Ovarian Clear Cell Carcinoma and Mature Cystic Teratoma Transformed to PNET and Carcinosarcoma: A Case Report with an Immunohistochemical Investigation.

Ovarian tumors include neoplasms derived from somatic cells and germ cells, including teratoma. Sometimes, tumors of the somatic cell type may develop from teratoma, causing diagnostic perturbation. We experienced a case of a tumor composed of several types of tissue in the ovary with a teratoma. When findings of teratoma and somatic tumor coexist in an ovary, it is difficult to differentiate whether a somatic tumor was mixed with a teratoma or a teratoma unitarily caused transformation to a somatic cell tumor. A 72-year-old Japanese woman (gravida, 3; para, 1) presented to our hospital with severe constipation and frequent urination, and a large intrapelvic tumor was detected by computed tomography (CT). Soon after admission, ultrasonography (US) and magnetic resonance imaging (MRI) revealed a large multilocular cystic tumor on her left ovary. Based on the clinical diagnosis of ovarian cancer, she underwent a left ovariectomy, appendectomy, and partial omentectomy. We observed an ovarian tumor consisting of teratoma, primitive neuroectodermal tumor (PNET), adenocarcinoma, various types of sarcomas, and clear cell carcinoma on the H and E-stained sections. The component of clear cell carcinoma showed a nuclear positive reaction against PAX8 and napsin A, as well as a loss of ARID1A, suggesting typical endometriosis-derived clear cell carcinoma. On the other hand, the expression of ARID1A was maintained in teratoma, PNET, non-specific adenocarcinoma, and various types of sarcomas, suggesting that these tumors had an origin different from that of clear cell carcinoma. These findings indicated that the ovarian tumor of this patient contained a clear cell carcinoma derived from a somatic cell and a teratoma that transformed to a wide variety of somatic cell types of tumors, which coexisted on one ovary. The appropriate use of immunohistochemistry was diagnostically effective in this case.

MR imaging findings of uterine pyomyoma: radiologic-pathologic correlation.

A 69-year-old postmenopausal female with a spontaneously occurring uterine pyomyoma was described with emphasis on the MR imaging findings. On unenhanced T1- and T2-weighted MR images, a huge mottled mass suspected to contain blood products, necrotic tissue, or purulent or viscous fluid was demonstrated within anterior myometrial wall of uterine body. The mass was surrounded by a peripheral rim that was hyperintense on T1-weighted images and hypointense on T2-weighted images. On gadolinium-enhanced MR images, most of the mass was unenhanced, but the peripheral rim was equally enhanced with the surrounding myometrium. Pathological examination revealed an intramural uterine pyomyoma surrounded by fibrous capsules with abundant lymphocytes and neutrophils. Our findings indicate that pyomyoma should be considered when MR images demonstrate a myometrial cystic lesion accompanied by a peripheral rim.

Expression of cyclooxygenase-2 related to angiogenesis in uterine cervical cancers.

Angiogenesis is essential for development, growth and advancement of solid tumors. Cyclooxygenase (COX)-2 is recognized as an angiogenic factor in various tumors. This prompted us to study the clinical implications of COX-2 expression related to angiogenesis in uterine cervical cancers. There was a significant correlation between microvessel counts and COX-2 levels in uterine cervical cancers. COX-2 localized in the cancer cells, but not in the stromal cells of uterine cervical cancer tissues. COX-2 levels increased with advancement, and the prognosis of the 30 patients with high COX-2 expression in uterine cervical cancers was poor (60%), while the 24-month survival rate of the other 30 patients with low COX-2 expression was 90%. Furthermore, COX-2 levels significantly correlated with VEGF levels in uterine cervical cancers. VEGF associated with COX-2 might work on angiogenesis in advancement. Therefore, long-term administration of COX-2 inhibitors might be effective on the suppression of regrowth or recurrence after intensive treatment for advanced uterine cervical cancers.

Plausible linkage of hypoxia inducible factor-1alpha in uterine cervical cancer.

