Translational genomics of ovarian clear cell carcinoma.

Ovarian clear cell carcinomas (OCCC) are rare aggressive, chemo-resistant tumours comprising approximately 13% of all epithelial ovarian cancers, which have distinct clinical and molecular features, when compared to other gynaecological malignancies. At present, there are no specific licensed targeted therapies for OCCC, although a number of candidate targets have been identified. This review focuses on recent knowledge underpinning our understanding of the pathogenesis of OCCC including direct and synthetic-lethal therapeutic strategies in particular focussing on ARID1A deficiency. We also discuss current targeted clinical trials and immunotherapeutic approaches.

Comparison of clear cell carcinoma and benign endometriosis in episiotomy scar - two cases report and literature review.

BACKGROUND: Malignant endometriosis in an episiotomy scar is rare; only seven cases have been reported previously. Here, we compare two cases of benign endometriosis and clear cell carcinoma. CASE PRESENTATION: The first case was a 54-year-old woman who presented with a large perineal lesion in her episiotomy scar with high 18F-fluorodeoxyglucose uptake. This location had a history of endometriosis many years ago. She underwent radical excision of the mass and bilateral inguinal lymph node dissection. Histological and immunohistochemical analysis confirmed the presence of clear cell carcinoma arising from endometriosis. Assisted radiotherapy was performed after surgery due to a positive lymph node. No recurrence was detected over a 1-year follow-up period. The second case deals with a 3 × 2 cm mass in the episiotomy scar of a 33-year-old woman. Part of the anal sphincter was resected because of the close proximity of the lesion. Because the disease lay very close to the anus, she received anal sphincter reconstruction combined with mass excision. Pathology result showed typical endometrial glands and interstitial tissues. CONCLUSIONS: Deleterious change only happens in patients experiencing perineal endometriosis. Complete excision is crucial for this form of disease; sometimes impairment of the anal sphincter is also necessary. Patients with malignancy required a combination of treatments in order to improve their prognosis.

The Many Faces of Endometriosis-Related Neoplasms in the Same Patient: A Brief Report.

INTRODUCTION: Endometriosis is a common benign gynecological condition that can be associated with a slightly increased risk of developing a wide range of malignancies. CASE PRESENTATION: We herein report a singular case of a 62-year-old woman with a history of pelvic endometriosis, referred to our institution for chronic pelvic pain and uterine bleeding, with clinical and radiological evidence of left ovarian mass of 18 cm in largest diameter and multiple nodular mural lesions of the uterine cavity. The patient underwent exploratory laparotomy followed by hysterectomy, bilateral salpingo-oophorectomy, and omentectomy with pelvic lymph-node sampling. The histological examination of the ovarian mass revealed a clear-cell ovarian carcinoma arising from an endometriotic cyst. The microscopic examination of the uterine cavity showed multiple conventional leiomyomas, diffuse foci of adenomyosis, and a 1.5-cm yellow nodule diagnosed as low-grade endometrial stromal sarcoma associated with glandular atypical differentiation and with extension into parametrial and omental tissues. Following the diagnosis, the patient was treated with chemotherapy, radiation therapy, and hormonal therapy and after 9 months of follow-up is alive without local recurrences and distant metastases. DISCUSSION/CONCLUSIONS: To the best of our knowledge, the present case represents the first evidence of the simultaneous occurrence of clear-cell carcinoma and low-grade endometrial stromal sarcoma arising within ovarian and uterine endometriotic foci, respectively.

Cancers associated with extraovarian endometriosis at less common/rare sites: A nationwide survey in Japan.

