Extranodal Extension Status Research Articles

Primary Penile Cancer: The Role of Adjuvant Radiation Therapy in the Management of Extranodal Extension in Lymph Nodes

BackgroundIn head and neck cancer, the presence of extranodal extension (ENE) in lymph nodes (LNs) has been shown prospectively to require adding chemotherapy to postoperative radiation therapy (RT). Limited data exist regarding ENE in LNs from primary penile cancer (PeCa). ObjectiveTo determine the association of RT and ENE in PeCa. Design, setting, and participantsWe retrospectively analyzed the outcomes of 93 patients with pT1–4 N3 M0 (American Joint Committee on Cancer 7th edition) squamous cell carcinoma of the penis across four international centers. InterventionIf the inguinal nodal specimen had ENE or two or more positive inguinal LNs, RT was delivered to an ipsilateral inguinal field. An ipsilateral pelvic field was added for positive pelvic LNs on dissection. The delivered dose was usually 50Gy in 25 daily fractions. Outcome measurements and statistical analysisClinical and demographic characteristics of relapse-free (RFS), disease-specific (DSS), and overall (OS) survival were compared by ENE status and receipt of adjuvant RT. Results and limitationsSeventy-two percent of patients had inguinal ENE, and 49% had pelvic ENE. On multivariable analysis (MVA) of ENE-negative patients, an OS benefit was noted with postoperative chemotherapy (p=0.038) and inguinopelvic RT (p=0.037). RFS suffered with worsening grade of the lesion (moderately: p=0.027; poorly: p=0.038), but was improved with groin (p=0.016) and inguinopelvic (p=0.006) RT. On MVA of patients with ENE, inguinopelvic RT was associated with better DSS (p=0.041). Grade impacted DSS (moderately: p=0.043; poorly: p=0.033), and poorly differentiated lesions impacted RFS (p=0.013). ConclusionsInguinopelvic RT may benefit regional control in PeCa patients with positive pelvic LNs, but this appears to be limited to those without ENE. Patient summaryFor patients with penile cancer and positive pelvic lymph nodes, postoperative radiation therapy was found to decrease the likelihood of disease recurrence in the groin or pelvis only if extranodal extension was absent.

High-Risk TP53 Mutations Are Associated with Extranodal Extension in Oral Cavity Squamous Cell Carcinoma.

Purpose: Development of extranodal extension (ENE) has been associated with poor survival in patients with oral cavity squamous cell carcinoma (OSCC). Here, we sought to confirm the role of ENE as a poor prognostic factor, and identify genomic and epigenetic markers of ENE in order to develop a predictive model and improve treatment selection.Experimental Design: An institutional cohort (The University of Texas MD Anderson Cancer Center) was utilized to confirm the impact of ENE on clinical outcomes and evaluate the genomic signature of primary and ENE containing tissue. OSCC data from The Cancer Genome Atlas (TCGA) were analyzed for the presence of molecular events associated with nodal and ENE status.Results: ENE was associated with decreased overall and disease-free survival. Mutation of the TP53 gene was the most common event in ENE+ OSCC. The frequency of TP53 mutation in ENE+ tumors was higher compared with ENE- tumors and wild-type (WT) TP53 was highly represented in pN0 tumors. pN+ENE+ patients had the highest proportion of high-risk TP53 mutations. Both primary tumors (PT) and lymph nodes with ENE (LN) exhibited a high rate of TP53 mutations (58.8% and 58.8%, respectively) with no significant change in allele frequency between the two tissue sites.Conclusions: ENE is one of the most significant markers of OSCC OS and DFS. There is a shift toward a more aggressive biological phenotype associated with high-risk mutations of the TP53 gene. Prospective clinical trials are required to determine whether TP53 mutational status can be used for personalized treatment decisions. Clin Cancer Res; 24(7); 1727-33. ©2018 AACR.

The Prevalence of Extranodal Extension in Papillary Thyroid Cancer Based on the Size of the Metastatic Node: Adverse Histologic Features Are Not Limited to Larger Lymph Nodes.

Extranodal extension (ENE) is a prognostic indicator of aggressiveness for papillary thyroid cancer (PTC). The association between the size of metastatic nodes and the prevalence of ENE has not been previously explored. However, there is a common belief that small lymph nodes with metastatic disease do not significantly impact patient outcome. This study investigates the relationship between the prevalence of ENE and the size of a positive lymph node. Linear dimensions and malignant histological characteristics of 979 metastatic lymph nodes from 152 thyroid cancer patients were retrospectively analyzed. Data was analyzed using chi-square tests and multilevel logistic regression modeling. ENE was present in 144 of 979 lymph nodes; the sizes of the involved lymph nodes ranged from 0.9 to 44mm. ENE was identified in 7.8% of lymph nodes measuring ≤ 5mm, 18.9% between 6 and 10mm, 23.1% between 11 and 15mm, 25.0% between 16 and 20mm, and 14.0% between 21 and 25mm in size. The association between node size and ENE status was significant (odds ratio (OR) = 1.07, confidence interval (CI) = [1.04, 1.11]). The size of the metastatic focus directly correlated with ENE (OR = 1.07, 95% CI = [1.07, 1.14], p value < 0.001). Increasing lymph node size increases the likelihood of ENE for metastatic PTC. Importantly, small positive lymph nodes can also harbor ENE to a significant extent. Further studies are required to determine the clinical and prognostic significance of lymph node size and the presence of ENE.

