Carcinosarcomas (Malignant Mixed Müllerian Tumor) of the Uterus: Advances in Elucidation of Biologic and Clinical Characteristics

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1 550 Carcinosarcomas (Malignant Mixed Müllerian Tumor) of the Uterus: Advances in Elucidation of Biologic and Clinical Characteristics Lauren E. Kernochan, MD, and Rochelle L. Garcia, MD, Seattle, Washington Key Words Malignant mixed Müllerian tumor, carcinosarcoma, uterus Abstract Carcinosarcoma of the uterus (malignant mixed Müllerian tumor [MMMT]) is an uncommon, typically extremely aggressive neoplasm histologically composed of malignant epithelial and mesenchymal (stromal) elements. Although the literature contains some debate, most authors now agree that most MMMTs derive from sarcomatous differentiation in a high-grade carcinoma. This article reviews the clinical and histopathologic features of this interesting neoplasm, with particular emphasis on recent data supporting MMMTs as primarily epithelial malignant neoplasms with areas of mesenchymal/spindle cell differentiation. (JNCCN 2009;7: ) Medscape: Continuing Medical Education Online Medscape, LLC is pleased to provide online continuing medical education (CME) for this journal article, allowing clinicians the opportunity to earn CME credit. Medscape, LLC is accredited by the Accreditation Council for Continuing Medical Education (AC- CME) to provide CME for physicians. Medscape, LLC designates this educational activity for a maximum of 0.5 AMA PRA Category 1 Credits. Physicians should only claim credit commensurate with the extent of their participation in the activity. All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test and/or complete the evaluation at www. medscape.com/cme/jnccn; (4) view/print certificate. Learning Objectives Upon completion of this activity, participants will be able to: Identify the clinical features of uterine carcinosarcoma Specify the most common anatomic site of metastasis of uterine carcinosarcoma Specify the most important prognostic factor for uterine carcinosarcoma Describe the molecular data of uterine carcinosarcoma Carcinosarcoma of the uterus (malignant mixed Müllerian tumor [MMMT]), is a biphasic neoplasm composed of malignant epithelial and mesenchymal components. These are uncommon neoplasms, with an incidence of fewer than 2 per 100,000 women per year. They have an From the Department of Pathology, University of Washington School of Medicine, Seattle, Washington. Submitted January 13, 2009; accepted for publication March 5, Correspondence: Rochelle L. Garcia, MD, Department of Pathology, University of Washington Medical School, Box , 1959 N.E. Pacific, Seattle, WA rochelle@u.washington.edu EDITOR Kerrin G. Robinson, MA, Medical/Scientific Editor, Journal of the National Comprehensive Cancer Network Disclosure: Kerrin G. Robinson, MA, has disclosed no relevant financial relationships. AUTHORS AND CREDENTIALS Lauren E. Kernochan, MD, Department of Pathology, University of Washington School of Medicine, Seattle, Washington Disclosure: Lauren E. Kernochan, MD, has disclosed no relevant financial relationships. Rochelle L. Garcia, MD, Department of Pathology, University of Washington School of Medicine, Seattle, Washington Disclosure: Rochelle L. Garcia, MD, has disclosed no relevant financial relationships. CME AUTHOR Charles P. Vega, MD, FAAFP, Associate Professor; Residency Director, Department of Family Medicine, University of California, Irvine Disclosure: Charles P. Vega, MD, FAAFP, has disclosed no relevant financial relationships.

