Early tumor regrowth is a contributor to impaired survival in patients with completely resected advanced ovarian cancer. An exploratory analysis of the Intergroup trial AGO-OVAR 12.

OBJECTIVE: Surgical assessment of residual tumor provides the strongest prognostic information in advanced ovarian cancer (AOC), with the best outcome observed after complete resection. Postoperative radiological assessment before initiation of chemotherapy can supplement the information obtained by surgical assessment; however, it may also reveal conflicting findings. METHODS: Patients with AOC enrolled in the AGO-OVAR 12 trial underwent baseline imaging before the first chemotherapy cycle. The findings from surgical and radiologic assessment for disease extend were compared. Additionally, an integrated approach was assessed. RESULTS: Complete data from all 3 assessment methods were available for 1345 patients. Of 689 patients with complete resection, tumor was observed in 28% and 22% of patients undergoing radiologic and integrated assessment, respectively. Patients with surgical- radiological and surgical-integrated concordant findings showed a 5-year overall survival (5Y-OS) of 72% and 71%, whereas patients with surgical-radiological and surgical-integrated discordant results showed inferior 5Y-OS of 47% and 49%, respectively. Patients with surgically assessed residual disease had a 5-YOS of 37%. The interval between surgery and baseline assessment was independently associated with discordance between assessment methods, which might reflect early tumor regrowth. CONCLUSIONS: Baseline tumor assessment before chemotherapy provides information that stratifies patients with complete resection into different prognostic groups. Integrating the data from different assessment methods might lead to improved definitions of prognostic groups. Further investigation to determine if earlier initiation of chemotherapy after debulking surgery could increase survival of patients with early tumor regrowth is warranted.

Incidence of uterine leiomyosarcoma and endometrial stromal sarcoma in Nordic countries: results from NORDCAN and NOCCA databases.

OBJECTIVES AND STUDY DESIGN: Uterine sarcomas are an uncommon and heterogeneous group of malignancies. Their etiology is mainly unknown. Here, we analyzed trends in incidence and occupational variation in risk of uterine leiomyosarcomas (LMS) and endometrial stromal sarcomas (ESS) in the Nordic countries aided by NORDCAN and NOCCA (Nordic Occupational Cancer) databases. MAIN OUTCOME MEASURES: Incidence rates per 100,000 and Standardized incidences rates (SIR) obtained from NORDCAN and NOCCA databases. RESULTS: The incidence rates were about 0.3 per 100,000 for ESS and about 0.4 per 100,000 for LMS in Denmark, Finland, Iceland, and Norway. During the study-period (1978-2007), the incidence rates in each country were quite similar and constant. The age-specific incidence of LMS showed a peak around menopause. Significantly increased risk for LMS occurred in shoe and leather workers, farmers and teachers, whereas significantly low risk was detected with packers in the NOCCA data from Finland, Norway, and Sweden. For ESS no occupations showed either increased or decreased incidences. CONCLUSIONS: The incidence trends of LMS and ESS in our study were constant in four Nordic countries over time. The elevated risk for LMS with women exposed to leather work and animal dust indicates further exploration.

Prognostic role of CIP2A expression in serous ovarian cancer.

BACKGROUND: Cancerous inhibitor of protein phosphatase 2A (CIP2A) is an oncoprotein expressed in several solid cancers. Our purpose was to study its role in serous ovarian cancer patients, and the association to clinicopathological variables and molecular markers. METHODS: We collected retrospectively 562 consecutive serous ovarian cancer patients treated at the Helsinki University Central Hospital. We stained tumour tissue microarrays for CIP2A by immunohistochemistry and constructed survival curves according to the Kaplan-Meier method. Associations to clinicopathological and molecular markers were assessed by the χ(2)-test. RESULTS: We found strong cytoplasmic CIP2A immunoreactivity in 212 (40.4%) specimens, weak positivity in 222 (42.4%) specimens, and negative in 90 (17.2%). Immunopositive CIP2A expression was associated with high grade (P<0.0001), advanced stage (P=0.0005), and aneuploidy (P=0.001, χ(2)-test). Cancerous inhibitor of protein phosphatase 2A overexpression was also associated with EGFR protein expression (P=0.006) and EGFR amplification (P=0.043). Strong cytoplasmic CIP2A immunopositivity predicted poor outcome in ovarian cancer patients (P<0.0001, log-rank test). CONCLUSION: Our results show that CIP2A associates with reduced survival and parameters associated with high grade in ovarian cancer patients, and may thus be one of the factors that identify aggressive subtype (type II) of this disease.

