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Increased androgenic activity in well-differentiated endometrial adenocarcinoma
GYNECOLOCX
ONCOLOGY
14, 40-48 (1982)
Increased Androgenic Activity in Well-Differentiated Endometrial Adenocarcinoma RENZO GRATTAROLA, Hormone Research Laboratory,
M.D.’
Istituto Nazionale dei Tumori, Via Venezian 1, Milan, Italy Received June 23, 1981
Well-differentiated adenocarcinoma of the endometrium was diagnosed in 3 patients with polycystic ovary syndrome (PCO) and in 2 long-term users of an oral contraceptive (ethinylestradiol plus dimethisterone), all 5 at premenopausal age (from 28 to 36 years). These patients had high urinary testosterone. None underwent hysterectomy; the 3 with PC0 were treated by wedge resection of the ovaries, and the 2 oral contraceptive users by simple curettage and discontinuation of oral contraception. The treatment was able to revert the endometrial pattern to normal as well as decrease the urinary level of testosterone. These patients were followed up for 3 to 10 years since the hormonal study and none has so far had a recurrence. The testosterone excretion level was determined in an additional 26 patients with well-differentiated adenocarcinoma and in 14 with undifferentiated adenocarcinoma of the endometrium. It was found that the testosterone excretion level was significantly increased in patients with well-differentiated adenocarcinoma but not in patients with undifferentiated adenocarcinoma of the endometrium.
INTRODUCTION The occurrence of endometrial adenocarcinoma in patients with polycystic ovary syndrome (PCO) [3,4,8,9,18] and in patients on long-term sequential oral contraception has been described [ 10,13,16]. These patients were all young (from 23 to 34 years) and all underwent total hysterectomy and bilateral ovariectomy. In none of these cases has the carcinoma been reported to recur or metastasize r31. In almost all these patients the histologic study revealed a well-differentiated adenocarcinoma of the endometrium. Since it is sometimes difficult to differentiate an atypical adenomatous hyperplasia from a well-differentiated adenocarcinoma [lo] and since this lesion is usually a disease of post-menopausal women, the diagnosis of endometrial adenocarcinoma in young women with associated PC0 or following prolonged estrogen treatment has been viewed with skepticism, and wedge resection of the ovaries [l-4] or curettage alone [14] has been the only effective therapeutic approach. This paper reports on five young patients with a histologic diagnosis of welldifferentiated adenocarcinoma of the endometrium who were treated conservatively and followed for years without any evidence of recurrence of the disease. Three patients underwent ovarian wedge resection for PCO, and two patients, ’ Send reprint requests to: Antonietta Grattarola, M.D., Ottava Strada 32, 20090 Milan0 Sifelice, Italy. 40 0090-8258/82/040040-09$01.00/0 Copyright 0 1982 by Academic Press, Inc. AU rights of reproduction in any form reserved.
ANDROGENS
AND
WELL-DIFFERENTIATED
ENDOMETRIAL
ADENOCARCINOMA
41
who were taking oral contraceptive agents, underwent simple curettage. The testosterone excretion level was above normal in all these patients. In the present study the excretion level of testosterone was determined in other pre- and postmenopausal patients who had undergone total hysterectomy and bilateral ovariectomy for well-differentiated endometrial adenocarcinoma and was found to be above normal. In other patients, pre- and postmenopausal, with undifferentiated endometrial adenocarcinoma, the urinary testosterone level was normal. MATERIALS
AND METHODS
We examined 45 patients, 19 premenopausal (ages 28 to 48 years) and 26 postmenopausal (ages 45 to 79 years). The testosterone excretion level was determined in these patients before any final treatment and a few days after histologic study of the endometrial biopsy had revealed the presence of an adenocarcinoma. In 3 premenopausal patients with elevated urinary testosterone and symmetrically enlarged ovaries, revealed by pelvic pneumography (gynecography), the final treatment was wedge resection of the ovaries. In 2 other premenopausal patients, who were long-term users of oral contraceptives and had increased testosterone levels, the final treatment was simple curettage. The sequential oral contraceptive used by these 2 patients was a combination of ethinylestradiol and dimethisterone (17@hydroxy-6-ol-methyl-17-(1-propynyl) androst-4-en-3-one), the former being taken at a dose of 0.1 mg daily for 21 days of each cycle and the latter, acting as the progestational component, at a dose of 25 mg daily from Day 17 through Day 21 of each cycle. These two patients had been on oral contraceptives for 5 and 6 years, respectively, after which they started to have intermittent periods of amenorrhea lasting 2-3 months, followed by profuse bleeding. The remaining 14 premenopausal patients and all 26 postmenopausal patients underwent total abdominal hysterectomy and bilateral salpingoovariectomy followed by intravaginal radium treatment a week later. The urinary testosterone (17@-hydroxyandrost-4-en-3-one) level was determined in all these patients by the method previously described [7]. Eleven patients received human chorionic gonadotropin (HCG) im (5000 IU daily for 3 days; total dose 15,000 IU) to induce an increase of testosterone excretion. Nine were postmenopausal. The urinary testosterone was also determined in 18 premenopausal women and in 21 postmenopausal women, acting as normal controls. They were selected, as previously reported [7], from a sample of all patients attending our outpatient clinic for the Pap test and were matched to our patients for age, height, and weight. The data obtained from the patients with endometrial adenocarcinoma and those from normal controls were compared by Student’s t test after the conversion of the data to a logarithmic scale. P < 0.05 was considered significant. RESULTS No significant difference in urinary testosterone levels was found between preand postmenopausal normals. The 24-hr urinary testosterone excretion in mi-
42
RENZO GRATTAROLA
crograms ranged from 0.0 to 12.7 (mean value: 6.5 + 0.8) in the premenopausal controls and from 0.0 to 13.0 (mean value: 5.2 2 1.1) in the postmenopausal controls. In normal premenopausal women, histologic examination of the endometrium, obtained at the premenstrual period together with the urine collection for testosterone determination, showed a progestational pattern and in postmenopausal women, a hypotrophic pattern [6]. In all 45 patients examined, histologic study revealed adenocarcinoma: in 31 well-differentiated and in 14 undifferentiated. In the group of patients with well-differentiated adenocarcinoma (31 patients, including 3 with adenoacanthoma) the urinary testosterone was significantly above normal (Table 1) and the range, in micrograms/24 hr, was 0.0 to 60.0. Sixteen of these patients (age range 28 to 48) were premenopausal and 15 (age range 45 to 64) were postmenopausal: mean urinary testosterone excretion values did not differ significantly in these two groups. In the group of patients with undifferentiated adenocarcinoma (14 patients), presenting a less prominent glandular pattern and solid epithelial mass or diffusely cellular growth, the urinary testosterone was not different from the normal value (Table l), the range in micrograms/24 hr being 0.0 to 12.6. In this group 3 patients were premenopausal (age range 31 to 43) and 11 postmenopausal (age range 61 to 79). Apart from the five premenopausal patients, who were not treated by hysterectomy, all others, pre and postmenopausal, with well-differentiated or undifferentiated endometrial adenocarcinoma underwent hysterectomy and bilateral ovariectomy. There are no adequate follow-up data for these patients, because only 1-2 years have elapsed from surgical treatment. It is, however, known that of the 14 patients with undifferentiated adenocarcinoma 4 died within a year after surgery (2 of the 3 premenopausal patients), but none of the patients with welldifferentiated adenocarcinoma has died. Of the 5 patients who did not undergo hysterectomy and bilateral ovariectomy, 3 underwent ovarian wedge resection (patients 8R-41, 13R-39, and 27R-57) for PCO, and 2 simple curettage (patient 3OR-35 and 32R-50) together with interruption of oral contraceptives. TABLE TESTOSTERONE
(T)
EXCRETION
LEVEL
1
IN PATIENTS WITH WELL-DIFFERENTIATED ENWMETRIAL ADENOCARCINOMA
OR UNDIFFERENTIATED
Histology
No. of cases
bd24 W
Adenoacanthoma Well-differentiated adenocarcinoma Undifferentiated adenocarcinoma
3 (2) 28 (14) 14 (3)
19.08 * 1.9b 20.80 2 3.2b 7.20 f 4.5’
Normal controls Premenopause Postmenopause
18 21
a Number of premenopausal b Mean f SE. ’ N.S., not significant.
patients in parentheses.
T
6.50 -c 0.8 5.20 2 1.1
Significance 0.01 0.01 N.S.’
