Extranodal extension (ENE) is a well-established poor prognosticator and an indication for adjuvant treatment escalation in patients with head and neck squamous cell carcinoma (HNSCC). Identification ...of ENE on pretreatment imaging represents a diagnostic challenge that limits its clinical utility. We previously developed a deep learning algorithm that identifies ENE on pretreatment computed tomography (CT) imaging in patients with HNSCC. We sought to validate our algorithm performance for patients from a diverse set of institutions and compare its diagnostic ability to that of expert diagnosticians.
We obtained preoperative, contrast-enhanced CT scans and corresponding pathology results from two external data sets of patients with HNSCC: an external institution and The Cancer Genome Atlas (TCGA) HNSCC imaging data. Lymph nodes were segmented and annotated as ENE-positive or ENE-negative on the basis of pathologic confirmation. Deep learning algorithm performance was evaluated and compared directly to two board-certified neuroradiologists.
A total of 200 lymph nodes were examined in the external validation data sets. For lymph nodes from the external institution, the algorithm achieved an area under the receiver operating characteristic curve (AUC) of 0.84 (83.1% accuracy), outperforming radiologists' AUCs of 0.70 and 0.71 (
= .02 and
= .01). Similarly, for lymph nodes from the TCGA, the algorithm achieved an AUC of 0.90 (88.6% accuracy), outperforming radiologist AUCs of 0.60 and 0.82 (
< .0001 and
= .16). Radiologist diagnostic accuracy improved when receiving deep learning assistance.
Deep learning successfully identified ENE on pretreatment imaging across multiple institutions, exceeding the diagnostic ability of radiologists with specialized head and neck experience. Our findings suggest that deep learning has utility in the identification of ENE in patients with HNSCC and has the potential to be integrated into clinical decision making.
Identification of nodal metastasis and tumor extranodal extension (ENE) is crucial for head and neck cancer management, but currently only can be diagnosed via postoperative pathology. Pretreatment, ...radiographic identification of ENE, in particular, has proven extremely difficult for clinicians, but would be greatly influential in guiding patient management. Here, we show that a deep learning convolutional neural network can be trained to identify nodal metastasis and ENE with excellent performance that surpasses what human clinicians have historically achieved. We trained a 3-dimensional convolutional neural network using a dataset of 2,875 CT-segmented lymph node samples with correlating pathology labels, cross-validated and fine-tuned on 124 samples, and conducted testing on a blinded test set of 131 samples. On the blinded test set, the model predicted ENE and nodal metastasis each with area under the receiver operating characteristic curve (AUC) of 0.91 (95%CI: 0.85-0.97). The model has the potential for use as a clinical decision-making tool to help guide head and neck cancer patient management.
Data are limited on the prognostic value of human papillomavirus (HPV) status for head and neck carcinoma subsites.
To determine whether HPV positivity at each head and neck subsite is associated ...with improved overall survival.
This retrospective population-based cohort study used the National Cancer Database to identify patients diagnosed with head and neck squamous cell carcinomas from January 1, 2010, to December 31, 2014. Patients were classified according to the location of their primary malignancy into 1 of the 6 main subsites of the upper aerodigestive tract: oral cavity, oropharynx, nasopharynx, hypopharynx, larynx, and sinonasal tract. Patients were also classified by their HPV status. Data collection for this study took place from January 1, 2010, to December 31, 2014. Data analysis was conducted from August 1, 2017, to September 30, 2017.
The difference in 5-year overall survival between patients with HPV-positive status and those with HPV-negative status in various head and neck carcinoma subsites; the role of HPV status in an unadjusted Cox multivariate regression model.
