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Suggested prophylaxis for ovarian cancer
Suggested prophylaxis A 20 year report E. Grand
KENT
GIBBS,
Rapids,
for ovarian cancer
from cases at Butterworth
Hospital
M.D.*
Michigan
From 1949 to 1969,236 cases of ovarian malignancy were seen at Butterworth Hospital, Grand Rapids, Michigan. Of these cases, 85.6 per cent occurred beyond age 41. Sixty-nine per cent of the ovarian cancer was in Stages III and IV. The over-all 5 year survival for all stages is 15.7 per cent. Previous operations had been performed in 126 patients. Twenty-eight patients had prior hysterectomies. The expected incidence of ovarian carcinoma following hysterectomy was observed. Ovarian cancer may develop in patients having prior irradiation to the ovaries and breast 07 gastrointestinal malignancy. It is suggested that a radical approach to pelvic operation in women beyond age 35 could prevent 20 per cent of all ovarian carcinoma seen.
complaints, and weight loss were investigated. Findings of physical examination, gravidity and parity, family history, age of menopause, and previous pelvic or other surgical procedures were reviewed. Tumor cell types and the stage of disease were ascertained from the operative and pathologic records. Follow-up reports were obtained from the patient’s chart or from the patient’s personal physician. Autopsy records were also reviewed.
1 N T H E United States between 1949 and 1966, ovarian cancer deaths increased by 12 per cent, while uterine cancer deaths decreased by 37 per cent. In New York State, cancer of the ovary has become the leading cause of genital cancer death in women as of 1964.l~ 2 For 1970, 14,000 new cases of ovarian cancer are expected.3 The 5 year survival is reported at 18 to 30 per cent for all stages of ovarian cancer in several series.“wG The increasing importance of ovarian cancer as the leading killer of women with genital malignancy has become more clear. Since the cure for ovarian cancer may not immediately appear on medicine’s horizon, either early diagnosis or prophylaxis is the main available avenue to prevent more deaths from ovarian cancer. Materials
and
Results Over the 20 year period, 236 cases of ovarian malignancy were seen at Butterworth Hospital. Age incidence. Fig. 1 shows that the peak incidence occurred in the 10 year age group of 51 to 60 followed by the age group of 61 to 70 years. Eighty-five and six-tenths per cent of cases occurred beyond age 41. Only 2 cases were in Negro patients, both fatal&one a granulosa cell tumor and the other a papillary adenocarcinoma. Presenting complaint. Table I depicts the chief complaints. Abdominal pain and increasing abdominal size were the most frequent complaints. Pelvic pressure, vaginal bleeding, and the bowel problems listed were about equally frequent. Twenty-three pa-
methods
An in-depth review of all cases of ovarian cancer seen at Butterworth Hospital, Grand Rapids, Michigan, between January, 1949, and December, 1969, was done. The age at diagnosis, length of symptoms, presenting From the Department Gynecology, Butterworth
of Obstetrics Hospital.
and
‘Present address: The Budge Clinic, 225 East Fourth North, Logan, Utah 84321. 75x
Ovarian
Volume 111 Number 6
O-10
Fig.
1. Age
11-20
distribution
21-30
by
31-40
10 year
periods
tients had asymptomatic pelvic masses,and an equal number of patients had found their own abdominal mass. Similar findings were elucidated by Stone and Weingold.% Length of symptoms. The average duration of symptoms was 4.23 months for 197 patients, Weight change. Seventy-three individuals complained of weight loss at the time of their initial admission. Eighteen reported weight gain, and 59 reported no weight change. In 87 patients, weight change was not recorded. Parity. In this series (Fig. 2)) 71 of 202 patients (35.1 per cent) were nulligravidas. Stone and Weingold6 stated, “In the general population, an estimated 20.3 per cent are nulliparous, and their prognosis with ovarian cancer seemsto be about one-half as favorable as with gravida females.” Menopausal age. The average age of menopause centered about the 46- to 50year-old group (Fig. 3). Family history of cancer. In 61 cases,a positive family history of cancer was obtained; 52 had no lmown previous cancer in the family.
41-50
(85.6
per
51-60
61-70
cent
of cases occur
Stage
of disease
cancer
71-80
beyond
757
SO+
age
41).
