Networking for ovarian rare tumors: a significant breakthrough improving disease management.

BACKGROUND: Rare ovarian tumors represent >20% of all ovarian cancers. Given the rarity of these tumors, natural history, prognostic factors are not clearly identified. The extreme variability of patients (age, histological subtypes, stage) induces multiple and complex therapeutic strategies. METHODS: Since 2011, a national network with a dedicated system for referral, up to 22 regional and three national reference centers (RC) has been supported by the French National Cancer Institute (INCa). The network aims to prospectively monitor the management of rare ovarian tumors and provide an equal access to medical expertise and innovative treatments to all French patients through a dedicated website, www.ovaire-rare.org. RESULTS: Over a 5-year activity, 4612 patients have been included. Patients' inclusions increased from 553 in 2011 to 1202 in 2015. Expert pathology review and patients' files discussion in dedicated multidisciplinary tumor boards increased from 166 cases in 2011 (25%) to 538 (45%) in 2015. Pathology review consistently modified the medical strategy in 5-9% every year. The rate of patients' files discussed in RC similarly increased from 294 (53%) to 789 (66%). An increasing number (357 in 5 years) of gynecologic (non-ovarian) rare tumors were also registered by physicians seeking for pathological or medical advice from expert tumor boards. CONCLUSION: Such a nation-wide organization for rare gynecological tumors has invaluable benefits, not only for patients, but also for epidemiological, clinical and biological research.

[Melanoma in HIV patients: 14 cases]. / Mélanomes chez des patients séropositifs pour le VIH : 14 cas.

BACKGROUND: a clinical study of 14 patients presenting both malignant melanoma and HIV infection, and analysis of the literature to determine the frequency and specific features of this association. PATIENTS AND METHODS: ten men and four women of median age 43 years were included. In 50% of cases, the primary melanoma consisted of spreading superficial melanoma with a mean Breslow thickness of 2.83 mm. In two cases, regional lymph node metastasis was discovered but with no primary melanoma being identified. HIV infection was already documented on diagnosis of melanoma in 11 cases, and it was discovered in three cases at the time of surgery for melanoma (treatment of the primary melanoma in two cases, and in one case, regional lymph node dissection two years after the initial diagnosis). Eight patients died within a mean period of 39 months, with melanoma being the cause of death in six cases. Following relapse of melanoma, the course of the disease was severe, with mean stage IV survival of 3.6 months. No response to chemotherapy was observed where such treatment was feasible. DISCUSSION: the presence of HIV appears to be an aggravating factor for the outcome of metastatic melanoma. CONCLUSION: our study suggests the importance of clinical examination of pigmented lesions in HIV patients in order to ensure early identification of melanoma.

Luteinizing hormone pulsatility in patients with major ovarian hyperandrogenism.

Hyperandrogenism and ovulatory dysfunction are common in women with either polycystic ovary (PCOS) or ovarian virilizing tumor. However, contrasting with the numerous studies that have extensively described gonadotropin secretory abnormalities, principally increased LH pulse amplitude and frequency, few studies have concerned gonadotropin secretion in patients with ovarian virilizing tumors; low gonadotropin levels have occasionally been reported, but never extensively studied. The goal of the present study was to further evaluate the pulsatility of LH secretion in women with ovarian virilizing tumor compared with that of PCOS patients. Eighteen women with major hyperandrogenism (plasma testosterone level >1.2 ng/ml) were studied (5 women with ovarian virilizing tumor, 13 women with PCOS, and 10 control women). Mean plasma LH level, LH pulse number and amplitude were dramatically low in patients with ovarian tumors when compared to both PCOS (p<0.001) and controls (p<0.001). In case of major hyperandrogenism, LH pulse pattern differs markedly between women with ovarian virilizing tumor or PCOS, suggesting different mechanisms of hypothalamic or pituitary feedback.

Expression and localization of alpha-fetoprotein mRNA and protein in human early villous trophoblasts.

