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

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Original Article

Lauren E. Kernochan, MD, and Rochelle L. Garcia, MD, Seattle, Washington

Key Words the extent of their participation in the activity. All other clinicians Malignant mixed Müllerian tumor, carcinosarcoma, uterus 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; Abstract (3) take the post-test and/or complete the evaluation at www. Carcinosarcoma of the uterus (malignant mixed Müllerian tumor medscape.com/cme/jnccn; (4) view/print certificate. [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 Learning Objectives sarcomatous differentiation in a high-grade carcinoma. This article Upon completion of this activity, participants will be able to: reviews the clinical and histopathologic features of this interest- • Identify the clinical features of uterine carcinosarcoma ing neoplasm, with particular emphasis on recent data supporting • Specify the most common anatomic site of metastasis of MMMTs as primarily epithelial malignant neoplasms with areas of uterine carcinosarcoma mesenchymal/spindle cell differentiation. (JNCCN 2009;7:550–557) • Specify the most important prognostic factor for uterine carcinosarcoma • Describe the molecular data of uterine carcinosarcoma Medscape: Continuing Medical Education Online Medscape, LLC is pleased to provide online continuing medical education (CME) for this journal article, allowing clinicians the Carcinosarcoma of the uterus (malignant mixed Mülle- opportunity to earn CME credit. Medscape, LLC is accredited by rian tumor [MMMT]), is a biphasic neoplasm composed the Accreditation Council for Continuing Medical Education (AC- of malignant epithelial and mesenchymal components. CME) to provide CME for physicians. Medscape, LLC designates this These are uncommon neoplasms, with an incidence of educational activity for a maximum of 0.5 AMA PRA Category 1 fewer than 2 per 100,000 women per year. They have an Credits™. Physicians should only claim credit commensurate with

From the Department of Pathology, University of Washington School of AUTHORS AND CREDENTIALS Medicine, Seattle, Washington. Lauren E. Kernochan, MD, Department of Pathology, University of Submitted January 13, 2009; accepted for publication March 5, 2009. Washington School of Medicine, Seattle, Washington Correspondence: Rochelle L. Garcia, MD, Department of Pathology, Disclosure: Lauren E. Kernochan, MD, has disclosed no relevant financial University of Washington Medical School, Box 356100, 1959 N.E. Pacific, relationships. Seattle, WA 98195. E-mail: [email protected] Rochelle L. Garcia, MD, Department of Pathology, University of Washington School of Medicine, Seattle, Washington EDITOR Disclosure: Rochelle L. Garcia, MD, has disclosed no relevant financial Kerrin G. Robinson, MA, Medical/Scientific Editor, Journal of the relationships. National Comprehensive Cancer Network Disclosure: Kerrin G. Robinson, MA, has disclosed no relevant financial CME AUTHOR relationships. 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.

