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Uterine sarcoma in Israel: A study of 104 cases
GYNECOLOGIC
ONCOLOGY
20, 354-363 (1985)
Uterine Sarcoma in Israel: A Study of 104 Cases 2. SCHWARTZ, Department
M.D.,’ R. DGANI, M.D., M. LANCET, M.D., AND I. KESSLER, M.D.
of Obstetrics and Gynecology,
Kaplan Hospital,’
Rehovot,
Israel
Received February 6, 1984 Data gathered during the first epidemiologic study of sarcoma of the uterus in Israel are presented. In the 7-year period of this survey, 104 new cases of sarcoma of the uterus were diagnosed, representing an incidence of 1..55/100,000females over the age of 20. Half of the patients were in their fifth and sixth decades of life at the diagnosis of the tumor. Uterine sarcomas were more prevalent in women of European-American origin than in those of Asian-African descent. In 54.9% of the patients the diagnosis was made while the disease was in stage I. A definite correlation between sarcoma of the uterus, diabetes, hypertension, and obesity was not found. The S-year survival rate in the present survey was 38%. Factors affecting prognosis were the clinical stage of the disease at diagnosis, histologic type, and the method of treatment. o 1985 Academic PXSS, IK.
INTRODUCTION
Sarcoma of the uterus is the fourth commonest gynecologic malignant neoplasm in Israel after ovarian cancer, endometrial cancer, and carcinoma of the cervix [l]. This type of tumor appears in various forms, is a relatively rare form of malignant disease, and often presents diagnostic problems. The prognosis is extremely poor except in the early stages, when the tumor is still confined to the body of the uterus. The purpose of the present investigation was to study the epidemiology and clinical course of uterine sarcoma in Israel during the 7-year period of 1969 through 1975. MATERIALS
AND METHODS
This report includes all the cases of sarcoma of the uterus diagnosed in Israel between January 1, 1969 and December 31, 1975. The material was taken from the Israel Cancer Registry, operated by the Ministry of Health in cooperation with the Israel Cancer Association. The basis for the calculation of morbidity and mortality for the various population groups was supplied by the Central Bureau of Statistics [2]. During this 7-year period, 104 new cases of sarcoma of the uterus were reported. The diagnosis was based on the histopathologic study of the tumor. The histologic classification used was the one accepted by the gynecology-oncology group [3]. ’ To whom reprint requests should be addressed. * Affiliated to the Medical School of the Hebrew University and Hadassah, Jerusalem, Israel. 354 009O-8258/85$1.50 Copyright All rights
0 1985 by Academic Press, Inc. of reproduction in any form reserved.
UTERINE
SARCOMA
IN
ISRAEL
35.5
Only four major histologic variants were considered: leiomyosarcoma (LMS), mixed mtillerian sarcoma (MMS, mixed homologous and mixed heterologous), endometrial stromal sarcoma (ESS), and miscellaneous groups consisting of other types of sarcoma. Follow-up extended until December 1979. The report includes cases treated until 1975 in order to evaluate the 5-year survival. Slides were reviewed by pathologists at the various institutions where the patients had been treated initially. The criteria for establishing the diagnosis of leiomyosarcoma were 10 or more mitoses per 10 high-power fields (HPF). In cases of 5-9 mitoses per 10 HPF, cytologic atypia had to be present. In cases of endometrial stromal sarcoma, 6 or more mitoses per 10 HPF had to be found. RESULTS Incidence of Sarcoma of the Uterus The incidence of sarcoma of the uterus in Israel during the period under study was 1.55/100,000 women over 20 years of age. Official population statistics and epidemiologic research divide the residents of Israel into two groups: Jews and non-Jews. A further division of the immigrant Jews is by “continent of birth” and “country of birth.” The Jewish population may thus be divided into two main groups: those of European-American and those of Asian-African origin. Those who were born in Israel are referred to as “Israel born.” Figure 1 shows that the incidence of the disease in women of European-American origin is twice as high as in those of Asian-African background. The disease is five times more prevalent among the Jewish population than among the non-Jewish females in Israel. Incidence of Age The ages ranged between 22 and 85 years (mean 55.7 years). Half of the patients were in the fifth and sixth decades of life when the tumor was diagnosed. Eleven patients (10.5%) were younger than 40 years. Twenty-nine patients were
IS
Ismelt Born Jews
EL An
n
Asmn and n African JSWS JSWS
FIG. 1. The incidence of uterine sarcoma by ethnic origin (age > 20 years).
356
SCHWARTZ
ET AL.
TABLE 1 UTERINE
SARCOMA:
DISTRIBUTION
OF PATIENTS BY MEAN
Histologic diagnosis Leiomyosarcoma Mixed homologous mtillerian sarcoma Mixed heterologous mtillerian sarcoma Endometrial stromal sarcoma Others (rhabdomyosarcoma) Total
AGE AND HISTOLOW
Mean age
No. of patients
Percentage
52.1* 62.8 67.3* 63.3 52.6
83 5 3 3 10 104
79.8 4.8 2.9 2.9 9.6 100.0
* The difference by age between the two groups is statistically significant (proportion test P < 0.01).
premenopausal, with a mean age of 42.6, and 75 were postmenopausal, with a mean age of 62.1. The mean interval from menopause to diagnosis in the postmenopausal group was 15.5 years. The distribution of patients by ages and types of sarcoma appears in Table 1 and Fig. 2. Leiomyosarcoma was found most frequently (79.8%) with a mean age of 52.1. The oldest were those patients with mixed heterologous mtillerian sarcoma at a mean age of 67.3 years. Parity
The number of deliveries varied between 0 and 9. Only 6% were nulliparous. The mean number of deliveries was 2.8 per woman, which is similar to the average rate in Israel (2.91). Clinical
Signs
The most frequent presenting sign was abnormal vaginal bleeding (Table 2). In premenopausal women there was often a history of metrorrhagia (75%). In q q
Lelomyosarcomo
•i
Endometriol
I
Others
Mued
Mbllermn
Sarcoma
Stromol
Sarcoma
24
years FIG.
