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Keywords:

  • endometrial cancer;
  • ovarian cancer;
  • synchronous cancers

Abstract

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Results
  5. Discussion
  6. References

Simultaneous detection of malignancy in the endometrium and ovary represents an uncommon event. The objective of the study was to clarify the possible factors that influenced on the survival. From 1977 to 2005, totally 27 patients fulfilled the criteria and were included in the study. The medical records and the pathologic reports were reviewed. The histologic determination was followed by the World Health Organization Committee classification, and cancer stage was based on the staging system of the FIGO. The Kaplan–Meier survival analyses were generated and compared by the log-rank test. The incidence of synchronous primary endometrial and ovarian cancers was 3.3% in patients with endometrial cancer and 2.7% in patients with ovarian cancer. The mean survival in the group of similar histology (n= 15) was 63 months, and 48 months in the group of dissimilar histology (n= 12) (P= 0.63). The mean survival in the group of early stage (n= 21) was 68 months and 15 months in the group of advanced stage (n= 6) with statistic significance (P= 0.0003). However, the impact of adjuvant therapy on survival did not reach statistic significance (P= 0.15 for chemotherapy; P= 0.69 for radiotherapy). We conclude that the majority of the patients belonged to concordant endometrioid histology in endometrium and ovary, and it tends to be early stage and low grade with favorable prognosis. The stage had more significant influence on the survival than the histology. Adjuvant therapy should be given especially in patients with advanced stage although the optimal management remained to be determined.

Simultaneous detection of malignancy in the endometrium and ovary represent an uncommon event. It occurred in 5% of the patients with endometrial cancer and 10% of the patients with ovarian cancer(1). It is possible to encounter difficulty in definite diagnosis of simultaneously detected cancers in both endometrium and ovary, which could present one of the three conditions: primary endometrial cancer with ovarian metastasis, primary ovarian cancer with endometrial metastasis, or synchronous primary endometrial and ovarian cancers. However, the differentiation is important because it would influence on cancer staging, management, and prognosis. Pathologic criteria to distinguish synchronous primary cancers from metastatic lesions were proposed by Ulbright and Roth(2) first, and were revised in more detail by Scully et al.(3). Several authors described methods of molecular analysis in order to differentiate the dilemma of diagnosis more definitely, but there is no consensus about the most appropriate method now. Previous studies pointed out that the prognosis of synchronous primary cancers of the endometrium and ovary is favorable, especially for early stage and low grade(1,4). In this retrospective study, we reviewed the records of the patients with synchronous primary endometrial and ovarian cancers in past three decades to study the characteristics and prognosis of the patients with this unusual diagnosis.

Materials and methods

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Results
  5. Discussion
  6. References

From the National Taiwan University Hospital Cancer Registry database, we retrospectively reviewed the medical records and pathologic reports during the period from 1977 to 2005. The pathologic specimens were diagnosed by our pathologists with the pathological criteria proposed by Ulbright and Roth(2) and Scully et al.(3). Totally 27 patients fulfilled the criteria, and they were included in the study. All of these 27 patients received management and were followed up at our institution. The basic information including initial presenting symptoms, age at diagnosis, parity, menstrual status, hormone use, medical comorbidities (such as diabetes mellitus or hypertension), and family history of malignancy were collected from medical records. The pathologic findings including histology, grade, invasion of myometrium, lymphovascular permeation, involvement of lymph nodes, and extrapelvic extension were obtained from pathologic reports. The histologic determination followed the World Health Organization Committee classification, and cancer stage was based on the staging system of the FIGO. For analysis of possible prognostic factors to overall survival, the patients were assigned to subgroups based on the symptoms, the histology, the stage, and the adjuvant therapy. The data were analyzed by Statistical Package of Social Studies software (SPSS for Windows, version 10.0.7C, SPSS Inc., Chicago, IL). The Kaplan–Meier survival analyses were generated and compared by the log-rank test. The probability value of less than 0.05 was defined as statistical significance.

