Erika Tóth

Human papillomavirus in head and neck cancer: Molecular biology and clinicopathological correlations

Human papillomaviruses are known to cause cancers of the cervix and other anogenital tract sites. Epidemiologic and molecular pathology studies have also suggested that HPV infection may be associated with cancers of the head and neck. Modes of transmission of HPV infection in the head and neck region have not been fully resolved; however, perinatal transmission and an association between sexual behavior and risk for HPV-positive cancers have been presented.Among the HPV types infecting the mucosa, high-risk, intermediate-risk and low-risk genotypes are defined, depending on their presence in carcinoma or precursor lesions. The phylogenic groups of HPVs also showed a definite correlation with the morphology of head and neck tumors. The groups A6, A7, and A9 include viruses that are frequently demonstrated in basaloid and verrucosus squamous cell carcinomas known to associate with HPV infection. Integration of HPV DNA into the host cell genome occurs early in cancer development and is an important event in malignant transformation.There is a trend for patients with HPV-positive tumors to be nondrinkers or light drinkers, the majority of these patients are females, and the median age is lower than in the case of HPV-negative tumors, but this latter difference was not always statistically significant. In the Kaplan-Meier survival model, the HPV-positive verrucous and basaloid squamous cell carcinomas showed better survival rates than the HPV-negative typical squamous cell carcinomas. An increased radiocurability of HPV-positive head and neck squamous cell carcinoma (HNSCC) has also been demonstrated.

Osteoclastoma-like giant cell tumor of the lung

The main components of an unusual form of lung tumor were osteoclast-like multinucleated giant cells and mononuclear stromal cells. Besides, scattered islands of moderately differentiated squamous cells also appeared. Both the mononuclear and the osteoclast-like giant cells reacted with antibodies against CD68 and vimentin, but did not react with antibodies against cytokeratin, EMA and CEA, or lysozyme and α-1-antitrypsin. The p53 and PCNA antigens were positive only in mononuclear cells and not the osteoclast-like giant cells, suggesting that mononuclear cells represent proliferating elements with histiocytic differentiation while osteoclast-like giant cells are stromal, presumably reactive components of the tumor.

Serrated Pathway Adenocarcinomas: Molecular and Immunohistochemical Insights into Their Recognition

Introduction Colorectal adenocarcinomas (CRC) developed through serrated pathway seem to present particular behavior compared with the non-serrated ones, but recognition of them is difficult to do. The aim of our paper was to establish some criteria to facilitate their identification. Materials and Methods In 170 consecutive CRCs, we performed immunohistochemical staining with Cytokeratin 7 (CK7) and Cytokeratin 20 (CK20) and also with p53 and MLH-1. At the same time, we analyzed BRAF and K-ras mutations and the microsatellite status of CRC. Results 26.47% of cases expressed CK7, and 16.47% were CK20-negative. Diffuse positivity for CK7 was associated in the proximal colon with CK20 negativity or weak positivity, BRAF mutations, lack of K-ras mutations, and p53 and MLH-1 negativity. All these cases were microsatellite-unstable and were diagnosed in stage II. Those cases from the distal colon and rectum that expressed CK7 were K-ras-mutated and had low p53 index and MLH-1 positivity, independent of the CK20 expression. Conclusions CK7, associated with MLH-1 and p53 expression, and also with the microsatellite status, BRAF and K-ras pattern, might be used to identify the CRC potentially going through serrated pathway. The serrated pathway adenocarcinomas of the proximal colon that do not display the morphological features of this pattern are more frequent CK7+/p53−/MLH-1−/BRAF-mutated/K-ras-wt/MSI cases, but those located in the distal colorectal segments seem to be CK7+/CK20+/p53−/MLH-1+/BRAF wt/K-ras-mutated/MSS cases.

