Does Endometriosis Impact the Prognosis of Endometrial Cancer?

JCOG 2019;29(3):88-93 88 ndometriosis ,whichispoorly understoodinapathophysiological sense,isa hormone -dependentinflammatory chronic gynecological disease.Itisdescribedasthepresenceof ectopicendometrial glands andstroma outside the uterinecavityandisassociatedwithpelvicpain,dys - m enorrhea,andinfertility. 1 Retrograde menstruation, menstrualtissueim - plantation ,and impairedimmune response are the most commonly observed conditions .Endometriosisisafairlycommon condition, prevalent in ~10% of the women ofreproductive age. An estimated176 million women areaffectedbythisdisease worldwide. 2 An increaseintheoverall cancerincidenceinpatientswithendometriosis hasbeen reportedbyvar - iousstudies. However,littleisknown abouttheeffectofendometriosison cancersurvival. 3 Most ofthepreviousinvestigations on theimpactofendometriosis on cancerhad focused on itsrelationto ovariancancer. Therefore,whilethe re - lationshipbetweenendometriosisandovariancancer iswellknown, itsas - DoesEndometriosisImpactthePrognosisof EndometrialCancer? AA BBSS TT RR AA CCTT OO bbjjeeccttiivvee:: Despite the well-known relationship between endometriosis and the risk and prognosis of ovarian cancer, studies on the association the two are rare. Moreover, the impact of endometriosis on the prognosis of endometrial cancer has not been described in the literature. In this study, we attempted to investigate whether endometriosis had an effect on the prognosis of endometrial cancer. MM aatteerriiaall aanndd MM eetthhooddss::This retrospective study was carried out on data from endometrial cancer patients between January 1996 and February 2016 at the Gynecological On - cology Department of Çukurova University Balcalı Hospital in Adana, Turkey. The pathological reports of 920 cases, operated after the diagnosis of endometrial cancer, were screened. Among these cases, 764 patients were found to be eligible for enrollment in this study. The patients were distributed into two groups based on the presence or absence of endometriosis in the pathological materials. The prognosis of the groups was compared using the Kaplan-Meier method. RR eessuullttss::The endometriosis group was associated with younger age, less parity, more infertility, and a higher risk of simultaneous ovarian cancer. There were non-significant differences between the groups re - garding pathological risk factors such as myometrial invasion, lymphovascular space involvement, lymph node positivity, and stage of progression. No recurrences or deaths were observed in the en - dometriosis group, although this observation was not statistically significant. CCoonncclluussiioonn:: It is sug - gested that endometriosis does not influence the prognosis of endometrial cancer. However, a conclusive assessment could not be made by this study alone and, therefore, further studies are needed and researchers are encouraged to focus more on this subject. KK eeyywwoorrddss:: Endometrial cancer; endometriosis; endometriosis-associated cancers Ghanim KHATIB a, İsa TEMUR b, Ümran KÜÇÜKGÖZ GÜLEÇ a, Ahmet Barış GÜZEL a, Mete SUCU a, Emine BAĞIR c, Derya GÜMÜRDÜLÜ c, Mehmet Ali VARDAR a aDepartment of Obstetrics and Gynecology, Çukurova University Faculty of Medicine, Adana, TURKEY bClinic of Obstetrics and Gynecology, Kahramanmaraş Necip Fazıl City Hospital, Kahramanmaraş, TURKEY cDepartment of Pathology, Division of Gynecologic Pathology, Çukurova University Faculty of Medicine, Adana, TURKEY Re ce i ved: 12 Jun 2019 Received in revised form: 20 Jul 2019 Ac cep ted: 22 Aug 2019 Available online : 22 Oct 2019 Cor res pon den ce: Ghanim KHATIB Çukurova University Faculty of Medicine, Department of Obstetrics and Gynecology, Adana, TURKEY [email protected] Cop yright © 2019 by Tür ki ye Kli nik le ri DOI: 10.5336/jcog.2019-70088 ORIGINAL RESEARCH sociation with other malignancies remains contro - versial. Recently, clear cell endometrioid and sero- m ucinous ovarian carcinomas were accepted as endometriosis-associated ovarian cancers (EAOC). The endometrioid subtype is known to be the m ost commonly associated histopathologic type with si - m ultaneous endometrial and ovarian cancers. Nearly 30% of the simultaneous cases were re - ported to harbor endometriosis. 