Results

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Results
  5. Discussion
  6. References

Totally 844 patients had endometrial cancer and 1004 patients had ovarian cancer in our institution during the period. Twenty-seven patients fulfilled the pathologic criteria proposed by Ulbright and Roth(2) and Scully et al.(3), and they were included in the study. Of these patients enrolled in our studies, the mean age at diagnosis was 47 years (range: 31–59 years). The incidence of synchronous primary endometrial and ovarian cancers was 3.3% in patients with endometrial cancer and 2.7% in patients with ovarian cancer. The mean body mass index was 26.5 kg/m2 (range: 20–33 kg/m2). Diabetes mellitus was noted in six patients (22%), and endometriosis was also noted in six patients (22%). Nine patients were nulliparous (33%), and ten patients were menopausal (37%). None had used hormone agent, such as hormone replacement therapy or oral pills. The common presenting symptoms were abnormal uterine bleeding (AUB) (41%), abdominal pain (22%), abdominal fullness (18%), elevated CA-125 level (7%), abdominal mass (4%), body weight loss (4%), and constipation (4%). The histology of endometrial cancer consisted of clear cell carcinoma (4%) and endometrioid adenocarcinoma (96%), including grade 1 (64%), 2 (24%), and 3 (12%). The FIGO stage of the endometrial cancer consists of IA (48%), IB (40%), IIA (4%), IIB (4%), and IIIA (4%). The histology of ovarian cancer includes endometrioid (58%), clear cell (11%), mixed endometrioid and clear cell (11%), mixed mucinous and endometrioid (4%), serous adenocarcinoma (4%), malignant mixed müllerian tumor (4%), Brenner tumor (4%), and granulosa cell tumor (4%). The grade of histology included grade 1 (62%), 2 (28%), 3 (10%). The FIGO stage of ovarian cancer consists of IA (44%), IC (24%), IIA (4%), IIC (8%), IIIA (4%), and IIIC (16%) (Table 1). Fifteen patients (56%) had similar histology in both primaries. However, dissimilar histology was noted in the other 12 patients (44%). All of the patients received surgical intervention (at least hysterectomy and bilateral salpingo-oophorectomy). Four patients did not receive any postoperative adjuvant therapy. Seventeen patients received platin-based adjuvant chemotherapy, and seven patients received adjuvant radiotherapy postoperatively. Two patients received both adjuvant chemotherapy and radiotherapy. Five patients had recurrence (18%), including abdomen (three patients with the mean interval of 15 months), vagina (one patient with the interval of 10 months), and neck lymphadenopathy (one patient with the interval of 3 months). One patient died of acute renal failure in postoperational period, and another patient died of recurrence 8 months after initial treatment. The mean duration of follow-up was 59 months (range: 6–153 months). The mean survival was 56 months. The five-year survival rate was about 85%. If dividing to two groups upon initial presentation of AUB, there were 11 patients in the AUB group and 16 patients in the non-AUB group. The mean survival in the AUB group was 60 months, and 54 months in the non-AUB group. It did not reach statistic significance (P= 0.90). Classified upon histology on each primary site of malignancy, the group of similar histology (n= 15) meant the same histology of endometrium and ovary, and different histology in the dissimilar group (n= 12). The mean survival in the group of similar histology was 63 months, and 48 months in the group of dissimilar histology. It also did not reach statistic significance (P= 0.63). Based upon FIGO stage, the group of advanced stage included stage III/IV endometrial (n= 1) or ovarian cancer (n= 5) and stage I/II endometrial or ovarian cancer in the group of early stage (n= 21). The mean survival in the group of early stage was 68 months, and 15 months in the group of advanced stage. Statistic significance was noted (P= 0.0003, Fig. 1). However, the impact of adjuvant therapy on survival did not reach statistic significance (P= 0.15 for chemotherapy, Fig. 2a; P= 0.69 for radiotherapy, Fig. 2b). The results of survival analysis based on these factors were summarized in Table 2.

Table 1.  FIGO stage of the 27 patients with synchronous endometrial and ovarian cancers
 EndometriumOvary
Stage I88 (%)68 (%)
 A4844
 B400
 C024
Stage II8 (%)12 (%)
 A44
 B40
 C8
Stage III4 (%)20 (%)
 A44
 B00
 C016
Stage IV0%0%
image

Figure 1. Survival analysis of 27 patients with synchronous endometrial and ovarian cancers in stage. Patients with advanced stage showed significantly poorer overall survival than those with early stage (P= 0.0003, log-rank test).

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image

Figure 2. Survival analysis of 27 patients with synchronous endometrial and ovarian cancers with adjuvant chemotherapy or radiotherapy. a) Adjuvant chemotherapy. There was no statistical difference in the overall survival of patients with or without adjuvant chemotherapy (P= 0.15, log-rank test). b) Adjuvant radiotherapy. There was no statistical difference in the overall survival of patients with or without adjuvant radiotherapy, either (P= 0.69, log-rank test).