Of the 175 223 total number of patients identified (129 634 74.0% male; 45 589 26.0% female; mean SD age, 63.1 11.9 years), 133 273 (76.1%) were ineligible and 41 950 (23.9%) were included in the sample. This sample included 16 644 patients (39.7%) with HPV-positive tumors and 25 306 (60.3%) with HPV-negative tumors. Patients with an HPV-positive status were more likely to be younger, be white, be male, present with local T category tumors, and have poor differentiation on histologic examination. HPV-positive status was associated with survival at 4 tumor subsites: oral cavity (hazard ratio HR, 0.76; 95% CI, 0.66-0.87), oropharynx (HR, 0.44; 95% CI, 0.41-0.47), hypopharynx (HR, 0.59; 95% CI, 0.45-0.77), and larynx (HR, 0.71; 95% CI, 0.59-0.85). The HPV status was the greatest factor in survival outcome between the HPV-positive and -negative cohorts at the oropharynx subsite (77.6% vs 50.7%; survival difference, 26.9%; 95% CI, 25.6%-28.2%) and hypopharynx subsites (52.2% vs 28.8%; survival difference, 23.4%; 95% CI, 17.5%-29.3%). For the nasopharynx (HR, 1.03; 95% CI, 0.75-1.42) and sinonasal tract (HR, 0.63; 95% CI, 0.39-1.01) subsites, HPV-positive status was not an independent prognostic factor.
Human papillomavirus positivity was associated with improved survival in 4 subsites (oropharynx, hypopharynx, oral cavity, and larynx), and the largest survival difference was noted in the oropharynx and hypopharynx subsites. In the nasopharynx and sinonasal tract subsites, HPV positivity had no association with overall survival. Given these results, routine testing for HPV at the oropharynx, hypopharynx, oral cavity, and larynx subsites may be warranted.
Invadopodia are branched actin-rich structures associated with extracellular matrix (ECM) degradation that collectively form the invasive machinery of aggressive cancer cells. Cortactin is a ...prominent component and a specific marker of invadopodia. Amplification of cortactin is associated with poor prognosis in head and neck squamous cell carcinomas (HNSCC), possibly because of its activity in invadopodia. Although the role of cortactin in invadopodia has been attributed to signaling and actin assembly, it is incompletely understood. We made HNSCC cells deficient in cortactin by RNA interference knockdown methods. In these cortactin knockdown cells, invadopodia were reduced in number and lost their ability to degrade ECM. In the reverse experiment, overexpression of cortactin dramatically increased ECM degradation, far above and beyond the effect on formation of actin/Arp3-positive invadopodia puncta. Secretion of matrix metalloproteinases (MMP) MMP-2 and MMP-9, as well as plasma membrane delivery of MT1-MMP correlated closely with cortactin expression levels. MMP inhibitor treatment of control cells mimicked the cortactin knockdown phenotype, with abolished ECM degradation and fewer invadopodia, suggesting a positive feedback loop in which degradation products from MMP activity promote new invadopodia formation. Collectively, these data suggest that a major role of cortactin in invadopodia is to regulate the secretion of MMPs and point to a novel mechanism coupling dynamic actin assembly to the secretory machinery, producing enhanced ECM degradation and invasiveness. Furthermore, these data provide a possible explanation for the observed association between cortactin overexpression and enhanced invasiveness and poor prognosis in HNSCC patients.
Highlights • Regulation of RelA dephosphorylation is important for restraining RelA activity. • Two families of phosphatases have been identified as direct RelA phosphatases. • The tumor suppressor, ...LZAP, is associated with dephosphorylation of RelA and regulating PPM family members. • Proteins that accelerate RelA dephosphorylation display tumor suppressor-like activities.
We hypothesized that chronic inhibition of epidermal growth factor receptor (EGFR) by cetuximab, a monoclonal anti-EGFR antibody, induces up-regulation of its ligands resulting in resistance and that ...microRNAs (miRs) play an important role in the ligand regulation in head and neck squamous cell carcinoma (HNSCC).
