A randomized trial comparing limited-excision conisation to Large Loop Excision of the Transformation Zone (LLETZ) in cervical dysplasia patients.

OBJECTIVE: To show noninferiority of a limited-excision (resection of the dysplastic lesion only) vs. classical Large Loop Excision of the Transformation Zone (LLETZ). METHODS: In this prospective, randomized, multicenter trial, women with human papillomavirus (HPV) positive cervical intraepithelial neoplasia grade 3 were randomized into two groups (1:1). Primary outcome was the rate of negative HPV tests after 6 months, secondary outcomes included cone size, complete resection rates as well as cytological and histological results after 6 and 12 months. A sample size of 1,000 was calculated to show noninferiority of the limited-excision compared to the LLETZ group using a noninferiority margin of 5%. Enrollment was stopped after 100 patients due to slow accrual. RESULTS: Patients in the limited-excision group did not show a lower number of negative HPV tests (78% [LLETZ]-80% [limited-excision]=-2%; 90% confidence interval=-15%, 12%). The limited-excision resulted in a substantially lower cone size (LLETZ: 1.97 mL vs. limited-excision: 1.02 mL; p<0.001) but higher numbers of involved margins (LLETZ: 8% vs. limited-excision: 20%). Although postoperative cytological results slightly differed, histological results were similar in both groups. One limited-excision patient received immediate re-conisation, whereas one patient in each group was scheduled for re-conisation after 6 months. CONCLUSION: The limited-excision could represent a promising option to reduce the surgical extent of conisations while maintaining oncological safety. The trial was not sufficiently powered to reach statistical significance due to early termination. Nevertheless, the study provides important insights in the feasibility of a limited-excision and could serve as a pilot study for future trials. TRIAL REGISTRATION: German Clinical Trials Register Identifier: DRKS00006169.

Short interval between two Pap smears: effect on the result of the second smear? A prospective randomized trial.

PURPOSE: A repeat Pap smear is sometimes necessary after a short time interval or even immediately, when patients seek for a second opinion or due to study participation. Only limited information is available on the possible impact of a short interval between two Pap smears. Most institutions therefore practice a minimum time span of 6-8 weeks before obtaining a second smear since a short interval is commonly believed to be associated with an increase of false negative results in the second smear. METHODS: Two consecutive Pap smears were obtained from 81 women. 41 smears were processed using the conventional technique, whereas liquid-based cytology was used in the remaining 40 women. Smears were independently evaluated by four different cytopathologists. We analyzed the effect of time interval, both processing techniques and inter-observer variance in cytological evaluation. RESULTS: While the result of the second smear shows a tendency towards a more benign outcome (odds ratio (OR) 1.436, 95% CI 0.972-2.121), this difference was not statistically significant (p = 0.07). No significant differences were observed between conservative and liquid-based cytology (OR 1.554, 95% CI 0.659-3.667, p = 0.31). There was considerable inter-observer variability, and the observer was a strong predictor of the cytological result (OR 0.632-5.083, 95% CI 0.355-8.975, p < 0.01). CONCLUSIONS: We document a tendency towards a more benign outcome without statistical significance in the second smear. Inter-observer variability of different cytopathologists is high and should be kept in mind when evaluating cytology results.

Prevalence of human papillomavirus infection of the anal canal in women: A prospective analysis of high-risk populations.