Carcinosarcomas of the Uterus extremely poor prognosis, with a 5-year survival rate of their respective organ systems. of 33% to 39%.1 Although relatively rare, carcino- This article reviews current understanding of sarcomas of the uterus, and of the gynecologic and the clinical and pathologic features of uterine car- urinary tracts in general, are more common than in cinosarcomas, emphasizing recent data supporting other sites, such as lung, possibly because the epithe- divergent differentiation of a primarily epithelial lial stem cells are mesodermal in origin.2,3 neoplasm (carcinoma) underlying the pathogenesis Clinicopathologic data support separation of of this interesting neoplasm. carcinomas arising in the endometrium into 2 types. The more common type of neoplasm, type 1, is typically associated with hyperestrogenism, obesity (due Clinical Features to aromatization of androgens into estrogen), and Müllerian carcinosarcomas most commonly arise in hyperlipidemia, have well or moderately differenti- the uterus, but may also arise in the ovaries, fallo- ated, typically endometrioid histology, and have a pian tubes, vagina, and peritoneum.8–10 As expected, good prognosis (approximately 85%–90% 5-year clinical presentation depends on disease distribu- survival rate). They are frequently associated with tion. Uterine carcinosarcomas typically present with PTEN mutations. Type 2 endometrial carcinomas, abnormal vaginal bleeding and may present with which represent 10% to 15% of endometrial carci- bloody discharge, watery discharge, abdominal pain, nomas, are typically seen in women without these or an abdominal mass.11 Through imaging, uterine clinical features. They typically have poorly differen- carcinosarcoma typically appears as a mass within tiated endometrioid or serous histology and a worse the uterine cavity, with accompanying dilation of prognosis (55%–60% 5-year survival rate) and are the cavity and myometrial invasion, most often in- more often associated with p53 mutations.4,5 Car- volving the fundus.12 cinosarcomas are part of the type 2 group, with an Although some smaller studies have found no epithelial component that most often resembles high difference in age at presentation,13 a recent analysis grade endometrioid, serous or clear cell carcinoma. of the Surveillance Epidemiology and End Results Previous debates about the derivation of this (SEER) data, which included over 5024 women with neoplasm have centered on whether carcinosarco- grade 3 endometrioid and 3962 with uterine carci- ma is a biclonal or monoclonal process. In the “col- nosarcoma, found that women with carcinosarcoma lision tumor” theory, synchronous sarcoma and car- were slightly older (70 vs. 66 years; P < .001), more cinoma arise from separate stem cells and merge in often non-white (23% vs. 15%; P < .001), and pre- a biclonal process. In the “combination” and “con- sented with more advanced disease4 (41% vs. 31% version” tumor theories, a single common stem cell had stage III/IV; P < .001). Additionally, analysis of precursor gives rise to a monoclonal neoplasm with 453 women, 29 of whom had carcinosarcoma, found divergent or metaplastic differentiation.3,6,7 Molecu- carcinosarcomas are generally diagnosed at a higher lar studies indicate that most neoplasms diagnosed stage, with 27% of MMMTs presenting at stage III or as carcinosarcoma of the uterus are monoclonal, IV, and only 9% of uterine carcinomas presenting at suggesting that although a minority may be true col- stage III or IV (P = .004).13 lision tumors/separate neoplasms, most represent a Carcinosarcomas and carcinomas of the uterus single neoplastic process. Based on molecular, epi- have similar risk factor profiles. Their incidence is demiologic, genetic, and histologic data, most au- increased in association with increased exposure to thors now believe that most carcinosarcomas are es- estrogen through marked obesity, nulliparity, or use sentially high-grade carcinomas with sarcomatous/ of exogenous estrogen, and with pelvic radiation,13 stromal differentiation, similar to what is seen in whereas the incidence is decreased in association other organ systems (e.g., metaplastic carcinoma of with oral contraceptive use.14 Tamoxifen, which has the breast, sarcomatoid renal cell carcinoma, spin- been shown to be beneficial in women with estrogen dle cell carcinoma of the larynx). Therefore, it may receptor–positive breast cancer, has weak estrogenic be more appropriate to refer to this lesion as sarco- effects and confers an increased risk for endometrial matoid carcinoma of the uterus and perhaps to refer carcinoma, particularly type 2 carcinomas, includ- to all of these neoplasms as sarcomatoid carcinomas ing carcinosarcoma.

Kernochan and Garcia

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

A 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.

