Analysis of head and neck carcinoma progression reveals novel and relevant stage-specific changes associated with immortalisation and malignancy.

We report changes in the genomic landscape in the development of head and neck squamous cell carcinomas HNSCC from potentially premalignant lesions (PPOLS) to malignancy and lymph node metastases. Likely pathological mutations predominantly involved a relatively small set of genes reported previously (TP53, KMT2D, CDKN2A, PIK3CA, NOTCH1 and FAT1) but also other predicted cancer drivers (MGA, PABPC3, NR4A2, NCOR1 and MACF1). Notably, all these mutations arise early and are present in PPOLs. The most frequent genetic changes, which follow acquisition of immortality and loss of senescence, are of consistent somatic copy number alterations (SCNAs) involving chromosomal regions enriched for genes in known and previously unreported cancer-related pathways. We mapped the evolution of SCNAs in HNSCC progression. One of the earliest SCNAs involved deletions of CSMD1 (8p23.2). CSMD1 deletions or promoter hypermethylation were present in all of the immortal PPOLs and occurred at high frequency in the immortal HNSCC cell lines. Modulation of CSMD1 in cell lines revealed significant suppression of proliferation and invasion by forced expression, and significant stimulation of invasion by knockdown of expression. Known cancer drivers NOTCH1, PPP6C, RAC1, EIF4G1, PIK3CA showed significant increase in frequency of SCNA in transition from PPOLs to HNSCC that correlated with their expression. In the later stages of progression, HNSCC with and without nodal metastases showed some clear differences including high copy number gains of CCND1, hsa-miR-548k and TP63 in the metastases group.

Therapeutic targeting of cathepsin C: from pathophysiology to treatment.

Cathepsin C (CatC) is a highly conserved tetrameric lysosomal cysteine dipeptidyl aminopeptidase. The best characterized physiological function of CatC is the activation of pro-inflammatory granule-associated serine proteases. These proteases are synthesized as inactive zymogens containing an N-terminal pro-dipeptide, which maintains the zymogen in its inactive conformation and prevents premature activation, which is potentially toxic to the cell. The activation of serine protease zymogens occurs through cleavage of the N-terminal dipeptide by CatC during cell maturation in the bone marrow. In vivo data suggest that pharmacological inhibition of pro-inflammatory serine proteases would suppress or attenuate deleterious effects mediated by these proteases in inflammatory/auto-immune disorders. The pathological deficiency in CatC is associated with Papillon-Lefèvre syndrome (PLS). The patients however do not present marked immunodeficiency despite the absence of active serine proteases in immune defense cells. Hence, the transitory pharmacological blockade of CatC activity in the precursor cells of the bone marrow may represent an attractive therapeutic strategy to regulate activity of serine proteases in inflammatory and immunologic conditions. A variety of CatC inhibitors have been developed both by pharmaceutical companies and academic investigators, some of which are currently being employed and evaluated in preclinical/clinical trials.

Genetic Contributions to The Association Between Adult Height and Head and Neck Cancer: A Mendelian Randomization Analysis.

With the aim to dissect the effect of adult height on head and neck cancer (HNC), we use the Mendelian randomization (MR) approach to test the association between genetic instruments for height and the risk of HNC. 599 single nucleotide polymorphisms (SNPs) were identified as genetic instruments for height, accounting for 16% of the phenotypic variation. Genetic data concerning HNC cases and controls were obtained from a genome-wide association study. Summary statistics for genetic association were used in complementary MR approaches: the weighted genetic risk score (GRS) and the inverse-variance weighted (IVW). MR-Egger regression was used for sensitivity analysis and pleiotropy evaluation. From the GRS analysis, one standard deviation (SD) higher height (6.9 cm; due to genetic predisposition across 599 SNPs) raised the risk for HNC (Odds ratio (OR), 1.14; 95% Confidence Interval (95%CI), 0.99-1.32). The association analyses with potential confounders revealed that the GRS was associated with tobacco smoking (OR = 0.80, 95% CI (0.69-0.93)). MR-Egger regression did not provide evidence of overall directional pleiotropy. Our study indicates that height is potentially associated with HNC risk. However, the reported risk could be underestimated since, at the genetic level, height emerged to be inversely associated with smoking.

