{"paper_id":"8eaa8bc0-2501-4117-9289-d529818cf43e","body_text":"Diagnostic Benefit of the Detection of Mitotic Figures\nin Endometriotic Lesions\nDiagnostischer Vorteil des Nachweises von Mitosefiguren\nin endometriotischen Läsionen\nAuthors\nMichelle Wetzk 1, Nannette Grübling 1, Almuth Forberger 2,J ö r gK l e n g e l1, Jan Dominik Kuhlmann 1, Pauline Wimberger 1,\nMaren Goeckenjan 1\nAffiliations\n1 Department of Obstetrics and Gynecology, Technische\nUniversität Dresden, Dresden, Germany\n2 Institute for Pathology, Technische Universität Dresden,\nDresden, Germany\nKey words\nendometriosis, mitotic rate, infertility, laparoscopy,\nendometriosis ‑associated ovarian cancer\nSchlüsselwörter\nEndometriose, Mitoserate, Infertilität, Laparoskopie,\nendometrioseassoziiertes Ovarialkarzinom\nreceived 22. 4. 2021\naccepted after revision 5. 8. 2021\nBibliography\nGeburtsh Frauenheilk 2022; 82: 85 –92\nDOI 10.1055/a-1580-0601\nISSN 0016‑5751\n© 2022. The Author(s).\nThis is an open access article published by Thieme under the terms of the Creative\nCommons Attribution-NonDerivative-NonCommercial-License, permitting copying\nand reproduction so long as the original work is given appropriate credit. Contents\nmay not be used for commercial purposes, or adapted, remixed, transformed or\nbuilt upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)\nGeorg Thieme Verlag KG, Rüdigerstraße 14,\n70469 Stuttgart, Germany\nCorrespondence\nMaren Goeckenjan M. D.\nDepartment of Obstetrics and Gynecology,\nTechnische Universität Dresden\nFetscherstraße 74, 01307 Dresden, Germany\nmaren.goeckenjan@uniklinikum-dresden.de\nABSTRACT\nObjectives Endometriosis is a chronic disease which is diag-\nnosed by surgical intervention combined with a histological\nwork-up. Current international and national recommenda-\ntions do not require the histological determination of the pro-\nliferation rate. The diagnostic and clinical importance of the\nmitotic rate in endometriotic lesions still remains to be eluci-\ndated.\nMethods In this retrospective study, the mitotic rates and\nclinical data of 542 patients with histologically diagnosed\nendometriosis were analyzed. The mean patient age was\n33.5 ± 8.0 (17 –72) years, and the mean reproductive lifespan\nwas 21.2 ± 7.8 (4 –41) years. Patients were divided into two\ngroups and patients ʼ reproductive history and clinical endo-\nmetriosis characteristics were compared between groups.\nThe study group consisted of women with confirmed mitotic\nfigures (n = 140, 25.83 %) and the control group comprised\nwomen without proliferative activity according to their mi-\ntotic rates (n = 402, 74.27 %).\nResults Women with endometriotic lesions and histologically\nconfirmed mitotic figures were significantly more likely to\nhave a higher endometriosis stage (p = 0.001), deep infiltrat-\ning endometriosis (p < 0.001), ovarian endometrioma\n(p = 0.012), and infertility (p = 0.049). A mitotic rate > 0 was\nseen significantly less often in cases with incidental findings\nof endometriosis (p = 0.031). The presence of symptoms and\nbasic characteristics such as age, age at onset of menarche,\nreproductive lifespan and parity did not differ between the\ngroup with and the group without mitotic figures.\nConclusion This study shows that a simple histological as-\nsessment of the mitotic rate offers additional diagnostic value\nfor the detection of advanced stages of endometriosis. The\npossible role as a predictive marker for the recurrence of en-\ndometriosis or the development of endometriosis-associated\ncancer will require future study.\nGebFra Science | Original Article\n85Wetzk M et al. Diagnostic Benefit of … Geburtsh Frauenheilk 2022; 82: 85 –92 | © 2022. The author(s).\nArticle published online: 2022-01-10\n\nIntroduction\nEndometriosis is a common gynecological disease which is typi-\ncally diagnosed by a histological examination after laparoscopy.