Munasarjan granuloosasolukasvaimen epidemiologinen ja kliininen kuva sekä ennustetekijät

Adult-type granulosa cell tumors (AGCTs) belong to the sex cord-stromal group of ovarian tumors and account for 3-5% of ovarian neoplasms. Etiological factors of AGCTs remain mostly unknown, although studies have found a somatic missense mutation in the transcription factor FOXL2. AGCTs are usually diagnosed at an early stage and have a favorable prognosis compared with the more common epithelial ovarian cancer. However, tumor recurrence develops in up to 35% of patients, even in early-stage disease - often unpredictably and several years or even decades after the primary diagnosis. The aims of this study were to determine the incidence and epidemiological background of AGCTs in a large, multinational Nordic cohort and to estimate the incidence of other, especially endocrine-related primary malignancies among patients with AGCT. Furthermore, the objective was to describe the clinical characteristics and prognostic factors linked to AGCT–related recurrence and survival, and to introduce an optimal follow-up strategy for these patients. Our epidemiological registry study on AGCT incidence utilized the Finnish, Icelandic, Norwegian, and Swedish Cancer Registry data on AGCTs over several decades. We showed that the age-adjusted incidence rates were quite constant in 1953-2012: about 0.6-0.8 per 100,000 for most of the study period. The age-specific incidence was highest at 50-64 years of age, and there were no occupations with significantly increased risk of AGCT. The conclusions drawn from these results point to AGCT as a primarily sporadic, not exposure-related cancer, typically occurring in peri- or postmenopause. We estimated the incidence of other primary malignancies among AGCT patients using data from the Finnish Cancer Registry in 1968-2013. After AGCT, we found increased risks for cancers of the soft tissue and thyroid as well as leukemia, which likely indicate shared risk factors and therapy-induced side effects. The incidence of AGCT was significantly increased among women with previous breast cancer, suggesting shared hormonal etiology or treatment-induced effects. To evaluate the clinical and prognostic factors, all AGCT patients diagnosed at Helsinki University Hospital during nearly six decades were included in the clinical study cohort (n=240). After a histological review, we analyzed the clinical data for association with both AGCT-related and overall survival and tumor relapse. Of the original study cohort, the diagnosis was histologically confirmed in 78% of patients and molecularly confirmed for the FOXL2 mutation in 68% of patients. In multivariate analysis, stage was the only independent prognostic factor related to AGCT-specific survival. Spontaneous or iatrogenic tumor rupture was independently associated with tumor recurrence. By utilizing the extensive cancer registry data together with the internationally unique, large and carefully validated single-institute patient cohort, these studies reveal the diagnostic challenges of AGCTs, and provide novel epidemiological data and evidence-based tools to develop follow-up strategies for this rare cancer.Aikuistyypin munasarjan granuloosasolukasvain (AGSK) kuuluu sukupienakasvaimiin ja käsittää 3-5 % kaikista munasarjasyövistä. Tyypillisesti AGSK erittää hormoneja, kuten estrogeenia ja inhibiinejä. Kasvaimen synty tunnetaan huonosti, mutta sille on osoitettu pistemutaatio transkriptiotekijä FOXL2:a koodaavassa geenissä. Tämän tutkimuksen tarkoituksena oli tutkia AGSK:n kansainvälistä esiintyvyyttä ja epidemiologista taustaa laajassa pohjoismaisessa aineistossa, sekä selvittää muiden, erityisesti hormoniriippuvaisten syöpien esiintyvyyttä kyseisillä potilailla. Lisäksi pyrkimyksenä oli määrittää AGSK:n taudinkuvaa ja ennustetekijöitä. Tulosten avulla pyrimme muodostamaan näille potilaille optimaalisen seurantastrategian kasvaimen toteamisen jälkeen. Rekisteritutkimuksemme hyödynsi Suomen, Ruotsin, Norjan ja Islannin syöpärekisteritietoja usean vuosikymmenen ajalta. Ikäkorjattu ilmaantuvuus pysyi vuosina 1953-2012 melko tasaisena, noin 0,6-0,8/100 000. Ilmaantuvuus oli korkeimmillaan 50-64-vuotiaiden ryhmissä, eikä erityisiä ammattialtisteita löydetty eri ammattiryhmiä tutkittaessa. Johtopäätöksenä tuloksista voidaan todeta, että AGSK on pikemmin satunnaisesti ilmaantuva kuin altistesidonnainen syöpä, joka ilmenee tyypillisesti vaihdevuosi-iässä tai tämän jälkeen. AGSK-potilailla ilmeneviä muita syöpiä tutkittiin käyttämällä Suomen Syöpärekisterin aineistoa vuosilta 1968-2013. AGSK:n jälkeen todettiin merkitsevästi enemmän pehmytkudos- ja kilpirauhassyöpää sekä leukemiaa, mikä todennäköisesti viittaa yhteisiin riskitekijöihin sekä syöpähoitojen myöhäisiin haittavaikutuksiin. Rintasyövän sairastaneilla naisilla esiintyi merkitsevästi enemmän AGSK:ta, mikä saattaa viitata näille kasvaimille yhteiseen hormonaaliseen taustaan tai rintasyövän hoitojen vaikutukseen. Kliininen aineistotutkimus kattoi HYKS Naistenklinikalla hoidetut AGSK-potilaat lähes kuuden vuosikymmenen ajalta (N=240). Diagnoosi varmistettiin ensin sekä patologin tutkimuksessa että myöhemmin FOXL2-mutaatin osalta, ja aineisto analysoitiin sekä kokonais- ja tautikohtaisen kuolleisuuden että kasvaimen uusiutumisen suhteen. Kasvaimen levinneisyys toteamishetkellä oli ainoa itsenäinen ennustetekijä tautikohtaisen kuolleisuuden suhteen, mutta kasvaimen puhkeaminen joko spontaanisti tai leikkauksen aikana ennusti itsenäisesti AGSK:n uusiutumista. Nämä kansainvälisesti ainutlaatuisen laajan ja tarkkaan vahvistetun potilasaineiston sekä kattavan syöpärekisteriaineiston avulla tehdyt tutkimukset osoittavat AGSK:n diagnostiset haasteet ja tuovat tämän harvinaisen syövän osalta sekä uutta epidemiologista tietoa että välineitä kehittää näyttöön perustuvia seurantastrategioita