2 551 Carcinosarcomas of the Uterus extremely poor prognosis, with a 5-year survival rate of 33% to 39%. 1 Although relatively rare, carcinosarcomas of the uterus, and of the gynecologic and urinary tracts in general, are more common than in other sites, such as lung, possibly because the epithelial stem cells are mesodermal in origin. 2,3 Clinicopathologic data support separation of carcinomas arising in the endometrium into 2 types. The more common type of neoplasm, type 1, is typically associated with hyperestrogenism, obesity (due to aromatization of androgens into estrogen), and hyperlipidemia, have well or moderately differentiated, typically endometrioid histology, and have a good prognosis (approximately 85% 90% 5-year survival rate). They are frequently associated with PTEN mutations. Type 2 endometrial carcinomas, which represent 10% to 15% of endometrial carcinomas, are typically seen in women without these clinical features. They typically have poorly differentiated endometrioid or serous histology and a worse prognosis (55% 60% 5-year survival rate) and are more often associated with p53 mutations. 4,5 Carcinosarcomas are part of the type 2 group, with an epithelial component that most often resembles high grade endometrioid, serous or clear cell carcinoma. Previous debates about the derivation of this neoplasm have centered on whether carcinosarcoma is a biclonal or monoclonal process. In the collision tumor theory, synchronous sarcoma and carcinoma arise from separate stem cells and merge in a biclonal process. In the combination and conversion tumor theories, a single common stem cell precursor gives rise to a monoclonal neoplasm with divergent or metaplastic differentiation. 3,6,7 Molecular studies indicate that most neoplasms diagnosed as carcinosarcoma of the uterus are monoclonal, suggesting that although a minority may be true collision tumors/separate neoplasms, most represent a single neoplastic process. Based on molecular, epidemiologic, genetic, and histologic data, most authors now believe that most carcinosarcomas are essentially high-grade carcinomas with sarcomatous/ stromal differentiation, similar to what is seen in other organ systems (e.g., metaplastic carcinoma of the breast, sarcomatoid renal cell carcinoma, spindle cell carcinoma of the larynx). Therefore, it may be more appropriate to refer to this lesion as sarcomatoid carcinoma of the uterus and perhaps to refer to all of these neoplasms as sarcomatoid carcinomas of their respective organ systems. This article reviews current understanding of the clinical and pathologic features of uterine carcinosarcomas, emphasizing recent data supporting divergent differentiation of a primarily epithelial neoplasm (carcinoma) underlying the pathogenesis of this interesting neoplasm. Clinical Features Müllerian carcinosarcomas most commonly arise in the uterus, but may also arise in the ovaries, fallopian tubes, vagina, and peritoneum As expected, clinical presentation depends on disease distribution. Uterine carcinosarcomas typically present with abnormal vaginal bleeding and may present with bloody discharge, watery discharge, abdominal pain, or an abdominal mass. 11 Through imaging, uterine carcinosarcoma typically appears as a mass within the uterine cavity, with accompanying dilation of the cavity and myometrial invasion, most often involving the fundus. 12 Although some smaller studies have found no difference in age at presentation, 13 a recent analysis of the Surveillance Epidemiology and End Results (SEER) data, which included over 5024 women with grade 3 endometrioid and 3962 with uterine carcinosarcoma, found that women with carcinosarcoma were slightly older (70 vs. 66 years; P <.001), more often non-white (23% vs. 15%; P <.001), and presented with more advanced disease 4 (41% vs. 31% had stage III/IV; P <.001). Additionally, analysis of 453 women, 29 of whom had carcinosarcoma, found carcinosarcomas are generally diagnosed at a higher stage, with 27% of MMMTs presenting at stage III or IV, and only 9% of uterine carcinomas presenting at stage III or IV (P =.004). 13 Carcinosarcomas and carcinomas of the uterus have similar risk factor profiles. Their incidence is increased in association with increased exposure to estrogen through marked obesity, nulliparity, or use of exogenous estrogen, and with pelvic radiation, 13 whereas the incidence is decreased in association with oral contraceptive use. 14 Tamoxifen, which has been shown to be beneficial in women with estrogen receptor positive breast cancer, has weak estrogenic effects and confers an increased risk for endometrial carcinoma, particularly type 2 carcinomas, including carcinosarcoma.

