Synchronous tonsillar tumors with differing histopathology: A case report and review of the literature.

BACKGROUND: Tonsillar squamous cell carcinoma (TSCC) due to human papillomavirus (HPV) infection has seen a dramatic increase in recent years. Bilateral tonsillar squamous cell carcinoma (biTSCC) has a much lower incidence than unilateral TSCC and three main hypotheses of biTSCC pathogenesis prevail: field carcinogenesis, single-clone, and multiple HPV infections. CASE: A 49-year-old Male with a remote history of chewing tobacco presented with symptoms of spitting up tissue and occasional hemoptysis. Physical exam showed a sole left tonsillar mass which was confirmed to be TSCC on biopsy. The patient's computed tomographic (CT) scan was consistent with this finding; however, positron emission tomography (PET) scan indicated a second tumor in the contralateral right tonsil. Surgical resection of both masses and selective neck dissection was performed, and the specimens were sent for further pathological analysis. No complications of surgery were noted and the final diagnosis of synchronous biTSCC was made. The tumors were a T2N0M0 left poorly differentiated TSCC (p16+, EGFR+, bcl2+) with basaloid features, and a T1N0M0 right well to moderately differentiated TSCC (p16+, EGFR+, bcl2-). CONCLUSION: Our present case was notable for differing tumor pathology and karyotype analysis between the right and left masses, directly supporting the multiple HPV infections hypothesis of biTSCC pathogenesis. Further genetic characterization of tonsillar tumors is needed to better characterize TSCC and best guide medical/surgical therapy.

Combined large cell neuroendocrine carcinoma and squamous cell carcinoma of the oropharynx: A collision course of tumors.

Combined large cell neuroendocrine carcinoma (LCNEC) and squamous cell carcinoma (SCC) of the H&N are exceptionally rare. We present the case of combined p16 negative SCC and LCNEC of the oropharynx treated with combination chemotherapy. This is the third reported case of combined neuroendocrine carcinoma and SCC of the oropharynx.

3-Mercaptopyruvate sulfurtransferase supports endothelial cell angiogenesis and bioenergetics.

BACKGROUND AND PURPOSE: During angiogenesis, quiescent endothelial cells (ECs) are activated by various stimuli to form new blood vessels from pre-existing ones in physiological and pathological conditions. Many research groups have shown that hydrogen sulfide (H2 S), the newest member of the gasotransmitter family, acts as a proangiogenic factor. To date, very little is known about the regulatory role of 3-mercaptopyruvate sulfurtransferase (3-MST), an important H2 S-producing enzyme in ECs. The aim of our study was to explore the potential role of 3-MST in human EC bioenergetics, metabolism, and angiogenesis. EXPERIMENTAL APPROACH: To assess in vitro angiogenic responses, we used EA.hy926 human vascular ECs subjected to shRNA-mediated 3-MST attenuation and pharmacological inhibition of proliferation, migration, and tube-like network formation. To evaluate bioenergetic parameters, cell respiration, glycolysis, glucose uptake, and mitochondrial/glycolytic ATP production were measured. Finally, global metabolomic profiling was performed to determine the level of 669 metabolic compounds. KEY RESULTS: 3-MST-attenuated ECs subjected to shRNA or pharmacological inhibition of 3-MST significantly reduced EC proliferation, migration, and tube-like network formation. 3-MST silencing also suppressed VEGF-induced EC migration. From bioenergetic and metabolic standpoints, 3-MST attenuation decreased mitochondrial respiration and mitochondrial ATP production, increased glucose uptake, and perturbed the entire EC metabolome. CONCLUSION AND IMPLICATIONS: 3-MST regulates bioenergetics and morphological angiogenic functions in human ECs. The data presented in the current report support the view that 3-MST pathway may be a potential candidate for therapeutic modulation of angiogenesis. LINKED ARTICLES: This article is part of a themed section on Hydrogen Sulfide in Biology & Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.4/issuetoc.

