Histological Types Of Ovarian Cancer Research Articles

Whole-Genome Allelotyping Identified Distinct Loss-of-Heterozygosity Patterns in Mucinous Ovarian and Appendiceal Carcinomas

Mucinous adenocarcinoma of the ovary is one of the common histologic types of ovarian cancer. Its pathogenesis is largely unknown. In addition, the differential diagnosis of metastatic mucinous carcinomas to the ovaries, particularly those originating from the appendix, remains challenging. The purpose of this study is to identify molecular biomarkers for mucinous ovarian adenocarcinoma and compare them with those of appendiceal origin. Genome-wide loss-of-heterozygosity (LOH) analysis was done on DNA isolated from 28 microdissected primary mucinous ovarian carcinomas and five appendiceal adenocarcinomas. Markers from high-loss regions were selected for further analysis on a total of 32 ovarian and 14 appendiceal cancers. High levels of LOH rates (>40%) were detected on chromosome arms 9p, 17p, and 21q in mucinous ovarian carcinoma cases. The frequency of allelic loss was similar between high-grade and low-grade mucinous ovarian carcinoma cases but was significantly higher in ovarian versus appendiceal cases. In addition, LOH rates on five chromosomal loci were statistically different between ovarian and appendiceal carcinomas. A high frequency of LOH can be found in mucinous ovarian adenocarcinomas independent of grade. Despite histologic similarities between mucinous ovarian carcinomas and metastatic appendiceal carcinomas, they have distinct LOH profiles, which may be used for distinguishing the two diseases.

Identification of Overexpression and Amplification of ABCF2 in Clear Cell Ovarian Adenocarcinomas by cDNA Microarray Analyses

Patients with ovarian clear cell adenocarcinoma generally have a poor response to combination chemotherapy and have overall poorer prognosis than patients with other histologic types of ovarian cancer. Genetic changes in this group of cancer have not been thoroughly explored. Identification of these changes may provide us new therapeutic targets to treat this disease. Genomic and expression array analyses were applied on 30 clear cell ovarian cancer cases and 19 serous cases using a 10,816-element cDNA microarray platform. Further validation and clinical correlation studies were done on differentially expressed genes that are related to chemoresistance. Based on array analyses, 12 genes showed a significant increase in DNA and mRNA copy number and 5 genes showed a significant decrease in DNA and RNA copy number in clear cell tumors compared with those in the serous type. One of the genes was ABCF2, which belongs to the ATP-binding cassette gene superfamily and has been shown to amplify in other tumor types. Validation studies were done using real-time quantitative PCR and immunohistochemistry. The results showed significantly higher ABCF2 DNA and mRNA copy number and protein levels in clear cell cases compared with those in serous cases. Furthermore, in 20 clear cell cases with chemo-response data available, ABCF2 cytoplasmic staining was significantly higher in nonresponders than that in the responders (60.0% versus 28.5%; P = 0.0002). These data suggest that ABCF2 protein may be a prognostic marker for ovarian clear cell ovarian adenocarcinoma.

Calcitonin gene polymorphismCALCA-624 (T/C) and ovarian cancer

In a previous analysis, we reported an inverse association of dietary calcium intake with the risk of ovarian cancer (Goodman et al. 2002. Am J Epidemiol 156:148-57). The CALCA gene codes for calcitonin, an important regulator of bone calcium metabolism. Data from a population-based case-control study conducted in Hawaii were used to examine the hypothesis that a T --> C transition 624 base pairs upstream (-624) of the translation initiation codon of the CALCA gene influences the risk of ovarian malignancy. A structured interview was conducted for 182 histologically confirmed ovarian cancer cases and 219 controls. Blood specimens were collected from the subjects at their homes. A significant negative trend (P for trend: 0.02) in the odds ratios (ORs) was found with increasing intake of calcium. Women with any CALCA C allele were at nonsignificantly higher risk of ovarian cancer (OR: 1.5, 95% CI: 0.9-2.3) compared to women with the TT genotype and the risk increased with the number of C alleles (P for trend: 0.05). When further analyzed within ethnic subgroups, a significant positive association was found among Japanese for CALCA CT (OR: 2.3, 95% CI: 1.0-5.3) and CALCA CC (OR: 7.2, 95% CI: 1.1-46.0) compared with Japanese women who were homozygous for the T allele. The trend in risk associated with the C allele was most significant among women who had used oral contraceptives (P for trend: 0.05), had been pregnant (P for trend: 0.04), and had nonmucinous histological types of ovarian cancer (P for trend: 0.02). However, the association of ovarian cancer risk with the CALCA genotype was not significantly modified by any of the dietary, nondietary, or clinical variables included in this study. These preliminary data suggest a strong positive association of the CALCA C allele with the risk of ovarian cancer among some subgroups.