\nAround 10 % of women aged 15 –50 years suffer from dysmenor-\nrhea, dyspareunia, abdominal and pelvic pain as well as infertility\nand are diagnosed with endometriosis [1]. The presentation of\nsymptoms in women with endometriosis is suggestive for the lo-\ncation of the endometriotic lesions and the clinical stage [2], but\nup to now, the definitive diagnosis of endometriosis needs sur-\ngery. Serum markers for endometriosis are being investigated\nbut have not yet been clinically established [3, 4].\nInternational and national guidelines recommend a histologi-\ncal assessment after surgical procedures to make a diagnosis of\nendometriosis [5, 6]. An initiative to evaluate the quality of care\nin endometriosis centers in German-speaking countries in Europe\nwas recently published [7]. It reported that all certified endome-\ntriosis centers took biopsies to confirm endometriosis histologi-\ncally.\nNevertheless, the current guidelines give no clear statements\nabout the specific procedures for the histological assessment [5,\n6]. Standardized quality indicators for diagnosis and therapy have\nnot been implemented to date [7].\nMitotic figures as a marker of cell proliferation in endometriotic\nlesions were initially described by Nisolle and Donnez [8, 9]. The\ndetection of mitotic figures and determination of the mitotic rate\nper 10 high-power fields after staining with hematoxylin and eo-\nsin is an established marker of cellular proliferation in oncology\n[6]. The disadvantages of counting mitotic figures are the high in-\nter- and intra-observer variation rates and limited reproducibility\n[10, 11]. Another marker of cell proliferation proposed for the di-\nagnosis of endometriosis is Ki-67 [12].\nUsing the mitotic rate as an additional histopathological as-\nsessment of cellular proliferation is an established, cost-efficient\nprocedure and part of the routine histological examination. It is\nroutinely used not only in oncology but also for the histological\ndiagnosis of endometriosis.\nAtypical ovarian endometriosis is known to be especially asso-\nciated with an increased risk of malignancy [13]. Currently, molec-\nular mechanisms and biomarkers are being carefully investigated\nin women with endometriosis to find a diagnostic algorithm for\nthe prediction and possibly prevention or treatment of women\nwith an increased risk of endometriosis-associated malignancies\n[14]. Histological parameters of cell proliferation may have an ad-\nditional diagnostic value when assessing the severity of endome-\ntriosis but could also serve as predictive markers for the develop-\nment of malignant epithelial tumors.\nZUSAMMENFASSUNG\nZiele Endometriose ist eine chronische Erkrankung, die durch\neinen chirurgischen Eingriff und einen histologischen Nach-\nweis diagnostiziert wird. Laut den aktuellen internationalen\nund nationalen Empfehlungen ist der histologische Nachweis\nder Proliferationsrate nicht nötig. Die diagnostische und kli-\nnische Bedeutung der Mitoserate in endometriotischen Läsio-\nnen ist immer noch ungeklärt.\nMethoden In dieser retrospektiven Studie wurden die Mito-\nseraten und die klinischen Daten von 542 Patientinnen mit\nhistologisch nachgewiesener Endometriose analysiert. Das\ndurchschnittliche Alter der Patientinnen betrug 33,5 ± 8,0\n(17–72) Jahre, und ihre durchschnittliche Reproduktions-\nspanne lag bei 21,2 ± 7,8 (4 –41) Jahren. Die Reproduktions-\ngeschichte und klinischen Endometriosemerkmale wurden\nverglichen. Die Studiengruppe bestand aus Frauen, bei denen\nMitosefiguren nachgewiesen wurden (n = 140, 25,83 %), und\ndie Kontrollgruppe bestand aus Frauen ohne Proliferations-\naktivität (n = 402, 74,27 %).\nErgebnisse Frauen mit endometriotischen Läsionen und\neinem histologischen Nachweis von Mitosefiguren hatten sig-\nnifikant häufiger ein klinisch höheres Endometriosestadium\n(p = 0,001), tief infiltrierende Endometriose (p < 0,001), ova-\nrielle Endometriome (p = 0,012) oder Infertilität (p = 0,049).