Occult, high-risk endometrial cancer

GYNECOLOGIC

ONCOLOGY

22, 154-161 (1985)

Occult, High-Risk Endometrial M. SMITH* *University

AND

Cancer

A. J. MCCARTNEY?

Department of Obstetrics and Gynaecology and fOncology Memorial Hospital for Women, Bagot Road, Subiaco, Western

Service, Australia

King Edward 6008

Received July 2, 1984 In a series of 173 consecutive patients with endometrial cancer treated by a fixed protocol 62 tumors (36%) appear “estrogen independent,” i.e., there is no history of estrogen ingestion and no recognized risk factors such as obesity or diabetes mellitus. A high proportion of these tumors are of advanced stage and grade. Prognosis is poorer and mortality higher than for “estrogen-dependent” tumors. Twenty-two tumors were truly occult (no spontaneous vaginal bleeding). Factors which identify this high-risk group are described and the reasons for delay in diagnosis discussed. Spread by intraperitoneal dissemination is considered a major factor in the poorer prognosis. Cytology of peritoneal washings is a useful diagnostic and prognostic aid. An estrogen provocation test is suggested as a means of earlier recognition which could reduce mortality in this group. c 1985 Academic Press, Inc.

INTRODUCTION

Much research effort has been directed toward estrogen-dependent endometrial cancer since there is now clear evidence that endometrium exposed long term to unopposed estrogen stimulation may develop cancer; and the source of this estrogen may be endogenous or exogenous [l-3]. Recent review of risk factors [4,14,15] includes references from 1947 on this subject which will not be requoted here. Bokman [5] recently presented a hypothesis of two different pathogenetic types of endometrial cancer, one estrogen related the other not apparently so. He noted the poorer prognosis in the latter group. We also note that patients fall into two groups. One group we designate “estrogen dependent” (E +ve), because there are recognized factors which increase endogenous estrogen production or the patient has been treated with exogenous estrogens. The other group we designate “estrogen independent” (E - ve), having none of the risk factors. Many of these cases were truly occult (the patient did not have any vaginal bleeding). In these cases presentation was often late and the tumor was widespread within the abdominal cavity. METHODS

Since 1977 the Oncology Unit of this hospital has used the following protocol in the management of endometrial cancer. Initial diagnosis and staging is by diagnostic curettage, cystoscopy, and sigmoidoscopy. An intravenous pyelogram is done. Plasma levels of estradiol, estrone, testosterone, and sex hormone 0090~8258/85 $1.50 CopyrIght All rights

0 1985 by Academic Press, Inc. of reproduction in any form recerved.

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CANCER

binding globulin are measured. A fasting plasma glucose or a glucose tolerance test is used to detect diabetes. Chest X ray and ECG are routine in elderly patients as anesthetic assessment. No preoperative radiotherapy is used. (Prior to 1977 the usual protocol was intrauterine radium followed after 6 weeks by abdominal hysterectomy). Before laparotomy the cervix is packed with gauze and sutured, to prevent spill of endometrial cells into the vagina. At laparotomy the Pouch of Douglas is irrigated with 100 ml of normal saline which is then aspirated. Tubal washings are also taken. These fluids are examined cytologically for malignant cells. Paraaortic nodes are biopsied unless access is impossible or the patient’s general condition precludes it. Total hysterectomy and bilateral salpingo-oophorectomy is performed; portions of the tumor are selected for receptor studies and the remainder sent for histopathology. Estrogen receptors are estimated by saturation analysis. Estradiol binding levels below 4 fmole/mg protein are considered receptor negative and binding greater than 4 fmole/mg receptor positive. Progesterone receptors are estimated by saturation analysis. Progestagen binding levels below 10 fmole/mg protein are considered receptor negative and binding greater than 10 fmole/mg receptor positive. Subsequent management is based on the stage and grade of tumor, myometrial penetration, presence of malignant cells in the washings, deposits in nodes, and receptor activity. RESULTS Classijication