2. Age distribution among 104 cases of uterine sarcoma.
UTERINE
SARCOMA
357
IN ISRAEL
TABLE 2 UTERINE SARCOMA: PRESENTINGSYMPTOMS
Presenting symptoms
No. of patients
Percentage
Vaginal bleeding Abdominal pain Abdominal mass Urinary disturbances Weight loss Vaginal discharge
67 25 23 6 2 2
64.4 24.0 22.1 5.1 1.9 1.9
the postmenopausal patients, vaginal spotting was a common sign (60%). Uterine enlargement was found in all patients, the size of the organ ranging between 8 and 15 gestational weeks. The enlarged uterus was interpreted as uterine leiomyoma, except in those who were diagnosed as having sarcoma by dilatation and curettage (see below). Associated problems were obesity in 18.2% (a feature especially prominent in postmenopausal women); clinical diabetes in 9.6%, and hypertension in 8.6%. Only 4% of the patients had all three entities. Only one of the patients had had prior pelvic irradiation because of dysfunctional uterine bleeding; 23 years later a mixed mesodermal tumor was diagnosed. Diagnosis
Of the 104 patients a diagnostic curettage was done in 92 but it established the diagnosis in only 28 (30.4%). The reason for the curettage was vaginal bleeding in 72.8%, uterine mass in 17.4%, and in 9.8% the reason was unknown. In 1 patient the diagnosis was made at postmortem examination and in 3 patients at explorative laparotomy done for other reasons. Among the 72 patients in whom the diagnosis was not made prior to the operation it was established by postoperative histologic examination. ClassiJcation
of Uterine Sarcoma by Clinical
Staging and Histology
The classification accepted by FIG0 for endometrial carcinoma was employed in the current investigation. Approximately 55% of our cases were stage I disease, and 14.4% were stage IV disease (Table 3). As mentioned above, the histologic classification used was that accepted by the gynecology-oncology group [3], and it is given in Table 1. TABLE 3 DISTRIBUTION OF PATIENTS BY STAGES
Stage I
II III IV
No. of patients
Percentage
57 17
54.9 16.3
15
14.4
15
14.4
358
SCHWARTZ
ET AL.
Treatment
In 91% of the patients the treatment was total abdominal hysterectomy and bilateral salpingooophorectomy. In 36% postoperative irradiation was added. Radiotherapy alone was administered to 3% of the patients. Prognosis
One hundred patients of the 104 have been followed for more than 5 years or until they expired. During that period 72 patients died (72%). The major cause of death was advanced sarcoma. Ten patients died from immediate postoperative complications (pulmonary embolism-four cases; myocardial infarction-two cases; sepsis-four cases). The 5-year survival rate for the entire series was 38%. Table 4 shows the type of treatment and .5-year survival. Factors Affecting
Prognosis
Clinical stage of malignancy. This factor appears to be the most important. The highest 5-year survival rate was noted in stage I (52.6%). In stage II the survival rate was 29.4%, in stage III 13.3%, and in stage IV 4.7% only (Fig. 3). Age. The patients were divided into two groups: group A comprising patients up to the age of 50, and group B patients between 51 and 85 years of age. The 5-year survival rate in group A was 53.6% compared to 21% in group B (P < 0.001). Menopause. Twenty-nine patients were premenopausal and 75 were postmenopausal. It was found that the premenopausal women had a more favorable prognosis than the others (5-year survival of 58.6% and 29.6%, respectively (0.01 < P < 0.05)). Histologic
type of tumor. Five-year survival was 39.2% in patients with LMS, 33.3% in the ESS, 20% in mixed homologous miillerian sarcoma, 33.3% in mixed heterologous miillerian sarcoma, and 40% in the other types. In this study, survival results are valid only in the LMS group, because the other groups are too small.
60
r
stage I FIG. 3.
Five-year
survival
staqe II
rate according
stage In to clinical
stoqe m stages of the malignancy.
U Abbreviations radiation therapy;
TAH TAH + PORT TAH + BSO TAH + BSO + PORT Radiation therapy Total
Type of treatment
33.3 100.0 42.3
31.8 0 39.2
3 1 52
22 1 79
SURVIVAL
50.0 25.0 0 25
4 2 8
% S-Year survival
2
No. of cases
Mixed miillerian sarcoma
SARCOMA:
used: LMS, leiomyosarcoma; ESS, endometrial BSO, bilateral salpingooophorectomy.
% 5-Year survival
No. of cases
LMS
UTERINE
4
stromal
TAH,
33.3
33.3
o/r 5-Year survival
ESS
total
AND HISTOLOGIC
sarcoma;
3
3
No. of cases
BY TREATMENT
TABLE
hysterectomy;
40.0
57.0
0 0
survival
% 5-Year
Other
abdominal
IO
7
2 1
No. of cases
TYPE”
PORT,
33 3 100
3 3 58
No. of cases
postoperative
36.4 0 38.0
33.3 33.3 41.4
% 5-Year survival
Total
:
r
z t;
P
T E
5 E f m
360
SCHWARTZ
ET AL.
