Is adenomyosis associated with the risk of endometrial cancer?

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1 ORIGINAL ARTICLE Is adenomyosis associated with the risk of endometrial cancer? İsmet Gün 1, Öznur Öner 1, Serkan Bodur 2, Özkan Özdamar 1, Vedat Atay 1 1 Department of Obstetrics and Gynecology, GATA Haydarpaşa Training Hospital, İstanbul, 2 Department of Obstetrics and Gynecology, Maresal Cakmak Military Hospital, Erzurum; Turkey ABSTRACT Aim To evaluate an association of adenomyosis with endometrial cancer and to determine the frequency of adenomyosis at hysterectomy specimens. Methods This study was carried out retrospectively on pathologic specimens of hysterectomies. A total of 472 women in the period enrolled to the study. All pathologies seen in hysterectomy specimens were noted. The frequency of adenomyosis and the accompanying pathologies were determined. These women were categorized into two groups according to the presence of adenomyosis. The incidence of adenomyosis was analyzed together with the endometrial cancer. Corresponding author: İsmet Gün Department of Obstetrics and Gynecology, GATA Haydarpasa Training Hospital, İstanbul, Turkey Phone: ; fax.: ; drismetgun@gmail.com Original submission: 16 January 2012; Revised submission: 05 March 2012; Accepted: 12 March Results The incidence of adenomyosis was 20.8% at hysterectomy specimens. There was no statistically significant difference between the mean age of the two groups (p = 0.069). There were 98 cases with adenomyosis and the only pathologic finding was adenomyosis, in 28 (28.5%) cases. The most common accompanying pathologies with adenomyosis were uterine myomas in 51 (52%), uterine polyps in 16 (16.3%) and endometrial carcinomas in 11 (11.2%) cases. However, statistically significant association of the presence of adenomyosis with uterine myoma (p = 0.227) and endometrial polyps (p = 0.997) and endometrial carcinoma (p = 0.771) was not found. Conclusion In hysterectomy specimens, no statistically significant difference was determined between the groups with and without adenomyosis in terms of co-occurence with endometrial carcinoma. Key words: abnormal uterine bleeding, endometrial hyperplasia, hysterectomy, uterine myoma, uterine polyp. Med Glas Ljek komore Zenicko-doboj kantona 2012; 9(2):

2 Gün et al Adenomyosis and endometrial cancer INTRODUCTION Adenomyosis is an estrogen-dependent, chronic gynecologic disorder. It is a common condition but still little is known about the etiopathology of this disorder (1). Adenomyosis is defined as a localized or diffuse presence of ectopic endometrial glandular or stromal tissue in myometrium (2,3). In adenomyotic uterus endometrial glands scatter randomly within the myometrium (3). Microscopically, ectopic non-neoplastic endometrial glands and stroma are surrounded by hypertrophic and hyperplastic myometrium (2,3). Adenomyosis is asymptomatic in 30% of the cases or it has nonspecific findings in the most of the symptomatic cases (4). Although ultrasonography and magnetic resonance imaging (MRI) are important tools in diagnosis (5-8), they may not be enough. For today adenomyosis is therefore mostly diagnosed by pathologic examination of hysterectomy specimens. cancer is the most common gynecologic malignancy in the world (9). Obesity, early menarche, late menopause, nulliparity, unopposed estrogen (no or low levels of progesterone), previous pelvic radiation, tamoxifen use more than five years, diabetes and hypertension are the known risk factors for endometrial cancer (9). In addition, endometrial glandular hyperplasia is a precursor lesion for type I endometrial carcinoma (3). In some studies, it is also suggested that the presence of adenomyosis, uterine polyps and/or uterine myoma are the additional precursor lesions for endometrial cancer (3,9). Although adenomyosis is considered to be a benign condition, it shares some common characteristics with malignant cells. Some researchers have therefore been focused on the relationship between adenomyosis and endometrial carcinoma (10-18). However, current evidence is not sufficient to draw any definitive conclusion