The correlation between women's various gynaecological diseases to ovarian cancer in Sulaimaniyah City, Iraq

Ovarian cancer (OC) is considered a life-threatening disease in women with reproductive tumours because it is the second most common cause of death in diagnosed women worldwide. 1 Generally, the majority of cases of OC are detected when the disease has already progressed significantly, which results in poor outcomes even if the patient receives the correct therapies or undergoes surgery. 2 A comprehensive ultrasonographic assessment of the female reproductive organs and the measurement of serum biomarkers such as cancer antigen (CA)-125 are the preferred strategies to detect gynaecological cancers. 2 Novel therapeutic modalities related to the molecular description of OC are required. However, treatment does not reduce OC morbidity or mortality and an increased frequency of recurrence was found even after initial treatment. 3 , 4 In the US, 21 750 OC patients and 13 940 deaths due to OC were reported in 2020, which accounted for 1.2% of all cancer cases in that country and the 5-year survival rate for well-treated women with OC was 48.6%. 5 A previous study in India reported that 15.7% of cases were identified at the local stage and these cases had a 92.6% survival rate, whereas the 58% of cases that were detected at the metastatic stage had a survival rate of 30.2%. 6 In terms of the histological classification of OC, the epithelial type is the most common (90%), which based on their histology are either serous, mucinous, endometrioid or clear cell tumours. 7 OC can be further classified into two subtypes known as type I and type II carcinomas, the latter being the more fatal variant, which is thought to be caused by continuous ovarian cycles resulting in inflammation and endometriosis. 8 Regarding parity, nulliparous women have a higher risk of OC mainly due to ongoing regular ovulation that might increase the risk of repeated minor injury to the superficial ovarian epithelium during the ovulation process. 9 Postmenopausal women have a high incidence rate of OC and a low survival rate. 10 This group of women have type I OC, especially those > 50 years. 8 However, premenopausal women are more likely to have hereditary OC. 8 Furthermore, a family history of having breast cancer/OC is considered the greatest risk factor of OC; and an individual history of breast cancer similarly increases the risk of OC. 11 Similarly, pelvic inflammatory disease (PID) is a risk factor for OC development. 12 Uterine fibroid (UF) is a benign tumour of the womb that grows mainly during reproductive age in approximately 70% of women. 13 However, 50% of women do not show clinical signs related to UF, which might include abdominal ache, high menstrual bleeding and anaemia. 14 The development of UF is 2–3 times more likely in obese women than in those with average body weight. 15 Subsequently, UF might have the exactly the same pathophysiology of reproductive organ malignancy, especially endometrial/OCs. 16 Endometriosis is a common oestrogen-related disorder found in approximately 10% of women of reproductive age, which can be associated with pelvic pain, although asymptomatic cases are found that sometimes result in infertility. 17 The burden of endometriosis during reproductive life changes after the menopause, when ovarian hormones stop stimulating the lesions and the major issue is the risk of malignant transformation. 18 Moreover, endometriosis is suggested to be associated with a significantly increased risk of invasive OC because mutations of the AT-Rich Interaction Domain 1A gene have been demonstrated in endometriosis, which suggests an initial stage in the pathogenesis of endometriosis-associated ovarian cancer. 19 Prolonged inflammation is important in the formation and development of endometriosis via the production of proinflammatory cytokines such as matrix metalloproteinase-3, interleukin (IL)-6/IL-8, intercellular adhesion molecule-1 and tumour necrosis factor-alpha. 20 Approximately one-third of patients with OC are asked to use contraceptive hormones for a long time to reduce the possibility of OC recurrence. 21 In this regard, it was found that receiving contraceptive hormones for > 15 years reduced the risk of the OC by roughly 50%. 21 This current retrospective observational study aimed to evaluate the correlation between benign gynaecological disorders and the development of OC.

