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Objective
Our study’s primary aim was to compare the incidence of endometrial carcinoma in patients with a presurgical diagnosis of endometrial intraepithelial neoplasia confined to the endometrium (EIN-E) versus endometrial intraepithelial neoplasia confined to a polyp (EIN-P). Our secondary aim was to examine the difference in pathological features, prognostic risk groups and sentinel lymph node involvement between the two groups.
Methods We conducted a retrospective cohort study between January 2014 and December 2020 in a tertiary university-affiliated medical center. The study considered the characteristics of women who underwent hysterectomy with sentinel lymph node dissection for endometrial intraepithelial neoplasia (EIN). We compared EIN-E diagnosed by endometrial sampling via dilatation curettage or hysteroscopic curettage vs EIN-P. A multivariate logistic regression analysis was used to assess risk factors for endometrial cancer.
Results Eighty-eight women were included in the study, of those, 50 were women with EIN-P (EIN-P group) and 38 were women with EIN following an endometrial biopsy (EIN-E group).
The median age was 57.5 years (range; 52–68) in the EIN-P group as compared with 63 years (range; 53–71) in the EIN-E group (p=0.47). Eighty-nine percent of the women in the EIN-E group presented with abnormal uterine bleeding whereas 46% of the women in the EIN-P group were asymptomatic (p=0.001). Pathology results following hysterectomy revealed concurrent endometrial carcinoma in 26% of women in the EIN-P group compared with 47% of women in the EIN-E group (p=0.038). Multivariate analysis showed that endometrial cancer was significantly less common in the EIN-P group (overall response (OR)=0.3 95% confidence interval (CI)=0.1–0.9, p=0.03). Eighty-four percent of cancers were grade one in the EIN-P group compared with 50% in the EIN-E group (p=0.048).
Conclusions Concurrent endometrial cancer is less frequent with EIN-P than with EIN-E. The high incidence of endometrial carcinoma in both groups supports the current advice to perform hysterectomy for post-menopausal women. Our data does not support performing sentinel lymph node dissection for EIN-P that was completely resected. The benefit of sentinel lymph node dissection for women with pre-operative EIN-E is yet to be determined.
- Endometrial Hyperplasia
- Uterine Cancer
Data availability statement
Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
There is little data regarding the rate of concurrent endometrial cancer in women with endometrial intraepithelial neoplasia within an endometrial polyp and whether this pathology is associated with high-risk disease.
WHAT THIS STUDY ADDS
The incidence of endometrial cancer is smaller for atypical endometrial polyp compared with endometrial intraepithelial neoplasia. High-intermediate risk factors are more prevalent in cancers following non-polypoid endometrial intraepithelial neoplasia compared with atypical endometrial polyp.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
Lymph node involvement is negligible in patients with atypical endometrial polyp and lymph node assessment does not seem to be necessary. Patients with endometrial intraepithelial neoplasia should be consulted by a gynecologist oncologist.
Introduction
Premalignant lesions of the endometrium carry a 30% risk of progression to endometrial cancer.1 Moreover, concurrent endometrial cancer may be present in 42–50% of the cases at the time of diagnosis.2–5 There are currently two main classifications that are in common usage: the 2014 WHO system and the endometrial intraepithelial neoplasia (EIN) system.6 7 The 2014 WHO system is based on architectural disruption and cytological atypia and contains two categories: non-atypical endometrial hyperplasia (benign hyperplasia) and atypical endometrial hyperplasia.8 In contrast, the EIN system that is based on morphometric analysis and molecular genetics consists of three disease categories classified as benign, indeterminate, or EIN.9 Previous studies have shown that EIN schema has a better prediction for disease progression and outcome compared with the WHO 1994 classification.10 Moreover, it was recently shown that many of the EIN lesions arise within endometrial polyps (43.3%).11
When fertility preservation is not desired, the standard treatment for EIN is a hysterectomy with or without salpingo-oophorectomy. Although the majority of women with concurrent endometrial cancer following a diagnosis of EIN will have low risk early-stage disease, lymph node involvement was shown to occur in up to 10% of women.12 As such, performing surgical staging with either full lymphadenectomy or sentinel lymph node sampling would result in overtreatment and possibly will increase morbidity. In contrast, there is a subset of patients in whom lymph node assessment is important and may influence the need for additional treatment. Moreover, as hysterectomy disrupts lymphatic channels, sentinel lymph node sampling is not possible in a second surgery to complete surgical staging.13–15 Accordingly, there is no consensus regarding the “optimal surgical management” of these patients.
