Lysosomal and cytoskeletal events in epithelial salivary tumours as assessed by imunohistochemistry for CD63 and HSP27.

Little attention has been paid to immunohistochemically assessed, lysosomal activities in salivary neoplasia. In an attempt to remedy this, the present investigation applied immunohistochemistry for CD63 antigen (a lysosomal membranous protein) and HSP27 (a molecular chaperone with roles in intracellular homeostasis) to archival paraffin-embedded surgical specimens of 101 benign and malignant, epithelial salivary tumours. Diffuse cytoplasmic CD63 immunoreactivity was seen in serous cells in acinic cell carcinoma, and mucous cells in mucoepidermoid carcinoma, pleomorphic adenoma (PA) and Warthin tumour. Apical rims or bands of CD63 immunoreactivity were also seen in simple cells lining tubular structures in PA, acinic cell carcinoma, mucoepidermoid carcinoma and polymorphous (low-grade) adenocarcinoma; and, occasionally, oncocytic luminal cells in Warthin tumour. HSP27 immunoreactivity was usually seen in non-luminal cells of PA, basal cells of oncocytic tumours, epidermoid cells of mucoepidermoid carcinoma and PA, and cells outlining aggregates or pseudolumina of adenoid cystic carcinoma. Expression of CD63 is preferentially associated with differentiated or simple luminal cell phenotypes in epithelial salivary tumours and possibly reflects autophagy of secretory granules or absorption of luminal material. Expression of HSP27 is preferentially associated with non-luminal cells and possibly reflects remodelling of the cytoskeleton.

Metastatic Epithelial-Myoepithelial Carcinoma in a Female Presenting with Neck Mass and Lytic Lesion in Acetabulum: A Diagnostic Challenge on Cytology.

Epithelial-myoepithelial carcinoma (EMC) is a rare, low-grade, malignant salivary neoplasm. Establishing an accurate cytological diagnosis is often challenging owing to its rarity, bland cytologic appearance and variable representation of cell populations in the smears. The diagnostic struggle is more so when the aspiration is from a metastatic site with an unknown primary, as in such cases the list of differential diagnoses expands further. A 58-year-old female presented with a low-back pain from last one month. On examination, she also had a level III, right cervical swelling for the last 20 years. Radiology revealed a lytic lesion in the left acetabulum. She had undergone surgery 35 years ago for a right-sided upper neck swelling, the medical records of which were not available. Fine needle aspiration (FNA) from the cervical swelling was performed. The smears were cellular and showed predominantly dispersed, round to polygonal tumor cells with mild pleomorphism, eccentric nuclei, coarse chromatin, occasional nucleoli and moderate cytoplasm with some showing vacuolations. The cell-block section revealed tumor cells arranged in the form of tubules lined by dual layer of tumor cells without any chondromyxoid stroma. On immunocytochemistry, the luminal cells showed positivity for CK7 (epithelial marker) and the abluminal cells showed positivity for p63 (myoepithelial marker). Based on these features, a final diagnosis of metastatic epithelial-myoepithelial carcinoma was rendered. The present report highlights the characteristic cytomorphological and immunocytochemical features of EMC and reiterates the diagnostic accuracy of FNAC for diagnosis of such challenging cases.

PD-1 and PD-L1 expression in thymic epithelial tumours and non-neoplastic thymus.

AIMS: We explored the relationships between programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) expression and the pathological and clinical features of thymic epithelial tumours and thymic hyperplasia. METHODS: We evaluated PD-1 and PDL-1 expressions within epithelial and microenvironmental components in thymic epithelial tumours (n=44) and thymic hyperplasias (n=8), immunohistochemically. We compared the results with demographic, clinical and histopathological features of the cases. RESULTS: We found 48% epithelial expression and 82.7% microenvironment expression for PD-1 and 11.5% epithelial expression and 34.6% microenvironment expression for PD-L1. There was no PD-1 expression, in either the epithelial or microenvironment, in the thymic hyperplasia group. PD-1 and PD-L1 positivity was more significant in thymic epithelial tumours than thymic hyperplasia. Patients with PD-1-positive microenvironments exhibited significantly shorter mean estimated survival time than their negative counterparts. CONCLUSION: These findings suggest that anti-PD-1 and anti-PD-L1 therapies may benefit patients due to high release of PD-1 and PD-L1 in thymic epithelial tumours.