Combination chemotherapy with paclitaxel and platinum in the treatment for advanced or recurrent ovarian clear cell adenocarcinoma: Multicenter trial

5101 Background: Patients with clear cell adenocarcinoma of the ovary (CC) have a poor response to chemotherapy and have a significantly worse prognosis than other histological types of ovarian cancer. However, the therapeutic effect of a combination of paclitaxel (PTX) and platinum (PLT) in CC patients with measurable disease has yet to be elucidated. In this study, we evaluated the treatment results of a combination of PTX and PLT in CC patients with measurable disease by retrospective review. Methods: Twenty–eight patients with measurable residual CC (12 primary cases and 16 recurrent cases), who were treated with combination chemotherapy with PTX and PLT, were identified through the medical records from 10 institutions. Patients with serous adenocarcinoma were selected as a control for comparison. Histological evaluation was performed under the central pathological review. Clinical response to chemotherapy was compared between CC and serous adenocarcinoma patients using RECIST criteria. Results: In primary cases, 7 of 12 CC patients (58.3%) and 17 of 22 serous adenocarcinoma patients (77.3%) responded to chemotherapy, and the difference was not significant. In recurrence CC cases, 3 of 16 CC patients (18.8%) responded to the chemotherapy. The difference of response rate between primary and recurrent cases in CC patients was statistically significant (P<0.05). Conclusion: The response rate of this combination chemotherapy for primary residual CC patients was relatively high and was comparable with those of serous adenocarcinoma. Our results indicate that the combination of PTX and PLT has a sufficient potential as first–line chemotherapy to this ‘assumed’ chemo–resistant tumor. No significant financial relationships to disclose.

Combination chemotherapy with paclitaxel and platinum in the treatment for advanced or recurrent ovarian clear cell adenocarcinoma: Multicenter trial

5101 Background: Patients with clear cell adenocarcinoma of the ovary (CC) have a poor response to chemotherapy and have a significantly worse prognosis than other histological types of ovarian cancer. However, the therapeutic effect of a combination of paclitaxel (PTX) and platinum (PLT) in CC patients with measurable disease has yet to be elucidated. In this study, we evaluated the treatment results of a combination of PTX and PLT in CC patients with measurable disease by retrospective review. Methods: Twenty–eight patients with measurable residual CC (12 primary cases and 16 recurrent cases), who were treated with combination chemotherapy with PTX and PLT, were identified through the medical records from 10 institutions. Patients with serous adenocarcinoma were selected as a control for comparison. Histological evaluation was performed under the central pathological review. Clinical response to chemotherapy was compared between CC and serous adenocarcinoma patients using RECIST criteria. Results: In primary cases, 7 of 12 CC patients (58.3%) and 17 of 22 serous adenocarcinoma patients (77.3%) responded to chemotherapy, and the difference was not significant. In recurrence CC cases, 3 of 16 CC patients (18.8%) responded to the chemotherapy. The difference of response rate between primary and recurrent cases in CC patients was statistically significant (P<0.05). Conclusion: The response rate of this combination chemotherapy for primary residual CC patients was relatively high and was comparable with those of serous adenocarcinoma. Our results indicate that the combination of PTX and PLT has a sufficient potential as first–line chemotherapy to this ‘assumed’ chemo–resistant tumor. No significant financial relationships to disclose.

