Synchronous primary neoplasms of the female reproductive tract

GYNECOLOGIC ONCOLOGY

33, 33%339(1989)

Synchronous Primary Neoplasms of the Female Reproductive Tract’ ROBIN Division

of Gynrcologic

F.

EISNER,

M.D.,

ROBERTA

K.

NIEBERG,

M.D.,

AND JONATHAN

Oncology, Depurtments of Obstetrics and Gynecology, und Pathology, Jonsson Comprehensive Cuncer Center, Los Angeles, Culiforniu

S. BEREK, UCLA 90024

School

M.D.2 of Medicine,

and the

Received November 9, 1987

of the “secondary miillerian system” was proposed 121 A histopathologicreviewof synchronousprimary neoplasmsof to explain the observation of multiple similar neoplasms the femalereproductivetract is presented.During a 30.yearperiod, in 3863patients with femalegenital malignancieswere accessioned the female genital tract [4]. The theory purports that to the UCLA Tumor Registry: 958 had ovarian cancer,776 en- the epithelia of the cervix, uterus, fallopian tubes, ovaries, dometrialcancer,1556cervicalcancer,and 573other gynecologic and peritoneal surfaces simultaneously respond to a carmalignancies.Twenty-six(0.7%)patientswith invasivesynchronous cinogenic stimulus. Sica et al. [5] suggested that shared primary cancerswere identified. The most frequentsynchronous hormonal receptors, e.g., estrogen receptors, may be genitallesionswereovarianand endometrialcancersin 11 patients responsible for the development of multiple primary ma(0.3%). No associationwas documentedbetweengenital and ex- lignancies in predisposed tissue. Thus, embryologic, hortragenital cancers.Patients with synchronousovarian and en- monal, or other phenomena may be associated with the dometrial cancerseach were low stageand low grade, and the development of malignancies arising simultaneously in prognosiswasexcellent.Their detectionin a relatively early stage genital tissues. suggestsdiagnosismay be facilitated by early symptomsfrom the Riemer et al. [6] and others [7,8] have identified an endometrialcarcinoma,and that theselesionsare biologically of increased incidence of primary malignancies of the enrelatively low grade.Thesedata supportthe conclusionthat there dometrium, colon, lung, and breast in patients with primary is an associationbetweenlow-stageepithelial carcinomaof the ovarian cancer. Axelrod et al. [9] found an increased ovary and endometrialcarcinoma. o 1989AcademicPWS,IIK. incidence of primary malignancy of the cervix, ovary, fallopian tube, breast, and colon in patients with primary INTRODUCTION endometrial cancer. Moertel et al. [7] studied 37,580 paThe observation that synchronous multiple primary tients and found multiple primary malignancy to be present neoplasms occur in the same individual is clinically of in 1052 patients (2.8%). Simultaneous primary malignancies of the ovary and interest. While the etiology and pathogenesis of this phenomenon are unclear, it has been postulated that em- endometrium have been documented in several studies. bryologically similar tissues, when simultaneously sub- Silverman et al. [lo] noted that of 413 patients with jected to hormonal influences or to carcinogen(s), may ovarian cancer, 16 patients (3.8%) had a simultaneous primary tumor of the endometrium. Eifel et al. [ 1l] sugdevelop synchronous neoplasms [ 1,2]. As early as 1912, Goodall [3] postulated the common gested in a recent study of 29 patients with synchronous embryologic origin of epithelia of the upper female genital malignant epithelial neoplasms of the ovary and endotract and peritoneal surfaces. Laughlan [4], and recently metrium that the prognosis of the patients was more Woodruff et al. [2], suggested that malignancies arising favorable than one might expect with more advanced in spatially separate foci may represent metaplasia oc- stage ovarian cancer. A retrospective study of the clinical and tumor registry curring in similar histopathologic epithelia. The theory records and histopathologic data of patients with syn’ Supported by a grant from the Patricia Wells Ovarian Cancer Re- chronous multiple primary malignancies treated at the search Fund. UCLA Medical Center during a 30-year period is pre’ TO whom requests for reprints should be addressed: Division of GynecologicOncology, Department of Obstetrics and Gynecology, sented. The objective of this study was to identify and describe the histopathological types of tumors that ocUCLA School of Medicine, Room 24-127, CHS, Los Angeles, CA 90024. curred simultaneously. 335 0090-8258189$1SO Copyright 0 1989 by Academic Press, Inc. All rights of reproduction in any form reserved.

