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Case presentation
A patient in her early 40s referred to our center from her primary gynecologist with the diagnosis of endometrioid adenocarcinoma G2 of the endometrium and endometrioid adenocarcinoma G2 of left ovary. Patient reported heavy vaginal bleeding. Family history was significant for colon cancer in her mother. She did not have any previous surgeries. She reported no allergies, pregnancies, or medical histrory. Transvaginal ultrasound showed a left ovarian complex cyst 9.3 × 8.8 cm and a 1.6 cm intracavitary fibroid. Carcinoembryonic antigen (CEA) and CA-125 were within normal limits. The primary gynecologist performed a laparoscopic left salpingo-oophorectomy and hysteroscopy. Findings at hysteroscopy revealed multiple polyps seen in the cavity. The uterine cavity appeared to be compressed partially by an intramural fibroid and submuscosal fibroids. Polyps and submucosal fibroids were shaved with a morcellator.
The patient was asymptomatic at the time she was evaluated at Houston Methodist Hospital. Physical examination and vital signs were normal. Pelvic examination revealed normal external genitalia and speculum examination showed macroscopically normal cervix. No vaginal bleeding was noted. Bimanual examination did not reveal any pelvic mass. Pathological anatomy was re-evaluated at Houston Methodist Hospital.
Dr Deavers: What did the pathology from that surgery reveal?
According to the gross description, the left ovary was received fragmented and appeared cystic with admixed pink-tan polypoid-appearing tissue measuring 9.3 × 8.8 × 4.2 cm in aggregate. No normal ovarian stroma was grossly identified. Histologically, the majority of the ovarian tumor consisted of an endometrioid borderline tumor. Scattered within the borderline tumor were foci of solid growth, measuring at least 5 mm, that contained atypical nuclei consistent with endometrioid adenocarcinoma (Figure 1). Focal endometriosis was noted. In submitted immunohistochemical slides, the tumor within the left ovary was positive for ER, PR (patchy), and PAX8. It was negative for WT1. MLH1 and PMS2 were retained, while MSH2 (Figure 2) and MSH6 had loss of expression.
(A) Endometrioid adenocarcinoma arising in an endometroid borderline tumor of the ovary (hematoxylin & eosin (H&E), 40x). (B) Higher magnification of endometrioid adenocarcinoma within the ovarian borderline tumor (right) (H&E, 100x).
Loss of expression in the ovarian carcinoma for MSH2. Background stromal cells are positive.
The endometrial curettage contained foci of crowded glands and solid growth consistent with endometrioid adenocarcinoma (Figure 3). There was a background of secretory endometrium and decidualized stroma. In submitted slides there was staining for PAX8, ER, and PR. WT1 was negative and there was wild-type staining for p53.
Focus of endometrioid adenocarcinoma in the endometrial biopsy (hematoxylin & eosin (H&E), 100x).
Dr Deavers: Are these findings consistent with a primary endometrial or ovarian tumor that has spread to the other organ or two separate primary tumors?
There are a number of features taken into account when evaluating simultaneous endometrial and ovarian carcinomas: histological similarity (or dissimilarity) of the tumors, sizes of the tumors, depth of myometrial invasion, presence of lymphovascular space invasion, spread elsewhere consistent with an endometrial or ovarian primary, unilateral versus bilateral ovarian tumors, surface involvement or a multinodular pattern in the ovary, and presence of endometriosis or a borderline tumor in the ovary. In this case, there was histological similarity as both tumors were moderately differentiated endometrioid adenocarcinomas. However, multiple other features support independent synchronous primaries. The foci of endometrial carcinoma were relatively small, there was associated atypical hyperplasia, and there was no myometrial invasion or lymphovascular involvement. The ovarian involvement was unilateral and there was endometriosis present. In particular, the carcinoma arising within a borderline tumor is consistent with an independent ovarian primary.
Dr Suri: What are your thoughts regarding the origin of these tumors?
