Whether surgical procedure can improve the prognosis of endometrial cancer arising in adenomyosis (EC-AIA)? A systematic review and meta-analysis

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Highlights The Kaplan–Meier curves revealed that patients receiving lymphadenectomy favored better progression-free survival compared to those who did not undergo lymphadenectomy ( P =0.016), but there was no significant difference in overall survival. Univariate ( P =0.025, HR=0.25, 95% CI=0.08–0.84) and multivariate ( P =0.042, HR=0.13, 95% CI=0.020–0.930) COX regression analysis revealed that lymphadenectomy was an independent protective factor for progression-free survival. Four studies have showed endometrial cancer arising in adenomyosis seemed to be more inclined to low stage. In our study, the percentage of patients with early stages (I, II) was 58.93% compared to 30.35% for late stages (III, IV). For patients with endometrial cancer arising in adenomyosis found after initial surgery, a second supplementary lymphadenectomy should be performed. With the improvement of living standards and changes in lifestyle, the incidence rate of endometrial cancer (EC) has increased in recent years 1 , 2 . EC is the fourth most common malignant gynecologic tumor occurring in developed countries, resulting in ~320 000 new cases annually on a global scale 3 – 5 . Studies have shown that adenomyosis is the most common benign histopathologic finding in hysterectomy specimens of EC patients 6 , and the coexistence of these two conditions varies greatly, ranging from 0 to 70% 7 – 10 . This may be categorized as either EC coexisting with adenomyosis (EC-A) or that arising in adenomyosis (EC-AIA). Moreover, the incidence of EC-AIA is extremely low at only 1.35% 11 , 12 . EC-AIA is the malignant transformation of ectopic endometrium in adenomyosis. The criteria for the differential diagnosis between these two diseases have been established by Colman and Rosenthal 11 . The main clinical symptoms of EC-AIA are nonspecific (e.g. abnormal vaginal bleeding, heavy menstrual flow, and anemia) 13 – 15 . Nowadays, most EC patients have a favorable prognosis with standard therapy according to the National Comprehensive Cancer Network guidelines 16 . However, because of the low incidence rate of EC-AIA, most related studies are limited to a series of case reports. Its clinical features have been summarized in a recent systematic review 17 , but its therapeutic strategy remains unclear. Most patients are diagnosed with EC-AIA after hysterectomy for benign diseases, such as uterine fibroids and adenomyosis 18 . Therefore, the clinical dilemma is whether such patients should undergo secondary lymphadenectomy to improve prognosis. Currently, there are no studies exploring this issue. Here, we conducted a review of articles on EC-AIA as of May 2023. We summarized the clinical characteristics of EC-AIA, and further explored whether supplementary lymphadenectomy could improve EC-AIA patient prognosis.

Y.S. and S.L.: drafted the paper; Y.S., W.W., and F.N.: conducted articles screening; Y.L., J.W., and X.C.: extracted and analyzed the data; Y.S., W.Y., and Q.L.: made the tables and figures; F.R. and S.L.: supervised and revised the paper. All authors approved the final version of the manuscript.

Not applicable.

This meta-analysis has no ethical approval.

