Uterine Carcinosarcomas: Incidence and Trends in Management and Survival

GYNECOLOGIC ONCOLOGY ARTICLE NO.

65, 158–163 (1997)

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Uterine Carcinosarcomas: Incidence and Trends in Management and Survival CONCEPCION D. ARRASTIA, M.D., RACHEL G. FRUCHTER, PH.D., MELISSA CLARK, B.A., MITCHELL MAIMAN, M.D., JEAN CLAUDE REMY, M.D., MILAGROS MACASAET, M.D., E. JASON GATES, M.D., THERESA DI MAIO, M.D.,* AND TOMASZ MARZEC, M.D.* Department of Obstetrics and Gynecology and *Department of Pathology, State University of New York–Health Science Center at Brooklyn, Brooklyn, New York 11203 Received October 2, 1996

Our study’s aim was to determine the incidence of uterine sarcomas in New York City (NYC) and evaluate trends in frequency, treatment, and survival of carcinosarcomas in two Brooklyn hospitals. Population-based cancer registry data for 1976–1985 were used to calculate the incidence of uterine sarcomas in NYC women. Medical records and histology slides of carcinosarcomas at two central Brooklyn hospitals from 1960 to 1995 were reviewed. The incidence of uterine sarcomas in black and white women in NYC was 33.4 and 17.0 per million (P õ 0.01). Among 97 women with carcinosarcomas diagnosed in 1960–1995, 75% were diagnosed preoperatively, 82% had a hysterectomy, and 45% of those in clinical stage I were upstaged. Predictors of mortality included the presence of extrauterine extension, deep myometrial invasion, vascular space invasion, and gross residual disease, with only the first two being independent predictors of survival in a multivariate analysis. Adjunctive therapy shifted from radiation in 1960–1969 to cisplatin-based chemotherapy after 1980. In surgical stage III, survival increased significantly between 1960–1979 and 1980– 1995, but improvement could not be ascribed to particular therapies. The incidence of uterine sarcomas in black women was twice that in white women. Surgical staging including omentectomy is recommended in the management of carcinosarcomas. Modern medical care may have improved the short-term prognosis of carcinosarcomas. q 1997 Academic Press

INTRODUCTION

Uterine sarcomas are among the least common gynecologic malignancies and different histologic types of sarcoma have different characteristics and prognosis. As a result, there are few studies of incidence rates, particularly those that address both histologic type and racial differences. Furthermore, the number of substantial clinical studies of sarcomas evaluating management, prognostic factors, and treatment outcomes is also limited. In our clinical practice over more than 30 years, we have seen steadily increasing numbers of women with uterine sarcomas, such that sarcomas

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METHODS

Information on all cases of uterine cancer among New York City (NYC) residents in the years 1976–1985 was obtained from the New York State Cancer Registry. Quality control data from the registry [2] indicate that for uterine cancer less than 2% of cases were identified by death certificates only, and more than 95% were histologically confirmed. In the registry, histology was coded according to the International Classification of Diseases for Oncology and in these analyses codes 880 through 903 were used in defining sarcomas. Code 889 was used for leiomyosarcomas (LMS), code 893 for endometrial stromal sarcomas (ESS), and codes 894, 895, 898, and 899 for carcinosarcomas (CS). The distribution of the NYC population by age and geographic area was obtained from the standard data used by the NYC Department of Health derived from the 1980 census. Women whose race/ethnicity was classified as Hispanic were included as white. In 1980, 61% of the Hispanic population was of Puerto Rican origin, with the remainder including origins in Latin America. In the cancer registry racial categories included white, black, and other or unknown, and a second category specified ‘‘Spanish’’ origin. Cases of other or unknown race but of Spanish origin were classified as white in our analyses. The age-adjusted incidence was computed by the direct method and standardized to the 1970

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now comprise one-quarter of malignancies of the uterine corpus at our institutions. While these increasing numbers led us to evaluate incidence in relation to the shifting demography of the community, the increasing need for therapeutic decision making about complex, toxic, and expensive regimens led us to evaluate our experience with changing management and multimodality treatment regimens. This report builds on our earlier study of 35 carcinosarcoma (CS) patients which identified surgical stage of disease and lymphvascular invasion as the critical predictors of outcome [1].

