The association between endometriosis and gynecological cancers and breast cancer: a review of epidemiological data

Objective

This article critically reviews the literature on the association between endometriosis and gynecological cancers and breast cancer, based on epidemiologic data.

Methods

Literature review of the English language literature based on searching in the MEDLINE (PubMed) database and additional collection of reports by systematically reviewing all references from retrieved papers.

Results

Data from large cohort and case–control studies indicate that endometriosis patients only have an increased risk of ovarian cancer among the gynecological malignancies and breast cancer, although most of the observed associations are modest. Data on the association between endometriosis and breast cancer are inconsistent. Endometriosis patients have a reduced risk of cervical cancer, and there is no association between endometriosis and endometrial cancer. Endometriosis-associated ovarian cancer seems to be a distinct clinical entity; patients are younger, diagnosed in earlier stages, have lower grade lesions and a better survival. Further, endometriosis-associated ovarian cancers are predominantly clear cell and endometrioid histologic subtypes.

Conclusions

Endometriosis seems to be a precursor of epithelial ovarian cancer, especially clear cell and endometrioid adenocarcinomas. However, current evidence is insufficient to draw any definitive conclusions whether this association represents causality or the sharing of similar risk factors and/or antecedent mechanisms.     

Prevalence of endometriosis in ovarian cancer

Endometriosis may be the precursor of clear cell or endometrioid ovarian cancer. In this review, we focus on the prevalence of endometriosis in ovarian cancer and related clinical and epidemiological issues. According to 15 published reports, the rank order of the prevalence of endometriosis in each histologic type was clear cell (39.2%) > endometrioid (21.2%) > serous (3.3%) > mucinous type (3.0%). The high prevalence of endometriosis in clear cell and endometrioid types is a consistent finding in Japan and western countries. However, the incidence of the clear cell type is much higher (15-20% vs. 7-8%), and that of the endometrioid type is lower (7-16% vs. 18-26%), in Japan compared with western countries. This review is also concerned with the relationship between the presence of ovarian endometriosis and clinical features such as age, parity, menopausal status, clinical stage, and survival in ovarian cancer patients.     

The polycystic ovary syndrome and gynecological cancer risk

Abstract

This review updates the knowledge regarding the association between the polycystic ovary syndrome (PCOS) and the risk of gynecological cancer. We performed a literature review of clinical and epidemiological studies concerning PCOS and the risk of breast, endometrial and ovarian cancer after selecting information by quality of scientific methodology. It was found that evidence does not support a link between PCOS and breast cancer risk. There is an increased risk of endometrial cancer, while data concerning ovarian cancer are contradictory. Regarding PCOS and its association to cervical, fallopian tube, and vulvar cancer, the quality of evidence is heterogeneous. In conclusion, women with PCOS should be screened for endometrial cancer and more research is warranted to determine in this population the true risk of developing other gynecological cancers such as breast and ovarian.     

Pathological conditions predisposing to infertility and gynaecological neoplasia

Some of the conditions long blamed for female factor infertility are now acknowledged as well established risk factors of gynecological neoplasia. This realization has lead to the proposition that infertility might be a risk factor for the development of several types of gynecological neoplasms. This review addresses different conditions that play a role in both infertility and gynaecological neoplasia. An intricate interplay between growth factors and hormonal factors (estrogens and progestins, androgens and gonadotropins) is said to link the state of infertility to some gynecological tumors. The relation between endometriosis -as one of the well established causes of female infertility - and ovarian cancer is well known. Endometriosis has been particularly related to endometrioid and clear-cell ovarian carcinomas. Another evidence for this association is embodied in finding endometriotic lesions adjacent to ovarian cancers. The polycystic ovary syndrome (PCOS), one of the most prevalent endocrine disorders and a long studied cause of female infertility increases the risk of endometrial carcinoma. The link between PCOS and endometrial carcinoma seems to be endometrial hyperplasia. PCOS-associated endometrial carcinoma tends to present at a younger age and early stage, with lower grade and lower risk of metastasis. Turner’s syndrome and other types of ovarian dysgenesis constitute a rare cause of infertility and are known to confer a definite risk of germ cell tumors. There seems to be a link between infertility and an increased risk of gynecological neoplasia. Hence, it is important to assess the risk of malignancy in each category of infertile patients so as to provide optimal and timely intervention.     

