Prognostic factors in adult granulosa tumor of the ovary

ArticleinCancer 79(10):1951 - 1955 · May 1997with 962 Reads
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Abstract
BACKGROUND The clinical course of adult granulosa cell tumor of the ovary is characterized by indolent growth tending toward late recurrence. A variety of clinical and pathologic parameters have previously been evaluated for prognostication with inconclusive results.METHODS The clinical records and tumor sections of 70 patients with adult granulosa cell tumors of the ovary were reviewed. Patients with recurrent tumors (REC) (n = 19) were compared with patients who remained without disease (NED) (n = 51).RESULTSSignificant differences in stage and tumor size were noted between the two groups; however, after logistic regression analysis, only stage remained statistically significant. Pathologic evaluation revealed that Call-Exner bodies occurred more frequently in tumors of the NED patients. Cellular atypia and high mitotic rates were more frequent in the REC group; however, after logistic regression analysis, only atypia remained statistically significant. When early (<10 years) and late recurring tumors (>10 years) were compared, statistically significant differences were again noted: early recurring tumors had fewer Call-Exner bodies, higher mitotic rates, and higher degrees of atypia; late recurring tumors were similar to tumors in the NED patients.CONCLUSIONS Tumor stage and, to a lesser extent, tumor size are the only clinical parameters of prognostic importance in adult granulosa cell tumors. Cellular atypia and, to lesser extents, mitotic rate and the absence of Call-Exner bodies are the only significant pathologic prognosticators. It is difficult to predict early recurrences and impossible to predict late recurrences using these clinical and pathologic parameters. Cancer 1997; 79:1951-5. © 1997 American Cancer Society.

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  • Article
    Full-text available
    Background Among classes of ovarian tumor, granulosa cell tumors are the least common. In approximately 10% of cases of granulosa cell tumor, androgen will be secreted which will present with hirsutism and hyperandrogenemia. We describe a woman with ovarian granulosa cell tumor who presented with hirsutism. Case presentation A 50-year-old woman of Amhara ethnicity, para III, abortion I (induced), presented with excessive hair on her face and lower abdomen of 4 years’ duration which affected her quality of life. Her menopause started 7 years ago. Her body mass index was 29.8 kg/m². She had hair on her upper lip, chin, and lower abdomen; she had a Ferriman–Gallwey score of 10. A pelvic examination revealed that her uterus was of normal size and there was no adnexal mass. Ultrasound finding: her right ovary measured 5 × 4 cm. Her serum testosterone was 254 ng/dl; she was counseled to undergo an exploratory laparotomy but she declined. She presented to our out-patient department 10 months later with a complaint of excessive vaginal bleeding of 18 days’ duration. A sonographic evaluation showed a 12 by 15 cm right adnexal cystic mass. With preoperative diagnosis of testosterone-producing sex cord–stromal tumor of the ovary, an exploratory laparotomy was performed. The laparotomy revealed a 20 by 30 cm right ovarian mass with pathology result of adult granulosa cell tumor. Conclusion In postmenopausal women with new hirsutism that is severe or rapidly progressive, the possibility of an androgen-secreting tumor must be suspected and a thorough evaluation is needed before initiating treatment for idiopathic hirsutism.
  • Chapter
    Die malignen, nichtepithelialen Tumoren des Ovars machen ca. 10% der Ovarialmalignome aus. Die beiden wichtigsten Vertreter sind die Keimzelltumoren und die Keimstrang-Stroma-Tumoren. Bei Ersteren kann zwischen Dysgerminom und den nichtdysgerminalen Keimzelltumoren unterschieden werden. Bei den nichtdysgerminalen Keimzelltumoren spielen das unreife Teratom und der endodermale Sinustumor die wichtigste Rolle. Ein Teil der Keimzelltumoren weist endokrine Aktivität auf. Das Dysgerminom ist der häufigste maligne Ovarialtumor im Kindes-, Jugend- und frühen Erwachsenenalter. Bei Keimzelltumoren ist unter der Voraussetzung eines sorgfältigen chirurgischen Stagings die einseitige Adnexektomie mit Erhaltung der Fertilität im FIGO-Stadium Ia möglich. Mit Ausnahme von reinen Dysgerminomen im FIGO-Stadium Ia sowie malignen Teratomen Grad 1 im FIGO-Stadium Ia ist eine postoperative Chemotherapie indiziert, wobei die Kombination Bleomycin/Etoposid/Cisplatin (BEP) derzeit als Chemotherapie der Wahl angesehen wird. Keimstrang-Stroma-Tumoren haben als wichtigsten Vertreter den Granulosazelltumor, den häufigsten nichtepithelialen Ovarialtumor. Man unterscheidet adulte Granulosazelltumoren (95%) von den viel selteneren, prognostisch günstigen juvenilen Formen (5%), welche in den ersten zwei Lebensdekaden auftreten. Bei Tumoren mit hohem malignem Potenzial (Granulosazelltumor, Sertoli-Leydig-Zell-Tumor G2/G3) wird ein sorgfältiges operatives Staging inklusive Lymphonodektomie empfohlen. Bei einem fertilitätserhaltenden Vorgehen sollte eine diagnostische Hysteroskopie mit fraktionierter Kürettage durchgeführt werden, um nicht ein mögliches Endometriumkarzinom zu übersehen.