The meta-analysis was carried out under the guidance of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) (Supplemental Digital Content 1, http://links.lww.com/JS9/C20 , Supplemental Digital Content 2, http://links.lww.com/JS9/C21 ) Statement 19 and Assessing the Methodological quality of Systematic Reviews (AMSTAR) (Supplemental Digital Content 3, http://links.lww.com/JS9/C22 ) Guidelines 20 . This study has been registered and approved at PROSPERO. MEDLINE, Web of Science, PubMed, EMBASE, and Cochrane Library were searched for studies published from inception to May 2023. The Medical Subject Headings (MESH) terms included ‘Endometria neoplasms’ and ‘Adenomyosis’. These search themes were combined using the Boolean operator ‘and’ in several combinations without restrictions. The full search terms per database were displayed in the Supplemental Material (Supplemental Digital Content 4, http://links.lww.com/JS9/C23 ). Previous meta-analysis or systematic reviews were used for reference in making the detailed search strategy for each database. The inclusion criteria were as follows: (1) the patients underwent surgery; (2) the postoperative pathological evidence was confirmed by two or more senior pathologists: EC-AIA; (3) age ≥18 years; (4) no adjuvant therapy before operation. In addition, we included articles in all types of languages. Two investigators found relevant articles based on the search formula. Two researchers checked the articles separately based on inclusion eligibility. Divergences of opinion were resolved through discussion and consensus between the two reviewers or sought help from professor F.R. if needed. We collected the following data from each included study: basic information (author, publication date, and country), relevant clinical information (age, parity, clinical symptoms, preoperative diagnosis, surgical approach, pathology, FIGO stage, adjuvant treatment, and survival outcome). With regard to the surgical approach, some patients simultaneously underwent lymphadenectomy during the primary surgery, while some patients performed lymphadenectomy as the second surgery. Regarding the FIGO stage of included studies, most articles gave the specific stage directly. For those studies which did not use the FIGO 2009 criteria, we had restaged them according to the pathologic findings. Furthermore, for those patients whose stage was not clearly defined in these articles, we also restaged them based on their pathological information. The data of menopause, tumor markers, and immunohistochemical expression in the information profile of most patients was missing. The quality of enrolled studies was evaluated using the methodological index for non randomized studies (MINORS) 21 . In detail, seven domains related to risk of bias were assessed, when applicable, as follows: (1) study aim; (2) patient inclusion; (3) data collection; (4) study endpoints; (5) unbiased study endpoints; (6) follow-up; (7) loss to follow-up less than 5%. All seven domains were applicable for case series, while only four domains (i.e. domains #1, #4, #5, and #6) were applicable for case reports. Certainty of the evidence identified was assessed by the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) tool 22 . We used SPSS 26.0 and Rev Man Version 5.3 software for the statistical analysis. Quantitative data were expressed as mean± SD after the normality test, which obeyed normal distribution, and non-normal distribution was expressed as a median. Qualitative data were compared using the χ 2 test, continuous corrected χ 2 test or Fisher test. We analyzed the risk factors for survival using univariable and multivariable Cox regression analysis. Survival was also calculated using the Kaplan–Meier method and compared using the log-rank test. Progression-free survival (PFS) was defined as the time from surgery until recurrence or the last follow-up time and overall survival (OS) was defined as the time from surgery until death or the last follow-up time. P -values were two-sides and the results were considered statistically significant if P <0.05.