Clinical benefit and risk of death with endocrine therapy in ovarian cancer: A comprehensive review and meta-analysis.

BACKGROUND: Steroid hormones promote epithelial ovarian cancer (EOC) growth and their receptor expression is associated with disease outcome. Hormone therapy is frequently used in pretreated EOC, but the magnitude of activity overall and by specific agents or tumor characteristics is unknown. METHODS: Clinical Benefit Rates (CBR) and deaths from clinical trials of endocrine agents were meta-analyzed. Summary estimates of CBR (SCBR) and Odd Ratio for death (SOR) were calculated according with type of drug, ER and PgR status, platinum resistance, line of therapy, tumor grade and tamoxifen dose. RESULTS: Fifty-three trials in 2490 patients were analyzed. Overall, SCBR was 41% (95%CI, 0.34-0.48) for any endocrine treatment, 43% (95%CI, 0.30-0.56) for tamoxifen, 39% (95%CI, 0.29-0.50) for aromatase inhibitors and 37% (95%CI, 0.26-0.48) for progestins. The SCBR for ER+ and/or PgR+ tumors was 46% (95%CI, 0.34-0.57) versus 37% (95%CI, 0.27-0.48) in tumors with unknown receptors and 55% in platinum sensitive (95%CI, 0.28-0.80) versus 40% (95%CI, 0.29-0.51) in platinum resistant tumors The SOR for death calculated from 6 out of 9 randomized clinical trials (RCTs) showed a reduced mortality with endocrine therapy (SOR=0.69, 95%CI, 0.50-0.97), with a possible tendency for a greater effect in first line and low grade tumors. The overall quality of the RCTs was low. CONCLUSIONS: The activity of endocrine therapy in advanced EOC is worth considering and seems to support large properly designed randomized trials in the first treatment of hormone sensitive EOC.

A randomised, open-label, phase 2 study of the IDO1 inhibitor epacadostat (INCB024360) versus tamoxifen as therapy for biochemically recurrent (CA-125 relapse)-only epithelial ovarian cancer, primary peritoneal carcinoma, or fallopian tube cancer.

OBJECTIVE: Indoleamine 2,3-dioxygenase-1 (IDO1) is a key regulator of immune tolerance in ovarian cancer. This study investigated efficacy and safety of the IDO1 enzyme inhibitor epacadostat versus tamoxifen in patients with biochemical-only recurrence (CA-125 elevation) following complete remission after first-line chemotherapy for advanced epithelial ovarian, primary peritoneal, or fallopian tube cancer. METHODS: In this open-label, phase 2 study (NCT01685255), patients were randomised 1:1 to epacadostat 600mg or tamoxifen 20mg twice daily for successive 28-day cycles and stratified by time since completion of first-line chemotherapy to first CA-125 elevation (3 to <12 or ≥12months). The primary endpoint was investigator-assessed progression-free survival (PFS; RECIST v1.1). Secondary endpoints included CA-125 response (Gynecologic Cancer InterGroup criteria), overall survival, safety, and tolerability. RESULTS: The study was terminated primarily due to slow accrual and lack of evidence of superiority. Median PFS was 3.75months for epacadostat (n=22) versus 5.56months for tamoxifen (n=20; HR, 1.34 [95% CI, 0.58-3.14]; P=0.54). Of evaluable patients, 1 (5.0%) epacadostat and 3 (15.8%) tamoxifen patients had confirmed CA-125 responses. The most common treatment-emergent adverse event was fatigue (epacadostat, 36.4%; tamoxifen, 40.0%). Immune-related adverse events, observed with epacadostat only, were primarily rash (18.2%) and pruritus (9.1%). Epacadostat pharmacokinetics/pharmacodynamics were consistent with its known mechanism of action. IDO1 expression was observed in 94% of archival tumour samples. CONCLUSIONS: This first report of immunotherapy evaluation in biochemical-only relapse ovarian cancer and of IDO1 inhibitor monotherapy in ovarian cancer found no significant difference in efficacy between epacadostat and tamoxifen. Epacadostat was generally well tolerated.

Immunohistochemical evaluation of epithelial ovarian carcinomas identifies three different expression patterns of the MX35 antigen, NaPi2b.

