Transformation Of Endometriosis Research Articles

New insights about endometriosis-associated ovarian cancer: pathogenesis, risk factors, prediction and diagnosis and treatment.

Previous studies have shown that the risk of malignant transformation of endometriosis in premenopausal women is approximately 1%, significantly impacting the overall well-being and quality of life of affected women. Presently, the diagnostic gold standard for endometriosis-associated ovarian cancer (EAOC) continues to be invasive laparoscopy followed by histological examination. However, the application of this technique is limited due to its high cost, highlighting the importance of identifying a non-invasive diagnostic approach. Therefore, there is a critical need to explore non-invasive diagnostic methods to improve diagnostic precision and optimize clinical outcomes for patients. This review presents a comprehensive survey of the current progress in comprehending the pathogenesis of malignant transformation in endometriosis. Furthermore, it examines the most recent research discoveries concerning the diagnosis of EAOC and emphasizes potential targets for therapeutic intervention. The ultimate objective is to improve prevention, early detection, precise diagnosis, and treatment approaches, thereby optimizing the clinical outcomes for patients.

Endometriosis in clear cell and endometrioid carcinoma ovary: its impact on clinicopathological characteristics and survival outcomes.

Malignant transformation in endometriosis was first described by Sampson in 1925. There is now sufficient evidence of its association specifically with endometrioid (EOC) and clear cell ovarian cancer (CCOC). Whether endometriosis-associated ovarian cancer (EAOC) is a distinct clinicopathological entity from non-endometriosis-associated ovarian cancer (NEAOC) remains uncertain. This study aimed to assess the impact of endometriosis on clinical characteristics and survival outcomes in EOC and CCOC. This is a retrospective single-institution analysis of patients diagnosed with CCOC AND EOC between 2010 and 2021. Demographic and clinical presentation data were obtained from medical records. Patients were followed up till March 2023. Statistical analysis was done using the IBM SPSS Statistics 20 Windows. Of the 77 cases of CCOC and EOC ovary, 38 had histopathologically proven endometriosis. There was no difference in age (51.62 and 50.05 years, respectively), body mass index, parity, menopausal status and CA 125 levels at presentation. Ascites was more frequent in the absence of endometriosis (30% versus 8.1%, p = 0.015). However, this did not translate to a statistical difference in the stage, with the majority presenting in the early stage. (94% versus 83%). All 78 patients underwent primary cytoreduction with equal rates of optimal resection.There was no difference in the mean disease-free interval between EAOC and NEAOC (107.6 and 109.4 months, p 0.484). Recurrences were predominantly pelvic in both groups. The disease-specific survival was 111.7 and 120.1 months, respectively, with and without endometriosis. This was however not statistically significant (p 0.751). In the Indian population, endometriosis did not have any impact on the age at presentation, CA 125 levels, stage of the disease and survival outcomes in EOC and CCOC ovary.

Malignant transformation of endometriosis on vaginal cuff after hysterectomy: a case report

Objective. Endometriotic tissue implants rarely transform to malignant tissue, especially in a patient with a hysterectomy and bilaterally salpingo-oophorectomy. However, several cases with cancer arising from endometriosis after hysterectomy were reported in the literature. Hormone replacement therapy only with estrogen is a crucial risk factor for malignant transformation of persistent endometriotic tissue. Case Report. The present case demonstrates an endometrioid adenocarcinoma arising from persistent endometriosis tissue in a patient who was performed hysterectomy with bilateral salpingectomy 3 years ago. The histopathologic specimens of the previous surgery did not include any malignant tissue. After 3 years, she applied to the hospital with abnormal vaginal bleeding, and her histopathologic examination result found an ulcerated mass at the upper one-third of the vagina that is compatible with endometrioid adenocarcinoma. Conclusion. It is crucial to keep in mind the endometriosis history of the patient, to be able to diagnose cancer arising from endometriosis while evaluating the patient with a hysterectomy.