at diagnosis
Of 224 cases, 100 were Stage IV (44.2 per cent) and 55 (24.8 per cent) were Stage III. Thus combined, the most advanced disease states accounted for 69.0 per cent of all the ovarian cancer seen over the last 20 years in this study. The corrected mortality rate including those lost to follow-up was 71.4 and 84.9 per cent for Stages III and IV, respectively. The duration until death for Stage IV averaged 10.1 months; and for Stage III, 15.3 months. For all stages, 31 of 197 patients reached 5 years of survival. The over-all 5 year survival stands at 15.7 per cent. (An additional 28 patients are alive with under 5 years of follow-up [ TabIes II to V] .) Survival of patients with Stage I and II ovarian cancer was in the 6.5 to 75 per cent range. However, only one third of all cases are in the earlier stages of disease at the time of diagnosis (Fig. 4) . Treatment
and
response
In a general hospital, many surgeonstreat ovarian cancer. The approach to therapy varies widely. The figures presented are not
758 Gibbs
Table I. Presenting complaint with carcinoma of ovary
in patients
Complaint Abdominal pain ( 1 following trauma) Increasing abdominal size Pelvic pressure Vaginal bleeding Constipation Asymptomatic pelvic mass Fatigue and malaise Patient found mass Leg edema or pain Nausea and vomiting Epigastric distress Dyspnea and chest pain Rectal bleeding Carcinoma found incidental to operation Jaundice X-ray mass Vaginal discharge Diarrhea Anemia Mucus stool Obstruction Fever and chills Syncope Dyspareunia Positive Papanicolaou smear Labial mass Drainage from umbilicus
No. of patients
38
36 32 23 22 21
11 11 7 5 3 3
; 2 2 2
1 1 1 1 1 1 1 1
significantly great in any modality of therapy to draw valid conclusions as to the success of any given method of treatment (Table VI). Papillary adenocarcinoma of the serous type was the most common, followed by undifferentiated adenocarcinoma and mutinous adenocarcinoma. These account for over 88 per cent of the cancers? (Table VII). Previous
operative
experience
Of the 236 patients, 126 had previous surgery. In this series, 7 patients had previous vaginal hysterectomy. In 3 of the 7, the operation was done 4 years or less before the diagnosis of ovarian cancer. In 1, the ovarian neoplasm was discovered at the time of planned vaginal hysterectomy. All were done on patients over age 39 (range 39 to 63). Twenty-one patients had previous total or subtotal hysterectomy, with 5 of these
having 1 ovary removed. In 9 cases, hysterectomy was done within 10 years prior to development of ovarian cancer. Twenty of these patients were over age 35 at the time of hysterectomy. Sixteen patients were 39 years old or over at the time of hysterectomy (76.1 per cent). Eight patients with ovarian cancer had received irradiation for the induction of menopause. The age range of these patients was 40 to 48 years, and the interval until the development of ovarian cancer varied from 10 to 30 years, with an average of 19.5 years. Greene and associates1 and Grabe? stated, “Previous breast or gastrointestinal surgery may be associated with an increased incidence of genital tract cancer.” In this series, 5 had previous breast cancer and 8 patients had previous colon malignancy to antedate the development of ovarian cancer. There were 14 patients who had adnexal operation prior to ovarian cancer. Eight were for ovarian cysts, 2 being endometriomas of the ovary. There were 3 tubal pregnancies; in one case the ovarian cancer was found concomitantly with the ectopic pregnancy (patient’s age was 31) . Three patients had previous tubal ligations for sterilization. One patient, a Negro, aged 27, at the time of operation for bilateral peIvic inflammatory disease had “total” oophorectomy. She later developed a retroperitoneal granulosal cell tumor which was fatal.* Three patients, ages 29, 39, and 55, who had vaginal repair, developed ovarian cancer 8, 2, and 3 years later, respectively. Two patients had uterine suspension for pelvic relaxation; their ages at operation were not given. Eight additional patients, 5 with vaginal bleeding (2 to 16 months prior), 2 with abnormal Papanicolaou smears, 1 with a perineal lesion (where biopsy showed fibrodeveloped carcinoma of ma), subsequently the ovary, and one patient with endometrial carcinoma developed carcinoma of the ovary 3 months later.
Volume Number
Ovarian
111 6
cancer
80 TOTAL
CASES 202
70 60 50 40 30 20 lo-
Nulliparous
n Gravida I
Fig. 2. Children (gravida not achieved pregnancy).
Gravida II
distribution)
4( I-*
Gravida III
1 11
Multigravida over
Gravida .IV
4
(35.1 per cent of women with ovarian cancer have
TOTAL
CASES
88 3: 5
-’
3c )-
2:i-
2c )-
15
1
IO
5
Under
45
Fig. 3. Spontaneous menopausal menopause-48 years.
46-50 51-55 55t age. These cases center about the average expected age of
759
760 Gibbs
Table
II. Ovarian
cancer
(Stage
I, 37 cases
)
Died
Alive
Unrelated, Unrelated, Unrelated, Total
5 days, pulmonary embolus (age 70,1 2% months, pulmonary embolus (age 68) 2% years, sprue secondary to treatment 3 cases
Died
disease
from
7 cases
(average
survival,
21.3 months;
range,
8 to 60
monthsj
and well Up to 2 years 2 years 3 years 5 years 7 years 10 years and over Total
Lost
to
2 1 1 6 (includes 5 7 22
follow-up
Not seen after operation 1 month postoperatively 17 months postoperatively Total Corrected
Table
2 lost to follow-up)
mortality
III.
rate
Ovarian
2 2 1 5
24.1%
cancer
(Stage II, 32 cases)
Died Unrelated Death postoperatively 10 days 14% months of congestive heart Total 2 cases Died from disease Alive
and well Up to 2 years 2 years 3 years
over
to follow-up None immediately-see Corrected mortality rate
(age
9 cases (average
5 (includes 4 (includes 3 (includes 2 (includes 0 7 21
5 years
7 years 10 years and Total
failure
74, exploratory survival,
1 who
laparotomy, 20.3 months;
at 9 months
no disease range,
5 to 52%
at 1 year) months)
had disease)
1 lost to follow-up) 1 lost to follow-up) 1 at 4 years,
4 months
lost to follow-up)
Lost
Incidental
surgical
above 30.0%
procedures
Sixteen patients with ovarian cancer had previous cholecystectomies; in 1 the cancer was found at operation. Twelve of the 16 cholecystectomies were done in women over the age of 40 at the time of operation. In 1 patient, age 52, an ovarian cyst was found at cholecystectomy, and no treatment was instituted. One year later, the patient was found to have ovarian cancer and subsequently died after operation.
-
Eight patients had previous appendectomies. Ten patients had previous breast biopsy for benign disease. Ten additional cases of ovarian cancer were found in patients in whom elective surgical procedures had been performed within 5 years of the diagnosis of malignancy of the ovary; 9 were extra-abdominal procedures. No pelvic examination had been performed on 2 patients, 1 of which complained of menopausal bleeding.