\nFrauen, bei denen eine Endometriose als Zufallsbefund ent-\ndeckt wurde, hatten signifikant weniger oft eine Mitoserate\nvon > 0 (p = 0,031). Es gab keine Unterschiede in den Sympto-\nmen und Charakteristika wie Alter, Menarche, Reproduktions-\nspanne und Parität zwischen der Gruppe mit und der Gruppe\nohne Mitosefiguren.\nSchlussfolgerung Diese Studie zeigt, dass eine einfache his-\ntologische Evaluierung der Mitoserate für die Erkennung einer\nEndometriose im fortgeschrittenen Stadium einen diagnosti-\nschen Mehrwert bietet. Um die Bedeutung der Mitoserate als\nprädiktiven Marker für das Wiederauftreten einer Endo-\nmetriose bzw. für die Entwicklung von endometrioseassoziier-\ntem Krebs zu evaluieren, werden weitere Untersuchungen be-\nnötigt.\nn = 812\nPatients with a diagnosis of endometriosis (ICD N80.0–N80.9)\nat a certified university endometriosis center\n(study period: 01/01/2013–31/12/2016)\nn=5 1\nRepeat surgical treatmentn=1 0\nMissing surgical data n = 180\nMissing clinical datan=1 6\nMissing mitotic index n=1 3\nEndometriosis not\nhistologically confirmed\nn = 542\nPatients with histologically confirmed endometriosis\nand mitotic index (66.75%)\n▶ Fig. 1 Flowchart showing the inclusion into the retrospective\nstudy of patients treated for endometriosis at a university center.\n86 Wetzk M et al. Diagnostic Benefit of … Geburtsh Frauenheilk 2022; 82: 85 –92 | © 2022. The author(s).\nGebFra Science | Original Article\n\n\nThis study aimed to assess the diagnostic impact of detected\nmitotic figures as a marker of proliferation in endometriotic le-\nsions in a retrospective study carried out at a tertiary university\nendometriosis center.\nMaterial and Methods\nA total of 812 patients with a diagnosis of endometriosis were\ntreated at the Department of Gynecology and Obstetrics in a ter-\ntiary university center during the study period from 2013 to 2016.\nThe patients ʼ clinical data were analyzed after ethical approval of\nthe study protocol (by the local Ethics Committee of TU Dresden,\nEK 189062018) and the consent of study participants treated in\nthe University Endometriosis Center was obtained.\nPatient characteristics\nAfter patients without biopsies showing endometriosis and a his-\ntological assessment which included a mitotic figure count in\nstandardized HPF areas after H & E staining were excluded, a total\nof 542 patients remained and were included in this study. No ad-\nditional staining to evaluate cellular proliferation, e.g., using\nKi‑67, was performed. Each patient was only included once in the\nstudy even if they underwent repeat surgical treatment in the\nsame hospital. The inclusion chart of the study is shown in\n▶ Fig. 1.\nMeasurements\nThe following parameters were assessed: diagnosis based on the\ninternational classification of diseases, symptoms, medical history\nincluding medication, previous pregnancies, abortions and births,\norgan manifestations, endometriosis stage based on the rASRM\nscore (revised score of the American Society of Reproductive\nMedicine) [15], histology, surgical intervention and recom-\nmended endocrine treatment. The ENZIAN classification was used\nfor deep infiltrating endometriosis [16]. As not all lesions were\ndocumented photographically, further classification of each en-\ndometriotic lesion into typical or atypical as proposed by Nisolle\net al. [17] could not be performed systematically in the setting of\na retrospective study.\nThe mitotic figure count was determined after H & E staining\nand performed as a standardized procedure used for histological\nassessment in oncology. The method was described by Barry et\nal. in 2001 [11].\nStatistical analysis\nStatistical analysis was performed using SPSS V. 25.0 (IBM, Ar-\nmonk, NY, USA). χ\n2 and Fisher ʼse x a c tt e s t sw e r eu s e df o rt h ea n a l -\nysis of categorical variables. Quantitative variables were com-\npared using Mann-Whitney U test. A p-value < 0.05 was consid-\nered statistically significant.