Current classification of vascular anomalies of the head and neck.

Vascular anomalies of the head and neck comprise a wide spectrum of phenotypically diverse lesions. Optimal diagnosis and management of these lesions are critically dependent upon establishment of uniform and well-defined histopathologic, clinical, and radiological criteria, but these remain subject of debate. In this paper, we describe the International Society for the Study of Vascular Anomalies classification scheme, which was first published in 1996 and updated in 2014. The strength of this proposal rests on its distinction between vascular malformations and tumors, and is responsible for its wide adoption. This paradigm serves as a developing platform for diagnosis, inter-collegial communication, and treatment, and adhering to it will help clinicians to improve the management of vascular anomalies.

Angiosarcomas of the head and neck: Impact of large data analysis on clinical management.

Angiosarcoma is a rare but often fatal malignancy from blood and lymphatic vessels that can arise anywhere in the body and often affects the head and neck region. Although its dismal prognosis is predominantly explained by its aggressive biology, several secondary factors contribute to poor outcomes. These include a phenotypic resemblance to innocuous blood vessel lesions, which contributes to a significant degree of late diagnosis. Another important factor is the rarity of angiosarcoma, which has impaired scientific determination of its optimal treatment significantly. As a result, treatment of angiosarcomas has largely been guided by information derived from the study of sarcomas at large, themselves a highly heterogeneous group of mesenchymal cancers both from a diagnostic as well as therapeutical perspective. The Digital Revolution and resultant Information Age promise to transform the clinical management of rare cancers from a generic to a more customized approach. In this paper, we review the current understanding of head and neck angiosarcomas within the context of this process.

Improvement of oral cancer screening quality and reach: The promise of artificial intelligence.

Oral cancer is easily detectable by physical (self) examination. However, many cases of oral cancer are detected late, which causes unnecessary morbidity and mortality. Screening of high-risk populations seems beneficial, but these populations are commonly located in regions with limited access to health care. The advent of information technology and its modern derivative artificial intelligence (AI) promises to improve oral cancer screening but to date, few efforts have been made to apply these techniques and relatively little research has been conducted to retrieve meaningful information from AI data. In this paper, we discuss the promise of AI to improve the quality and reach of oral cancer screening and its potential effect on improving mortality and unequal access to health care around the world.

Genetic abnormalities associated with chemoradiation resistance of head and neck squamous cell carcinoma.

PURPOSE: To identify reliable predictors of chemoradiation resistance of advanced head and neck squamous cell carcinoma (HNSCC). EXPERIMENTAL DESIGN: We did a matched-pair analysis of 20 chemoradiation-resistant and 20 sensitive HNSCCs, identified among a series of 104 consecutively treated cases. We compared the global DNA copy number profiles derived from comparative genomic hybridization analysis of both groups to identify genetic markers associated with chemoradiation resistance. RESULTS: Although sensitive and resistant case groups were characterized by a similar total number of genetic aberrations, high-level amplifications were more frequent in resistant tumors. Resistant tumors were characterized by a different profile of genetic changes. Gains of 3q11-q13, 3q21-q26.1, and 6q22-q27 and losses of 3p11-pter and 4p11-pter were significantly associated with chemoradiation resistance. High-level amplifications unique to resistant cases involved the chromosomal regions 1p32, 3q24, 7p11.1, 7p11.2-12, 8p11.1, 8p11.1-12, 12q15, 13q21, 15q12, 18p11.3, and 18q11. CONCLUSIONS: Sensitive and resistant HNSCCs are characterized by divergent genomic profiles. These profiles may be valuable as predictive markers of treatment failure.

Clinical impact of molecular analysis on thyroid cancer management.

Thyroid cancer constitutes a progressive continuum of disease ranging from indolent well-differentiated carcinomas to aggressive poorly differentiated carcinomas and universally fatal anaplastic carcinomas. The wide divergence in clinical behavior is poorly predicted for by current clinicopathological factors. Moreover, therapeutic armentarium against aggressive thyroid cancers remains limited. Recent studies have identified a range of molecular alterations in thyroid cancers. Clinical implications of the molecular alterations include their utility in diagnostic evaluation, staging and targeted treatment. Continued molecular analysis of thyroid cancers promises to increase our understanding of its biologic behavior and is expected to have further impact on its clinical management.

