Synchronous Endometrial and Ovarian Cancers: A Case Study and Literature Review

Introduction

The term synchronous refers to 2 or more primary independent malignancies, when the second (or subsequent) arises within 6 months after diagnosis of the first malignancy.1 Synchronous endometrial and ovarian cancers are found in 10% of patients with ovarian cancer and 5% of patients with endometrial cancer.2 In the setting of these diseases, the key is to recognize the proper group of patients: those with endometrial cancer with metastasis to the adnexa, ovarian cancer with metastasis to the endometrium, or synchronous primary cancer of the endometrium and the ovary. Patients with synchronous primary tumors have a favorable prognosis compared with other groups.3 Pathologic criteria introduced by Scully et al and by Ulbright and Roth help distinguish synchronous primary tumors from metastatic disease.4,5 In this paper, we present a case of synchronous primary cancer of the endometrium and the ovary with a short literature review.

Case Presentation

A 47-year-old premenopausal woman was admitted to the emergency unit of the Obstetrics and Gynecology Department due to abdominal pain that started the previous day. The obstetrical history included gravida 2, para 2; no chronic diseases, no previous operations. The patient’s last menstrual period was 28 days before admission. Her body mass index (BMI) was 26.6. During the physical examination, a peritoneal sign was observed in the lower left abdominal quadrant, and the transvaginal ultrasound showed a hyperechogenic mass in the left ovary, with dimensions of 41 mm × 35 mm. A hemorrhagic ovarian cyst was suspected. In contrast-enhanced CT scans (Figure), a thickened outline of the left ovary with collections of fluid was observed. The left ovary was 60 mm × 30 mm. The heterogeneous right ovary was 37 mm × 25 mm. Of note, 37 mm of fluid in the pouch of Douglas in anteroposterior dimension was observed.

At admission, laboratory tests showed a C-reactive protein (CRP) concentration of 65 mg/dL. Over the following days of hospitalization, the patient’s pain improved significantly. After 2 days of conservative treatment, the patient had no signs of abdominal pain or infection (CRP, 12 mg/dL; leukocyte count, 5200 cells/µL) and was discharged home.

One month later, the patient had similar symptoms and was readmitted. The patient’s last menstrual period was 11 days previous. The ultrasound scan showed a solid cystic lesion of 150 mm in diameter in the right ovary. The Risk of Ovarian Malignancy Algorithm was 21.03%; the CA-125 concentration was 19.50 IU/mL. During the physical examination, a palpable solid mass up to the umbilicus level was noted. Due to the abdominal pain, positive peritoneal symptoms, and the suspicion of an ovarian tumor, the patient was urgently qualified for surgery.

During surgery, a solid-cystic lesion of the left ovary, 150 mm in diameter, was found. The left adnexa were excised and sent for intraoperative pathologic examination. In the frozen section, the malignant lesion of the left ovary was confirmed. No macroscopic foci of metastases in the greater omentum, parietal peritoneum of the diaphragm, mesentery, stomach, small and large intestines, or liver were identified. A hysterectomy with right adnexectomy and omentectomy was performed, the inguinal-obturator lymph nodes from the right and left sides were excised, and slices of the peritoneum from the right and left paracolic spaces were taken.

On the first day after surgery, CRP concentration was 145 mg/dL, hemoglobin concentration was 8.9 g/dL, and leukocyte count was 13,410 cells/µL. Two units of concentrated red blood cells were transfused, and piperacillin with tazobactam was ordered. This regimen was consistent with the protocol of antibiotic therapy in patients with such laboratory parameters after surgical treatment. Additionally, to reduce the risk of wound infection, a negative-pressure wound therapy system was applied. The next day, after a blood transfusion, the patient’s hemoglobin concentration was 10.2 g/dL. After 4 days of antibiotic therapy, CRP concentration was 39 mg/dL, and leukocyte count was 6270 cells/µL. Five days after the operation, the patient was in good general condition, with significant improvement in laboratory parameters, and was discharged home.

