In 2020, endometrial cancer continues to be the most common gynecologic malignancy in the United States. The majority of endometrial cancer is low grade, and nearly 1 of every 8 low-grade endometrial cancer diagnoses occurs in women younger than 50 years with early-stage disease. The incidence of early-stage, low-grade endometrial cancer is increasing particularly among women in their 30s. Women with early-stage, low-grade endometrial cancer generally have a favorable prognosis, and hysterectomy-based surgical treatment alone can often be curative. In young women with endometrial cancer, consideration of ovarian conservation is especially relevant to avoid both the short-term and long-term sequelae of surgical menopause including menopausal symptoms, cardiovascular disease, metabolic disease, and osteoporosis. Although disadvantages of ovarian conservation include failure to remove ovarian micrometastasis (0.4%–0.8%), gross ovarian metastatic disease (4.2%), or synchronous ovarian cancer (3%–5%) at the time of surgery and the risk of future potential metachronous ovarian cancer (1.2%), ovarian conservation is not negatively associated with endometrial cancer-related or all-cause mortality in young women with early-stage, low-grade endometrial cancer. Despite this, utilization of ovarian conservation for young women with early-stage, low-grade endometrial cancer remains modest with only a gradual increase in uptake in the United States. We propose a framework and strategic approach to identify young women with early-stage, low-grade endometrial cancer who may be candidates for ovarian conservation. This evidence-based schema consists of a 2-step assessment at both the preoperative and intraoperative stages that can be universally integrated into practice.
Content Overview
The primary goal of this clinical opinion article is to outline the evidence-based advantages and disadvantages of preserving the ovaries at the time of hysterectomy-based surgical treatment of young women with early-stage, low-grade endometrial cancer. The secondary goal is to propose a framework and strategic approach to identify candidates for ovarian conservation, consisting of a 2-step assessment (preoperative and intraoperative).
Endometrial Cancer
Epidemiology of endometrial cancer
Endometrial cancer is an epithelial tumor arising in the endometrium of the uterine corpus. The tumors most commonly have hormone-receptor-expressing, low-grade, endometrioid histology. Endometrial cancer is the most common gynecologic malignancy in the United States. In 2020, 65,620 women were diagnosed with endometrial cancer, reflecting an increase in population incidence over the past 2 decades (23.9 to 28.1 per 100,000 from 2000 to 2017). Aging and obesity are known risk factors for endometrial cancer; thus, both an aging population and the obesity epidemic likely are key contributors to this recent increase in the incidence of this disease. It is estimated that the projected incidence of endometrial cancer will exceed 40 per 100,000 in the United States by 2030.
Significance of young women with early-stage, low-grade endometrial cancer
Although the median age of diagnosis of low-grade endometrial cancer is 61 years, 15.4% of women with low-grade endometrial cancer are under the age of 50 years and 4.2% of women are under the age of 40 years at diagnosis ( Figure 1 A). The vast majority of low-grade endometrial cancer is early-stage disease confined to the uterine corpus (stage I, 81.3%) ( Figure 1 B). Collectively, women under the age of 50 years with stage I disease comprise 12.5% of all low-grade endometrial cancers.
Another important observation is that incidence of early-stage, low-grade endometrial cancer is increasing among certain age groups of young women in recent years ( Figure 2 ), particularly those at the age of 35 to 39 years (2.2 to 4.0 per 100,000 from 2000 to 2017) and 30 to 34 years (0.7 to 2.0 per 100,000 from 2000 to 2017) (both, P <.05). These population trends describing an increasing incidence of endometrial cancer in young women suggest that discussions regarding ovarian conservation will become increasingly relevant at the time of surgical treatment.
Treatment Principles in Endometrial Cancer
Surgery is the mainstay of treatment for the vast majority of women with endometrial cancer, and in early-stage, low-grade endometrial cancer with good prognosis, surgical treatment alone can be curative. Standard surgical staging includes total hysterectomy, bilateral salpingo-oophorectomy, and additional lymphadenectomy for selected patients with a high risk of nodal metastases. The rationale for oophorectomy for endometrial cancer is 3-fold. First, the ovary is adjacent to the uterine corpus and can be a site of endometrial cancer metastasis. Second, a second primary cancer may originate from the ovary either at the time of endometrial cancer diagnosis or at a later time. Third, endometrial tumors are often hormonally sensitive, and oophorectomy removes the source of endogenous hormones.
