CD44 Expression in Clear Cell Renal Cell Carcinoma (ccRCC) Correlates with Tumor Grade and Patient Survival and Is Affected by Gene Methylation.

Clear cell RCC (ccRCC) represents the most common type of kidney cancer, with surgery being the only potential curative treatment. Almost one-third of ccRCC patients relapse either locally or as cases of distant metastases. Several biomarkers have been employed in order to separate ccRCC patients with better prognosis or to predict treatment outcomes, with limited results. CD44 is a membrane glycoprotein with multiple roles in normal development but also cancer. Recently, the CD44 standard isoform has been implicated in tumor progression and the metastasis cascade through microenvironment interactions. Here, through CD44 immunohistochemical staining of ccRCC patient samples and TCGA data analysis, we sought to elucidate the expression patterns (mRNA and protein) of CD44 in clear cell RCC and correlate its expression with clinicopathological parameters. We were able to show that CD44 expression presents a positive association with tumor grade and overall survival, predicting a worse patient outcome in ccRCC. In addition, our data indicate that the CD44 mRNA upregulation can be attributed to reduced gene methylation, implicating epigenetic gene regulation in ccRCC development and progression.

Impact of PD-L1 Protein Expression on Renal Cell Carcinoma Histo-differentiation.

BACKGROUND/AIM: Renal cell carcinoma (RCC) comprises a variety of pathological entities. Many RCCs are aggressive, demanding efficient targeted and immunetherapeutic strategies. Programmed cell death ligand-1 (PD-L1) is expressed mainly in hematopoietic cells and also in epithelial cells. The aim of this study was to correlate PD-L1 protein expression in a series of RCC tissues with their histo-pathological features. MATERIALS AND METHODS: One hundred (n=100) archival, formalin-fixed and paraffin-embedded RCC tissue specimens were analysed by immunohistochemistry. Conventional tumor proportion score (TPS) qualitative assay was applied for evaluating protein expression levels. RESULTS: Based on the TPS evaluation, 8 (8%) cases were characterized as positive, and the rest of them (n=92; 92%) as negative. A progressive increase in PD-L1 positivity was significantly associated with the differentiation grade of the examined malignancies (p=0.001). CONCLUSION: Although PD-L1 over-expression is detected in low rates in RCCs, its correlation with differentiation grade should be considered as a factor for discriminating sub-groups of patients with specific histo-pathological features eligible for targeted anti-PD-L1 immunotherapy strategies.

Erratum to "Primary Angiosarcoma of the Spleen: An Oncological Enigma".

[This corrects the article DOI: 10.1155/2014/193036.].

Angiodrastic Chemokines in Colorectal Cancer: Clinicopathological Correlations.

AIM: To study the expression of angiodrastic chemokines in colorectal tumors and correlate findings with clinicopathological parameters and survival. METHODS: The proangiogenic factor VEGF, the angiogenic chemokines CXCL8 and CXCL6, and the angiostatic chemokine CXCL4 were measured by ELISA in tumor and normal tissue of 35 stage II and III patients and correlated with the histopathology markers Ki67, p53, p21, bcl2, EGFR, and MLH1 and 5-year survival. The Wilcoxon and chi-square tests were used for statistical comparisons. RESULTS: There was a significant increase of CXCL6 (p = 0.005) and VEGF (p = 0.003) in cancerous tissue compared to normal. Patients with lower levels of CXCL8 and CXCL4 lived significantly longer. Patients with loss of EGFR expression had higher levels of CXCL8 while p21 loss was associated with higher levels of CXCL6. Chemokine levels were not correlated with TNM or Dukes classification. Strong expression of p53 was accompanied by decreased survival. CONCLUSIONS: (1) The angiogenic factors CXCL6 and VEGF are increased in colorectal cancer tissue with no association with the clinical stage of the disease or survival. (2) However, increased levels of tissue CXCL8 and CXCL4 are associated with poor survival. (3) Strong expression of p53 is found in patients with poor survival.

Solitary Plasmacytoma of the Mesentery: A Systematic Clinician's Diagnosis.