Volume Number
Ovarian
111 6
cancer
761
Table IV. Ovarian cancer (Stage III, 55 cases) Died Unrelated 7 years, 4 months, Total 1 case Died from disease Alive
Lost
died
CVA,
6 years
free of disease 35 cases (average
and well Under 1 year l-2 years 2-4 years 5-10 years Over 10 years Total
survival,
15.3 months;
range,
1 to 91 months)
1 5 (includes1 at 14 month lost to follow-up) 2 (includes 1 at 49 months lost to follow-up) 4 2 14
to follow-up Not seen after operation Under 1 year after operation
2 3
(1 died ( ?) 2% monthspostoperatively) Total Corrected
mortality
5 rate
71.4%
Table V. Ovarian cancer (Stage IV, 100 cases) Died Unrelated 3 days, operating room ( ?) death 1 with diagnosis made at autopsy Total 2 cases Died from disease 71 cases (average Alive
Lost
and well Under 1 year l-2 years years 2-4 5-10 years Over 10 years Total
survival,
10.1 months;
range,
2 days to 54 months)
7 4 :, 1 13 cases
to follow-up
Not seenafter operation Refused operation Under 1 year after Total Corrected
mortality
rate
operation
7 1 6 14
84.9%
Comment
That the incidence of ovarian malignancy in patients previously subjected to conservative or incomplete pelvic operation is great enough to justify a more radical approach has been suggested by several authors. In the largest series, that of Counseller, Hunt, and Haigler,g there were 1,500 patients, of whom 67 had previous hysterectomy, and 67 per cent of these were done after age 40. Reycraft reported 4,500 patients with hyster-
ectomies, of whom 0.2 per cent developed cancer of the ovaries.22 Funck-BrentanolO reported 580 patients with an incidence of subsequent ovarian cancer of 0.17 per cent. SpeerP in 260 patients with ovarian cancer showed that 26 per cent had previous pelvic operation. Fagan12 reports on 172 patients with 7.5 per cent having previous operation, 57 per cent after the age of 40. Bloom13reports 141 casesof ovarian cancer, 10.6 per cent following hysterectomy. DiMasi and
762
Gibbs
100 10.
95 -
?
mc’n’;ns
till deat?? -__--__---corret itin Mortality F4.Q$z
90 85 80 75 70 65 60 55 -
51
50 -
4.8 3f ase
45 40 35 30 -
r -L 17.2 of ase
25 20 15 IO 5-
STAGE I
23.1 months till death __________-_ Corrected Mortality 24.1%
13.7 of Case n
15.3 months _till _ _ - _ - death - -- -- Corrected Mortality 7:.4%
20.3 months till death _______-___Corrected Mortality 30.0%
II 1
I
STAGE III
STAGE II
Fig. 4. Stage of disease at diagnosis Stage III or IV at the time of diagnosis).
(69
Groganl* had a 4.6 per cent incidence of previous operation, 50 per cent over the age of 50. SmithI noted a 4 per cent malignant change in residual ovaries where hysterectomy was done after the age of 39 years. Ten5 reported on 624 patients with ovarian cancers, 55 having previous operations for an 8.8 per cent incidence. GrogarP in 1967 reported an 8.2 per cent malignancy rate in 122 cases. Conversely, Whitelaw17 with 1,215 hysterectomies and Gevaertsz3 with 303 hysterectomies found no cases of ovarian cancer which followed operation. de Neef and Hollenbeckz2 reported 207 patients with hysterectomies, 7 needing subsequent operation with no malignancy found. In the press rlt study of 236 patients with ovarian cancer, 28 had hysterectomies (vaginal, supracervical, or total abdominal), or 11.8 per cent. Thirteen additional patients with previous breast and colon cancer and 8 patients who had pelvic irradiation to induce menopause can be added as prospective “radically” treated cases. These 49 cases represent 20.7 per cent of all the cases of
per
cent
of ovarian
STAGfi IV
cancer
was
found
to
be in
ovarian cancer seen during the 20 year period. In the series of Terz,5 the incidence of 8.8 per cent or 1 in 12 cases was felt to be sufficient to justify prophylactic oophorectomy. Twenty-four patients from this series were over the age of 40 at the time of hysterectomy, representing 10.2 per cent of the total series of cases. The Metropolitan Life Insurance Company figures estimate that 37 of each 100,000 women will develop ovarian cancer. Assuming that the incidence (0 to 0.3 per cent) is no higher in women who have retained ovaries at hysterectomy, one would save between 3 in every 10,000 patients with hysterectomies and 3 in every 1,000 patients with hysterectomies from future ovarian cancer. At Butterworth Hospital from 1949 to 1969, a total of 5,490 abdominal and 2,908 vaginal hysterectomies were done. The expected figure then could be about 25 cases of carcinoma of the ovary in posthysterectomy patients. In fact, a total of 28 cases, about the expected, was found in this report. That ovarian dysfunction is important in
Volume Number
111 6
Ovarian
cancer
763
Table VI. Treatment by stage and therapy modality
of
Method
Stage I
treatment
Surgery
alone
Surgery
and irradiation
Surgery, irradiation, chemotherapy
Alive* (%)
Stage II
Alive+ (%)
20
55
10
5
80
2 6
Stage III
Alive* (%)
70
6
33
1
Alive’ (%) 0
9
77
16
12
5
20
40
0
3
0
13
15
12
17
13
50
2
50
0
3
33
30.8
50
15
0
5.8
and
Simple cystectomy oophorectomy
or
Irradiation Chemotherapy Biopsy
0
and
Surgery
close
and chemotherapy
Oophorectomy
and
Irradiation
and
irradiation
irradiation,
Oophorectomy therapy
and
14
13
0
0
0
1
0
1
0
2
0
0
2
50
2
0
12
25
5
0
19
1
0
9
33
30
2
0
2
0
11
8
0
0
and 2
50
3
0
1
0
1
0
chemo-
Total cases Survival by stage irrespective
14 22
1
chemotherapy
Oophorectomy, chemotherapy
*Survival
Stage IV
Alive by treatment f%) 54
39
31
56
51 of length
100
48
12.5
226 9
-
of time.