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TABLE 1 Incidence of Uterine Sarcomas by Race, Histology, and Geographic Area Cases (10 years)

Incidencea (95% confidence interval)

SEER ratea [3]

New York City Total sarcomas Black White Leiomyosarcoma Black White Carcinosarcoma Black White

286 567

33.0 (29.1, 36.9) 15.2 (13.9, 16.5)

33.4 17.0

116 193

12.6 (10.4, 15.0) 6.0 (5.1, 6.8)

9.9 6.1

127 274

15.5 (12.9, 18.3) 6.3 (5.6, 7.1)

20.3 7.5

Brooklyn Total sarcomas Black White Standardized to 1980 standard population Black White

100 155

31.4 (25.6, 37.8) 14.8 (12.4, 17.3)

100 155

32.9 (26.8, 39.9) 15.3 (12.9, 17.8)

33.4 17.0

a

Cases per million women per year, adjusted for age to the standard 1970 U.S. population.

U.S. standard population to allow comparison with rates from the Surveillance Epidemiology and End Results (SEER) program [3]. Hospital tumor registry records indicated that 176 patients with uterine sarcomas were diagnosed and treated at the Kings County Hospital Center and the University Hospital of Brooklyn between 1960 and 1995. Clinical and pathologic data were obtained by review of the medical records of all patients. A detailed analysis of the most common histologic type—carcinosarcoma—was undertaken. Histopathologic slides were reviewed by one of two pathologists and the diagnosis of CS was made using conventional criteria [4]. CS with either heterologous or homologous elements were included. All available slides were reviewed for evidence of myometrial invasion and vascular space invasion (VSI). In cases with no evident myometrial invasion, the uterus was entirely embedded and evaluated. Depth of myometrial invasion was classified as none, inner, middle, or outer third. VSI was classified independently of depth of invasion. Other clinical and surgical variables included clinical and surgicopathologic stage, sites of tumor metastasis and recurrence, progression-free interval, and survival time. Thirty-four of the CS patients in this study were included in an earlier review [1] Confidence intervals (CI) of incidence rates were computed using a Poisson distribution as described by Lilienfeld

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and Lilienfeld [5]. Survival data were evaluated using the Statistical Package for the Social Sciences (SPSS) version 6.1 [6]. Survival was calculated by the Kaplan–Meier method and the survival between groups was compared using the log rank and Breslow tests. Deaths due to causes other than carcinosarcoma were censored in the analyses. Multiple predictors of survival were compared using Cox regression analysis. RESULTS

Incidence. From 1976 through 1985, a total of 864 uterine sarcomas were registered in New York City residents comprising 9.8% of 8782 corpus cancers. The sarcomas included 398 CS, 314 LMS, and 76 ESS, with 286 sarcomas occurring in black women and 567 in white women. The ageadjusted and standardized incidence of sarcomas by race/ ethnicity and histologic type are shown in Table 1. Incidence data from the SEER program for 1973–1981 are shown for comparison [3]. The NYC data show that the incidence in black women was consistently about twice the rate in white women including both histologic types. The incidence rates for Brooklyn, standardized to both the 1970 and 1980 U.S. standard populations, are also shown in Table 1. A difference between LMS and CS in age-specific incidence was found, with the peak incidence in LMS occurring at age 40–55 years, while the incidence of CS increased steadily with age (Fig. 1). This pattern was similar for both black and white women. Hospital series. At our two institutions, the number of cases per year increased from 2.9 in 1956–1965 to 4.1 in 1966–1975, 5.3 in 1976–1985, and 8.9 in 1986–1995. The proportion of sarcoma patients of African descent increased from 62 to 87% over the same period, while the proportion of CS increased from 57 to 69%. A total of 186 patients with uterine sarcomas were diagnosed from 1960 to 1995, including 97 (52%) with CS, 65 (35%) with LMS, 17 (9%)

FIG. 1. Age-specific incidence of uterine sarcomas in New York City, 1976–1985 (cases per million women per year). CS, carcinosarcomas; LMS, leiomyosarcomas.

