Population-based study on the role of atypical endometriosis in the development of ovarian cancer
Dr. R.L.M. Bekkers, gynecologic oncologist, Catharina Hospital Eindhoven
Michelangelolaan 2 5623 EJ Eindhoven
Dr. H.A.A.M. van Vliet, gynecologist, special interest endometriosis, Catharina Hospital Eindhoven
Michelangelolaan 2 5623 EJ Eindhoven
Dr. A.G. Siebers, Postdoc, PALGA, Houten, Nederland, and Pathology, RadboudUMC Nijmegen
Dr. A. van Altena, gynecologic oncology, department of obstetrics and gynecology, RadboudUMC Nijmegen
Geert Grote plein 10, 6500 HB Nijmegen
Ovarian cancer is the second most common gynecological malignancy in developed countries and has the highest mortality rate in cancers of the female reproductive system.(1) Worldwide, each year about 200,000 women are diagnosed with ovarian cancer and 125,000 women die from this disease.(2) The high mortality rate is due to the fact that approximately two third of these women are diagnosed at an advanced stage of disease; stage III-IV, consequently resulting in a poor survival. Despite advances in radical surgery and chemotherapy, overall survival has increased only marginal in the past 30 years.(3) The overall five-year survival rate of epithelial ovarian cancer (EOC) lies around 45%.(4)
Endometriosis is defined as the presence of endometrial-like glands and stroma outside of the uterine cavity and features estrogen dependency and inflammation.(5-7) It is estimated to affect 5-12% of women of reproductive age, with the main symptoms being dysmenorrhea and subfertility.(5, 8, 9) Although endometriosis is considered to be a benign condition, it carries similar characteristics to malignant tumors. These include development of local and distant metastases, attachment, invasion and subsequent damage of adjacent tissues, the risk of recurrence and its resistance to apoptosis.(10-12) Endometriotic lesions are identified mainly on the ovaries, pelvic peritoneum, and rectovaginal septum; in rare cases, also extraperitoneal lesions have been reported.(5, 13) The etiology of endometriosis is not fully understood, but the most accepted hypothesis considers retrograde menstruation as an important causal factor for the implantation of extra-uterine endometrial tissue.(14) The gold standard for diagnosis is a laparoscopy, preferably combined with histological confirmation.(15)
Endometriosis has been linked with an increased risk of developing various malignancies, mainly ovarian cancer. Already in 1925, Sampson et al. described a case of ovarian cancer arising from endometriosis in that organ. This was followed by abundant epidemiologic, genetic and histopathologic studies, suggesting endometriosis to be linked to EOC, mainly the endometrioid and clear-cell type.(10, 16-35) Recent studies have described different possible pathways of the pathophysiology of malignant transformation of endometriosis into EOC. One of the possible causal factors could be the repeated episodes of hemorrhage that occur in endometriosis at the onset of menstruation. Extracellular hemoglobin, heme, and iron derivatives in endometriosis may cause oxidative stress leading to genetic abnormalities, which could lead to malignant progression.(9, 36-38) Also, in the inflammatory microenvironment of endometriosis macrophages secrete immunosuppressive factors that could lead to promotion of malignant transformation.(9, 36) The exact mechanism by which malignant transformation in endometriosis occurs has not yet been demonstrated, however based on these theories it seems to be a complex, multifactorial pathogenesis.(6, 39) The progression of endometriosis to cancer is usually slow, possibly enabling diagnosis at an early stage of the disease.(40) Based on the available literature, atypical endometriosis is considered an intermediate lesion between endometriosis and ovarian cancer.(1, 41, 42)
Several definitions for atypical cells in endometriosis have been described; the criteria from Thomas and Campbell are most often used(43). In other studies the criteria of Czernobilsky(44) or LaGrenade(45) were used. However, all these criteria are susceptible for inter-person variation and not been validated in large studies. Currently, there is no effective screening method to detect ovarian cancer at an early stage. In the literature risk factors for developing ovarian cancer are described to be BRCA1/2 gene mutations, Lynch syndrome, family history, tobacco use, and incessant ovulation or menstruation due to early menarche, late menopause, polycystic ovarian syndrome, infertility and/or nulliparity.(21, 46-51) Strategies are developed to prevent women from getting ovarian cancer since screening seems ineffective. The main strategy nowadays in BRCA gene mutation carriers is to perform a prophylactic salpingo-oophorectomy. However, different subtypes of ovarian cancer are believed to have different pathways through which benign tissue turns into a pre-malignant condition and then into the invasive form i.e. ovarian cancer. With endometrioid or clear cell type ovarian cancer, endometriosis could well be the precursor that can lead to premalignant and ultimately malignant disease. A subgroup of patients with endometriosis might well be suitable for regular surveillance, even after the menopause. Current practice is that endometriosis patients are discharged from follow-up once they have been diagnosed as post- menopausal, since symptoms are then self-limiting in the majority of patients. Another strategy in high-risk endometriosis patients could be to aim for an endometriosis-free pelvis by performing more aggressive surgical procedures. Further research of possible risk factors for malignant transformation in endometriosis is warranted to be able to identify patients at risk. It is unclear what amount of patients with endometriosis shows hyperplasia or atypical cells in the pathology results, nor is it clear what should be the consequences of these findings. Furthermore, it is not clearly known whether peritoneal or rectovaginal deep- infiltrating endometriosis increases the risk of developing ovarian cancer.(52) A recent study by Anglesio et al. found that lesions in deep infiltrating endometriosis, which are associated with virtually no risk of malignant transformation, harbor somatic cancer driver mutations.(53)
A case-control study, conducted by Melin et al., suggests that the risk of developing ovarian cancer could be cut by 70% if all visible endometriotic lesions are removed.(54) However, this remains speculative. To date, no other case-control studies have taken surgical completeness of endometriosis surgery into consideration to reduce the risk of cancer. More research on these topics is needed to gain a better understanding of possible risk factors for malignant transformation of ovarian endometriomas.