Infection with certain types of human papillomavirus (HPV) has been associated with the development of cervical and anal cancer. Worldwide, the incidence of anal cancer has increased markedly. The present study aimed to evaluate the prevalence of HPV infection of the uterine cervix and anal canal in human immunodeficiency virus (HIV)- and non-HIV-infected risk populations. Cervical and anal HPV swabs and cytology samples were collected from 287 patients at the University Hospital of Munich, Germany between 2011 and 2013. Patients were divided into HIV-negative controls (G1) and two risk groups, including HIV-negative patients with cytological abnormalities of the cervix (G2) and HIV-infected patients (G3). Data, including clinical parameters, were analysed. The risk groups had significantly more positive results for HPV in the anus (71.03 and 83.15% for G2 and G3, respectively), as compared with G1. The predominant HPV genotypes found in the anus were high-risk HPV genotypes, which were significantly correlated with concomittant cervical HPV findings. In the risk groups, a significant association between the cytological findings and HPV detection in the cervix was found, while the results of the anus revealed no significance. The results of the present study suggested that the prevalence of HPV infection in the anal canal of risk populations is high. Furthermore, patients with abnormal cervical cytology results and HIV-infected women, irrespective of their individual cervical findings, may have a risk of concomittant anal high-risk HPV infection. Based on the predominant HPV genotypes found in the study, HPV vaccination could reduce the incidence of anal cancer. Nevertheless, high-risk patients should be intensively screened for anal squamous intraepithelial abnormalities to avoid invasive cancer stages.

Cervical screening program and the psychological impact of an abnormal Pap smear: a self-assessment questionnaire study of 590 patients.

PURPOSE: Invasive cervical cancer is today the fourth most common cancer of women in western civilization. Screening programs have led to a continuously decrease. Nevertheless, both screening and a positive test result are known to be associated with a negative psychological impact. Screening programs in European countries differ and thus psychological impact might as well. The aim of this study was to evaluate the psychological impact of women with an abnormal Pap smear in a German cohort. METHODS: Between July 2013 and May 2014, a self-assessment questionnaire was distributed to 595 patients that were referred to a special clinic for cervical dysplasia for further evaluation of an abnormal Pap smear. Patients were recruited in five different centers. RESULTS: Most patients (45.9 %) were informed about the test result via phone call by their doctor. 68.8 % of the patients felt anxious and 26.3 % even felt panic. After having talked to their physician, 51.4 % of our cohort still felt worried and only 24.4 % felt reassured. Concerning disease management, 48.4 % underwent a control Pap smear in 6 months. The preferred information source was the physician (63.9 %). Compared to the results in other European countries, our study cohort showed differences concerning age distribution, patients living in a partnership, number of children and especially disease management. CONCLUSION: Cancer screening itself and abnormal test results have an impact on patient's feelings. To reduce the psychological impact, patients need to be better informed about the risks and benefits of cancer screening programs and in case of cervical cancer screening about the meaning of an abnormal test result. Our results underline the importance of a trustful physician-patient relationship in that matter.

Cervical conisation and the risk of preterm delivery: a retrospective matched pair analysis of a German cohort.

PURPOSE: Since the routine screening program for cervical dysplasia by Pap smear was established in the early 1970s, the rate of cervical cancer has continually dropped. Even if a high percentage of cervical dysplasia shows spontaneous restitution, the only effective therapy for persisting cervical dysplasia is local ablation or excision which might be associated with an increased risk of preterm delivery in subsequent pregnancies. However, data from German patients are missing, so the aim of this study was to evaluate the risk of preterm delivery and associated risks in a cohort of patients who had undergone cervical conisation previous to their pregnancies. METHODS: A total of 144 patients with conisation and subsequent pregnancy were identified. They were compared regarding week of delivery and preterm birth, fetal birth weight, fetal outcome and birth procedure (spontaneous delivery, vacuum extraction, primary and secondary cesarean section) with their matched partners. RESULTS: 135 patients with singleton pregnancies and their matched partners were evaluated in the final analysis. The mean age was 33.5 years. Comparing the case and control group we reached significant different results for week of delivery, but not preterm birth defined as birth prior to 37 weeks of gestation. CONCLUSIONS: Within this German cohort cervical conisation did not increase the risk for preterm birth, cesarean section or poor fetal outcome. We therefore conclude that cervical conisation is an appropriate method to treat women with cervical dysplasia also at childbearing age when prevention of cervical cancer is needed.

Diagnosis of vaginal discharge by wet mount microscopy: a simple and underrated method.

