Objective Endometrial cancer in pre-menopausal patients aged ≤40 years is rare and poses both diagnostic and management challenges. The goal of this study was to investigate the clinical and pathologic factors associated with endometrial cancer in this group and their impact on survival.
Methods Patients with endometrial cancer treated between January 2004 and August 2016 were retrospectively reviewed. Patients who underwent either primary surgical treatment or fertility-sparing therapy were included. Exclusion criteria were age >60 years and patients who received neoadjuvant chemotherapy or primary radiation. Age at diagnosis was used to classify patients into two groups: ≤40 and 41–60 years. Clinical and pathologic variables were compared between the groups. Progression-free survival and overall survival were estimated using Cox proportional hazards.
Results A total of 551 patients were evaluated, of which 103 (18.7%) patients were ≤40 years and 448 (81.3%) were 41–60 years. Age ≤40 years was associated with higher body mass index (38.8 vs 35.8 kg/m2, p=0.008), non-invasive cancers (54.2% vs 32.6%, p<0.001), lower uterine segment involvement (27.2% vs 22.5%, p<0.001), and less lymphovascular space invasion (16.8% vs 29.1%, p=0.015). The rate of synchronous ovarian cancer was 9.2% vs 0.7% in age 41–60 years (p<0.001), and 19% of women with endometrial cancer aged ≤40 years underwent fertility-sparing therapy. Grade, stage, myometrial invasion, lymphovascular space invasion, and lymph node status were associated with survival, and fertility-sparing therapy adversely affected the recurrence rate of the age ≤40 years cohort. Among all patients aged ≤60 years, mismatch repair deficiency due to MLH1 methylation was associated with worse progression-free survival, 48.6% vs 83.3% (HR 1.98, 95% CI 1.06 to 3.17, p=0.032), and overall survival, 56.5% vs 90.0% (HR 2.58, 95% CI 1.13 to 5.90, p=0.025).
Conclusions Patients aged ≤40 years with endometrial cancer have more favorable prognostic factors and higher rates of synchronous tumors. Fertility-sparing therapy was associated with higher recurrence rates. The prognostic value of MLH1 methylation in this population warrants further investigation.
- endometrial neoplasms
- ovarian neoplasms
- lynch syndrome II
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.
Endometrial cancer in women aged ≤40 years is associated with higher body mass index, non-invasive tumors, lower uterine segment involvement, and absence of lymphovascular space invasion.
Synchronous ovarian cancer occurs in 9.2% of patients with endometrial cancer aged ≤40 years.
MLH1 methylation may have prognostic implications in patients aged ≤60 years.
Endometrial cancer is the most common gynecologic malignancy in the United States, and its incidence is steadily increasing. An estimated 61 880 new cases were diagnosed in 2019, and 12 160 women died of the disease.1 The median age of diagnosis of endometrial cancer is 65 years. Women with endometrial cancer classically present with post-menopausal bleeding that facilitates early diagnosis. However, the pre-operative diagnosis of endometrial cancer in pre-menopausal women is a clinical challenge.
A limited number of studies have reported the characteristics of endometrial cancer in young pre-menopausal women, and most studies included small cohorts of patients. The age cut-offs used in these studies are variable, ranging from diagnosis before age 40 years up to age 50 years. Young women diagnosed with endometrial cancer have a higher likelihood of obesity (52%–58%), nulliparity, infertility, irregular menses, and diabetes.2–5 The pathologic characteristics have been described to include endometrioid histology, lower stage, lower grade,4 6 7 and a higher prevalence of synchronous ovarian cancers.2 3 6 7 Furthermore, Lynch syndrome has been associated with endometrial cancer diagnosed at a younger age.8–11
It is generally accepted that young age at diagnosis is a positive prognostic factor for endometrial cancer, and older age has been used to stratify patients into high-risk groups.12 The positive disease-specific outcomes of young patients are generally attributed to the favorable histologic characteristics of these cancers. However, this group is heterogeneous with regard to treatment, and some cancers in young women display an aggressive phenotype.3 5 13 A better understanding of prognostic factors for women ≤40 years of age is crucial for counseling and decision-making. In this study, we evaluate the clinical, pathologic, and molecular characteristics associated with the diagnosis of endometrial cancer in pre-menopausal patients aged ≤40 years. We quantify the risk of recurrence and death, and describe the contribution of fertility-sparing therapy to overall outcomes.