Table VII. Distribution of casesby cell types Stage Cell type Serous Undifferentiated adenocarcinoma Mutinous Granulosa cell Endometrioid Dysgerminoma Embryonal cell Teratocarcinoma Carcinosarcoma Mesonephric adenocarcinoma Papillary squamous cell carcinoma (dermoid) Adenoacanthoma Lymphoma Krukenberg tumor Total cases
I
1
II
1
18 3 8 3 1 1 1 0 0 0 0
12 3 5 2 2 2 1
0 0 0
the pathogenesisof ovarian cancer can only be suspected by the nulliparity rates which are higher than in the general public. Abnormal bleeding accounted for between 20.6 and 36.6 per cent of casesin the cause for
III
1
No stage given
IV 37 41 6 0
:, 1 0
32 14 6 1 0 0 0 1 0 0 0
0 0 0
I 0 0
Total
:, 1
5 2 0 1 0 1 0 0 0 0 0
104 65 25 7 5 4 2 2 1 1 1
0 0 1
0 1 0
1 1 1
; 0 0
220
hysterectomy in Grogan’P study. Vaginal bleeding as an indicator of ovarian cancer is not frequent, 15.1 per cent in this series, except in the case of functioning ovarian tumor which may be benign or malignant.
764 Gibbs
Eight additional cases in this study arising in gynecologic patients admitted for seemingly unrelated problems strengthen the contention “that any patient with a positive Papanicolaou smear, vaginal bleeding, and a negative dilatation and curettage and cervical biopsy should be considered as having ovarian cancer and should have an exploratory laparotomy, colpotomy,“Z~ l8 or laparoscopy. Ovarian cancer might best be detected by frequent pelvic examinations and good health-care follow-up. Women who have had previous pelvic operation with removal of the organ which provides them with a monthly indicator of their femininity certainly do tend to forget their routine examinations. Symptoms suggesting pelvic pathology were present on the average 4.23 months in this study. A recent article by Ode11 and Ortiz18 discusses the problem of the patient with a “normal” pelvic examination presenting with ovarian carcinoma in a following examination some 3 to 9 months later. Conclusions The malignant potential of retained ovaries is about as found by the Metropolitan Life tables. This report of 236 cases of ovarian cancer from Butterworth Hospital, Grand Rapids, Michigan, covering the 20 year period from 1949 to 1969, shows that over 20 per cent could have been prevented by radical surgical pelvic procedures in patients over the age of 35. Discontinuance of irradiation as a preferred method of castration should result in lowering of the incidence of ovarian cancer.
REFERENCES
1. 2. 3. 4. 5. 6.
Greene, H. J., Grusetz, M. W., and Mackles, A.: Clin. Obstet. Gynecel. 12: 972, 1969. &aber, E. A.: Clin. Obstet. Gpeeol. 12: 958, 1!%9. Robe-, D. W. T., and Haines, M.: Br. Mod. J. 2: 917, 1965. Silverberg, E., and Holleb, A. I.: CA 21: 13, 19711. Ten, J. J.: Am. J. Surg. 113: 511, 1967. Stoue, M. L., and Weingold, A. B.: Clin. Obstat. Gynecol. 12: 1025, 1969.
Prophylactic removal of the ovaries in breast or bowel malignancy has gained more support, as the chance of recurrence and nrl\’ growth in remaining ovaries seems to br enhanced.‘, In. ?” The malignant potential of retained ovaries must not be overlooked, especially if we as physicians hope to decrease the incidence of ovarian cancer. The best cure available at present is prophylaxis. If for any valid reason the ovaries are to be preserved in a patient over 40 years of age, the ovaries should be bisected and biopsied, if needed, before they are retained. The importance of an admitting pelvic examination and Papanicolaou smear cannot be stressed enough, on all women, regardless of age and regardless of how long ago this was performed. Probably 50 per cent of women having total oophorectomy will not need immediate replacement estrogen. *l The benefit of oophrectomy in the prevention of ovarian cancer can be shown ; the positive influence of natural estrogen withdrawal needs to be finalized. Data collected have shown the risk of subsequent ovarian cancer to be about as expected following pelvic operation. Could not the patient benefit from one fifth of the ovarian cancers being eliminated by prophylactic oophorectomy at the time of pelvic operation over the age of 35 or 40? Appreciation is expressed to Drs. Kenneth VanderKolk and Russell Paalman for their assistance in the organization of the large amount of data and to Mrs. Suzanne Wells for the technical preparation of this paper.
7. 8. 9.
10. 11. 12. 13.
Abell, M. R.: Can. Med. Assoc. J. 94: 1102, 1966. VanderKolk, K.: Eldersveld, H. C., and Unpublished data. Counseller, V. S., Hunt, W., and Haigler, F. GYNECOL. 69: 538, H., Jr.: AM. J. OBSTET. 1955. Funck-Brentano, P.: Rev. Fr. Gynecol. Obstet. 53: 217, 1958. Speert, S. H.: Ann. Surg. 1s: 468, 1949. Fagan, G. E.: Obstet. Gynecol. 7: 498, 1956. Bloom, M. L.: S. Aft-. Med. J. 36: 714, 1!9(i2.
Volume
111
Number
6
14. 15. 16. 17. 18. 19.
DiMasi, F. T., and Grogan, R. H.: Obstet. Gynecol. 15: 315, 1960. Smith, G. V.: Am. J. Surg. 95: 336, 1958. Grogan, R. H.: AM. J. OBSTET. GYNECOL. 97: 124, 1967. Whitelaw, R. G.: J. Obstet. Gynecol. 6: 413, 1959. Odell, L. D., and Ortiz, R.: J, Reprod. Med. 5: 127, 1970. Wheelock, M. Cl., and Putong, P.: Obstet. Gynecol. 14: 291, 1959.
Ovarian
20. 21.
22. 23.
cancer
765
Randall, C. L.: Clin. Obstet. Gynecol. 4: 855, 1961. Randall, C. L.: In Meigs, and Sturgis, editors: Ovarian conservation, Progress in Gynecology, New York, 1963, Grune & Stratton, Inc., vol. 4, p. 457. de Neef, J. C., and Hollenbeck, Z. J. R.: AM. J. OBSTET. GYNECOL. 96: 1088, 1966. Gevaerts, P. 0. H.: Abdominale totale uterus extirpatie of supravaginale uterus amputatie? Thesis, Leiden, Holland, 1963.