3 552 Kernochan and Garcia In the SEER data from 1980 to 2000, patients who underwent tamoxifen treatment for breast cancer had a 2.3-fold increased risk for developing endometrial carcinoma and an 8-fold increase in risk for developing endometrial carcinosarcoma 8 years posttherapy. 15 Because carcinosarcoma is a rare diagnosis, the absolute risk is low and represents a small proportion of uterine neoplasms in any population. Notably, no statistically significant increase in risk for sarcoma was seen in that analysis. Radiation exposure increases risk for developing genital tract carcinomas and carcinosarcomas, and is particularly associated with more aggressive neoplasms. 13 Of the 7 vaginal carcinosarcoma cases reported in the literature, 4 had a history of prior irradiation. 10 These clinical and epidemiologic data indicate that the biologic behavior of carcinosarcoma of the uterus is akin to a high-grade carcinoma. Gross, Microscopic, and Immunohistochemical Features A Patients with uterine carcinosarcomas often present with a bulky, polypoid mass distending the uterine cavity and protruding through the cervical os (Figure 1). 16 They may also have diffuse enlargement of the uterus as the neoplasm infiltrates and expands the wall, or they may develop a large pelvic mass without an identifiable uterus. 11 On gross examination, the cut surface of carcinosarcomas is often fleshier (because of high cellularity and sarcomatous differentiation) than adenocarcinomas, with areas of necrosis, and occasionally gritty or hard areas corresponding to osseous or cartilaginous differentiation. 16,17 According to histologic examination of standard hematoxylin and eosin-stained sections, carcinosarcoma is composed of malignant-appearing epithelial and stromal (mesenchymal) components (Figure 2). The 2 morphologies may be intimately admixed or may appear as 2 distinct components. Carcinoma can have the histologic appearance of any of the malignant epithelial neoplasms seen in the female genital tract, including serous, endometrioid, clear cell, mucinous, and squamous growth patterns. 17 In the authors experience, a serous growth pattern is observed in a larger proportion of uterine carcinosarcomas than in standard uterine carcinomas. Histologic patterns unusual to conventional adenocarcinoma are more commonly seen in the epithelial component of carcinosarcoma. These include solid areas with marked pleomorphism, bizarre cells, primitive or embryonal glandular growth patterns, and lace-like arrangements of cells. 17 The stromal component may resemble mesenchymal cell types normally present in the uterus (homologous differentiation), with histologic features of leiomyosarcoma, endometrial stromal sarcoma, or fibrosarcoma, or may have heterologous elements (i.e., those not normally found in the uterus), such as rhabdomyosarcoma, chondrosarcoma, and osteosarcoma, in decreasing order of frequency. 17 Frequently, the histologic pattern is simply high-grade sarcoma, without appreciable specific differentiation. B Figure 1 Gross photographs of malignant müllerian mixed tumor. A) Bivalved uterus with tubes and ovaries, and polypoid fleshy mass in the uterine cavity. B) Axial cross-section through uterus and mass.

4 553 Carcinosarcomas of the Uterus Immunohistochemistry shows that neoplastic cells generally express markers of epithelial and stromal differentiation in relation to their histologic appearance. Epithelial membrane antigen (EMA) and pancytokeratin are expressed in the epithelial component and often focally expressed in the spindle cell component 2,18 because they are in many uterine sarcomas, particularly leiomyosarcoma. In 15 cases of carcinosarcoma, Chung et al. 19 found desmin expression in areas with muscle differentiation, myoglobin expression in rhabdomyoblasts, and S-100 expression in areas with chondroid and lipomatous differentiation. Carcinosarcomas often express WT-1 and p53 (up to 70% and 82%, respectively) in the carcinomatous and sarcomatous components, similar to high-grade carcinomas. 20,21 Schipf et al. 22 found that the cellular proliferation index based on Ki-67 immunostaining was moderate to strong in 25 of 25 cases, with significantly higher (P <.001) proliferation index in carcinomatous rather than sarcomatous areas (mean of 70% and 28% of cells positive, respectively). Anatomic and Histologic Pattern of Metastasis The distribution of metastatic disease seen in carcinosarcoma is more similar to aggressive carcinomas than sarcomas. Carcinomas generally spread through lymphatic channels to nearby lymph nodes or recur locally. Conversely, uterine sarcomas, including leiomyosarcoma and endometrial stromal sarcoma, more often metastasize to the peritoneal cavity or hematogenously to the lungs, and rarely metastasize to lymph nodes. Bitterman et al. 18 studied 22 cases of uterine carcinosarcoma and found the spread of metastasis was predominantly to lymph nodes, ovaries, fallopian tubes, and omentum, with occasional involvement of parametrium, bowel, liver, and tonsil. No lung metastases were seen, and all metastatic foci were composed of carcinoma only. In both carcinosarcomas and carcinomas, the traditionally higher-grade histologic patterns of endometrial carcinoma, serous, and clear cell, are associated with greater likelihood of metastasis at original resection when adjusted for stage. 