One hundred and thirteen cases (64%) had risk factors (E+ ve). Sixty-two cases (36%) had no risk factors (E - ve). Of the E -ve group 22 patients were truly occult; 4 had no bleeding at all; the lesion was discovered at hysterectomy for other reasons. Nine patients had vaginal discharge (clear or purulent), 3 patients had vaginal bleeding provoked by coitus, and 6 patients had bleeding provoked by estrogen therapy (local or systemic) for less than 2 months. Age and Parity:

Table I

All E - ve tumors occurred in postmenopausal women. None of these patients had an early (before age 40) or late (after age 55) menopause. The average age TABLE

1

PARITY

E-ve

E+ve

No.

No.

%

Nulliparous Para 1 Para 2+

34 21 118

23 8 31

37 13 50

Total

173

62

No. 11 13 87 111

% 10 12 78

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SMITH AND MC CARTNEY

for the E - ve group was 65 whereas for the E + ve group it was 55. Thirty-seven percent of the E-ve group were nulliparous. Ten percent of the E+ve group were nulliparous. Risk Factors: Table 2 We defined obesity as weight of 70 kg or more. The recognized risk factors occur in the E + ve group since we used these criteria to categorize cases. We include in the table two other suggested risk factors viz., lack of sexual intercourse, and arthritis treated with nonsteroidal anti-inflammatory drugs. We note that many women over the age of 60 are no longer sexually active either from lack of a partner or because of dyspareunia related to genital atrophy. Ninety percent of the E-ve group were no longer (or never) sexually active while 50% of the E + ve group were still sexually active. (This may be a factor which determines whether the tumor presents early or late.) In each group 30% of women had arthritis treated on a regular basis with nonsteroidal anti-inflammatory drugs. These may affect cervical patency and thus delay diagnosis because bleeding is initially occult. Stage and Grade of Tumor: Tables 3 and 4 The E - ve group had 20% of cases in Stage II-IV compared with only 5.5% of the E + ve group. The E - ve tumors had a higher frequency of grades II and III (67.5% compared to 48%), though this may not be statistically significant. Penetration

of Tumor:

Table 5

E - ve tumors (61.5%) penetrated more than halfway through the endometrium (6.5% were full thickness) as opposed to E + ve 21.5% (also 6.5% full thickness). Receptor Activity: Table 6 Estrogen receptor activity (ER) was measured in 111 cases. Estrogen receptors were positive in 93 cases-18 of these (29%) were in the E -ve group and 75 TABLE RISK

2

FACTORS

E-ve No. Recognized Exogenous estrogen Obesity Diabetes Suggested No sexual intercourse Arthritis

20 74 47 111 52

E+ve

No.

% No. %

-

-

20 18 74 67 47 42

56 19

90 30

55 50 33 30

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TABLE

157

3

E+ve Stage

Total

Ia Ib II III IV

101 42 11 7 5

E-ve

No.

%

No.

%

73 25 5 0 1

66 22.5 4.5 0 1

28 17 6 7 4

45 27 10 11 6

TABLE

4

E+ve Grade

E-ve

Total

No.

%

71 70 30

57 37 15

52 34 14

1 2 3

TABLE PENETRATION

No. 14 33 1.5

IN UTERINE E-ve

No.

%

0 % Full thickness Not known

41 29 42 45 11 5

7 9 12 28 4 2

11 14.5 20 45 6.5

Total

173

62

Receptor ER ER

Activity POS NEG

No.

