Carcinosarcoma of the ovary accounts for 1-5% of all ovarian cancers Carcinosarcoma of the uterus accounts for less than 5 % of uterine corpus cancers The uterus is the most common gynecologic site for carcinosarcoma 80% in postmenopausal women of low parity, mostly aged 50-70 A higher percentage of patients with carcinosarcoma are African-American as compared to endometrioid endometrial cancer (28% as compared to 8%) (Zelmanowicz A. et al. 1998)
Carcinosarcoma tumors contain both sarcomatous malignant epithelial and sarcomatous epithelial (mesenchymal) elements epithelial component: ◦ serous ◦ endometrioid ◦ undifferentiated adenocarcinoma ◦ clear cell adenocarcinoma ◦ squamous cell carcinoma sarcomatous element: ◦ homologous tissue native to the ovary/ uterus ◦ heterologous tissue not native to the ovary/uterus The carcinomatous (epithelial) portion predominates within metastatic sites, and thus, determines the clinical course of advanced carcinosarcoma
Biclonal Monoclonal 1 stem cell precursor 2 different stem cells 1stem cell Differentiation in 1 cell type Then differentiation in the second cell type Combination ConversionCollision theory theory theory
A study of 30 ovarian carcinosarcoma performed comparative genomic hybridization and fluorescence in situ hybridization (Schipf A. et al., 2008) . Chromosomal amplification of the c-myc proto-oncogene on chromosomes 8q and 20q was genetic analysis of 12 uterine observed suggesting a and 3 ovarian carcinosarcomas monoclonal origin for these (Jin Z. et al., 2003) analyzing X- tumors. chromosome inactivation, It was also noted that genetic identification of p53 mutations, aberrations were similar to and microsatellite analysis led serous carcinomas in that these to the conclusion of all ovarian tumors could also be metaplastic carcinosarcomas being consistent with the conversion monoclonal in origin supporting theory . the combination theory An evaluation of loss of 1 case of carcinosarcoma was heterozygosity, p53 mutation, reported where clonal loss of and microsatellite analysis in 2 BRCA2 allele and a somatic ovarian serous epithelial mutation in p53 were found in carcinomas which recurred as both carcinoma and carcinosarcomas showed sarcomatous components. identical findings in the primary These results lend further tumor and recurrent support to the combination carcinosarcoma, thus lending theory (Sonoda Y., et al., 2000) support to the conversion theory (Gallardo A. et al., 2002)Collision theory Combination theory Conversion theory
In the United States the incidence is approximately 7 per 100,000 women over age 35 and comprises only 1.2 % of uterine neoplasms [Brooks, SE, 2002]. The median age at diagnosis is 62 to 67 years old [Gadducci A. et al., 2007]. Blacks in the United States have a twofold increase in uterine carcinosarcoma incidence compared with non-Hispanic whites [Sherman ME et al., 2003; Bansal N et al., 2008]. Uterine carcinosarcomas share similar risk factors with endometrial carcinomas. Both neoplasms are associated with obesity, nulliparity, and use of exogenous estrogen and tamoxifen. Oral contraceptives are protective against both types of neoplasms A history of exposure to pelvic radiation appears to be associated with an increased risk of developing uterine carcinosarcoma Approximately 30 % of women have extrauterine disease at time of diagnosis
vaginal bleeding abdominal distention symptoms related to distant metastases (eg, pulmonary symptoms) On pelvic examination, the uterus is often enlarged, and in some patients, part of the tumor may protrude through the cervical os
Uterine carcinosarcoma is staged surgically according to the InternationalFederation of Gynecologists and Obstetricians staging system for endometrialcarcinoma International Federation of Gynaecology and Obstetrics (FIGO) staging for carcinoma of the endometrium Stage 1 Confined to the corpus uteri 1a Tumour limited to endometrium 1b Invasion to less than one half of the myometrium 1c Invasion to greater than one half of the myometrium Involves the corpus and the cervix, but has not extended Stage 2 outside the uterus 2a Endocervical glandular involvement only 2b Cervical stromal invasion Stage 3 Extends outside the uterus but is confined to the true pelvis Tumour invades serosa and / or adnexa and / or positive peritoneal 3a cytology 3b Vaginal metastases 3c Metastases to pelvic and / or para-aortic lymph nodes Involves the bladder or bowel mucosa or has metastasised to Stage 4 distant sites 4a Tumour invasion of bladder and / or bowel mucosa Distant metastases, including intra-abdominal and / or inguinal lymph 4b nodes
Total extrafascial hysterectomy with bilateral salpingo-oophorectomy is the standard surgical procedure for uterine carcinosarcoma [Gadducci A et al., 2007]. As with other endometrial malignancies, complete staging also includes cytology of peritoneal washings and biopsy of any areas where metastases are suspected. Some surgeons also perform omentectomy due to the relatively high risk of upper abdominal spread. There are no data regarding the benefits of optimal cytoreduction in women with advanced carcinosarcoma. However, debulking is a reasonable approach based upon evidence from histologically similar advanced endometrial tumors.
