Ovarian Endometrioid Adenocarcinoma Research Articles

The role of CnTI‐SonoVue in the diagnosis of ovarian masses with papillary projections: a preliminary study

To describe sonographically the distribution patterns of a second-generation contrast agent in the microcirculation of unilocular and multilocular ovarian masses with papillary projections, and to investigate whether qualitative evaluation of the passage of the contrast agent can improve the performance of sonography in distinguishing between benign and malignant masses with papillary projections. Thirty-three patients with unilocular or multilocular ovarian masses with papillary projections were enrolled into the study in three clinical centers. The contrast-enhanced transvaginal examination was performed using 'Contrast Tuned Imaging' (CnTI) technology and SonoVue ultrasound contrast agent. Twenty-four (73%) lesions were benign, eight (24%) were borderline ovarian tumors, and one patient presented with an endometrioid ovarian adenocarcinoma. On color and power Doppler examinations the presence of vessels was demonstrated in 17 papillary projections, while on CnTI-SonoVue examination, the presence of vessels was shown in these 17 and in six additional cases. In all cases with absent papillary perfusion after SonoVue intravenous injection, the cyst wall appeared unequivocally regular. The sensitivity and specificity of conventional color Doppler examination with regard to malignancy were 100% and 67% and the positive and negative likelihood ratios were 3.03 and 0.16, respectively. For the contrast-enhanced examination the corresponding values were 100%, 42%, 1.7 and 0.26. The difference in specificity was statistically significant (P<0.05) because 14 cases, in which papillary perfusion was detected after SonoVue injection, proved to be benign on pathological examination. Qualitative evaluation of blood circulation in papillary projections using CnTI-SonoVue examination does not improve the discrimination of benign from borderline/malignant ovarian masses with papillary projections.

Mouse Model of Human Ovarian Endometrioid Adenocarcinoma Based on Somatic Defects in the Wnt/β-Catenin and PI3K/Pten Signaling Pathways

One histologic subtype of ovarian carcinoma, ovarian endometrioid adenocarcinoma (OEA), frequently harbors mutations that constitutively activate Wnt/beta-catenin-dependent signaling. We now show that defects in the PI3K/Pten and Wnt/beta-catenin signaling pathways often occur together in a subset of human OEAs, suggesting their cooperation during OEA pathogenesis. Deregulation of these two pathways in the murine ovarian surface epithelium by conditional inactivation of the Pten and Apc tumor suppressor genes results in the formation of adenocarcinomas morphologically similar to human OEAs with 100% penetrance, short latency, and rapid progression to metastatic disease in upwards of 75% of mice. The biological behavior and gene expression patterns of the murine cancers resemble those of human OEAs with defects in the Wnt/beta-catenin and PI3K/Pten pathways.

Ovarian Sertoli-Leydig Cell Tumors With Pseudoendometrioid Tubules (Pseudoendometrioid Sertoli-Leydig Cell Tumors)

The propensity for ovarian endometrioid adenocarcinomas to morphologically mimic Sertoli, Sertoli-Leydig, and granulosa cell tumors, is well known. The converse situation, mimicry of an endometrioid neoplasm by a sex cord-stromal tumor, has not been emphasized. In this report, we describe 9 ovarian Sertoli-Leydig cell tumors (5 well differentiated, 4 of intermediate differentiation) with areas containing hollow, sometimes dilated, tubules which resemble endometrioid glands; we refer to these as pseudoendometrioid tubules. The age of the patients ranged from 14 to 57. The tumors, all of which were unilateral except for one, ranged from 3.5 to 19 cm and were variously described as tan, pale, yellow, or gold. The proportion of the tumor made up of pseudoendometrioid tubules ranged from 10% to >90%. When widespread, their presence sometimes resulted in consideration of a borderline endometrioid adenofibroma or a well-differentiated endometrioid adenocarcinoma. However, all the neoplasms contained typical Sertoli tubules and one or more of the characteristic patterns of Sertoli-Leydig cell tumors as well as Leydig cells, although the latter cells were inconspicuous in some cases. Immunohistochemistry, performed in 4 cases, showed that the pseudoendometrioid tubules, as well as the more typical Sertoli cell elements, were either positive for alpha inhibin (3 of 4 cases) or calretinin (3 of 4 cases) or both, although sometimes focally so. These elements were negative with epithelial membrane antigen and cytokeratin 7. In all 4 cases, the pseudoendometrioid tubules were positive with the broad spectrum cytokeratin AE1/3. This report illustrates the potential for ovarian Sertoli-Leydig cell tumors to contain tubules with a pseudoendometrioid appearance which mimic a borderline or malignant endometrioid neoplasm. The presence of more typical Sertoli cell elements and Leydig cells, an absence of squamous elements, endometriosis or associated adenofibroma, and the characteristic immunophenotype assist in diagnosis.