The occurrence of endometriosis with ovarian carcinomas is not purely coincidental

Objective

To explore the association between epithelial ovarian cancer (EOC) and common benign gynecological disorders.

Study design

The medical records of 226 patients with EOC treated at Peking Union Medical College Hospital between March 2011 and March 2012 were reviewed. Histological evaluations had been performed to determine the presence of coexisting pelvic endometriosis (n = 17), uterine leiomyoma (n = 66), adenomyosis (n = 22), or endometrial polyps (n = 17).

Results

Coexistence of endometriosis occurred in 35.3% and 36.4% of cases of the clear cell and endometrioid subtypes of EOC histology, respectively. Endometriosis was more likely associated with clear cell or endometrioid ovarian carcinoma, but less likely with high grade serous cancer. No differences were observed in the concurrence of uterine myoma, adenomyosis or endometrial polyps among the different subtypes of EOC.

Conclusions

In contrast to other common benign gynecological disorders, endometriosis showed close relationships with the clear cell and endometrioid subtypes of EOC specifically.     

Evidence that endometriosis behaves in a malignant manner

It is well known that certain aspects of endometriosis are similar to those of malignant disease. For example, like cancer, endometriosis can be both locally and distantly metastatic; it attaches to other tissues, invades, and damages them. Endometriosis is a common disease that does not create a cachectic or catabolic state, and is rarely fatal. There are, however, numerous reported cases of malignancy arising from endometriotic deposits and substantial histologic evidence that endometriosis is associated with endometrioid carcinoma and clear cell carcinoma of the ovary. A large review article by Mostoufizadeh and Scully investigated the association between endometriosis and endometrioid carcinoma, noting that women who had both diseases tended to be younger [1]. They found no association between endometriosis and serous or mucinous carcinoma of the ovary, and reported that malignant transformation of endometriosis was rare and associated with the use of exogenous estrogens. An epidemiological study of Swedish women reported a higher incidence of breast and ovarian cancer and non-Hodgkin's lymphoma in women with endometriosis compared with controls [2]. Vercellini and colleagues also reported a higher incidence of endometrioid and clear cell carcinoma in women with endometriosis compared with controls [3]. Mutations in genes associated with galactose metabolism have been identified as one possible mechanism for this association. These mutations are more common in ovarian cancer and have been reported to be more common in women with endometriosis. We compared 78 women with endometriosis with 248 controls and were unable to demonstrate an increased frequency of these mutations in any of these groups.     

子宫内膜异位症与卵巢癌关系的研究进展

子宫内膜异位症(endometriosis,EMs)是一种良性妇科疾病,但具有恶性行为。流行病学及病理学等研究证实EMs可增加卵巢癌,尤其是透明细胞癌和子宫内膜样癌的风险。近年国内外关于EMs相关卵巢癌(endometriosis associated ovarian cancer,EAOC)的报道不断增加,已证实这是一类特定类型的卵巢癌,EAOC的病因、发病机制和临床特点的研究已成为热点。通过阅读大量文献,分析目前报道的EAOC的危险因素、发病机制、临床特点及诊断方法,以提高对该病的认识。     

Association between endometriosis and cancer: a comprehensive review and a critical analysis of clinical and epidemiological evidence

