Annika Riska

Parity, tubal sterilization, hysterectomy and risk of primary fallopian tube carcinoma in Finland, 1975 2004

We studied the possible relationship among parity, female sterilization, hysterectomy and the risk of primary fallopian tube carcinoma (PFTC) in a case–control study in Finland in cases occurring between 1975 and 2004. A total of 573 PFTC cases were identified from the Finnish Cancer Registry, and10 age‐matched controls per case were randomly selected from the Finnish Central Population Registry. In multivariate analysis (including 189 PFTC cases and 1764 controls) parity was protective: the odds ratio (OR) for 1–2 deliveries was 0.63 (95% CI 0.44–0.91) and for ≥3 deliveries, 0.32 (95% CI 0.19–0.52). The OR for sterilization was 0.74 (95% CI 0.42–1.30) and for hysterectomy 1.27 (95% CI 0.73–2.21). Our findings suggest a possible hormonal background as regards the development of PFTC.

Clinical characteristics and survival of patients with an adult-type ovarian granulosa cell tumor: a 56-year single-center experience.

Objective The objective of this study was to evaluate clinical prognostic factors and survival of patients with ovarian granulosa cell tumors (GCTs) in a long-term follow-up study. Methods A total of 240 adult-type GCTs diagnosed in Helsinki University Central Hospital from 1956 to 2012 were histologically reevaluated. Data were analyzed for several clinical factors in relation to major developments in imaging, surgery, and chemotherapy: the old era (1956–1983) and the new era (1984–2012). Prognostic factors for survival were evaluated in the univariate and multivariate analyses. Results The original diagnosis was confirmed in 187 (77.9%) patients. The International Federation of Gynecology and Obstetrics stage I disease was present in 89.2%; stage II, in 7.0%; stage III, in 3.8%; and stage IV, in 0% of cases. The mean age at diagnosis (52.9 years) and the mean tumor size (10.8 cm) did not change significantly over time. The most common presenting symptom was abnormal bleeding, but 14% were asymptomatic. The mean follow-up period was 15.7 years. Recurrence rate was similar in both eras. The GCT-specific 5-, 10-, and 20-year survival rates were 95.6%, 88.1%, and 79.8% in the old era as well as 97.2%, 94.8%, and 94.8% in the new era, respectively. In the univariate analyses, old era, patient age older than 60 years, tumor size greater than 10 cm, advanced stage, residual tumor, and use of hormonal adjuvant treatment were associated with GCT-related deaths. Prior use of oral contraceptives and history of infertility improved survival rates. In the multivariate analysis, stage was the only independent prognostic factor for GCT-specific survival. Conclusions An accurate histological diagnosis of GCT is essential. Stage IV disease is an extreme rarity. However, tumor stage overcomes other possible clinical prognostic factors for GCT-specific survival. Fertility-sparing surgery, the use of oral contraceptives, or hormonal replacement therapy seems not to be risk factors for survival.

Characteristics and outcome of recurrence in molecularly defined adult-type ovarian granulosa cell tumors

OBJECTIVE Adult-type ovarian granulosa cell tumors (AGCTs) have an unpredictable tendency to relapse. In a carefully validated patient cohort, we evaluated the prognostic factors related to AGCT recurrence. METHODS We identified all patients diagnosed with AGCT during 1956-2014 in Helsinki University Hospital, with a minimum follow-up of one year (n=240). After a histological review supplemented with FOXL2 (402C-G) mutation status analysis, we analyzed the clinical data for association with relapse. RESULTS The final cohort included 164 (68%) molecularly defined AGCTs (MD-AGCTs). The majority of the women were postmenopausal (63%), and 92% of tumors were stage I. The median follow-up time was 15.5years. Fifty-two (32%) patients developed tumor recurrence, of whom 55% had successive recurrences. Multiple-site recurrences were common, and nearly half of the recurrences were asymptomatic. The median time to the first relapse was 7.4years, and 75% of relapses occurred within ten years after primary diagnosis. The median disease-free survival was 11.3years. Premenopausal status at initial diagnosis, FIGO stage Ic versus Ia, and tumor rupture associated with relapse. However, tumor rupture was the only independent predictive factor. Of the relapsed patients, 48% died of AGCT in a median time of 15.3years. CONCLUSION Tumor rupture is the strongest predictive factor for recurrence, and these patients might benefit from a more aggressive initial treatment approach. AGCT requires active follow up for 10 to 15years after primary diagnosis, since recurrences may develop late, asymptomatically and in multiple anatomical locations.