Type of treatment. Total abdominal hysterectomy and bilateral salpingooophorectomy (TAH and BSO) afforded better survival results than the combination of surgery and irradiation or irradiation alone (Table 4). Six patients were treated with hysterectomy only because the intraoperative diagnosis was uterine leiomyoma in young women. In three of the six patients, postoperative irradiation was added. Five-year survival was 41.4% for those who were treated with TAH and BSO, while in those who were treated with additional irradiation, the survival rate was 36.4% (difference not significant statistically). From those who were treated with irradiation alone, no one survived for 5 years or more (Table 4). Metastases. Metastases appeared in 71 patients. Metastatic sites were established by clinical examination, pathologic study of biopsies, specimens, X-ray studies, and autopsies. The most common sites were the abdomen (36.6%), lungs (33.8%), and liver (22.5%). In one patient, a distant metastasis was found in the mandible. Most of the metastases (82%) were found outside the pelvis (Table 5). While reviewing the case histories, it was noted that four patients had other primary tumors which presented either before or after the diagnosis of the uterine sarcoma: carcinoma of the lung, adenocarcinoma of the rectum, meningioma, and leiomyoblastoma of the stomach. DISCUSSION
Sarcoma of the uterus accounts for 1.67% of all cases of genital malignancies among the female population of Israel. The incidence of uterine sarcoma in Israel is 1.55/100,000 women over the age of 20 and did not show a definite rise during the period under study. The latest reported incidence of sarcoma of the uterus in the literature is 0.67/100,000 women aged 20 years or more [6]. There is no previous study of the incidence of sarcoma among a Jewish population, therefore it is hard to arrive at a definite conclusion, but the possibility exists that the disease is more prevalent among Jews. According to the data presented above, uterine sarcomas have occurred twice as frequently in Jewish women of western background than in those coming from Asia or Africa. The same trend was shown in endometrial carcinoma in Israel [4]. The relatively higher incidence of TABLE
5
SITE OF METASTASES OF SARCOMA OF THE UTERUS
Site Pelvic” Pelvis + ovary Distant” Abdomen and retroperitoneum (extrapelvic) Lung Liver Colon Bone Kidney Mandible
No. of patients
Percentage
18
25.3
26 24 16 6 6 2 I
36.6 33.8 22.5 8.6 8.6 2.9 1.4
* Includes 12 patients who had both pelvic and distant metastases.
UTERINE
SARCOMA
IN ISRAEL
361
the disease among women of western (Ashkenazi) origin is interesting, but its importance can be clarified only by further research, emphasizing the ethnic origin of the patients. Although the disease has appeared mainly in the 40- to 60-year age group, 10% of the women were under the age of 40. These data are similar to those reported by others [5-l 11. In general, the younger group of patients had a better prognosis. According to Vardi and Tovell [61, the age of the patients with leiomyosarcoma is of some prognostic significance. Montague et al. [20] thought that this difference may be in part due to the duration of the disease prior to the diagnosis, which is shorter in premenopausal patients. Contrary to patients with adenocarcinoma of the uterus who have typical stigmata (obesity, hypertension, diabetes, nulliparity, and being postmenopausal) [12], no such factors were reported in patients with sarcoma of the uterus [5,6]. Most authors state that nulliparous women are as likely to have sarcoma of the uterus as parous ones [8,13-H]. The incidence of obesity, diabetes mellitus, and hypertension was not higher in the patients reported here than in the general Jewish female population in Israel (M. Modan, personal communication). It is known that preoperative diagnosis of uterine sarcoma is very difficult as there are no characteristic signs or symptoms [5,7,11]. The triad of vaginal bleeding, abdominal pain, and rapidly enlarging pelvic mass [16] can also be associated with leiomyomata or adenocarcinoma of the uterus and in advanced cases of ovarian carcinoma [6]. The value of diagnostic uterine curettage is limited, because the tumor usually spreads in a centrifugal pattern and not directly into the endometrium [6]. A negative result should not exclude the diagnosis of sarcoma [5-7,111. In this report only 30.4% were diagnosed by curettage. Finn [13] in his series, established the diagnosis by curettage in 48.5% of the patients; Gallup and Cordray reported a positive curettage in 25% [15]. Boutselis et al. [l l] did a curettage in 28 cases and a positive diagnosis was found in 16 [57.1%]. In their opinion, this procedure is of value in mixed mesodermal and stromal cell sarcoma. Prior pelvic irradiation was administered to only 1 of the 104 patients because of dysfunctional uterine bleeding. Norris and Taylor have noted a history of prior pelvic irradiation for benign conditions in 12% of the patients with uterine sarcoma [ 171. Aaro et al. found 7 of 105 patients [18], Spiro and Koss reported on 4 of 62 [19], and Montague et al. found 1 of 38 [20]. Currently, irradiation is only rarely used for benign bleeding. Sarcoma of the uterus has always carried a poor prognosis. In the present series, the 5-year survival rate was 38%; Finn reported 21% [13], Williams 15% [Zl], and Christopherson et al. 20.7% [22]. Several factors affect the prognosis: the stage of the disease, the histologic type, and the type of treatment. We have recorded a 5-year survival rate of 52.6% in stage I whereas in stage III and IV, l.be respective percentages decreased to 13.3 and 4.7%. Salazar et ~1. [23] noted that when the disease was confined to the corpus (stage I) the 5-year survival is significantly higher [54%] than patients with more advanced disease at diagnosis [l l%]. They also claim that for a given stage there were no differences in the S-year survival of patients with LMS, ESS, or MSS. A review of the literature, including almost 900 cases, showed a 5-year survival rate of patients with LMS of 38%, MMS 22%, and those with ESS 39%.
362
SCHWARTZ
ET AL.
There is general agreement that the primary treatment of the tumor should be total abdominal hysterectomy and bilateral salpingooophorectomy. The value of adjuvant treatment is still controversial [18,22-271. In some centers the combination of surgery and irradiation is the treatment of choice [10,18]. The role of radiation therapy and its influence on the results of treatment of LMS is unclear. Aaro et al. [I81 and Christopherson et al. [22] claim little or no benefit from the addition of radiation therapy, whether used pre or postoperatively. Perez et al. [27] suggested that patients with stage I and II malignant mixed mullerian tumors of the uterus should be treated with preoperative radiation and total hysterectomy with bilateral salpingooophorectomy. Patients with more advanced disease have extremely poor prognosis and should be treated with radiation therapy alone. Charache [26] claims that carcinosarcoma is radioresistant and according to Hill and Miller [28], no cases of carcinosarcoma have shown any significant response even to heavy radiation. According to Salazar et al. [23] adjuvant radiation therapy significantly improved disease control in the pelvis although it may not have dramatically affected the final outcome. The ineffectiveness of radiation therapy alone has also been reported by other authors [14,18,23]. From our findings it is evident that women treated by surgery alone and surgery and radiotherapy have similar prognosis (41.4% 5-year survival versus 36.4%; this difference is statistically not significant). Since sarcoma of the uterus has a high propensity to spread through hematogenous and lymphatic routes [15,26,27], adjuvant systemic chemotherapy is being investigated in many centers. Perez et al. [27] mentioned a few responses with Adriamycin. According to van Dinh and Woodruff [291,the most promising agents are Adriamycin and dacarbazin. Barlow et al. [30] reported about 10 patients with uterine sarcoma following chemotherapy after surgery, 7 with Adriamycin alone and 3 with the combination of Adriamycin plus bleomycin. Five of the seven patients treated with Adriamycin and 1 of the 3 patients treated with Adriamycin plus bleomycin had a partial response. In his opinion, Adriamycin has a high degree of antitumor activity against uterine sarcomas and might possibly be of value as adjunctive chemotherapy to resectable stage I and stage II sarcomas. Currently we treat sarcoma of the uterus by surgery and chemotherapy. During laparotomy we obtain peritoneal washings, omentectomy is performed, total abdominal hysterectomy and bilateral salpingooophorectomy, and selective biopsies from the pelvic and paraaortic lymph nodes are done. Three weeks later adjuvant chemotherapy is started with Adriamycin. This new protocol was started in our department in 1981 and results are still pending. ACKNOWLEDGMENT The authors wish to thank Dr. R. Steinitz and Dr. L. Katz of the Israel Cancer Registry for their helpful advice.