Endometrial polyps are focal neoplasms of the endometrium and consist of endometrial glands, stroma and blood vessels.16 Women can be either symptomatic, presenting with abnormal uterine bleeding or be diagnosed incidentally, following a routine ultrasound exam.17 The majority of endometrial polyps are benign, therefore, management may be conservative especially when less than 10 mm in size, as these polyps tend to regress spontaneously.18 Malignant and pre-malignant changes can be found in endometrial polyps, and their prevalence has been reported to range between 3.4% and 4.9% in postmenopausal women and 1.1% in premenopausal women.19 20 The risk of concurrent endometrial cancer in patients with EIN within endometrial polyp (EIN-P) was shown to range between 5.6% and 31% in previous reports.21 22
The diagnosis of EIN via endometrial sampling presents a real concern for either an underlying carcinoma or progression to carcinoma.2–4 Currently, there is a paucity of data regarding the rate of concurrent endometrial cancer in women with EIN-P. Moreover, the optimal surgical management of these patients is unclear and the need for lymph node staging at the time of surgery is questionable. The primary aim of the present study was to compare the incidence of endometrial carcinoma in the hysterectomy specimens of patients with a presurgical diagnosis of EIN confined to the endometrium (EIN-E) vs EIN-P. Our secondary outcome was to examine the differences in pathologic features, prognostic risk groups and disease progression (lymph node involvement) between the two groups.
Methods
A retrospective cohort study was conducted between January 2014 and December 2020 at the Department of Gynecology Oncology in Tel-Aviv Sourasky Medical Center, a tertiary university-affiliated medical center. The institutional review board approved the study design, protocol, and waiver of informed consent (IRB approval number: 0530–22 TLV). Included were women older than 18 years with no desire for fertility preservation and who underwent at least hysterectomy for the diagnosis of EIN following hysteroscopic polypectomy or endometrial biopsy via dilatation curettage or hysteroscopic curettage. All women who underwent hysteroscopic polypectomy had a complete polyp removal during the hysteroscopic procedure. Women in whom EIN was diagnosed via office biopsy (pipelle) were referred for additional endometrial sampling via operative curettage or hysteroscopic curettage to exclude concurrent endometrial cancer. Patients who did not have a hysterectomy or were lost to follow-up before hysterectomy were excluded. Women who were diagnosed with EIN-P (EIN-P group) were compared with women with EIN-E (EIN-E group). Patients were identified following an electronic medical records search, according to International Classification of Diseases, Ninth Revision, using the diagnosis codes for endometrial intraepithelial neoplasia (621.35) hyperplasia endometrium, endometrial with atypia (621.33) and endometrial polyp (621.0).
Following the diagnosis of EIN, patients were consulted for the potential risk of concurrent endometrial cancer and surgical staging was recommended (hysterectomy, bilateral salpingo-oophorectomy, and sentinel lymph node assessment). Patients were not required to have preoperative imaging. Information regarding ultrasound in women in the EIN-P group was obtained. Since 2017, sentinel lymph node mapping using a minimally invasive technique with intra-operative cervical injection of indocyanine green was performed routinely in accordance with the adapted protocol. Before 2017, it was preformed according to the surgeon’s discretion.23 The pathological diagnosis of EIN was performed by a specialist gynecologic pathologist and in controversial cases was verified by a second pathologist. The following criteria were used for EIN diagnosis: (1) largest diameter of the lesion exceeding 1 mm, (2) the glandular volume exceeding the stroma, (3) cytological distinction from the surrounding glands, (4) excluding benign and cancerous processes.24 Sentinel lymph node s were ultra-staged in accordance with our department’s protocol.25
Following surgery women were categorized to prognostic risk groups according to guidelines from the European Society of Gynaecological Oncology (ESGO), the European Society for Radiotherapy and Oncology (ESTRO), and the European Society of Pathology (ESP), and a multi-disciplinary team decision regarding adjuvant treatment was made according to the risk assessment.26 Data were obtained from electronic medical records and included patient demographics and medical history (age, body mass index (BMI), menopausal status, medical comorbidities and the use of tamoxifen, hormone replacement therapy (HRT) or letrozole) mechanism of diagnosis (hysteroscopy, curettage), clinical presentation before diagnosis (postmenopausal bleeding, perimenopausal bleeding and asymptomatic), pathological data (including grade, depth of myometrial invasion, lymph-vascular space invasion (LVSI) and lymph node involvement), prognostic risk group categorization and adjuvant treatment requirement (radiation therapy, brachytherapy and chemotherapy). Premenopausal bleeding symptoms included heavy menstrual bleeding, irregular bleeding, and a combination of these symptoms. Postmenopausal bleeding was defined as vaginal bleeding after a period of at least 12 months of amenorrhea. Post-menopausal women with no vaginal bleeding or premenopausal women with regular bleeding were considered asymptomatic.
