Extranodal Extension In Patients Research Articles

Prognostic significance of extranodal extension in patients with pathologic N1 non-small cell lung cancer undergoing complete resection.

The prognostic significance of extranodal extension (ENE) remains unclear in patients with pathologic N1 (pN1) non-small-cell lung cancer (NSCLC) undergoing surgery. We evaluated the prognostic impact of ENE in patients with pN1 NSCLC. From 2004 to 2018, we retrospectively analyzed the data of 862 patients with pN1 NSCLC who underwent lobectomy and more (lobectomy, bilobectomy, pneumonectomy, sleeve lobectomy). According to their resection status and the presence of ENE, patients were classified into R0 without ENE (pure R0) (n=645), R0 with ENE (R0-ENE) (n=130), and incomplete resection (R1/R2) groups (n=87). The primary and secondary endpoints were 5-year overall survival (OS) and recurrence-free survival (RFS), respectively. The prognosis of the R0-ENE group was significantly worse than the pure R0 group for both OS (5-year rate: 51.6% vs. 65.4%, P=0.008) and RFS (44.4% vs. 53.0%, P=0.04). According to the recurrence pattern, a difference of RFS was found only for distant metastasis (55.2% vs. 65.0%, P=0.02). The multivariable Cox analysis revealed that the presence of ENE was a negative prognostic factor in patients who did not undergo adjuvant chemotherapy [hazard ratio (HR) =1.58; 95% confidence interval (CI): 1.06-2.36; P=0.03], but it was not in those with adjuvant chemotherapy (HR =1.20; 95% CI: 0.80-1.81; P=0.38). For patients with pN1 NSCLC, the presence of ENE was a negative prognostic factor for both OS and RFS, regardless of resection status. The negative prognostic effect of ENE was significantly associated with an increase in distant metastasis and was not observed in patients who underwent adjuvant chemotherapy.

Extranodal extension influences prognosis in pancreatic head cancer: A retrospective cohort study.

Extranodal extension (ENE) is an established prognostic factor in several gastrointestinal cancers. However, the prognostic impact remains unclear. Here, we investigated the prognostic implications of ENE in patients with surgically resected pancreatic cancer. We retrospectively reviewed 476 surgically resected pancreatic head cancer patients who consecutively underwent upfront pancreaticoduodenectomy for pathologically confirmed pancreatic ductal adenocarcinoma between January 2009 and December 2013. We compared the disease-free survival (DFS) rates of the patients according to ENE status. Among the 476 patients, patients with ENE had lower DFS rates than those without ENE (N0, 13 months; LN+/ENE-, 7months; LN+/ENE+, 6months; P < .001). In addition, even in the same N stage, patients with ENE had lower DFS rates than those without ENE (N0, 13 months; N1/ENE- 8months; N1/ENE+, 7months; N2/ENE-, 7months; N2/ENE+, 4months, P < .001). However, there was no significant difference in survival rates between patients in the N1/ENE+ group and those in the N2/ENE- group. Additionally, ENE was an independent prognostic factor for pancreatic cancer. Extranodal extension significantly predicted a poor prognosis among patients with pancreatic head cancer, especially those with nodal metastasis. Therefore, ENE should be considered a prognostic factor in future editions of the staging system.

Extranodal extension influences prognosis in pancreatic head cancer.