Patients with endometrial cancer treated between January 2004 and August 2016 were retrospectively reviewed on the electronic medical record. Patients who underwent either primary surgical treatment or fertility-sparing therapy were included. Since age is a known adverse prognostic factor in endometrial cancer,12 14 patients >60 years of age were excluded in order to select for similar-risk patient groups. Those receiving neoadjuvant chemotherapy or primary radiation therapy were excluded. Age at diagnosis was used to classify patients into two groups: ≤40 years and 41–60 years.
Pathologic and clinical variables were compared between the two age groups. Synchronous endometrial and ovarian cancers were defined using the following pathologic criteria: (1) endometrial cancer with endometrioid cell type, International Federation of Gynecology and Obstetrics (FIGO) grade 1 or 2, non-invasive or with superficial myometrial invasion, and no lymphovascular space invasion and (2) ovarian cancer with a unilateral single expansile mass of well-differentiated endometrioid histology without surface involvement or vascular invasion. When both conditions were met, these lesions were considered synchronous cancers. When there was discrepancy in the histologic types of the endometrial and ovarian cancers, these were also considered synchronous.
Universal screening for Lynch syndrome with immunohistochemistry for mismatch repair (MMR) proteins MLH1, MSH2, PMS2, and MSH6 was performed prospectively starting in 2012 at our institution.15 Tumors with MLH1 and/or PMS2 deficiency were further evaluated with MLH1 methylation testing. MMR status was classified as ‘MMR-proficient’ if all four proteins were expressed, and ‘MMR-deficient’ if any of the four proteins were not expressed. The MMR-deficient group was further subdivided into two subgroups according to MLH1 methylation status.
For the age group comparisons, Student’s t-test was used for continuous variables and Pearson’s chi-square test for categorical variables. All p values were two-sided with 0.05 as level of statistical significance and 95% CI. Progression-free survival and overall survival were evaluated using Cox proportional hazards regression with right-censored univariate analysis. Exploratory multivariable models were built based on stepwise selection. Patients who underwent fertility-sparing treatment were included in the analysis. Initial response in this group was defined as achieving at least one benign endometrial biopsy after initiation of progestin therapy. Patients who had persistent or progressive disease were defined to have a progression-free interval of zero (0); all of these patients underwent hysterectomy. Remission was defined as benign pathology at the end of therapy. Patients who recurred during or after progestin therapy were treated with hysterectomy.
All statistical analyses were performed using Statistical Analysis System software version 9.4 (SAS Institute Inc., Cary, NC, USA). Data were managed using the REDCap electronic data capture tool hosted at the Cleveland Clinic.16 All research activities were approved by the Institutional Review Board.
Demographics and Co-morbidities
During the study period, 1188 patients were diagnosed with endometrial cancer. Overall, 551 patients were eligible for inclusion, of which 103 (18.7%, 8.7% of total) patients were aged ≤40 years and 448 (81.3%, 37.7% of total) patients were aged 41–60 years. The demographic and clinical characteristics of these two cohorts are shown in Table 1. Age ≤40 years was associated with a significantly higher rate of nulliparity (68.0% vs 33.8%, p<0.001) and a higher mean body mass index (38.8±12.2 vs 35.8±9.9 kg/m2, p=0.008). In patients aged ≤40 years, the prevalence of polycystic ovarian syndrome, irregular uterine bleeding, hypertension, diabetes, infertility, and endometriosis was 35.5%, 31.8%, 19.6%, 16.8%, 15.9%, and 8.4%, respectively (online supplementary S1).
