Carcinosarcoma arising from high-grade serous carcinoma of the ovary without estrogen receptor, WT-1, and PAX8 immunoreactivity.

OBJECTIVE: We encountered a case of high-grade serous carcinoma (HGSC) of the ovary which recurred as carcinosarcoma of the sigmoid colon. Tumor cells of both the primary carcinoma and the secondary carcinosarcoma were negative for estrogen receptor (ER), WT-1, and PAX8. It is well known that most ovarian carcinomas arising from the Müllerian duct are immunoreactive for these biologic parameters. To our knowledge, this is the first case report that provides the results of immunohistochemical analysis of WT-1 and PAX8 for a primary carcinoma and recurrent carcinosarcoma. CASE REPORT: A 61-year-old woman had an advanced right ovarian HGSC. After a primary debulking surgery (hysterectomy, bilateral salpingo-oophorectomy and omentectomy) and adjuvant chemotherapy, complete remission was achieved. However, four and a half years later, a tumor arising beside the sigmoid colon was detected. A tumorectomy was performed through combined partial resection of the ileum and sigmoid colon. Microscopically, the tumor was diagnosed as carcinosarcoma of the sigmoid colon, which had originated from HGSC of the ovary. Interestingly, the malignant cells of the primary carcinoma and epithelial components of the recurrent carcinosarcoma were negative for ER, WT-1, and PAX8. These immunohistochemical features were unusual. Three cycles of chemotherapy with the previously used regimen and three additional cycles of doxorubicin and ifosfamide combination chemotherapy were administered. Currently, 3 years after the final chemotherapy was administered, the patient remains healthy. CONCLUSION: HGSC of the ovary can recur as carcinosarcoma. Tumor cells of the primary HGSC without ER, WT-1, and PAX8 expression may have dedifferentiated and recurred as carcinosarcoma.

Multiple metastatic gestational trophoblastic disease after a twin pregnancy with complete hydatidiform mole and coexisting fetus, following assisted reproductive technology: Case report and literature review.

OBJECTIVE: Twin pregnancy with complete hydatidiform mole and coexisting fetus (CHMCF) is rare and associated with severe complications during pregnancy and subsequent gestational trophoblastic disease (GTD). We encountered a case of multiple metastatic GTD after a twin pregnancy with CHMCF, following conventional in vitro fertilization (IVF). Only one case of metastatic GTD after CHMCF due to assisted reproductive technology (ART) has been reported. Here, we present the clinical course and reveal the clinical features of CHMCF after ART through a literature review. CASE REPORT: A 42-year-old primigravida woman had an abnormal pregnancy (i.e., CHMCF) by IVF. She had persisting severe vaginal bleeding, which led to termination of her pregnancy at 10 weeks of gestation. Pathohistological examination revealed that this was a case of CHMCF. Five weeks after the termination, the serum ß-human chorionic gonadotropin level was still extremely high, and systemic contrast-enhanced computed tomography revealed a tumor in the uterine corpus and more than 30 lung nodules. After 11 cycles of combination chemotherapy with etoposide, methotrexate, actinomycin-D, cyclophosphamide, and vincristine (EMA/CO) to treat high-risk GTD, hysterectomy was needed as radical therapy. CONCLUSION: Cases of CHMCF following ART may also have higher malignant potential and higher risk of GTD development and become more aggressive biologically. The clinical course of CHMCF after ART seems to be almost the same as that without ART based on the results of literature review.

Magnetic Resonance Imaging and Flexible Hysterofiberscopic Findings of a Uterine Adenofibroma: Case Report and Literature Review.

To our knowledge, highly detailed findings of flexible hysterofiberscopy in patients with adenofibroma have not been described. A 75-year-old nulliparous asymptomatic woman presented with a uterine polyp, which exhibited punctate heterogeneous hyperintensity or islands of isointense-to-hypointense signals on T2-weighted magnetic resonance imaging (MRI), hypointense signals on T1-weighted images (T1WI), and a little enhancement on contrast-enhanced T1WI. Flexible hysterofiberscopy revealed a red-pink polyp with a white-yellow, cobblestone-like surface easily deformed by perfusion fluid. The tumor was diagnosed histologically as an adenofibroma. Total abdominal hysterectomy and bilateral salpingo-oophorectomy were performed. The tumor in the uterus was necrotic macroscopically and histologically, and a residual adenofibroma could not be confirmed. At present, two years after surgery, the patient remains healthy. MRI and hysterofiberscopy can reveal the histological features of uterine adenofibromas and be useful for their diagnosis.

Epigenetic dysregulation of endometriosis susceptibility genes (Review).