BACKGROUND: To characterize the expression of the membrane transporter NaPi2b and antigen targeted by the MX35 antibody in ovarian tumor samples. The current interest to develop monoclonal antibody based therapy of ovarian cancer by targeting NaPi2b emphasizes the need for detailed knowledge and characterization of the expression pattern of this protein. For the majority of patients with ovarian carcinoma the risk of being diagnosed in late stages with extensive loco-regional spread disease is substantial, which stresses the need to develop improved therapeutic agents. METHODS: The gene and protein expression of SLC34A2/NaPi2b were analyzed in ovarian carcinoma tissues by QPCR (n = 73) and immunohistochemistry (n = 136). The expression levels and antigen localization were established and compared to the tumor characteristics and clinical data. RESULTS: Positive staining for the target protein, NaPi2b was detected for 93% of the malignant samples, and we identified three separate distribution patterns of the antigen within the tumors, based on the localization of NaPi2b. There were differences in the staining intensity as well as the distribution pattern when comparing the tumor grade and histology, the mucinous tumors presented a significantly lower expression of both the targeted protein and its related gene. CONCLUSION: Our study identified differences regarding the level of the antigen expression between tumor grade and histology. We have identified differences in the antigen localization between borderline tumors, type 1 and type 2 tumors, and suggest that a pathological evaluation of NaPi2b in the tumors would be helpful in order to know which patients that would benefit from this targeted therapy.

Expression of PD-1 and PD-L1 in thymic epithelial neoplasms.

Thymic epithelial neoplasms are rare tumors that are difficult to diagnose and treat. Programmed death 1 (PD-1) receptor and its ligand (PD-L1) are expressed by various malignancies and are considered a prognostic factor and immunotherapeutic target. We examined the expression of both antibodies in 100 thymic epithelial neoplasms to assess their use as a biomarker and to correlate their expression with clinicopathological parameters. Whole-tissue sections of 74 thymomas and 26 thymic carcinomas were examined. Expression of PD-1 and PD-L1 was evaluated by immunohistochemistry and scored by the percentage of positive T-cells or tumor cells, respectively. Cases with strong membranous reactivity of the antibody in ≥5% of T-cells (PD-1) or tumor cells (PD-L1), respectively, were considered positive. Expression of PD-1 was detected in 52/100 cases (52%) including 6/26 thymic carcinomas (23%) and 46/74 thymomas (62%). PD-L1 was positive in 61/100 cases (61%) including 14/26 thymic carcinomas (54%) and 47/74 thymomas (64%). A total of 82 cases (82%) showed expression of PD-1 or PD-L1. PD-1+ cases were associated with higher stage in thymic carcinoma (P=0.01) and PD-1- cases with thymic carcinoma histology (P=0.0014), whereas PD-L1+ cases were associated with neoadjuvant therapy in thymoma (P=0.0065). There was no statistical difference between PD-1 or PD-L1 expression status and other clinicopathological parameters including overall survival. PD-1 and/or PD-L1 are expressed in up to 82% of thymic epithelial neoplasms. These results confirm that these tumors should be considered for PD-1/PD-L1-targeted therapy, however their predictive value in terms of prognosis remains uncertain.

New biomarkers in epithelial ovarian cancer: needed or redundant?

OBJECTIVE: For many years, intensive research has been dedicated to the development of sensitive biomarkers to detect various malignant diseases, including for the differentiation between a benign or malignant ovarian mass. One of these biomarkers is human epididymal protein 4 (HE4), which has been shown to have a higher specificity than, and comparable sensitivity to CA 125. HE4 is included in some predictive models. These new models have not yet been widely implemented in standard clinical care. The authors investigated the perceived need for new biomarkers and prediction models among Dutch gynecologists. MATERIALS AND METHODS: A web-based survey containing 38 questions was sent to all gynecologists (in training) registered by the Dutch Society of Obstetrics and Gynecology. RESULTS: 313 respondents completed the survey (23% response rate), of which 29% were specialized in or devoted at least part of their practice to oncology. Approximately two-thirds of the respondents indicated that there is a need for a new biomarker. Respondents indicated that they would use HE4 primarily as a diagnostic tool in the case of a pelvic mass (57%), followed by screening in case of risk factors (30%), detection of recurrent disease (23%), monitoring therapy response (22%), and as a prognostic factor (10%). Only 11% would not use HE4 at all. CONCLUSION: Evaluating the need for new technologies and diagnostics, including biomarkers, is important to avoid expensive research with min- imal clinical implications. In general, there is a perceived need for a new biomarker, if it can be used to improve the accuracy of diagnosis in patients with a pelvic mass.

