Immunohistochemical expression pattern of metastasis suppressor KISS-1 protein in adenomyosis lesions and normal endometrium.

OBJECTIVE: Kisspeptins are multifunctional peptides; it has been shown that they act as inhibitors of tumor metastasis in a range of cancers and that they are also involved in cell invasion through regulation of matrix metalloproteinases (MMPs). The aim of this study was to investigate the expression of KISS-1 protein in adenomyosis lesions compared with matched eutopic endometrium, as well as with endometrium from patients without adenomyosis. STUDY DESIGN: In this comparative, non-interventional study, adenomyosis and corresponding eutopic endometrium samples from women with histologically proven adenomyosis after hysterectomy, and eutopic endometrium samples from women without adenomyosis were analysed. Expression of KISS-1 protein was analyzed immunohistochemically in formalin-fixed, paraffin-embedded adenomyotic tissue specimens (n=29), matched eutopic endometrium from the same patients (n=29) and normal endometrium from patients without adenomyosis (n=29). RESULTS: Using a semi-quantitative immunohistochemical score, we found that KISS-1 protein expression was higher in the adenomyotic as compared with matched eutopic glandular endometrium (p<0.05), in which in turn KISS-1 protein expression was higher than those from patients without adenomyosis (p<0.001). The inverse correlation was found in the stroma, between adenomyosis lesions and matched eutopic endometrium (p<0.01), while no statistically significant correlation was found in KISS-1 protein expression in the stroma between patients with and without adenomyosis. CONCLUSIONS: KISS-1 protein expression appears to be up-regulated in adenomyotic as compared with eutopic glandular endometrium of patients with, as well as women without adenomyosis. These findings are suggestive of the involvement of KISS-1 protein in the pathogenesis and maintenance of adenomyosis. Future studies should investigate whether KISS1 protein could be used as a marker for early and minimally invasive detection of adenomyosis, based on its differential protein expression pattern in the eutopic endometrium of patients with and without adenomyosis.

ERBB2 (HER2) protein expression in uterine sarcomas.

PURPOSE: Multiple clinical trials in recent years have shown that breast cancer patients with primary tumors overexpressing ERBB2 can be effectively treated with specific forms of modern anti-ERBB2-targeted therapy. The aim of the present study was to analyze the expression of the ERBB2 (HER2) protein in uterine sarcomas, in order to investigate the possibility of applying this treatment modality in uterine sarcomas. METHODS: The expression of ERBB2 has been analyzed immunohistochemically in formalin-fixed paraffin-embedded primary uterine sarcomas (n = 11). RESULTS: Using a semi-quantitative immunohistochemical score, we found that ERBB2 expression was very weak in the majority of tumors, with only three sarcomas showing moderate ERBB2 expression. Published studies evaluating the same issue in small numbers of uterine sarcomas reached similar findings. CONCLUSION: Overall, ERBB2 expression appears to be weak in uterine sarcomas. However, targeted treatment might still be feasible in a subgroup of patients with uterine sarcomas overexpressing ERBB2.

Virilizing ovarian hilus (Leydig) cell tumor with concurrent contralateral hilus cell hyperplasia: a rare diagnosis.

Ovarian hilus or Leydig cell tumor and ovarian hilus cell hyperplasia are rare clinical entities, causing virilization in both pre- and postmenopausal women. Differentiation between these two conditions is not always straightforward; the former is usually unilateral appearing as a single, grossly visible, circumscribed mass of hilus cells, while the latter is usually bilateral, appearing as diffuse microscopic aggregates of hilus cells. We report herein an extremely rare case of ovarian hilus or Leydig cell tumor, presenting concurrently with contralateral ovarian hilus cell hyperplasia in a postmenopausal woman with virilization. To the best of our knowledge, only four such cases have been previously reported in the literature. Ovarian hilus cell tumors and hilus hyperplasia almost always have benign biological behavior, thus making bilateral salpingo-oophorectomy an appropriate and sufficient therapeutic approach.

