Gun Yoon

Benign Metastasizing Leiomyoma with Multiple Lymph Node Metastasis: A Case Report

This is a case report about benign metastasizing leiomyoma with multiple lymph node metastasis. A 34-year-old woman received an abdominal myomectomy for a suspicious leiomyoma. On the pathology report, atypical leiomyoma was suspected. Due to the suspicion of multiple lymph node metastasis on pelvis computed tomography (CT) 1 year after the operation, she was transferred to the Samsung Medical Center on October, 2009 for further work up. According to original slide review, it was determined to be a benign leiomyoma with a mitotic count <5/10 high-power fields, little cytological atypia and no tumor cell necrosis. Additional immunostaining was done. Multiple lymph node metastasis and a small lung nodule were identified on positron emission tomogarphy-CT and chest CT. Extensive debulking surgery and diagnostic video-assisted thoracoscopic surgery (VATS) wedge resection were subsequently done. Metastatic lesions were reported to have a histology similar to that of the original mass. VATS right upper lobectomy with mediastinal lymph node dissection was performed because of the pathology result of VATS (adenocarcinoma). She started taking an aromatase inhibitor (Letrozole®) and there was no evidence of recurrence of disease on an imaging study and no post-operative complications until recently.

Sphingosine kinase 1 as a potential therapeutic target in epithelial ovarian cancer

Sphingosine kinase 1 (SK1) is over‐expressed in multiple types of human cancer. SK1 has growth‐promoting effects and has been proposed as a potential therapeutic target. We investigated the therapeutic effects of SK1 inhibition in epithelial ovarian carcinoma (EOC). SK1 siRNA or inhibitors were tested in EOC cell lines, including A2780, SKOV3ip1, A2780‐CP20, SKOV3‐TR, ES2 and RMG2. Cells were treated with SK inhibitor or FTY720, and cell proliferation, apoptosis, angiogenesis and invasion were examined by MTT, FACS, ELISA and wound‐healing assays, respectively. In vivo experiments were performed to test the effects of FTY720 on tumor growth in orthotopic mouse xenografts of EOC cell lines A2780 or SKOV3ip1 and a patient‐derived xenograft (PDX) model of clear cell ovarian carcinoma (CCC). Blocking SK1 with siRNA or inhibitors significantly reduced proliferation, angiogenesis and invasion, and increased apoptosis in chemosensitive (A2780 and SKOV3ip1) and chemoresistant (A2780‐CP20, SKOV3‐TR, ES2 and RMG2) EOC cells. SK1 inhibitors also decreased the intracellular enzymatic activity of SK1. Furthermore, FTY720 treatment significantly decreased the in vivo tumor weight in xenograft models of established cell lines (A2780 and SKOV3ip1) and a PDX model for CCC compared to control (p < 0.05). These results support therapeutic targeting of SK1 as a potential new strategy for EOC.

Proton pump inhibitors enhance the effects of cytotoxic agents in chemoresistant epithelial ovarian carcinoma

This study was designed to investigate whether proton pump inhibitors (PPI, V-ATPase blocker) could increase the effect of cytotoxic agents in chemoresistant epithelial ovarian cancer (EOC). Expression of V-ATPase protein was evaluated in patients with EOC using immunohistochemistry, and patient survival was compared based on expression of V-ATPase mRNA from a TCGA data set. In vitro, EOC cell lines were treated with chemotherapeutic agents with or without V-ATPase siRNA or PPI (omeprazole) pretreatment. Cell survival and apoptosis was assessed using MTT assay and ELISA, respectively. In vivo experiments were performed to confirm the synergistic effect with omeprazole and paclitaxel on tumor growth in orthotopic and patient-derived xenograft (PDX) mouse models. Expression of V-ATPase protein in ovarian cancer tissues was observed in 44 patients (44/59, 74.6%). Higher expression of V-ATPase mRNA was associated with poorer overall survival in TCGA data. Inhibition of V-ATPase by siRNA or omeprazole significantly increased cytotoxicity or apoptosis to paclitaxel in chemoresistant (HeyA8-MDR, SKOV3-TR) and clear cell carcinoma cells (ES-2, RMG-1), but not in chemosensitive cells (HeyA8, SKOV3ip1). Moreover, the combination of omeprazole and paclitaxel significantly decreased the total tumor weight compared with paclitaxel alone in a chemoresistant EOC animal model and a PDX model of clear cell carcinoma. However, this finding was not observed in chemosensitive EOC animal models. These results show that omeprazole pretreatment can increase the effect of chemotherapeutic agents in chemoresistant EOC and clear cell carcinoma via reduction of the acidic tumor microenvironment.