Mounting evidence supports the oncologic safety of ovarian conservation in young women with early-stage, low-grade endometrial cancer. Since 2018, the clinical practice guidelines from the National Comprehensive Cancer Network (NCCN) have stated that in clinical stage I endometrioid endometrial cancer, ovarian conservation may be safe in selected premenopausal women when meeting the following 3 criteria: absence of family history for breast or ovarian cancer, absence of Lynch syndrome, and normal-appearing ovaries. However, a rationale and detailed strategic schema is not provided beyond these criteria.
Ovarian Conservation in Endometrial Cancer
Utilization of ovarian conservation
Historically, ovarian conservation at hysterectomy was infrequently performed for young women with early-stage, low-grade endometrial cancer; less than 10% of women under the age of 50 years with stage I endometrioid endometrial cancer had ovarian conservation between the 1980s and the early 2010s (7.2%–9.7%). , Furthermore, ovarian conservation rapidly declined after the age of 37 years. Over the past decade, there has been a gradual increase in the utilization of ovarian conservation such that 1 in 6 to 8 women under the age of 50 years with endometrial cancer had ovarian conservation in the early to mid-2010s (11.8% in 2012, 16.4% in 2012–2014). , However, there still remains substantial variability in the utilization of ovarian conservation for young women with early-stage, low-grade endometrial cancer based on patient, surgical, and hospital factors, clearly implying that there is an unmet need for establishing a universal clinical practice guideline for ovarian conservation at surgical treatment.
Advantages and disadvantages of ovarian conservation
Both patients and surgeons benefit from a thorough discussion of the advantages and disadvantages of ovarian conservation at the time of surgical planning for young women with early-stage, low-grade endometrial cancer ( Table ). The oncologic disadvantages of ovarian conservation in terms of unrecognized extrauterine disease, disease recurrence, or other future adverse ovarian events are rare in young women with early-stage endometrial cancer and seem to be salvageable in most cases. The advantages of ovarian conservation include avoidance of menopausal symptoms immediately after oophorectomy and long-term cardiovascular and bone protection. Ultimately, ovarian conservation is not associated with an increased risk of endometrial cancer mortality but rather a decreased risk of cardiovascular mortality.
| Management type | Advantage | Disadvantage |
|---|---|---|
| Removal of ovarian tissue |
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| Conservation of ovarian tissue |
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Oncologic Aspects of Ovarian Conservation
Ovarian micrometastasis in endometrial cancer
Ovarian metastasis of endometrial cancer is seen in approximately 3% to 5% of stage I to III endometrial cancers. , Ovarian involvement is most commonly seen grossly (84.2%), and in these cases, oophorectomy is undoubtedly warranted. Ovarian micrometastasis refers to the histologic foci of tumor cells in the normal ovary despite a grossly normal-appearing ovary intraoperatively. The incidence of ovarian micrometastasis depends on other tumor factors. One study reported an incidence of 0.8%; however, the cases examined had high-risk tumor characteristics (age >50 years, poorly differentiated tumor, deep myometrial invasion, and cervix or nodal metastasis). , , Another study showed a lower incidence of ovarian micrometastasis among stage IA low-grade tumors (0.4%). Among women with stage IA disease, tumor differentiation seems to be the most pertinent risk factor for ovarian micrometastasis; with grade 2 tumors, the incidence of ovarian micrometastasis may be more than double that of grade 1 tumors (2.2% vs 0.8%).
Synchronous endometrial and ovarian cancers
Approximately 2% of women with endometrial cancer have concurrent ovarian cancer at the time of the diagnosis of endometrial cancer. Younger women in particular with endometrial cancer have a higher incidence of synchronous ovarian cancer, estimated at 3% to 5% before the age of 50 years, than older women (peak age, 47 years [5.0%]) ( Figure 3 ). In cases of a synchronous ovarian cancer, the ovarian morphology is generally grossly abnormal. Most commonly, both are diagnosed as stage I disease with endometrioid histology (45.6%) with an overall good prognosis. In fact, women with synchronous stage I endometrioid endometrial cancer and stage I endometrioid ovarian cancer have been shown to have comparable survival compared with those with stage I endometrioid endometrial cancer alone. ,
The diagnosis of synchronous endometrial and ovarian cancers is made by the Scully criteria based on the histopathologic findings of the tumors in the uterus and ovary, respectively. When histologic types are concordant between the 2 organs, the diagnosis of synchronous tumors is often challenging to distinguish from metastatic endometrial cancer to the ovary (stage IIIA endometrial cancer) or metastatic ovarian cancer to the uterus (stage IIB ovarian cancer). In such cases, expert gynecologic pathologic review and molecular clonality testing are key to diagnosis. Recently, microenvironment-compatible organ sites of metastasis restricted to the endometrium and ovary without the involvement of other organs are suggested as the pathogenesis of synchronous endometrial and ovarian cancers. ,
Subsequent ovarian cancer after ovarian conservation
In the United States, the 30-year cumulative ovarian cancer incidence and mortality are overall less than 1.0% for women aged 30 to 50 years ( Figure 4 ). Owing to the infrequent utilization of ovarian conservation in endometrial cancer, subsequent ovarian cancer after ovarian conservation for endometrial cancer has not been well studied. One United States study found that 16 of 1322 women (1.2%) under the age of 50 years with stage I endometrioid endometrial cancer who had ovarian conservation developed subsequent ovarian cancer with a median follow-up duration of 7.4 years. Ovarian cancer risk was higher in women younger than 40 years than those at the age of 40 to 49 years (10-year cumulative incidence, 2.6% vs 0.4%; hazard ratio, 5.00; 95% confidence interval, 1.60–15.7).