This retrospective observational study enrolled 100 women with confirmed OC and other associated gynaecological diseases. The mean ± SD age of the cohort of women with OC was 55.0 ± 15.0 years. In terms of the age distribution, 63% (63 of 100 patients) were aged 40–59 years, 28% (28 of 100 patients) were aged 60–79 years and 9.0% (nine of 100 patients) were aged > 80 years ( Table 1 ). The mean ± SD BMI of the cohort of women with OC was 28.7 kg/m 2 ; of which 80% (80 of 100 patients) were overweight and obese. The majority of women (77%; 77 of 100 patients) were married and illiterate (56%; 56 of 100 patients). Medical comorbidities were identified in 56 of 100 patients (56%) and were as follows: hypertension (19 of 56 patients; 33.9%); anaemia (eight of 56 patients; 14.3%); diabetes mellitus (seven of 56 patients; 12.5%); cardiac disease (six of 56 patients; 10.7%); or they had a combination of comorbidities. A total of 37 of 100 patients (37%) had a history of a first-degree relative with breast/OC. A total of 27 of 100 patients (27%) had a history of current and passive smoking. Regarding parity, 20 of 100 patients (20%) were nulliparous and 80 of 100 patients (80%) were multiparous. A total of 10 of 100 patients (10%) were infertile and had used medication for ovulation induction. Of the 100 patients, three (3%) used oral contraceptive pills and only one (1%) had undergone a hysterectomy. Demographic and clinical characteristics of women ( n  = 100) with ovarian cancer (OC) that were included in a retrospective observational study aimed to evaluate the correlation between benign gynaecological diseases and the development of OC. a Current and passive smoking history. The gynaecological diseases observed in the cohort of women with OC were simple ovarian cyst (44 of 100 patients; 44%) and benign uterine tumours (56 of 100 patients; 56%); the latter of which included UF (22 of 100 patients; 22%), adenomyosis (15 of 100 patients; 15%), PID (13 of 100 patients; 13%) and endometriosis (six of 100 patients; 6%) ( Table 2 ). The histological findings of the OC tumour masses were as follows; high grade serous OC (59 of 100 patients; 59%), mucinous OC (20 of 100 patients; 20%), low grade serous OC (nine of 100 patients; 9%), granulosa cell tumour (five of 100 patients; 5%), yolk sac tumour (four of 100 patients; 4%) and endometrioid (one of 100 patients; 1%). A total of 52 patients (52%) had stage I/II OC and 48 patients (48%) had stage III/IV OC. Gynaecological conditions and characteristics of ovarian cancer (OC) in women ( n  = 100) included in a retrospective observational study aimed to evaluate the correlation between benign gynaecological diseases and the development of OC. The identification of tumour biomarkers in the cohort of women with OC are presented in Table 3 . Increased levels of CA-125 (65 of 100 patients; 65%), CA19-9 (21 of 100 patients; 21%), β-hCG (eight of 100 patients; 8%), LDH (nine of 100 patients; 9%) and CEA (two of 100 patients; 2%) were measured. Some patients had increased levels of more than one biomarker: CA-125 + CA19-9 (nine of 100 patients; 9%), β-hCG + LDH (two of 100 patients; 2%), CA-125 + LDH (six of 100 patients; 6%) and CA-125 + β-hCG (four of 100 patients; 4%) ( Table 3 ). Increased tumour biomarker levels of women ( n  = 100) with ovarian cancer (OC) that were included in a retrospective observational study aimed to evaluate the correlation between benign gynaecological diseases and the development of OC. CA, cancer antigen; CEA, carcinoembryonic antigen; β-hCG, β human chorionic gonadotropin; LDH, lactate dehydrogenase. Analysis of the relationship between the origin of the benign disease and OC tumour histology demonstrated a significant association ( P  = 0.03) between high grade serous OC histology with both benign ovarian and uterine diseases ( Table 4 ). There was a significant association between β-hCG ( P  = 0.009) and LDH ( P  = 0.03) biomarkers and benign uterine tumours. There were no other significant associations observed for the other biomarkers and benign ovarian/uterine tumours. Relationship between ovarian cancer (OC) histology, staging and tumour biomarkers according to benign gynaecological disease origin in women ( n  = 100) with OC that were included in a retrospective observational study aimed to evaluate the correlation between benign gynaecological diseases and the development of OC. CA, cancer antigen; CEA, carcinoembryonic antigen; β-hCG, β human chorionic gonadotropin; LDH, lactate dehydrogenase. a χ 2 -test was used to compare categorical data and Fisher’s exact test was used to compare categorical data when the expected variables were < 20% of total variables; NS, no significant association ( P  ≥   0.05). There was a significant association ( P  < 0.001) between