18,23 Histologic appearance of neoplastic nests in lymphovascular spaces and metastases more often mimics the epithelial component of the neoplasm (Figure 3). 6,18,24 Figure 2 Carcinomatous cells of malignant Müllerian mixed tumor with glandular differentiation in the epithelial component; note numerous mitotic figures in the stromal component. Sarcomatoid metastases have been seen more frequently in anatomic sites with hollow spaces that allow polypoid growth, such as the peritoneal cavity and vagina, and in late metastases, particularly after administration of chemotherapeutic agents active against the carcinomatous component. 24 Initial studies suggested heterologous elements within the sarcomatoid portion portended a worse prognosis; however, subsequent studies have not supported a prognostic significance for any histologic features of the sarcomatous component. 23 These findings suggest that, although sarcomatoid differentiation may be a marker of more aggressive behavior and of regression to a more primitive stem cell like phenotype with the ability to give rise to epithelial or stromal progenitor cells, it is usually the epithelial component driving metastasis. Prognosis and Treatment Prognosis for a given disease site is generally worse than for high-grade carcinoma of the corresponding site. Women with uterine carcinosarcomas have poorer outcomes than those with endometrial carcinoma, particularly type 1 carcinomas, with 18- and 36-month median survival times for all patients, respectively. Stage is the most significant prognostic indicator, although age and depth of myometrial invasion (independent of stage) are also significant on univariate analysis. 25 More women with carcinosarcoma present with advanced stage disease (53%),

5 554 Kernochan and Garcia Figure 3 Epithelioid morphology of malignant müllerian mixed tumor metastatic to a lymph node. similar to rates of advanced presentation seen in clear cell and serous (type 2) carcinoma of the endometrium, 1 and in contrast to women with type 1 endometrial carcinoma who generally present with disease confined to the uterus. In addition, metastasis is often present in patients with no documented myometrial invasion. Standard treatment for carcinosarcoma of the uterus is surgical, including hysterectomy, bilateral salpingo-oophorectomy, lymph node dissection, and resection of all gross disease, with adjuvant radiation for locoregional control, and chemotherapy depending on stage. 26 Similar to carcinomas, carcinosarcomas often respond to platinum-based chemotherapy. Additionally, agents with activity against sarcomas, including DNAalkylating agents such as ifosfamide, are helpful in combination with agents active against carcinomas. Although the rarity of this diagnosis has precluded large trials of chemotherapy regimens for carcinosarcoma of any site, most trials have found a survival benefit from treating with adjuvant platinum-based therapy together with taxane, a mitotic inhibitor, or ifosfamide Molecular Data Genetic and molecular data provides compelling evidence supporting a monoclonal origin of most carcinosarcomas. In array comparative genomic hybridization array studies, DNA from the neoplasm and normal cells is co-hybridized to labeled probes that span the entire genome at frequent intervals, identifying gains, amplifications, and losses of regions of DNA in the tumor cells relative to non-neoplastic cells. When applied to carcinosarcomas of the female genital tract, gains or amplifications of 8q are the most common genetic aberration in both carcinosarcomas 22,31 and endometrial adenocarcinomas. 22 Schulten et al. 31 were able to separately evaluate the sarcomatous and carcinomatous components in 3 lesions, and found that 2 cases had similar karyotypic abnormalities with additional abnormalities in the sarcomatous components, suggesting a monoclonal origin with additional genetic aberrations in areas having undergone sarcomatous transformation. 31 One of the genes located within 8q is c-myc (8q24), found to be amplified in 18 of 23 uterine and ovarian carcinosarcomas through fluorescence in situ hybridization 22 and overexpressed in 9 of 9 uterine carcinosarcomas through immunohistochemistry. 32 C-myc amplification is often present in carcinomas but was also present in 6 of 12 uterine leiomyomas and 11 of 23 uterine leiomyosarcomas. 32 Maternally versus paternally inherited alleles in an individual s DNA can be distinguished from each other using highly polymorphic sequences, such as microsatellites. At informative loci, different sequences are present in the maternal and paternal alleles. Loss of heterozygosity (LOH) in tumor DNA, detected through loss of either the maternal or paternal allele at a given locus, is one mechanism through which tumor suppressor genes can be inactivated. These deletional events are believed to target tumor suppressor genes, but may include additional bystander genes. Once a deletion occurs in a tumor cell, it is present in that cell s progeny and hence, tumors derived from the same clone often share the same LOH. Abeln et al. 3 found concordant loss of heterozygosity in the carcinomatous and sarcomatous areas of 6 of 6 cases of carcinosarcoma. Jin et al. 7 found concordant loss of heterozygosity in at least 1 locus in 18 of 21 cases of uterine and ovarian carcinosarcoma. Fujii et al. 33 used loss of heterozygosity studies at 41 loci in 172 foci from 17 carcinomasarcomas to find shared allelic losses and retentions at multiple foci in each case and identical patterns of loss and retention at all sites tested in 8 cases, concluding that these cases were monoclonal. Most cases within these 3 published studies had concordant loss of heterozygosity, highly suggestive of monoclonality. The