INTRODUCTION: Plasmacytoma is an uncommon plasma cell neoplasm and its localized form is solitary plasmacytoma of the bone and solitary extramedullary plasmacytoma. Solitary plasmacytoma of the mesentery is extremely rare, reported only in a handful of cases. CASE PRESENTATION: A 47-year-old man with nonspecific abdominal complains was found to have an ill-defined mass on his mesenteric root. Laparoscopic biopsy and stepwise histopathological examination revealed a mesenteric plasmacytoma, and extensive imaging and laboratory investigations led to the diagnosis of the solitary mesenteric plasmacytoma. The patient underwent definitive radiotherapy and remains under remission one year later. DISCUSSION: Plasma cell dyscrasias include a variant of proliferative disease, characterized by clonal expansion of bone marrow plasma cells, producing a massive quantity of monoclonal immunoglobulin called paraprotein or M-protein. Solitary extramedullary plasmacytoma accounts for only 3-5% of all plasma cell neoplasms. Meticulous adherence to the established diagnostic criteria helps the clinician to set the correct, yet very unusual and unexpected diagnosis.

Prognostic Evaluation of Vimentin Expression in Correlation with Ki67 and CD44 in Surgically Resected Pancreatic Ductal Adenocarcinoma.

Purpose. Radical surgical resection with adjuvant chemotherapy or chemo-radiotherapy is the most effective treatment for pancreatic ductal adenocarcinoma (PDAC). However, relatively few studies investigate the prognostic significance of biological markers in PDAC. This study aims to look into the expressions of vimentin, Ki67, and CD44 in PDAC surgical specimens and their potential prognostic implications in survival. Method. The study was designed as retrospective, and vimentin, Ki67, and CD44 expressions were evaluated by immunohistochemistry in 53 pancreatic ductal adenocarcinoma cases. Overall survival was assessed by the Kaplan-Meier method. Results. Patients' median age was 68 years. The median survival was 18 months. The tumors were T3-4 in 40/53 (75.5%), and metastases in lymph nodes were found in 42 out of 53 (79.2%) cases. On multivariate analysis, the size of primary tumor (p < 0.001), the surgical resection margin status (p = 0.042), and vimentin expression (p = 0.011) were independently correlated with overall survival. Conclusions. Long-term survival after resection of PDAC is still about 15%. Vimentin expression is a potential independent adverse prognostic molecular marker and should be included in histopathological reports. Also, CD44 expression correlates with high Ki67, vimentin positivity, and N stage and may represent a potential target of novel therapeutic modalities in pancreatic adenocarcinoma patients.

Aggressive angiomyxoma of the vulva: a bizarre perineal lesion.

Introduction. Aggressive angiomyxoma is a rare, slowly growing, and benign tumour of mesenchymal origin, which affects women of reproductive age and is associated with a high risk of local recurrence. Case Presentation. A case of a 47-year-old white female is presented herein, with a large polypoid, gelatinous mass on the right labia majora, measuring 26 × 21 × 6 cm. Histopathologically, the lesion was composed of spindle and stellate-shaped cells embedded in a myxoid matrix. Another specific feature was the presence of variable-sized thin-walled capillaries and thick-walled vascular channels. The patient underwent wide local excision of the tumour with clear margins and developed local recurrence 18 months later. Discussion. Aggressive angiomyxoma of the vulva needs to be distinguished from benign myxoid tumors with a low risk of local recurrence as well as from malignant myxoid neoplasms. Usually wide local excision with tumour-free margins and occasionally hormonal manipulation is the treatment of choice.

Proximal shift of colorectal cancer. A persistent phenomenon with multiple causes, patterns and clinical implications.

A considerable change in the anatomical distribution of colorectal cancer (CRC) towards more proximal sites has been observed in Western countries within the last 6-7 decades. As a result, tumors located proximally to the splenic flexure are now accounting for 30-40% (or even more) of overall CRC cases. This proximal migration is not always representing a true increase of proximal cancer, arising from various combinations of changes in the rates of proximal and distal cancer (e.g. proximal increase with distal stability/reduction, or decline in both sites albeit higher distally etc) in different areas and periods. Principal potential causes include ageing in Western populations (since proximal cancers are more common among the aged), various potentially site-specific exposures (lifestyle and medical) and systematic screening. Their effect is reflected in the particular shift patterns; for instance, widespread screening in USA has led to an overall CRC decline, more evident distally (for technical, anatomical and morphological reasons). Segmental disparities in particular characteristics (age, gender, morphology) and responses to various exposures are etiologically associated (for the most part) with underlying genetic differences between proximal and distal tumors. From clinical aspect, proximal shift necessitates a more generalized use of colonoscopy in screening programs. Potential interventions in treatment (segmental patient stratification) and prevention (identification of particular site-specific exposures) require further investigation.