on whether adenomyosis is to be a precursor and/or a risk factor of endometrial cancer. The purpose of this study is to evaluate possible association between adenomyosis and endometrial cancer as well as to determine the incidence of adenomyosis and accompanying pathologies with adenomyosis in hysterectomy specimens. PATIENTS AND METHODS Institutional Review Board approval was obtained before the initiation of this study. This study was performed in Istanbul GATA Medical Faculty, Department of Gynecology and Obstetrics between January 2007 and June In our clinic hysterectomy-including all abdominal and vaginal operation files and pathology results were extracted from the archive and reviewed. These women were categorized into two groups according to the presence of adenomyosis on postoperative histopathological diagnosis. The incidence of adenomyosis and the coexistence with the endometrial cancer were analyzed. Total number of 472 hysterectomy-including operation cases were included in the study. Of these, 98 cases were in the adenomyosis group while 347 were included in the group without adenomyosis. Adenomyosis is defined as the presence of endometrial mucosa within the myometrium. It causes globular and cystic enlargement of the myometrium with some cysts filled with extravasated, often haemolysed red blood cells and siderophages. They were seen 2 mm or deeper from the endomyometrial junction in the myometrium. Postoperative histopathological diagnosis of adenomyosis was made both macroscopically by means of determining trabecular and hemorrhagic areas in the myometrium, and microscopically by way of establishing the presence of ectopic endometrial glandular or stromal tissue in myometrium. In addition, all other abnormal pathologies detected in hysterectomy specimens in both groups were noted. There was no age limit as an inclusion criterion. Records of gynecologic examination and cervical smear before the operation were reviewed for each patient. A Voluson E8 Expert scanner (GE Healthcare, Wauwatosa, WI, USA) was used to perform transvaginal ultrasonography. Hysteroscopy and fractionated curettage records were also reviewed if performed. Patient s age, complaints, preoperative diagnosis, performed operation, presence of adenomyosis and associated pathology were noted for each patient. The patients, for whom sufficient data could not obtained, were excluded from the study. Afterwards, any significant difference between two groups was detected in terms of primary endometrial carcinoma and additionally co-occuring other pathologies. Similarly, the complete group was divided into two according to the presence of endometrial carcinoma. Two groups were compared whether there was any difference in terms of uterine pathologies such as adenomyosis, myomas, polyps, endometrial hyperplasia and cervical pathologies. 269

3 Medicinski Glasnik, Volumen 9, Number 2, August 2012 Statistical analysis was performed by using the Statistical Package for the Social Sciences for Windows 15.0 software (SPSS, Chicago, IL., USA). Descriptive statistics were given as mean, standard deviation, frequency and percentage. Pearson chi-square test and Fisher s exact test were used to compare categorical variables. A p-value <0.05 was considered statistically significant. RESULTS Pathologic examination results of 472 hysterectomy specimens were evaluated. In this study, the incidence of adenomyosis in hysterectomy specimens was found to be 20.8% (98/472). The mean age of 98 cases with adenomyosis was ± while the mean age of 374 cases without adenomyosis was ± (p = 0.10). Uterine myoma and/or abnormal uterine bleeding were the indications for hysterectomy in 57 of 98 cases (58.16%). The hysterectomy indications for the other cases with adenomyosis were as follows; adnexial mass in 15 (15.3%), endometrial cancer in 10 (10.2%), uterine descensus in 8 (8.16%), endometrial hyperplasia in five (for one of which adenomyosis had been suspected) (5.1%), premalignant cervical lesion in two (2.04%) cases, and cervical cancer in one (1.02%) case. The pure adenomyosis was observed only in 28 (28.5%) patients of the 98 cases with