Expression of a novel endothelial marker, C-type lectin 14A, in epithelial ovarian cancer and its prognostic significance.

OBJECTIVE: The purpose of this study was to evaluate microvessel density (MVD) as assessed by C-type lectin 14A (CLEC14A), which is a new marker for endothelial cells, and compare its expression to CD31 and CD105 in epithelial ovarian cancer (EOC). METHODS: MVD was evaluated in tumors (n = 50) from patients with EOC who underwent primary surgery and in patients with EOC who received preoperative chemotherapy (n = 49) using immunohistochemistry with antibodies to CLEC14A, CD31 and CD105. The median duration of follow-up was 24.5 months (range 1-101 months). The effect of prognostic factors on event-free survival (EFS) and overall survival (OS) was assessed using the Cox regression model. RESULTS: The amount of residual disease was found to be an independent prognostic factor in multivariate analysis with respect to EFS (P = 0.009) and OS (P < 0.001). The mean MVD of CLEC14A (MVD = 6), in tumors from patients who underwent primary surgery, was significantly lower than that of CD31 (MVD = 25, P < 0.0001) and CD105 (MVD = 11, P = 0.018). However, there was no significant correlation between MVD as detected by these markers and clinical outcome. There was no expression of CLEC14A in tumors from patients who received preoperative chemotherapy and the MVD of CD31 and CD105 was significantly reduced (P = 0.001 and 0.006, respectively) in this set of patients. CONCLUSION: This study demonstrates MVD as detected by CLEC14A in EOC. Treatment with chemotherapy reduces tumor blood vessels significantly. We suggest that CLEC14A may be a more specific endothelial marker to assess tumor angiogenesis.

HPIP expression predicts chemoresistance and poor clinical outcomes in patients with epithelial ovarian cancer.

This study aims to investigate the expression of the hematopoietic pre-B-cell leukemia transcription factor-interacting protein (HPIP) and its association with platinum resistance in epithelial ovarian cancer (EOC). The protein expression of HPIP was analyzed by immunohistochemistry in 248 patients with EOC. Furthermore, we analyzed the association between HPIP expression and clinicopathological features including prognosis in EOC samples. High HPIP expression was correlated with platinum resistance in EOCs. HPIP in platinum-resistant cases was overexpressed compared with that in platinum-sensitive cases (P<.001). Platinum resistance was independently correlated with the International Federation of Gynecology and Obstetrics stage and HPIP overexpression. High HPIP expression was positively correlated with International Federation of Gynecology and Obstetrics stage, histologic grade, residual tumor size, lymph node metastasis, serum levels of CA125, and poor prognosis. Our findings indicate that HPIP overexpression is an independent predictor of platinum-based chemotherapy resistance and that it may also be a potential biomarker for targeted therapy.

Seromucinous borderline tumor of the testis-A case report.

Tumors of ovarian epithelial type of testis are rare entities. After ruling out metastasis, especially from gastrointestinal origins, these neoplasms are categorized according to their ovarian correspondents, now including a new group of seromucinous tumors, which was introduced by the World Health Organization in 2013. Here we present the case of a 60-year-old man with a testicular tumor, showing focally stratified, immunohistochemical PAX8-positive epithelium and endometrioid-like stroma, supporting the diagnosis of seromucinous borderline tumor of ovarian-type surface epithelium. The two main competing hypotheses for the etiology of these neoplasms are development either by metaplasia of the mesothelium of the tunica vaginalis testis, or from remnants of Mullerian duct, which is supported by the notable positivity for PAX8 in our case. To our knowledge, we are the first to describe this newly defined entity of seromucinous borderline tumor of the testis in the English-speaking literature.

The CD47 "don't eat me signal" is highly expressed in human ovarian cancer.