OBJECTIVE: This review was aimed to critically evaluate observational, cohort, and case-control studies performed so far in order to assess the association between endometriosis and malignant diseases. Based on the observations herein presented, clinical indications that might avoid physicians' mismanaging of affected patients are proposed. METHODS: Search strategies included online searching of the MEDLINE database and hand searching of relevant publications and reviews. Additional reports were collected by systematically reviewing all references from retrieved papers. RESULTS: Endometriosis is not associated with an increased risk of cancer in general. Data from large cohort and case-control studies indicate an increased risk of ovarian cancers in women with endometriosis. The observed effect sizes are modest varying between 1.3 and 1.9. Evidence from clinical series consistently demonstrates that the association is confined to the endometrioid/clear-cell histotypes. Available studies are characterized by several limitations, some of which potentially bias results towards the null hypothesis whereas others leading to overestimate the association. Evidence for an association with melanoma and non-Hodgkin's lymphoma is increasing but still to be verified whereas an increased risk for other gynecological cancer types is not supported. CONCLUSIONS: Epidemiological findings on the association between endometriosis and cancer are still elusive. At present, endometriosis should not be considered a medical condition associated with a clinically relevant risk of any specific cancer. On the basis of the present findings, modifications of the standard treatment options for the disease are not justifiable.     

Effects of tamoxifen on the human female genital tract: review of the literature

Tamoxifen is a non-steroidal triphenylethylene derivate, with clear antioestrogenic effects on the breast, that is orally administrated for the treatment of breast cancer and its prevention in a high-risk population. This article analyzes the effects of tamoxifen on the adult human female genital tract and considers its carcinogenicity in the gynaecological reproductive organs. It has been found that tamoxifen causes oestrogenic changes of the vaginal and cervical squammous epithelium and increases the incidence of cervical and endometrial polyps. The action of tamoxifen on the human endometrium in postmenopausal women is connected with simple oestrogenic effects including hyperplasia, while in others with endometrial cystic atrophy. In cases where tamoxifen induces endometrial polyps and hyperplasia, the extensive fibrosis accounts for difficulties in obtaining endometrial biopsy or resecting the polyps. In premenopausal patients tamoxifen disrupts the menstrual cycles and causes ovarian cysts, while in postmenopausal patients it induces ovarian cystic tumors and endometriomas. Also, postmenopausal patients treated with tamoxifen may develop endometriosis, adenomyosis and leiomyomata. In addition, randomized trials have shown a link between tamoxifen use in breast cancer patients and the development of endometrial carcinomas. Moreover, of note is the fact that the association of tamoxifen therapy with uterine mesenchymal neoplasms is higher than expected. In conclusion, the most worrying gynaecological side-effect of tamoxifen is the well-known increased risk of endometrial carcinomas. Women with breast cancer treated with tamoxifen should undergo annual gynaecological examination, but endometrial sampling should be obtained only in the event of endometrial bleeding.     

Malignome auf dem Boden einer Endometriose

Potentially malignant tumors can arise from endometriosis. This malignant transformation can basically affect every tissue that harbors endometriosis. A direct carcinogenic transformation of benign endometriosis via atypia seems to be possible. Histologically, endometriosis-associated malignancies mostly present as clear-cell and endometrioid carcinomas and also rarely as other histological types. The overall risk of malignant transformation of endometriosis tissue has been estimated in older studies as 1?% and for ovarian endometriomas 2.5?% with a range between 2?% and 17?%. Mutations in the phosphatase and tensin homolog (PTEN) and AT rich interactive domain 1A (ARID1A) genes as well as loss of heterozygosity have been reported as molecular biological findings. In the case of ovarian manifestation a more favorable prognosis has been discussed for these tumors compared to high-grade serous ovarian carcinomas. The Endometriosis Research Foundation (SEF) and the working group gynecological oncology (AGO) are currently conducting a joint retrospective study to characterize these endometriosis-associated tumors including an expert histopathological second opinion in a reference laboratory.     

The association between endometriosis and ovarian cancer: a review of histological, genetic and molecular alterations

Objective

This article represents a review of histologic and genetic findings in endometriosis and describes the mechanisms whereby genetic and non-genetic factors potentially contribute to the neoplastic progression of endometriosis.