Endometriosis, hormonal therapy and oncological risks

Endometriosis is now considered as benign disease. However, a correlation was found between endometriosis and several types of cancer. Endometriomas are found in 17–44% of patients with endometriosis and can be frequent precursors of ovarian cancer (endometrioid and clear cell ovarian tumors are more common). This process can be realized through several mechanisms: predominance of certain cytokines, oxidative stress and local hyperestrogenia, genetic mutations including PTEN, PIK3CA, ARID1A, Wnt/β-catenin, microsatellite instability, Src and KRAS.There are no generally accepted approaches to non-invasive early diagnosis of ovarian cancer, especially in borderline tumors and early stages of malignancy. The lack of accurate screening programs for ovarian cancer emphasizes the importance of identifying high-risk, moderate-risk, and low-risk groups. Screening is not recommended in the general population in the low-risk group. Annual CA125 evaluation and transvaginal pelvic ultrasound with general and special gynecological examination are recommended in the moderate-risk group in postmenopause. Transvaginal ultrasound of the pelvic organs with CA125 evaluation is performed every 6 months in the high-risk group, starting from 30 years or 5–10 years before the youngest age of ovarian cancer onset in relatives. The main method of diagnosing tumors is expert ultrasound of the pelvic organs (simultaneously with transabdominal ultrasound). The main tumor markers are CA125 (single evaluation has low diagnostic value), risk malignancy index (RMI) and HE4.Clinical trials are going on and various methods of prevention, screening and treatment of these diseases are being developed. Probably, dienogest can help to solve the problem. Existing results of research are promising, but insufficient since they show both the positive effects of progestin therapy and minor cases of cancer detection during therapy that are not related to the use of progestins, but probably indicate unknown mechanisms of transformation in endometriosis.

The multistep process of vaginal cancer arising from deep infiltrating endometriosis: a case report

BackgroundMalignant transformation of endometriosis in extraovarian sites remains rare. Furthermore, the process is not definitely understood.Case presentationHerein, we report the case of a 40-year-old premenopausal nulligravida woman who presented with vaginal bleeding and who was finally diagnosed with a vaginal cancer originating from endometriosis and with a synchronous endometrial cancer. A gynecologic examination revealed a multiple polypoid mass on the posterior vaginal fornix. Magnetic Resonance Imaging of the pelvis showed two masses abutting respectively on the anterior uterine wall, and in the rectovaginal septum. The patient underwent a total laparoscopic excision of the rectovaginal mass, radical hysterectomy and low anterior resection of the rectum. The lesions were diagnosed as endometriosis, endometriosis-associated complex hyperplasia and endometrioid cancer. Furthermore, a synchronous endometrioid endometrial cancer was reported.ConclusionsThis case revealed the multistep process of malignant transformation of deep infiltrating endometriosis. The progression was individualized between implantation sites and in the same organ.

PROBLEMATIC ISSUES IN THE ETIOLOGY AND PATHOGENESIS OF ADENOMYOSIS

Nowadays, adenomyosis represents one of the most common pathology of female genital system. It occurs at different ages, including nulliparous, infertile and multiparous women. The etiology of adenomyosis is still under investigation. Despite the fact that there are many different theories, none of them fully explain the mechanisms of adenomyoisis development. The pathogeneis of adenomyosis is also less studied. Many studies indicate the involvement of female sex hormone receptors, cell proliferation and apoptosis, as well as the involvement of inflammation. Some investigators describe the malignant transformation of adenomyosis, which makes the study of the disease etiology and pathogenesis more important. In current review, we discuss the different theories of adenomyosis development, as well as the risk of malignant transformation.

Role of CD10 expression in endometriosis-associated mesenchymal stem cells on the progression of endometriosis-associated carcinoma.