Primary angiosarcoma of the spleen: an oncological enigma.

Introduction. Primary splenic angiosarcoma is an extremely unusual neoplasm originating from sinusoidal vascular endothelium. Surgical extirpation is the mainstay of treatment of this highly malignant disease. Case Presentation. An 82-year-old woman was admitted with left pleural effusion and a palpable left upper quadrant abdominal mass, secondary to splenomegaly by two large splenic tumors. Classic open splenectomy was performed and angiosarcoma of the spleen was the final histopathological diagnosis, which was primary since no other disease site was revealed. Discussion. The incidence of the disease is 0.14-0.23 cases per million, with slight male predominance. Etiology is not established and clinical presentation may confuse even experienced physicians. Imaging modalities cannot differentiate the lesion from other vascular splenic neoplasms and the correct diagnosis is mainly set after histopathological examination of the resected spleen. As with other sarcomas, surgery is the only curative approach, while chemo- and radiotherapy have poor results. Prognosis remains dismal.

Differences in telomerase activity between colon and rectal cancer.

BACKGROUND: Colorectal cancer is one of the most common cancers and the third leading cause of cancer death in both sexes. The disease progresses as a multistep process and is associated with genetic alterations. One of the characteristic features of cancer is telomerase activation. We sought to evaluate the differences in telomerase activity between colon cancer and adjacent normal tissue and to correlate the differences in telomerase activity between different locations with clinicopathological factors and survival. METHODS: Matched colon tumour samples and adjacent normal mucosa samples 10 cm away from the tumour were collected during colectomy. We assessed telomerase activity using real time polymerase chain reaction. Several pathological characteristics of tumours, including p53, Ki-67, p21, bcl2 and MLH1 expression were also studied. RESULTS: We collected samples from 49 patients. There was a significantly higher telomerase activity in colon cancer tissue than normal tissue. Adenocarcinomas of the right colon express significantly higher telomerase than left-side cancers. Colon cancers and their adjacent normal tissue had significantly more telomerase and were more positive to MLH1 than rectal cancers. The expression of p53 negatively correlated to telomerase activity and was linked to better patient survival. CONCLUSION: Colon and rectal cancers seem to have different telomerase and MLH1 profiles, and this could be another factor for their different biologic and clinical behaviour and progression. These results support the idea that the large bowel cannot be considered a uniform organ, at least in the biology of cancer.

CONTEXTE: Le cancer colorectal est l'un des cancers les plus répandus; il arrive au troisième rang des décès attribuables au cancer chez les hommes et les femmes. La maladie progresse en plusieurs étapes et est associée à des anomalies génétiques. L'une des principales caractéristiques du cancer est l'activation de la télomérase. Nous avons voulu évaluer les différences d'activité de la télomérase entre les tissus touchés par le cancer du côlon et les tissus adjacents normaux afin d'établir une corrélation entre les différences d'activité de la télomérase selon la localisation d'une part et les facteurs clinicopathologiques et la survie d'autre part. MÉTHODES: Lors de colectomies, nous avons recueilli des échantillons tissulaires jumelés de tumeur du côlon et de muqueuse adjacente normale à 10 cm du foyer tumoral. Nous avons mesuré l'activité de la télomérase à l'aide de la réaction en chaîne de la polymérase en temps réel. Plusieurs caractéristiques pathologiques des tumeurs ont aussi été analysées, y compris l'expression des gènes p53, Ki-67, p21, bcl2 et MLH1. RÉSULTATS: Nous avons recueilli des échantillons auprès de 49 patients. Nous avons noté une activité nettement plus intense de la télomérase dans les tissus touchés par le cancer du côlon que dans les tissus normaux. Les adénocarcinomes du côlon ascendant expriment une activité de la télomérase significativement plus intense que les cancers du côlon descendant. Les cancers du côlon et les tissus adjacents normaux présentaient une activité significativement plus intense de la télomérase et étaient plus souvent positifs à l'égard du MLH1 comparativement aux cancers rectaux. L'expression du p53 a été en corrélation négative avec l'activité de la télomérase et a été associée à une meilleure survie chez les patients. CONCLUSION: Les cancers du côlon et du rectum semblent avoir des profils différents au plan de la télomérase et du gène MLH1. Ce facteur pourrait entre autre expliquer leur comportement et leur progression biologiques et cliniques distincts. Ces résultats appuient l'hypothèse selon laquelle le côlon ne peut être considéré comme un organe uniforme, du moins en ce qui concerne la biologie du cancer.

