Man Soo Yoon

Significance of E2F-1 overexpression in epithelial ovarian cancer

E2F-1 is a downstream regulator of the Rb pathway and is a transcription factor that plays a key role in the control of cell cycle progression. Deregulation of E2F-1 expression and Rb pathway is involved in carcinogenesis. The aim of this study was to evaluate E2F-1 expression and Rb pathway alteration and to elucidate their correlation with clinical and pathologic parameters in epithelial ovarian cancer (EOC). We investigated overexpression of E2F-1 and alterations of p16INK4a, cyclin D1, CDK4, and pRb using immunohistochemistry and tissue microarray methods in 72 EOC patients. Overexpression of E2F-1 was detected in 45.8% of samples. The overall abnormal expression frequencies of p16INK4a, cyclin D1, CDK4, and pRb were 33.3%, 11.1%, 12.5%, and 38.9%, respectively. E2F-1 overexpression was not associated with alteration of the Rb pathway. E2F-1 overexpression was correlated with FIGO stage, histologic grade, and mitotic index; it was a valuable prognostic variable along with FIGO stage in the multivariated analysis. The results suggest that E2F-1 has a growth-promoting effect in EOC and that E2F-1 overexpression may provide a useful prognostic indicator for EOC.

Expression and significance of the TLR4/MyD88 signaling pathway in ovarian epithelial cancers

BackgroundToll-like receptors (TLR) are a family of pattern recognition receptors that constitutes a major part of the innate immune system. The TLR4/(Myeloid differentiation factor 88 (MyD88) signaling pathway has been shown to have oncogenic effects.MethodsTo demonstrate the role of TLR4/MyD88 signaling in ovarian epithelial cancers (OECs), we examined the expression of TLR4, MyD88 and nuclear factor- κB (NF-κB) in OECs. The expression of TLR4, MyD88, and NF-κB was detected by immunohistochemistry, and the relationships between these and clinicopathologic features in 123 cases of OECs were also analyzed.ResultsThe expression of TLR4, MyD88, and NF-κB in OECs was observed in 46.3% (57/123), 36.6% (45/123) and 65% (80/123) of OEC cases, respectively. The TLR4, MyD88, and NF-κB expressions were associated with the histologic type of OECs, particularly with the clear cell type of OEC. There was no significant correlation between TLR4 or NF-κB expression and histologic grade, tumor size, mitotic count, FIGO (International Federation of Gynecology and Obstetrics) stage, disease recurrence. However, there was a significant correlation between MyD88 expression and FIGO stage, disease recurrence as well as histologic type. In univariate analysis, the expression of TLR4 and MyD88, and the coexpression of TLR4/MyD88 and TLR4/MyD88/NF-κB had a significant impact on the survival of patients with OECs. Only MyD88 expression had an independent prognostic significance in multivariate analysis.ConclusionsOur findings suggest that the TLR4/MyD88 signaling pathway is associated with the survival of patients with OECs, and that MyD88 is an independent prognostic predictor in patients with OECs. The TLR4/MyD88 signaling pathway may be a mechanism responsible for poor prognosis in patients with clear cell type of OEC.

High-throughput DNA hypermethylation profiling in different ovarian epithelial cancer subtypes using universal bead array

DNA hypermethylation is common and plays a critical role in the regulation of gene expression. It is considered a major cause of carcinogenesis. High-throughput profiling method has been developed to analyze the methylation status of hundreds of pre-selected genes simultaneously. The aim of this study was to analyze promoter hypermethylation profiles of each subtype of ovarian epithelial cancer (OEC), to improve the understanding of the role of epigenetic silencing in carcinogenesis. DNA hypermethylation profiles on fresh frozen tissue samples of 5 serous, 3 mucinous, 5 endometrioid and 4 clear cell types of OEC, as well as 5 normal ovarian tissue samples as control. We used a high-throughput method for analyzing the hypermethylation status of 1,505 CpG loci selected from 871 genes simultaneously by GoldenGate Methylation Cancer Panel I (Illumina Human-6 v2 Expression BeadChip). Methylation status of seven genes was verified by methylation specific PCR (MSP). We identified 20, 37, 15 and 56 hypermethylated CpG locations in serous, mucinous, endometrioid and clear cell type OEC compared to control. Only 6 CpG loci were commonly hypermethylated across all subtypes of OEC. Hypermethylated loci of serous 17 (81.0%) and endometrioid type 10 (71.4%) were identical to that of clear cell type. However, mucinous type showed 17 peculiar loci (43.6%) out of 39 hypermethylated loci. The unique DNA hypermethylation patterns identified in different OEC subtypes suggest that their cause may involve different epigenetic mechanisms and the Bead chip used in this study is a useful tool to analyze DNA hypermethylation.

