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Multiple and multifocal carcinomas in female genital organs and breast
GYNECOLOGIC ONCOLOGY 3, 181-190 (1975)
Multiple and Multifocal Carcinomas in Female Genital Organs and Breast L I A N E DELIGDISCH, M . D . 1 AND A . E . SZULMAN
M.B., C H . B .
Visiting Professor of Pathology, Associate Professor of Pathology, Department of Pathology Magee Women's Hospital (B. Klionsky, director), University of Pittsburgh Medical School, Pittsburgh, Pennsylvania Received December 17, 1973 Sixty-seven cases of multiple primary malignant tumors of the genital organs and breast were analyzed in their different combinations. A percentage of 5.4% of multiple primary tumors was found in a cancer population of 1235. In addition, cases of multifocal primary carcinoma in symmetrical organs (breasts and ovaries) were discussed. A higher incidence of multiple primary cancers was found in embryologically related organs, such as vulva, vagina and uterine exocervix, or endometrium and ovary. Endometriosis w i t h malignant loci was frequently found associated with the multiple primary tumors of the mullerian derived organs. Carcinoma in situ was found synchronously with overt multiple and multifocal carcinoma of the female genital organs and breasts and therefore considered as a previous stage of the carcinomatous progression. The area response of the embryologically related organs was discussed as a factor in the genesis of the multiple and multifocal multiple primary tumors of the female genital organs and breast.
The problem of multiple primary carcinoma is treated in the literature with increasing interest. Volkman (1874) and Billroth (1889) established the first criteria for the diagnosis of multiple primary malignant tumors. Because of the rigidity of those criteria (each primary tumor had to be located far away from the other in order to have a different histological pattern and to have its own metastases), very few cases of primary multiple tumors were reported by the end of the last century and in the first three decades of this century. The criteria of Billroth were abandoned 40 yr ago, and different authors have since published case reports on multiple primary tumors. The increased number is due probably to earlier diagnosis, better prognosis, and longer survival of the patients. The number of multiple primary tumors is still increasing, and the case reports have become numerous [3,15,20,21,24,25,29]. Statistics published during the last decade show an incidence of from 0.9% to 6.8% of multiple primary tumors among the total population of cancer patients [3,20,23,24]. The incidence of multiple primary tumors in females, according to Becker [3], 1 Reprint requests should be sent to Liane Deligdisch, M.D., Associate Pathologist, Department of Pathology, Tel-Aviv Medical School, Ichilov Municipal Hospital, 6, Weizman Street, Tel-Aviv, Israel. 181 Copyright© 1975by AcademicPress, Inc. All rightsof reproductionin any formreserved.
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is twice that occurring in males, with a peak incidence in the 45-50-yr age group. We want to emphasize the multifocal capacity to develop cancer of the female reproductive organs, which occurs as a "synchronous" or "metachronous" (delayed) response to carcinogenic influences. All the cases that could have represented metastic tumors were carefully excluded from our material. We considered synchronous the cases that either appeared clinically simultaneously or were detected at an interval of less than 1 yr and metachronous the cases that were detected at intervals of more than 1 yr.
MATERIALS AND METHODS All the material was obtained from the records of the Tumor Registry of the Women's Magee Hospital. During 5 yr (1966-70) among a total population of 1235 cancer patients, 67 cases of multiple carcinoma of the female genital organs and breast were found, representing 5.4% of this total. In addition, in 13 cases multifocal primary tumors were found appearing in similar organs (breasts, ovaries). Cases of carcinoma in situ are included in our material. The age of the patients was between 29 and 83 yr, with a mean average of 55.4 yr. Our material includes seven cases in which more than two multiple primary tumors were found. The combinations of the different multiple primary tumors were as follows: Female genital organs or breast and extra genital (23) Breast and female genital organs (17) Cervix and vulva or vagina (13) Endometrium and ovary (10) Cervix and endometrium (5) Ovary and cervix (2) The total of these combinations is 70, exceeding the 67 cases of multiple primary tumors reported because of the presence of more than two multiple primary tumors in some patients. The association between female genital or breast tumors and extragenital tumors, comprising 23 cases, was found in patients with a mean age of 62 yr, 14 being synchronous and nine metachronous. In four cases there were two primary cancers arising in the genital organs and a third primary cancer arising extragenitally. The different extragenital locations are summarized in Table 1. The association between breast primary tumors and female genital tumors, comprising 17 cases, was found in patients with a mean age of 58.7 yr, five of them being synchronous and 12 metachronous. The genital location of the primary tumor associated with a primary breast tumor was the cervix in six cases, the ovary in six cases, and the endometrium in five cases. The association of primary malignant tumors of the cervix with primary malignant tumors of the vagina or vulva, including carcinomata in situ, comprises 13 cases. The patients had an average of 54.5 yr; nine cases were synchronous, and four metachronous. In seven cases, carcinoma in situ was found with invasive squamous cell carcinoma in various combinations and time sequences (Table 2).