Nucleolin mediates the binding of cancer cells to L-selectin under conditions of lymphodynamic shear stress.

Head and neck squamous cell carcinoma (HNSCC) cells bind to lymphocytes via L-selectin in a shear-dependent manner. This interaction takes place exclusively under low-shear stress conditions, such as those found within the lymph node parenchyma. This represents a novel functional role for L-selectin-selectin ligand interactions. Our previous work has characterized as-of-yet unidentified L-selectin ligands expressed by HNSCC cells that are specifically active under conditions of low shear stress consistent with lymph flow. Using an affinity purification approach, we now show that nucleolin expressed on the surface of HNSCC cells is an active ligand for L-selectin. Parallel plate chamber flow-based experiments and atomic force microscopy (AFM) experiments show that nucleolin is the main functional ligand under these low-force conditions. Furthermore, AFM shows a clear relationship between work of deadhesion and physiological loading rates. Our results reveal nucleolin as the first major ligand reported for L-selectin that operates under low-shear stress conditions.

Dynamic biochemical tissue analysis detects functional selectin ligands on human cancer tissues.

Cell adhesion mediated by selectins (expressed by activated endothelium, activated platelets, and leukocytes) binding to their resepective selectin ligands (expressed by cancer cells) may be involved in metastasis. Therefore, methods of characterizing selectin ligands expressed on human tissue may serve as valuable assays. Presented herein is an innovative method for detecting functional selectin ligands expressed on human tissue that uses a dynamic approach, which allows for control over the force applied to the bonds between the probe and target molecules. This new method of tissue interrogation, known as dynamic biochemical tissue analysis (DBTA), involves the perfusion of molecular probe-coated microspheres over tissues. DBTA using selectin-coated probes is able to detect functional selectin ligands expressed on tissue from multiple cancer types at both primary and metastatic sites.

Differences in the viral genome between HPV-positive cervical and oropharyngeal cancer.

Human papillomavirus (HPV)-driven oropharyngeal cancer incidence in the United States has steadily increased in the past decades and has now become the most frequently diagnosed HPV-associated cancer type, surpassing cervical cancer. Variations in the HPV genome correlate with tumorigenic risk, and the distribution of genetic variants is extensively studied in cervical cancer, but very little is known about new mutations or the distribution of HPV types and variants in oropharyngeal cancer. Here we present an archival tissue cohort study that compares genomic characteristics of HPV associated with cervical versus oropharyngeal tumors using DNA sequence analysis. We found HPV16 to be more prevalent in oropharyngeal samples than in cervical samples (91.2% versus 52.9%), while HPV18 (1.5% versus 18.2%) and HPV45 (0.7% versus 9.9%) were much less prevalent. Differences between cervix and oropharynx in HPV16 variants distribution were more subtle, but the combined European + Asian (EUR+AS) variant group was more prevalent (90.2% versus 71.4%), while the American Asian 1 + American Asian 2 (AA1+AA2) variant group was much less prevalent (4.4% versus 22.5%) in oropharyngeal cancers. HPV prevalence in oropharyngeal cancers showed an increasing trend from 60% in 2003 to 80% in 2016. We also identified over nine times more nonsynonymous mutations in the HPV E6 gene amplified from oropharyngeal samples, but for E7 the difference in mutation rates between the two anatomical locations was not significant. Overall, we showed that HPV genome in oropharyngeal cancer presents important differences when compared to cervical cancer and this may explain the distinct pathomechanisms and susceptibility to treatment of HPV-associated oropharyngeal cancer.

Prevalence of oral human papillomavirus by vaccination status among young adults (18-30years old).