DDX4 (DEAD box polypeptide 4) colocalizes with cancer stem cell marker CD133 in ovarian cancers.

DDX4 (DEAD box polypeptide 4), characterized by the conserved motif Asp-Glu-Ala-Asp (DEAD), is an RNA helicase which is implicated in various cellular processes involving the alteration of RNA secondary structure, such as translation initiation, nuclear and mitochondrial splicing, and ribosome and spliceosome assembly. DDX4 is known to be a germ cell-specific protein and is used as a sorting marker of germline stem cells for the production of oocytes. A recent report about DDX4 in ovarian cancer showed that DDX4 is overexpressed in epithelial ovarian cancer and disrupts a DNA damage-induced G2 checkpoint. We investigated the relationship between DDX4 and ovarian cancer stem cells by analyzing the expression patterns of DDX4 and the cancer stem cell marker CD133 in ovarian cancers via tissue microarray. Both DDX4 and CD133 were significantly increased in ovarian cancer compared to benign tumors, and showed similar patterns of expression. In addition, DDX4 and CD133 were mostly colocalized in various types of ovarian cancer tissues. Furthermore, almost all CD133 positive ovarian cancer cells also express DDX4 whereas CD133-negative cells did not possess DDX4, suggesting a strong possibility that DDX4 plays an important role in cancer stem cells, and/or can be used as an ovarian cancer stem cell marker.

Clinicopathological significance of atypical glandular cells on Pap smear.

Objective To investigate the clinical significance of atypical glandular cells (AGC) by analyzing the prevalence and histologic outcomes of patients with AGC according to Pap smear. Methods The medical records of 83 patients who were diagnosed AGC on Pap tests at the Pusan National University Hospital outpatient department and health care center from January 1998 to March 2006 were reviewed. Results The prevalence of AGC was 55 of 54,160 (0.10%) and 28 of 54,160 (0.05%) for AGC-not otherwise specified (NOS) and neoplastic associated AGC, respectively. The histopathologic results of the AGC-NOS group (n=55) were as follows: low-grade squamous intraepithelial lesion, 7 (12.7%); high-grade squamous intraepithelial lesion, 4 (7.2%); adenocarcinoma of cervix, 3 (5.4%); endometrial carcinoma, 2 (3.6%); and other malignancies including 2 ovarian cancer cases and 1 breast cancer case, 3 (5.4%). The histopathologic results for the AGC-associated neoplastic group (n=28) were as follows: low-grade squamous intraepithelial lesion, 1 (3.5%); high-grade squamous intraepithelial lesion, 3 (10.7%); adenocarcinoma of cervix, 5 (17.8%); endometrial carcinoma, 4 (4.8%); and additional malignancies including 3 stomach cancer cases, 2 ovarian cancer cases, and 2 breast cancer cases; 7 (25%). Conclusion AGCs may represent a variety of benign and malignant lesions. AGC-associated neoplastic findings may be related to gynecological or extrauterine malignancies. Thus, when AGCs, especially neoplastic AGCs, are encountered, it is best to evaluate the cervix not only for typical maladies, but also for gynecological and non-gynecological malignancies.

Tumor-infiltration of T-lymphocytes is inversely correlated with clinicopathologic factors in endometrial adenocarcinoma.

Objective The aim of this study was to determine the distribution of T-lymphocytes and their relationship with clinicopathologic factors in endometrial carcinoma. Methods Samples were collected from 89 patients with endometrial endometrioid adenocarcinoma treated in Pusan National University Hospital from 2004 to 2011. Normal endometrial tissues were obtained from 30 hysterectomized women with benign adnexal masses and served as controls. Paraffin-embedded sections were immunohistochemically stained for CD8 (cytotoxic) and CD4 (helper) T-lymphocytes. The relationship of these cells with stage, histological grade, myometrial invasion, and lymph node metastasis was analyzed. Results The proportion of CD8+ and CD4+ lymphocytes in the endometrial endometrioid adenocarcinoma tissues was 67.4% (60/89) and 44.9% (40/89), respectively, which was significantly higher (P<0.05) than in the control group. The extent of CD8+ lymphocyte expression was negatively correlated with histologic grade, myometrial invasion, and lymph node metastasis. The proportion of infiltration of the CD4+ lymphocytes was negatively correlated with histologic grade and myometrial invasion. Conclusion The high rate of infiltration of T-lymphocytes was negatively correlated with histologic grade, myometrial invasion, and lymph node metastasis. Our findings suggest that tumor-infiltrating T-lymphocytes may be used as pathologic prognostic factors in endometrial carcinoma.