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TABLE 1 EXTRAGENITAL LOCATION OF PRIMARY TUMORS ASSOCIATED WITH FEMALE GENITAL OR BREAST PRIMARY TUMOR
Number
Extragenital site
12
Gastrointestinal tract (6 adenocarcinoma of colon) (4 carcinoid of appendix) (2 adenocarcinoma of Papilla Vateri) Skin (4 squamous cell carcinoma of skin) (1 squamous cell carcinoma of gingiva) Urinary bladder Leukemia Lung (oat-cell carcinoma)
5
2 2 l Total 22
The association of primary endometrial and primary ovarian carcinoma was found in 10 cases. The mean age of the patients was 53.7 yr. Nine of the 10 cases were synchronous (in the only metachronous case, the two primary tumors were separated by an interval of 2 yr). The histological pattern of the ovarian tumors (Table 3) was endometrioid in six patients with endometriosis being present in the ovary and elsewhere in all six. Areas of transition between endometriosis and endometrioid carcinoma were identified (Figs. 1,2). The association between primary tumors of the cervix and of the endometrium comprises five cases. The patients had an average age of 60.4 yr. There was a history of radium therapy in all the three cases of metachronous primary tumors (Table 4). The association of cervix and ovarian primary tumors was found in two cases, the mean age of the patients being 44 yr. In one case, mucinous adenocarcinoma of the endocervix was associated with bilateral mucinous adenocarcinoma of the ovaries found synchronously and independently although showing an identical histological pattern. TABLE 2 ASSOCIATION BETWEEN OVERT CARCINOMA AND CARCINOMA In Situ OF EXOCERVIC, VAGINA, AND VULVA Squamous cell carcinoma
Carcinoma
No.
in situ
Time sequence
1 2 3 4 5 6 7
Cervix Vagina Cervix Cervix Cervix Cervix Cervix
Vagina Cervix Vagina Vagina Vulva Vagina Vagina
Synchronous Metachronous Synchronous Synchronous Synchronous Metachronous Metachronous
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LIANE DELIGDISCH TABLE 3 ASSOCIATION BETWEEN OVARIAN CARCINOMA AND PRIMARY ENDOMETRIAL CARCINOMA
No.
Histological pattern of ovarian tumors associated with primary endometrial carcinoma Endometrioid carcinoma Granulosa cell carcinoma Endometrioid carcinoma Endometrioid carcinoma Serous papillary adenocarcinoma Endometrioid carcinoma
7 8 9 10
Serous papillary adenocarcinoma Endometrioid carcinoma Endometrioid carcinoma Serous papillary adenocarcinoma
Time sequence Synchronous Synchronous Synchronous Synchronous Synchronous Metachronous (2-yr interval) Synchronous Synchronous Synchronous Synchronous
Endometriosis One ovary Absent Both ovaries and parametrium Both ovaries and sigma Absent Both ovaries Absent Both ovaries Both ovaries Absent
Since our analysis was concerned, not only with multiple primary tumors, but also w i t h m u l t i f o c a l l y m a l i g n a n t t u m o r s a r i s i n g in s i m i l a r s y m m e t r i c a l o r g a n s , w e r e v i e w e d t h e b i l a t e r a l b r e a s t a n d b i l a t e r i a l o v a r i a n c a r c i n o m a s in t h e c a s e s w h e r e m e t a s t a s i s f r o m o n e side to t h e o t h e r d e f i n i t e l y c o u l d b e r u l e d out. W e c o n s i d e r e d t r a n s i t i o n h i s t o l o g i c a l l y f r o m n o r m a l to m a l i g n a n t t i s s u e as e v i d e n c e for e x i s t e n c e o f a p r i m a r y f o c u s .
FIG. 1. Ovarian endometriosis showing transition to endometroid papillary carcinoma.
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Fro. 2. O v a r i a n endometriosis showing atypical ceils with bizarre nuclei. No invasion of the underlying stroma can be seen.
There were 13 cases of bilateral primary breast carcinoma, the mean age of the patients being 49 yr. Five cases were synchronous, and eight metachronous (1-13 yr interval). In four cases, bilateral lobular carcinoma in situ was found synchronously with infiltrating carcinoma of the same or of the opposite breast. Out of the eight metachronous tumors, four showed mammary dysplasia of the opposite breast at the time of the diagnosis of carcinoma in one breast. One to nine years afterward, a renewed biopsy of the previously diagnosed dysplastic TABLE 4 ASSOCIATION BETWEEN PRIMARY CERVIX CARCINOMA AND PRIMARY ENDOMETRIAL CARCINOMA
No.
