The diagnosis of endometrial cancer in a young, premenopausal woman may present the patient and her physician with the question of conservative management or ovarian preservation. Standard treatment includes hysterectomy and bilateral salpingo-oophorectomy (BSO) and results in an abrupt loss of fertility as well as surgical menopause with its attendant symptoms. The option of conservative treatment with progestins, usually in the context of fertility preservation, has been advocated as a safe alternative by a number of groups.1–7 However, there are also reports of a higher incidence of ovarian malignancy in this young subset of women who may be considering uterine or ovarian preservation, with a range of 5 to 29% reported in the literature.8–11
Knowledge of the potential risk for a coexisting ovarian malignancy has important implications for counseling and management of young patients with endometrial cancer. Our objectives in this study were to determine the frequency of coexisting ovarian malignancies in young women with endometrial cancer and to identify predictors for coexisting ovarian malignancy that might assist with clinical decision making.
MATERIALS AND METHODS
Institutional review board approval was obtained at Cedars-Sinai Medical Center, University of California Los Angeles Medical Center, Olive View-UCLA, and Kaiser-Sunset Medical Center to perform this study. Patients aged 45 years or younger with a histologic diagnosis of endometrial cancer treated with hysterectomy between 1996 and 2004 were identified through a search of pathology and gynecologic oncology databases and gynecologic oncology clinic records. A single investigator (C.W.) reviewed all pathology reports to identify eligible patients. Patients with type 2 endometrial cancer (uterine papillary serous carcinoma or clear cell carcinoma), advanced stage (stage 4) endometrial cancer, or both were excluded from the analysis, because these patients would be unlikely candidates for conservative treatment.
Pathology specimens were reviewed by a gynecologic pathologist at the time of original diagnosis, and ovarian malignancy was classified as synchronously arising or metastatic based upon features of the malignancies at the 2 sites.12 Approximately one half (54%) of the cases with adnexal involvement were available for re-review by a gynecologic pathologist, who confirmed the presence of malignancy in the ovary in all cases. A diagnosis of synchronously arising tumors was assigned based upon superficial or no myometrial invasion, low grade and stage of the endometrial tumor, low grade and stage of the ovarian tumor, dissimilar grades between the uterine and ovarian sites, or dissimilar tumor histologies. Metastasis from the endometrium to the ovary was characterized by deep myometrial invasion, lymph–vascular space invasion, high-grade histologies, the pattern of tumor in the adnexa, and the pattern of extra-pelvic tumor metastases. However, the distinction between synchronous and metastatic disease was limited by the uncertainties of assignment by pathologic criteria alone. Information regarding patient age, body mass index, medical and family histories, reproductive history, preoperative and intraoperative evaluation, use of adjuvant treatment, and follow-up were abstracted from the medical record.
One hundred two young patients, aged 45 years or younger, underwent hysterectomy for type 1 endometrial cancer. Table 1 reviews their clinical and reproductive characteristics. The majority of patients were overweight, with a body mass index of greater than 25. A significant proportion of patients had some reproductive abnormality, with either irregular menses, history of polycystic ovarian syndrome, or infertility. It is striking that in this young population, 11% and 15% of patients carried a diagnosis of diabetes or hypertension, respectively. One half of the patients had a diagnosis of cancer in a first or second-degree relative, but no patient had a family history that met the Amsterdam II criteria for hereditary nonpolyposis colorectal cancer syndrome.13 Before hysterectomy, 26 (25%) patients were treated with hormones for a range of 1–48 months. At the time of hysterectomy, 16 (16%) patients chose ovarian preservation. The majority of uterine tumors were early stage, low grade, endometrioid adenocarcinomas.
Among the 102 women who had a hysterectomy for endometrial cancer, 26 (25%) had coexisting ovarian malignancies. Table 2 demonstrates the pathologic characteristics of the endometrial and ovarian tumors in all 26 patients, including 1 patient who had a subsequent diagnosis of ovarian malignancy 9 months after hysterectomy with ovarian preservation (case S3). The remaining 25 patients were diagnosed at the time of initial surgical exploration with hysterectomy and BSO.
All ovarian tumors were of epithelial origin. There were no granulosa cell tumors. With the exception of 1 patient with a mucinous ovarian cancer (case S16), all of the patients had endometrioid or adenosquamous histology of the ovary (Table 2). Of note, 18 of the 26 cases (69%) occurred in patients with grade 1 endometrial cancer and 15 (58%) occurred in patients with less than 50% myometrial invasion (stage 1A or 1B endometrial cancer). In the first 23 cases (S1–S23), pathologic findings were suggestive for synchronous endometrial and ovarian primaries. The remaining 3 cases (M1–M3), were characterized as metastases from the endometrial tumor to the adnexa.
