Clinical features, diagnosis, staging, and treatment of uterine carcinosarcoma
- Richard T Penson, MD, MRCP
Richard T Penson, MD, MRCP
- Associate Professor of Medicine
- Harvard Medical School
- Matthew A Powell, MD
Matthew A Powell, MD
- Associate Professor, Division of Gynecologic Oncology
- Director, Gynecologic Oncology Fellowship
- Section Editors
- Barbara Goff, MD
Barbara Goff, MD
- Section Editor — Gynecologic Oncology
- Professor of Gynecologic Oncology
- University of Washington
- Don S Dizon, MD, FACP
Don S Dizon, MD, FACP
- Section Editor – Gynecologic Oncology
- Clinical Co-Director, Gynecologic Oncology
- Founder and Director, The Oncology Sexual Health Clinic
- Massachusetts General Hospital Cancer Center
- Associate Professor of Medicine
- Harvard Medical School
- Deputy Editors
- Sadhna R Vora, MD
Sadhna R Vora, MD
- Deputy Editor — Oncology
- Instructor in Medicine
- Harvard Medical School
- Sandy J Falk, MD, FACOG
Sandy J Falk, MD, FACOG
- Director, Editorial Relations — UpToDate
- Deputy Editor — Obstetrics, Gynecology and Women's Health
- Instructor of Obstetrics, Gynecology and Reproductive Biology, Part-time
- Harvard Medical School
Uterine carcinosarcomas (previously called malignant mixed Müllerian tumors) are dedifferentiated (metaplastic) carcinomas comprised of carcinomatous and sarcomatous elements arising from a single malignant clone. They may represent a stable disruption of the epithelial mesenchymal transition [1-3]. They are considered a high-risk variant of endometrial adenocarcinoma because carcinosarcomas share similarities in epidemiology, risk factors, and clinical behavior more closely with endometrial carcinoma as opposed to uterine sarcomas.
The clinical features, diagnosis, staging, and treatment of uterine carcinosarcoma will be discussed in this topic review. Other types of endometrial cancer and uterine sarcomas are reviewed separately. (See "Uterine sarcoma: Classification, clinical manifestations, and diagnosis" and "Overview of endometrial carcinoma" and "Classification and treatment of endometrial stromal sarcoma and uterine adenosarcoma".)
EPIDEMIOLOGY AND RISK FACTORS
Uterine carcinosarcomas are rare tumors that account for less than 5 percent of all uterine malignancies . As an example, in the United States, the incidence of carcinosarcoma is approximately 1 to 4 per 100,000 women . Carcinosarcomas occur in older women; the median age at diagnosis ranges from 62 to 67 years . Blacks have a twofold higher incidence of uterine carcinosarcoma compared with non-Hispanic whites [7,8].
Uterine carcinosarcomas share similar risk factors with endometrial carcinomas. Both neoplasms are associated with obesity, nulliparity, and use of exogenous estrogen and tamoxifen [9-17]. Progestin-containing contraceptives are protective against both types of neoplasms. A history of exposure to pelvic radiation is also associated with an increased risk of developing uterine carcinosarcoma [18-20].
It is not possible to distinguish carcinosarcoma from endometrial carcinoma or uterine sarcoma based on clinical features. The diagnosis requires histologic evaluation. The typical features of carcinosarcoma are reviewed below. (See "Endometrial carcinoma: Clinical features and diagnosis", section on 'Clinical presentation'.)
- Chaffer CL, San Juan BP, Lim E, Weinberg RA. EMT, cell plasticity and metastasis. Cancer Metastasis Rev 2016; 35:645.
- Zhao S, Bellone S, Lopez S, et al. Mutational landscape of uterine and ovarian carcinosarcomas implicates histone genes in epithelial-mesenchymal transition. Proc Natl Acad Sci U S A 2016; 113:12238.
- Somarelli JA, Boss MK, Epstein JI, et al. Carcinosarcomas: tumors in transition? Histol Histopathol 2015; 30:673.
- Arend R, Doneza JA, Wright JD. Uterine carcinosarcoma. Curr Opin Oncol 2011; 23:531.
- Brooks SE, Zhan M, Cote T, Baquet CR. Surveillance, epidemiology, and end results analysis of 2677 cases of uterine sarcoma 1989-1999. Gynecol Oncol 2004; 93:204.