336

EISNER, NIEBERG, AND BEREK

MATERIALS

AND METHODS

Patients

The UCLA Central Tumor Registry was searched for patients in whom synchronous multiple primary malignancies existed. At least one of the primary tumors in each patient arose in the female genital tract. The period of review was 1955 through 1986. The medical records and pathology were reviewed to confirm the diagnosis and stage of the tumors. Stage was assigned according to criteria of the International Federation of Gynecology and Obstetrics (FIGO). Pathology

Pathology specimens of the synchronous primary cancers were reviewed to confirm the original histology type and grade. The tumor grades for ovarian and endometrial cancers were assigned as follows: grade 1 (well differentiated), grade 2 (moderately differentiated), and grade 3 (poorly differentiated). Degree of nuclear anaplasia and glandular differentiation were the criteria used to determine grade. The histologic classification of epithelial ovarian neoplasms was determined according to Hart and Morrow [12] using WHO criteria.

TABLE 1 Synchronous Malignant Neoplasms (IV = 26) Both primaries occurring within genital tract Genital site 1

Genital site

Ovary Endometrium Ovary Vulva Vulva Endometrium Total

Endometrium Cervix Cervix Cervix Vulva Fallopian tube

2

11 4

1 1 1 1

19

One primary occurring outside the genital tract Genital site Ovary Vagina Ovary Cervix Vagina Vulva Endometrium Total

Extragenital site Colon Bladder Lung Blood Blood Lung Breast

dometrial tumor, 15 patients (88%) had stage I tumors, 1 patient (6%) had a stage II lesion, and 1 patient (6%) RESULTS had a stage III tumor. Ten patients (59%) had grade 1 During the 30-year period, 3863 patients with female lesions, 6 patients (35%) had grade 2 lesions, and 1 patient genital malignancies were identified: 858 patients had (6%) had a grade 3 lesion. uterine corpus cancer, 776 had endometrial cancer, 1556 Of the 14 patients with a primary ovarian cancer, 9 patients had cervical cancer, 958 had ovarian cancer, patients (64%) had stage I disease, 3 patients (21%) had and 573 had other gynecologic malignancies. Twenty-six stage II disease, and 2 patients (15%) had stage III disease. (0.7%) patients with synchronous primaries were identified. Nine (64%) had grade 1 lesions, 4 (28%) had grade 2 Data from these patients’ medical records and their his- lesions, and 1 patient (8%) a grade 3 lesion. Eight patients had either a primary cervical lesion or tologic specimens were reviewed. Nineteen patients had simultaneous multiple primary malignancies of the female vulvar cancer: all the cervical cancers were stage I, and genital tract, and seven patients had primary extragenital all three patients with vulvar cancer had stage I, grade malignancies in addition to a single primary genital tract 1 disease. One patient had a primary stage I, grade 2 fallopian tube cancer. malignancy (Table 1). Histopathology

Synchronous

Ovarian and Endometrial

Cancers

The most frequently documented synchronous maligThirteen patients had adenocarcinoma of the endometrium. Two had mixed mesodermal tumors, and one nancies were those of the ovary and endometrium, which each had a stromal sarcoma and an adenoacanthoma. were seen in 11 patients (Table 2). In this group, 5 patients Fourteen patients had ovarian cancer, seven serous, four had an endometrioid carcinoma and 5 had a serous cysendometrioid, and three mutinous. All carcinomas of the tadenocarcinoma of the ovary, each associated with an cervix and vagina were squamous. One patient with a adenocarcinoma of the endometrium. One patient with primary vulvar malignant melanoma had a concurrent a mutinous cystadenocarcinoma of the ovary had an cervical squamous carcinoma, and one patient with a adenocarcinoma of the endometrium. The simultaneous primary malignancies in this group sebaceous gland adenocarcinoma of the vulva had a sepwere predominantly of low stage. Seven of the patients arate syringocystadenoma with malignant transformation. Most endometrial malignancies were both low stage in this group had stage I disease of both the ovary and and low grade. Of the 17 patients with a primary en- the endometrium: three patients had stage II and I disease,