both adenomyosis and UF and high grade OC ( Table 5 ). A significant association ( P =  0.008) was observed between endometriosis and stages III/IV of OC. Relationship between ovarian cancer (OC) histology, benign gynaecological disease origin and cancer stage in women ( n  = 100) with OC that were included in a retrospective observational study aimed to evaluate the correlation between benign gynaecological diseases and the development of OC. Data presented as n of patients (%). PID, pelvic inflammatory disease. a χ 2 -test was used to compare categorical data and Fisher’s exact test was used to compare categorical data when the expected variables were < 20% of total variables; NS, no significant association ( P  ≥ 0.05). There was a significant association ( P  = 0.009) between younger age and benign uterine diseases ( Table 6 ). There was a significant association ( P <  0.001) between no education and benign uterine diseases. There was a significant association ( P  = 0.02) between a history of medical comorbidities and benign uterine diseases, especially hypertension ( P  = 0.004). There were no significant correlations between the menstrual status, marital status, BMI, first-degree female relative with breast/OC and smoking status and both benign ovarian and uterine diseases. There was a significant correlation ( P  = 0.04) between the use of oral contraceptive pills > 5 years and benign ovarian diseases. There were no significant correlations between IUD use, parity, ovulation inducer use and hysterectomy and both benign ovarian and uterine diseases. Relationship between benign gynaecological disease origin and demographic/clinical characteristics of women ( n  = 100) with OC that were included in a retrospective observational study aimed to evaluate the correlation between benign gynaecological diseases and the development of OC. a χ 2 -test was used to compare categorical data and Fisher’s exact test was used to compare categorical data when the expected variables were < 20% of total variables; NS, no significant association ( P  ≥ 0.05). DM, diabetes mellitus; HT, hypertension; IUD, intrauterine device.

This retrospective observational study enrolled consecutive women with confirmed OC and other associated gynaecological diseases at Hiwa Haematology/Oncology Hospital, Shorsh Hospital and the Maternity Teaching Hospital, Sulaimaniyah, Republic of Iraq between 1 January 2020 and 30 June 2021. The inclusion criteria were as follows: (i) women with confirmed primary OC based on a histopathological evaluation of the tumour mass after surgery; (ii) women with a history of other benign gynaecological diseases; (iii) women of any age. The exclusion criteria were as follows: (i) women with other gynaecological malignancies, such as endometrial cancer, cervical cancer, valvular cancer and other secondary metastases. Ethical approval for this study was provided by the Arab Board of Health Specializations (no. 2/03022020-COM-UOS) following the appropriate guidelines and regulations belonging to the declaration of Helsinki. Approval was also provided by the Institutional Review Boards of the three hospital authorities. Written informed consent was provided by all study participants and their data were de-identified. The reporting of this study conforms to STROBE guidelines. 22 Data were collected using a well-designed and detailed questionnaire directly from the patients or their relatives that included sociodemographic data such as age, marital status, educational level, smoking status, parity; and anthropometric data (height and weight to determine body mass index [BMI]). Data on medical problems (such as comorbidities), a family history of OC and breast cancer, a history of using contraceptive pills/intrauterine device (IUD), a history of hysterectomy, as well as a history of infertility and using medication for ovulation induction were also obtained. Information on other gynaecological disorders was collected. The histological findings of the excised ovarian tumour/mass and stage of OC were reported. Levels of OC biomarkers including CA-125, cancer antigen 19-9 (CA19-9), carcinoembryonic antigen (CEA), β human chorionic gonadotropin (β-hCG) and lactate dehydrogenase (LDH) were determined using enzyme-linked immunosorbent assays and the data were collected from the patient’s records. All statistical analyses were performed using IBM SPSS Statistics for Windows, Version 25.0 (IBM Corp., Armonk, NY, USA). Continuous data are presented as mean ± SD and categorical data are presented as n of patients (%). χ 2 -test was used to compare categorical data and Fisher’s exact test was used to compare categorical data when the expected variables were < 20% of total variables. A P -value < 0.05 was considered statistically significant.