5561 Background: Endometriosis-associated carcinomas (EACs) such as ovarian clear cell cancer (OCCC) are rare, aggressive, chemo-resistant malignancies. While endometriosis is a known chronic inflammatory condition, the molecular mechanisms for the malignant transformation of endometriosis is unknown. Mesenchymal stem cells (MSC) are a critical component of the ovarian cancer microenvironment. Cancer cells reprogram MSCs to form carcinoma-associated MSCs (CAMSCs), which promote cancer growth, chemotherapy resistance, and metastases. MSCs are also found within the endometriotic microenvironment. CD10, a surface protein expressed by endometrial stromal cells, is also expressed on endometriosis-associated MSCs (enMSCs). Preliminary data demonstrate CD10 expression is lost in a subset of enMSCs and this loss is correlated with the acquisition of tumor-promoting properties. We hypothesized that the CD10 negative subset of enMSCs behave similarly to CAMSCs and support the growth of OCCC. Methods: EnMSCs were isolated from primary human benign endometriosis deposits involving the ovary or fallopian tubes. Flow cytometry was used to measure surface CD10 expression. We investigated the role of low CD10 enMSCs versus high CD10 enMSCs on OCCC tumor cell growth, chemotherapy resistance and stem-like cell properties in vitro and tumor cell engraftment, growth, and metastases in vivo. Luciferase-expressing OCCC cells were (1) used alone, (2) mixed with low CD10 enMSCs, or (3) mixed with high CD10 enMSCs and injected orthotopically into the ovarian bursa of NSG mice. In vivo imaging system was used to follow tumor progression and metastasis. Results: Our results demonstrated that enMSCs have variable CD10 expression. EnMSCs with low CD10 expression significantly enhanced OCCC proliferation, resistance to cisplatin, and sphere formation compared to OCCC alone. In contrast, high CD10 expressing enMSCs significantly reduce OCCC proliferation and sphere formation. Interestingly, low CD10 enMSCs selectively enhanced OCCC cell growth and had no effect on high grade serious ovarian cancer cell growth. Moreover, a reduction of CD10 expression was observed over time when high CD10 enMSCs were co-cultured with OCCC cells. Our results also showed enhanced tumor engraftment when OCCC cells were co-injected with low CD10 enMSCs to 100% one week post-injection, compared to 40% with OCCC and high CD10 enMSCs and 60% with OCCC alone. Further, mice co-injected with low CD10 enMSCs demonstrated increased metastasis and decreased survival compared to mice co-injected with high CD10 enMSCs. Conclusions: Our results indicate there is a sub population of enMSCs, marked by decreased CD10 expression, which selectively enhances OCCC growth. This highlights the existence of a tumor-promoting stromal cell within endometriosis which may be critical to the formation and propagation of EACs.

Combination of Ferulic Acid, Ligustrazine and Tetrahydropalmatine attenuates Epithelial-mesenchymal Transformation via Wnt/β-catenin Pathway in Endometriosis.

Previously the potential therapeutic action of ferulic acid, ligustrazine and tetrahydropalmatine (FLT) are discovered with unclear mechanism in rat autograft endometriosis. However, the effect of FLT on endometrial cells and allograft endometriosis is still unclear. This study is designed to elucidate the influence of FLT on epithelial-mesenchymal transformation in allograft endometriosis and endometrium cells. In vivo, fluorescent xenogeneic endometriosis model was established. In vitro, invasion and metastasis were analyzed after treating FLT. Epithelial-mesenchymal transformation and Wnt/β-catenin pathway were inspected in vitro and in vivo. Activator or inhibitor of Wnt/β-catenin signaling was performed to inspect mechanism of epithelial-mesenchymal transformation. In vivo, FLT not only decreased fluorescent intensity and volume of ectopic lesion, but also ameliorated pathological morphology. E2 and PROG levels in serum were reduced by FLT. In endometrial cells, FLT significantly inhibited the invasion and metastasis. Meantime, epithelial-mesenchymal transformation was reversed, accompanied by suppression of Wnt/β-catenin pathway. In-depth study, activation of Wnt/β-catenin pathway lead to promotion of epithelial-mesenchymal transformation, which was reversed by FLT. FLT prevented fluorescent allograft endometriosis and endometrium cells, which was related to suppress epithelial-mesenchymal transformation through inactivating Wnt/β-catenin pathway. The findings disclose molecular mechanism of epithelial-mesenchymal transformation in endometriosis by FLT, and contribute to further application.