Mucocele of the appendix mimicking an adnexal mass: a case report.

Mucocele of the appendix is a rare entity usually mimicking an adnexal tumour. There is no specific imaging or screening method to determine the diagnosis with certainty preoperatively. Appendiceal malignancy can be the underlying cause, although it is not common. We present a case of an appendiceal mucocele mimicking an ovarian tumour by both clinical and imaging (TVS and MRI) methods. This pathological condition should be considered by all the gynaecologists in the differential diagnosis of a right-sided pelvic mass.

A unique case of palatinate tonsil metastasis from endometrial cancer.

Metastases from malignancies of the female genital tract to the tonsils have never been reported. A case of a 55-year-old woman presenting with a palatinate tonsil tumour two and half years after primary diagnosis of endometrioid endometrial adenocarcinoma (FIGO Stage IB, G2) and six months after local disease recurrence is presented. The tonsillar malignancy was poorly differentiated and tumour cells were immunohistochemically positive to LMW keratin and EMA, and negative to HMW keratin and LCA, strongly suggesting a possible endometrial origin of the tumour. Metastatic disease was treated with systemic chemotherapy, but the patient soon succumbed due to rapid disease progression. In conclusion, a unique case of a palatinate tonsil tumour as the first metastatic site in an endometrial cancer patient is reported.

A rare case of renal cell carcinoma metastasizing to the uterine cervix.

Metastatic tumors to the uterine cervix originating from malignancies in other organs are very rare. A case of a 45-year-old white woman presenting with vaginal bleeding, due to renal cell carcinoma metastasizing to the cervix, is reported. The patient had been treated four years and five months earlier due to two primary malignancies: colon adenocarcinoma and renal cell carcinoma. After D&C, microscopic examination and immunohistochemical staining showed that the tumor was metastatic, originating from the renal cell carcinoma. Radical hysterectomy with bilateral salpingo-oophorectomy and pelvic lymph node resection followed, and postoperatively the patient received targeted therapy with sutinib malate. The possibility of metastasis from another primary should be considered in the differential diagnosis of tumors of the uterine cervix in order to plan optimal management.

Human placental lactogen and color Doppler in predicting expulsion of retained adherent placenta: a new clinical observation.

PURPOSE: To present a new clinical observation made in three cases of retained adherent placenta, a rare obstetrical complication, associated with potentially life-threatening hemorrhage. METHODS: Three consecutive cases of retained adherent placenta are presented. RESULTS: Diagnosis of placenta increta in two and placenta percreta in one case was established with ultrasound and MRI. Methotrexate 50 mg i.v. (300 mg total dose) and follinic acid 0.1 mg/kg were administered on alternating days, over 12 days. On follow-up, placental perfusion on color Doppler was present up to the point when circulating hPL levels were no longer detectable; this was followed in all cases by spontaneous placental expulsion within 10 days. CONCLUSIONS: The observation that both color Doppler and human placental lactogen can be used to monitor response to therapy and predict placental expulsion should be evaluated in future cases of retained adherent placenta.

Hormone therapy for postmenopausal breast cancer survivors: a survey among obstetrician-gynaecologists.

PURPOSE OF INVESTIGATION: To investigate the attitude of Greek obstetrician-gynaecologists towards prescription of hormone therapy to postmenopausal breast cancer survivors. METHODS: An anonymous questionnaire was sent to members of the Hellenic Society of Obstetrics and Gynaecology with a hypothetical case and a series of relevant questions. RESULTS: Three hundred valid answers were received. Hormone therapy would be prescribed to a breast cancer survivor by only 8%; 80% of these would prefer tibolone. In contrast, 92% would not prescribe hormone therapy; 97% would do so due to the risk of disease recurrence; 70% would not prescribe any alternative therapy, 21% would prescribe CNS-active compounds and 7% SERMs. CONCLUSIONS: The vast majority of Greek obstetrician-gynaecologists would not prescribe hormone therapy for menopausal symptoms in breast cancer survivors due to the theoretical risk of disease recurrence. Among those who would not prescribe hormone therapy, 21% would opt to CNS-active compounds.

