GYNECOLOGIC
ONCOLOGY
39, 337-346
(1990)
Endometrioid Carcinoma of the Ovary: Retrospective Review of 145 Cases RICHARD
*Ochsner
C.
KLINE
7 M.D.,*,’
J. TAYLOR WHARTON, M.D. ,t E. NEELY ATKINSON, PH.D. ,t T. W. BURKE, M.D.,? D. M. GERSHENSON, M.D.,? AND CREICHTONL. EDWARDS,M.D.?
Clinic and Alton Ochsner Medical Foundation, 1514 Jefferson Highway, New Orleans, Louisiana 70121, and TDepartment Gynecology, University of Texas, M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030 Received
of
April 19, 1990
From 1967through December1987, 145 patients with endometrioid carcinoma of the ovary were treated at the University of Texas M. D. Anderson Cancer Center. Thirty-eight patients (26.2%)had stageI disease,28 (19.3%) stageII, 60 (41.4%)stage III, and 11 (7.6%) stage IV; 8 patients (5.5%) were unstaged. Grade 2 or 3 histology was seenin 119 patients (82.1%). In addition to surgicaltherapy, 128patientsunderwent chemotherapy, including single-agenttherapy, noncisplatin combination therapy, and cisplatin-basedtherapy. No statistically significant improvement in median survival was noted among thesethree chemotherapygroups for stagesII, III, and IV (P = 0.22). A significant improvement in median survival wasnoted for those patients who achieveda completeclinical response,regardlessof type of chemotherapy(96 or more monthsfor single-agenttherapy, P = 0.001; 31.5 monthsfor noncisplatincombinationtherapy, P = 0.016; and 85 monthsfor cisplatin-basedtherapy, P = 0.0001).Synchronousovarian and uterine malignancieswereseen in 18 patients (12.4%). No difference in survival was seenfor patientswith endometriosis(P = 0.13) or endometrialcancer(P = 0.09) when compared with those who did not have these histologicfindings. 8 1990 Academic Press, Inc. INTRODUCTION
Ovarian carcinoma is the fifth leading cause of cancer death in women in the United States, with 20,500 new cases and 12,400 deaths predicted for 1990 [l]. Ninety percent of all ovarian cancers are epithelial in origin. The World Health Organization in 1964 recognized the term endometrioid carcinoma of the ovary [2]. In 1925, Sampson [3] described endometrioid carcinoma of the ovary, although it was not yet known by this name. Long and Taylor [4] in 1964 described the basic histologic criteria
for endometrioid carcinoma. As a result of the report by Santesson [S] to the International Federation of Gynecology and Obstetrics (FIGO) in 1961, the term endometrioid carcinoma was proposed. In the Radiumhemmet experience, Santesson showed that 24.4% of epithelial carcinomas of the ovary were endometrioid, an incidence surpassed only by that of serous carcinoma (39.3%). Before this time, cystadenocarcinomas with a similar histology were termed adenoacanthomas [6] and endometrial-like carcinoma [7,8]. Squamous elements may be very frequent. Presence of a malignant squamous component may be a prognostic factor. Admixture with other mullerian elements may also be present. According to Czemobilsky et al. [2], patients whose tumors have other mullerian elements (“mixed tumor”) do as well as those whose tumors do not have other mullerian elements. This study reviews cases of endometrioid carcinoma of the ovary treated at the University of Texas M. D. Anderson Cancer Center (UT/MDACC), in Houston, from 1967 through 1987. Information about stage, grade, survival, presence of endometriosis and synchronous uterine adenocarcinoma, type of surgery, amount of residual tumor, and effectiveness of various chemotherapy protocols is presented, as well as prognosis as it relates to these various parameters. During this period, 2300 epithelial ovarian carcinomas were seen at UT/MDACC, of which 268 were recorded as having an endometrioid pattern (12%). Endometrioid carcinoma was surpassed only by serous carcinoma (68%). MATERIALS
Patient
’ To whom correspondenceand reprint requestsshould be addressed.
Selection
AND METHODS
and Criteria for Treatment
The gynecologic data base at UT/MDACC cessed to identify patients with endometrioid
was accarcinoma
337 OOW-8258/90 $1.50 Copyright 0 1990 by Academic Press, Inc. All rights of reproduction in any form reserved.
338
KLINE
of the ovary. From 1967 through 1987, 268 patients with a diagnosis of endometrioid carcinoma of the ovary were identified. All charts and microfilm records were reviewed to confirm histologic diagnosis and that either surgery and/or chemotherapy was performed at UT/ MDACC. If initial surgery was performed elsewhere, chemotherapy and second-look laparotomy, when performed, must have been at UT/MDACC; 145 patients were found to meet these criteria. The other patients were excluded for a variety of reasons, including those with nonendometrioid histology and those seen in consultation only or whose second-look laparotomy was performed elsewhere. Histologic confirmation and grade were obtained from UT/MDACC pathology reports. All patients had histologic review at the time of initial evaluation. For those who did not undergo reexploration, initial stage was obtained from clinic notes and operative and pathologic reports. For those patients who underwent reexploration, the stage at time of reexploration was used. Stage was determined according to the 1974 FIG0 classification. Histologic grading was performed by the staff of the Department of Pathology at UT/MDACC, according to a pattern-grading system [91. Grade 1 represents well differentiated, grade 2 moderately differentiated, and grade 3 poorly differentiated. Primary Surgical Therapy
Patients underwent initial surgery at other hospitals or at UT/MDACC. The surgery at UT/MDACC represented either primary tumor reduction in patients referred with a pelvic mass or secondary exploration in those who had already been operated upon. Some patients who entered clinical trials and reexploration to assess extent of disease and to further reduce tumor burden prior to starting chemotherapy. Tumor reductive surgery, when performed, was radical and attempted to reduce tumor to a residual of 2 cm or less. For patients not undergoing reexploration, by careful review of operative dictations and pathology reports and from telephone calls to referring physicians the extent and amount of residual tumor were determined before therapy was begun. Generally, patients did not undergo reexploration when outside operative and pathology reports and initial gynecologic examination at UT/MDACC indicated stage I disease or residual tumor diameters 2 cm or less. Patients whose reports indicated advanced stage (II, III, or IV) or whose physical examination showed residual disease were reexplored. Patients were divided into two groups, those with residual disease of 2 cm or less and those with residual disease greater than 2 cm. Of the 145 patients, 4 had
ET
AL.
TABLE
1
Criteria of Response Complete Clinical
No
clinically
months No visible
Surgical
detectable or longer disease
rotomy (A ther defined
Partial Clinical
positive;
response biopsies:
S (-)
=
3 lapais furS (+)
microscopic
in palpable tumor the sum of two perpen-
which
persisted
3 months
or
longer 50% or greater reduction in the sum of tumor masses measured at time of second-look
Surgical
response”
No
operation tumor regression detectable more courses of chemotherapy of new
Source. I’ Patients therapy operation
diameters,
persisting
of second-look
surgical on review
50% or greater reduction masses, calculated by dicular
No
at time
complete based
= microscopic negative.)
disease
Reproduced, with no
who are
develop considered
with clinically
lesions permission, detectable
after two or or appearance
or effusions from Ref. [IO]. disease at onset
palpable disease prior to have progressive
to planned disease and
of chemosecond-look no response
to chemotherapy.
biopsy only, 45 had simple tumor reduction (which usually included total abdominal hysterectomy and bilateral salpingo-oophorectomy), and 83 had tumor reductive surgery (which included total abdominal hysterectomy and bilateral salpingo-oophorectomy, omentectomy, extensive pelvic dissection, and resection of bowel). Thirteen had incomplete tumor reduction with greater than 2 cm of remaining residual disease. The 2-cm or less group included those undergoing both simple and more aggressive tumor reduction. In 111 patients (77%) residual tumors were judged to be 2 cm or less, and in 33 patients (23%), greater than 2 cm. Residual disease was not recorded for 1 patient. Chemotherapy
Since this report spans 20 years, multiple prospective randomized trials of chemotherapeutic agents were undertaken, including melphalan; fluorouracil; hexamethylmelamine and doxorubicin; hexamethylmelamine, doxorubicin, and cyclophosphamide; cisplatin and melphalan; and cisplatin and cyclophosphamide. Responses were classified as clinical in those not undergoing secondlook laparotomy or surgical in those undergoing secondlook laparotomy. Responses were judged according to the criteria in Table 1 [lo]. Patients were examined at monthly intervals, and measurable disease was evaluated. An adequate trial of each therapeutic agent consisted of a minimum of 60 days.