Human papillomavirus infection and primary fallopian tube carcinoma: a seroepidemiological study.

OBJECTIVE: To evaluate the role of human papillomavirus (HPV) types 6, 11, 16, 18, 31 or 33 infection in primary fallopian tube carcinoma (PFTC). DESIGN: A retrospective case-control study. SETTING: Department of Obstetrics and Gynaecology, Helsinki University Hospital, Finland. POPULATION: Seventy-eight consecutive women with PFTC diagnosed between 1985 and 2000 were studied. For each case, two healthy controls were selected. METHODS: Serum immunoglobulin G antibodies to HPV types 6, 11, 16, 18, 31 and 33 were measured from women with PFTC and their healthy controls. MAIN OUTCOME MEASURES: Analysis of HPV 6, 11, 18, 31 and 33 seropositivity among women with PFTC and controls. RESULTS: Seropositivity rates of non-oncogenic or oncogenic HPV types did not differ between cases and controls, odds ratios being 1.04-1.30 for oncogenic HPVs and 1.08-1.19 for non-oncogenic HPVs, similarly. We did not find any multiplicative joint effect in PFTC by antibodies to more than one oncogenic HPV type; neither did we find any antagonistic effect among women with antibodies to non-oncogenic and oncogenic HPV types. CONCLUSIONS: Our results do not suggest any link between PFTC and serological evidence for HPV infection.

Past chlamydial infection is not associated with primary fallopian tube carcinoma.

We conducted a retrospective seroepidemiological study to evaluate the relationship between past chlamydial infection and primary fallopian tube carcinoma (PFTC). Postoperative serum samples were drawn from 79 consecutive patients treated for PFTC in 1985-2000. For each case two controls were selected. Serum samples were analysed for IgG antibodies to different C. trachomatis serotype pools and to C. pneumoniae. Seropositivity in general or serum antibody levels to different C. trachomatis serovars or C. pneumoniae did not differ between PFTC patients and controls. The lack of association between anti-chlamydial antibodies and PFTC suggests that past chlamydial infection does not play a role in the etiopathogenesis of PFTC. However, because chlamydial infection is common at young age and PFTC develops decades later, we cannot definitively exclude the possibility that C.trachomatis contributes to the development of PFTC.

Preoperative serum hCGbeta as a prognostic marker in primary fallopian tube carcinoma.

OBJECTIVES: It was the aim of this study to evaluate the prognostic value of the pretreatment serum concentrations of the beta-subunit of human chorionic gonadotropin (hCGbeta), CA 125 and tumour-associated trypsin inhibitor (TATI) in primary fallopian tube carcinoma (PFTC). METHODS: The pretreatment serum concentrations of hCGbeta, CA 125 and TATI were analyzed in serum samples from 60 women with a mean age of 61 years, treated for PFTC between 1985 and 2000. Of the 91 patients treated during this period, 31 were excluded because no serum sample was available. The patients were followed-up for recurrence and survival until February 14, 2003. The prognostic value of the serum markers were compared with those of stage, grade and histological type. RESULTS: The median survival time was 27 months and the overall 5-year survival rate 33%. Stage and size of the residual tumour (<1 vs. > or =1 cm) predicted both overall and disease-free survival (p < 0.050). Histology (serous vs. others) (p = 0.023) also influenced overall survival. Overall 5-year survival was 38% when serum hCGbeta was below 3.5 pmol/l, while it was 18% when the level was higher (p = 0.052). The corresponding disease-free 5-year survival was 38 and 20%, respectively (p = 0.014). Patients with CA 125 values above 1,017 kU/l had an overall 5-year survival of 39% as compared with 14% for those with lower values (p = 0.009), while the disease-free survival was 37 and 23%, respectively (p = 0.096). Serum TATI was not a prognostic marker. Serum concentrations of hCGbeta and CA 125 correlated significantly with stage (p = 0.049 and p = 0.050, respectively). In multivariate Cox proportional hazards regression analysis, only hCGbeta, stage and histology emerged as independent prognostic factors. CONCLUSIONS: Clearly elevated serum concentrations of hCGbeta and CA 125 predict survival in fallopian tube carcinoma, but in multivariate analyses, only hCGbeta is a prognostic factor independent of stage and histology.

