Best Practice & Research Clinical Obstetrics and Gynaecology 25 (2011) 733749

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Best Practice & Research Clinical Obstetrics and Gynaecology

journal homepage: www.elsevier.com/locate/bpobgyn

Staging of uterine sarcomas

Ka Yu Tse, MBBS, MRCOG, Dr a, b, *, Robin Crawford, MD, FRCOG, Dr b, Hextan Y.S. Ngan, MD, FRCOG, Professor a
a b

6/F, Professorial Block, Department of Obstetrics and Gynaecology, Queen Mary Hospital, The University of Hong Kong, Hong Kong Department of Gynaecology, Cambridge University Hospitals NHS Foundation Trust, Addenbrookes Hospital, Cambridge, UK

Keywords: leiomyosarcoma endometrial stromal sarcoma undifferentiated endometrial sarcoma adenosarcoma carcinosarcoma staging

Uterine sarcomas comprise leiomyosarcoma, endometrial stromal sarcoma, adenosarcoma, undifferentiated endometrial sarcoma, and their variants. Carcinosarcoma is historically classied as sarcoma, but it is now regarded as a metaplastic carcinoma. Uterine sarcomas are rare, and are traditionally staged in the same way as endometrial carcinoma. Because of their different clinical and biological behaviours, the International Federation of Gynecology and Obstetrics introduced a new staging system in 2009 for leiomyosarcoma, endometrial stromal sarcoma and adenosarcoma, and carcinosarcoma, respectively. Following an extensive literature review no good evidence was found to support the modication of the staging system. This is mainly because of the rarity of the sarcomas and the heterogeneity of the reports, the different diagnostic criteria and treatments changing over the decades the retrospective nature and small sample size in most studies, and the lack of uniform pathological review even in large studies. Currently, evidence is still lacking about the use of preoperative imaging for staging purpose, and uterine sarcomas remain to be surgically staged. Total hysterectomy is the cornerstone for both staging and treatment. Newer evidence shows that routine lymphadenectomy and bilateral salpingo-oophorectomy may not be necessary, unless in the presence of extra-uterine spread, suspicious ovaries or lymph nodes, and certain poor histological types, such as undifferentiated endometrial sarcoma and adenosarcoma with sarcomatous overgrowth. More research and data collection are denitely needed in order to verify and further revise the current staging systems. 2011 Elsevier Ltd. All rights reserved.

* Corresponding author. Department of Obstetrics and Gynaecology, Queen Mary Hospital, The University of Hong Kong, Hong Kong. Tel: 852 22554265; Fax: 852 28550947. E-mail address: tseky@hkucc.hku.hk (K.Y. Tse). 1521-6934/$ see front matter 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.bpobgyn.2011.05.011

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Introduction Uterine sarcomas are rare, accounting for 38% of all uterine malignancies.1,2 They consist of a heterogeneous group of tumours, mainly leiomyosarcoma (LMS), endometrial stromal sarcoma (ESS), adenosarcoma, undifferentiated endometrial sarcoma (UES), and their variants. Uterine carcinosarcoma, also known as malignant mixed Mllerian tumour, is now regarded as a variant of endometrial carcinoma rather than a pure sarcoma, The sarcomatous component is the result of the metaplastic or de-differentiated change of the epithelial component.3,4 It is important to have a reliable and objective staging system to stratify women into different groups so that their prognosis can be predicted and treatment planned accordingly. A universally agreed staging system also allows different centres to compare their treatment outcomes. Such a system is developed on the basis of different clinical prognostic factors that are measurable, reproducible and easily available. In the 1988 staging system of the International Federation of Gynecology and Obstetrics (FIGO), uterine sarcomas were staged under the same system of endometrial carcinoma (Table 1).5 This received much criticism because uterine sarcoma and endometrial carcinoma are separate disease entities with different clinical and biological behaviours. In 2009, the FIGO committee introduced a new staging system for uterine sarcomas with specication to LMS, ESS and adenosarcoma, and carcinosarcoma, respectively (Table 2).6 Surgical staging is still the mode of assessment. Imaging is not incorporated into the staging procedure because it may not be available in developing countries, and the interpretation of the image results can be subjective. More importantly, at least half of the sarcomas are diagnosed as benign leiomyomas preoperatively,7,8 and there is no strong evidence to suggest that imaging modalities can accurately detect uterine sarcomas and metastasis.9 In a recent retrospective study of 92 women with sarcoma, only 9% had a change in surgical or post-surgical treatment as a result of their imaging studies.10 Many studies on uterine sarcomas are small because of the rarity of the tumours. It is also not clearly documented how the new FIGO system was derived. For this chapter, we conducted a search on Pubmed, and reviewed references of relevant articles and the evidence behind the modication of the staging system, with an emphasis on LMS and ESS. Information on adenosarcoma, however, is lacking and carcinosarcoma is regarded as a variant of endometrial carcinoma. Leiomyosarcoma Leiomyosarcoma accounts for 22.5 to 44% of all uterine sarcomas, and is the most common type of uterine sarcoma after carcinosarcoma.3,7,11,12 It is an aggressive tumour, with a 5-year survival rate from 18.8 to 68%.1325 Although many studies show that stage is a strong and independent prognostic factor in LMS,1517,20,2432 the 5-year survival rate varies widely (4085%) and recurrence rate is 3850%, even for stage III disease.12,14,19,24,27,3033 The wide range of reported survival rates and high recurrence
Table 1 1988 International Federation of Gynecology and Obstetrics staging system for carcinoma of corpus. Stage* I Ia Ib Ic II IIa IIb III IIIa IIIb IIIc IV IVa IVb Tumour conned to the corpus Tumour limited to the endometrium Invasion to less than half of the myometrium Invasion equal to or more than half of the myometrium Tumour involving cervix Endocervical glandular involvement only Cervical stromal invasion Tumour limited to the pelvis Tumour invades the serosa of the corpus uteri, adnexae, or both, and/or positive cytological ndings Vaginal metastases Metastases to pelvic, para-aortic lymph nodes, or both Tumour invades local structures or metastases in distant sites Tumour invasion of bladder, bowel mucosa, or both Distant metastases, including intra-abdominal metastasis, inguinal lymph nodes, or both

*Each stage is subdivided in grade 1, 2 and 3 based on tumour grade.

K.Y. Tse et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 25 (2011) 733749 Table 2 2009 International Federation of Gynecology and Obstetrics staging system for uterine sarcomas. Leiomyosarcoma and endometrial stromal sarcoma* Stage I Tumour limited to uterus Ia Less than 5 cm Ib Over 5 cm II Tumour extends to the pelvis IIa Adnexal involvement IIb Tumour extends to extrauterine pelvis tissue III Tumour invades abdominal tissues (not just protruding into the abdomen) IIIa One site IIIb More than one site IIIc Metastases to pelvic, para-aortic lymph nodes, or both IV IVa Tumour invades bladder, rectum, or both IVb Distant metastases Adenosarcomas Stage I Tumour limited to uterus Ia Tumour limited to endometrium or endocervix with no myometrial invasion Ib Less than or equal to half myometrial invasion 1c More than half myometrial invasion II Tumour extends to the pelvis IIa Adnexal involvement IIb Tumour extends to extrauterine pelvis tissue III Tumour invades abdominal tissues (not just protruding into the abdomen) IIIa One site IIIb More than one site IIIc Metastases to pelvic, para-aortic lymph nodes, or both IV IVa Tumour invades bladder, rectum, or both IVb Distant metastases Carcinosarcoma Carcinosarcoma should be staged as carcinomas of the endometrium. *Simultaneous tumours of the uterine corpus and ovary or pelvis in association with ovarian or pelvic endometriosis should be classied as independent primary tumours.

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rates of early staged disease are most likely a result of small sample sizes as well as the different diagnostic and inclusion criteria used in most studies. This also implies that the staging system is not ideal in categorising individuals into different prognostic groups. Before the development of the new staging system, most centres modied the 1988 FIGO staging system for LMS; stage I included tumour conned to the uterus; stage II included tumours involving the cervix; stage III included invasion of uterine serosa, positive peritoneal cytology, spread to pelvic organs and lymph nodes; and stage IV meant distant metastasis. Other soft-tissue sarcomas, however, are staged by the system developed by the American Joint Committee on Cancer (AJCC), which incorporates size and grade of tumours (Table 3). The AJCC system regards all retroperitoneal and pelvic sarcomas as deep tumours. Hence, uterine LMS does not have T1a and T2a, and stages II and III differ by the size of the tumours only (5 cm v >5 cm). Two recent studies compared the predictive values of the modied FIGO and AJCC staging systems in uterine LMS, and both studies showed that neither of these two systems could classify women into four clinically meaningful subsets.34,35 For instance, in a study by Raut et al.,34 involving 230 women, a signicant difference was reported in progression-free survival only between women diagnosed with FIGO stage I and stage III (adjusted P 0.0029 where adjusted P value <0.017 was signicant) or stage IV uterine LMS (adjusted P < 0.0001) but not between other stages.34 Similarly, signicant difference in overall survival was only observed between FIGO stages I and IV (adjusted P < 0.0001), with no difference between other stages. Substantial changes have been made in the FIGO staging system for LMS. Not all, however, are evidence-based.