Determinants of incidence of primary fallopian tube carcinoma (PFTC).

Primary fallopian tube carcinoma (PFTC) is a rare malignancy, but its incidence has been rising during the last decades and varies between 2.9/1,000,000 and 5.7/1,000,000. The epidemiology of PFTC has been sparsely studied. In Finland, the incidence rate has been rising during the last decades. The rise has been highest in the cities, in higher social classes, and in certain specific occupations. Parity gives protection against this disease, as does a previous sterilization procedure. Earlier thoughts of a previous salpingitis as a possible promoter of PFTC seem not to hold. Previous infections such as Chlamydia trachomatis infections or human papillomavirus infections cannot be regarded as risk factors. In this chapter, we clarify the possible epidemiological factors behind 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).

Second primary malignancies in females with primary fallopian tube cancer.

Primary fallopian tube cancer (PFTC) is a rare disease, and its aetiological factors are poorly understood. Studies on PFTC in the setting of 2nd primary malignant neoplasms can provide clues on aetiology and also define the possible side effects of different treatment modalities for PFTC. A cohort of 2,084 cases with first PFTC was extracted from the data from 13 cancer registries from Europe, Canada, Australia and Singapore and followed for second primary cancers within the period 1943–2000. Standardized incidence ratios (SIRs) were calculated and Poisson regression analyses were done to find out the RRs related to age at, period of and time since the PFTC diagnosis. There were 118 cancer cases observed after first PFTC (SIR 1.4, 95%CI 1.1–1.6). Elevated SIRs were seen for colorectal cancer (1.7, 95%CI 1.0–2.6), for breast cancer (1.5, 95%CI 1.1–2.2), for bladder cancer (2.8, 95%CI 1.0–6.0), for lung cancer (1.8, 95% CI 0.9–3.2) and for nonlymphoid leukaemia (3.7, 95%CI 1.0–9.4). Significant risk increases were detected for colorectal cancer during the 2nd to 5th year after the first PFTC diagnosis, for breast cancer in follow‐up 10+ and for nonlymphoid leukaemia during the 2nd to 10th year. The clustering of cancers of the lung and bladder in PFTC patients may suggest shared smoking aetiology. The excess of colorectal and breast cancers after PFTC may indicate a genetic aetiology.

Occupation and risk of primary fallopian tube carcinoma in Nordic countries.

The aetiology of primary Fallopian tube carcinoma (PFTC) is poorly understood. Occupational exposures may contribute to PFTC risk. We studied incidence of PFTC in occupational categories in the Nordic female population aged 30–64 years during the 1960, 1970, 1980/1981 and/or 1990 censuses in Denmark, Finland, Iceland, Norway and Sweden. Standardized incidence ratios (SIRs) for the years following inclusion in the study up to 2005 were calculated for 53 occupations; the expected numbers of cases were based on PFTC incidence in the national populations. Altogether 2,206 PFTC cases were detected during follow up via data linkages with the Nordic cancer registries. Significantly increased risks of PFTC were observed for smelting workers (SIR 3.99, 95% confidence interval 1.46–8.68, Obs = 6), artistic workers (2.64, 1.44–4.43, Obs = 14), hairdressers (2.18, 1.41–3.22, Obs = 25), packers (1.62, 1.11–2.29, Obs = 32), nurses (1.49, 1.14–1.92, Obs = 60), shop workers (1.25, 1.07–1.46, Obs = 159) and clerical workers (1.20, 1.07–1.35, Obs = 271) and these sustained over times and different Nordic countries. There was a nonsignificant increased risk for PFTC among welders, printers, painters and chemical process workers. The risk was significantly and consistently low for women working in farming (0.68, 0.47–0.95, Obs = 34) and among economically inactive women (0.88, 0.82–0.94, Obs = 833). The possible role of occupational exposures to the PFTC risks found in this study must be further evaluated in studies with a possibility to adjust for possible confounding factors, such as reproductive and life‐style factors, which was not possible in our study.