Loss of epithelial markers is an early event in oral dysplasia and is observed within the safety margin of dysplastic and T1 OSCC biopsies.

Oral squamous cell carcinoma (OSCC) is a highly aggressive cancer that is associated with poor 5-year patient survival. Disease treatment is further compounded by the difficulty in predicting pre-cancerous tissues that will progress to OSCC and the high recurrence rates following surgical resection. Here we have assessed expression of the oral epithelial markers E-cadherin, EMP1 and 5T4 and the pro-invasive N-cadherin proteins using fully characterised antibodies and quantitative immunofluorescence microscopy in normal tissue (NT), fibroepithelial polyp (FEP), low-grade dysplasia (LGD), high-grade dysplasia (HGD), T1 OSCC and T4 OSCC biopsies. Decreased E-cadherin expression was associated with FEP, LGD and HGD biopsies, demonstrating that loss of E-cadherin is an early event within abnormal epithelium and occurs in the absence of an E- to N-cadherin switch, the latter of which was only observed in T4 OSCC. Furthermore, loss of E-cadherin and EMP1 is an indicator of LGD (p = 0.0006) and loss of E-cadherin, EMP1 and 5T4 an indicator of HGD (p = 0.0006). Expression patterns of E-cadherin, EMP1 and N-cadherin could predict abnormal epithelium in LGD, HGD, T1 and T4 OSCC biopsies (z-value = 0 for all disease grades) and allowed classification of LGD (z = 1.47), HGD (z = 2.138), T1 (z = 1.05) and T4 OSCC (z = 1.49) biopsies. Therefore, these markers provide a useful means to predict abnormal epithelium in patient biopsies. Linear regression and coefficient of determination analysis revealed positive correlation with a NT>LGD>HGD disease transition but low correlation with a putative HGD>T1 OSCC>T4 OSCC disease transition. Furthermore, expression of E-cadherin, EMP1, 5T4 and N-cadherin in pathologically normal surgical safety margins of LGD, HGD and T1 OSCC patient biopsies revealed significant differences to NT and the use of safety margins or FEP as 'normal tissue' controls introduced Type II errors in all patient cohorts. This work forms the basis for further investigation of the role of E-cadherin loss in abnormal epithelium and in the development of automated analyses for use in cancer diagnostics.

Characterization of neutrophil function in Papillon-Lefèvre syndrome.

Papillon-Lefévre syndrome is a rare, inherited, autosomal-recessive disease, characterized by palmoplantar keratosis and severe prepubertal periodontitis, leading to premature loss of all teeth. Papillon-Lefévre syndrome is caused by a mutation in the cathepsin C gene, resulting in complete loss of activity and subsequent failure to activate immune response proteins. Periodontitis in Papillon-Lefévre syndrome is thought to arise from failure to eliminate periodontal pathogens as a result of cathepsin C deficiency, although mechanistic pathways remain to be elucidated. The aim of this study was to characterize comprehensively neutrophil function in Papillon-Lefévre syndrome. Peripheral blood neutrophils were isolated from 5 patients with Papillon-Lefévre syndrome, alongside matched healthy control subjects. For directional chemotactic accuracy, neutrophils were exposed to the chemoattractants MIP-1α and fMLP and tracked by real-time videomicroscopy. Reactive oxygen species generation was measured by chemiluminescence. Neutrophil extracellular trap formation was assayed fluorometrically, and proinflammatory cytokine release was measured following overnight culture of neutrophils with relevant stimuli. Neutrophil serine protease deficiencies resulted in a reduced ability of neutrophils to chemotax efficiently and an inability to generate neutrophil extracellular traps. Neutrophil extracellular trap-bound proteins were also absent in Papillon-Lefévre syndrome, and Papillon-Lefévre syndrome neutrophils released higher levels of proinflammatory cytokines in unstimulated and stimulated conditions, and plasma cytokines were elevated. Notably, neutrophil chemoattractants MIP-1α and CXCL8 were elevated in Papillon-Lefévre syndrome neutrophils, as was reactive oxygen species formation. We propose that relentless recruitment and accumulation of hyperactive/reactive neutrophils (cytokines, reactive oxygen species) with increased tissue transit times into periodontal tissues, alongside a reduced antimicrobial capacity, create a locally destructive chronic inflammatory cycle in Papillon-Lefévre syndrome.

