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.

Preoperative serum concentration of hCGbeta as a prognostic factor in ovarian cancer.

In spite of a gradual improvement, survival in epithelial ovarian cancer is disappointingly low. New therapeutic regimens are emerging, and it would be important to be able to predict the prognosis and to stratify patients for clinical trials before therapy. We have evaluated the prognostic value of the pretreatment serum concentrations of 3 tumor markers. The free beta subunit of human chorionic gonadotropin (hCGbeta), CA125 and tumor-associated trypsin inhibitor (TATI) were measured in pretreatment serum samples from 146 patients treated for ovarian cancer between 1990-1995. The patients were followed up until 1998. Elevated concentrations of hCGbeta, CA125 and TATI were observed in 29%, 79% and 33%, respectively. When tested as single variables in Cox's proportional hazards model, stage, grade, size of residual tumor and hCGbeta (all p < 0.001) and CA125 (p = 0.004) correlated with prognosis. However, when fitted as multiple variables together with stage, grade and age in the same model, hCGbeta (RR = 3.42) stage (RR = 2.77) and grade (RR = 3.80) were the only significant variables. When serum hCGbeta was normal, 5-year survival was 80%, but it was only 22% when hCGbeta was elevated. In patients with stage III or IV and minimal residual disease, 5-year survival was 75% if hCGbeta was normal compared with 0% if hCGbeta was elevated. hCGbeta in serum is a strong independent prognostic factor in epithelial ovarian cancer, and its prognostic value is similar to that of grade and stage. The availability of this marker before surgery could facilitate selection of treatment modalities.

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.

Skin metastases of gynecologic adenocarcinomas affect serum levels of hCGbeta but not those of SCC antigen.

Squamous cell carcinoma antigen (SCC-Ag) has been shown to be elevated in patients with epidermoid carcinoma of the cervix but also in patients with benign tumors of epithelial origin and in benign skin disorders. Elevated serum levels of the free beta subunit of human chorionic gonadotropin (hCGbeta) have been observed in patients with cancer of different types, and cancer aggressiveness is related to hCGbeta expression. Therefore, we expected that extensive metastatic skin dissemination of gynecologic malignancies would cause a rise in the serum levels of SCC-Ag and hCGbeta. The serum levels of SCC-Ag, hCGbeta and CA 125 were monitored in 2 patients with extensive skin dissemination of ovarian and endometrial adenocarcinoma. Skin metastases had no effect on serum levels of SCC-Ag but they caused an increase in serum levels of hCGbeta. SCC-Ag is not a marker for metastatic skin lesions of gynecologic carcinomas of nonepidermoid origin. hCGbeta expression is associated with aggressiveness of cancer and may be a useful marker indicating therapy resistance.

Identification of choriocarcinoma by the hCG beta-to-hCG proportion in patients with delayed diagnosis caused by contraceptive use.

The use of contraceptives, especially subdermal implants and levonorgestrel-containing intrauterine device (IUD), often cause irregular bleeding. Thus, they may mask unsuspected choriocarcinoma, which also often presents with abnormal bleeding. Choriocarcinoma is mostly curable with combination chemotherapy, but delayed diagnosis can lead to treatment failure. Two cases of choriocarcinoma with considerable delay in diagnosis, due partly to contraceptive use, are reported. The proportion of human chorionic gonadotropin-beta (hCG beta) and total hCG immunoreactivity showed that the proportion of hCG beta was elevated at presentation in both cases.

PIP: Irregular bleeding is a common side effect of the use of contraceptives, especially subdermal implants and the levonorgestrel-containing IUD. However, these methods may mask choriocarcinoma, which also presents with abnormal bleeding. About 50% of choriocarcinoma cases are associated with a complete hydatidiform mole, 25% follow an abortion or tubal pregnancy, and 25% follow a term gestation. Although this carcinoma is generally curable with combination chemotherapy, delayed diagnosis can produce a fatal outcome. Presented are two cases of gestational choriocarcinoma drawn from a sample of 27 Finnish women with a molar pregnancy in which the method of contraception caused a considerable delay in diagnosis. In both cases, the proportion of beta-human chorionic gonadotropin (hCG) was elevated (6% of total hCG immunoreactivity) at hospital presentation. At diagnosis (by dilatation and curettage for irregular bleeding) 15 months after Norplant insertion, the first patient had a beta-hCG proportion of 80%. Even after chemotherapy, this ratio remained in the 40-50% range and the woman died 2 years after diagnosis. The second patient underwent a dilatation and curettage for irregular bleeding 9 months after insertion of a levonorgestrel-releasing IUD. The proportion of beta-hCG was 9%, indicating malignant trophoblastic disease, but this ratio returned to normal after successful chemotherapy. These findings confirm that the proportion of beta-hCG out of total hCG immunoreactivity differentiates between malignant and benign disease. Determination of this proportion is thus recommended in all women with molar pregnancies to identify those who are likely to develop choriocarcinoma.

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.

Malignant tumors of the ovary or the breast in association with infertility: a report of thirteen cases.