Possible predictive value of Maspin expression in colorectal cancer

INTRODUCTION The aim of our study was to correlate Maspin expression, a serine protease with possible antiangiogenic and antiproliferative effects, with angiogenesis and to realize a synthesis of the literature data regarding the novel patented compounds used in colorectal cancer (CRC). MATERIALS AND METHODS In 110 cases with CRC, immunohistochemical stains were performed using Maspin, p53, VEGFA, CD31, and CD105. The results were correlated with the tumor stage and microsatellite status. A new scoring system for Maspin, based on the dual cytoplasmic-nuclear expression, with possible predictive value, was proposed. RESULTS The angiogenesis presented an oscillating pattern, the VEGF expression was more intense in Stage IV, but the endothelial area that quantified with both CD31 and CD105 was smaller than in those cases diagnosed in Stages II and III. Most of the p53 negative cases with Maspin nuclear predominance, which seems to respond to 5-Fluorouracil, were microsatellite instability (MSI) cases. In Stage II, Maspin nuclear positivity was more specific for pT4 tumors and aggressive cases with high p53 index. Thirty-three percent of CRC diagnosed in Stage II and 27% of those from Stage III presented Maspin expression in the endothelial cells. No cases from Stage IV had Maspin vascular positivity. CONCLUSIONS Maspin nuclear expression, associated with p53 ones, might be used either to select the high-risk microsatellite stable (MSS) colorectal carcinomas diagnosed in Stage II or those MSI cases which can respond to 5-Fluorouracil.

Dynamic Contrast-Enhanced MRI Parameters as Biomarkers in Assessing Head and Neck Lesions After Chemoradiotherapy Using a Wide-Bore 3 Tesla Scanner.

Pilot studies have shown promising results in characterizing head and neck tumors (HNT) using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), differentiating between malignant and benign lesions and evaluating changes in response to chemoradiotherapy (CRT). Our aim was to find DCE-MRI parameters, biomarkers in evaluating the post-CRT status. Two hundred and five patients with head and neck lesions were examined with DCE-MRI sequences. The time intensity curves (TIC) were extracted and processed to acquire time-to-peak (TTP), relative maximum enhancement (RME), relative wash-out (RWO), and two new parameters attack and decay. These parameters were analyzed using univariate tests in SPSS (Statistical Package for the Social Sciences, version 17, SPSS Inc. Chicago, USA) to identify parameters that could be used to infer tumor malignancy and post-CRT changes. Multiple parameters of curve characteristics were significantly different between malignant tumors after CRT (MACRT) and changes caused by CRT. The best-performing biomarkers were the attack and the decay. We also found multiple significant (p < 0.05) parameters for both the benign and malignant status as well as pre- and post-CRT status. Our large cohort of data supports the increasing role of DCE-MRI in HNT differentiation, particularly for the assessment of post-CRT status along with accurate morphological imaging.

Non-Epstein–Barr virus associated lymphoepithelioma-like carcinoma of the esophagogastric junction with microsatellite instability, K-ras wild type

A 60-year-old male was admitted to our hospital for gastric cancer. Considering his general condition, total gastrectomy and dissection of regional lymph nodes were performed. Macroscopically, a 45 mm × 20 mm × 10 mm-sized, ulcero-infiltrative tumor located in the esophagogastric junction was described. Microscopically, the tumor consisted of a poorly differentiated adenocarcinoma intermingled with dense lymphoid infiltration predominantly composed of T-cell lymphocytes. The tumor cells infiltrated the submucosa, muscularis and subserosal layers of the stomach, respectively the esophageal adventitia. No metastases were noticed in the 58 regional lymph nodes. Based on the histopathological features, the diagnosis was lymphoepithelioma-like carcinoma, pT3N0 stage. In situ hybridization for Epstein-Barr virus showed no nuclear signal in tumor cells. The p53 expression was observed in fewer than 10% of the tumor cells. Real-time PCR analysis showed microsatellite instability without K-ras mutation in codon 12. No recurrences or metastases were reported 6 months after surgical intervention. No adjuvant therapy was performed.

