{"paper_id":"1549931a-2031-4272-82ff-6c942da2e25a","body_text":"Ovarian cancer (OC) is considered a life-threatening disease in women with\nreproductive tumours because it is the second most common cause of death in\ndiagnosed women worldwide. \n 1 \n  Generally, the majority of cases of OC are detected when the disease has\nalready progressed significantly, which results in poor outcomes even if the patient\nreceives the correct therapies or undergoes surgery. \n 2\nA comprehensive ultrasonographic assessment of the female reproductive organs and the\nmeasurement of serum biomarkers such as cancer antigen (CA)-125 are the preferred\nstrategies to detect gynaecological cancers. 2  Novel therapeutic\nmodalities related to the molecular description of OC are required. However,\ntreatment does not reduce OC morbidity or mortality and an increased frequency of\nrecurrence was found even after initial treatment. 3 , 4\nIn the US, 21 750 OC patients and 13 940 deaths due to OC were reported in 2020,\nwhich accounted for 1.2% of all cancer cases in that country and the 5-year survival\nrate for well-treated women with OC was 48.6%. \n 5 \n  A previous study in India reported that 15.7% of cases were identified at the\nlocal stage and these cases had a 92.6% survival rate, whereas the 58% of cases that\nwere detected at the metastatic stage had a survival rate of 30.2%. \n 6\nIn terms of the histological classification of OC, the epithelial type is the most\ncommon (90%), which based on their histology are either serous, mucinous,\nendometrioid or clear cell tumours. \n 7 \n  OC can be further classified into two subtypes known as type I and type II\ncarcinomas, the latter being the more fatal variant, which is thought to be caused\nby continuous ovarian cycles resulting in inflammation and endometriosis. \n 8\nRegarding parity, nulliparous women have a higher risk of OC mainly due to ongoing\nregular ovulation that might increase the risk of repeated minor injury to the\nsuperficial ovarian epithelium during the ovulation process. \n 9 \n  Postmenopausal women have a high incidence rate of OC and a low survival rate. \n 10 \n  This group of women have type I OC, especially those > 50 years. \n 8 \n  However, premenopausal women are more likely to have hereditary OC. \n 8 \n  Furthermore, a family history of having breast cancer/OC is considered the\ngreatest risk factor of OC; and an individual history of breast cancer similarly\nincreases the risk of OC. \n 11 \n  Similarly, pelvic inflammatory disease (PID) is a risk factor for OC development. \n 12\nUterine fibroid (UF) is a benign tumour of the womb that grows mainly during\nreproductive age in approximately 70% of women. \n 13 \n  However, 50% of women do not show clinical signs related to UF, which might\ninclude abdominal ache, high menstrual bleeding and anaemia. \n 14 \n  The development of UF is 2–3 times more likely in obese women than in those\nwith average body weight. \n 15 \n  Subsequently, UF might have the exactly the same pathophysiology of\nreproductive organ malignancy, especially endometrial/OCs. \n 16\nEndometriosis is a common oestrogen-related disorder found in approximately 10% of\nwomen of reproductive age, which can be associated with pelvic pain, although\nasymptomatic cases are found that sometimes result in infertility. \n 17 \n  The burden of endometriosis during reproductive life changes after the\nmenopause, when ovarian hormones stop stimulating the lesions and the major issue is\nthe risk of malignant transformation. \n 18 \n  Moreover, endometriosis is suggested to be associated with a significantly\nincreased risk of invasive OC because mutations of the AT-Rich Interaction Domain 1A\ngene have been demonstrated in endometriosis, which suggests an initial stage in the\npathogenesis of endometriosis-associated ovarian cancer. \n 19 \n  Prolonged inflammation is important in the formation and development of\nendometriosis via the production of proinflammatory cytokines such as matrix\nmetalloproteinase-3, interleukin (IL)-6/IL-8, intercellular adhesion molecule-1 and\ntumour necrosis factor-alpha. \n 20\nApproximately one-third of patients with OC are asked to use contraceptive hormones\nfor a long time to reduce the possibility of OC recurrence. \n 21 \n  In this regard, it was found that receiving contraceptive hormones\nfor > 15 years reduced the risk of the OC by roughly 50%. \n 21\nThis current retrospective observational study aimed to evaluate the correlation\nbetween benign gynaecological disorders and the development of OC.