The aim of the present review was to illustrate how dysregulation of hormonal signaling regulates expressional changes of spatially associated genes in endometriosis. From a multi­platform endometriosis dataset, an integrated analysis was performed of epigenomic changes of several biologically relevant genes that have been validated in the literature. Estrogen receptor (ER) may act as a direct epigenetic driver for endometriosis establishment, maintenance and progression. A majority of endometriosis susceptibility genes may be present in functional downstream targets of ER and located near the known imprinting genes. Previous studies have shed light on the overlapping genetic signatures between endometriosis development and the defective decidualization process. The steroid hormone­mediated decidualization signaling pathway was shown to be frequently dysregulated in endometriosis. DNA methylation is associated with various intragenic or intergenic epigenetic modifications of chromatin. Chromatin architecture may be established in temporal and spatial orchestration of the recruitment of genes specifically downregulated in endometriosis. In conclusion, defective chromatin architecture at the ER target locus may have a key role in endometriosis. Endometriosis represents an interesting model to explore the variation of expression of spatially associated genes.

Concurrent Malignant Solitary Fibrous Tumor Arising from the Omentum and Grade 3 Endometrial Endometrioid Adenocarcinoma of the Uterus with p53 Immunoreactivity.

A malignant solitary fibrous tumor arising from the omentum is extremely rare. To our knowledge, this is the first case of a malignant solitary fibrous omentum tumor coexisting with uterine corpus cancer. A 62-year-old woman presented to our hospital with vaginal discharge. Endometrioid adenocarcinoma was diagnosed by endometrial curettage. In addition, a solid tumor in front of the uterus was detected following computed tomography and/or magnetic resonance imaging, which was suspected to be a primary (or secondary) malignant tumor arising from the omentum. Hysterectomy, bilateral salpingo-oophorectomy, omentectomy, and lymphadenectomy were performed. A malignant solitary fibrous tumor of the omentum and grade 3 endometrioid adenocarcinoma of the uterus were diagnosed by pathohistological analysis. Interestingly, the tumor cells were immunoreactive for p53. Adjuvant chemotherapy was administered for the uterine corpus cancer and the patient remains healthy 48 months after the surgery. These tumors may have become malignant due to the presence of p53 mutations.

Genes Downregulated in Endometriosis Are Located Near the Known Imprinting Genes.

There is now accumulating evidence that endometriosis is a disease associated with an epigenetic disorder. Genomic imprinting is an epigenetic phenomenon known to regulate DNA methylation of either maternal or paternal alleles. We hypothesize that hypermethylated endometriosis-associated genes may be enriched at imprinted gene loci. We sought to determine whether downregulated genes associated with endometriosis susceptibility are associated with chromosomal location of the known paternally and maternally expressed imprinting genes. Gene information has been gathered from National Center for Biotechnology Information database geneimprint.com. Several researchers have identified specific loci with strong DNA methylation in eutopic endometrium and ectopic lesion with endometriosis. Of the 29 hypermethylated genes in endometriosis, 19 genes were located near 45 known imprinted foci. There may be an association of the genomic location between genes specifically downregulated in endometriosis and epigenetically imprinted genes.

Pathogenesis of endometriosis: the role of initial infection and subsequent sterile inflammation (Review).

Endometriosis is a common type of chronic inflammatory disease with an immunological background. In this review, we aimed to explore the contemporary literature on the infection and sterile inflammation that support the pathogenesis of endometriosis. This article reviews the English­language literature on inflammatory, environmental, immunological and oxidative factors associated with endometriosis in an effort to identify factors that cause a predisposition to endometriosis. Intrauterine microbes may be critical for the initiation of endometriosis; the initial activation of pathogen recognition receptors by microbial stimuli results in the activation of proinflammatory pathways and innate immunity. In addition to their response to various exogenous pathogen­associated molecular patterns, Toll­like receptors (TLRs) also recognize a wide range of endogenous danger­associated molecular patterns (DAMPs). The increased expression levels of DAMPs may be involved in the subsequent process of nuclear transcription factor­κB­dependent sterile inflammation. Oxidative stress, secondary to the influx of iron during retrograde menstruation, is involved in the progression of endometriosis. DAMP­mediated danger signals and oxidative stress are bidirectional during sterile inflammation (danger signal spiral). This review supports the hypothesis that there are at least two distinct phases of endometriosis development: The initial wave of TLR activation in modulating innate immune responses would be followed by the second big wave of sterile inflammation.

Identification of multiple pathways involved in the malignant transformation of endometriosis (Review).