Subsequent ovarian cancer after ovarian conservation for young women with early-stage, low-grade endometrial cancer often has favorable tumor characteristics. In the aforementioned study, the median age at subsequent ovarian cancer diagnosis was 40.5 years and most tumors had endometrioid histology (81.3%) and were stage I disease (75.0%). No patient died of ovarian cancer during the 11.6-year follow-up. This is in contrast to ovarian cancer in the general population in which most tumors have high-grade serous histology and present at an advanced stage with a 5-year survival rate of 48.6%. , A clinical dilemma is that if the histology type of subsequent ovarian cancer is identical to endometrial cancer, distinguishing secondary primary ovarian cancer from ovarian recurrence of endometrial cancer is difficult but both need to be recognized as adverse ovarian event.
It is speculated that secondary ovarian tumors in endometrial cancer patients may be related to Lynch syndrome, a germline mutation in the DNA mismatch repair genes ( MLH1 , MSH2 , MSH6 , and PMS2 ), rather than sporadic ovarian cancers. Women carrying this hereditary gene mutations have an approximately 8% cumulative risk of developing ovarian cancer by the age of 70 years and most tumors are nonserous. The average age of Lynch syndrome–related ovarian cancer is 42 to 49 years, and risk-reducing salpingo-oophorectomy is recommended upon completion of childbearing or by the early to mid-40s to reduce ovarian cancer risk.
Recurrence and endometrial cancer death
A recent meta-analysis of 7 retrospective studies showed that ovarian conservation was not associated with an increased risk of disease recurrence in young women with early-stage, low-grade endometrial cancer. One recent large-scale United States study also showed similar findings (adjusted-hazard ratio for recurrence-free survival, 0.83; 95% confidence interval, 0.19–3.66; P =.805). In Japanese women, ovarian conservation may possibly be associated with an increased local recurrence risk compared with oophorectomy but did not impact overall survival. More than half of recurrences occurred after several years, but all were salvaged. As previously discussed, it can also be challenging to distinguish ovarian recurrence from subsequent secondary ovarian cancer if the histologic type is concordant. Reassuringly, 2 United States studies also confirmed that ovarian conservation was not associated with an increased risk of endometrial cancer mortality compared with oophorectomy among young women with early-stage, low-grade endometrial cancer. ,
Endocrine Aspects of Early Oophorectomy
Menopause symptomatology and quality of life considerations
Oophorectomy and resulting surgical menopause may lead to menopausal symptoms that are more severe and prolonged compared with natural menopause , and can include but are not limited to vasomotor symptoms, mood changes, sleep disturbances, vulvovaginal dryness, and sexual dysfunction. This is secondary to the abrupt cessation of sex steroid hormone production by the ovaries in contrast to the more gradual decline in natural menopause. In addition, surgical removal of the ovaries results in complete absence of ovarian sex steroid hormone production, whereas the postmenopausal ovary often retains a very limited production of hormones. In particular, testosterone production continues after menopause, which may have a protective effect with regard to bone resorption and fracture risk. In endometrial cancer, younger women had a higher incidence of menopausal symptom with hot flushes.
