Immunohistochemical expression of cytochrome P4A11 (CYP4A11), carbonic anhydrase 9 (CAIX) and Ki67 in renal cell carcinoma; diagnostic relevance and relations to clinicopathological parameters.

BACKGROUND: Cytochrome P4A11 (CYP4A11) is a member of cytochrome p450 family, which is involved in arachidonic acid metabolism that participates in promoting malignant cell proliferation, progression, and angiogenetic capacity. Carbonic Anhydrase 9 (CAIX) is a transmembrane protein that plays an integral part in regulating hypoxia which affects cancer cell metabolism, proliferation and promotes metastasis. The aim of this study was to evaluate the immunohistochemical expression of CYP4A11, CAIX and ki67 in RCC subtypes in relation to clinicopathological parameters and to evaluate the diagnostic significance of CYP4A11 and CAIX in differentiating renal cell carcinoma (RCC) subtypes. MATERIALS AND METHODS: one hundred primary RCC cases, collected from Pathology Department, Faculty of Medicine, Tanta University and from private laboratories, were evaluated for immunohistochemical expression of CYP4A11, CAIX and ki67. RESULTS: CYP4A11 was expressed in 59% of RCC; with 91.7% sensitivity and 90% specificity in differentiating clear cell and non-clear cell subtypes. CAIX was expressed in 50% of RCC; with 95% sensitivity, 80% specificity. High expression of CYP4A11 was statistically positively associated with higher tumor grade, high expression of CAIX was statistically positively associated with lower tumor grade and absence of necrosis and high ki67 labeling index was significantly associated with clear cell subtype, larger tumor sizes, higher tumor grade, advanced tumor stage, fat invasion and vascular invasion. CONCLUSIONS: CYP4A11 and CAIX can be used as diagnostic markers to differentiate clear cell RCC from other subtypes. CYP4A11 is more diagnostically accurate and specific than CAIX. High expression of CYP4A11, low CAIX expression and high ki67 labeling index were related to features of aggressive tumor behavior.

Evaluation of the prognostic significance of receptor tyrosine kinase-like orphan receptor 1 (ROR1) in lung carcinoma and its relation to lymphangiogenesis and epithelial mesenchymal transition.

Exploring the carcinogenic mechanisms of lung carcinoma helps to discover novel prognostic biomarkers and develop new therapeutic options to improve patient's survival. Receptor Tyrosine Kinase-Like Orphan Receptor 1 (ROR1), a transmembrane protein, contributes to cancer progression and metastasis; via stimulation of epithelial mesenchymal transition (EMT) and promotion of angiogenesis. This makes ROR1 an important target for tumor therapy. This study aimed to evaluate expression of ROR1, E-cadherin (a marker of EMT), and D2-40 (a marker of lymphangiogenesis) in lung carcinoma and associate their expressions with the available clinicopathological parameters and patients' survival. Immunohistochemical staining using ROR1, E-cadherin, and D2-40 was performed for 78 cases of lung carcinoma. Kaplan-Meier survival curves and Cox-regression analysis were done. High ROR1 expression was detected in 46.2% of cases. Significant relations were found between high ROR1 expression and larger tumor size (P < 0.001), poorly differentiated tumors (P = 0.001), advanced tumor stages (P < 0.001), positive lymph nodal status (P < 0.001), decreased E-cadherin expression (P < 0.001), and high lymphovascular density (LVD) (P < 0.001). Patients' progression free survival (PFS) and overall survival (OS) were shorter with high ROR1 expression. High ROR1 expression, high LVD, large tumor size, and adenocarcinoma histopathological type were independent risk factors for OS in lung carcinoma patients. High ROR1 expression is associated with poor prognostic parameters in lung carcinoma patients including higher grade, advanced stages, high LVD, epithelial mesenchymal transition, as well as decreased PFS and OS.

Medulloblastoma: clinicopathological parameters, risk stratification, and survival analysis of immunohistochemically validated molecular subgroups.