Risk factors for different histological types of ovarian cancer.

Various histological types of ovarian cancer may develop from different etiological aspects. Data separated by histological subtypes collected in the framework of a large case-control study on ovarian cancer conducted in Italy were analyzed. The cases were women below the age of 75 years, admitted to a network of hospitals in Milan. Cases were grouped into four categories by histological type: mucinous tumor (n = 52), serous tumor (n = 680), endometrioid tumor (n = 41), and other histologies including clear-cell and undifferentiated epithelial tumors (n = 50). Controls were 2758 patients admitted to the same network of hospitals for a wide spectrum of acute, nongynecological, non-hormone-related, non-neoplastic conditions. In comparison with nulliparae, the risk of serous, endometrioid, and other histologies of ovarian cancer tended to be lower in parous women, but the odds ratios (OR) were above unity for mucinous ovarian cancer. Oral contraceptive use was associated with OR lower than unity for serous (OR = 0.7) and endometrioid (OR = 0.8) ovarian cancers but not for mucinous (OR = 1.4) and other histologies (OR = 1.6). Finally, our results on dietary fat intake did not show substantial differences in all histological types of ovarian cancer.

Risk factors for different histological types of ovarian cancer

Risk factors for different histological types of ovarian cancer

Expression and methylation status of 14-3-3 sigma gene can characterize the different histological features of ovarian cancer

We hypothesize that 14-3-3 sigma gene expression and its regulation by methylation can characterize histological types of primary human epithelial ovarian cancer. To test this hypothesis, ovarian cancer cell lines and 54 ovarian cancer tissue samples were analyzed for expression and methylation of 14-3-3 sigma gene using methylation specific PCR. The results of our experiments demonstrate that 14-3-3 sigma gene was methylated and inactivated in ES-2 ovarian cell line, which was derived from clear cell adenocarcinoma. Treatment of this cell line with demethylating agent 5-aza-2 ′-deoxycytidine restored the expression of 14-3-3 sigma gene. In human ovarian cancer tissues, the expression of 14-3-3 sigma protein was inactivated in most of the ovarian clear cell carcinoma tissues. Interestingly, 14-3-3 sigma protein expression was positive in significantly higher percentages of serous (89.5%), endometrioid (90%), and mucinous (81.8%) ovarian adenocarcinoma tissues. The ovarian clear cell carcinoma samples with inactivated 14-3-3 sigma protein were highly methylated, suggesting that inactivation of 14-3-3 sigma gene is through DNA methylation. Using direct DNA sequencing, 14-3-3 sigma gene methylation on all the 17 CpG sites was significantly higher in ovarian clear cell carcinoma as compared to other histological types of ovarian cancer (serous, endometrioid, and mucinous). This is the first report suggesting that 14-3-3 sigma gene expression and methylation status can characterize histological features of different types of ovarian cancer.

Thymidine phosphorylase-mediated angiogenesis regulated by thymidine phosphorylase inhibitor in human ovarian cancer cells in vivo

Metastasis or progression of ovarian cancer cells is known to be due to the action of various angiogenic factors. We determined the expression of thymidine phosphorylase/platelet-derived endothelial cell growth factor (TP/PD-ECGF) and vascular endothelial growth factor (VEGF) in cell lines established from 3 serous adenocarcinomas, 3 clear cell carcinomas and 2 mucinous carcinomas of the human ovary. TP activity and the TP mRNA level were much higher in the serous adenocarcinoma cells than in the clear cells and mucinous carcinoma cells, and TP expression was extremely low in the clear cell carcinoma cells. Expression of VEGF mRNA was variable, but not significantly different between the 3 histological types of ovarian cancer. In vivo angiogenesis in the ovarian cancer cells was evaluated by the dorsal air sac assay and revealed that SHIN-3 and HRA serous adenocarcinoma cells, which have high levels of TP expression, induced angiogenesis, while KK clear cell carcinoma cells with low TP expression, did not. The degree of ovarian-cancer-induced angiogenesis seemed to be independent of expression of VEGF in the cells. To confirm that the serous adenocarcinoma-induced angiogenesis is dependent on TP levels, a potent and specific inhibitor of TP was administered orally to mice implanted with a chamber containing SHIN-3 or HRA cells. The TP inhibitor significantly inhibited the angiogenesis induced by the serous adenocarcinoma cells. These results suggest that the angiogenic potency of ovarian cancer cells differs with the histological type and is controlled by expression of TP/PD-ECGF, not by VEGF, and that TP-mediated angiogenesis may be the main factor responsible for progression or metastasis of ovarian serous adenocarcinomas.