Aggressive differentiated thyroid cancer.

Differentiated thyroid cancer is characteristically associated with an innocuous clinical course, but a minority of cases may manifest surprisingly aggressive behaviour. Such aggressive DTC are directly responsible for the majority of thyroid cancer related deaths. Moreover, they contribute indirectly to increased DTC-related morbidity, because our inability to differentiate these tumours from innocuous DTC at an early stage fuels a significant degree of DTC overtreatment around the globe. In the present paper we describe how improved understanding of the clinicopathological thyroid tumour progression model and optimization of clinical staging systems continues to improve our ability to diagnose and treat aggressive DTC. Early recognition of aggressive DTC allows instillation of an aggressive management strategy which is based upon surgical-oncologic completeness, and minimization of treatment-related sequelae through continued development of reconstructive options and focussed delivery of adjuvant treatments.

Optimization of the risk-benefit ratio of differentiated thyroid cancer treatment.

The vast majority of differentiated thyroid cancers (DTC) are characterized by an innocuous nature, excellent patient survival, and limited treatment requirement. However, a significant proportion of affected patients is prone to receiving overtreatment, due to undertreatment concerns associated with the difficulty to differentiate them from a small minority affected by aggressive DTC. Identification of prognostic factors and development of staging systems has helped to reduce the proportion of overtreatment in DTC. However, the absolute number of overtreated patients continues to increase, as a result of an on-going incidence surge in early DTC associated with the increased application and sensitivity of modern diagnostic tools. In the present paper, we describe how DTC treatment can be optimized by thoughtful evidence-based balancing of oncologic safety against treatment associated morbidity.

Fanconi anemia and homologous recombination gene variants are associated with functional DNA repair defects in vitro and poor outcome in patients with advanced head and neck squamous cell carcinoma.

Mutations in Fanconi Anemia or Homologous Recombination (FA/HR) genes can cause DNA repair defects and could therefore impact cancer treatment response and patient outcome. Their functional impact and clinical relevance in head and neck squamous cell carcinoma (HNSCC) is unknown. We therefore questioned whether functional FA/HR defects occurred in HNSCC and whether they are associated with FA/HR variants. We assayed a panel of 29 patient-derived HNSCC cell lines and found that a considerable fraction is hypersensitive to the crosslinker Mitomycin C and PARP inhibitors, a functional measure of FA/HR defects. DNA sequencing showed that these hypersensitivities are associated with the presence of bi-allelic rare germline and somatic FA/HR gene variants. We next questioned whether such variants are associated with prognosis and treatment response in HNSCC patients. DNA sequencing of 77 advanced stage HNSCC tumors revealed a 19% incidence of such variants. Importantly, these variants were associated with a poor prognosis (p = 0.027; HR = 2.6, 1.1-6.0) but favorable response to high cumulative cisplatin dose. We show how an integrated in vitro functional repair and genomic analysis can improve the prognostic value of genetic biomarkers. We conclude that repair defects are marked and frequent in HNSCC and are associated with clinical outcome.

Patterns of expression of cell cycle/apoptosis genes along the spectrum of thyroid carcinoma progression.

BACKGROUND: Genetic screening studies suggest that genetic changes underlie progression from well differentiated to anaplastic thyroid cancers. The aim of this study is to determine to what extent cell cycle/apoptosis regulators contribute to cancer progression. METHODS: Tissue microarrarys (TMAs) were constructed from well-differentiated papillary thyroid carcinoma (WDPTC; n = 41), poorly differentiated thyroid carcinoma (PDTC; n = 43), and anaplastic thyroid carcinoma (ATC; n = 22). TMAs were immunostained for 7 different cell cycle/apoptosis-related genes (p53, Ki-67, bcl-2, mdm-2, cyclin D1, p21, and p27). RESULTS: p53 (0%, 12%, 32%) and Ki-67 (5%, 49%, 82%) were expressed with increasing frequency, and bcl-2 (68%, 42%, 0%) and p21 (40%, 7%, 0%) with decreasing frequency in WDPTC to PDTC and ATC, respectively (P < .001). Interestingly, mdm-2 (54%, 5%, 0%) showed decreased expression along the progression axis (P < .001). p27 and cyclin D1 were expressed in <15% of cases, with a trend toward decreasing expression from WDPTC to PDTC to ATC. CONCLUSIONS: These data confirm the presence of increasing genetic complexity with progressive dedifferentiation in thyroid cancer, with aberrant tumor suppressor activity and increased proliferative activity being most prevalent in ATC. The data also confirm the intermediate position of PDTC in the classification scheme of thyroid carcinomas.