Our patient presented with a grade 2 endometrioid adenocarcinoma in the endometrium and left ovary. Both tumors showed mismatch repair deficiency, by loss of MSH2 expression. In addition, loss of MSH6 expression was also observed at the ovarian level. Several studies on microsatellite instability have shown that loss of MSH6 expression can occur during tumor progression, making it highly likely that endometrial cells that have undergone this loss metastasize to the ovary. 1 However, in this case, the presence of an endometrioid borderline tumor of the left ovary, which is also the predominant anatomo-pathological finding in the ovary, makes it more likely that these are two independent endometrioid adenocarcinomas.
A CT scan of the chest abdomen and pelvis was ordered.
Dr Chang: What did the imaging show at this time?
This imaging showed a 7 cm uterine mass in the left uterine corpus, displacing the endometrial cavity to the right (Figure 4). This could be a fibroid versus myometrial extension of the known endometrial cancer. Right adnexal hypodensity appeared tubular and with fluid density, suggesting a mild hydrosalpinx (Figure 5). No definite lymphadenopathy was detected. Upper normal left external iliac and obturator nodes were observed, and normal sized though somewhat increased number of periaortic nodes. Attention on follow-up was advised.
A 7 cm uterine mass in the left uterine corpus.
Right adnexal hypodensity (arrow) suggesting hydrosalpinx.
Dr Suri: Based on this information, what FIGO stage would you assign this patient considering the new classification?
At the endometrial level, we are dealing with a non-aggressive histological type (low-grade endometrioid adenocarcinoma), p53 wild-type and confined to the endometrium, as myometrial invasion is not identified. Therefore, this would be classified as an International Federation of Gynecology and Obstetrics (FIGO) 2023 IA1 stage. 2
It is important to note that if both tumors had a common endometrial origin, according to the FIGO 2020 classification of endometrial cancer, our patient would present a FIGO stage IIIA (adnexal involvement). In the FIGO 2020 classification, despite the tumor being a locally/regionally advanced endometrial tumor (stage III) generally managed by surgery followed by post-operative external beam radiotherapy and/or adjuvant chemotherapy, it is recommended that in synchronous low-grade endometrioid carcinomas of the ovary and endometrium, due to their favorable prognosis, conservative management could be suggested after adequate staging and provided that the following criteria are met: (1) both tumors are low grade; (2) less than 50% myometrial invasion; (3) no involvement of any other site; and (4) absence of extensive lymphovascular space invasion at any location. 3
The new FIGO 2023 classification of endometrial cancer introduces three new subgroups within stage IA. FIGO stage IA3 is defined as low-grade (grade 1–2) endometrioid carcinomas confined to the uterus and ovary. These cases considered as stage IA3 must be differentiated from those in which there is metastatic extension of an endometrial tumor to the ovary (stage IIIA), for which it is essential that the following criteria are met: (1) no more than superficial myometrial invasion is present (<50%); (2) absence of extensive/substantial lymphovascular space invasion; (3) absence of additional metastases; and (4) the ovarian tumor is unilateral, limited to the ovary, without capsule invasion/rupture (equivalent to pT1a). Furthermore, given the favorable prognosis associated with these cases (stage IA3), the use of adjuvant treatment is not recommended. 2 It should be noted that in this context, if an intra-abdominal rupture of the cyst occurs during surgery, the FIGO classification 2023 would be IIIA and therefore adjuvant treatment would be indicated.
Regarding the ovarian tumor, it is an endometrioid adenocarcinoma G2 (high-grade) FIGO 2018 IC1 stage, due to an accidental intra-abdominal rupture of the cyst during surgery. If such a rupture had not occurred, we would have a FIGO 2018 stage IA (tumor limited to one ovary, no capsular involvement, and negative peritoneal cytology). This is of great importance as it not only modifies the prognosis, but if it were stage IA, confirmed after adequate surgical staging, observation would be a reasonable option without the need for adjuvant chemotherapy. 4
Endometrioid borderline tumor is also classified as a FIGO 2018 stage 1C1.
Dr Suri: What is the recommendation for molecular testing in a case such as this one?
As we have a low-grade histological type and a low-risk group (no myometrial invasion, lymphovascular space invasion-negative), it would be appropriate to omit the analysis of DNA polymerase epsilon (POLE) mutations. 5 The p53 mutational study is essential because according to the new FIGO 2023 classification for endometrial cancer, if p53 is mutated in FIGO stages I-II, this stage will be modified to stage IIC2 (p53-mutated) with the prognostic and therapeutic implications that this entails. 2
Dr Suri: Is further surgery necessary for the treatment/staging of the case?