A rare truncating BRCA2 variant and genetic susceptibility to upper aerodigestive tract cancer.

Deleterious BRCA2 genetic variants markedly increase risk of developing breast cancer. A rare truncating BRCA2 genetic variant, rs11571833 (K3326X), has been associated with a 2.5-fold risk of lung squamous cell carcinoma but only a modest 26% increase in breast cancer risk. We analyzed the association between BRCA2 SNP rs11571833 and upper aerodigestive tract (UADT) cancer risk with multivariable unconditional logistic regression adjusted by sex and combinations of study and country for 5942 UADT squamous cell carcinoma case patients and 8086 control patients from nine different studies. All statistical tests were two-sided. rs11571833 was associated with UADT cancers (odds ratio = 2.53, 95% confidence interval = 1.89 to 3.38, P = 3x10(-10)) and was present in European, Latin American, and Indian populations but extremely rare in Japanese populations. The association appeared more apparent in smokers (current or former) compared with never smokers (P het = .026). A robust association between a truncating BRCA2 variant and UADT cancer risk suggests that treatment strategies orientated towards BRCA2 mutations may warrant further investigation in UADT tumors.

The 12p13.33/RAD52 locus and genetic susceptibility to squamous cell cancers of upper aerodigestive tract.

Genetic variants located within the 12p13.33/RAD52 locus have been associated with lung squamous cell carcinoma (LUSC). Here, within 5,947 UADT cancers and 7,789 controls from 9 different studies, we found rs10849605, a common intronic variant in RAD52, to be also associated with upper aerodigestive tract (UADT) squamous cell carcinoma cases (OR = 1.09, 95% CI: 1.04-1.15, p = 6x10(-4)). We additionally identified rs10849605 as a RAD52 cis-eQTL inUADT(p = 1x10(-3)) and LUSC (p = 9x10(-4)) tumours, with the UADT/LUSC risk allele correlated with increased RAD52 expression levels. The 12p13.33 locus, encompassing rs10849605/RAD52, was identified as a significant somatic focal copy number amplification in UADT(n = 374, q-value = 0.075) and LUSC (n = 464, q-value = 0.007) tumors and correlated with higher RAD52 tumor expression levels (p = 6x10(-48) and p = 3x10(-29) in UADT and LUSC, respectively). In combination, these results implicate increased RAD52 expression in both genetic susceptibility and tumorigenesis of UADT and LUSC tumors.

Human papillomavirus infections and upper aero-digestive tract cancers: the ARCAGE study.