Alpha-fetoprotein (AFP) is a major plasma protein produced during human fetal life. It is a good marker for several possible disorders affecting gestation. We previously reported that afp gene expression, which takes place mainly in yolk sac and fetal liver, also occurs in normal human placenta, specifically in early pregnancy. The aim of the present study was to determine the precise location of AFP synthesis sites within the placental villi. In situ hybridization and immunohistochemical experiments were performed on sections obtained from placentas of first-trimester and full-term pregnancies. We found that the pattern of afp gene expression was restricted to specific villous trophoblastic areas in early placentas. Both afp transcripts and AFP protein were mainly located in discontinuous regions, at junctions between two villi and at budding sites. In contrast, no AFP expression was detected in the cytotrophoblastic extravillous proliferative zone or in other placental cell types. According to the earlier studies, no AFP synthesis was detected in placental villous tissue from full-term pregnancies, using in situ hybridization and immunohistochemistry.

[Levonorgestrel-releasing intrauterine system in the treatment of dysfunctional uterine bleeding: A French multicenter study]. / Efficacité et tolérance du système intra-utérin au lévonorgestrel dans la prise en charge des ménorragies fonctionnelles: étude française multicentrique.

OBJECTIVE: To evaluate the levonorgestrel-releasing intra-uterine system as an alternative to surgical treatment in patients presenting with menorrhagia. PATIENTS AND METHODS: In the set of a prospective multicenter study, 49 patients with menorrhagia resistant to medical treatment and/or referred for hysterectomy or endometrial ablation were included. Medical visits were organized 3, 6, 12, 24 and 36 months after insertion of the levonorgestrel-releasing intra-uterine system. Visual score of menstrual bleeding and satisfaction index were noted on each visit. Transvaginal ultrasound, pap smear, endometrial biopsy, and clinical data were retrieved one month before and 12 months after inclusion for tolerance evaluation. RESULTS: Renouncement rate was 90.0% (95% CI = 80.7-96.6%). After a twelve months follow-up, 86.1% of patients were satisfied or very satisfied with their clinical state. We found a significant increase of hemoglobin rates from baseline (14,0 versus 12,9 g/dl; P < 10(-4)). Similar increases were also found in serum iron and ferritin. DISCUSSION AND CONCLUSION: This study confirms the efficacy of the levonorgestrel-releasing intra-uterine system in the control and reduction of menstrual blood loss in patients with dysfunctional uterine bleeding. The high rate of surgery cancellation is a proof of the potential role of the levonorgestrel-releasing intra-uterine system as an alternative treatment in these patients.

Delayed puberty and primary amenorrhea associated with a novel mutation of the human follicle-stimulating hormone receptor: clinical, histological, and molecular studies.

Inactivating mutations of the FSH receptor have been described in rare cases of premature ovarian failure. Only one mutation was associated with a complete phenotype, including delayed puberty, primary amenorrhea, and small ovaries. We describe here a new patient presenting a similar complete phenotype of premature ovarian failure, with high plasma FSH levels associated with very low estrogen and inhibin B levels. No biological response to high doses of recombinant FSH was detected. A novel homozygous Pro(519)Thr mutation was found in this patient. This mutation is located in the second extracellular loop of the FSH receptor, within a motif highly conserved in gonadotropin and TSH receptors. The mutation totally impairs adenylate cyclase stimulation in vitro. FSH binding experiments and confocal microscopy showed that this mutation alters the cell surface targeting of the mutated receptor, which remains trapped intracellularly. Histological studies of the ovaries of the patient showed an increase in the density of small follicles compared with age-matched normal women. A complete block in follicular maturation after the primary stage was also observed. Immunocytochemical studies allowed detection of the expression of c-Kit and proliferation cellular nuclear antigen, whereas no apoptosis was shown by the 3'-end-labeling method. This observation supports the concept that in humans FSH seems mandatory for the initiation of follicular growth only after the primary stage. In our patient complete FSH resistance yields infertility, which is remarkably associated with the persistence of a high number of small follicles.

Potentiation response of cultured human uterine leiomyoma cells to various growth factors by endothelin-1: role of protein kinase C.