A study of Smad4 and Smad7 expression in surgically resected samples of gastric adenocarcinoma and their correlation with clinicopathological parameters and patient survival.

PURPOSE: The canonical signaling pathway for the transforming growth factor-beta (TGF-ß) family is through the Smad proteins which are pivotal intracellular mediators of TGF-ß family members. Recently, disruption of the TGF-ß pathway in cancer has been demonstrated at the level of the Smad signal transducers. In this study, we examined Smad4 and Smad7 expression in gastric carcinomas to elucidate their role in tumor progression. METHODS: The immunohistochemical expression of Smad4 and Smad7 was evaluated in 151 surgically resected samples of gastric adenocarcinoma in order to examine their correlation with clinicopathologic findings and patients' survival. RESULTS: Smad4 and Smad7 expression (low, moderate or strong) was observed in 86.7% (131/151) and 33.1% (50/151) of gastric adenocarcinoma tumor samples, respectively. Our results revealed that the loss of Smad4 expression correlated significantly with the intestinal type, male sex, depth of tumor and poor survival. Smad7 expression was significantly more frequent in intestinal type and well differentiated gastric adenocarcinomas and significantly correlated with the duration of disease-free survival. CONCLUSION: Smad signal transducers are considered as important molecules in tumor development and progression and the evaluation of their expression in human gastric cancer could be useful in selecting stage I patients who should be considered as candidates for adjuvant chemotherapy.

The prognostic role of ephrin A2 and endothelial growth factor receptor pathway mediators in patients with advanced colorectal cancer treated with cetuximab.

BACKGROUND: Patients with colorectal cancer (CRC) with wild-type KRAS mutations are often treated with the endothelial growth factor receptor (EGFR) monoclonal antibody cetuximab. Despite the presence of a specific molecular target, most patients still do not derive benefit from this biological treatment. Our study explores the role of ephrin A2 (EphA2) receptor expression and of EGFR pathway mediators as predictors of cetuximab benefit. PATIENTS AND METHODS: Formalin-fixed paraffin-embedded (FFPE) tumor biopsy samples from 226 cetuximab-treated patients with CRC were studied for mRNA expression of insulin growth factor binding protein 2 (IGFBP2), insulin growth factor receptor 1 (IGF1R), cMET, EphA2, human epidermal growth factor receptor 2 (HER2), HER3, and HER4 by means of TaqMan reverse-transcribed polymerase chain reaction (RT-PCR). RESULTS: Of the 226 patients evaluable for exploratory analysis, 222 had complete data from follow-up visits. The univariate analysis revealed the following significant adverse prognostic factors for risk of death: high EphA2 mRNA levels (hazard ratio [HR], 1.61; P = .015), high HER2 mRNA levels (HR, 1.51; P = .045), and high IGF1R mRNA levels (HR, 1.56; P = .021). Low EphA2 tumor expression was significantly associated with objective response to cetuximab therapy. In multivariate analysis of a broad biomarker panel, factors with independent prognostic value included EphA2 mRNA levels (HR, 1.67; P = .029), high amphiregulin (AREG) mRNA levels in KRAS wild-type tumors (HR, 0.17; P < .0001), and high epiregulin (EREG) mRNA levels (HR, 0.38; P = .006). CONCLUSION: High EphA2 receptor expression in CRC was associated with a worse outcome in patients treated with cetuximab-based therapy. Prospective validation in treated and control patients is required to dissect the predictive from prognostic role in advanced CRC.

Vascular endothelial growth factor receptors 1,3 and caveolin-1 are implicated in colorectal cancer aggressiveness and prognosis--correlations with epidermal growth factor receptor, CD44v6, focal adhesion kinase, and c-Met.

