Blood Vessel Invasion Is an Independent Prognostic Factor in Endometrial Endometrioid Carcinoma Compared to Lymph Vessel Invasion and Myometrial Invasion Pattern.

We studied 115 cases of EEC diagnosed on hysterectomy specimens. Double immunohistochemical staining (D2-40/CD31) was performed in all 115 cases to show LVI and BVI on the same slide. MELF pattern invasion was present in 24/115 (21%) cases. MELF-positive tumors had a higher frequency of LVI than MELF-negative tumors (58% and 23%, respectively); the frequency of BVI was twice as high in MELF-positive tumors in comparison to MELF-negative tumors (25% and 12%, respectively). These differences were significant (p ˂ 0.0001). All tumors with positive BVI also had a concomitant LVI. The presence of MELF invasion had no impact on overall survival, confirming previous studies. 5-year survival rates were almost equal in cases with negative LVSI and cases with positive isolated LVI (98% vs. 97%). However, in cases where BVI was also present, the 5-year survival rate was significantly lower, 63% (p ˂ 0.0001). Furthermore, BVI proved to be an independent prognostic factor for overall survival, disease-free survival, and recurrence in the multivariate analysis. In conclusion, MELF pattern invasion is a good predictor of lymphatic and blood vessel invasion but has no prognostic value. Our results suggest that BVI in EEC has greater clinical value than isolated LVI or myometrial invasion patterns, and the therapeutic approach should be guided by BVI presence. Therefore, we hope this study will promote the routine evaluation of BVI in the context of EEC diagnostic procedures.

Pitfalls in gynecological cytology - review of the common and less frequent entities in Pap test.

BACKGROUND: Pitfalls in Pap test could be defined as false positive, false negative or underdiagnosed results which can lead to unnecessary diagnostic procedures or delayed and inadequate treatment. It can be a consequence of misinterpretation of certain morphological entities which are described in this paper. SUMMARY: the paper presents the overview of the morphological features and look-alikes of the common sources of pitfalls such as atrophy, repair, IUD change, tubal metaplasia, hyperchromatic crowded groups, and radiation changes. Rare causes of pitfalls such as Arias-Stella changes, pemphigus, tumor diathesis per se, rare types of cervical cancer, including verrucous and papillary squamous cell cancer, gastric type and endometrioid adenocarcinoma are also described. KEY MESSAGES: The awareness of pitfalls in cervical cytology is important for cytopathologists and clinicians to avoid future errors. Review of Pap tests with erroneous diagnosis is important for quality control in cytology laboratory, and it must be considered as educational and experience building procedure. Cytopathologist should not pull back in significant diagnoses, especially in HPV negative cases.

Hysteroscopic diode laser myolysis: from a case series to literature review of incisionless myolysis techniques for managing heavy menstrual bleeding in premenopausal women.

PURPOSE: This case series examined the safety and effectiveness of hysteroscopic myolysis using laser-induced interstitial thermo-therapy (LITT) for treating heavy menstrual bleeding (HMB) in premenopausal women with FIGO type 1 or 2 uterine fibroids, not planning for future fertility. Additionally, a comprehensive review of innovative, minimally invasive, incisionless myolysis techniques was conducted. METHODS: Women with HMB, sonographically diagnosed with a single FIGO type 1 or 2 fibroid, underwent hysteroscopic myolysis using the Leonardo® diode laser. Effectiveness was assessed via transvaginal ultrasound measurement of myoma size, volume and vascularization pre and post-procedure. Moreover, we also evaluated any improvements in symptoms using the Pictorial Blood Loss Assessment Chart (PBAC score) scores. RESULTS: The procedure resulted in significant HMB reductions and noticeable fibroid size, volume, and vascularization decrease in all three patients, with no reported complications. The literature review revealed both advantages and limitations of the minimally invasive, incisionless myolysis techniques. CONCLUSIONS: Hysteroscopic laser myolysis is a safe and effective therapeutic intervention for patients experiencing HMB, diagnosed with FIGO type 1 or 2 fibroids, and not planning for future fertility. The procedure resulted in significant reductions in menstrual blood loss and fibroid size. Despite the promising results, it is essential to note the limitations of this report, including its case series design, a small number of patients, and a short follow-up period. Further research is necessary to confirm these results.

Concentration of total proteins in urine as a non-invasive biomarker of endometriosis.