OBJECTIVE: Factors responsible for the abnormal proliferation of myometrial cells that accompanies leiomyoma formation are unknown, although steroid hormones and peptide growth factors have been implicated. We hypothesized that endothelin-1 (ET-1) is a physiological regulator of tumor growth. DESIGN: In this study, we investigated the role of ET-1 on growth of human leiomyoma cells and its synergistic effect with growth factors, as well as the signaling pathway involved in this interaction. METHODS: Leiomyoma cell proliferation was assayed by [H]thymidine incorporation and cell number. Protein kinase C (PKC) isoforms were analyzed by Western blot using specific antibodies. RESULTS: ET-1 on its own was unable to stimulate DNA synthesis but potentiated the leiomyoma cell growth effects of basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), IGF-I and IGF-II. The failure of a protein tyrosine kinase (PTK) inhibitor, tyrphostin 51, to affect the potentiating effect of ET-1, supports the hypothesis of non-involvement of PTK in this process. The inhibition of PKC by calphostin C or its down-regulation by phorbol 12,13-dibutyrate (PDB) eliminated the potentiating effect of ET-1, but did not block cell proliferation induced by the growth factors alone. Five PKC isoforms (alpha, beta1, epsilon, delta and zeta) were detected in leiomyoma cells, but only phorbol ester-sensitive PKC isoforms (PKCalpha, epsilon and delta) contribute to the potentiating effect of leiomyoma cell growth by ET-1. CONCLUSIONS: We have demonstrated that ET-1 potentiates leiomyoma cell proliferation to growth factors through a PKC-dependent pathway. These findings suggest a possible involvement of ET-1 in the pathogenesis of leiomyomas.

EndothelinA receptors in human uterine leiomyomas.

OBJECTIVE: To determine if there are endothelin receptors on human uterine leiomyomas. METHODS: Samples of leiomyomas from eight patients were analyzed for [iodine (I)-125]endothelin-1 binding. Several subtype-selective ligands were used to determine the endothelin receptor population. RESULTS: Binding of [125I]endothelin-1 to uterine leiomyoma membranes was specific and saturable, with a mean +/- dissociation constant 85.5 +/- 8.4 pM. Competition binding studies showed that the order of potency was endothelin-1 > endothelin-3, which was consistent with the presence of the endothelinA receptor subtype. Binding of [125I]endothelin-1 was displaced by an endothelinA-selective antagonist, but not by sarafotoxin 6c, an endothelinB-selective agonist. An endothelins-selective ligand was not specifically bound to leiomyoma. CONCLUSION: These results indicate that only endothelinA receptors are present in human uterine leiomyomas. We speculate that endothelin-1 may act through these endothelinA receptors to influence the development or regulation of hypertrophy and proliferation of the human myometrium during pregnancy and in uterine disorders like leiomyomas.

Tubal causes of ectopic pregnancy.

We did complete histologic study on 148 gravid tubes and found that nearly 90% showed chronic lesions. CS was the most frequent lesion encountered (95.5%), followed by SIN (32.6%). Most frequently the lesions were extensive and both the ampulla and isthmus were involved. We therefore question the conservative approach in the treatment of certain TPs.

French gynecologic cytology.

Diagnostic schema may be developed on a national or global level, but may be varied depending on the local conditions. In this article, the differences between French and North American gynecologic cytology are discussed. This article emphasizes the training, diagnostic, technologic, and regulatory differences that exist in France. By studying such differences, local practices can learn potential benefits and why their currently used systems may be optimal.

Histological patterns of bone and articular tissues after orthopaedic reconstructive surgery (artificial joint implants).

Revision surgery after failures of joint replacements leads to histological studies on joint and bone tissues close to the implanted material. Aspectic loosening is the main complication. The surgical pathologist has to identify wear debris (metal, polyethylene, polymethylmethacrylate, chiefly) which promotes a histiocytic granuloma. Some surgical procedures such as cup or resurfacing arthroplasties create a new articular surface and a bone remodeling or necrosis. Cemented joint prostheses show various membrane structures between bone and the cement mantle while there is an association of bone resorption and formation. Non-cemented, porous-coated joint prostheses induce little bone ingrowth, even in satisfactory clinical results. Mechanical factors are predominant in massive limb prostheses. For silicone elastomer implants or artificial ligaments, wear of material promotes many tissular reactions. Often used bone grafts show little creeping substitution process in case of homografts, even well-incorporated on X-rays. More retrieval specimen studies are necessary to delineate precise topographical histological lesions, including non-loosened joint implants.

Cost-effectiveness of monolayers and human papillomavirus testing compared to that of conventional Papanicolaou smears for cervical cancer screening: protocol of the study of the French Society of Clinical Cytology.