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 component2,18 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, myo- globin expression in rhabdomyoblasts, and S-100 expression in areas with chondroid and lipoma- tous differentiation. Carcinosarcomas often express WT-1 and p53 (up to 70% and 82%, respectively) in the carcinomatous and sarcomatous components, Figure 2 Carcinomatous cells of malignant Müllerian mixed similar to high-grade carcinomas.20,21 Schipf et al.22 tumor with glandular differentiation in the epithelial component; note numerous mitotic figures in the stromal component. found that the cellular proliferation index based on Ki-67 immunostaining was moderate to strong in Sarcomatoid metastases have been seen more fre- 25 of 25 cases, with significantly higher P( < .001) quently in anatomic sites with hollow spaces that proliferation index in carcinomatous rather than allow polypoid growth, such as the peritoneal cav- sarcomatous areas (mean of 70% and 28% of cells ity and vagina, and in late metastases, particularly positive, respectively). after administration of chemotherapeutic agents active against the carcinomatous component.24 Initial Anatomic and Histologic Pattern studies suggested heterologous elements within the of Metastasis sarcomatoid portion portended a worse prognosis; however, subsequent studies have not supported a The distribution of metastatic disease seen in carci- prognostic significance for any histologic features of nosarcoma is more similar to aggressive carcinomas 23 than sarcomas. Carcinomas generally spread through the sarcomatous component. These findings suggest lymphatic channels to nearby lymph nodes or re- that, although sarcomatoid differentiation may be a cur locally. Conversely, uterine sarcomas, including marker of more aggressive behavior and of regression leiomyosarcoma and endometrial stromal sarcoma, to a more primitive stem cell–like phenotype with more often metastasize to the peritoneal cavity or the ability to give rise to epithelial or stromal pro- hematogenously to the lungs, and rarely metastasize genitor cells, it is usually the epithelial component to lymph nodes. Bitterman et al.18 studied 22 cases of driving metastasis. uterine carcinosarcoma and found the spread of metastasis was predominantly to lymph nodes, ovaries, Prognosis and Treatment fallopian tubes, and omentum, with occasional in- volvement of parametrium, bowel, liver, and tonsil. Prognosis for a given disease site is generally worse No lung metastases were seen, and all metastatic foci than for high-grade carcinoma of the correspond- were composed of carcinoma only. ing site. Women with uterine carcinosarcomas have In both carcinosarcomas and carcinomas, the poorer outcomes than those with endometrial carci- traditionally higher-grade histologic patterns of en- noma, particularly type 1 carcinomas, with 18- and dometrial carcinoma, serous, and clear cell, are asso- 36-month median survival times for all patients, ciated with greater likelihood of metastasis at origi- respectively. Stage is the most significant prognos- nal resection when adjusted for stage.18,23 Histologic tic indicator, although age and depth of myometrial appearance of neoplastic nests in lymphovascular invasion (independent of stage) are also significant spaces and metastases more often mimics the epi- on univariate analysis.25 More women with carcino- thelial component of the neoplasm (Figure 3).6,18,24 sarcoma present with advanced stage disease (53%),

Kernochan and Garcia

span the entire genome at frequent intervals, iden- tifying 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 carci- nosarcomas22,31 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), Figure 3 Epithelioid morphology of malignant müllerian found to be amplified in 18 of 23 uterine and ovarian mixed tumor metastatic to a lymph node. carcinosarcomas through fluorescence in situ hybrid- ization22 and overexpressed in 9 of 9 uterine carcino- similar to rates of advanced presentation seen in sarcomas through immunohistochemistry.32 C-myc clear cell and serous (type 2) carcinoma of the en- amplification is often present in carcinomas but was 1 dometrium, and in contrast to women with type 1 also present in 6 of 12 uterine leiomyomas and 11 of endometrial carcinoma who generally present with 23 uterine leiomyosarcomas.32 disease confined to the uterus. In addition, metasta- Maternally versus paternally inherited alleles sis is often present in patients with no documented in an individual’s DNA can be distinguished from myometrial invasion. Standard treatment for carci- each other using highly polymorphic sequences, nosarcoma of the uterus is surgical, including hys- such as microsatellites. At informative loci, differ- terectomy, bilateral salpingo-oophorectomy, lymph ent sequences are present in the maternal and pater- node dissection, and resection of all gross disease, nal alleles. Loss of heterozygosity (LOH) in tumor with adjuvant radiation for locoregional control, DNA, detected through loss of either the maternal and chemotherapy depending on stage.26 Similar or paternal allele at a given locus, is one mechanism to carcinomas, carcinosarcomas often respond to through which tumor suppressor genes can be inacti- platinum-based chemotherapy. Additionally, agents vated. These deletional events are believed to target with activity against sarcomas, including DNA- tumor suppressor genes, but may include additional alkylating agents such as ifosfamide, are helpful in bystander genes. Once a deletion occurs in a tumor combination with agents active against carcinomas. cell, it is present in that cell’s progeny and hence, Although the rarity of this diagnosis has precluded tumors derived from the same clone often share the large trials of chemotherapy regimens for carcinosar- same LOH. Abeln et al.3 found concordant loss of coma of any site, most trials have found a survival heterozygosity in the carcinomatous and sarcoma- benefit from treating with adjuvant platinum-based tous areas of 6 of 6 cases of carcinosarcoma. Jin et al.7 therapy together with taxane, a mitotic inhibitor, found concordant loss of heterozygosity in at least 1 or ifosfamide.27–30 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 Molecular Data to find shared allelic losses and retentions at multiple Genetic and molecular data provides compelling ev- foci in each case and identical patterns of loss and idence supporting a monoclonal origin of most car- retention at all sites tested in 8 cases, concluding cinosarcomas. In array comparative genomic hybrid- that these cases were monoclonal. Most cases within ization array studies, DNA from the neoplasm and these 3 published studies had concordant loss of het- normal cells is co-hybridized to labeled probes that erozygosity, highly suggestive of monoclonality. The

