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Effect of coexisting adenomyosis on patients with endometrioid adenocarcinoma: Determination of intraoperative risk factors for tumor metastasis and estimation of prognosis


1 Department of Obstetrics and Gynecology, Gynecologic Oncology Surgery, Izmir Katip Celebi University, Ataturk Training and Research Hospital, İzmir, Turkey
2 Department of Obstetrics and Gynecology, Izmir Katip Celebi University, Ataturk Training and Research Hospital, İzmir, Turkey

Date of Submission31-Aug-2020
Date of Decision09-Oct-2020
Date of Acceptance01-Jan-2021
Date of Web Publication24-Jul-2021

Correspondence Address:
Aysegul Gulbahar,
Department of Obstetrics and Gynecology, Izmir Katip Celebi University, Ataturk Training and Research Hospital, İzmir
Turkey
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_1277_20

 > Abstract 


Context: We sought to clarify the impact of adenomyosis on the clinical and pathological prognosis of endometrial cancer to aid the selection of appropriate surgical intervention based on the diagnosis of adenomyosis.
Aims: Our study aimed to report the frequency of adenomyosis in patients with endometrioid cancer and correlate its incidence rate with the survival and prognostic factors.
Materials and Methods: This retrospective study included 357 patients. Patients with endometrioid adenocarcinoma were divided into two groups based on the presence of adenomyosis. The groups were compared in terms of tumor diameter, lymphovascular space invasion (LVSI), low-high risk pathologic status, stage of the disease, and survival outcome.
Statistical Analysis Used: Continuous variables were analyzed using the Student's t or Mann–Whitney U-test. Survival data were analyzed using the Kaplan–Meier test.
Results: The average age was similar between the two groups. In total, 47 (13.2%) of 357 patients had adenomyosis. A total of 43 (91.4%) cases with adenomyosis and 258 (83.2%) cases without adenomyosis had Stage I endometrioid adenocarcinoma (n = 301, 84.3%). Moreover, 32 (68.1%) cases with adenomyosis and 187 (60.3%) cases without adenomyosis were in the low-risk group. There was no statistically significant correlation between the risk groups (P = 0.309) and overall survival between the two groups (P = 0.416).
Conclusion: No correlation was seen between the characteristics of endometrioid type endometrial cancer and survival rates in patients with or without adenomyosis. The impact of adenomyosis as a factor in evaluating the perioperative prognosis and planning postoperative adjuvant therapy for endometrial cancer should be assessed by further studies.

Keywords: Adenomyosis, endometrial cancer, neoplasm, tumor staging



How to cite this URL:
Yilmaz A, Cokmez H, Gulbahar A. Effect of coexisting adenomyosis on patients with endometrioid adenocarcinoma: Determination of intraoperative risk factors for tumor metastasis and estimation of prognosis. J Can Res Ther [Epub ahead of print] [cited 2021 Nov 29]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=322270




 > Introduction Top


Adenomyosis is a common gynecological disease and is characterized by the presence of ectopic endometrial glands and stroma located within the myometrium.[1] Endometrial cancer is the most common female genital tract malignancy in many developed countries.[2] It has a considerable disease burden in many countries worldwide, with a higher incidence in Northern America and Europe than the rest of the world.[3] Adenomyosis often coincides with endometrial cancer.[4],[5] Similar to the effect of unopposed estrogen on Type 1 endometrial cancers, a local hyperestrogenic effect contributes to the development of adenomyosis, as seen in the formation of endometrial hyperplasia and leiomyoma.[6] Many studies have correlated adenomyosis with tumor progression in endometrial cancer.[1],[4],[5] In the present study, we sought to clarify the impact of adenomyosis on the clinical and pathological prognosis of endometrial cancer to potentially use the presence or absence of adenomyosis to guide surgical decision making. Our study aimed to report the frequency of adenomyosis in patients with endometrioid cancer. Furthermore, we aimed to assess the correlation between the incidence of adenomyosis and factors indicative of the survival and prognosis in endometrioid cancer, including tumor size, grade, lymphovascular space invasion (LVSI), risk factors for lymph node involvement, and surgical stage.