%

34 20 30 17 7 3

31 18 27 15 6.5

111

6 ACTIVITY

= 93 18 111

WALL E+ve

Total

TABLE

22.5 53 24

5

OF TUMOR

RECEPTOR

%

E-ve 18 14

(29%) (79%)

E+ve 75 4

(67%) (23%)

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(67%) in the E+ve group. Estrogen receptors were negative in 18 cases-18 (77%) were in the E-ve group, 4 (23%) in the E+ve group. Progesterone receptors were estimated in only 45 cases therefore results are not significant but it is noted that 30 cases were positive and 15 negative. Four of the E -ve group had positive progesterone receptor activity while 26 cases in the E+ve had progesterone receptor activity. Paraaortic

Nodes

Paraaortic node biopsies were positive in 8% of E-ve and 4.5% of E+ve cases. In 20 cases nodes were not biopsied, mainly due to operative difficulty such as extreme obesity. Peritoneal

and Tubal Washings

In 20 cases washings were not taken. In 35% of E-ve cases malignant cells were identified in the tubes or the peritoneal aspirate as against 15% in E+ve cases. Deaths

Twenty-three patients died within 5 years; 13 of disease, 10 of other causes. Of those caused by tumor, 10 were E - ve (7 occult). Three were E + ve; 1 was caused by exogenous estrogens, 2 caused by endogenous estrogen activity. All these patients presented late (Stage II or more) and it is suggested that delay in diagnosis was a contributing factor. DISCUSSION

Bokman’s [5] two pathogenetic types are confirmed by our figures. Thirty-six percent of our cases appear E - ve. Interest centered on E + ve tumors [l-4] has led to safer hormone therapy in menopause clinics and a steadily declining incidence of cancer from exogenous estrogens is noted in those women who receive progestagen therapy as well for at least 10 days each month [6-9,201. Women with endocrine stigmata such as diabetes, obesity, and persistent anovulation are recognized and curettage is undertaken for abnormal bleeding. Thus the estrogen-dependent (or related) tumor is discovered at an early stage and grade and should carry a good prognosis. In fact a recent article [ 111 claims that endometrial cancer is “common but curable.” However, women in whom diagnosis is delayed may not be curable. This may occur because of delay by the patient or doctor in investigation of vaginal bleeding [12]. It may also occur because bleeding is occult. Such women may present at a menopause clinic with signs of estrogen deficiency (genital atrophy, osteoporosis). Laufer et al. [13] compare physical characteristics and sex hormone levels in patients with osteoporosis and endometrial cancer and state that these conditions are mutually exclusive because of estrogen deficiency in osteoporosis and slight excess of estrogen in the cancer cases. Our own data suggest that the older thinner women with signs of estrogen deficiency has an increased risk not only of osteoporosis but of the aggressive (because often occult) endometrial cancer.

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In our study 62 cases (36%) had no classical risk factors. These we designate E - ve; the other 111 cases (64%) we call E + ve. We have compared, age, parity, risk factors, stage, grade, receptor activity, and spread of tumor in these two groups. To the risk factors we have added two not generally so considered, viz., “lack of sexual intercourse” and “arthritis treated for 6 months or longer with nonsteroidal anti-inflammatory drugs.” We consider that both of these may alter cervical patency by altering prostaglandin activity (in addition to the physiological stenosis of age and estrogen deficiency). In the E - ve group 22 cases were truly occult, i.e., had no vaginal bleeding; 4 tumors were discovered at hysterectomy for other reasons, 6 had bleeding provoked by coitus or administration of estrogens for less than 2 months; 12 had vaginal discharge only, without frank bleeding. The other 40 E - ve cases presented with unprovoked bleeding but this was very often late in the course of the disease. In 50% of E - ve tumours there was deep myometrial penetration and in 35% there was evidence of transtubal spread. It is generally believed that endometrial cancer is estrogen dependent, though factors such as previous irradiation are shown to increase the risk by a factor of 8 [14,15]. In the E - ve group the initiating factor is similarly unknown. It seems unlikely that extremely low levels of estrogen can stimulate undue endometrial activity even over a very long time. These patients have the physical signs of estrogen deficiency; the tumor appears to have arisen in an estrogen “desert.” The normal shedding capacity of the endometrium is lost after the menopause. In addition, the cervix deprived of estrogens shrinks and becomes stenosed. Bleeding from a tumor may fail to escape, thus the tumor develops and spreads into the uterine wall or through the fallopian tubes causing microscopic and later macroscopic peritoneal seeding. If the patient or her doctor ignore vaginal bleeding tumor may also spread in similar manner [20]. The value of looking for malignant cells in peritoneal washings has been recorded [16-191 and our own study amply confirms the sinister prognostic significance of positive washings. This department has previously assessed the value of hormone receptor measurements in endometrial cancer [20-231. The present series demonstrates that not all estrogen-dependent tumors are receptor positive nor all estrogen-independent tumors receptor negative. Nevertheless, receptor activity offers a prognostic aid which may help to assess the usefulness of endocrine manipulation in the advanced case [24]. The 22 occult cases in our series had no vaginal bleeding at all or else presented with very late bleeding provoked either by intercourse or by administration of estrogen for a few weeks only. Six patients reported bleeding after administration of dienoestrol cream or oral estrogens for vaginal atrophy. This leads us to suggest that an estrogen provocation test may be a useful indicator of an occult malignancy in the thin elderly estrogen-deficient woman who has a tightly stenosed cervix not admitting a sound or any kind of curette. Daily application of estrogen cream to the vagina for 4 weeks or oral estrogen (10 pg of ethinyl estradiol) for 4-6 weeks will be followed by vaginal bleeding if there is a preexistent lesion. Such a short course of hormones cannot induce cancer but only reveal the hidden tumor by softening the cervix and allowing the escape of previously hidden blood