\n\nThis retrospective observational study enrolled consecutive women with confirmed\nOC and other associated gynaecological diseases at Hiwa Haematology/Oncology\nHospital, Shorsh Hospital and the Maternity Teaching Hospital, Sulaimaniyah,\nRepublic of Iraq between 1 January 2020 and 30 June 2021. The inclusion criteria\nwere as follows: (i) women with confirmed primary OC based on a\nhistopathological evaluation of the tumour mass after surgery; (ii) women with a\nhistory of other benign gynaecological diseases; (iii) women of any age. The\nexclusion criteria were as follows: (i) women with other gynaecological\nmalignancies, such as endometrial cancer, cervical cancer, valvular cancer and\nother secondary metastases.\nEthical approval for this study was provided by the Arab Board of Health\nSpecializations (no. 2/03022020-COM-UOS) following the appropriate guidelines\nand regulations belonging to the declaration of Helsinki. Approval was also\nprovided by the Institutional Review Boards of the three hospital authorities.\nWritten informed consent was provided by all study participants and their data\nwere de-identified. The reporting of this study conforms to STROBE guidelines. \n 22\nData were collected using a well-designed and detailed questionnaire directly\nfrom the patients or their relatives that included sociodemographic data such as\nage, marital status, educational level, smoking status, parity; and\nanthropometric data (height and weight to determine body mass index [BMI]). Data\non medical problems (such as comorbidities), a family history of OC and breast\ncancer, a history of using contraceptive pills/intrauterine device (IUD), a\nhistory of hysterectomy, as well as a history of infertility and using\nmedication for ovulation induction were also obtained. Information on other\ngynaecological disorders was collected. The histological findings of the excised\novarian tumour/mass and stage of OC were reported. Levels of OC biomarkers\nincluding CA-125, cancer antigen 19-9 (CA19-9), carcinoembryonic antigen (CEA),\nβ human chorionic gonadotropin (β-hCG) and lactate dehydrogenase (LDH) were\ndetermined using enzyme-linked immunosorbent assays and the data were collected\nfrom the patient’s records.\nAll statistical analyses were performed using IBM SPSS Statistics for Windows,\nVersion 25.0 (IBM Corp., Armonk, NY, USA). Continuous data are presented as\nmean ± SD and categorical data are presented as  n  of patients\n(%). χ 2 -test was used to compare categorical data and Fisher’s exact\ntest was used to compare categorical data when the expected variables\nwere < 20% of total variables. A  P -value < 0.05 was\nconsidered statistically significant.\n\nThis retrospective observational study enrolled 100 women with confirmed OC and other\nassociated gynaecological diseases. The mean ± SD age of the cohort of women with OC\nwas 55.0 ± 15.0 years. In terms of the age distribution, 63% (63 of 100 patients)\nwere aged 40–59 years, 28% (28 of 100 patients) were aged 60–79 years and 9.0% (nine\nof 100 patients) were aged > 80 years ( Table 1 ). The mean ± SD BMI of the cohort\nof women with OC was 28.7 kg/m 2 ; of which 80% (80 of 100 patients) were\noverweight and obese. The majority of women (77%; 77 of 100 patients) were married\nand illiterate (56%; 56 of 100 patients). Medical comorbidities were identified in\n56 of 100 patients (56%) and were as follows: hypertension (19 of 56 patients;\n33.9%); anaemia (eight of 56 patients; 14.3%); diabetes mellitus (seven of 56\npatients; 12.5%); cardiac disease (six of 56 patients; 10.7%); or they had a\ncombination of comorbidities. A total of 37 of 100 patients (37%) had a history of a\nfirst-degree relative with breast/OC. A total of 27 of 100 patients (27%) had a\nhistory of current and passive smoking. Regarding parity, 20 of 100 patients (20%)\nwere nulliparous and 80 of 100 patients (80%) were multiparous. A total of 10 of 100\npatients (10%) were infertile and had used medication for ovulation induction. Of\nthe 100 patients, three (3%) used oral contraceptive pills and only one (1%) had\nundergone a hysterectomy.