Role of endocervical curettage in the preoperative staging of endometrial carcinoma

Objective, The presence of cervical involvement is important to establish a rational treatment for endometrial cancer patients. We investigated the value of preoperative endocervical curettage (ECC) in predicting cervical involvement. Methods. Preoperative ECC of 290 patients with clinical stage I epithelial endometrial cancer was compared with histopathology of the uterus. Results, Amongst all ECCs, 245 (84.5%) were negative and 45 (15.5%) were positive for endometrial cancer. in the uterine specimen, cervical involvement was found in 20% (58/290). PPV and NPV of ECC were 86.7% and 92.2%. False negative and false positive ECC occurred in 6.6% and 2.1%, Of all patients with positive ECC, 46.7% had FIGO stage II disease and 46.7% had extra uterine tumor spread (FIGO III, IV). Conclusion. ECC is an acceptable diagnostic tool to predict the presence or absence of cervical involvement in early stage endometrial cancer patients. (C) 2008 Elsevier Inc. All rights reserved

Programmed death-1 ligands are expressed in the majority of advanced serous epithelial ovarian cancer

Introduction: Immunotherapeutic strategies have been developed and tested in ovarian carcinoma patients, but no single approach has proven clinical effective yet. These disappointing clinical results were explained by immune escape mechanisms such as the immune suppressive pathway of the programmed death-1 (PD-1) receptor, and its ligands PD-L1 and PD-L2. Objective: We determined the prognostic importance of immune inhibitory ligands PD-L1 and PD-L2, in a well-defined homogeneous subgroup of epithelial ovarian cancer (EOC). Methods: PD-L1/L2 expression was evaluated in primary advanced serous EOC tissue of 127 patients by immunohistochemistry using tissue microarrays (TMAs). PD-L1/L2 expression, was correlated with the number of tumor infiltrating lymphocytes (TIL) and TIL-subsets data, i.e. CD8+ cytotoxic- (CTL), FoxP3+ regulatory- (Tregs) and CD45R0+ memory T-lymphocytes. Results: PD-L1 and PD-L2 expression was observed in 65 (61.9%) and 77 (73.3%) of 127 tumor samples, respectively. Prognosis was not influenced by the expression of PD-L1 or PD-L2 in advanced serous EOC patients. Moreover, PD-L1 expression did not correlate with the number of one of the TIL subsets. PD-L2 expression correlated negatively with the number of memory T-cells [odds ratio (OR), 0.2; 95% confidence interval (95% CI), 0.1-0.5; P = 0.001] and positively with the number of CTL (OR, 3.2; 95% CI, 1.1-9.5, P = 0.037). Conclusion: Despite high expression rates of PD-L1/L2, PD-Ls have no prognostic impact in advanced serous EOC. Blockade of the PD-1/PD-Ls pathway may not provide a beneficial effect for immunotherapeutic treatment of advanced serous EOC

Status of cellular immunity lacks prognostic significance in vulvar squamous carcinoma

Objective. It is generally recognized that the immune system has an important role in regulating cancer development. Evidence indicating a prognostic role of the immune system in vulvar carcinoma is scarce. This study investigated the presence and prognostic significance of several aspects of the immune system in vulvar squamous carcinoma. Methods. The number of intratumoral CD8(+) and Foxp3(+) T-lymphocytes, next to HLA class I (HLA-A, HLA-B/C and beta(2)-m) and indoleamine 2,3-dioxygenase (IDO) expression was determined by immunohistochemistry in a consecutively selected cohort of 286 vulvar squamous carcinoma patients, all treated in the University Medical Center Groningen, the Netherlands. Associations between immunohistochemistry expression and the influence on survival were determined. Results. The number of tumor-infiltrating CD8(+) T-lymphocytes was significantly lower in tumors with loss of HLA-A (p=0.004), HLA-B/C (p=0.024) or beta(2)-m (p=0.025) expression compared with tumors with expression of HLA class I. No association was found between the number of intratumoral CD8(+) T-lymphocytes and Foxp3(+) T-lymphocytes, HLA class I and IDO expression and survival of vulvar squamous carcinoma patients. Conclusion. Our results indicate that the immune system does not seem to have a major influence on prognosis of patients with vulvar squamous carcinoma. (C) 2011 Elsevier Inc. All rights reserved