adenomyosis, 70 cases had accompanying pathologies such as uterine myoma, endometrial pathologies (endometrial polyps, endometrial premalignant lesions, endometrial cancer), cervical pathologies and adnexal pathologies. The most common accompanying pathology with adenomyosis was the uterine myoma in 51 (52%) cases. Histologically seven (7.1%) cases had adenomyosis together with endometrial hyperplasia (two of them were together Table 1. The uterine pathologies associated with adenomyosis No (%) of patients (Adenomyosis) Uterine pathologies p No Yes Total Uterine No 154 (41.2%) 47 (48%) 201 (42.6%) myomas Yes 220 (58.8%) 51 (52%) 271 (57.4%) Uterine polyps (endometrial and cervical) hyperplasia carcinoma Cervical pathologies No 313 (83.7%) 82 (83.7%) 395 (83.7%) Yes 61 (16.3%) 16 (16.3%) 77 (16.3%) No 364 (97.3%) 91 (92.9%) 455 (96.4%) 0.06 Yes 10 (2.7%) 7 (7.1%) 17 (3.6%) No 328 (87.7%) 87 (88.8%) 415 (87.9%) Yes 46 (12.3%) 11 (11.2%) 57 (12.1%) No 360 (96.3%) 95 (96.9%) 455 (96.4%) 1.00 Yes 14 (3.7%) 3 (3.1%) 17 (3.6%) with uterine myoma, one of them with endometrial polyp, three of them with endometrial cancer). There were 16 cases of adenomyosis together with endometrial and cervical polyps (16.3%) (seven of them were together with uterine myoma, two of them with simple hyperplasia without atypia, one of them with endometrial cancer, three of them with cervical pathologies). Also there were 11 (11.2%) cases with endometrial cancer. Four cases with uterine myoma, three cases with endometrial hyperplasia and one case with uterine polyp were defined among cases with adenomyosis and endometrial cancer together. Histopathologic examination results of four out of 11 cases, diagnosed as endometrial cancer, were not the same with their histopathologic examination results of the hysterectomy specimens. In addition, cancer was not observed on their hysterectomy specimens. One case was operated with an indication of uterine leiomyomatosis and diagnosed as endometrial cancer after the histopathological examination of hysterectomy specimen (Table 1). Overall there was a total 57 cases with endometrial cancer. The pathologies that were associated with endometrial cancer were as follows: eleven (19.3%) cases with uterine myoma, five (8.8%) cases with endometrial and/or cervical polyp, seven (12.3%) cases with endometrial hyperplasia, and eleven (19.3%) cases with adenomyosis (Table 2). The frequency of adenomyosis and uterine polyps was not statistically different in women with and without endometrial cancer (p > 0.05). However, the number of cases with uterine myoma and endometrial hyperplasia was statistically different in women with and without endometrial cancer (62.7% vs 19.3%, p < 0.001; 12.3% vs 2.4%, p = 0.002, respectively). Table 2. The uterine pathologies defined together with endometrial cancer Uterine myomas Uterine polyps hyperplasia No (%) of patients (endometrial cancer) p No Yes Total No 155 (37.3%) 46 (80.7%) 201 (42.6%) < Yes 260 (62.7%) 11 (19.3%) 271 (57.4%) 0.001* No 343 (82.7%) 52 (91.2%) 395 (83.7%) Yes 72 (17.3%) 5 (8.8%) 77 (16.3%) 0.10 No 405 (97.6%) 50 (87.7%) 455 (96.4%) Yes 10 (2.4%) 7 (12.3%) 17 (3.6%) 0.002* Adenomyosis No 328 (79%) 46 (80.7%) 374 (79.2%) Yes 87 (21%) 11 (19.3%) 98 (20.8%) Cervical No 398 (95.9%) 57 (100%) 455 (96.4%) pathologies Yes 17 (4.1%) 0 (.0%) 17 (3.6%) * significant, p < 0.05, chi-square test 270

4 Gün et al Adenomyosis and endometrial cancer DISCUSSION Adenomyosis is a disease involving myometrial invasion by endometrial glands and stroma (2,3). It has two forms called diffuse type (known as adenomyosis) and the focal type (known as adenomyoma) (3). The preoperative diagnosis of adenomyosis may be made by means of symptomatology, ultrasonography and magnetic resonance imaging (4, 6-8, 19). However, currently the most reliable way to diagnose adenomyosis is the pathologic examination of hysterectomy specimen (2). In the literature, the reported incidence of adenomyosis in hysterectomy specimens is between 5% and 70% (1,19-21). Despite of this knowledge, the exact incidence of adenomyosis still can not be known because the diagnosis of adenomyosis needs