ENDOMETRIOID
CARCINOMA
OF THE
OVARY
339
had stage I disease, 28 (19.3%) stage II, 60 (41.4%) stage III, and 11 (7.6%) stage IV; 8 (5.5 %) patients were unstaged. Fifteen patients (10.3%) had grade 1 lesions, 59 (40.7%) grade 2, and 60 (41.4%) grade 3; in 11 patients (7.6%) the grade was unknown. Eighteen patients Radiation (12.4%) had a synchronous endometrial carcinoma (Table 2), 11 (7.6%) had a histologic diagnosis of endomeRadiation therapy has long been a mainstay of ovarian triosis, 4 (2.8%) had endometrial hyperplasia, and 112 cancer treatment. Radiation treatment for ovarian cancer (77.2%) had no associated pathology. Survival was not had been administered at UT/MDACC initially by movaffected by presence of endometrial cancer (P = 0.09). ing-strip technique to the whole abdomen. Using this Median survival in this group was 96 or more months. technique, 2600-2800 cGy was delivered. After wholeMultiple symptoms are associated with ovarian cancer. abdomen irradiation was completed, an additional 2000 Abdominal distension was the most frequent symptom cGy was delivered through parallel, opposed 15 x 15 (39 patients) followed by pelvic pain or pressure (33 pacm portals. In later years, the moving-strip technique tients). Abdominal pain was present in 25 patients. Sixwas abandoned in favor of open portal, whole-abdomen teen patients had no complaints. Vaginal bleeding and a radiation. Appropriate shielding with half-value layers of combination of symptoms were seen in 13 patients each. lead to the liver and kidneys was accomplished in stanPulmonary and gastrointestinal complaints were present dard fashion. in 2 patients each. Seven patients had liver metastases. For patients to be eligible for radiation therapy as a Ten patients had pulmonary metastases including posiprimary treatment, residual disease could not exceed 2 tive pleural effusions and 17 patients had lymph node cm nor could disease be present along the areas of shieldmetastases. Patient characteristics are seen in Table 3. ing to the liver or kidneys. Radiation therapy as firstChemotherapy was used in several clinical trials for line treatment was discontinued in 1975. 128 patients. As a first-line chemotherapy regimen, 46 patients (3 1.7%) received cisplatin and cyclophosphaAssociated Pathology mide, 37 (25.5%) received melphalan, 20 (13.8%) reThe presence of endometriosis or endometrial carci- ceived melphalan and cisplatin, and 7 (4.8%) received a noma associated with endometrioid carcinoma of the combination of hexamethylmelamine, doxorubicin, and ovary was recorded. Of patients with endometrioid car- cyclophosphamide. The remaining 18 patients (12.5%) cinoma, 7.6% also had histologic documentation of en- received single-agent hexamethylmelamine (1); fluorourdometriosis; 12.4% of patients had concurrent endomeacil (1); doxorubicin (1); cisplatin (3); hexamethylmelatrial carcinoma. Clinical staging of these concurrent mine and cyclophosphamide (3); cisplatin, doxorubicin, malignancies is difficult and unclear. Whether they rep- and cyclophosphamide (6); and cisplatin-melphalan alresent synchronous primaries or metastases from ovary ternating with hexamethylmelamine, doxorubicin, and to uterus or from uterus to ovary has not been detercyclophosphamide (3). Forty-two patients (29.0%) remined. Eighty percent of patients had no histologic evi- ceived 12 courses; 29 (20.0%) received 6 courses; the dence of endometriosis or endometrial carcinoma. Sur- others received either no chemotherapy or varying numvival was not influenced by the presence of endomebers of courses. Of the 128 patients who received chetriosis (P = 0.13) or by the presence of a synchronous motherapy, 86 (67.2%) achieved a complete clinical reendometrial carcinoma (P = 0.09). sponse; 32 (25.0%) developed progressive disease while receiving first-line chemotherapy, and 10 (7.8%) had a Statistical Analysis partial response or stable disease while receiving chemotherapy. Survival and progression-free interval were calculated Median survival was calculated for stage II, III, and using the life-table methods of Berkson and Gage [l 11. The statistical significance of the various factors was IV patients. Stage I was excluded in analysis because of a higher incidence of grade I lesions associated with tested by the Lee-Desu statistical method [12]. stage I carcinoma. A statistically significant improvement in median survival for stage II, III, and IV patients was RESULTS seen in patients who achieved a complete clinical reOf the 145 cases of endometrioid carcinoma of the sponse after treatment with a single agent (P = O.OOl), ovary reviewed in this study, 130 patients (89.7%) were a noncisplatin combination (P = 0.016), or cisplatinwhite, 11 (7.6%) were Hispanic, 3 (2.1%) were black, based therapy (P = 0.0001) versus those who had either and 1 (0.7%) was Asian. The mean age was 52.2 years partial or no response. Median survival for single-agent (range 27-83 years). Of these 145 patients, 38 (26.2%) chemotherapy was 96 or more months for complete clin-
Patients with documented progressive changed to second-line therapy. Those failed second-line treatment were changed motherapeutic agents including hormonal
disease were patients who to other cheprotocol.
340
KLINE
Synchronous
Endometrioid
Stage/grade
TABLE 2 Cancer of the Ovary and Endometrial
Myometrial invasion
Age (years)
Ovary
Uterus
40
IC/3
IB/2
62
III/2
IIIC/2
42
IV/3
IB/I
Inner half
47
IA/2
IB/2
Inner half
68
IV/2
IIIA/2
47
III/2
IB/I
Inner half
42
III/2
IB/2
Inner half
8
56
III/2
IC/2
Outer half
9
72
III/l
IB/I
Inner half
IO
33
IA/I
IA/I
Endometrium
11
67
IA/3
IIA/2
12
47
III/2
IA/2
Outer half Cervical gland Endometrium only
13
45
III/2
IBj2
Inner half
14 15
62 55
IA/l IB/l
IB/l IIAl3
Inner half Inner half Cervical Gland
16
46
III/l
IB/l
Inner half
I7
47
Unstaged/3
IB/2
Inner half
18
58
IC/3
IB/2
Inner half
Patient
Cancer
Treatment
Inner half
Outer half + Pelvic node
Serosal
-
ET AL.