\nResults\nA total of 542 patients with histologically confirmed endometrio-\nsis were included in the study. The mean age of these patients was\n33.5 ± 8.0 years. The majority of the women were nulligravida\n(n = 313, 58.29 %); 350 (66.04 %) had not previously given birth.\n▶ Table 1 Baseline characteristics of women with histologically con-\nfirmed endometriosis (n = 542). Data are presented as mean ± standard\ndeviation (median, range) or number (%).\nClinical characteristics Patients\nAge (years) 33.5 ± 8.0 (17 –72)\nObstetric history\n▪ No prior pregnancies (n = 537) 313 (58.29 %)\n▪ No prior births (n = 530) 350 (66.04 %)\nAge at onset of menarche (years) 13.0 ± 1.50 (9 –17)\nReproductive lifespan (years) 21.2 ± 7.8 (4 –41)\nMean duration of menstrual cycle (n = 286) 29.5 ± 7.6 (13 –90)\nMean duration of menstrual bleeding (n = 314)  5.7 ± 1.8 (2–15)\nPrevious history of endometriosis\n▪ No, first diagnosis 404 (74.54 %)\n▪ Yes, recurrent disease 128 (23.61 %)\nMain reason for surgery\n▪ Acute or chronic pain 192 (35.42 %)\n▪ Infertility 130 (23.99 %)\n▪ Incidental finding 100 (18.45 %)\nSymptoms prior to surgery\n▪ Cyclic pelvic pain 238 (43.91 %)\n▪ Dysmenorrhea  56 (10.33 %)\n▪ Dysuria  42 (7.75 %)\n▪ Dyspareunia 103 (19.00 %)\n▪ Primary and secondary infertility 210 (38,74 %)\n▪ Abnormal uterine bleeding  80 (14.8 %)\nConcomitant gynecological diagnoses\n▪ Uterine malformations  32 (5.90 %)\nSurgery\n▪ Outpatient treatment 152 (28.04 %)\n▪ Hospitalization after surgery 390 (71.96 %)\n▪ Laparoscopy 496 (91.51 %)\n▪ Laparotomy  36 (6.60 %)\nOccurrence of endometriosis\n▪ Adenomyosis  58 (10.70 %)\n▪ Ovarian endometriosis 180 (33.21 %)\n▪ Deep infiltrating endometriosis 103 (19.00 %)\n▪ Peritoneal adhesions 185 (34.13 %)\nrASRM classification (n = 523)\n1\n▪ Stage I 214 (40.92 %)\n▪ Stage II  95 (18.16 %)\n▪ Stage III 111 (21.22 %)\n▪ Stage IV 103 (19.69 %)\nHormonal treatment at the time of surgery 102 (18.82 %)\nMean number of probes for histological assessment  3.2 ± 1.8 (1–13)\nMean mitotic rate  0.4 ± 0.8 (0–7)\nrASRM: revised classification of the American Society of Reproductive\nMedicine [9].\n1 In 19 cases no rARSM classification was given; 9 of those women had\nendometriosis of the abdominal wall without laparoscopy and 10 women\nhad adenomyosis. The ENZIAN score was used for those clinical entities.\n87Wetzk M et al. Diagnostic Benefit of … Geburtsh Frauenheilk 2022; 82: 85 –92 | © 2022. The author(s).\n\n\nAnalysis and mitotic figure count\nAfter mitotic figures were counted, 402 women (74.27 %) were\nfound to have no mitotic figures in 10 microscopic high-power\nfields (HPF). These women were assigned to the control group of\nwomen without proliferative activity based on mi totic figures.\n140 women (25.83 %) had at least one mitotic figure in 10 HPFs\nand were diagnosed as having endometriosis with proliferative ac-\ntivity based on the presence of mitotic figures. The mean number\nof mitotic figures was 0.4 ± 0.8 (0 –7) for all patients included in\nthe study. Six women had three mitotic figures, four and five mi-\ntoses were counted in three women respectively, and seven mi-\ntotic figures were counted in one woman. As the number of wom-\nen with a higher mitotic index was small, no additional statistical\nanalysis was performed to assess the association between mitotic\nindex and disease severity.\nThe baseline characteristics of the patients are shown in\n▶ Table 1 .\nPresence of mitotic figures and clinical characteristics\nThe clinical data of the two subgroups were compared based on\nthe presence of mitotic figures in up to 10 HPF. The results of this\ncomparison are shown in\n▶ Table 2 . Surgery was planned signifi-\ncantly more often because of acute or chronic pain (p = 0.018) in\nthe subgroups with mitotic figures. The predominant reason for\nsurgery was infertility, and there were no significant differences\nbetween the two subgroups with regard to infertility, whereas a\ndiagnosis of endometriosis during surgery for other reasons was\nmore frequent in the group without mi totic figures (p = 0. 