593 Background: Extranodal extension (ENE) is an established prognostic factor of several gastrointestinal cancers; furthermore, ENE is already included as one component of nodal category of oral cavity, penis, and vulvar cancers. However, the prognostic impact of ENE in pancreatic cancer remains unclear. In this study, we aimed to investigate prognostic implication of ENE in patients with surgically resected pancreatic cancer. Methods: We retrospectively reviewed electronic medical records and pathologic slides of 503 surgically resected pancreatic head cancer patients, who consecutively underwent pancreaticoduodenectomy for pathologically confirmed pancreatic ductal adenocarcinoma between January 2009 and December 2013. Patients were categorized into subgroups according to ENE status and AJCC 8th pancreatic cancer staging system. We compared the disease-free survival rates of the patients according to ENE status. Cox proportional hazard analysis was performed to evaluate prognostic factors for the disease-free survival of pancreatic head cancer. Results: ENE-positive patient group showed a larger tumor size, a higher rate of lymph node metastasis, and a tendency to be positive for lymphovascular invasion, perineural invasion, and resection margin (p &lt; 0.001). Patients with ENE had lower overall survival (OS) and disease-free survival (DFS) rates compared with those without ENE (N0, 30 months; LN+/ENE-, 20 months; LN+/ENE+, 16 months; p &lt; 0.001), (N0, 13 months; LN+/ENE-, 8 months; LN+/ENE+, 5 months; p &lt; 0.001). Patients with higher N categories had lower OS and DFS rates. In addition, even in the same N stage, patients with ENE showed lower OS and DFS rates than those without ENE (p &lt; 0.001). However, there was no significant difference in survival rates between patients in the N1/ENE+ group and the N2/ENE- group. Additionally, ENE was an independent prognostic factor for pancreatic cancer. Conclusions: ENE significantly influenced adverse prognosis among patients with pancreatic head cancer especially for those with nodal metastasis. Therefore, ENE should be considered as a prognostic factor in the future editions of the AJCC staging system.

A Study on the Clinicopathological Characteristics Associated with Cervical Lymph Mode Metastasis and Extra-nodal Extension in Patients with Oral Cancer

Background/Objectives: Extra-nodal extension (ENE) is one of the strongest prognosticators in oral cancers. Here we tried to evaluate clinicopathological factors associated with the presence of ENE.Materials &amp; Methods: We retrospectively analyzed clinical information of 120 patients who diagnosed with oral cancer and received curative surgery at our hospital from Mar 2012 to Apr 2020. We comparatively analyzed clinicopathological factors associated with the presence of lymph node (LN) metastasis and ENE, respectively.Results: Variable factors of primary tumor characteristics such as lymphovascular invasion, perineural invasion, largest diameter of tumor, depth of invasion and maximum standardized uptake value were significantly associated with the presence of cervical LN metastasis. The largest diameter of tumor was statistically significant also in multivariate analysis for predicting the LN metastasis. Meanwhile, the association between primary tumor characteristics and the presence of ENE were not statistically significant except the primary tumor size. Importantly, factors associated with LN characteristics including the maximum diameter and number of metastatic LNs were significantly associated with ENE.Conclusion: In this study, several factors affecting cervical LN metastasis and ENE in oral cancer patients were identified. The ENE seems to be influenced by the status of the metastatic LNs, such as the number of metastatic LNs, rather than the characteristics of the primary tumor itself.

Radiomic Analysis of Primary GTV and CTV for Prediction of Extranodal Extension Using Diagnostic CT Images in Patients With Oropharyngeal Squamous Cell Carcinoma

<h3>Purpose/Objective(s)</h3> Prediction of extranodal extension (ENE) status of the involved lymph nodes has been shown to be an important factor in the prognosis and treatment of patients with Oropharyngeal Squamous Cell Carcinomas (OPSCC). Official diagnosis of ENE occurs pathologically at the time of surgery, and typically necessitates aggressive adjuvant treatment with radiation and concurrent chemotherapy. Due to higher toxicity with trimodality therapy, definitive chemoradiation can be a preferred treatment option up front instead of surgery if there is high clinical suspicion of ENE. This study investigates the potential value of radiomic features extracted from pre-treatment primary gross tumor volume (GTV) and clinical target volume (CTV) on diagnostic contrast enhanced Computed Tomography (CE-CT) images for prediction of ENE in patients with OPSCC. <h3>Materials/Methods</h3> For this study we identified 26 patients with pathologically confirmed OPSCC who went on to receive surgery and neck nodal dissection. Out of this group 13 were p16 positive, 13 were p16 negative, 7 were pathologic ENE positive, and 19 pathologic ENE negative. We contoured the primary tumor GTV on their pre-surgery CE-CT and added a 1 cm to create the CTV for radiomic analysis. For each patient, two sets of IBSI (Image Biomarker Standardization Initiative) validated radiomic features (N = 192 features from 11 different feature categories) were extracted from primary GTV and CTV on the diagnostic CE-CT images. Levene and Kolmogorov-Smirnov's (KS, <i>P</i> < 0.05) tests with confidence level of 95% along with absolute biserial correlation (|BSC|) with a threshold of > 0.2 were used to statistically reveal significant associations between ENE status and radiomics features. The Belsley collinearity diagnostics test was applied on the discriminant radiomic features for removing highly correlated features. Eight different Generalized-Linear Models (GLMs) were trained and tested using each individual feature along with two combined feature sets (combined discriminant features extracted from GTV and CTV). Balanced Accuracy Score (BAS), Positive predictive and negative predictive values (<b>PPV</b> and <b>NPV</b>, respectively) were used to evaluate the performance of the classifiers. <h3>Results</h3> Four GTV-based radiomic features and two CTV-based radiomic features (both from textural feature categories) were found to be statistically significant discriminators between the two ENE cohorts. Performances for prediction of the ENE for the two classifiers trained with the combined feature sets were: GTV-based GLM: BAS/PPV/NPV = 0.765/0.724/0.805 and CTV-based GLM: 0.875/0.928/0.822. Results imply that the CTV-based features have greater predictive value compared to GTV-based features for characterization of ENE. <h3>Conclusion</h3> This pilot study, albeit subject to confirmation in a larger patient population, suggests potential for the use of radiomics-based signatures extracted from the primary tumor for prediction of ENE in patients with OPSCC.