histopathological confirmation and also there is a lack of agreement in the histological criteria (2,22). In addition, most of the studies have a limitation related to the small number of patients; they should only be referred to the group of women with hysterectomy, and cannot be generalized to the general population. The pathogenesis of the majority of uterine pathologies such as adenomyosis, uterine polyps and uterine myomas is not clearly known. Although a few theories are proposed, there is no theory that can fully explain this disease. Currently, the most commonly accepted theory for adenomyosis is the invasion of endometrial glands and stroma into the myometrium from fissures formed due to tissue injury and repair (2,23). If the onset and growth of diseases such as adenomyosis, endometriosis and polyp are related to dysregulation of a physiological inflammatory process, this hypothesis may explain their formation. On ultrasonography, in the uteri of patients with adenomyosis, in the junctional zone is often seen to be quiet fissurae (24). It is thought that interventions to uterus (especially cesarean section and induced abortion) may be the cause of these tissue defects (1,5,21,22). In addition, several studies have shown an increased risk of adenomyosis with an increasing number of births which are thought to be due to disruption of the barrier between basal endometrium and the myometrium (1). The ratio of endometrial surgical intervention in our study group was 42% in 98 cases with the diagnosis of adenomyosis. Cases with adenomyosis are rarely isolated cases. Most of them are accompanied with additional pathologies. The most frequent accompanying pathologies are uterine myomas (35-55%), endometrial polyps (2.3%), hyperplasia (10.5%) and endometrial adenocarcinoma (1.4%) (3). Actually, it is not surprising that these three diseases are seen together because the diseases such as adenomyosis, fibroids, uterine polyps and endometriosis are under the control of the same steroid hormones. Adenomyosis is a distinct entity different from uterine fibroids and uterine polyps while endometriosis and adenomyosis may be the variants of the same disease (9,10). Previous studies concluded that fibroids are equally common in the specimens with and without adenomyosis (19,21). Indraccolo et al demonstrate an association between adenomyosis and uterine polyps (25). Although adenomyosis is a benign disease, there are some studies that accept adenomyosis as a precursor lesion for endometrial cancer and arising from uterine adenomyosis with or without endometrial involvement (10,11,15,16). Koshiyama et al showed that the adenocarcinoma ratio was 16% in cases with adenomyosis (12). Evidence to support this hypothesis includes the increased endometrioid cancers in the presence of adenomyosis, and molecular similarities between adenomyosis and cancer. When endometrial carcinoma is associated with adenomyosis it may be difficult to distinguish whether the carcinoma arises from the adenomyosis that invades the endometrium or the eutopic endometrium that invades the myometrium. In such cases arising from adenomyosis over-expression of mutated P53 gene has also been reported (10,26). Nevertheless, there is no sufficient evidence supporting the hypothesis that adenomyosis is a neoplastic process and showing the relationship between adenomyosis and cancer. In conclusion, in this study no association emerged between endometrial carcinoma and frequency of adenomyosis. In hysterectomy specimens, no statistically significant difference was determined between the groups with and without adenomyosis in terms of cooccurence with endometrial carcinoma. Other perspective, adenomyosis has probably not been seen as a precursor lesion for endometrial cancer. 271