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TABLE 2 Carcinosarcomas: Clinical and Surgical/Pathologic Stage Distribution Clinical stage

Laparotomy

Surgical stage

Stage

N

%

N

%

N

%

N

%

I II III IV Not staged

44 14 15 23 1

45 14 15 24 1

43 13 11 14 —

98 93 73 61 —

18 6 4

44 46 27

—

—

25 9 20 37 6

26 9 21 38 6

Total

97

100

81

84

28

35

97

100

with ESS, and 7 others. CS comprised 53% of 143 sarcomas in black women and 51% of 41 sarcomas in white women. Whereas only 39% of LMS and 27% of ESS were diagnosed in the advanced stage, 72% of CS were advanced at diagnosis (Odds Ratio (OR) Å 4.5, 95% CI Å 2.3, 8.9, P õ 0.001). Black women were more likely to have advancedstage sarcomas (35%) than white women (18%), but the difference was not statistically significant. The mean ages at diagnosis for CS, LMS, and ESS cell type were 65.7, 48.2, and 41.6 years, respectively. Carcinosarcomas. Between 1960 and 1995, 97 women were diagnosed or treated for primary CS. Five percent had a history of prior radiation therapy. Nine patients in clinical stage IV were operated for presumed ovarian cancer without a preoperative dilatation and curettage. Among 88 patients with initial endocervical or endometrial curettage (EMC), 95% had evidence of malignancy with 66 (75%) having an indication of sarcoma, 18 (20%) had an indication of carcinoma, and 3 (3%) had no signs of malignancy. The proportion with evidence of sarcoma in the EMC did not vary by stage. Eighty patients (82%) had a hysterectomy and salpingooophorectomy as part of their initial treatment and one had exploratory surgery without hysterectomy, so that surgical– pathologic staging was available for 81 patients. The proportion treated by initial surgery was 82% of 38 patients in 1960–1979 and 85% of 59 patients in 1980–1995. Lymph nodes were biopsied during the surgical procedure with increasing frequency during the study period, increasing from 0% of 9 hysterectomies in 1960–1969 through 19% of 21 in 1970–1979 to 68% of 50 after 1980. As shown in Table 2, 28 of the 73 patients (38%) in clinical stages I–III were upstaged at surgery. In 1960–1979, 32% of 31 patients with initial surgery were upstaged compared to 36% of 50 patients in 1980–1995. Thirteen of 58 patients (22%) with clinical stages I–II were upstaged to stage III. The metastatic sites for upstaging include adnexa, pelvic and para-aortic nodes, and peritoneum as well as positive peritoneal cytology. In 1960–1979, 4 (14%) were upstaged to stage III compared to 9 (18%) in

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Upstaged

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1980–1995. Thirteen of 73 patients (21%) in clinical stages I–III were upstaged to stage IV as a result of surgery. In nine patients the metastases had spread to the omentum, in three to the bladder or rectum, and in one to the liver. There was no difference in the proportion upstaged to stage IV in the two time periods. Of 12 patients with clinical stage I–II carcinosarcoma and no myometrial invasion, two were upstaged to stage III and two to stage IV on exploration. Of 17 patients with clinical stages I–II and superficial myometrial invasion, two were upstaged to stage III and two to stage IV on exploration. Thirty-five of 81 patients (43%) had gross residual disease after surgery. The majority of these patients (35/45, 76%) had preoperative evidence of disease outside the uterus. The most frequent sites of gross residual disease were lung (37%), omentum (37%), and pelvis (17%). Depth of invasion was known in 96% of 80 patients with hysterectomy. Tumor invaded more than one-third of the myometrium in 38% of 34 patient in stages I–II compared to 70% in stages III–IV (Table 3). Vascular space invasion in the myometrium was known in 66 (83%) of 80 subjects who had a hysterectomy, and VSI increased significantly TABLE 3 Carcinosarcomas: Depth of Invasion and Vascular Space Invasion by Stage More than 13 myometrial invasion

Vascular space invasion

Pathologic stage

N

%

N

%

I II III IV

25 9 19 24

40 33 73 67

22 5 17 22

23 20 76 77

Total

77

56

66

56

Note. Stages I–II vs III–IV. More than one-third myometrial invasion: Odds ratio Å 3.7 (95% CI Å 1.3, 10.9), P Å 0.01. Vascular space invasion: Odds ratio Å 11.7 (95% CI Å 3.2, 45.8), P õ 0.001.