031).\nWe found no statistical difference between the two groups\nwith regard to self-reported symptoms prior to surgery. Only in-\nfertility was more common in women with mitotic figures\n(45.0 %) than in the subgroup without detected mi totic figures\n(36,4 %). The mean reproductive lifespan from the onset of men-\narche to surgery for endometriosis was significantly shorter in\nwomen with detected mitotic figures in endometriotic lesions\n(19.4 vs. 21.9 years, cf.\n▶ Table 2 ).\nSignificantly more lesions showed mitotic figures in the group\nof women with deep infiltrating endometriosis (p < 0.001), ovar-\nian endometrioma (p = 0.012) and infertility (p = 0.049). Mi totic\nfigures and countable mitotic rates were more common in wom-\nen with multiple endometriotic lesions (p < 0.001). Surgery was\nperformed in the majority of cases via laparoscopy (91.51 %).\nOur results showed that there was no significant difference\nwith regard to the presence of mitotic figures in the biopsies of\nwomen undergoing concurrent hormonal treatment at the time\nof surgery compared to women without endocrine treatment\n(p = 0.210). Forty-nine women were treated with combined oral\ncontraceptives, 12 (24.5 %) of whom had mitotic activity.\nTwenty-six patients took progestin only pills, mainly dienogest\n(n = 19), and three of them had mitotic activity (15.8 %). Only\none woman was treated with long-acting agonists of gonadotro-\npin-releasing hormone (GnRH); no mitosis was detected in this\nwoman. In the group receiving endocrine treatment, no differ-\nence was detected with regard to different medications\n(p = 0.793).\nThe percentages for the different stages based on the rASRM\nand ENZIAN scores for the groups with inactive and active prolif-\neration are shown in\n▶ Fig. 2 a and b. rASRM stages differed signif-\nicantly between the two subgroups (p = 0.001). In spite of the\nhigher occurrence of deep infiltrating endometriosis, the distribu-\ntion of the lesions classified using the ENZIAN score does not show\nsignificant differences (\n▶ Fig. 2 b).\nDiscussion\nSince the first description of mitotic figures in endometriotic le-\nsions [8, 9] only a few studies have been published on the topic\nof active proliferation in endometriotic lesions. The detection of\nmitotic figures as a marker of active proliferation in cancer cells\nafter H & E staining is a standardized procedure [18]. Assessment\nis easy to perform without further staining or additional costs.\nUsually, 10 HPF are controlled and the number of mitotic figures\nis counted and documented. It appears that proliferative cellular\nactivity does not change during the menstrual cycle in the ectopic\nendometrial tissue of women with endometriosis [17]. Nisolle et\nal. identified the mitotic rate as a histological marker for the intra-\noperative appearance of endometriotic lesions during surgery and\nas a morphological criterion for typical and atypical lesions [17].\nThe mitotic rate was a histological correlate for the macroscopic\nappearance of proliferation. In our study, we defined one mitotic\nfigure and more in 10 HPFs as a sign of active cellular proliferation.\nIn this retrospective analysis of clinical data from one single cen-\nter, we examined the correlation between baseline characteristics\nand the presence of mitotic figures in the tissue of endometriotic\nlesions from more than 500 women.\nThe presence of mitotic figures had a significant additional di-\nagnostic value with regard to the severity of endometriosis. After\ncomparing the characteristics of women in our two subgroups,\nwe found a statistically significant higher risk of severe endome-\ntriosis, with higher rASRM stages and deep infiltrating endome-\ntriosis, in the group with confirmed mitotic figures.