{"paper_id":"4763bbfa-4bca-4d2b-b5f1-84edfdad18dc","body_text":"This prospective cross sectional study consisted of 100 consecutive specimens of total abdominal hysterectomy with bilateral salpingo-oophorectomy (BSO) referred to the Department of Pathology, Peshawar Medical College, Peshawar, Pakistan by its attached teaching hospitals (Kuwait and Mercy Teaching Hospitals) from January 2011 to December 2012.\nTotal abdominal hysterectomy with BSO specimens in the above study period were taken. Out of these cases, patients having an ovarian cysts with concomitant adenomyosis were included in the study. An identical number of cases of adenomyosis without ovarian cysts were taken as controls.\nPatients having any malignancy were excluded from the study.\nInformed consent from the patients was obtained before recording the data of history, clinical findings, and relevant investigations. The integrity and impartiality of the research was ensured according to the Ethical Principles of Medical Research involving human subjects in accordance with the Declaration of Helsinki 1964. 14  The study was Also approved by the Institutional Ethical Committee.\nThe tissue processing of specimen was conducted at the Histopathology Section of the Department of Pathology, Peshawar Medical College, Peshawar, Pakistan. Each hysterectomy with BSO specimen was grossly examined in detail. The representative sections from the wall of the uterus, adenomyotic lesion, and both ovaries were taken and processed for hematoxylin and eosin stain. The microscopic findings were recorded.\nThe criteria for the diagnosis of adenomyosis was taken by the presence of: 1) Endometrial glands/stroma or both at one low power (2.5 mm) depth from the basal endometrium; and 2) Plump/hypertrophied smooth muscle fibers immediately surrounding the endometrial tissue deep in the myometrium.\nImmunohistochemical (IHC) stain was performed at the Department of Pathology, Institute of Medical Sciences, Islamabad, Pakistan. A section from the adenomyotic lesion was taken from both cases and controls for IHC staining for ER by using the Novocastra Max Polymer Detecting System (Leica Biosystems Ltd., Newcastle, United Kingdom). The immunohistochemically stained slides were examined microscopically, and the ER positivity was assessed by using the H-scoring system taking nuclear staining with a score >50 as positive. 15\nThe statistical analysis was carried out using the Statistical Package for Social Sciences version 19 (IBM Corp., Armonk, NY, USA). The difference between positive and negative ER status of adenomyotic foci and ovarian cysts was analyzed by using Fischer’s exact test. The difference between the ER status of the cases and controls was analyzed using the Chi Square test. The value of  p ≤0.05 was considered statistically significant.\n\nOut of the 100 specimens of hysterectomy with BSO, 25% had adenomyotic foci with ovarian cysts. The age of the patients with adenomyosis ranged from 30-60 years, and was more commonly found between 40-49 years (60%) standard deviation ±5.2. Out of these 25 cases, 76% were multiparous and 24% nulliparous. Histologically, all the cases were diagnosed as having chronic cervicitis. Besides, most also had leiomyoma (80%) followed by endometrial hyperplasia (44%), chronic endometritis (12%), and endometrial polyp (12%). Among adenomyotic foci, 20% cases were positive for ER, while 80% cases were negative. The details of histologic type of ovarian cyst and its relationship with ER positivity of adenomyotic foci are given in  Table 1 .\nOvarian cysts with ER status of adenomyosis.\nIn ER positive adenomyosis cases with cystic lesions in ovary 03 (60%) had follicular cysts, while 02 (40%) showed cystic follicles ( Figure 1 ). The ER expression of adenomyotic foci in relation to functional and nonfunctional ovarian cysts was statistically highly significant ( p =0.0004). The ER expression of cases and controls is given in  Table 2 . The  p -value of ER status of adenomyotic foci in cases and controls was found to be insignificant. Furthermore, the details of ovarian cysts without concomitant adenomyosis is given in  Table 3 . The comparison of functional and nonfunctional ovarian cysts with and without adenomyosis resulted with a value of  p =0.1572, which is statistically insignificant ( Table 4 ).\nEstrogen receptor (ER) expression of adenomyotic foci with concomitant ovarian cysts.\nEstrogen receptor (ER) status of cases and controls.\nOvarian cysts without concomitant adenomyosis.\nComparison of functional and nonfunctional ovarian cysts with and without adenomyosis.\n\nAdenomyosis is always disguised behind other associated uterine pathologies until discovered with the help of ultrasound, or more commonly found on hysterectomy for other complaints. Therefore, patients have suffered and gynecologists are confused on how to handle adenomyosis. The clinical presentation is often masked by signs and symptoms due to leiomyomata, endometrial hyperplasia, and endometritis so that timely treatment for the adenomyosis is delayed. We aimed to find an association of adenomyosis with co-existent benign ovarian cysts and their possible role in its causation.