Repetitive endoscopic sinus surgery failure: a role for radical surgery?

OBJECTIVES: Endoscopic sinus surgery (ESS) is considered to be the golden standard for surgery in patients with chronic rhinosinusitis and nasal polyposis. However, there is still a small group of patients unresponsive despite repetitive surgery. Radical surgery aimed at reduction of the inflammatory burden and optimization of drainage of the sinuses has been suggested as a last resort for these patients. STUDY DESIGN: A prospective, questionnaire-based study was conducted in a group of 23 patients who underwent Denker's procedure for refractory chronic rhinosinusitis. Symptoms were evaluated before Denker's procedure and 12 months and 2 years after surgery. RESULTS: Patients reported improvement of feelings of congestion in 74%, rhinorrhea in 70%, and nasal obstruction in 60% of the cases. The following postoperative improvements were statistically significant: rhinorrhea (P = 0.001), feelings of congestion (P = 0.02), and nasal obstruction (P = 0.03). Reduced olfactory perception and asthma did not improve. CONCLUSION: Radical surgery may be a viable treatment option in case of recurrent ESS failure. EBM RATING: C-4.

Genome-wide profiling of papillary thyroid cancer identifies MUC1 as an independent prognostic marker.

Clinicopathological variables used at present for prognostication and treatment selection for papillary thyroid carcinomas (PTCs) do not uniformly predict tumor behavior, necessitating identification of novel prognostic markers. Complicating the assessment is the long natural history of PTC and our rudimentary knowledge of its genetic composition. In this study we took advantage of differences in clinical behavior of two distinct variants of PTC, the aggressive tall-cell variant (TCV) and indolent conventional PTC (cPTC), to identify molecular prognosticators of outcome using complementary genome wide analyses. Comparative genome hybridization (CGH) and cDNA microarray (17,840 genes) analyses were used to detect changes in DNA copy number and gene expression in pathological cPTC and TCV. The findings from CGH and cDNA microarray analyses were correlated and validated by real-time PCR and immunohistochemical analyses on a series of 100 cases of cPTC and TCV. Genes identified by this approach were evaluated as prognostic markers in cPTC by immunohistochemistry on tissue arrays. CGH identified significant differences in the presence (76 versus 27%; P = 0.001) and type of DNA copy number aberrations in TCV compared with cPTC. Recurrent gains of 1p34-36, 1q21, 6p21-22, 9q34, 11q13, 17q25, 19, and 22 and losses of 2q21-31, 4, 5p14-q21, 6q11-22, 8q11-22, 9q11-32, and 13q21-31 were unique to TCV. Hierarchical clustering of gene expression profiles revealed significant overlap between TCV and cPTC, but further analysis identified 82 dysregulated genes differentially expressed among the PTC variants. Of these, MUC1 was of particular interest because amplification of 1q by CGH correlated with MUC1 amplification by real-time PCR analysis and protein overexpression by immunohistochemistry in TCV (P = 0.005). Multivariate analysis revealed a significant association between MUC1 overexpression and treatment outcome, independent of histopathological categorization (P = 0.03). Analysis of a validation series containing a matched group of aggressive and indolent cPTCs confirmed the association between MUC1 overexpression and survival (relative risk, 2.3; 95% confidence interval, 1.1-5.5; P = 0.03). Our data suggest that MUC1 dysregulation is associated with aggressive behavior of PTC and may serve as a prognostic marker and potential therapeutic target in this disease.

Influence of extracapsular nodal spread extent on prognosis of oral squamous cell carcinoma.