The French Society of Clinical Cytology is conducting a study to compare the cost-effectiveness of monolayers and human papillomavirus (HPV) testing with that of conventional Papanicolaou (Pap) smears for cervical cancer screening. The protocol of this study is presented. It includes 3,000 women who will be evaluated by the three methods (conventional Pap smears, or monolayers with or without HPV testing) and by the reference method: colposcopy followed, in cases with abnormalities, by cervical biopsy. Efficacy or performance of the methods will be compared on the basis of sensitivity. Cost comparisons and cost-effectiveness modeling will be based on the costs associated with methods themselves and also the costs of "false positives." This will require specific collection of data concerning the costs of the three methods, as these costs have not previously been accurately documented. Patient recruiting and data collection started in September 1999 and will be complete in June 2000. The first results are expected to be available in spring 2001.

[Contribution of computers and telepathology in cancerologic pathology]. / Apport de l'informatique et de la télépathologie en anatomocytopathologie cancérologique.

The histologic or cytologic diagnosis of a tumoral lesion may be sometimes very difficult to do even for a senior pathologist. Nevertheless, it is necessary to recognize a malignant process with reliability and security. The usual way to solve some difficult problems is firstly to search documentations in books or atlas and then to discuss the slides in common. Sometimes it is necessary to dispatch the original documents to a national or international expert. Now computers are used in any private or public department of Pathology. Some new informatics developments allow to send good digitized pictures to an expert and to discuss with him. It is also possible to elaborate a data base of digitized images which can be edited on CD-Rom. We describe the development and the use of these technics in France and elsewhere. It seems that they could have an increasing role for quality assurance in tumoral pathology.

Pathological classification and grading of primary ovarian carcinoma: experience of the ARTAC ovarian study group.

One hundred and fifty-seven cases of high stage ovarian carcinomas (FIGO stage III and IV) have been selected for therapeutic protocol under the aegis of ARTAC. One hundred and forty-six cases have been reviewed, of which 15 were peritoneal tumors: eight ovarian tumors were excluded. One hundred and twenty-three primary ovarian carcinomas have been graded and classified. The slides were reviewed independently by three pathologists with a perfect correlation and no significant difference was observed with the initial diagnosis. The World Health Organisation classification of ovarian epithelial tumors was used as a basis for the study (98 serous types, three mucinous tumors, five endometrioid tumors, two clear cell tumors, five mixed epithelial tumors, seven undifferentiated tumors and three unclassified). The adopted grading associates the degree of architecture differentiation and the cytological features using Broder's classification. The architecture grading or degree of differentiation includes well differentiated, moderately differentiated, poorly differentiated and undifferentiated patterns. The nuclear grading is based on pleomorphism of size and form, hyperchromatism, nucleoli, mitotic figures. The proposed grading based on well-known criterions is simple to use and easily reproducible. Grade 1 (6.5%) are well differentiated tumors with no atypia. Grade 2 (17.89%) are moderately well differentiated tumors without nuclear atypia. Grade 3 (32.52%) correspond to moderately well differentiated tumors with nuclear atypia. Grade 4 (43.09%) are poorly differentiated or undifferentiated tumors with nuclear atypia. The authors consider the different correlations between grade, histological type, stage and prognosis. The implications of these findings are discussed and the results are compared to those of the literature.

[Endothelin receptors in benign human tumours of uterine muscle]. / Récepteurs des endothélines dans les tumeurs bénignes du muscle utérin humain.

The endothelins (ET1, ET2, ET3) are a family of peptides that exert vasoactive and mitogenic effects. ETs bind to at least two subtypes of receptors: the ETA subtype is ET1 selective whereas the ETB subtype binds ET1, ET2 and ET3. By RT-PCR, we detected ETA receptor mRNA and ETB receptor mRNA in leiomyoma and in homologous myometrium distal from the tumor. Despite the presence of four spliced variants of ETA receptors, we identified a single class of ETA-binding sites. The level of ETB receptor mRNA was found to be higher in myometrium versus leiomyomas. Using complementary pharmacologic approach, we demonstrated the predominance of ETA receptors in normal myometrium (75% of total receptors). Both ETA and ETB transcripts coexist in leiomyomas, but we have reported only ETA binding sites. Because of growth properties of ET1, we suggest a role for this peptide in the tumoral development of human uterine smooth muscle.