Clinical and Pathologic Characteristics
Hysterectomy was performed in 96.1% of patients aged ≤40 years and all patients aged 41–60 years. Twenty patients aged ≤40 years (19.4%) initially opted for fertility-sparing treatment with progestin therapy. Additionally, 61.0% of patients aged ≤40 years underwent bilateral salpingo-oophorectomy at the time of surgery compared with 98.7% of patients aged 41–60 years. A total of 36.4% and 41.3% of the patients had lymph node assessment in the ≤40 years and 41–60 years groups, respectively (p=0.36). There was no significant difference in stage distribution, histology, or tumor size between the two groups (Table 1). The majority of patients aged ≤40 years had stage I-II disease, endometrioid histology, tumor size >2 cm, and grade 1 differentiation. Age ≤40 years was associated with a significantly higher rate of lower uterine segment involvement (27.2% vs 22.5%, p<0.001) and lower rate of lymphovascular space invasion (16.8% vs 29.1%, p=0.015). More than half of the patients aged ≤40 years had non-invasive cancer (54.2%) compared with 32.6% in the 41–60 years group (p<0.001). After dividing the age groups further by decades, the incidence of lymphovascular space invasion and myometrial invasion increased with age, and the rate of lower uterine segment involvement decreased (online supplementary S2).
The rate of synchronous ovarian cancer was 9.2% in patients aged ≤40 years compared with 0.67% in those aged 41–60 years (p<0.001). There was no difference in the rate of ovarian metastasis (3.1% stage IIIA endometrial cancer in both groups). In total, synchronous ovarian cancers were observed in 12 patients. The three patients in the older group who had synchronous cancers were aged 48, 52, and 54 years. Endometrial cancer characteristics in patients with synchronous ovarian cancer were stage I/II (100%), endometroid histology (83.3%), tumor size <2 cm (41.7%), lacking lymphovascular space invasion (81.8%), and <50% myometrial invasion (90.9%) (online supplementary S3). The ovarian cancers in this group were predominantly stage IA (75%) and endometrioid histology (58.3%). Other histologic diagnoses in this group included serous, clear cell, granulosa cell tumor, and borderline tumor. Of the 12 patients with synchronous ovarian cancer, only one patient recurred. This patient was diagnosed at age 38 years with stage IVB grade 3 endometrioid ovarian cancer (with liver metastasis) and stage IA grade 1 endometrioid endometrial cancer. She developed brain metastasis within 2 months of adjuvant chemotherapy.
Adjuvant Therapy, Recurrence, and Survival
The rate of administration of adjuvant therapy was 26.2% in patients aged ≤40 years and 36.4% in patients aged 41–60 years (p=0.05, Table 1). In particular, patients aged ≤40 years were less likely than the older group to receive vaginal brachytherapy (15.5% vs 25.4%, p=0.033). The use of chemotherapy and pelvic radiation was not significantly different (Table 1). Twenty patients aged ≤40 years with endometrial cancer opted to undergo fertility-sparing therapy. Practice patterns were consistent throughout the study period with 10 patients receiving fertility-sparing treatment prior to 2010 and the remaining 10 receiving treatment after 2010. Treatment regimens included low- and high-dose megestrol acetate, medroxprogesterone, and the levonorgestrel intrauterine device (Figure 1). Nine of 20 patients had an initial response defined as one or more negative endometrial biopsies. Two of these patients recurred while on progestin therapy (final pathology showed grade 1 endometrioid and grade 2 endometrioid cancers, respectively). Seven patients achieved remission at the end of therapy with endometrial biopsy showing benign pathology or endometrial hyperplasia without atypia. These patients were allowed to discontinue progestin therapy to attempt conception. Median time to remission was 25 (range 6–57) months. The remaining patients underwent definitive treatment with hysterectomy for documented progression or persistent atypia. Four patients achieved a durable response beyond the end of therapy, and only one patient successfully conceived.
On univariate analysis, younger age was associated with worse progression-free survival (HR 1.92, 95% CI 1.12 to 3.28, p=0.017, Table 2) and better overall survival (HR 0.23, 95% CI 0.07 to 0.78, p=0.018). Factors associated with both progression-free and overall survival were high-grade histology, lymphovascular space invasion, positive lymph nodes, and stage III-IV (all p<0.001). Greater than 50% myometrial invasion was associated with worse progression-free survival but not overall survival.