BACKGROUND: Medulloblastoma (MB) is a heterogeneous disease, displaying distinct genetic profiles with specific molecular subgroups. This study aimed to validate MB molecular subgrouping using surrogate immunohistochemistry and associate molecular subgroups, histopathological types, and available clinicopathological parameters with overall survival (OS) and progression-free survival (PFS) of MB patients. This study included 40 MBs; immunohistochemical staining, using ß-catenin and GRB2-Associated Binding Protein 1 (GAB1) antibodies, was used to classify MB cases into wingless signaling activated (WNT), sonic hedgehog (SHH), and non-WNT/SHH molecular subgroups. Nuclear morphometric analysis (for assessment of degree of anaplasia) and Kaplan-Meier survival curves were done. RESULTS: MB cases were classified into WNT (10%), SHH (30%), and non-WNT/SHH (60%) subgroups. Histopathological types differed significantly according to tumor location (p< 0.001), degree of anaplasia (p = 0.014), molecular subgroups (p < 0.001), and risk stratification (p = 0.008). Molecular subgroups differed significantly in age distribution (p = 0.031), tumor location (p< 0.001), histopathological variants (p < 0.001), and risk stratification (p < 0.001). OS was 77.5% and 50% after 1 and 2 years, while PFS was 65% and 27.5% after 1 and 2 years, respectively. OS and PFS were associated significantly with histopathological variants (p < 0.001 and 0.001), molecular subgroups (p = 0.012 and 0.005), and risk stratification (p < 0.001 and < 0.001), respectively. CONCLUSIONS: Medulloblastoma classification based on molecular subgroups, together with clinicopathological indicators, mainly histopathological types; accurately risk stratifies MB patients and predicts their survival.

Tight junction protein claudin 4 in gastric carcinoma and its relation to lymphangiogenic activity.

BACKGROUND AND STUDY AIMS: Gastric cancer is the second most common cause of cancer-related death worldwide. Claudins are a family of tight junction proteins that are biologically relevant in many cancer progression steps. This study aimed to investigate the expression of the intestinal claudin (claudin 4) in gastric carcinoma and to evaluate its relation to the different clinicopathologic prognostic parameters, especially lymphangiogenesis (production of new lymphatic vessels, measured by lymphovascular density (LVD)) and lymphovascular invasion (LVI). PATIENTS AND METHODS: Fifty-five gastric carcinoma specimens were immunohistochemically stained for claudin 4 and D2-40 (for detection of lymphatic vessel endothelium). RESULTS: High expression of claudin 4 was detected in 26 of 55 (47.3%) cases. Low expression of claudin 4 was related to poorly differentiated type (p=0.001), non-intestinal (diffuse) type (p=0.001), deeper tumour invasion (p<0.001), lymph node metastasis (p=0.001), and higher stage (p=0.001). In addition, higher LVD was related to poorly differentiated types (p=0.001), non-intestinal type (p=0.001), lymph node metastasis (p=0.015), and higher tumour, node, metastasis (TNM) stage (p=0.001). LVI was related to lymph node metastasis (p=0.025), higher TNM stage (p=0.001), and LVD (p=0.001). Claudin 4 significantly correlated with both LVD (p=0.009) and LVI (p=0.009). CONCLUSIONS: High expression of claudin 4 was associated with the more differentiated intestinal-type gastric carcinoma and lost in poorly differentiated diffuse type. So, claudin 4 may be used as one of the differentiating markers between the two major types of gastric carcinoma (intestinal vs. diffuse). LVD and LVI were related to higher incidence of lymph node metastasis and therefore could be used as predictive markers for lymph node metastasis in limited specimens during early gastric carcinoma to determine the need for more invasive surgery. Low expression of claudin 4 was related to lymphangiogenesis. This may shed light on the relation of tight junction protein expression and lymphangiogenesis.