P < P <
ANDROGENS
AND
WELL-DIFFERENTIATED
ENDOMETRIAL
TABLE CASES
OF END~METRIAL WITH PROLONGED
Case
Age
2
ADEN~CARCINOMA ASSOCIATED WITH POLYCYSTIC OVARY DISEASE USE OF SEQUENTIAL ORAL CONTRACEPTION (ETHINYLESTRADIOL DIMETHISTERONE)
Remarks
Testosterone @g/24 hr)
43
ADENOCARCINOMA
(PCO)
OR
+
(OC)
Endometrial carcinoma
Treatment
8R-4 1
35
PC0
22.0
Well differentiated
13R-39
33
PC0
30.0
Adenoacanthoma
27R-57
28
PC0
20.7
Well differentiated
30R-35
36
16.0
Adenoacanthoma
32R-50
33
OC (for 6 ye=s) OC (for 5 years)
Ovarian wedge resection Ovarian wedge resection Ovarian wedge resection Curettage
13.2
Well differentiated
Curettage
Observation period (years) 8 10 3 3 3
These patients have been followed up for 3 to 10 years since the hormonal study and none has so far had a recurrence (Table 2). The tissue removed from the ovaries of the patients subjected to ovarian wedge resection was examined histologically and the findings were consistent with polycystic ovarian disease: follicular cysts with prominent luteinized theta cells and interstitial cell hyperplasia. In 10 premenopausal patients and in 10 postmenopausal patients who underwent hysterectomy and bilateral ovariectomy, the ovaries were examined histologically; interstitial cell hyperplasia was found to be present in all the patients with well-differentiated adenocarcinoma and high urinary testosterone levels. In 2 (13R-36 and 7R-70) out of 7 patients with undifferentiated adenocarcinoma the interstitial cell hyperplasia was shown together with metastases in the ovarian stroma and no increase in urinary testosterone. Urinary testosterone levels after HCG. HCG, 15,000 IU, was injected in 6 patients with well-differentiated adenocarcinoma and in 5 patients with undifferentiated adenocarcinoma. Before HCG stimulation 2 patients with well-differentiated adenocarcinoma, but none of the patients with undifferentiated adenocarcinoma, presented high urinary testosterone levels (Table 3). After injection of 15,000 IU HCG 5 of the 6 patients with well-differentiated and 2 of the 5 patients with undifferentiated adenocarcinoma had increased testosterone levels; these 2 patients (13R-36 and 7R-70) were those who presented interstitial cell hyperplasia and metastases on histologic examination of the ovaries. DISCUSSION The histologic distinction between atypical endometrial hyperplasia and welldifferentiated adenocarcinoma is not easy, even in the presence of malignant features, like irregular configuration of the glands and nuclear atypia with increased chromatin irregularly distributed in the nuclei [3]. The morphologic type
44
RENZO
GRATTAROLA TABLE
TESTOSTERONE UNDIFFERENTIATED
EXCRETION
(B)
VALUES
ENWMETRIAL
IN PATIENTS
3 WITH
ADENOCARCINOMA
(A)
WELL-DIFFERENTIATED
BEFORE
AND
AFTER
OR
ADMINISTRATION
OF
15,ooO IU HCG B
A Patient 13R-79 12R-56 12R-23 14R-24 8R-70 12R-74
Before
(M) (M) (M) (M) (M)
8.0 5.0 27.0 0.0 21.6 10.5
After 34.0 25.2 42.5 1.5 72.0 25.0
Patient 14R-38 13R-36 7R-70 13R-78 9R-47
(M) (M) (M) (M)
Before
After
8.0 9.2 3.6 0.0 3.0
8.0 18.0b 24.0b 1.2 7.5
’ Menopause. b Ovarian metastases.
of lesion does not always guarantee its biological behavior, as proved by the reversion to normality of histologic patterns of endometrial carcinoma following ovarian resection or, as shown in this study, discontinuation of sequential oral contraceptives. We would emphasize that the definition of “carcinoma” is an epithelial lesion which, once established, grows progressively locally and often metastasizes, whereas the endometrial change that regresses following withdrawal of a promoter of cell proliferation is a reversible change and not a carcinoma, as pointed out many years ago by Novak and Rutledge [ 141, We wonder how many of the endometrial adenocarcinomas reported in the literature, even recently, following contraceptive or estrogen treatment or in the presence of polycystic ovaries, were really adenocarcinoma of the endometrium. We suggest that young patients with a histologic diagnosis of well-differentiated adenocarcinoma and high androgen excretion levels should not be subjected to hysterectomy, but should be kept under strict observation after withdrawal of the abnormal hormonal stimulation. In the present study, as in previous published papers, we have shown that atypical endometrial hyperplasia or misdiagnosed well-differentiated adenocarcinoma in premenopausal women is frequently accompanied by increased androgenic activity, which may have its origin in the ovary because of polycystic disease [41 or in the adrenal [5] because of an androgen-producing adenoma or in the progestational component of the sequential oral contraceptive-dimethisteronea steroid of the androstane series, which still bears the 17-hydroxy group responsible for the androgenic activity. We do not dispute the conventional view that estrogens are responsible for endometrial hyperplasia and malignancy. We merely point out that: (1) endometrial malignancy is more frequent in patients at an advanced postmenopausal age, when the ovary no longer produces estrogens, but secretes significant quantities of androgenic hormones [6,17]; (2) the ovarian tumors associated with a high incidence of endometrial adenocarcinoma are more frequently thecomas, which are androgen-producing tumors [ 111; (3) even if some authors have called women with PC0 “fully feminized” [12], it is well known that this syndrome
FIGS. 1, 2. Endometrium of patient 32R-50, before any treatment, at two magnifications (X 50, x 120). Well-differentiated atypical glands ; are crowded and lined by stratified epithelium, with a scant amount of stromal tissue. In some areas epidermoid endome trium.