Epidemiology of hydatidiform mole in Finland, 1975 to 2001.

PURPOSE: Broad variations in the incidence of gestational trophoblastic diseases have been reported in different parts of the world. Recent time trends in the incidence of hydatidiform mole in Western countries have not been elucidated. We studied the epidemiology of hydatidiform mole in Finland over a period of 27 years. METHODS: Women reported to have hydatidiform mole from 1975-2001 were identified from the National Research and Development Center for Welfare and Health. Women with choriocarcinoma were identified from the Finnish Cancer Registry. RESULTS: We identified 1659 cases of hydatidiform mole between 1975 and 2001. This gives an incidence of 73/10(6) women or 984/10(6) deliveries. The overall incidence remained fairly constant over the study period. The incidence was higher in women below 20 years and above 39 years than in women in the other age groups. Forty-nine percent of choriocarcinomas identified during the study period were associated with a preceding hydatidiform mole. The risk of choriocarcinoma after a hydatidiform mole was 2.2%. CONCLUSIONS: The incidence of hydatidiform mole in Finland follows the same patterns as in other Western countries. The incidence has not changed considerably in recent decades.

Genetic alterations and protein expression of KIT and PDGFRA in serous ovarian carcinoma.

KIT and PDGFRA are receptor tyrosine kinases that can be specifically inactivated by small-molecule tyrosine kinase inhibitors, notably imatinib mesylate. In ovarian carcinoma, expression of KIT and PDGFRA protein has been documented, but the frequency and the molecular background of expression are poorly known. We analysed the expression of KIT and PDGFRA by immunohistochemistry in 522 serous ovarian carcinomas, and mutations of KIT and PDGFRA by denaturing high-performance liquid chromatographyin 125 and 187 serous ovarian carcinomas, respectively. No mutations of KIT or PDGFRA were detected. KIT expression was detected in 12% of carcinomas: low expression in 10% and high expression in 2% of cases. Using normal serous epithelium as a reference, decreased PDGFRA expression was detected in 12% and increased expression in 13% of carcinomas. Both KIT and PDGFRA expression were associated with high tumour grade, high proliferation index and poor patient outcome. By fluorescence in situ hybridisation, no KIT amplification was found in carcinomas with high KIT expression, but two cases showed a relative gain of chromosome 4. In conclusion, no mutations of KIT or PDGFRA were found, but a subset of serous ovarian carcinoma showed overexpression of the proteins, which was associated with aggressive tumour characteristics.

Collagenases (MMP-1, -8 and -13) and trypsinogen-2 in fluid from benign and malignant ovarian cysts.