AIM: Endometriosis mostly affects the ovary but can also be present outside of the ovary including the pelvic peritoneum, intestine, urinary tract and lung. In case of ovarian endometriotic cyst, an increased risk of ovarian cancer, especially of clear cell and endometrioid histology, has been reported. However, because of the rarity, cancer occurrence from endometriosis at less common sites/rare sites is poorly understood. METHODS: We conducted a nationwide survey on the less common/rare site endometriosis in 3539 authorized facilities in Japan. We requested to complete a case report form for each case, including information on the history of endometriosis, treatment for endometriosis, type of surgery, involved site(s) of cancer and endometriosis, histology of cancer, chemotherapy and outcome. RESULTS: Out of 1397 confirmed cases of less common/rare site endometriosis, 11 cases of rare site endometriosis-associated cancer (RSEAC) were reported: seven of them were associated with intestinal endometriosis, three were associated with urinary tract endometriosis and one was associated with umbilical endometriosis. Interestingly, the histology was endometrioid in seven (64%) cases, and serous, seromucinous borderline, clear cell and mucinous in one case each (10%), differing from the case of ovarian endometriosis-associated cancer, in which clear cell carcinoma are more common. CONCLUSION: Our nationwide survey on RSEAC has revealed that: (i) the incidence of malignant transformation may be lower than ovarian endometriosis, (ii) malignant transformation from endometriosis outside the abdominal cavity may be extremely rare and (iii) the histology of RSEAC is predominantly endometrioid type, suggesting an association of a hormonal effect.

Malignant transformation of vaginal adenosis to clear cell carcinoma without prenatal diethylstilbestrol exposure: a case report and literature review.

BACKGROUND: We report an extremely rare case of vaginal clear cell carcinoma, which originated from the malignant transformation of vaginal adenosis without prenatal diethylstilbestrol (DES) exposure. CASE PRESENTATION: In this case, the patient was a Chinese woman with a history of two decades of intermittent vaginal pain, sexual intercourse pain and vaginal contact bleeding. On September 1, 2011, when the patient was 39 years old, a vaginal biopsy revealed vaginal adenosis. After intermittent drug and laser treatment, her symptoms did not improve. Four years later, on March 4, 2015, another vaginal biopsy for abnormal vaginal cytology revealed atypical vaginal adenosis. After treatment with sirolimus, her symptoms and abnormal vaginal cytology results persisted, and she underwent laparoscopic hysterectomy with bilateral salpingo-oophorectomy and excision of the vaginal lesions. One year after the hysterectomy, on August 15, 2017, the vaginal cytology results suggested atypical glandular cells, and a biopsy revealed vaginal clear cell carcinoma originating from the atypical vaginal adenosis. A wide local resection of the vaginal lesions was performed, followed by concurrent chemoradiotherapy. Regular follow-up over 16 months showed no evidence of the recurrence of vaginal adenosis or cancer. CONCLUSIONS: Based on the evolution of a series of pathological evidence, we report the fourth case in the world of vaginal clear cell carcinoma originating from vaginal adenosis without prenatal DES exposure. Wide local excision with radiotherapy provided at least 16 months of disease-free survival.

Mixed endometrioid and clear cell carcinoma arising from laparoscopic trocar site endometriosis.

Laparoscopic port site endometriosis is less common in abdominal wall endometriosis, and malignant transformation of abdominal wall endometriosis is rare. We reported a case of mixed endometrioid and clear cell carcinoma arising from port site endometriosis. The patient was a 49-year-old woman with a history of laparoscopic excision of ovarian endometrioma. Physical examination revealed a subcutaneous solid tumor around the laparoscopic surgical scar. Imaging showed a suspicious malignancy. She underwent radical marginal resection of the abdominal wall tumor, flap reconstruction of the abdominal wall, hysterectomy, bilateral salpingo-oophorectomy and omental biopsy. Histological examination revealed mixed endometrioid and clear cell carcinoma. Computed tomography scan showed no evidence of recurrence after six cycles of chemotherapy. This is the first case of malignant transformation from laparoscopic trocar site endometriosis.

Anti-Müllerian hormone and risk of ovarian cancer in nine cohorts.