BACKGROUND: Although there is evidence that human papillomavirus (HPV) vaccination may protect against oral HPV infection, no current research has demonstrated this in the general population. METHODS: We used repeated cross-sectional data from the National Health and Nutrition Examination Survey (NHANES) between 2009 and 2014. Participants 18-30years who indicated whether they had received the HPV vaccine and provided an adequate oral sample were included (N=3040). Oral HPV types were grouped by vaccine-type (types 6, 11, 16, 18) and by risk (high or low risk). Chi-square analyses compared oral HPV prevalence by vaccination status. RESULTS: Vaccinated adults had a lower prevalence of vaccine-type oral HPV (types 6, 11, 16, 18) compared to unvaccinated adults. Prevalence of non-vaccine high-risk oral HPV was similar between HPV vaccinated and unvaccinated participants. CONCLUSIONS: HPV vaccination appears to provide protection against vaccine-type oral HPV infection among males and females in the general population.

Dynamic biochemical tissue analysis detects functional L-selectin ligands on colon cancer tissues.

A growing body of evidence suggests that L-selectin ligands presented on circulating tumor cells facilitate metastasis by binding L-selectin presented on leukocytes. Commonly used methods for detecting L-selectin ligands on tissues, e.g., immunostaining, are performed under static, no-flow conditions. However, such analysis does not assay for functional L-selectin ligands, specifically those ligands that promote adhesion under shear flow conditions. Recently our lab developed a method, termed dynamic biochemical tissue analysis (DBTA), to detect functional selectin ligands in situ by probing tissues with L-selectin-coated microspheres under hemodynamic flow conditions. In this investigation, DBTA was used to probe human colon tissues for L-selectin ligand activity. The detection of L-selectin ligands using DBTA was highly specific. Furthermore, DBTA reproducibly detected functional L-selectin ligands on diseased, e.g., cancerous or inflamed, tissues but not on noncancerous tissues. In addition, DBTA revealed a heterogeneous distribution of functional L-selectin ligands on colon cancer tissues. Most notably, detection of L-selectin ligands by immunostaining using HECA-452 antibody only partially correlated with functional L-selectin ligands detected by DBTA. In summation, the results of this study demonstrate that DBTA detects functional selectin ligands to provide a unique characterization of pathological tissue.

Racial and Ethnic Disparities in Nasopharyngeal Cancer Survival in the United States.

Objective To determine whether patient race and ethnicity affect nasopharyngeal cancer survival. Study Design Retrospective database analysis. Setting National Cancer Institute's SEER database (Surveillance, Epidemiology, and End Results), 1988-2010. Subjects and Methods Nasopharyngeal carcinoma cases were extracted according to site codes and histology recode-broad groupings. The cohort of 5427 patients was used to calculate disease-specific survival in regard to race and ethnicity. Extracted data were further analyzed through direct comparisons and multivariable Cox regression models controlling for patient, tumor, and treatment characteristics. Results Unadjusted survival curves for all nasopharyngeal carcinomas considered together showed a statistically significant better disease-specific survival for the African American race ( P = .02) and Asian ethnicity ( P = .01) relative to Caucasian patients. The survival advantage for both these groups was eliminated after controlling for the age and sex of the patients. Conclusion African American and Asian patients with nasopharyngeal cancer have better disease-specific survival as compared with Caucasian patients, while Hispanic ethnicity has no effect relative to Caucasians. This disparity is accounted for by diagnosis at an older age in Caucasian patients but remains poorly explained in regard to Hispanic patients.

PDGF-AA mediates mesenchymal stromal cell chemotaxis to the head and neck squamous cell carcinoma tumor microenvironment.