  • Chapter
    Compared with epithelial ovarian cancers, nonepithelial ovarian tumors are uncommon, constituting <10% of all ovarian malignancies. They include germ cell malignancies, sex-cord–stromal tumors, carcinomas metastatic to the ovary, and a variety of extremely rare ovarian cancers, including sarcomas and lipoid cell tumors. Although there are many similarities in the presentation, evaluation, and management of patients, these tumors also have unique features that require special approaches to management. Germ cell malignancies are derived from primordial germ cells of the ovary and can be distinguished by histotype and expression of the biomarkers alpha-fetoprotein (AFP) and/or human chorionic gonadotropin (hCG). They include dysgerminomas (AFP−hCG−), embryonal carcinomas (AFP+hCG+), immature teratomas (AFP−hCG−), endodermal sinus (yolk sac) tumors (AFP+hCG−), and ovarian choriocarcinomas (AFP−hCG+). Germ cell tumors occur in premenarchal girls and young women, grow rapidly, and can present with a symptomatic pelvic mass. As preservation of fertility is often an important priority, unilateral salpingo-oophorectomy can often be performed followed by adjuvant platinum-based therapy. Among the germ cell tumors, dysgerminomas can be bilateral in 10–15% of cases and are associated with gonadal dysgenesis in 5% of cases. Metastatic germ cell cancers can be quite sensitive to chemotherapy and the long-term survival rate is high, even in advanced stages. At some institutions, young patients with stage IA germ cell tumors are followed carefully after resection and chemotherapy given only if there is recurrence with excellent outcomes. Sex-Cord-Stromal tumors include Granulosa-Stromal tumors, Juvenile Granulosa tumors, and Sertoli–Leydig cell tumors. Granulosa-Stromal tumors can occur at all ages and produce estrogen resulting in pseudoprecocious puberty in a small fraction of girls, amenorrhea in pre-menopausal women, and endometrial hyperplasia in postmenopausal adults. Granulosa-Stromal tumors are indolent and often confined to one ovary where surgery can cure stage I disease in more than 75% of cases. Adjuvant chemotherapy is generally not given after complete resection. Late recurrence has, however, been observed. Persistent or recurrent disease has responded to platinum based and hormonal therapy, including progestational agents, luteinizing hormone-releasing hormone agonists, and aromatase inhibitors. Inhibin B has been a useful biomarker. Sertoli–Leydig cell tumors generally present in the third or fourth decade, produce androgens, and induce virilization in more than 70% of patients. As many Sertoli–Leydig cell tumors are in early stage and rarely bilateral, unilateral salpingo-oophorectomy is often performed with 70–90% 5-year survival.
  • Chapter
    Stromal tumors of the ovary are uncommon tumors which have a distinct phenotype and natural history. They occur in both adolescent and older women, and often tend to have an indolent course. Recent investigations have led to the discovery of the driver mutations for adult granulosa cell tumors and some Sertoli--Leydig cell tumors. Additionally, advances have been made in the surgical care and therapy options for these patients.
  • Article
    Granulosa cell tumors (GCTs) comprise 2% to 5% of ovarian neoplasms, with unpredictable patterns of recurrence. The HER family, GATA4, and SMAD3 genes are reportedly involved in GCT proliferation and apoptosis and may serve as new predictors of recurrence. The aim of the study was to evaluate novel predictors of recurrence in GCT from a large single institution cohort. Patients diagnosed with GCTs (n=125) between 1975 and 2014 were identified. Clinicopathologic parameters were obtained and immunohistochemical evaluation was performed on calretinin, inhibin, HER2, CD56, SMAD3, and GATA4. Statistical analyses were conducted using Fisher exact test and Kaplan-Meier survival curves and Cox regression analysis. The median follow-up period was 120 months (range, 1–465 mo). Recurrence was noted in 12/125 (9.6%) patients. Kaplan-Meier analysis showed a shorter mean disease-free interval in whites versus blacks (P=0.001), stage III-IV versus stage I-II (P=0.0001), patients treated with surgery+chemotherapy versus surgery (P=0.0001), mitotic rate ≥4 (P=0.005), severe nuclear pleomorphism (P=0.013), high HER2 expression (P=0.001), high CD56 expression (P=0.001), and high SMAD3 expression (P=0.001). On Cox regression analysis, SMAD3 and type of treatment received were the only 2 independent prognostic factors for disease-free interval (P=0.03 and P=0.007, respectively). On subanalysis for early-stage (stage I) GCTs, the need for adjuvant chemotherapy and high expression of SMAD3 continued to be independent predictors of recurrence (HR=10.2, P=0.01 and HR=8.9, P=0.001, respectively).