\nDemographic and clinical characteristics of women ( n  = 100)\nwith ovarian cancer (OC) that were included in a retrospective observational\nstudy aimed to evaluate the correlation between benign gynaecological\ndiseases and the development of OC.\na Current and passive smoking history.\nThe gynaecological diseases observed in the cohort of women with OC were simple\novarian cyst (44 of 100 patients; 44%) and benign uterine tumours (56 of 100\npatients; 56%); the latter of which included UF (22 of 100 patients; 22%),\nadenomyosis (15 of 100 patients; 15%), PID (13 of 100 patients; 13%) and\nendometriosis (six of 100 patients; 6%) ( Table 2 ). The histological findings of the\nOC tumour masses were as follows; high grade serous OC (59 of 100 patients; 59%),\nmucinous OC (20 of 100 patients; 20%), low grade serous OC (nine of 100 patients;\n9%), granulosa cell tumour (five of 100 patients; 5%), yolk sac tumour (four of 100\npatients; 4%) and endometrioid (one of 100 patients; 1%). A total of 52 patients\n(52%) had stage I/II OC and 48 patients (48%) had stage III/IV OC.\nGynaecological conditions and characteristics of ovarian cancer (OC) in women\n( n  = 100) included in a retrospective observational\nstudy aimed to evaluate the correlation between benign gynaecological\ndiseases and the development of OC.\nThe identification of tumour biomarkers in the cohort of women with OC are presented\nin  Table 3 . Increased\nlevels of CA-125 (65 of 100 patients; 65%), CA19-9 (21 of 100 patients; 21%), β-hCG\n(eight of 100 patients; 8%), LDH (nine of 100 patients; 9%) and CEA (two of 100\npatients; 2%) were measured. Some patients had increased levels of more than one\nbiomarker: CA-125 + CA19-9 (nine of 100 patients; 9%), β-hCG + LDH (two of 100\npatients; 2%), CA-125 + LDH (six of 100 patients; 6%) and CA-125 + β-hCG (four of\n100 patients; 4%) ( Table\n3 ).\nIncreased tumour biomarker levels of women ( n  = 100) with\novarian cancer (OC) that were included in a retrospective observational\nstudy aimed to evaluate the correlation between benign gynaecological\ndiseases and the development of OC.\nCA, cancer antigen; CEA, carcinoembryonic antigen; β-hCG, β human\nchorionic gonadotropin; LDH, lactate dehydrogenase.\nAnalysis of the relationship between the origin of the benign disease and OC tumour\nhistology demonstrated a significant association ( P  = 0.03) between\nhigh grade serous OC histology with both benign ovarian and uterine diseases ( Table 4 ). There was a\nsignificant association between β-hCG ( P  = 0.009) and LDH\n( P  = 0.03) biomarkers and benign uterine tumours. There were no\nother significant associations observed for the other biomarkers and benign\novarian/uterine tumours.\nRelationship between ovarian cancer (OC) histology, staging and tumour\nbiomarkers according to benign gynaecological disease origin in women\n( n  = 100) with OC that were included in a retrospective\nobservational study aimed to evaluate the correlation between benign\ngynaecological diseases and the development of OC.\nCA, cancer antigen; CEA, carcinoembryonic antigen; β-hCG, β human\nchorionic gonadotropin; LDH, lactate dehydrogenase.\na χ 2 -test was used to compare categorical data and\nFisher’s exact test was used to compare categorical data when the\nexpected variables were < 20% of total variables; NS, no significant\nassociation ( P  ≥   0.05).\nThere was a significant association ( P  < 0.001) between both\nadenomyosis and UF and high grade OC ( Table 5 ). A significant association\n( P =  0.008) was observed between endometriosis and stages\nIII/IV of OC.\nRelationship between ovarian cancer (OC) histology, benign gynaecological\ndisease origin and cancer stage in women ( n  = 100) with OC\nthat were included in a retrospective observational study aimed to evaluate\nthe correlation between benign gynaecological diseases and the development\nof OC.\nData presented as  n  of patients (%).\nPID, pelvic inflammatory disease.