SYNCHRONOUS OVARIAN AND ENDOMETRIAL

337

CANCERS

TABLE 2 Simultaneous Multiple Primary Malignancies of the Endometrium and Ovary Endometrial adenocarcinoma

Ovarian adenocarcinoma

Patient

Grade

Stage

Histology

1 2 3 4 5 6 7 8 9 IO 11”

1 2 2 I I 2 I 1 1 1 2

I I I I I I I I I I I

Endometrioid Serous Serous Endometrioid Serous Serous Mutinous Serous

Endometrioid Endometrioid Endometrioid

Stage

Status

Months

I

II

2 1

II I I

DOD NED DOD NED NED NED DOD DOD NED NED DOD

36 3 258 9 340 3

Grade

1 1

I III

2 1 2 3

I

I I I II

1 2

113 192 25 4 39

a Third primary (mixed mesodermal sarcoma of the ovary, stage IV). b Third primary (adenocarcinoma of the colon, Duke’s I).

respectively; and only one patient had stage III and 1 disease, respectively (Table 2). All patients were treated with a total abdominal hysterectomy and bilateral salpingo-oophorectomy. Five patients received chemotherapy: two with a combination of cisplatin, Adriamycin, and Cytoxan, one with a combination of cisplatin and Cytoxan, one with a combination of Adriamycin, vincristine, Cytoxan, and one with 5fluorouracil (5FU). Five patients were treated with pelvic radiation. Follow-up was 3 to 340 months (median = 40 months). Patients survived 24 to 258 months (median survival = 76 months). The follow-up for patients with both an endometrioid carcinoma of the ovary and an adenocarcinoma of the endometrium ranged from 4 to 39 months (median = 9 months) (Table 2). Two patients died at 36 and 39 months, respectively. Three Primaries

Two patients had three separate synchronous multiple primary malignant neoplasms. One patient had a stage I endometrioid carcinoma of the ovary, a stage I adenocarcinoma of the endometrium, and a stage IV mixed mtillerian tumor of the contralateral ovary. She survived 25 months before succumbing to hepatic metastases from the mixed miillerian tumor. The other patient had a stage II endometrioid carcinoma of the ovary, a stage I adenocarcinoma of the endometrium, and a Duke’s “C” adenocarcinoma of the colon, for which she was treated with a total abdominal hysterectomy, bilateral salpingooophorectomy, and a left hemicolectomy. She died 34 months later with hepatic and intraabdominal metastasis from her colon carcinoma.

Other Synchronous

Genital Cancers

Four patients had a primary malignancy of the endometrium and the cervix. These patients had squamous carcinomas of the cervix, three associated with adenocarcinoma of the endometrium and one with a mixed mtillerian tumor of the endometrium. One patient had a sebaceous carcinoma of the vulva, and a separate syringocystadenoma with malignant transformation in the vulva. She is alive and free of disease 3 years after a radical vulvectomy. Synchronous

Genital and Extragenital

Cancers

One patient each had a synchronous serous cystadenocarcinoma of the ovary and adenocarcinoma of the colon, an endometrial adenocarcinoma and an infiltrating ductal carcinoma of the breast, a squamous cell carcinoma of the vagina and a transitional cell carcinoma of the bladder. These three patients all died of metastatic disease 1 to 32 months after diagnosis, all expiring from nongenital primaries. Two patients, one with synchronous melanoma of the vulva and an oat cell carcinoma of the lung, and another with a squamous cell carcinoma of the vagina and a non-Hodgkin’s lymphoma, are alive and free of disease at 35 and 5 months, respectively. DISCUSSION Our data support the conclusion that there is an association between low-stage carcinomas of the ovary and the endometrium. This pair of multiple primary malignancies occurs synchronously more often than one would expect by chance. The associated low-grade histologies