  • Chapter
    Sex cord–stromal tumors (SCSTs) account for approximately 10% of all malignant ovarian neoplasms. The low incidence, the histological heterogeneity, and the variable biologic behavior, makes their optimal management difficult. SCSTs constitute a heterogeneous group of tumors and according to the World Health Organization, they are classified into these categories: pure stromal tumors, pure sex cord tumors (i.e. granulosa cell tumor) and mixed sex cordstromal tumors (Sertoli-Leydig cell tumors). Histologically, these tumors are considered malignant neoplasms; their natural history, however, is indolent with a very favorable long-term prognosis. Treatment principles have generally based on small series and borrowed from clinical management of epithelial tumors. Adequate knowledge of these neoplasms is imperative to the appropriate diagnosis, choice of surgical treatment and adjuvant therapy.
  • Article
    Objective Adult granulosa cell tumors (AGCTs) account for less than 5 % of all ovarian malignancies, whereas the majority (95 %) occurs after the age of 30 (adult-type) and present at an early stage. Aim of this study is to identify clinical and pathological risk factors for recurrence in early stage AGCTs. Methods Retrospective review of patients with AGCT of the ovary, treated surgically at our institution from 1996 to 2011. Clinical, pathological and follow-up data were collected. Systematic analysis was performed to determine variables for predicting recurrence. Results In total, 43 patients were identified. The mean age at diagnosis was 54.3 years and 65.1 % of them were postmenopausal. All patients underwent surgical staging and intraoperative rupture of the tumor occurred in four of them (9.3 %). The majority of the cases were staged as IA (72.1 %) while 10 (23.3 %) were staged as IC and only two patients as IIB. Mitotic index was 4 or more in 34.9 % of the patients and nuclear atypia was moderate to high in 60.5 %. During follow-up period (mean 9.2 years), recurrence occurred in three patients (7 %) with no deaths recorded so far. The cumulative recurrence free rate for the first 2 years was 97.6 % (SE = 2.4 %), for 5 years 94.9 % (SE = 3.5 %) and for 10 years 91.0 % (SE = 5.1 %).Tumor size, stage and mitotic index proved to be independent predictors for recurrence at the multivariate analysis. Conclusions Recurrence in early stage AGCT seems to be associated with stage, tumor size and mitotic index. All the above should be taken into consideration when tailored postoperative management is planned.
  • Chapter
    Die malignen nichtepithelialen Tumoren des Ovars machen etwa 10% der Ovarialmalignome aus. Die beiden wichtigsten Vertreter sind die Keimzelltumoren und die Keimstrang-Stroma-Tumoren. Bei Ersteren kann zwischen Dysgerminom und den “nichtdysgerminalen Keimzelltumoren„ unterschieden werden. Bei den “nichtdysgerminalen Keimzelltumoren„ spielen das unreife Teratom und der endodermale Sinustumor die wichtigste Rolle. Ein Teil der Keimzelltumoren weist eine endokrine Aktivität auf. Das Dysgerminom stellt den häufigsten malignen Ovarialtumor im Kindes-, Jugend- und frühen Erwachsenenalter dar. Bei Keimzelltumoren ist unter der Voraussetzung des sorgfältigen chirurgischen Stagings die einseitige Adnexektomie mit Erhaltung der Fertilität im Stadium FIGO la möglich. Mit Ausnahme von reinen Dysgerminomen im Stadium FIGO la sowie malignen Teratomen Grad 1 im Stadium FIGO la ist eine postoperative Chemotherapie indiziert, wobei die Kombination Bleomycin/Etoposid/Cisplatin (BEP) derzeit als Chemotherapie der Wahl angesehen wird. Keimstrang-Stroma-Tumoren haben als wichtigsten Vertreter den Granulosazelltumor, der den häufigsten nichtepithelialen Ovarialtumor darstellt. Man unter scheidet adulte Granulosazelltumoren (95%) von den viel selteneren, prognostisch günstigen juvenilen Formen (5%), welche in den ersten 2 Lebensdekaden auftreten. Bei Tumoren mit hohem malignem Potenzial (Granulosazelltumor, Sertoli-Leydig-Zell-Tumor G2/G3) wird ein sorgfältiges operatives Staging inklusive Lymphadenektomie empfohlen. Bei einem fertilitätserhaltenden Vorgehen sollte eine diagnostische Hysteroskopie mit fraktionierter Kürettage durchgeführt werden, um nicht ein mögliches Endometriumkarzinom zu übersehen.