- Gadducci A, Cosio S, Romanini A, Genazzani AR. The management of patients with uterine sarcoma: a debated clinical challenge. Crit Rev Oncol Hematol 2008; 65:129.
- Sherman ME, Devesa SS. Analysis of racial differences in incidence, survival, and mortality for malignant tumors of the uterine corpus. Cancer 2003; 98:176.
- Bansal N, Herzog TJ, Seshan VE, et al. Uterine carcinosarcomas and grade 3 endometrioid cancers: evidence for distinct tumor behavior. Obstet Gynecol 2008; 112:64.
- Zelmanowicz A, Hildesheim A, Sherman ME, et al. Evidence for a common etiology for endometrial carcinomas and malignant mixed mullerian tumors. Gynecol Oncol 1998; 69:253.
- Schwartz SM, Weiss NS, Daling JR, et al. Exogenous sex hormone use, correlates of endogenous hormone levels, and the incidence of histologic types of sarcoma of the uterus. Cancer 1996; 77:717.
- McCluggage WG, Perenyei M. Microglandular adenocarcinoma of the endometrium. Histopathology 2000; 37:285.
- McCluggage WG, McManus DT, Lioe TF, Hill CM. Uterine carcinosarcoma in association with tamoxifen therapy. Br J Obstet Gynaecol 1997; 104:748.
- Fotiou S, Hatjieleftheriou G, Kyrousis G, et al. Long-term tamoxifen treatment: a possible aetiological factor in the development of uterine carcinosarcoma: two case-reports and review of the literature. Anticancer Res 2000; 20:2015.
- Treilleux T, Mignotte H, Clement-Chassagne C, et al. Tamoxifen and malignant epithelial-nonepithelial tumours of the endometrium: report of six cases and review of the literature. Eur J Surg Oncol 1999; 25:477.
- Friedrich M, Villena-Heinsen C, Mink D, et al. Carcinosarcoma, endometrial intraepithelial carcinoma and endometriosis after tamoxifen therapy in breast cancer. Eur J Obstet Gynecol Reprod Biol 1999; 82:85.
- Evans MJ, Langlois NE, Kitchener HC, Miller ID. Is there an association between long-term tamoxifen treatment and the development of carcinosarcoma (malignant mixed Müllerian tumor) of the uterus? Int J Gynecol Cancer 1995; 5:310.
- Wickerham DL, Fisher B, Wolmark N, et al. Association of tamoxifen and uterine sarcoma. J Clin Oncol 2002; 20:2758.
- Pothuri B, Ramondetta L, Martino M, et al. Development of endometrial cancer after radiation treatment for cervical carcinoma. Obstet Gynecol 2003; 101:941.
- Pothuri B, Ramondetta L, Eifel P, et al. Radiation-associated endometrial cancers are prognostically unfavorable tumors: a clinicopathologic comparison with 527 sporadic endometrial cancers. Gynecol Oncol 2006; 103:948.
- Hagiwara T, Mori T, Kaku T. Development of endometrial cancer following radiation therapy for cervical carcinoma. Eur J Gynaecol Oncol 2005; 26:191.
- Dave KS, Chauhan A, Bhansali R, et al. Uterine carcinosarcomas: 8-year single center experience of 25 cases. Indian J Med Paediatr Oncol 2011; 32:149.
- Callister M, Ramondetta LM, Jhingran A, et al. Malignant mixed Müllerian tumors of the uterus: analysis of patterns of failure, prognostic factors, and treatment outcome. Int J Radiat Oncol Biol Phys 2004; 58:786.
- Salazar OM, Bonfiglio TA, Patten SF, et al. Uterine sarcomas: natural history, treatment and prognosis. Cancer 1978; 42:1152.
- Hosh M, Antar S, Nazzal A, et al. Uterine Sarcoma: Analysis of 13,089 Cases Based on Surveillance, Epidemiology, and End Results Database. Int J Gynecol Cancer 2016; 26:1098.
- Teo SY, Babagbemi KT, Peters HE, Mortele KJ. Primary malignant mixed mullerian tumor of the uterus: findings on sonography, CT, and gadolinium-enhanced MRI. AJR Am J Roentgenol 2008; 191:278.
- Shah SH, Jagannathan JP, Krajewski K, et al. Uterine sarcomas: then and now. AJR Am J Roentgenol 2012; 199:213.