S100 expression in dendritic cells is inversely correlated with tumor grade in endometrial carcinoma

Objective The aim of this study was to determine the expression of S100 positive dendritic cells (DCs) and the relationship with clinicopathologic factors in endometrial carcinoma. Methods Samples were collected from 89 patients with endometrial endometrioid adenocarcinoma treated in Pusan National University Hospital from 2004 to 2011. Normal endometrial tissues were obtained from 30 hysterectomized women with benign adnexal masses and served as controls. Paraffin-embedded sections were immunohistochemically stained for S100 was performed, and the number of positive DCs was counted. The relationship of these cells to the stage, histological grade, myometrial invasion, and lymph node metastasis was analyzed. Results The proportion of S100-positive DCs in the endometrial endometrioid adenocarcinoma was 31.5% (28/89), which was significantly higher (P<0.05) than in the control group. The proportion of S100-positive DC expression was negatively correlated with the histologic grade, but was not associated with the stage, myometrial invasion, or lymph node metastasis. Conclusion High DC density was inversely correlated with histologic grade in endometrial carcinoma. Tumor-infiltrating S100+ DCs may be used as pathologic marker in endometrial carcinoma.

A giant endometrial polyp with tamoxifen therapy in postmenopausal woman

836 A GIANT ENDOMETRIAL POLYP WITH TAMOXIFEN THERAPY IN POSTMENOPAUSAL WOMAN Soo Hyeon Moon, MD, Seong Eui Lee, MD, In Kook Jung, MD, Ju Eun Jeong, MD, Won Young Park, MD, Woo Hee Yi, MD, Dong Soo Suh, MD, Man Soo Yoon, MD, Ki Hyung Kim, MD Departments of Obstetrics and Gynecology, Pathology, Pusan National University School of Medicine; Department of Obstetrics and Gynecology, Busan St. Mary’s Medical Center, Busan, Korea

Ruptured Hemorrhagic Corpus Luteum Cyst in an Undescended Ovary: A Rare Cause of Acute Abdomen

BACKGROUND Undescended ovaries are typically detected during infertility evaluations and are frequently associated with uterine malformations. Ruptured hemorrhagic corpus luteum cyst of an undescended ovary is an unusual cause of acute abdomen in an adolescent. CASE A 15-year-old girl presented with right lower quadrant pain, nausea, and vomiting, and transabdominal sonography and magnetic resonance imaging of the pelvis showed a 10 cm × 5 cm sized cystic mass at the level of the pelvic brim, anterior to the psoas muscle suggestive of a retroperitoneal hemorrhagic cyst. At surgery, the uterus and left adnexa appeared normal, but the right ovary was not visible within the pelvic cavity, and the right pelvic retroperitoneum was distended. After opening the retroperitoneum and aspirating blood clots, the undescended ovary with a ruptured cyst was visualized within the retroperitoneum. Right ovarian wedge resection was performed and the right ovary was repositioned in the pelvic cavity. SUMMARY AND CONCLUSION Rupture of a corpus luteum cyst in an undescended ovary should be included in the differential diagnosis of acute abdomen in adolescents.

THE CLINICOPATHOLOGICAL RELEVANCE FOR THE EXPRESSION OF SECRETED PROTEIN ACIDIC AND RICH IN CYSTEINE IN EPITHELIAL OVARIAN TUMORS

Methods Epithelial ovarian cancer (n=69), borderline tumor (n=18), benign tumor (n=10) and normal ovary tissues were obtained after operation. SPARC protein expression was examined using immunohistochemistry. With a retrospective review, patients’ characteristics and slide samples were analyzed. Results Cytoplasmic SPARC immunoreactivity was observed in stromal cells in nearly all cases of normal ovary, benign and borderline tumors (100%, 94.7%, and 100%). In contrast, SPARC was detected in the stroma of 63.8% (44/69) and the score of immunoreactivity was signifi cantly reduced in malignant tumors ( P<0.001). SPARC expression in ovarian epithelial cancers was signifi cantly associated with International Federation of Gynecology and Obstetrics stage. However, it was not correlated with other clinicopathologic parameters, including histologic type, tumor grade, nuclear grade, mitosis, tumor size, local recurrence, distant metastasis, and survival. Conclusion This study showed that reduction of SPARC expression in ovarian epithelial tumors is significantly correlated with tumor invasiveness and SPARC may act as tumor suppressor.