Proteolytic enzymes, such as matrix metalloproteinases (MMPs) and tumor-associated trypsinogens (TAT), play a pivotal role in tumor invasion and metastasis. Among MMPs, the interstitial collagenases (MMP-1, -8 and -13) can initiate collagenolysis. In this study, we have studied the levels of MMP-1, -8 and -13 in relation to the level of trypsinogen-2 in fluid from benign and malignant ovarian cysts. Elevated MMP-8 levels occur in many ovarian cyst fluids, and high MMP-8 levels are associated with malignancy. The concentrations of trypsinogen-2 correlate with those of MMP-8, but it remains to be shown whether trypsin-2 plays a role as its activator in vivo. The strong expression of MMP-8 over MMP-1 and MMP-13 in malignant ovarian tumors may indicate that MMP-8 participates in the protease cascades associated with the invasiveness of ovarian tumors.

The levels of trypsinogen isoenzymes in ovarian tumour cyst fluids are associated with promatrix metalloproteinase-9 but not promatrix metalloproteinase-2 activation.

Proteolysis mediated by matrix metalloproteinases (MMPs) and serine proteinases is associated with cancer invasion and metastasis. Activation of latent proMMPs, and especially the proforms of the type IV collagen degrading gelatinases A and B (proMMP-2 and proMMP-9), is thought to be a critical step in this process. We have recently found that human tumour-associated trypsin-2 is a potent activator of proMMP-9 and it also activates proMMP-2 in vitro. Trypsinogen, MMP-2, and MMP-9 are expressed in ovarian cancer. To elucidate the function of trypsin in vivo, we studied whether high concentrations of trypsinogen-1, trypsinogen-2, their alpha(1)-proteinase inhibitor (API) complexes, and tumour-associated trypsin inhibitor (TATI) are associated with proMMP-2 and proMMP-9 activation in ovarian tumour cyst fluids. Zymography and immunofluorometric analysis of 61 cyst fluids showed a significant association between high trypsin concentrations and the activation of MMP-9 (P = 0.003-0.05). In contrast, the trypsin concentrations were inversely associated with the activation of MMP-2 (P = 0.01-0.02). Immunohistochemical analysis of ovarian tumour tissue demonstrated expression of trypsinogen-2 and TATI in the secretory epithelium. MMP-2 was detected both in stromal and epithelial cells whereas MMP-9 was detected in neutrophils and macrophage-like cells in stromal and epithelial areas. These results suggest that trypsin may play a role in the regulation of the MMP-dependent proteolysis associated with invasion and metastasis of ovarian cancer.

Incidence of cancer among women using long versus monthly cycle hormonal replacement therapy, Finland 1994-1997.

OBJECTIVE: This study was initiated as a consequence of a clinical observation in one hospital of several endometrial carcinomas among users of a fixed combination of a 3-month cycle oral hormonal replacement therapy (HRT), which has been marketed in Finland since 1990. We studied whether the use of 3-month ("long") cycle HRT is accompanied by a higher risk of endometrial cancer than the use of monthly cycle HRT. METHODS: A nationwide cohort of 15,956 long cycle and 78,549 monthly cycle HRT users since January 1994 was extracted from the files of the national medical reimbursement register and followed up for cancer incidence through the Finnish Cancer Registry up to the end of 1997. RESULTS: There were 61 cases of endometrial cancer among long cycle HRT users which significantly exceeds the average incidence in the Finnish population (standardized incidence ratio (SIRlong) 2.0, 95% confidence interval (CI) 1.6-2.6). The SIR among users of monthly cycle HRT products (SIRmonthly) was 1.3 (1.1-1.6) and the ratio SIRlong/SIRmonthly thus 1.5 (95% CI 1.1-2.1). Endometrial cancers among long cycle HRT users occur more often in early stages than in the general population and are more often highly differentiated. A survey of a sample of endometrial cancer patients in the long cycle HRT group revealed that all of them also had a history of other HRT. Users of both long and monthly cycle HRT had a similar statistically significant 30% excess of breast cancer in comparison to national incidence rates, while the incidence of colon cancer was decreased in both groups. There was no difference between the HRT groups in overall cancer morbidity. CONCLUSIONS: Our results imply that all HRT users have an increased risk of endometrial cancer, and long cycle HRT carries a higher relative risk than monthly cycle HRT. However, in this non-randomized setting it is impossible to judge whether this excess is attributable to the type of HRT or to patient selection. In-depth studies are needed to find out possible dose-response associations and to evaluate the role of potential confounders in detail.