6 555 Carcinosarcomas of the Uterus heterogeneous patterns of loss of heterozygosity seen in some cases could represent genetic progression or divergence, or biclonality. Because X chromosome inactivation is conserved during mitotic cell divisions, the same X chromosome is typically inactivated in all cells from a monoclonal process. The presence of identical X inactivation patterns in both components of the lesion could arise from a monoclonal process, but will also occur 50% of the time in a biclonal process. However, if the pattern of X inactivation is different, this provides strong evidence for a biclonal process. Wada et al. 2 studied 25 carcinosarcomas looking at X chromosome inactivation, along with K-ras and p53 sequence mutations. They found identical patterns of chromosome X inactivation in 19 cases, consistent with monoclonal derivation. Interestingly, 3 cases had different patterns of X chromosome inactivation, indicating that a minority of these lesions are likely biclonal. In all cases with p53 mutations, identical mutations were found in the sarcomatous and carcinomatous components, and in 5 of 6 cases with K-ras mutations, identical mutations were present. K-ras mutations occur frequently in carcinomas, but are rarely found in pure endometrial stromal sarcoma or leiomyosarcoma. 2 Although coincident X chromosome inactivation will occur by chance 50% of the time in biclonal neoplasms, identical K-ras and p53 mutations would be an extremely rare finding in a biclonal neoplasm, and provide strong support for a monoclonal origin. Similarly, Jin et al. 7 found the same pattern of X inactivation in 8 of 9 uterine and ovarian carcinosarcoma cases, and different X inactivation in 1 of 9. In cases with p53 mutations, 2 of 4 had identical mutations, and 1 each had p53 mutations in only the sarcoma or carcinoma component. No cases had different mutations in the different histologic areas. In summary, the presence of similar chromosomal aberrations, concordant loss of heterozygosity, identical p53 and K-ras mutations, and matching X inactivation patterns in both histologic components of most carcinomasarcoma cases studied support the conclusion that most of these lesions are monoclonal. Additionally, the specific patterns of genetic aberrations are more consistent with a high-grade carcinoma than a sarcoma, providing strong support for divergent differentiation within a primarily epithelial neoplasm (carcinoma) as the histogenesis. Wada et al., 2 Jin et al., 7 and Sreenan et al. 6 also found that a subset of carcinosarcomas (2 of 15, 1 of 9, and 3 of 21, respectively) was biclonal according to X chromosome inactivation studies in the first 2 studies and clinicopathologic criteria in the third, indicating that a subset is composed of 2 separate malignant clones giving rise to the sarcomatous and carcinomatous components in a true collision tumor. Interestingly, Seidman and Chauhan 34 examined 26 carcinosarcomas and recorded the presence of adenosarcoma-like components (malignant stroma admixed with benign-appearing epithelium) in 4 cases, suggesting that many of the true collision lesions may arise from malignant transformation of either benign epithelium within an adenosarcoma or adjacent benign epithelium. Additional studies are needed to further explore this intriguing hypothesis. The clinical implication of an individual patient s carcinosarcoma being monoclonal or biclonal is uncertain. Differences in response to chemotherapy are unknown. Overall, the carcinomatous component has been shown to have more aggressive behavior and be a better predictor of clinical outcome in carcinosarcomas; however, this has not been examined specifically within the subset of tumors that are biclonal. Conclusions Carcinosarcomas are a biphasic neoplasm composed of malignant epithelial and mesenchymal components, which usually seem to arise from transformation of pluripotent stem cell capable of giving rise to cells with divergent differentiation. They can arise anywhere in the female genital tract, most commonly from the endometrium, and tend to behave as aggressive carcinomas with similar prognosis and response to treatment. Recent data have advanced understanding of the biology of this lesion, and clinical trials are underway to determine the most efficacious chemotherapeutic regimens. References 1. Vaidya AP, Horowitz NS, Oliva E, et al. Uterine malignant mixed mullerian tumors should not be included in studies of endometrial carcinoma. Gynecol Oncol 2006;103: Wada H, Enomoto T, Fujita M, et al. Molecular evidence that most but not all carcinosarcomas of the uterus are combination tumors. Cancer Res 1997;57:

7 556 Kernochan and Garcia 3. Abeln EC, Smit VT, Wessels JW, et al. Molecular genetic evidence for the conversion hypothesis of the origin of malignant mixed mullerian tumours. J Pathol 1997;183: Bansal N, Herzog TJ, Seshan VE, et al. Uterine carcinosarcomas and grade 3 endometrioid cancers: evidence for distinct tumor behavior. Obstetrics and Gynecology 2008;112: Di Cristofano E, Ellenson LH. Endometrial carcinoma. Annu Rev Pathol Mech Dis 2007;2: 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: Jin Z, Ogata S, Tamura G, et al. Carcinosarcomas (malignant mullerian mixed tumors) of the uterus and ovary: a genetic study with special reference to histogenesis. Int J Gynecol Pathol 2003;22: Barnholtz-Sloan JS, Morris R, Malone JM Jr, Munkarah AR. 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Gynecol Oncol 1998;69: McCluggage WG. Uterine carcinosarcomas (malignant mixed Mullerian tumors) are metaplastic carcinomas. Int J Gynecol Cancer 2002;12: Curtis RE, Freedman DM, Sherman ME, Fraumeni JF Jr. Risk of malignant mixed mullerian tumors after tamoxifen therapy for breast cancer. J Natl Cancer Inst 2004;96: Cotran RS, Kumar V, Collins T, eds. Robbins Pathologic Basis of Disease. 6th ed. Philadelphia: W.B. Saunders Company; Crum CP, Lee KR, eds. Diagnostic Gynecologic and Obstetric Pathology. China: Elsevier Saunders; Bitterman P, Chun B, Kurman RJ. The significance of epithelial differentiation in mixed mesodermal tumors of the uterus. A clinicopathologic and immunohistochemical study. Am J Surg Pathol 1990;14: Chung MT, Mukai K, Teshima S, et al. Expression of various antigens by different components of uterine mixed mullerian tumors. An immunohistochemical study. Acta Pathol Jpn 1988;38: Dupont J, Wang X, Marshall DS, et al. 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8 557 Carcinosarcomas of the Uterus Carcinosarcoma of the Uterus To obtain credit, you should first read the journal article. After reading the article, you should be able to answer the following, related, multiple-choice questions. To complete the questions and earn continuing medical education (CME) credit, please go to Credit cannot be obtained for tests completed on paper, although you may use the worksheet below to keep a record of your answers. You must be a registered user on Medscape.com. If you are not registered on Medscape.com, please click on the New Users: Free Registration link on the left hand side of the website to register. Only one answer is correct for each question. Once you successfully answer all post-test questions you will be able to view and/or print your certificate. For questions regarding the content of this activity, 1. Which of the following statements about clinical features of Müllerian carcinosarcomas is most accurate? A. They may arise in the vagina or peritoneum B. Carcinosarcomas appear at a significantly younger age compared with endometrioid carcinomas C. Nulliparity reduces the risk for Müllerian carcinosarcomas D. The use of tamoxifen reduces the risk for Müllerian carcinosarcomas 2. Which of the following is the most likely site of metastases from uterine carcinosarcoma? A. Lymph nodes B. Lung C. Liver D. Bone contact the accredited provider, CME@medscape.net. For technical assistance, contact CME@webmd.net. American Medical Association s Physician s Recognition Award (AMA PRA) credits are accepted in the US as evidence of participation in CME activities. For further information on this award, please refer to html. The AMA has determined that physicians not licensed in the US who participate in this CME activity are eligible for AMA PRA Category 1 Credits. Through agreements that the AMA has made with agencies in some countries, AMA PRA credit is acceptable as evidence of participation in CME activities. If you are not licensed in the U.S. and want to obtain an AMA PRA CME credit, please complete the questions online, print the certificate and present it to your national medical association. 3. Which of the following factors is the most important prognostic indicator among women with uterine carcinosarcoma? A. Patient age B. Tumor stage C. Marked pleomorphism on histologic analysis D. Depth of myometrial invasion 4. All of the following statements about molecular data of uterine carcinosarcoma are accurate except: A. Genetic and molecular data support a monoclonal origin of carcinosarcomas B. Abnormalities of 8q are the most common genetic aberration of uterine carcinosarcomas C. C-myc amplification is very specific for carcinosarcomas D. Patterns of genetic aberrations of carcinosarcomas resemble those of high-grade carcinoma rather than sarcoma Activity Evaluation 1. The activity supported the learning objectives. Strongly Disagree Strongly Agree The material was organized clearly for learning to occur. Strongly Disagree Strongly Agree The content learned from this activity will impact my practice. Strongly Disagree Strongly Agree The activity was presented objectively and free of commercial bias. Strongly Disagree Strongly Agree To obtain credit, visit Medscape online at