- Tanaka YO, Nishida M, Tsunoda H, et al. Smooth muscle tumors of uncertain malignant potential and leiomyosarcomas of the uterus: MR findings. J Magn Reson Imaging 2004; 20:998.
- Tanaka YO, Tsunoda H, Minami R, et al. Carcinosarcoma of the uterus: MR findings. J Magn Reson Imaging 2008; 28:434.
- Kosary CL. Cancer of the corpus uteri. In: SEER Survival Monograph: Cancer Survival Among Adults: U.S. SEER Program, 1988-2001, Patient and Tumor Characteristics., Ries LAG, Young JL, Keel GE, et al. (Eds), National Cancer Institute, Bethesda 2007. p.130.
- Lee HJ, Park JY, Lee JJ, et al. Comparison of MRI and 18F-FDG PET/CT in the preoperative evaluation of uterine carcinosarcoma. Gynecol Oncol 2016; 140:409.
- Huang GS, Chiu LG, Gebb JS, et al. Serum CA125 predicts extrauterine disease and survival in uterine carcinosarcoma. Gynecol Oncol 2007; 107:513.
- Crum C, Lee KR. Diagnostic Gynecologic and Obstetric Pathology, Elsevier Saunders, Amsterdam 2006.
- Gorai I, Yanagibashi T, Taki A, et al. Uterine carcinosarcoma is derived from a single stem cell: an in vitro study. Int J Cancer 1997; 72:821.
- Silverberg SG, Major FJ, Blessing JA, 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.
- Sreenan JJ, Hart WR. Carcinosarcomas of the female genital tract. A pathologic study of 29 metastatic tumors: further evidence for the dominant role of the epithelial component and the conversion theory of histogenesis. Am J Surg Pathol 1995; 19:666.
- Gonzalez Bosquet J, Terstriep SA, Cliby WA, et al. The impact of multi-modal therapy on survival for uterine carcinosarcomas. Gynecol Oncol 2010; 116:419.
- Castilla MÁ, Moreno-Bueno G, Romero-Pérez L, et al. Micro-RNA signature of the epithelial-mesenchymal transition in endometrial carcinosarcoma. J Pathol 2011; 223:72.
- Bansal N, Herzog TJ, Burke W, et al. The utility of preoperative endometrial sampling for the detection of uterine sarcomas. Gynecol Oncol 2008; 110:43.
- Sagae S, Yamashita K, Ishioka S, et al. Preoperative diagnosis and treatment results in 106 patients with uterine sarcoma in Hokkaido, Japan. Oncology 2004; 67:33.
- Tirumani SH, Ojili V, Shanbhogue AK, et al. Current concepts in the imaging of uterine sarcoma. Abdom Imaging 2013; 38:397.
- NCCN Guidelines Version 3.2012- Endometrial carcinoma http://www.nccn.org/professionals/physician_gls/pdf/uterine.pdf (Accessed on September 19, 2012).
- Fader AN, Java J, Tenney M, et al. Impact of histology and surgical approach on survival among women with early-stage, high-grade uterine cancer: An NRG Oncology/Gynecologic Oncology Group ancillary analysis. Gynecol Oncol 2016; 143:460.
- 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.
- Park JY, Kim DY, Kim JH, et al. The role of pelvic and/or para-aortic lymphadenectomy in surgical management of apparently early carcinosarcoma of uterus. Ann Surg Oncol 2010; 17:861.
- Tanner EJ, Leitao MM Jr, Garg K, et al. The role of cytoreductive surgery for newly diagnosed advanced-stage uterine carcinosarcoma. Gynecol Oncol 2011; 123:548.
- Page BR, Pappas L, Cooke EW, Gaffney DK. Does the FIGO 2009 endometrial cancer staging system more accurately correlate with clinical outcome in different histologies? Revised staging, endometrial cancer, histology. Int J Gynecol Cancer 2012; 22:593.
- Reed NS, Mangioni C, Malmström H, 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.
- Omura GA, Blessing JA, Major F, et al. A randomized clinical trial of adjuvant adriamycin in uterine sarcomas: a Gynecologic Oncology Group Study. J Clin Oncol 1985; 3:1240.
- Cantrell LA, Havrilesky L, Moore DT, et al. A multi-institutional cohort study of adjuvant therapy in stage I-II uterine carcinosarcoma. Gynecol Oncol 2012; 127:22.