Vascular endothelial growth factor receptor-1 (VEGFR-1) and caveolin-1 have been shown to act both as tumor-promoting and tumor-suppressing proteins in various malignancies as well as in colorectal cancer (CRC), while VEGFR-3's lymphagiogenic involvement and connection to tumor parameters has yielded heterogenic results. This study was designed to investigate the expression of these molecules in 183 human CRC tissue specimens and explore their effect in both clinicopathological parameters and disease prognosis. We also utilize our previous results regarding epidermal growth factor receptor (EGFR), c-Met, CD44v6, and focal adhesion kinase, in an attempt to further clarify their distinct role in tumor prognosis and their crosstalk. Caveolin-1 was more freely distributed in the neoplasms of the right colon and restricted towards the left and the rectal cancer samples (p = 0.022); VEGFR-3 was associated with higher nodal metastasis' status (p = 0.001) and staging (p = 0.006), and loss of VEGFR-1 predicted distant metastasis (p = 0.026) and advanced stage (p = 0.049). Prompted by previous reports, we performed all analyses also in the patient group of early (I and II) tumor stage where it was evident that VEGFR-1 was more frequently expressed in patients under 60 years old (p = 0.014) and VEGFR-3 was significantly elevated in left colon cancers (p = 0.039) and female patients (p = 0.038). Within the advanced stage (III and IV), the absence of VEGFR-1 exhibited a tendency for higher M status (p = 0.067) and lack of caveolin-1 signified worse AJCC classification (p = 0.053). Additionally, patient survival was influenced from VEGFR-3 (p = 0.019) for the whole sample, whereas subgroup analyses provided a correlation between caveolin-1 expression and improved survival in the early detection group of patients (p = 0.022). Using Cox regression for all available markers, FAK, CD44v6, and Caveolin-1 [corrected] emerged in this study as potential surrogate markers, the latter having positive prognostic significance. We further explored the multiple receptor correlations that were identified.

FAK, CD44v6, c-Met and EGFR in colorectal cancer parameters: tumour progression, metastasis, patient survival and receptor crosstalk.

PURPOSE: Research for reliable and patient-specific markers in colorectal cancer (CRC) is based on solid evidence that staging alone is not informative enough. Employing four cellular receptors, we embarked to identify aggressive tumour behaviour and impact of surrogate marker expression on patient prognosis. METHODS: One-hundred eighty-three CRC patients were enrolled in our investigation that focused on an array of biological markers, namely epidermal growth factor receptor (EGFR), c-Met, focal adhesion kinase (FAK) and CD44v6. Tissue samples, clinicopathological data and patient's follow-up information were collected, and immunohistochemical assays evaluated the levels of the aforementioned molecules. All available data were correlated with tumour grade, stage, patient age, gender and survival. RESULTS: Expression of all receptors correlated closely with tumour stage (P < 0.01) exhibiting a connection with cancer's invasiveness and progress. Survival also proved to depend significantly on molecular expression (log-rank test for Kaplan-Meier; EGFR P = 0.030, c-Met P = 0.050, FAK P < 0.001, CD44v6 P < 0.001). Stage, FAK and CD44v6 emerged as independent predictors of survival in a stepwise regression analysis (FAK P = 0.001 Exp(B) = 2.517, 95 % confidence interval (CI) = 1.704-5.831 and CD44v6 P = 0.005, Exp(B) = 2.299, 95 % CI = 1.287-4.110). T-stage, nodal metastasis, all metastatic types (N/M) and size correlated with at least one of the receptors or their co-expression. Notably, increased staining for each receptor was followed by statistically significant expression elevation of at least one of the other markers. CONCLUSIONS: Our results suggest that the selected cellular receptors are suitable for use as biomarkers of survival and tumour progression in CRC. Furthermore, we provide additional evidence for receptor interaction, properly clarifying their importance, which could potentially lead to more effective anti-CRC regimens.

Prognostic significance of transforming growth factor beta (TGF-ß) signaling axis molecules and E-cadherin in colorectal cancer.