Downregulation of SPOCK2 promotes the proliferation, adhesion, and invasion of endometrial epithelial cells

Purpose A previous study found that a lack of SPOCK2 expression was an early event that occurs during the malignant transformation of endometriosis (EMS); however, the role played by SPOCK2 in the pathogenesis of endometriosis and its malignant transformation remains unclear. Materials and methods In this study, SPOCK2 expression in human endometrial epithelial cells (hEECs) was downregulated by transfection with shRNA, and the biological behavior of the transfected cells was observed. Results We found that downregulation of SPOCK2 promoted cell proliferation, adhesion, and invasion. Conclusions Our data suggest that downregulation of SPOCK2 might participate in the pathogenesis and progression of EMS, as well as its malignant transformation, by promoting the proliferation, adhesion, and invasion of endometrial epithelial cells.

A Systematic Review and Bioinformatics Study on Genes and micro-RNAs Involving the Transformation of Endometriosis into Ovarian Cancer.

BackgroundAlong with the description of tumorigenesis processes in endometriosis-related ovarian cancer, identifying dysregulated miRNAs, the target genes of these miRNAs, and the processes abnormally affected by dysregulated miRNAs is essential, which was our goal.MethodsTwo reviewers individually evaluated the articles which collected relevant information including genes and miRNAs involved in the transformation of endometriosis into ovarian cancer. To assess the mature sequence of miRNAs and also their chromosomal positions, miRPathDB software was employed. To determine the main target gene predicted for each considered miRNAs, the TargetScanS Web server was applied. The interaction of each gene with other genes associated with endometrial-related ovarian cancer was determined by GeneMANIA software. Finally, to design integrated model of miRNAs-targeted genes interaction network, the Cytoscape software was used.ResultsThe final number of studies available for analysis was 6 manuscripts including 22 miRNAs described as involved in the transformation of endometriosis into different subtypes of ovarian cancers (14 miRNAs up-regulated and 8 miRNAs down-regulated). Three miRNAs of miR-141 (up-regulated), miR-205 (down-regulated), and miR-125b (down-regulated) were revealed as the originator for genetic interactions leading to carcinogenesis. We could show some common loops and pathways including uncontrolled cell proliferation and abnormal apoptosis (mediated by PTEN gene induced by miR-21 and miR-214), and disaggregation and epithelialization (mediated by ZEB1 and ZEB2 genes induced by miR-200).ConclusionAccording to our analysis, up-regulation of miR-141 and down-regulation of miR-205 and miR-125b have a central role in transforming endometriosis to ovarian cancer.

Endometrioid adenocarcinoma of the rectovaginal septum with invasion of the rectum: a case report and review of literature

BackgroundMalignant transformation of endometriosis in the rectovaginal septum is rare and usually misdiagnosed as a colorectal or gynecological tumor. We report a rare case of primary endometrioid adenocarcinoma of the rectovaginal septum with invasion of the rectum.Case presentationA 57-year-old overweight woman presented with vaginal bleeding and self-reported left lower abdominal pain during the previous 2 weeks. Preoperative imaging showed a large pelvic mass with invasion of the rectum, suggestive of a gynecologic malignancy. Multiple endoscopic biopsies and immunohistochemical analyses of specimens was performed. The patient received joint gynecological-surgical laparotomy, and there were no intra- or postoperative complications. The histopathological diagnosis was rectovaginal endometrioid adenocarcinoma with rectum infiltration. The patient received adjuvant chemotherapy and achieved good treatment response, with no early complications. At 12 months after surgery, there was no evidence of recurrence.ConclusionsA high index of clinical suspicion is required for the diagnosis of endometrioid adenocarcinoma in the rectovaginal septum. Surgery combined with additional chemotherapy or radiotherapy seems to be a standard treatment, and hormonal therapy is optional. The efficacies of other therapies, including targeted medication and immunotherapy, are unknown.