Immunohistochemistry as a diagnostic aid in cervical pathology

As with biopsies from other sites in the female genital tract, immunohistochemistry is now being increasingly used in cervical pathology as an aid to diagnosis. In this review, I discuss applications of immunohistochemistry in diagnostic cervical pathology with a particular focus on recent developments. It is emphasised that immunohistochemistry is to be used as an adjunct to routine morphological examination and that no marker is totally specific or sensitive for a given lesion. Although much of this review focuses on glandular lesions, the value of markers, such as MIB1 and p16, in the assessment of pre-invasive cervical squamous lesions is discussed. In the broad field of cervical glandular lesions, topics covered include: the value of markers such as MIB1, p16 and bcl-2 in distinguishing adenocarcinoma in situ and glandular dysplasia from benign mimics; markers of mesonephric lesions, including CD10; markers of value in the diagnosis of minimal deviation adenocarcinoma, such as HIK1083; markers of value in distinguishing metastatic cervical adenocarcinoma in the ovary from primary ovarian endometrioid or mucinous adenocarcinoma. Rarely ectopic prostatic tissue occurs in the cervix, which can be confirmed by positive staining with prostatic markers. A panel of markers, comprising oestrogen receptor, vimentin, monoclonal carcinoembryonic antigen and p16, is of value in distinguishing between a cervical adenocarcinoma and an endometrial adenocarcinoma of endometrioid type. Markers of use in the diagnosis of cervical neuroendocrine neoplasms, including small cell and large cell neuroendocrine carcinoma, are discussed. It is stressed that small cell neuroendocrine carcinomas may be negative with most of the commonly used neuroendocrine markers and this does not preclude the diagnosis. p63, a useful marker of squamous neoplasms within the cervix, is of value in distinguishing small cell neuroendocrine carcinoma (p63 negative) from small cell squamous carcinoma (p63 positive) and in confirming that a poorly differentiated carcinoma is squamous in type.

Drosophila split ends Homologue SHARP Functions as a Positive Regulator of Wnt/β-Catenin/T-Cell Factor Signaling in Neoplastic Transformation

Wnt ligands have pleiotropic and context-specific roles in embryogenesis and adult tissues. Among other effects, certain Wnts stabilize the beta-catenin protein, leading to the ability of beta-catenin to activate T-cell factor (TCF)-mediated transcription. Mutations resulting in constitutive beta-catenin stabilization underlie development of several human cancers. Genetic studies in Drosophila highlighted the split ends (spen) gene as a positive regulator of Wnt-dependent signaling. We have assessed the role of SHARP, a human homologue of spen, in Wnt/beta-catenin/TCF function in mammalian cells. We found that SHARP gene and protein expression is elevated in human colon and ovarian endometrioid adenocarcinomas and mouse colon adenomas and carcinomas carrying gene defects leading to beta-catenin dysregulation. When ectopically expressed, the silencing mediator for retinoid and thyroid receptors/histone deacetylase 1-associated repressor protein (SHARP) protein potently enhanced beta-catenin/TCF transcription of a model reporter gene and cellular target genes. Inhibition of endogenous SHARP function via RNA inhibitory (RNAi) approaches antagonized beta-catenin/TCF-mediated activation of target genes. The effect of SHARP on beta-catenin/TCF-regulated genes was mediated via a functional interaction between SHARP and TCF. beta-Catenin-dependent neoplastic transformation of RK3E cells was enhanced by ectopic expression of SHARP, and RNAi-mediated inhibition of endogenous SHARP in colon cancer cells inhibited their transformed growth. In toto, our findings implicate SHARP as an important positive regulator of Wnt signaling in cancers with beta-catenin dysregulation.