DETECTION OF N-MYC GENE AMPLIFICATION IN NEUROBLASTOMA BY COMPARATIVE, IN SITU,AND REAL-TIME POLYMERASE CHAIN REACTION

We have used semiquantitative comparative and real-time quantitative polymerase chain reactions (PCR) to detect n-myc gene-amplification in 20 frozen neuroblastoma biopsies and IMR 32 cell line to predict biological behavior of the tumors. Two primer pairs were used for the semiquantitative method to co-amplify a 520-bp fragment of the beta-globin gene--used as a single copy reference standard--and a 258-bp fragment of the n-myc gene. After 30 cycles the PCR products were electrophoresed through an agarose gel and were compared to each other with use of a gel-densitometer. Real-time quantitative analyses were performed in a LightCycler instrument. A single primer pair was used to amplify a 120-bp fragment of the n-myc oncogene and a LC640-labeled fluorescent probe pair to detect the product. Calibration curve, set up from a serial dilution including samples with 1, 2, 10, 13, 25-fold n-myc oncogene amplification, was used for quantitative analysis. The semiquantitative method did not show distinct difference between tumor groups with no amplification and less than 10-fold amplification, whereas quantitative LightCycler analysis was able to detect even 2-fold amplification. Differentiated neuroblastomas seldom show n-myc amplification. In spite of this, we have found two partly differentiated tumor samples that contained n-myc amplification. In these cases in situ PCRs were performed to examine the tumor heterogeneity. We used biotinated ATP labeling and the same primer pair as for the LightCycler analysis. In both cases differentiated cells did not show n-myc gene amplification, whereas considerable amplification was detected in the neuroblasts.

Angiolymphoid hyperplasia with eosinophilia: report of a lesion mimicking soft tissue tumor of extremely long duration.

We present a large sized lesion of the right upper arm in which characteristics of the angiolymphoid hyperplasia with eosinophilia (ALHE) intermingled with those of Kimuras disease (KD). The laboratory findings, the prominent vascular proliferation and the features of endothelial cells were suggestive of ALHE. However, the long duration of the disease, the site of involvement, the abundant lymphoid component forming lymph follicles with germinal centers and the fibrosis are features of KD. In agreement with other reports, our case shows that clinicopathologically there is an overlap between ALHE and KD.

RAS mutation prevalence among patients with metastatic colorectal cancer: A meta-analysis of real-world data

Aim: A confirmed wild-type RAS tumor status is commonly required for prescribing anti-EGFR treatment for metastatic colorectal cancer. This noninterventional, observational research project estimated RAS mutation prevalence from real-world sources. Materials & methods: Aggregate RAS mutation data were collected from 12 sources in three regions. Each source was analyzed separately; pooled prevalence estimates were then derived from meta-analyses. Results: The pooled RAS mutation prevalence from 4431 tumor samples tested for RAS mutation status was estimated to be 43.6% (95% CI: 38.8–48.5%); ranging from 33.7% (95% CI: 28.4–39.3%) to 54.1% (95% CI: 51.7–56.5%) between sources. Conclusion: The RAS mutation prevalence estimates varied among sources. The reasons for this are not clear and highlight the need for further research.

The EGFR and KRAS Mutation Status and Correlations with the Prevalence ofBone Metastases - The Results of Three Year Retrospective Analysis

Lung cancer is the leading cause of cancer related mortality all over the world. The development of molecular pathology methods has become increasingly important in the prediction of chemotherapy sensitivity and mutation analysis to identify driver mutations as important targets of new therapeutic agents. These agents give an opportunity to provide a new standard of care. Therefore testing EGFR, KRAS mutations and ALK rearrangements in patients with advanced lung adenocarcinoma should be incorporated into routine clinical practice. Bone is the most frequent type of distant metastases in case of Non-Small Cell Lung Cancer (NSCLC). During the disease this is developing 30-40%. Because of the short survival (6 months) the treatment possibilities were not in the aim of scope. After the changes of treatment guidelines – first the platinum based chemotherapy, later the step of EGFR TK inhibitors therapy – the Overall Survival (OS) became more longer. The relevant clinical studies concluded that: bone metastases and Skeletal Related Events (SRE) are more frequently observed in men, heavy smokers and without treatment of EGFR TK inhibitors. In our retrospective study we collected 224 most relevant clinical data patient with lung adenocarcinoma. We investigated the correlations between the EGFR, KRAS mutations status and the prevalence of bone metastases and survival. We have found that EGFR and KRAS mutation status are both predictive factors for the treatment efficacy and are prognostic factors for the disease progression but these are not predictors of the presence of bone metastases. The presence of bone metastases is an independent prognostic marker what correlates with the poor performance and worse Quality of Life (QL).