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Table 2.  Survival analysis based on prognostic risk factors
 Mean survival (months)P value
Initial presentationAUB (n= 11):60Non-AUB (n= 16):540.90
HistologySimilar (n= 15):63Dissimilar (n= 12):480.63
StageEarly (n= 21):68Advanced (n= 6):150.0003
Adjuvant therapyChemotherapy (n= 17):47No chemotherapy (n= 10):740.15
Radiotherapy (n= 7):63No radiotherapy (n= 20):550.69

Discussion

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Results
  5. Discussion
  6. References

Synchronous primary cancers of the endometrium and ovary represent an uncommon event. According to previous literature, coexistence of carcinoma in endometrium and ovary occurred in about 5% of the patients with endometrial cancer and 10% of the patients of ovarian cancer(1). In our study, the incidence was 3.3% of patients with endometrial cancer and 2.7% of patients with ovarian cancer. Our study was conducted in a single institution rather than multicenter analysis, and we only included cases with confirmed diagnosis of synchronous tumors and excluded other conditions such as primary endometrial cancer with ovarian metastasis or primary ovarian cancer with endometrial metastasis. It might explain why the incidence of synchronous endometrial and ovarian cancers was lower in our series.

Simultaneous detection of malignancy at endometrium and ovary often challenges the clinicians and pathologists to make correct diagnosis and arrange appropriate managements. It consists of one of the following conditions: primary endometrial cancer with ovarian metastasis, primary ovarian cancer with endometrial metastasis, or synchronous primary endometrial and ovarian cancer. If the histology of both sites is dissimilar, the answer is straightforward. However, the problem occurs especially when the histology of both sites are similar like the 15 patients in our series. According to cancer staging system, it may represent more advanced stage of single cancer, such as stage IIIA endometrial cancer or stage IIA ovarian cancer, in spite of synchronous primary double cancers. The majority of previous reports enrolled patients with similar histology of malignancy at endometrium and ovary synchronously, especially endometrioid adenocarcinoma.

The prognosis of these patients was more favorable than stage II ovarian cancer or stage III endometrial cancer, and therefore, it seemed to represent another entity other than single cancer with metastasis. Ulbright and Roth(2) proposed pathologic criteria for differentiation in 1985, including either a multinodular ovarian pattern (major criterion) or two or more of the following minor criteria: small (less than 5 cm) ovary (ies), bilateral ovarian involvement, deep myometrial invasion, vascular invasion, and tubal lumen involvement. Scully et al.(3) further developed the pathologic criteria in detail to more extensive degree. Several methods of molecular analysis had been developed to add in differentiating synchronous primary tumors from metastatic disease, such as DNA flow cytometry(5), loss of heterozygosity on chromosome(6), X-chromosome inactivation(7), PTEN/MMAC1(8,9), beta-catenin(10), and microsatellite instability(11). However, the numbers of cases in these studies are small, and there is still no consensus about the most appropriate method. To date, the majority of published studies like our study depended mainly on morphologic pathologic criteria.

The pathogenesis of synchronous endometrial and ovarian cancer is unclear. The theory of “secondary Müllerian system” proposed that the epithelia of cervix, uterus, fallopian tubes, ovaries, and peritoneal surface had shared molecular receptors responding to carcinogenic stimulus leading to the development of multiple primary malignancies synchronously(12–15). The hypothesis could provide explanation to synchronous malignancies of similar histology. It may not be the case in synchronous cancers of dissimilar histology, and there should be another mechanism underlying the interesting phenomenon. Further studies are needed to disclose the possible pathogenesis of synchronous endometrial and ovarian cancer.

The mean age at diagnosis was 47.2 years in our series and comparable to previous reports(1,4). It is younger than that of ovarian or endometrial cancer occurring predominantly in women during 60 or 70 years. In synchronous endometrial and ovarian primaries of endometrioid histology, the age at diagnosis tended to be younger. In contrast, the age was older in patients of dissimilar histology. In the study of Soliman et al.(4), women with synchronous endometrioid/endometrioid tumors (50-year-old) were younger than those with synchronous endometrioid/serous tumors (63-year-old). They thought this difference could indicate different pathogenesis in these two groups of patients. In our study, the mean age of diagnosis was 48 years in the 15 patients of similar histology. Twelve patients had dissimilar histology with the mean age of 46.3 years (range: 28–58 years) at diagnosis. It differed from previous literature and the exact cause was unknown. Early presentation of AUB may contribute to the incidental simultaneous ovarian malignancy of dissimilar histology. In addition, limited case numbers with wide age range could also have influence on it.