Multi-omics Study on the Pathogenesis of Malignant Transformation of Adenomyosis

Multi-omics Study on the Pathogenesis of Malignant Transformation of Adenomyosis

Endometriosis-assEndometriosis-associated ovarian tumors: morphological and immunohistochemical features

Background. In 2016, the World Health Organization published an updated version of the Histological Classification for ovarian tumors presenting a new category of endometriosis-associated tumors. The predictors of malignant transformation of endometriosis have not been clearly defined so far.Purpose. The search for histological and immunohistochemical markers of endometriosis-associated malignancy.Materials and methods. 28 female patients with endometrioid ovarian cancer and 11 patients with clear cell ovarian carcinoma were enrolled. Histological and immunohistochemical studies were carried out using conventional techniques. Immunohistochemistry was applied to determine the hormone receptor status: expression of steroid hormone receptors, BAF250a (ARID1A), PTEN, P-catenin, MSH6, PMS2, р-53, WT-1, proliferative index (Ki-67). Microsatellite instability (MSI) testing was conducted according to the standard protocol.Results. In all cases of ovarian cancer, histological examination showed one of the endometriosis features. Atypical endometriosis was found in 39 % (11 / 28) of endometrioid tumors and in 9% (1/ 11) of clear cell carcinomas. Endometrioid ovarian cancer was found to be ER (74±7,8%) — and PR (67±5,4%) — positive; Ki-67 index was 68,2±3,7 %; loss of BAF250a (ARID1A) expression was observed in 14% (4/ 28), loss of PTEN expression in 29 % (8 / 28), nuclear expression of P-catenin in 32% (9/28) of cases. Loss of MMR expression was detected in 7% (2/28) of cases. MSI was found in one case only, which was also associated with loss of expression of BAF250a (ARID1A) and MSH6. Clear cell carcinoma of the ovary showed histological criteria for endometriosis; however, there were no changes immunohistochemical markers expression that were typical for endometriosis-associated malignancies. It could be due to a small number of patients in the group so further research is needed.Conclusion. Atypical endometriosis may be a morphological precursor of endometrioid and clear cell carcinoma of the ovary. Comprehensive assessment of a marker panel consisting of BAF250a (ARID1A), P-catenin, PTEN, p53, Ki-67 index, PMS2 and MSH6 will allow improving the diagnosis of atypical endometriosis and endometriosis-associated ovarian cancer.

Effects of Ovarian Pathologies and Uterine Inflammations on Adenomyosis in Bitches

Background: Adenomyosis is a non-neoplastic condition, characterized by the presence of endometrial glands or cells in the myometrium. Adenomyosis is defined by post-operative microscopic examination of uterine tissue and a rarely seen infertility problem in bitches. The process of transformation of healthy uterus into adenomiotic uterus is still a mystery. We aimed to determine role of ovarian pathologies and uterine inflammations on pathogenesis of uterine adenomyosis in bitches.Cases: After ovariohysterectomy, the uteri were fixed and processed by routine methods. Sections were stained with HematoxylinEosin, Masson’s trichrome and Periodic-Acid-Schiff and immunohistochemically; with p53 protein, Ki-67, α-smooth-muscle actin, cytokeratin-CK 8, 14, 19 antibodies, estrogen and progesterone receptors by Avidin-Biotin-Complex-Peroxidase method. Histopathologically, 7 of the collected tissue samples (n = 38) were diagnosed as adenomyosis. There were unilateral (n = 6) or bilateral (n = 1) adenomyosis in which endometrial glands had broken through the myometrium, and in some cases there were fibromyoma, inflammation, papillary hyperplasia and cysts in glands. Vaginal fibroma, fibromyoma and benign mix tumor (n = 1), simple carcinoma (n = 3), carcinosarcoma (n = 3) in mammary gland were determinated histopathologically. In addition to these findings, follicular cysts (n = 4), parovarian cyst (n = 1), adenocarcinoma and Rete ovarii adenoma were diagnosed in some ovaries. The CK 19 was scored at endometrial glands (n = 2) positively and also, muscle fibers were stained positively with α-smooth-muscle actin antibody (n = 7).Discussion: Adenomyosis is an infertility problem in adult dogs and is hard to detect with routine gynecological examinations. Adenomyosis can be seen unaccompanied by other gynecological problems such as endometritis or leiomyomas, while mammary tumors with adenomyosis have been previously reported in women and in only one case of a bitch. Little is known of the interrelationships between gross pathological and endocrine features of ovarian cysts in bitches. Due to the local hormonal imbalance, most of these ovarian tumors and cystic structures might be accompanied with uterine-vaginal and mammary gland pathologies, cystic endometrial hyperplasia-pyometra, adenomyosis, vaginal fibroma and mammary tumors. The hyperestrogenic metabolic state may promote both the invagination process and the overall spreading of adenomyosis into the myometrium. Adenomyosis is often associated with polyps, anovulation, hyperplasia without cytological atypia, and uterine leiomyoma which are produced by hyperestrogenic states. Prolactin appears to induce adenomyosis in mice and hyperprolactinemia may cause myometrial degeneration/weakness and subsequent endometrial invasion in the presence of ovarian steroids in women. Premature decline in progesterone, a problem ensues with prolactin release which can promote hyperprolactinemia or endogenous prolactin release. In addition to hormonal problems, uterine infections, immune factors and their products like cytokines and inflammatory mediators, oxidative stress and free radical metabolism also might have roles in the occurrence of adenomyosis. In the present study, four of seven adenomyotic uterine tissues had inflammation and 3 of 7 cases had pre-inflammatory changes. Changes in uterine tissues may increase cell infiltration and proliferation as well as the activity of immune cells which may promote development of adenomyosis in bitches. It is therefore possible that a defect in the p53 tumor suppressor gene may play an important role in the de novo neoplastic transformation of adenomyosis. In conclusion, adenomyosis can be observed bilaterally or unilaterally in dogs. Tissue damage under the influence of inflammation or hormonal disturbances might have a role in the occurrence of uterine adenomyosis.