1
adenocarcinon na: the differentiation of the
R
46
RENZO
GRATTAROLA
FKX 5, 6. Endometrium of patient 13R-39, before any treatment (X 120, x 220). Well-differentiated adenocarcinoma: crowding of the glands with little intervening stroma. Although the glandular architecture is preserved, the gland spaces display a great variation in size. Heaping up of the epithelium in papillary intraglandular projection. The cells lining the glands show a variation in size and shape of the nuclei, with loss of polarity.
48
RENZO GRATTAROLA
is accompanied by androgenicity, clinically evidenced by hirsutism and elevated blood and urine androgen levels [9,15,18]. We do not know whether androgens act as promoters of abnormal cell proliferation alone or act in concert with estrogens. We simply recommend caution before undertaking ablative surgery, like hysterectomy, when androgens are present in abnormal amounts in young women with well-differentiated adenocarcinoma of endometrium. REFERENCES 1. Chamlian, D. L., and Taylor, H. B. Endometrial 36, 659-665 2. 3.
4. 5. 6.
hyperplasia in young women, Obstet.
Gynecol.
(1970).
Eddy, W. A. Endometrial carcinoma in Stein-Leventhal syndrome treated with hydroxyprogesterone caproato, Amer. J. Obstet. Gynecol. 131, 581-582 (1978). Fechner, R. E., and Kaufman, R. H. Endometrial adenocarcinoma in Stein-Leventhal syndrome, Cancer 34, 444-452 (1974). Grattarola, R. Misdiagnosis of endometrial adenocarcinoma in Young women with polycystic ovarian disease, Amer. J. Obstet. Gynecol. 105, 498-502 (1969). Grattarola, R. Misdiagnosis of endometrial adenoacanthoma in a 27-year-old woman with adrenocortical tumor, Oncology 28, 246-252 (1973). Grattarola, R., Secrete, G., Recchione, C., and Castellini, W. Androgens in breast cancer. II. Endometrial adenocarcinoma and breast cancer in married post-menopausal women, Amer. J. Obstet.
Gynecol.
118, 173-178
(1974).
7. Grattarola, R. Anovulation and increased androgenic activity as breast cancer risk in women with fibrocystic disease of the breast, Cancer Res. 38, 3051-3054 (1978). 8. Gusberg, S. B. Precursors of corpus carcinoma, estrogens and adenomatous hyperplasia, Amer. J. Obstet. Gynecol. 54, 905-927 (1947). 9. Jafari, K., Javaheri, G., and Ruiz, G. Endometrial adenocarcinoma and the Stein-Leventhal syndrome, Obstet. Gynecol. 51, 97-100 (1978). 10. Kaufman, R. H., Reeves, K. O., and Dougherty, C. M. Severe atypical endometrial changes and sequential contraceptive use, J. Amer. Med. Assoc. 236, 923-926 (1976). 11. Klopper, A., and Farr, V. The epidemiology of endometrial cancer, In Frontiers of hormone research, Vol. 5, Estrogen therapy: The benefits and risks (C. Lauritzen and P. A. vanKeep, Eds), van Wimersma Greidanus, Utrecht, pp. 89-100 (1978). 12. Landau, R. L. What you should know about estrogens, J. Amer. Med. Assoc. 24147-51 (1979). 13. Lyon, F. A. The development of adenocarcinoma of the endometrium in young women receiving long-term sequential oral contraception, Amer. J. Obstet. Gynecol. 123, 299-301 (1975). 14. Novak, E., and Rutledge, F. Atypical hyperplasia endometrial simulating adenocarcinoma, Amer. J. Obstet. 15.
Gynecol.
55, 46-63
(1948).
Raj, S. G., Thompson, I. E., Berger, M. J., Tale& L. M., and Taymor, M. L. Diagnostic value of androgens measurements in polycystic ovary syndrome, Obstet. Gynecol. 52, 169-171 (1978).
Silverberg, S. G., and Makowski, E. L. Endometrial carcinoma in young women taking oral contraceptive agents, Obstet. Gynecol. 46, 503-506 (1975). 17. Studd, J. W., Collins, W. P., and Chakravarti, S. Plasma hormone profiles after the menopause and bilateral oophorectomy, Postgrad. Med. J. 54(Suppl.), 25-30 (1978). 18. Wood, G. P., and Boronow, R. C. Endometrial adenocarcinoma and the polycystic ovary syndrome, Amer. J. Obstet. Gynecol. 124, 140-142 (1976). 16.