OBJECTIVES: The CD47 "don't eat me" signal allows tumor immune evasion. We tested the association of CD47 expression with outcomes in EOC. METHODS: CD47 expression was examined within the TCGA database for ovarian carcinoma. For validation, IHC was performed on a TMA consisting of specimens from 265 patients with EOC. The medical records of the patients were also retrospectively reviewed to correlate demographic and survival data. RESULTS: CD47 was amplified in 15/316 (5%) ovarian serous cancers in TCGA. In the validation cohort, the majority of patients had stage III/IV disease (208/265, 78.4%). CD47 expression was seen in 210/265 (79.2%). Patients were categorized into CD47hi (129/265; 48.7%) versus CD47lo (136/265; 51.3%). Patients with CD47lo tumors were more likely to have a complete response to adjuvant therapy than CD47hi (65% vs 50%, p=0.026). Although there was a trend towards an increase in median OS (37.64 vs 45.26months, p=0.92) in the CD47lo group compared with CD47hi, the difference was not significant. CONCLUSIONS: CD47 is expressed at high frequency in EOC. Patients with CD47lo EOC had a better treatment response to standard therapy, and trended towards improved OS. This demonstrates that while CD47 may be an immunologic shield that may be considered for targeted therapies, it is likely that it operates in concert with other mechanisms of immune evasion. Future studies to evaluate CD47 expression with other known mechanisms of immune escape in the tumor microenvironment may help further define its role.

The comparison of glycosphingolipids isolated from an epithelial ovarian cancer cell line and a nontumorigenic epithelial ovarian cell line using MALDI-MS and MALDI-MS/MS.

Glycosphingolipids (GSLs) are important biomolecules, which are linked to many diseases such as GSL storage disorders and cancer. Consequently, the expression of GSLs may be altered in ovarian cancer cell lines in comparison to apparently healthy cell lines. Here, differential expressions of GSLs in an epithelial ovarian cancer cell line SKOV3 and a nontumorigenic epithelial ovarian cell line T29 were studied using matrix-assisted laser desorption/ionization-mass spectrometry (MALDI-MS) and MALDI-MS/MS. The isolation of GSLs from SKOV3 and T29 cell lines was carried out using Folch partition. GSLs were successfully detected by MALDI-MS, and structurally assigned by a comparison of their MALDI-MS/MS fragmentation patterns with MS/MS data found in SimLipid database. Additionally, LIPID MAPS was used to assign GSL ion masses in MALDI-MS spectra. Seventeen neutral GSLs were identified in Folch partition lower (chloroform/methanol) phases originating from both cell lines, while five globo series neutral GSLs were identified only in the Folch partition lower phase of SKOV3 cell line. Several different sialylated GSLs were detected in Folch partition upper (water/methanol) phases of SKOV3 and T29 cell lines. Overall, this study demonstrates the alteration and increased glycosylation of GSLs in an epithelial ovarian cancer cell line in comparison to a nontumorigenic epithelial ovarian cell line.

The associations between serum VEGF, bFGF and endoglin levels with microvessel density and expression of proangiogenic factors in malignant and benign ovarian tumors.

AIM OF THE STUDY: To investigate whether serum levels of VEGF, bFGF and endoglin correlate with tumor VEGF and bFGF expression or microvessel density (MVD) in ovarian cancer. PATIENTS AND METHODS: Forty five patients with epithelial ovarian cancers (EOCs) and 38 patients with benign ovarian tumors (BOTs) were included into the study. Serum levels of VEGF, bFGF and endoglin were assessed using ELISA. The expression of VEGF and bFGF in tumor samples were evaluated using ELISA of supernatants obtained from tumor homogenization. MVD was analyzed using immunohistochemistry with antibodies against CD31, CD34 and CD105. RESULTS: Serum VEGF levels were significantly higher in EOCs than in BOTs (436.6pg/ml [19.67-2860] vs 295.5pg/ml [123-539], P=0.025). Serum endoglin levels were lowered in the group EOCs when compared to BOTs (33,720g/ml [12,220-73,940] vs 42,390pg/ml [19,380-56,910], P=0.015). There were no differences in bFGF levels between studied groups. EOCs have significantly higher CD105 MVD (25 vessels/mm2 [0-57] vs 6 vessels/mm2 [0-70], P<0.001) and tumor VEGF (405.9pg/mg protein [0-3000] vs 2.225 [0-634.7], P<0.001) expression than BOTs, while, bFGF expression was higher in BOTs than in EOCs (2076pg/mg protein [668.1-8718] vs 847.3pg/mg protein [188.9-8333], P=0.003). In patients with EOCs we have observed negative correlation between serum VEGF concentration and its tissue expression (r Spearman=-0.571, P=0.0261), and serum VEGF concentration correlated positively with CD34-MVD (r Spearman=0.545, P=0.0289). In a multiple regression analysis we have observed only the negative correlation between serum VEGF and CD105-MVD (r=-0.5288, P=0.0427). CONCLUSIONS: Serum VEGF is a useful marker for prediction of ovarian cancer MVD and tumor VEGF expression.