Menopausal Hormone Replacement Therapy and Risk of Ovarian Cancer

Most retrospective studies have failed to find an association between hormone replacement therapy (HRT) at menopause and the development of ovarian cancer. In addition, most studies have not distinguished between estrogen-only HRT (ERT) and combined estrogen-progestin therapy (EPRT). The investigators have now analyzed data from the Breast Cancer Detection Demonstration Project (BCDDP) follow-up study, a prospective cohort of 44,241 postmenopausal women seen at 29 US clinical centers. Their mean age at the outset was 56.6 years. Follow-up averaged 13.4 years, totaling close to 590,000 person-years. During this time a total of 329 women developed ovarian cancer. Ovarian cancer correlated inversely with parity, oral contraceptive use, and hysterectomy. No relationship with age at menopause or body mass index was apparent. In the 70% of subjects asked, one fourth of those with ovarian cancer had a first-degree relative with either ovarian or breast cancer. After adjusting for age, type of menopause, and oral contraceptive use, the relative risk (RR) of ovarian cancer in women using ERT only was 1.6. The risk increased with the duration of ERT-only use, reaching 3.2 at 20 or more years of use. Most of these long-term ERT users had undergone hysterectomy. The risk was not limited to particular histological types of ovarian cancer. Compared with women never using ERT, the RR for those using ERT only within the past 2 years was 2.0. Women using EPRT had a RR of only 1.1 compared with those not reporting any form of ERT. When EPRT use followed ERT, the RR was 1.5. The risk of ovarian cancer was not associated with the duration of EPRT. This large-scale prospective study shows that women using ERT, especially for a decade or longer, were at significantly increased risk of developing ovarian cancer. Both long-term ERT users who have had a hysterectomy and others who changed to EPRT were at elevated risk. Short-term EPRT (with no prior ERT) did not seem to increase the cancer risk, but this requires further study.

Expression of prostaglandin D synthase in ovarian cancer.

Lipocalin-type prostaglandin D synthase (L-PGDS) has recently been shown to be expressed in human brain tumors and breast tumors. However, L-PGDS expression has not been investigated in ovarian cancer. The objective of this study was to determine whether L-PGDS is expressed in human ovarian cancer. Lipocalin prostaglandin D synthase mRNA was cloned and sequenced by RT-PCR. Using in situ hybridization (ISH) technique, the expression of L-PGDS mRNA in 54 ovarian cancer was investigated. Expression of L-PGDS mRNA was found in tumor cells of all various types of ovarian cancers. Patterns of staining of tumor cells varied among different histological types of ovarian cancer. Significant discrepancy between the intensity of the staining and histological types of ovarian cancer could be established (p<0.01). It is reported for the first time that the expression of mRNA of L-PGDS exists in the ovarian cancer, and is related to the cancer type. This may have significance for the progress of ovarian cancer.

Significance of Serum and Peritoneal Fluid Lactate Dehydrogenase Levels in Ovarian Cancer

We investigated prospectively whether the detection of serum lactate dehydrogenase (LDH) and/or peritoneal fluid LDH levels may serve as a reliable biochemical marker in discriminating ovarian carcinoma from benign ovarian tumors. In this series, postoperatively 20 of 50 patients had a diagnosis of ovarian cancer while the remaining 30 patients had benign ovarian tumor. No significant difference in peritoneal fluid LDH levels was observed between patients with ovarian cancer and benign ovarian tumor (p > 0.05). Serum LDH levels in ovarian cancer patients were significantly higher than those in patients with benign ovarian tumor (p < 0.05). Statistically significant differences were not observed in LDH levels of different histological types of ovarian cancer and different stages of the disease. Serum LDH levels presented diagnostic accuracy with high specificity and may have a potential use as a biochemical marker.