Apert syndrome: the current role of prenatal ultrasound and genetic analysis in diagnosis and counselling.

Apert syndrome is a rare congenital malformation syndrome characterized by the triad of cutaneous and progressive bony syndactyly, midfacial hypoplasia and craniosynostosis. Two missense mutations of the gene encoding the fibroblast growth factor receptor 2 (FGFR2) have been implicated in most cases. We report a case of Apert syndrome detected on prenatal ultrasound. Postnatal genetic analysis showed, for the first time, that the previously reported P253R mutation of the FGFR2 gene is also prevalent in southeast Europe. After prenatal sonographic detection of anomalies suggestive of Apert syndrome, parents should be counselled about prognosis and risk of recurrence, and the option of amniocentesis should be offered.

Vaginal wall fibroid.

Localization of leiomyomas in the vaginal wall is very rare. We report about a case of a vaginal leiomyoma in the anterior vaginal wall, preoperatively identified with sonography and CT. Surgical enucleation was performed. Surgical removal in these cases is safe and usually with minimal bleeding.

Cervical human papillomavirus infection in women attending gynaecological outpatient clinics in northern Greece.

Human papillomavirus (HPV) is the necessary cause for the development of invasive cervical cancer. Identification of HPV determinants may contribute to the targeting of high-risk groups for cervical cancer. The study was aimed at estimating HPV prevalence and its determinants among 1296 women attending six gynaecological outpatient clinics in northern Greece. Information was available through personal interview and the study of cervical exfoliated cells. HPV DNA was detected by reverse line-blot polymerase chain reaction using the L1 primers PGMY09/11. The overall HPV prevalence was 2.5%. After controlling for potential confounders, the two independent risk factors associated with an increased prevalence were young age and parity. The prevalence odds ratio (POR) for those younger than 27 years against those older than 42 years was 5.31 (95% confidence interval (CI)=1.53-18.44) and the POR for nulliparous women compared with women with two or more children was 4.15 (95% CI=1.35-12.76). HPV was present in 10 of 12 women with low-grade cervical intraepithelial lesions (CIN) (83.3%) and in 3 of 4 with high-grade CIN (75%). The prevalence of genital HPV infections in the study population was among the lowest ever reported internationally.

Interleukin-1 beta and tumor necrosis factor-alpha in normal/infertile men.

Cytokines play an important role in intercellular communications. Human sperm contains a wide spectrum of cytokines. such as interleukin-1 beta (IL-1beta) and tumor necrosis factor alpha (TNF-alpha). Their effects on semen quality are subject to debate. The aim of this study was to determine concentrations of IL-1beta and TNF-alpha in normal fertile men and in different groups of male infertility in an attempt to clarify the physiology and suggest possible clinical uses. Sixty-six subfertile male patients with varicocele (n = 22). infection of accessory genital glands (n = 14), varicocele plus infection (n = 4), chronic epididymitis (n = 8). post-renal transplantation status (n = 5), idiopathic oligoasthenoteratospermia (n = 9), cryptorchidism (n = 1), and homozygous beta-thalassemia (n = 3) as well as 5 male controls were studied through history, physical examination, spermiograms, plasma basal hormonal levels, and IL-1beta and TNF-alpha levels in seminal fluid. There was no significant statistical difference regarding IL-1beta and TNF-alpha among fertile men and subfertile patients of any cause. 1L-1beta and TNF-alpha were in tight positive correlation (p<.001). Determination of IL-1beta and TNF-alpha does not provide useful information in male routine infertility workup. Nevertheless, a better understanding of these mediators in semen of normal men and infertile patients may contribute to a new approach to the management of male infertility.

Ambiguous genitalia, 45,X/46,XY mosaic karyotype, and Y chromosome microdeletions in a 17-year-old man.