4-6 Both en - dometriosis and endometrial cancer have the same origin; they have an identical molecular profile and etiological mechanisms such as chronic inflamma - tion and the estrogen effect. Therefore, it is possi - ble that endometriosis might affect the risk and prognosis of endometrial cancer. 4,7-9 Despite these facts, due attention has not been given to the endometriosis-endometrial cancer as - sociation. T o the best of our knowledge, no study in the literature has discussed the impact of en - dometriosis on the prognosis of endometrial can - cer. Hence, this paper investigates the possible impact of endometriosis on the prognosis of en - dometrial cancer. For this purpose, we retrospec - tively analyzed the cases of endometrial cancer over the last 20 years at our center. In addition, the subgroups for endometrioid and non-endometrioid endometrial cancer cases were compared . MAT ERIAL AND METH ODS T his study was carried out on patients of endome - trial cancer that were operated at the Gynecologi - cal Oncology Department of a Tertiary University H ospital between January 1996 and February 2016 . The study was conducted in accordance with the Helsinki Declaration. Ethical approval was not re - quired for this study because of its retrospective na - ture. Written informed consent was obtained from all the participants of the study. The electronic and archival records were retrospectively reviewed and 920 endometrial cancer patients that were operated at our clinic during this period were identified . Amon g them ,detailed pathology records of 764 cases were obtained and utilized for this study. T he demographic, clinicopathologic ,and fol - low-up data of the patients were recorded . All these cases were operated and pathologically eval - uated at the same center by expert gynecological pathologists. The major surgical procedures in - volved total hysterectomy with bilateral salpingo- oophorectomy (via laparotomy or laparoscopy) and pelvic-para-aortic lymphadenectom y (except those with low risk). Omentectomy was performed in the non-endometrioid histologies. FIGO 2009 gu ide - lines were used for staging. All the pathological re - ports of the operated cases were reviewed to identify the presence of endometriosis in the sur - gical specimens. The patients were then distributed into two groups based on the presence or absence of endometriosis in the pathological materials. Only the diagnosis of endometriosis that was proven using histopathology was taken into ac - count. The patients were followed up every three months for the first two years after the operation , every six months for the next three years , and an - nually thereafter . The period in months between the dates of histopathological diagnosis and recur - rence was considered as disease-free survival (DFS) , and from diagnosis to the date of death as the over - all survival (OS). The descriptive statistics used were mean ±standard deviation, median ,and minimum-maxi - mum values. Categorical data were analyzed using Chi-square or Fisher’s exact tests. Mann-W hitney U test was performed for analysis of the numerical data. Kaplan-Meier method was followed to test the effect of endometriosis on survival. The differ - ences between survival curves were evaluated using the log-rank test. The statistical software SPSS version 23.0 (IBM, Armonk, NY, USA) was used for all analyses . RESULT S During the study period, 92 0 endometrial cancer patients were operated at our clinic. Among them, the detailed pathological records of 764 cases were obtained and endometriosis was reported in 17 (2.2%) of them. The average and median age of all the patients was 57.2 ±10.5 years and 58 (27-91) years, respectively. Median parity of the patients was 3 (0-15). Mean ages of the endometriosis and non-endometriosis groups were 50.59±8.3 and 