Synchronous Ovarian Endometrioid Adenocarcinoma and Endocervical Mucinous Adenocarcinoma

We report a rare case of synchronous cancer consisting of ovarian endometrioid adenocarcinoma and endocervical mucinous adenocarcinoma. Related literature was reviewed and it appeared that no similar case had been reported previously. A 30-year-old (gravida 1, para 1, abortus 0) woman complained of abdominal fullness, chest tightness and dyspnea on exertion of several days' duration. Gynecologic sonography showed a right complex adnexal cyst, 16 x 14 cm in size. Computed tomography showed an 18 x 16 cm right pelvic tumor, with both cystic and solid components, ascites and bilateral massive pleural effusion. Cytology of the pleural effusion showed no malignant cells. The patient underwent staging surgery. Histology showed moderately to poorly differentiated endometrioid adenocarcinoma of the right ovary with extensive lymphovascular permeation, as well as paraaortic and bilateral pelvic lymph node metastases. Extensive tumor thrombi were observed in the lymphovascular channels of the left ovary, bilateral tubes and uterus. Endocervical adenocarcinoma, < 3 mm in depth, was also identified on the cervix. The final surgical-pathologic stage of ovarian endometrioid adenocarcinoma was stage IIIc and of endocervical mucinous adenocarcinoma was stage IA1. Adjuvant chemotherapy with carboplatin and paclitaxel was prescribed postoperatively, but the malignancy was not controlled due to lung, brain and vulva metastases. The patient died of respiratory failure. The coexistence of primary neoplasms in the ovary and cervix is rare. Diagnosis should be based on histologic examination and requires appropriate treatment for both tumors.

Fibroblast Growth Factor 9 Has Oncogenic Activity and Is a Downstream Target of Wnt Signaling in Ovarian Endometrioid Adenocarcinomas

Wnt signaling plays a key role in development and adult tissues via effects on cell proliferation, motility, and differentiation. The cellular response to Wnt ligands largely depends on their ability to stabilize beta-catenin and the ability of beta-catenin to bind and activate T-cell factor (TCF) transcription factors. Roughly 40% of ovarian endometrioid adenocarcinomas (OEA) have constitutive activation of Wnt signaling as a result of oncogenic mutations in the beta-catenin protein or inactivating mutations in key negative regulators of beta-catenin, such as the adenomatous polyposis coli and Axin tumor suppressor proteins. We used oligonucleotide microarrays to identify genes of which expression was activated in OEAs with beta-catenin dysregulation compared with OEAs lacking Wnt/beta-catenin pathway defects. Using microarray and quantitative PCR-based approaches, we found that fibroblast growth factor (FGF9) expression was increased >6-fold in primary OEAs with Wnt/beta-catenin pathway defects compared with OEAs lacking such defects. Evidence that beta-catenin and TCFs regulate FGF9 expression in several epithelial cell lines was obtained. We found FGF9 was mitogenic for epithelial cells and fibroblasts and FGF9 could stimulate invasion of epithelial and endothelial cells through Matrigel in transwell assays. Furthermore, FGF9 could promote neoplastic transformation of the E1A-immortalized RK3E epithelial cell line, and short hairpin RNA-mediated inhibition of endogenous FGF9 expression in the OEA cell line TOV112D, which carries a beta-catenin mutation, inhibited neoplastic growth properties of the cells. Our findings support the notion that FGF9 is a key factor contributing to the cancer phenotype of OEAs carrying Wnt/beta-catenin pathway defects.