only
Preop radium TAH, BSO Melphalan Negative second look TAH, BSO Melphalan x 5 Medroxyprogesterone TAH, BSO Melphalan x I2 Medroxyprogesterone Negative second look TAH, BSO War + WP TAH, BSO Melphalan Megestrol acetate TAH, BSO Melphalan x I2 Negative second look Preop radium TAH, BSO Melphalan x 12 Medroxyprogesterone Negative second look TAH, BSO HAC x 12 TAH, BSO CDDP/cyclo x 6 Positive second look Megestrol acetate TAH, BSO Melphalan x I2 Megestrol acetate TAH, BSO PAC x I2 TAH, BSO CDDP/cyclo x I2 Positive second look TAH, BSO CDDP/cyclo x 9 Megestrol acetate TAH, BSO TAH, BSO PAC x 10 Negative second look TAH, BSO CDDP/cyclo x 6 Negative second look TAH, BSO CDDP/cyclo x 6 Positive second look TAH, BSO CDDP/cyclo x 6 Negative second look
Symptom Abdominal
distension
Survival NED I83 months
Vaginal bleeding
DOD 22 months
Abdominal
NED 163 months
distension
Vaginal spotting Abdominal pain Vaginal bleeding
NED I65 months
Abdominal
pain
NED II3 months
Vaginal bleeding
NED I I9 months
Abdominal
pain
DOD 83 months
Abdominal
distension
NED 34 months
DOD 3 months
Pelvic and abdominal pain
NED 109 months
Abdominal
distension
DOD 77 months
Abdominal
pain
NED 89 months
Shortness of breath Abdominal distension
NED 80 months
Vaginal bleeding Rectal pressure
NED 58 months NED 39 months
Pelvic pain
NED 31 months
None
DOD 14 months
Vaginal bleeding Pelvic pain
NED 19 months
G TAH, total abdominal hysterectomy; BSO, bilateral salpingo-oophorectomy; NED, no evidence of disease; DOD, dead of disease; CDDP, cisplatin; cycle, cyclophosphamide; HAC, hexamethylmelamine/Adriamycin/Cytoxan; PAC, cisplatin, Adriamycin, Cytoxan; WAR, wholeabdomen radiation; WP, whole-pelvis radiation.
ENDOMETRIOID
CARCINOMA
TABLE 3 Patient Characteristics All patients
Number
P value
Age =z45 145 >45 Stage I 38 Overall 28 I vs II II III 60 I vs III IV I1 II vs III Unknown 8 III vs IV Grade I IS I vs 2 2 59 1 vs 3 3 60 2 vs 3 11 Unknown Chemotherapy 127 Overall i. Single agent 40 i vs ii ii. Non-DDP 12 i vs iii iii. DDP 75 ii vs iii Complete responder vs nonresponder + partial responder i. Single agent ii. Non-DDP iii. DDP Complete responder Overall i. Single agent i vs ii ii. Non-DDP i vs iii iii. DDP ii vs iii Residual disease c2 cm 110 33 >2 cm 2 Unknown Pathology Endometriosis II Endometrial cancer 18 Grade vs stages I-IV 1 2 3
0.08
O.oool 0.001 O.oool 0.24 0.009 0.3 0.003 0.004 0.21 0.15 0.11 0.8 0.001 0.016 0.0001 0.08 0.068 0.077 0.39 O.oool
0.13 0.09 0.07 0.003 0.048
ical response and 15 months for no response (P = 0.003). Median survival with noncisplatin combination chemotherapy was 31.5 months for complete clinical response
341
OF THE OVARY
and 13.5 months for no response (P = 0.016). No patients receiving noncisplatin combination therapy achieved a partial response. Median survival for cisplatin-based chemotherapy was 85 months for complete clinical response, 16.5 months for partial response, and 10.6 months for no response (P = 0.0001). For patients achieving a complete clinical response, no difference was seen with regard to the type of chemotherapy (P = 0.31). No difference in the complete clinical response rates for single agent, noncisplatin combination, and cisplatin combinations was seen for patients with stage I, II, III, and IV disease (P = 0.08) (Table 4). No statistically significant difference in survival was noted among the different chemotherapy regimens (P = 0.21) regardless of stage. Sixty patients had stage III endometrioid carcinoma of the ovary. Three of these were grade 1, 19 grade 2, and 34 grade 3; in 4 patients the grade was unknown. Analysis was performed for grades 2 and 3. The groups were analyzed according to single agent, noncisplatin combination, and cisplatin combination. No statistical significance in median survival for grade 2 lesions was detected between single agent, noncisplatin combination, and cisplatin combination (P = 0.7). No significant difference in median survival for grade 3 lesions was detected between the three chemotherapy regimens tested (P = 0.43). The median lengths of survival for stage II grade 3 lesions were 28.5 and 35 months, respectively, for noncisplatin combination and cisplatin combination and was not statistically significant (P = 0.9). No statistically significant difference in survival rates was noted for those 45 years and younger compared with those older than 45 years (P = 0.08). Stage was a statistically significant variable (P = 0.0001) in regard to survival rates. Stage I patients fared better than stage II, III, or IV patients. Stage III patients fared significantly better than stage IV patients (P = 0.0009), and no statistically significant difference was seen between patients with stages II and III (P = 0.24). The median survival for stage I was 96 or more months, stage II 52 months, stage III 34 months, stage IV 10.5
TABLE 4 ResponseversusChemotherapyRegimen
Regimen
Number of patients
CRC”
PRc
CRC + PRc
CRC median survival (month$
Single agent Noncisplatin combination Cisplatin
40 12 75
26 (65%) 8 (66%) 50 (66%)
1 (2.5%) 0 5 (6%)
27 (67.5%) 8 (66%) 55 (72%)
96+ 84 88
y CRC, complete clinical response; PRc, partial clinical response. b P = 0.08.
342
KLINE
ET AL. 10
0.6
0.6 u I b 2
0.6
0.6 -
2 p E
PROGRESSK)FCFREE 0.4
0.4 -
iz H
0.2 -
o.o!
. 0
, 20
, 40
.
, 60
, 60
I 100
0
20
40
60
60
100
MONTHS MONTHS
FIG. 1. Survival according to stage.
months, and for the unstaged group 78 or more months. The progression-free intervals for stages I, II, III, and IV were 96 or more months, 42 months, 15 months, and 6.5 months, respectively. Stage was a significant factor for progression-free interval (P = 0.0001). Grade also was a statistically significant factor for survival. Patients with grade 3 lesions did worse than those with grade 1 (P = 0.003) and grade 2 (P = 0.004) lesions. No difference was seen between grade 1 and grade 2 (P = 0.33). Median lengths of survival were 96+ months, 96+ months, and 27 months for grades I, 2, and 3, respectively. The five-year survival rates for stages I, II, III, and IV were 87, 48, 41, and 20%, respectively (Fig. 1). The overall 5-year survival for the UT/MDACC group was 53%. Residual disease was a significant factor with regard to survival. Patients with residual tumors 2 cm or less had a significantly longer median survival (P = 0.0001) and progression-free interval (P = 0.0001) than those with residual tumors greater than 2 cm. The median survival was 96 or more months for those with residual tumors 2 cm or less versus 17.4 months in those with residual tumors greater than 2 cm. Progression-free interval was 96 or more months versus 8.4 months (Figs. 2 and 3). The excellent median survival and progressionfree interval reflect that nearly one-half of the patients were stage I or II and subsequently were more likely to have less than 2 cm residual disease. Second-line therapy was received by 62 patients because of progression of disease or as a result of secondlook Iaparotomy, including 12 (19.3%) who received hexamethylmelamine, doxorubicin, and cyclophosphamide; IO (16.1%) cisplatin and cyclophosphamide; 7 (11.3%) ethinyl estradiol and medroxyprogesterone acetate; and 6 (9.7%) hexamethylmelamine and cyclophosphamide.