338

EISNER, NIEBERG, AND BEREK

indicate that they have arisen as synchronous separate, multifocal primary lesions, and not as metastases from one to the other site. The prognosis in these patients is favorable. Annegers and Malkasian found that 24 of 1192 (2%) patients with endometrial carcinoma had simultaneous ovarian cancers [ 131. Cramer and Cutler [14] and others [lo,151 have reported the overall incidence of a simultaneous ovarian malignancy and another primary tumor as 2.2 to 8.9%. Silverman et al. [lo] noted that the incidence of primary ovarian malignancy coexisting with primary endometrial cancer to be 3.8%. Our series documents a lower incidence for this association, 1.4%. The reason for the lower incidence is not clear. The presence of these morphologically similar ovarian and uterine epithelial neoplasms may be, in part, explained by Laughlan’s theory of the “extended or secondary mtillerian system,” i.e., multifocal oncogenic transformation [4]. The mtillerian epithelia may undergo multifocal metaplasia responding synchronously to an offending carcinogen. The multifocality may be expressed by the fact that, at the time of diagnosis, the majority of patients have low-stage disease. In the present series, 11 of 11 patients had stage I endometrial cancer at the time of diagnosis, 7 had stage I disease of both ovary and endometrium, and 7 had stage I disease of ovary. In a series of 49 synchronous multiple neoplasm of the ovary and the uterus, Choo and Naylor [16] found that 74.5% of patients with ovarian carcinoma and 93.6% of patients with endometrial carcinoma had stage I lesions, all of low grade. Similarly, 94% of all our patients who had endometrial carcinomas were stage I or II, and 85% of patients with ovarian cancer had stage I or II disease, all of low grade. These findings are in sharp contrast to the 70% of primary ovarian carcinoma patients whose disease has spread beyond the pelvis at the time of diagnosis [17]. Endometrial cancer usually produces early symptoms, and is diagnosed in over 70% of patients when it is still confined to the uterus. Eifel et al. [l l] found that abnormal bleeding was present in the majority (80%) of patients, while a palpable adnexal mass was present in the minority of patients with primary ovarian cancer. Of the 17 patients with a primary endometrial tumor in this series, 14 patients (86%) had abnormal bleeding. In these patients, a clinically silent cancer of the ovary was diagnosed earlier because of the symptomatic endometrial cancer. This may account for the more favorable outcome in these patients. Alternatively, these lesions may possess an inherently more favorable prognosis by virtue of being relatively low grade and, therefore, biologically less aggressive than ovarian cancers that occur as a single primary. Eifel et al. [ 1l] reported 29 patients with simultaneous ovarian and uterine endometrioid carcinomas whose le-