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Table 3 American Joint Committee on Cancer staging system Stage I II III IV TNM* T1a/b T2a/b T1a/b T2a T2b Any T N0 N0 N0 N1 N0 M0 M0 M0 M0 M1 Grade G1 G2-3 G23 Any G

*T1, less than 5 cm; T2, over 5 cm; a, supercial tumour; b, deep tumour; N0/1, lymph-node metastasis absent/present; M0/1, distant metastasis absent/present; G1/2/3, low/intermediate/high grade.

Stage I Leiomyosarcoma arises from the smooth muscle of the uterus and so stage 1a in the 1988 FIGO staging system literally does not exist. Some investigators have attempted to determine the association of the depth of myometrial invasion with survival in LMS.8,17,30,36 In a small study by Bodner et al.,17 involving 21 women with LMS, univariate analysis showed that deep myometrial invasion was associated with poor overall survival (P 0.006).17 In another study, Hsieh et al.30 found no signicant difference in 5-year, disease-free survival between women with and without myometrial invasion (37% v 88%; P 0.129). Mostly, however, the assessment of myometrial invasion is considered to be difcult and may not carry any clinical relevance, especially in big tumours. Instead of sub-staging stage I tumours according to the myometrial invasion, the current FIGO staging system divides it into stage Ia and stage Ib on the basis of tumour size, using 5 cm as the cut-off. Nevertheless, little evidence supports this. First, only 1023% of the tumours are 5 cm or less,15,22,32,34 and the median size is 79 cm.20,24,29,30 Second, only a few studies suggested that tumour size was important. Nordal et al.25 reviewed 70 women with LMS, of whom 10% had tumours 5 cm or less. They found that 5-year survival reduced from 86% to 42% when the tumour increased from 5 cm to 10 cm (relative hazard [RH] 1.51, 95% CI 1.08 to 2.11; P 0.016).25 Giuntoli et al.29 examined 208 women with LMS whose median tumour size was 9 cm. They showed that tumour size had signicant prognostic value in disease-specic survival in the univariate analysis, where the median survival was over 30 years for 33 individual with tumours 5 cm or less, and reduced to 3.5 years for another 128 individuals with tumours greater than 5 cm (P 0.007). Tumour size was not evaluated in the multivariate analysis owing to the lack of reporting in some cases. In a Norwegian study32 involving 259 women with LMS and its variants, tumour size of over 10 cm was an independent prognostic factor in 5-year crude survival (RH 2.7; P < 0.001). Wu et al.20 also found in 51 women, that tumour size using 11 cm as cut-off correlated with 5-year overall survival (RR 11.63, 95% CI 2.14 to 63.12; P 0.004) and relapse-free survival (RR 5.69, 95% CI 1.68 to 19.25; P 0.005).20 Two other studies also showed that tumour size was a signicant prognostic indicator for survival, but they mixed all sarcomas in the analysis, so the result must be interpreted with caution.7,22 Contrary evidence has been presented in a number of studies. Pelmus et al.24 studied 72 women with LMS stage III, and found that tumour size using 7 cm as cut-off was not a prognostic factor in 5year overall survival. In the AJCC staging system, which takes tumour size into account, Raut et al.34 showed no difference in progression-free survival and overall survival between stage II (5 cm) and stage III (>5 cm) (P 0.4162 and P 0.5867, respectively). Zivanovic et al.35 also found an overlap in the survival outcomes between the AJCC stages II and III, where the 5-year progression-free survival rate was 24% and 16%, and the 5-year overall survival rate was 45% and 48% in stages II and III, respectively. In the United States and Canadian Academy of Pathology annual meeting in 2010, Soslow et al. presented 123 women with stage I LMS. They found that only 23 people had tumours 5 cm or less. The overall survival for people with tumours 5 cm or less was 77 months (95% CI 0 to 169.2 months), compared with 73.9 months (95% CI 55.9 to 91.9 months) for larger tumours (P 0.3). The investigators challenged that their data did not support the sub-staging of stage I for LMS in the 2009 FIGO system.

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Stage II The new FIGO staging system does not take cervical involvement into consideration as does the AJCC system. Some investigators have considered the invasion of the cervix might in fact be the extension of myometrium instead of genuine invasion as in endometrial carcinoma.35 Also, the incidence of cervical involvement is only 014%,7,13,1517,1921,24,25,27,2931,3437 and the reported 5-year survival rate ranges from 25100%.8,14,3032,35 In a recent report from the Surveillance, Epidemiology and End Results (SEER) database,31 which included 1396 people with LMS, only 3.1% had cervical involvement. In addition, Raut et al.34 showed no difference in progression-free survival and overall survival in stage II from those in stage I or III. Zivanovic et al.35 also reported a prognostic overlap between FIGO stages II and III, where the 5-year progression-free survival rate was 8% in both stages, and the 5-year overall survival rate in stage II was even worse than in stage III (29% and 35%, respectively). The FIGO revised staging system downstages adnexal spread from stage IIIa to IIa. In general, women in the previous stage III category have a poor prognosis, with 5-year survival rate ranging from 044.9%.8,14,30,31,34 The incidence of adnexal metastasis, however, is only about 3.5%.35,37,38 The survival outcomes of pure adnexal metastasis alone are not clearly known. In the Gynecologic Oncology Group study published in 1993,37 multivariate analysis showed that adnexal spread was not a signicant prognostic factor related to progression-free interval. Similarly, few data could be found on extrauterine pelvic spread. Raut et al.34 reported that the incidence of uterine serosal and vaginal invasion was 19.1% and 0.4%, respectively, and serosal involvement accounted for 94.6% of all women with stage III disease in their study. Because no signicant difference was found in progression-free survival and overall survival between stages III and IV (adjusted P 0.5153 and adjusted P 0.0346), they suggested that women with serosal involvement had similar prognosis as individuals with stage IV diseases. On the basis of these limited data, it is difcult to draw conclusions about whether it is appropriate to place ovarian and extra-uterine spread in stage II; further studies are needed. Stage III As in carcinoma of corpus, the FIGO committee also removed peritoneal cytology from the staging system for sarcoma. Benito et al.7 studied 89 women with uterine sarcoma. Among the 20 women with LMS, only 5% had positive peritoneal cytology, 30% had negative cytology, and 65% did not have any record at all. Similarly, Leitao et al.38 found that, out of 41 women of whom peritoneal washing was taken (4.9%), only two women had positive peritoneal cytology. When studying all the sarcomas as a group, peritoneal cytology had no effect in overall survival in the multivariate analysis. Major et al.37 in their Gynecologic Oncology Group study, showed that positive peritoneal cytology was signicantly related to progression-free survival in carcinosarcoma but not LMS. We could not locate any information about the incidence of metastasis to abdominal tissues (excluding lymph node and distant metastasis), as transcoelomic spread is not a main route of metastasis in LMS. Similarly, the importance of the number of abdominal spread, as in stages IIIa and IIIb in the revised staging system, is also not known. Retroperitoneal lymph-node metastasis remains to be staged as IIIc. The reported incidence of lymph-node metastasis varies from 028%.20,27,2931,34,3740 Many studies are limited by the small number of women receiving lymphadenectomy, and most of them do not dene the extent of lymphadenectomy. In the largest study from the SEER database, which involved 348 women undergoing lymphadenectomy, lymph-node metastasis was identied in 23 women (6.6%).31 Those who had negative lymph nodes had a better 5-year, disease-specic survival rate than those with positive lymph nodes (64.2% v 26.0%; P < 0.001). Also, women with one positive lymph node had better prognosis than those with more than two positive lymph nodes (42.4% v 0%; P 0.001). More studies are needed to ascertain whether the number of positive lymph nodes is important. Stage IV Stage IV includes bladder, rectum and all distant metastasis as in other cancer types. In general, women with stage IV disease have poor prognosis, with a 5-year survival rate of 028.7%.8,14,3032,35