FIG. 2. Survival and progression-free s2 cm.
interval for residual disease
The remainder received various single or combination chemotherapies, hormonal therapy, or biological response modifiers. Clinical responses to second-line therapy included 9 patients (15%) who achieved a complete clinical response and 53 (85%) who had either partial response or progressive disease. Of the 9 patients who had complete clinical response to second-line therapy, 5 have no evidence of disease (range 35-174 months) and 4 are dead of disease. Second-line therapy in these 9 patients included cisplatin and cyclophosphamide (5), cyclophosphamide (2), melphalan (l), and megestrol acetate (1). Twelve patients (8.3%) received radiation therapy as initial therapy for endometrioid carcinoma. All but one received whole-abdomen radiation (mean dose 2415 cGy) with whole-pelvis boost (mean dose 2023 cGy). One patient received only whole-pelvis radiation. Of these 12 patients, 8 have been free of disease for 81 to 252 months
0.6 PROGRESSCWFREE
0.0, 0
, 20
.
, 40
, 60
.
I 60
I 100
MONTHS
FIG. 3. Survival and progression-free interval for residual disease >2 cm.
ENDOMETRIOID
CARCINOMA
(mean 170 months); 4 died of recurrent disease at a mean time to death of 94 months (range 16-223 months). The median survival for these 12 patients is 96 or more months. Five patients had stage I disease, 5 stage II, and 1 stage II; 1 patient was unstaged. Seven patients received radiation for positive secondlook laparotomy findings. Of these, 5 received wholeabdomen radiation (mean dose 2700 cCy), 4 of whom are dead of disease (80%). The other 2 patients received only whole-pelvis radiation for positive second-look findings, and both are dead of disease. Seven patients received radiation therapy to recurrent disease. All are dead of disease. One patient with a concomitant uterine carcinoma received a postoperative vaginal ovoid. One patient received concomitant wholeabdomen radiation plus 5fluorouracil systemic chemotherapy. The UT/MDACC data revealed 18 patients with synchronous primary tumors. The stage, grade, and outcome are presented in Table 2. The patients were retrospectively staged for endometrial carcinoma using a modification of the 1988 FIG0 classification. The uterine cancer stage was determined by depth of myometrial invasion, cervical involvement, cytology, and node status only. Ovarian involvement was not used to determine stage. The median survival is 96 or more months. No significant improvement in survival was seen for patients with synchronous primaries (P = 0.09). The mean age for patients with synchronous primaries was 52 years versus 52.2 years for those with only endometrioid carcinoma of the ovary. Only 6 of 18 patients (33%) with concomitant lesions presented with vaginal bleeding. Nine of eighteen patients had abdominal complaints. In addition, one had rectal pressure, one was asymptomatic, and one had pelvic pain as her only complaint. Ten of eighteen patients had stage III or IV ovarian carcinoma on the basis of nodal or omental involvement or malignant pleural effusions. Despite a 56% incidence of stage III or IV ovarian carcinoma with synchronous endometrial carcinoma, only 3 of these advanced-stage patients are dead of disease (30%). Five of eighteen patients (28%) with synchronous primaries are dead of disease, including four who had deep myometrial invasion. Patients with one adenocarcinoma are often at risk for another adenocarcinoma. This is also true for patients with endometrial carcinoma. Schottenfeld and Berg [13] showed a 1.3- to 2-fold increase in risk of breast carcinoma in patients with primary endometrial carcinoma. In the review of 75 cases of endometrioid carcinoma of the ovary by Czernobilsky et al. [2], 5 patients (6.6%) had breast carcinoma. The incidence of breast carcinoma in the United States is estimated to be 1 in 10 women. In our UT/MDACC group, 12 women (8.3%) had evi-
OF THE
343
OVARY
dence of breast carcinoma that predated, occurred concomitantly with, or occurred after their having been diagnosed with ovarian carcinoma. Sixty-seven percent of these predated the diagnosis of ovarian cancer. DISCUSSION Santesson [5] in 1961 presented to the Cancer Committee of the International Federation of Gynecology and Obstetrics a study of the frequency of histologic types of primary ovarian tumors treated at the Radiumhemmet. His report showed the following frequencies for the three largest groups: papillary serous cystadenocarcinoma, 39.3%; tumors with the appearance of endometrial carcinoma, 24.4%; and mutinous cystadenocarcinoma, 9.4%. Santesson’s report prompted the proposal of endometrioid carcinoma as a separate entity [4]. The frequency of endometrioid carcinoma of the ovary varies from less than 10% [14] to 23.8% [2] in published series. Endometriosis
The possibility of endometriosis as a precursor to ovarian cancer has been debated in the literature since 1925 when Sampson [3] first reported seven cases of carcinoma of the ovary arising from endometriosis. He had stringent criteria for the diagnosis of endometriosis as a precursor and concluded that only two of his seven cases fulfilled his criteria. However, he also speculated that the endometrial-type carcinoma of the ovary could occur de novo from the germinal epithelium of the ovary. The presence of endometriosis and endometrioid carcinoma varies from less than 1 to 21.3% [2,13-181. Within our series, 11 patients (7.6%) were found to have histologic evidence of endometriosis and endometrioid carcinoma, which compares favorably with the incidence reported in the literature. The presence of endometriosis did not affect survival (P = 0.13). In the series of Czernobilsky et al. [2], 16 of 75 patients with endometrioid carcinoma had endometriosis; 13 of these 16 had endometriosis and carcinoma within the same ovary (one of Sampson’s criteria for indicating endometriosis as a precancerous lesion). Only 3 patients had histologically proven continuity between endometriosis and endometrioid carcinoma (another of Sampson’s criteria). Scully et al. [14] and Ulbright and Roth [ 151 concluded that there is no clear association between endometriosis and endometrioid carcinoma of the ovary. A review by Schueller and Kirol [19] included four patients in whom endometrioid carcinoma of the ovary resulted from benign endometrial cysts. These four fulfilled the criteria of Sampson [31 and Scott [20] for origin from endometriosis.
344
KLINE
Electron microscopy has shown similarities between endometrioid carcinoma of the ovary, normal endometrium, and grade I endometrial carcinoma [21]. Endometrioid carcinoma, like other epithelial tumors of the ovary, arises from the coelomic epithelium of the ovary
Ml. Synchronous
Primaries
When carcinoma is present within the uterus and ovary, designation as primary or metastatic lesions is difficult. If the histology of the carcinoma within the uterus and ovary is different, the carcinomas are most likely independent lesions. However, if the histologic type is identical, the question is whether the lesions represent a stage IIA ovarian carcinoma with uterine metastases or a stage IIIA uterine carcinoma with ovarian metastases. Annegers and Malkasian [22] reported the incidence of ovarian carcinoma diagnosed concomitantly with endometrial carcinoma to be 2%. Silverman ef al. [23] noted that 3.8% of primary ovarian carcinomas had an endometrial lesion. Eisner et al. [24] reported that the most frequent synchronous genital lesions were ovarian and endometrial carcinoma. To answer the question of primary versus metastatic lesions, several authors have suggested criteria that must be fulfilled to indicate separate primaries [14,1.51. The criteria of Scully et al. [14] for independent endometrial carcinoma included a low-grade lesion, disproportionately small and with minimal myometrial invasion. UIbright and Roth [15] classified synchronous primaries by “empirically developed criteria” that included major and minor criteria. They classified tumors as endometrial primary with ovarian metastases if the ovarian pattern was multinodular: a major criterion. A tumor also received the same classification if two or more minor criteria were present: small ovary or ovaries (
ONCOLOGY
39, 337-346
(1990)
Endometrioid Carcinoma of the Ovary: Retrospective Review of 145 Cases RICHARD
*Ochsner
C.