ONCOLOGY
14, 40-48 (1982)
Increased Androgenic Activity in Well-Differentiated Endometrial Adenocarcinoma RENZO GRATTAROLA, Hormone Research Laboratory,
M.D.’
Istituto Nazionale dei Tumori, Via Venezian 1, Milan, Italy Received June 23, 1981
Well-differentiated adenocarcinoma of the endometrium was diagnosed in 3 patients with polycystic ovary syndrome (PCO) and in 2 long-term users of an oral contraceptive (ethinylestradiol plus dimethisterone), all 5 at premenopausal age (from 28 to 36 years). These patients had high urinary testosterone. None underwent hysterectomy; the 3 with PC0 were treated by wedge resection of the ovaries, and the 2 oral contraceptive users by simple curettage and discontinuation of oral contraception. The treatment was able to revert the endometrial pattern to normal as well as decrease the urinary level of testosterone. These patients were followed up for 3 to 10 years since the hormonal study and none has so far had a recurrence. The testosterone excretion level was determined in an additional 26 patients with well-differentiated adenocarcinoma and in 14 with undifferentiated adenocarcinoma of the endometrium. It was found that the testosterone excretion level was significantly increased in patients with well-differentiated adenocarcinoma but not in patients with undifferentiated adenocarcinoma of the endometrium.
INTRODUCTION The occurrence of endometrial adenocarcinoma in patients with polycystic ovary syndrome (PCO) [3,4,8,9,18] and in patients on long-term sequential oral contraception has been described [ 10,13,16]. These patients were all young (from 23 to 34 years) and all underwent total hysterectomy and bilateral ovariectomy. In none of these cases has the carcinoma been reported to recur or metastasize r31. In almost all these patients the histologic study revealed a well-differentiated adenocarcinoma of the endometrium. Since it is sometimes difficult to differentiate an atypical adenomatous hyperplasia from a well-differentiated adenocarcinoma [lo] and since this lesion is usually a disease of post-menopausal women, the diagnosis of endometrial adenocarcinoma in young women with associated PC0 or following prolonged estrogen treatment has been viewed with skepticism, and wedge resection of the ovaries [l-4] or curettage alone [14] has been the only effective therapeutic approach. This paper reports on five young patients with a histologic diagnosis of welldifferentiated adenocarcinoma of the endometrium who were treated conservatively and followed for years without any evidence of recurrence of the disease. Three patients underwent ovarian wedge resection for PCO, and two patients, ’ Send reprint requests to: Antonietta Grattarola, M.D., Ottava Strada 32, 20090 Milan0 Sifelice, Italy. 40 0090-8258/82/040040-09$01.00/0 Copyright 0 1982 by Academic Press, Inc. AU rights of reproduction in any form reserved.
ANDROGENS
AND
WELL-DIFFERENTIATED
ENDOMETRIAL
ADENOCARCINOMA
41
who were taking oral contraceptive agents, underwent simple curettage. The testosterone excretion level was above normal in all these patients. In the present study the excretion level of testosterone was determined in other pre- and postmenopausal patients who had undergone total hysterectomy and bilateral ovariectomy for well-differentiated endometrial adenocarcinoma and was found to be above normal. In other patients, pre- and postmenopausal, with undifferentiated endometrial adenocarcinoma, the urinary testosterone level was normal. MATERIALS
AND METHODS
We examined 45 patients, 19 premenopausal (ages 28 to 48 years) and 26 postmenopausal (ages 45 to 79 years). The testosterone excretion level was determined in these patients before any final treatment and a few days after histologic study of the endometrial biopsy had revealed the presence of an adenocarcinoma. In 3 premenopausal patients with elevated urinary testosterone and symmetrically enlarged ovaries, revealed by pelvic pneumography (gynecography), the final treatment was wedge resection of the ovaries. In 2 other premenopausal patients, who were long-term users of oral contraceptives and had increased testosterone levels, the final treatment was simple curettage. The sequential oral contraceptive used by these 2 patients was a combination of ethinylestradiol and dimethisterone (17@hydroxy-6-ol-methyl-17-(1-propynyl) androst-4-en-3-one), the former