  • Article
    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.
  • Article
    Background: This study describes the cytologic features of 26 angiosarcomas diagnosed on fine-needle aspiration. Methods: Twenty-six angiosarcomas from 20 patients were confirmed by cytomorphology and immunocytochemical (immunohistochemistry) positivity for at least 2 of 3 vascular markers. Specimens were examined for spindled/epithelioid/plasmacytoid single cells, 3-dimensional clusters, multiple prominent/bar-shaped nucleoli (5 times longer than their width), chromatin strands, abnormal mitoses, necrosis, and vasoformative features. Results: Eight males and 12 females with a mean age of 52 years (range, 2-94 years) underwent aspiration of tumors in the following: soft tissue or skin/subcutis (n = 10), bone (n = 4), nodes (n = 5), lung (n = 2), liver (n = 2), heart (n = 1), parotid gland (n = 1), and pleural fluid (n = 1). An angiosarcoma diagnosis was rendered for 24 of the 26 cases (92%); 1 was diagnosed as "atypical cells, cannot exclude angiosarcoma," and another was diagnosed as a malignant vascular neoplasm. Abnormal mitoses were most frequent (85%), and they were followed by single malignant cells (81%: epithelioid [69%], spindled [62%], and plasmacytoid [19%]), 3-dimensional clusters (54%), multiple prominent (62%) or bar-shaped nucleoli (54%), and chromatin strands (31%). Vasoformative features, including hemophagocytosis (54%), cytoplasmic lumina/vacuoles (69%) containing red blood cells (54%)/neutrophils (31%), and endothelial wrapping (69%), were seen in 88%; 23% had all vasoformative features, 88% had at least 1, and 12% had none. Conclusions: Angiosarcomas show a range of cytomorphologic features that make them potentially recognizable on cytology. Although vasoformative features are highly suggestive, they are not specific for angiosarcoma and may be seen in some nonvascular neoplasms. Immunohistochemistry and a high index of suspicion are required for an accurate diagnosis. Cancer Cytopathol 2016. © 2016 American Cancer Society.
  • Chapter
    Approximativement 8 % des tumeurs ovariennes dérivent du stroma et/ou des cordons sexuels. Ces tumeurs sont généralement fonctionnelles puisque la plupart peuvent synthétiser des hormones (oestrogènes, androgènes, corticoïdes). Leur pronostic est difficile à établir, certaines étant de comportement presque toujours bénin (tumeurs à cellules de Sertoli, tumeurs à cellules de Leydig), d’autres de comportement malin mais avec des récidives locorégionales plus ou moins tardives. Les critères histologiques d’agressivité sont mal connus de telle sorte qu’il est difficile de proposer une classification anatomopathologique dichotomique bénin/malin et s’il n’y a pas de critères cliniques de «malignité», ces tumeurs sont classées comme étant de pronostic incertain. Dans ce groupe de tumeurs, celles qui auraient plutôt un comportement «malin» sont les suivantes: les tumeurs de la granulosa, les androblastomes (ou tumeurs de Sertoli-Leydig), les tumeurs des cordons sexuels avec tubules annelés, les tumeurs à cellules stéroïdiennes sans autre précision et les fibrosarcomes (1).
  • Article
    BACKGROUND: Late recurrence can be extensive with initial, clinically undetectable, microscopic granulosa cell tumor of the ovary. CASE: We describe an 83-year-old patient who presented with extensive recurrent granulosa cell tumor of the ovary 6 years after undergoing abdominal hysterectomy and bilateral salpingo-oophorectomy for atypical endometrial hyperplasia with an incidental microscopic finding of ovarian granulosa cell tumor. CONCLUSION: Patients must be monitored closely after a diagnosis of ovarian granulosa cell tumor, even if the tumor is occult.
  • Chapter
    Although majority of sex cord-stromal tumor is benign, some granulosa cell tumor and Sertoli-Leydig tumors show malignant behavior. Stage is the most important prognostic factor. The recurrent sex cord-stromal tumors are usually peritoneal seeding or retroperitoneal nodule, occasionally containing intratumoral hemorrhage.