Animal and experimental data suggest that anti-Müllerian hormone (AMH) serves as a marker of ovarian reserve and inhibits the growth of ovarian tumors. However, few epidemiologic studies have examined the association between AMH and ovarian cancer risk. We conducted a nested case-control study of 302 ovarian cancer cases and 336 matched controls from nine cohorts. Prediagnostic blood samples of premenopausal women were assayed for AMH using a picoAMH enzyme-linked immunosorbent assay. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using multivariable-adjusted conditional logistic regression. AMH concentration was not associated with overall ovarian cancer risk. The multivariable-adjusted OR (95% CI), comparing the highest to the lowest quartile of AMH, was 0.99 (0.59-1.67) (Ptrend : 0.91). The association did not differ by age at blood draw or oral contraceptive use (all Pheterogeneity : ≥0.26). There also was no evidence for heterogeneity of risk for tumors defined by histologic developmental pathway, stage, and grade, and by age at diagnosis and time between blood draw and diagnosis (all Pheterogeneity : ≥0.39). In conclusion, this analysis of mostly late premenopausal women from nine cohorts does not support the hypothesized inverse association between prediagnostic circulating levels of AMH and risk of ovarian cancer.

Imaging in gynecological disease (14): clinical and ultrasound characteristics of ovarian clear cell carcinoma.

OBJECTIVE: To describe the clinical and ultrasound characteristics of ovarian pure clear cell carcinoma. METHODS: This was a retrospective study involving data from 11 ultrasound centers. From the International Ovarian Tumor Analysis (IOTA) database, 105 patients who had undergone preoperative ultrasound examination by an experienced ultrasound examiner between 1999 and 2016 were identified with a histologically confirmed pure clear cell carcinoma of the ovary. An additional 47 patients diagnosed with pure clear cell carcinoma between 1999 and 2016 and with available complete preoperative ultrasound reports were identified retrospectively from the databases of the departments of gynecological oncology in the participating centers. The ultrasound images of all tumors were described using IOTA terminology. Clinical and ultrasound characteristics were analyzed for the whole group, and separately, for patients with and those without histologically confirmed endometriosis, and for patients with evidence of tumor developing from endometriosis. RESULTS: Median age of the 152 patients was 53.5 (range, 28-92) years and 92/152 (60.5%) tumors were FIGO Stage I. Most tumors (128/152, 84.2%) were unilateral. On ultrasound examination, all tumors contained solid components and 36/152 (23.7%) were completely solid masses. The median largest diameter of the lesion was 117 (range, 25-310) mm. Papillary projections were present in 58/152 (38.2%) masses and, in most of these (51/56, 91.1%), vascularized papillary projections were seen. Information regarding the presence, site and type of pelvic endometriosis at histology was available for 130/152 patients. Endometriosis was noted in 54 (41.5%) of these. In 24/130 (18.6%) patients, the tumor was judged to have developed from endometriosis. Patients with, compared to those without, evidence of tumor developing from endometriosis were younger (median 47.5 vs 55.0 years, respectively), and ground-glass echogenicity of cyst fluid was more common in pure clear cell cancers developing from endometriosis (10/20 vs 13/79 (50.0% vs 16.5%), respectively). CONCLUSIONS: Ovarian pure clear cell carcinoma is usually diagnosed at an early stage and typically appears as a large unilateral mass with solid components. Patients with clear cell carcinoma developing from endometriosis are younger than other patients with clear cell carcinoma, and clear cell cancers developing from endometriosis more often manifest ground-glass echogenicity of cyst fluid. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Three cases of clear-cell adenocarcinoma arising from endometrioma during hormonal treatments.

Endometrioma is known to be an occurrence site of ovarian cancer, but there is no evidence on how to reduce the risk of canceration. Here, we report three cases of ovarian cancer arising from endometrioma during hormone therapies of GnRH analogue and tamoxifen, low-dose estrogen-progestin (LEP) and dienogest. In all cases, each hormonal treatment was effective in shrinking the size of the endometrioma. During hormonal treatments, solid parts inside endometrioma were observed, which was followed by surgery. The histology of the solid parts was clear-cell adenocarcinoma in all cases. An immunohistochemistry study demonstrated that the estrogen receptor (ER) and progesterone receptor (PR) were positive in the endometriosis part but negative in the cancer part, while the human EGF receptor (HER) 2 was negative or very weak in the benign part and positive in the malignant part in all three cases. Even though hormonal treatments seem to be effective to regulate endometrioma, careful observation is needed to follow-up patients with endometrioma.