being taken at a dose of 0.1 mg daily for 21 days of each cycle and the latter, acting as the progestational component, at a dose of 25 mg daily from Day 17 through Day 21 of each cycle. These two patients had been on oral contraceptives for 5 and 6 years, respectively, after which they started to have intermittent periods of amenorrhea lasting 2-3 months, followed by profuse bleeding. The remaining 14 premenopausal patients and all 26 postmenopausal patients underwent total abdominal hysterectomy and bilateral salpingoovariectomy followed by intravaginal radium treatment a week later. The urinary testosterone (17@-hydroxyandrost-4-en-3-one) level was determined in all these patients by the method previously described [7]. Eleven patients received human chorionic gonadotropin (HCG) im (5000 IU daily for 3 days; total dose 15,000 IU) to induce an increase of testosterone excretion. Nine were postmenopausal. The urinary testosterone was also determined in 18 premenopausal women and in 21 postmenopausal women, acting as normal controls. They were selected, as previously reported [7], from a sample of all patients attending our outpatient clinic for the Pap test and were matched to our patients for age, height, and weight. The data obtained from the patients with endometrial adenocarcinoma and those from normal controls were compared by Student’s t test after the conversion of the data to a logarithmic scale. P < 0.05 was considered significant. RESULTS No significant difference in urinary testosterone levels was found between preand postmenopausal normals. The 24-hr urinary testosterone excretion in mi-
42
RENZO GRATTAROLA
crograms ranged from 0.0 to 12.7 (mean value: 6.5 + 0.8) in the premenopausal controls and from 0.0 to 13.0 (mean value: 5.2 2 1.1) in the postmenopausal controls. In normal premenopausal women, histologic examination of the endometrium, obtained at the premenstrual period together with the urine collection for testosterone determination, showed a progestational pattern and in postmenopausal women, a hypotrophic pattern [6]. In all 45 patients examined, histologic study revealed adenocarcinoma: in 31 well-differentiated and in 14 undifferentiated. In the group of patients with well-differentiated adenocarcinoma (31 patients, including 3 with adenoacanthoma) the urinary testosterone was significantly above normal (Table 1) and the range, in micrograms/24 hr, was 0.0 to 60.0. Sixteen of these patients (age range 28 to 48) were premenopausal and 15 (age range 45 to 64) were postmenopausal: mean urinary testosterone excretion values did not differ significantly in these two groups. In the group of patients with undifferentiated adenocarcinoma (14 patients), presenting a less prominent glandular pattern and solid epithelial mass or diffusely cellular growth, the urinary testosterone was not different from the normal value (Table l), the range in micrograms/24 hr being 0.0 to 12.6. In this group 3 patients were premenopausal (age range 31 to 43) and 11 postmenopausal (age range 61 to 79). Apart from the five premenopausal patients, who were not treated by hysterectomy, all others, pre and postmenopausal, with well-differentiated or undifferentiated endometrial adenocarcinoma underwent hysterectomy and bilateral ovariectomy. There are no adequate follow-up data for these patients, because only 1-2 years have elapsed from surgical treatment. It is, however, known that of the 14 patients with undifferentiated adenocarcinoma 4 died within a year after surgery (2 of the 3 premenopausal patients), but none of the patients with welldifferentiated adenocarcinoma has died. Of the 5 patients who did not undergo hysterectomy and bilateral ovariectomy, 3 underwent ovarian wedge resection (patients 8R-41, 13R-39, and 27R-57) for PCO, and 2 simple curettage (patient 3OR-35 and 32R-50) together with interruption of oral contraceptives. TABLE TESTOSTERONE
(T)
EXCRETION
LEVEL
1
IN PATIENTS WITH WELL-DIFFERENTIATED ENWMETRIAL ADENOCARCINOMA
OR UNDIFFERENTIATED
Histology
No. of cases
bd24 W
Adenoacanthoma Well-differentiated adenocarcinoma Undifferentiated adenocarcinoma
3 (2) 28 (14) 14 (3)
19.08 * 1.9b 20.80 2 3.2b 7.20 f 4.5’
Normal controls Premenopause Postmenopause
18 21
a Number of premenopausal b Mean f SE. ’ N.S., not significant.
patients in parentheses.
T
6.50 -c 0.8 5.20 2 1.1
Significance 0.01 0.01 N.S.’