Time sequence
1 2
Synchronous Metachronous
3
Metachronous (18-yr interval) Synchronous Metachronous
First
Second
First p r i m a r y
primary tumor
primary tumor
therapy
-Endornetrium
-Cervix
-Radium
Cervix
Endometrium
Radium
-Cervix
-Endometrium
(lyr interval)
4 5
(8-yr interval)
therapy therapy -Radium
therapy
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breast showed infiltrating carcinoma. Of the five synchronous tumors, three also showed associated mammary dysplasia. Bilateral primary carcinoma of the ovaries occurred in six cases, all of them synchronous, the mean age being 49 yr. In four cases, the histological pattern was papillary cystadenocarcinoma, and in the other two, endometrioid carcinoma. In three cases endometriosis was found in both ovaries, and in the two cases of endometrioid carcinoma, trasition areas between the endometriosis and the endometrioid carcinoma could be demonstrated. In five cases both ovarian tumors were associated with other primary malignant tumors (two carcinomas of the breast, two of the endometrium, and one of the appendix). These have been included in the respective groups of multiple primary tumors already discussed. One of these cases was a 37-yr-old patient who had bilateral primary tumor of the breast 8 yr prior to bilateral primary tumor of the ovaries. This patient had metastases in the pelvic lymph nodes and is still living now, 13 yr after the bilateral radical mastectomy and 5 yr after the bilateral oophorectomy. In seven cases, an association of more than two primary malignant tumors was found. The mean age of these patients was 69 yr. The involved organs were breast, ovary, endometrium, cervix, vagina, urinary bladder, and appendix in various combinations and time sequences (Table 5). In case No. 7 (a 74-yr-old patient, 9 yr after undergoing a left mastectomy for mucinous adenocarcinoma of the breast), a primary carcinoma was found in the other breast (diagnosed as Paget's disease and ductal carcinoma) synchronously with adenocarcinoma of the endocervix and endometrioid carcinoma of both ovaries. In case No. 4 (a 72-yr-old patient presented synchronously with primary carcinoma of both ovaries and carcinoma in situ of the endometrium, 2 months after radical hysterectomy), a primary carcinoma of the left breast with metastases to the axillary lymph nodes was found. Endometriosis of ovaries and myometrium (adenomyosis) was found in 14 patients, nine of which had ovarian and endometrial carcinoma. A history of radium therapy was found in five cases, all of them with metachronously appearing tumors. DISCUSSION The percentage (5.4%) of multiple primary tumors of the female genital organs and breast in our material is lower than that reported by Hansen and Collins TABLE 5 MORE THAN TWO PRIMARY MULTIPLE TUMORS IN DIFFERENT LOCATIONS No.
Time sequence
Location
1 2 3 4 5 6 7
Synchronous Metachronous Metachronous Synchronous Synchronous Metachronous Metachronous
Cervix, vagina, appendix Vagina, cervix, urinary bladder Cervix, vagina, left breast Both ovaries, left breast, endometrium Left breast, left ovary, rectum Endometrium, left ovary, left breast Right breast, left breast, cervix, both ovaries
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(6.8%) [10] and higher than that of Protzen (4.05%) [23]. Earlier diagnosis, better treatment, and increased survival achieved in recent years seem to have permitted the recently increasing number of reported cases of multiple primary tumors. In light of the different associations of primary tumors, several points can be made. In the association between breast primary cancers and primary cancers of genital location, a striking feature is the fact that although there were 91 ovarian carcinomas and 406 cervix cancers, there were 6 patients with breast and cervix cancer and 6 patients with breast and ovarian cancer. Because breast cancer and uterine cervix cancer both have a high incidence in the female population, we could consider their association in the same patients a coincidental finding. However, the association of primary breast carcinoma with primary ovarian carcinoma, the incidence of which, in our figures is less than four times in the considered cancer population, may bear significance. The literature [20,23] also reports a frequent association between these tumors and refers to factors related to a common hormonal background [12]. The relatively frequent (13 cases) association between primary carcinoma of the exocervix, vagina, and vulva, which are organs closely related by their embryological development from the cloaca, seems to have significance. In one case, primary carcinoma of the cervix and vagina and, in another case, primary carcinoma of the vulva were associated with carcinoma of the urinary bladder, the origin of which, as well, is the cloaca. As reported in the literature [10,26,27] the "cloacogenic" multiple carcinomata may result from a common etiology: the predisposing fact of common embryologic heritage or "area predisposition" in which there is a multifocal response to carcinogens. Tissues related through their embryological development show an increased receptivity to the same carcinogens. The response to carcinogens may be delayed in some areas, and this could be the reason for simultaneous occurence of overt carcinomas and in situ carcinomas in the same "area." The association, also relatively frequent, of endometrial and ovarian primary carcinoma may suggest, as emphasized by Woodruff, a multifocal response to carcinogenic influence of tissues related by their embryologic development, since the mullerian paramasonephric tissue develops in close relationship with the celomic epithelium [31 ]. The associated findings of endometriosis in most of the cases of primary tumors of the endometrium and ovary and its malignant transformation to endometrioid carcinoma in the ovary and to adenocarcinoma of the uterus (Fig. 3) may support the idea of "solidarity" in the response to carcinogens by the mullerian epithelium regardless of its location. The association between cervix and endometrial primary carcinomas, despite their close topographical neighborship, is relatively rare (five cases). It is less frequent than the association between cervical and ovarian and between vulva and vaginal tumors, which may be more related histologically and functionally. In this group, the radiation therapy of the first primary cancer could be related to the appearance (after 1, 8, and 18 yr) of a second primary cancer.
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FIG. 3. Adenocarcinomatous glands in an area of uterine endometriosis (adenomyosis).