REFERENCES 1. Israel Cancer Registry, Ministry of Health, Division of Chronic Diseases, Cancer in Israel, (1979). 2. Central Bureau of Statistics, Sfatisticd abstracf of Israel, Jerusalem. Special series (1977).
UTERINE SARCOMA IN ISRAEL
363
3. Disaia, P. J., and Creasman, W. T. Chid gynecology oncology, Mosby. St. Louis, p. 154 (1981). 4. Schenker, J. G., and Tal, J. Adenocarcinoma of endometrium in Israel 1960-1968. Ctrncer- 46, 2752-2758 (1980).
5. Bartsich, E. G., O’Leary, J. A., and Moore, J. G. Carcinosarcoma of the uterus. A 50-year review of 32 cases, Obstet. Gynecol. 30, 518-523 (1967). 6. Vardi, J. R., and Tovell, M. M. Leiomyosarcoma of the uterus: Clinicopathologic study, Ohsret. Gynecol. 56, 428-434 (1980). 7. Bartsich, E. G., Bowe, E. T., and Moore, J. G. Leiomyosarcoma of the uterus. A SO-year review of 42 cases, Obstet. Gynrcol. 32, 101-106 (1968). 8. Crawford, E. J. Sarcoma of the uterus, Amer. J. Obstet. Gynecol. 77, 286-291 (1959). 9. Herman, L., and Barrows, D. Sarcoma of the uterus, Obstet. Gynecol. 6, 18-37 (1955). IO. MacFarlane, K. T. Sarcoma of the uterus. Amer. J. Obstrf. Gynecol. 59, 1304-1320 (1950). 11. Boutselis, J. G., and Ullery, J. C. Sarcoma of the uterus, Obsret. Gynecol. 20, 23-35 (1962).
12. Wynder, E. L., Escher, G. C., and Mantel, N. An epidemiological investigation of cancer of the endometrium, Cancer 19, 489-520 (1966). 13. Finn, W. F. Sarcoma of uterus, Amer. J. Obstet. Gynecol. 60, 1254-1262 (1950). 14. Webb, G. A. Uterine sarcoma, Obstet. Gynecol. 6, 38-50 (1955). 15. Gallup, D. G., and Cordray, D. R. Leiomyosarcoma of the uterus: Case reports and a review, Obsfet. Gynecol.
Sure. 34, 300-312 (1979).
16. Chabon, 1.. Mann, R., Sedlis, A., and Weingold, A. B. Carcinosarcoma of uterus, Obstet. Gynecol.
21, 597-601 (1963).
17. Norris, H. J., and Taylor, H. B. Post irradiation sarcoma of the uterus, Obstet. Gynrcol.
26,
689-694 ( 1965). 18. Aaro, L. A., Symmonds, R. E., Dockerty, M. B. Sarcoma of uterus, Amer. /. Obster. Gyned.
94, 101-109 (1966). 19. Spiro, R. H.. and Koss, L. G. Myosarcoma of the uterus, Cancer 18, 571-588 (1966). 20. Montague, A. C.-W., Swartz, D. P., and Woodruff, J. D. Sarcoma arising in a leiomyoma of the uterus, Amer. .I. Obstet. Gynecol. 92, 421-427 (1965). 21. Williams, G. S. Sarcoma of uterus, Amer. J. Obstet. Gynecol. 67, 92-101 (1954). 22. Christopherson, W. M., Williamson, E. O., and Gray, L. A. Leiomyosarcoma of the uterus, Cancer 29, 1512-1517 (1972). 23. Salazar, 0. M., Bonfiglio, T. A., Patten, S. F., Keller, B. E., Feldstein, M., Dunne. M. E., and Rudolph, J. Uterine sarcomas, Cancer 42, 1152-l 160 (1978). 24. Corscaden, J. A., Singh, B. P. Leiomyosarcoma of the uterus, Amer. 1. Obstet. Gynecol. 75, 149-155 (1958). 25. Gudgeon, D. H. Leiomyosarcoma of the uterus, Obstef. Gynecol. 32, 96-100 (1968). 26. Charache, H. Carcinoma of the uterus. A review of the literature and report of four new cases, Amer. J. Surg. 100, 522-526 (1960).
27. Perez, C. A., Askin, F., Baglan, R. J., Ming-Shian, K. A. O., Kraus, F. T., Perez, A. M., Williams, C. F., and Weiss, D. Effects of irradiation on mixed Mtillerian tumors of the uterus. Cancer 43, 1274-1284 (1979). 28. Hill, R. P., and Miller, F. N. Carcinosarcoma of the uterus, Cancer 4, 803-807 (1951). 29. Dinh, T. V., and Woodruff, J. D. Leiomyosarcoma of the uterus. Amer. J. Obsret. Gynecol. 144, 817-823 (1982).
30. Barlow, J. J., Piver, M. S., Chuang, J. T., Cortes, E. P., Ohnuma, T., and Holland, J. F. Adriamycin and bleomycin alone and in combination in gynecologic cancer, Cancer 32, 735743 (1973).