  • Article
    Objective: In this study, we aimed to demonstrate characteristics, recurrence rates, survival numbers, and factors associated with survival of patients with adult granulosa cell tumor (AGCT) from a single institution. Our secondary goal was to evaluate the necessity of staging surgery and the importance of a comprehensive lymphadenectomy in these patients. Methods: The data of 158 patients in our institution who were diagnosed with AGCT between 1988 and 2013 were evaluated. The data were obtained from the files of the patients, electronic database of the gynecologic oncology clinic, operation notes, and pathology records. Results: The median (range) age of the patients was 50.3 (22-82) years. The main symptom was postmenopausal bleeding (25.9%). Seventy-six percent of the patients underwent staging surgery including lymphadenectomy. Among these patients, 3 (2.5%) had lymph node metastasis. The median (range) follow-up time was 97 (1-296) months. In the follow-up period, 18 patients (12.5%) had recurrence. Menopausal status (P = 0.016), advanced age (P = 0.024), cyst rupture (P = 0.001), poorly differentiated tumor (P = 0.002), and advanced stage (P < 0.001) were associated with recurrence. Stage was the only independent prognostic factor for the development of recurrence. None of the patients had lymph node failure. Conclusions: In the present study with a long follow-up period and in which most of the patients had staging surgery including lymphadenectomy (76.6%), lymph node recurrence was not observed and the total recurrence rate (12.5%) was lower than that reported in the literature. The study showed the importance of surgical staging in patients with AGCT.
  • Chapter
    Sex cord stromal neoplasms are composed of various cell types derived from gonadal stroma and sex cords. This chapter describes the various types of sex cord stromal lesions of the ovary: stromal hyperplasia, stromal hyperthecosis, Leydig cell hyperplasia, massive edema and fibromatosis, luteinized thecoma with sclerosing peritonitis, large solitary luteinized follicle cyst of pregnancy, hyperreactio luteinalis, ectopic decidua, granulosa cell proliferations of pregnancy, pregnancy luteoma, fibroma, fibrosarcoma, thecoma, sclerosing stromal tumors, microcystic stromal tumors, granulosa cell tumors, Sertoli–Leydig cell tumors, Sertoli cell tumor, sex cord tumor with annular tubules, stromal luteoma, steroid tumor NOS, and gynandroblastoma. The macroscopic and microscopic features, prevalence, clinical presentation, differential diagnosis, and treatment and outcomes of these tumors are discussed.
  • Article
    Purpose Granulosa cell tumors account for 2-3% of ovarian malignancies. Treatment recommendations are based loosely on those for ovarian carcinoma, although the two entitites differ considerably in tumor biology and prognosis. Methods: We reviewed 25 women (median age, 51 years; range, 26-75) who received chemotherapy after surgery for ovarian granulosa cell tumors. Eighteen patients received adjuvant chemotherapy as a component of primary treatment (9 FIGO stage I, 9 stage II-IV) and seven after recurrence. Nine chemotherapy regimens were used and 15 patients received platinum-based regimens. Results: The median follow-up was 98 months (range, 6-189). Although the number of patients was small, there was no significant difference in overall survival between patients who received platinum-based regimens and those who received chemotherapy without platinum. The average overall survival was 96.6 months (95% CI, 78-115). The average overall survival of women with stage II-IV disease or recurrence was 81.4 months (95% CI, 54-109). Conclusion: The rarity of ovarian granulsa cell tumors suggests a need for a central registry and prospective studies to compare chemotherapy regimens.
  • Article
    Ovarian granulosa cell tumors represent uncommon neoplasms with estrogen-secreting capacity. Due to their association with persistently increased levels of estrogen, modifications of the endometrial tissue ranging from hyperplasia to malignant degeneration may be encountered. We present the case of a 65-year-old patient who presented for post-menopausal vaginal bleeding. The endometrial biopsy raised the suspicion of an atypical endometrial hyperplasia and the patient was submitted to surgery. Histopathological studies of the specimen of total hysterectomy with bilateral adnexectomy revealed the presence of a well-differentiated endometrial carcinoma associated with a granulosa cell tumor of the ovary. In conclusion whenever a modified aspect of the endometrium is found preoperatively, attention should be given on other possible underlying modifications and a radical approach should be taken in consideration.
  • Article
    Full-text available
    The aim of this study is to evaluate the long-term outcome of ovarian recurrent granulosa cell tumors (GCTs) in a large series of patients treated in Taiwanese Gynecologic Oncology Group (TGOG) centers and to define the prognostic parameters for survival. A retrospective multi-institutional review of patients with recurrent ovarian GCTs treated in TGOG centers was conducted. The clinical and pathological characteristics, treatment, and outcomes of patients with ovarian recurrent GCTs were analyzed using Kaplan-Meier and Cox proportional hazards analyses to determine the predictors for survival. A total of 44 patients from 16 medical centers were identified between January 1994 and December 2010. The median disease-free survival (DFS), postrecurrence survival, and overall survival (OS) were 61.5 months (range, 3.7-219.3 months), 55.8 months (range, 4.6-193.7 months), and 115.3 months (range, 17.2-390.6 months), respectively. In multivariate analysis, DFS (> 61.5 months versus ≤ 61.5 months, hazard ratio (HR) 0.15, 95% confidence interval (CI) 0.03-0.78, p = 0.024) at the initial operation after diagnosis of relapse was the only predictor that correlated with OS. DFS after the initial operation was the only important predictor for overall survival in patients with recurrent GCTs, regardless of treatment, suggesting that the natural behavior of the tumor is a critical factor for patients with recurrent GCTs. Copyright © 2015. Published by Elsevier B.V.