BACKGROUND: Human papillomavirus (HPV) is causally implicated in a subset of cancers of the upper aero-digestive tract (UADT). METHODS: Associations between type-specific HPV antibodies were examined among 1496 UADT cancer case subjects and 1425 control subjects by estimating odds ratios (ORs) in logistic regression analyses adjusted for potential confounders. The agreement between serology and tumor markers of HPV infection, including presence of HPV DNA and p16 expression, were examined in a subset of tumors. RESULTS: HPV16 L1 seropositivity was associated with increased risk of oral cavity and oropharyngeal cancer (OR = 1.94, 95% confidence interval [CI] = 1.03 to 3.65; OR = 8.60, 95% CI = 5.21 to 14.20, respectively). HPV16 E6 antibodies were present in 30.2% of oropharyngeal case subjects and only 0.8% of control subjects (OR = 132.0, 95% CI = 65.29 to 266.86). Combined seropositivity to HPV16 E6 and E7 was rare (n = 1 of 1425 control subjects). An agreement of 67% was observed between HPV16 E6 serology and the corresponding presence of an HPV-related cancer: four of six HPV DNA-positive/p16-overexpressing tumors were HPV16 E6 antibody positive. An HPV16 independent association was observed for HPV18 and oropharyngeal cancer (OR = 8.14, 95% CI = 2.21 to 29.99 for HPV18 E6 seropositivity) and HPV6 and laryngeal cancer (OR = 3.25, 95% CI = 1.46 to 7.24 for HPV6 E7 seropositivity). CONCLUSIONS: These results confirm an important role for HPV16 infection in oropharyngeal cancer. HPV16 E6 antibodies are strongly associated with HPV16-related oropharyngeal cancers. Continuing efforts are needed to consider both HPV serology and p16 staining as biomarkers relevant to the etiology and natural history of HPV16-related oropharyngeal tumors. These results also support a marginal role for HPV18 in oropharyngeal cancer and HPV6 in laryngeal cancer.

The expression of FHIT in salivary carcinoma ex pleomorphic adenoma.

BACKGROUND: Carcinoma ex-pleomorphic adenoma (Ca-ex-PA) is considered to be a malignant transformation product of pre-existing pleomorphic salivary adenoma (PSA). AIM: Our study aimed to characterise alterations in the immunohistochemical expression of the Fragile Histidine Traid (FHIT) and Cyclin-dependent Kinase Inhibitor 2A (CDKN2A) (p16(INK4a)) genes during tumour progression model from PSA to Ca-ex-PA in a cross sectional study. MATERIALS AND METHODS: Paraffin blocks of 29 cases of PSA which were surrounded by normal parotid gland, and 26 cases of Ca-ex-PA were retrieved and validated. In all cases of Ca-ex-PA, a PSA 'ghost' was identified and the malignant element was either undifferentiated carcinoma or adenocarcinoma. Immunohistochemical staining and evaluation for CDKN2A and FHIT in 55 specimens were undertaken. RESULTS: The results showed positive nuclear expression of p16 and FHIT in normal parotid gland. None (0%) of the PSA cases demonstrated loss of expression of nuclear FHIT, while 6/26 (23.1%) showed loss of FHIT express. Loss of CDKN2A expression was found in 12/29 (41.4%) of PSAs and 8/26 (30.8%) of Ca-ex-PAs. The nuclear expression pattern for FHIT was significantly more frequent in Ca-ex-PAs compared to PSAs (p=0.014). CONCLUSION: Our data suggest that inactivation of tumour suppressor genes plays an important role in the evolution of Ca-ex-PA. Furthermore, alteration of CDKN2A expression was found to be an early event in the malignant transformation of pleomorphic adenoma and could be considered as a target for gene therapy. More interestingly, we found that nuclear FHIT expression could be used as a good marker to distinguish PSA from Ca-ex-PA.

Using prior information from the medical literature in GWAS of oral cancer identifies novel susceptibility variant on chromosome 4--the AdAPT method.

