Multiple primaries and gynecologic malignancies DOLORES A. BUCHLER, M.D. Madison, Wisconsin
An analysis was done on all gynecologic malignancies over a 13 year period to review the frequency and types of multiple primaries. A surprising spectrum of malignancy is seen and certain radiologic studies are of particular value. The time from occurrence of the various extragenital and genital tract cancers to the original gynecologic malignancy is shown. The per cent and types qf malignancies that subsequently develop after a genital tract cancer are discussed.
As A PART of our continuing analysis of gynecologic oncology care rendered at the University of Wisconsin Center for Health Sciences, we have examined the records of all patients from 1960 through 1973 admitted for gynecologic malignancies who either had a previous malignancy, had a second primary discovered during that admission, or are now known to have developed an additional malignancy since that admission. Data derived from this review emphasize the importance of a thorough initial radiologic evaluation in the management of these patients and that a surprising spectrum of malignancy can be expected to occur among the survivors. In particular colon x-rays, which are often neglected during the initial evaluation of genital tract malignancies, are of significant value. Follow-up for certain gynecologic malignancies beyond the conventional 10 years appears to be desirable and the small number of patients with a genital tract primary who develop a second gynecologic malignancy may be overlooked unless the oncologist is particularly attuned to this possibility. There have been reviews concerning the development of multiple malignancies in the same patient beginning with Billroth. Some have been autopsy studies, others have been retrospective analyses, but no consistent approach to the review of such statistics
has been made. 1 • 2 Thus comparison of these data with previous studies is difficult.
Method In the Department of Gynecology and Obstetrics, the treatment data and follow-up information of all patients with gynecologic malignancies are stored in our Linc-8 computer for easy access. The records of patients with multiple primary malignancies which occurred either before, during, or after the initial admission to this hospital, were reviewed in detail. Whenever there was a question concerning the diagnosis of multiple primary, the histology and timing of the development of the second primary were reviewed. All those in which the histology did not confirm the double primary condition by clear-cut differences or where a vaginal carcinoma developed less than 10 years after an invasive cervical cancer with similar histology were excluded. Skin cancers and any variety of carcinoma in situ were not considered as a second neoplasm. Results and comment Table I shows the frequency of additional primary malignancies associated with the various sites of the genital malignancy found at the first University Hospital admission. Table II shows the time of occurrence of the additional primary in relation to the genital tract site for which the patient entered the University Hospitals. It is evident that half (50 per cent) of the multiple primary malignancies occurred before the gynecologic cancer that brought the patient to our attention. Twenty-eight (13 per cent) were simultaneously found and 77 (37 per cent) developed while under subsequent observation. The additional sites of malignancy occurring either
From the Departments of GynecolofSY and Obstetrics and RadiolofSY of the University of Wisconsin Center for Health Sciences. This research lws been supported in part by a grant from the National Cancer Institute CA-14520 entitled "Wisconsin Clinical Cancer Center." Presented by invitation at the Ninety-eighth Annual Meeting of the American Gynecological Society, Coronadc, Califarnia, Apri/9-12, 1975. Reprint requests: Dr. Dolores A. Buchler, University of Wisconsin Medical Center, Madison, Wisconsin 53706.
376
Multiple primaries and gynecologic malignanciee
Volume 123 Number 4
Table IV. Common sites of extragenital malignancies in women admitted for genital cancers
Table I. Frequency of multiple primaries by site of gynecologic malignancy, 1960-1973 Patients with additional primaries Site* Vulva Vagina Cervix Corpus Ovary Total
I
No.
No.
77 872
Vulva Vagina Cervix Corpus Ovarv Total
% 2.6 8.9 7.7 9.3 8.4t
59
764 664 2,504
62 209
Genitourinary
Site*
6.3
8 2 78
127
377
l l
l
I
0
0
0
7 2 3
14
8
21 22
10 _1_1__ 30
0 3 5 0
14
(7%)
5'8
-s-
(149f)
(28%)
i4%)t
*First UW admission. tThirteen miscellaneous sites (see text).
*First University Hospitals admission. tEJeven of these patients developed a third malignancy.
Table II. Time of occurrence of additional malignancy
Table V. Miscellaneous sites of extragenital malignancies Sites
No.