OBJECTIVE: The disease in which we observe the invasion and growth of endometrial cells on extrauterine tissues and organs with the creation of a chronic inflammatory state is called endometriosis. It causes infertility and is present in more than 30% of patients with endometriosis. Diagnosis and treatment of the disease is most often delayed for about 8 years after the first symptoms were reported. The symptomatology of endometriosis is varied, and there is no non-invasive way of diagnosis, and this is the reason for the delayed start of treatment. The development of endometriosis activates pathological processes such as the invasion and proliferation of endometriotic cells, the formation of adhesions and the activation of the immune system, which result in increased protein expression. The aim of this research is to compare the concentrations of total proteins in the urine of subjects with endometriosis with those of the control group and possibly identify a biomarker for the diagnosis of endometriosis. METHODS: Prospective urine analysis of 141 patients who were hospitalized and surgically treated at the Clinic for Gynecology and Obstetrics of KBC Rijeka from 08/21/2021 until 07/30/2022. The urine of subjects with endometriosis (N=84) and without endometriosis (n=57) was analyzed. RESULTS: Total protein in the urine is increased in the urine of subjects with endometriosis, but the total amount of protein does not correlate with the degree of disease progression. CONCLUSIONS: An increase in the level of total proteins in urine in subjects with endometriosis is a possible non-invasive diagnostic biomarker. Patients with endometriosis are grouped after the concentration of total proteins greater than 5000 µg/µl.

Proteins in urine - Possible biomarkers of endometriosis.

In the pathogenesis of endometriosis, a number of pathological reactions occur. Proteins secreted in the urine are thought to interact with each other and stimulate the pathological processes in endometriosis. Identifying one or more proteins that are specific enough and could serve as biomarkers for endometriosis is both a challenge and a necessity that would facilitate diagnosis. The urine of patients treated in a tertiary university hospital between July 1, 2020 and June 30, 2021 was analyzed. The studied group consists of patients who were treated surgically for endometriosis and in whom the diagnosis was confirmed by pathohistological analysis. The control group consists of patients who were operated for functional ovarian cysts. Urinary proteins were analyzed by chromatography and mass spectrometry (LC-MS/MS). We identified 17 proteins in urine whose concentrations were statistically significantly different in the group with endometriosis (N = 16) compared with the control groups (N = 16). The detected proteins were classified into groups according to their function in invasion, migration and proliferation, proteolysis, immune system, cell adhesion and vascular system. For all mentioned proteins the difference in concentration is statistically significant p < 0.005. Proteins are secreted in the urine of patients with endometriosis that may be involved in the pathogenesis of the disease and are possible biomarkers for endometriosis.

Diagnostic Three Slides Pap Test Compared to Punch Biopsy and Endocervical Curettage in Confirmed HSIL+ Diagnosis.

OBJECTIVE: The aim of the study was to evaluate the accuracy of the diagnostic Pap test (DPT) on three slides and punch biopsy and endocervical curettage (PB/ECC) compared with the final biopsy material in the detection of high-grade squamous intraepithelial lesion (HSIL). MATERIALS AND METHODS: Patients treated with conization after previous DPT and PB/ECC were analyzed. The findings of the DPT and PB/ECC as well as of the endocervical brush cytology and ECC were compared with the final conus histology. RESULTS: 150 patients were analyzed, and final histology verified 145 cases of HSIL and 3 cancers. The percentage of confirmed HSIL cytology was 97%, while for PB/ECC it was 79% with 30/145 false negative results. The correlation between Pap test and PB/ECC showed that the diagnostic accuracy of DPT is significantly higher (p < 0.0001). Endocervical brush cytology confirmed HSIL+ in the endocervical canal in 83% and ECC in 35% of cases (p < 0.0001). CONCLUSION: The DPT on three slides enables better detection of HSIL compared to PB/ECC, particularly for lesions localized in the endocervical canal sampled with a cytobrush. A high quality DPT could represent a surrogate for PB/ECC and open the possibility of direct access to therapeutic procedure.

The Immunohistochemical Pattern of Epithelial-Mesenchymal Transition Markers In Endometrial Carcinoma.