The statistical analysis was performed with the IBM SPSS statistic software (version 27; IBM Corporation, New York, NY). Two-sided Student’s t-test was used to compare normally distributed, continuous variables. Categorical variables were compared by the Chi-squared test or Fisher’s exact test, as appropriate. A multivariate logistic regression analysis was performed for the primary outcome, adjusting for possible confounders. A probability value of <0.05 was considered statistically significant.
Results
During the study period, 1872 women underwent hysteroscopic polypectomy at our institution, of whom, 50 (2.6%) women were diagnosed with EIN-P. Two women who were lost to follow-up and one who was treated with megestrol acetate (Megace) for fertility preservation, were excluded from the current analysis. The mean polyp size in the EIN-P group was 1.9 cm±1.1 cm. A total of 38 women were diagnosed with EIN-E following endometrial biopsy via dilatation curettage or hysteroscopic curettage. Demographic data and clinical characteristics of the two groups are shown in Table 1. There was no difference in women’s age, BMI, hormonal treatment, and the presence of comorbidities between the two groups. However, the proportion of pre-menopausal women in the EIN-P group was significantly higher compared with the EIN-E group (28% vs 10.5%, p=0.041). In addition, women in the EIN-E group were more likely to present with abnormal uterine bleeding (post/perimenopausal) as compared with women in the EIN-P group (89.5% vs 54%, p=0.043). Pathology results following surgical staging are shown in Table 2. All endometrial cancers were of endometroid histology. The presence of concurrent endometrial cancer was significantly more common in the EIN-E group compared with the EIN-P group (47% vs 26%, p=0.038). A multivariate logistic regression showed that endometrial cancer was significantly less common in the EIN-P group (adjusted OR=0.24 95% CI 0.08 to 0.70 0.3, p<0.001) after controlling for patients’ age, BMI, and peri/postmenopausal bleeding (Table 3).
Group characteristics and demographics
Pathology results after hysterectomy
Multivariate analysis: influence of clinicopathologic parameters on the diagnosis of endometrial cancer
Among women with endometrial cancer, the presence of grade-1 disease was significantly more common in the EIN-P group (84.6% vs 50%, p=0.048). Among women in the EIN-E group, 7 women (38%) were diagnosed with grade-2 endometrial cancer and 2 women (11.1%) with grade-3. There were no cases of grade-3 endometrial cancer in the endometrial polyp group. Sentinel lymph-node macro-metastasis was present in only one woman in the EIN-E group (5.6%). Five women (27%) in the EIN-E group were categorized as having either intermediate or intermediate/high prognostic risk (two women with stage II grade three disease (one of whom with LVSI involvement), one woman with stage III disease, one woman with stage IB disease and LVSI involvement and one woman with stage IB disease) compared with one woman (7.6%) in the EIN-P group (with stage II disease). There was no significant difference regarding the need for adjuvant treatment following surgery between the two groups (7.6% vs 27.7%, p=0.35).
Finally, we sought to examine the association between endometrial polyp size and the presence of concurrent endometrial cancer among women in the EIN-P group. There was no difference in the mean polyp size between women with and without concurrent endometrial cancer in the final pathology specimen (1.5 cm±0.61 cm vs 2.05 cm±1.09 cm, respectively, p=0.1).
Discussion
Summary of Main Results
Our study shows that the incidence of endometrial carcinoma is significantly higher in hysterectomy specimens of patients with a presurgical diagnosis of EIN-E vs EIN-P (47% vs 26% p=0.03). A multivariate logistic regression confirmed our findings that endometrial cancer was significantly less common in the EIN-P group (OR=0.3 95% CI=0.1–0.9, p=0.03). Moreover, women with a preoperative diagnosis of EIN-E and endometrial cancer on final pathology had a significantly higher risk for having grade two or three disease (49.1% vs 15.4%, p=0.048).
Results in the Context of Published Literature
Our study results agree with previous reports regarding the proportion of cases with concurrent endometrial cancer diagnosis on final pathology in patients with EIN.27 While the risk of progression to cancer in women diagnosed with EIN from endometrial sampling is well studied, there is limited information regarding the risk of concurrent endometrial cancer in cases of EIN-P. In a recent systematic review that included 10 studies with a total of 127 women, the incidence of endometrial cancer in patients with EIN-P was 5.6%.22 Importantly, there was a wide variation in the percentage of endometrial cancer across the studies, ranging from 0% to 23.8%, as was depicted by the broad confidence interval (95% CI 0.2 to 17.6%). In contrast, in the study by Jacbs et al, the incidence of EIN-P in women who underwent hysteroscopic polypectomy was 2.7%, of whom 30.7% had concomitant endometrial cancer on final pathology.21 Similarly, in our study EIN was diagnosed in 2.6% of the women who underwent hysteroscopic polypectomy, of those 26% were diagnosed with concomitant endometrial cancer.