KLINE
7 M.D.,*,’
J. TAYLOR WHARTON, M.D. ,t E. NEELY ATKINSON, PH.D. ,t T. W. BURKE, M.D.,? D. M. GERSHENSON, M.D.,? AND CREICHTONL. EDWARDS,M.D.?
Clinic and Alton Ochsner Medical Foundation, 1514 Jefferson Highway, New Orleans, Louisiana 70121, and TDepartment Gynecology, University of Texas, M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030 Received
of
April 19, 1990
From 1967through December1987, 145 patients with endometrioid carcinoma of the ovary were treated at the University of Texas M. D. Anderson Cancer Center. Thirty-eight patients (26.2%)had stageI disease,28 (19.3%) stageII, 60 (41.4%)stage III, and 11 (7.6%) stage IV; 8 patients (5.5%) were unstaged. Grade 2 or 3 histology was seenin 119 patients (82.1%). In addition to surgicaltherapy, 128patientsunderwent chemotherapy, including single-agenttherapy, noncisplatin combination therapy, and cisplatin-basedtherapy. No statistically significant improvement in median survival was noted among thesethree chemotherapygroups for stagesII, III, and IV (P = 0.22). A significant improvement in median survival wasnoted for those patients who achieveda completeclinical response,regardlessof type of chemotherapy(96 or more monthsfor single-agenttherapy, P = 0.001; 31.5 monthsfor noncisplatincombinationtherapy, P = 0.016; and 85 monthsfor cisplatin-basedtherapy, P = 0.0001).Synchronousovarian and uterine malignancieswereseen in 18 patients (12.4%). No difference in survival was seenfor patientswith endometriosis(P = 0.13) or endometrialcancer(P = 0.09) when compared with those who did not have these histologicfindings. 8 1990 Academic Press, Inc. INTRODUCTION
Ovarian carcinoma is the fifth leading cause of cancer death in women in the United States, with 20,500 new cases and 12,400 deaths predicted for 1990 [l]. Ninety percent of all ovarian cancers are epithelial in origin. The World Health Organization in 1964 recognized the term endometrioid carcinoma of the ovary [2]. In 1925, Sampson [3] described endometrioid carcinoma of the ovary, although it was not yet known by this name. Long and Taylor [4] in 1964 described the basic histologic criteria
for endometrioid carcinoma. As a result of the report by Santesson [S] to the International Federation of Gynecology and Obstetrics (FIGO) in 1961, the term endometrioid carcinoma was proposed. In the Radiumhemmet experience, Santesson showed that 24.4% of epithelial carcinomas of the ovary were endometrioid, an incidence surpassed only by that of serous carcinoma (39.3%). Before this time, cystadenocarcinomas with a similar histology were termed adenoacanthomas [6] and endometrial-like carcinoma [7,8]. Squamous elements may be very frequent. Presence of a malignant squamous component may be a prognostic factor. Admixture with other mullerian elements may also be present. According to Czemobilsky et al. [2], patients whose tumors have other mullerian elements (“mixed tumor”) do as well as those whose tumors do not have other mullerian elements. This study reviews cases of endometrioid carcinoma of the ovary treated at the University of Texas M. D. Anderson Cancer Center (UT/MDACC), in Houston, from 1967 through 1987. Information about stage, grade, survival, presence of endometriosis and synchronous uterine adenocarcinoma, type of surgery, amount of residual tumor, and effectiveness of various chemotherapy protocols is presented, as well as prognosis as it relates to these various parameters. During this period, 2300 epithelial ovarian carcinomas were seen at UT/MDACC, of which 268 were recorded as having an endometrioid pattern (12%). Endometrioid carcinoma was surpassed only by serous carcinoma (68%). MATERIALS
Patient
’ To whom correspondenceand reprint requestsshould be addressed.
Selection
AND METHODS
and Criteria for Treatment
The gynecologic data base at UT/MDACC cessed to identify patients with endometrioid
was accarcinoma
337 OOW-8258/90 $1.50 Copyright 0 1990 by Academic Press, Inc. All rights of reproduction in any form reserved.
338
KLINE
of the ovary. From 1967 through 1987, 268 patients with a diagnosis of endometrioid carcinoma of the ovary were identified. All charts and microfilm records were reviewed to confirm histologic diagnosis and that either surgery and/or chemotherapy was performed at UT/ MDACC. If initial surgery was performed elsewhere, chemotherapy and second-look laparotomy, when performed, must have been at UT/MDACC; 145 patients were found to meet these criteria. The other patients were excluded for a variety of reasons, including those with nonendometrioid histology and those seen in consultation only or whose second-look laparotomy was performed elsewhere. Histologic confirmation and grade were obtained from UT/MDACC pathology reports. All patients had histologic review at the time of initial evaluation. For those who did not undergo reexploration, initial stage was obtained from clinic notes and operative and pathologic reports. For those patients who underwent reexploration, the stage at time of reexploration was used. Stage was determined according to the 1974 FIG0 classification. Histologic grading was performed by the staff of the Department of Pathology at UT/MDACC, according to a pattern-grading system [91. Grade 1 represents well differentiated, grade 2 moderately differentiated, and grade 3 poorly differentiated. Primary Surgical Therapy
Patients underwent initial surgery at other hospitals or at UT/MDACC. The surgery at UT/MDACC represented either primary tumor reduction in patients referred with a pelvic mass or secondary exploration in those who had already been operated upon. Some patients who entered clinical trials and reexploration to assess extent of disease and to further reduce tumor burden prior to starting chemotherapy. Tumor reductive surgery, when performed, was radical and attempted to reduce tumor to a residual of 2 cm or less. For patients not undergoing reexploration, by careful review of operative dictations and pathology reports and from telephone calls to referring physicians the extent and amount of residual tumor were determined before therapy was begun. Generally, patients did not undergo reexploration when outside operative and pathology reports and initial gynecologic examination at UT/MDACC indicated stage I disease or residual tumor diameters 2 cm or less. Patients whose reports indicated advanced stage (II, III, or IV) or whose physical examination showed residual disease were reexplored. Patients were divided into two groups, those with residual disease of 2 cm or less and those with residual disease greater than 2 cm. Of the 145 patients, 4 had
ET
AL.
TABLE
1
Criteria of Response Complete Clinical
No
clinically
months No visible
Surgical
detectable or longer disease
rotomy (A ther defined
Partial Clinical
positive;
response biopsies:
S (-)
=
3 lapais furS (+)
microscopic
in palpable tumor the sum of two perpen-
which
persisted
3 months
or
longer 50% or greater reduction in the sum of tumor masses measured at time of second-look
Surgical
response”
No
operation tumor regression detectable more courses of chemotherapy of new
Source. I’ Patients therapy operation
diameters,
persisting
of second-look
surgical on review
50% or greater reduction masses, calculated by dicular
No
at time
complete based
= microscopic negative.)
disease
Reproduced, with no
who are
develop considered
with clinically
lesions permission, detectable
after two or or appearance
or effusions from Ref. [IO]. disease at onset
palpable disease prior to have progressive
to planned disease and
of chemosecond-look no response
to chemotherapy.
biopsy only, 45 had simple tumor reduction (which usually included total abdominal hysterectomy and bilateral salpingo-oophorectomy), and 83 had tumor reductive surgery (which included total abdominal hysterectomy and bilateral salpingo-oophorectomy, omentectomy, extensive pelvic dissection, and resection of bowel). Thirteen had incomplete tumor reduction with greater than 2 cm of remaining residual disease. The 2-cm or less group included those undergoing both simple and more aggressive tumor reduction. In 111 patients (77%) residual tumors were judged to be 2 cm or less, and in 33 patients (23%), greater than 2 cm. Residual disease was not recorded for 1 patient. Chemotherapy
Since this report spans 20 years, multiple prospective randomized trials of chemotherapeutic agents were undertaken, including melphalan; fluorouracil; hexamethylmelamine and doxorubicin; hexamethylmelamine, doxorubicin, and cyclophosphamide; cisplatin and melphalan; and cisplatin and cyclophosphamide. Responses were classified as clinical in those not undergoing secondlook laparotomy or surgical in those undergoing secondlook laparotomy. Responses were judged according to the criteria in Table 1 [lo]. Patients were examined at monthly intervals, and measurable disease was evaluated. An adequate trial of each therapeutic agent consisted of a minimum of 60 days.
