• endometrial cancer
• immune evasion mechanisms
• immune response
• immunosuppressive microenvironment
• immunotherapy

• Barrett’s esophageal adenocarcinoma
• CD31
• D2–40

• Adenocarcinoma/etiology
• Adenocarcinoma/pathology
• Adenocarcinoma/surgery
• Adult
• Aged
• Aged, 80 and over
• Antibodies, Monoclonal, Murine-Derived/analysis
• Barrett Esophagus/complications
• Eosine Yellowish-(YS)/analysis
• Esophageal Neoplasms/etiology
• Esophageal Neoplasms/pathology
• Esophageal Neoplasms/surgery
• Esophagectomy
• Esophagus/pathology
• Esophagus/surgery
• Female
• Hematoxylin/analysis
• Humans
• Lymph Nodes/pathology
• Lymphatic Metastasis/diagnosis
• Male
• Middle Aged
• Mucous Membrane/pathology
• Neoplasm Invasiveness/diagnosis
• Neoplasm Recurrence, Local/pathology
• Platelet Endothelial Cell Adhesion Molecule-1/analysis
• Retrospective Studies
• Single-Blind Method
• Staining and Labeling/methods
• Treatment Outcome

Lymphovascular space invasion (LVSI) in endometrial cancer (EC) is an important prognostic variable impacting on a patient's individual recurrence risk and adjuvant treatment recommendations. Recent work has shown that grading the extent of LVSI further improves its prognostic strength in patients with stage I endometrioid EC. Despite this, there is little information on the reproducibility of LVSI assessment in EC. Therefore, we designed a study to evaluate interobserver agreement in discriminating true LVSI from LVSI mimics (Phase I) and reproducibility of grading extent of LVSI (Phase II).

Scanned haematoxylin and eosin (H&E) slides of endometrioid EC (EEC) with a predefined possible LVSI focus were hosted on a website and assessed by a panel of six European gynaecological pathologists. In Phase I, 48 H&E slides were included for LVSI assessment and in Phase II, 42 H&E slides for LVSI grading. Each observer was instructed to apply the criteria for LVSI used in daily practice. The degree of agreement was measured using the two‐way absolute agreement average‐measures intraclass correlation coefficient (ICC). Reproducibility of LVSI assessment (ICC = 0.64, P < 0.001) and LVSI grading (ICC = 0.62, P < 0.001) in EEC was substantial among the observers.

Given the good reproducibility of LVSI, this study further supports the important role of LVSI in decision algorithms for adjuvant treatment.

• LVSI
• LVSI grading
• endometrial neoplasms
• interobserver study
• lymphovascular space invasion
• observer variation

• Human Papilloma Virus
• cervical cancer
• endometrial cancer
• estrogens
• fibroblasts
• lymphocytes
• ovarian cancer
• pericytes
• tumor-associated macrophages

• Actins
• Chemokines/metabolism
• Cytokines/metabolism
• Endometrial Neoplasms/immunology
• Endometrial Neoplasms/metabolism
• Estrogen Receptor alpha/metabolism
• Estrogens/metabolism
• Female
• Fibroblasts/metabolism
• Humans
• Immune Tolerance
• Lymphocytes/metabolism
• Lymphocytes, Tumor-Infiltrating/metabolism
• Macrophages/metabolism
• Mesoderm/metabolism
• Oncogene Proteins/metabolism
• Ovarian Neoplasms/immunology
• Ovarian Neoplasms/metabolism
• Papillomaviridae
• Pericytes/metabolism
• Receptor, Platelet-Derived Growth Factor beta/metabolism
• Signal Transduction
• Stromal Cells/immunology
• Stromal Cells/metabolism
• Tumor Microenvironment/immunology
• Tumor Microenvironment/physiology
• Uterine Cervical Neoplasms/immunology
• Uterine Cervical Neoplasms/metabolism

• endometrial neoplasms
• lymphovascular space invasion
• survival analysis

• Adult
• Aged
• Aged, 80 and over
• Endometrial Neoplasms/pathology
• Endometrial Neoplasms/surgery
• Female
• Humans
• Lymph Node Excision
• Lymph Nodes/pathology
• Lymph Nodes/surgery
• Lymphatic Metastasis
• Lymphatic Vessels/pathology
• Lymphatic Vessels/surgery
• Middle Aged
• Neoplasm Invasiveness
• Prognosis
• Retrospective Studies
• Risk