  • Article
    The nuclear DNA content of 50 ovarian tumors initially diagnosed as granulosa cell tumors was measured by flow cytometry using paraffin-embedded archival material. The follow-up period of the patients ranged from 4 months to 19 years. Thirty-eight tumors were diploid or near-diploid, while 5 were aneuploid. DNA profiles of 7 tumors could not be evaluated. All 50 tumors were immunohistochemically tested for expression of intermediate filament proteins vimentin and cytokeratin and epithelial membrane antigen. The cells of all but 3 tumors expressed vimentin. These 3 vimentin-negative tumors were positive for cytokeratin and epithelial membrane antigen. They were highly aneuploid and though originally diagnosed as granulosa cell tumors, most likely represent undifferentiated carcinomas. Hence, only 2 typical granulosa cell tumors were aneuploid. In addition, frozen tissue samples from 9 of 10 granulosa cell tumors showed a DNA diploid content. Our results indicate that granulosa cell tumors tend to be diploid or have only minor ploidy abnormalities which is in line with their relatively benign character. An undifferentiated carcinoma should be considered in the differential diagnosis of tumors with a high DNA index.
  • Article
    Clinical and pathologic data from a series of 41 patients with granulosa cell tumor are reviewed. An attempt is made to correlate these data with basic research data which relate to the pathogenesis, pathophysiology, and experimental production of these tumors. The pathologic factors related to survival are the degree of anaplasia of the tumor and the stage of the disease. The treatment of choice is complete surgical extirpation of the internal genitals, followed by irradiation in cases beyond Stage I. Conservative operation is justified only in patients with Stage I disease, who desire further childbearing. On the basis of animal experiments, it appears that postoperative estrogen administration may be useful adjunctive therapy, and this is recommended.
  • Article
    In lifetesting, medical follow-up, and other fields the observation of the time of occurrence of the event of interest (called a death) may be prevented for some of the items of the sample by the previous occurrence of some other event (called a loss). Losses may be either accidental or controlled, the latter resulting from a decision to terminate certain observations. In either case it is usually assumed in this paper that the lifetime (age at death) is independent of the potential loss time; in practice this assumption deserves careful scrutiny. Despite the resulting incompleteness of the data, it is desired to estimate the proportion P(t) of items in the population whose lifetimes would exceed t (in the absence of such losses), without making any assumption about the form of the function P(t). The observation for each item of a suitable initial event, marking the beginning of its lifetime, is presupposed. For random samples of size N the product-limit (PL) estimate can be defined as follows: List and label the N observed lifetimes (whether to death or loss) in order of increasing magnitude, so that one has \(0 \leqslant t_1^\prime \leqslant t_2^\prime \leqslant \cdots \leqslant t_N^\prime .\) Then \(\hat P\left( t \right) = \Pi r\left[ {\left( {N - r} \right)/\left( {N - r + 1} \right)} \right]\), where r assumes those values for which \(t_r^\prime \leqslant t\) and for which \(t_r^\prime\) measures the time to death. This estimate is the distribution, unrestricted as to form, which maximizes the likelihood of the observations. Other estimates that are discussed are the actuarial estimates (which are also products, but with the number of factors usually reduced by grouping); and reduced-sample (RS) estimates, which require that losses not be accidental, so that the limits of observation (potential loss times) are known even for those items whose deaths are observed. When no losses occur at ages less than t the estimate of P(t) in all cases reduces to the usual binomial estimate, namely, the observed proportion of survivors.
  • Article
    A retrospective study of 118 cases of granulosa cell tumor of the ovary with a follow-up from 5 to more than 30 years was made. Abnormal bleeding before, during, or after the menopause was the most common presenting symptom. Of the 64 examined endometria, 84% showed signs of estrogen stimulation, while atypical adenomatous hyperplasia was seen in 1.6%, and adenocarcinoma in 3.1%. Histologically, the diffuse growth pattern was found in one-half of the tumors, but it had no significant influence on prognosis. There was a positive correlation between cellular atypia and a high number of mitoses and increased mortality. The clinical stage had important prognostic significance. No patient younger than 40 years died from her tumor. The overall relative survival at 10 years was 80 versus 86% in Stage I. Surgery is the primary treatment of choice. Irradiation should be added in Stage II or higher. In Stage I patients, radiotherapy did not improve the prognosis. Recurrences developed as late as 22 years following primary treatment, and occurred in 21% of the patients. The prognosis in such instances is poor, and aggressive treatment is recommended. Patients with granulosa cell tumors should be followed for the rest of their lives.
