.C., Futoran R.J., et al.: “A gynecologic oncology group randomized phase III trial of whole abdominal irradiation (WAI) vs. cisplatin-ifosfamide and mesna (CIM) as post-surgical therapy in stage I-IV carcinosarcoma (CS) of the uterus”. Gynecol. Oncol., 2007, 107, 177.

[57] Reed N.S., Mangioni C., Malmström 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, 808.

[58] Dickson E.L., Vogel R.I., Gehrig P.A., Pierce S., Havrilesky L., Secord A.A., et al.: “A multi-institutional study of outcomes in stage IIII uterine carcinosarcoma”. Gynecol. Oncol., 2015, 139, 275.

[59] Berton-Rigaud D., Devouassoux-Shisheboran M., Ledermann J.A., Leitao M.M., Powell M.A., Poveda A., et al.: “Gynecologic Cancer InterGroup (GCIG) consensus review for uterine and ovarian carcinosarcoma”. Int. J. Gynecol. Cancer, 2014, 24, S55.

[60] Miller B.E., Blessing J.A., Stehman F.B., Shahin M.S., Yamada S.D., Secord A.A., et al.: A phase II evaluation of weekly gemcitabine and docetaxel for second-line treatment of recurrent carcinosarcoma of the uterus: a gynecologic oncology group study. Gynecol. Oncol., 2010, 118, 139.

[61] Sutton G., Brunetto V.L., Kilgore L., Soper J.T., McGehee R., Olt G., et al.: “A phase III trial of ifosfamide with or without cisplatin in carcinosarcoma of the uterus: A Gynecologic Oncology Group Study”. Gynecol. Oncol., 2000, 79, 147.

[62] Homesley H.D., Filiaci V., Markman M., Bitterman P., Eaton L., Kilgore L.C., et al.: Gynecologic Oncology Group: Phase III trial of ifosfamide with or without paclitaxel in advanced uterine carcinosarcoma: a Gynecologic Oncology Group Study”. J. Clin. Oncol., 2007, 25, 526.

[63] Galaal K., van der Heijden E., Godfrey K., Naik R., Kucukmetin A., Bryant A., et al.: “Adjuvant radiotherapy and/or chemotherapy after surgery for uterine carcinosarcoma”. Cochrane Database Syst. Rev., 2013, 2, CD006812.

[64] Toyoshima M., Akahira J., Matsunaga G., Niikura H., Ito K., Yaegashi N., et al.: “Clinical experience with combination paclitaxel and carboplatin therapy for advanced or recurrent carcinosarcoma of the uterus”. Gynecol. Oncol., 2004, 94, 774.

[65] Hoskins P.J., Le N., Ellard S., Lee U., Martin L.A., Swenerton K.D., et al.: “Carboplatin plus paclitaxel for advanced or recurrent uterine malignant mixed mullerian tumors. The British Columbia Cancer Agency experience”. Gynecol. Oncol., 2008, 108, 58.

[66] Powell M.A., Filiaci V.L., Rose P.G., Mannel R.S., Hanjani P., Degeest K., et al.: “Phase II evaluation of paclitaxel and carboplatin in the treatment of carcinosarcoma of the uterus: a Gynecologic Oncology Group study”. J. Clin. Oncol., 2010, 28, 2727.

[67] Lacour R.A., Euscher E., Atkinson E.N., Sun C.C., Ramirez P.T., Coleman R.L., et al.: “A phase II trial of paclitaxel and carboplatin in women with advanced or recurrent uterine carcinosarcoma”. Int. J. Gynecol. Cancer, 2011, 21, 517.

[68] Pectasides D., Pectasides E., Papaxoinis G., Xiros N., Sykiotis C., Papachristodoulou A., et al.: “Combination chemotherapy with carboplatin, paclitaxel and pegylated liposomal doxorubicin for advanced or recurrent carcinosarcoma of the uterus: clinical experience of a single institution”. Gynecol. Oncol., 2008, 110, 299.

[69] Khawaja M.R., Nick A.M., Madhusudanannair V., Fu S., Hong D., et al.: “Phase I dose escalation study of temsirolimus in combination with metformin in patients with advanced/refractory cancers”. Cancer Chemother. Pharmacol., 2016, 77, 973.

[70] Diver E.J., Foster R., Rueda B.R., Growdon W.B.: “The therapeutic challenge of targeting HER2 in endometrial cancer”. Oncologist, 2015, 20, 1058.

[71] McMeekin D.S., Sill M.W., Darcy K.M., Abulafia O., Hanjani P., Pearl M.L., et al.: “A phase II trial of thalidomide in patients with refractory uterine carcinosarcoma and correlation with biomarkers of angiogenesis: a Gynecologic Oncology Group study”. Gynecol. Oncol., 2012, 127, 356.