BACKGROUND: Genome-wide association studies (GWAS) require large sample sizes to obtain adequate statistical power, but it may be possible to increase the power by incorporating complementary data. In this study we investigated the feasibility of automatically retrieving information from the medical literature and leveraging this information in GWAS. METHODS: We developed a method that searches through PubMed abstracts for pre-assigned keywords and key concepts, and uses this information to assign prior probabilities of association for each single nucleotide polymorphism (SNP) with the phenotype of interest--the Adjusting Association Priors with Text (AdAPT) method. Association results from a GWAS can subsequently be ranked in the context of these priors using the Bayes False Discovery Probability (BFDP) framework. We initially tested AdAPT by comparing rankings of known susceptibility alleles in a previous lung cancer GWAS, and subsequently applied it in a two-phase GWAS of oral cancer. RESULTS: Known lung cancer susceptibility SNPs were consistently ranked higher by AdAPT BFDPs than by p-values. In the oral cancer GWAS, we sought to replicate the top five SNPs as ranked by AdAPT BFDPs, of which rs991316, located in the ADH gene region of 4q23, displayed a statistically significant association with oral cancer risk in the replication phase (per-rare-allele log additive p-value [p(trend)] = 2.5×10(-3)). The combined OR for having one additional rare allele was 0.83 (95% CI: 0.76-0.90), and this association was independent of previously identified susceptibility SNPs that are associated with overall UADT cancer in this gene region. We also investigated if rs991316 was associated with other cancers of the upper aerodigestive tract (UADT), but no additional association signal was found. CONCLUSION: This study highlights the potential utility of systematically incorporating prior knowledge from the medical literature in genome-wide analyses using the AdAPT methodology. AdAPT is available online (url: http://services.gate.ac.uk/lld/gwas/service/config).

Facial infiltrating lipomatosis: A case report and review of literature.

Infiltrating lipomatosis of the face has been described as a congenital disorder in which mature lipocytes invade adjacent tissues in the facial region. The presentation is always unilateral with hypertrophy of hard and soft structures on the affected side of the face. We present a case of a 27-year-old female who reported with a complaint of recurrent unilateral facial swelling with history of two previous resections, the histopathology or details of these surgeries were not available. The patient underwent resection of tumour and the histopathology confirmed it to be infiltrating lipomatosis. The surgery resulted in a definite improvement in the facial asymmetry and the patient is being closely followed up with no evidence of recurrence. The pathogenesis of the condition is unclear, though it has been postulated that the condition is at one end of a spectrum of overgrowth syndromes with classic Proteus syndrome on the other extreme. Management of this condition involves resection of the tumour which in most cases is subtotal to reduce the risk of damage to facial nerve. There is a controversy regarding both timing and extent of resection in the literature and we think the subtotal resection of tumour in an adolescent or older patient can give good aesthetic outcome without compromising facial nerve function. However, the patients should be informed about high rate of recurrence and increase risk of complications with any subsequent surgery.

A molecular analysis of individuals with neurofibromatosis type 1 (NF1) and optic pathway gliomas (OPGs), and an assessment of genotype-phenotype correlations.

BACKGROUND: Neurofibromatosis type 1 (NF1) affects 1 in 2500 people, and 15% of these may develop an optic pathway glioma (OPG). OPGs behave differently in NF1, and, given their frequency, surveillance is important. However, this is difficult because of the additional complications these patients may have, such as learning difficulties. Management is also different given that NF1 results from loss of function of tumour suppressor gene. A genotype-phenotype correlation may help to determine who is at risk of developing these tumours, aid focused screening, and shed light on response to treatments. METHODS: As part of a long-term follow-up study of patients with NF1 OPGs, the authors assessed genotype-phenotype correlation. Fluorescein in situ hybridisation was performed to identify large deletions, and then a full gene screen for mutations, by denaturing high-performance liquid chromatography. RESULTS: 80 patients with NF1 OPGs were identified, and molecular analyses were performed in a subset of 29. A clustering of pathogenic changes in the 5' tertile of the gene was found. The authors combined these results with those for another two NF1 OPG cohorts and collectively found the same trend. When compared with a control population of NF1 patients without an OPG, the OR of a mutation being present in the 5' tertile was 6.05 (p=0.003) in the NF1 OPG combined cohorts. CONCLUSION: It is possible that genotype is a significant determinant of the risk of development of OPGs in NF1.

A sex-specific association between a 15q25 variant and upper aerodigestive tract cancers.