Multiple Gene Expression Analyses in Paraffin-Embedded Tissues by TaqMan Low-Density Array: Application to Hedgehog and Wnt Pathway Analysis in Ovarian Endometrioid Adenocarcinoma

Recent studies have shown the hedgehog and Wnt families of signaling proteins to be associated with tumor initiation, growth, and survival. However, these pathways remain unexplored in ovarian endometrioid adenocarcinoma (OEA). Here, we describe a novel TaqMan low-density array to examine the expression of 26 and 20 genes in the hedgehog and Wnt pathways, respectively, in six matched snap-frozen and formalin-fixed, paraffin-embedded (FPE) OEA specimens. Expression values were normalized to uninvolved ovarian epithelium. Gene expression in matched frozen and FPE tissues demonstrated significant concordance (r = 0.92, P < 0.0001). However, comparison of amplified and unamplified RNA from frozen OEA tissues revealed an altered molecular profile in amplified RNA. Amplification of RNA from FPE tissues was not successful. The expression of Desert hedgehog (DHH), Indian hedgehog (IHH), Hedge-hog interacting protein (HHIP), Wnt10B, Wnt9B, and Wnt inhibitory factor (WIF1) were tumor-specific with no detectable expression in normal ovarian epithelium. In addition, several genes were significantly (P < 0.025) down-regulated in OEA, including cyclin E2, Porcupine, c-Myc, and Axin 2 (4.8-, 3.6-, 2.9-, and 1.9-fold, respectively). TaqMan low-density array provides an effective multivariate technique for examining gene expression in RNA isolated from either snap-frozen or archival FPE tissues and can identify tumor-specific genes, possibly leading to novel treatments.

Higher frequency of chromosomal aberrations in ovarian endometriosis compared to extragonadal endometriosis: a possible link to endometrioid adenocarcinoma

Endometriosis may progress to invasive endometrioid adenocarcinoma, particularly in the ovary. Up to now, little is known of the molecular mechanisms possibly involved in the malignant transformation of endometriosis. Therefore, in this study, extragonadal endometriosis (n=10), ovarian endometriosis without malignancy (n=10), ovarian endometriosis with direct transition into endometrioid adenocarcinoma (n=8), and normal endometrium (n=12) were investigated for numerical chromosomal aberrations by fluorescence in situ hybridization using centromere enumeration probes. The proportions of cells with aneusomies were semiquantitatively assessed. Trisomies 1 and 7, and monosomies 9 and 17 were found in endometriosis, ovarian endometrioid adenocarcinoma, and normal endometrium. The proportions of aneusomic cells were significantly higher in ovarian endometrioid carcinoma compared with ovarian endometriosis (P<0.001), and in ovarian endometriosis compared with extragonadal endometriosis and normal endometrium (P<0.001). The data provide new evidence of a common lineage of endometriosis and ovarian endometrioid carcinoma. The higher frequency of chromosomal aberrations in endometrioid carcinoma than in endometriosis may reflect an expansion of aberrant cell clones already present in endometriosis during the progression to cancer. The higher frequency of chromosomal aberrations in ovarian endometriosis than in extragonadal endometriosis suggests a role of the ovarian stromal milieu in the induction of genetic changes, which may eventually lead to invasive cancer.