Carcinosarcomas of the Uterus heterogeneous patterns of loss of heterozygosity seen Wada et al.,2 Jin et al.,7 and Sreenan et al.6 also in some cases could represent genetic progression or found that a subset of carcinosarcomas (2 of 15, 1 divergence, or biclonality. of 9, and 3 of 21, respectively) was biclonal accord- Because X chromosome inactivation is con- ing to X chromosome inactivation studies in the served during mitotic cell divisions, the same X first 2 studies and clinicopathologic criteria in the chromosome is typically inactivated in all cells from third, indicating that a subset is composed of 2 sepa- a monoclonal process. The presence of identical X rate malignant clones giving rise to the sarcomatous inactivation patterns in both components of the le- and carcinomatous components in a true collision sion could arise from a monoclonal process, but will tumor. Interestingly, Seidman and Chauhan34 ex- also occur 50% of the time in a biclonal process. amined 26 carcinosarcomas and recorded the pres- However, if the pattern of X inactivation is different, ence of adenosarcoma-like components (malignant this provides strong evidence for a biclonal process. stroma admixed with benign-appearing epithelium) Wada et al.2 studied 25 carcinosarcomas looking at X in 4 cases, suggesting that many of the true collision chromosome inactivation, along with K-ras and p53 lesions may arise from malignant transformation of sequence mutations. They found identical patterns either benign epithelium within an adenosarcoma or of chromosome X inactivation in 19 cases, consis- adjacent benign epithelium. Additional studies are tent with monoclonal derivation. Interestingly, 3 needed to further explore this intriguing hypothesis. cases had different patterns of X chromosome inacti- The clinical implication of an individual pa- vation, indicating that a minority of these lesions are tient’s carcinosarcoma being monoclonal or biclonal likely biclonal. In all cases with p53 mutations, iden- is uncertain. Differences in response to chemother- tical mutations were found in the sarcomatous and apy are unknown. Overall, the carcinomatous com- carcinomatous components, and in 5 of 6 cases with ponent has been shown to have more aggressive be- K-ras mutations, identical mutations were present. havior and be a better predictor of clinical outcome K-ras mutations occur frequently in carcinomas, but in carcinosarcomas; however, this has not been ex- are rarely found in pure endometrial stromal sarcoma amined specifically within the subset of tumors that or leiomyosarcoma.2 Although coincident X chro- are biclonal. mosome 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 Conclusions a biclonal neoplasm, and provide strong support for Carcinosarcomas are a biphasic neoplasm composed a monoclonal origin. Similarly, Jin et al.7 found the of malignant epithelial and mesenchymal compo- same pattern of X inactivation in 8 of 9 uterine and nents, which usually seem to arise from transforma- ovarian carcinosarcoma cases, and different X inac- tion of pluripotent stem cell capable of giving rise to tivation in 1 of 9. In cases with p53 mutations, 2 of cells with divergent differentiation. They can arise 4 had identical mutations, and 1 each had p53 muta- anywhere in the female genital tract, most com- tions in only the sarcoma or carcinoma component. monly from the endometrium, and tend to behave No cases had different mutations in the different as aggressive carcinomas with similar prognosis and histologic areas. response to treatment. Recent data have advanced In summary, the presence of similar chromo- understanding of the biology of this lesion, and clini- somal aberrations, concordant loss of heterozygosity, cal trials are underway to determine the most effica- identical p53 and K-ras mutations, and matching X cious chemotherapeutic regimens. inactivation patterns in both histologic components of most carcinomasarcoma cases studied support the conclusion that most of these lesions are monoclo- References nal. Additionally, the specific patterns of genetic 1. Vaidya AP, Horowitz NS, Oliva E, et al. Uterine malignant mixed aberrations are more consistent with a high-grade mullerian tumors should not be included in studies of endometrial carcinoma than a sarcoma, providing strong support carcinoma. Gynecol Oncol 2006;103:684–687. 2. Wada H, Enomoto T, Fujita M, et al. Molecular evidence that most for divergent differentiation within a primarily epi- but not all carcinosarcomas of the uterus are combination tumors. thelial neoplasm (carcinoma) as the histogenesis. Cancer Res 1997;57:5379–5385.