UNLABELLED: Vaginal discharge is highly variable in quality and quantity among different individuals, and even in the same individual during different periods of life. Vaginal discharge is most commonly caused by infection with sexually transmitted organisms or increased colonization by different facultative pathogenic microorganisms (i.e., Gardnerella vaginalis). Noninfectious causes of vaginal discharge are quite rare (10% noninfectious as compared to 90% infectious causes). Most common in women with a vaginal infection is bacterial vaginosis (40%-50% of cases), followed by vulvovaginal candidosis (20%-25%), and then trichomoniasis (15%-20%). If infection is suspected as the primary cause, a sample of the vaginal discharge should be taken and examined microscopically. When evaluating vaginal secretions by phase-contrast wet mount microscopy, knowledge of what is normal versus abnormal is very important. Knowledge of the sensitivity and specificity of wet mount microscopy in different clinical settings is also important. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians LEARNING OBJECTIVES: After completing this CME activity, physicians should be better able to evaluate lifetime changes in vaginal secretions, characterize the physiological and pathological appearance of vaginal discharge, assess the clinical practicality and usefulness of wet mount microscopy and use wet mount microscopy to diagnose bacterial vaginosis and other common vaginal infections.

Inhibin/activin-betaE subunit is expressed in normal and pathological human placental tissue including chorionic carcinoma cell lines.

BACKGROUND: Inhibins and activins are important regulators of the female reproductive system. Recently, a novel inhibin subunit, named betaE, has been identified and shown to be expressed in several human tissues. However, only limited data on the expression of this novel inhibin-betaE subunit in normal and pathological human placenta as well as and human chorionic carcinoma cell lines exist. MATERIALS AND METHODS: Tissue specimens of normal, preeclamptic and HELLP pregnancies (n = 18) were obtained at the course of an cesarean section. Normal and pathological placental tissues as well as chorionic carcinoma cells (BeWo and JEG) were analyzed by using immunohistochemistry and RT-PCR. RESULTS: Expression of the inhibin betaE subunit could be demonstrated at the protein level by means of immunohistochemical evaluation and at the transcriptional level by betaE-specific RT-PCR analysis. The immunoreactive score for inhibin-betaE did not show any significant differences between normal, preeclamptic and HELLP tissue in extravillous trophoblast and syncytiotrophoblast cells. Expression of inhibin betaE could further be demonstrated for the human chorionic carcinoma cell lines JEG and BeWo. DISCUSSION: We demonstrated that inhibin-betaE is expressed in normal and pathological human placenta tissues. Although the precise role of this novel inhibin subunit for human placenta development is quite unclear, similarities with the well-characterized betaA- and betaB-subunits suggest an involvement in autocrine/paracrine signaling pathways, angiogenesis, decidualization and tissue remodeling under normal as well as malignant conditions. Additionally, the human chorionic carcinoma cell lines JEG and BeWo synthesize this subunit and therefore can be used as a cell culture model for further functional analysis of this subunit in human placental tissue.

Immunolabelling of the inhibin/activin-ßC subunit in normal and malignant human uterine cervical tissue and cervical cancer cell lines.

Inhibins are dimeric glycoproteins, composed of an α-subunit and one of two possible ß-subunits (ßA or ßB), with substantial roles in human reproduction and in endocrine-responsive tumours. Recently a novel ß subunit named ßC was described, although it is still unclear if normal or cancerous cervical epithelial cells as well as cervical cancer cell lines can synthesise the inhibin-ßC subunit. Four normal cervical tissue samples together with specimens of well-differentiated squamous cervical cancer and adenocarcinoma of the cervix were immunohistochemically analyzed. Additionally, two cervical carcinoma cell lines (HeLa and CaSKi) were analyzed by immunofluorescence for the expression of this novel subunit. We demonstrated for the first time an immunolabelling of the inhibin-ßC subunit in normal and malignant cervical tissue, as well as cervical cancer cells. Although the physiological role is still unclear in cervical tissue, the inhibin-ßC subunit might play important roles in carcinogenesis. Moreover, the synthesis of this subunit in cervical carcinoma cell lines of squamous and epithelial origins allows the use of these cell lines in elucidating its functions in cervical pathogenesis.