Abstract DPOC-014: BEYOND CODING MUTATIONS: USING RETROTRANSPOSONS TO PREDICT OVARIAN CANCER DEVELOPMENT

Abstract PURPOSE: Women with endometriosis, a painful condition caused by displaced endometrial tissue, have a 3-fold increased risk of developing endometrioid ovarian cancer (ENOC) and clear cell ovarian cancer (CCOC). How two distinct cancers arise from the same precursor lesion is unknown. Sensitive biomarkers are needed to identify women with endometriosis at risk of developing cancer. We performed whole genome sequencing on 29 ENOC and 36 CCOC cases and observed a highly frequent insertion event originating from an active LINE-1 (L1) retrotransposon in the TTC28 gene. L1 retrotransposons are mobile genetic elements that can take downstream DNA pieces and insert them into random genomic locations in a process called 3' transduction. L1s are epigenetically silenced in normal tissues, but are known to become activated in a variety of cancers. A recent study showed a stepwise loss of methylation across various L1 loci between normal endometrium, contiguous endometriosis (endometriosis adjacent to tumor), and ENOC/CCOC tissues. We hypothesize that TTC28 L1 retrotransposon is an early event in the transformation of endometriosis into ENOC and CCOC and such events could be used as biomarkers for endometriosis with high cancer risk. METHODS: We compared the presence of TTC28 L1 3' transductions to six SNVs and frame shifts mutations in normal, endometriosis, and tumor tissues from different anatomical sites in four ENOC and four CCOC cases. PCR followed by Sanger sequencing was used to detect TTC28 L1 insertions, and micro-fluidic PCR assay followed by MiSeq sequencing used to detect SNV/frameshift mutations. To broaden the analysis we will use a target capture sequencing method to track novel TTC28 and other L1 transductions. In these experiments probes tiling 1kbp downstream of L1s will be used to capture DNA fragments containing L1 transductions; the captured fragments will be sequenced on the MiSeq. We will assess the difference in TTC28 L1 methylation status between normal, endometriosis, and tumor tissues via the sequencing of bi-sulfite treated DNA. RESULTS: TTC28 L1 retrotransposition insertion is present at all 5 tumor sites in 75% (6/8) of cases, and is present in 3/5 or 4/5 tumor sites in the remaining cases. Analysis shows that TTC28 L1 insertion preceded some SNV and/or frameshift mutations. Preliminary results show that TTC28 L1 promoters are unmethylated in tumors with L1 insertions. Future experiments involving additional cases with endometriosis tissues will be performed. We expect to see L1 promoter hypomethylation and L1 transductions in endometriosis tissues. CONCLUSION: TTC28 L1 promoter hypomethylation and TTC28 L1 transductions may be early events in the transformation of endometriosis to cancer that can be explored as a method to predict tumor development. The development of a target capture assay to detect novel L1 transductions will be crucial for investigating cases without whole genome sequencing data. Ultimately, we hope to detect L1 insertions in plasma samples, and use L1 insertions as a biomarker to identify high-risk endometriosis cases. Citation Format: Zhouchunyang Xia, Dawn Cochrane, Michael S Anglesio, Tayyebeh M Nazeran, Janine Senz, Amy Lum, Ali Bashashati, Yi Kan Wang, Sohrab P Shah, David Huntsman. BEYOND CODING MUTATIONS: USING RETROTRANSPOSONS TO PREDICT OVARIAN CANCER DEVELOPMENT [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr DPOC-014.