Sphingosine kinase 1 is a reliable prognostic factor and a novel therapeutic target for uterine cervical cancer

Sphingosine kinase 1 (SPHK1), an oncogenic kinase, has previously been found to be upregulated in various types of human malignancy and to play a crucial role in tumor development and progression. Although SPHK1 has gained increasing prominence as an important enzyme in cancer biology, its potential as a predictive biomarker and a therapeutic target in cervical cancer remains unknown. SPHK1 expression was examined in 287 formalin-fixed, paraffin-embedded cervical cancer tissues using immunohistochemistry, and its clinical implications and prognostic significance were analyzed. Cervical cancer cell lines including HeLa and SiHa were treated with the SPHK inhibitors SKI-II or FTY720, and effects on cell survival, apoptosis, angiogenesis, and invasion were examined. Moreover, the effects of FTY720 on tumor growth were evaluated using a patient-derived xenograft (PDX) model of cervical cancer. Immunohistochemical analysis revealed that expression of SPHK1 was significantly increased in cervical cancer compared with normal tissues. SPHK1 expression was significantly associated with tumor size, invasion depth, FIGO stage, lymph node metastasis, and lymphovascular invasion. Patients with high SPHK1 expression had lower overall survival and recurrence-free survival rates than those with low expression. Treatment with SPHK inhibitors significantly reduced viability and increased apoptosis in cervical cancer cells. Furthermore, FTY720 significantly decreased in vivo tumor weight in the PDX model of cervical cancer. We provide the first convincing evidence that SPHK1 is involved in tumor development and progression of cervical cancer. Our data suggest that SPHK1 might be a potential prognostic marker and therapeutic target for the treatment of cervical cancer.

Clinicopathological and immunohistochemical characterization of papillary proliferation of the endometrium: A single institutional experience.

Papillary proliferation of the endometrium is an unusual lesion that is composed of papillae with fibrovascular stromal cores covered with benign-appearing glandular epithelium. We studied the clinicopathological and immunohistochemical features of four cases of endometrial papillary proliferations. All patients were postmenopausal. Two lesions were incidental findings in hysterectomy specimens, and two lesions were detected in endometrial curettage specimens. Based on the degree of architectural complexity and extent of proliferation, we classified papillary proliferations histopathologically into “simple” or “complex” growth patterns. Three cases were classified as simple papillary proliferation, and one case was classified as complex papillary proliferation. Simple papillary proliferations were characterized by slender papillae with delicate stromal cores. In contrast, complex papillary proliferations had intracystic papillary projections and cellular clusters with frequent branching and occasional cytological atypia. All cases showed coexistent metaplastic epithelial changes, including mucinous metaplasia, eosinophilic cell change, and ciliated cell metaplasia. One patient with simple papillary proliferations had coexistent well-differentiated endometrioid carcinoma. One patient had subsequent hyperplasia without atypia, and another patient had subsequent atypical hyperplasia/endometrioid intraepithelial neoplasia; both patients underwent total hysterectomy within four months. Our observations are consistent with previous data demonstrating that endometrial papillary proliferations coexist with or develop into atypical hyperplasia/endometrioid intraepithelial neoplasia or endometrioid carcinoma. It is very important for pathologists to discriminate papillary proliferations from neoplastic lesions (including atypical hyperplasia/endometrioid intraepithelial neoplasia and well-differentiated endometrioid carcinoma) and benign mimickers (including papillary syncytial metaplasia).