 > Materials and Methods Top


The present study included 357 patients who underwent hysterectomy for endometrioid type endometrial cancer between January 2008 and December 2018 at our institute. Epidemiological, clinical, and pathological data were retrieved from the pathological records of the patient. Patients with concomitant malignancy, nonendometrioid type or mixed type (≥10 nonendometrioid component) endometrium cancer and hormone replacement, raloxifene, and levothyroxine treatment history were excluded from the study. Furthermore, patients whose follow-up performed at other hospitals were excluded from the study. Endometrioid type adenocarcinomas were included retrospectively. Patients with endometrioid adenocarcinoma were divided into two groups according to the presence of adenomyosis. The groups were compared in terms of tumor diameter, LVSI, pathologic risk groups, disease stage, and survival outcome. Low-risk groups met the following criteria: Tumors <2 cm in diameter and endometrioid adenocarcinoma grade 1–2 with tumor invasion less than half of the myometrium. High-risk groups had tumors with Grade 3 histopathology or tumor invading more than half of the myometrium, irrespective of grade. The correlation between adenomyosis and tumor markers, such as CA125 and CA19-9, was also evaluated. The study was approved by the Institutional Review Board (No.: 223/Date: June 20, 2018). Written consent was waived due to the retrospective nature of the study. The study was performed in accordance with the principles outlined in the declaration of Helsinki of 1964.

Statistical analysis

The data were analyzed using the SPSS software version 20.0 (Armonk, NY, USA: IBM Corp.). Continuous variables were tested for normality using the Kolmogorov–Smirnov test. Normally distributed data were expressed as mean ± standard deviation and analyzed using Student's t-test. Nonnormally distributed data were expressed as median (range) and analyzed using the Mann–Whitney U-test. The effect of adenomyosis on the patient survival was investigated using the log-rank test. The Kaplan–Meier survival estimates were calculated. Categorical data were presented as counts and percentages, and categorical variables were analyzed by the Pearson's Chi-square test or Fisher's exact test. P < 0.05 was considered statistically significant.


 > Results Top


Age

There was no statistically significant inter-group difference in mean age. The mean age of patients with endometrioid adenocarcinoma with or without adenomyosis was 59.3 ± 9.1 and 60.1 ± 9.9 years, respectively.

Frequency

Out of 357 patients, 47 (13.2%, 95% confidence interval, β = 13.34%) had adenomyosis, whereas 310 (86.8%, 95% confidence interval, β = 2.02%) did not.

Both groups were investigated in terms of tumor size, grade, LVSI, risk group, stage, and tumor marker [Table 1].
Table 1: Correlation of endometrioid adenocarcinoma characteristics in patients with or without adenomyosis

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Tumor size

We found no correlation between adenomyosis and other prognostic factors such as tumor size, grade, and LVSI. A total of 28/47 (59.7%) patients with adenomyosis and 177/310 (57.1%) patients without adenomyosis had a tumor diameter >2 cm (P = 0.749).

Grade

The incidence of adenomyosis did not correlate with tumor grade. Grade 1 tumors were seen in 32/47 (68.1%) patients with adenomyosis and in 179/310 (57.7%) patients without adenomyosis (P = 0.179).

Lymphovascular space invasion

A total of 301/357 (84.3%) patients had Stage I disease; however, only 211/301 (70.1%) had records concerning LVSI. Adenomyosis did not significantly affect LVSI. LVSI was present in 4/35 (11.4%) patients with Stage I endometrioid adenocarcinoma coincident with adenomyosis and in 17/176 (9.7%) patients without adenomyosis (P = 0.758).

Risk factors for lymph nodal spread

The incidence of adenomyosis did not correlate with the risk factors of lymph nodal spread. A total of 32/47 (68.1%) cases with adenomyosis and 187/310 (60.3%) cases without adenomyosis were in the low-risk group (tumor diameter ≤2 cm, myometrial invasion <50%, Grade 1-2). There was no significant correlation between the risk groups (P = 0.309).

Surgical stage

The presence of adenomyosis and surgical stage were not statistically correlated. A total of 43/47 (91.4%) cases with adenomyosis and 258/310 (83.2%) of the cases without adenomyosis had Stage I endometrioid adenocarcinoma (P = 0.147) (n = 301/357, 84.3%).

CA125 and CA19-9 serum levels

A total of 211 (50.1%) and 179 (59.1%) patients had preoperative CA125 and CA19-9 levels, respectively. No significant difference in the levels of tumor markers was detected between the groups. The mean serum levels of CA125 for patients with and without adenomyosis were 30.2 versus 29.4, respectively (P = 0.919). The mean serum levels of CA19-9 for patients with and without adenomyosis were 23.4 and 42.8, respectively (P = 0.394).