BACKGROUND: The robust desmoplasia associated with head and neck squamous cell carcinoma (HNSCC) suggests that the tumor microenvironment may be an important component in the pathophysiology of this cancer. Moreover, the high recurrence rate and poor clinical response to chemotherapy and radiation treatment further underscores that the non-cancerous cells of the microenvironment, such as mesenchymal stromal cells (MSCs), cancer associated fibroblasts (CAFs), and pericytes, may be important in the pathophysiology of HNSCC. METHODS: Confocal microscopy and immunohistomchemistry approaches were used to identify MSCs tumor microenvironment from patients with oral cavity and oral pharyngeal squamous cell carcinoma (SCC). In vitro Boyden chamber assays and multiplex magnetic bead assays were used to measure MSC chemotaxis and to identify the chemokines secreted by JHU-011, -012, -019, three cells lines derived from patients with oral pharyngeal SCC. RESULTS: We show here that MSCs reside in the tumor microenvironment of patients with oral cavity and oral pharyngeal SCC and are recruited via paracrine mediated tumor cell secretion of (platelet derived growth factor) PDGF-AA. The MSC markers CD90+, CD105+, and gremlin-1+ were found to co-localize on cells within the tumor microenvironment in oral cavity SCC specimens distinct from α-smooth muscle actin staining CAFs. The conditioned media from JHU-011, -012, and -019 caused a significant increase in MSC migration (>60%) and invasion (>50%; p < 0.0001) compared to oral keratinocyte (OKT) controls. Tumor cell induced MSC chemotaxis appears to be mediated through paracrine secretion of PDGF-AA as inhibition of the PDGF-AA receptor, PDGFR-α but not PDGFR-ß, resulted in near arrest of MSC chemotaxis (p < 0.0001). CONCLUSIONS: Tumor microenvironment expression of PDGFR-α has been shown to correlate with a worse prognosis in patients with prostate, breast, ovarian, non-small cell lung cancer and osteosarcoma. This is the first evidence that a similar signaling paradigm may be present in HNSCC. PDGFR-α inhibitors have not been studied as adjunctive treatment options in the management of HNSCC and may prove to be an important driver of the malignant phenotype in this setting.

The surgical plane for lingual tonsillectomy: an anatomic study.

BACKGROUND: The presence of a plane between the lingual tonsils and the underlying soft tissue has not been confirmed. The objective of this study is to ascertain the presence and the characteristics about this plane for surgical use. METHODS: Five cadaver heads were obtained for dissection of the lingual tonsils. Six permanent sections of previous tongue base biopsies were reviewed. Robot assisted lingual tonsillectomy was performed using the dissection technique from the cadaver dissection. RESULTS: In each of the 5 cadavers, an avascular plane was revealed deep to the lingual tonsils. Microscopic review of the tongue base biopsies revealed a clear demarcation between the lingual tonsils and the underlying minor salivary glands and muscle tissue. This area was relatively avascular. Using the technique described above, a lingual tonsillectomy using TORS was performed with similar findings from the cadaver dissections. CONCLUSIONS: A surgical plane for lingual tonsillectomy exists and may prove to have a role with lingual tonsillectomy with TORS.

Sinonasal Carcinoma: Racial and Ethnic Disparities in Survival--A Review of 4714 Patients.

OBJECTIVE: To determine whether or not patient race and ethnicity affect sinonasal cancer survival. STUDY DESIGN: Retrospective database analysis. SETTING: National Cancer Institute's Surveillance, Epidemiology, and End Results Database, 1988-2010. SUBJECTS AND METHODS: Sinonasal carcinoma cases were extracted according to site codes and histology recode-broad groupings. The cohort was used to calculate disease-specific survival in regard to race and ethnicity. Extracted data were further analyzed through direct comparisons and multivariable Cox regression models controlling for patient, tumor, and treatment characteristics. RESULTS: Unadjusted survival curves for all sinonasal carcinomas showed poorer disease-specific survival for black versus white patients (P = .02), which was eliminated after controlling for tumor characteristics (hazard ratio: 1.02, P = .86). Specifically for sinonasal squamous cell carcinoma, significantly poorer disease-specific survival was found for both black (P = .01) and Hispanic (P = .01) patients as compared with white patients. Similarly, when controlling for tumor characteristics, the disease-specific survival disparity was eliminated for black (hazard ratio: 0.93, P = .59) and Hispanic patients (hazard ratio: 1.01, P = .94). CONCLUSION: Black race is a risk factor for poorer disease-specific survival when all sinonasal histologic subtypes are examined together. Specifically for sinonasal squamous cell carcinoma, both black race and Hispanic ethnicity are risk factors for poorer disease-specific survival. When tumor characteristics are controlled for in this cohort, the survival disparity is eliminated, demonstrating that the disparity can be accounted for exclusively by more advanced disease at presentation, opposed to the more complex effect seen in other subsites of the head and neck.