Stromal p16 expression is significantly increased in malignant ovarian neoplasms

Alterations in p16 protein expression have been reported to be associated with tumor development and progression. However, p16 expression status in the peritumoral stroma has been rarely investigated. We investigated the stromal p16 expression in ovarian neoplasms using immunohistochemistry, and differences in the expression status depending on the degree of malignancy and histological type were analyzed. This study included 24, 21, and 46 cases of benign, borderline, and malignant ovarian lesions, respectively, of which 29, 25, and 32 cases were serous, mucinous, and endometriosis-associated lesions. Most benign lesions showed negative or weak expression, whereas borderline lesions showed focal, moderate expression. Malignant lesions showed markedly elevated stromal p16 expression compared with benign or borderline lesions. There were significant differences in stromal p16 expression between benign and borderline lesions (P < 0.001) and between borderline and malignant lesions (P < 0.001). These significances remained when analysis was performed based on lesion classification as serous, mucinous, and endometriosis-associated. In contrast, differences in stromal p16 expression among the histological types were not significant. Stromal p16 expression in ovarian neoplasms was absent or weak in benign and focal, moderate in borderline lesions, whereas malignant lesions exhibited diffuse, moderate-to-strong p16 immunoreactivity. Our observations suggest that stromal p16 expression is involved in the development of ovarian carcinoma. Further studies are necessary to confirm our preliminary results.

Down-regulation of osteoprotegerin expression as a novel biomarker for colorectal carcinoma

A better understanding of tumor biology is important in the identification of molecules that are down-regulated in malignancy and in determining their role in tumor suppression. The aim of this study was to analyze osteoprotegerin (OPG) expression in colorectal carcinoma (CRC) and to investigate the underlying mechanism for changes in the expression of OPG. OPG expression was assessed in CRC tissue samples and cell lines. The methylation status of the OPG promoter region was determined, and the effects of demethylation on OPG expression were analyzed. The effects of recombinant OPG (rOPG) administration on cellular functions were also investigated. Clinical and prognostic implications of OPG protein expression in CRC patients were analyzed. The CRC tissues and cells showed significantly lower OPG expression. Pyrosequencing of OPG-silenced CRC cells revealed that the OPG gene promoter was highly methylated. Treatment with demethylating agent significantly elevated OPG mRNA and protein expression. rOPG significantly decreased cell viability and MMP-2 and VEGF-A production in CRC cells. Reduced OPG immunoreactivity was associated with aggressive oncogenic behavior in CRC. Also, OPG expression was found to be an independent predictor of recurrent hepatic metastasis and independent prognostic factor for worse survival rates. We demonstrated that OPG silencing in CRC occurs through epigenetic repression, and is involved in the development and progression of CRC. Our data suggest that OPG is a novel prognostic biomarker and a new therapeutic target for the treatment of patients with CRC.

Stromal p16 expression is significantly increased in endometrial carcinoma.