Survival

We were able to access the survival data for 319/357 (89.3%) patients. Mean follow-up time was 115 ± 2.8 months (110–120.9). A total of 31/278 patients without adenomyosis (11.2%, 95% confidence interval = 0.0797-0.1539, β = 2.11%) and 3/41 of patients with adenomyosis (7.3%, 95% confidence interval = 0.0252–0.1943, β = 14.31%) did not survive. There was no difference in the overall survival between the two groups (P = 0.416). [Figure 1] shows the overall survival rates of both groups by time.
Figure 1: A comparison of survival between endometrial cancer patients with and without adenomyosis

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 > Discussion Top


Adenomyosis is frequently coincident with endometrial cancer, due to its higher frequency and estrogenic effect. The ratio of adenomyosis in patients with endometrial cancer ranges between 10% and 70%.[7] In our study, adenomyosis was present in 47 of 357 patients (13.2%). Adenomyosis is linked to the increased incidence and severity of endometrial cancer.[8] Recent reports regarding the coincidence of endometrial cancer with adenomyosis showed that the presence of adenomyosis improves the prognosis.[9] The inflammatory response around the adenomyotic focus forms a barrier to tumor invasion. Therefore, the presence of adenomyosis may be an important predictor of better clinical outcomes.[9] Endometrial patients who also present with adenomyosis have been reported to have younger ages at the cancer diagnosis and higher incidence of cancer in the premenopausal period.[1] In this study, there was no difference between the two groups; patients with endometrioid cancer with and without coincident adenomyosis had mean ages of 59.3 ± 9.1 years and 60.1 ± 9.9 years, respectively. The lower grade tumors, less myometrial invasion, negative LVSI, and less lymph node metastasis seen in the presence of adenomyosis are reportedly likely due to the association of adenomyosis with hormone-responsive and well-differentiated endometrioid adenocarcinomas that are often diagnosed at earlier stages.[10] In our study, the presence of adenomyosis was associated with a lower grade, less myometrial invasion, negative LVSI, and lymph node involvement. When the grade of tumor and the depth of invasion were not considered, adenomyosis was associated with increased survival, suggesting that the presence of adenomyosis was associated with a lower risk of lymph node metastasis in patients with LVSI. This may be because the adenomyosis prevents access to the lymphovascular space in low-grade tumors or reduces the potential for metastasis.[11] In this study, we found no difference between LVSI and tumor grades between the two groups.

The occurrence and the prognostic role of adenomyosis in endometrioid adenocarcinoma are associated with lower International Federation of Gynecology and Obstetrics stages, myometrial invasion, lymphovascular space, lymph node involvement, and tumor size.[12] Uterine adenomyosis is associated with deep myometrial invasion in Stage I endometrioid adenocarcinoma, but this does not affect recurrence or mortality rates.[13] A cohort study of patients with Stage I–IV endometrial cancer and endometrial hyperplasia confirmed that the presence of adenomyosis was significantly associated with Grade 1-2 tumors, earlier stage disease, and a lower likelihood of deep myometrial or cervical invasion.[14] In the present study, the incidence of adenomyosis had no effect on the stage of endometrioid adenocarcinoma. Moreover, previously identified risk factors of lymph node spread were not statistically different between the two groups. Boonlak et al. found that the presence of uterine adenomyosis in context of endometrial cancer was associated with deep myometrial invasion and LVSI but did not have a significant impact on survival.[15] In our study, the incidence of uterine adenomyosis incidence was not associated with stage, LVSI, or overall survival. Moreover, there was no correlation between adenomyosis and the level of tumor markers CA125 and CA19-9.

The present study has limitations due to its retrospective nature. We attempted to conduct a reliable study by using a large sample size (99% power, α = 0.05, effect size = 1.47%). Nevertheless, future studies are warranted to confirm the findings reported in this study. Intraoperative evaluation of adenomyotic lesions with endometrial cancer in multi-center prospective studies may clarify the pathological progression of adenomyosis with endometrial cancer and guide the selection of the most appropriate surgical treatment.