Other Primary Malignancies Among Women With Adult-Type Ovarian Granulosa Cell Tumors

Objective: The aim of this study was to determine the incidence of new primary malignancies after adult-type granulosa cell tumor (AGCT) and the incidence of AGCT after breast and uterine cancer using nationwide population-based registry data. Methods: We used the Finnish Cancer Registry to identify all patients diagnosed with AGCT in 1968 to 2013 (n = 986). The number of subsequent primary malignancies among women with AGCT and the number of AGCTs in women with previous breast or uterine cancer were compared with the expected number of cases and expressed as standardized incidence ratios (SIRs). Results: There were 122 cases of subsequent cancers diagnosed at least 6 months after the primary diagnosis of AGCT (SIR, 1.09; 95% confidence interval [CI], 0.91-1.3). In particular, the observed number of cancers of the soft tissue (SIR, 4.13; 95% CI, 1.33-12.8), thyroid (SIR, 3.42; 95% CI, 1.54-7.62), and leukemia (SIR, 2.67; 95% CI, 0.98-5.82) exceeded the number of expected cases. The SIR for breast cancers after AGCT was 1.26 (95% CI, 0.92-1.73), and the SIR for AGCT after breast cancer was 1.59 (95% CI, 1.04-2.29). The risk for subsequent AGCT was more than 2-fold in breast cancer patients younger than 50 years, and over 15 years after primary diagnosis. Conclusions: There is an increased risk for thyroid and soft tissue cancer as well as leukemia after AGCT, which may be associated with late effects of carcinogenic treatments and possibly shared risk factors. After breast cancer, the risk for AGCT was higher, which may indicate a shared hormonal etiology.Peer reviewe

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 15.5 years. 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 7.4 years, and 75% of relapses occurred within ten years after primary diagnosis. The median disease-free survival was 11.3 years. Premenopausal status at initial diagnosis, FIGO stage Ic versus la, and tumor rupture associated with relapse. However, tumor rupture was the only independent predictive factor. Of the relapsed patients, 48% died of AGO' in a median time of 153 years. 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 15 years after primary diagnosis, since recurrences may develop late, asymptomatically and in multiple anatomical locations. (C) 2016 Elsevier Inc. All rights reserved.Peer reviewe

Parity, menopausal hormone therapy, and risk of ovarian granulosa cell tumor – A population-based case-control study

Objective: Adult-type ovarian granulosa cell tumors (AGCTs) are hormonally active neoplasms with limited epidemiological data available. We evaluated the effect of parity and postmenopausal hormone therapy (HT) use on the risk of AGCT in a population-based case-control setting. Methods: We identified all women diagnosed with AGCT during 1994–2015 (n = 505) from the Finnish Cancer Registry. For each case, five controls matched for age were selected from the National Population Registry, which also provided data on parity and ages at deliveries. Information on postmenopausal HT by different regimens (estradiol-only, sequential estrogen-progestin and continuous estrogen-progestin) was obtained from nationwide Prescription Register. The association between parity, ages at deliveries, HT use, and AGCT incidence was evaluated by odds ratios (ORs) using a conditional logistic regression model and stratified by age at index date (<55 years or ≥ 55 years). Results: Parity and age at first or last delivery had no significant effect on AGCT risk. Systemic postmenopausal HT had been used by 20.4% of women who were later diagnosed with AGCT. The risk for subsequent AGCT was significantly decreased among users of estradiol-only therapy for at least five years (OR 0.28; 95% confidence interval 0.08–0.94) and continuous estradiol-progestin therapy for 6 months to 5 years (0.23; 0.08–0.71). Conclusions: Unlike in epithelial ovarian cancer, AGCT development is not clearly associated with parity, and users of postmenopausal HT do not seem to carry an excess risk for AGCT formation.acceptedVersionPeer reviewe

Molecularly Defined Adult Granulosa Cell Tumor of the Ovary : the clinical phenotype

The histopathologic features of Adult Granulosa Cell Tumors (AGCTs) are relatively non-specific, resulting in misdiagnosis of other cancers as AGCT, a problem that has not been well characterized. FOXL2 mutation testing was used to stratify 336 AGCTs from three European centers into three categories: 1) FOXL2 mutant molecularly defined AGCT (MD-AGCT)(n=256 of 336), 2) FOXL2 wild-type AGCT (n=17 of 336), 3) misdiagnosed other tumor types (n=63 of 336). All statistical tests were two-sided. The overall and disease-specific survival of the misdiagnosed cases was lower than in the MD-AGCTs (P<0.001). The misdiagnosed cases accounted for 71.9% of disease-specific deaths within five years. In the population-based cohort, overall survival of MD-AGCT patients was not different from age-matched population-based controls. Even though 35.2% of all the MD-AGCT patients, in our study, experienced a relapse, AGCT is usually an indolent disease. The historical, pre-molecular data underpinning our clinical understanding of AGCT was likely skewed by inclusion of misdiagnosed cases, and future management strategies should reflect the potential for surgical cure and long survival even after relapse.Medicine, Faculty ofNon UBCObstetrics and Gynaecology, Department ofPathology and Laboratory Medicine, Department ofReviewedFacultyPostdoctoralGraduateOthe