57.28 ±10.2, respectively. There was a significant G hanim KHA TIB et al. JCOG 2019;29(3):88-93 89 G hanim KHATIB et al. JCOG 2019;29(3):88-93 90 difference in the mean age of both groups (p=0.007). The Body Mass Indices (BMI) of both groups were similar (P=0.530). The clinicopatho - logical characteristics of the patients are demon - strated in Table 1 . Th e percentages of premenopausal patients in the endometriosis and non-endometriosis groups were 35.3% and 20.3% , respectively . The propor - tions of premenopausal patients were statistically similar (p=0.132). The percentage of infertility - linked cases in the endometriosis and non-en - dometriosis groups were 35.3% and 14.5%, respec - tively, showing a significant difference between groups (p=0.017). In the endometriosis group, there were three (17.6% ) cases of simultaneous ovarian cancer, whereas 35 (4.8%) cases were recorded in the non-endometriosis group. This difference was found to be statistically significant (p=0.018). Both the groups had similar rates of en - dometrioid (70.6% versus 76.5%) and non-en - Variable Endometriosis N (%) Non-endometriosis N (%) P Age Mean±SD 50.59±8.3 57.28±10.3 0.007 Body mass index Mean±SD 33.88±5.4 35.53±7.4 0.652 Parity Median (min.-max.) 1 (0-9) 3 (0-15) 0.002 Menopausal status Premenopause 6 (35.3) 151 (20.3) 0.132 Postmenopause 11 (64.7) 592 (79.7) Infertility No 11 (64.7) 632 (85.5) 0.017 Yes 6 (35.3) 107 (14.5) Synchronous ovarian tumor No 14 (82.4) 690 (95.2) 0.018 Yes 3 (17.6) 35 (4.8) Histology Endometrioid 12 (70.6) 566 (76.5) 0.571 Non-endometrioid 5 (29.4) 174 (23.5) Stage Stage 1-2 12 (70.6) 617 (84.2) 0.132 Stage 3-4 5 (29.4) 116 (15.8) Grade 1 10 (66.7) 345 (54.0) 0.375 2 3 (20.0) 238 (37.2) 3 2 (13.3) 56 (8.8) Myometrial invasion <50 12 (75.0) 485 (66.4) 0.473 ≥50 4 (25.0) 245 (33.6) Lymphovascular space invasion No 12 (70.6) 471 (63.9) 0.570 Yes 5 (29.4) 266 (36.1) Cytology Negative 3 (17.6) 117 (16.2) 0.809 Positive 0 (0.0) 17 (2.4) Wasn't taken 14 (82.4) 587 (81.4) Lymph node involvement Negative 14 (82.4) 658 (89.6) 0.333 Positive 3 (17.6) 76 (10.4) Omental metastasis No 3 (17.6) 184 (25.0) 0.303 Yes 2 (11.8) 32 (4.3) No omentectomy 12 (70.6) 521 (70.7) Adjuvant treatment No 9 (52.9) 436 (58.9) 0.621 Yes 8 (47.1) 304 (41.1) Recurrence No 17 (100) 726 (97.8) 0.541 Yes 0 (0.0) 16 (2.2) Life status Alive 17 (100) 579 (86.5) 0.105 Ex 0 (0.0) 90 (13.5) TABLE 1: Demographic and clinical characteristics of patients. dometrioid (29.4% versus 23.5%) histology (p=0.571). The tumor was confined to the uterus (stage 1-2 ) in 70.6% and 84.2% of the endometrio - sis and non-endometriosis groups ,respectively, and the difference was not statistically significant . The distribution of tumor grade between the groups was also not significant (p=0.375). Myometrial in - vasion of ≥50% was observed in 25% of the en - dometriosis and 33.6% of the non-endometriosis group, which was not significantly different (p=0.473). Lymphovascular space invasion (LVS I) was reported in 29.4% and 36.1% of the en - dometriosis and non-endometriosis groups, respec - tively (p=0.570). The occurrence of positive cytology between groups (0% versus 2.4%) was sta - tistically similar . Lymph node (LN) involvement was reported in 17.6% of the endometriosis and 10.4% of the non-endometriosis groups, and these rates were not significantly different. Omental metastases were observed in 11.8% and 4.3% of the endometriosis and non-endometriosis groups , re - spectively, which were not significantly different (p=0.303). Statistically similar rates of adjuvant treatments were applied to both the groups (47.1% versus 41.1%). No recurrence in the endometriosis group and 2.2% recurrence in the non-en - dometriosis group were recorded, but this differ - ence was statistically nonsignificant. While 13.5% of the non-endometriosis group patients died, no death was reported among those in the en - dometriosis group. However, this observation was not statistically significant (p=0.105). T he average follow-up period of the cohort was 51 months. T he mean