The most common presenting symptoms were AUB (41%), abdominal pain (22%), and abdominal fullness (18%) in our study. Endometrial cancer usually produces early symptoms like AUB even when malignancy is still confined to the uterus. In contrast to vague symptoms of ovarian cancer and generally late detection of disease, AUB usually causes these women to seek for help that results in detecting the disease earlier. In other words, the silent ovarian malignancy was diagnosed earlier due to the symptomatic endometrial malignancy(15–18). In our study, there were 11 patients presenting with AUB. The mean survival in the AUB group was 60 months, and 54 months in the non-AUB group. The results supported the viewpoint as mentioned above although it did not reach the statistic significance (P= 0.90). It also partially accounts for favorable prognosis of these patients because of early detection and treatment.

Early stage and low histologic grade are also the characteristics of synchronous endometrial and ovarian tumors, especially in subtype of endometrioid/endometrioid histology(1), to have favored overall prognosis of these patients. Ayhan et al.(19) concluded that stage of ovarian cancer and grade of endometrial cancer are important prognostic factors.The histology of endometrial cancer was almost endometrioid adenocarcinoma with low grade and early stage in our series. The majority of ovarian cancer was endometrioid adenocarcinoma with low grade and early stage. The mean survival in the group of similar histology (n= 15) was 63 months, and 48 months in the group of dissimilar histology (n= 12). The mean survival in the group of early stage (n= 21) was 68 months, and 15 months in the group of advanced stage (n= 6). Our results showed that the stage had more significant influence on the survival than the histology. The patients of concordant endometrial and ovarian endometrioid adenocarcinoma had good survival potential and favorable prognosis. We think that the advanced stage would have detrimental influence on survival and was exactly a poor prognostic indicator.

Primary surgical staging is the mainstay of the management for the patients of synchronous endometrial and ovarian cancers(2,13,19,20). However, the adjuvant treatment for these patients is still controversial(2,13,21). In our study, the patients all received surgical intervention, and the majority received postoperative platinum-based chemotherapy. It is difficult to evaluate the prognosis of these patients without consideration of the impact of adjuvant chemotherapy. Although the optimal management needed to be determined, we believed that the adjuvant therapy should be given especially in patients with advanced stage of ovarian cancer in addition to primary surgical staging procedure.

Cancer occurring at younger age and multiple sites would make us think of the possibility of familial cancer syndrome. Women with Lynch syndrome (hereditary nonpolyposis colorectal cancer) would have a lifetime risk of 60% to develop endometrial cancer and 12% lifetime risk of ovarian cancer. Are the patients of synchronous primary endometrial and ovarian cancers related to Lynch syndrome? Shannon et al.(22) thought that synchronous primary carcinomas of the ovary and endometrium are unlikely to be part of the hereditary nonpolyposis colorectal cancer syndrome in their study of microsatellite instability in synchronous tumors. Soliman et al.(23) found that only 7% of women with synchronous endometrial and ovarian cancer had either clinical or molecular criteria suggestive of Lynch syndrome. As mentioned previously, several molecular methods are proposed to assist diagnosis, but there is still no consensus about the most appropriate method. The possible genetic defect underlying this phenomenon needs further evaluation.

The major limitations of the study are limited numbers and retrospective review. The diagnosis of synchronous malignancy was confirmed only after pathologic examinations and it was hard to predict before surgical staging. In addition, the incidence of the disease was truly low. Therefore, it was difficult to conduct a prospective study for the uncommon condition in a single institution. Although the retrospective study could help to have an idea of the synchronous dual primary cancer, there should be further studies to find out the possible etiology, mechanism of pathogenesis, and the optimal treatment plans.

In summary, the synchronous primary endometrial and ovarian cancer was an unusual condition. AUB was the most frequent complaint, and it helped for early detection and treatment. The majority of the patients belonged to concordant endometrioid histology in endometrium and ovary, and it tends to be early stage and low grade with favorable prognosis. The optimal management remained to be determined, but the adjuvant therapy should be given especially in patients with advanced stage that would have detrimental influence on survival.

References

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Results
  5. Discussion
  6. References
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