Anal cytology as a screening tool for early detection of anal dysplasia in HIV-infected women.

BACKGROUND AND AIM: HIV-infected patients show a high rate of anal dysplasia and anal carcinoma but there is no gold standard for early detection. Therefore, the objectives of this prospective study were: a) evaluation of an anal screening using anal/perianal cytology; b) in case of a positive result to investigate its relation to immune status, clinical symptoms of HIV infection and antiretroviral therapy. PATIENTS AND METHODS: In every HIV-infected woman visiting our gynaecological outpatient clinic, an anal and perianal swab for anal cytology was taken. One experienced cytologist examined all specimens. Relevant details of the HIV-related history such as CDC classification, CD4 count, viral load, actual antiretroviral therapy etc. were documented. RESULTS: Altogether, 104 HIV-infected women were enrolled on this study. The results of 13 (13.5%) anal cytologies were classified as suspicious for low-grade or high-grade anal dysplasia and 6 of these were confirmed in an anal biopsy. A total of 9 out of 13 also had a cervical dysplasia and 12 were positive for high-risk HPV at the cervix. Ten of these women had already experienced clinical symptoms of their HIV infection and 8 showed a nadir of the CD4 count below 200 cells/microl. All but one took a highly active antiretroviral therapy. CONCLUSION: In this pilot study, anal screening using anal cytology showed 13.5% suspected anal dysplasia in HIV-infected women. All performed biopsies revealed the presence of a high-grade anal lesion. The majority of these women already had an advanced disease and/or immune defect related to their HIV infection. In summary, we found anal cytology to be a useful tool to early detect anal dysplasia of high-risk patients such as HIV-infected women. How far this screening method contributes to the prevention of anal cancer has to be evaluated in further investigations.

Is lymphadenectomy a prognostic marker in endometrioid adenocarcinoma of the human endometrium?

BACKGROUND: During surgery for endometrial cancer, a pelvic lymphadenectomy with or without para-aortic lymphadenectomy is performed at least in patients with risk factors (stage I, grading 2 and/or histological subtypes with higher risk of lymphatic spread), and is hence recommended by the International Federation of Obstetrics and Gynecology (FIGO). Although lymph node metastases are important prognostic parameters, it has been contentious whether a pelvic lymph node dissection itself has a prognostic impact in the treatment of endometrial cancer, especially in endometrioid adenocarcinoma. Therefore, this study evaluated whether lymphadenectomy has a prognostic impact in patients with endometrioid adenocarcinoma. METHODS: The benefits of lymphadenectomy were examined in 214 patients with a histological diagnosis of endometrial adenocarcinoma. Tumour characteristics were analysed with respect to the surgical and pathological stage. RESULTS: Of the 214 patients with endometrial adenocarcinoma, 171 (79.9%) were classified as FIGO stage I, 15 (7.0%) FIGO stage II, 21 (9.8%) FIGO stage III and 7 (3.3%) FIGO stage IV. One hundred and thirty four (62.6%) of the patients had a histological grade 1 tumour, while 56 (26.2%) and 24 (11.2%) had a histological grade 2 or grade 3 tumour, respectively. Lymphadenectomy was performed in 151 (70.6%) patients. Only 11 (5.1%) patients showed metastatic disease in the lymph nodes. The performance of a lymphadenectomy resulted in significantly increased cause-specific and overall survival, while progression-free survival was not affected by this operative procedure. CONCLUSIONS: The performance of an operative lymphadenectomy resulted in better survival of patients with endometrioid adenocarcinoma. This increase was significant for cause-specific and overall survival, while there was a tendency only towards increased progression-free survival. Therefore, even in endometrioid adenocarcinoma, a pelvic and/or para-aortic lymphadenectomy should be performed.