ENDOMETRIOID
CARCINOMA
OF THE
OVARY
339
had stage I disease, 28 (19.3%) stage II, 60 (41.4%) stage III, and 11 (7.6%) stage IV; 8 (5.5 %) patients were unstaged. Fifteen patients (10.3%) had grade 1 lesions, 59 (40.7%) grade 2, and 60 (41.4%) grade 3; in 11 patients (7.6%) the grade was unknown. Eighteen patients Radiation (12.4%) had a synchronous endometrial carcinoma (Table 2), 11 (7.6%) had a histologic diagnosis of endomeRadiation therapy has long been a mainstay of ovarian triosis, 4 (2.8%) had endometrial hyperplasia, and 112 cancer treatment. Radiation treatment for ovarian cancer (77.2%) had no associated pathology. Survival was not had been administered at UT/MDACC initially by movaffected by presence of endometrial cancer (P = 0.09). ing-strip technique to the whole abdomen. Using this Median survival in this group was 96 or more months. technique, 2600-2800 cGy was delivered. After wholeMultiple symptoms are associated with ovarian cancer. abdomen irradiation was completed, an additional 2000 Abdominal distension was the most frequent symptom cGy was delivered through parallel, opposed 15 x 15 (39 patients) followed by pelvic pain or pressure (33 pacm portals. In later years, the moving-strip technique tients). Abdominal pain was present in 25 patients. Sixwas abandoned in favor of open portal, whole-abdomen teen patients had no complaints. Vaginal bleeding and a radiation. Appropriate shielding with half-value layers of combination of symptoms were seen in 13 patients each. lead to the liver and kidneys was accomplished in stanPulmonary and gastrointestinal complaints were present dard fashion. in 2 patients each. Seven patients had liver metastases. For patients to be eligible for radiation therapy as a Ten patients had pulmonary metastases including posiprimary treatment, residual disease could not exceed 2 tive pleural effusions and 17 patients had lymph node cm nor could disease be present along the areas of shieldmetastases. Patient characteristics are seen in Table 3. ing to the liver or kidneys. Radiation therapy as firstChemotherapy was used in several clinical trials for line treatment was discontinued in 1975. 128 patients. As a first-line chemotherapy regimen, 46 patients (3 1.7%) received cisplatin and cyclophosphaAssociated Pathology mide, 37 (25.5%) received melphalan, 20 (13.8%) reThe presence of endometriosis or endometrial carci- ceived melphalan and cisplatin, and 7 (4.8%) received a noma associated with endometrioid carcinoma of the combination of hexamethylmelamine, doxorubicin, and ovary was recorded. Of patients with endometrioid car- cyclophosphamide. The remaining 18 patients (12.5%) cinoma, 7.6% also had histologic documentation of en- received single-agent hexamethylmelamine (1); fluorourdometriosis; 12.4% of patients had concurrent endomeacil (1); doxorubicin (1); cisplatin (3); hexamethylmelatrial carcinoma. Clinical staging of these concurrent mine and cyclophosphamide (3); cisplatin, doxorubicin, malignancies is difficult and unclear. Whether they rep- and cyclophosphamide (6); and cisplatin-melphalan alresent synchronous primaries or metastases from ovary ternating with hexamethylmelamine, doxorubicin, and to uterus or from uterus to ovary has not been detercyclophosphamide (3). Forty-two patients (29.0%) remined. Eighty percent of patients had no histologic evi- ceived 12 courses; 29 (20.0%) received 6 courses; the dence of endometriosis or endometrial carcinoma. Sur- others received either no chemotherapy or varying numvival was not influenced by the presence of endomebers of courses. Of the 128 patients who received chetriosis (P = 0.13) or by the presence of a synchronous motherapy, 86 (67.2%) achieved a complete clinical reendometrial carcinoma (P = 0.09). sponse; 32 (25.0%) developed progressive disease while receiving first-line chemotherapy, and 10 (7.8%) had a Statistical Analysis partial response or stable disease while receiving chemotherapy. Survival and progression-free interval were calculated Median survival was calculated for stage II, III, and using the life-table methods of Berkson and Gage [l 11. The statistical significance of the various factors was IV patients. Stage I was excluded in analysis because of a higher incidence of grade I lesions associated with tested by the Lee-Desu statistical method [12]. stage I carcinoma. A statistically significant improvement in median survival for stage II, III, and IV patients was RESULTS seen in patients who achieved a complete clinical reOf the 145 cases of endometrioid carcinoma of the sponse after treatment with a single agent (P = O.OOl), ovary reviewed in this study, 130 patients (89.7%) were a noncisplatin combination (P = 0.016), or cisplatinwhite, 11 (7.6%) were Hispanic, 3 (2.1%) were black, based therapy (P = 0.0001) versus those who had either and 1 (0.7%) was Asian. The mean age was 52.2 years partial or no response. Median survival for single-agent (range 27-83 years). Of these 145 patients, 38 (26.2%) chemotherapy was 96 or more months for complete clin-
Patients with documented progressive changed to second-line therapy. Those failed second-line treatment were changed motherapeutic agents including hormonal
disease were patients who to other cheprotocol.
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Synchronous
Endometrioid
Stage/grade
TABLE 2 Cancer of the Ovary and Endometrial
Myometrial invasion
Age (years)
Ovary
Uterus
40
IC/3
IB/2
62
III/2
IIIC/2
42
IV/3
IB/I
Inner half
47
IA/2
IB/2
Inner half
68
IV/2
IIIA/2
47
III/2
IB/I
Inner half
42
III/2
IB/2
Inner half
8
56
III/2
IC/2
Outer half
9
72
III/l
IB/I
Inner half
IO
33
IA/I
IA/I
Endometrium
11
67
IA/3
IIA/2
12
47
III/2
IA/2
Outer half Cervical gland Endometrium only
13
45
III/2
IBj2
Inner half
14 15
62 55
IA/l IB/l
IB/l IIAl3
Inner half Inner half Cervical Gland
16
46
III/l
IB/l
Inner half
I7
47
Unstaged/3
IB/2
Inner half
18
58
IC/3
IB/2
Inner half
Patient
Cancer
Treatment
Inner half
Outer half + Pelvic node
Serosal
-
ET AL.
