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Objective. The expression of the CDK inhibitor p27Kip1 and the extent of endogenous oxidative DNA damage were evaluated in the multistep cervical carcinogenesis.Methods. Archival specimens of low-grade (L) squamous intraepithelial lesions (SILs) (n = 32), high-grade (H) SILs (n = 24) and invasive carcinomas (n = 48) of the cervix were included in the analysis compared with normal cervical squamous epithelium (n =15). Expression level of p27Kip1 was evaluated by immunostaining. Immunohistochemical detection of 8-hydroxydeoxyguanosine (8-OHdG) was considered as marker of oxidative DNA damage in the same tissues.Results. p27Kip1 was constantly expressed in normal epithelium with a mean percentage of positive cells higher than 50%. A progressive significant reduction in the mean percentage of positive cells was observed in L-SIL (18.1%), H-SIL (7.3%) and in invasive carcinomas (2.5%). A progressive significant increase in the levels of 8-OHdG and in the percentage of mean positive cells was observed from L-SIL (2.2%) to H-SIL (12.5%) to invasive carcinomas (25.2%). p27Kip1 and 8-OHdG expression displayed a significant inverse relationship.Conclusions. Expression of p27Kip1 is down-regulated while oxidative DNA damage increases during cervical carcinogenesis. Both parameters are altered at early stages of the process and might help to predict patients at high risk of progression. [Copyright &y& Elsevier]

Over recent years, there has been significant progress in the development of immunotherapeutic molecules designed to block the PD-1/PD-L1 axis. These molecules have demonstrated their ability to enhance the immune response by prompting T cells to identify and suppress neoplastic cells. PD-L1 is a type 1 transmembrane protein ligand expressed on T lymphocytes, B lymphocytes, and antigen-presenting cells and is considered a key inhibitory checkpoint involved in cancer immune regulation. PD-L1 immunohistochemical expression in gynecological malignancies is extremely variable based on tumor stage and molecular subtypes. As a result, a class of monoclonal antibodies targeting the PD-1 receptor and PD-L1, known as immune checkpoint inhibitors, has found successful application in clinical settings. In clinical practice, the standard method for identifying suitable candidates for immune checkpoint inhibitor therapy involves immunohistochemical assessment of PD-L1 expression in neoplastic tissues. The most commonly used PD-L1 assays in clinical trials are SP142, 28–8, 22C3, and SP263, each of which has been rigorously validated on specific platforms. Gynecologic cancers encompass a wide spectrum of malignancies originating from the ovaries, uterus, cervix, and vulva. These neoplasms have shown variable response to immunotherapy which appears to be influenced by genetic and protein expression profiles, including factors such as mismatch repair status, tumor mutational burden, and checkpoint ligand expression. In the present paper, an extensive review of PD-L1 expression in various gynecologic cancer types is discussed, providing a guide for their pathological assessment and reporting. • Immune checkpoint inhibitors targeting PD-1 and PD-L1 found successful applications in clinical settings. • Immunohistochemistry for PD-L1 represents the standard method to select patients for immunotherapy. • PD-L1 expression in gynecologic malignancies is extremely variable, based on tumor stage and molecular subtypes. • Gynecologic cancers have shown variable response to immunotherapy. • PD-L1 expression in different gynecologic malignancies is discussed, with a guide for assessment and reporting. [ABSTRACT FROM AUTHOR]

Abstract: Objectives. : Alterations of the β subunit of tubulin have been reported to be predictive of resistance to radiation and antitubulin agents in several solid tumors. The aim of the study was to investigate the clinical role of β III tubulin expression as prognostic factor for survival and as a predictive parameter of response to preoperative radiochemotherapy in a single institutional series of locally advanced cervical cancer (LACC) patients. Methods. : The study included 98 LACC patients admitted to the Gynecologic Oncology Unit, Catholic University of Rome and Campobasso between January 1998 and January 2005. Immunohistochemistry was performed by using the polyclonal rabbit anti-β III tubulin antibody (Covance, Princeton, NJ, USA). The value of 10% immunostained tumor cells was arbitrarily chosen as cut-off value to distinguish cases with high versus low β III tubulin content. Results. : In the whole series, β III tubulin immunoreaction was detectable in 66/98 cases (67.3%), and the percentage of positively stained cells ranged from 0 to 100% (median=10%). The percentages of cases with high β III tubulin expression were shown not to be differently distributed according to clinico-pathological characteristics. There was no statistically significant difference in the distribution of cases with high β III tubulin expression according to clinical and pathological response to treatment. During the follow-up period, recurrence and death of disease occurred in 15 and 13 cases, respectively. There was no difference in disease-free and overall survival in cases with high versus low β III tubulin expression. Conclusions. : The assessment of class III β tubulin status seems of little usefulness in order to identify LACC patients with poor chance of response to concomitant radiochemotherapy and unfavorable prognosis. [Copyright &y& Elsevier]