p16 is a negative regulator of cell proliferation and is considered a tumor suppressor protein. Alterations in p16 protein expression are associated with tumor development and progression. However, the p16 expression status in the peritumoral stroma has not been investigated in the endometrium. Therefore, we evaluated stromal p16 expression in different types of endometrial lesions using immunohistochemistry. Differences in the p16 expression status according to the degree of malignancy and histological type were analyzed. This study included 62, 26, and 36 cases of benign, precancerous, and malignant endometrial lesions, respectively. Most benign lesions showed negative or weak expression, whereas precancerous lesions showed a variable degree of staining proportion and intensity. Atypical hyperplasia/endometrial intraepithelial neoplasia (AH/EIN) and serous endometrial intraepithelial carcinoma (SEIC) had significantly higher stromal p16 expression levels than benign lesions. Endometrioid carcinoma (EC), serous carcinoma (SC), and carcinosarcoma showed significantly elevated stromal p16 expression levels compared with benign and precancerous lesions. In addition, there were significant differences in stromal p16 expression between AH/EIN and SEIC and between EC and SC. In contrast, differences in stromal p16 expression among nonpathological endometrium, atrophic endometrium, endometrial polyp, and hyperplasia without atypia were not statistically significant. Our observations suggest that stromal p16 expression is involved in the development and progression of endometrial carcinoma, and raise the possibility that p16 overexpression in the peritumoral stroma is associated with aggressive oncogenic behavior of endometrial SC.

High-grade squamous intraepithelial lesion arising adjacent to vulvar lymphangioma circumscriptum: a tertiary institutional experience

Lymphangioma circumscriptum of the vulva occurs in patients who have undergone radical hysterectomy, lymph node dissection, or radiation therapy for management of advanced uterine cancer. Since vulvar lymphangioma circumscriptum typically presents as multiple, grossly verrucous vesicles of various sizes, it may be impossible to clinically distinguish vulvar lymphangioma circumscriptum from other vulvoperineal cutaneous diseases. In the present study, 16 (1.6%) out of the 1,024 vulvar biopsy or excision specimens were diagnosed as lymphangioma circumscriptum. In two (12.5%) out of the 16 cases, unusual histopathological findings were observed. Both patients had previously undergone radical hysterectomy with lymph node dissection and postoperative radiation therapy or concurrent chemoradiation therapy for advanced cervical cancer. Microscopic examination revealed high-grade squamous intraepithelial lesions, which were located immediately adjacent to the normal squamous epithelium covering the dilated subepithelial lymphatic vessels. Further, human papillomavirus genotyping confirmed that both patients were infected with high-risk human papillomavirus. High-grade squamous intraepithelial lesion cannot be grossly distinguished from vulvar lymphangioma circumscriptum because the multiple, verrucous vesicles that constitute the characteristic gross appearance of vulvar lymphangioma circumscriptum hinder its distinction. In this regard, our cases of high-grade squamous intraepithelial lesion, located adjacent to vulvar lymphangioma circumscriptum, support the notion that active surgical excision is necessary for the treatment of vulvar lymphangioma circumscriptum.

Gastric acid response to acute exposure to hypergravity

The influence of environmental stressors on the pathogenesis of gastrointestinal disease has received increased awareness. Stress affects different physiological functions of the gastrointestinal tract, including gastric acid secretion and mucosal blood flow. Repeated exposures of rapid-onset, highly-sustained hypergravity cause severe physical stress in the pilot. Although the effects of exposure to hypergravity on cardiovascular and cerebral functions have been the subjects of numerous studies, crucial information regarding pathophysiological changes in the gastrointestinal tract following hypergravity exposure is lacking. In this study, we investigated the effects of acute exposure to hypergravity on gastric secretory activity and gastrin release. Male Sprague-Dawley rats were exposed to +10Gz three times for 3 min. Gastric juice and blood were collected. The volume and total acidity of gastric juice, and the plasma gastrin level was measured. Acute exposure to +10Gz significantly decreased the gastric juice parameters. The gastric juice volume and total acidity of hypergravity-exposed rats were 3.54 ± 0.32 mL/100 g and 84.90 ± 5.17 mEq/L, respectively, which were significantly lower than those of the nonexposed rats (4.62 ± 0.39 mL/100 g and 97.37 ± 5.42 mEq/L; P < 0.001 and P < 0.001, respectively). In contrast, plasma gastrin level was not significantly altered following hypergravity exposure. We demonstrated that acute exposure to hypergravity led to a significant decrease in the gastric juice volume and acidity but did not alter the plasma gastrin level.