  • Article
    Sixty-one patients with granulosa cell tumors of the ovary were treated in the A.M. Evans Clinic of the British Columbia Cancer Control Agency between 1944 and 1974. Their treatment and follow-up are reviewed, and while the 5-year survival rate was 78%, the 15-year rate fell to 50%. The material suggests that the trend to total hysterectomy and bilateral salpingo-oophorectomy has improved the prognosis, but other explanations are, of course, possible as this is a historical comparison.
  • Article
    Ninety-two cases of granulosa cell tumor of the ovary have been studied. The clinical and pathologic data from this group were similar to that obtained in previous series. Because of the long natural history of many granulosa cell tumors, crude death rates over a relatively short period give little indication of the true malignant potential of these neoplasms and hence corrected survival rates were calculated; these show that, if no patient died from any other disease, approximately half of the women with this neoplasm would die, as a result of the tumor, within 20 years. Factors indicating a relatively poor survival rate were: age over 40 at the time of diagnosis, a presentation with abdominal symptoms, a palpable mass, a solid large tumor, bilateral tumors, extraovarian spread, and numerous mitotic figures in the tumor. It is suggested that all granulosa cell tumors should be considered as malignant and that the factors pointing to a poor prognosis are those indicating that a particular tumor has been diagnosed at a late stage in its natural history, either because it has been present for a long time or because it is highly malignant. There are no definite criteria for defining the prognosis in a case in which the tumor has been removed at any early stage in its natural life history.
  • Article
    The nuclear DNA content and S-phase fraction of 23 ovarian granulosa cell tumors were measured from paraffin-embedded tissue with flow cytometry. Crude survival of the patients with a euploid tumor (17 diploid, one tetraploid) was more favorable than that of the patients with an aneuploid tumor (n = 5, P = 0.02). The percentage of S-phase cells was a good predictor of survival. If more than 6% S-phase cells were present in the DNA histogram, both crude survival (P = 0.0001) and survival corrected for intercurrent deaths (P = 0.0001) were clearly inferior as compared with tumors with less than 6% S-phase cells. The results indicate that DNA flow cytometric study may provide a rapid and valuable method to predict the biological behavior of granulosa cell tumors of the ovary.
  • Article
    Paraffin blocks from 17 granulosa tumors, nonmetastatic (n = 10) and metastatic (n = 7), were analyzed by flow cytometry. Three neoplasms, one with and two without metastases, were found to have cells with an abnormal DNA (DNA aneuploid) content. The occurrence or absence of DNA aneuploid cells did not predict behavior. In addition, there was no correlation of tumor DNA content with tumor size or patient age at the time of surgery. There was no significant difference in cell proliferation (%S + %G2/M) between metastatic and nonmetastatic DNA diploid tumors, however, there was an increase in cell proliferation in tumors with a DNA aneuploid stemline. Granulosa tumors are low-grade neoplasms. At least 90% are seen in Stage I, and metastasis occurs subsequently in 5% to 15% of these cases. Features of Stage I neoplasms associated with subsequent metastasis in some reports, but not all, are involvement of the capsule (Stage IC), large size, and high mitotic rate, 1-5 Providing definitive statements about the behavior of granulosa tumors is hampered by their rarity, the subjectivity of the diagnosis, and their sluggish behavior. We attempted to determine if flow cytometric analysis of DNA could identify granulosa tumors with metastatic potential. We compared DNA histograms from ten Stage IA granulosa tumors that did not metastasize during 22 to 47 years of follow-up with seven granulosa tumors that showed malignant behavior.
  • Although the diagnosis of granulosa-cell tumors of the ovary is usually consistent and reproducible, in some cases the differentiation from poorly differentiated adenocarcinomas can be difficult. To investigate our subjective impression of the similarity of nuclei in both types of tumors, seven granulosa-cell tumors and eight poorly differentiated adenocarcinomas were studied with morphometry, with a variety of nuclear parameters measured in 100 nuclei per case. The findings showed that, in general, granulosa-cell tumors have a slightly higher mean nuclear contour index (NCI), which is a measure of the nuclear indentation or grooving, and a somewhat lower mean nuclear area than do adenocarcinomas. There is considerable overlap, however, with the nuclear patterns of the two types of tumors forming a morphologic continuum. Multivariate analysis gave a better discrimination but did not entirely eliminate the overlap. The maximum NCI was the best single discriminator. While only one of the granulosa-cell tumors had a maximum NCI less than 5.11, none of the adenocarcinomas exceeded this value. The only granulosa-cell tumor with a maximum NCI below the threshold was in a case with a much less favorable clinical course. The results of this study indicate that objective morphometric nuclear criteria are useful in the diagnosis of granulosa-cell tumors and possibly have some prognostic value.