• Blood vessel
• CD31
• Endometrial cancer
• Lympho-vascular invasion
• Podoplanin

• D2-40
• Intratumoral
• Lymphovascular invasion
• Merkel cell carcinoma
• Metastasis
• Peritumoral

• Cervical
• Endometrial
• Gynecologic cancers
• Microenvironment
• Ovarian
• Tumor-associated macrophages

Vulvar cancer is rare but incidence rates are increasing due to an aging population and higher frequencies of young women being affected. In locally advanced, metastatic or recurrent disease prognosis is poor and new treatment modalities are needed. Immune checkpoint blockade of the PD-1/PD-L1 pathway is one of the most important advancements in cancer therapy in the last years. The clinical relevance of PD-L1 expression in vulvar cancer, however, has not been studied so far. We determined PD-L1 expression, numbers of CD3⁺ T cells, CD20⁺ B cells, CD68⁺ monocytes/macrophages, Foxp3⁺ regulatory T cells and CD163⁺ tumor-associated macrophages by immunohistochemistry in 103 patients. Correlation analysis with clinicopathological parameters was undertaken; the cause-specific outcome was modeled with competing risk analysis; multivariate Cox regression was used to determine independent predictors of survival. Membranous PD-L1 was expressed in a minority of tumors, defined by HPV-negativity. Its presence geographically correlated with immunocyte-rich regions of cancer islets and was an independent prognostic factor for poor outcome. Our data support the notion that vulvar cancer is an immunomodulatory tumor that harnesses the PD-1/PD-L1 pathway to induce tolerance. Accordingly, immunotherapeutic approaches might have the potential to improve outcome in patients with vulvar cancer and could complement conventional cancer treatment.

• HPV
• PD-L1
• immune checkpoint
• prognostic factor
• vulvar cancer

• Endometrial cancer
• distant metastasis
• immunohistochemistry
• lymph node metastasis
• vascular invasion

To assess the prognostic value of lymphovascular invasion (LVI) in Bismuth-Corlette type IV hilar cholangiocarcinoma (HC) patients.

A retrospective analysis was performed on 142 consecutively recruited type IV HC patients undergoing radical resection with at least 5 years of follow-up. Survival analysis was performed by the Kaplan-Meier method, and the association between the clinicopathologic variables and survival was evaluated by log-rank test. Multivariate analysis was adopted to identify the independent prognostic factors for overall survival (OS) and disease-free survival (DFS). Multiple logistic regression analysis was performed to determine the association between LVI and potential variables.

LVI was confirmed histopathologically in 29 (20.4%) patients. Multivariate analysis showed that positive resection margin (HR = 6.255, 95%CI: 3.485-11.229, P < 0.001), N1 stage (HR = 2.902, 95%CI: 1.132-7.439, P = 0.027), tumor size > 30 mm (HR = 1.942, 95%CI: 1.176-3.209, P = 0.010) and LVI positivity (HR = 2.799, 95%CI: 1.588-4.935, P < 0.001) were adverse prognostic factors for DFS. The independent risk factors for OS were positive resection margin (HR = 6.776, 95%CI: 3.988-11.479, P < 0.001), N1 stage (HR = 2.827, 95%CI: 1.243-6.429, P = 0.013), tumor size > 30 mm (HR = 1.739, 95%CI: 1.101-2.745, P = 0.018) and LVI positivity (HR = 2.908, 95%CI: 1.712-4.938, P < 0.001). LVI was associated with N1 stage and tumor size > 30 mm. Multiple logistic regression analysis indicated that N1 stage (HR = 3.312, 95%CI: 1.338-8.198, P = 0.026) and tumor size > 30 mm (HR = 3.258, 95%CI: 1.288-8.236, P = 0.013) were associated with LVI.

LVI is associated with N1 stage and tumor size > 30 mm and adversely influences DFS and OS in type IV HC patients.