The aim of the study was to analyze the accuracy, the positive and negative predictive values, the specificity, and the sensitivity of the pelvic node frozen section examination in endometrial (EC) and cervical cancer (CC) patients. An accurate evaluation of the results of the frozen section examination in patients submitted to neoadjuvant treatments (chemotherapy and radiochemotherapy), and a comparison between specialist and general pathologist results were performed.A total of 186 consecutive patients with endometrial [52 cases (27.9%)] and cervical [134 cases (72.1%)] cancer underwent surgery at our Department between January 2000 and September 2003. All patients underwent a systematic pelvic lymphadenectomy. While all definitive diagnosis were primarily performed or secondarily revised by the specialist pathologist, the frozen section examination was performed in 65 (35%) cases by the specialist pathologist and in 121 (65%) cases by a general pathologist.Two thousand seven hundred eighteen out of a total of 6710 pelvic lymph nodes, which underwent a definitive histological analysis, were also analyzed at intraoperative frozen section examination. In our series, we observed 10 false negative and five false positive cases. Six out of the 10 (60%) false negative cases and two out of the five (40%) false positive were found in the neoadjuvant treated cervical cancer patients. In this subgroup, five out the six (83.3%) false negative and the two false positive diagnoses were made by the general pathologist, while the specialist pathologist registered only one false negative diagnosis.Intraoperative examination of pelvic lymph nodes during surgery for endometrial and cervical cancer can be considered a safe procedure in the presence of an expert gynecologic oncological team, and can be safely performed in patients submitted to neoadjuvant treatments. [Copyright &y& Elsevier]

Lymph vascular space involvement (LVSI) is one of the most important prognostic factors in early stage cervical cancer. Its qualitative evaluation represents a milestone for patient risk stratification and treatment choice, but a semi-quantitative analysis of LVSI may offer a more truthful risk model, as already demonstrated for endometrial cancer. The present study aims to investigate the performances of a semi-quantitative evaluation of LVSI in terms of patient risk assessment. In this retrospective study were enrolled patients underwent surgical treatment for early cervical cancer from January 2009 to October 2018. A semi-quantitative evaluation such as the "three-tiered approach" was used to classify the LVSI pathway: negative vs. focal vs. diffuse. Diffuse LVSI was found to be a risk factor for lymph node metastasis (OR: 9.844, p < 0.001), and parametrial involvement (OR: 5.566, p < 0.001). Lymph nodal recurrences were more frequent in diffuse LVSI group (LVSI negative vs. focal LVSI p = 0.369; LVSI negative vs. diffuse LVSI p = 0.002; Focal LVSI vs. diffuse LVSI p = 0.214); and so distant recurrences (LVSI negative vs. focal LVSI p = 0.623; LVSI negative vs. diffuse LVSI p = 0.002; Focal LVSI vs. diffuse LVSI p = 0.026). Patients with diffuse LVSI showed a worse disease-free survival (DFS) than patients with focal or absent involvement (DFS LVSI negative vs. focal LVSI p = 0.938; LVSI negative vs. diffuse LVSI p < 0.001; focal LVSI vs. diffuse LVSI p = 0.036). Semi-quantitative evaluation of LVSI may be useful to identify risk patients for shorter disease-free survival and lymphatic and distant recurrences in patients with early stage. • In Early stage Cervical cancer, diffuse Lymph Vascular Space Involvement (LVSI) are a risk factor for lymph node metastasis. • Patients with diffuse LVSI show a worse disease-free survival (DFS) than patients with focal or absent involvement. • Lymph nodal and distant recurrences are more frequent in patients with diffuse LVSI. [ABSTRACT FROM AUTHOR]