The review of the "multifocal" primary tumor's arising primarily in both breasts supports the statements in the literature [30] that lobular carcinoma in situ appears mostly bilateral. The simultaneous finding of "in situ" lobular carcinoma with infiltrating carcinoma in one or both breasts may represent a delayed response to carcinogens of the various parts of the breast tissue. No conclusion could be drawn about the eventual pathogenic relationship between mammary dysplasia and carcinoma of the breast, since mammary dysplasia was found both synchronously and metachronously with overt and in situ carcinomas of the breasts. The bilateral primary ovarian carcinomas, frequently associated with endometriosis, may emphasize the reciprocal response to carcinogens of the mullerian epithelium of various locations. The almost always synchronous occurence of these tumors in contrast to other multiple primary tumor combinations may confirm this idea. Multiple primary tumor development probably requires, not only a common embryologic origin (why is multiple primary tumor association not seen more frequently in fallopian tube epithelium?), but a carcinogenic influence that is operative nearly equally throughout. This may be an environmental carcinogen, such as hormones, radiation, or others. The controversial subject of the hormonal influence in the genesis of the malignant tumors in the female genital organs and breasts evokes different
MULTIPLE CARCINOMA IN FEMALE ORGANS
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opinions. A history of hormonal disturbances or prolonged estrogen effect is not an uncommon background of endometrial, ovarian, and breast carcinomas. Other factors may be partly responsible for the multiple primary tumors: the histological and functional similarity of the tissues, which may explain the more frequent occurence of multiple carcinoma in the vagina, vulva, exocervix, and skin and gingiva (as in one of our cases), or the cancers arising in the mucinous epithelium of the gastro-intestinal tract associated with the mucinous carcinoma of the ovary and of the endocervix (or of the association of the latter two, as seen in one of our cases). The "precancerous" lesions, the carcinoma in situ accompanying overt carcinoma, may represent various stations in the carcinomatous progression in time and space. The occurence of a third or even fourth primary malignant tumor of the female genital organs and breasts, topographically separated, in older patients may be explained by the fact that better diagnosis and treatment of previous cancer permitted a longer survival, with longer time at risk for development of new primary tumors.
CONCLUSIONS 1. The incidence of the multiple primary tumors in the Womens Magee Hospital during the period 1966-1970 was 5.4% (67 out of 1235 cases of cancer in the same period). 2. The "area response" to carcinogens of embryologicaUy related organs, the exocervix, vulva, vagina, and urinary bladder or endometrium and ovary, was pointed out. 3. Malignant changes in endometrioid foci was frequently associated with the simultaneous occurrence of ovarian and endometrial carcinoma. This represents a multifocal response to carcinogens of mullerian derivatives in topographically different locations. 4. Carcinomas in situ frequently were found simultaneously with multifocal primary carcinoma. They may be considered the result of a delayed response of some areas to the carcinogen that produces multifocal primary carcinoma. 5. Benign lesions such as endometriosis and dysplasias of the breast were frequently associated with multiple and multifocal carcinoma of the female genital system.
REFERENCES 1. 2. 3. 4.
Anderson, W. A. D. Pathology, The C. V. Mosby Co., St. Louis (1971). Alan, B. Mixed carcinoma of the endometrium, Amer. J. Obstet. Gynecol. 102, 506 (1968). Becker, H. Klinik und Pathologie der multiplen Malignome, Med. Klin. 65, 1775 (1970). Bettinger, H. F. Hyperplasia and carcinoma of the endometrium, Amer. J. Obstet. Gynecol. 109, 194 (1971). 5. Bnehl, I., Vellios, F., Carter, J. E., and Huber, C. P. Carcinoma in situ of the endometrium, Amer. J. Clin. Pathol. 42, 594 (1964). 6. Chamlian, D., and Taylor, H. B. Endometrial hyperplasia in young women, Obstet. Gynecol. 36, 659 (1970). 7. Charles, D., and Bellett, L. J. A. Endometrial carcinoma-Endocrinological and clinical studies, Amer. J. Obstet. Gynecol. 91, 1050 (1965).