Considering that we have a patient with FIGO 2023 stage IA1 endometrial cancer, the indicated treatment would be total hysterectomy and bilateral salpingo-oophorectomy together with sentinel lymph node biopsy since it is a low-risk group. The minimally invasive approach is the choice for this procedure. Cervical injection of indocyanine green is the preferred technique for sentinel node detection. 5 According to the European Society of Gynaecological Oncology (ESGO) 2020 guidelines for the management of patients with endometrial cancer, lymph node staging could be omitted in patients with low- or intermediate-risk disease and no myometrial invasion. 5
In the case of ovarian endometrioid tumor, as it is an early-stage tumor, surgical management would consist of restaging surgery. A laparoscopic approach would be reasonable in this case, as open surgery is considered to be a choice only when laparoscopy may entail a higher risk of intra-abdominal rupture of the cyst. Peritoneal staging consisting of peritoneal biopsies, peritoneal washing, and infracolic omentectomy is indicated in restaging although the result does not change the indication for adjuvant treatment. Regarding lymph node staging (bilateral pelvic and para-aortic lymphadenectomy to the level of the renal vein), this can be omitted when we are performing restaging surgery and provided that its result will not alter subsequent patient management, due to the increased morbidity that it may entail. 6
For a borderline tumor, staging would be completed by performing ometectomy, peritoneal washing, and multiple peritoneal biopsies (which may increase the stage in up to 30% of cases). Pelvic and para-aortic lymphadenectomies are not required for the staging of borderline tumors as they have not been shown to have an impact on overall survival. 4 Restaging surgery in borderline tumors should be considered only in the following cases: (1) patients with a higher risk of extra-ovarian microscopic implants (serous tumor with micropapillary patterns) or (2) patients with incomplete visual exploration of the abdomino-pelvic peritoneum during the first surgery, given its questionable benefit in other situations and the increased morbidity it may entail. 6
Dr Suri: Could fertility preservation be considered if the patient were to have unfulfilled reproductive wishes?
Fertility-sparing treatment may be considered in patients with endometrioid endometrial carcinoma grade 1 without myometrial invasion (FIGO 2023 IA1) and without other risk factors. Although evidence is more limited in grade 2 endometrioid carcinoma, fertility preservation could be considered on an individual basis in these patients, as long as they meet all the previously described criteria. Regarding ovarian preservation, it can be considered in pre-menopausal women under 45 years of age with a low-grade endometrioid adenocarcinoma and myometrial invasion of less than 50%, as long as no extra-uterine disease is identified.5
Fertility preservation in patients with ovarian cancer would consist of unilateral salpingo-oophorectomy together with complete surgical staging. It may be considered in low-grade ovarian carcinomas (low-grade serous carcinomas, mucinous expansile subtype, endometrioid G1) FIGO stage IA or IC, as well as in patients with borderline ovarian tumors. 6
Our patient would therefore not be a candidate for fertility-sparing treatment, as she presents a grade 2 FIGO IC1 endometrioid ovarian adenocarcinoma. She was scheduled for robotic-assisted laparoscopic surgery, consisting of total hysterectomy, right salpingo-oophorectomy, bilateral sentinel lymph node mapping, peritoneal biopsies, peritoneal washing, and ometectomy.
Dr Deavers: What did the final pathology report reveal?
The subsequent hysterectomy demonstrated only foci of complex atypical hyperplasia. No residual adenocarcinoma was found, despite submitting the entire endometrium for microscopic examination. The hyperplasia was found to have loss of expression for MSH2, while having retained expression of MLH1 and PMS2. The right ovary, lymph nodes, peritoneal biopsies, peritoneal washing, and omentum were all free of tumor. The loss of MSH2 and MSH6 in the endometrium and ovary are indicative of a high probability of Lynch syndrome.
Dr Suri: Given the final pathological result, does our patient require any adjuvant treatment?