Methods

Literature review of the English language literature based on searching in the MEDLINE (PubMed) database and additional collection of reports by systematically reviewing all references from retrieved papers.

Results

Atypical endometriosis seems to represent a transition from benign endometriosis to carcinoma. Endometriosis is characterized by genetic instability: like neoplasms endometriosis seems to be monoclonal in origin, several studies have documented loss of heterozygosity (LOH) in endometriosis, data suggest that mutation of the tumor suppressor gene PTEN play a part in the malignant transformation of endometriosis, some studies have revealed TP53 mutations in endometriotic lesions, and mutation of ARID1A seems to be an important early event in the malignant transformation of endometriosis to endometrioid and clear cell carcinomas. Heme and iron induced oxidative stress, inflammation, and hyperestrogenism are possible links between endometriosis and cancer.

Conclusions

The histological and genetic alterations in endometriosis seem to explain why endometriosis can be a precursor of some ovarian cancers, especially clear cell and endometrioid carcinomas. However, the exact molecular mechanisms that may lead to this malignant transformation of endometriosis are not completely understood. More and larger studies are needed to clarify how exactly endometriotic tissue undergoes malignant transformation.     

Hormonal suppressive therapy for endometriosis may not improve patient health

OBJECTIVE: To critically examine the possible association between hormonal treatment of endometriosis and ovarian cancer. RESULT(S): The malignant potential of endometriosis has been suggested by several clinical studies. Although controversial, ovarian carcinoma of the endometrioid and clear cell subtypes has been associated with endometriosis, particularly among subjects with a longstanding disease. Furthermore, a significantly higher frequency of endometriosis has been found in patients undergoing surgery for endometrioid, clear cell, and mixed subtypes of ovarian carcinoma, as compared with the other subtypes. Changes in the genomic material in endometriotic implants were observed by many investigators in chromosomes 1, 5, 6, 7, 16, and 22 by several methods (fluorescent in situ hybridization, comparative genomic hybridization, and others). Because hormonal ablative treatments may suppress the normal, eukaryotic cells more than the aneuploid cells bearing chromosomal aberrations, it may increase the rate of dyskaryotic cells in the endometriotic implants, possibly augmenting the risk of malignant transformation. A recent published association between Danazol and ovarian cancer suggests that such a theoretical risk may occur. CONCLUSION(S): The hormonal ablative treatment of endometriosis may increase the risk of malignant transformation in the endometriotic implants by causing a negative selection and increasing the rate of dyskaryosis and loss of heterozygosity.     

Endometriosis and ovarian cancer: thoughts on shared pathophysiology

BACKGROUND: Endometriosis appears to predispose to ovarian cancer. How this may occur has been little discussed. STUDY DESIGN: This article reviews the English language literature for in vitro, animal, clinical, and epidemiologic studies linking the two conditions. RESULTS: Pathology case series consistently report endometrioid and clear cell types of ovarian cancer arising from endometriotic foci. Epidemiologic studies have been consistent with this association. There are also marked similarities between the proposed etiology of ovarian cancer and the observed pathophysiology of endometriosis. Specifically, both are characterized by immune alterations. Both conditions are promoted by estrogen excess and by progesterone deficit. Finally, steroid hormones interacting with the immune system may stimulate both endometriosis and ovarian cancer. I propose that the biology common to endometriosis and ovarian cancer represents not just a parallelism, but instead a causal pathway: aberrant immune function, fed by and feeding on estrogens, unbalanced by progesterone, may create a positive feed-forward loop that enhances the growth and invasiveness of endometriosis and promotes its malignant transformation. CONCLUSIONS: The same pathophysiology may orchestrate the progression of endometriosis and its transformation to endometroid and clear cell ovarian neoplasias. This notion of a unifying biology suggests a directed approach to future research and identifies possible chemoprevention strategies for women with endometriosis.     

Ovarian carcinoma associated with endometriosis

Objectives

Previous studies have suggested an association between endometriosis and development of ovarian cancer. A study was performed to evaluate the cases of ovarian carcinoma associated with endometriosis.