\na χ 2 -test was used to compare categorical data and\nFisher’s exact test was used to compare categorical data when the\nexpected variables were < 20% of total variables; NS, no significant\nassociation ( P  ≥ 0.05).\nThere was a significant association ( P  = 0.009) between younger age\nand benign uterine diseases ( Table 6 ). There was a significant association\n( P <  0.001) between no education and benign uterine diseases.\nThere was a significant association ( P  = 0.02) between a history of\nmedical comorbidities and benign uterine diseases, especially hypertension\n( P  = 0.004). There were no significant correlations between the\nmenstrual status, marital status, BMI, first-degree female relative with breast/OC\nand smoking status and both benign ovarian and uterine diseases. There was a\nsignificant correlation ( P  = 0.04) between the use of oral\ncontraceptive pills > 5 years and benign ovarian diseases. There were no\nsignificant correlations between IUD use, parity, ovulation inducer use and\nhysterectomy and both benign ovarian and uterine diseases.\nRelationship between benign gynaecological disease origin and\ndemographic/clinical characteristics of women ( n  = 100)\nwith OC that were included in a retrospective observational study aimed to\nevaluate the correlation between benign gynaecological diseases and the\ndevelopment of OC.\na χ 2 -test was used to compare categorical data and\nFisher’s exact test was used to compare categorical data when the\nexpected variables were < 20% of total variables; NS, no significant\nassociation ( P  ≥ 0.05).\nDM, diabetes mellitus; HT, hypertension; IUD, intrauterine device.\n\nOvarian cancer is a common gynaecological cancer worldwide, especially in older women. \n 23 \n  Despite the advances in medical technology, the exact pathogenesis of OC is\nnot fully understood. \n 24 \n  The relationship between benign gynaecological diseases and OC remains\nuncertain despite ongoing research. \n 8\nThis current retrospective observational study demonstrated that 56% of the women\nwith OC had benign uterine diseases, most commonly UF and adenomyosis. This finding\nwas consistent with the results a previous large population-based case–control study\nin the US that reported that multiple gynaecological diseases in women increased the\nrisk of OC. \n 25 \n  In the current study, 22% of women with OC had UF. This finding was very\nsimilar to the results of a population-based cohort study conducted in Denmark,\nwhich demonstrated a strong association between benign gynaecological diseases\n(especially UF) and the risk of OC. \n 26 \n  An explanation of the mechanisms involved in the relationship between benign\ngynaecological diseases and OC might involve hormonal changes, benign tumour risk\nfactors and a higher surveillance rate of women with benign conditions, which could\nsubsequently lead to a higher OC identification rate. \n 27 \n  In the current study, 15% of women with OC also had adenomyosis, which was\nsimilar to the findings of a previous case–control study in China that found no\nsignificant relationship between women with UF or endometriosis and risk of OC; but\nthe risk of OC was high among women with adenomyosis. \n 28\nIn the current study, 13% of women with OC had PID, which was similar to the results\nof a previous study conducted in Denmark, which found that women with PID had a\ntwo-fold increased risk of subsequent OC. \n 29 \n  In addition to the effect of frequent ovulation and high gonadotropin levels\non the pathogenesis of OC, inflammation plays a significant biological role in the\ndevelopment of OC. \n 28 \n  Moreover, PID related to genital tract infections increases the risk of OC. \n 30\nIn the current study, 6% of women with OC had endometriosis. Similarly, a previous\nstudy undertaken in Italy reported that both endometriosis and OC had a common\npathological mechanism and shared a common preventive strategy. \n 31 \n  The reason for the relationship between endometriosis and OC remains mainly\nunknown, but it might be attributed to the microenvironment at the endometriosis\nsite. 