P < P <
ANDROGENS
AND
WELL-DIFFERENTIATED
ENDOMETRIAL
TABLE CASES
OF END~METRIAL WITH PROLONGED
Case
Age
2
ADEN~CARCINOMA ASSOCIATED WITH POLYCYSTIC OVARY DISEASE USE OF SEQUENTIAL ORAL CONTRACEPTION (ETHINYLESTRADIOL DIMETHISTERONE)
Remarks
Testosterone @g/24 hr)
43
ADENOCARCINOMA
(PCO)
OR
+
(OC)
Endometrial carcinoma
Treatment
8R-4 1
35
PC0
22.0
Well differentiated
13R-39
33
PC0
30.0
Adenoacanthoma
27R-57
28
PC0
20.7
Well differentiated
30R-35
36
16.0
Adenoacanthoma
32R-50
33
OC (for 6 ye=s) OC (for 5 years)
Ovarian wedge resection Ovarian wedge resection Ovarian wedge resection Curettage
13.2
Well differentiated
Curettage
Observation period (years) 8 10 3 3 3
These patients have been followed up for 3 to 10 years since the hormonal study and none has so far had a recurrence (Table 2). The tissue removed from the ovaries of the patients subjected to ovarian wedge resection was examined histologically and the findings were consistent with polycystic ovarian disease: follicular cysts with prominent luteinized theta cells and interstitial cell hyperplasia. In 10 premenopausal patients and in 10 postmenopausal patients who underwent hysterectomy and bilateral ovariectomy, the ovaries were examined histologically; interstitial cell hyperplasia was found to be present in all the patients with well-differentiated adenocarcinoma and high urinary testosterone levels. In 2 (13R-36 and 7R-70) out of 7 patients with undifferentiated adenocarcinoma the interstitial cell hyperplasia was shown together with metastases in the ovarian stroma and no increase in urinary testosterone. Urinary testosterone levels after HCG. HCG, 15,000 IU, was injected in 6 patients with well-differentiated adenocarcinoma and in 5 patients with undifferentiated adenocarcinoma. Before HCG stimulation 2 patients with well-differentiated adenocarcinoma, but none of the patients with undifferentiated adenocarcinoma, presented high urinary testosterone levels (Table 3). After injection of 15,000 IU HCG 5 of the 6 patients with well-differentiated and 2 of the 5 patients with undifferentiated adenocarcinoma had increased testosterone levels; these 2 patients (13R-36 and 7R-70) were those who presented interstitial cell hyperplasia and metastases on histologic examination of the ovaries. DISCUSSION The histologic distinction between atypical endometrial hyperplasia and welldifferentiated adenocarcinoma is not easy, even in the presence of malignant features, like irregular configuration of the glands and nuclear atypia with increased chromatin irregularly distributed in the nuclei [3]. The morphologic type
44
RENZO
GRATTAROLA TABLE
TESTOSTERONE UNDIFFERENTIATED
EXCRETION
(B)
VALUES
ENWMETRIAL
IN PATIENTS
3 WITH
ADENOCARCINOMA
(A)
WELL-DIFFERENTIATED
BEFORE
AND
AFTER
OR
ADMINISTRATION
OF
15,ooO IU HCG B
A Patient 13R-79 12R-56 12R-23 14R-24 8R-70 12R-74
Before
(M) (M) (M) (M) (M)
8.0 5.0 27.0 0.0 21.6 10.5
After 34.0 25.2 42.5 1.5 72.0 25.0
Patient 14R-38 13R-36 7R-70 13R-78 9R-47
(M) (M) (M) (M)
Before
After
8.0 9.2 3.6 0.0 3.0
8.0 18.0b 24.0b 1.2 7.5
’ Menopause. b Ovarian metastases.
of lesion does not always guarantee its biological behavior, as proved by the reversion to normality of histologic patterns of endometrial carcinoma following ovarian resection or, as shown in this study, discontinuation of sequential oral contraceptives. We would emphasize that the definition of “carcinoma” is an epithelial lesion which, once established, grows progressively locally and often metastasizes, whereas the endometrial change that regresses following withdrawal of a promoter of cell proliferation is a reversible change and not a carcinoma, as pointed out many years ago by Novak and Rutledge [ 141, We wonder how many of the endometrial adenocarcinomas reported in the literature, even recently, following contraceptive or estrogen treatment or in the presence of polycystic ovaries, were really adenocarcinoma of the endometrium. We suggest that young patients with a histologic diagnosis of well-differentiated adenocarcinoma and high androgen excretion levels should not be subjected to hysterectomy, but should be kept under strict observation after withdrawal of the abnormal hormonal stimulation. In the present study, as in previous published papers, we have shown that atypical endometrial hyperplasia or misdiagnosed well-differentiated adenocarcinoma in premenopausal women is frequently accompanied by increased androgenic activity, which may have its origin in the ovary because of polycystic disease [41 or in the adrenal [5] because of an androgen-producing adenoma or in the progestational component of the sequential oral contraceptive-dimethisteronea steroid of the androstane series, which still bears the 17-hydroxy group responsible for the androgenic activity. We do not dispute the conventional view that estrogens are responsible for endometrial hyperplasia and malignancy. We merely point out that: (1) endometrial malignancy is more frequent in patients at an advanced postmenopausal age, when the ovary no longer produces estrogens, but secretes significant quantities of androgenic hormones [6,17]; (2) the ovarian tumors associated with a high incidence of endometrial adenocarcinoma are more frequently thecomas, which are androgen-producing tumors [ 111; (3) even if some authors have called women with PC0 “fully feminized” [12], it is well known that this syndrome
FIGS. 1, 2. Endometrium of patient 32R-50, before any treatment, at two magnifications (X 50, x 120). Well-differentiated atypical glands ; are crowded and lined by stratified epithelium, with a scant amount of stromal tissue. In some areas epidermoid endome trium.