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8. Decker, P. J., Hirsch, N. B., and Garnet, J. D. Mixed mesodermal (mullerian) tumor of the ovary, Cancer 21, 926 (1968). 9. Garusi, G., and Donati, E. Tumori della Mammella bilaterali o associati a tumori dell'utero, Tumori 56, 83 (1970). 10. Hansen, L., and Collins, C. Multicentric squamous cell carcinoma of the lower female genital tract, Amer. J. Obstet. Gynecol. 98, 982 (1967). 11. Hertig, A. T., Sheldon, C. S., and Bengloff, H. Genesis of endometrial carcinoma, Cancer 2, 964 (1949). 12. Hertz, R. The role of steroid hormones in the etiology and pathogenesis of cancer, Amer. J. Obstet. Gynecol. 98, 1013 (1967). 13. Huber, H. Die intra- und extragenitale Tumormultiplizitat beim Genital Karzinom, Z. Krebsforsch. 58, 103 (1951). 14. Hunter, C. Adenomatous hyperplasia of the endometrium associated with estrogen-producing ovarian tumor, Amer. J. Obstet. Gynececol. 110, 782 (1971). 15. Konig, H. Maligne Doppel tumoren der Frau, Arch. Geschwulstforsch. 32, 380 (1968). 16. Laughlan, S. Conception unity of the mullerian tumor group, Cancer 22, 601, (1968). 17. Lewison, E. The management of the contralateral breast, Hosp. Pract. 101 (1970). 18. Lohr, H., and Huber, H. Mammacarcinoma und Genitalcarcinoma als Multiplizitatstumoren, Strahlentherapie 11, 257 (1961). 19. Mansell, H., and Hertig, A. Granulosa-theca cell tumors and endometrial carcinoma, Obstet. Gynececol. 6, 385 (1955). 20. Marzotko, F. Primar Multiple Karzinome in der Gynakologie, Zentralbl. Gynaekol. Heft 50, 1632 (1969). 21. Moertel, C. G. Multiple primary malignant neoplasms, Recent Results Cancer Res. No. 7, Springer, Berlin, Heidelberg, New York (1966). 22. Novak's Textbook o f Gynecology, The Williams and Wilkins Co., Baltimore, 8th ed. (1970). 23. Protzen, H. Untersuchungen yon Fallen mit verschiedenen bosartigen Geschwulsten, Zentralbl. Gynaekol. 89, 1016 (1967). 24. Schonberg, B. S., Greenberg, R. A., and Eisenberg, H. Occurence of certain multiple primary cancers in females, J. Nat. Cancer Inst. 43, 15 (1969). 25. Schottenfeld, D., and Berg, J. Incidence of multiple primary cancers: Cancers of the female breast and genital organs, J. Nat. Cancer Inst. 46, 161 (1971). 26. Steg, A., Boccon-Gibod, L., and Galian, P. Les tumeurs malignes primitives multiples de l'appareil uro-genital, Ann. Urol. 4, 159 (1970). 27. Stern, B., and Kaplan, L. Multicentric foci of carcinomas arising in structures of cloacal origin, Amer. J. Obstet. Gynecol. 104, 255 (1969). 28. Tatra, G., and Kratochwil, A. Zervixkerzinom bei primarer Tumor multiplizitat, Wien. Med. Wochenschr. 121, 202 (1971). 29. Thoma, G. W., and Anderson, M. D. The incidence and significance of multiple primary malignant tumors, Amer. J. Med. Sci. 247, 427 (1964). 30. Urban, J. Bilaterallity of cancer of the breast, Cancer 20, 1867 (1967). 31. Woodruff, D. Multiple malignancy in the upper genital canal, Amer. J. Obstet. Gynecol. 103, 810 (1968).
Multiple and Multifocal Carcinomas in Female Genital Organs and Breast L I A N E DELIGDISCH, M . D . 1 AND A . E . SZULMAN
M.B., C H . B .
Visiting Professor of Pathology, Associate Professor of Pathology, Department of Pathology Magee Women's Hospital (B. Klionsky, director), University of Pittsburgh Medical School, Pittsburgh, Pennsylvania Received December 17, 1973 Sixty-seven cases of multiple primary malignant tumors of the genital organs and breast were analyzed in their different combinations. A percentage of 5.4% of multiple primary tumors was found in a cancer population of 1235. In addition, cases of multifocal primary carcinoma in symmetrical organs (breasts and ovaries) were discussed. A higher incidence of multiple primary cancers was found in embryologically related organs, such as vulva, vagina and uterine exocervix, or endometrium and ovary. Endometriosis w i t h malignant loci was frequently found associated with the multiple primary tumors of the mullerian derived organs. Carcinoma in situ was found synchronously with overt multiple and multifocal carcinoma of the female genital organs and breasts and therefore considered as a previous stage of the carcinomatous progression. The area response of the embryologically related organs was discussed as a factor in the genesis of the multiple and multifocal multiple primary tumors of the female genital organs and breast.
The problem of multiple primary carcinoma is treated in the literature with increasing interest. Volkman (1874) and Billroth (1889) established the first criteria for the diagnosis of multiple primary malignant tumors. Because of the rigidity of those criteria (each primary tumor had to be located far away from the other in order to have a different histological pattern and to have its own metastases), very few cases of primary multiple tumors were reported by the end of the last century and in the first three decades of this century. The criteria of Billroth were abandoned 40 yr ago, and different authors have since published case reports on multiple primary tumors. The increased number is due probably to earlier diagnosis, better prognosis, and longer survival of the patients. The number of multiple primary tumors is still increasing, and the case reports have become numerous [3,15,20,21,24,25,29]. Statistics published during the last decade show an incidence of from 0.9% to 6.8% of multiple primary tumors among the total population of cancer patients [3,20,23,24]. The incidence of multiple primary tumors in females, according to Becker [3], 1 Reprint requests should be sent to Liane Deligdisch, M.D., Associate Pathologist, Department of Pathology, Tel-Aviv Medical School, Ichilov Municipal Hospital, 6, Weizman Street, Tel-Aviv, Israel. 181 Copyright© 1975by AcademicPress, Inc. All rightsof reproductionin any formreserved.