Table 3 illustrates the preoperative endometrial sampling, imaging, and intraoperative findings among young women with endometrial cancer (26 with and 76 without adnexal involvement). Traditional factors associated with low-risk disease such as low-grade did not reliably predict absence of adnexal pathology. Among 62 patients with a grade 1 tumor on preoperative endometrial sampling, 12 (19%) were ultimately found to have malignant adnexal pathology. Alternatively, among 26 patients with malignant adnexal involvement, 12 (46%) had grade 1 tumor on preoperative endometrial sampling.
Among the 26 patients with confirmed adnexal malignancy, 14 patients had preoperative imaging with pelvic ultrasound, computed tomography, magnetic resonance imaging, or a combination of modalities. Ten of the 14 (71%) had abnormal imaging of the adnexa, with masses ranging from 2.8 cm to 14 cm in size. Four patients (29%) had benign imaging findings of the adnexa: the ovaries appeared normal in 2 cases and contained small (less than 2 cm) physiologic-appearing cysts in the other 2 cases. Stated differently, 4 of 46 (9%) of patients with normal imaging of the adnexa were ultimately found to have adnexal malignancy.
Information regarding intraoperative adnexal findings was available for 21 of the 26 patients with adnexal involvement. Ovarian masses ranging in size from 3 cm to 12 cm were present in 14 (67%), surface excrescences were present in 3 (14%), and no gross abnormalities were found in 4 (19%). In 3 of these 4 cases, the operative reports commented on slightly cystic but otherwise normal-appearing ovaries. Final pathologic examination of the specimens revealed these ovaries to harbor a 0.8-cm metastasis, a 0.1-cm synchronous ovarian tumor, and a 2.5-cm endometrioid ovarian cancer. In the fourth case, the operative report commented on benign-appearing ovaries, and final pathology revealed a 4.5-cm endometrioid ovarian adenocarcinoma arising in endometriosis.
Twenty-six patients underwent hormonal treatment for endometrial cancer for a range of 1 to 48 months before ultimate surgical management. There were four cases (15%) of ovarian cancer diagnosed among this cohort. In the first case (Table 2, case M1), a 43 year-old patient had an initial diagnosis of grade 1 endometrioid adenocarcinoma on an endometrial biopsy and was successfully treated with megestrol acetate (Megace, Bristol-Myers Squibb, Princeton, NJ) 240 mg each day. Results of a follow-up biopsy 7 months later were negative, and she was changed to oral contraceptive pills. Her endometrial cancer recurred 41 months later and was notable for metastases to both ovaries and extension to the parametria, cervical stroma, and outer myometrium at the time of surgical treatment. Two additional cases (M2, M3) were found to have endometrial cancer metastases to the ovaries after unsuccessful hormonal treatment for 2 and 5 months. In the fourth case (S3), a 37 year-old patient underwent hormonal treatment for 7 months before hysterectomy with ovarian conservation for a stage IA, grade 1 endometrial cancer. During a subsequent infertility workup with a plan for egg aspiration and surrogate gestational carrier, she was found to have a 4-cm ovarian cyst. She underwent a second staging surgery 9 months after hysterectomy and was found to have a stage IC, grade 1 endometrioid ovarian cancer.
Overall, 16 patients had ovarian preservation at the time of hysterectomy for endometrial cancer. All had stage IA or IB endometrioid endometrial cancers and normal intraoperative evaluation of the adnexa except for the finding of polycystic ovaries in 2 cases. During a median follow-up time of 13 months (range 1 to 50 months), 3 of the 16 patients developed adnexal abnormalities requiring surgical removal, including case S3 reported above. The other 2 patients had pelvic masses detected during follow-up and underwent BSO 40 months and 46 months after hysterectomy. Pathology revealed benign cysts including bilateral cystadenofibromas in the first patient and a cystadenofibroma and corpus luteum in the second patient. The remaining 14 patients had not developed any adnexal pathology during follow-up.
An additional case that deserves mention is S18. This patient was diagnosed with a stage 2A, grade 1 endometrial cancer with a synchronous stage 1C, grade 1 endometrioid adenocarcinoma of the right ovary at the age of 35. Six years previously, she had been diagnosed with a stage IC endometrioid adenocarcinoma of the left ovary that was 13 cm in size. At the time, she was conservatively managed with a left salpingo-oophorectomy followed by no adjuvant therapy and a negative second look surgery.
Adjuvant treatment was administered to 21 of the 26 patients (81%) with coexisting ovarian and endometrial malignancies (Table 4). There were 5 recurrences and 1 case of progression during adjuvant therapy. A subsequent ovarian cancer diagnosis and a vaginal recurrence were both successfully salvaged with surgical treatment. Two recurrences to the lymph nodes were also managed surgically and a peritoneal recurrence was successfully treated with salvage chemotherapy. The case of progression was treated with chemotherapy. Over a median follow-up time of 34 months (range 3–103 months), 22 patients had no evidence of disease, and 4 patients were alive with disease and undergoing treatment.
In young women with a diagnosis of endometrial cancer, preservation of ovarian function is a complex, controversial issue. We found coexisting ovarian malignancies in 25% of our cohort of women aged 45 years or younger with type 1 endometrial cancer. This is within the range reported by other investigators8–11 and underscores the importance of careful adnexal assessment in the management of these young patients.