Several risk factors have been proposed to be associated with the presence of endometrial carcinoma, including obesity, un-opposed estrogen, diabetes, and menopausal status.9 18 In our study, most women were postmenopausal, however, the percentage of premenopausal patients was significantly higher in the EIN-P group (28% vs 10.5%, p=0.041). Moreover, 46% of the women with EIN-P were asymptomatic compared with 10.5% of the women with EIN-E (p<0.001). These differences can be explained by ascertainment bias as the presence of a polyp by itself is a contributor for surgical intervention and a discovery for EIN.
Current recommendations regarding treatment of patients with EIN identified by endometrial sampling include hysterectomy with or without salpingo-oophorectomy in post- and pre-menopausal women who have completed their fertility plans whereas hormonal treatment with progestogens is reserved for women who wish to preserve fertility.9 The importance of fertility preservation is even greater in women with EIN-P, hence, these women may benefit from ovarian preservation as the rate of premenopausal women is significantly higher. However, currently there is insufficient evidence to recommend hormonal treatment for women diagnosed with EIN-P.9 As EIN-P is presumed to be a local uterine pathology, an important question is whether hysteroscopic resection is a sufficient treatment for these women.
Our study findings show that a residual lesion can be found in a substantial percentage of the patients (44% with residual EIN and 26% with endometrial cancer) with apparent normal uteri at the end of the hysteroscopic procedure. In the present study, most women in the EIN-P group had an office hysteroscopic polypectomy and therefore, uterine curettage was not performed. Importantly, no suspicious endometrial findings were reported during the hysteroscopic procedures. It is possible that performing routine endometrial sampling following hysteroscopic polypectomy might reveal cases with multiple sources of EIN or endometrial cancer. In a study by Naaman et al, the rate of concurrent EIN/endometrial cancer in women who had hysteroscopic polypectomy followed by endometrial curettage was 48%.28 As such, the advantage of subjecting these women to a secondary diagnostic procedure is questionable. We believe that hysterectomy should be offered to women with EIN-P who have completed their fertility plans. In contrast, whenever fertility preservation is desired, women should be consulted for the risk of concurrent endometrial cancer and treatment with high dose progestins together with a close follow-up.
According to our study results, EIN-P may carry a lower risk for underlying cancer than EIN-E (p=0.03), but it also seems the invasiveness of endometrial cancer in women with EIN-P is lower. Although not significant, and therefore the interpretation should be considered with caution, women with EIN-E following endometrial biopsy had a higher rate of intermediate/high-intermediate risk factors (27% vs 7.6%, p=0.35), as defined by the presence of deep myometrial invasion (>50% with any grade), grade 2 or 3 carcinomas with any myometrial invasion, or positive lympho-vascular space invasion.29 A possible explanation for these differences between the two groups can be attributed to earlier identification of EIN-P compared with EIN-E, as depicted by higher percentage of premenopausal and asymptomatic women in the EIN-P group that were most probably detected by an incidental ultrasound finding and referred to hysteroscopy.