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3. Abeln EC, Smit VT, Wessels JW, et al. Molecular genetic evidence tumors. An immunohistochemical study. Acta Pathol Jpn for the conversion hypothesis of the origin of malignant mixed 1988;38:35–45. mullerian tumours. J Pathol 1997;183:424–431. 20. Dupont J, Wang X, Marshall DS, et al. Wilms Tumor Gene (WT1) 4. Bansal N, Herzog TJ, Seshan VE, et al. Uterine carcinosarcomas and p53 expression in endometrial carcinomas: a study of 130 cases and grade 3 endometrioid cancers: evidence for distinct tumor using a tissue microarray. Gynecol Oncol 2004;94:449–455. behavior. Obstetrics and Gynecology 2008;112:64–70. 21. Kounelis S, Jones MW, Papadaki H, et al. Carcinosarcomas 5. Di Cristofano E, Ellenson LH. Endometrial carcinoma. Annu Rev (malignant mixed mullerian tumors) of the female genital tract: Pathol Mech Dis 2007;2:57–85. comparative molecular analysis of epithelial and mesenchymal 6. Sreenan JJ, Hart WR. Carcinosarcomas of the female genital tract. components. 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Carcinosarcomas of the Uterus

Carcinosarcoma of the Uterus contact the accredited provider, [email protected]. To obtain credit, you should first read the journal ar- For technical assistance, contact [email protected]. ticle. After reading the article, you should be able to American Medical Association’s Physician’s Rec- answer the following, related, multiple-choice ques- ognition Award (AMA PRA) credits are accepted in tions. To complete the questions and earn continuing the US as evidence of participation in CME activities. medical education (CME) credit, please go to http:// For further information on this award, please refer to www.medscape.com/cme/jnccn. http://www.ama-assn.org/ama/pub/category/2922. Credit cannot be obtained for tests completed on html. The AMA has determined that physicians not paper, although you may use the worksheet below to licensed in the US who participate in this CME activ- keep a record of your answers. You must be a registered ity are eligible for AMA PRA Category 1 Credits™. user on Medscape.com. If you are not registered on Through agreements that the AMA has made with Medscape.com, please click on the New Users: Free Registration link on the left hand side of the website agencies in some countries, AMA PRA credit is ac- to register. ceptable as evidence of participation in CME activi- Only one answer is correct for each question. ties. If you are not licensed in the U.S. and want to Once you successfully answer all post-test questions obtain an AMA PRA CME credit, please complete you will be able to view and/or print your certificate. the questions online, print the certificate and present For questions regarding the content of this activity, it to your national medical association.

1. Which of the following statements about clinical fea- 3. Which of the following factors is the most important tures of Müllerian carcinosarcomas is most accurate? prognostic indicator among women with uterine car- A. They may arise in the vagina or peritoneum cinosarcoma? B. Carcinosarcomas appear at a significantly A. Patient age younger age compared with endometrioid B. Tumor stage carcinomas C. Marked pleomorphism on histologic analysis C. Nulliparity reduces the risk for Müllerian D. Depth of myometrial invasion carcinosarcomas D. The use of tamoxifen reduces the risk for 4. All of the following statements about molecular data Müllerian carcinosarcomas of uterine carcinosarcoma are accurate except: A. Genetic and molecular data support a 2. Which of the following is the most likely site of me- monoclonal origin of carcinosarcomas tastases from uterine carcinosarcoma? B. Abnormalities of 8q are the most common A. Lymph nodes genetic aberration of uterine carcinosarcomas B. Lung C. C-myc amplification is very specific for C. Liver carcinosarcomas D. Bone D. Patterns of genetic aberrations of carcinosarcomas resemble those of high-grade carcinoma rather than sarcoma

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