3 \n 1\nThe current study demonstrated that the most common histology was high grade serous\nOC (59% of patients), which agrees with a previous retrospective study undertaken in\nthe Republic of Iraq that found that high grade serous OC was common (57%). \n 32 \n  In the current study, 52% of women had stage I/II OC and 48% had stage III/IV\nOC, which was inconsistent with the findings of a study undertaken in Maysan,\nRepublic of Iraq that reported that 76% of patients had stage III/IV OC. \n 33 \n  This inconsistency might be attributed to better OC diagnosis and treatment\nfacilities in the Kurdistan Region than other areas of the Republic of Iraq.\nWith regard to tumour biomarkers, this current study showed that the CA-125 level was\nincreased in 65% of women with OC, which was similar to the results of Canadian\nstudy that reported that CA-125 is an accurate biomarker of OC with moderate\nsensitivity and high specificity. \n 34\nThe current study demonstrated a significant association ( P  = 0.009)\nbetween younger age and benign uterine diseases, which agreed with the findings of\nan Italian study. \n 35 \n  The current study also showed a significant association\n( P  < 0.001) between no education and benign uterine diseases.\nThis current finding was consistent with a US study that demonstrated that the risk\nof OC was increased in women with low educational and socioeconomic levels, which is\npossibly due to illiteracy resulting in low levels of awareness of the risk factors\npreceding OC such as benign gynaecological diseases. \n 36\nIn the present study, there was a significant association ( P  = 0.02)\nbetween a history of medical comorbidities and benign uterine diseases, which was\nsimilar to the results of a study conducted in Mexico. \n 37 \n  The current study also found a significant association\n( P  = 0.004) between hypertension and benign uterine diseases,\nconsistent with the results a previous Danish study, which found that women with\nhypertension had a higher risk of OC and uterine tumours. \n 26\nThe current study demonstrated a significant association ( P =  0.03)\nbetween high grade serous OC histology with both benign ovarian and uterine\ndiseases. This finding was similar to the results of a US study that reported that\nwomen with OC accompanied with a benign ovarian mass had a higher grade of cancer. \n 38\nIn the present study, there was a significant association\n( P  = 0.009) between β-hCG and benign uterine tumours. This current\nfinding parallels the results of other studies that reported the role of a β-hCG in\nboth OC and benign uterine tumours. 39 , 40  This current study also\ndemonstrated a significant association ( P  = 0.03) between LDH and\nbenign uterine tumours, which was consistent with the results of a Japanese study\nthat reported that LDH levels were useful in distinguishing endometriosis-related OC\nand ovarian endometrioma. \n 41\nThe current study demonstrated was a significant association\n( P  < 0.001) between both adenomyosis and UF and high grade OC,\nfindings that agreed with the results of a large population-based case–control study\nin the US, which demonstrated that the risk of high grade serous OC increased with\nthe risk of accompanying benign gynaecological disorders. \n 25 \n  The current study also found a significant association\n( P =  0.008) between endometriosis and stages III/IV of OC, which\nwas similar to the results of a previous Italian study. \n 31\nThe current study had several limitations. First, it was undertaken during the\ncoronavirus COVID-19 lockdown. Secondly, the sample size was small. Thirdly, there\nwas a time limitation due to the fact that a postgraduate student (Soz Mustafa Hagi\nKarim) was collecting the data.\nIn conclusion, benign gynaecological diseases are accompanied by the high risk of the\ndevelopment of OC. Common benign gynaecological diseases associated with OC were\nuterine fibroids and adenomyosis. The risk of OC might be further increased by a low\neducational level and the presence of other comorbidities, especially hypertension.\nThe presence of benign gynaecological disease is a risk for high grade OC histology\nand advanced stages of OC. These findings suggest that there should be mandatory\nhealth education about OC provided to women with benign gynaecological\nconditions.","source_license":"CC0","license_restricted":false}