5 Medicinski Glasnik, Volumen 9, Number 2, August 2012 FUNDING No specific funding was received for this study. TRANSPARENCY DECLARATIONS Competing interests: none to declare. REFERENCES 1. Parazzini F, Mais V, Cipriani S, Busacca M, Venturini P. Determinants of adenomyosis in women who underwent hysterectomy for benign gynecological conditions: Results from a prospective multicentric study in Italy. Eur J Obstet Gynecol Reprod Biol 2009; 143: Ferenczy A. Pathophysiology of adenomyosis. Hum Reprod Update 1998; 4: Bergeron C, Amant F, Ferenczy A. Pathology and physiopathology of adenomyosis. Best Pract Res Clin Obstet and Gynaecol 2006; 20: Peric H, Fraser IS. The symptomatology of adenomyosis. Best Pract Res Clin Obstet Gynaecol 2006; 20: Atri M, Reinhold C, Mehio AR, Chapman WB, Bret PM. Adenomyozis: US features with histologic correlation in an in vitro study. Radiology 2000; 215: Huang RT, Chou CY, Chang CH, Yu CH, Huang SC, Yao BL. Differentiation between adenomyoma and uterine myoma with transvaginal ultrasonography. Ultrasound Obstet Gynecol 1995; 5: Reinhold C, Tafazoli F, Mehio A, Wang L, Atri M, Siegelman ES, Rohoman L. Uterine adenomyosis: endovaginal US and MR imaging features with histopathologic correlation. Radiographics 1999; 19: Bazot M, Cortez A, Darai E, Rouger J, Chopier j, Antoine JM, Uzan S. Ultrasonography compared with magnetic resonance imaging for the diagnosis of adenomyosis:correlation with histopathology. Human Reprod 2001; 16: Rowlands IJ, Nagle CM, Spurdle AB, Webb PM. Gynecological conditions and the risk of endometrial cancer. Gynecol Oncol. 2011; 123: Koshiyama M, Suzuki A, Ozawa M, Fujita K, Sakakibara A, Kawamura M, Takahashi S, Fujii H, Hirano T, Okagaki A, Nagano T, Ban C. Adenocarcinoma arising from uterine adenomyosis: a report of four cases. Int J Gynecol Pathol 2002; 21: Colman HI, Rosenthal AH. Carcinoma developing in areas of adenomyosis. Obset Gynecol 1959; 14: Koshiyama M, Okamoto T & Ueta M. The relationship between endometrial carcinoma and coexistent adenomyosis uteri, endometriosis externa and myoma uteri. Cancer Detect Prev 2004; 28: Takai N, Akizuki S, Nasu K, Etoh Y, Miyakawa I. Endometrioid adenocarcinoma arising from adenomyosis. Gynecol Obstet Invest 1999; 48: Hall JB, Young RH, Nelson Jr JH. The prognostic significance of adenomyosis in endometrial carcinoma. Gynecol Oncol 1984; 17: Motohara K, Tashiro H, Ohtake H, Saito F, Ohba T, Katabuchi H. Endometrioid adenocarcinoma arising in adenomyosis: elucidation by periodic magnetic resonance imaging evaluations. Int J Clin Oncol 2008; 13: Takeuchı K, Yamanaka Y, Hamana S, Ohara N, Maruo T. Invasive adenocarcinoma arising from uterine adenomyosis involving the rectosigmoid colon. Int J Gynecol Cancer 2004; 14: Boes AS, Tousseyn T, Vandenput I, Timmerman D, Vergote I, Moerman P, Amant F. Pitfall in the diagnosis of endometrial cancer: case report of an endometrioid adenocarcinoma arising from uterine adenomyosis. Eur J Gynaecol Oncol. 2011; 32: Couto D, Mota F, Silva T, de Oliveira C. Adenocarcinoma arising in adenomyosis: report of an unusual case. Acta Obstet Gynecol Scand 2004; 83: Bergholt T, Eriksen L, Berendt N, Jacobsen M, Hertz JB. Prevalence and risk factors of adenomyosis at hysterectomy. Hum Reprod 2001; 16: Manyonda I, Sinthamoney E, Belli AM. Controversies and challenges in the modern management of uterine fibroids. Br J Obstet Gynecol 2004; 111: Vercellini P, Parazzini F, Oldani S, Panazza S, Bramante T, Crosignani PG. Adenomyosis at hysterectomy: a study on frequency distribution and patient characteristics. Hum Reprod 1995; 10: Farquhar C, Brosens I. Medical and surgical management of adenomyosis. Best Pract Res Clin Obstet Gynaecol. 2006; 20: Leyendecker G, Wildt L, Mall G. The pathophysiology of endometriosis and adenomyosis: tissue injury and repair. Arch Gynecol Obstet 2009; 280: Hulka CA, Hall DA, McCarthy K, Simeone J. Sonographic findings in patients with adenomyosis: can sonography assist in predicting extent of disease? AJR Am J Roentgenol 2002; 179: Indraccolo U, Barbieri F. Relationship between adenomyosis and uterine polyps. Eur J Obstet Gynecol Reprod Biol 2011; 157: Taskin M, Lallas TA, Shevchuk M, Barber HR. P53 Expression in adenomyosis in endometrial carcinoma patients. Gynecol Oncol 1996; 62:

Adenomyosis: Back to the future?

Facts Views Vis Obgyn, 2017, 9 (1): 15-20 Original paper Adenomyosis: Back to the future? Z. Ferraz 1, N. Nogueira-Martins 2, F. Nogueira-Martins 2 1 Obstetrics and Gynecology Unit, Coimbra University