Long-term survival of a patient with malignant transformation of extragonadal endometriosis treated solely with chemotherapy: A case report.

A 52-year-old woman presented to our hospital complaining of genital bleeding and was found to have a 50-mm vaginal tumor that involved the bladder, rectum, and small bowel and extended to the left pelvic side wall. Her history included a bilateral salpingo-oophorectomy and a total abdominal hysterectomy for fibroids and endometriosis. She had been prescribed estrogen replacement therapy (1.25 mg/day) following the second surgery and continued it for 8 years. The pathology of the vaginal biopsy showed endometrioid adenocarcinoma. Total pelvic exenteration was recommended for complete resection, but she chose chemotherapy (paclitaxel 175 mg/m2 and carboplatin AUC:6). Clinical complete remission was obtained for 11 years. She had a recurrence 11 years later. She was again found to have a 5-cm vaginal tumor. Surgical excision with upper vaginectomy was performed. The tumor was resected without invasion of the bladder, rectum and small bowel. Histologic examination of the specimen confirmed clear cell carcinoma with endometriosis. Chemotherapy may be the first-line treatment that can preclude aggressive surgery for malignant transformation of extragonadal endometriosis. However, combined chemotherapy and surgery is necessary for this disease.

Kidney-specific knockout of Sav1 in the mouse promotes hyperproliferation of renal tubular epithelium through suppression of the Hippo pathway.

We have previously reported that Salvador homologue 1 (SAV1), a component of the Hippo pathway, is significantly down-regulated in high-grade clear cell renal cell carcinoma (ccRCC) due to 14q copy number loss, and that this down-regulation contributes to the proliferation and survival of renal tubular epithelial cells through activation of Yes-associated protein 1 (YAP1), a downstream target of the Hippo pathway. However, the impact of SAV1 loss on the proliferation and survival of kidney cells in vivo remained to be determined. To address this issue, we generated kidney-specific Sav1-knockout (Cdh16-Cre;Sav1(fl/fl) ) mice. Sav1 deficiency enhanced the proliferation of renal tubular epithelial cells in Cdh16-Cre;Sav1(fl/fl) mice, accompanied by nuclear localization of Yap1, suggesting suppression of the Hippo pathway. Sav1 deficiency in renal tubules also caused structural and cellular abnormalities of the epithelial cells, including significant enlargement of their nuclei. Furthermore, Cdh16-Cre;Sav1(fl/fl) mice developed both glomerular and tubular cysts. Although lining cells of the glomerular cysts showed no atypia, those of the tubular cysts showed variations in cell size and nuclear shape, which became more severe as the mice aged. In aged Cdh16-Cre;Sav1(fl/fl) mice, we observed focal disruption of proximal tubules and perivascular lymphocytic infiltration. In conclusion, Sav1 is required for the maintenance of growth, nuclear size and structure of renal tubules under physiological conditions, and its deficiency leads to the acquisition of enhanced proliferation of renal epithelial cells through suppression of Hippo signalling.

Models of endometriosis and their utility in studying progression to ovarian clear cell carcinoma.