OBJECTIVE: To describe clinical and laboratory features of a patient with 45,X/46,XY mosaic karyotype and Y chromosome microdeletions and to discuss the diagnostic problems in his management. DESIGN: Case report. SETTING: University department. PATIENT(S): A 17-year-old man with ambiguous genitalia, 45,X/46,XY mosaic karyotype, and Y chromosome microdeletions. INTERVENTION(S): Testicular ultrasonography, karyotype, open testicular biopsy, polymerase chain reaction (PCR) screening for cystic fibrosis, PCR screening for Y chromosome microdeletions in peripheral blood and testicular tissue, and reverse transcriptase PCR in testicular tissue for Y chromosome microdeletions. MAIN OUTCOME MEASURE(S): Avoidance of dissemination of testicular cancer. RESULT(S): The patient was referred for bilateral orchiectomy. CONCLUSION(S): 45,X/46,XY mosaic karyotype is associated with a broad spectrum of phenotypes that includes female with Turner syndrome, male with mixed gonadal dysgenesis, male pseudohermaphroditism, and apparently normal male. Microdeletions of the long arm of the Y chromosome may be associated with Y chromosomal instability, leading to formation of 45,X cell lines. 45,X/46,XY males carry an increased risk for gonadal tumors and must be followed closely.

Clinical implications of uterine malformations and hysteroscopic treatment results.

Uterine malformations consist of a group of miscellaneous congenital anomalies of the female genital system. Their mean prevalence in the general population and in the population of fertile women is approximately 4.3%, in infertile patients approximately 3.5% and in patients with recurrent pregnancy losses approximately 13%. Septate uterus is the commonest uterine anomaly with a mean incidence of approximately 35% followed by bicornuate uterus (approximately 25%) and arcuate uterus (approximately 20%). It seems that malformed uterus and especially septate uterus is not an infertility factor in itself. However, it may have a part in the delayed natural conception of women with mainly secondary infertility. On the other hand, patients with uterine malformations seem to have an impaired pregnancy outcome even as early as their first pregnancy. Overall term delivery rates in patients with untreated uterine malformations are only approximately 50% and obstetric complications are more frequent. Unicornuate and didelphys uterus have term delivery rates of approximately 45%, and the pregnancy outcome of patients with untreated bicornuate and septate uterus is also poor with term delivery rates of only approximately 40%. Arcuate uterus is associated with a slightly better but still impaired pregnancy outcome with term delivery rates of approximately 65%. Women who have undergone hysteroscopic septum resection and have been reported in the different series comprise a highly selected group of symptomatic patients with term delivery and live birth rates of only approximately 5%. Hysteroscopic treatment seems to restore an almost normal prognosis for the outcome of their pregnancies with term delivery rates of approximately 75% and live birth rates of approximately 85%. It seems, therefore, that hysteroscopic septum resection can be applied as a therapeutic procedure in cases of symptomatic patients but also as a prophylactic procedure in asymptomatic patients in order to improve their chances for a successful delivery.

Ovarian remnant syndrome: a case report and review of the literature.

The ovarian remnant syndrome in an unusual complication of bilateral oophorectomy, usually presenting with pelvic mass and pain. A case of the syndrome is described in a 35-year-old woman with a history of abdominal hysterectomy and bilateral oophorectomy. We suggest that ovarian remnant syndrome should be considered in the differential diagnosis of chronic pelvic pain after recorded oophorectomy.

p53 codon 72 polymorphism and risk of intra-epithelial and invasive cervical neoplasia in Greek women.