BACKGROUND: An objective definition of clinically relevant extracapsular nodal spread (ECS) in head and neck squamous cell carcinoma (SCC) is unavailable. METHODS: Pathologic review of 245 pathologically positive oral cavity SCC neck dissection specimens was performed. The presence/absence of ECS, its extent (in millimeters), and multiple nodal and primary tumor risk factors were related to disease-specific survival (DSS) at a follow-up of 73 months. RESULTS: ECS was detected in 109 patients (44%). DSS was significantly better for patients without ECS than patients with ECS. Time-dependent receiver operator curve (ROC) analysis identified a prognostic cutoff for ECS extent at 1.7 mm. In multivariate analyses, DSS was significantly lower for patients with major ECS compared with patients with minor ECS, but not significantly different between patients with minor ECS and patients without ECS. CONCLUSION: ECS is clinically relevant in oral cavity SCC when it has extended more than 1.7 mm beyond the nodal capsule. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1192-E1199, 2016.

Identification of novel prognosticators of outcome in squamous cell carcinoma of the head and neck.

PURPOSE: The goal of this study was to identify chromosomal aberrations associated with poor outcome in patients with head and neck squamous cell carcinoma (HNSCC). PATIENTS AND METHODS: We assessed the global genomic composition of 82 HNSCCs from previously untreated patients with comparative genomic hybridization (CGH). The CGH data were subcategorized into individual cytogenetic bands. Only genomic aberrations occurring in more than 5% of cases were analyzed, and redundancies were eliminated. Each aberration was submitted to univariate analysis to assess its relationship with disease-specific survival (DSS). We used Monte Carlo simulations (MCS) to adjust P values for the log-rank approximate chi(2) statistics for each abnormality and further applied the Hochberg-Benjamini procedure to adjust the P values for multiple testing of the large number of abnormalities. We then submitted abnormalities whose univariate tests resulted in an adjusted P value of less than.15 together with significant demographic/clinical variables to stepwise Cox proportional hazards regression. We again verified and adjusted P values for the chi(2) approximation of the final model by MCS. RESULTS: CGH analysis revealed a recurrent pattern of chromosomal aberrations typical for HNSCC. Univariate analysis revealed 38 abnormalities that were correlated with DSS. After controlling for multiple comparisons and confounding effects of stage, five chromosomal aberrations were significantly associated with outcome, including amplification at 11q13, gain of 12q24, and losses at 5q11, 6q14, and 21q11 (MCS adjusted P =.0009 to P =.01). CONCLUSION: HNSCC contains a complex pattern of chromosomal aberrations. A sequential approach to control for multiple comparisons and effect of confounding variables allows the identification of clinically relevant aberrations. The significance of each individual abnormality merits further consideration.

MUC1 plays a role in tumor maintenance in aggressive thyroid carcinomas.

BACKGROUND: We recently identified MUC1 as a target driving selection for 1q21 amplification and validated it as an independent marker of aggressive behavior in thyroid cancer (TC). The aims of this study were to determine whether TC cell lines retain MUC1 expression patterns that are seen in primary tumors, assess the role of MUC1 in tumor maintenance, and develop a virally delivered anti-MUC1 RNA interference (RNAi) that is effective in decreasing MUC1 expression in vitro. METHODS: Fifteen TC cell lines were screened for MUC1 protein expression. Cell lines with varying MUC1 protein levels were treated with anti-MUC1 monoclonal antibody to assess cell viability. A recombinant retroviral short hairpin RNAi delivery system against MUC1 was developed. Efficacy and optimal dosing of short hairpin RNA against MUC1 was determined. RESULTS: MUC1 expression patterns in TC cell lines were found to be similar to that seen in primary tumors. Treatment with anti-MUC1 antibody resulted in a significant decrease in cell viability in MUC1 over-expressing cell lines. MUC1-779 RNAi construct showed excellent infection efficiency and reproducible silencing. CONCLUSION: These data offer functional evidence that implicates MUC1 over-expression as a key molecular event in the pathogenesis of aggressive TC. Retrovirally delivered anti-MUC1 RNAi is effective in silencing MUC1 and merits further investigation to establish therapeutic efficacy and safety in anticipation of potential clinical application.