only
Preop radium TAH, BSO Melphalan Negative second look TAH, BSO Melphalan x 5 Medroxyprogesterone TAH, BSO Melphalan x I2 Medroxyprogesterone Negative second look TAH, BSO War + WP TAH, BSO Melphalan Megestrol acetate TAH, BSO Melphalan x I2 Negative second look Preop radium TAH, BSO Melphalan x 12 Medroxyprogesterone Negative second look TAH, BSO HAC x 12 TAH, BSO CDDP/cyclo x 6 Positive second look Megestrol acetate TAH, BSO Melphalan x I2 Megestrol acetate TAH, BSO PAC x I2 TAH, BSO CDDP/cyclo x I2 Positive second look TAH, BSO CDDP/cyclo x 9 Megestrol acetate TAH, BSO TAH, BSO PAC x 10 Negative second look TAH, BSO CDDP/cyclo x 6 Negative second look TAH, BSO CDDP/cyclo x 6 Positive second look TAH, BSO CDDP/cyclo x 6 Negative second look
Symptom Abdominal
distension
Survival NED I83 months
Vaginal bleeding
DOD 22 months
Abdominal
NED 163 months
distension
Vaginal spotting Abdominal pain Vaginal bleeding
NED I65 months
Abdominal
pain
NED II3 months
Vaginal bleeding
NED I I9 months
Abdominal
pain
DOD 83 months
Abdominal
distension
NED 34 months
DOD 3 months
Pelvic and abdominal pain
NED 109 months
Abdominal
distension
DOD 77 months
Abdominal
pain
NED 89 months
Shortness of breath Abdominal distension
NED 80 months
Vaginal bleeding Rectal pressure
NED 58 months NED 39 months
Pelvic pain
NED 31 months
None
DOD 14 months
Vaginal bleeding Pelvic pain
NED 19 months
G TAH, total abdominal hysterectomy; BSO, bilateral salpingo-oophorectomy; NED, no evidence of disease; DOD, dead of disease; CDDP, cisplatin; cycle, cyclophosphamide; HAC, hexamethylmelamine/Adriamycin/Cytoxan; PAC, cisplatin, Adriamycin, Cytoxan; WAR, wholeabdomen radiation; WP, whole-pelvis radiation.
ENDOMETRIOID
CARCINOMA
TABLE 3 Patient Characteristics All patients
Number
P value
Age =z45 145 >45 Stage I 38 Overall 28 I vs II II III 60 I vs III IV I1 II vs III Unknown 8 III vs IV Grade I IS I vs 2 2 59 1 vs 3 3 60 2 vs 3 11 Unknown Chemotherapy 127 Overall i. Single agent 40 i vs ii ii. Non-DDP 12 i vs iii iii. DDP 75 ii vs iii Complete responder vs nonresponder + partial responder i. Single agent ii. Non-DDP iii. DDP Complete responder Overall i. Single agent i vs ii ii. Non-DDP i vs iii iii. DDP ii vs iii Residual disease c2 cm 110 33 >2 cm 2 Unknown Pathology Endometriosis II Endometrial cancer 18 Grade vs stages I-IV 1 2 3
0.08
O.oool 0.001 O.oool 0.24 0.009 0.3 0.003 0.004 0.21 0.15 0.11 0.8 0.001 0.016 0.0001 0.08 0.068 0.077 0.39 O.oool
0.13 0.09 0.07 0.003 0.048
ical response and 15 months for no response (P = 0.003). Median survival with noncisplatin combination chemotherapy was 31.5 months for complete clinical response
341
OF THE OVARY
and 13.5 months for no response (P = 0.016). No patients receiving noncisplatin combination therapy achieved a partial response. Median survival for cisplatin-based chemotherapy was 85 months for complete clinical response, 16.5 months for partial response, and 10.6 months for no response (P = 0.0001). For patients achieving a complete clinical response, no difference was seen with regard to the type of chemotherapy (P = 0.31). No difference in the complete clinical response rates for single agent, noncisplatin combination, and cisplatin combinations was seen for patients with stage I, II, III, and IV disease (P = 0.08) (Table 4). No statistically significant difference in survival was noted among the different chemotherapy regimens (P = 0.21) regardless of stage. Sixty patients had stage III endometrioid carcinoma of the ovary. Three of these were grade 1, 19 grade 2, and 34 grade 3; in 4 patients the grade was unknown. Analysis was performed for grades 2 and 3. The groups were analyzed according to single agent, noncisplatin combination, and cisplatin combination. No statistical significance in median survival for grade 2 lesions was detected between single agent, noncisplatin combination, and cisplatin combination (P = 0.7). No significant difference in median survival for grade 3 lesions was detected between the three chemotherapy regimens tested (P = 0.43). The median lengths of survival for stage II grade 3 lesions were 28.5 and 35 months, respectively, for noncisplatin combination and cisplatin combination and was not statistically significant (P = 0.9). No statistically significant difference in survival rates was noted for those 45 years and younger compared with those older than 45 years (P = 0.08). Stage was a statistically significant variable (P = 0.0001) in regard to survival rates. Stage I patients fared better than stage II, III, or IV patients. Stage III patients fared significantly better than stage IV patients (P = 0.0009), and no statistically significant difference was seen between patients with stages II and III (P = 0.24). The median survival for stage I was 96 or more months, stage II 52 months, stage III 34 months, stage IV 10.5
TABLE 4 ResponseversusChemotherapyRegimen
Regimen
Number of patients
CRC”
PRc
CRC + PRc
CRC median survival (month$
Single agent Noncisplatin combination Cisplatin
40 12 75
26 (65%) 8 (66%) 50 (66%)
1 (2.5%) 0 5 (6%)
27 (67.5%) 8 (66%) 55 (72%)
96+ 84 88
y CRC, complete clinical response; PRc, partial clinical response. b P = 0.08.
342
KLINE
ET AL. 10
0.6
0.6 u I b 2
0.6
0.6 -
2 p E
PROGRESSK)FCFREE 0.4
0.4 -
iz H
0.2 -
o.o!
. 0
, 20
, 40
.
, 60
, 60
I 100
0
20
40
60
60
100
MONTHS MONTHS
FIG. 1. Survival according to stage.
months, and for the unstaged group 78 or more months. The progression-free intervals for stages I, II, III, and IV were 96 or more months, 42 months, 15 months, and 6.5 months, respectively. Stage was a significant factor for progression-free interval (P = 0.0001). Grade also was a statistically significant factor for survival. Patients with grade 3 lesions did worse than those with grade 1 (P = 0.003) and grade 2 (P = 0.004) lesions. No difference was seen between grade 1 and grade 2 (P = 0.33). Median lengths of survival were 96+ months, 96+ months, and 27 months for grades I, 2, and 3, respectively. The five-year survival rates for stages I, II, III, and IV were 87, 48, 41, and 20%, respectively (Fig. 1). The overall 5-year survival for the UT/MDACC group was 53%. Residual disease was a significant factor with regard to survival. Patients with residual tumors 2 cm or less had a significantly longer median survival (P = 0.0001) and progression-free interval (P = 0.0001) than those with residual tumors greater than 2 cm. The median survival was 96 or more months for those with residual tumors 2 cm or less versus 17.4 months in those with residual tumors greater than 2 cm. Progression-free interval was 96 or more months versus 8.4 months (Figs. 2 and 3). The excellent median survival and progressionfree interval reflect that nearly one-half of the patients were stage I or II and subsequently were more likely to have less than 2 cm residual disease. Second-line therapy was received by 62 patients because of progression of disease or as a result of secondlook Iaparotomy, including 12 (19.3%) who received hexamethylmelamine, doxorubicin, and cyclophosphamide; IO (16.1%) cisplatin and cyclophosphamide; 7 (11.3%) ethinyl estradiol and medroxyprogesterone acetate; and 6 (9.7%) hexamethylmelamine and cyclophosphamide.