In 1998, Storey and co-workers suggested that individuals homozygous for arginine (Arg) at codon 72 of the p53 gene are about seven times more susceptible to human papillomavirus (HPV)-related carcinogenesis than heterozygotes. Since then, several studies from Northern Europe, Japan and the USA have failed to demonstrate a similar correlation. By contrast, a study in Brazil as well as one recent study in Italian and Swedish populations showed strong positive associations. We examined the frequency of p53 codon 72 polymorphism in samples from both invasive and intra-epithelial cervical neoplasias (CIN), and compared them with samples from healthy controls. All 88 samples came from women with a Greek ethnic background. Tissue specimens were collected from archival material with histologically diagnosed low-grade CIN (LGCIN), high-grade CIN (HGCIN) or cervical cancer (CxCa). As a control, we used cellular material newly collected by cytobrush from the cervices of 30 healthy women with normal cytological and colposcopical examinations. p53 Arg homozygosity (Arg/Arg) alone was associated with four-, six- or eight-fold increased risks for LGCIN, HGCIN or invasive cancer, respectively. The frequency of the p53Arg/Arg genotype and of the proline (Pro) allele showed significant linear trends according to the degree of severity of the lesion (P = 0.0007 and P = 0.0009, respectively). Exclusion of the ten HPV16/18-negative cases did not substantially alter the Arg/Arg frequency among the groups nor the significant linear trend. Our results confirm the initial findings of Storey and co-workers, as well as the data of the Brazilian and the recent European study, but do not accord with those of the other aforementioned studies. Variations in ethnic background, laboratory performance, verification of the HPV status, definition of controls, and sample size are the most plausible explanations for this controversy. In all our samples, the distribution of the p53 alleles fits the Hardy-Weinberg equilibrium and the 0.48 frequency of the Pro allele in our controls accords well with the percentages previously reported for different ethnic groups as characteristic of the assumed north-south cline. Some authors assert that the discrepancy in the results could not be attributed to differences in the methods; however, the Brazilian study emphasized the effect of inter-laboratory variation in detecting the association between p53 polymorphism and cervical cancer. Regarding the control group, our samples were only from women with a cytologically and colposcopically benign cervical epithelium. We think that simply choosing 'normal volunteers' for collecting control DNA blood samples without knowing the status of their cervical epithelium is indeed a possible source of bias. Finally, it is very unlikely that loss of heterozygosity at the p53 locus could be a factor interfering with the allelotype distribution. Our present small study results, which suggest a biologically relevant association, provide strong evidence that homozygous arginine at codon 72 of p53 may confer a higher susceptibility to HPV-associated intra-epithelial and invasive cervical neoplasia.

Management of hydrosalpinx: reconstructive surgery or IVF?

Tubal disease remains the most important factor in female infertility. Many investigators reported that patients with hydrosalpinx had a decreased clinical pregnancy rate and an increased miscarriage rate, resulting in a decreased ongoing pregnancy rate when compared to that of patients with other types of tubal disease. Different studies showed a deleterious effect of the presence of hydrosalpinx on the outcome of in vitro fertilization-embryo transfer, because toxic agents flowing from the hydrosalpinx to the uterus impair the implantation rate. Operative laparoscopy is effective in the treatment of hydrosalpinges (Stage I or II). Fertility outcome is related to tubal damage. Patients with Stage III and IV disease should be managed from the beginning with in vitro fertilization. Excision of hydrosalpinx(-ges) improves the pregnancy potential after in vitro fertilization. We believe that assisted reproductive technology and reproductive surgery can be complementary. The development of laparoscopic surgery and in vitro fertilization improved the pregnancy rate in patients with tubal factor infertility.

Etiopathology of endometriosis.

Although endometriosis is one of the most frequent problems in gynecology, its pathogenesis remains controversial and poorly understood. Many theories relating to the etiopathology of this disorder have been proposed. The celomic metaplasia hypothesis states that peritoneal mesothelium undergoes metaplasia, forming typical endometrial-like glands and stroma. The transplantation theory suggests implantation and subsequent growth of retrogradely shed, viable endometrial cells. The induction theory states that unknown substances released from shed endometrium induce undifferentiated mesenchyma to form endometriotic tissue. Regardless of which theory is correct, additional factors may be responsible for the expression of the disease. The possibility that the development and progression of endometriosis is associated with abnormal immune function and an inadequate response of the peritoneal defense system is currently the most recent hypothesis for the etiopathology of this disease.