Development and Validation of a Nomogram for the Prediction of Inguinal Lymph Node Metastasis Extranodal Extension in Penile Cancer.

PurposeTo determine whether a clinicopathologic and laboratory-based nomogram is capable of predicting the risk of lymph node extranodal extension (ENE) in patients with penile cancer.Materials and MethodsFrom June 2006 to January 2021, 234 patients who underwent bilateral inguinal lymph node dissection (ILND) surgery were included in the analysis. A Lasso regression model was utilized to select the most useful predictive features from among 46 laboratory variables. Then, a logistic regression analysis was used to develop the prediction model. Calibration curves, concordance index (C-index) and Areas under the receiver-operating characteristic curves (AUCs) were performed to evaluate the performance of the nomogram. We also investigated model fit using changes in Akaike Information Criteria (AICs). Decision curve analyses (DCAs) were applied to assess the clinical usefulness of this nomograms. Its internal validation was confirmed.ResultsAmong the 234 patients, 53 were confirmed to have ENE. The platelet-lymphocyte ratio (PLR) and Squamous cell carcinoma antigen (SCC-Ag) were significantly associated with ENE (P<0.05). The individualized prediction nomogram, including the PLR, SCC-Ag, lymphovascular invasion (LVI), and pathologic tumor stage(pT-stage), showed good discrimination, with a C-index of 0.817 (95% CI, 0.745 to 0.890) and good calibration. Clinical-laboratory nomogram (AIC, 180.034) become the best-fitting model. DCA findings revealed that the clinical-laboratory nomogram was more clinically useful than the pT-stage or tumor grade.ConclusionsThis study presents a clinicopathologic and laboratory-based nomogram that incorporates PLR, SCC-Ag, lymphovascular invasion (LVI), and pT-stage, which can be conveniently utilized to facilitate the individualized prediction of lymph node metastasis ENE in patients with penile cancer.

Prognostic impact of extranodal extension in patients with pN1-N2 lung adenocarcinoma.

Lymph node involvement is one of the important prognostic factors of patients with lung adenocarcinoma. In the tumor, node, and metastasis classification, lymph node involvement is categorized only according to the anatomical station and not the involvement pattern. The aim of this study was to investigate which morphological pattern of lymph node involvement affects the prognosis of patients with surgically resected lung adenocarcinoma. We retrospectively reviewed 168 consecutive patients who underwent surgical resection for primary lung adenocarcinoma with lymph node involvement. The morphological patterns of lymph node involvement (tumor area, number of metastatic lymph nodes, presence of necrosis, and extranodal extension) were histologically examined. The relationships between the patterns of lymph node involvement, clinicopathological features, and survival of patients were analyzed. Eighty patients had N1 disease, and 88 patients had N2 disease. Univariate analysis revealed that invasive size, history of adjuvant chemotherapy, and presence of extranodal extension were significant prognostic factors in N1 patients, and vascular invasion, pleural invasion, presence of epidermal growth factor receptor mutation, history of adjuvant chemotherapy, and presence of extranodal extension were significant prognostic factors in N2 patients. In a bivariate analysis including other clinicopathological factors and patterns of lymph node involvement, the presence of extranodal extension was significantly associated with poor 3-year overall and recurrence-free survival of both N1 and N2 patients. In patients who underwent surgical resection for lung adenocarcinoma with lymph node involvement, the extranodal extension was the most important prognostic factor among morphological lymph node involvement patterns.