Prognostic role of excision repair cross complementing-1 and topoisomerase-1 expression in epithelial ovarian cancer.

OBJECTIVE: Epithelial ovarian cancer is the most lethal gynecologic cancer worldwide and chemoresistance is one of the major causes of treatment failure. We investigated whether ERCC1, TAU, TOPO2A, TOPO1, P53, and C-MYC expression could be used as predictors for treatment outcomes. MATERIALS AND METHODS: Immunohistochemical staining was used to examine the expression of these biomarkers in resected tumor specimens from 38 patients treated in our institute. Clinicopathological data including demographics, staging, histological type, treatment response, expression of the biomarkers, and patient outcomes were analyzed. RESULTS: The median follow-up period was 47.5 months (range, 10-135 months) and the median overall survival was 56.0 months. Patients who did not have expression of ERCC1, and those who had expression of TOPO1 had significantly better overall survival. Cox regression analysis also confirmed that these two biomarkers were significant independent factors predicting survival (ERCC1, hazard ratio 5.51, 95% confidence interval: 2.02-14.00, p = 0.001; TOPO1, hazard ratio 0.22, 95% confidence interval: 0.06-0.77, p = 0.017). CONCLUSION: We concluded that poor overall survival was significantly associated with positive ERCC1 and negative TOPO1 expression. The results might be the consequence of chemoresistance to platinum and camptothecins, both of which are commonly used regimens in the treatment of epithelial ovarian cancer.

Clear cell carcinomas of the ovary: a mono-institutional study of 73 cases in China with an analysis of the prognostic significance of clinicopathological parameters and IMP3 expression.

BACKGROUND: Ovarian clear cell carcinoma (CCC) is an uncommon subtype of ovarian epithelial tumor. The prognostic significance of its clinicopathological parameters is discordant, with the exception of stage as the adverse prognostic factor. The present study aimed to evaluate the prognostic significance of its clinicopathological characteristics and the expression of IMP3 (Insulin-like growth factor-II mRNA-binding protein 3, IMP3 or IGF2BP3) in Chinese patients with primary pure CCC. METHODS: We collected clinicopathological data from 73 cases with a minimum of 5 years of follow-up and evaluated the expression of IMP3 by immunohistochemistry. RESULTS: In total, 49.3 % of the patients were in stage I. Advanced stages were closely related to poor prognosis of disease-free survival (DFS) and overall survival (OS) (P < 0.005). Patients with CCC coexisting with endometriosis tended to be younger and to have unilateral involvement but did not exhibit differences in prognosis compared with patients with CCC without endometriosis. Other histological features such as growth pattern, mitosis, and necrosis did not have prognostic significance. IMP3 was positive in 63 % of patients (46 of 73 cases); Thus, positive expression of IMP3 is an adverse prognostic marker in terms of OS (P = 0.012), even in stage I patients (P = 0.038). CONCLUSIONS: The present study demonstrates that IMP3 expression is a prognostic marker, with the exception of stage. IMP3 represents a biomarker of unfavorable prognosis even in stage I patients.

Morphologic, Immunophenotypic, and Molecular Features of Epithelial Ovarian Cancer.