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Staging procedure Leiomyosarcoma is surgically staged, and so the primary procedure should have staging and ideally curative effects. The gold standard is total hysterectomy and removal of as much tumour as possible,3,4143 and this has been proven to have survival benet.31 Although several case reports on myomectomy have been published20,27,29,44,46 on subtotal hysterectomy24,29 and trachelectomy,29 these are still not regarded as a standard procedure, and failure has been reported in women receiving myomectomy alone.45,46 In the past, bilateral salpingo-oophorectomy was frequently carried out. Recent evidence, however, shows that routine bilateral salpingo-oophorectomy and lymphadenectomy are not necessary. Bilateral salpingo-oophorectomy As mentioned previously, adnexal spread is uncommon. Leitao et al.38 found that the incidence of ovarian metastasis was similar between clinically stage III and stage IIIIV diseases (2.8% v 5.4%). They also reported that the presence of lymphovascular invasion, tumour grade, serosal and cervical involvement could not predict ovarian metastasis. This implies that no clinical predictor can guide clinicians on whether to perform bilateral salpingo-oophorectomy. Nevertheless, Nordal et al.25 showed that no micrometastasis could be found in macroscopically normal ovaries. Bilateral salpingo-oophorectomy in primary procedure may not have any therapeutic effect. Only one case report has been published of regression of pulmonary recurrence in two women with lowgrade LMS after bilateral salpingo-oophorectomy.47 On the other hand, a retrospective study by Giuntoli et al.29 showed that bilateral salpingo-oophorectomy at primary surgery seemed to have an adverse effect on disease-specic survival (RR 3.25; P 0.006). The investigators carried out a further case-control analysis, which included 25 pre-menopausal women with ovarian preservation and 25 control women with bilateral salpingo-oophorectomy matched bu stage, grade and age. No difference in disease-specic survival (median survival greater than 30 years in both arms; P 0.489) and recurrence-free survival (14.3 years without bilateral salpingo-oophorectomy v greater than 25 years with BSO; P 0.970) was found. In addition, Kapp et al.31 showed no difference in 5-year diseasespecic survival in women who did not undergo oophorectomy compared with those who did (72.3% v 66.2%; P 0.15). Among women younger than 50 years with stage III disease, the 5-year disease-specic survival was also similar between those who had and who had not undergone oophorectomy (83.2% v 83.2%; P 0.445). Gadducci et al.27 showed that, among women diagnosed as stage I who were younger than 50 years, and who had undergone total hysterectomy, disease recurred in seven out of 21 women (33.3%) with bilateral salpingo-oophoectomy compared with ve out of 21 women (23.8%) who retained one or two ovaries (P > 0.05). Although no clear predictor for ovarian metastasis exists, ovarian preservation can be considered in premenopausal women because the incidence of ovarian metastasis is low and the premature menopause carries no strong therapeutic benet. Lymph-node evaluation Lymph-node metastasis is also rare, and some investigators have suggested lymph-node sampling only in selected cases. Most studies have not specied the extent of lymphadenectomy or lymph-node sampling, and the numbers of lymph nodes taken in different centres vary. Giuntoli et al.29 reported four women with lymph-node metastases out of 36 women (11%) who had lymph-node evaluation. Among these four women, one had no extra-uterine disease or enlarged lymph nodes. In the Gynecologic Oncology Group study, Goff et al.39 found that none of the nine women with clinically stage I disease had positive lymph nodes, compared with four out of six (66.6%) women with stage IV or recurrent diseases. This result was consistent with other subsequent studies, which found no lymphnode metastasis in tumours clinically conned to the uterus and cervix.27,31,38 In particular, Leitao et al.38 showed that extra-uterine diseases were a predictor of lymph-node metastasis, where none of the 27 women (0%) with stage III disease had lymph-node metastasis, compared with three out of 10 (30%) women diagnosed with stage IIIIV disease who had clinically suspicious and enlarged lymph nodes (P 0.015); the presence of lymphovascular invasion, tumour grade, serosal and cervical involvement could not predict lymph-node metastasis.38

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Several studies have shown that lymphadenectomy carries no therapeutic effect. The largest study by Kapp et al. included 348 who had undergone lymphadenectomy and 1047 women who had not undergone lymphadenectomy.31 The investigators showed that lymphadenectomy failed to have any prognostic signicance, as the 5-year disease-specic survival was similar between those who had and had not undergone lymphadenectomy (61.9% v 66.9%; P 0.249). Another study by Ayhan et al.48 showed no difference in median disease-free survival (2.51 v 2.36 years; P 0.4) and median overall survival (2.44 v 3.16 years; P 0.7) between women who had and had not undergone lymphadectomy. The number of the resected lymph nodes was also not signicant for both disease-free and overall survival. Giuntoli et al.29 found no difference in disease-specic survival between women diagnosed with stage I disease with histologically proven negative lymph nodes (with lymph-node sampling) and those with clinically negative lymph nodes (without lymph-node sampling).29 On the basis of the evidence above, lymph-node sampling should only be carried out in women with clinically advanced diseases. Leitao et al.38 suggested that, if a diagnosis of LMS has been made by an intra-operative frozen section, lymph-node dissection should be carried out because of the possibility of carcinosarcoma on nal pathological review. Endometrial stromal sarcoma The nomenclature of endometrial stromal tumours was rst introduced by Norris and Taylor in 1966.49 According to the World Health Organization classication, endometrial stromal tumour is composed of cells that resemble endometrial stromal cells of the proliferative endometrium.50 ESS, one of the subtype of endometrial stromal tumours, accounts for 0.2% of all uterine malignancies and 1.5 20% of all uterine sarcomas, including carcinosarcoma.3,7,11,32,5156 In the past, EES has been divided into low grade and high grade, depending on the presence and severity of nuclear atypia, mitotic activity, pattern of vascular and myometrial invasion. These two tumours, however, have different biological behaviours and clinical outcomes. Low-grade ESS tends to be hormone-sensitive, has an indolent clinical course, and an overall 5-year survival rate of 73100%32,54,5665; however, 1460% of women have late recurrence.54,58,60,61,64,6673 In contrast, high-grade ESS lacks endometrial stromal differentiation and has an aggressive behaviour. Its 5-year survival rate is 2555%,32,54,56,57,60,6265 and can be as low as 17% in the presence of vascular invasion.32 Therefore, high-grade ESS is now classied as undifferentiated or poorly differentiated endometrial sarcoma, restricting the term ESS to the formerly low-grade ESS.7476 A recent study divided non-low-grade endometrial sarcomas morphologically into UES with nuclear uniformity and UES with nuclear pleomorphism, and found that lowgrade ESS shared some molecular genetic and immunohistochemical characteristics with the rst group but not the latter. This suggests that there is an intermediate group between low-grade ESS and undifferentiated endometrial sarcoma.77 Such classication requires more studies for conrmation. As in other cancers, stage seems to be the most signicant indicator for survival.32,59,62,78,80 However, no good evidence supports this. Some older studies included both low-grade and highgrade ESS together, with an assumption that they had similar behaviours. Secondly, most of the previous high-grade tumours were diagnosed solely by the number of mitotic counts without addressing whether there was any endometrial stromal differentiation. In other words, some of them may in fact be ESS (low-grade) according to the current classication. Thirdly, most studies had a small sample size, which might be prone to sampling bias. Even for those studies with a large sample size, no pathology review was undertaken, and some important information, such as whether previous oophorectomy was carried out before primary surgery, was lacking.65 Most studies were carried out over many years, and the evolution of different management protocols might affect survival and recurrence. For clarity and simplicity sake, we specify the tumours into low grade and high grade as described in the original studies, and all were dened by mitotic activity unless otherwise specied. Stage I Similar to LMS, the revised FIGO staging system for ESS replaces the depth of myometrial invasion by tumour size for the sub-staging of stage I. ESS is characterised by myometrial invasion and myometrial vein permeation, which ESS (low-grade) often has an inltrative pattern whereas UES has

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a destructive pattern.3,9,75,80,81 In theory, ESS should not just be conned to the endometrium. Nevertheless, several studies have reported that 1122% of low-grade ESS have no myometrial invasion.56,60,65,72,79 On the other hand, as ESS is a predominantly intramural neoplasm, there may be no signicance in determining the depth of myometrial invasion. Nonetheless, Bodner et al.66 found that invasion to less than one-third of the myometrium was associated with an improved survival in 31 women with ESS (P < 0.008).66 Their study, however, included women with both low-grade and highgrade ESS, and the sample size was too small to allow multivariate analysis. Tumour size has also been found to be associated with survival in several studies. Nordal et al.57 studied 48 women with all grades of ESS, and found that the 5-year survival dropped from 88.9% for tumours 5 cm or less to 33.3% for tumours over 10 cm (HR 8.68, 95% CI 2.34 to 32.19; P 0.001). No difference was observed between tumours 5 cm or less and those 610 cm.57 De Fusco et al., 51 examined 24 women with high-grade (dened by mitotic activity and nuclear atypia grade) ESS and divided them into three groups (eight women with tumours less than 6 cm, six with tumours 610 cm, and seven with tumours over 10 cm). They found that the median time to recurrence was not reached for the rst two groups but was only 174 days in the last group (P 0.016). Size was also correlated with median survival, which was 11 years, 4.9 years and 312 days, respectively (P 0.03). Multivariate analysis, however, was not carried out owing to small sample size. The latest study, based on the SEER database by Garg et al.65 evaluated the validity of the 2009 FIGO staging system on stage I diseases. A total of 310 low-grade (including well- and moderately differentiated) women with ESS and 96 women with high-grade ESS were included in the study. They found that more than 60% of women with both tumours had myometrial invasion, and myometrial invasion was not a signicant predictor of survival for the entire cohort in their univariate analysis (P 0.6). In addition, a signicant difference was found in the median tumour size between the two diseases (8 cm in low-grade ESS and 5.3 cm in high-grade ESS; P < 0.001). Using the revised staging system, a signicant difference was found in 5-year survival between stages Ia and Ib in low-grade ESS (100% v 93.5%; P 0.003), but not in high-grade ESS (51.4% v 43.5%; P 0.27). No difference was observed between tumour sizes 5.110 cm and over 10 cm in each group. The investigators concluded that the current staging system for stage I was appropriate for low-grade ESS but not high-grade ESS. Abeler et al.32 examined 83 women with ESS and 20 women with UES using the current WHO classication.32 Thirty-six women with ESS (43%) and six women with UES (30%) had tumours 5 cm or less. They found that tumour size had no prognostic signicance in either ESS or UES. Chang et al.78 included 92 women with low-grade and 14 women with high-grade ESS, and found that seven out of 24 (29%) women with stage I disease with tumours less than 4 cm relapsed, whereas disease in the two women with tumours over 10 cm did not recurr.78 Clearly, more data are needed to see whether it is appropriate to use tumour size for the sub-staging of stage I tumours. Stage II Cervical involvement is abandoned from the current FIGO staging system. It is present in 08% of high-grade ESS57,58,60,71,72,78 and 09.6% of low-grade ESS.39,58,60,63,64,67,72,78,79 Garg et al.65 showed that 5.2% of low-grade ESS and 18.1% of high-grade ESS were in stage II under the 1988 FIGO staging system. They found that cervical involvement was an independent poor prognostic index in high-grade ESS, which the 5-year overall survival rates were 24.4% and 49.6% for those with and without cervical invasion (P 0.02). No signicant association was found in low-grade ESS. We found no other study that examined the prognostic signicance of cervical involvement specically for ESS. Obviously, it is difcult to draw any conclusion based on one study. Nonetheless, as UES has a different clinical course from ESS (low grade), it seems that the former needs a separate staging system as the investigators suggested. On the other hand, extra-uterine pelvic extension, commonly involving the ovaries, is found in up to one-quarter to one-half of women at presentation even with low-grade disease3,32,63,64,72,78; this replaces cervical invasion as stage II in the current FIGO staging system. Again, the rationale behind such modication is not clearly documented. Chang et al.78 found that, in ve out of 11 women with stage III disease with all grades of ESS, disease was caused by ovarian metastasis. Using the 1988 FIGO staging system, Abeler et al.32 showed that the 5-year crude survival of women diagnosed with stage III