When confronted with the question of conservative nonsurgical management, ovarian preservation, or both in a young woman with endometrial cancer, it is important to counsel the patient about the risk of ovarian pathology and the lack of absolutely reliable preoperative or intraoperative predictors to guide decision-making. Candidates for fertility preservation with progestin treatment are restricted to those with low-grade endometrial histology. In our study, carcinoma of the adnexa was found in 19% who met this criterion. Additionally, a patient who successfully resolved her endometrial cancer on megestrol acetate recurred more than 3 years later with advanced disease that had metastasized to the ovaries.
Our tools for preoperative detection of ovarian malignancy are relatively insensitive and of limited value for preoperative counseling. Of the patients with negative preoperative imaging of the adnexa, 9% (4 of 46) were subsequently found to have a coexisting ovarian malignancy. Even intraoperative assessment of ovarian pathology is fallible, and 4 patients with benign-appearing ovaries at the time of surgery were found to have tumor in the adnexa on final pathologic examination. The presence of occult malignancy harbored in grossly normal-appearing ovaries in this population of young women has been reported by other authors.10 Additionally, normal adnexal findings at the time of hysterectomy do not protect the patient from developing a subsequent ovarian cancer, as was seen in 1 of our patients who chose ovarian preservation.
Ovarian tumors coexisting with endometrial malignancy have been generally regarded as synchronous primaries rather than metastases from one site to another based on the observation of a more favorable clinical prognosis9,14–27 as well as the pathologic appearance of the malignancy at the 2 sites.12 Several molecular studies have supported the hypothesis of independent origins by demonstrating different patterns of X chromosome inactivation and dissimilar mutations in PTEN, p53, or K-ras.28–30 However, a recent analysis based on loss of heterozygosity patterns reported a mere 53% concordance rate between the genetic and histopathologic diagnoses for dual site cancers, highlighting our difficulty in accurately making the distinction.31 Despite the majority of our cases being classified as synchronous primaries, the vast majority received adjuvant chemotherapy, further underscoring the uncertainty of the diagnosis or the optimal treatment. It was not the primary objective of our study to differentiate between synchronously arising tumors and ovarian metastases, but rather to determine the rate of any type of adnexal involvement in young patients with endometrial cancer.
Nevertheless, this phenomenon of synchronously arising malignancies of the female genital tract seems to be more commonly seen in premenopausal women than postmenopausal women.10 The occurrence of multiple malignancies decades earlier than expected raises the question of genetic susceptibility. In our study, we did not find any family histories that were clearly suggestive of an inherited genetic syndrome. However, the unusual characteristics of this cohort, including the high incidence of concordant endometrioid histology24,32 and the young age of onset of malignancy warrant further investigation. In the general population, endometrioid histology accounts for 16–24% of the epithelial ovarian carcinomas.23,33 In our study, 96% of ovarian tumors found concurrently with type 1 endometrial cancers were endometrioid or adenosquamous. In the literature, figures as high as 88% endometrioid ovarian histology in simultaneously detected endometrial and ovarian carcinomas are reported.32 No stimulating factor has yet been described to account for the effect, although estrogens,34 androgens,10 and endometriosis35,36 have been hypothesized as contributing factors.
The cause of the simultaneously arising neoplasms has yet to be elucidated. It has been suggested that embryologically similar tissues, such as those of the female genital tract, may be subject to the same carcinogenic or hormonal stimuli and thereby develop synchronous neoplasms.37–39 Interestingly, in our case series, we describe a 29-year-old patient diagnosed with stage IC endometrioid adenocarcinoma of the ovary with a subsequent diagnosis of stage 2A, grade 1 endometrial cancer with a synchronously arising stage IC, grade 1 endometrioid adenocarcinoma of the remaining ovary 6 years later. This case may illustrate a persistent carcinogenic effect and risk of future development of an endometrioid adenocarcinoma of preserved ovaries or endometrium.
Based on our data, we would recommend a cautious approach to ovarian preservation in young patients with endometrial cancer. The high incidence of coexisting malignancy in the ovaries and the young age of diagnosis suggest an increased susceptibility of the reproductive organs to carcinogenic transformation. This elevated risk may reflect a different underlying biology that is at play in the reproductive tracts of young women who develop endometrial cancer. We would suggest the need for a heightened awareness of the risk of concurrent adnexal malignancy in these young patients. Others have suggested the use of laparoscopy to rule out adnexal pathology before embarking on conservative hormonal treatment.40 If a BSO is performed, careful intraoperative evaluation and possible frozen section may minimize the possibility of delayed detection of adnexal malignancy. If the ovaries are preserved at the time of hysterectomy, patients may need continued postoperative surveillance of the retained adnexa. At the minimum, careful assessment of the adnexa by some method is warranted in all young patients with endometrial cancer.
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