ONCOLOGY
20, 354-363 (1985)
Uterine Sarcoma in Israel: A Study of 104 Cases 2. SCHWARTZ, Department
M.D.,’ R. DGANI, M.D., M. LANCET, M.D., AND I. KESSLER, M.D.
of Obstetrics and Gynecology,
Kaplan Hospital,’
Rehovot,
Israel
Received February 6, 1984 Data gathered during the first epidemiologic study of sarcoma of the uterus in Israel are presented. In the 7-year period of this survey, 104 new cases of sarcoma of the uterus were diagnosed, representing an incidence of 1..55/100,000females over the age of 20. Half of the patients were in their fifth and sixth decades of life at the diagnosis of the tumor. Uterine sarcomas were more prevalent in women of European-American origin than in those of Asian-African descent. In 54.9% of the patients the diagnosis was made while the disease was in stage I. A definite correlation between sarcoma of the uterus, diabetes, hypertension, and obesity was not found. The S-year survival rate in the present survey was 38%. Factors affecting prognosis were the clinical stage of the disease at diagnosis, histologic type, and the method of treatment. o 1985 Academic PXSS, IK.
INTRODUCTION
Sarcoma of the uterus is the fourth commonest gynecologic malignant neoplasm in Israel after ovarian cancer, endometrial cancer, and carcinoma of the cervix [l]. This type of tumor appears in various forms, is a relatively rare form of malignant disease, and often presents diagnostic problems. The prognosis is extremely poor except in the early stages, when the tumor is still confined to the body of the uterus. The purpose of the present investigation was to study the epidemiology and clinical course of uterine sarcoma in Israel during the 7-year period of 1969 through 1975. MATERIALS
AND METHODS
This report includes all the cases of sarcoma of the uterus diagnosed in Israel between January 1, 1969 and December 31, 1975. The material was taken from the Israel Cancer Registry, operated by the Ministry of Health in cooperation with the Israel Cancer Association. The basis for the calculation of morbidity and mortality for the various population groups was supplied by the Central Bureau of Statistics [2]. During this 7-year period, 104 new cases of sarcoma of the uterus were reported. The diagnosis was based on the histopathologic study of the tumor. The histologic classification used was the one accepted by the gynecology-oncology group [3]. ’ To whom reprint requests should be addressed. * Affiliated to the Medical School of the Hebrew University and Hadassah, Jerusalem, Israel. 354 009O-8258/85$1.50 Copyright All rights
0 1985 by Academic Press, Inc. of reproduction in any form reserved.
UTERINE
SARCOMA
IN
ISRAEL
35.5
Only four major histologic variants were considered: leiomyosarcoma (LMS), mixed mtillerian sarcoma (MMS, mixed homologous and mixed heterologous), endometrial stromal sarcoma (ESS), and miscellaneous groups consisting of other types of sarcoma. Follow-up extended until December 1979. The report includes cases treated until 1975 in order to evaluate the 5-year survival. Slides were reviewed by pathologists at the various institutions where the patients had been treated initially. The criteria for establishing the diagnosis of leiomyosarcoma were 10 or more mitoses per 10 high-power fields (HPF). In cases of 5-9 mitoses per 10 HPF, cytologic atypia had to be present. In cases of endometrial stromal sarcoma, 6 or more mitoses per 10 HPF had to be found. RESULTS Incidence of Sarcoma of the Uterus The incidence of sarcoma of the uterus in Israel during the period under study was 1.55/100,000 women over 20 years of age. Official population statistics and epidemiologic research divide the residents of Israel into two groups: Jews and non-Jews. A further division of the immigrant Jews is by “continent of birth” and “country of birth.” The Jewish population may thus be divided into two main groups: those of European-American and those of Asian-African origin. Those who were born in Israel are referred to as “Israel born.” Figure 1 shows that the incidence of the disease in women of European-American origin is twice as high as in those of Asian-African background. The disease is five times more prevalent among the Jewish population than among the non-Jewish females in Israel. Incidence of Age The ages ranged between 22 and 85 years (mean 55.7 years). Half of the patients were in the fifth and sixth decades of life when the tumor was diagnosed. Eleven patients (10.5%) were younger than 40 years. Twenty-nine patients were
IS
Ismelt Born Jews
EL An
n
Asmn and n African JSWS JSWS
FIG. 1. The incidence of uterine sarcoma by ethnic origin (age > 20 years).
356
SCHWARTZ
ET AL.
TABLE 1 UTERINE
SARCOMA:
DISTRIBUTION
OF PATIENTS BY MEAN
Histologic diagnosis Leiomyosarcoma Mixed homologous mtillerian sarcoma Mixed heterologous mtillerian sarcoma Endometrial stromal sarcoma Others (rhabdomyosarcoma) Total
AGE AND HISTOLOW
Mean age
No. of patients
Percentage
52.1* 62.8 67.3* 63.3 52.6
83 5 3 3 10 104
79.8 4.8 2.9 2.9 9.6 100.0
* The difference by age between the two groups is statistically significant (proportion test P < 0.01).
premenopausal, with a mean age of 42.6, and 75 were postmenopausal, with a mean age of 62.1. The mean interval from menopause to diagnosis in the postmenopausal group was 15.5 years. The distribution of patients by ages and types of sarcoma appears in Table 1 and Fig. 2. Leiomyosarcoma was found most frequently (79.8%) with a mean age of 52.1. The oldest were those patients with mixed heterologous mtillerian sarcoma at a mean age of 67.3 years. Parity
The number of deliveries varied between 0 and 9. Only 6% were nulliparous. The mean number of deliveries was 2.8 per woman, which is similar to the average rate in Israel (2.91). Clinical
Signs
The most frequent presenting sign was abnormal vaginal bleeding (Table 2). In premenopausal women there was often a history of metrorrhagia (75%). In q q
Lelomyosarcomo
•i
Endometriol
I
Others
Mued
Mbllermn
Sarcoma
Stromol
Sarcoma
24
years FIG.