The final histopathologic examination of the left adnexa found endometrioid ovarian cancer, grade 2, with focal squamous metaplasia and extensive necrosis. The histopathological examination of the right ovary found endometrioid ovarian cancer, grade 2 (1.5 cm in diameter), with focal squamous metaplasia and extensive necrosis. In immunohistochemical tests, the patient was p53 negative (p53–); estrogen receptor–positive (ER+) 30%; and progesterone receptor–positive (PR+) 20%. Cancer spread in the peritoneum from the left and right paracolic space was confirmed. In the TNM staging system, the disease was classified as pT3cN0.

The histopathologic examination of the corpus uteri noted grade 2 endometrioid endometrial cancer. Tumor invasion was noted in less than half the myometrium. Regarding immunohistochemistry, the patients results were: p53–, ER+ 40%, PR–, MSH6+ 40%, MSH2+ 40 %, and PMS2, MLH1 negative. In the TNM staging system, the patient’s disease was classified as pT1aN0. The foci of cancer in the ovaries and the endometrium most likely developed independently.

After genetic evaluation, no mutations were found in POLE, TP53, MLH1, MSH2, MSH6, or PMS2. The patient’s endometrial cancer was classified as having no specific molecular profile, and she was referred for platinum-based chemotherapy.

Discussion and Review of the Literature

The incidence of endometrial cancer concomitant with ovarian cancer in the general female population is not very rare. In women younger than 50 years, the incidence of synchronous ovarian cancer in patients diagnosed with endometrial cancer could be up to 19%.6 In other study in women aged 24 to 45 years, such relationship could be up to 25%.7 Additional data demonstrated that the incidence of ovarian cancer in women diagnosed with endometrial cancer was 9.4%.8 

Soliman et al assessed 84 patient cases with 2 concomitant cancers. These patients were relatively young, with a median age of 50 years and a median BMI of 28; 51% were premenopausal and 33% were nulliparous. The most common clinical symptom was abnormal vaginal bleeding.3 These data partially overlap with the medical history and clinical characteristics of our patient, a 47-year old premenopausal woman with symptoms of abdominal pain. A palpable pelvic mass is characteristic of patients with concomitant endometrial and ovarian cancers.8

To help make the diagnosis, the criteria introduced by Ulbright and Roth were introduced: absence of multinodular ovarian pattern (major criterion) or 2 or more of the following minor criteria: absent deep myometrial invasion, unilateral ovarian involvement, absent lymphovascular invasion, lack of tubal lumen involvement, and an enlarged ovary (> 5 cm).5 In this case, there was the absence of multinodular ovarian pattern; superficial focal invasion of the myometrium, absent lymphovascular invasion, lack of tubal invasion, and a 150-mm diameter tumor in the left ovary. Scully et al introduced even more detailed criteria for distinguishing concomitant cancers from metastasis. In this patient, the following features were consistent: no or only superficial myometrial invasion of endometrial tumor, no vascular space invasion of endometrial tumor, absence of other evidence of spread of endometrial tumor, ovarian tumor located in parenchyma, and absence of other evidence of spread of ovarian tumor. 4

In the literature, we found data showing that in patients with synchronous primary diseases, the overall prognosis is better than in patients with the primary cancer with metastasis.9-11 Histological subtype of endometrioid/endometrioid tumors was a good predictor of outcome. These patients have a favorable prognosis, with median survival approaching 10 years (median overall survival was 119 months vs 48 months in groups with other histological subtypes; P = .02).3 In the Gynecologic Oncology Group study, patients with simultaneously confirmed endometrial and ovarian cancers had a 5-year overall survival rate of 86% and a 10-year overall survival rate of 80%.2 The histological subtype combination, endometrioid/endometrioid tumor, seen in our patient was also the most common in patients with synchronous primary cancers.2,3,9

The similar histology of the primary ovarian tumor and primary endometrial lesion may indirectly indicate the pathogenesis of this phenomenon. According to the secondary Mülleriansystem theory, the epithelium of the cervix, uterus, fallopian tubes, ovaries, and peritoneum shares molecular receptors that respond to carcinogenic stimuli, leading to primary synchronous malignancies.12,13 This hypothesis, however, could not explain the cases of dissimilar histology of the ovarian and endometrial tumors.14