- del Carmen MG, Birrer M, Schorge JO. Uterine papillary serous cancer: a review of the literature. Gynecol Oncol 2012; 127:651.
- Wolfson AH, Brady MF, Rocereto T, 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.
- Galaal K, van der Heijden E, Godfrey K, et al. Adjuvant radiotherapy and/or chemotherapy after surgery for uterine carcinosarcoma. Cochrane Database Syst Rev 2013; :CD006812.
- Sorbe B, Johansson B. Prophylactic pelvic irradiation as part of primary therapy in uterine sarcomas. Int J Oncol 2008; 32:1111.
- Makker V, Abu-Rustum NR, Alektiar KM, et al. A retrospective assessment of outcomes of chemotherapy-based versus radiation-only adjuvant treatment for completely resected stage I-IV uterine carcinosarcoma. Gynecol Oncol 2008; 111:249.
- Einstein MH, Klobocista M, Hou JY, et al. Phase II trial of adjuvant pelvic radiation "sandwiched" between ifosfamide or ifosfamide plus cisplatin in women with uterine carcinosarcoma. Gynecol Oncol 2012; 124:26.
- Cha J, Kim YS, Park W, et al. Clinical significance of radiotherapy in patients with primary uterine carcinosarcoma: a multicenter retrospective study (KROG 13-08). J Gynecol Oncol 2016; 27:e58.
- Odei B, Boothe D, Suneja G, et al. Chemoradiation Versus Chemotherapy in Uterine Carcinosarcoma: Patterns of Care and Impact on Overall Survival. Am J Clin Oncol 2017.
- Amant F, de la Rey M, Dorfling CM, et al. PTEN mutations in uterine sarcomas. Gynecol Oncol 2002; 85:165.
- Sartori E, Bazzurini L, Gadducci A, et al. Carcinosarcoma of the uterus: a clinicopathological multicenter CTF study. Gynecol Oncol 1997; 67:70.
- Arrastia CD, Fruchter RG, Clark M, et al. Uterine carcinosarcomas: incidence and trends in management and survival. Gynecol Oncol 1997; 65:158.
- Bodner-Adler B, Bodner K, Obermair A, et al. Prognostic parameters in carcinosarcomas of the uterus: a clinico-pathologic study. Anticancer Res 2001; 21:3069.
- Macasaet MA, Waxman M, Fruchter RG, et al. Prognostic factors in malignant mesodermal (mullerian) mixed tumors of the uterus. Gynecol Oncol 1985; 20:32.
- Inthasorn P, Carter J, Valmadre S, et al. Analysis of clinicopathologic factors in malignant mixed Müllerian tumors of the uterine corpus. Int J Gynecol Cancer 2002; 12:348.
- Hoskins PJ, Le N, Ellard S, 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.
- Hoskins PJ, Le N. Preoperative tumor markers at diagnosis in women with malignant mixed müllerian tumors/carcinosarcoma of the uterus. Int J Gynecol Cancer 2008; 18:1200.
- Powell MA, Filiaci VL, Rose PG, 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.
- Lacour RA, Euscher E, Atkinson EN, 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.
- Homesley HD, Filiaci V, Markman M, et al. Phase III trial of ifosfamide with or without paclitaxel in advanced uterine carcinosarcoma: a Gynecologic Oncology Group Study. J Clin Oncol 2007; 25:526.
- Sutton G, Brunetto VL, Kilgore L, 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.
- EPIDEMIOLOGY AND RISK FACTORS
- CLINICAL FEATURES
- - Ultrasound
- - MRI
- - CT scan
- - FDG PET/CT
- Laboratory findings
- - CA-125
- EVALUATION OF SUSPECTED DISEASE
- Post-diagnostic evaluation
- DIFFERENTIAL DIAGNOSIS
- TREATMENT APPROACH
- Diagnosis based on biopsy
- Diagnosis post-hysterectomy
- ADJUVANT THERAPY
- Stage IA
- Stage IB to IV
- - Choice of regimen
- Chemotherapy plus radiation therapy
- Investigational approaches
- POSTTREATMENT SURVEILLANCE
- TREATMENT OF METASTATIC DISEASE
- Isolated vaginal recurrence
- Metastatic disease, no prior chemotherapy
- - Carboplatin plus paclitaxel
- - Ifosfamide-based regimens
- Metastatic disease, prior chemotherapy
- SUMMARY AND RECOMMENDATIONS