Radiological assessment of extranodal extension in patients with head and neck squamous cell carcinoma

Journal of Cancer Metastasis and Treatment is an open access journal, focusing on basic and clinical studies related to cancer cell, cell biology, oncology, radiation therapy and radiology, obstetrics and gynecology, pediatrics, surgery, hematology, neuro-oncology, etc.

Prognostic value of radiologic extranodal extension in patients with hypopharyngeal cancer treated with primary chemoradiation

Background and purposeWe aimed to evaluate the prognostic value of radiologic extranodal extension (rENE) in patients with hypopharyngeal cancer (HPC) treated with primary chemoradiation. Materials and methodsCancer registry data were reviewed from 2005 to 2014. Inclusion criteria included HPC, clinical N1–3 disease (AJCC staging system, 7th edition), and receiving radiotherapy. Patients with M1 diseaseor with synchronous/metachronous cancer were excluded. Staging images were reviewed by two radiologists. rENE was defined as infiltration of adjacent fat/muscles, irregular nodal surface, or irregular capsular enhancement. Clinical stage, rENE status, and clinical outcome were analyzed. ResultsOverall, 355 patients were included. Patients with rENE had lower 3-year overall survival (OS) and recurrence-free survival (RFS) rates. Univariate analysis showed that clinical T4 or N3 stage, overall stage IV, and rENE correlated with OS and RFS. In multivariate analysis, clinical T4 or N3 stage correlated with poor OS, while clinical T4 or N3 stage and rENE were independent predictors of poor RFS. N1/2 without rENE was designated as Group 1, N1/2 with rENE as Group 2, and N3 with/without rENE as Group 3. The 3-year RFS rates in Groups 1, 2, and 3 were 55.8%, 41.0%, and 29.3%, respectively. The 3-year RFS rate in Group 1 was significantly higher than that in the other two groups. ConclusionsrENE is an adverse prognostic factor for survival in patients with HPC treated with primary chemoradiation. It correlated with inferior RFS regardless of N stage. rENE may be used as a criterion for clinical ENE in future staging systems.

The diagnostic performance of CT and MRI for detecting extranodal extension in patients with head and neck squamous cell carcinoma: a systematic review and diagnostic meta-analysis.

To review the diagnostic performance of CT and MRI for detecting extranodal extension (ENE) in head and neck squamous cell carcinoma (HNSCC) patients. MEDLINE and EMBASE databases were searched up to October 7, 2019. Studies that evaluated the diagnostic performance of CT and/or MRI for detecting ENE in HNSCC patients were included. A 2 × 2 table was reconstructed for each study. Pooled sensitivity and specificity were calculated using the bivariate model and hierarchical summary receiver operating characteristic (HSROC) model. Subgroup analyses were performed according to HPV status and radiological features. Pooled correlation coefficient for interobserver agreement was calculated. Twenty-two studies including 2478 patients were included. The pooled sensitivity and specificity for detecting ENE were 73% (95% CI, 62-82%) and 83% (95% CI, 75-89%), respectively, for CT, and 60% (95% CI, 49-70%) and 96% (95% CI, 85-99%), respectively, for MRI. There was substantial heterogeneity for both CT and MRI. A threshold effect was present for MRI. On subgroup analysis, the pooled specificity of CT was significantly lower in patients with HPV+ OPSCC than in patients with HPV‑ oral cavity cancer or all HNSCC (74% vs. 87%; p = 0.01). Central node necrosis showed significantly higher pooled sensitivity (81% vs. 51%; p = 0.02), while infiltration of adjacent planes showed significantly higher pooled specificity (94% vs. 65%; p = 0.03). The pooled correlation coefficient was 0.72 (95% CI, 0.60-0.81). Both CT and MRI show reasonable diagnostic performance for detecting ENE in HNSCC patients and interobserver agreement was substantial. • Pooled sensitivity and specificity were 73% and 83% for CT and 60% and 96% for MRI without significant difference. • Pooled specificity was lower for HPV+ OPSCC than for HPV‑ oral cavity cancer or all HNSCC (74% vs. 87%, p = 0.01), likely due to central node necrosis. • Central node necrosis showed higher sensitivity (81% vs. 51%; p = 0.02), while infiltration of adjacent planes showed higher specificity (94% vs. 65%; p = 0.03).