• Bismuth-Corlette classification
• Disease-free survival
• Lymphovascular invasion
• Overall survival
• Hilar cholangiocarcinoma

• Adult
• Aged
• Bile Duct Neoplasms/diagnostic imaging
• Bile Duct Neoplasms/mortality
• Bile Duct Neoplasms/pathology
• Bile Duct Neoplasms/surgery
• Cholangiography/methods
• Disease-Free Survival
• Female
• Follow-Up Studies
• Hepatic Duct, Common/diagnostic imaging
• Hepatic Duct, Common/pathology
• Hepatic Duct, Common/surgery
• Humans
• Kaplan-Meier Estimate
• Klatskin Tumor/diagnostic imaging
• Klatskin Tumor/mortality
• Klatskin Tumor/pathology
• Klatskin Tumor/surgery
• Lymphatic Metastasis
• Male
• Middle Aged
• Neoplasm Invasiveness/diagnostic imaging
• Neoplasm Invasiveness/pathology
• Neoplasm Staging
• Prognosis
• Retrospective Studies
• Risk Factors
• Young Adult

• Adjuvant therapy
• Endometrial cancer
• Lymph node metastasis
• Lymphovascular space invasion
• Nomogram

VEGF and podoplanin (PDPN) have been identified as angiogenesis and/or lymphangiogenesis regulators and might be essential to restrict tumor growth, progression, and metastasis. In the present study, we evaluate the association between the expression of these markers and CIN grade. Immunohistochemistry was performed in 234 uterine cervical samples using conventional histologic sections or TMA with the monoclonal antibodies to VEGF (C-1 clone) and podoplanin (D2-40 clone). Positive-staining rates of VEGF in 191 CIN specimens were significantly associated with histological grade (P < 0.001). Negative and/or focal immunostaining for PDPN were more frequent in CIN 3 (P = 0.016). We found that patients with CIN 3 more frequently had strong and more diffuse staining for VEGF and diminished staining for PDPN (P = 0.018). Strong and more diffuse VEGF immunoexpressions in CIN 2 and CIN 3 were detected when compared to CIN 1. Negative and/or focal PDPN immunoexpression appear to be more frequent in CIN 3. Moderate to strong VEGF expression may be a tendency among patients with high-grade lesions and diminished PDPN expression.

• Lymphangiogenesis
• Lymphatic vascular endothelial progenitor cells
• Ovarian cancer
• VEGF-C

To investigate the meaning of lymphadenectomy (LNE) in women with endometrial cancer (EC) for clinical outcome and secondly to determine the impact of the method of adjuvant radiotherapy (RT) on survival as well as to define prognostic factors.

322 patients (pts) underwent adjuvant RT for endometrioid EC at our department from 2004 until 2012 and were included in this retrospective study. Chi-square test, LogRank test and Cox regression were used for statistical analyses.

Median age at diagnosis: 66 years. FIGO stages: FIGO I 69.4 %, FIGO II 15.3 %, FIGO III 14.5 %, FIGO IV 0.9 %. Surgical staging: 30.6 % pelvic/paraaortic LNE, 45 % sole pelvic LNE, 8.8 % sampling of suspicious lymph nodes, 15.6 % no LNE. Adjuvant chemotherapy (ChT): 3.2 %. Sole intravaginal brachytherapy (IVB): 60.2 %. IVB + external beam radiotherapy (EBRT): 39.8 %. 5-year local recurrence free survival (LRFS): 90.6 %, distant metastases free survival (DMFS): 89.8 %, overall survival (OS):79.3 %. In multivariate analysis age (p = .007), pT stage (p = .029), lymph node status (p = .003), grading (p = .011) and lymphovascular space invasion (LVSI; p = .008) remained as independent prognostic factors for OS. Resection status (p = .01) and LVSI (p = .014) were independent prognostic factors for LRFS and LVSI (p = .008) was the only independent prognostic factor for DMFS. There was no statistically significant survival benefit from LNE in LRFS (p = .561), DMFS (p = .981) or OS (p = .791). 5-year LRFS in stage I and II: 96.0 and 82.9 % after sole IVB, 90.8 and 81.6 % after combined IVB/EBRT (p = .105; p = .970). 5-year OS rates for stage I and II: 86.5 and 71.3 % after sole IVB, 84.2 % and 69.2 % after combined IVB/EBRT (p = .153; p = .619).