The association between endometriosis and malignant transformation has often been described in the medical literature. A search was conducted between 1966 and 2010 through the English language literature (online Medline PubMed database) using the keywords endometriosis combined with malignant transformation. The search revealed an increase in reports describing endometriosis and malignancy. Approximately 1.0% of women with endometriosis have lesions that undergo malignant transformation. The malignant processes that are associated with endometriosis may be classified into three groups: i) epithelial ovarian cancers (endometrioid adenocarcinoma and clear cell carcinoma), ii) other Müllerian-type tumors, including Müllerian-type mucinous borderline tumor and serous borderline tumor and iii) sarcomas such as adenosarcoma and endometrial stromal sarcoma in the female pelvic cavity. Persistent oxidative stress induced by endometriosis-dependent hemorrhage may be associated with carcinogenesis. In conclusion, the malignant transformation of endometriosis has multiple pathways of development and may share a common pathogenic mechanism; iron-induced oxidative stress derived from repeated hemorrhage.

The dichotomy in the histogenesis of endometriosis-associated ovarian cancer: clear cell-type versus endometrioid-type adenocarcinoma.

The histogenesis of endometriosis and endometriosis-associated ovarian cancer is one of the most mysterious aspects of pathology. To better understand the histogenesis of endometriosis and endometriosis-associated ovarian cancer, we analyzed the possibility of a link of endometrium, ovarian surface epithelium, and a cortical inclusion cyst to ovarian endometriosis and endometriosis-associated ovarian cancer by immunohistochemistry using the epithelial membrane antigen (an epithelial marker), calretinin (a mesothelial marker), and hepatocyte nuclear factor (HNF)-1ß (a clear cell carcinoma-specific transcription factor). During ovarian surface epithelium invagination, cortical inclusion cyst epithelial cells may, in some cases, undergo mesothelial-epithelial transition and subsequently differentiate into endometriosis. This case of endometriosis that has undergone Müllerian metaplasia arises from the HNF-1ß-negative cells. The remaining endometriosis may develop from the late secretory and menstrual endometria, with HNF-1ß-positive staining, by retrograde menstruation. Endometrioid adenocarcinoma and clear cell carcinoma arise from the HNF-1ß-negative and HNF-1ß-positive epithelial cells of endometriosis, respectively. It has been proposed that clear cell and endometrioid-type adenocarcinomas arise from distinct types of endometriosis with different cells of origin.

Targeted molecular therapies for ovarian cancer: an update and future perspectives (Review).

Identification of the potential gene expression profiles of epithelial ovarian cancer and the arrival of newly targeted therapies have advanced the strategies used for treatment of this disease. This review focuses on the design of ongoing and planned clinical trials and offers a synopsis of the English-language literature for preclinical and clinical targeted therapies for epithelial ovarian cancer. Among many targeted agents, a promising, novel class of targeted drugs for special patient populations expected to improve the effectiveness of current therapy include inhibitors of angiogenesis, poly (ADP ribose) polymerase (PARP) and DNA repair mechanisms. Inhibition of PARP or homologous recombination (HR) repair mediated by Chk1 (checkpoint kinase 1) would selectively sensitize p53 mutation, BRCAness phenotype (serous type ovarian cancer) or HNF (hepatocyte nuclear factor)-1ß-overexpressing tumor cells (clear cell type ovarian cancer) to chemotherapeutic agents. The therapeutic response is likely to be limited to a targeted patient, but not to the broad population. This review discusses some of the key current developments and existing challenges.

A potential link of oxidative stress and cell cycle regulation for development of endometriosis.

BACKGROUND: The roles of molecular alteration such as genomic instability and cell survival are debated aspects of the pathogenesis of endometriosis. To review the contemporary literature on potential factors and their signaling pathways that support prolonged survival of endometriotic cells. METHODS: This article reviews the English-language literature for molecular, pathogenetic, and pathophysiological studies on endometriosis. This review is focused on the association of hepatocyte nuclear factor (HNF)-1ß with endometriosis. RESULTS: The iron-induced oxidative stress plays a fundamental role for the pathogenesis of endometriosis. Oxidative stress, secondary to influx of iron during retrograde menstruation, modifies lipids and proteins, leading to cell and DNA damage. Recent studies demonstrated HNF-1ß overexpression in endometriotic foci. HNF-1ß increases the survival of endometriotic cells under iron-induced oxidative stress conditions possibly through the activation of forkhead box (FOX) transcription factors and/or endometriosis-specific expression of microRNAs. Endometriotic cells expressing HNF-1ß also display cell cycle checkpoint pathways required to survive DNA damaging events. CONCLUSIONS: HNF-1ß in endometriosis might be a factor that controls the cell cycle and DNA damage checkpoints.