EGFR expression is associated with groin node metastases in vulvar cancer, but does not improve their prediction

Objectives. High morbidity of elective inguinofemoral lymphadenectomy in early stage vulvar cancer patients urges the need for defining a group of low-risk patients in whom inguinofemoral lymphadenectomy can be safely omitted. Aim of the study was to evaluate whether in addition to 'classic' clinicopathological factors determination of EGFR expression in vulvar cancer can be helpful in defining such a 'low-risk' group. Methods. Formalin-fixed paraffin-embedded tumor tissue samples of 197 surgically treated T1/2 patients were collected in a Tissue Micro Array (TMA). On this TMA, immumohistochemistry for EGFR was performed. Logistic regression analyses were performed including histopathological characteristics with the presence of nodal metastases as outcome. A predictive model was constructed, and absolute risks were calculated. Results. EGFR expression was present in 68% of the vulvar tumors and related to the presence of lymph node metastases (OR 2.12, 95% CI 1.09-4.10). Our predictive model with only clinicopathological factors was able to define a group of patients with a likelihood of absence of lymph node metastases of 13% (95% CI 5-36), which could be decreased to 6% (95% CI 0-29) after inclusion of EGFR expression (P=0.07). Conclusions. EGFR expression is present in the majority of vulvar tumors and is associated with groin node metastases in vulvar cancer. Current classic clinicopathological predictive factors for inguinofemoral lymph node metastases with or without EGFR analysis are not strong enough for identification of "sufficiently low" risk T1/2 vulvar cancer patients. Our predictive model approach however is excellent for evaluation of new cell biological parameters, associated with clinical outcome. (c) 2006 Published by Elsevier Inc

The role of chemokines in lymphocyte infiltration in ovarian cancer: from MRNA microarray to tissue microarray

Introduction: High numbers of CD8+ cytotoxic T lymphocytes (CTL) are associated with a survival advantage in ovarian cancer. Chemokines may play a role in T lymphocyte recruitment to the tumor, but they are also linked to metastasis and angiogenesis. Aim: To determine to what extent chemokines are involved in lymphocyte infiltration of ovarian cancer. Methods: We used microarray technology to rank chemokines based on their differential expression levels between tumors with many and few tumor infiltrating CTL. Next, we further investigated these results using immunohistochemistry and cytokine bead arrays. Results: Six chemokines and chemokine receptors were differentially expressed between 24 CTL high and 35 CTL low tumors. Based on these data and previous literature, we selected CXCL9, CXCL10, CXCL6 and CXCR6 for further validation. Stainings for these chemokines were performed on 254 tumor samples using tissue microarrays. There were no associations between chemokine (receptor) staining intensity and CTL infiltration. However, for CXCL10, high expression was associated with high stage, serous tumors, and >2 cm residual tumor after surgery. In univariate survival analysis, CXCL10 was associated with a worse prognosis. Next, we analyzed soluble CXCL10 at the serum level. For 98 patients, both tissue and serum were available. There were no associations between CXCL10 staining and serum concentrations. However, we found a positive correlation between CXCL10 in serum and CTL infiltration in the tumor. Conclusion: After validation of microarray results, we found a very limited role for chemokines in lymphocyte migration. However, CXCL10 is implicated in more aggressive tumor behavior

The epidermal growth factor receptor pathway in relation to pelvic lymph node metastasis and survival in early-stage cervical cancer