Functionally impactful TP53 mutations are associated with increased risk of extranodal extension in clinically advanced oral squamous cell carcinoma.

The treatment of advanced oral squamous cell carcinoma (OSCC) is a clinical challenge because it is unclear which therapeutic approaches are the best for this highly heterogeneous group of patients. Because TP53 mutations are the most common genetic event in these tumors, the authors investigated whether they could represent an ancillary biomarker in the management of advanced OSCC. The TP53 gene was sequenced in 78 samples from patients with advanced OSCC who received treatment at 2 institutions located in the United States and Brazil. TP53 mutations were classified according to an in-silico impact score (the evolutionary action score of p53 [EAp53]), which identifies mutations that have greater alterations of p53 protein function (high-risk). Associations between TP53 mutation status/characteristics and clinicopathologic characteristics were investigated. The relevant findings were validated in silico by analyzing 197 samples from patients with advanced OSCC from The Cancer Genome Atlas. No differences in clinical outcomes were detected between patients with TP53-mutant and wild-type TP53 disease. However, patients who had tumors carrying high-risk TP53 mutations had a significantly increased risk of developing extranodal extension (ENE) compared with those who had wild-type TP53-bearing tumors. The increased chances of detecting ENE among patients who had high-risk TP53 mutations was validated among patients with advanced OSCC from The Cancer Genome Atlas cohort. High-risk TP53 mutations are associated with an increased chance of detecting ENE in patients with advanced OSCC. Because ENE is 1 of the major factors considered for OSCC patient management, TP53 mutation status may represent a potential ancillary biomarker for treatment decisions regarding postoperative adjuvant therapy.

Diagnostic Value of FDG-PET/CT for the Identification of Extranodal Extension in Patients With Head and Neck Squamous Cell Carcinoma.

We evaluated the diagnostic value of functional imaging with [18F]-fluoro-2-deoxy-D-glucose (FDG)-positron emission tomography/computed tomography (PET/CT) for the identification of extranodal extension (ENE) in patients with head and neck squamous cell carcinoma (HNSCC). In this study, 94 patients with HNSCC who underwent FDG-PET/CT were enrolled. We recorded the maximum standardized uptake value (SUVmax), compared the results with pathologic findings, and evaluated the diagnostic performance of using a SUVmax cut-off value for ENE. Of the 566 dissected levels examined, 53 (9.4%) exhibited ENE. The mean SUVmax of LN with and without ENE were 6.67 and 1.64, respectively (p<0.001). A receiver operating characteristics (ROC) curve analysis for SUVmax showed an area under the ROC curve of 0.913. A SUVmax cut-off of 3.0 achieved diagnostic performance for identifying ENE with sensitivity, specificity, and accuracy of 81.1%, 94.3% and 93.1%, respectively. FDG-PET/CT findings using a SUVmax cut-off of 3.0 provides appropriate diagnostic value in identifying ENE.

Nuclear Magnetic Resonance Metabolomics Biomarkers for Identifying High Risk Patients with Extranodal Extension in Oral Squamous Cell Carcinoma.