\nNo statistically significant differences were seen between the\ntwo groups with regard to medical history, mean age at surgery,\nage at onset of menarche, menstrual cycle, or typical endometrio-\nsis-associated symptoms. The study shows the representative\nclinical baseline data of women with endometriosis, which were\ncomparable to former studies on the clinical characteristics of en-\ndometriosis [18 – 20]. Interestingly, we found a statistically signifi-\ncant difference with regard to the interval between onset of men-\narche and surgery as a surrogate marker for reproductive lifespan\nand mitotic rate, with shorter reproductive lifespan in women\nwith higher rates. It could be hypothesized that a longer repro-\nductive lifespan with a longer cumulative exposure to estrogen\nmay be correlated with active cellular proliferation. But our results\nsuggest that endometriosis is diagnosed significantly earlier in\nwomen with active proliferative disease.\nAccording to current guidelines and clinical algorithms, the in-\ndication for surgery is usually based on three indicators: pain, in-\nfertility, and clinical signs of endometriosis [21]. In our study, pain\nwas the main reason for surgery significantly more often in the\nsubgroup of women with detected mitotic figures, which corre-\nsponded to more advanced stages of endometriosis. Although\ndetection of mitotic figures correlated with clinical stage and\nespecially with deep infiltrating endometriosis, no significant dif-\n88 Wetzk M et al. Diagnostic Benefit of … Geburtsh Frauenheilk 2022; 82: 85 –92 | © 2022. The author(s).\nGebFra Science | Original Article\n\n\n▶ Table 2 Clinical characteristics of the subgroups without and with mitotic figures as a marker of active proliferation in 542 women with\nhistologically confirmed endometriosis.\nClinical characteristics Endometriosis without\nmitotic figures (n = 402)\nEndometriosis with a\nmitotic rate ≥ 1( n=1 4 0 )\np-value\nAge (years)  33.9 ± 8.2 (17–72)  32.5 ± 7.2 (19–55)  0.134\nObstetric history\n▪ No prior pregnancies (n = 537) 233 (58.25%)  80 (58.39 %)  0.772\n▪ No prior births (n = 530) 263 (65.91%)  87 (63.50 %)  0.925\nAge at onset of menarche (years)  13.1 ± 1.5 (9–17)  12.9 ± 1.4 (9–16)  0.667\nReproductive lifespan (years)  21.9 ± 8.1 (4–41)  19.4 ± 6.5 (5–35)  0.023*\nMean duration of menstrual cycle (n = 286)  29.3 ± 7.3 (13–90)  29.9 ± 8.2 (21–90)  0.643\nMean duration of menstrual bleeding (n = 314)   5.6 ± 1.8 (2–14)   5.9 ± 2.0 (3–15)  0.138\nPrevious history of endometriosis (n = 397)\n▪ No, first diagnosis 305 (76.83%)  99 (73.31 %)  0.239\n▪ Yes, recurrent disease  92 (23.17%)  36 (26.69 %)\nPredominant reason for surgery\n▪ Acute or chronic pain 150 (37.78%)  42 (31.11 %)  0.018*\n▪ Infertility  90 (22.67%)  40 (29.62 %)  0.415\n▪ Diagnosis of endometriosis during surgery\nfor other indications 1\n 83 (20.64%)  17 (12.14 %)  0.031*\nSymptoms prior to surgery\n▪ Deep pelvic pain 255 (63.43%)  86 (61.42 %)  0.685\n▪ Dysmenorrhea 178 (44.28%)  60 (42.9 %)  0.843\n▪ Dysuria  35 (8.71%)   7( 5 . 0 0 % )  0.199\n▪ Dyspareunia  82 (20.40%)  21 (15.00 %)  0.171\n▪ Dyschezia  44 (10.95%)  12 (8.57 %)  0.268\n▪ Primary and secondary infertility 147 (36.37%)  63 (45.00 %)  0.049*\n▪ Abnormal uterine bleeding  63 (15.67%)  17 (12.14 %)  0.336\nSurgery\n▪ Laparoscopy 373 (93.02%) 123 (87.86 %)  0.036*\n▪ Laparotomy  23 (5.74%) 123 (9.29 %)\nrASRM classification (n = 523)\n▪ Stage I 179 (45.90 %)  35 (26.32 %)\n▪ Stage II  67 (17.18%)  28 (21.05 %)  0.001*\n▪ Stage III  74 (18.97%)  37 (27.82 %)\n▪ Stage IV  70 (17.95%)  33 (24.81 %)\nHormonal treatment  81 (20.15%)  21 (15.00 %)  0.210\n▪ Combined oral contraceptives  55 (13.7%)  \n18 (12.9 %)  0.886\nOnly one biopsy for histological assessment  71 (17.67%)  12 (8.56 %) < 0.001**\nOccurrence of endometriosis (n = 542)\n▪ Adenomyosis  42 (10.42%)  16 (11.43 %)  0.752\n▪ Ovarian endometrioma 121 (30.31%)  59 (42.14 %)  0.012*\n▪ Deep infiltrating endometriosis according\nto the ENZIAN score\n 37 (9.20%)  32 (22.86 %) < 0.001*\nPeritoneal adhesions 140 (34.83%)  45 (32.14 %)  0.606\nOther ovarian cysts  49 (12.19%)  15 (10.71 %)  0.761\nUterine malformations (n = 451)  27 (6.72%)   5( 3 . 