Tongue Larynx Retroperitoneal sarcoma Tonsil Urethra-melanoma Sarcoma-lower extremity Bronchogenic Gallbladder Sarcoma-chest wall Stomach Maxillary antrum Leukemia
l I
No. of additional cancers Site, First UW admission
Before
0 0 13 10
3
Vulva Vagina Cervix Corpus Ovary Total
Total
Simultaneous
1
26
32 42
5 1 39 17 15
5
28
104
77
8
2 78
59 62 209
Table III. Site of additional gynecologic malignancies in the genital tract Site* Vulva Vagina Cervix Corpus Ovary
Vulva
Vagina
Cervix
0
4
1
0
0 12
0
8 2 3
9
2 3
0 3
Corpus
Ovary 0
3 1 I I 1 1
2
Table VI. The occurrence of breast carcinoma in women with genital tract malignancy
I
9 9
9
*First UW admission.
before, during, or after the gynecologic malignancy among the 209 patients with multiple cancers are divided for discussion into genital and extragenital sites. Table Ill shows the place of the additional genital primary arranged by the site of the primary seen on admission. Patients with cervical primaries had the greatest number of second malignancies. This most likely results from the fact that in most instances, therapy for a cervical malignancy does not involve surgical resection of the internal genitalia and these patients were younger at the time of diagnosis. Table IV shows the major extragenital sites of the additional malignancies. As one might expect, breast (28 per cent) and colon (14 per cent) were the most common. Undoubtedly, this association relates to the over-all frequency of these malignancies in the general
Simultaneous or After*t
Before Site*
No.
No.
Corpus Ovary Cervix Total
21
17 19
22 14
57
I
7
43
I
%
No.
30
4
7
32
3 _]_
5 13
14
25
13
75
%
*First UW admission. t Five were simultaneous tumors.
population. In addition to the common sites listed in Table IV, there were many other extragenital sites of malignancy (Table V). There appeared to be no particular pattern among these sites with relat1on to the genital tumors. Table VI shows the number of breast cancers detected before and simultaneously or after the gynecologic malignancy of the first admission. It is dear that 75 per cent of such tumors occur before the development of the genital tract malignancy. Forty-three of the 58 breast carcinomas were associated with pri-
378 Buchler
October 15, 1!!7.1
Am.
Table VII. Simultaneous primaries by site of gynecologic malignancy Genital site
Other
Cervix
2
7
Corpus Ovary Total
2 j_ 5
_l
3
Larynx (1) Tonsil (l) Hodgkins (1) Gallbladder ( l) Hodgkins (2) Liposarcoma (1)
4 0 5
ll
Table VIII. Years between the genital tract cancers and development of subsequent malignancies Site
Vulva Vagina Cervix Corpus Ovary Total
lOyr.
5-10 yr.
0 0 8
0 16
1 4
1 4
1
IT
22
Table IX. Types of subsequent malignancies causing death Subsequent cancers
No.
Angiosarcoma Bronchogenic carcinoma Gallbladder carcinoma Melanoma Leukemia Liposarcoma
1 I 1 1 1 1
maries of the corpus or ovaries. Schottenfeld3 and Schoenber( and their co-workers have suggested that breast carcinoma is more often encountered in women who subsequently develop genital carcinoma of the corpus and ovary, suggesting some common (endocrine?) factor. Our data are insufficient to show a significant association with corpus and ovary as compared with cervical carcinoma. Table VII indicates the site of the second malignancy found during the admission for diagnosis and therapy of the primary gynecologic malignancy. The most common simultaneous non-genital tract malignancy in these 28 patients was colon carcinoma (11 patients). It is interesting that between the years 1970 to 1973, there were seven colon carcinomas detected as a simultaneous malignancy and in the previous I 0 years from 1960 to 1969 only four such malignancies were found. Further, as our definition of "simultaneous" excludes malignancies found after the treatment period, six of