Immunolabeling of the inhibin-ßA and -ßB subunit in normal and malignant human cervical tissue and cervical cancer cell lines.

OBJECTIVES: Inhibins, dimeric peptide hormones composed of an α-subunit and 1 of 2 possible ß subunits (ßA or ßB), exhibit substantial roles in human reproduction and in endocrine-responsive tumors. However, it is still unclear whether normal and cancerous cervical tissues as well as cervical cancer cell lines express the inhibin-ßA and -ßB subunits. MATERIALS AND METHODS: Normal human uterine cervical tissue was obtained from 4 premenopausal nonpregnant patients. In addition, a total of 32 specimens of cervical intraepithelial neoplasia (CIN) of different stages were obtained (CIN 1 = 10, CIN 2 = 9, and CIN 3 = 13). Moreover, 30 squamous cervical cancer samples of well-differentiated (grade 1; n = 10), moderate differentiated (grade 2; n = 10), and poorly differentiated (grade 3; n = 10) grading were analyzed. RESULTS: An immunohistochemical staining reaction for inhibin-ßA and -ßB subunits could be observed in normal and malignant cervical tissue as well as in cervical cancer cell lines. Regarding inhibin-ßA significant differences were observed between normal tissue and CIN 1 and CIN 3. Moreover, the immunohistochemical staining reaction for inhibin-ßA was significantly higher in CIN 3 compared with that in cervical carcinoma grades 1 and 2. The inhibin-ßB expression was higher in CIN and cervical cancer compared with that in normal cervical tissue. Inhibin-ßB was significantly higher in CIN 2 and CIN 3 compared with cancer tissues of histological grade 1. In addition, a significant increase of the staining intensity was observed between cervical cancer grades 1 and 2 as well as grade 3. CONCLUSIONS: Both inhibin-ß subunits demonstrated a differential expression in CIN and squamous cancer, suggesting important roles in cervical carcinogenesis. Inhibin-ßA might be important during progression of CIN, whereas the inhibin-ßB subunit could exert a substantial function during differentiation of cervical carcinomas. Moreover, the synthesis of this subunit in cervical carcinoma cell lines also allows the use of this cell line to elucidates their functions in cervical cancer pathogenesis.

Intrauterine fetal bone retention after late-term abortion by external force in the 20th week of pregnancy.

OBJECTIVES: Intrauterine retention of fetal bones is a rare complication of spontaneous miscarriages or termination of pregnancy. RESULTS: We present a case with fetal bone retention after a miscarriage that occurred after external assault in about the 20th week of gestation. CONCLUSIONS: Since the global mobility has rapidly increased, women from a totally different lifeworld (i.e. escaping from civil war areas in underdeveloped countries) could abruptly present themselves as patients in industrial countries, so every physician should be aware of the described implications.

Inhibin/activin-betaE subunit in normal and malignant human cervical tissue and cervical cancer cell lines.

Inhibins are dimeric glycoproteins, composed of an alpha-subunit and one of two possible beta-subunits (betaA or betaB), with substantial roles in human reproduction and in endocrine-responsive tumours. Recently a novel beta subunit named betaE was described, although it is still unclear if normal or cancerous cervical epithelial cells as well as cervical cancer cell lines can synthesise the novel inhibin-betaE subunit. About 4 normal cervical tissue samples together with 10 specimens of well-differentiated squamous cervical cancer and adenocarcinoma of the cervix were immunohistochemical analyzed. Additionally, two cervical carcinoma cell lines (HeLa and CaSki) were analyzed by immunofluorescence and RT-PCR for the expression of this novel subunit. We demonstrated for the first time an immunolabelling of the inhibin-betaE subunit in normal and malignant cervical tissue, as well as cervical cancer cells. Although the physiological role is still quite unclear in cervical tissue, inhibin-betaE might play important roles in carcinogenesis. Moreover, the synthesis of this subunit in cervical carcinoma cell lines of squamous and glandular epithelial origins also allows the use of these cell lines in elucidating its functions in cervical cancer pathogenesis. However, since the expression of the inhibin-betaE is minimal in HeLa cells as assessed by immunofluorescence and RT-PCR, the CaSki cell line might be a better model for further functional experiments regarding cervical cancer pathogenesis.