Data from the literature show that most of the patients with synchronous primary cancers of the endometrium and ovary are likely to be nulliparous. Data from 2 studies showed a range of 33% to 50%,3,9 with women with primary synchronous cancers having a lower than expected mean parity than patients with endometrial or ovarian cancer alone, respectively.15

Obesity remains a well-known risk factor for the development of endometrial cancer.16 However, in the study conducted by Beard et al, the incidence of endometrial cancer increased during the study period, and the incidence of synchronous endometrial cancer and ovarian cancer remained low. These results suggest that obesity may not contribute to the incidence of synchronous endometrial and ovarian cancers.17

Multiple sites of primary cancers, especially in younger patients, may point to familial cancer syndromes. One of these familial cancer syndromes is Lynch syndrome, or hereditary nonpolyposis colorectal cancer (HNPCC), an autosomal dominant cancer predisposition syndrome associated with younger patients and the development of different types of cancer, including colorectal, endometrial, and ovarian. It is caused by a germline mutation in one of the mismatch repair (MMR) genes.18,19 Diagnosis of Lynch syndrome is based on revised Amsterdam criteria or molecular criteria.20 Patients with Lynch syndrome have a 60% of developing endometrial cancer and a 12% lifetime risk of developing ovarian cancer.19 In the study conducted by Soliman et al, 7% of patients with synchronous endometrial and ovarian cancers had the clinical or molecular criteria for Lynch syndrome. All these patients had a prior history or a first-degree relative with an HNPCC-associated cancer.21 Patients with synchronous endometrial and ovarian cancers in the absence of family history who met the revised Amsterdam criteria were unlikely to have Lynch syndrome.22 Relating to this case, the patient had a negative family history, and no MMR mutations were confirmed.

The age of this patient, 47 years, was the same as the median age in the report conducted by Chiang et al and comparable with other reports.2,3,14 Patients with similar histology of endometrial and ovarian cancers (endometrioid/endometrioid) had an average age of 50 years, younger than patients with dissimilar histology (endometrioid/serous cancer), with an average age of63 years.3

In this case, the patient has International Federation of Gynecology and Obstetrics (FIGO) stage IA endometrial cancer and FIGO stage IIIC ovarian cancer. According to literature data, at the time of diagnosis, patients with synchronous endometrial and ovarian cancer had stage I endometrial cancer in 82%, 93.3%, 88%, 80%, and 83% of cases, respectively.

In contrast, stage I ovarian cancer was observed in 58%, 73.3%, 68%, 62%, and 55% of cases at diagnosis.3,8,14,21,23 FIGO stage III ovarian cancer was diagnosed in 32%, 20%, and 40% of the cases.3,14,23 Cases found in the literature are summarized in the Table.

Primary surgical staging remains the gold standard for treating patients with synchronous endometrial and ovarian cancers.23-25 From the previous reports, we found that adjuvant treatment in the cases of synchronous endometrial and ovarian cancers remains controversial. In the described sources, most patients were diagnosed with stage I endometrial cancer and stage I ovarian cancer.14,25,26 In some sources, adjuvant chemotherapy did not have a significant impact on survival.14 There was no controversy in using adjuvant chemotherapy for more advanced cases of ovarian cancer, as in this case.27

Conclusions

The diagnosis of synchronous endometrial and ovarian cancers may pose difficulties, especially in placing the patient in the proper group: endometrial cancer with metastasis to the adnexa, ovarian cancer with metastasis to the endometrium, or synchronous primary cancer of the endometrium and the ovary. This, in turn, translates into proper adjuvant treatment. Genetic evaluation of patients with a positive family history may be crucial for reaching a quicker diagnosis and identifying patients with familial cancer syndrome.

Acknowledgment

We wish to express our gratitude to everyone who helped during the writing of this case report.

CORRESPONDING AUTHOR

Michał Kostrzanowski, MD

Department of Gynecology and Gynecological Oncology, Center for Postgraduate Medical Education, 01-809, Warsaw, Poland

Phone: +48 790-231-177

Email: mkostrzan@gmail.com

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