survival period for all the endometrial cancer cases was 191.2 ±10.5 months (95% CI= 17 0.7-211.8). No deaths were ob - served in the endometriosis group during the fol - low-up period. The 5-year and 10-year survival rates in the non-endometriosis group were 86% and 74% ,respectively. The period and rate of sur - vival between endometriosis and non-endometrio - sis groups were not statistically significant (p=0.171) (Figure 1 ). T he survival rates of the endometrioid and non-endometrioid endometrial cancer subgroups were also compared and were found to be statisti - cally similar . Th e p-values for the endometrioid and non-endometrioid subgroups were 0.315 and 0.341, respectively . DIS CUSSION Despite the association of endometriosis with ovar - ian cancer being widely investigated, that with en - dometrial cancer has been rarely studied and with conflicting results. 4,10,11 While some studies have re - ported an increased risk of endometrial cancer as - sociated with endometriosis, others have reported contradictory findings .4,7,10-18 Moreover, two studies reported a non-significant decrease, while one study reported a significant decrease in the risk of endometrial cancer associated with endometrio - sis .18-20 Th ree large case -control studies from Taiwan (n=15,488) , A ustralia (n=1 ,399), and Denmark (n=1 ,398) reported an increased risk of endometrial cancer in the cases of endometriosis. 4,14,15 How ever, this risk reflected a higher chance of detecting en - dometrial cancer among women with endometrio - sis more than the actual risk.s reported in a recent, large-volume prospective cohort (n=97,109) from the USA. 7 Kok et al . published a population-based study on the relation between endometriosis and the risk of developing several cancers ,including endome - trial cancer. 21 They observed a significantly increased risk of endometrial cancer among women G hanim KHA TIB et al. JCOG 2019;29(3):88-93 9 1 FIGURE 1: S urvival curves of the groups. with endometriosis and/or adenomyosis. However, it was evident that histopathology was not the main diagnostic tool in this study, especially in the adenomyosis patients, thus making the starting point of the study and its results questionable. Munksgaard and Blaakaer reviewed seven population-based cohorts that investigated the as - sociation between the risk of endometrial cancer and endometriosis and reported that no clear asso - ciation was observed in these studies. 13 Although some studies did point to a possible association, they concluded that the relatively small sample sizes precluded any definitive interpretation about the possible association. Our study was different in its nature and de - sign from the above-mentioned studies. The cases of endometrial cancer that were operated at our center were retrospectively reviewed , and those with histopathological diagnosis of endometriosis (17 patients) were compared with the non-en - dometriosis patients . T o the best of our knowledge, no previous studies in the literature had focused on the association between endometriosis and en - dometrial cancer prognosis. It was observed that the patients in the endometriosis group were sig - nificantly younger than the non-endometriosis pa - tients. The median value of parity in the endometriosis group was lesser, possibly due to the close relationship between endometriosis and in - fertility. About 75% of the cases in each group showed endometrioid histology. The tumor histology of both groups was similar . The patients in the en - dometriosis group demonstrated a higher but sta - tistically insignificant extra-uterine spread of the tumor (stage 3 -4, 29.4% versus 14.8%). In addition, the tumor grade distribution was similar in both groups (p=0.375) . Frequencies of myometrial inva - sion of at least 50% and LVSI were observed to be lesser by 8.6% and 6.7% in the endometriosis group, although this difference was not statistically significant . LN involvement was higher by 7.3% in the endometriosis group than the non-en - dometriosis group, although this difference