J. Obstet. Gvnewl.
the colon cancers considered "subsequent" malignancies could have been simultaneous since they were found within 6 months of treatment of the gynecologic malignancy. This would increase the discrepancy between the two periods of time significantly. As colon x-rays became routine only after 1970 in the evaluation of all gynecologic cancer patients, one wonders whether several such malignancies were never detected. In Table VIII the number of years elapsing between the genital tract cancer and subsequent malignancy is indicated. Again, it is clear that patients with cervical cancer because of their youth and retained genital organs are more likely to develop a subsequent malignancy. Of the 39 cervical cancer patients 16 (41 per cent) developed the second malignancy more than I 0 years after treatment. These data suggest that patients treated for cervical malignancy are at greater risk than patients with other genital tumors for a second primary and should be carefully followed beyond 10 years. Patients' symptomatology should not be categorized as radiation enteritis or proctitis without a thorough evaluation, which may need to be done on more than one occasion. Figs. 1 and 2 show the fate of the 77 patients who subsequently developed a second malignancy after treatment of the first at the University Hospitals. These patients were followed at regular intervals throughout the one to 14 years that have elapsed since 1960, most often in our gynecologic tumor clinic. The usual pattern of decreasing frequency of follow-up through the tenth year has been used. In some cases, this observation has been shared with the family physician. In no instance have any patients been lost to follow-up, but the cause of death and the results of autopsy have in general been determined in the patients' community. The 77 patients who developed subsequent malignancies after treatment of the first have again been divided into two groups: those who developed genital tract malignancy and those who developed an extragenital malignancy. Sixty-one per cent of the patients developing a second genital malignancy (Table VIII) initially had carcinoma of the cervix. It is evident that in this group those developing a vulvar or cervical carcinoma as their second primary survived more frequently than did those developing corpus, vaginal, or ovarian carcinomas. It is not surprising that those developing ovarian cancer did poorly because of the recognized difficulty in detecting this disease early, but at present one can only speculate about the other reasons for this difference.
Multiple primaries and gynecologic malignancies
Volume 123 Number 4
mLiving 15
•
Living with Co
0
Died from 2nd Co
~Living Died from 2nd Co Died from I st Co
0 B FA
15
•
10 Number of Patients
10 Number of Patients
5
5
Second Site
< c < 0
() CD
'"" < )(
()
0 "0
'""
c
(/)
0
< 0
'"" '
An analysis was done on all gynecologic malignancies over a 13 year period to review the frequency and types of multiple primaries. A surprising spectrum of malignancy is seen and certain radiologic studies are of particular value. The time from occurrence of the various extragenital and genital tract cancers to the original gynecologic malignancy is shown. The per cent and types qf malignancies that subsequently develop after a genital tract cancer are discussed.
As A PART of our continuing analysis of gynecologic oncology care rendered at the University of Wisconsin Center for Health Sciences, we have examined the records of all patients from 1960 through 1973 admitted for gynecologic malignancies who either had a previous malignancy, had a second primary discovered during that admission, or are now known to have developed an additional malignancy since that admission. Data derived from this review emphasize the importance of a thorough initial radiologic evaluation in the management of these patients and that a surprising spectrum of malignancy can be expected to occur among the survivors. In particular colon x-rays, which are often neglected during the initial evaluation of genital tract malignancies, are of significant value. Follow-up for certain gynecologic malignancies beyond the conventional 10 years appears to be desirable and the small number of patients with a genital tract primary who develop a second gynecologic malignancy may be overlooked unless the oncologist is particularly attuned to this possibility. There have been reviews concerning the development of multiple malignancies in the same patient beginning with Billroth. Some have been autopsy studies, others have been retrospective analyses, but no consistent approach to the review of such statistics
has been made. 1 • 2 Thus comparison of these data with previous studies is difficult.