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from 22% in surgical stages I–II to 77% in stages III–IV (P õ 0.001) (Table 3). The association between VSI and metastatic disease was stronger than the association between depth of myometrial invasion and metastatic disease. Depth of invasion and VSI were associated with each other, with 22% of 27 patients with no or superficial invasion having VSI compared to 76% of 38 patients with deeper myometrial invasion (P õ 0.001 in x2 test). Over the 36 years of this report, the adjunctive treatment modalities fell into four groups corresponding to innovations in chemotherapy. Of 89 patients receiving treatment, 74 survived more than 2 months and were therefore candidates for adjunctive treatment. From 1960 through 1968, half the 8 patients had primary or adjunctive radiotherapy, but no adjunctive chemotherapy. From 1969 through 1979, 13 of 19 patients (68%) received adjunctive chemotherapy including various modifications of vincristine, actinomycin D, and cyclophosphamide, while only 4 patients (21%) received primary or adjunctive radiotherapy, without chemotherapy. From 1980 through 1990, 20 of 33 patients (61%) received adjunctive chemotherapy with cis-platinum alone or in combination, while 6 received radiotherapy alone or after hysterectomy. After 1990, 11 of 14 patients (79%) received adjunctive chemotherapy including platinum and ifosfamide or paclitaxel, while one received only adjunctive radiotherapy. Thus, over the 36 years, there was a consistent pattern of adjunctive therapy after primary surgery, but a major switch from radiation to chemotherapy and a change in chemotherapeutic agents. There were too few patients in each treatment category to analyze the outcome of specific regimens. For survival analyses, follow-up was complete to death or 1996 for 94% of patients. Of the 97 carcinosarcoma patients, 8 refused treatment or died rapidly without treatment. Of the 89 treated patients, 4 (4%) in stages I–III did not have a hysterectomy. For these 4, we assumed that the surgical stage was the same as the clinical stage. There was a significant trend toward poorer survival at higher stage, with 24-month survival decreasing steadily from 74% in surgical stage I, through 39% in stage II, 32% in stage III to 3% in stage IV (P õ 0.0001) (Table 4). Among 35 patients with persistent (gross residual) disease at initial surgery, 37% died within 3 months with a 24-month survival of 23%, in contrast to a 24-month survival of 61% in 46 patients without gross residual disease. Among these 46 patients, 29 recurred with a median time to recurrence of 9 months. The site of first recurrence included both distant (lung and extraabdominal) and local (pelvis) sites, with 38% recurring in the pelvis alone, and 28% recurring at distant sites. The 8 patients with distant recurrence had a median time to recurrence of 7 months in contrast to pelvic recurrences with a median time to recurrence of 17 months. In multivariate Cox regression analysis, both gross residual disease (rate ratio 3.1, 95% CI Å 2.4, 3.7; P Å 0.001) and

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TABLE 4 Carcinosarcomas: Survival by Stage and Treatment Period Period Stage I

II

III

IV

Total

Survival measure N 12-month 24-month 36-month N 12-month 24-month N 12-month 24-month N 12-month 24-month N 12-month 24-month

survival % survival % survival % survival % survival % survival % survival % survival % survival % survival % survival %

1960–1979

1980–1995

10 (30%) 90 80 70 5 (15%) 60 30 6 (18%) 33 0* 12 (36%) 8 1 33 (100%) 45 29

16 (29%) 93 71 63 5 (9%) 75 50 16 (27%) 56 44* 19 (36%) 28 6 56 (100%) 54 38

Total 26 92 74 65 10 66 39 22 50 32 31 19 3 89 49 33

(29%)

(11%)

(25%)

(35%)

(100%)

* In stage III, the survival difference between the two periods was statistically significant (P Å 0.02).