Hormonal aspects of epithelial ovarian cancer: review of epidemiological evidence.

Epithelial ovarian cancer is fairly common with high rates in Scandinavia, intermediate rates in western Europe and North America and low rates in the developing countries and in Japan. The 5-year survival rate is less than 40%. Increasing parity consistently gives a strong protection against epithelial ovarian cancer. A lesser degree of protection is probably derived from incomplete pregnancies and lactation. Ages at menarche and menopause are most probably weak predictors of epithelial ovarian cancer risk. Ever users of oral contraceptives (OC) have 30% lower risk compared to never users. The protection increases with duration of OC use, being about 50% after 5 years. The reduced risk among past OC users persists for at least 10 years after cessation of use. Results concerning hormone replacement therapy (HRT) and epithelial ovarian cancer risk are conflicting, but most data point to a weak or no association, but as an increasing number of women use HRT it still seems important to resolve any potential effect. Infertility adds to epithelial ovarian cancer risk in nulliparous women, while temporary fertility problems in parous women do not appear to increase risk. A possible independent risk effect of fertility drug use has not been easy to assess and remains unresolved. It has been particularly difficult to separate the effects of fertility drugs from those of infertility. Tubal ligation and hysterectomy convey protection against epithelial ovarian cancer, possibly through a suppressed ovarian hormone production. The causes of epithelial ovarian cancer are poorly understood, but reproductive hormones are thought to be involved in the aetiology. For a long time the 'incessant' and 'gonadotrophin' hypotheses have been promoted in relation to carcinogenesis. Both hypotheses find support in ovarian cancer epidemiology, and recent progress in molecular biology adds to the understanding of possible aetiological mechanisms. Another hypothesis focuses on the retrograde transport of contaminants or carcinogens through the Fallopian tubes. It is important to establish if the same risk factors apply to the various histological types of ovarian cancer, as particularly the mucinous ovarian tumours seem to present with different risk factors. Another question to resolve is if sporadic vs. inherited cases carry distinct risk profiles. As the hypotheses above do not explain all of the results derived from ovarian cancer epidemiology, there is a need to test additional hypotheses to possibly define preventive programmes and to come closer to the cause of ovarian cancer.

Peritoneal Fluid Lactate Dehydrogenase in Ovarian Cancer

In attempt to identify patients with ovarian carcinoma and differentiate them from patients with benign ovarian tumor or other gynecological malignancies, peritoneal fluid and serum lactate dehydrogenase (LDH) levels were measured in 51 patients: 15 with ovarian carcinoma, 15 with endometrial carcinoma, 4 with cervical carcinoma, and 17 with benign ovarian tumor. Peritoneal fluid and serum LDH levels in ovarian cancer patients were significantly higher than those in patients with benign ovarian tumor (P< 0.001) or other gynecological malignancies (P< 0.001 andP< 0.03, respectively). Yet, peritoneal fluid LDH demonstrated higher diagnostic sensitivity (87%) and greater diagnostic accuracy (90%) than serum LDH (60 and 77%, respectively) or serum CA-125 (73 and 83%, respectively). Comparing the histological types of ovarian cancer, serous cystadenocarcinoma presented higher peritoneal fluid LDH levels than endometrioid or mucinous cystadenocarcinoma. No difference in peritoneal fluid LDH was observed comparing different stages of ovarian cancer. The results suggest that peritoneal fluid LDH may be an efficient biochemical marker in diagnosis of ovarian cancer.