BACKGROUND: Sequence variants located at 15q25 have been associated with lung cancer and propensity to smoke. We recently reported an association between rs16969968 and risk of upper aerodigestive tract (UADT) cancers (oral cavity, oropharynx, hypopharynx, larynx, and esophagus) in women (OR = 1.24, P = 0.003) with little effect in men (OR = 1.04, P = 0.35). METHODS: In a coordinated genotyping study within the International Head and Neck Cancer Epidemiology (INHANCE) consortium, we have sought to replicate these findings in an additional 4,604 cases and 6,239 controls from 10 independent UADT cancer case-control studies. RESULTS: rs16969968 was again associated with UADT cancers in women (OR = 1.21, 95% CI = 1.08-1.36, P = 0.001) and a similar lack of observed effect in men [OR = 1.02, 95% CI = 0.95-1.09, P = 0.66; P-heterogeneity (P(het)) = 0.01]. In a pooled analysis of the original and current studies, totaling 8,572 UADT cancer cases and 11,558 controls, the association was observed among females (OR = 1.22, 95% CI = 1.12-1.34, P = 7 × 10(-6)) but not males (OR = 1.02, 95% CI = 0.97-1.08, P = 0.35; P(het) = 6 × 10(-4)). There was little evidence for a sex difference in the association between this variant and cigarettes smoked per day, with male and female rs16969968 variant carriers smoking approximately the same amount more in the 11,991 ever smokers in the pooled analysis of the 14 studies (P(het) = 0.86). CONCLUSIONS: This study has confirmed a sex difference in the association between the 15q25 variant rs16969968 and UADT cancers. IMPACT: Further research is warranted to elucidate the mechanisms underlying these observations.

Loss of CSMD1 expression is associated with high tumour grade and poor survival in invasive ductal breast carcinoma.

CUB and SUSHI multiple domain protein 1 (CSMD1) is a candidate tumour suppressor gene that maps to chromosome 8p23, a region deleted in many tumour types including 50% of breast cancers. CSMD1 has homologies to proteins implicated in carcinogenesis. We aimed to study the expression pattern of the CSMD1 protein and evaluate its prognostic importance in invasive ductal carcinoma (IDC). An anti-CSMD1 antibody was developed and validated. The expression pattern of CSMD1 in normal breast and IDC samples was investigated by immunohistochemistry in 275 patients. Univariate and multivariate Cox regression analyses were performed. In normal breast duct epithelial cells, luminal, membranous and cytoplasmic CSMD1 staining was identified. Reduced expression of CSMD1 was detected in 79/275 (28.7%) of IDC cases. Low CSMD1 expression was significantly associated with high tumour grade (P = 0.003). CSMD1 expression was associated with overall survival (OS; HR = 0.607, 95%CI: 0.4-0.91, P = 0.018) but not with disease-free survival (DFS; HR = 0.81, 95%CI: 0.46-1.43, P = 0.48). Multivariate analysis showed that CSMD1, together with Nottingham Prognostic Index, was considered an independent predictor of OS (HR = 0.607, 95%CI: 0.4-0.91, P = 0.018) but not DFS (HR = 0.84, 95%CI: 0.46-1.5, P = 0.573). Reduction of CSMD1 expression was significantly associated with high tumour grade and decreased OS. Therefore, our results support the idea that CSMD1 is a tumour suppressor gene and suggest its possible use as a new prognostic biomarker. The membrane expression pattern of CSMD1 suggests that it may be a receptor or co-receptor involved in the process of signal transduction.

Imaging mass spectrometry using chemical inkjet printing reveals differential protein expression in human oral squamous cell carcinoma.

Matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS) is a recently developed technique that generates molecular profiles usually of peptide and protein signals directly from the surface of thin tissue sections and can be coupled with automation to generate two-dimensional ion density maps. This allows specific information to be obtained on the relative abundance and spatial distribution of the analytes of interest. The technique has potential for application in many diseases including cancer with respect to elucidating the molecular pathology and identifying potential biomarkers. In this proof-of-principle study we have evaluated inkjet printing of the sinapinic acid matrix used for MALDI-IMS directly onto the surface of human oral squamous cell carcinoma biopsy specimens. This MS profiling technique produced reproducible informative chemical images for clinical pathology. Analysis of the resulting protein profiles of highly expressed protein in squamous cell carcinoma of the tongue reveals spectral features at approximately 4500 and approximately 8360 Da.