Endometriosis is a common benign gynaecological condition affecting at least 10% of women of childbearing age and is characterized by pain--frequently debilitating. Although the exact prevalence is unknown, the economic burden is substantial (∼$50 billion a year in the USA alone) and it is associated with considerable morbidity. The development of endometriosis is inextricably linked to the process of menstruation and thus the models that best recapitulate the human disease are in menstruating non-human primates. However, the use of these animals is ethically challenging and very expensive. A variety of models in laboratory animals have been developed and the most recent are based on generating menstrual-like endometrial tissue that can be transferred to a recipient animal. These models are genetically manipulable and facilitate precise mechanistic studies. In addition, these models can be used to study malignant transformation in epithelial ovarian carcinoma. Epidemiological and molecular evidence indicates that endometriosis is the most plausible precursor of both clear cell and endometrioid ovarian cancer (OCCA and OEA, respectively). While this progression is rare, understanding the underlying mechanisms of transformation may offer new strategies for prevention and therapy. Our ability to pursue this is highly dependent on improved animal models but the current transgenic models, which genetically modify the ovarian surface epithelium and oviduct, are poor models of ectopic endometrial tissue. In this review we describe the various models of endometriosis and discuss how they may be applicable to developing our mechanistic understanding of OCCA and OEA.

A first reported case of clear cell carcinoma associated with delayed extrusion of midurethral tape.

We present the first reported case of clear cell carcinoma associated with a midurethral tape (MUT), the possible hypotheses and the management pitfalls we encountered. We report a 58-year-old woman who presented with symptoms of urinary tract infection and acute retention of urine associated with vaginal tape exposure 10 years after placement of an inside-out transobturator tape. She subsequently had a partial transobturator tape excision and a diagnostic cystoscopy, which revealed inflammatory changes within the urethra. Postoperatively, her symptoms persisted and the vaginal epithelium healed poorly. A biopsy of the friable tissue reported clear cell carcinoma. Imaging showed a locally invasive periurethral mass and bony and lymphatic metastases. This was treated with palliative radiation therapy. She was still receiving palliative care 5 months after the initial surgery.

Ovarian cancer: new developments in clear cell carcinoma and hopes for targeted therapy.

Until recently, ovarian clear cell carcinoma was recognized by its unique morphology and unfavorable patient outcome primarily due to tumor chemoresistance. Recently, specific molecular characteristics of ovarian clear cell carcinoma, such as PI3CA mutation, ARID1a mutation and MET amplification, have been elucidated. In addition, an association between endometriosis and the tumor has also been a focus of research in recent years. The aim of this review is to discuss the specificity and importance of molecular changes and various intriguing points that are not solved until today. Finally, future aspects, including hopes for the development of novel therapies, are discussed.

Endometriosis-Associated Abdominal Wall Cancer: A Poor Prognosis?

OBJECTIVE: Endometriosis-associated abdominal wall cancer (EAAWC) is rare, and few reports are available. This article provides a review of reports in the literature on the pathology, diagnosis, management, and outcome of patients with EAAWC. METHOD: We performed a review of existing reports in the English language literature on cancer arising from abdominal wall endometriosis. MEDLINE and EMBASE searches were conducted for articles published from September 1986 to August 2014 using combinations of medical subject heading terms. RESULTS: We identified 26 articles reporting on EAAWC and added 1 patient who was treated at our institution. In all of these patients, EAAWC was described after uterine surgery (mostly cesarean section). The delay between the first surgery and the diagnosis of malignant disease was more than 20 years. Clear cell carcinoma was the most common histology, followed by endometrioid carcinoma. Death was described in 44% of women within a few months of diagnosis. CONCLUSIONS: Endometriosis-associated abdominal wall cancer is rare and aggressive. It seems to be associated with cesarean section, and it shows poor prognosis. The mainstay of treatment remains extensive surgery and chemotherapy.

[Ovarian clear cell carcinoma derived from endometriotic cyst: a clinicopathological analysis of 54 cases].