2. Age distribution among 104 cases of uterine sarcoma.
UTERINE
SARCOMA
357
IN ISRAEL
TABLE 2 UTERINE SARCOMA: PRESENTINGSYMPTOMS
Presenting symptoms
No. of patients
Percentage
Vaginal bleeding Abdominal pain Abdominal mass Urinary disturbances Weight loss Vaginal discharge
67 25 23 6 2 2
64.4 24.0 22.1 5.1 1.9 1.9
the postmenopausal patients, vaginal spotting was a common sign (60%). Uterine enlargement was found in all patients, the size of the organ ranging between 8 and 15 gestational weeks. The enlarged uterus was interpreted as uterine leiomyoma, except in those who were diagnosed as having sarcoma by dilatation and curettage (see below). Associated problems were obesity in 18.2% (a feature especially prominent in postmenopausal women); clinical diabetes in 9.6%, and hypertension in 8.6%. Only 4% of the patients had all three entities. Only one of the patients had had prior pelvic irradiation because of dysfunctional uterine bleeding; 23 years later a mixed mesodermal tumor was diagnosed. Diagnosis
Of the 104 patients a diagnostic curettage was done in 92 but it established the diagnosis in only 28 (30.4%). The reason for the curettage was vaginal bleeding in 72.8%, uterine mass in 17.4%, and in 9.8% the reason was unknown. In 1 patient the diagnosis was made at postmortem examination and in 3 patients at explorative laparotomy done for other reasons. Among the 72 patients in whom the diagnosis was not made prior to the operation it was established by postoperative histologic examination. ClassiJcation
of Uterine Sarcoma by Clinical
Staging and Histology
The classification accepted by FIG0 for endometrial carcinoma was employed in the current investigation. Approximately 55% of our cases were stage I disease, and 14.4% were stage IV disease (Table 3). As mentioned above, the histologic classification used was that accepted by the gynecology-oncology group [3], and it is given in Table 1. TABLE 3 DISTRIBUTION OF PATIENTS BY STAGES
Stage I
II III IV
No. of patients
Percentage
57 17
54.9 16.3
15
14.4
15
14.4
358
SCHWARTZ
ET AL.
Treatment
In 91% of the patients the treatment was total abdominal hysterectomy and bilateral salpingooophorectomy. In 36% postoperative irradiation was added. Radiotherapy alone was administered to 3% of the patients. Prognosis
One hundred patients of the 104 have been followed for more than 5 years or until they expired. During that period 72 patients died (72%). The major cause of death was advanced sarcoma. Ten patients died from immediate postoperative complications (pulmonary embolism-four cases; myocardial infarction-two cases; sepsis-four cases). The 5-year survival rate for the entire series was 38%. Table 4 shows the type of treatment and .5-year survival. Factors Affecting
Prognosis
Clinical stage of malignancy. This factor appears to be the most important. The highest 5-year survival rate was noted in stage I (52.6%). In stage II the survival rate was 29.4%, in stage III 13.3%, and in stage IV 4.7% only (Fig. 3). Age. The patients were divided into two groups: group A comprising patients up to the age of 50, and group B patients between 51 and 85 years of age. The 5-year survival rate in group A was 53.6% compared to 21% in group B (P < 0.001). Menopause. Twenty-nine patients were premenopausal and 75 were postmenopausal. It was found that the premenopausal women had a more favorable prognosis than the others (5-year survival of 58.6% and 29.6%, respectively (0.01 < P < 0.05)). Histologic
type of tumor. Five-year survival was 39.2% in patients with LMS, 33.3% in the ESS, 20% in mixed homologous miillerian sarcoma, 33.3% in mixed heterologous miillerian sarcoma, and 40% in the other types. In this study, survival results are valid only in the LMS group, because the other groups are too small.
60
r
stage I FIG. 3.
Five-year
survival
staqe II
rate according
stage In to clinical
stoqe m stages of the malignancy.
U Abbreviations radiation therapy;
TAH TAH + PORT TAH + BSO TAH + BSO + PORT Radiation therapy Total
Type of treatment
33.3 100.0 42.3
31.8 0 39.2
3 1 52
22 1 79
SURVIVAL
50.0 25.0 0 25
4 2 8
% S-Year survival
2
No. of cases
Mixed miillerian sarcoma
SARCOMA:
used: LMS, leiomyosarcoma; ESS, endometrial BSO, bilateral salpingooophorectomy.
% 5-Year survival
No. of cases
LMS
UTERINE
4
stromal
TAH,
33.3
33.3
o/r 5-Year survival
ESS
total
AND HISTOLOGIC
sarcoma;
3
3
No. of cases
BY TREATMENT
TABLE
hysterectomy;
40.0
57.0
0 0
survival
% 5-Year
Other
abdominal
IO
7
2 1
No. of cases
TYPE”
PORT,
33 3 100
3 3 58
No. of cases
postoperative
36.4 0 38.0
33.3 33.3 41.4
% 5-Year survival
Total
:
r
z t;
P
T E
5 E f m
360
SCHWARTZ
ET AL.