Racial and Ethnic Disparities in Salivary Gland Cancer Survival.

IMPORTANCE: Several recent US studies have documented racial disparities in head and neck cancer outcomes, but few have investigated racial and ethnic differences in salivary gland cancer (SGCA) survival. OBJECTIVE: To determine whether patient race or ethnicity affects SGCA survival. DESIGN, SETTING, AND PARTICIPANTS: Retrospective survival analysis of all patients with SGCA from 1988 through 2010 in the Surveillance, Epidemiology, and End Results database. MAIN OUTCOMES AND MEASURES: Disease-specific survival according to race and ethnicity. End points assessed included age at diagnosis, sex, tumor grade, tumor size at diagnosis, extension at diagnosis, lymph node involvement at diagnosis, and treatment. Results were further analyzed by histologic subtype of SGCA. RESULTS: Of 11,007 patients with SGCA, 1073 (9.7%) were black, and 1068 (9.7%), Hispanic. Whites' mean age at diagnosis was 63 years vs 53 and 52 years for blacks and Hispanics, respectively (P < .001). Twenty-year disease-specific survival rates for all SGCA histologic subtypes combined for whites, blacks, and Hispanics were 78%, 79%, and 81%, respectively. Unadjusted survival curves showed no significant difference between blacks and whites and an apparent advantage for Hispanics. However, multivariable Cox regression models controlling for patient, tumor, and treatment characteristics showed poorer disease-specific survival vs whites for blacks (hazard ratio [HR], 1.22 [95% CI, 1.03-1.46]; P = .03) but not for Hispanics (HR, 0.97 [0.79-1.19]; P = .77). The overall disease-specific survival disparity was due to poorer disease-specific survival for blacks vs whites with mucoepidermoid (P = .03) and squamous cell carcinomas (P = .05). Less surgical treatment for blacks than whites (57.26% vs 76.94%; P < .001) was a source of the survival disparity for squamous cell but not mucoepidermoid SGCA. CONCLUSIONS AND RELEVANCE: Black race is a risk factor for poorer disease-specific survival for patients with mucoepidermoid or squamous cell carcinoma, whereas Hispanic ethnicity has no effect. Differing treatment between black and white patients affects survival in squamous cell but not mucoepidermoid SGCA. Differences in chemotherapy treatment, comorbidities, socioeconomic status, tumor genetic factors, and environmental exposures are potential but unproven additional sources of the racial survival disparities for mucoepidermoid and squamous cell SGCA.

Temporal characterization of lymphatic metastasis in an orthotopic mouse model of oral cancer.

BACKGROUND: The overall mortality rate in cases of head and neck squamous cell carcinoma (HNSCC) has not improved over the past 30 years, mostly because of the high treatment failure rate among patients with regionally metastatic disease. To better understand the pathobiologic processes leading to lymphatic metastasis development, there is an urgent need for relevant animal models. METHODS: HNSCC cell lines were implanted into the tongues of athymic nude mice. Histology, immunohistochemistry, and ex vivo 2-photon microscopy were used to evaluate tumor progress and spread. RESULTS: Orthotopic xenografts of different HNSCC cell lines produced distinct patterns of survival, tumor histology, disease progression rate, and lymph node metastasis development. Remarkably, all injected cell types reached the lymph nodes within 24 hours after injection, but not all developed metastasis. CONCLUSION: This orthotopic xenograft model closely mimics several characteristics of human cancer and could be extremely valuable for translational studies focusing on lymphatic metastasis development and pathobiology.