surgical stage (rate ratio 1.5, 95% CI Å 1.2, 1.8); P Å 0.007) were independently predictive of survival. Information on VSI was available in 66 of the 89 treated patients. VSI was strongly predictive of poor survival with 21% of patients with VSI surviving 2 years compared to 56% of those without VSI (rate ratio Å 1.6, 95% CI Å 1.1, 1.9; P Å 0.003). Information on depth of myometrial invasion was available in 77 patients, and patients with deep invasion of the outer one-third of the myometrium had significantly poorer 2-year survival (9%) than those with less deep invasion (47%) (rate ratio Å 1.8, 95% CI Å 1.5, 2.1; P Å 0.0002). In a multivariate analysis of 65 patients of the four variables significant in univariate analyses, surgical stage (rate ratio Å 2.3, 95% CI Å 1.8, 2.7; P õ 0.001) and depth of myometrial invasion (rate ratio Å 1.8, 95% CI Å 1.4, 2.2; P Å 0.002) were significant independent predictors of survival, while gross residual disease (rate ratio Å 1.3, 95% CI Å 0.3, 2.3; P ú 0.5) and VSI (rate ratio Å 1.1, 95% CI Å 0.7, 1.5; P ú 0.5) were no longer significant. Table 4 shows the survival at 12 and 24 months for each stage group for 1960–1979 compared to 1980–1995. In stage I with more than 90% 12-month survival in both periods, the marginally lower 24- and 36-month survivals in the second period probably reflect the shorter follow-up time of surviving patients from the later period. However, in each of stages II through IV, survival improved in the later time period with both 12- and 24-month survival increasing. However, only in stage III did the difference in survival reach statistical significance.

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DISCUSSION

Very few reports of the incidence of uterine sarcomas are available due to the rarity of these tumors. Harlow et al. [3] reporting on 1452 cases diagnosed in 1973–1981 including 1251 white women and 201 black women in the SEER registry demonstrated that the incidence in white women was about half the rate in black women whether one considered all sarcomas or carcinosarcomas and leiomyosarcomas separately. Polednak [7] evaluating leiomyosarcomas diagnosed in New York State in 1976–1981 reported an incidence of 11.1 per million in black women (87 cases) and 5.9 per million in white women (256 cases). A study from Jamaica reported an incidence of 4.5 per million population (or about 9 per million women), with sarcomas comprising 23% of all corpus cancers [8]. Our study, which includes more black women (286) than any of these previous studies, confirms that the incidence of uterine sarcomas in black women is twice as high as that in whites. The age-specific incidence in our study showed a marked difference between LMS and CS, with the former peaking in the perimenopausal years at ages 40–54 and then declining before increasing again at older ages, whereas the incidence of CS did not increase substantially until after age 50 and then rose steeply to age 75. These age distributions are similar to those reported by Harlow and Polednak. The early peak in LMS may be due to the detection of low-grade LMS incidental to hysterectomy. Both Harlow and Polednak also reported that blacks had twice the incidence of nonuterine sarcomas as whites. Polednak suggests that the high incidence of sarcomas in people of African descent may reflect genetic factors. In the United States, black women have higher mortality from cancer of the uterine corpus than do white women and socioeconomic and behavioral factors have been shown to contribute to the higher mortality. However, since sarcomas with poor survival comprise 10–20% of corpus cancers in black women, compared to 3–4% in whites, it is important to stratify for histology when evaluating preventible factors in corpus cancer mortality. Although the overall population of Brooklyn has remained fairly stable since 1960, the black female population of Brooklyn has increased from 205,100 in 1960 to almost 500,000 in 1990. Assuming that the twofold higher incidence of sarcomas in blacks than in whites has been consistent, the population shift is probably sufficient to explain the steady increase in patients with sarcoma at our center over 36 years. While multicenter studies with large numbers and selected eligibility criteria such as those of the GOG [9, 10] have provided important insights into specific prognostic factors, this study, the third largest in the literature, provides a comprehensive perspective in a nonselected population. The majority (95%) of our carcinosarcoma patients had evidence of malignancy in the endometrial or endocervical curettage. This concurs with the findings of 68% by Dinh et al. [11],