Type of treatment. Total abdominal hysterectomy and bilateral salpingooophorectomy (TAH and BSO) afforded better survival results than the combination of surgery and irradiation or irradiation alone (Table 4). Six patients were treated with hysterectomy only because the intraoperative diagnosis was uterine leiomyoma in young women. In three of the six patients, postoperative irradiation was added. Five-year survival was 41.4% for those who were treated with TAH and BSO, while in those who were treated with additional irradiation, the survival rate was 36.4% (difference not significant statistically). From those who were treated with irradiation alone, no one survived for 5 years or more (Table 4). Metastases. Metastases appeared in 71 patients. Metastatic sites were established by clinical examination, pathologic study of biopsies, specimens, X-ray studies, and autopsies. The most common sites were the abdomen (36.6%), lungs (33.8%), and liver (22.5%). In one patient, a distant metastasis was found in the mandible. Most of the metastases (82%) were found outside the pelvis (Table 5). While reviewing the case histories, it was noted that four patients had other primary tumors which presented either before or after the diagnosis of the uterine sarcoma: carcinoma of the lung, adenocarcinoma of the rectum, meningioma, and leiomyoblastoma of the stomach. DISCUSSION
Sarcoma of the uterus accounts for 1.67% of all cases of genital malignancies among the female population of Israel. The incidence of uterine sarcoma in Israel is 1.55/100,000 women over the age of 20 and did not show a definite rise during the period under study. The latest reported incidence of sarcoma of the uterus in the literature is 0.67/100,000 women aged 20 years or more [6]. There is no previous study of the incidence of sarcoma among a Jewish population, therefore it is hard to arrive at a definite conclusion, but the possibility exists that the disease is more prevalent among Jews. According to the data presented above, uterine sarcomas have occurred twice as frequently in Jewish women of western background than in those coming from Asia or Africa. The same trend was shown in endometrial carcinoma in Israel [4]. The relatively higher incidence of TABLE
5
SITE OF METASTASES OF SARCOMA OF THE UTERUS
Site Pelvic” Pelvis + ovary Distant” Abdomen and retroperitoneum (extrapelvic) Lung Liver Colon Bone Kidney Mandible
No. of patients
Percentage
18
25.3
26 24 16 6 6 2 I
36.6 33.8 22.5 8.6 8.6 2.9 1.4
* Includes 12 patients who had both pelvic and distant metastases.
UTERINE
SARCOMA
IN ISRAEL
361
the disease among women of western (Ashkenazi) origin is interesting, but its importance can be clarified only by further research, emphasizing the ethnic origin of the patients. Although the disease has appeared mainly in the 40- to 60-year age group, 10% of the women were under the age of 40. These data are similar to those reported by others [5-l 11. In general, the younger group of patients had a better prognosis. According to Vardi and Tovell [61, the age of the patients with leiomyosarcoma is of some prognostic significance. Montague et al. [20] thought that this difference may be in part due to the duration of the disease prior to the diagnosis, which is shorter in premenopausal patients. Contrary to patients with adenocarcinoma of the uterus who have typical stigmata (obesity, hypertension, diabetes, nulliparity, and being postmenopausal) [12], no such factors were reported in patients with sarcoma of the uterus [5,6]. Most authors state that nulliparous women are as likely to have sarcoma of the uterus as parous ones [8,13-H]. The incidence of obesity, diabetes mellitus, and hypertension was not higher in the patients reported here than in the general Jewish female population in Israel (M. Modan, personal communication). It is known that preoperative diagnosis of uterine sarcoma is very difficult as there are no characteristic signs or symptoms [5,7,11]. The triad of vaginal bleeding, abdominal pain, and rapidly enlarging pelvic mass [16] can also be associated with leiomyomata or adenocarcinoma of the uterus and in advanced cases of ovarian carcinoma [6]. The value of diagnostic uterine curettage is limited, because the tumor usually spreads in a centrifugal pattern and not directly into the endometrium [6]. A negative result should not exclude the diagnosis of sarcoma [5-7,111. In this report only 30.4% were diagnosed by curettage. Finn [13] in his series, established the diagnosis by curettage in 48.5% of the patients; Gallup and Cordray reported a positive curettage in 25% [15]. Boutselis et al. [l l] did a curettage in 28 cases and a positive diagnosis was found in 16 [57.1%]. In their opinion, this procedure is of value in mixed mesodermal and stromal cell sarcoma. Prior pelvic irradiation was administered to only 1 of the 104 patients because of dysfunctional uterine bleeding. Norris and Taylor have noted a history of prior pelvic irradiation for benign conditions in 12% of the patients with uterine sarcoma [ 171. Aaro et al. found 7 of 105 patients [18], Spiro and Koss reported on 4 of 62 [19], and Montague et al. found 1 of 38 [20]. Currently, irradiation is only rarely used for benign bleeding. Sarcoma of the uterus has always carried a poor prognosis. In the present series, the 5-year survival rate was 38%; Finn reported 21% [13], Williams 15% [Zl], and Christopherson et al. 20.7% [22]. Several factors affect the prognosis: the stage of the disease, the histologic type, and the type of treatment. We have recorded a 5-year survival rate of 52.6% in stage I whereas in stage III and IV, l.be respective percentages decreased to 13.3 and 4.7%. Salazar et ~1. [23] noted that when the disease was confined to the corpus (stage I) the 5-year survival is significantly higher [54%] than patients with more advanced disease at diagnosis [l l%]. They also claim that for a given stage there were no differences in the S-year survival of patients with LMS, ESS, or MSS. A review of the literature, including almost 900 cases, showed a 5-year survival rate of patients with LMS of 38%, MMS 22%, and those with ESS 39%.
362
SCHWARTZ
ET AL.
There is general agreement that the primary treatment of the tumor should be total abdominal hysterectomy and bilateral salpingooophorectomy. The value of adjuvant treatment is still controversial [18,22-271. In some centers the combination of surgery and irradiation is the treatment of choice [10,18]. The role of radiation therapy and its influence on the results of treatment of LMS is unclear. Aaro et al. [I81 and Christopherson et al. [22] claim little or no benefit from the addition of radiation therapy, whether used pre or postoperatively. Perez et al. [27] suggested that patients with stage I and II malignant mixed mullerian tumors of the uterus should be treated with preoperative radiation and total hysterectomy with bilateral salpingooophorectomy. Patients with more advanced disease have extremely poor prognosis and should be treated with radiation therapy alone. Charache [26] claims that carcinosarcoma is radioresistant and according to Hill and Miller [28], no cases of carcinosarcoma have shown any significant response even to heavy radiation. According to Salazar et al. [23] adjuvant radiation therapy significantly improved disease control in the pelvis although it may not have dramatically affected the final outcome. The ineffectiveness of radiation therapy alone has also been reported by other authors [14,18,23]. From our findings it is evident that women treated by surgery alone and surgery and radiotherapy have similar prognosis (41.4% 5-year survival versus 36.4%; this difference is statistically not significant). Since sarcoma of the uterus has a high propensity to spread through hematogenous and lymphatic routes [15,26,27], adjuvant systemic chemotherapy is being investigated in many centers. Perez et al. [27] mentioned a few responses with Adriamycin. According to van Dinh and Woodruff [291,the most promising agents are Adriamycin and dacarbazin. Barlow et al. [30] reported about 10 patients with uterine sarcoma following chemotherapy after surgery, 7 with Adriamycin alone and 3 with the combination of Adriamycin plus bleomycin. Five of the seven patients treated with Adriamycin and 1 of the 3 patients treated with Adriamycin plus bleomycin had a partial response. In his opinion, Adriamycin has a high degree of antitumor activity against uterine sarcomas and might possibly be of value as adjunctive chemotherapy to resectable stage I and stage II sarcomas. Currently we treat sarcoma of the uterus by surgery and chemotherapy. During laparotomy we obtain peritoneal washings, omentectomy is performed, total abdominal hysterectomy and bilateral salpingooophorectomy, and selective biopsies from the pelvic and paraaortic lymph nodes are done. Three weeks later adjuvant chemotherapy is started with Adriamycin. This new protocol was started in our department in 1981 and results are still pending. ACKNOWLEDGMENT The authors wish to thank Dr. R. Steinitz and Dr. L. Katz of the Israel Cancer Registry for their helpful advice.