Method In the Department of Gynecology and Obstetrics, the treatment data and follow-up information of all patients with gynecologic malignancies are stored in our Linc-8 computer for easy access. The records of patients with multiple primary malignancies which occurred either before, during, or after the initial admission to this hospital, were reviewed in detail. Whenever there was a question concerning the diagnosis of multiple primary, the histology and timing of the development of the second primary were reviewed. All those in which the histology did not confirm the double primary condition by clear-cut differences or where a vaginal carcinoma developed less than 10 years after an invasive cervical cancer with similar histology were excluded. Skin cancers and any variety of carcinoma in situ were not considered as a second neoplasm. Results and comment Table I shows the frequency of additional primary malignancies associated with the various sites of the genital malignancy found at the first University Hospital admission. Table II shows the time of occurrence of the additional primary in relation to the genital tract site for which the patient entered the University Hospitals. It is evident that half (50 per cent) of the multiple primary malignancies occurred before the gynecologic cancer that brought the patient to our attention. Twenty-eight (13 per cent) were simultaneously found and 77 (37 per cent) developed while under subsequent observation. The additional sites of malignancy occurring either
From the Departments of GynecolofSY and Obstetrics and RadiolofSY of the University of Wisconsin Center for Health Sciences. This research lws been supported in part by a grant from the National Cancer Institute CA-14520 entitled "Wisconsin Clinical Cancer Center." Presented by invitation at the Ninety-eighth Annual Meeting of the American Gynecological Society, Coronadc, Califarnia, Apri/9-12, 1975. Reprint requests: Dr. Dolores A. Buchler, University of Wisconsin Medical Center, Madison, Wisconsin 53706.
376
Multiple primaries and gynecologic malignanciee
Volume 123 Number 4
Table IV. Common sites of extragenital malignancies in women admitted for genital cancers
Table I. Frequency of multiple primaries by site of gynecologic malignancy, 1960-1973 Patients with additional primaries Site* Vulva Vagina Cervix Corpus Ovary Total
I
No.
No.
77 872
Vulva Vagina Cervix Corpus Ovarv Total
% 2.6 8.9 7.7 9.3 8.4t
59
764 664 2,504
62 209
Genitourinary
Site*
6.3
8 2 78
127
377
l l
l
I
0
0
0
7 2 3
14
8
21 22
10 _1_1__ 30
0 3 5 0
14
(7%)
5'8
-s-
(149f)
(28%)
i4%)t
*First UW admission. tThirteen miscellaneous sites (see text).
*First University Hospitals admission. tEJeven of these patients developed a third malignancy.
Table II. Time of occurrence of additional malignancy
Table V. Miscellaneous sites of extragenital malignancies Sites
No.
Tongue Larynx Retroperitoneal sarcoma Tonsil Urethra-melanoma Sarcoma-lower extremity Bronchogenic Gallbladder Sarcoma-chest wall Stomach Maxillary antrum Leukemia
l I
No. of additional cancers Site, First UW admission
Before
0 0 13 10
3
Vulva Vagina Cervix Corpus Ovary Total
Total
Simultaneous
1
26
32 42
5 1 39 17 15
5
28
104
77
8
2 78
59 62 209
Table III. Site of additional gynecologic malignancies in the genital tract Site* Vulva Vagina Cervix Corpus Ovary
Vulva
Vagina
Cervix
0
4
1
0
0 12
0
8 2 3
9
2 3
0 3
Corpus
Ovary 0
3 1 I I 1 1
2
Table VI. The occurrence of breast carcinoma in women with genital tract malignancy
I
9 9
9
*First UW admission.
before, during, or after the gynecologic malignancy among the 209 patients with multiple cancers are divided for discussion into genital and extragenital sites. Table Ill shows the place of the additional genital primary arranged by the site of the primary seen on admission. Patients with cervical primaries had the greatest number of second malignancies. This most likely results from the fact that in most instances, therapy for a cervical malignancy does not involve surgical resection of the internal genitalia and these patients were younger at the time of diagnosis. Table IV shows the major extragenital sites of the additional malignancies. As one might expect, breast (28 per cent) and colon (14 per cent) were the most common. Undoubtedly, this association relates to the over-all frequency of these malignancies in the general
Simultaneous or After*t
Before Site*
No.
No.
Corpus Ovary Cervix Total
21
17 19
22 14
57
I
7
43
I
%
No.
30
4
7
32
3 _]_
5 13
14
25
13
75
%
*First UW admission. t Five were simultaneous tumors.
population. In addition to the common sites listed in Table IV, there were many other extragenital sites of malignancy (Table V). There appeared to be no particular pattern among these sites with relat1on to the genital tumors. Table VI shows the number of breast cancers detected before and simultaneously or after the gynecologic malignancy of the first admission. It is dear that 75 per cent of such tumors occur before the development of the genital tract malignancy. Forty-three of the 58 breast carcinomas were associated with pri-
378 Buchler
October 15, 1!!7.1
Am.