Angiogenesis is essential for the development, growth and advancement of solid tumors. Angiogenesis is induced by hypoxia with angiogenic transcription factor hypoxia inducible factors (HIF). This prompted us to study the clinical implications of HIF relative to angiogenesis in uterine cervical cancers. Although there was no significant difference in HIF-1alpha histoscores and mRNA levels according to histopathological type or lymph node metastasis, HIF-1alpha histoscores and mRNA levels increased significantly with advancing cancer stages. The prognosis of 30 patients with high HIF-1alpha in uterine cervical cancers was poor (73% survival), whereas the 24-month survival rate of the other 30 patients with low HIF-1alpha was 93%. HIF-1alpha histoscores and mRNA levels were correlated with the levels of the angiogenic factors thymidine phosphorylase and interleukin-8, and HIF-1alpha might be linked with these factors in cervical cancer tissue. HIF-1alpha is a candidate for prognostic indicator as an angiogenic mediator in uterine cervical cancer.

Clinical implications of expression of cyclooxygenase-2 related to angiogenesis in ovarian cancer.

Angiogenesis is essential for the development, growth and advancement of solid tumors. Cyclooxygenase (cox)-2 is recognized as an angiogenic factor in various tumors. This prompted us to study the clinical implications of cox-2 expression and angiogenesis in ovarian cancer. There was a significant correlation between microvessel counts and cox-2 levels. Cox-2 localized in the cancer cells, but not in the stromal cells of ovarian cancer tissue. Cox-2 levels increased with the advancement, and the prognosis of the 30 patients with high cox-2 expression was extremely poor (33%), while the 24-month survival rate of the other 30 patients, those with low cox-2 expression, was 67%. Furthermore, cox-2 levels significantly correlated with VEGF levels. VEGF associated with cox-2 might work on angiogenesis with advancement. Therefore, long-term administration of cox-2 inhibitors might be effective on the suppression of regrowth or recurrence after intensive treatment for advanced ovarian cancer.

Plausible linkage of hypoxia-inducible factor (HIF) in uterine endometrial cancers.

OBJECTIVE: Angiogenesis is essential for the development, growth and advancement of solid tumors. Angiogenesis is induced by hypoxia with the angiogenic transcription factor hypoxia-inducible factor (HIF). This prompted us to study the clinical implications of HIF relative to angiogenesis in uterine endometrial cancers. METHODS: Sixty patients underwent curative resection for uterine endometrial cancers. In the tissue of 60 uterine endometrial cancers, HIF-1alpha, HIF-2alpha and HIF-1beta mRNA levels, and the ratio of angiopoietin (Ang)-2 to Ang-1 (Ang-2/Ang-1) mRNA levels were determined by RT real-time PCR; histochemical scores and localization of HIF-1alpha were determined by immunohistochemistry. Levels of basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), thymidine phosphorylase (TP) and interleukin-8 (IL-8) were determined by enzyme immunoassay. RESULTS: In stage I uterine endometrial cancers, HIF-1alpha histochemical scores and mRNA levels significantly increased with myometrial invasion of uterine endometrial cancers. HIF-1alpha histochemical scores and mRNA levels correlated with the levels of Ang-2/Ang-1 and IL-8. CONCLUSION: The angiogenic mediator HIF-1alpha, linked to Angs and IL-8, might work on angiogenesis with myometrial invasion of cancer cells in uterine endometrial cancers.

Estrogen-related receptor expression in placenta throughout gestation.

Estrogen receptor (ER) alpha and beta mRNA levels increased from the first to the second trimester and then decreased until normal term delivery. Estrogen-related receptor (ERR) alpha, beta and gamma mRNA levels gradually increased up to the second trimester and then comparatively rapidly increased until normal term delivery. ERRs can bind to the steroid receptor coactivator family without any ligands and drive transcription activity of the target genes. The manner of ERR and ER gene expressions might show a competitive interaction associated with the use of common cofactors. It is speculated that the up-regulation of ERRs is related to placental growth after the down-regulation of ERs because of the remarkably high concentration of estrogens for ERs from the second trimester until delivery.

Sex steroid-dependent angiogenesis in uterine endometrial cancers.

In general, tumors induce angiogenic factors specific to them, which leads to angiogenesis with advancement. However, angiogenesis in uterine endometrial cancers is complicated because hormone dependency in growth also modifies the angiogenic potential. Therefore, anti-angiogenic therapy for tumor dormancy in uterine endometrial cancers must be thoroughly considered. The upstream of vascular endothelial growth factor (VEGF) gene conserves estrogen-responsive elements. Progesterone primed with estrogen induces thymidine phosphorylase (TP) in uterine endometrium. Sex steroid-dependent VEGF and TP are highly expressed in cases of early stage and well-differentiated uterine endometrial cancers, and basic fibroblast growth factor (bFGF) in cases of advanced and poorly differentiated uterine endometrial cancers. A transcriptional factor for angiogenesis, ETS-1, is linked to VEGF in well-differentiated uterine endometrial cancers, and to bFGF in poorly differentiated uterine endometrial cancers. Therefore, even if dedifferentiation and angiogenic switching occur due to advancement and long-term hormone therapy, the inhibition of ETS-1 along with main angiogenic factors might be an effective strategy to suppress uterine endometrial cancers as a novel anti-angiogenic therapy.