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(hematometra), or by causing a withdrawal bleeding from the endometrium. Obviously if there is a high index of suspicion of an occult lesion then formal curettage is required but it is not necessary to perform curettage on every thin elderly woman. At present there is no reliable screening program for endometrial cancer [25]. Koss et al 1261conducted a feasibility study of detection of endometrial cancer. They described 8 cases with occult endometrial cancer 7 of which were related to estrogens (patient was obese or had ingested estrogen). In such cases sampling of the endometrium is usually simple and reliable. We are concerned more with the occult case where estrogen deficiency makes the cervix unnegotiable. Since this series was collected a further 4 patients with no previous vaginal bleeding have had bleeding following the application of estrogen cream to the vagina for 4 weeks. Although this is a very small series it does seem that an estrogen provocation test merits consideration. After the estrogen application aspiration curettage is made easy by the softening of the cervix so that this can be done as an outpatient procedure. REFERENCES 1. Armstrong, B. Endocrine factors in human carcinogenesis, in Host factors in human carcinogenesis (B. Armstrong and H. Bartsch, Eds.), Lyon, (IARC Scientific Publications No: 39), pp. 193221 (1982). 2. Armstrong, B. K. Cancer after hormone therapy, Cancer Sum. 1, pp. 625-652 (1982). 3. Davies, J. L., Rosenshein, N. B., Antunes, C. M. F., and Stolley, P. D. A review of the risk factors for endometrial carcinoma, Obsfet. Gynecol. Surv. 36(3), 107-I 16 (1981). 4. Ziel, H. K. Estrogen’s role in endometrial cancer, Obstet. Gynecol. 60, 509-515 (1982). 5. Bokhman, J. V. Two pathogenetic types of endometrial cancer, Gynecol. Oncol. 15, lo-17 (1983).

6. Gambrel], R. D., Bagnell, C. A., and Greenblatt, R. B. Role of estrogens and progesterone in the aetiology and prevention of endometrial cancer: Review, Amer. J. Obstet. Gynecol. 146, 696-707 (1983). 7. Whitehead, M. I., Townshend, P. T., Pryse-Davies, J., Ryder, T. A., and King, R. J. B. Effects of estrogens and progestins on the biochemistry and morphology of the postmenopausal endometrium, N. Engl. J. Med. 305, 1599-1605 (1981). 8. Mugglestone, C. J., Swinhoe, J. R., and Craft, I. L. Combined estrogen and progestogen for the menopause, Acta Obsret. Gynecol. &and. 59, 327-329 (1980). 9. Judd, H. L., Cleary, R. E., Creasman, W. T., Figge, D. C., Kase, N., Rosenwaks, Z., and Tagatz, G. E. Estrogen replacement therapy, Obstet. Gynecol. 58, 267-275 (1981). 10. Hammond, C. B., and Maxson, W. S. Current status of estrogen therapy for the menopause, Fertil.