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ESS was 40%, whereas all women diagnosed with UES other than stage I died within 5 years. It was not known, however, how many stage III diseases were attributed to adnexal spread. Thomas et al.64 reviewed 24 women with ESS who underwent exploratory laparotomy. The presence of extrauterine disease was associated with a worse 5-year progression-free survival (77% v 32%; P 0.03) and overall survival (77% v 32%; P 0.01). This analysis, however, included women with both lowgrade and high-grade ESS, and it was not clear if those extra-uterine diseases included lymph node and other distant metastases. Similarly, Gadducci et al.58 reported that one out of six women with lowgrade ESS (16.7%) with extra-uterine disease and nine out of 12 women with high-grade ESS with extra-uterine diseases had recurrence.58 All these women, however, had stage IIIIV diseases, and the true incidence of recurrence in those with sole extra-uterine pelvic or adnexal spread was not known. Stage III Similar to LMS, positive peritoneal cytology is no longer used in the current staging system. One of the reasons was the lack of evidence on its effect on survival and recurrence. The other reason was that positive peritoneal cytology was a rare event in both ESS and UES. Sagae et al.8 found that ascites was present in seven out of 20 women with all grades of ESS but none were positive. Park et al.36 carried out peritoneal washing in 15 out of 37 women with all grades of ESS and also none was positive. It is not clear which stage should be assigned for those with serosal involvement in the current system. De Fusco et al.51 found that ve out of 24 women with high-grade ESS had serosal involvement. Those with serosal involvement had worse median survival than those with disease limited to the uterus (129 days v 0.5 years; P 0.0009). As all the women had other abdominal or pelvic spread, including bowel, fallopian tubes, ovaries, peritoneum, vagina, pelvic sidewall, bladder and omentum, the true survival data for those with only serosal involvement could not be determined. On the other hand, vaginal metastasis, the previous stage IIIb, which is present in 1.4% of women with low-grade ESS and 0% of women with high-grade ESS (dened as >10 mitoses/10 HPF) in one report,72 is also not included in the current staging system. Currently, the FIGO system assigns women with abdominal metastasis as stage III, and sub-stages it into stage IIIa and IIIb according to the number of abdominal metastasis as LMS. However we could not nd any report about the incidence and importance of such a system. Lymph-node metastasis is assigned as stage IIIc as before. Goff et al.39 found none of the seven women with all grades of ESS who underwent lymph-node dissection had positive lymph nodes. Leath et al.72 found that the incidence of pelvic (18% v 9%; P 0.44) and para-aortic (15% v 0%; P 0.15) were insignicantly higher in high-grade ESS compared with low-grade ESS.72 Shah et al.63 extracted 384 women with low-grade ESS (including well- and moderately differentiated tumours) from the SEER database, and found that seven out of 100 patients who underwent lymphadenectomy (7%) had lymphnode metastasis compared with 26 out of 143 (18%) in women with high-grade ESS (P 0.013). In women with low-grade EES, no difference was found in 5-year survival rate between those with and without lymph-node metastasis (85.7% v 95.2%; P 0.234). In women with high-grade EES, those with lymph-node metastasis had a shorter median survival than those without lymph-node metastasis (8 months v 24 months; P < 0.001). In another SEER database study by Chan et al.,62 which included 831 women with all grades of ESS, the incidence of lymph-node metastasis was 9.9% for the whole cohort who underwent lymphadenectomy, 6.1% in women with grade 1, 8.9% in grade 2, and 12.6% with grade 3 ESS. With the inclusion of women with both low-grade and high-grade ESS, the prognosis was much worse for those with lymph-node metastasis than those without (5-year disease-specic survival 35.3% v 80.1%; P < 0.001). On the basis of the above information, it seems to be appropriate to assign lymphnode metastasis in UES as stage III, but it is still questionable in ESS (low-grade). Stage IV Stage IV includes tumours with bladder, rectum and distant metastasis. Gadducci et al.58 found that stage IV disease was present in 7.7% and 20% of women with low-grade and high-grade, respectively. Low-grade and high-grade tumours were combined, and the 5-year survival rate of stage IV disease was 050%.57,64,78

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Staging procedure Some investigators have suggested that preoperative imaging is mandatory because ESS can spread to the lungs and the peritoneum,9 and treating these metastases might potentially be curative as ESS has an indolent course. Seventy-ve per cent of the 22 women with ESS were diagnosed with leiomyomas preoperatively in one report.8 It would be useful to consider a full radiological survey, such as chest X-ray, computed tomography abdomen and pelvis, if the sarcoma is found after initial surgery. This would provide a baseline for future management. The standard staging procedure is total hysterectomy and bilateral salpingo-oophorectomy, and exploration of the peritoneal cavity.3,9,41,42 Similar to LMS, the roles of bilateral salpingo-oophorectomy and lymph-node evaluation in ESS are still being debated. Bilateral salpingo-oophorectomy Endometrial stromal sarcoma commonly expresses oestrogen and progesterone receptors,77,8284 and a few small case studies have also shown that oestrogen therapy increases the risk of recurrence in ESS.67,85,86 Hence, it seems logical to remove the ovaries in women with ESS. Also, in the study by Berchuck et al.,87 disease recurred in six women with endolymphatic stromal myosis with ovarian preservation compared with only six out of 13 women with bilateral salpingo-oophorectomy (100% v 43%).87 Li et al.61 showed that the recurrence rate of women with and without preserving ovaries were 100% (9/9) and 22.7% (10/44), respectively (P < 0.001). The study, however, combined women with low-grade ESS, high-grade ESS, and those with unclear differentiation in the analysis. More recent studies, however, have provided counter-evidence showing that ovarian preservation does not affect survival. In the population-based study by Chan et al.62 which included both low-grade and high-grade ESS, no difference was found in the 5-year disease-specic survival between those with and without oophorectomy (78.1% v 72.9%; P 0.06). In particular, for the 240 women under 50 years old with stage III diseases, the survival was 91.6%and 96.2% for those with and without oophorectomy, respectively (P 0.1). The study, however had no information whether the women had any prior oophorectomy before the diagnosis and treatment of ESS. In a small multi-centre case-control study by Li et al.,68 12 women with stage I low-grade ESS with ovarian preservation were matched with 24 women with bilateral salpingo-oophorectomy. No difference was observed in progression-free survival (91.3 v 68.6 months; P 0.44) and overall survival (median survival not yet reached v 406 months; P 0.82). Similarly, Shah et al.63 showed no difference in 5-year survival among women with low-grade ESS with and without bilateral salpingo-oophorectomy (92% v 94%; P 0.267), and all women with stage I EES had survival time more than 190 months regardless of ovarian status (P 0.672).63 Gadducci et al.58 also showed that the median follow up for those who did not develop recurrence was 68.5 months (range 43116 months) for those with oophorectomy and 80 months (range 23115 months) for those with residual ovarian tissues among women with low-grade ESS below the age of 50 years.58 In summarising the latest evidence, no great difference was observed in recurrence rate between women with ESS stage I with and without bilateral salpingo-oophorectomy (Table 4).58,67,68,71,73,87,88 So, on the basis of the above information, it seems safe to preserve ovaries for women with clinically stage I ESS. Amant et al.9 suggested thorough counselling with patients, and made a personal comment that they would accept ovarian preservation in women younger than 35 years with small ESS (<23 cm). As for high-grade ESS, Shah et al.63 found no difference in survival for women with and without bilateral salpingo-oophorectomy (P 0.279), and Garg et al.65 also showed that ovarian status was not an independent prognostic factor. Nevertheless, some investigators recommend ovarian removal because of its aggressiveness.58 Lymph-node evaluation It is controversial whether lymph nodes should be evaluated in ESS. Similar to LMS, most studies have not stated clearly the extent of lymphadenectomy. From the diagnostic point of view, lymph-node sampling can assign a more accurate stage with the knowledge of the lymph-node status. In general, the incidence of lymph-node metastasis is below 10% as described above. Riopel et al.,69 however, reported ve out of 15 women (33.3%) with lymph-node metastases among women with low-grade ESS. They included one women whose positive lymph nodes were found in the second operation 3 months after primary surgery, and two other women whose lymph nodes were found in the operation