Ovarian cancer is a common gynaecological cancer worldwide, especially in older women. 23 Despite the advances in medical technology, the exact pathogenesis of OC is not fully understood. 24 The relationship between benign gynaecological diseases and OC remains uncertain despite ongoing research. 8 This current retrospective observational study demonstrated that 56% of the women with OC had benign uterine diseases, most commonly UF and adenomyosis. This finding was consistent with the results a previous large population-based case–control study in the US that reported that multiple gynaecological diseases in women increased the risk of OC. 25 In the current study, 22% of women with OC had UF. This finding was very similar to the results of a population-based cohort study conducted in Denmark, which demonstrated a strong association between benign gynaecological diseases (especially UF) and the risk of OC. 26 An explanation of the mechanisms involved in the relationship between benign gynaecological diseases and OC might involve hormonal changes, benign tumour risk factors and a higher surveillance rate of women with benign conditions, which could subsequently lead to a higher OC identification rate. 27 In the current study, 15% of women with OC also had adenomyosis, which was similar to the findings of a previous case–control study in China that found no significant relationship between women with UF or endometriosis and risk of OC; but the risk of OC was high among women with adenomyosis. 28 In the current study, 13% of women with OC had PID, which was similar to the results of a previous study conducted in Denmark, which found that women with PID had a two-fold increased risk of subsequent OC. 29 In addition to the effect of frequent ovulation and high gonadotropin levels on the pathogenesis of OC, inflammation plays a significant biological role in the development of OC. 28 Moreover, PID related to genital tract infections increases the risk of OC. 30 In the current study, 6% of women with OC had endometriosis. Similarly, a previous study undertaken in Italy reported that both endometriosis and OC had a common pathological mechanism and shared a common preventive strategy. 31 The reason for the relationship between endometriosis and OC remains mainly unknown, but it might be attributed to the microenvironment at the endometriosis site. 3 1 The current study demonstrated that the most common histology was high grade serous OC (59% of patients), which agrees with a previous retrospective study undertaken in the Republic of Iraq that found that high grade serous OC was common (57%). 32 In the current study, 52% of women had stage I/II OC and 48% had stage III/IV OC, which was inconsistent with the findings of a study undertaken in Maysan, Republic of Iraq that reported that 76% of patients had stage III/IV OC. 33 This inconsistency might be attributed to better OC diagnosis and treatment facilities in the Kurdistan Region than other areas of the Republic of Iraq. With regard to tumour biomarkers, this current study showed that the CA-125 level was increased in 65% of women with OC, which was similar to the results of Canadian study that reported that CA-125 is an accurate biomarker of OC with moderate sensitivity and high specificity. 34 The current study demonstrated a significant association ( P  = 0.009) between younger age and benign uterine diseases, which agreed with the findings of an Italian study. 35 The current study also showed a significant association ( P  < 0.001) between no education and benign uterine diseases. This current finding was consistent with a US study that demonstrated that the risk of OC was increased in women with low educational and socioeconomic levels, which is possibly due to illiteracy resulting in low levels of awareness of the risk factors preceding OC such as benign gynaecological diseases. 36 In the present study, there was a significant association ( P  = 0.02) between a history of medical comorbidities and benign uterine diseases, which was similar to the results of a study conducted in Mexico. 37 The current study also found a significant association ( P  = 0.004) between hypertension and benign uterine diseases, consistent with the results a previous Danish study, which found that women with hypertension had a higher risk of OC and uterine tumours. 26 The current study demonstrated a significant association ( P =  0.03) between high grade serous OC histology with both benign ovarian and uterine diseases. This finding was similar to the results of a US study that reported that women with OC accompanied with a benign ovarian mass had a higher grade of cancer. 38 In the present study, there was a significant association ( P  = 0.009) between β-hCG and benign uterine tumours. This current finding parallels the results of other studies that reported the role of a β-hCG in both OC and benign uterine tumours. 39 , 40 This current study also demonstrated a significant association ( P  = 0.03) between LDH and benign uterine tumours, which was consistent with the results of a Japanese study that reported that LDH levels were useful in distinguishing endometriosis-related OC and ovarian endometrioma. 41 The current study demonstrated was a significant association ( P  < 0.001) between both adenomyosis and UF and high grade OC, findings that agreed with the results of a large population-based case–control study in the US, which demonstrated that the risk of high grade serous OC increased with the risk of accompanying benign gynaecological disorders. 25 The current study also found a significant association ( P =  0.008) between endometriosis and stages III/IV of OC, which was similar to the results of a previous Italian study. 31 The current study had several limitations. First, it was undertaken during the coronavirus COVID-19 lockdown. Secondly, the sample size was small. Thirdly, there was a time limitation due to the fact that a postgraduate student (Soz Mustafa Hagi Karim) was collecting the data. In conclusion, benign gynaecological diseases are accompanied by the high risk of the development of OC. Common benign gynaecological diseases associated with OC were uterine fibroids and adenomyosis. The risk of OC might be further increased by a low educational level and the presence of other comorbidities, especially hypertension. The presence of benign gynaecological disease is a risk for high grade OC histology and advanced stages of OC. These findings suggest that there should be mandatory health education about OC provided to women with benign gynaecological conditions.