Extranodal extension (ENE) is an independent adverse prognostic factor in oral squamous cell carcinoma (OSCC), and is difficult to identify preoperatively. We aimed to discover biomarkers for high risk patients with ENE. Tandem tissue, plasma, and urine samples of 110 patients with OSCC were investigated through 600-MHz nuclear magnetic resonance (NMR) metabolomics analysis. We found that the levels of creatine, creatine phosphate, glycine, and tyramine in plasma significantly decreased in stage IV ENE positive OSCC compared with stage IV ENE negative OSCC. To understand the underlying mechanism behind the alteration of plasma metabolites, our tissue analysis revealed that the carnitine level significantly increased in tumors but significantly decreased in the adjacent normal tissue in advanced stage OSCC, in addition to decreased levels of alanine and pyruvate in tumor tissues. The global metabolomics analysis on tumor tissues also showed that stage IV tumors with an ENE positive status demonstrated higher levels of aspartate, butyrate, carnitine, glutamate, glutathione, glycine, glycolate, guanosine, and sucrose but lower levels of alanine, choline, glucose, isoleucine, lactate, leucine, myo-inositol, O-acetylcholine, oxypurinol, phenylalanine, pyruvate, succinate, tyrosine, valine, and xanthine than tumors with an ENE negative status. We concluded that metabolomics alterations in tumor tissues correspond to an increase in the tumor stage and are detectable in plasma samples. Metabolomic alterations of OSCC can serve as potential diagnostic markers and predictors of ENE in patients with stage IV OSCC.

Extranodal Extension as an Independent Prognostic factor in Laryngeal Squamous Cell Carcinoma Patients.

The presence of Lymph node metastasis with extranodal extension (ENE) is considered to be an important adverse prognostic factor for survival in patients with head and neck cancer. The aim of this study was to determine the prognostic significance of ENE in patients with laryngeal squamous cell carcinoma (LSCC). Three hundred and fifty-five patients with LSCC who underwent surgical resection and neck dissection were included. The status of cervical lymph node was classified into three groups: pathological negative nodal (pN-), pathological positive nodal without ENE (ENE-), and pathological positive nodal with ENE (ENE+). A total of 85 of 355 (23.9%) LSCC were pathological nodal positive, and ENE was detected in 22/355 (6.2%) patients. ENE was associated with drinking (p=0.005), T stage (p=0.000), tumor location (p=0.000), and differentiation degree (p=0.000). The number of lymph node metastasis in ENE+ group was associated with almost twice compared to ENE- group (p=0.005). The 5-year overall survival rates for patients in the pN-, ENE-, and ENE+ groups were 86.4±2.6%, 75.9±6.3%, and 53.7±12.7%, respectively (p=0.000). After adjusting for confounding variables, ENE+ was associated with more than five times the hazard of death than pN- cases (p=0.000), and more than twice the hazard of death than ENE- cases (p=0.036). Compared to N2-3/ENE- cases, N2-3/ENE+ cases had the poorest survival rate (p=0.013). ENE+ was associated with worse outcomes compared to pN - or ENE- status. ENE is an independent prognostic factor in LSCC, and could be an indicator of the need for adjuvant treatment.

Multi-Institutional Validation of Deep Learning for Pretreatment Identification of Extranodal Extension in Head and Neck Squamous Cell Carcinoma.

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 (P = .02 and P = .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 (P < .0001 and P = .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.

Extranodal extension is a strong prognosticator in HPV-positive oropharyngeal squamous cell carcinoma.

To comprehensively examine the prognostic significance of extranodal extension (ENE) in human papillomavirus-positive oropharyngeal squamous cell carcinoma (HPV-positive OPSCC). Retrospective cohort of cases diagnosed with HPV-positive OPSCC from 2010 to 2015 in the National Cancer Database. Inclusion of all OPSCC HPV-positive cases with appropriate International Classification of Diseases-0-3 codes that received surgery with a neck dissection. Univariate and multivariable analyses were conducted. Hazard ratios (HR) for the independent effects of ENE and N stage on overall survival were estimated by Cox proportional hazards regression. Cases that were ENE-negative had the highest 5-year survival (92.6%; 95% confidence interval [CI]: 90.5%-94.7%). ENE-positive cases had the lowest 5-year survival (84.0%; 95% CI: 80.7%-87.4%). After adjusting for confounding variables, ENE-positivity was associated with almost twice the hazard of death (HR = 1.90; 95% CI: 1.35-2.67) compared to ENE-negative cases. Nodal (N) category 1, ENE-positive status was associated with an increased risk of death (HR = 1.88; 95% CI: 1.26-2.80) compared with N1, ENE-negative status. Compared to N1/ENE-negative cases, N2/ENE-positive cases had the poorest survival (HR: 2.93; 95% CI: 1.94-4.43). Both microscopic and macroscopic ENE were associated with worse outcomes compared to node-positive/ENE-negative status. The implementation of the American Joint Committee on Cancer 8th edition staging system provides a much-improved framework to develop and discuss treatment plans for HPV-positive OPSCC. We feel that careful consideration should be given to the importance of ENE in patients with HPV-positive OPSCC. 4 Laryngoscope, 130:939-945, 2020.