An initial literature search yielded 1541 potentially relevant titles. Following the evaluation of titles and abstracts, 45 were found to be relevant. Of these, six and one articles were excluded owing to serious data deficiency and overlapping data, respectively. A flow chart for the study selection was outlined in Figure 1 . Flowchart of the eligible study selection for the meta-analysis. In total, 38 articles 23 – 60 (56 patients) were included, five of which were case series, and the remainder were case report (Table 1 ). The outcomes of the quality evaluation for the included studies were presented in Figure 2 . For the "study aim" "patient inclusion" "data collection" "study endpoints" and "loss to follow-up" domains, all studies conforming standards were considered at low risk. For the "unbiased study endpoints" domain, the risk was considered high in nine studies, whereas it was unclear in four studies. The level of evidence from the meta-analysis estimated by the GRADE tool was considered low (Fig. 3 ). The mean age±SD of the patients was 56.23±9.5 years (Table 2 ). The proportion of those who had given birth to children was 37.5% (21/56). The most common clinical manifestation was abnormal vaginal bleeding or discharge (23/56, 41.07%). A preoperative diagnosis of malignancy was confirmed in 32.14% (18/56) of the patients, whereas 28.57% (16/56) were diagnosed with uterine leiomyoma or adenomyosis before surgery. Characteristics of included studies. Assessment of the risk of bias. Summary of the risk of bias for each study. Plus sign: low risk of bias; minus sign: high risk of bias; question mark: unclear risk of bias. Grading of Recommendations Assessment, Development, and Evaluation (GRADE) summary of findings table for the outcomes of the systematic review and meta-analysis. Basic information and clinical characteristics of all patients. EC-AIA, endometrial cancer arising in adenomyosis. Total hysterectomy was done in the entire cohort, of which 67.86% (38/56) underwent lymphadenectomy. Of the lymphadenectomy patients, 68.42% (26/38) were subjected to the pelvic lymphadenectomy, whereas 31.58% (12/38) underwent pelvic and para-aortic lymphadenectomy. In the lymphadenectomy group, 57.89% (22/38) underwent lymphadenectomy as part of the primary surgery, 13.16% (5/38) underwent lymphadenectomy as the secondary procedure, whereas 28.95% (11/38) of the patients did not have information regarding this. The percentages of all included patients in stages I, II, III, and IV were 57.14 (32/56), 1.79 (1/56), 19.64 (11/56), and 10.71% (6/56), respectively. Of the detected pathological types, the most common was endometrioid endometrial carcinoma (33/56, 58.93%) followed by uterine serous carcinoma (9/56, 16.07%), uterine clear cell carcinoma (7/56, 12.50%), and uterine mullerian adenosarcoma (5/56, 8.93%). Of these patients, 50% (28/56) received adjuvant chemotherapy alone, 5.36% (3/56) had radiotherapy alone, 5.36% (3/56) underwent adjuvant radio-chemotherapy, 5.36% (3/56) refused adjuvant treatments, 25% (14/56) did not require follow-up, and no data was available for 8.93% (5/56). As for the FIGO stage, the data we mentioned were staged according to FIGO 2009. There were nine articles involving FIGO staging that required special attention 29 – 31 , 41 , 44 , 46 , 47 , 51 , 60 . For eight of these, the FIGO stage was not specified; however, we were able to determine the stages based on the pathological findings. In addition, the stage mentioned in one of the articles was IB; however, left pelvic lymph node metastasis was clearly indicated, so we revised the stage to III. The above information was listed in Table 3 . The features not addressed because of severe data deficiencies included the following: only 3.57% (2/56) of patients had menopausal status, 60.71% (34/56) of the cases did not mention tumor markers, and 57.14% (32/56) did not reveal the immunohistochemical results. Treatment, prognosis, and pathology information for all patients. EC-AIA, endometrial cancer arising in adenomyosis; LND, lymph node dissection; TH, total hysterectomy. A total of 44 patients had prognosis mentioned in the articles. We divided these patients into two groups based on the type of intervention: lymphadenectomy and without lymphadenectomy. There were no significant differences between these two groups in terms of age, parity, FIGO stage, pathological type, adjuvant therapy, the number of recurrences, and recurrence location Table 4 . Regarding the location of recurrence, recurrence in the vaginal or pelvic lymph nodes was defined as vagina/pelvic, and that in other locations was designated distant type, and the presence of both conditions was defined as mixed. The mean follow-up time±SD in the lymphadenectomy group was 40.44±28.42 months and consisted of 16.63±19.39 months for the no lymphadenectomy group. The median (IQR) recurrence time for the former was 30.5 (12.75, 63.75) months, and it was 7 (3.75, 10.75) months for the latter. We analyzed Kaplan–Meier curves to compare the differences in PFS and OS rates. Patients in the lymphadenectomy group exhibited a better prognosis with respect to PFS ( P =0.016), but not OS ( P =0.393) compared with those in no lymphadenectomy group (Fig. 4 ). Furthermore, we identified independent prognostic factors that may affect PFS rates using univariable and multivariable Cox regression analyses. As shown in Table 5 , parity (HR =0.005, 95% CI=0–0.120, P <0.001) and lymphadenectomy (HR=0.134, 95% CI=0.019–0.926, P =0.042) were the independent protective factors for PFS. Moreover, we identified the factors that may affect OS (Table 6 ), and no independent prognostic factors were found using univariable analysis. The survival curves. (A) OS of all patients in different subgroups ( P =0.393). (B) PFS of all patients in different subgroups ( P =0.016). OS, overall survival; PFS, progression-free survival. Baseline characteristics of patients with survival outcomes. EEC, endometrioid endometrial carcinoma; IQR, inter quartile range; UCC, uterine clear cell carcinoma; UMA, uterine mullerian adenosarcoma; USC, uterine serous carcinoma. Univariable and multivariable Cox regression analysis for PFS. EEC, endometrioid endometrial carcinoma; PFS, progression-free survival; UCC, uterine Clear Cell Carcinoma; UMA, uterine mullerian adenosarcoma; USC, uterine serous carcinoma. Univariate and multivariate Cox regression analysis for OS. EEC, endometrioid endometrial carcinoma; OS, overall survival; UCC, uterine clear cell carcinoma; UMA, uterine mullerian adenosarcoma; USC, uterine serous carcinoma.

This work was financially supported by Henan Province Medical Science and Technology Research Plan Provincial and Ministerial Co-construction Project (SBGJ202302075), Scientific Research and Innovation Team of The First Affiliated Hospital of Zhengzhou University (ZYCXTD2023004), Leading Discipline Leader of Henan Province, and the Excellent Youth Funding of Henan Provincial Foundation Committee (222300420091).

Name of the registry: PROSPERO. Unique identifying number or registration ID: CRD42023442900. Name of the registry: PROSPERO. Unique identifying number or registration ID: CRD42023442900.

Fang Ren.