Laminin interactions with head and neck cancer cells under low fluid shear conditions lead to integrin activation and binding.

Lymphatic metastasis of cancer cells involves movement from the primary tumor site to the lymph node, where the cells must be able to productively lodge and grow. It is there that tumor cells encounter cellular and non-cellular constituent elements that make up the lymph node parenchyma. Our work shows that head and neck squamous cell carcinoma (HNSCC) cell lines are able to bind to laminin, fibronectin, vitronectin, and hyaluronic acid, which are extracellular matrix elements within the lymph node parenchyma. HNSCC cell lines bound to laminin under lymphodynamic low shear stress (0.07 dynes/cm(2)), consistent with lymph flow via ß1 integrins, including α2ß1, α3ß1, and α6ß1. Binding occurred in the presence of shear stress and not in the absence of flow. Additionally, tumor cell binding to laminin under flow did result in calcium signaling. Our data indicate a novel role for ß1 integrin-mediated binding of HNSCC cells to laminin under conditions of lymphodynamic flow that results in intracellular calcium signaling within the cancer cell.

Carcinoma matrix controls resistance to cisplatin through talin regulation of NF-kB.

Extracellular matrix factors within the tumor microenvironment that control resistance to chemotherapeutics are poorly understood. This study focused on understanding matrix adhesion pathways that control the oral carcinoma response to cisplatin. Our studies revealed that adhesion of HN12 and JHU012 oral carcinomas to carcinoma matrix supported tumor cell proliferation in response to treatment with cisplatin. Proliferation in response to 30 µM cisplatin was not observed in HN12 cells adherent to other purified extracellular matrices such as Matrigel, collagen I, fibronectin or laminin I. Integrin ß1 was important for adhesion to carcinoma matrix to trigger proliferation after treatment with cisplatin. Disruption of talin expression in HN12 cells adherent to carcinoma matrix increased cisplatin induced proliferation. Pharmacological inhibitors were used to determine signaling events required for talin deficiency to regulate cisplatin induced proliferation. Pharmacological inhibition of NF-kB reduced proliferation of talin-deficient HN12 cells treated with 30 µM cisplatin. Nuclear NF-kB activity was assayed in HN12 cells using a luciferase reporter of NF-kB transcriptional activity. Nuclear NF-kB activity was similar in HN12 cells adherent to carcinoma matrix and collagen I when treated with vehicle DMSO. Following treatment with 30 µM cisplatin, NF-kB activity is maintained in cells adherent to carcinoma matrix whereas NF-kB activity is reduced in collagen I adherent cells. Expression of talin was sufficient to trigger proliferation of HN12 cells adherent to collagen I following treatment with 1 and 30 µM cisplatin. Talin overexpression was sufficient to trigger NF-kB activity following treatment with cisplatin in carcinoma matrix adherent HN12 cells in a process disrupted by FAK siRNA. Thus, adhesions within the carcinoma matrix create a matrix environment in which exposure to cisplatin induces proliferation through the function of integrin ß1, talin and FAK pathways that regulate NF-kB nuclear activity.

Receptor-tyrosine-kinase-targeted therapies for head and neck cancer.

Molecular therapeutics for treating epidermal growth factor receptor-(EGFR-) expressing cancers are a specific method for treating cancers compared to general cell loss with standard cytotoxic therapeutics. However, the finding that resistance to such therapy is common in clinical trials now dampens the initial enthusiasm over this targeted treatment. Yet an improved molecular understanding of other receptor tyrosine kinases known to be active in cancer has revealed a rich network of cross-talk between receptor pathways with a key finding of common downstream signaling pathways. Such cross talk may represent a key mechanism for resistance to EGFR-directed therapy. Here we review the interplay between EGFR and Met and the type 1 insulin-like growth factor receptor (IGF-1R) tyrosine kinases, as well as their contribution to anti-EGFR therapeutic resistance in the context of squamous cell cancer of the head and neck, a tumor known to be primarily driven by EGFR-related oncogenic signals.