Radiologic-Pathologic Correlation of Extranodal Extension in Patients With Squamous Cell Carcinoma of the Oral Cavity: Implications for Future Editions of the TNM Classification

To evaluate the accuracy and prognostication of the presence of radiologic extranodal extension (rENE) versus pathologic extranodal extension (pENE) in patients with oral cavity squamous cell carcinoma (OSCC). A retrospective review was conducted for all newly diagnosed OSCC patients who underwent neck dissection in our institution from 2010 to 2015 with available records of preoperative computed tomography or magnetic resonance imaging. Two head and neck neuroradiologists reviewed the presence of rENE (defined as ill-defined lymph node borders) on imaging independently, being blinded regarding the pathology report. The impact of the imaging-surgery interval, imaging modalities, and intrarater and interrater concordance of rENE was assessed. The diagnostic accuracy of rENE versus pENE was evaluated. Overall survival (OS) was compared between those with and without rENE. Multivariate analysis evaluated the prognostic value of rENE. Among the 508 patients, rENE and pENE were identified in 57 and 121 cases, respectively. The diagnostic accuracy of rENE versus pENE was identical (73%) for cases with the imaging-surgery interval ≤4 weeks (n = 276) and 4 to 8 weeks (n = 207) but lower (48%) for those >8 weeks (n = 25). Computed tomography displayed higher accuracy on rENE assessment versus magnetic resonance imaging (80% vs 63%, P = .011). Interrater and intrarater concordance (n = 93) was good (κ = 0.79) and excellent (κ = 0.94), respectively. Excluding the 25 cases with a >8 weeks imaging-surgery interval, the sensitivity, specificity, positive predictive value, and negative predictive value of rENE versus pENE in the remaining 483 cases were 52%, 96%, 93%, and 66%, respectively. Patients with rENE (n = 55) had inferior OS versus those without rENE (n = 202), and both had lower OS than node-negative (n = 226) patients (3-year OS: 31% vs 68% vs 81%, P < .001). Multivariate analysis, adjusted for age, T category, N category, and performance status, confirmed the prognostic value of rENE for OS (hazard ratio 3.3, 95% confidence interval 2.4-5.3, P < .001). This large cohort study shows a high specificity but low sensitivity of rENE for pENE. Similar to pENE, the presence of rENE is associated with reduced survival in OSCC.

Extranodal extension of nodal metastases is a poor prognostic moderator in non-small cell lung cancer: a meta-analysis.

Extranodal extension (ENE) of nodal metastasis is defined as the extension of metastatic cells through the nodal capsule into the perinodal tissue. This morphological parameter, recently proposed as an important prognostic factor in different types of malignancy, has not been included in the TNM staging system for non-small cell lung cancer (NSCLC). In this systematic review with meta-analysis, we weighted the prognostic role of ENE in patients with lymph node-positive NSCLC. Two independent authors searched SCOPUS and PubMed through 28 February 2017. Prospective and retrospective studies on NSCLC, comparing patients with presence of ENE (ENE+) ENE+) vs. only intranodal extension (ENE-) and including data regarding prognosis, were considered as eligible. Data were summarized using risk ratios (RR) for the number of deaths/recurrences, and hazard ratios (HR) with 95% confidence intervals (CI) for time-dependent risk related to ENE+, adjusted for potential confounders. We identified 13 studies, including 1709 patients (573 ENE+ and 1136 ENE-) with a median follow-up of 60months. ENE was associated with a significantly increased risk of mortality of all causes (RR = 1.39, 95% CI: 1.18-1.65, P < 0.0001, I2= 70%; HR = 1.30, 95% CI: 1.01-1.67, P = 0.04, I2= 0%) and of disease recurrence (RR = 1.32, 95% CI: 1.04-1.68, P = 0.02, I2= 42%; HR = 1.93, 95% CI: 1.53-2.44, P < 0.0001, I2= 0%). We conclude that in NSCLC, requirements for assessment of ENE should be included in gross sampling and ENE status should be included in the pathology report. Inclusion of ENE status in oncology staging systems will allow further assessment of its role as prognostic parameter.