KENT
GIBBS,
Rapids,
for ovarian cancer
from cases at Butterworth
Hospital
M.D.*
Michigan
From 1949 to 1969,236 cases of ovarian malignancy were seen at Butterworth Hospital, Grand Rapids, Michigan. Of these cases, 85.6 per cent occurred beyond age 41. Sixty-nine per cent of the ovarian cancer was in Stages III and IV. The over-all 5 year survival for all stages is 15.7 per cent. Previous operations had been performed in 126 patients. Twenty-eight patients had prior hysterectomies. The expected incidence of ovarian carcinoma following hysterectomy was observed. Ovarian cancer may develop in patients having prior irradiation to the ovaries and breast 07 gastrointestinal malignancy. It is suggested that a radical approach to pelvic operation in women beyond age 35 could prevent 20 per cent of all ovarian carcinoma seen.
complaints, and weight loss were investigated. Findings of physical examination, gravidity and parity, family history, age of menopause, and previous pelvic or other surgical procedures were reviewed. Tumor cell types and the stage of disease were ascertained from the operative and pathologic records. Follow-up reports were obtained from the patient’s chart or from the patient’s personal physician. Autopsy records were also reviewed.
1 N T H E United States between 1949 and 1966, ovarian cancer deaths increased by 12 per cent, while uterine cancer deaths decreased by 37 per cent. In New York State, cancer of the ovary has become the leading cause of genital cancer death in women as of 1964.l~ 2 For 1970, 14,000 new cases of ovarian cancer are expected.3 The 5 year survival is reported at 18 to 30 per cent for all stages of ovarian cancer in several series.“wG The increasing importance of ovarian cancer as the leading killer of women with genital malignancy has become more clear. Since the cure for ovarian cancer may not immediately appear on medicine’s horizon, either early diagnosis or prophylaxis is the main available avenue to prevent more deaths from ovarian cancer. Materials
and
Results Over the 20 year period, 236 cases of ovarian malignancy were seen at Butterworth Hospital. Age incidence. Fig. 1 shows that the peak incidence occurred in the 10 year age group of 51 to 60 followed by the age group of 61 to 70 years. Eighty-five and six-tenths per cent of cases occurred beyond age 41. Only 2 cases were in Negro patients, both fatal&one a granulosa cell tumor and the other a papillary adenocarcinoma. Presenting complaint. Table I depicts the chief complaints. Abdominal pain and increasing abdominal size were the most frequent complaints. Pelvic pressure, vaginal bleeding, and the bowel problems listed were about equally frequent. Twenty-three pa-
methods
An in-depth review of all cases of ovarian cancer seen at Butterworth Hospital, Grand Rapids, Michigan, between January, 1949, and December, 1969, was done. The age at diagnosis, length of symptoms, presenting From the Department Gynecology, Butterworth
of Obstetrics Hospital.
and
‘Present address: The Budge Clinic, 225 East Fourth North, Logan, Utah 84321. 75x
Ovarian
Volume 111 Number 6
O-10
Fig.
1. Age
11-20
distribution
21-30
by
31-40
10 year
periods
tients had asymptomatic pelvic masses,and an equal number of patients had found their own abdominal mass. Similar findings were elucidated by Stone and Weingold.% Length of symptoms. The average duration of symptoms was 4.23 months for 197 patients, Weight change. Seventy-three individuals complained of weight loss at the time of their initial admission. Eighteen reported weight gain, and 59 reported no weight change. In 87 patients, weight change was not recorded. Parity. In this series (Fig. 2)) 71 of 202 patients (35.1 per cent) were nulligravidas. Stone and Weingold6 stated, “In the general population, an estimated 20.3 per cent are nulliparous, and their prognosis with ovarian cancer seemsto be about one-half as favorable as with gravida females.” Menopausal age. The average age of menopause centered about the 46- to 50year-old group (Fig. 3). Family history of cancer. In 61 cases,a positive family history of cancer was obtained; 52 had no lmown previous cancer in the family.
41-50
(85.6
per
51-60
61-70
cent
of cases occur
Stage
of disease
cancer
71-80
beyond
757
SO+
age
41).
at diagnosis
Of 224 cases, 100 were Stage IV (44.2 per cent) and 55 (24.8 per cent) were Stage III. Thus combined, the most advanced disease states accounted for 69.0 per cent of all the ovarian cancer seen over the last 20 years in this study. The corrected mortality rate including those lost to follow-up was 71.4 and 84.9 per cent for Stages III and IV, respectively. The duration until death for Stage IV averaged 10.1 months; and for Stage III, 15.3 months. For all stages, 31 of 197 patients reached 5 years of survival. The over-all 5 year survival stands at 15.7 per cent. (An additional 28 patients are alive with under 5 years of follow-up [ TabIes II to V] .) Survival of patients with Stage I and II ovarian cancer was in the 6.5 to 75 per cent range. However, only one third of all cases are in the earlier stages of disease at the time of diagnosis (Fig. 4) . Treatment
and
response
In a general hospital, many surgeonstreat ovarian cancer. The approach to therapy varies widely. The figures presented are not
758 Gibbs
Table I. Presenting complaint with carcinoma of ovary
in patients