Focal palmoplantar and gingival hyperkeratosis: a case report.

UNLABELLED: We report a rare genetic condition characterized by gingival hyperkeratosis with skin changes affecting the hands and feet. The patient presented with asymptomatic oral lesions and the diagnosis was reached by taking a full clinical history and biopsy tests. Palmoplantar keratosis can be a feature of a range of different syndromes and can be associated with periodontal destruction, benign oral keratosis or cancer of the oesophagus. It is important for dentists to be aware that clues to diagnosis can be gained from examination of the hands and feet, in addition to an oral examination, particularly in recognizing oral genetic disorders. CLINICAL RELEVANCE: To inform clinicians of both the intra-oral and extra-oral features of focal palmoplantar and gingival hyperkeratosis.

Tumor expression of major vault protein is an adverse prognostic factor for radiotherapy outcome in oropharyngeal carcinoma.

PURPOSE: Vaults are multi-subunit structures that may be involved in nucleo-cytoplasmic transport, with the major vault protein (MVP or lung resistance-related protein [LRP]) being the main component. The MVP gene is located on chromosome 16 close to the multidrug resistance-associated protein and protein kinase c-beta genes. The role of MVP in cancer drug resistance has been demonstrated in various cell lines as well as in ovarian carcinomas and acute myeloid leukemia, but nothing is known about its possible role in radiation resistance. Our aim was to examine this in head-and-neck squamous cell carcinoma (HNSCC). METHODS AND MATERIALS: Archived biopsy material was obtained for 78 patients with squamous cell carcinoma of the oropharynx who received primary radiotherapy with curative intent. Immunohistochemistry was used to detect MVP expression. Locoregional failure and cancer-specific survival were estimated using cumulative incidence and Cox multivariate analyses. RESULTS: In a univariate and multivariate analysis, MVP expression was strongly associated with both locoregional failure and cancer-specific survival. After adjustment for disease site, stage, grade, anemia, smoking, alcohol, gender, and age, the estimated hazard ratio for high MVP (2/3) compared with low (0/1) was 4.98 (95% confidence interval, 2.17-11.42; p = 0.0002) for locoregional failure and 4.28 (95% confidence interval, 1.85-9.95; p = 0.001) for cancer-specific mortality. CONCLUSION: These data are the first to show that MVP may be a useful prognostic marker associated with radiotherapy resistance in a subgroup of patients with HNSCC.

Why oral histopathology suffers inter-observer variability on grading oral epithelial dysplasia: an attempt to understand the sources of variation.

The present study attempted to assess the reasons behind the inter-observer variation in grading oral epithelial dysplasia (OED). Three oral pathologists and one general pathologist examined 68 histological slides of OED lesions of variable grade for scoring the presence of each individual characteristic of the architecture and cytology changes that were established by the 2005 WHO classification. The assigned features in each case were correlated with clinical outcomes to understand which features are more commonly associated with malignant transformation. Interestingly, for all individual characteristics, the pairwise inter-examiner and group kappa values ranged from poor to moderate. It appeared that for each characteristic separately there was much dissension. Despite these observations, comparing these data with that from our previous paper on the same slides showed that the inter-observer agreement on the degree of dysplasia either by using the new binary system of "low-risk" or "high-risk" or by using the 2005 WHO classification turned out to be better than the agreement on the individual characteristics of architecture and cytology changes. Certain features show significant association with the clinical outcomes. In the discussion, some explanations to help understanding the sources of variation in grading OED are put forward. In conclusion, grading dysplasia is not an exact science and pathologists are doing their best to reach optimal results. Improvement in the standard of the histopathology reporting of OED lesions could be achieved by consideration of several issues. Of these, there is need for a universal definition of the architectural and cytological features that are the basis of any OED grading process. A minimum dataset for reporting OED lesions should be set up. Also, the use of a consensus scoring process between two or more observers should be encouraged as this would improve inter-observer agreement.