Comprehensive surgical staging is rarely performed and may be omitted in women with endometrioid EC in stages I-II. Sole IVB delivers equally good local control as combined IVB/EBRT in pts with FIGO stage I and II disease. LVSI deserves more attention as a prognostic factor and these pts may require a combined local and systemic therapy.

• CD34
• D2-40
• T1 tumor
• esophagogastric adenocarcinoma
• lymphovascular invasion

• Adenocarcinoma/pathology
• Aged
• Antigens, CD34/analysis
• Biomarkers/analysis
• Blood Vessels/pathology
• Esophageal Neoplasms/pathology
• Female
• Humans
• Immunohistochemistry
• Lymph Nodes/pathology
• Lymphatic Vessels/pathology
• Male
• Membrane Glycoproteins/analysis
• Neoplasm Invasiveness
• Neoplasm Recurrence, Local
• Prognosis
• Stomach Neoplasms/pathology

• BRAFV600E
• histone marks
• immunohistochemistry
• melanocytic differentiation

• P30 CA016672 NCI NIH HHS

Type II (papillary serous and clear cell) endometrial carcinoma (EC) is a rare subgroup and is considered to have an unfavorable prognosis. The purpose of this retrospective analysis was to elucidate the meaning of adjuvant radiotherapy (RT) for clinical outcome and to define prognostic factors in these patients (pts).

From 2004-2012 forty-two pts with type II EC underwent surgery followed by adjuvant RT at our department. Median age was 72 years. The majority were early stage carcinomas (FIGO I n = 27 [64.3%], FIGO II n = 4 [9.5%], FIGO III n = 11 [26.2%]. Seven pts (16.7%) received adjuvant chemotherapy (ChT). Pts were treated with external beam radiotherapy (EBRT) and brachytherapy (IVB) boost.

Five-year local recurrence free survival (LRFS), distant metastases free survival (DMFS) and overall survival (OS) were 85.4%, 78%, and 64.5% respectively. LRFS was better with lower pT stage, without lymphangiosis (L0), without haemangiosis (V0) and negative resection margins (R0). DMFS was prolonged in lymph node negatives (N0), L0, V0 and R0. OS was improved in younger pts, N0, L0, V0 and after lymphadenectomy (LNE). Multivariate analysis revealed haemangiosis (V1) as the only independent prognostic factor for OS (p = .014) and DMFS (p = .008). For LRFS pT stage remained as an independent prognostic factor (p = .028).

Adjuvant RT with EBRT/IVB ensures adequate local control in type II EC, but control rates remain lower than in type I EC. A benefit of additional adjuvant ChT could not be demonstrated and a general omission of EBRT cannot be recommended at this point. Lymphovascular infiltration and pT stage might be the best predictive factors for a benefit from combined local and systemic treatment.

ERG, a member of the ETS family of transcription factors, is a highly specific endothelial marker. We investigated whether the use of ERG immunostaining can help pathologists detect lymphovascular invasion (LVI) and decrease interobserver variability in LVI diagnosis.

Fifteen cases of surgically resected colorectal cancers with hepatic metastasis were selected and the most representative sections for LVI detection were immunostained with ERG, CD31, and D2-40. Eight pathologists independently evaluated LVI status on hematoxylin and eosin (H&E) and the corresponding immunostained sections and then convened for a consensus meeting. The results were analyzed by kappa (κ) statistics.

The average rate of LVI positivity was observed in 43% with H&E only, 10% with CD31, 29% with D2-40, and 16% with ERG. Agreement among pathologists was fair for H&E only (κ=0.27), D2-40 (κ=0.21), ERG (κ=0.23), and was moderate for CD31 (κ=0.55). Consensus revealed that ERG nuclear immunoreactivity showed better visual contrast of LVI detection than the other staining, with improved agreement and LVI detection rate (κ=0.65, LVI positivity rate 80%).

The present study demonstrated a superiority with ERG immunostaining and indicated that ERG is a promising panendothelial marker that might help pathologists increase LVI detection and decrease interobserver variability in LVI diagnosis.

• CD31
• ERG
• Endothelial marker
• Immunohistochemistry
• Lymphovascular invasion