Epithelial ovarian cancer comprises a heterogeneous group of tumors. The four most common subtypes are serous, endometrioid, clear cell, and mucinous carcinoma. Less common are transitional cell tumors, including transitional cell carcinoma and malignant Brenner tumor. While in the past these subtypes were grouped together and designated as epithelial ovarian tumors, these tumor types are now known to be separate entities with distinct clinical and biologic behaviors. From a therapeutic standpoint, current regimens employ standard chemotherapy based on stage and grade rather than histotype. However, this landscape may change in the era of personalized therapy, given that most subtypes (with the exception of high-grade serous carcinoma) are relatively resistant to chemotherapy. It is now well-accepted that high-grade and low-grade serous carcinomas represent distinct entities rather than a spectrum of the same tumor type. While they are similar in that patients present with advanced-stage disease, their histologic and molecular features are entirely different. High-grade serous carcinoma is associated with TP53 mutations, whereas low-grade serous carcinomas are associated with BRAF and KRAS mutations. Endometrioid and clear cell carcinomas typically present as early-stage disease and are frequently associated with endometriosis. Mucinous carcinomas typically present as large unilateral masses and often show areas of mucinous cystadenoma and mucinous borderline tumor. It must be emphasized that primary mucinous carcinomas are uncommon tumors, and metastasis from other sites such as the appendix, colon, stomach, and pancreaticobiliary tract must always be considered in the differential diagnosis. Lastly, transitional cell tumors of the ovary, specifically malignant Brenner tumors, are quite uncommon. High-grade serous carcinoma often has a transitional cell pattern, and adequate sampling in most cases shows more typical areas of serous carcinoma. Immunohistochemical markers are routinely employed in the diagnosis of epithelial ovarian carcinomas. However, molecular testing of these tumors, unlike in endometrial carcinoma, is not routinely used in clinical practice.

Acute-phase glycoprotein N-glycome of ovarian cancer patients analyzed by CE-LIF.

Epithelial ovarian cancer (EOC) is the most frequent cause of death from all gynecological malignancies because of its late diagnosis. As N-glycosylation is modified in the course of ovarian cancer, it is a promising source of tumor biomarkers. In this work, serum glycoproteins, depleted from albumin and IgG, were separated by 2DE. Protein spots of acute-phase proteins were identified by peptide mapping and their corresponding glycan moieties were released enzymatically, fluorescently labeled and analyzed by CE-LIF. In the positive acute-phase proteins, haptoglobin, α1-antitrypsin, and α1-antichymotrypsin, an increase of antennarity and Lewis(X) motif could be measured in EOC patients on tri- and/or tetraantennary N-glycans. Tetraantennary N-glycans containing three Lewis(X) epitopes and triantennary N-glycans containing a ß(1-6) branch and a Lewis(X) epitope were only present in EOC patients. We also showed for the first time that the core-fucosylated biantennary digalactosylated N-glycan of α1-acid glycoprotein is a potential biomarker for EOC. To conclude, core-fucosylated biantennary N-glycans on α1-acid glycoprotein as well as higher antennarity and increased amounts of Lewis(X) motif on haptoglobin, α1-antitrypsin, and α1-antichymotrypsin are promising biomarkers for EOC. Nevertheless, their specificity and selectivity for the early detection of EOC should be evaluated in a larger study.

Fascin-1 expression as stratification marker in borderline epithelial tumours of the ovary.

AIMS: To evaluate the actin-bundling protein fascin-1 (FSCN1) as marker for borderline ovarian tumours (BOTs). METHODS: We analysed a retrospective cohort of 140 BOTs with validated diagnosis by an independent pathologist. Immunohistochemical detection of FSCN1 was quantified as combined immunoreactive score (CIS) blinded to clinical patient data. Analyses were first performed for FSCN1 positive versus negative, and then verified using three categories derived from the observed distribution (negative, weak, strong; CIS 0, 1-2, 3-9). RESULTS: We detected FSCN1 positivity in 51.4%, and strong expression (CIS 3-9) in 14.3% of the samples. FSCN1 positivity was associated with serous subtype (p<0.001) and micropapillary pattern (p<0.001). Correlation with micropapillary pattern remained significant within the serous BOT (SBOT) subgroup (p=0.022). Strong FSCN1 expression (CIS 3-9) was associated both with the presence of implants (p=0.022), and a higher International Federation of Gynecology and Obstetrics (FIGO) stage (p=0.020). CONCLUSIONS: Our analysis links FSCN1 with SBOT with micropapillary pattern. Strong expression is associated with higher FIGO stage and the presence of implants, both related to elevated risk of recurrence. Hence, FSCN1 is an interesting marker worth further analyses of its prognostic value in BOTs.