Comparison between personal learning curves for abdominal and laparoscopic hysterectomy.

BACKGROUND: To compare personal learning curves for abdominal and laparoscopic hysterectomy. METHODS: The first 200 patients scheduled for abdominal hysterectomy and the first 200 patients scheduled for laparoscopic hysterectomy by a single operator were compared using learning curves according to operation time, operative blood loss, and occurrence of complications. RESULTS: Learning curves for both types of hysterectomy were rather similiar, but the learning of the laparoscopic procedure seemed to be quicker. With increasing experience the operating time decreased by 25% in abdominal and by 41% in laparoscopic hysterectomies. The mean operating time in abdominal hysterectomy was 74 min and 70 min in laparoscopic hysterectomy. Operative blood loss decreased by 50% and 44%, respectively. The mean operative blood loss was smaller (203 vs 295 ml, p<0.0001) in laparoscopic hysterectomy. Increased experience had no effect on complication rates in abdominal hysterectomies, but a decrease of 44% was seen in laparoscopic hysterectomies (p<0.05). The overall complication rate (26% vs 22%) were similar for the two techniques, and only a few patients (1.5% vs 1%) had major (bladder or ureteric) complications. CONCLUSIONS: A trained gynecologist can learn the laparoscopic technique for hysterectomy at least as quickly as the abdominal technique.

Wound complications in patients with carcinoma of the vulva. Comparison between radical and modified vulvectomies.

OBJECTIVE: To evaluate complications after different vulvectomies performed because of vulvar cancer. STUDY DESIGN: Retrospective analysis of 149 patients who underwent vulvectomy. RESULTS: Wound infections was found in 58%. Overweight, central or bilateral location of the tumor, and non-radical surgery were significant predictors of wound infections. Patients with a wound infection had more often wound breakdown (P<0.001), prolonged healing time (P<0.000), and lymphedema (P<0.001) than patients without infection. Antimicrobial prophylaxis did not prevent wound infection. Wound infections were found in 75% after radical en bloc vulvectomy (RV) and in 47% after modified vulvectomies (MV) (P<0.001). Also wound breakdown (47 versus 20%) (P<0.001) and lymphedema (48 versus 12%) (P<0.0001) were more common in RV group than in MV group. Lymphocysts were found in 7%, and showed no association with wound infection or type of operation. The mean hospital stay was 26 days in patients with wound infection and 12 days in patients without infection, 31 days in RV group and 12 days in MV group, respectively. CONCLUSIONS: Wound infections are major determinants for both acute and late complications. Postoperative complications reduce with increasing use of modified vulvectomies.

Reproductive features in women developing ovarian granulosa cell tumour at a fertile age.

Ovarian granulosa cell tumour (GCT) is a rare malignancy, which has been linked to both infertility and infertility treatment with ovulation inducers. The reproductive features were analysed of 146 women with GCT diagnosed between 1956 and 1996. During the study period no changes were found in the mean age (53 years), menopausal status (59% postmenopausal), parity (32% nulliparous) or tumour size or stage at diagnosis. The clinical features in women with GCT at fertile age were compared with GCT diagnosed later in life and to population-based data. Nulliparity (50%) and history of infertility (22%) were more frequent if the tumour occurred at fertile age (n = 50). Of the 12 infertile cases, seven had anovulatory infertility (58%); 11 occurred during the era of ovulation inducers, but only five had used these drugs (clomiphene citrate in five patients, gonadotrophins in two, and tamoxifen in one patient) and no patient had undergone in-vitro fertilization. Endometrial hyperplasia was associated with GCT at all ages, while endometrial cancer was found solely after the age of 45 years. In conclusion, GCT at fertile age is associated with nulliparity and with a clinical presentation of anovulatory infertility, while GCT later in life is associated with a more normal average fertility pattern and with occurrence of endometrial cancer.