P16 Expression in the Female Genital Tract and Its Value in Diagnosis

p16 is a cyclin-dependent kinase-4 inhibitor that is expressed in a limited range of normal tissues and tumors. In recent years, immunohistochemistry with p16 antibodies has been used as a diagnostic aid in various scenarios in gynecologic pathology. Diffuse (as opposed to focal) positivity with p16 in the cervix can be regarded as a surrogate marker of the presence of high-risk human papillomavirus (HPV). In cervical squamous lesions, p16 is positive in most high-grade cervical intraepithelial neoplasia (CIN) and in some cases of low-grade CIN, usually those associated with high-risk HPV. p16 may be useful to identify small focal high-grade CIN lesions, to distinguish some cases of CIN involving immature metaplastic squamous epithelium from immature metaplastic squamous epithelium not involved by CIN and to distinguish high-grade CIN from benign mimics. Most cervical carcinomas of squamous, glandular, and small cell type are p16-positive. In cervical glandular lesions, p16 is useful, as part of a panel, in the distinction between adenocarcinoma in situ (diffusely positive) and benign mimics, including tuboendometrial metaplasia and endometriosis, which are usually p16-negative or focally positive. p16 may be used, in combination with other markers, to distinguish between a cervical adenocarcinoma (diffuse positivity) and an endometrioid-type endometrial adenocarcinoma (negative or focally positive). Some uterine serous carcinomas are diffusely positive. In the vulva, p16 is positive in HPV-associated vulval intraepithelial neoplasia (VIN) but negative in VIN not associated with HPV. Similarly, HPV-associated invasive squamous carcinomas are p16-positive, whereas the more common non-HPV-associated neoplasms are largely negative or focally positive. In the uterus, p16 positivity is more common and widespread in leiomyosarcomas than leiomyomas, and this may be a useful aid to diagnosis, although problematic uterine smooth muscle neoplasms have not been extensively studied. Metastatic cervical adenocarcinomas in the ovary are usually diffusely p16-positive, and because these may closely mimic a primary ovarian endometrioid or mucinous adenocarcinoma, this may be a valuable diagnostic aid, although p16 expression in primary ovarian adenocarcinomas of these morphologic subtypes has not been widely investigated. Some ovarian serous carcinomas, similar to their uterine counterparts, are p16-positive.

Postmenopausal endometriosis and malignant transformation of endometriosis: a case series

Endometriosis is a common problem in women in their reproductive years but is much less frequent in the postmenopausal state, with an incidence of around 2%. Malignant change in endometriotic deposits was first described by Sampson in 1925. Since then, the risk of malignant transformation has been well documented but continues to be a relatively rare occurrence, occurring mainly (79%) in the ovary. The vast majority of women with this condition are premenopausal or taking exogenous hormones. We undertook a retrospective review of hospital notes identified from our database of endometriosis cases undergoing surgery. We identified two cases of benign disease and two cases of endometriosis-associated adenocarcinoma presenting in menopausal women. The first patient presented with haematuria and rectal bleeding. At laparotomy, she was found to have a substantial endometriotic nodule involving the bladder and sigmoid colon. The second patient presented with abdominal pain and dyschezia. She was found to have uterosacral disease at laparoscopy. The third patient presented with an inoperable endometrioid adenocarcinoma, having previously had a total abdominal hysterectomy and bilateral salpingo-oophorectomy. The fourth patient presented with pain and an abdominal mass. At laparotomy there was stage IV endometriosis, and histology subsequently revealed an ovarian endometrioid adenocarcinoma. In conclusion, endometriosis can arise de novo in the menopause, perhaps triggered by peripheral conversion of androstenedione or as a consequence of hormone replacement. Persistence of endometriosis past the menopause raises the risk of malignancy. Future research will help to differentiate between those who require radical treatment and those who can be managed conservatively.

Histologic Type, Organ of Origin, and Wnt Pathway Status: Effect on Gene Expression in Ovarian and Uterine Carcinomas