A case of stage IB2 cervical cancer at 27 weeks of pregnancy, treated with neoadjuvant chemotherapy followed by radical Cesarean hysterectomy with full pelvic and infra-mesenteric lymphadenectomy, and adjuvant chemo-radiation is described. While she remains without disease, her baby was diagnosed with acute myelogenous leukemia. We highlight the pre-operative work-up, treatment options, safety, feasibility, and outcomes for the mother and her fetus. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To compare the diagnostic accuracy of ultrasound (US) and magnetic resonance imaging (MRI) in the preoperative assessment of early-stage cervical cancer using pathologic findings as the reference standard. Patients and methods: Prospective multi-center trial enrolling 209 consecutive women with early-stage cervical cancer (FIGO IA2–IIA) scheduled for surgery. The following parameters were assessed on US and MRI and compared to pathology: remaining tumor, size, tumor stromal invasion<2/3 (superficial) or ≥2/3 (deep), and parametrial invasion. Results: Complete data were available for 182 patients. The agreement between US and pathology was excellent for detecting tumors, correctly classifying bulky tumors (>4cm), and detecting deep stromal invasion (kappa values 0.84, 0.82, and 0.81 respectively); and good for classifying small tumors (<2cm) and detecting parametrial invasion (kappa values 0.78 and 0.75, respectively). The agreement between MRI and histology was good for classifying tumors as <2cm, or >4cm, and detecting deep stromal invasion (kappa values 0.71, 0.76, and 0.77, respectively). It was moderately accurate in tumor detection, and in assessing parametrial invasion (kappa values 0.52 and 0.45, respectively). The agreement between histology and US was significantly better in assessing residual tumor (p <0.001) and parametrial invasion (p <0.001) than the results obtained by MRI. Imaging methods were not significantly influenced by previous cone biopsy. Conclusion: US and MRI are highly accurate for the preoperative assessment of women with early-stage cervical cancer, although US may be more accurate in detecting residual tumors and assessing parametrial invasion. [Copyright &y& Elsevier]

Abstract: Objective. : No thorough investigation of the diagnostic performance of frozen section analysis in predicting the final status of lymph nodes after exposure to concomitant chemoradiation (CT/RT) has been performed until now. The aim of the study was to analyze the accuracy of pelvic lymph node frozen section examination in a large, consecutive series of locally advanced cervical cancer (LACC) patients undergoing preoperative CT/RT. Methods. : A total of 123 consecutive LACC patients underwent preoperative CT/RT followed by radical hysterectomy according to Piver classification, with bilateral systematic pelvic lymphadenectomy. If pelvic nodes were intraoperatively defined as positive for tumor metastasis, para-aortic lymphadenectomy up to inferior mesenteric artery was carried out. The diagnostic performance of frozen section examination of pelvic lymph nodes was assessed by calculating the negative predictive value (NPV), the positive predictive value (PPV), specificity, sensitivity, and overall accuracy. Results. : A total of 1647 and 4345 pelvic lymph nodes were analyzed by frozen section examination and at final diagnosis, respectively. Lymph node metastases were found in 11 cases (8.9%) at frozen section examination, and in 14 cases (11.4%) at definitive histological diagnosis. We found 7 incorrect diagnoses at frozen section examination, represented by 5 false negative and 2 false positive cases. Specificity, sensitivity, overall accuracy, NPV, and PPV were 98.2%, 64.3%, 94.3%, 95.5% and 81.8%, respectively. Conclusions. : Preoperative chemoradiation does not impair the role of frozen section analysis in predicting the pelvic lymph node involvement in LACC patients. [Copyright &y& Elsevier]

Abstract: Objectives. : Cervical and vulvar cancers develop through well-defined precursor lesions but their exact pathogenesis is still unknown. The dystroglycan complex is a transmembrane glycoprotein that forms a continuous link from the extracellular matrix to the actin cytoskeleton. Deregulated expression of dystroglycan has been reported in human malignancies and related to tumor differentiation and aggressiveness. In this study, expression of dystroglycan was evaluated in the multistep cervical and vulvar tumorigenesis. Methods. : Expression of the dystroglycan complex was evaluated by immunostaining in lesions representing different stages of vulvar and cervical tumorigenesis using a monoclonal antibody which recognizes carbohydratic epitopes on the α-dystroglycan subunit. Results. : α-dystroglycan was constantly detected in normal cervical epithelium with a mean percentage of positive cells higher than 80%. A progressive significant reduction in the mean percentage of positive cells was observed in low (67%) and high grade SIL (14%) and in invasive carcinomas (2.6%) of the cervix. In cancers, no differences were observed in terms of percentage of positive cells when cases were stratified according with either tumor grade or stage. A progressive significant reduction in the mean percentage of positive cells was also observed from normal vulvar epithelium (90%) to VIN1 (66%), VIN2 (28%) and invasive vulvar carcinomas (22%). No significant decrease in the α-dystroglycan staining was observed in squamous cell hyperplasia lesions (85%) while lichen sclerosus displayed a percentage of positive cells (47%) significantly lower than normal epithelium. Conclusions. : Detection of α-dystroglycan is frequently lost in human cervical and vulvar tumorigenesis and further studies are warranted to verify whether evaluation of this molecule might serve as marker of risk progression of preneoplastic lesions and to better understand its significance in terms of cancer development. [Copyright &y& Elsevier]