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is twice that occurring in males, with a peak incidence in the 45-50-yr age group. We want to emphasize the multifocal capacity to develop cancer of the female reproductive organs, which occurs as a "synchronous" or "metachronous" (delayed) response to carcinogenic influences. All the cases that could have represented metastic tumors were carefully excluded from our material. We considered synchronous the cases that either appeared clinically simultaneously or were detected at an interval of less than 1 yr and metachronous the cases that were detected at intervals of more than 1 yr.
MATERIALS AND METHODS All the material was obtained from the records of the Tumor Registry of the Women's Magee Hospital. During 5 yr (1966-70) among a total population of 1235 cancer patients, 67 cases of multiple carcinoma of the female genital organs and breast were found, representing 5.4% of this total. In addition, in 13 cases multifocal primary tumors were found appearing in similar organs (breasts, ovaries). Cases of carcinoma in situ are included in our material. The age of the patients was between 29 and 83 yr, with a mean average of 55.4 yr. Our material includes seven cases in which more than two multiple primary tumors were found. The combinations of the different multiple primary tumors were as follows: Female genital organs or breast and extra genital (23) Breast and female genital organs (17) Cervix and vulva or vagina (13) Endometrium and ovary (10) Cervix and endometrium (5) Ovary and cervix (2) The total of these combinations is 70, exceeding the 67 cases of multiple primary tumors reported because of the presence of more than two multiple primary tumors in some patients. The association between female genital or breast tumors and extragenital tumors, comprising 23 cases, was found in patients with a mean age of 62 yr, 14 being synchronous and nine metachronous. In four cases there were two primary cancers arising in the genital organs and a third primary cancer arising extragenitally. The different extragenital locations are summarized in Table 1. The association between breast primary tumors and female genital tumors, comprising 17 cases, was found in patients with a mean age of 58.7 yr, five of them being synchronous and 12 metachronous. The genital location of the primary tumor associated with a primary breast tumor was the cervix in six cases, the ovary in six cases, and the endometrium in five cases. The association of primary malignant tumors of the cervix with primary malignant tumors of the vagina or vulva, including carcinomata in situ, comprises 13 cases. The patients had an average of 54.5 yr; nine cases were synchronous, and four metachronous. In seven cases, carcinoma in situ was found with invasive squamous cell carcinoma in various combinations and time sequences (Table 2).
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TABLE 1 EXTRAGENITAL LOCATION OF PRIMARY TUMORS ASSOCIATED WITH FEMALE GENITAL OR BREAST PRIMARY TUMOR
Number
Extragenital site
12
Gastrointestinal tract (6 adenocarcinoma of colon) (4 carcinoid of appendix) (2 adenocarcinoma of Papilla Vateri) Skin (4 squamous cell carcinoma of skin) (1 squamous cell carcinoma of gingiva) Urinary bladder Leukemia Lung (oat-cell carcinoma)
5
2 2 l Total 22
The association of primary endometrial and primary ovarian carcinoma was found in 10 cases. The mean age of the patients was 53.7 yr. Nine of the 10 cases were synchronous (in the only metachronous case, the two primary tumors were separated by an interval of 2 yr). The histological pattern of the ovarian tumors (Table 3) was endometrioid in six patients with endometriosis being present in the ovary and elsewhere in all six. Areas of transition between endometriosis and endometrioid carcinoma were identified (Figs. 1,2). The association between primary tumors of the cervix and of the endometrium comprises five cases. The patients had an average age of 60.4 yr. There was a history of radium therapy in all the three cases of metachronous primary tumors (Table 4). The association of cervix and ovarian primary tumors was found in two cases, the mean age of the patients being 44 yr. In one case, mucinous adenocarcinoma of the endocervix was associated with bilateral mucinous adenocarcinoma of the ovaries found synchronously and independently although showing an identical histological pattern. TABLE 2 ASSOCIATION BETWEEN OVERT CARCINOMA AND CARCINOMA In Situ OF EXOCERVIC, VAGINA, AND VULVA Squamous cell carcinoma
Carcinoma
No.
in situ
Time sequence
1 2 3 4 5 6 7
Cervix Vagina Cervix Cervix Cervix Cervix Cervix
Vagina Cervix Vagina Vagina Vulva Vagina Vagina
Synchronous Metachronous Synchronous Synchronous Synchronous Metachronous Metachronous
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LIANE DELIGDISCH TABLE 3 ASSOCIATION BETWEEN OVARIAN CARCINOMA AND PRIMARY ENDOMETRIAL CARCINOMA
No.
Histological pattern of ovarian tumors associated with primary endometrial carcinoma Endometrioid carcinoma Granulosa cell carcinoma Endometrioid carcinoma Endometrioid carcinoma Serous papillary adenocarcinoma Endometrioid carcinoma
7 8 9 10
Serous papillary adenocarcinoma Endometrioid carcinoma Endometrioid carcinoma Serous papillary adenocarcinoma
Time sequence Synchronous Synchronous Synchronous Synchronous Synchronous Metachronous (2-yr interval) Synchronous Synchronous Synchronous Synchronous
Endometriosis One ovary Absent Both ovaries and parametrium Both ovaries and sigma Absent Both ovaries Absent Both ovaries Both ovaries Absent
Since our analysis was concerned, not only with multiple primary tumors, but also w i t h m u l t i f o c a l l y m a l i g n a n t t u m o r s a r i s i n g in s i m i l a r s y m m e t r i c a l o r g a n s , w e r e v i e w e d t h e b i l a t e r a l b r e a s t a n d b i l a t e r i a l o v a r i a n c a r c i n o m a s in t h e c a s e s w h e r e m e t a s t a s i s f r o m o n e side to t h e o t h e r d e f i n i t e l y c o u l d b e r u l e d out. W e c o n s i d e r e d t r a n s i t i o n h i s t o l o g i c a l l y f r o m n o r m a l to m a l i g n a n t t i s s u e as e v i d e n c e for e x i s t e n c e o f a p r i m a r y f o c u s .