  • Article
    Clinical and pathologic data from a series of 41 patients with granulosa cell tumor are reviewed. An attempt is made to correlate these data with basic research data which relate to the pathogenesis, pathophysiology, and experimental production of these tumors. The pathologic factors related to survival are the degree of anaplasia of the tumor and the stage of the disease. The treatment of choice is complete surgical extirpation of the internal genitals, followed by irradiation in cases beyond Stage I. Conservative operation is justified only in patients with Stage I disease, who desire further childbearing. On the basis of animal experiments, it appears that postoperative estrogen administration may be useful adjunctive therapy, and this is recommended.
  • Article
    The clinical course and histologic features of 118 granulosa cell tumors and 82 theca cell tumors were reviewed. Although the 2 cell types are related, important differences exist in their behavior. Theca cell tumors (TCTs) are virtually benign, while granulosa cell tumors (GCTs) exhibit less malignant activity than most ovarian carcinomas. Characteristically detected at an early stage, GCTs may recur locally years after the initial diagnosis. Survival figures depend on tumor stage. Recurrence of GCTs is associated with a high mortality rate. The cornerstone of treatment is total abdominal hysterectomy and bilateral salpingo-oophorectomy, regardless of age. Adjuvant radiation or chemotherapy may be helpful when lesions are higher than stage lai. Therapy for recurrence usually requires operative excision combined with radiation, chemotherapy, or both.
  • Article
    Over the period 1923--72 a total of 305 patients with granulosa-cell, theca-cell tumor and mixed tumor were seen at Radiumhemmet. The commonest symptom was abnormal uterine bleeding. Twenty-three per cent of married women were nulliparous. The menarche seems to have occurred earlier in this group than in the general population. Eight of the granulosa-cell tumor group gave birth to 12 children after treatment for the tumor. Nineteen women with granulosa-cell tumor and 4 with thecoma had received radiotherapy earlier in life for benign lesions. The risk of endometrial cancer was approximately 10 times greater for the women with granulosa- or theca-cell tumor than for the general population. Two hundred and fifty-two patients were given both surgical treatment and radiotherapy. Fifty-three received only surgery (37 granulosa-cell and 16 theca-cell tumors). None of the thecoma patients but 21 per cent of those with granulosa-cell tumor died from their disease. The 5-year survival for the latter group, all stages, was 85 per cent.
  • Article
    A histological reevaluation was performed on 198 women with granulosa- and granulosa-theca-cell tumors treated at Radiumhemmet 1923–1972. Ninety-one percent of the patients were of clinical stage I (FIGO). The mean age at diagnosis was 52.6 years. All patients underwent surgery and all but 11% received complementary radiotherapy. Concomitant endometrial carcinoma was found in 6%. At the follow-up (1977–1978) 42 women had died from their granulosa-cell tumor. Advanced clinical stage, the presence of tumor rupture and pronounced nuclear atypia were associated with a poor prognosis. A high number of mitotic figures were of prognostic value only in stages II–IV. In stage I tumor size was related to outcome. The histological pattern of the granulosa-cell component was of no prognostic value.
  • Article
    Granulosa and theca cell tumors of the ovary account for 2-3% of ovarian malignancies. This study includes 54 patients with the diagnosis of granulosa cell tumors of the ovary treated between 1953 and 1987. Median age at diagnosis was 57 (27-83) years. The lesions were staged according to FIGO. The number of patients in various stages was IA, 41; IB, 3; IC, 3; IIB, 6; and III, 1. Median tumor size, 11 cm; range, 0.5-30 cm. Post-menopausal bleeding was diagnosed in 48%, MHC in 37%, proliferative endometrium in 32%, and atypia of endometrial cells in 13% of the cases. Fifty patients were treated with primary surgery, 48 patients were treated with adjuvant external radiotherapy, and 3 patients received complementary chemotherapy. The survival rates in stage I were 94 and 88% after 5 and 10 years, respectively, and in stages II-III were 44% after 5 and 10 years. Overall survival was 90% at 5 years. The frequency of observed mitosis influenced the survival rate: with less or equal 4/10 HPF the survival was 100% in 5 years, with 5-9/10 HPF the survival was 80% in 5 years with a median survival time of 9 years, and with more or equal 10/10 HPF the longest survival was 4 years. At the end of the study, 45 patients (83%) are alive with no evidence of disease, 1 patient is alive with disease, 4 patients are dead of recurrent disease, and 4 patients are dead from intercurrent disease. Endometrial carcinoma was detected in 5 patients. The total survival is better than that with epithelial ovarian cancer as the hormonal symptoms make an early diagnosis possible. Stage for stage the survival is equal. There is an increased incidence of endometrial carcinoma and concomitant other malignancies. The mitotic rate is a well-defined parameter and influences the survival significantly and should be considered the most important prognostic factor at treatment planning.