Estrogen-related receptor in reproductive organs.

Estrogen-related receptor (ERR) was studied in the placenta and uterine endometrium, especially endometrial cancers, among reproductive organs. In the placenta, the estrogen receptor (ER) alpha and beta mRNA levels increased from the first to the second trimester, and then decreased until normal term delivery. Estrogen-related receptor alpha, beta and gamma mRNA levels gradually increased up to the second trimester, and then comparatively rapidly increased until normal term delivery. In endometrial cancers, ER alpha and beta mRNA levels decreased with clinical stage, myometrial invasion and dedifferentiation. Estrogen-related receptor alpha levels increased with clinical stage and myometrial invasion, and the ERR gamma levels increased with myometrial invasion. Estrogen-related receptors can bind to the steroid receptor coactivator family without any ligands, and drive transcription activity of the target genes. The manner of ERR and ER gene expressions might show a competitive interaction associated with the use of common cofactors. It is speculated that the upregulation of ERR is related to the placental growth after the downregulation of ER from the second trimester until delivery, and that ERR alpha and gamma are candidates for prognostic factors in endometrial cancer, although ERR are not directly related to tumor growth and advancement of endometrial cancer. (Reprod Med Biol 2005; 4: 129-131).

Clinical implications of expression of ETS-1 related to angiogenesis in metastatic lesions of ovarian cancers.

OBJECTIVE: ETS-1 has been identified as a proto-oncogene and a transcription factor for tumor angiogenesis, which is essential for the growth, invasion and metastasis of solid tumors. The aim is to investigate the clinical implications of ETS-1 expression in peritoneal metastatic lesions of ovarian cancers. METHODS: In primary tumors and peritoneal metastatic lesions from 30 patients with stage III ovarian cancers, ETS-1 histoscores and ets-1 mRNA levels were determined by immunohistochemistry and competitive RT-PCR-Southern blot analysis using recombinant RNA, respectively. RESULTS: Immunohistochemical staining revealed that ETS-1 was expressed in the cancer cells and vascular endothelial cells. ETS-1 histoscores in the endothelial cells and ets-1 mRNA levels were significantly (p < 0.05) increased in 20 of 30 peritoneal metastatic lesions of ovarian cancers. There was a significant correlation between microvessel counts (MVCs) and ETS-1 histoscores in the endothelial cells (p < 0.001) and between MVCs and ets-1 mRNA levels in the primary tumor and the peritoneal metastatic lesion of ovarian cancers (p < 0.001). Furthermore, the 24-month survival rate of patients with significantly increased ets-1 mRNA level (2/20, 10%) was significantly (p < 0.01) lower than that of patients with no change in the level (6/10, 60%) from the primary tumor to the peritoneal metastatic lesion. CONCLUSIONS: ETS-1 might be associated with peritoneal metastasis dominantly as an angiogenic mediator and additionally as an oncogene product to activate tumor invasion in ovarian cancers.

Expression of E26 transformation specific (ETS-1) related to angiogenesis in ovarian endometriosis.

ETS-1 in ovarian endometriomas was significantly positively correlated with microvessel counts (MVCs), but ETS-1 and MVC were not significantly altered during the menstrual cycle. Because ETS-1 persistently expresses in the subepithelial area of endometriotic endometrium, this might contribute to the growth of ovarian endometriomas via subepithelial angiogenesis independently of the menstrual cycle.

Clinical implications of expression of ETS-1 in relation to angiogenesis in ovarian cancers.