1
adenocarcinon na: the differentiation of the
R
46
RENZO
GRATTAROLA
FKX 5, 6. Endometrium of patient 13R-39, before any treatment (X 120, x 220). Well-differentiated adenocarcinoma: crowding of the glands with little intervening stroma. Although the glandular architecture is preserved, the gland spaces display a great variation in size. Heaping up of the epithelium in papillary intraglandular projection. The cells lining the glands show a variation in size and shape of the nuclei, with loss of polarity.
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is accompanied by androgenicity, clinically evidenced by hirsutism and elevated blood and urine androgen levels [9,15,18]. We do not know whether androgens act as promoters of abnormal cell proliferation alone or act in concert with estrogens. We simply recommend caution before undertaking ablative surgery, like hysterectomy, when androgens are present in abnormal amounts in young women with well-differentiated adenocarcinoma of endometrium. REFERENCES 1. Chamlian, D. L., and Taylor, H. B. Endometrial 36, 659-665 2. 3.
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Eddy, W. A. Endometrial carcinoma in Stein-Leventhal syndrome treated with hydroxyprogesterone caproato, Amer. J. Obstet. Gynecol. 131, 581-582 (1978). Fechner, R. E., and Kaufman, R. H. Endometrial adenocarcinoma in Stein-Leventhal syndrome, Cancer 34, 444-452 (1974). Grattarola, R. Misdiagnosis of endometrial adenocarcinoma in Young women with polycystic ovarian disease, Amer. J. Obstet. Gynecol. 105, 498-502 (1969). Grattarola, R. Misdiagnosis of endometrial adenoacanthoma in a 27-year-old woman with adrenocortical tumor, Oncology 28, 246-252 (1973). Grattarola, R., Secrete, G., Recchione, C., and Castellini, W. Androgens in breast cancer. II. Endometrial adenocarcinoma and breast cancer in married post-menopausal women, Amer. J. Obstet.
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7. Grattarola, R. Anovulation and increased androgenic activity as breast cancer risk in women with fibrocystic disease of the breast, Cancer Res. 38, 3051-3054 (1978). 8. Gusberg, S. B. Precursors of corpus carcinoma, estrogens and adenomatous hyperplasia, Amer. J. Obstet. Gynecol. 54, 905-927 (1947). 9. Jafari, K., Javaheri, G., and Ruiz, G. Endometrial adenocarcinoma and the Stein-Leventhal syndrome, Obstet. Gynecol. 51, 97-100 (1978). 10. Kaufman, R. H., Reeves, K. O., and Dougherty, C. M. Severe atypical endometrial changes and sequential contraceptive use, J. Amer. Med. Assoc. 236, 923-926 (1976). 11. Klopper, A., and Farr, V. The epidemiology of endometrial cancer, In Frontiers of hormone research, Vol. 5, Estrogen therapy: The benefits and risks (C. Lauritzen and P. A. vanKeep, Eds), van Wimersma Greidanus, Utrecht, pp. 89-100 (1978). 12. Landau, R. L. What you should know about estrogens, J. Amer. Med. Assoc. 24147-51 (1979). 13. Lyon, F. A. The development of adenocarcinoma of the endometrium in young women receiving long-term sequential oral contraception, Amer. J. Obstet. Gynecol. 123, 299-301 (1975). 14. Novak, E., and Rutledge, F. Atypical hyperplasia endometrial simulating adenocarcinoma, Amer. J. Obstet. 15.
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Raj, S. G., Thompson, I. E., Berger, M. J., Tale& L. M., and Taymor, M. L. Diagnostic value of androgens measurements in polycystic ovary syndrome, Obstet. Gynecol. 52, 169-171 (1978).
Silverberg, S. G., and Makowski, E. L. Endometrial carcinoma in young women taking oral contraceptive agents, Obstet. Gynecol. 46, 503-506 (1975). 17. Studd, J. W., Collins, W. P., and Chakravarti, S. Plasma hormone profiles after the menopause and bilateral oophorectomy, Postgrad. Med. J. 54(Suppl.), 25-30 (1978). 18. Wood, G. P., and Boronow, R. C. Endometrial adenocarcinoma and the polycystic ovary syndrome, Amer. J. Obstet. Gynecol. 124, 140-142 (1976). 16.