\nAdenomyosis peaks when a woman enters the menopausal transition period with ovarian ageing and concomitant hormonal changes, and characteristically presents as abnormal uterine bleeding in most of the cases. 5  Similarly, most of our patients with adenomyosis (60%), fell in the age range of 40-49 years. This fifth decade predominance was reflected as 67% 16  and 69.3% 17  nationally, 46.3% 18  and 51% 19  regionally, and 45% 20  internationally. In our study, the age range coincides with parity, because the prevalence was twice as high in multiparous women than in nulliparous, a relationship, which has been reflected in other studies. 20 , 21  Repeated pregnancies may facilitate formation of adenomyosis by allowing adenomyotic foci to be included in the myometrium due to the invasive nature of the trophoblast on the extension of myometrial fibers. 22\nAdenomyosis was found in 25% of hysterectomies in our study. Figures ranging from as low as 5% and as high as 70% have been reported, 23  but most studies corroborate our findings nationally 20.6%, 16  regionally 23.4%, 24  and internationally as 24.9%. 20  The results from Karachi are exceptionally high (56.5%), 17  which the authors claim that the condition might have been underdiagnosed in the past, but it could be due to the sampling technique, because when 3 routine sections were taken in a study, 31% of hysterectomy specimens contained adenomyosis and at 6 sections, the rate increased to 61%. 25\nAmong other pathological entities in our study, association of adenomyosis with uterine leiomyomata was found in 80% of cases, which was equally common in the group without adenomyosis and is much higher than another study carried out in Khyber Pakhtunkhwa province in Pakistan (39%), 16  and a study conducted in India (12.2%). 18  Conversely speaking, in a study of leiomyomata 33.3% cases also had adenomyosis. 22  The reason for a higher figure in our cases can be because all the 25 cases had concomitant benign ovarian cysts, which may influence the formation of leiomyomata through production of estrogen and progesterone besides other factors. 26\nEndometrial hyperplasia was seen in 44% cases, endometrial polyp and chronic endometritis in 12% each. The comparable figures are for endometrial hyperplasia 13% 16  and 23% 27  and for endometrial polyps 4% 27  and 25%. 16  Although endometrial polyps show a lower figure in our study, endometrial hyperplasia appears significantly on the higher side and the explanation can be the same as for a high percentage of leiomyomata. In our study, the endometritis appears to be a coincidental finding and may not have a direct association with adenomyosis.\nVarious authors have performed studies related to adenomyotic foci and ovarian cysts, but none of them commented on their co-existence and correlation with ER positivity of adenomyotic foci. For example, in a case-series, 21.4% of hysterectomies with adenomyosis were associated with ovarian cysts, but were not correlated with ER status of adenomyotic foci. 28\nIn our study, the adenomyotic foci were ER positive in 71.5% cases of cystic follicles and follicular cysts, but all the adenomyotic foci associated with non-functional cysts were ER negative. The  p -value was 0.0004, which is statistically highly significant ( Figure 1 ). Cystic follicles and follicular cysts are functional cysts and contain estrogen in their luminal fluid, especially follicular cysts, 29 , 30  but non-functional ovarian cysts do not secrete estrogen. 31\nIn contrast to the previous findings in our study, there was also a significant number of functional ovarian cysts with no concomitant adenomyosis, which included cystic follicles (22.7%) and follicular cysts (21.3%) ( Table 3 ).\nNo statistically significant results could be obtained when comparing the ER expression of controls and cases. This indicates other factors, such as aberrant ER gene expression, tissue injury and repair mechanisms, and localized aromatase activity may also be responsible for adenomyosis besides functional ovarian cysts. 32  These factors could not be included in our study due to financial constraints.\nIn conclusion, besides functional ovarian cysts, other factors may be responsible for the development of adenomyosis. Our study also suggests that in a multiparous woman findings of ovarian cysts or leiomyoma on ultrasonography may point at the possibility of concomitant adenomyosis. Patients having abnormal uterine bleeding or diagnosed with endometrial hyperplasia, endometrial polyp, or endometritis should also be investigated for adenomyosis as a cause of their gynecological problem. It is recommended that localized aromatase activity in adenomyotic foci, analysis of contents of ovarian cysts present concomitantly, and genetic aberrations may be studied.","source_license":"CC0","license_restricted":false}