Table VII. Simultaneous primaries by site of gynecologic malignancy Genital site
Other
Cervix
2
7
Corpus Ovary Total
2 j_ 5
_l
3
Larynx (1) Tonsil (l) Hodgkins (1) Gallbladder ( l) Hodgkins (2) Liposarcoma (1)
4 0 5
ll
Table VIII. Years between the genital tract cancers and development of subsequent malignancies Site
Vulva Vagina Cervix Corpus Ovary Total
lOyr.
5-10 yr.
0 0 8
0 16
1 4
1 4
1
IT
22
Table IX. Types of subsequent malignancies causing death Subsequent cancers
No.
Angiosarcoma Bronchogenic carcinoma Gallbladder carcinoma Melanoma Leukemia Liposarcoma
1 I 1 1 1 1
maries of the corpus or ovaries. Schottenfeld3 and Schoenber( and their co-workers have suggested that breast carcinoma is more often encountered in women who subsequently develop genital carcinoma of the corpus and ovary, suggesting some common (endocrine?) factor. Our data are insufficient to show a significant association with corpus and ovary as compared with cervical carcinoma. Table VII indicates the site of the second malignancy found during the admission for diagnosis and therapy of the primary gynecologic malignancy. The most common simultaneous non-genital tract malignancy in these 28 patients was colon carcinoma (11 patients). It is interesting that between the years 1970 to 1973, there were seven colon carcinomas detected as a simultaneous malignancy and in the previous I 0 years from 1960 to 1969 only four such malignancies were found. Further, as our definition of "simultaneous" excludes malignancies found after the treatment period, six of
J. Obstet. Gvnewl.
the colon cancers considered "subsequent" malignancies could have been simultaneous since they were found within 6 months of treatment of the gynecologic malignancy. This would increase the discrepancy between the two periods of time significantly. As colon x-rays became routine only after 1970 in the evaluation of all gynecologic cancer patients, one wonders whether several such malignancies were never detected. In Table VIII the number of years elapsing between the genital tract cancer and subsequent malignancy is indicated. Again, it is clear that patients with cervical cancer because of their youth and retained genital organs are more likely to develop a subsequent malignancy. Of the 39 cervical cancer patients 16 (41 per cent) developed the second malignancy more than I 0 years after treatment. These data suggest that patients treated for cervical malignancy are at greater risk than patients with other genital tumors for a second primary and should be carefully followed beyond 10 years. Patients' symptomatology should not be categorized as radiation enteritis or proctitis without a thorough evaluation, which may need to be done on more than one occasion. Figs. 1 and 2 show the fate of the 77 patients who subsequently developed a second malignancy after treatment of the first at the University Hospitals. These patients were followed at regular intervals throughout the one to 14 years that have elapsed since 1960, most often in our gynecologic tumor clinic. The usual pattern of decreasing frequency of follow-up through the tenth year has been used. In some cases, this observation has been shared with the family physician. In no instance have any patients been lost to follow-up, but the cause of death and the results of autopsy have in general been determined in the patients' community. The 77 patients who developed subsequent malignancies after treatment of the first have again been divided into two groups: those who developed genital tract malignancy and those who developed an extragenital malignancy. Sixty-one per cent of the patients developing a second genital malignancy (Table VIII) initially had carcinoma of the cervix. It is evident that in this group those developing a vulvar or cervical carcinoma as their second primary survived more frequently than did those developing corpus, vaginal, or ovarian carcinomas. It is not surprising that those developing ovarian cancer did poorly because of the recognized difficulty in detecting this disease early, but at present one can only speculate about the other reasons for this difference.
Multiple primaries and gynecologic malignancies
Volume 123 Number 4
mLiving 15
•
Living with Co
0
Died from 2nd Co
~Living Died from 2nd Co Died from I st Co
0 B FA
15
•
10 Number of Patients
10 Number of Patients
5
5
Second Site
< c < 0
() CD
'"" < )(
()
0 "0
'""
c
(/)
0
< 0
'"" '