Molecular profiling of tumor progression in head and neck cancer.

OBJECTIVE: To assess gene expression changes associated with tumor progression in patients with squamous cell carcinoma of the oral cavity. DESIGN: A microarray containing 17 840 complementary DNA clones was used to measure gene expression changes associated with tumor progression in 9 patients with squamous cell carcinoma of the oral cavity. Samples were taken for analysis from the primary tumor, nodal metastasis, and "normal" mucosa from the patients' oral cavity. SETTING: Tertiary care facility. Patients Nine patients with stage III or stage IV untreated oral cavity squamous cell carcinoma. RESULTS: Our analysis to categorize genes based on their expression patterns has identified 140 genes that consistently increased in expression during progression from normal tissue to invasive tumor and subsequently to metastatic node (in at least 4 of the 9 cases studied). A similar list of 94 genes has been identified that decreased in expression during tumor progression and metastasis. We validated this gene discovery approach by selecting moesin (a member of the ezrin/radixin/moesin [ERM] family of cytoskeletal proteins) and one of the genes that consistently increased in expression during tumor progression for subsequent immunohistochemical analysis using a head and neck squamous cell carcinoma tissue array. CONCLUSION: A distinct pattern of gene expression, with progressive up- or down-regulation of expression, is found during the progression from histologically normal tissue to primary carcinoma and to nodal metastasis.

Prognostic value of vascular invasion in well-differentiated papillary thyroid carcinoma.

BACKGROUND: Vascular invasion (VI) is an important predictor of distant metastasis and possible radioactive iodine (RAI) benefit in follicular, Hürthle cell, and poorly differentiated thyroid carcinomas, but its role in well-differentiated papillary thyroid cancer (WDTC) remains unclear. METHODS: Archived pathological material of all differentiated thyroid carcinoma patients undergoing primary surgical treatment at Memorial Sloan-Kettering Cancer Center between 1986 and 2003 was reviewed by two dedicated thyroid pathologists. Only WDTCs were included in the present study. Standard statistical methods were used to assess the relationship between VI and outcomes of interest, including 10-year disease-specific survival (DSS), regional recurrence-free survival (RRFS), and distant recurrence-free survival (DRFS). RESULTS: VI was present in 47 of 698 WDTC (6.7%). VI was significantly associated with tumor size >4.0 cm, extrathyroidal extension, distant metastasis, and RAI treatment. On univariate analysis, VI was predictive of decreased 10-year DRFS, but not DSS or RRFS. On multivariate analysis, VI was not an independent predictor of DRFS. Univariate survival analysis of 422 RAI-naïve WDTC showed that both size >4 cm and VI were predictors of outcome, but only size remained independently predictive on multivariate analysis. CONCLUSION: The presence of VI is not an independent predictor of outcome in WDTC.

Chromosomal aberrations in patients with head and neck squamous cell carcinoma do not vary based on severity of tobacco/alcohol exposure.

BACKGROUND: Head and neck squamous cell carcinomas (HNSCC) have been causally associated with tobacco and alcohol exposure. However, 10-15% of HNSCC develop in absence of significant carcinogen exposure. Several lines of evidence suggest that the genetic composition of HNSCC varies based on the extent of tobacco/alcohol exposure, however, no genome wide measures have been applied to address this issue. We used comparative genomic hybridization (CGH) to screen for the genetic aberrations in 71 patients with head and neck squamous cell carcinoma and stratified the findings by the status of tobacco/alcohol exposure. RESULTS: Although the median number of abnormalities (9), gains (6) and losses (2) per case and the overall pattern of abnormalities did not vary significantly by the extent of tobacco/alcohol exposure, individual abnormalities segregating these patients were identified. Gain of 1p (p = 0.03) and 3q amplification (p = 0.05) was significantly more common in patients with a history of tobacco/alcohol exposure. CONCLUSIONS: This data suggests that the overall accumulated chromosomal aberrations in head and neck squamous cell carcinoma are not significantly influenced by the severity of tobacco/alcohol exposure with limited exceptions.