Ovarian and uterine carcinomas manifest several differentiation patterns resembling those seen in nonneoplastic epithelia of the gynecologic tract. Specific oncogene and tumor suppressor gene defects have been associated with particular differentiation patterns in carcinomas arising in either the uterus or ovary. For instance, ovarian and uterine carcinomas with endometrioid differentiation frequently show beta-catenin mutations. Whereas type of differentiation is considered in the treatment of uterine carcinomas, it does not presently contribute to decisions about treatment of ovarian carcinomas. A widely accepted view is that the accumulation of specific gene defects and gene expression changes underlies phenotypic traits of cancers, including their response to treatment. Using oligonucleotide microarrays to assess gene expression in 103 primary ovarian and uterine carcinomas, we sought to address whether organ of origin or type of differentiation (histotype; endometrioid versus serous) had a more substantial effect on gene expression patterns. We found that effects on gene expression due to organ of origin and histotype are similar in magnitude and are parallel in that organ effects are similar in the two histotypes and histotype effects are similar in the two organs. In addition, ovarian and uterine endometrioid adenocarcinomas with beta-catenin defects show a common gene expression signature largely distinct from that seen in tumors lacking such defects. Our results illustrate how organ of origin, type of differentiation, and specific molecular defects all contribute to gene expression in the most common types of ovarian and uterine cancers. The findings also imply gene expression data will be of value for stratifying ovarian cancer patients for new treatment approaches.

Ovarian carcinomas, including secondary tumors: diagnostically challenging areas

The differential diagnosis of ovarian carcinomas, including secondary tumors, remains a challenging task. Mucinous carcinomas of the ovary are rare and can be easily confused with metastatic mucinous carcinomas that may present clinically as a primary ovarian tumor. Most of these originate in the gastrointestinal tract and pancreas. International Federation of Gynecology and Obstetrics (FIGO) stage is the single most important prognostic factor, and stage I carcinomas have an excellent prognosis; FIGO stage is largely related to the histologic features of the ovarian tumors. Infiltrative stromal invasion proved to be biologically more aggressive than expansile invasion. Metastatic colon cancer is frequent and often simulates ovarian endometrioid adenocarcinoma. Although immunostains for cytokeratins 7 and 20 can be helpful in the differential diagnosis, they should always be interpreted in the light of all clinical information. Occasionally, endometrioid carcinomas may exhibit a microglandular pattern simulating sex cord-stromal tumors. However, typical endometrioid glands, squamous differentiation, or an adenofibroma component are each present in 75% of these tumors whereas immunostains for calretinin and alpha-inhibin are negative. Endometrioid carcinoma of the ovary is associated in 15-20% of the cases with carcinoma of the endometrium. Most of these tumors have a favorable outcome and they most likely represent independent primary carcinomas arising as a result of a Mullerian field effect. Although the criteria for distinguishing metastatic from independent primary carcinomas rely mainly upon conventional clinicopathologic findings, loss of heterozygosity and gene mutation analyses can be helpful. Transitional cell carcinomas are distinguished from undifferentiated carcinomas by the presence of thick, undulating papillae with smooth luminal borders, microspaces, and tumor cells with distinctive 'urothelial' appearance. Krukenberg tumors are metastatic adenocarcinomas traditionally perceived as composed of mucin-filled signet-ring cells associated with a striking proliferation of the ovarian stroma but many variations on this pattern occur.

Ovarian carcinomas, including secondary tumors: diagnostically challenging areas

The differential diagnosis of ovarian carcinomas, including secondary tumors, remains a challenging task. Mucinous carcinomas of the ovary are rare and can be easily confused with metastatic mucinous carcinomas that may present clinically as a primary ovarian tumor. Most of these originate in the gastrointestinal tract and pancreas. International Federation of Gynecology and Obstetrics (FIGO) stage is the single most important prognostic factor, and stage I carcinomas have an excellent prognosis; FIGO stage is largely related to the histologic features of the ovarian tumors. Infiltrative stromal invasion proved to be biologically more aggressive than expansile invasion. Metastatic colon cancer is frequent and often simulates ovarian endometrioid adenocarcinoma. Although immunostains for cytokeratins 7 and 20 can be helpful in the differential diagnosis, they should always be interpreted in the light of all clinical information. Occasionally, endometrioid carcinomas may exhibit a microglandular pattern simulating sex cord-stromal tumors. However, typical endometrioid glands, squamous differentiation, or an adenofibroma component are each present in 75% of these tumors whereas immunostains for calretinin and alpha-inhibin are negative. Endometrioid carcinoma of the ovary is associated in 15–20% of the cases with carcinoma of the endometrium. Most of these tumors have a favorable outcome and they most likely represent independent primary carcinomas arising as a result of a Müllerian field effect. Although the criteria for distinguishing metastatic from independent primary carcinomas rely mainly upon conventional clinicopathologic findings, loss of heterozygosity and gene mutation analyses can be helpful. Transitional cell carcinomas are distinguished from undifferentiated carcinomas by the presence of thick, undulating papillae with smooth luminal borders, microspaces, and tumor cells with distinctive ‘urothelial' appearance. Krukenberg tumors are metastatic adenocarcinomas traditionally perceived as composed of mucin-filled signet-ring cells associated with a striking proliferation of the ovarian stroma but many variations on this pattern occur.