The incidence of regional lymph node metastases is approximately 20 %, thus, pelvic and paraaortic lymphadenectomy are indicated for complete intraoperative evaluation for metastatic disease. The number of lymph nodes collected correlates to risk of recurrence and survival. Disease-free and overall survival are greater in patients with higher lymph node count. (FIGO I and II) [Gadducci A et al., 2007; Temkin SM et al. 2007] A study using data from a United States national cancer database (Surveillance Epidemiology and End Results) demonstrated an association between lymphadenectomy and significantly improved survival (54 months in women who underwent lymphadenectomy versus 25 months in those who did not) [Nemani D et al., 2008]
Chemotherapy with either pelvic radiation therapy or vaginal brachytherapy for adjuvant treatment for women with stage Ib-IVa optimally resected carcinosarcoma (Grade 2 C). Adjuvant whole abdominal irradiation is also an option. Cisplatin-based adjuvant chemotherapy regimens such as cisplatin and doxorubicin or cisplatin, doxorubicin, and paclitaxel (TAP) (Grade 2C). Hematopoietic growth factor support is given with the three-drug regimen, TAP cisplatin, doxorubicin, and paclitaxel (TAP) for palliative chemotherapy in women with recurrent or metastatic disease (Grade 2C). Ifosfamide regimens, such as ifosfamide/paclitaxel, or carboplatin/paclitaxel are also commonly used
There is a significant risk, approaching 60 %, that carcinosarcoma will recur following surgery and adversely affect survival [Arrastia CD et al., 1997; Yamada SD et al., 2000; Major FJ et al., 1993; Callister M et al., 2004]. With many recurrences occurring in the pelvis (40 to 55 %), it is reasoned that adjuvant pelvic radiation therapy (RT) might improve survival by decreasing recurrences [Arrastia CD et al., 1997; Yamada SD et al., 2000; Callister M et al., 2004]. Limited prospective data suggest a possible decrease in local recurrences, but no survival benefit with RT.
A high rate of recurrences outside of the pelvis (45 to 60 %) suggests a potential role for adjuvant chemotherapy [Yamada SD et al., 2000; Major FJ et al., 1993; Callister M et al., 2004]. There is little evidence, much of it from uncontrolled studies, regarding the effectiveness and choice of agents for adjuvant chemotherapy. Both single agent ifosfamide and the combination of cisplatin, ifosfamide, and mesna have demonstrated tolerability and favorable survival endpoints in uncontrolled studies [Sutton G et al., 2005; Kushner DM et al., 2000]. No improvement in progression-free survival or overall survival was gained from adjuvant single agent doxorubicin in the adjuvant setting in a trial of resected, early stage uterine sarcoma, in which carcinosarcoma patients represented nearly half of the study population [Omura GA et al., 1985]. Despite the lack of data demonstrating clear superiority over other agents, we and others favor a cisplatin-containing regimen [Gonzalez Bosquet J et al., 2010,Gadducci A et al., 2001]. We approach adjuvant therapy for carcinosarcomas as we would for women with high-grade endometrial carcinomas. Although we favor cisplatin, doxorubicin, and paclitaxel (TAP), which requires hematopoietic growth factor (G-CSF) support, others use cisplatin and doxorubicin.