REFERENCES 1. Israel Cancer Registry, Ministry of Health, Division of Chronic Diseases, Cancer in Israel, (1979). 2. Central Bureau of Statistics, Sfatisticd abstracf of Israel, Jerusalem. Special series (1977).
UTERINE SARCOMA IN ISRAEL
363
3. Disaia, P. J., and Creasman, W. T. Chid gynecology oncology, Mosby. St. Louis, p. 154 (1981). 4. Schenker, J. G., and Tal, J. Adenocarcinoma of endometrium in Israel 1960-1968. Ctrncer- 46, 2752-2758 (1980).
5. Bartsich, E. G., O’Leary, J. A., and Moore, J. G. Carcinosarcoma of the uterus. A 50-year review of 32 cases, Obstet. Gynecol. 30, 518-523 (1967). 6. Vardi, J. R., and Tovell, M. M. Leiomyosarcoma of the uterus: Clinicopathologic study, Ohsret. Gynecol. 56, 428-434 (1980). 7. Bartsich, E. G., Bowe, E. T., and Moore, J. G. Leiomyosarcoma of the uterus. A SO-year review of 42 cases, Obstet. Gynrcol. 32, 101-106 (1968). 8. Crawford, E. J. Sarcoma of the uterus, Amer. J. Obstet. Gynecol. 77, 286-291 (1959). 9. Herman, L., and Barrows, D. Sarcoma of the uterus, Obstet. Gynecol. 6, 18-37 (1955). IO. MacFarlane, K. T. Sarcoma of the uterus. Amer. J. Obstrf. Gynecol. 59, 1304-1320 (1950). 11. Boutselis, J. G., and Ullery, J. C. Sarcoma of the uterus, Obsret. Gynecol. 20, 23-35 (1962).
12. Wynder, E. L., Escher, G. C., and Mantel, N. An epidemiological investigation of cancer of the endometrium, Cancer 19, 489-520 (1966). 13. Finn, W. F. Sarcoma of uterus, Amer. J. Obstet. Gynecol. 60, 1254-1262 (1950). 14. Webb, G. A. Uterine sarcoma, Obstet. Gynecol. 6, 38-50 (1955). 15. Gallup, D. G., and Cordray, D. R. Leiomyosarcoma of the uterus: Case reports and a review, Obsfet. Gynecol.
Sure. 34, 300-312 (1979).
16. Chabon, 1.. Mann, R., Sedlis, A., and Weingold, A. B. Carcinosarcoma of uterus, Obstet. Gynecol.
21, 597-601 (1963).
17. Norris, H. J., and Taylor, H. B. Post irradiation sarcoma of the uterus, Obstet. Gynrcol.
26,
689-694 ( 1965). 18. Aaro, L. A., Symmonds, R. E., Dockerty, M. B. Sarcoma of uterus, Amer. /. Obster. Gyned.
94, 101-109 (1966). 19. Spiro, R. H.. and Koss, L. G. Myosarcoma of the uterus, Cancer 18, 571-588 (1966). 20. Montague, A. C.-W., Swartz, D. P., and Woodruff, J. D. Sarcoma arising in a leiomyoma of the uterus, Amer. .I. Obstet. Gynecol. 92, 421-427 (1965). 21. Williams, G. S. Sarcoma of uterus, Amer. J. Obstet. Gynecol. 67, 92-101 (1954). 22. Christopherson, W. M., Williamson, E. O., and Gray, L. A. Leiomyosarcoma of the uterus, Cancer 29, 1512-1517 (1972). 23. Salazar, 0. M., Bonfiglio, T. A., Patten, S. F., Keller, B. E., Feldstein, M., Dunne. M. E., and Rudolph, J. Uterine sarcomas, Cancer 42, 1152-l 160 (1978). 24. Corscaden, J. A., Singh, B. P. Leiomyosarcoma of the uterus, Amer. 1. Obstet. Gynecol. 75, 149-155 (1958). 25. Gudgeon, D. H. Leiomyosarcoma of the uterus, Obstef. Gynecol. 32, 96-100 (1968). 26. Charache, H. Carcinoma of the uterus. A review of the literature and report of four new cases, Amer. J. Surg. 100, 522-526 (1960).
27. Perez, C. A., Askin, F., Baglan, R. J., Ming-Shian, K. A. O., Kraus, F. T., Perez, A. M., Williams, C. F., and Weiss, D. Effects of irradiation on mixed Mtillerian tumors of the uterus. Cancer 43, 1274-1284 (1979). 28. Hill, R. P., and Miller, F. N. Carcinosarcoma of the uterus, Cancer 4, 803-807 (1951). 29. Dinh, T. V., and Woodruff, J. D. Leiomyosarcoma of the uterus. Amer. J. Obsret. Gynecol. 144, 817-823 (1982).
30. Barlow, J. J., Piver, M. S., Chuang, J. T., Cortes, E. P., Ohnuma, T., and Holland, J. F. Adriamycin and bleomycin alone and in combination in gynecologic cancer, Cancer 32, 735743 (1973).