5 7 % )  0.214\nSignificant differences: * p < 0.05, ** p < 0.001.\n1 Other indications for surgery were: ovarian cysts not suspicious for endometriosis (n = 45), surgery for fibroids (n = 29), hysterectomy (n = 14),\nectopic pregnancy (n = 6), suspected uterine malformation (n = 3), cryopreservation of ovarian tissue (n = 2), tubal sterilization (n = 1).\n89Wetzk M et al. Diagnostic Benefit of … Geburtsh Frauenheilk 2022; 82: 85 –92 | © 2022. The author(s).\n\n\nference was seen with regard to overall clinical symptoms\n(▶ Table 2). This may be explained by the high variability of symp-\ntoms. The results of studies investigating endometriosis-related\npain and clinical staging or localization are conflicting. In an Italian\nstudy with 1000 patients, Vercellini et al. reported a higher sever-\nity of pain symptoms in patients with higher rASRM stages [22]. In\ncontrast, a study by the US-American group of Sinai et al. with a\nsimilar sample size found that women with lower rASRM stages\n(I–II) suffered more frequently from dyspareunia. There were no\ndifferences with regard to other symptoms between the group\nwith low rASRM stages and the group with a high rASRM stage\n[19]. The heterogenous clinical symptoms of endometriosis may\nrASRM I\nENZIAN A ENZIAN B\na\nb\n45.9\n17.2\n19 17.9\n26.3\n22.2\n52.8\n36.1\n30.6\n25\n36.1\n2.8\n50\n29\n45.2\n19.3 19.3\n6.4\n45.2\n6.4\np = 0.592\np = 0.809\np = 1.000\np = 0.052\np = 0.401\np = 0.176\np = 0.627\np = 0.581\n48.4\n21.1\n27.8\n24.8\nrASRM classification (n = 423)\nENZIAN classification (n = 67)\nrASRM II\nENZIAN C\nrASRM III\nFA –\nadenomyosis\nFB –\nbladder\nFI –\nintestine\nFU –\nureter\nFO –\nother locations\nrASRM IV\nPercentage of stages (%)\nPercentage of stages (%)\n60\n55\n50\n45\n40\n35\n30\n25\n20\n15\n10\n5\n0\n60\n55\n50\n45\n40\n35\n30\n25\n20\n15\n10\n5\n0\nNo proliferative activity (n = 390)\nNo proliferative activity (n = 36)\nProliferative activity (n = 133)\nProliferative activity (n = 31)\n▶ Fig. 2 Comparison of stages using the rASRM ( a) and the ENZIAN score ( b) in patients without and with detected mitotic figures as a marker\nof proliferative activity.\n90 Wetzk M et al. Diagnostic Benefit of … Geburtsh Frauenheilk 2022; 82: 85 –92 | © 2022. The author(s).\nGebFra Science | Original Article\n\n\nexplain why our study did not find any statistical differences in the\nmitotic rate with regard to most symptoms. A prospective multi-\ncenter study evaluating longitudinal clinical data in combination\nwith repeated standardized pain questionnaires might find statis-\ntical differences. Women with symptoms of infertility have higher\nstages of endometriosis after an invasive diagnosis [20, 24].\nThere was no significant difference in the number of women\nwith adenomyosis and typical clinical symptoms of dysmenorrhea\nand abnormal uterine bleeding in the groups with and without ac-\ntive proliferation (p = 0.752). Adeno myosis is a highly proliferative\ndisease of the uterus, and higher Ki-67 cell indices were found in\nuterine myometrial tissue [25]. Nevertheless, we calculated the\ncellular proliferative rate for adenomyosis and endometriotic tis-\nsue.