After adjusting for grade 3 histology (HR 4.29, 95% CI 1.96 to 9.40, p<0.001) and lymphovascular space invasion (HR 2.69, 95% CI 1.38 to 5.26, p=0.004) in multivariable analysis, younger age was associated with worse progression-free survival (HR 3.96, 95% CI 2.17 to 7.22, p<0.001, Table 3). Overall survival was adjusted for stage (stage III-IV HR 6.24, 95% CI 3.07 to 12.67, p<0.001) and was not found to be significantly different between the two age groups (HR 0.31, 95% CI 0.09 to 1.04, p=0.057). When patients who underwent fertility-sparing therapy were excluded from the analysis, there was no difference in progression-free survival between the two age groups (HR 1.17, p=0.71, data not shown).
Among all patients that underwent screening for MMR deficiency (n=543), patients aged ≤40 years were more likely to have MMR-proficient tumors than patients aged 41–60 years (90.7% vs 74.9%, p<0.001, Table 1). MMR deficiency due to MLH1 methylation was observed in 15.9% of patients aged 41–60 years compared with 2.8% aged ≤40 years (p<0.001). Overall, only two patients in the ≤40 years group and four patients in the 41–60 years group had a known diagnosis of Lynch syndrome (p=0.32). Survival outcomes according to MMR status were evaluated for the entire study cohort. For MMR-proficient tumors, the progression-free survival was 83.3% and overall survival was 90.0% (Table 4, Figure 2). MMR-deficient tumors without MLH1 methylation had comparable outcomes to those with MMR-proficient tumors (progression-free survival, 81.3%, HR 1.25, 95% CI 0.53 to 2.95, p=0.61; and overall survival, 75.0%, HR 4.07, 95% CI 0.95 to 17.5, p=0.059, respectively). However, MMR deficiency due to MLH1 methylation was associated with significantly worse progression-free survival (48.6% vs 83.3%, HR 1.98, 95% CI 1.06 to 3.17, p=0.032) and overall survival (56.5% vs 90.0%, HR 2.47, 95% CI 1.08 to 5.63, p=0.031).
The prevalence of endometrial cancer is escalating worldwide in parallel to the epidemic of obesity. In turn, endometrial cancer is being increasingly diagnosed at an earlier age which makes detection, treatment, and counseling a clinical challenge. The incidence of endometrial cancer has been described to be approximately 15% for patients aged ≤50 years and 5% for those aged ≤40 years.5 Our data show that almost one in five cases of endometrial cancer at age ≤60 years are diagnosed in women aged ≤40 years. We found that patients aged ≤40 years had favorable clinical prognostic factors and were less likely to receive adjuvant therapy. After adjusting for grade 3 and lymphovascular space invasion, progression-free survival was found to be significantly worse in patients aged ≤40 years than in those aged 41–60 years. However, this higher rate of recurrence did not adversely impact the excellent overall survival, which was estimated to be 96%.
The higher recurrence rate and worse progression-free survival noted in patients aged ≤40 years sis directly attributed to the use of fertility-sparing treatment. Our study highlights the rate of fertility-sparing treatment to be approximately 20%. When these patients were excluded from the analysis, there was no difference in survival. Moreover, we observed that the long-term outcome of these patient is favorable, and fertility-sparing treatment may not be detrimental to overall survival. According to the National Comprehensive Cancer Network guidelines, “continuous progestin-based therapy may be considered for highly selected patients with grade I and stage IA endometrial cancer who desire fertility preservation”. Close monitoring with endometrial sampling is recommended every 3–6 months, and definitive hysterectomy should be performed when childbearing is complete, with documented progression, or with persistent disease after 6–12 months.17 The rate of remission after fertility-sparing therapy varies widely in the literature. Response is generally defined based on histologic finding after initiation of treatment, and varies between 42% and 78%.18–23 The small sample size and the heterogeneity in the therapeutic regimens likely account for this variation in response rates. Additionally, most studies included patients with complex hyperplasia with atypia. The rate of remission in our patient cohort with known endometrial cancer that underwent fertility-sparing therapy was 35%, as seven out of 20 patients were without evidence of disease at the completion of therapy, and four patients had durable remission. However, considering that the vast majority of patients will eventually require hysterectomy, and successful conception occurs in the minority of patients (5% in our study), the rationale for fertility-sparing treatment should be carefully discussed, and treatment should be individualized. The relatively high rate of treatment failure should be an integral consideration at the time of initial counseling and subsequent follow-up.