KRAS mutation coupled with p53 loss is sufficient to induce ovarian carcinosarcomas in mice.

Ovarian carcinosarcoma cancer is the most lethal form of gynecological malignancy, but the pathogenesis and biological function for this ovarian cancer remain unknown. We establishment the transgenic mouse model of K-rasG12D p53loxP/loxP and found that K-ras mutation and p53 deletion within the ovarian surface epithelium gave rise to ovarian lesions with a hyperproliferation and endometrioid glandular morphology. Furthermore, double mutant ovaries formed ovarian carcinosarcomas that were high grade and poorly differentiated. Induction was widely metastatic and spread to abdominal organs including liver, spleen, and kidney at 4 wk. We also confirmed the role of K-rasG12D in ovarian cancer cell lines MCAS and PA-1 and showed that K-rasG12D overexpression strongly induced cell proliferation, migration, and invasion. The ovarian cancer model we developed recapitulates the specific tumor histomorphology and the probable mechanism of malignant transformation in endometriosis.

Malignant transformation of adenomyosis with coexisting ovarian cancer: case report

Malignant transformation of adenomyosis with coexisting ovarian cancer: case report

Malignant Transformation of Endometriosis: An Unusual Diverticular Mass

Background Malignant transformation of endometriosis may occur years following hysterectomy and oophorectomy. It may present with a pelvic mass, pain or vaginal bleeding. Risk factors have been poorly defined, but may include exogenous or endogenous unopposed estrogens. Case This report presents a case of malignant transformation of endometriosis resulting in endometrioid adenocarcinoma of a colonic diverticulum in a patient on unopposed estrogen. Conclusions Patients with a history of endometriosis who present with a pelvic mass should be evaluated for the possibility of a tumor arising from the endometriosis, even long after definitive surgical treatment. Sampson's criteria for malignant transformation of endometriosis remain relevant. The continued practice of prescribing unopposed estrogen after hysterectomy to patients with a history of endometriosis may contribute to the frequency of this otherwise uncommon disease.

Possible relevance of tumor-related genes mutation to malignant transformation of endometriosis.