FIG. 1. Ovarian endometriosis showing transition to endometroid papillary carcinoma.
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Fro. 2. O v a r i a n endometriosis showing atypical ceils with bizarre nuclei. No invasion of the underlying stroma can be seen.
There were 13 cases of bilateral primary breast carcinoma, the mean age of the patients being 49 yr. Five cases were synchronous, and eight metachronous (1-13 yr interval). In four cases, bilateral lobular carcinoma in situ was found synchronously with infiltrating carcinoma of the same or of the opposite breast. Out of the eight metachronous tumors, four showed mammary dysplasia of the opposite breast at the time of the diagnosis of carcinoma in one breast. One to nine years afterward, a renewed biopsy of the previously diagnosed dysplastic TABLE 4 ASSOCIATION BETWEEN PRIMARY CERVIX CARCINOMA AND PRIMARY ENDOMETRIAL CARCINOMA
No.
Time sequence
1 2
Synchronous Metachronous
3
Metachronous (18-yr interval) Synchronous Metachronous
First
Second
First p r i m a r y
primary tumor
primary tumor
therapy
-Endornetrium
-Cervix
-Radium
Cervix
Endometrium
Radium
-Cervix
-Endometrium
(lyr interval)
4 5
(8-yr interval)
therapy therapy -Radium
therapy
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breast showed infiltrating carcinoma. Of the five synchronous tumors, three also showed associated mammary dysplasia. Bilateral primary carcinoma of the ovaries occurred in six cases, all of them synchronous, the mean age being 49 yr. In four cases, the histological pattern was papillary cystadenocarcinoma, and in the other two, endometrioid carcinoma. In three cases endometriosis was found in both ovaries, and in the two cases of endometrioid carcinoma, trasition areas between the endometriosis and the endometrioid carcinoma could be demonstrated. In five cases both ovarian tumors were associated with other primary malignant tumors (two carcinomas of the breast, two of the endometrium, and one of the appendix). These have been included in the respective groups of multiple primary tumors already discussed. One of these cases was a 37-yr-old patient who had bilateral primary tumor of the breast 8 yr prior to bilateral primary tumor of the ovaries. This patient had metastases in the pelvic lymph nodes and is still living now, 13 yr after the bilateral radical mastectomy and 5 yr after the bilateral oophorectomy. In seven cases, an association of more than two primary malignant tumors was found. The mean age of these patients was 69 yr. The involved organs were breast, ovary, endometrium, cervix, vagina, urinary bladder, and appendix in various combinations and time sequences (Table 5). In case No. 7 (a 74-yr-old patient, 9 yr after undergoing a left mastectomy for mucinous adenocarcinoma of the breast), a primary carcinoma was found in the other breast (diagnosed as Paget's disease and ductal carcinoma) synchronously with adenocarcinoma of the endocervix and endometrioid carcinoma of both ovaries. In case No. 4 (a 72-yr-old patient presented synchronously with primary carcinoma of both ovaries and carcinoma in situ of the endometrium, 2 months after radical hysterectomy), a primary carcinoma of the left breast with metastases to the axillary lymph nodes was found. Endometriosis of ovaries and myometrium (adenomyosis) was found in 14 patients, nine of which had ovarian and endometrial carcinoma. A history of radium therapy was found in five cases, all of them with metachronously appearing tumors. DISCUSSION The percentage (5.4%) of multiple primary tumors of the female genital organs and breast in our material is lower than that reported by Hansen and Collins TABLE 5 MORE THAN TWO PRIMARY MULTIPLE TUMORS IN DIFFERENT LOCATIONS No.