In generally, EC arising in adenomyosis is very rare. Rolly first reported such an EC case transformation in adenomyosis in 1897 61 . It is estimated that no more than 100 cases of EC-AIA have been documented to date 12 , 13 . In 1925, Sampson proposed the initial diagnostic criteria for EC-AIA 62 . The internationally recognized pathological diagnostic criteria for carcinoma arising in adenomyosis are as follows: (1) the carcinoma should not be located in the endometrium or elsewhere in the pelvic area; (2) the carcinoma must demonstrate a direct transition from benign to malignant, and stroma with epithelial elements must be identified; (3) endometrial stromal cells must be present to support a diagnosis of adenocarcinoma arising in adenomyosis. In this study, we performed a systematic review of the literature and briefly summarized the characteristics of such patients. The mean age and the main symptoms were consistent with other types of EC 63 . Four retrospective studies have showed EC-AIA seemed to be more inclined to low stage 7 , 64 – 66 , which were not included in our study because the required individual patient information was unavailable. Furthermore, the other two case reports were also not eligible because of a lack of patient information 67 , 68 . In our study, we observed that the percentage of patients with early-stage (I, II) disease was 58.93% (33/56) compared with 30.35% (17/56) late-stage (III, IV) patients. Previous studies indicated that the most frequent malignant transformation of EC-AIA was endometrioid carcinoma followed by uterine serous and uterine clear cell carcinomas 24 , 67 , 68 . We obtained similar findings in our study. Moreover, some patients were negative for EC even after preoperative hysteroscopy 32 , 46 , 48 . This may be related to the fact that malignancy in adenomyosis is derived from the myometrium and then invades the endometrium 34 . For this reason, when patients with EC-AIA are at an early-stage, the possibility of misdiagnosis can readily occur. Therefore, patients with adenomyosis should be monitored with ultrasound regularly. Once any changes are detected, MRI is feasible for further evaluation 46 . Because of the low incidence of EC-AIA 69 – 71 , there is a lack of standardized treatment recommendations. The therapeutic regimens for these patients are primarily based on the guidelines for EC. For those diagnosed with EC following hysterectomy (incomplete staging surgery), supplementary lymphadenectomy has been recommended 16 . However, it remains unclear whether lymphadenectomy can improve the prognosis of patients in whom EC-AIA was observed after hysterectomy for benign diseases. In our study, 44 patients with survival outcomes were assessed. The Kaplan–Meier survival curves revealed that the lymphadenectomy group had a better survival outcome with respect to PFS ( P =0.016). It is noteworthy that the follow-up time was statistically different between these two groups. We speculated the following possibilities. First, in the no lymphadenectomy group, the recurrence time was significantly shorter compared with that in the lymphadenectomy group ( P <0.05) (Table 6 ). Second, the proportion of recurrence (37.5%) in the former was higher compared with the latter (21.4%). Finally, our study included a few patients which may have also caused some bias in the data. Actually, as a retrospective study, the reported follow-up time was significantly affected by patient prognosis. More included patients or a series of subsequent prospective studies is necessary in the future. Furthermore, we determined the effects of various clinical parameters and therapies on prognosis (PFS and OS) in EC-AIA patients. Univariable and multivariable Cox regression analyses indicated that only fertility (yes vs. no) and lymphadenectomy (yes vs. no) were independent prognostic factors for PFS, and none of these were associated with OS. Based on the short follow-up period (31.20±26.77 months) of this study, we regarded PFS as the primary study endpoint; thus, we concluded that lymphadenectomy was effective for improving survival outcomes. For patients with EC-AIA diagnosed following hysterectomy for benign disease, supplementary lymphadenectomy is recommended. Molecular classification are correlated with prognosis, clinical management, and personalization of patient therapy 72 , 73 . The role of molecular classification in risk stratification and treatment of EC patients has been discussed in two recently published reviews 74 , 75 . If it is possible to stratify patients via the molecular classification, treatment for EC-AIA will be more accurate. However, molecular classification was not applied in our study and further studies related to the topic are necessary. We previously planned to perform a subgroup analysis to measure the effects of lymphadenectomy on different FIGO stages and pathological types. However, our data were obtained in a retrospective manner, and the related data was missing. We were equally concerned about the side effects of treatment not appearing in the articles, which can be critical for patient outcomes. Although we attempted to contact the corresponding authors in order to obtain this data, we were unsuccessful. To our knowledge, this is the first article to determine whether supplementary lymphadenectomy can improve the prognosis of EC-AIA patients. It may provide some clinical guidance for the treatment of such patients in the future. The strength of this study is its uniqueness in evaluating the surgical treatment of EC-AIA patients. However, there are still some limitations. First, only a small number of samples, which can cause the wide CI, were primarily extracted from a case report or series. Second, this article is a retrospective study that still requires prospective studies for validation. Thus, more eligible studies should be included to validate our findings in the future. In conclusion, EC-AIA is a very rare disease and is prone to be misdiagnosed. Therefore, long term follow-up and identification of patients with adenomyosis should be enhanced. For patients who are unexpectedly diagnosed with EC-AIA following hysterectomy for benign tumors, we recommend a second surgery of supplementary lymphadenectomy, which may be a better option based on our findings.

Not commissioned, externally peer-reviewed.

The author declares no conflict of interest.