Role of K-ras and Pten in the development of mouse models of endometriosis and endometrioid ovarian cancer

Epithelial ovarian tumors present a complex clinical, diagnostic and therapeutic challenge because of the difficulty of early detection, lack of known precursor lesions and high mortality rates. Endometrioid ovarian carcinomas are frequently associated with endometriosis, but the mechanism for this association remains unknown. Here we present the first genetic models of peritoneal endometriosis and endometrioid ovarian adenocarcinoma in mice, both based on the activation of an oncogenic K-ras allele. In addition, we find that expression of oncogenic K-ras or conditional Pten deletion within the ovarian surface epithelium gives rise to preneoplastic ovarian lesions with an endometrioid glandular morphology. Furthermore, the combination of the two mutations in the ovary leads to the induction of invasive and widely metastatic endometrioid ovarian adenocarcinomas with complete penetrance and a disease latency of only 7 weeks. The ovarian cancer model described in this study recapitulates the specific tumor histomorphology and metastatic potential of the human disease.

FGF-20 and DKK1 are transcriptional targets of β-catenin and FGF-20 is implicated in cancer and development

beta-catenin is the major effector of the canonical Wnt signaling pathway. Mutations in components of the pathway that stabilize beta-catenin result in augmented gene transcription and play a major role in many human cancers. We employed microarrays to identify transcriptional targets of deregulated beta-catenin in a human epithelial cell line (293) engineered to produce mutant beta-catenin and in ovarian endometrioid adenocarcinomas characterized with respect to mutations affecting the Wnt/beta-catenin pathway. Two genes strongly induced in both systems-FGF20 and DKK1-were studied in detail. Elevated levels of FGF20 RNA were also observed in adenomas from mice carrying the Apc(Min)allele. Both XFGF20 and Xdkk-1 are expressed early in Xenopus embryogenesis under the control of the Wnt signaling pathway. Furthermore, FGF20 and DKK1 appear to be direct targets for beta-catenin/TCF transcriptional regulation via LEF/TCF-binding sites. Finally, by using small inhibitory RNAs specific for FGF20, we show that continued expression of FGF20 is necessary for maintenance of the anchorage-independent growth state in RK3E cells transformed by beta-catenin, implying that FGF-20 may be a critical element in oncogenesis induced by the Wnt signaling pathway.

The role of hMSH3 and hMSH6 in ovarian endometrioid carcinoma and relationship with microsatellite instability phenotype

Frequent frameshift mutations in the DNA mismatch repair genes hMSH3, and hMSH6, have been reported in colorectal and endometrial cancers with microsatellite instability, however, it is unclear whether they are similarly altered in ovarian endometrioid carcinoma. In this study, we examined frequency of frameshift mutation and protein expression in hMSH3 and hMSH6 in ovarian endometrioid carcinoma with or without microsatellite instability. Only 1 frameshift mutation of the 16 cases with microsatellite instability-high phenotype (6%) was detected in poly(A)8 tract of the hMSH3, but not in poly(C)8 tract of hMSH6 genes. In addition, none of the 6 microsatellite instability-low or 20 microsatellite-stable tumors showed mutations in these regions in either gene. These results indicate that mutations in the mono-nucleotide tracts of hMSH3 and hMSH6 are infrequent in ovarian endometrioid adenocarcinomas, other mechanisms may play a more important role in the development of these tumors.