Steril.

37, 5-15

(1982).

11. Malkasian, G. D. Endometrial cancer--common but curable, Geriufrics 38, 107-112 (1983). 12. Franceschi, S., Lavecchia, C., Gallus, G., De Carli, A., Colombo, E., Mangioni, C., and Tognoni, G. Delayed diagnosis of endometrial cancer in Italy, Cancer 51, 1176-l 178 (1983). 13. Laufer, L. R., Davidson, B. J., Ross, R. K., Lagasse, L. D., Siiteri, P. K., and Judd, H. L. Physical characteristics and sex hormone levels in patients with osteoporotic hip fractures or endometrial cancer, Amer. J. Obstet. Gynecol. 145, 585-590 (1983). 14. Koss, L. G., Cramer, D., Ferenczy, G., Gurpide, E., Reagan, J. W., Siiteri, P. K., and Summers, S. C. Recent advances in endometrial neoplasia, Acta Gynecol. 24(7), 478-493 (1980). 15. MacMahon, B. Risk factors for endometrial cancer, Gynecol. Oncol. 2, 122-129 (1974). 16. Creasman, W. T., and Rutledge, F. The prognostic value of peritoneal cytology in gynecologic malignant disease, Amer. J. Obster. Gynecol. 110, 773-781 (1971). 17. Keettel, W. C., Pixley, E. E., and Buchsbaum, H. J. Experience with peritoneal cytology in the management of gynecologic malignancies, Amer. J. Obster. GynecoL. 120, 174-182 (1974).

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18. Szpak, C. A., Creasman, W. T., Vollmer, R. T., and Johnston, W. W. Prognostic value of cytologic examination of pritoneal washings in patients with endometrial carcinoma, Acra Cytol. 25, 638-640 (1981). 19. Hacker, N. F., Castoldok, T. W., Morrow, C. P., and Ballon, S. C. Positive pritoneal cytology in corpus carcinoma. Report of a fatal outcome, Amt. N.Z.J. Obstef. Gynaecol. 22, 103-106 (1982). 20. Evans, L. H., Martin, J. D., and Hahnel, R. Estrogen receptor concentration in normal and pathological human uterine tissues, J. Clin. Endocrinol. Metab. 38, 23-32 (1974). 21. Martin, J. D., and Hahnel, R. Oestrogen receptor studies in carcinoma of the endometrium, carcinoma of the uterine cervix and other gynaecological malignancies, Aust. N.Z.J. Obstet. Gynaecol. 18, 55-59 (1978). 22. Hahnel, R., Martin, J. D., Masters, A. M., Ratajczak, T., and Twaddle, E. Estrogen receptors and blood hormone levels in endometrial carcinoma, Gynecol Oncol. 8, 209-225 (1979). 23. Spona, J., Ulm, R., Bieglmayer, C., and Husslein, P. Hormone serum levels and hormone receptor contents of endometrium in women with normal menstrual cycles and patients bearing endometrial carcinoma, Gynecol. Obstet. Invest. 10, 71-75 (1979). 24. Hunter, R. E., Longcope, C., and Jordan, V. C. Steroid hormone receptors in adenocarcinoma of the endometrium, Gynecol. Oncol. 10, 152-161 (1980). 25. Reagan, J. W. Can screening for endometrial cancer be justified, Acta Cytol. 24, 87-89 (1980). 26. Koss, L. G., Schreiber, K., Oberlander, S. G., Moukhtar, M., Levine, H. S., and Moussouris, H. F. Screening of asymptomatic women for endometrial cancer, Obstet. Gynecol. 57, 681691 (1981).