BACKGROUND: Many questions have been raised recently about the relationship between infertility, fertility drugs and cancer. This prompted us to evaluate our patients having ovarian or breast cancer with a known history of infertility. METHODS: We report thirteen women who had been examined and/or treated for infertility before the occurrence of malignant tumors of the ovary or the breast at an age under 50 years in 1990-1995 in our unit. RESULTS: Mean age of the patients was 35 years (s.d. 5.9 years, range 28-47 years). Of the 11 ovarian tumors, one was a malignant teratoma, two were granulosa cell tumors and eight epithelial ovarian cancers. Ten women had received either clomiphene citrate alone or together with gonadotrophins, one had used only gonadotrophins, and in two patients ovarian cancer was detected during an infertility work-up but before any treatment. Four women had used clomiphene for more than twelve cycles. Two patients had ductal breast cancer. CONCLUSIONS: Our patients emphasize the need for follow-up and long-term prospective studies in infertile women who have been evaluated or treated for infertility.

Effect of interleukin 2 on urinary excretion of degradation products of prostacyclin and thromboxane A2 in patients with ovarian cancer.

We studied the effect of intraperitoneal recombinant interleukin 2 (rIL-2) on the production of prostacyclin (PGI2) and thromboxane A2 (TxA2) in six patients with metastatic ovarian malignancy. Time-span urine samples collected before and after 17 intraperitoneal instillations of IL-2 (6 x 10(5) IU m-2) were assessed for 2,3-dinor-6-keto-prostaglandin F1 alpha (dinor-6-keto; a metabolite reflecting the in vivo product of PGI2) and 2,3-dinor-thromboxane B2 (dinor-TxB2; a metabolite reflecting the production of TxA2). Analysis was by high-pressure liquid chromatography, followed by radioimmunoassay. Recombinant IL-2 administration was accompanied by a significant rise (85%; P < 0.02) in the output of dinor-6-keto within the first 2 h, and this elevation persisted for up to 6 h. Moreover, output of dinor-TxB2 also rose; this rise (30%) was significant (P < 0.02) 6 h after the instillation. These effects may, in some yet unknown manner, prove significant in the anti-cancer action of rIL-2.

Hereditary aspects of endometrial adenocarcinoma.

The importance of heredity in the etiology of endometrial cancer (EC) was examined in a series of 326 patients with EC diagnosed at age 60 years or less. If one or both of the proband's parents had died of cancer, a thorough family history of malignancies was studied. Altogether 291 cases with complete parental data were found. Nine kindred (3.1%) showed features compatible with the dominantly inherited cancer trait known as hereditary non-polyposis colorectal cancer (HNPCC). In another 9 cases, clustering of malignancies in 2 or more successive generations was indicative of familial cancer. Aspecific cancer aggregates were found in 112 probands' families, and family history was negative in 161 cases. No families had gynecological cancer as the only malignancy. HNPCC, the genetic etiology of which was recently revealed, seems to be an important risk factor for EC, indicating the significance of family-history investigations of all patients with EC. Colorectal carcinoma (CRC) was here associated with EC also in families with clusterings of malignancies, but in these families no typical features of any known hereditary cancer syndrome could be found. On the basis of the results of the present study, proper surveillance for colorectal cancer should be recommended for patients with endometrial carcinoma if they belong to a family with features indicative of HNPCC. Furthermore, healthy gene carriers in an HNPCC family also need careful surveillance for CRC, EC and perhaps for other extra-colonic malignancies typical for HNPCC. Prophylactic surgery should even be considered in these cases.

Therapeutic and prognostic considerations in primary carcinoma of the vagina.

We analyzed 46 patients with primary carcinoma of the vagina treated between 1969 and 1990. Median age of the patients was 67 years (range 33-89 years). Most (52%) of them were obese and 35% were nulliparous. Four (9%) had suffered from other gynecologic carcinoma and had been operated six to 23 years before the current carcinoma. Forty (87%) patients had squamous cell carcinoma. Stage 0 (carcinoma in situ) was found in three (7%) cases and stage I-IV in 21 (54%), 10 (22%), four (9%) and eight (17%) cases, respectively. Most (81%) of the patients were treated with radiotherapy (alone or in combination with other treatments): combination of brachytherapy and external radiotherapy were used in 45% of the cases. Surgery was used in all stage 0 cases and in 52% of stage I cases. Recurrence of the disease was found in 20 (43%) cases during the follow-up of 10 years. Most often (40%) site of the recurrence was the vagina. Both 5- and 10-year survival were 38%. Stage and extent of the tumor were independent prognostic factors in stepwise multivariate analysis.

Markers supplementing CA 125 in ovarian cancer.

Markers supplementing CA 125 are important for monitoring of the disease in patients with mucinous and non-epithelial ovarian cancers. Tumour-associated trypsin inhibitor (TATI) or one of the gastrointestinal mucin markers, CA 19-9 or CA 72.4 are good supplements to CA 125 in mucinous ovarian cancer. Chorionic gonadotrophin (hCG) and alpha fetoprotein (AFP) are the most useful markers for germ cell tumours, and hCG beta may provide additional information. In addition to hCG beta, M-CSF and inhibin show promise of becoming useful supplements to CA 125 in ovarian cancer in general. Markers other than CA 125 may also play a role as prognostic indicators. TATI and procollagen peptides appear useful for this purpose. If these markers prove to provide reliable prognostic information, they could be used to aid selection of optimal treatment regimens.