K.Y. Tse et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 25 (2011) 733749 Table 4 The risk of recurrence in stage I endometrial stromal sarcoma (low grade) with and without oophorectomy Authors Year of publication Proportion of early staged women with retained ovaries who developed recurrence 1/6 (16.7%) 2/6 (33.3%) 4/12 (33%) 5/11 (45.4%) 1/6 (16.7%) 2/5 (40%) 6/6 (100%) 21/49 (42.9%) Proportion of early staged women with oophorectomy who developed recurrence 2/6 (33.3%) NA 10/24 (41.6%) 5/11 (45.4%) 3/12 (25.0%) 0/1 (0%) 6/13 (46.2%) 26/67 (38.8%)

743

P value

Gadducci et al.58 Chu et al.67 Li et al.68 Kim et al.73 Amant et al.71 Mansi et al.88* Berchuck et al.87 Total

1996 2003 2005 2008 2009 1990 1990

>0.05 NA 0.63 1 NA NA NA NA

*Grade was dened by mitotic activity, degree of cytological atypia, pattern of myometrial invasion, and presence of tumour necrosis and haemorrhage; NA, not applicable.

for recurrent disease. Also, the two women with genuine lymph-node metastasis found at primary surgery had extra-uterine disease, implying that lymphadenectomy might not provide extra prognostic information. Thomas et al.64 also advocated pelvic and para-aortic lymphadenectomy because they found three out of 12 (25%) and two out of seven (29%) pelvic and para-aortic lymph node metastasis among women who underwent lymphadenectomy. The sample size, however, was small and the study combined both high-grade and low-grade ESS. On the other hand, Amant et al.71 found only one out of six lymph-node metastasis among women with lymph-node sampling, and they suggested that systematic lymphadenectomy had little clinical benet in early staged low-grade ESS. From a therapeutic point of view, again there is conicting evidence. Riopel et al.69 showed that recurrence occurred in two out of eight (25%) and seven out of seven (100%) women with and without lymph-node sampling at initial surgery. Garg et al.65 showed that lymphadenectomy failed to be a signicant prognostic indicator for survival in multivariate analysis in low-grade and high-grade ESS separately. Shah et al.63 showed that lymphadenectomy alone, irrespective of the lymph-node status, did not have any effect on overall survival in low-grade ESS. Other studies combining low-grade and high-grade ESS also showed similar ndings. In a retrospective analysis by Geller et al.,60 nine women with low-grade and four women with high-grade ESS who underwent lymphadenectomy had the same survival rate as those who did not (P 0.91). Barney et al.79 also found that lymphadenectomy had no benet on top of hysterectomy alone in cause-specic survival (HR 0.96, 95% CI 0.60 to 1.53; P 0.87) and overall survival (HR 0.82, 95% CI 0.59 to 1.15; P 0.248). Chan et al.,62 however, found no difference in 5-year disease-specic survival for women with and without lymphadenectomy (73.8% v 77.6%; P 0.351), and advocated to carry out lymphadenectomy in women with EES because of the unexpected high incidence (9.9%) of lymph-node metastasis found in those having the procedure, which could provide more accurate prognostic information and might guide subsequent adjuvant treatment. On the basis of the above information, it seems that lymph-node dissection is not benecial for predicting prognosis, particularly in ESS (low-grade), which has a good survival rate even with lymph-node metastasis.63 Nevertheless, some investigators suggested that the high recurrence rate of ESS might be caused by occult lymph-node metastasis and recommended lymphadenectomy in advanced ESS.89 Adenosarcoma Adenosarcoma was rst described by Clement and Scully in 1974. It is composed of a benign but occasionally atypical epithelial component and a sarcomatous, usually low-grade, stromal component.90 It is regarded as a mixed Mllerian tumour intermediate between adenobroma and carcinosarcoma.91 Adenosarcoma occurs in the endometrium in more than 70% of cases, and can be found in the myometrium, cervix, and extra-uterine tissues such as ovaries, or multiple areas.9294 Uterine adenosarcoma accounts for 5.59% of all uterine sarcomas.7,32,37,95 It is typically slow-growing, with overall 5-year survival above 80%,7,96 although recurrence is seen in 2545% of women9294,96,97 and 2025% of women die of the tumour.92,97 Only two studies, which included over 50 women with

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uterine adensarcoma, were published two decades apart.93,98 The evidence is too scarce for us to support or refute either the old or the new FIGO staging systems. In the new system, stage I is sub-classied according to the depth of myometrial invasion as before. Clement et al.93 studied 100 women, with follow-up data where available in 88 women.93 Among the 23 women (26.1%) who had recurrence, two just had local excision as the primary surgery. Eleven women had disease conned to the endometrium, ve had 25% or more myometrial invasion, one had 90% myometrial invasion and six had no information. Among those whose myometrium could be assessed, myometrial invasion was found in six out of 17 (35.3%) women with recurrence compared with seven out of 51 (13.7%) women who were alive without disease. The risk of recurrence in the presence of myometrial invasion was 46% compared with 12.7% in the absence of myometrial invasion. The investigators concluded that myometrial invasion was the only feature associated with recurrence. No statistical analysis, however, was carried out in this study. In another study,by Arend et al.,98 based on the SEER data and including 544 women with adenosarcoma, 89.5% of women were in early stage.98 Although the investigators found no difference in the survival among stage 1b (hazard ratio 1.27, 95% CI 1.00 to 1.61) and 1c (hazard ratio 1.84, 95% CI 1.42 to 2.39) compared with stage 1a, we are not sure if the old FIGO staging system was used as the investigators stated that the staging information was derived from the AJCC. Nevertheless, they stated that the 5-year survival was 6369% for those with myometrial invasion compared with 84% whose metastasis was conned to the endometrium. The other drawback of the study was the lack of pathology review and information regarding sarcomatous overgrowth (see below). Other small studies showed conicting results; some found that myometrial invasion was associated with poor survival,92,97 but the others did not.32,94 Therefore, it is difcult to validate the use of myometrial invasion in the sub-staging of stage I. The current stage I also includes tumours in the endocervix. This is understandable because they spread in a similar pattern as the uterine counterpart and it is sometimes difcult to differentiate them from those in the lower uterine segment. As for those tumours arising from adenomyosis in the myometrium, stage Ia does not exist and it is also questionable if the depth of myometrial invasion carries any clinical meaning. No large studies have examined other clinical prognostic indicators that are used in the staging systems for adenosarcoma. In the Gynecologic Oncology Group study by Kaku et al.,97 which included 31 women, extra-uterine spread (stage III) was associated with poor outcomes (P <0.001). Hence, the investigators advocated that staging laparotomy, including peritoneal cytology, should be carried out in clinically stage III disease. We cannot justify, however, routine use of lymphadenectomy, as nodal metastasis is only found in 06.5% of women.7,97,98 As for ovarian preservation, only a few case reports about its safety in women with adenosarcoma have been published.99101 Amant et al.9,102 showed that the sarcomatous component expressed oestrogen, progesterone receptors, or both, in 18 out of 20 women with adenosarcoma without sarcomatous overgrowth. The investigators suggested that the management of ESS should be extrapolated to adenosarcoma without sarcomatous overgrowth.9,102 Adenosarcoma with sarcomatous overgrowth (ASSO) is dened as adenosarcoma with sarcomatous component constituting more than 25% of the tumour.103 The sarcomatous component is usually composed of poorly differentiated sarcoma with more atypia and higher mitotic rate.91 Several studies have indicated that it has a worse outcome than the ordinary adenosarcoma, and the mortality is more than 50%.94,97,103105 Recurrence was found in six out of 10 women, and one had progressive disease in a study by Clement et al.103 In the study by Kaku et al.97 recurrence rate for 17 women with ASSO was 44% compared with 14% for 14 women with adenosarcoma without sarcomatous overgrowth, and 31% of women with ASSO died of disease compared with only 7% of those without sarcomatous overgrowth.97 Krivak et al.104 compared 11 women with ASSO with 33 women with carcinosarcoma, and found that the median survival of ASSO seemed worse than that of carcinosarcoma; this difference approached signicance (13 months v 33 months; P 0.0522).104 Clement et al.103 suggested if ASSO was suspected on endometrial biopsy, pre-operative evaluation of extra-uterine spread was needed. Staging should include peritoneal washing, omentectomy and inspection of peritoneal surfaces on top of hysterectomy. As Krivak et al.104 found that up to 27% and 9% of women had pelvic and para-aortic lymph-node metastasis, respectively, and one of the six (16.7%) women who had lymphadenctomy was upstaged to stage III,104 lymphadenectomy should be considered for those suspected to have ASSO. It is noteworthy that the nomenclature of adenosarcoma and related tumours are still controversial. For example, Gallardo et al.105 have shown that immunohistochemical proles of adenosarcoma were