Complaint Abdominal pain ( 1 following trauma) Increasing abdominal size Pelvic pressure Vaginal bleeding Constipation Asymptomatic pelvic mass Fatigue and malaise Patient found mass Leg edema or pain Nausea and vomiting Epigastric distress Dyspnea and chest pain Rectal bleeding Carcinoma found incidental to operation Jaundice X-ray mass Vaginal discharge Diarrhea Anemia Mucus stool Obstruction Fever and chills Syncope Dyspareunia Positive Papanicolaou smear Labial mass Drainage from umbilicus
No. of patients
38
36 32 23 22 21
11 11 7 5 3 3
; 2 2 2
1 1 1 1 1 1 1 1
significantly great in any modality of therapy to draw valid conclusions as to the success of any given method of treatment (Table VI). Papillary adenocarcinoma of the serous type was the most common, followed by undifferentiated adenocarcinoma and mutinous adenocarcinoma. These account for over 88 per cent of the cancers? (Table VII). Previous
operative
experience
Of the 236 patients, 126 had previous surgery. In this series, 7 patients had previous vaginal hysterectomy. In 3 of the 7, the operation was done 4 years or less before the diagnosis of ovarian cancer. In 1, the ovarian neoplasm was discovered at the time of planned vaginal hysterectomy. All were done on patients over age 39 (range 39 to 63). Twenty-one patients had previous total or subtotal hysterectomy, with 5 of these
having 1 ovary removed. In 9 cases, hysterectomy was done within 10 years prior to development of ovarian cancer. Twenty of these patients were over age 35 at the time of hysterectomy. Sixteen patients were 39 years old or over at the time of hysterectomy (76.1 per cent). Eight patients with ovarian cancer had received irradiation for the induction of menopause. The age range of these patients was 40 to 48 years, and the interval until the development of ovarian cancer varied from 10 to 30 years, with an average of 19.5 years. Greene and associates1 and Grabe? stated, “Previous breast or gastrointestinal surgery may be associated with an increased incidence of genital tract cancer.” In this series, 5 had previous breast cancer and 8 patients had previous colon malignancy to antedate the development of ovarian cancer. There were 14 patients who had adnexal operation prior to ovarian cancer. Eight were for ovarian cysts, 2 being endometriomas of the ovary. There were 3 tubal pregnancies; in one case the ovarian cancer was found concomitantly with the ectopic pregnancy (patient’s age was 31) . Three patients had previous tubal ligations for sterilization. One patient, a Negro, aged 27, at the time of operation for bilateral peIvic inflammatory disease had “total” oophorectomy. She later developed a retroperitoneal granulosal cell tumor which was fatal.* Three patients, ages 29, 39, and 55, who had vaginal repair, developed ovarian cancer 8, 2, and 3 years later, respectively. Two patients had uterine suspension for pelvic relaxation; their ages at operation were not given. Eight additional patients, 5 with vaginal bleeding (2 to 16 months prior), 2 with abnormal Papanicolaou smears, 1 with a perineal lesion (where biopsy showed fibrodeveloped carcinoma of ma), subsequently the ovary, and one patient with endometrial carcinoma developed carcinoma of the ovary 3 months later.
Volume Number
Ovarian
111 6
cancer
80 TOTAL
CASES 202
70 60 50 40 30 20 lo-
Nulliparous
n Gravida I
Fig. 2. Children (gravida not achieved pregnancy).
Gravida II
distribution)
4( I-*
Gravida III
1 11
Multigravida over
Gravida .IV
4
(35.1 per cent of women with ovarian cancer have
TOTAL
CASES
88 3: 5
-’
3c )-
2:i-
2c )-
15
1
IO
5
Under
45
Fig. 3. Spontaneous menopausal menopause-48 years.
46-50 51-55 55t age. These cases center about the average expected age of
759
760 Gibbs
Table
II. Ovarian
cancer
(Stage
I, 37 cases
)
Died
Alive
Unrelated, Unrelated, Unrelated, Total
5 days, pulmonary embolus (age 70,1 2% months, pulmonary embolus (age 68) 2% years, sprue secondary to treatment 3 cases
Died
disease
from
7 cases
(average
survival,
21.3 months;
range,
8 to 60
monthsj
and well Up to 2 years 2 years 3 years 5 years 7 years 10 years and over Total
Lost
to
2 1 1 6 (includes 5 7 22
follow-up
Not seen after operation 1 month postoperatively 17 months postoperatively Total Corrected
Table
2 lost to follow-up)
mortality
III.
rate
Ovarian
2 2 1 5
24.1%
cancer
(Stage II, 32 cases)
Died Unrelated Death postoperatively 10 days 14% months of congestive heart Total 2 cases Died from disease Alive
and well Up to 2 years 2 years 3 years
over
to follow-up None immediately-see Corrected mortality rate
(age
9 cases (average
5 (includes 4 (includes 3 (includes 2 (includes 0 7 21
5 years
7 years 10 years and Total
failure
74, exploratory survival,
1 who
laparotomy, 20.3 months;
at 9 months
no disease range,
5 to 52%
at 1 year) months)
had disease)
1 lost to follow-up) 1 lost to follow-up) 1 at 4 years,
4 months
lost to follow-up)
Lost
Incidental
surgical
above 30.0%
procedures
Sixteen patients with ovarian cancer had previous cholecystectomies; in 1 the cancer was found at operation. Twelve of the 16 cholecystectomies were done in women over the age of 40 at the time of operation. In 1 patient, age 52, an ovarian cyst was found at cholecystectomy, and no treatment was instituted. One year later, the patient was found to have ovarian cancer and subsequently died after operation.
-
Eight patients had previous appendectomies. Ten patients had previous breast biopsy for benign disease. Ten additional cases of ovarian cancer were found in patients in whom elective surgical procedures had been performed within 5 years of the diagnosis of malignancy of the ovary; 9 were extra-abdominal procedures. No pelvic examination had been performed on 2 patients, 1 of which complained of menopausal bleeding.