In light of the poor prognosis of patients with early stage resected carcinosarcoma, many centers manage carcinosarcoma patients with multimodality therapy. These include protocols of adjuvant chemotherapy, including cisplatin and ifosfamide or carboplatinum and paclitaxel, followed by pelvic radiotherapy. Favorable survival outcomes with sequential or multimodality therapy have been suggested by retrospective reviews of patients treated in this manner [Gonzalez Bosquet J et al., 2010; Wong L et al., 2006; Manolitsas TP et al., 2001; Menczer J et al., 2005; Makker V et al., 2008]. However, prospective, randomized trials are lacking.
Doxorubicin, ifosfamide, paclitaxel, cisplatin, pegylated liposomal doxorubicin, and topotecan all have reasonable single-agent activity in advanced or recurrent carcinosarcoma. No trial has directly compared these drugs to each other Several combination regimens are active, including ifosfamide plus paclitaxel , ifosfamide plus cisplatin [61,68], ifosfamide, cisplatin and doxorubicin , doxorubicin plus cyclophosphamide , doxorubicin, cisplatin, and dacarbazine , and paclitaxel plus carboplatin [71-73 Though some of these trials have prospectively compared multiagent and single-agent regimens, the superiority of any one approach has not been demonstrated [59,61,67]. It is clear that multiagent therapy is associated with greater toxicity.]. With the recognition of carcinosarcoma as poorly differentiated epithelial carcinoma, interest has focused on chemotherapy regimens used for high- grade endometrial carcinoma rather than sarcoma. These are predominately platinum-containing regimens, paclitaxel plus carboplatin, and cisplatin plus doxorubicin and paclitaxel (TAP).
Surveillance commonly consists of physical exam and vaginal cytology every three months for two years, then every six months for a total of five years. Optimal radiologic follow-up is not determined; however, some centers include whole body PET-CT or computed tomography of the chest, abdomen, and pelvis every six months for two years and then annually until five years. The poor prognosis associated with recurrent disease should be borne in mind when recommending a plan of post treatment surveillance.
Uterine carcinosarcomas are associated with a less favorable outcome than uterine carcinomas; estimated five year overall survival rates are 25 to 39 percent. Recurrences tend to occur early, usually within 12 months of treatment . The extent of tumor spread or surgical stage has been consistently found to be the most important prognostic factor [Sartori E. et al., 1997; Nemani, D. et al., 2008]. Five-year disease-specific survival rates stratified according to the new FIGO staging system ◦ Stage I or II (n = 67) — 59 percent ◦ Stage III (n = 19) — 22 percent ◦ Stage IV (n = 33) — 9 percent Other factors associated with prognosis: depth of myometrial invasion, lymphovascular space invasion, age, late onset menopause, race (African-Americans have a poorer prognosis than Caucasians), marital status, and the presence of gross residual disease Kaplan Meier Analysis by FIGO stage
Rare tumor with poor prognosis, most common location: uterus Risk factors: Obesity, nulliparity, TAM, exogenous estrogen, pelvic radiation, Staging according to endometrium carcinoma Treatment: Surgery (TAH-BSO, OE, paraaort/pelv. LNE), CTX (TAP or AP), (RTX) Follow up: Cytology and pelvic exams, imaging
Abdominal distension and bloating Palpable pelvic mass on examination 67-100% present with aszites >50% have metastastic nodal disease at presentation Unlike uterine carcinosarcoma, metastases (5%) are rarely found in the lungs or brain
reports in the literature estimate median survivals of 7 to 27 months Advanced stage, older age and suboptimal debulking worsen prognosis Recurrence rates of 50% were noted for stage I, 100% for stage II, 90% for stage III, and 100% for stage IV disease CA125 provides prognostic information and correlates with disease stage Harris MA et al., 2003
Optimal surgical cytoreduction Platinum-based CTX Whether platinum agents should be administered alone or in combination is undetermined. Common treatment combinations utilized to date include platinum and/or paclitaxel and platinum and/or ifosfamide No radiation therapy