Recent literature has stressed quality of life as a significant component of the decision making process to undergo oophorectomy. Quality of life assessments are consistently worse in women who undergo surgical menopause than natural menopause. A recent prospective study among women at high risk of ovarian cancer owing to inherited gene mutations ( BRCA1/2 , BRIP1 , RAD51C , and RAD51D ) showed that those who had early oophorectomy were more likely to have menopausal symptoms, weight gain, lower physical function, and decision regret than those who had delayed oophorectomy. ,
Metabolic considerations following of early oophorectomy
Hypoestrogenism associated with menopause is associated with several metabolic changes that alter body composition, adversely impact lipid profiles, and increase insulin resistance. , Weight gain itself has not been consistently shown to be associated with menopause and is likely secondary to advancing age; however, menopause leads to fat redistribution and an increase in central adiposity. Central adiposity is a major factor associated with insulin resistance and metabolic syndrome, which is increased 1.5-fold after surgical compared with natural menopause. Although the exact mechanism by which central adiposity contributes to insulin resistance is unknown, it has been suggested to relate to impaired fatty acid metabolism and hepatic steatosis with resulting aberrant gluconeogenesis, low adiponectin levels, or defective fat partitioning from subcutaneous tissues to more inefficient intraabdominal stores. Indeed, the risk of nonalcoholic fatty liver disease increases after surgical menopause in young patients with endometrial cancer, which was also associated with an increased risk of diabetes mellitus and hypercholesterolemia.
Menopause also leads to unfavorable changes in lipid profiles, including increases in low-density lipoprotein, total cholesterol, and triglycerides and a decrease in high-density lipoprotein. Adverse lipid profiles are associated with the risk of developing endometrial cancer, and statin use may improve survival in women with endometrial cancer, further motivating efforts to potentially improve lipid profiles in endometrial cancer patients via ovarian conservation. Low levels of sex hormone binding globin, a plasma transport protein that is produced in the liver and is involved in maintaining androgen to estrogen homeostasis, have been observed in postmenopausal women with hyperinsulinemia and obesity and may contribute to a postmenopausal androgenic state with an adverse effect on lipid profile and cardiovascular risk.
Cardiovascular disease morbidity and mortality
Cardiovascular disease is the leading cause of death among all women, and the incidence increases markedly after menopause. , Earlier age of menopause increases future risk of cardiovascular events, , and in women under the age of 40 years with premature menopause, the incidence of cardiovascular disease is increased nearly 2-fold. Hypoestrogenism is associated with oxidative stress and inflammation, which may contribute to endothelial dysfunction and atherosclerosis, and valvular heart disease; however, low estrogen levels may also exacerbate traditional risk factors for cardiovascular disease such as hypertension, vascular disease, and hyperlipidemia. Blood pressure and peripheral resistance have also been shown to increase abruptly after oophorectomy. Protective effects of ovarian conservation on all-cause mortality can sustain until the late 50s, primarily because of a decreased risk of coronary heart disease.
In endometrial cancer patients, cardiovascular disease remains the leading cause of mortality specifically 5 years after diagnosis , ; thus, minimizing cardiovascular risk is a mainstay of long-term care for these patients. Cardiovascular disease in the endometrial cancer population is likely the result of the excellent oncologic outcome for women with early-stage, low-grade disease. A recent study found that women with stage I grade 1 endometrioid endometrial cancer who have ovarian conservation have lower long-term cardiovascular risk and improved overall mortality compared with those who undergo oophorectomy.
Osseous health impact of early oophorectomy
Estrogen has a primary role in mediating bone remodeling and maintenance of bone microarchitecture and density. Bone loss occurs with age; however, the decline in estrogen levels at menopause triggers more rapid bone resorption, increasing the risk of osteoporosis. Osteoporotic fractures are associated with high morbidity and mortality and significant healthcare costs, and fracture risk is estimated to increase by 50% every 5 years after natural menopause.
Bone mineral density decreases soon after oophorectomy. At 18 months of follow-up after oophorectomy, a recent study found a decrease in bone mineral density of nearly 9% from the lumbar spine and 6% in each hip. Hormonal therapy may mitigate some of this bone loss, because randomized data from the Women’s Health Initiative on postmenopausal women showed more than a 30% reduction in hip and vertebral fractures, , ; however, this benefit is lost once hormonal therapy is discontinued.
Stepwise Approach of Ovarian Conservation
Preoperative assessment
A 2-step approach consisting of preoperative and intraoperative assessments may be employed systematically to evaluate and maximize candidates for ovarian conservation among young women with early-stage, low-grade endometrial cancer ( Figure 5 ). Primary candidates include premenopausal women at the age of 45 years or younger with grade 1 endometrioid endometrial cancer with clinical stage I disease who desire definitive surgical treatment with hysterectomy. This age cutoff is based on a previous study. Because the average age of menopause is 51 years, ovarian conservation beyond the age cutoff of 45 years may also be considered per case-by-case assessment.