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and 91% by Wheelock et al. [12]. This high rate is encouraging since preoperative diagnosis is critical to subsequent care including selection of detailed operative staging rather than simple hysterectomy and counseling the patient about the aggressive nature of the disease and her options for adjunctive therapy. In the GOG study [9], 20% of 301 patients with stage I– II CS were reassigned to surgical stages III–IV and Dinh et al. [11] also reported 20% upstaging. Olah et al. [13] reported ‘‘little’’ disparity between clinical and surgical staging. In our series however, 45% of clinical stage I– II patients were upstaged after surgery. Since we had no exclusionary criteria, but rather included everyone who had surgery in our analysis, our figures may represent the usual practice situation more accurately. Like the GOG study, we found metastases most frequently in the adnexa, lymph nodes, and omentum. The metastatic sites for extrapelvic disease are identical to those reported for endometrial carcinoma, but are encountered three times more frequently. By convention, uterine sarcomas are staged as endometrial adenocarcinomas. Since the rate of omental metastases in this series was more than twice that of bladder or rectal metastases, we recommend an omentectomy as part of the staging procedure in patients with CS as well as sampling of the pelvic and para-aortic nodes. As in the GOG study [9, 10] and our earlier report [1], depth of myometrial invasion was associated with metastatic spread. In comparison with adenocarcinomas of the corpus uteri in which less than 5% of patients with superficial myometrial invasion had metastases [14, 15], in our series about 20% had metastases with concomitant poor survival. As in the GOG study, VSI was strongly associated with metastatic disease and consequently with poor survival. However, with our limited numbers, we were not able to demonstrate an independent predictive role for VSI after taking depth of myometrial invasion, extrauterine spread, and gross residual disease into account. In adenocarcinoma of endometrium, VSI has been documented to be the single most important poor prognostic factor after positive paraaortic nodes [15]. The period of this study covered the change from simple hysterectomy to detailed exploratory laparotomy, node biopsy, and routine evaluation of histologic parameters such as depth of myometrial invasion and VSI. Unfortunately, lack of routine lymph node biopsy in the early years precludes evaluation of the prognostic significance of lymph nodes. However, our finding in this series that gross residual disease was the strongest predictor of poor survival suggests that tumor debulking may be advantageous with CS as it is with ovarian epithelial tumors. At the very least, the additional detailed information available from careful exploration not only has helped us understand the disease process, but also has allowed us to tailor therapy and discuss appropriate treatment with the patients in a more informed manner.

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This study of carcinosarcomas was initiated to determine whether the shifts in management over almost four decades had resulted in improved survival. Most clinical trials of radiation therapy and chemotherapeutic agents have failed to demonstrate a significant improvement in survival, whether of adjunctive treatments in stages I and II or treatment for residual disease in stages III to IV [17–22]. In our series, in stage III, there was a statistically significant improvement in survival over time, and small improvements in stages II, IV, and overall. In the 35 years of the study, surgery expanded to include node exploration, and although the proportions upstaged in the two time periods were similar, a shift of patients from clinical stages I–II to III might have contributed to improved survival. Adjunctive therapy for CS shifted from radiation to chemotherapy in 1970 with a further shift to platinum-based chemotherapy in 1980. However, at the same time as the increased use of chemotherapy and changes in specific agents, there were also improvements in perioperative hemodynamic and respiratory support, in parenteral nutrition, and, most important, in the management of chemotherapy and its dose modification. Therefore, it is impossible to ascribe the prolongation of survival to changes in surgical procedure or to the antitumor effects of the complex chemotherapy and radiotherapy protocols. However, the improved survival over time documented here has not been reported before and is encouraging. Finally, this study has three key implications. First, uterine sarcomas should be high in the differential diagnosis of uterine corpus malignancies in women of African descent. Second, accurate preoperative diagnosis, meticulous surgical exploration including node samping and omentectomy and possibly tumor debulking with careful review of histologic factors are essential in tailoring therapy and counseling patients appropriately. Third, the possible improvement in survival over recent decades emphasizes that further advances must include clinicians trained in both radical surgery and chemotherapy, excellent hospital care, and the development new clinical trials to evaluate adjunctive care. REFERENCES 1. Macasaet M, Waxman M, Fruchter RG, Boyce J, Hong P, Nicastri AD, Remy JC: Prognostic factors in malignant mesodermal (mullerian) mixed tumors of the uterus. Gynecol Oncol 20:32–42, 1985 2. New York State Cancer Registry: Time Trends in Cancer Incidence in New York State, 1977–85 Albany, NY, New York State Department of Health, 1990 3. Harlow BL, Weiss NS, Lofton S: The epidemiology of sarcomas of the uterus. Natl Cancer Inst 76:399–402, 1986 4. Kurman RJ (ed): Blaustein’s Pathology of the Female Genital Tract, 4th ed. New York, Springer Verlag, 1994, Chap 13, p 515