The majority of endometrial carcinoma are diagnosed at an early stage and exhibit a favorable prognosis. However, 10% to 15% of ECs recur and the majority are type II tumors which are high-grade carcinomas. The epithelial-mesenchymal transition (EMT) has been considered as a fundamental step for the development of the invasive phenotype of cancer cells. During EMT, many of epithelial surface markers, primarily E-cadherin disappear, and mesenchymal markers including N-cadherin gain. This feature resides predominantly at the invasive front (IF) of the tumor. Therefore, we examined the immunohistochemical expression of E-cadherin and N-cadherin at the IF, in central areas of the tumor and lymphovascular space, in type I and type II endometrial carcinoma. The association of each protein with the clinicopathologic features was also evaluated. Our results confirmed a stronger E-cadherin immunostaining in type I tumors indicating that the loss of E-cadherin may be responsible for a more aggressive behavior of type II ECs. In both types, E-cadherin was strongly expressed in central areas and the reactivity decreased toward the IF. On contrary, N-cadherin was overexpressed at the IF confirming an inverse relationship between these markers. In addition, a decrease in E-cadherin expression was observed in cells within the lymphovascular space. Downregulation of E-cadherin was associated only with high-grade tumors while no correlations between both markers and other clinicopathologic features were found. Our results confirm that EMT occurs at the IF that represents a critical interface between the tumor and the host.

The Role of CD44 and RHAMM in Endometrial (Endometrioid Type) Cancer: An Immunohistochemical Study.

Hyaluronan controls cell migration, differentiation, and proliferation, and it is involved in tumor invasion. The extracellular matrix containing hyaluronan regulates cell behavior via cell surface receptors such as CD44 and receptor for hyaluronan-mediated motility (RHAMM, CD168). We investigated the expression of CD44 and RHAMM in tissue samples of endometrial cancer and the relation of their expression with clinicopathologic parameters of patients. In order to evaluate the value of CD44 and RHAMM as prognostic factors, we investigated the relation of their expression with patients' survival. Our results demonstrated a statistically significant correlation with the depth of myometrial invasion, lymphovascular invasion (LVSI), The International Federation of Gynecology and Obstetrics stage of disease, and, in the case of RHAMM expression, a significant correlation with histologic tumor grade as well. CD44 expression was present in the cell membrane in all cases, but in a proportion of tumors in the cytoplasm as well. In this group of patients, we noticed a significantly greater number of cases with deeper myometrial invasion and LVSI. Finally, we sorted out the group of tumors with simultaneous strong CD44 and strong RHAMM expression, and found a statistically significant correlation with the depth of myometrial invasion and LVSI. Using an univariate analysis, we demonstrated that, in our sample of patients, CD44 expression showed a statistically significant influence on patients' 5-year survival. However, using a multivariate Cox regression analysis, neither CD44 nor RHAMM confirmed themselves as independent prognostic factors.

Adult Granulosa Cell Tumors of the Ovary: A Retrospective Study of 36 FIGO Stage I Cases with Emphasis on Prognostic Pathohistological Features.

OBJECTIVE: Adult granulosa cell tumors (AGCTs) represent 2%-5% of all ovarian malignancies. The aim of this study was to analyze clinical and pathohistological parameters and their impact on recurrence, overall, and disease-free survival in FIGO stage I AGCT patients. METHODS: The tumor specimens analyzed in this retrospective study were obtained from a total of 36 patients with diagnosis of ovarian AGCT surgically treated at the Department of Gynecology, Rijeka University Hospital Centre, between 1994 and 2012. Clinical, pathological, and follow-up data were collected. RESULTS: The mean age at diagnosis was 54.5 years with a range of 24-84. The majority of the patients, 30 (83%), were in FIGO stage IA, 3 (8%) in stage IC1, 1 (3%) in stage IC2, and 2 (6%) in stage IC3. During follow-up period (median 117.5 months, range 26-276), recurrence occurred in 4 patients (12%) with 2 deaths of the disease recorded. In univariate analysis, the 5-year survival rates were significantly shorter in patients with FIGO substage IC (p = 0.019), with positive LVSI (p = 0.022), with presence of necrosis (p = 0.040), and with hemorrhage (p = 0.017). In univariate analysis, the 5-year disease-free survival rates were significantly shorter in patients treated with fertility surgery (p = 0.004), with diffuse growth pattern (p = 0.012), with moderate and severe nuclear atypia (p = 0.032), and with presence of hemorrhage (p = 0.022). FIGO substage IC proved to be independent predictor for recurrence (OR = 16.87, p = 0.015, and OR = 23.49, p = 0.023, resp.) and disease-free survival (p = 0.0002; HR 20.84, p = 0.02) at the uni- and multivariate analyses. CONCLUSIONS: FIGO substage IC is predictive of recurrence and disease-free survival in patients with early-stage AGCTs. LVSI, presence of necrosis and hemorrhage, diffuse growth pattern, and nuclear atypia in AGCTs seem to be associated with overall and disease-free survival, so these pathological features should be taken into consideration when managing patients with AGCT.