Volume Number
Ovarian
111 6
cancer
761
Table IV. Ovarian cancer (Stage III, 55 cases) Died Unrelated 7 years, 4 months, Total 1 case Died from disease Alive
Lost
died
CVA,
6 years
free of disease 35 cases (average
and well Under 1 year l-2 years 2-4 years 5-10 years Over 10 years Total
survival,
15.3 months;
range,
1 to 91 months)
1 5 (includes1 at 14 month lost to follow-up) 2 (includes 1 at 49 months lost to follow-up) 4 2 14
to follow-up Not seen after operation Under 1 year after operation
2 3
(1 died ( ?) 2% monthspostoperatively) Total Corrected
mortality
5 rate
71.4%
Table V. Ovarian cancer (Stage IV, 100 cases) Died Unrelated 3 days, operating room ( ?) death 1 with diagnosis made at autopsy Total 2 cases Died from disease 71 cases (average Alive
Lost
and well Under 1 year l-2 years years 2-4 5-10 years Over 10 years Total
survival,
10.1 months;
range,
2 days to 54 months)
7 4 :, 1 13 cases
to follow-up
Not seenafter operation Refused operation Under 1 year after Total Corrected
mortality
rate
operation
7 1 6 14
84.9%
Comment
That the incidence of ovarian malignancy in patients previously subjected to conservative or incomplete pelvic operation is great enough to justify a more radical approach has been suggested by several authors. In the largest series, that of Counseller, Hunt, and Haigler,g there were 1,500 patients, of whom 67 had previous hysterectomy, and 67 per cent of these were done after age 40. Reycraft reported 4,500 patients with hyster-
ectomies, of whom 0.2 per cent developed cancer of the ovaries.22 Funck-BrentanolO reported 580 patients with an incidence of subsequent ovarian cancer of 0.17 per cent. SpeerP in 260 patients with ovarian cancer showed that 26 per cent had previous pelvic operation. Fagan12 reports on 172 patients with 7.5 per cent having previous operation, 57 per cent after the age of 40. Bloom13reports 141 casesof ovarian cancer, 10.6 per cent following hysterectomy. DiMasi and
762
Gibbs
100 10.
95 -
?
mc’n’;ns
till deat?? -__--__---corret itin Mortality F4.Q$z
90 85 80 75 70 65 60 55 -
51
50 -
4.8 3f ase
45 40 35 30 -
r -L 17.2 of ase
25 20 15 IO 5-
STAGE I
23.1 months till death __________-_ Corrected Mortality 24.1%
13.7 of Case n
15.3 months _till _ _ - _ - death - -- -- Corrected Mortality 7:.4%
20.3 months till death _______-___Corrected Mortality 30.0%
II 1
I
STAGE III
STAGE II
Fig. 4. Stage of disease at diagnosis Stage III or IV at the time of diagnosis).
(69
Groganl* had a 4.6 per cent incidence of previous operation, 50 per cent over the age of 50. SmithI noted a 4 per cent malignant change in residual ovaries where hysterectomy was done after the age of 39 years. Ten5 reported on 624 patients with ovarian cancers, 55 having previous operations for an 8.8 per cent incidence. GrogarP in 1967 reported an 8.2 per cent malignancy rate in 122 cases. Conversely, Whitelaw17 with 1,215 hysterectomies and Gevaertsz3 with 303 hysterectomies found no cases of ovarian cancer which followed operation. de Neef and Hollenbeckz2 reported 207 patients with hysterectomies, 7 needing subsequent operation with no malignancy found. In the press rlt study of 236 patients with ovarian cancer, 28 had hysterectomies (vaginal, supracervical, or total abdominal), or 11.8 per cent. Thirteen additional patients with previous breast and colon cancer and 8 patients who had pelvic irradiation to induce menopause can be added as prospective “radically” treated cases. These 49 cases represent 20.7 per cent of all the cases of
per
cent
of ovarian
STAGfi IV
cancer
was
found
to
be in
ovarian cancer seen during the 20 year period. In the series of Terz,5 the incidence of 8.8 per cent or 1 in 12 cases was felt to be sufficient to justify prophylactic oophorectomy. Twenty-four patients from this series were over the age of 40 at the time of hysterectomy, representing 10.2 per cent of the total series of cases. The Metropolitan Life Insurance Company figures estimate that 37 of each 100,000 women will develop ovarian cancer. Assuming that the incidence (0 to 0.3 per cent) is no higher in women who have retained ovaries at hysterectomy, one would save between 3 in every 10,000 patients with hysterectomies and 3 in every 1,000 patients with hysterectomies from future ovarian cancer. At Butterworth Hospital from 1949 to 1969, a total of 5,490 abdominal and 2,908 vaginal hysterectomies were done. The expected figure then could be about 25 cases of carcinoma of the ovary in posthysterectomy patients. In fact, a total of 28 cases, about the expected, was found in this report. That ovarian dysfunction is important in
Volume Number
111 6
Ovarian
cancer
763
Table VI. Treatment by stage and therapy modality
of
Method
Stage I
treatment
Surgery
alone
Surgery
and irradiation
Surgery, irradiation, chemotherapy
Alive* (%)
Stage II
Alive+ (%)
20
55
10
5
80
2 6
Stage III
Alive* (%)
70
6
33
1
Alive’ (%) 0
9
77
16
12
5
20
40
0
3
0
13
15
12
17
13
50
2
50
0
3
33
30.8
50
15
0
5.8
and
Simple cystectomy oophorectomy
or
Irradiation Chemotherapy Biopsy
0
and
Surgery
close
and chemotherapy
Oophorectomy
and
Irradiation
and
irradiation
irradiation,
Oophorectomy therapy
and
14
13
0
0
0
1
0
1
0
2
0
0
2
50
2
0
12
25
5
0
19
1
0
9
33
30
2
0
2
0
11
8
0
0
and 2
50
3
0
1
0
1
0
chemo-
Total cases Survival by stage irrespective
14 22
1
chemotherapy
Oophorectomy, chemotherapy
*Survival
Stage IV
Alive by treatment f%) 54
39
31
56
51 of length
100
48
12.5
226 9
-
of time.