The high rate of unrecognized cancer in women with a preoperative diagnosis of EIN is comparable to previous reports.27 30 In the GOG 167 trial, a prospective cohort study that evaluated the prevalence of concurrent endometrial cancer in 306 women with a precursor lesion of atypical endometrial hyperplasia, 42.6% of the women were diagnosed with invasive cancer on the final pathology. Of those, 35% had high risk disease (defined as either International Federation of Gynecology and Obstetrics (FIGO) grade two or three carcinoma or myometrial invasion). However, the risk of lymph node metastasis was only 6%.27 Discrepancies between preoperative diagnosis and final pathology could stem from endometrial sampling limitation, as the efficacy of pre-hysterectomy curettage was shown to be inadequate in 60% of the cases.31 The use of hysteroscopy with direct biopsy may enhance the accuracy of the diagnosis and may be considered in women with a diagnosis of EIN.32
It seems that patients with pre-operative EIN have low rates of lymph node metastases as was shown in our study and previous reports. Glassman et al estimated that 200 patients with EIN following endometrial biopsy would need to undergo sentinel lymph node dissection to identify one nodal involvement.33 Sullivan et al examined 141 patients with pre-cancerous lesions and found that only 5% met the “Mayo criteria” on final hysterectomy pathology and therefore concluded that patients with EIN are at low risk and that universal nodal assessment is of limited value.34 Touhami et al tried to determine the risk of endometrial cancer and lymph node involvement in patients with a preoperative diagnosis of “atypical hyperplasia – only” vs “atypical hyperplasia – cannot rule out carcinoma.” They found that the risk of lymph node metastasis in patients with a preoperative diagnosis of “atypical hyperplasia – only” was null, and therefore concluded that lymph node assessment can be omitted in those patients. However, 12.1% of patients with endometrial cancer with a pre-operative diagnosis of “atypical hyperplasia – cannot rule out carcinoma” had lymph node metastasis making the argument that sentinel lymph node dissection is a valuable staging procedure for those patients.35
In our study, none of the patients with preoperative EIN-P had lymph node involvement even when an endometrial cancer was found on final pathology, but conversely, the probability of lymph node involvement was 5.6% when a diagnosis of EIN-E was made preoperatively. According to our study and previous reports, performing routine lymph node dissection in women with EIN will subject more than 90% of the women to unnecessary lymphadenectomy with its potential complications. Accordingly some practitioners, including at our institution, favor performing an sentinel lymph node dissection on all patients with EIN before hysterectomy to avoid the morbidity of full pelvic lymphadenectomy.36 sentinel lymph node dissection has been validated in endometrial cancer and has been shown to have a high rate of detection of nodal involvement for patients with pre-operative cancer diagnoses but its role in pre-cancerous endometrial lesions is still debatable.36 A recent publication by Devon et al examined 378 patients with a preoperative diagnosis of EIN. Comparable to our study, 27% had invasive cancer, of those, 31% had high risk pathological features for nodal metastasis according to the Mayo criteria. In addition, a preoperative finding of endometrial stripe ≥15 mm was 2.5 times more likely to be associated with high-risk Mayo criteria on final pathology and thus may be a useful preoperative criterion for sentinel lymph node dissection in carefully selected patients with EIN.30
Implications for Practice and Future Research
The risk of endometrial carcinoma on final pathology in women with a preoperative diagnosis of EIN in general was substantial, therefore, these patients may benefit from counseling and careful risk assessment by a physician who has expertize in managing both hyperplasia and carcinoma. Our findings and others, support the importance of and clinical relevance of better triaging patients who would benefit from lymph node assessment.30 34 35 In light of our data, we believe that since the risk of lymph node involvement is virtually absent in patients with a preoperative diagnosis of EIN-P, lymph node assessment could be safely omitted in those patients. On the other hand, patients with endometrial cancer with a pre-operative diagnosis of non-polypoid EIN were diagnosed with grade 2 or 3 disease (49.1%), intermediate/high-intermediate risk factors (27%) and lymph node metastasis (5.6%).
Prospective studies are needed to further establish whether surgical evaluation of lymph nodes in those cases are warranted. Data from larger cohorts will identify risk factors of endometrial cancer and lymph node involvement that will further inform the use of selective sentinel lymph node dissection in this population.
Strengths and Weaknesses
To our knowledge, this is the first study to investigate the risk of cancer and lymph node involvement between patients with a pre-operative diagnosis of EIN on a polyp compared with non-polypoid EIN. Nonetheless, our study’s limitations include those inherent to its retrospective design and single institution setting that may lead to selection and information bias. In addition, the small number of patients may not be reflective of findings of a larger cohort of patients. There was also no pathology re-review of the samples included and the criteria for sentinel lymph node mapping was not implemented throughout the duration of data collection.
Conclusions
The incidence of endometrial carcinoma in women with EIN-P was lower compared with women with EIN-E. Still, the high percentage of cancer in these patients highlights the need for hysterectomy for those that are not opting to preserve fertility. Sentinel lymph node dissection seems unnecessary for this group of patients since the risk of lymph node involvement is negligible. Further research will be needed to examine the benefit of sentinel lymph node dissection for women with pre-operative non-polypoid EIN.
Data availability statement
Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information.
Ethics statements
Patient consent for publication
Ethics approval
This study involves human participants and was approved by the ethics committee of the Tel Aviv Sourasky Medical Center (IRB approval number: 0530-22-TLV).The institutional review board approved the study design, protocol, and waiver of informed consent (IRB approval number: 0530-22 TLV).
References
Footnotes
Contributors The authors declare no potential conflict of interests. Each author listed on the manuscript has seen and approved the submission of this version of the manuscript and takes full responsibility for the manuscript. IL is the author acting as guarantor.
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 All authors report no conflict of interest and that this research was non-funded.
Provenance and peer review Not commissioned; externally peer reviewed.