OBJECTIVE: To clarify the clinicopathological features of ovarian clear cell carcinoma derived from endometriotic cyst (EC-OCCC). METHODS: Totally 54 cases of EC-OCCC were recruited in the current retrospective study. The relation between ages, clinical symptoms and signs, surgical and pathological stages, serum CA125, findings of ultrasound, treatments and the sites of tumors, macro- and micro-features and expression of immunostainings were analyzed. RESULTS: (1) Clinical features: the ages of patients were (50±6) years old (range 31-62 years old). Pelvic mass was the major complaint of 50 patients (93% , 50/54). Forty-five cases belonged to International federation of Gynecology and Obstetrics (FIGO) stage I, 4 cases were stage II and another 5 cases were stage III. Serum CA125 was elevated in 21 cases (54%, 21/39) before therapy. Doppler ultrasound showed 46 cases (85%, 46/54) had solid masses in pelvis. (2) Pathological findings: 52 cases (96%, 52/54) had their tumor unilaterally, and 2 cases (4%, 2/54) occurred bilaterally. The maximal diameters of endometriotic cyst (EC) ranged from 1.5 to 23.0 cm and maximal diameters of ovarian clear cell carcinoma (OCCC) components were from 0.5 to 12.0 cm. Fifty-one cases (94%, 51/54) had their tumor within EC, which showed focally irregular protrudings, grey-white papillae or solid nodules attached to the cyst wall. Three cases (6%, 3/54) appeared as irregular thickened wall of the cysts, ranged from 1.5 to 6.0 cm in the maximal length, with the microscopic features of EC and OCCC and the transitional areas between the 2 morphologies. All cases expressed cytokeratin (CK) 7 and pan-CK AE1/AE3, 17 cases (33%, 17/51) expressed ER and 5 cases (10%, 5/51) expressed PR. TP53 showed mutational phenotype in 19 cases (36%, 19/53). Sixteen cases (30%, 16/54) combined with uterine adenomyosis and 25 cases (46%, 25/54) with endometriosis at other sites. (3) Survival survey: during the period of 39.1 months follow-up, 3 cases relapsed and 2 cases died. (4) There was a significant difference of serum CA125 between patients of early-and advanced-stages (P=0.049). There were no differences identified in ages, diameters of EC and OCCC, the expression level of ER, PR and TP53, the co-existence of adenomyosis and endometrosis, as well as ultrasonic findings (P>0.05). CONCLUSION: EC-OCCC could be recognized in early stage by symptoms and ultrasound due to accompanied endometriotic cysts, resulting in relatively good prognosis.

Significance of adenomyosis on tumor progression and survival outcome of endometrial cancer.

BACKGROUND: To examine the effects of adenomyosis on tumor progression and survival outcome of endometrial cancer patients. METHODS: This is a retrospective study examining stage I-IV endometrial cancer patients who underwent hysterectomy-based surgical staging (n = 571), and endometrial hyperplasia patients who underwent hysterectomy (n = 213). Clinical demographics, histopathological factors, and survival outcomes were analyzed based on the presence or absence of adenomyosis. RESULTS: Among the endometrial cancer cohort, adenomyosis was observed in 47.5 % of cases and was significantly associated with lower grade (grade 1-2 tumors, 81.2 vs. 73.3 %; p = 0.028), earlier stage (stage I disease, 74.8 vs. 64.3 %; p = 0.023), and lower likelihood of deep myometrial invasion (19.2 vs. 28.2 %; p = 0.039) and cervical invasion (13.7 vs. 21.2 %; p = 0.024) than those without adenomyosis. In survival analysis, endometrial cancer coexisting with adenomyosis was associated with a significantly better disease-free survival (5-year rate, 89.2 vs. 78.2 %; p < 0.001) and overall survival (91.8 vs. 83.9 %; p = 0.004) after hysterectomy. In multivariate analysis, controlling for other significant variables in univariate analysis, presence of adenomyosis remained an independent prognostic factor associated with decreased risk of disease recurrence after surgery (hazard ratio [HR] 0.53; 95 % confidence interval [CI] 0.30-0.92; p = 0.023). Endometrial hyperplasia had a significantly increased incidence of adenomyosis when compared with type I endometrial cancer (grade 1-2 endometrioid adenocarcinoma, n = 411) on multivariate analysis (62.9 vs. 48.9 %; HR 1.88; 95 % CI 1.32-2.69; p < 0.001). CONCLUSIONS: Adenomyosis appears to be associated with less aggressive tumor behavior of endometrial cancer, suggesting that it may have inhibitory effects on the progression of this disease.