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similar to adenobroma but not ASSO, suggesting adenobroma should be regarded as welldifferentiated adenosarcoma instead of a distinct disease entity. Soslow et al.106 also found that the expression of oestrogen receptors, progesterone receptors and CD10 was lost in ASSO compared with adenosarcoma, suggesting the former is the de-differentiated form of the latter. On the basis of this limited evidence, we question whether ASSO should warrant a separate staging system and urge for more studies in this regard. Carcinosarcoma Carcinosarcoma was once regarded as sarcoma. Nowadays, most investigators believe that it is monoclonal in origin and its sarcomatous component is a de-differentiation of the carcinomatous component.4,107 This is further supported by its similar disease pattern,7 risk factors,108 responsiveness to cisplatin-based chemotherapy,109,110 immunochemical and molecular studies111116 compared with endometrial cancer. Recurrence of endometrial carcinoma as carcinosarcoma has also been reported, suggesting the transformation of the epithelial tumour.117 Therefore, carcinosarcoma is staged in the same way as endometrial carcinoma, and this will not be discussed in this chapter. Nonetheless, recent studies have shown that the clinical outcomes of carcinosarcoma are worse than endometrioid adenocarcinoma.118122 More studies are still needed to determine the tumourigenesis of carcinosarcoma. Conclusion The nomenclature of uterine sarcomas was established decades ago. These tumours, however, remain shrouded in mystery to both pathologists and clinicians. Owing to their rarity and heterogeneity in behaviour, it is difcult to gather sufcient evidence to verify the revised FIGO staging system. It is equally difcult to establish a guideline on how these tumours should be staged. Nevertheless, with a unied staging system as well as more clear-cut diagnostic criteria, we hope that more patient data can be collected so that appropriate modication of the staging system and management protocols can be made. Practice points  The FIGO committee has introduced a new staging system for LMS and ESS, adenosarcoma and carcinosarcoma.  ESS is no longer classied as low-grade and high-grade ESS. Instead, the term ESS is restricted to the previous low-grade ESS, whereas the previous ESS, which lacks endometrial stromal differentiation, is now known as poorly differentiated or undifferentiated endometrial sarcoma.  Carcinosarcoma is no longer regarded as sarcoma but metaplastic carcinoma where the sarcomatous component is de-differentiated from the carcinomatous component.  Evidence on the signicance of different clinical prognostic markers is conicting, making it difcult to verify any staging system in uterine sarcomas.  In general ESS and adenosarcoma have a relatively more indolent clinical course compared with LMS, UES and ASSO.  Evidence on routine use of pre-operative imaging is limited.  Total hysterectomy is the cornerstone staging and treatment method for uterine sarcomas.  Routine bilateral salpingo-oophorectomy and lymphadenectomy do not have signicant prognostic and therapeutic values.  Most ovarian and lymph-node metastases are found in the presence of extra-uterine diseases and grossly abnormal ovaries and lymph nodes, although these ndings are from small case studies.  Thorough discussion of ovarian preservation should be made for premenopausal women who wish to preserve ovarian function.

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Research agenda  To carry out multi-centre or national studies on the prognostic factors and clinical outcomes in LMS, ESS, UES, adenosarcoma and ASSO individually.  To evaluate the role of pre-operative imaging.  To assess the safety of omitting routine bilateral salpingo-oophorectomy and lymphadenectomy.  To carry out molecular studies and determine if there is an intermediate form between ESS and UES.  To carry out molecular studies and determine if carcinosarcoma is a distinct tumour from endometrial carcinoma.

Conict of interest None declared.

References
1. Nordal RR & Thoresen SO. Uterine sarcomas in Norway 19561992: incidence, survival and mortality. Eur J Cancer 1997; 33: 907911. 2. Brooks SE, Zhan M, Cote T et al. Surveillance, epidemiology, and end results analysis of 2677 cases of uterine sarcoma 19891999. Gynecol Oncol 2004; 93: 204208. 3. DAngelo E & Prat J. Uterine sarcomas: a review. Gynecol Oncol 2010; 116: 1319. 4. McCluggage WG. Uterine carcinosarcomas (malignant mixed Mullerian tumors) are metaplastic carcinomas. Int J Gynecol Cancer 2002; 12: 687690. 5. Creasman WT, Odicino F, Maisonneuve P et al. Carcinoma of the corpus uteri. FIGO 6th annual report on the results of treatment in gynecological cancer. Int J Gynaecol Obstet 2006; 95(Suppl. 1): S105143. 6. FIGO Committee on Gynecologic Oncology. Corrigendum to FIGO staging for uterine sarcomas [International Journal of Gynecology and Obstetrics (2009) 104:179]. Int J Gynaecol Obstet 2009; 106: 277. 7. Benito V, Lubrano A, Arencibia O et al. Clinicopathologic analysis of uterine sarcomas from a single institution in the Canary Islands. Int J Gynaecol Obstet 2009; 107: 4449. 8. 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: 3339. 9. Amant F, Coosemans A, Debiec-Rychter M et al. Clinical management of uterine sarcomas. Lancet Oncol 2009; 10: 1188 1198. 10. Nugent EK, Zighelboim I, Case AS et al. The value of perioperative imaging in patients with uterine sarcomas. Gynecol Oncol 2009; 115: 3740. 11. Chauveinc L, Deniaud E, Plancher C et al. Uterine sarcomas: the Curie Institut experience. Prognosis factors and adjuvant treatments. Gynecol Oncol 1999; 72: 232237. 12. El Husseiny G, Al Bareedy N, Mourad WA et al. Prognostic factors and treatment modalities in uterine sarcoma. Am J Clin Oncol 2002; 25: 256260. 13. Blom R, Guerrieri C, Stl O et al. Leiomyosarcoma of the uterus: a clinicopathologic, DNA ow cytometric, p53, and mdm-2 analysis of 49 cases. Gynecol Oncol 1998; 68: 5461. 14. Friedrich M, Villena-Heinsen C, Mink D et al. Leiomyosarcomas of the female genital tract: a clinical and histopathological study. Eur J Gynaecol Oncol 1998; 19: 470475. 15. Mayerhofer K, Obermair A, Windbichler G et al. Leiomyosarcoma of the uterus: a clinicopathologic multicenter study of 71 cases. Gynecol Oncol 1999; 74: 196201. 16. Pautier P, Genestie C, Rey A et al. Analysis of clinicopathologic prognostic factors for 157 uterine sarcomas and evaluation of a grading score validated for soft tissue sarcoma. Cancer 2000; 88: 14251431. 17. Bodner K, Bodner-Adler B, Kimberger O et al. Evaluating prognostic parameters in women with uterine leiomyosarcoma. A clinicopathologic study. J Reprod Med 2003; 48: 95100. 18. Livi L, Paiar F, Shah N et al. Uterine sarcoma: twenty-seven years of experience. Int J Radiat Oncol Biol Phys 2003; 57: 13661373. 19. Dinh TA, Oliva EA, Fuller Jr. AF et al. The treatment of uterine leiomyosarcoma. Results from a 10-year experience (19901999) at the Massachusetts General Hospital. Gynecol Oncol 2004; 92: 648652. 20. Wu TI, Chang TC, Hsueh S et al. Prognostic factors and impact of adjuvant chemotherapy for uterine leiomyosarcoma. Gynecol Oncol 2006; 100: 166172. 21. Denschlag D, Masoud I, Stanimir G et al. Prognostic factors and outcome in women with uterine sarcoma. Eur J Surg Oncol 2007; 33: 9195.

K.Y. Tse et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 25 (2011) 733749