[An experimental study of bioglass implants in bone]. / Les bioverres et le tissu osseux: Etude expérimentale.

The tolerance and response of bone to bioglass have been studied using implants of various chemical constitution in animals.Glass discs were inserted between the inner and outer tables of the skull in 32 rabbits and small glass stick were implanted in the medullary cavity of long bones in 6 dogs. The results were analysed between 6 and 18 months later. High resolution radiographs and histopathological examination were performed.Some glass behaves like an inert material but other specimens are biodegradable and induce a satisfactory bone response in adjacent bone. Any new bone formation does not follow the classical stages of connective tissue, cartilage and woven bone. Bioglass is more suitable for bone than many other materials now in use and further applications in orthopaedic surgery may be considered.

[The monolayer technique: evolution or revolution in cervico-uterine cytology]. / La technique en monocouche: évolution ou révolution en cytologie cervico-utérine.

The Pap's smear technique, originally described by Papanicolaou is widely used to screen for cervical cancer. The new, recently introduced thin layer preparations also termed monolayer or liquid-based cytology preparations has prompted much debate among pathologists. A new technique always raises some doubt, especially concerning the economic implications. We present here a technical not providing helpful information and a certain amount of clarification.

[Spironolactone bodies. Light and electron microscope study apropos of 4 cases of adrenal adenomas with primary hyperaldosteronism]. / Les corps spironolactones. Etude en microscopie optique et électronique à propos de quatre cas d'adénomes surrénaliens avec hyperaldostéronisme primaire.

So-called Spironolactone bodies are reported in four adrenal cortical adenomas that were removed from patients with primary hyperaldosteronism, treated preoperatively with spironolactone. Their morphology is described optically : these round acidophilic cytoplasmic bodies have a laminated appearance that ranges in size from 2 to 20 mu in diameter. Electron microscopy of the zona glomerulosa non adenomatous cells and of adenomatous cells of glomerular type reveals numerous membranes arranged concentrically around a central core. Connections between the endoplasmic reticulum and mitochondria in the cytoplasm of the cell and lining layers of the body are described and analysed. The authors attempt to explain the formation and the increase of the bodies. Correlations appear between the number of spironolactone bodies and duration of administration of spironolactone and total drug dosage. The results are discussed with those of the literature.

[Guidelines for the evaluation of internal quality control of smears for screening of uterine cancer in France in the structures of Pathologic Anatomy and Cytology. French Association for Quality Assurance in Pathologic Anatomy and Cytology (AFAQAP)--Commission for cervical smears]. / Recommandations pour l'évaluation de qualité interne des frottis de dépistage du cancer du col utérin en France dans les structures d'Anatomie et Cytologie Pathologiques. Association Française pour l'Assurance de Qualité en Anatomie et Cytologie Pathologiques (AFAQAP)-Commission Frottis du col utérin.

A national organized mass-screening effective programme is the only way to reduce the risk of cervical cancer, if properly organized and correlated with a system of Quality Assurance. Since 1900, an Association for Quality Assurance was created by the French pathologists, named "AFAQAP". These pathologists thus demonstrated their interest in this kind of action that should be effective if women and clinicians are also implied. The pathologists have concluded the first part of their programme with these French guidelines for internal quality control of pap smears.

[Clinical, radiological and pathological study of Ewing's sarcoma of the lumbar spine. Round cell sarcomas. Report on three cases (author's transl)]. / Etude anatomo-radio-clinique des sarcomes d'Ewing du rachis lombaire. Sarcomes à cellules rondes. A propos de trois cas.

Two cases of primary bone condensation type Ewing's sarcoma of a lumbar vertebra are described in children aged 8 and 10 years, as well as one case of the osteolytic form in a 14-year-old child. Ewing's sarcoma very rarely occurs in the spine, and the type with bone condensation is almost exclusively of a primary nature. The tumour extends simultaneously into the epidural space and the perispinal planes. Intravenous urography and myelography with metrizamide are therefore essential for evaluating the degree of tumour extension. Computed tomography examinations are also now necessary. Prognosis is bad and current therapeutic possibilities limited. Histological diagnosis is the only means of distinguishing Ewing's sarcoma from other round cell sarcomas in or around the spine.