Complete hydatidiform mole in a perimenopausal woman with a subsequent severe thyriotoxicosis.

INTRODUCTION: Gestational trophoblastic disease is one form of abnormal pregnancy, with a median maternal age of 27-28 years. One complication of trophoblastic disease is the development of a secondary hyperthyroidism, which resolves rapidly after evacuation of the hydatidiform mole. CASE REPORT: We report a case of a 53-year-old woman presenting with a complete hydatidiform mole and who developed a severe thyrotoxicosis after suction evacuation of the hydatidiform mole. CONCLUSION: A severe thyriotoxicosis can occur even after surgical evacuation of the mole. Therefore, evaluation of the thyroid function prior to operation, especially with a high quantitative hCG, should be performed to avoid severe complications.

High recurrence rate of cervical dysplasia and persistence of HPV infection in HIV-1-infected women.

AIM: A) evaluation of the recurrence of cervical dysplasia after surgical treatment and of the rate of HPV persistence of HIV-infected women and b) the influence of antiretroviral therapy on the recurrence. PATIENTS AND METHODS: In a retrospective analysis, the follow-up data of HIV-positive women visiting our outpatient clinic regarding results of cervical cytology, cervical HPV detection, cervical biopsy, patient history of dysplasia and antiretroviral therapy were assessed. A total of 388 HIV-positive women had a mean follow-up of 2.7 years and a median of 2.5 outpatient visits. RESULTS: Out of the 344 patients (57.3%) tested for HPV, 197 showed at least one positive HPV result. Of the same group, 136 women had four or more HPV tests which showed that 84 of them (61.8%) had a persistent HPV-infection. Overall, 157/388 had cervical dysplasia and 70 needed surgery. Forty-one of the 70 patients (58.6%) received more than one surgical treatment because of a recurrence, all of this group had persistent HPV. DISCUSSION: The recurrence of cervical dysplasia in HIV-positive women after surgical treatment was found to be very high as was the associated long-term persistence of HPV-infection. HPV persistence represented an excellent marker for relapsing cervical dysplasia.

Is the histomorphological concept of the female pelvic floor and its changes due to age and vaginal delivery correct?

AIMS: To compare the histomorphology of pelvic floor specimens of 94 female cadavers, ten male cadavers, and 24 female symptomatic patients who underwent pelvic floor surgery, and to evaluate the association of age, parity, and sex to myogenic and/or neurogenic changes to the levator ani muscle (LAM). METHODS: The pelvic floor was biopsied at the pubococcygeus, the iliococcygeus and the coccygeus muscle. After staining, signs for myogenic/neurogenic changes to the muscle were evaluated (fibrosis, variation in fiber diameter, centralization of nuclei, small angulated fibers, and type grouping). To identify the intact neuromuscular junction stainings with NCAM (neuronal cell adhesion molecule) and acetylcholinesterase (ACE) were used. RESULTS: A significant influence of age and parity on the histomorphological criteria of myogenic cell-damage was shown in this study. Although these criteria were found even in young nulliparous women, there was a significant increase in older or parous women with at least one vaginal delivery. We failed to demonstrate significant changes between the nulliparous LAM, the male LAM, and the LAM from women with prolapse and incontinence. None of the specimen showed any obvious evidence of neuropathy. CONCLUSIONS: We have evaluated histological criteria adapted from the examination of limb muscles in the LAM of nulliparous young women. "Myogenic changes" seem to be a normal finding in the LAM. The increase of these changes with aging and parity points to mechanical stress to the LAM as the most plausible causative factor. We propose that further studies using histomorphological techniques of the pelvic floor muscle in nulliparous and parous women should clarify the potential role of our histological findings.