FIG. 2. Survival and progression-free s2 cm.
interval for residual disease
The remainder received various single or combination chemotherapies, hormonal therapy, or biological response modifiers. Clinical responses to second-line therapy included 9 patients (15%) who achieved a complete clinical response and 53 (85%) who had either partial response or progressive disease. Of the 9 patients who had complete clinical response to second-line therapy, 5 have no evidence of disease (range 35-174 months) and 4 are dead of disease. Second-line therapy in these 9 patients included cisplatin and cyclophosphamide (5), cyclophosphamide (2), melphalan (l), and megestrol acetate (1). Twelve patients (8.3%) received radiation therapy as initial therapy for endometrioid carcinoma. All but one received whole-abdomen radiation (mean dose 2415 cGy) with whole-pelvis boost (mean dose 2023 cGy). One patient received only whole-pelvis radiation. Of these 12 patients, 8 have been free of disease for 81 to 252 months
0.6 PROGRESSCWFREE
0.0, 0
, 20
.
, 40
, 60
.
I 60
I 100
MONTHS
FIG. 3. Survival and progression-free interval for residual disease >2 cm.
ENDOMETRIOID
CARCINOMA
(mean 170 months); 4 died of recurrent disease at a mean time to death of 94 months (range 16-223 months). The median survival for these 12 patients is 96 or more months. Five patients had stage I disease, 5 stage II, and 1 stage II; 1 patient was unstaged. Seven patients received radiation for positive secondlook laparotomy findings. Of these, 5 received wholeabdomen radiation (mean dose 2700 cCy), 4 of whom are dead of disease (80%). The other 2 patients received only whole-pelvis radiation for positive second-look findings, and both are dead of disease. Seven patients received radiation therapy to recurrent disease. All are dead of disease. One patient with a concomitant uterine carcinoma received a postoperative vaginal ovoid. One patient received concomitant wholeabdomen radiation plus 5fluorouracil systemic chemotherapy. The UT/MDACC data revealed 18 patients with synchronous primary tumors. The stage, grade, and outcome are presented in Table 2. The patients were retrospectively staged for endometrial carcinoma using a modification of the 1988 FIG0 classification. The uterine cancer stage was determined by depth of myometrial invasion, cervical involvement, cytology, and node status only. Ovarian involvement was not used to determine stage. The median survival is 96 or more months. No significant improvement in survival was seen for patients with synchronous primaries (P = 0.09). The mean age for patients with synchronous primaries was 52 years versus 52.2 years for those with only endometrioid carcinoma of the ovary. Only 6 of 18 patients (33%) with concomitant lesions presented with vaginal bleeding. Nine of eighteen patients had abdominal complaints. In addition, one had rectal pressure, one was asymptomatic, and one had pelvic pain as her only complaint. Ten of eighteen patients had stage III or IV ovarian carcinoma on the basis of nodal or omental involvement or malignant pleural effusions. Despite a 56% incidence of stage III or IV ovarian carcinoma with synchronous endometrial carcinoma, only 3 of these advanced-stage patients are dead of disease (30%). Five of eighteen patients (28%) with synchronous primaries are dead of disease, including four who had deep myometrial invasion. Patients with one adenocarcinoma are often at risk for another adenocarcinoma. This is also true for patients with endometrial carcinoma. Schottenfeld and Berg [13] showed a 1.3- to 2-fold increase in risk of breast carcinoma in patients with primary endometrial carcinoma. In the review of 75 cases of endometrioid carcinoma of the ovary by Czernobilsky et al. [2], 5 patients (6.6%) had breast carcinoma. The incidence of breast carcinoma in the United States is estimated to be 1 in 10 women. In our UT/MDACC group, 12 women (8.3%) had evi-
OF THE
343
OVARY
dence of breast carcinoma that predated, occurred concomitantly with, or occurred after their having been diagnosed with ovarian carcinoma. Sixty-seven percent of these predated the diagnosis of ovarian cancer. DISCUSSION Santesson [5] in 1961 presented to the Cancer Committee of the International Federation of Gynecology and Obstetrics a study of the frequency of histologic types of primary ovarian tumors treated at the Radiumhemmet. His report showed the following frequencies for the three largest groups: papillary serous cystadenocarcinoma, 39.3%; tumors with the appearance of endometrial carcinoma, 24.4%; and mutinous cystadenocarcinoma, 9.4%. Santesson’s report prompted the proposal of endometrioid carcinoma as a separate entity [4]. The frequency of endometrioid carcinoma of the ovary varies from less than 10% [14] to 23.8% [2] in published series. Endometriosis
The possibility of endometriosis as a precursor to ovarian cancer has been debated in the literature since 1925 when Sampson [3] first reported seven cases of carcinoma of the ovary arising from endometriosis. He had stringent criteria for the diagnosis of endometriosis as a precursor and concluded that only two of his seven cases fulfilled his criteria. However, he also speculated that the endometrial-type carcinoma of the ovary could occur de novo from the germinal epithelium of the ovary. The presence of endometriosis and endometrioid carcinoma varies from less than 1 to 21.3% [2,13-181. Within our series, 11 patients (7.6%) were found to have histologic evidence of endometriosis and endometrioid carcinoma, which compares favorably with the incidence reported in the literature. The presence of endometriosis did not affect survival (P = 0.13). In the series of Czernobilsky et al. [2], 16 of 75 patients with endometrioid carcinoma had endometriosis; 13 of these 16 had endometriosis and carcinoma within the same ovary (one of Sampson’s criteria for indicating endometriosis as a precancerous lesion). Only 3 patients had histologically proven continuity between endometriosis and endometrioid carcinoma (another of Sampson’s criteria). Scully et al. [14] and Ulbright and Roth [ 151 concluded that there is no clear association between endometriosis and endometrioid carcinoma of the ovary. A review by Schueller and Kirol [19] included four patients in whom endometrioid carcinoma of the ovary resulted from benign endometrial cysts. These four fulfilled the criteria of Sampson [31 and Scott [20] for origin from endometriosis.
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Electron microscopy has shown similarities between endometrioid carcinoma of the ovary, normal endometrium, and grade I endometrial carcinoma [21]. Endometrioid carcinoma, like other epithelial tumors of the ovary, arises from the coelomic epithelium of the ovary
Ml. Synchronous
Primaries
When carcinoma is present within the uterus and ovary, designation as primary or metastatic lesions is difficult. If the histology of the carcinoma within the uterus and ovary is different, the carcinomas are most likely independent lesions. However, if the histologic type is identical, the question is whether the lesions represent a stage IIA ovarian carcinoma with uterine metastases or a stage IIIA uterine carcinoma with ovarian metastases. Annegers and Malkasian [22] reported the incidence of ovarian carcinoma diagnosed concomitantly with endometrial carcinoma to be 2%. Silverman ef al. [23] noted that 3.8% of primary ovarian carcinomas had an endometrial lesion. Eisner et al. [24] reported that the most frequent synchronous genital lesions were ovarian and endometrial carcinoma. To answer the question of primary versus metastatic lesions, several authors have suggested criteria that must be fulfilled to indicate separate primaries [14,1.51. The criteria of Scully et al. [14] for independent endometrial carcinoma included a low-grade lesion, disproportionately small and with minimal myometrial invasion. UIbright and Roth [15] classified synchronous primaries by “empirically developed criteria” that included major and minor criteria. They classified tumors as endometrial primary with ovarian metastases if the ovarian pattern was multinodular: a major criterion. A tumor also received the same classification if two or more minor criteria were present: small ovary or ovaries (