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5. Lilienfeld AM, Lilienfeld D: Foundations of Epidemiology, 2nd ed. Oxford Univ Press, 1994, p 336 6. Norusis MJ: SPSS Advanced Statistics, Version 6.1, New York, SPSS Inc., 1996 7. Polednak AP: Incidence of soft-tissue cancers in blacks and whites in New York state. Int J Cancer 38:21–26, 1986 8. Sengupta BS, Sparke B: Uterine sarcoma in Jamaican women: A 15year clinicopathologic study. J R Coll Surg Edinb 26:94–98, 1981 9. Major FJ, Blessing JA, Silverberg SG, Morrow PC, Creasman WT, Currie JL, Yordan E, Brady MF: Prognostic factors in early-stage uterine sarcoma: A Gynecologic Oncology Group study. Cancer 71:1702– 1709, 1993 10. Silverberg SG, Major FJ, Blessing JA, Fetter B, Askin FB, Liao S-Y, Miller A: Carcinosarcoma (malignant mixed mesodermal tumor) of the uterus: A GOG pathologic study. Int J Gynecol Pathol 9:1–19, 1990 11. Dinh TV, Slavin RE, Bhagavan BS, Hannigan EV, Tiamson EM, Yandell RB: Mixed muellerian tumors of the uterus: A clinicopathologic study. Obstet Gynecol 74:388–392, 1989 12. Wheelock JB, Krebs HB, Schneider V, Goplerud DR: Uterine sarcoma: Analysis of prognostic variables in 71 cases. Am J Obstet Gynecol 151:1016–1022, 1985 13. Olah KS, Gee H, Blunt S, Dunn JA, Kelly K, Chan KK: Retrospective analysis of 318 cases of uterine sarcoma. Eur J Cancer 27:1095–1099, 1991 14. Boronow RC, Morrow CP, Creasman WT, DiSaia PJ, Silverberg SG, Miller A, Blessing JA: Surgical staging in endometrial cancer: Clinical– pathologic findings of a prospective study. Obstet Gynecol 63:825, 1984 15. Creasman WT, Morrow CP, Bundy BN, Homesley HD, Graham JE, Heller PB: Surgical pathologic spread patterns of endometrial cancer (a GOG study) Cancer 60:2035–2041, 1987 16. Moskovic E, MacSweeney E, Law M, Price A: Survival, patterns of spread and prognostic factors in uterine sarcoma: A study of 76 patients. Br J Radiol 66:1009–1015, 1993 17. Hannigan EV, Freedman RS, Elder KW, Rutledge FN: Treatment of advanced uterine sarcoma with viscristine, actinomycin D, and cyclophosphamide. Gynecol Oncol 15:224–229, 1983 18. Omura GA, Blessing JA, Major F, Lifshitz S, Ehrlich CE, Mangan C, Beecham J, Park R, Silverberg S: A randomized clinical trial of adjuvant Adriamycin in uterine sarcomas: A GOG study. J Clin Oncol 3:1240–1245, 1985 19. Salazar OM, Bonfiglio TA, Pattern SF, Keller BE, Feldstein M, Dunne ME, Rudolph J: Uterine sarcomas: Natural history, treatment and prognosis. Cancer 42:1152–1160, 1978 20. Hempling RE, Piver MS, Baker TR: Impact of progression-free survival of adjuvant cyclophosphamide, vincristine, doxorbicin (Adriamycin) and dacarbazine (CYVADIC) chemotherapy for stage I uterine sarcoma: A prospective trial. Am J Clin Oncol 18:282–286, 1995 21. Grosh WW, Jones HW, Burnett LS, Greco A: Malignant mixed mesodermal tumors of the uterus and ovary treated with cisplatin-based chemotherapy. Gynecol Oncol 25:334–339, 1986 22. Sutton GP, Blessing JA, Rosenshein N, Photopulos G, DiSaia PJ: Phase II trail of ifosfamide and mesna in mixed mesodermal tumors of the uterus (a Gynecologic Oncology Group study). Am J Obstet Gynecol 161:309–312, 1989

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