ETS-1 has been identified as a transcription factor involved in tumor angiogenesis, which is essential for the growth, invasion, and metastasis of solid tumors. This result prompted us to study whether ETS-1 works as an angiogenic mediator in ovarian cancers. Immunohistochemical staining revealed that ETS-1 was expressed in vascular endothelial cells and in cancer cells of ovarian cancers. There was a significant correlation between microvessel counts and both ETS-1 histoscores and ets-1 mRNA levels in ovarian cancers. Both ETS-1 histoscores and ets-1 mRNA levels increased with the progression of ovarian cancers. Furthermore, the 24-month survival rate of 30 patients with high ets-1 (high ETS-1 histoscores and high ets-1 mRNA levels) was 30%, while that of 30 other patients with low ets-1 (low ETS-1 histoscores and ets-1 mRNA levels) was 70%. There was a significant difference between the 24-month survival rates of the 30 patients with high ets-1 and the 30 with low ets-1. This indicates that ETS-1 might act as an angiogenic mediator in, and be a prognostic factor for, ovarian cancers.

Expression of ETS-1 related to angiogenesis in uterine endometrium during the menstrual cycle.

ETS-1 has been identified as a transcription factor for angiogenesis, which is essential for the development and growth of the uterine endometrium. This characteristic prompted us to study whether ETS-1 functions as an angiogenic mediator in uterine endometrium. Immunohistochemical staining revealed that the localization of ETS-1 was similar to that of vascular endothelial cells. There was a significant correlation between microvessel counts and both ETS-1 histoscores and ets-1 mRNA levels in uterine endometrium. The ETS-1 histoscores and ets-1 mRNA levels increased in the proliferative phase, reached a peak during peri-ovulation and decreased in the secretory phase. Furthermore, the ETS-1 histoscores and ets-1 mRNA levels correlated with vascular endothelial growth factor (VEGF) levels in the proliferative phase. This indicates that ETS-1 might be an angiogenic mediator in uterine endometrium linked to VEGF in the proliferative phase.

Expression of estrogen receptor beta exon-deleted variant mRNAs in ovary and uterine endometrium.

Various estrogen receptor beta exon-deleted variant (ER-beta EDV) mRNAs were expressed in human ovary and uterine endometrium. Estrogen receptor beta (ER-beta) completely or partially deleted exon n is expressed as ER-beta EnDV or En'DV, respectively. The mRNAs for ER-beta single exon-deleted variant (EDV), ER-beta E2DV, E4DV, E5DV and E6DV; for ER-beta double exon-deleted variants, ER-beta E1'+2DV, E4+5DV and E5+6DV; and for ER-beta triple exon-deleted variants, ER-beta E2'+3+4DV and E4+5+6DV were detected. In ER-beta E2DV, E4+5DV, E5DV and E6DV mRNAs, the new stop codon is made in the exon following the deleted exon(s), and the new proteins may lack the corresponding domains. In ER-beta E1'+2DV, E2'+3+4DV, E4DV, E4+5+6DV and E5+6DV mRNAs, the original stop codon is still present, and the new proteins may conserve the new short amino acid sequences surrounding the deleted exons. ER-beta E1'+2DV, E2DV, E2'+3+4DV, E4DV, E4+5DV and E4+5+6 are unlikely to work as a transcription factors. On the other hand, ER-beta E5DV, E6DV and E5+6DV lack only the ligand-binding domain, and might work as dominant positive or negative factors. Therefore, ER-beta E5DV, E6DV and E5+6DV, constitutively expressed in human ovary and uterine endometrium might, in part regulate estrogen responsiveness.

Clinical implications of the expression of estrogen receptor-alpha and -beta in primary and metastatic lesions of uterine endometrial cancers.

Novel human estrogen receptor (ER)-beta was identified in cDNA libraries from human testes. ER-beta specifically expresses in the testis, ovary, thymus, spleen, osteoblasts, fetus and uterine endometrium. ER-beta might not conserve the same physiological functions as does ER-alpha. Therefore, expressions of ER-alpha and ER-beta mRNAs in primary and metastatic lesions of uterine endometrial cancers were investigated. The levels of ER-beta mRNA were significantly lower than those of ER-alpha mRNA in uterine endometrial cancers and in normal uterine endometria. The ratio of ER-beta to ER-alpha mRNA in most primary uterine endometrial cancers was similar to that in normal uterine endometria (<0.4% of ER-beta mRNA to ER-alpha mRNA). On the other hand, in 14 of the 20 lymph node metastasis-positive cases of uterine endometrial cancers, the ratio in the metastatic lesion was significantly higher than that in the primary lesion of the corresponding case, and patient prognosis in these cases was extremely poor. Therefore, it is suggested that the intact synchronized expression of ER-beta interacting with ER-alpha might be disrupted, especially in most metastases of uterine endometrial cancers, leading to poor patient prognosis related to estrogen refractoriness.