Lichen sclerosus and risk of cancer

Malignant potential of lichen sclerosus (LS) has been suspected, but evidence is sparse. We used the population‐based Finnish Cancer Registry data to further study this connection.

Cancer risk of Lichen planus: A cohort study of 13,100 women in Finland

The association between Lichen planus (LP) and cancer has been under debate for decades. We studied the connection via population‐based Finnish register data. All women with the diagnosis of LP (n = 13,100) were identified from the Finnish Hospital Discharge Registry from 1969–2012. These patients were linked with subsequent cancer diagnoses from the Finnish Cancer Registry until 2014. Standardized incidence ratios (SIRs) were counted for different cancers by dividing the observed numbers of cancers by expected numbers, which were based on national cancer incidence rates. In total, 1,520 women with LP were diagnosed with cancer (SIR 1.15, 95% confidence interval [CI] 1.09–1.20). LP was associated with an increased risk of cancer of lip (SIR 5.17, 95% CI 3.06–8.16), cancer of tongue (SIR 12.4, 95% CI 9.45–16.0), cancer of oral cavity (SIR 7.97, 95% CI 6.79–9.24), cancer of esophagus (SIR 1.95, 95% CI 1.17–3.04), cancer of larynx (SIR of 3.47, 95% CI 1.13–8.10) and cancer of vulva (SIR 1.99, 95% CI 1.18–3.13). The risk of cancer was not increased in other locations where LP manifests (pharynx and skin). Patients with diagnosed LP have an increased risk of developing cancer of lip, tongue, oral cavity, esophagus, larynx and vulva. These data are important when considering treatment and follow‐up of patients with LP diagnosis.

Systematic drug sensitivity testing reveals synergistic growth inhibition by dasatinib or mTOR inhibitors with paclitaxel in ovarian granulosa cell tumor cells

OBJECTIVE Resistance to standard chemotherapy poses a major clinical problem in the treatment of ovarian cancer patients. Adult-type granulosa cell tumor (AGCT) is a unique ovarian cancer subtype for which efficient treatment options are lacking in advanced disease. To this end, systematic drug response and transcriptomics profiling were performed to uncover new therapy options for AGCTs. METHODS The responses of three primary and four recurrent AGCTs to 230 anticancer compounds were screened in vitro using a systematic drug sensitivity and resistance testing (DSRT) platform, coupled with mRNA sequencing. The responses of the AGCTs were compared with those of human granulosa luteal cells and bone marrow mononuclear cells. RESULTS Patient-derived AGCT cells showed selective sensitivity to the Src family tyrosine kinase inhibitor dasatinib. A combination of either dasatinib or an mTOR-inhibitor everolimus with paclitaxel resulted in synergistic inhibition of AGCT cell viability. The key kinase targets of dasatinib and members of the mTOR pathway were constantly expressed at mRNA and protein levels, indicating multikinase signal addictions in the AGCT cells. Transcriptomic characterization of the tumors revealed no known oncogenic mutations, suggesting that the drug sensitivity of AGCTs was rather conveyed by selective target expression. CONCLUSIONS We used a systematic functional approach to reveal novel treatment options for a unique gynecological cancer. The selective synergy found between taxanes and dasatinib or mTOR inhibitors warrants further clinical investigations of these combinations in relapsed or aggressive AGCTs and demonstrate that high-throughput drug screening and molecular profiling can provide an effective approach to uncover new therapy options.