Regarding endometrial tumor, as this is a low-risk group no adjuvant treatment is indicated. 5 If we have an endometrioid adenocarcinoma of endometrial origin with ovarian extension, multiple studies have shown that the prognosis of patients with stage I endometrioid carcinoma of the endometrium and ovary is equivalent to those with stage I endometrioid carcinoma of the endometrium alone, with no difference in survival between the two scenarios. Therefore, the use of adjuvant therapy in these cases (FIGO 2023 IA3) is not indicated. 7 Adjuvant treatment should be considered for FIGO stage IIIA, after complete cytoreductive surgery. 5 For the endometrioid borderline tumor FIGO stage IC1, adjuvant treatment is not indicated. The use of adjuvant chemotherapy can be considered in borderline tumors with invasive peritoneal implants. 4
Regarding G2 FIGO IC1 endometrioid ovarian adenocarcinoma, the 2019 ESGO-European Society for Medical Oncology (ESMO) consensus for the management of ovarian cancer indicates that in endometrioid adenocarcinoma grade 1 or 2 and FIGO IB or IC, the benefit of adjuvant chemotherapy is uncertain, indicating an individualized assessment in each case. Observation may be considered in patients with endometrioid adenocarcinoma grade 1 or 2 and FIGO stage IB or IC, provided that full surgical staging has been performed. Six cycles of carboplatin or six cycles of carboplantin/paclitaxel would both be appropriate. The administration of three cycles of carboplatin/paclitaxel would be adequate in early-stage ovarian cancer, as long as it is not a high-grade serous carcinoma or FIGO stage IC, as in our case. 6 The 2023 National Comprehensive Cancer Network (NCCN) ovarian cancer guideline recommends adjuvant treatment with carboplatin/paclitaxel in FIGO IC and grade 2 or 3 endometrioid adenocarcinomas. 4
In our patient it was decided to administer adjuvant chemotherapy (six cycles of carboplatin/paclitaxel).
Dr Suri: Should we perform further genetic testing on this patient?
Approximately 3% of all endometrial carcinomas and 10% of endometrial carcinomas with mismatch repair deficiency or microsatellite instability are causally linked to germline mutations of the mismatch repair deficiency genes (MLH1, PMS2, MSH2, and MSH6). Therefore, not all patients with endometrial cancer and mismatch repair deficiency detected by immunohistochemistry will have Lynch syndrome, as it is often due to somatic mutations or hypermethylation. Patients with mismatch repair deficiency and those with a family history suggestive of Lynch syndrome, regardless of mismatch repair deficiency protein status, should be screened for germline mutations associated with Lynch syndrome. 5 The presence of mismatch repair deficiency may be higher, according to some studies, in synchronous endometrial and ovarian carcinomas than in isolated endometrial carcinomas. 1 Endometrioid tumors of the ovary (both borderline and carcinomas) are also associated with Lynch syndrome, as well as endometriosis.
Our patient shows MSH2 deficiency in both tumors and MSH6 deficiency in the ovary. These findings, together with the presence of an endometrioid borderline tumor in the ovary, suggest a high probability of Lynch syndrome and therefore a genetic study should be performed on this patient. Conversely, our patient had endometriosis in the anatomo-pathological study, thus leading to an increased risk of endometrioid ovarian tumors.
The patient will be evaluated by the Genetics Department to rule out Lynch syndrome.
Dr Suri: What surveillance regimen would be appropriate for this patient?
For endometrial carcinoma, follow-up could consist of a physical and pelvic examination every 3–6 months, depending on the risk group, during the first 2–3 years, then every 6–12 months until year 5. Then annual follow-up may be performed. As for complementary tests, CA-125 in blood could be requested, and the request for imaging tests would be assessed according to the symptoms or suspicion of recurrence as well as the risk of recurrence. The 5-year overall survival in women with stage I endometrial carcinoma is 92%, compared with 48% in those with stage III at diagnosis. The stage at diagnosis is therefore the determinant for deciding on the follow-up of each patient. 5
For endometrioid ovarian borderline tumors, the recommendation for follow-up would be every 3–6 months for the first 5 years. It would consist of physical and pelvic examination. Both CA-125 blood testing and additional imaging tests are not routinely indicated. CA-125 is recommended if initially elevated . Imaging tests are indicated depending on clinical findings, CA-125 elevation, or suspicion of recurrence. The 5-year overall survival rate for stage I borderline tumors is 99% .