Study design

The study includes patients with ovarian carcinoma associated with endometriosis diagnosed between 2000 and 2010 at Hacettepe University Hospital, Ankara, Turkey. A total of 1086 patients who underwent surgical staging for ovarian carcinoma were analyzed retrospectively for the presence of histologically documented endometriosis. The clinical and pathological characteristics of 45 ovarian carcinoma patients associated with endometriosis were evaluated including histologic subtype, stage and grade.

Results

Ovarian carcinoma was found to be associated with endometriosis in 4.1% (45/1086) of the cases. Of them, 17 patients (37.8%) had clear cell, 15 (33.3%) had endometrioid, 6 (13.3%) had serous papillary, 4 (8.9%) had mucinous and the remaining 3 patients had an undifferentiated subtype of ovarian carcinoma. Twenty-three (51.1%) patients had stage I, 4 (8.9%) had stage II and 18 (40.0%) had stage III disease. The frequency of coexistence of endometriosis was 20.4% (17/83) for clear cell carcinoma and 9.3% (15/161) for endometrioid cell carcinoma.

Conclusions

Only a small proportion of ovarian cancer cases were found to be associated with endometriosis. Endometriosis was most frequently associated with clear cell and endometrioid types of ovarian carcinoma. Ovarian carcinoma associated with endometriosis seems to represent a distinct disease entity with different histological subtypes, early presentation and a relatively favorable outcome.     

子宫内膜异位症相关卵巢癌病因研究进展

子宫内膜异位症(endometriosis,EMs)在病理学表现上虽为良性病变,但具有与恶性肿瘤相似的浸润、种植生长、破坏周围组织、远处转移和极易复发的特点,并有一定比例的EMs会发生组织形态学改变,从非典型内膜异位组织进一步转变成癌。目前EMs恶变已受到世界各地学者的广泛关注。EMs和卵巢癌的组织联系虽早已被学者提出,并有公认的诊断标准,但是随着近年来EMs和卵巢癌发病率的增加,子宫内膜异位症相关卵巢癌(endometriosisassociated ovarian cancer,EAOC)愈发引起学者的重视,其病因、发病机制、流行病学特征等已成为近年的研究热点。就近年的研究成果主要从基因突变、细胞凋亡、炎症免疫、氧化应激、雌激素5个方面对EAOC的病因和发病机制进行阐述。     

Endometriosis and the development of malignant tumours of the pelvis. A review of literature

For several decades, endometriosis has been suspected of playing a role in the aetiology of ovarian cancer. The literature concerning a possible histogenesis of ovarian cancer from benign endometriosis is reviewed in this chapter. Epidemiological evidence from large-cohort studies confirms endometriosis as an independent risk factor for ovarian cancer. Further circumstantial evidence for this link was found in the common risk factors for ovarian cancer and endometriosis. These risk factors influence retrograde menstruation and endometriosis in the same positive or negative way. Based on data in the literature, the prevalence of endometriosis in epithelial ovarian cancer has been calculated to be 4.5, 1.4, 35.9, and 19.0% for serous, mucinous, clear-cell and endometrioid ovarian carcinoma, respectively. The risk of malignant transformation in ovarian endometriosis was calculated at 2.5% but this might be an underestimate. In addition, some authors described atypical endometriosis in a spatial and chronological association with ovarian cancer. Finally, molecular studies have detected common alterations in endometriosis and ovarian cancer. These data suggest that some tumours, especially endometrioid and clear-cell carcinomas, can arise from endometriosis. Moreover, endometriosis-associated ovarian cancer represents a distinct clinical entity, with a more favourable biological behaviour, given a lower stage distribution and better survival than non-endometriosis-associated ovarian cancer.     