747

22. Koivisto-Korander R, Butzow R, Koivisto AM et al. Clinical outcome and prognostic factors in 100 cases of uterine sarcoma: experience in Helsinki University Central Hospital 19902001. Gynecol Oncol 2008; 111: 7481. 23. Albrektsen G, Heuch I, Wik E et al. Prognostic impact of parity in 493 uterine sarcoma patients. Int J Gynecol Cancer 2009; 19: 10621067. 24. Pelmus M, Penault-Llorca F, Guillou L et al. Prognostic factors in early-stage leiomyosarcoma of the uterus. Int J Gynecol Cancer 2009; 19: 385390. 25. Nordal RR, Kristensen GB, Kaern J et al. The prognostic signicance of stage, tumor size, cellular atypia and DNA ploidy in uterine leiomyosarcoma. Acta Oncol 1995; 34: 797802. 26. Larson B, Silfverswrd C, Nilsson B et al. Prognostic factors in uterine leiomyosarcoma. A clinical and histopathological study of 143 cases. The Radiumhemmet series 19361981. Acta Oncol 1990; 29: 185191. 27. Gadducci A, Landoni F, Sartori E et al. Uterine leiomyosarcoma: analysis of treatment failures and survival. Gynecol Oncol 1996; 62: 2532. 28. Gadducci A, Sartori E, Landoni F et al. The prognostic relevance of histological type in uterine sarcomas: a Cooperation Task Force (CTF) multivariate analysis of 249 cases. Eur J Gynaecol Oncol 2002; 23: 295299. 29. Giuntoli 2nd RL, Metzinger DS, DiMarco CS et al. Retrospective review of 208 patients with leiomyosarcoma of the uterus: prognostic indicators, surgical management, and adjuvant therapy. Gynecol Oncol 2003; 89: 460469. 30. Hsieh CH, Lin H, Huang CC et al. Leiomyosarcoma of the uterus: a clinicopathologic study of 21 cases. Acta Obstet Gynecol Scand 2003; 82: 7481. *31. Kapp DS, Shin JY & Chan JK. Prognostic factors and survival in 1396 patients with uterine leiomyosarcomas: emphasis on impact of lymphadenectomy and oophorectomy. Cancer 2008; 112: 820830. 32. Abeler VM, Ryne O, Thoresen S et al. Uterine sarcomas in Norway. A histopathological and prognostic survey of a total population from 1970 to 2000 including 419 patients. Histopathology 2009; 54: 355364. 33. DAngelo E, Spagnoli LG & Prat J. Comparative clinicopathologic and immunohistochemical analysis of uterine sarcomas diagnosed using the World Health Organization classication system. Hum Pathol 2009; 40: 15711585. *34. Raut CP, Nucci MR, Wang Q et al. Predictive value of FIGO and AJCC staging systems in patients with uterine leiomyosarcoma. Eur J Cancer 2009; 45: 28182824. *35. Zivanovic O, Leitao MM, Iasonos A et al. Stage-specic outcomes of patients with uterine leiomyosarcoma: a comparison of the international Federation of Gynecology and Obstetrics and American Joint Committee on Cancer Staging Systems. J Clin Oncol 2009; 27: 20662072. 36. Park JY, Kim DY, Suh DS et al. Prognostic factors and treatment outcomes of patients with uterine sarcoma: analysis of 127 patients at a single institution, 19892007. J Cancer Res Clin Oncol 2008; 134: 12771287. *37. Major FJ, Blessing JA, Silverberg SG et al. Prognostic factors in early-stage uterine sarcoma. A Gynecologic Oncology Group study. Cancer 1993; 71(4 Suppl.). 17021709. 38. Leitao MM, Sonoda Y, Brennan MF et al. Incidence of lymph node and ovarian metastases in leiomyosarcoma of the uterus. Gynecol Oncol 2003; 91: 209212. 39. Goff BA, Rice LW, Fleischhacker D et al. Uterine leiomyosarcoma and endometrial stromal sarcoma: lymph node metastases and sites of recurrence. Gynecol Oncol 1993; 50: 1051099. 40. Ayhan A, Tuncer ZS, Tanir M et al. Uterine sarcoma: the Hacettepe hospital experience of 88 consecutive patients. Eur J Gynaecol Oncol 1997; 18: 146148. 41. Nam JH & Park JY. Update on treatment of uterine sarcoma. Curr Opin Obstet Gynecol 2010; 22: 3642. 42. Gadducci A, Cosio S, Romanini A et al. The management of patients with uterine sarcoma: a debated clinical challenge. Crit Rev Oncol Hematol 2008; 65: 129142. 43. Gard GB, Mulvany NJ & Quinn MA. Management of uterine leiomyosarcoma in Australia. Aust N Z J Obstet Gynaecol 1999; 39: 9398. 44. Younis JS, Okon E & Anteby SO. Uterine leiomyosarcoma in pregnancy. Arch Gynecol Obstet 1990; 247: 155160. 45. Lissoni A, Cormio G, Bonazzi C et al. Fertility-sparing surgery in uterine leiomyosarcoma. Gynecol Oncol 1998; 70: 348350. 46. Cormio G, Loizzi V, Carriero C et al. Conservative management of uterine leiomyosarcoma: report of a failure. Eur J Gynaecol Oncol 2009; 30: 206207. 47. Abu-Rustum NR, Curtin JP, Burt M et al. Regression of uterine low-grade smooth-muscle tumors metastatic to the lung after oophorectomy. Obstet Gynecol 1997; 89: 850852. 48. Ayhan A, Aksan G, Gultekin M et al. Prognosticators and the role of lymphadenectomy in uterine leiomyosarcomas. Arch Gynecol Obstet 2009; 280: 7985. 49. Norris HJ & Taylor HB. Mesenchymal tumors of the uterus. I. A clinical and pathological study of 53 endometrial stromal tumors. Cancer 1966; 19: 755766. 50. World Health Organization classication of tumours. In Tavassoli FA & Devilee P (eds.). Pathology and genetics of tumours of the breast and female genital organs. Lyon: IARC Press, 2003. 51. De Fusco PA, Gaffey TA, Malkasian Jr. GD et al. Endometrial stromal sarcoma: review of Mayo Clinic experience, 1945 1980. Gynecol Oncol 1989; 35: 814. 52. Echt G, Jepson J, Steel J et al. Treatment of uterine sarcomas. Cancer 1990; 66: 3539. 53. Larson B, Silfverswrd C, Nilsson B et al. Endometrial stromal sarcoma of the uterus. A clinical and histopathological study. The Radiumhemmet series 19361981. Eur J Obstet Gynecol Reprod Biol 1990; 35: 239249. lu F, Boran N et al. Endometrial stromal sarcoma of the uterus: analysis of 25 patients. Eur J Obstet 54. Haberal A, Kayikiog Gynecol Reprod Biol 2003; 109: 209213. 55. Huang KT, Chen CA, Tseng GC et al. Endometrial stromal sarcoma of twenty cases. Acta Obstet Gynecol Scand 1996; 75: 551555. 56. Bartosch C, Exposito MI & Lopes JM. Low-grade endometrial stromal sarcoma and undifferentiated endometrial sarcoma: a comparative analysis emphasizing the importance of distinguishing between these two groups. Int J Surg Pathol 2010; 18: 286291. 57. Nordal RR, Kristensen GB, Kaern J et al. The prognostic signicance of surgery, tumor size, malignancy grade, menopausal status, and DNA ploidy in endometrial stromal sarcoma. Gynecol Oncol 1996; 62: 254259.

748

K.Y. Tse et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 25 (2011) 733749