An increased risk of epithelial ovarian cancer in Taiwanese women with a new surgico-pathological diagnosis of endometriosis.

BACKGROUND: Epidemiological evidence of relationships between endometriosis and epithelial ovarian cancer (EOC) has been obtained mainly from Western countries. Our goal was to determine the risk of EOC due to endometriosis in Taiwanese women. METHODS: A retrospective cohort study was performed by linking to the National Health Insurance Research Database (NHIRD) of Taiwan. A total of 5,945 women with a new surgico-pathological diagnosis of endometriosis from 2000 to 2010 and 23,780 multivariable-matched controls (1:4) were selected. The Cox regression model adjusted for potential confounders was used to assess the risk of EOC due to endometriosis. RESULTS: The EOC incidence rate (IR) of the women with and without endometriosis was 11.64 and 2.66 per 10,000 person-years, contributing to a crude hazard ratio (HR) of 4.48 (95% confidence interval [CI] 2.84-7.06), and HR after adjustment for all confounders (adjusted HR) of 5.62 (95% CI 3.46-9.14); the risk was higher in clear-cell carcinoma subtypes (adjusted HR 7.36, 95% CI 1.91-28.33). The EOC IR of women with endometriosis consistently increased with increasing age, ranging from 4.99 (<30 years) to 35.81 (≥50 years) per 10,000 person-years, contributing to a progressively increased risk of EOC (crude HRs ranging from 2.80 to 6.74 and adjusted HRs ranging from 3.34 to 9.63) compared to age-matched women without endometriosis, whose EOC IR also increased with age. The older women (≥50 years) with endometriosis had a risk of EOC that was higher than both the age-matched women without endometriosis (adjusted HR 9.63, 95% CI 3.27-28.37) and the youngest women (<30 years) with endometriosis (adjusted HR 4.97, 95% CI 1.03-24.09). CONCLUSIONS: These significant findings corroborate the previously reported association between endometriosis and increased risk of EOC. Since the risk of EOC in women with a new surgico-pathological diagnosis of endometriosis constantly increased with age and this increased risk of EOC was more significant in women aged ≥50 years, active and intensive surgical intervention should be taken into consideration for older women with endometriosis.

Differences in LINE-1 methylation between endometriotic ovarian cyst and endometriosis-associated ovarian cancer.

BACKGROUND: Endometriosis in endometriosis-associated ovarian cancer (EAOC) refers to lesions that can derive from endometriotic ovarian cysts (ECs) that form in the ovarian endometrium with the potential to transform into full-blown ovarian cancer. Hypomethylation of long interspersed element-1 (LINE-1 or L1) is a common epigenomic event in several cancers and is strongly associated with ovarian cancer progression. OBJECTIVES: To evaluated alterations in LINE-1 methylation between EC, ovarian endometrioid adenocarcinoma (OEA), EAOC, and ovarian clear cell carcinoma (OCC). METHODS/ MATERIALS: First, LINE-1 methylation status in 19 normal endometrium, 29 EC, 35 OCC, and 22 OEA tissues from unrelated samples were compared. Then, specific areas of eutopic endometrium, contiguous endometriosis, and cancer arising from 16 EAOCs were collected by microdissection and analyzed for LINE-1 methylation status. RESULTS: The total LINE-1 methylation levels were significantly different among the endometrium, endometriosis, and ovarian cancer (P < 0.001). A stepwise decrease in LINE-1 methylation was observed in the following order: normal endometrium, EC, OEA, and OCC. Interestingly, endometriosis in EAOC of both OEA (P = 0.016) and OCC (P = 0.003) possessed a higher percentage of LINE-1 unmethylated loci than EC. CONCLUSION: Our data implicate that LINE-1 hypomethylation is an early molecular event involved in OEA and OCC malignant transformation. Precise measurements of LINE-1 methylation may help to distinguish EC and endometriosis in EAOC.