sions were all of relatively low grade, and all were alive and free of disease with a median of 4 years follow-up. Kottmeier [ 181reported a similar outcome in his patients. Our data also suggest that those patients have a significantly better survival than do patients with a single primary ovarian cancer. It is unclear from this limited experience if adjuvant treatment had any impact on survival of these low-stage tumors, because in the majority of patients the stage was low and the outcome favorable. In those patients whose ovarian cancer was of higher stage, the survival was poor. Moertel et al. [7] documented an incidence of 2.8% of primary genital malignant neoplasms associated with extragenital malignancies. Two of the most well-documented associations, carcinoma of the ovary and lung and carcinoma of the ovary and colon, were also present in our series. Two of our patients who had synchronous endometrial and ovarian adenocarcinomas also had a third primary tumor, and died of metastatic ovarian sarcoma and adenocarcinoma of the colon. A 1.3- to 2.0-fold increase in the risk of breast cancer in patients with primary endometrial cancer has been noted [19], but we did not document this in our patients. Newell et al. [20] and Basilar [21] noted strong associations between carcinoma of the cervix and lung and carcinoma of the cervix and bladder, but this was not found in our review. REFERENCES 1. Woodruff, J. A., and Julian, D. C. Multiple malignancy in the upper genital canal, Amer. .I. Obstet. Gynecol. 103, 810 (1969). 2. Woodruff, J. D., Solomon, D., and Sullivan, H. Multifocal disease in the upper genital canal, Obster. Gynecol. 65, 695 (1985). 3. Goodall,-J. R. The origin of epithelial new growths of the ovary, Surg. Gynecol. Obsret. 14, 584 (1911). 4. Laughlan, S. The secondary mtillerian system. Obstet. Gynecol. Surv. 27, 133-146 (1972). 5. Sica, V., Nola, E., Contieri, E., Bova, R., Masucci, M. T., Medici, N., Petrillo, A., Weisz, A., Molinari, A. M., and Puca, G. A. Estradiol and progesterone receptors in malignant gastrointestinal tumors, Cancer Res. 44(10), 4670-4674 (1984). 6. Riemer, R. R., Hoover, R., Fraumeni, J. F., et al. Second primary neoplasms following ovarian cancer, J. Natl. Cancer Inst. 61, 11951197 (1978). 7. Moertel, C., Dockerty, M. B., Baggenstoss, A. H., et al. Multiple primary malignant neoplasms. I. Introduction and presentation of data, Cancer 14, 221-230 (1961). 8. Schottenfeld, D., and Berg, J. Incidence of multiple primary cancers in females, J. Natl. Cancer Inst. 43, 16-29 (1969). 9. Axelrod, J. H., Fruchter, R., and Boyce, J. G. Multiple primaries among gynecologic malignancies, Gynecol. Oncol. 18,359-372 (1984). 10. Silverman, S., O’Neill, R. T., Mikuta, J. J., et al. Multiple malignant tumors associated with primary carcinoma of the ovary, Surg. Gynecol. Obstet. 134, 244-248 (1972). 11. Eifel, P., Henricksen, M., Ross, J., Ballon, S., Martinez, A., and Kempson, R. Simultaneous presentation of carcinoma involving the ovary and the uterine corpus, Cancer 50, 163-170 (1982).

SYNCHRONOUS OVARIAN AND ENDOMETRIAL 12. Hart, W. R., and Morrow, C. P. The ovaries, in Gynecology and obstetrics. The health cure of women (S. L. Romney, M. .I. Gray, and A. 0. Little, Eds.). McGraw-Hill, New York, 2nd ed. (1981). 13. Annegers, J. F., and Malkasian, G. B. Patterns of other neoplasia in patients with endometrial carcinoma, Cancer 48,856-859 (1981). 14. Cramer, D., and Cutler, S. Incidence and histopathology of malignancies of the female genital organs in the United States, Amer. J. Obstet. Gynecol. 118, 443-460 (1974). 15. Schoenberg, B. S., Greenberg, R. A., and Eisenberg, H. Occurrence of certain multiple primary cancers in females, J. Nat/. Cancer Inst. 43, 15-32 (1969). 16. Choo, Y. C., and Naylor, B. Multiple primary neoplasms of the ovary and uterus, Znt. J. Gynecol. O&et. 20, 327-334 (1982).

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17. Beck, W., Jr. Pelvic malignancies, in Obstetrics and gynecology (W. Beck, Jr., Ed.). Wiley, New York, pp. 299-309 (1986). 18. Kottmeier, H. L. The diagnosis and treatment of ovarian malignancies, Ann. Pathol. 37, 51 (1965). 19. Schottenfeld, D., and Berg, J. Incidence of multiple primary cancers: IV. Cancers of the female breast and genital organs, J. Natl. Cancer Inst. 46, 161-170 (1971). 20. Newell, G. R., Rawlings, W., Krementz, E. T., and Roberts, J. D. Multiple primary neoplasms in blacks compared to whites, J. Natl. Cancer Inst. 53, 369-373 (1974). 21. Basilar, J. C. The incidence of independent tumors among uterine cancer patients, Cancer 16, 842-853 (1963).