Serum and Tissue Measurements of CA72-4 in Ovarian Cancer Patients

Serum levels of cancer-associated antigen 72-4 (CA72-4) (tumor-associated glycoprotein 72; TAG-72) from 106 patients with primary ovarian cancer were measured by an immunoradiometric assay employing the monoclonal antibodies (MAbs) B72.3 and CC49. Immunohistochemical localization of TAG-72 was also investigated using immunoperoxidase methodology in conjunction with both light and electron microscopy. In using a cutoff value of 4.0 U/ml for the serum assay, sensitivity of all primary ovarian carcinomas was 63.2% (67.6% of mucinous cystadenocarcinomas and 66.7% of serous cystadenocarcinomas), while specificity of benign ovarian tumors was 91.1%. Diagnostic characteristics of CA125 and CA72-4 have been demonstrated by receiver-operating-characteristics analysis. Although CA125 expressed a remarkable diagnostic efficiency with serous cystadenocarcinoma, it was less efficient with mucinous cystadenocarcinoma. CA72-4, however, was highly detectable for any histological type of ovarian cancer. Immunohistochemical staining with MAbs B72.3 and CC49 in the cytoplasm was stronger than that in the cell membrane in tissues from mucinous cystadenocarcinomas. Also, histological localization of TAG-72 in the microvilli and apical cytoplasmic membrane was demonstrated by electron microscopy using MAb B72.3 and samples of seromucinous cystadenocarcinoma (mixed type). Consequently, TAG-72 was useful for the detection of ovarian carcinoma, especially for monitoring mucinous cystadenocarcinoma, and it is localized in the microvilli and apical cytoplasmic membrane of cystadenocarcinoma cells.

Metastatic patterns in histologic variants of ovarian cancer. An autopsy study.

The autopsy findings of 428 patients with various histologic types of ovarian cancer were studied to determine if metastatic patterns were different. Epithelial tumors were the most frequent (89%), followed by sarcomas (7.2%). Germ cell and stromal tumors each occurred in 1.9% of cases. Sites of metastasis were nearly identical, with no statistical difference among histologic types. The peritoneum was most frequently involved (83% to 100% of cases), but lymph node metastasis was common (50% to 60% of cases). Metastasis was more common to the paraaortic lymph nodes than to the pelvic lymph nodes. In seven of eight stromal tumors, hepatic metastasis was present but did not cause the patient's death. For epithelial tumors, metastasis to distant sites was dependent on nodal and intraperitoneal disease. However, this was not true in the 31 ovarian sarcomas or the series of germ cell or stromal tumors. This finding supports a hematogenous route of metastasis for ovarian sarcomas. Understanding the metastatic potential of ovarian cancer is important in designing effective treatment regimens.

Trends in the incidence of endometrioid and clear cell cancers of the ovary in the United States.

An increase in reported incidence of endometrioid and clear cell cancers of the ovary occurred in the United States during the 1970s, while no change occurred in the overall incidence of ovarian cancer. The authors can not rule out that this was due to a shift in the criteria for histologic classification or improved coding, although these seem unlikely to account entirely for the change. In the four areas where the trend for endometrioid and clear cell cancers of the ovary was examined, the per cent increases in their occurrence were correlated with the per cent increases in the occurrence of carcinoma of the uterine corpus. The concomitant trends and the biologic similarities between these histologic types of ovarian cancer and the uterine cancers suggest that common etiologic factors may be involved. The role of postmenopausal estrogen use in the etiology of ovarian cancer must be clarified by further epidemiologic studies, but such studies should take tumor histology into consideration.

Incidence of the histologic types of ovarian cancer: The U.S. Third National Cancer Survey, 1969–1971

Using data gathered in the U.S. Third National Cancer Survey, 1969–1971, the incidence of the major histologic types of primary ovarian cancer, as well as the variation in that incidence according to several demographic characteristics, was examined. All types of ovarian cancer except germ cell tumors increased in incidence until the seventh and eighth decades of life, after which the rates plateaued. Epithelial tumors were equally common in young whites and blacks but were substantially more common in whites among middle-aged and older women. The incidence of nonepithelial ovarian tumors was similar in the two races. Rates of epithelial tumors were greatest in single women, whereas nonepithelial tumor occurrence showed no correlation with marital status. There was little variation among the ovarian epithelial tumors in their relationship to age, race, and marital status, although true associations may have been obscured because of classification inconsistencies in the data.