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.

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.

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.

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.

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.

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.

Head and neck squamous cell carcinoma in young patients.

Epidemiologic analyses have shown disproportional increases of head and neck squamous cell carcinoma (HNSCC) incidence in a younger age group (younger than 45 years old), compared to patients above 45 years old. Although this group is small (5%), it includes a significant subset of the HNSCC patient population, and is characterized by a distinct clinical and etiological phenotype. HNSCC in young patients often presents without significant exposure to alcohol and tobacco and primarily affects the oropharynx and oral cavity. Exposure to human papilloma virus (HPV) has been identified as a major contributor to the pathogenesis of oropharyngeal carcinomas, and explains part of the observed incidence variation. Specific hereditary influences, including genetic predispositions accounting for an increased mutagen sensibility and inherited syndromes like Fanconi Anemia and Bloom's syndrome, have been identified as causative factors in a subgroup of young-onset HNSCC, but their cumulative influence remains at present likely underestimated. Circumstantial evidence suggests that young-onset HNSCC patients have a clinically different phenotype compared to older patients, however, the true impact of young age on HNSCC clinical behavior will remain difficult to determine unless multi-institutional databases will be combined. The rising incidence of young-onset HNSCC mandates intensification of research endeavors into its etiology, clinical phenotype and optimal management.

Oral and oropharyngeal squamous cell carcinoma in young patients: the Netherlands Cancer Institute experience.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) mainly affects patients between the fifth and seventh decade of life but is increasingly seen in young patients (<40 years old). Controversy exists in the literature regarding outcomes for younger patients with HNSCC. METHODS: A retrospective cohort analysis was performed comparing survival of 54 early-onset (<40 years) and 1708 older patients with oral and oropharyngeal squamous cell carcinomas (SCC) treated at The Netherlands Cancer Institute between 1977 and 2008. Survival analysis was performed using univariable and multivariable weighted Cox proportional hazards regression. The primary endpoint for the survival analysis was disease-specific survival (DSS). RESULTS: There was no difference in DSS between patients who were 40 years or younger and those older than 40 years (p = .878), although young patients had significantly better overall survival (OS). CONCLUSION: In this series, patients younger than 40 years with oral and oropharyngeal SCC showed no significant difference in DSS compared with patients older than 40 years, even when adjusted for tobacco and alcohol consumption.

Oropharyngeal squamous cell carcinoma: a unique disease on the rise?

Despite successful efforts to control tobacco and alcohol consumption in the western world, several developed countries report rising oropharyngeal squamous cell carcinoma (OPSCC) incidence figures, specifically in young individuals. Similar to anogenital cancers, a significant proportion of OPSCC (up to 60%) is caused by sexually acquired HPV infection and the rise in OPSCC has been attributed to changing sexual behaviours in the Western World. Accordingly, patients with HPV-positive OPSCC report divergent sexual histories and absence of classical risk factors as tobacco and alcohol exposure compared to patients with HPV-negative OPSCC. The profile of HPV-positive OPSCC differs from HPV-negative OPSCC in several other significant aspects, including a unique molecular biologic tumor characteristics and improved clinical behaviour. Thus, a further increase in HPV-positive OPSCC will impact significantly upon clinical management of OPSCC, unless it is halted by adequate preventive measures aimed at reduction of HPV-associated disease. HPV vaccination has been recently offered to young females in an attempt to reduce HPV-induced cervical cancer and may ultimately result in a decline of OPSCC incidence as well. Until then, close collaboration between otolaryngologists/head and neck surgeons and anogenital/genitourinary specialists is warranted to optimize clinical management of HPV-induced malignancy and improve detection of second primary tumor development.

Closure of tracheoesophageal fistula with prefabricated revascularized bilaminar radial forearm free flap.

BACKGROUND: Tracheoesophageal fistula (TEF) is a rare but serious complication associated with high mortality rates. Traditional management of TEF includes primary closure with or without interposition of regional tissue flaps but is associated with a significant recurrence risk, especially in case of larger fistulas. Application of microvascular free flap reconstruction is an emerging alternative in the surgical management of large TEFs, but may be limited by issues of flap bulkiness and requirement for neoepithelialization across the large inner flap surface. METHODS AND RESULTS: Here, we report prefabrication of a bilaminar radial forearm free flap to successfully close a large recurrent TEF that occurred years after tracheoesophageal puncture-based voice rehabilitation in a laryngectomized patient. CONCLUSION: The bilaminar radial forearm free flap may prove to be an important adjunct to the closure of large TEFs.

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.

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.

Downregulation of Fanconi anemia genes in sporadic head and neck squamous cell carcinoma.

BACKGROUND/AIMS: Much of our understanding of human cancer has come from studies of the hereditary cancer predisposition syndromes. Fanconi anemia (FA) is an autosomal recessive disorder characterized by cellular hypersensitivity to DNA crosslinking agents, progressive bone marrow failure, and cancer predisposition to solid malignancies, especially head and neck squamous cell carcinoma (HNSCC). Since FA pathway-deficient cells are hypersensitive to DNA crosslinking chemotherapy agents, the presence of somatic FA gene inactivation in sporadic cancers may be of clinical interest. This study sought to determine the frequency of FA gene downregulation in sporadic HNSCC. METHODS: The expression of the FA genes FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCJ, FANCL and FANCM in 11 HNSCC cell lines and 49 tongue carcinoma samples was studied with quantitative real-time polymerase chain reaction. RESULTS: Downregulation of at least one FA gene was observed in 3 of 11 HNSCC cell lines and 66% of tongue carcinoma samples. FANCB, FANCF, FANCJ and FANCM were most commonly affected by downregulation, whereas downregulation of FANCA, FANCE and FANCD2 was rare. CONCLUSION: Our data suggest that downregulation of FA genes is common in sporadic HNSCC. The clinical implications of this finding merit further study. .

Association of CD44 V3-containing isoforms with tumor cell growth, migration, matrix metalloproteinase expression, and lymph node metastasis in head and neck cancer.

BACKGROUND: The CD44 family of receptors includes multiple variant isoforms, some of which have been linked to tumor progression. The objective of this study was to investigate whether CD44 v3-containing isoforms are involved in head and neck squamous cell carcinoma (HNSCC) tumor progression. METHODS: Laboratory investigation utilizing HNSCC cell lines and clinical tissue specimens was performed. RESULTS: Investigation of 13 HNSCC cell lines revealed a diversity of CD44 isoform profiles, including expression of CD44 v3-containing isoforms. Two cell lines, HOC313 and MDA1483, were selected for further study based on their CD44 v3 expression profile. The HOC313 cell line, which highly expresses CD44 v3-containing isoforms, demonstrated hyaluronan-mediated CD44-dependent promotion of tumor cell growth and migration. Conditioned media from the HOC313 cell line also exhibited high matrix metalloproteinase expression on gelatin zymography. Immunohistochemical analysis of a series of metastatic HNSCC lymph nodes revealed CD44 overexpression as well as staining for CD44 v3-containing isoforms. CONCLUSION: CD44 v3-containing isoforms are associated with HNSCC growth, migration, and matrix metalloproteinase activity and can be identified in lymph node metastasis.