With regard to endometrioid ovarian adenocarcinoma, once adjuvant treatment has been completed, it is recommended to carry out controls every 2–4 months during the first 2 years, every 3–6 months during the following 3 years, and annually from the fifth year onwards. A physical and pelvic examination should be carried out, and imaging tests should be assessed on an individualized basis according to the risk of recurrence and clinical condition. CA-125 or other tumor markers will be requested if they were elevated initially or if recurrence is suspected. 4
In our patient it would be reasonable to propose a follow-up every 4 months, in which we would perform a physical and pelvic examination, for the first 2 years. At each visit, a CA-125 blood test could be requested, as well as an abdomino-pelvic CT scan. Further imaging tests would be assessed on the basis of symptoms and physical examination.
Closing summary
This case is of special interest since it makes us consider and decide from the initial diagnosis whether we are dealing with two tumors with a common or independent origin. This decision is of great importance since it determines the stage and management of the patient.
Synchronous endometrioid carcinomas of the ovary and endometrium are observed in 3.1% to 10% of patients with endometrial cancer and in 10% of patients with ovarian cancer. Three possible origins have classically been considered: two independent tumors, a tumor of endometrial origin metastasizing to the ovary, or an ovarian tumor metastasizing to the uterus. Dual origin has traditionally been associated with low histological grade, young women, early stages, and more favorable prognosis than cases considered to be metastatic disease.8
Histopathological features to differentiate primary dual disease were described by Herrington and Scully.8 Among the pathological criteria proposed by Scully et al suggesting a dual origin are: histological dissimilarity of the tumors; absent or superficial myometrial invasion; presence of atypical hyperplasia in the endometrium; presence of endometriosis in the ovary; absence of lymphovascular space invasion; absence of spread of endometrial tumor; unilateral ovarian involvement; ovarian parenchymal involvement without lymphovascular space invasion; absence of spread of ovarian tumor; and dissimilar ploidy, molecular genetic, or karyotypic abnormalities. However, in many situations the differentiation of the origin of these tumors according to the criteria proposed by these authors remained complex.
Recent studies in which molecular tests have been carried out on these tumors using next-generation sequencing technology have shown a clonal relationship between synchronous endometrioid endometrial and ovarian carcinomas. These studies found that up to 95% of tumors that were considered to be dual primary according to the classically used histopathological features were clonal tumors. However, despite their metastatic origin, the prognosis of these tumors was found to be equivalent to that of a non-metastatic endometrial or ovarian tumor when confined to these organs. This could be explained by the fact that this dissemination occurs through the fallopian tubes, and therefore the tumor cells do not have the same malignant potential as those with lymphovascular space invasion or peritoneal dissemination.8
More recent studies have evaluated the mutational profile of these clonal tumors in order to elucidate their primary origin. They observed a high frequency of alterations in the PI3K/AKT pathway. Theses alteration are observed in early phases of the endometrial neoplastic process. They also found a frequency of mismatch repair deficiency comparable to that observed in endometrial cancer.1 Therefore, we can consider that most synchronous ovarian and endometrial carcinomas are tumors with the same clonal origin and in most cases this could be endometrial, especially in endometrioid carcinomas.
In summary, endometrioid tumors, when occurring synchronously in the endometrium and ovary, are usually associated with a clonal origin at the endometrial level and tubal spread, which implies a good prognosis compared with classical routes of spread. Therefore, as long as the previously described criteria are met, these patients will be considered as FIGO 2023 stage IA3, according to the new classification of endometrial cancer. This has a major therapeutic and prognostic impact, determining the absence of the need for adjuvant treatment. In the case presented here, the majority presence of a borderline tumor in the ovary together with a minimal foci of endometrioid adenocarcinoma was the main factor that led us to think that they were two tumors of different origin and consequently manage them as such.
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Footnotes
Contributors Study conception and design: ERG, AS. Data collection and analysis: ERG, SC, MD. Manuscript writing and revising: ERG, MD, SC. Manuscript review: all authors.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Not commissioned; internally peer reviewed.