The objective of this study is to correlate the expression of epidermal growth factor receptor (EGFR) components with clinical behavior of early-stage cervical cancer. Tissue samples of 336 consecutive Federation of International Gynecologists and Obstetricians stage IB-IIA cervical cancer patients all treated primarily by radical surgery were collected. Clinicopathologic and follow-up data were prospectively obtained during standard treatment and follow-up. As representatives for the EGFR pathway, expression of EGFR, pEGFR, PTEN, pAKT, and pERK was assessed by immunohistochemistry on tissue microarrays. Positive immunostaining was observed for EGFR in 32.1%, for pEGFR in 21.0%, for PTEN in 38.3%, for pAKT in 5.3%, and for pERK in 4.3% of tumor samples. Positive EGFR immunostaining was associated with squamous cell carcinoma of the cervix (odds ratio [OR], 7.41; 95% confidence interval [CI], 3.38-16.23, P < .001), negative pEGFR immunostaining with poor differentiation (OR, 0.39; 95% CI, 0.20-0.73, P = .004), and negative PTEN immunostaining with metastatic pelvic lymph nodes (OR, 0.51; 95% CI, 0.30-0.90, P = .019). In multivariate analysis, only pelvic lymph node metastasis (hazard ratio, 6.11; 95% CI, 3.46-10.77, P < .001) and poor differentiation (hazard ratio, 1.91; 95% CI, 1.12-3.26, P = .018) were related to disease-specific survival. In early-stage cervical cancer, loss of PTEN expression is associated with pelvic lymph node metastasis, suggesting PTEN to be one of the tumor suppressor genes affecting pelvic lymph node metastasis. However, expression of EGFR pathway components does not appear to have prognostic impact in surgically treated early-stage cervical cancer

Potential target antigens for a universal vaccine in epithelial ovarian cancer

The prognosis of epithelial ovarian cancer (EOC), the primary cause of death from gynaecological malignancies, has only modestly improved over the last decades. Immunotherapeutic treatment using a cocktail of antigens has been proposed as a "universal" vaccine strategy. We determined the expression of tumor antigens in the context of MHC class I expression in 270 primary tumor samples using tissue microarray. Expression of tumor antigens p53, SP17, survivin, WT1, and NY-ESO-1 was observed in 120 (48.0%), 173 (68.9%), 208 (90.0%), 129 (56.3%), and 27 (11.0%) of 270 tumor specimens, respectively. In 93.2% of EOC, at least one of the investigated tumor antigens was (over) expressed. Expression of MHC class I was observed in 78.1% of EOC. In 3 out 4 primary tumors, (over) expression of a tumor antigen combined with MHC class I was observed. These results indicate that a multiepitope vaccine, comprising these antigens, could serve as a universal therapeutic vaccine for the vast majority of ovarian cancer patients

Tumor-infiltrating cytotoxic T Lymphocytes as independent prognostic factor in epithelial ovarian cancer with wilms tumor protein 1 overexpression

Immune response characterization at the primary tumor site enables the design of therapeutic vaccination strategies with higher efficacy in epithelial ovarian cancer (EOC). In this study, we related Wilms tumor protein 1 (WT1) overexpression, a well-established immunotherapeutic target, to clinicopathological characteristics, immunological parameters, and survival in primary EOC. WT1 overexpression was evaluated in primary EOC tissue of 270 patients by immunohistochemistry on tissue microarrays (TMAs). Clinicopathological characteristics, follow-up, and data on infiltration of CD8(+) cytotoxic T lymphocytes (CTLs), FoxP3(+) regulatory T lymphocytes (Tregs), major histocompatibility complex (MHC) class I, and II molecule expression, were derived from a previously published dataset. WT1 overexpression was defined as positive immunostaining for WT1. WT1 overexpression, present in 56.3% of EOC, was associated with infiltration of Tregs [ odds ratio (OR), 2.7; 95% confidence interval (95% CI), 1.6-4.7; P < 0.001] and up-regulation of MHC class II (OR, 2.2; 95% CI, 1.2-4.1; P = 0.014). Advanced stage (OR, 4.0; 95% CI, 1.9-8.6; P < 0.001) and serous histology (OR, 6.7; 95% CI, 3.2-13.6; P < 0.001) were independent predictors of WT1 overexpressing EOC. High number of CTL was an independent prognostic factor for progression-free survival (hazard ratio, 0.5; 95% CI, 0.3-0.8; P = 0.006) in WT1 overexpressing EOC. As WT1 overexpressing EOC is associated with CTL and Treg infiltration next to MHC class II up-regulation, future clinical trials should evaluate the combination of therapeutic WT1 vaccines with strategies depleting Tregs and/or up-regulating MHC class I, in an attempt to enhance clinical efficacy in EOC patients