Despite studies have suggested that endometriosis has malignant potential, the molecular mechanism underlying the malignant transformation of endometriosis is poorly understood so far. Endometriosis-associated ovarian cancer (EAOC) or ovarian cancer arising from endometriosis (OCEM) may provide an ideal model for genetic studies. To investigate the genetic alterations during transformation of ovarian endometriosis into cancer, the authors analysed mutations of tumour-related genes (PTEN and p53) in EAOC cases (n=23, group 1), including 19 cases which were detected co-existence of endometriosis and cancer and four cases which fulfilled the histological criteria in malignant transformation of endometriosis (OCEMs), and in atypical hyperplasia ovarian endometriosis (aEMs) (n = 10, group 2), as well as in solitary ovarian endometriosis (EMs) (n = 20, group 3), simultaneously, to study the correlation of the two genes in the development and progression of the ovarian endometriosis malignancy. Each paraffin block was sliced into serial ten-µm-thick sections. Extracted DNA was amplified by nested PCR. Mutations of PTEN and p53 were examined by bidirectional DNA sequencing. It was acknowledged by experiments that the PTEN and p53 mutation frequency in EAOCs were significantly higher than that in aEMs and EMs. There was significant difference to compare EAOCs with EMs (p < 0.01, p < 0.05), and converse to compare with aEMs (p > 0.05), respectively. No definite involvement between the frequency of PTEN and p53 mutations in EAOCs and age difference, histological type, clinical stage, pathological grade, and whether accompanied by metastasis (p > 0.05); however, a decreasing trend of PTEN mutation with the increased age, decreased clinical stage and pathological grade, and when accompanied by metastasis was detected. Adversely, an increasing trend of p53 mutation was represented. In EAOCs group, the authors detected eight PTEN and four p53 mutation events, respectively. Moreover, one case occurred PTEN and p53 mutation simultaneously. With 23 EAOCs, two cases which fulfilled the histological criteria in malignant transformation of endometriosis, which may be a specific entity distinct from non-endometriosis-associated ovarian cancer, the authors named them the OCEMs, occurred PTEN or p53 mutation, respectively. The present study suggested that the mutation and functional incapacitation of certain tumor-related genes may be involved in malignant transformation of endometriosis. PTEN mutation is the pristine event, but p53 mutation is the late.

(Partial) Loss of BAF250a (ARID1A) in rectovaginal deep-infiltrating endometriosis, endometriomas and involved pelvic sentinel lymph nodes.

Loss of protein BAF250a (ARID1A) expression is present in women with rectovaginal deep-infiltrating endometriosis (DIE) and endometriosis affecting the pelvic sentinel lymph nodes (PSLN). Partial loss of protein BAF250a was found in some of our patient samples, comprising all endometriosis entities, including rectovaginal DIE and endometriosis affecting the PSLN. Loss of BAF250a (BRG-associated factor 250a)/ARIDIA (AT-rich interactive domain 1A) protein expression was identified among endometriosis-associated ovarian carcinomas and ovarian endometriosis, and this phenomenon was described as a possible early event in the transformation of endometriosis into cancer. DIE affecting the bowel/rectovaginal site is the most aggressive presentation of endometriosis and its 'risk' of malignant transformation has not been studied so far. We evaluated the immunohistochemical expression of BAF250a protein in 70 samples from patients enrolled in this study who were surgically treated at a tertiary center, university Hospital. The samples submitted to investigation were from rectovaginal DIE (n= 25/30), endometriosis affecting the PSLN (n= 5/7), ovarian endometriosis (n= 20/20) and endometrium from patients without endometriosis used as controls (n= 20/20). Partial loss (i.e. in one tissue section some cells stained positive for BAF250a while other cells, usually an adjacent group, were negative) of BAF250a protein was identified in 36% (9/25) of rectovaginal DIE samples, 40% (2/5) of endometriosis lesions involving the PSLN, 30% (6/20) of endometriomas, and also in 25% (5/20) of endometrium from controls. We found no statistical correlation between occurrence of partial loss of BAF250a protein and the use or not of hormone medications (P = 0.106), cycle phase (P = 0.917) and stage of disease (P = 0.717). We only found partial loss of BAF250a protein expression, and in a small population of women, with relatively high frequency in all benign tissues assessed in the present analysis. Therefore, this finding alone should not be correlated directly with the risk of malignant transformation in these lesions. The occurrence of partial loss of BAF250a protein expression in women with rectovaginal DIE and endometriosis affecting the PSLN is described for the first time. The value of this finding as a predictor of malignant transformation in endometriosis must still be clarified and further studied in association with other molecular events, such as PTEN (phosphatase and tensin homolog) deletion and PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) mutation. We might then be able to identify in the future which patients with endometriosis are at higher risk of cancer. This study was supported by an internal Charité grant to the Endometriosis Research Center and the authors declare no conflicts of interest.