Ultrasound features of extranodal extension in the metastatic cervical lymph nodes of papillary thyroid cancer: a case-control study.

Objective:Extranodal extension in cervical lymph nodes is an important risk factor for the progression and prognosis of papillary thyroid cancer. The purpose of this study was to identify the common and characteristic preoperative ultrasonography features that are associated with the pathologic extranodal extension of metastatic papillary thyroid carcinoma.Methods:We retrospectively assessed and compared clinicopathologic and ultrasound features between 60 papillary thyroid cancer patients with extranodal extension and 120 control patients with papillary thyroid cancer without extranodal extension.Results:With respect to the pathological N stage and clinicopathologic features, N1b stage papillary thyroid carcinomas were more frequently found in patients who were extranodal extension-positive, in comparison with those who were extranodal extension-negative (78.3% vs. 63.3%, P=0.043). Extranodal extension was detected most frequently in level VI cervical lymph nodes (48.7%). In our univariate analysis of patients with papillary thyroid carcinoma, cervical lymph nodes with extranodal extension showed higher incidences of node matting, microcalcification, cystic area, aspect ratio <2, and larger diameter than those without extranodal extension (all P<0.05). Our multivariate analysis demonstrated that node matting and cystic area were independent risk factors for the presence of extranodal extension [odds ratio (OR): 4.751, 95% confidence interval (CI): 1.212~18.626, P=0.025; OR: 2.707, 95% CI: 1.127~6.502, P=0.026]. Conclusions:Common ultrasound features may indicate the presence of extranodal extension in patients with metastatic cervical lymph nodes of papillary thyroid carcinoma.

Prognostic significance of surgical extranodal extension in head and neck squamous cell carcinoma patients.

Lymph node metastasis with extranodal extension represents one of the most important adverse prognostic factors for survival in patients with head and neck squamous cell carcinoma. We propose that extranodal extension occurs to differing extents. The aim of this study was to determine the prognostic significance of extranodal extension in patients with head and neck squamous cell carcinoma. Two hundred and ninety-eight patients with head and neck squamous cell carcinoma who underwent surgical resection and neck dissection were included. Cervical lymph nodes were classified into four categories: (i) pathological N negative, (ii) extranodal extension negative, (iii) non-surgical extranodal extension and (iv) surgical extranodal extension. Lymph node metastases were detected in 67.1% of laryngeal/hypopharyngeal cancer patients and 52.7% of oral cancer patients. The 3-year disease-specific survival rates for patients in the pathological N negative, extranodal extension negative, non-surgical extranodal extension and surgical extranodal extension groups were 90.9%, 79.6%, 63.8% and 48.3%, respectively. In laryngeal/hypopharyngeal cancer patients, surgical extranodal extension was associated with a significantly poorer disease-specific survival than a pathological N negative, extranodal extension negative or non-surgical extranodal extension status. In oral cancer patients, no significant differences were observed between the non-surgical and surgical extranodal extension groups. However, non-surgical extranodal extension was associated with a poorer disease-specific survival than a pathological N negative or extranodal extension negative status. Surgical extranodal extension was a poor prognostic factor in patients with head and neck squamous cell carcinoma. The prognostic significance of surgical extranodal extension differed between laryngeal/hypopharyngeal and oral cancer patients. The clinical significance of surgical extranodal extension was much greater for patients with laryngeal/hypopharyngeal cancer than oral cancer.