Growth-inhibitory signals by activin A do not affect anticancer drug-sensitivity and acquired multi-drug-resistance in human ovarian endometrioid adenocarcinoma OVK-18 cells

Using the human ovarian adenocarcinoma cell line, OVK-18, which is sensitive to activin A-mediated inhibition of growth and various anticancer drugs, we determined whether activin A altered the sensitivity of these cells to seven anticancer drugs. The relationship between the sensitivity to activin and the resistance to anticancer drugs was also investigated in OVK-18 parent cells and OVK-18-derived CDDP-resistant cells. Activin A inhibited proliferation of OVK-18 parent cells in a dose-dependent manner, although it did not affect the sensitivity of OVK-18 parent cells to the seven anticancer drugs, CDDP, CBDCA, adriamycin, paclitaxel, SN38, terarubicin and etoposide (VP16). Both the sensitivity to activin A-mediated inhibition of growth and the sensitivity to anticancer drug-induced apoptosis were reduced in CDDP-resistant cells, while their sensitivity to the seven anticancer drugs was not affected by activin A. Flow cytometric analysis revealed a significant reduction in type IIA activin receptor expression on the surface of CDDP-resistant cells. These results indicate that the activin A-induced intracellular signals inhibiting cell growth are independent of the inhibition caused by the seven anticancer drugs, and suggest that the reduced sensitivity of CDDP-resistant cells to activin A is derived in part from reduced activin receptor expression and not acquired drug-resistance.

Complete remission of ovarian endometrioid adenocarcinoma associated with hyperamylasemia and liver metastasis treated by paclitaxel and carboplatin chemotherapy: a case report

Complete remission in the case of a 45-year-old woman with ovarian endometrioid adenocarcinoma associated with hyperamylasemia and liver metastasis is described. Ultrasound examination and CT scan revealed several large solid and cystic intra-abdominal tumors and a metastatic liver tumor. The serum amylase was 600 micro/l (normal value: 60-200 micro/l), and electrophoresis identified isoamylases of the salivary type. A total abdominal hysterectomy with bilateral salpingo-oophorectomy was performed for invasive carcinoma of the left ovary. The histology of the left ovary showed endometrioid adenocarcinoma. Immunohistochemically, the adenocarcinoma cells were diffusely and strongly positive for amylase. The patient received six courses of paclitaxel and carboplatin combination chemotherapy. Two years later, the patient is alive and well, without evidence of disease. The prognosis of patients with ovarian cancer metastatic to the liver is uniformly poor. This represents the first report of complete remission of such a patient in the literature.

Complete remission of ovarian endometrioid adenocarcinoma associated with hyperamylasemia and liver metastasis treated by paclitaxel and carboplatin chemotherapy: a case report

Complete remission in the case of a 45-year-old woman with ovarian endometrioid adenocarcinoma associated with hyperamylasemia and liver metastasis is described. Ultrasound examination and CT scan revealed several large solid and cystic intra-abdominal tumors and a metastatic liver tumor. The serum amylase was 600μ/l (normal value: 60–200 μ/l), and electrophoresis identified isoamylases of the salivary type. A total abdominal hysterectomy with bilateral salpingo-oophorectomy was performed for invasive carcinoma of the left ovary. The histology of the left ovary showed endometrioid adenocarcinoma. Immunohistochemically, the adenocarcinoma cells were diffusely and strongly positive for amylase. The patient received six courses of paclitaxel and carboplatin combination chemotherapy. Two years later, the patient is alive and well, without evidence of disease. The prognosis of patients with ovarian cancer metastatic to the liver is uniformly poor. This represents the first report of complete remission of such a patient in the literature.