\nThe strengths of this study are the large sample size and the\ndetailed information on symptoms, reproductive health and med-\nical history. Although the data was collected retrospecti vely, infor-\nmation about the extent of disease was obtained from surgical re-\ncords, and staging of the disease was standardized. The study was\nperformed in a single certified endometriosis center. While this is\na strength, it may also lead to a selection bias with a tendency to\nhigher stages. This can be seen in the percentage of women with\ndeep infiltrating endometriosis in our study (19.0 %). A recent\npublication reported a lower percentage (14.4 %) of deep infiltrat-\ning endometriosis in patients with endometriosis [26]. A detailed\nanalysis of ENZIAN stages and the distribution of endometriotic\nlesions in deep infiltrating endometriosis did not show significant\ndifferences.\nThe long-term follow-up is of special interest in view of the\ndata on recurrence and the possible development of cancerous le-\nsions. The lack of follow-up is one of the limitations of this study. A\nprospective follow-up study is currently being planned.\nThe presence of mitotic figures as a marker of severe disease\ncould be an additional factor when recommending that women\nreceive a longer follow-up and treatment to prevent recurrence\n[27]. We propose that women in whom mitotic figures are de-\ntected should have shorter postoperative follow-up intervals and\nthat the time to pregnancy in cases of infertility should be short-\nened. Assisted reproductive techniques could be proposed earlier\nfor women with confirmed mitotic figures.\nAlthough this retrospective study did not find an association\nbetween the mitotic rate and recurrence, further prospective val-\nidating studies could clarify the prognostic value of mitotic figures\nand their impact on recurrence.\nEndometriosis can lead to epithelial cancer, although the\nunderlying mechanisms are still not understood [28]. The mitotic\nrate could serve as an early prognostic marker for women who\nhave a higher risk of developing endometriosis-associated cancer\nand who therefore require intensified long-term follow-up.\nConclusion\nThe mitotic rate can be used as a simple additional histological as-\nsessment for endometriosis. Histology is already routinely used to\ninvestigate endometriosis, and this approach would not need ad-\nditional training of the pathologist or additional staining of the\nspecimen. We can confirm that the mitotic rate can be an effec-\ntive diagnostic tool in women with more severe endometriosis\nbased on their surgical findings. Our data strongly suggest that\nfurther studies should be carried out to investigate the association\nbetween mitotic rate and the rate of recurrence after the initial\ndiagnosis of endometriosis and pregnancy outcomes in women\nwith infertility.\nFunding\nNo funding was used for the study or preparation of the manu-\nscript.\nConflict of Interest\nThe authors declare that they have no conflict of interest.\nReferences\n[1] Giudice LC, Kao LC. Endometriosis. Lancet 2004; 364: 1789 –1799.\ndoi:10.1016/S0140-6736(04)17403-5\n[2] Nicolaus K, Reckenbeil L, Bräuer D et al. Cycle-related diarrhea and dys-\nmenorrhea are independent predictors of peritoneal endometriosis,\ncycle-related dyschezia is an independent predictor of rectal involve-\nment. Geburtshilfe Frauenheilkd 2020; 80: 307 –315\n[3] Bjorkman S, Taylor HS. 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Minerva Ginecol\n2020; 72: 43 –49. doi:10.23736/S0026-4784.20.04490-1\n[28] Bulun SE, Wan Y, Matei D. Epithelial Mutations in Endometriosis: Link to\nOvarian Cancer. Endocrinology 2019; 160: 626 –638. doi:10.1210/\nen.2018-00794\nErratum\nDiagnostic Benefit of the Detection of Mitotic Figures in\nEndometriotic Lesions\nWetzk M, Grübling N, Forberger A et al. Geburtshilfe\nFrauenheilkd 2022; 82: 85 –92. doi:10.1055/a-1580-0601\nIm oben genannten Artikel wurde der Name eines Ko-\nautors unvollständig angegeben. Richtig ist: Jan Dominik\nKuhlmann.\n92 Wetzk M et al. Diagnostic Benefit of … Geburtsh Frauenheilk 2022; 82: 85 –92 | © 2022. The author(s).\nGebFra Science | Original Article","source_license":"CC0","license_restricted":false}