 > Conclusion Top


Our study revealed that there is no statistically significant association between the characteristics of endometrioid type endometrial cancer and survival in patients with or without adenomyosis. Several factors related to and independent of tumor stage aid the decision to administer adjuvant therapies in patients with endometrial cancer. The impact of the coincidence of adenomyosis and endometrial cancer in perioperatively assessing prognosis and planning postoperative adjuvant therapy should be evaluated by further studies.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

1.
Kucera E, Hejda V, Dankovcik R, Valha P, Dudas M, Feyereisl J. Malignant changes in adenomyosis in patients with endometrioid adenocarcinoma. Eur J Gynaecol Oncol 2011;32:182-4.  Back to cited text no. 1
    
2.
Birmann BM, Barnard ME, Bertrand KA, Bao Y, Crous-Bou M, Wolpin BM, et al. Nurses' health study contributions on the epidemiology of less common cancers: Endometrial, ovarian, pancreatic, and hematologic. Am J Public Health 2016;106:1608-15.  Back to cited text no. 2
    
3.
Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015;136:E359-86.  Back to cited text no. 3
    
4.
Frankl O. Adenomyosis uteri. Am J Obstet Gynecol 1925;10:680-4.  Back to cited text no. 4
    
5.
Hever A, Roth RB, Hevezi PA, Lee J, Willhite D, White EC, et al. Molecular characterization of human adenomyosis. Mol Hum Reprod 2006;12:737-48.  Back to cited text no. 5
    
6.
Benagiano G, Habiba M, Brosens I. The pathophysiology of uterine adenomyosis: An update. Fertil Steril 2012;98:572-9.  Back to cited text no. 6
    
7.
Heo SH, Lee KH, Kim JW, Jeong YY. Unusual manifestation of endometrioid adenocarcinoma arising from subserosal cystic adenomyosis of the uterus: Emphasis on MRI and positron emission tomography CT findings. Br J Radiol 2011;84:e210-2.  Back to cited text no. 7
    
8.
Giammalvo JT, Kaplan K. The incidence of endometriosis interna in 120 cases of carcinoma of the endometrium. Am J Obstet Gynecol 1958;75:161-6.  Back to cited text no. 8
    
9.
Tetikkurt S, Çelik E, Taş H, Cay T, Işik S, Usta AT. Coexistence of adenomyosis, adenocarcinoma, endometrial and myometrial lesions in resected uterine specimens. Mol Clin Oncol 2018;9:231-7.  Back to cited text no. 9
    
10.
Mittal KR, Barwick KW. Endometrial adenocarcinoma involving adenomyosis without true myometrial invasion is characterized by frequent preceding estrogen therapy, low histologic grades, and excellent prognosis. Gynecol Oncol 1993;49:197-201.  Back to cited text no. 10
    
11.
Musa F, Frey MK, Im HB, Chekmareva M, Ellenson LH, Holcomb K. Does the presence of adenomyosis and lympho-vascular space invasion affect lymphnode status in patients with endometrioid adenocarcinoma of the endo-metrium? Am J Obstet Gynecol 2012;207:e1-6.  Back to cited text no. 11
    
12.
Gizzo S, Patrelli TS, Dall'asta A, DI Gangi S, Giordano G, Migliavacca C, et al. Coexistence of adenomyosis and endometrioid endometrial cancer: Role in surgical guidance and prognosis estimation. Oncol Lett 2016;11:1213-9.  Back to cited text no. 12
    
13.
Taneichi A, Fujiwara H, Takahashi Y, Takei Y, Machida S, Saga Y, et al. Influences of uterine adenomyosis on muscle invasion and prognosis of endometrioid adenocarcinoma. Int J Gynecol Cancer 2014;24:1429-33.  Back to cited text no. 13
    
14.
Matsuo K, Cahoon SS, Gualtieri M, Scannell CA, Jung CE, Takano T, et al. Significance of adenomyosis on tumor progression and survival outcome of endometrial cancer. Ann Surg Oncol 2014;21:4246-55.  Back to cited text no. 14
    
15.
Sarana B, Apiwat A, Chumnan K, Pilaiwan K, Bandit C, Sanguanchoke L, et al. Impact of coexisting uterine adenomyosis on the survival outcome of patients with endometrial cancer: A retrospective cohort study. Asian Pac J Cancer Prev 2019;20:1185-90.  Back to cited text no. 15
    


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