Case-matching analysis of head and neck squamous cell carcinoma in racial and ethnic minorities in the United States--possible role for human papillomavirus in survival disparities.

BACKGROUND: Several studies have documented disparities in head and neck cancer outcomes for black patients in the United States. Recent studies have found that differences in oropharyngeal tumor human papillomavirus (HPV) status may be a cause of this disparity. METHODS: In all, 76,817 cases of head and neck squamous cell carcinoma (HNSCC) recorded in the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program were analyzed. Racial/ethnic groups were studied, for disease-specific survival in both case-matched and nonmatched cohorts. Calculation of expected disparity magnitudes based on HPV status was performed using data reported in the literature. RESULTS: A disease-specific survival disparity was demonstrated for Hispanic patients. However, case matching eliminated this disparity. Conversely, the disparity for black patients persisted in matched cohorts. The oropharyngeal subsite was found to be the dominant contributor to this disparity. CONCLUSIONS: The survival disparity for Hispanic patients in SEER with HNSCC is explained by differences in presentation and treatment. Also, HPV tumor status is likely a key determinant of the disparity for black patients.

Clinicopathological predictors of lymphatic metastasis in HNSCC: implications for molecular mechanisms of metastatic disease.

Lymphatic metastasis is associated with up to a 50% decrease in survival, yet the molecular mechanisms driving their establishment remain poorly understood. This study assessed clinicopathological characteristics correlated to nodal metastasis among patients with head and neck squamous cell carcinoma for the identification of pathways on which to focus molecular studies. Pathology records were queried for cases diagnosed with invasive squamous cell cancer of the upper aerodigestive tract between 1993 and 2003. Charts and pathology reports were scored for 16 characteristics. The univariate association of each variable with lymph node status was assessed. Based on the univariate analysis, a multiple logistic regression model was developed to assess the simultaneous association of variables with lymph node status. Of the 644 cases identified, 234 had a surgical specimen analyzed. All variables were scored for 185 of the 234 cases. Multivariate stepwise regression analysis identified clinical stage (p = 0.0269), pathologic stage (p = 0.0162), grade (p = 0.0094), lymphovascular invasion (p = 0.0393), and family history of cancer (p = 0.0079) as independently predictive of lymphatic metastases. Our study confirms that grade, pathologic stage, clinical stage, and lymphovascular invasion are predictors of regional metastasis. These correlations suggest that studying the molecular mechanisms of differentiation, interstitial pressure at the primary tumor site, and peritumoral lymphangiogenesis may provide insight into lymphatic metastasis. Additionally, we identified family history of cancer as a new predictor of lymphatic metastasis. Thus, genetic analysis of families with cancer, irrespective of type, may identify genes important for regional metastasis.

Oral cavity squamous cell carcinoma and the clinically n0 neck: the past, present, and future of sentinel lymph node biopsy.

Oral cavity squamous cell carcinoma (OCSCC) has a yearly incidence of 274,000 patients. Twenty percent to 30% of patients will harbor occult regional metastases, an important feature that correlates with worse outcomes. Supraomohyoid neck dissection (SND) is the gold standard treatment, but because of recent successes of sentinel lymph node (SLN) biopsy in the management of breast cancer and melanoma, many have begun evaluating its use in head and neck mucosal cancers. SLN biopsy offers patients decreased morbidity compared with SND, and has shown reproducibly low false-negative rates, high-negative predictive values, and high sensitivities. Limitations with floor-of-mouth primaries and delayed secondary SNDs have been described, but a new agent designed to address these shortcomings, Lymphoseek (Neoprobe Corp.; Dublin, OH), is currently under investigation. This article reviews the current literature on SLN biopsy and introduces a phase 3 study evaluating the efficacy of Lymphoseek in SLN biopsy of OCSCCs.