The transforming growth factor beta (TGF-ß) signaling pathway has been considered both a tumor suppressor and a cancer promoter. Additionally, downregulation of cell adhesion molecules such as E-cadherin plays an important role in the metastatic potential of colorectal cancer (CRC). The aim of the present study was to evaluate TGF-ß, TGF-ß type I receptor (TGF-ßR1), TGF-ß type II receptor (TGF-ßR2), Smad4, pSmad2/3, and E-cadherin expression in colorectal carcinoma and to correlate the obtained data with other standard prognostic parameters, such as disease stage, metastases, and patient survival. TGF-ß, TGF-ßR1, TGF-ßR2, Smad4, pSmad2/3, and E-cadherin expression was evaluated immunohistochemically in 195 unrelated CRC specimens and the results subjected to various statistical analyses. TGF-ß was expressed in 71.28%, TGF-ßR1 in 61.0%, TGF-ßR2 in 54.4%, Smad4 in 61.5%, pSmad2/3 in 71.3%, and E-cadherin in 50.26% of the colorectal carcinoma samples tested. The correlation of immunoexpression with the clinicopathological parameters of CRC revealed that the high expression of TGF-ß and low expression of TGF-ßR1, TGF-ßR2, Smad4, pSmad2/3, and E-cadherin were correlated with tumor-node-metastasis (TNM) stage of disease. High TGF-ß expression and low TGF-ßR1, TGF-ßR2, Smad4, and pSmad2/3 expression were also correlated with lymph node metastasis. The Kaplan-Meier survival curves demonstrated a clear association of cancer-specific overall survival with high TGF-ß, as well as low TGF-ßR1, TGF-ßR2, Smad4, pSmad2/3, and E-cadherin expression. Our results suggest that TGF-ß, TGF-ßR1, TGF-ßR2, Smad4, pSmad2/3, and E-cadherin are closely related to TNM stage of CRC. Moreover, TGF-ß, TGF-ßR2, Smad4, pSmad2/3, and E-cadherin emerge as valuable independent biomarkers of prognosis in CRC patients.

TGF-beta signalling in colon carcinogenesis.

Colorectal cancer remains the most common cancer and the second leading cause of cancer mortality in Europe. There are a number of pathways that have been implicated in colorectal carcinogenesis, including TGF-beta (TGF-ß)/Smad signalling pathway. The TGF-ß pathway is involved in several biological processes, including cell proliferation, differentiation, migration and apoptosis. Here we review the role of TGF-ß signalling cascade in colorectal carcinogenesis and provide some new molecular insights that may aid efforts towards targeted antitumor therapies.

Angiofibroma of the spermatic cord: a case report and a review of the literature.

INTRODUCTION: Cellular angiofibroma is a benign vascular neoplasm that typically arises in the paratesticular region in men and is easily confused with inguinal or scrotal hernia. CASE PRESENTATION: We present a case of a cellular angiofibroma arising from the spermatic cord of a 74-year-old Caucasian man. Initially, the lesion was confused with a scrotal hernia, but imaging revealed a subcutaneous, inhomogeneous, but well-circumscribed lesion to the surrounding tissues with rich vasculature. Surgical resection of the lesion was performed. Histology revealed a benign tumor of vascular origin rich in fibroblasts. CONCLUSIONS: Angiofibroma can easily be confused with an inguinal hernia and should be differentiated from Schwann cell tumors, perineuromas, spindle-cell lipomas, aggressive angiomyxomas, angiomyofibroblastomas, solitary fibrous tumors, spindle-cell liposarcomas, and leiomyomas. A safe initial diagnosis is difficult because of its location, nature, and correlation with other structures of the area.

Sarcomatoid carcinoma of the urinary bladder: a clinicopathological study of 4 cases and a review of the literature.

Sarcomatoid carcinoma (SC) of urinary bladder is a rare tumor exhibiting aggressive behavior. Here we are reviewing the pathologic and clinical characteristics of 4 consecutive cases of this rare tumor. Three out of 4 patients were males and one female. The median age was 72.8 years (range, 60-79 years). Patients underwent transurethral resection of bladder tumor and the diagnosis of bladder SC was established on the pathologic examination of the resected bladder tissue. Despite treatment all patients died within 22 months of the diagnosis of SC. SC of the bladder are true biphasic malignant neoplasm exhibiting morphologic and immunohistochemical evidence of epithelial and mesenchymal differentiation with the presence or absence of heterologous elements. The aggressive of the tumor precludes radical therapy whenever possible, since adjuvant therapy seems to have little effect.