Time sequence
Location
1 2 3 4 5 6 7
Synchronous Metachronous Metachronous Synchronous Synchronous Metachronous Metachronous
Cervix, vagina, appendix Vagina, cervix, urinary bladder Cervix, vagina, left breast Both ovaries, left breast, endometrium Left breast, left ovary, rectum Endometrium, left ovary, left breast Right breast, left breast, cervix, both ovaries
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(6.8%) [10] and higher than that of Protzen (4.05%) [23]. Earlier diagnosis, better treatment, and increased survival achieved in recent years seem to have permitted the recently increasing number of reported cases of multiple primary tumors. In light of the different associations of primary tumors, several points can be made. In the association between breast primary cancers and primary cancers of genital location, a striking feature is the fact that although there were 91 ovarian carcinomas and 406 cervix cancers, there were 6 patients with breast and cervix cancer and 6 patients with breast and ovarian cancer. Because breast cancer and uterine cervix cancer both have a high incidence in the female population, we could consider their association in the same patients a coincidental finding. However, the association of primary breast carcinoma with primary ovarian carcinoma, the incidence of which, in our figures is less than four times in the considered cancer population, may bear significance. The literature [20,23] also reports a frequent association between these tumors and refers to factors related to a common hormonal background [12]. The relatively frequent (13 cases) association between primary carcinoma of the exocervix, vagina, and vulva, which are organs closely related by their embryological development from the cloaca, seems to have significance. In one case, primary carcinoma of the cervix and vagina and, in another case, primary carcinoma of the vulva were associated with carcinoma of the urinary bladder, the origin of which, as well, is the cloaca. As reported in the literature [10,26,27] the "cloacogenic" multiple carcinomata may result from a common etiology: the predisposing fact of common embryologic heritage or "area predisposition" in which there is a multifocal response to carcinogens. Tissues related through their embryological development show an increased receptivity to the same carcinogens. The response to carcinogens may be delayed in some areas, and this could be the reason for simultaneous occurence of overt carcinomas and in situ carcinomas in the same "area." The association, also relatively frequent, of endometrial and ovarian primary carcinoma may suggest, as emphasized by Woodruff, a multifocal response to carcinogenic influence of tissues related by their embryologic development, since the mullerian paramasonephric tissue develops in close relationship with the celomic epithelium [31 ]. The associated findings of endometriosis in most of the cases of primary tumors of the endometrium and ovary and its malignant transformation to endometrioid carcinoma in the ovary and to adenocarcinoma of the uterus (Fig. 3) may support the idea of "solidarity" in the response to carcinogens by the mullerian epithelium regardless of its location. The association between cervix and endometrial primary carcinomas, despite their close topographical neighborship, is relatively rare (five cases). It is less frequent than the association between cervical and ovarian and between vulva and vaginal tumors, which may be more related histologically and functionally. In this group, the radiation therapy of the first primary cancer could be related to the appearance (after 1, 8, and 18 yr) of a second primary cancer.
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FIG. 3. Adenocarcinomatous glands in an area of uterine endometriosis (adenomyosis).
The review of the "multifocal" primary tumor's arising primarily in both breasts supports the statements in the literature [30] that lobular carcinoma in situ appears mostly bilateral. The simultaneous finding of "in situ" lobular carcinoma with infiltrating carcinoma in one or both breasts may represent a delayed response to carcinogens of the various parts of the breast tissue. No conclusion could be drawn about the eventual pathogenic relationship between mammary dysplasia and carcinoma of the breast, since mammary dysplasia was found both synchronously and metachronously with overt and in situ carcinomas of the breasts. The bilateral primary ovarian carcinomas, frequently associated with endometriosis, may emphasize the reciprocal response to carcinogens of the mullerian epithelium of various locations. The almost always synchronous occurence of these tumors in contrast to other multiple primary tumor combinations may confirm this idea. Multiple primary tumor development probably requires, not only a common embryologic origin (why is multiple primary tumor association not seen more frequently in fallopian tube epithelium?), but a carcinogenic influence that is operative nearly equally throughout. This may be an environmental carcinogen, such as hormones, radiation, or others. The controversial subject of the hormonal influence in the genesis of the malignant tumors in the female genital organs and breasts evokes different
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189
opinions. A history of hormonal disturbances or prolonged estrogen effect is not an uncommon background of endometrial, ovarian, and breast carcinomas. Other factors may be partly responsible for the multiple primary tumors: the histological and functional similarity of the tissues, which may explain the more frequent occurence of multiple carcinoma in the vagina, vulva, exocervix, and skin and gingiva (as in one of our cases), or the cancers arising in the mucinous epithelium of the gastro-intestinal tract associated with the mucinous carcinoma of the ovary and of the endocervix (or of the association of the latter two, as seen in one of our cases). The "precancerous" lesions, the carcinoma in situ accompanying overt carcinoma, may represent various stations in the carcinomatous progression in time and space. The occurence of a third or even fourth primary malignant tumor of the female genital organs and breasts, topographically separated, in older patients may be explained by the fact that better diagnosis and treatment of previous cancer permitted a longer survival, with longer time at risk for development of new primary tumors.
CONCLUSIONS 1. The incidence of the multiple primary tumors in the Womens Magee Hospital during the period 1966-1970 was 5.4% (67 out of 1235 cases of cancer in the same period). 2. The "area response" to carcinogens of embryologicaUy related organs, the exocervix, vulva, vagina, and urinary bladder or endometrium and ovary, was pointed out. 3. Malignant changes in endometrioid foci was frequently associated with the simultaneous occurrence of ovarian and endometrial carcinoma. This represents a multifocal response to carcinogens of mullerian derivatives in topographically different locations. 4. Carcinomas in situ frequently were found simultaneously with multifocal primary carcinoma. They may be considered the result of a delayed response of some areas to the carcinogen that produces multifocal primary carcinoma. 5. Benign lesions such as endometriosis and dysplasias of the breast were frequently associated with multiple and multifocal carcinoma of the female genital system.
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