All pathology results from patients with endometriosis that have had surgery for ovarian endometriosis in our Radboud University Medical Center between 1980 and 2016 have recently been evaluated. We were able to study the pathology reports of 936 patients. From these, the presence of atypical cells was mentioned in 74 cases (8%). From these 74 cases, 18 patients were reported to have atypical cells and 3 had complex hyperplasia in the ovarian endometriosis. A discussion among several gyneco-pathologists revealed the lack of agreement of the criteria for atypia on the one hand and the clinical consequences on the other hand. It is likely that there has been an underreporting of atypia, since based on a study by Prefumo et al, the prevalence of hyperplasia and atypia in endometriomas was found to be 9.4% and 5.9%, respectively.(55)
In the Netherlands, a nationwide pathology database has been in place since 1989 with more than 95% coverage of all histological and cytological diagnoses in the Netherlands. With this unique database it is possible to study women with histologically proven endometriosis with a complete follow up of all histological and cytological diagnoses thereafter. The number of patients diagnosed in this database between 1990 and 2015 is about 133,000 unique women who have a follow-up of 2- 27 years. This database makes it possible to perform a matched cohort study in order to give a more definite answer on whether the relation between endometriosis and ovarian cancer exists and whether this risk is concerning specific histological subgroups.
Research Design and Methods:
To further focus on endometriosis and ovarian cancer we will perform a retrospective regional study. Patients from the Endometriosis Network South-East of the Netherlands (ENSEN) will be included through an extensive PALGA search for pathology results of endometriosis tissue. This region includes 2 academic hospitals and 4 large teaching hospitals, with an overall area of coverage of 5.600.000 inhabitants. An extensive study database, which has designed recently, will be used for data collection of medical and general patient characteristics. Once data collection is completed, statistical analyses can be done for various hypotheses based on these characteristics.
A thorough literature study led to a collection of factors that could play a role in the malignant transformation in endometriosis. This knowledge was used to determine the following subjects and variables for the study database: general information (e.g. age, ethnic group, BMI, tobacco use and pack years), type of endometriosis (ovarian endometriosis, peritoneal- and/or deep infiltrating endometriosis), anatomical location of endometriotic lesions, history of abdominal and pelvic surgery, status of removal of lesions (complete removal or locations/size of residual lesions), histopathological abnormalities such as atypia, chronic inflammation and/or complex hyperplasia, co-occurrence of adenomyosis and/or uterine fibroids, gynecological and obstetrical history, hereditary predisposition for malignancies, history and/or diagnoses of malignancies in follow-up period.
Experimental data collection was done to assess the study’s feasibility and to optimize the study database and codebook. Data collection of 14 patients in the newly designed study database led to optimization of the study database and codebook.
This population-based retrospective database will be used to look at several aspects we aimed to study.
– Using our nation-wide Pathology Analysis Registration System (PALGA), pathology reports will be analyzed on the occurrence of atypia and/or hyperplasia in endometriosis.
- – In a subset of patients gyne-pathologists will be asked to further look at tissue samples to study the inter- and intra-observer variety of diagnosing hyperplasia and atypia in endometriosis.
- – Together with the Dutch Pathology Association and international authorities we aim to come to an agreement on terminology and criteria for both hyperplasia and atypia in endometriosis.
- – We will study the results of surgical procedures performed in all endometriosis patients. The situation at the end of a procedure will be classified. The number of residuals, location of residual disease, and size of the largest residuals will be determined.
- – Using the PALGA database we are able to determine the development of ovarian cancer cases in our population. Risk factors on developing ovarian cancer in our population will be studied using the full database, but with a focus on pathology results and surgical results. Statistical methods A crude search identified 133,000 women with a histological diagnosis of endometriosis in PALGA between 1990 and 2015. We estimate that after checking for inclusion criteria, about 125.000 women will be illegible for this study. Given this number of patients with a median follow up of 13 years, and a yearly incidence (ESR, European standardized ratio) of invasive ovarian of 10.7, precise risk estimation is possible. In the regional part of the study, all patient, surgical and histo-pathological data will be studied by means of univariate and multivariate analysis to determine their role in the development of ovarian cancer. These data will help to discover which endometriosis patients are at high risk of developing ovarian cancer. The acquired knowledge will hopefully lead to preventive methods in women and clear guidelines around the diagnosis and follow-up of atypical endometriosis.
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