was sta - tistically nonsignificant . It is possible that the higher LN positivity and the occurrence of extra- uterine disease in the endometriosis group make the adjuvant treatments more suitable for this group (47.1% versus 41.1%). Despite these nega - tive factors, no recurrences or deaths were ob - served in the endometriosis patients , when compared to the 2.2% rate of recurrence and 13.5% rate of death in the non-endometriosis group. Nev - ertheless, the rates of recurrence or survival status were not significantly different between the groups. The average follow-up period of the cohort was 51 months. The mean survival period for all the cases of endometrial cancer was 191.2 ±10.5 months (170.7 -2 11.8; 95% CI). As no deaths were observed in the endometriosis group during the fol - low-up period, survival rates could not be calcu - lated for this group. On the other hand , 5-year and 10 -year survival rates in the non-endometriosis group were 86% and 74%, respectively. However, survival in both groups was statistically similar (p=0.171). In addition, when a subgroup analysis was made for the endometrioid and non-en - dometrioid endometrial cancer histology, no sig - nificant difference in survival was observed between the endometriosis and non-endometriosis patients. As expected, the endometriosis group showed a significant association with infertility and syn - chronous ovarian cancer. Both these conditions were significantly higher in the endometriosis group compared to the non-endometriosis group . The strengths of this study were the fairly large number of endometrial cancer cases , as well as the length of the study period at the same cen - ter with the same surgical procedures and pathol - ogy team . These factors increased the consistency and reliability of the results of this study. However, the retrospective nature of this study and the rela - tively small size of the endometriosis group were the main weaknesses of this study. CONCLU SION In this study, it was observed that the prognosis of endometrial cancer patients was neither positively nor negatively affected by endometriosis. How - G hanim KHATIB et al. JCOG 2019;29(3):88-93 92 G hanim KHA TIB et al. JCOG 2019;29(3):88-93 9 3 ever, the relatively small sample size in the en - dometriosis group precludes making any definitive conclusions. Therefore, further studies should be encouraged in this field. SSoouurrccee ooff FFiinnaannccee During this study, no financial or spiritual support was received neither from any pharmaceutical company that has a direct connection with the research subject, nor from a company that provides or produces medical instruments and materials which may negatively affect the evaluation process of this study. CCoonnfflliicctt ooff IInntteerreesstt No conflicts of interest between the authors and / or family members of the scientific and medical committee members or members of the potential conflicts of interest, counseling, ex - pertise, working conditions, share holding and similar situa - tions in any firm. AA uutthhoorrsshhiipp CCoonnttrriibbuuttiioonnss IIddeeaa//CCoonncceepptt:: Ghanim Khatib, Derya Gümürdülü, Mehmet Ali Vardar; DDeessiiggnn:: G hanim Khatib, Ümran Küçükgöz Güleç; CCoonn-- ttrrooll//SSuuppeerrvviissiioonn:: M ehmet Ali Vardar, Ahmet Barış Güzel; DDaattaa CCoolllleeccttiioonn aanndd//oorr PP rroocceessssiinngg:: Ghanim Khatib, İsa Temur, Mete Sucu, Emine Bağır; AA nnaallyyssiiss aanndd//oorr IInntteerrpprreettaattiioonn:: Ghanim Khatib, Emine Bağır, Ümran Küçükgöz Güleç; LLiitteerraattuurree RR ee-- vviieeww:: Ghanim Khatib, İsa Temur; WW rriittiinngg tthhee AA rrttiiccllee:: Ghanim Khatib; CCrriittiiccaall RR eevviieeww:: Üm ran Küçükgöz Güleç, Ahmet Barış Güzel, Mehmet Ali Vardar; RR eeffeerreenncceess aanndd FFuunnddiinnggss:: Ghanim Khatib, İsa Temur, Mete Sucu, Emine Bağır. 1. Hickey M, Ballard K, Farquhar C. En - dometriosis. BMJ. 2014;348:g1752. [Crossref] [PubMed] 2. Interinstitutional group of Mexican postgradu - ate students. 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