58. Gadducci A, Sartori E, Landoni F et al. Endometrial stromal sarcoma: analysis of treatment failures and survival. Gynecol Oncol 1996; 63: 247253. 59. Blom R, Malmstrm H & Guerrieri C. Endometrial stromal sarcoma of the uterus: a clinicopathologic, DNA ow cytometric, p53, and mdm-2 analysis of 17 cases. Int J Gynecol Cancer 1999; 9: 98104. 60. Geller MA, Argenta P, Bradley W et al. Treatment and recurrence patterns in endometrial stromal sarcomas and the relation to c-kit expression. Gynecol Oncol 2004; 95: 632636. 61. Li N, Wu LY, Zhang HT et al. Treatment options in stage I endometrial stromal sarcoma: a retrospective analysis of 53 cases. Gynecol Oncol 2008; 108: 306311. *62. Chan JK, Kawar NM, Shin JY et al. Endometrial stromal sarcoma: a population-based analysis. Br J Cancer 2008; 99: 12101215. *63. Shah JP, Bryant CS, Kumar S et al. Lymphadenectomy and ovarian preservation in low-grade endometrial stromal sarcoma. Obstet Gynecol 2008; 112: 11021108. 64. Thomas MB, Keeney GL, Podratz KC et al. Endometrial stromal sarcoma: treatment and patterns of recurrence. Int J Gynecol Cancer 2009; 19: 253256. *65. Garg G, Shah JP, Toy EP et al. Stage IA vs. IB endometrial stromal sarcoma: does the new staging system predict survival? Gynecol Oncol 2010; 118: 813. 66. Bodner K, Bodner-Adler B & Obermair A. Prognostic parameters in endometrial stromal sarcoma: a clinicopathologic study in 31 patients. Gynecol Oncol 2001; 81: 160165. 67. Chu MC, Mor G, Lim C et al. Low-grade endometrial stromal sarcoma: hormonal aspects. Gynecol Oncol 2003; 90: 170176. 68. Li AJ, Giuntoli 2nd RL, Drake R et al. Ovarian preservation in stage I low grade endometrial stromal sarcomas. Obstet Gynecol 2005; 106: 13041308. 69. Riopel J, Plante M, Renaud MC et al. Lymph node metastases in low-grade endometrial stromal sarcoma. Gynecol Oncol 2005; 96: 402406. 70. Ashraf-Ganjoei T, Behtash N, Shariat M et al. Low grade endometrial stromal sarcoma of uterine corpus, a clinicopathological and survey study in 14 cases. World J Surg Oncol 2006; 4: 50. 71. Amant F, De Knijf A, Van Calster B et al. Clinical study investigating the role of lymphadenectomy, surgical castration and adjuvant hormonal treatment in endometrial stromal sarcoma. Br J Cancer 2007; 97: 11941199. 72. Leath 3rd CA, Huh WK, Hyde Jr. J et al. A multi-institutional review of outcomes of endometrial stromal sarcoma. Gynecol Oncol 2007; 105: 630634. 73. Kim WY, Lee JW, Choi CH et al. Low-grade endometrial stromal sarcoma: a single centers experience with 22 cases. Int J Gynecol Cancer 2008; 18: 10841089. 74. Evans HL. Endometrial stromal sarcoma and poorly differentiated endometrial sarcoma. Cancer 1982; 50: 21702182. 75. Oliva E, Clement PB & Young RH. Endometrial stromal tumors: an update on a group of tumors with a protean phenotype. Adv Anat Pathol 2000; 7: 257281. 76. Amant F, Vergote I & Moerman P. The classication of a uterine sarcoma as high-grade endometrial stromal sarcoma should be abandoned. Gynecol Oncol 2004; 95: 412413. 77. Kurihara S, Oda Y, Ohishi Y et al. Endometrial stromal sarcomas and related high-grade sarcomas: immunohistochemical and molecular genetic study of 31 cases. Am J Surg Pathol 2008; 32: 12281238. 78. Chang KL, Crabtree GS, Lim-Tan SK et al. Primary uterine endometrial stromal neoplasms. A clinicopathologic study of 117 cases. Am J Surg Pathol 1990; 14: 415438. 79. Barney B, Tward JD, Skidmore T et al. Does radiotherapy or lymphadenectomy improve survival in endometrial stromal sarcoma? Int J Gynecol Cancer 2009; 19: 12321238. 80. Chew I & Oliva E. Endometrial stromal sarcomas: a review of potential prognostic factors. Adv Anat Pathol 2010; 17: 113121. 81. Prat J. Classication and staging of endometrial sarcomas: one disease or two different tumor types? Gynecol Oncol 2010; 118: 12. 82. Navarro D, Cabrera JJ, Len L et al. Endometrial stromal sarcoma expression of estrogen receptors, progesterone receptors and estrogen-induced srp27 (24K) suggests hormone responsiveness. J Steroid Biochem Mol Biol 1992; 41: 589596. 83. Sabini G, Chumas JC & Mann WJ. Steroid hormone receptors in endometrial stromal sarcomas. A biochemical and immunohistochemical study. Am J Clin Pathol 1992; 97: 381386. 84. Reich O, Regauer S, Urdl W et al. Expression of oestrogen and progesterone receptors in low-grade endometrial stromal sarcomas. Br J Cancer 2000; 82: 10301034. 85. Spano JP, Soria JC, Kambouchner M et al. Long-term survival of patients given hormonal therapy for metastatic endometrial stromal sarcoma. Med Oncol 2003; 20: 8793. 86. Pink D, Lindner T, Mrozek A et al. Harm or benet of hormonal treatment in metastatic low-grade endometrial stromal sarcoma: single center experience with 10 cases and review of the literature. Gynecol Oncol 2006; 101: 464469. 87. Berchuck A, Rubin SC, Hoskins WJ et al. Treatment of endometrial stromal tumors. Gynecol Oncol 1990; 36: 6065. 88. Mansi J, Ramachandra S, Wiltshaw E et al. Endometrial stromal sarcomas (case Report). Gynecol Oncol 1990; 36: 113118. 89. Reich O, Winter R & Regauer S. Should lymphadenectomy be performed in patients with endometrial stromal sarcoma? Gynecol Oncol 2005; 97: 982. 90. Clement P & Scully R. Mullerian adenosarcoma of the uterus: a clinicopathologic analysis of ten cases of a distinctive type of Mullerian mixed tumor. Cancer 1974; 34: 11381149. 91. McCluggage WG. Mullerian adenosarcoma of the female genital tract. Adv Anat Pathol 2010; 17: 122129. 92. Zaloudek CJ & Norris HJ. Adenobroma and adenosarcoma of the uterus: a clinicopathologic study of 35 cases. Cancer 1981; 48: 354366. *93. Clement PB & Scully RE. Mullerian adenosarcoma of the uterus: a clinicopathologic analysis of 100 cases with a review of the literature. Hum Pathol 1990; 21: 363381. 94. Verschraegen CF, Vasuratna A, Edwards C et al. Clinicopathologic analysis of Mullerian adenosarcoma: the M.D. Anderson Cancer Center experience. Oncol Rep 1998; 5: 939944.

K.Y. Tse et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 25 (2011) 733749

749

95. Shi Y, Liu Z, Peng Z et al. The diagnosis and treatment of Mullerian adenosarcoma of the uterus. Aust N Z J Obstet Gynaecol 2008; 48: 596600. 96. Blom R & Guerrieri C. Adenosarcoma of the uterus: a clinicopathologic, DNA ow cytometric, p53 and mdm-2 analysis of 11 cases. Int J Gynecol Cancer 1999; 9: 3743. 97. Kaku T, Silverberg SG, Major FJ et al. Adenosarcoma of the uterus: a Gynecologic Oncology Group clinicopathologic study of 31 cases. Int J Gynecol Pathol 1992; 11: 7588. *98. Arend R, Bagaria M, Lewin SN et al. Long-term outcome and natural history of uterine adenosarcomas. Gynecol Oncol 2010; 119: 305308. 99. Ozmen B, Uzum N, Unlu C et al. Surgical conservation of both ovaries in an adolescent with uterinemllerian adenosarcoma: a case report. J Minim Invasive Gynecol 2007; 14: 375378. 100. Michener CM & Simon NL. Ovarian conservation in a woman of reproductive age with Mullerian adenosarcoma. Gynecol Oncol 2001; 83: 424427. 101. Han XY, Xiang Y, Guo LN et al. Clinicopathological analysis of Mullerian adenosarcoma of the uterus. Chin Med J (Engl) 2010; 123: 756759. 102. Amant F, Schurmans K, Steenkiste E et al. Immunohistochemical determination of estrogen and progesterone receptor positivity in uterine adenosarcoma. Gynecol Oncol 2004; 93: 680685. *103. Clement PB. Mllerian adenosarcomas of the uterus with sarcomatous overgrowth. A clinicopathological analysis of 10 cases. Am J Surg Pathol 1989; 13: 2838. 104. Krivak TC, Seidman JD, McBroom JW et al. Uterine adenosarcoma with sarcomatous overgrowth versus uterine carcinosarcoma: comparison of treatment and survival. Gynecol Oncol 2001; 83: 8994. 105. Gallardo A & Prat J. Mullerian adenosarcoma: a clinicopathologic and immunohistochemical study of 55 cases challenging the existence of adenobroma. Am J Surg Pathol 2009; 33: 278288. 106. Soslow RA, Ali A & Oliva E. Mullerian adenosarcomas: an immunophenotypic analysis of 35 cases. Am J Surg Pathol 2008; 32: 10131021. 107. Kernochan LE & Garcia RL. Carcinosarcomas (malignant mixed Mllerian tumor) of the uterus: advances in elucidation of biologic and clinical characteristics. J Natl Compr Canc Netw 2009; 7: 550556. 108. 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: 253257. 109. Hoskins PJ, Le N, Ellard S, et alBritish Columbia Cancer Agency. Carboplatin plus paclitaxel for advanced or recurrent uterine malignant mixed Mullerian tumors. The British Columbia Cancer Agency experience. Gynecol Oncol 2008; 108: 5862. 110. 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. Clin Oncol 2010; 28: 27272731. 111. Mayall F, Rutty K, Campbell F et al. p53 immunostaining suggests that uterine carcinosarcomas are monoclonal. Histopathology 1994; 24: 211214. 112. Abeln EC, Smit VT, Wessels JW et al. Molecular genetic evidence for the conversion hypothesis of the origin of malignant mixed Mllerian tumours. J Pathol 1997; 183: 424431. 113. Kounelis S, Jones MW, Papadaki H et al. Carcinosarcomas (malignant mixed Mullerian tumors) of the female genital tract: comparative molecular analysis of epithelial and mesenchymal components. Hum Pathol 1998; 29: 8287. 114. 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: 368373. 115. Abargel A, Avinoach I, Kravtsov V et al. Expression of p27 and p53: comparative analysis of uterine carcinosarcoma and endometrial carcinoma. Int J Gynecol Cancer 2004; 14: 354359. 116. Schipf A, Mayr D, Kirchner T et al. Molecular genetic aberrations of ovarian and uterine carcinosarcomas A CGH and FISH study. Virchows Arch 2008; 452: 259268. 117. Ferrandina G, Zannoni GF, Martinelli E et al. Endometrial carcinoma recurring as carcinosarcoma: report of two cases. Pathol Res Pract 2007; 203: 677681. 118. George E, Lillemoe TJ, Twiggs LB et al. Malignant mixed Mllerian tumor versus high-grade endometrial carcinoma and aggressive variants of endometrial carcinoma: a comparative analysis of survival. Int J Gynecol Pathol 1995; 14: 3944. 119. Amant F, Cadron I, Fuso L et al. Endometrial carcinosarcomas have a different prognosis and pattern of spread compared to high-risk epithelial endometrial cancer. Gynecol Oncol 2005; 98: 274280. 120. 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: 684687. 121. Bansal N, Herzog TJ, Seshan VE et al. Uterine carcinosarcomas and grade 3 endometrioid cancers: evidence for distinct tumor behavior. Obstet Gynecol 2008; 112: 6470. 122. Bland AE, Stone R, Heuser C et al. A clinical and biological comparison between malignant mixed Mllerian tumors and grade 3 endometrioid endometrial carcinomas. Int J Gynecol Cancer 2009; 19: 261265.