Table VII. Distribution of casesby cell types Stage Cell type Serous Undifferentiated adenocarcinoma Mutinous Granulosa cell Endometrioid Dysgerminoma Embryonal cell Teratocarcinoma Carcinosarcoma Mesonephric adenocarcinoma Papillary squamous cell carcinoma (dermoid) Adenoacanthoma Lymphoma Krukenberg tumor Total cases
I
1
II
1
18 3 8 3 1 1 1 0 0 0 0
12 3 5 2 2 2 1
0 0 0
the pathogenesisof ovarian cancer can only be suspected by the nulliparity rates which are higher than in the general public. Abnormal bleeding accounted for between 20.6 and 36.6 per cent of casesin the cause for
III
1
No stage given
IV 37 41 6 0
:, 1 0
32 14 6 1 0 0 0 1 0 0 0
0 0 0
I 0 0
Total
:, 1
5 2 0 1 0 1 0 0 0 0 0
104 65 25 7 5 4 2 2 1 1 1
0 0 1
0 1 0
1 1 1
; 0 0
220
hysterectomy in Grogan’P study. Vaginal bleeding as an indicator of ovarian cancer is not frequent, 15.1 per cent in this series, except in the case of functioning ovarian tumor which may be benign or malignant.
764 Gibbs
Eight additional cases in this study arising in gynecologic patients admitted for seemingly unrelated problems strengthen the contention “that any patient with a positive Papanicolaou smear, vaginal bleeding, and a negative dilatation and curettage and cervical biopsy should be considered as having ovarian cancer and should have an exploratory laparotomy, colpotomy,“Z~ l8 or laparoscopy. Ovarian cancer might best be detected by frequent pelvic examinations and good health-care follow-up. Women who have had previous pelvic operation with removal of the organ which provides them with a monthly indicator of their femininity certainly do tend to forget their routine examinations. Symptoms suggesting pelvic pathology were present on the average 4.23 months in this study. A recent article by Ode11 and Ortiz18 discusses the problem of the patient with a “normal” pelvic examination presenting with ovarian carcinoma in a following examination some 3 to 9 months later. Conclusions The malignant potential of retained ovaries is about as found by the Metropolitan Life tables. This report of 236 cases of ovarian cancer from Butterworth Hospital, Grand Rapids, Michigan, covering the 20 year period from 1949 to 1969, shows that over 20 per cent could have been prevented by radical surgical pelvic procedures in patients over the age of 35. Discontinuance of irradiation as a preferred method of castration should result in lowering of the incidence of ovarian cancer.
REFERENCES
1. 2. 3. 4. 5. 6.
Greene, H. J., Grusetz, M. W., and Mackles, A.: Clin. Obstet. Gynecel. 12: 972, 1969. &aber, E. A.: Clin. Obstet. Gpeeol. 12: 958, 1!%9. Robe-, D. W. T., and Haines, M.: Br. Mod. J. 2: 917, 1965. Silverberg, E., and Holleb, A. I.: CA 21: 13, 19711. Ten, J. J.: Am. J. Surg. 113: 511, 1967. Stoue, M. L., and Weingold, A. B.: Clin. Obstat. Gynecol. 12: 1025, 1969.
Prophylactic removal of the ovaries in breast or bowel malignancy has gained more support, as the chance of recurrence and nrl\’ growth in remaining ovaries seems to br enhanced.‘, In. ?” The malignant potential of retained ovaries must not be overlooked, especially if we as physicians hope to decrease the incidence of ovarian cancer. The best cure available at present is prophylaxis. If for any valid reason the ovaries are to be preserved in a patient over 40 years of age, the ovaries should be bisected and biopsied, if needed, before they are retained. The importance of an admitting pelvic examination and Papanicolaou smear cannot be stressed enough, on all women, regardless of age and regardless of how long ago this was performed. Probably 50 per cent of women having total oophorectomy will not need immediate replacement estrogen. *l The benefit of oophrectomy in the prevention of ovarian cancer can be shown ; the positive influence of natural estrogen withdrawal needs to be finalized. Data collected have shown the risk of subsequent ovarian cancer to be about as expected following pelvic operation. Could not the patient benefit from one fifth of the ovarian cancers being eliminated by prophylactic oophorectomy at the time of pelvic operation over the age of 35 or 40? Appreciation is expressed to Drs. Kenneth VanderKolk and Russell Paalman for their assistance in the organization of the large amount of data and to Mrs. Suzanne Wells for the technical preparation of this paper.
7. 8. 9.
10. 11. 12. 13.
Abell, M. R.: Can. Med. Assoc. J. 94: 1102, 1966. VanderKolk, K.: Eldersveld, H. C., and Unpublished data. Counseller, V. S., Hunt, W., and Haigler, F. GYNECOL. 69: 538, H., Jr.: AM. J. OBSTET. 1955. Funck-Brentano, P.: Rev. Fr. Gynecol. Obstet. 53: 217, 1958. Speert, S. H.: Ann. Surg. 1s: 468, 1949. Fagan, G. E.: Obstet. Gynecol. 7: 498, 1956. Bloom, M. L.: S. Aft-. Med. J. 36: 714, 1!9(i2.
Volume
111
Number
6
14. 15. 16. 17. 18. 19.
DiMasi, F. T., and Grogan, R. H.: Obstet. Gynecol. 15: 315, 1960. Smith, G. V.: Am. J. Surg. 95: 336, 1958. Grogan, R. H.: AM. J. OBSTET. GYNECOL. 97: 124, 1967. Whitelaw, R. G.: J. Obstet. Gynecol. 6: 413, 1959. Odell, L. D., and Ortiz, R.: J, Reprod. Med. 5: 127, 1970. Wheelock, M. Cl., and Putong, P.: Obstet. Gynecol. 14: 291, 1959.
Ovarian
20. 21.
22. 23.
cancer
765
Randall, C. L.: Clin. Obstet. Gynecol. 4: 855, 1961. Randall, C. L.: In Meigs, and Sturgis, editors: Ovarian conservation, Progress in Gynecology, New York, 1963, Grune & Stratton, Inc., vol. 4, p. 457. de Neef, J. C., and Hollenbeck, Z. J. R.: AM. J. OBSTET. GYNECOL. 96: 1088, 1966. Gevaerts, P. 0. H.: Abdominale totale uterus extirpatie of supravaginale uterus amputatie? Thesis, Leiden, Holland, 1963.