Genome-wide changes in gene and miR expression were determined in cetuximab-sensitive cell line, SCC1, and its resistant derivative 1Cc8 using DNA microarrays and RT-PCR. The effects of differentially expressed EGFR ligands and miRs were examined by MTS, colony formation, ELISA, and western blot assays. Heparin-binding EGF-like growth factor (HB-EGF) and its regulator, miR-212, were differentially expressed with statistical significance when SCC1 and 1Cc8 were compared for gene and miR expression. Stimulation with HB-EGF induced cetuximab resistance in sensitive cell lines. Inhibition of HB-EGF and the addition of miR-212 mimic induced cetuximab sensitivity in resistant cell lines. MicroRNA-212 and HB-EGF expression were inversely correlated in an additional 33 HNSCC and keratinocyte cell lines. Six tumors and 46 plasma samples from HNSCC patients were examined for HB-EGF levels. HB-EGF plasma levels were lower in newly diagnosed HNSCC patients when compared to patients with recurrent disease.
Increased expression of HB-EGF due to down-regulation of miR-212 is a possible mechanism of cetuximab resistance. The combination of EGFR ligand inhibitors or miR modulators with cetuximab may improve the clinical outcome of cetuximab therapy in HNSCC.
Objectives/Hypothesis
The objective was to characterize incidence, treatment, and survival for hypopharyngeal cancer in the United States between 1988 and 2010, and to analyze associations between ...changes in treatment modality and survival.
Study Design
Retrospective cohort study.
Methods
A total of 3,958 adult patients with hypopharyngeal cancer were identified in the Surveillance, Epidemiology, and End Results database. Incidence, treatment, and survival, controlling for patient demographics and disease severity, were analyzed using two‐tailed t tests, Kaplan‐Meier analysis, and univariate and multivariate Cox regression.
Results
The incidence of hypopharyngeal cancer decreased from 1973 to 2010 with an average annual percent change (APC) of −2.0% every year (P < .05). Treatment with laryngopharyngectomy decreased (−2.5% APC, P < .001), treatment with radiotherapy without surgery increased (+2.0% APC, P < .001), and treatment with neither surgery nor radiotherapy increased (+0.5% APC, P < .001) between 1988 and 2010. There was a significant increase in the 5‐year overall survival between 1988 and 1990 and between 1991 and 1995 (P = .024) with no other significant temporal trends in survival. Multivariate analysis revealed that age (65–74, 75–84, or 85+ relative to 18–54 years old), race (white relative to non‐African races), T stage (T2, T3, or T4 relative to T1), N stage (N2 or N3 relative to N0), and treatment modality (−surgery/−radiation, −surgery/+radiation, and +surgery/−radiation relative to +surgery/+radiation) were all significantly associated with worse survival.
Conclusions
Hypopharyngeal cancer has had a decreasing incidence with little change in patient or tumor characteristics. Treatment has increasingly involved radiation without laryngopharyngectomy. This has not been associated with a decrease in survival. Controlling for patient demographics and disease severity, radiation with laryngopharyngectomy is associated with improved survival.
Level of Evidence
2b Laryngoscope, 124:2064–2069, 2014
DNA methylation in human papillomavirus-associated (HPV
) head and neck squamous cell carcinoma (HNSCC) may have importance for continuous expression of HPV oncogenes, tumor cell proliferation, and ...survival. Here, we determined activity of a global DNA-demethylating agent, 5-azacytidine (5-aza), against HPV
HNSCC in preclinical models and explored it as a targeted therapy in a window trial enrolling patients with HPV
HNSCC.
Sensitivity of HNSCC cells to 5-aza treatment was determined, and then 5-aza activity was tested
using xenografted tumors in a mouse model. Finally, tumor samples from patients enrolled in a window clinical trial were analyzed to identify activity of 5-aza therapy in patients with HPV
HNSCC.
Clinical trial and experimental data show that 5-aza induced growth inhibition and cell death in HPV
HNSCC. 5-aza reduced expression of HPV genes, stabilized p53, and induced p53-dependent apoptosis in HNSCC cells and tumors. 5-aza repressed expression and activity of matrix metalloproteinases (MMP) in HPV
HNSCC, activated IFN response in some HPV
head and neck cancer cells, and inhibited the ability of HPV
xenografted tumors to invade mouse blood vessels.
5-aza may provide effective therapy for HPV-associated HNSCC as an alternative or complement to standard cytotoxic therapy.
.
PDF