Although the distinction between synchronous ovarian cancer and metastasis is challenging, the most clinically relevant method of classification is based on pathologic criteria as described in the Methods section. The rate of synchronous ovarian cancer in young patients with endometrial cancer has been reported to be 10%–29%.3 6 7 24 Our observation of 9% is closer to that found by AlHilli et al (9.4%) based on a large population-based study of women aged <50 years.25 Despite the increased incidence of synchronous ovarian cancer in patients aged ≤40 years, the endometrial cancer presents at an earlier stage, is lower grade, smaller tumor size, less myometrial invasion, and negative lymphovascular space invasion at diagnosis, consistent with previous reports. In turn, the ovarian cancer also tends to have prognostically favorable histopathology.26–29 Therefore, despite the higher occurrence of synchronous ovarian cancer in young endometrial cancer patients, this does not impact overall survival.
Several studies have reported the rate of MMR deficiency in young patients with endometrial cancer to be between 5% and 34%.9 30–32 We found that only 9% of our cohort of patients aged ≤40 years were MMR-deficient. The high rate of intact MMR expression in patients aged ≤40 years is in accordance with previous studies showing that Lynch syndrome is not associated with a younger age of diagnosis of endometrial cancer.2 10 Moreover, an interesting finding is the correlation between MMR deficiency and prognosis. We found that MMR deficiency due to MLH1 methylation portends a worse progression-free survival and overall survival in patients aged ≤60 years. This finding is supported by other studies that report an association between MMR deficiency and worse progression-free survival.33–35 While the biologic basis of this finding is not well understood, these data highlight the importance of MMR testing and incorporation of these results into patient counseling and treatment decision-making. Further studies are needed to understand the molecular determinants of disease recurrence and survival in young patients with endometrial cancer.
The limitations of our study include its retrospective nature, and the inherently small cohort of young patients with endometrial cancer. Moreover, the practice pattern of a tertiary referral center such as ours may inflate the proportion of patients seeking specialty care such as fertility-sparing cancer treatment. Given the statistically low rate of recurrence and death in patients with low-grade endometrioid endometrial cancer, which comprised more than 85% of our study population, outcomes in high-risk subgroups could not be calculated. Additionally, patients diagnosed with endometrial cancer at age >60 years were not included in our study, which limits the generalizability of our age comparison findings. However, since age is a known adverse prognostic factor in endometrial cancer,12 14 focusing on patients aged ≤60 years allowed comparison of similar-risk patients groups. Additionally, since universal Lynch syndrome screening in endometrial cancer was an important component of our study, and age 60 years has been suggested as a possible age cut-off for screening,8 using age 60 years as the cut-off was deemed to be appropriate. Despite these limitations, our study is one of the largest cohort of patients under age 40 years to date with comprehensive single-institution data, including MMR deficiency status.
In conclusion, our results provide further reassurance of the excellent prognosis of young patients with endometrial cancer. When fertility-sparing treatment is not considered, the rate of recurrence and progression is considerably low in these patients. Molecular characterization of these tumors including MMR testing may shed light on potential targeted therapies that may improve prognosis.
Dr Michener is a consultant for Clovis Oncology outside of this study.
Contributors JS: study design, data collection abstraction, and manuscript writing. JM, CC, AP: data collection abstraction. MY, MR: statistical analysis. CMM: manuscript review and editing. MA: study design, data analysis, manuscript writing and editing.
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.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.