Spread of ovarian cancer after laparoscopic surgery: report of eight cases.

OBJECTIVE: The aim of this study was to describe early occurrences of metastases after laparoscopy of ovarian masses later found to be malignant. METHODS: The hospital charts of eight women having undergone laparoscopic surgery for ovarian mass were reviewed and analyzed. RESULTS: The mean age of the patients was 40 years (range 25 to 66). Size of the tumor ranged from 2 to 15 cm. In four patients the ovarian mass was suspected to be malignant in the laparoscopy. Diagnostic procedure (biopsy of the tumor) was performed in two and salpingo-oophorectomy in six patients. Staging laparotomy was performed within the mean of 17 days (range 7-29). In four patients (50%) the cancer had spread from a localized to an advanced stage during the delay. Ascites was present in the laparoscopy in two of the four patients with port site or abdominal wall metastases. CONCLUSIONS: Laparoscopic surgery of ovarian mass later found to be malignant can cause considerable and early spread of the cancer.

Nationwide data on falling incidence of ovarian granulosa cell tumours concomitant with increasing use of ovulation inducers.

The genesis of ovarian granulosa cell tumours (GCT) has been linked to high gonadotrophin levels, and therefore also to the use of ovulation inducers and combined contraceptive pills (OC). We analysed the occurrence of GCT in the whole of Finland in 1965-1994, the period when ovulation inducers and OC became available. All women with GCT were traced from the Finnish Cancer Registry. The numbers of courses of clomiphene citrate and gonadotrophin (human menopausal gonadotrophin: HMG) and number of courses of OC used in Finland during the same period were calculated from sales statistics on these agents. In 1965-1994, 590 patients contracted GCT. The incidence of GCT declined by nearly 40% from 0.74/100000 in 1965-1969 to 0.47/100000 in 1985-1994, a fall occurring at the same time that the use of clomiphene citrate increased 13-fold, that of HMG 200-fold and that of OC 5-fold. Our nationwide data on the incidence of GCT falling concomitantly with increasing use of ovulation inducers can be seen as one piece of evidence that ovulation inducers are unlikely to cause GCT.

Pre-operative serum level of tumour-associated trypsin inhibitor and residual tumour size as prognostic indicators in Stage III epithelial ovarian cancer.

OBJECTIVE: To evaluate the use of the pre-operative tumour-associated trypsin inhibitor (TATI) level and residual tumour size at primary surgery as a prognostic indicators for patients with Stage III epithelial ovarian cancer. DESIGN: Retrospective cohort study. SETTING: Department of Obstetrics and Gynaecology, University Hospital, Helsinki, Finland. PARTICIPANTS: Ninety-eight women with Stage III ovarian cancer. METHODS: TATI was measured by radioimmunoassay from serum samples obtained within one week before surgery. A cutoff value of 22 microg/L was used. Multivariate analysis included pre-operative TATI level, age, histologic grade and histologic type. Mantel-Cox test was used for calculating statistical significance of differences in survival between groups. MAIN OUTCOME MEASURES: Cumulative five-year survival, pre-operative serum TATI level and residual tumour size. RESULTS: Surgery was optimal (residual tumour size < or = 2 cm) in 55 patients and suboptimal (residual tumour size > 2 cm) in 43. Pre-operative TATI level < or = 22 microg/L predicted better prognosis both in patients with optimal and suboptimal surgery compared with patients with pre-operative TATI level > 22 microg/L. Patients with optimal surgery and a pre-operative TATI > 22 microg/L had a twofold relative risk of death compared with those with a pre-operative TATI < or = 22 microg/L. The cumulative survival was less than three years for patients with suboptimal surgery and pre-operative TATI > 22 microg/L. CONCLUSIONS: Pre-operative serum TATI in combination with residual tumour size may be useful in stratifying patients with Stage III ovarian cancer into different categories in randomised treatment trials.