子宫内膜异位症和子宫腺肌病对生育功能的影响

子宫内膜异位症及子宫腺肌病是常见的妇科疾病之一,近年来发病率明显增高,由于子宫内膜异位症及子宫腺肌病患者盆腔结构改变,卵巢子宫内膜功能及免疫功能异常等,常合并不孕、流产,严重影响了妇女的生育功能。     

Endometrioid adenocarcinoma of the ovary and endometriosis

OBJECTIVE: We present a retrospective analysis of 22 cases of endometrioid ovarian carcinoma, reviewed to identify endometriosis and its malignant transformation. STUDY DESIGN: Twenty-two patients with endometrioid ovarian cancer were included in the review. Their clinical and histological data were retrospectively reviewed. The origin of the tumours was considered endometriosis-related when the presence of malignant changes in endometriosis glands leading to endometrioid carcinoma were found. RESULTS: Endometriosis was detected in three cases (3/22=14%). One of them presented a clearly benign to malignant transformation area. In another patient, the transition zone was abrupt and present in both ovaries. In the third, a pre-menopausal woman, ovarian endometriosis with only focal endometrioid carcinoma was observed. The three of them had a clear-cell carcinoma component. The presence of a clear-cell component was significantly greater in patients with endometriosis than in patients without endometriosis Each patient had a different clinical presentation: increase in abdominal perimeter, post-menopausal vaginal haemorrhage and hypermenorrhea. Preoperative CA 125 levels were avalaible in 15 of the patients (15/22=68%). Endometriosis was found in two of these 15 patients, both with the highest CA 125 measured levels, exceeding 1700 U/ml. In the remaining of the patients, CA 125 value did not exceed 35 U/ml. CONCLUSION: Although this association is not very frequent, patients with ovarian endometriosis and a high CA 125 serum level should be managed with special care, regardless of their pre-menopausal or post-menopausal status.     

Endometriosis anatomoclinical entities

The aim of this literature review is to precise definition, anatomoclinical entities and natural history of endometriosis to allow clinical guideline establishment. DEFINITION: Endometriosis is defined as the presence of endometrial tissue (glands and stroma) outside the uterus. This histologic definition does not implicate symptoms. Macroscopic lesions supposed to be endometriosis are not always confirmed by histology. Histology is recommended to confirm endometriosis. Negative histology does not exclude endometriosis. ANATOMOCLINICAL ENTITIES: Three endometriosis entities are described: peritoneal endometriosis, ovarian endometrial cyst, and deeply infiltrating endometriosis. There is no evidence to establish a different pathogenesis of theses entities. ENDOMETRIOSIS NATURAL HISTORY: It is not well known. It may progress or regress with or without treatment. There is no evidence of treatment in case of asymptomatic endometriosis. There is an association between endometriosis and ovarian cancer. The risk of endometriosis malignant transformation is still a subject of controversy. There is no evidence for a specific oncologic follow-up of woman having endometriosis.     

Malignancy in endometriosis: frequency and comparison of ovarian and extraovarian types.

One thousand consecutive cases of surgically proven endometriosis were reviewed to evaluate the frequency and types of pelvic cancers that were associated with ovarian and extraovarian endometriosis. The frequency and types of histologic abnormalities present in the eutopic endometrium when cancers were noted in endometriosis were also evaluated. In the large subset of cases for which the authors were the primary pathologists and all foci of endometriosis were recorded, the frequency of malignancy was 10.8%. In contrast, the frequency was only 3.2% in cases diagnosed by others previously in our institution. Cancers were more commonly found in ovaries when endometriosis was present in that ovary (5%) compared to when endometriosis was present at other sites (1%). Clear cell and endometrioid carcinomas were the malignancies most commonly seen in ovaries containing endometriosis, while clear cell adenocarcinoma and adenosarcoma were most commonly seen in conjunction with extraovarian endometriosis. The association of endometriosis with endometrioid and clear cell carcinoma was much stronger than that of serous and mucinous tumors (p < .01). Concurrent endometrial pathology was commonly seen in cases of malignant transformation of endometriosis (32% of cases).