Primary Carcinosarcoma of the Vagina Associated With Differentiated Squamous Intraepithelial Neoplasia in a Patient With Complete Uterine Prolapse: Case Report and Review of the Literature.

Vaginal carcinosarcomas (VCSs) are rare and clinically aggressive neoplasms. Primary vaginal malignancies are among the rarest malignant tumors, so clear management guidelines and optimal therapy, especially in the presence of significant pelvic organ prolapse, has not been determined. Here, we present a case of primary VCS closely associated with differentiated squamous intraepithelial neoplasia (DSIN), from which it appeared to have arisen in a postmenopausal patient with complete uterine prolapse. The unusual presentation of our case with DSIN in the adjacent vaginal epithelium with possible diagnostic pitfalls emphasizes the need for systemic presentation of these cases to help pathologists and clinicians know that such lesions can initially present in a patient with complete uterine prolapse. To our knowledge, this is the first case of vaginal DSIN described in the literature to date.

[Ovarian cancer - screening and diagnosis]. / Karcinom jajnika - probir i dijagnoza.

Despite advances in gynecologic oncology, ovarian cancer is still mostly diagnosed very late or in advanced stages, which leads to adverse outcome of the disease. The pathogenesis of this disease as well as the risk factors for its development are not completely understood, while symptoms in the early stage of disease are sometimes nonspecific and delay earlier diagnosis. The aim is to present recent knowledge about the screening and diagnosis of ovarian cancer, with sp6cial reference to the role of ultrasound in recognizing the disease and referring patients for further consultation.

Vaginal delivery and continuous epidural analgesia: should we change our clinical approach?

The aim of the study was to investigate the effects of continuous epidural analgesia (EA) on the course of vaginal delivery with an emphasis on duration of labor and instrumental interventions. In a prospective 2-year trial, the study group included singleton vaginal births between 35 and 41 gestational weeks with a vertex fetus, in which continuous EA with bupivacaine or chirocaine in concentration of 0.125% combined with 2-4 microg of fentanyl or 0.5 microg of sufenta was used. The control group was created randomly from laboring patients with singleton pregnancies but without EA. The groups were adjusted for epidemiological characteristics and compared regarding the obstetric data and perinatal outcome. Student t-test and Mann-Whitney U-test were performed for normally and non-normally distributed results, respectively. Out of 1284 patients, 551 pregnant women were included in the study group and 733 in the control group. The statistically significant differences between the groups related to duration of the first and second stage of labor, frequency of premature rupture of membranes, intrapartal complications, and incidence of operative deliveries were found. Both stages of labor were significantly protracted and the incidence of operative deliveries was higher in the study group of patients compared with controls. There is a need for an active obstetric approach and management of vaginal deliveries of women who receive continuous EA, particularly if it is medically indicated.

Role of bone morphogenetic proteins in human prostate cancer pathogenesis and development of bone metastases: immunohistochemical study.

Bone morphogenetic proteins (BMP) have the ability to induce ectopic bone formation. The findings of their expression in prostate cancers have been linked with specifically tumor progression to bone and development of osteosclerotic metastases. We investigated the expression pattern of BMP-2/4, -6 and -7 and the receptors BMPR-IA,-IB and -II in normal human prostate, organ-localized and metastatic prostate cancers. The expression we also examined in skeletal metastases caused by prostate cancer. In localized prostate cancers we found increased expression of BMP-6 and decreased expression of BMP-2/4 and -7. In metastatic prostate cancers the expression of examined BMPs decreased. The expression of BMPRs showed the tendency to be lower with progression of prostate cancer but the expression of BMPR-II was completely absent in metastatic prostate cancers. In bone metastases caused by prostate cancer we found high expression of BMP-2/4, -6 and -7. Decreased expression of BMPs and lose of BMPR-II expression, could suggest that the influence of BMPs on prostate cancer cells is inhibited and plays an important role in prostate cancer pathogenesis. High expression of osteogenic BMPs in prostate cancer bone metastases could explain their osteosclerotic properties.