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.

Prognostic Value of Radiographically-Defined Extranodal Extension is Modulated by Human Papillomavirus Status in Locally Advanced Oropharyngeal Carcinoma

Risk-stratification based on clinical and pathologic factors is central to the management of head and neck cancers. The prognostic value of extranodal extension (ENE) in the setting of HPV-associated oropharyngeal squamous cell carcinoma (OPSCC) has been questioned. Using radiologic criteria for the presence of ENE we examined its value in HPV-related and unrelated OPSCC. Consecutive patient records from a single institution were identified by pathologic diagnosis of OPSCC and reviewed for appropriateness for further analysis. Records contained information on HPV status and nodal disease with adequate pre-treatment radiographic evaluation. The presence and extent of ECE was determined at time of diagnosis by neuroradiology as reflected by their reports. HPV status was assayed by in-situ hybridization, p16 immunohistochemistry, or both. Kaplan-Meier methods and Cox regression were used to assess the impact of ENE on survival and disease progression. 212 patients with OPSCC diagnosed between April 2008 and December 2014 were included for analysis with median follow-up of 3.3 years. Median age was 58.5 years, 168 patients (79%) had HPV-associated disease, and were predominantly stage IVA (87%). 98% of patients received definitive radiation therapy, and 92% concurrent chemotherapy. Group stage did not differ significantly based on ENE status. Overall, 42 deaths were reported, and 42 patients demonstrated disease progression, accounting for 56 overall events. In patients with HPV-unrelated OPSCC, ENE was associated with a higher rate of death (54.5% vs 31.8%), and overall events (54.5% vs 40.9%). For HPV-related disease, rate of death (24% vs 20.7%) and overall events (16.3% vs 16.1%) were not significantly associated with ENE. In HPV-associated OPSCC, radiographic ENE was not correlated with a higher rate of deaths or overall events. As expected for classic oropharyngeal cancer, ENE was associated with a higher mortality and total events.

Extranodal extension of lymph node metastasis as a prognostic indicator of recurrence and survival in papillary thyroid carcinoma.

Stratification of extranodal extension (ENE) extent has the potential to improve the accuracy of risk estimations in papillary thyroid carcinoma (PTC). This study examined the prognostic importance of nodal factors, including ENE, in PTC patients. This study enrolled 2071 consecutive patients with treatment-naïve PTC who underwent thyroidectomy between 2006 and 2010. Microscopic/macroscopic ENE was determined by pathological and operative findings. Univariate and multivariate analyses were used to identify the relationship of factors with recurrence and survival in all study patients and in the node-positive subset. Of 2071 patients, 975 (47.1%) had positive lymph nodes, and 271 (13.1%) and 70 (3.4%) had microscopic and macroscopic ENE, respectively. During a median follow-up of 96 months, 114 (5.5%) patients had post-treatment recurrence. Multivariate analyses showed that, in all patients, the number of positive nodes, lymph node ratio, ENE status, and ATA risk group were independent variables affecting recurrence (P < 0.05). T4 and macroscopic ENE were independent variables associated with shorter overall survival (P < 0.05). Macroscopic ENE was significantly associated with macroscopic extrathyroidal extension. Macroscopic ENE has a significant adverse impact on recurrence and survival after treatment for PTC. ENE is considered a high risk factor for recurrence.

Extranodal extension status is a powerful prognostic factor in stage III colorectal cancer

PurposeThe present study aimed to evaluate the clinicopathologic characteristics of patients with extranodal extension (ENE) and the prognostic implications of ENE in stage III colorectal cancer (CRC).ResultsENE was more frequent in younger patients and those with rectal cancer, higher T stage, higher N stage, lymphovascular invasion (LVI), and perineural invasion (PNI). Five-year disease-free survival (DFS) and overall survival (OS) were lower in patients with ENE-positive than in those with ENE-negative tumors (DFS, 66.4% vs. 80.1%; and OS, 74.8% vs. 85.6%, respectively; P < 0.001 both). In multivariate analysis, pathologic stage, the presence of ENE, LVI, PNI, and no adjuvant chemotherapy were significant independent prognostic factors for DFS and OS. There were no statistically significant differences in DFS and OS between ENE-positive stage IIIB tumors and ENE-negative stage IIIC tumors.Materials and MethodsThe records of 1,948 stage III CRC patients who underwent curative surgery between January 2003 and December 2010 were retrospectively reviewed.ConclusionsThe presence of ENE is independently and significantly associated with lower DFS and OS rates after curative resection for stage III CRC. ENE status should be considered in both the pathologic report and CRC staging system.

Extranodal Extension Is a Powerful Prognostic Factor in Bladder Cancer Patients with Lymph Node Metastasis

BackgroundLymph node metastasis (LNM) is the most powerful pathologic predictor of disease recurrence after radical cystectomy (RC). However, the outcomes of patients with LNM are highly variable. ObjectiveTo assess the prognostic value of extranodal extension (ENE) and other lymph node (LN) parameters. Design, setting, and participantsA retrospective analysis of 748 patients with urothelial carcinoma of the bladder and LNM treated with RC and lymphadenectomy without neoadjuvant therapy at 10 European and North American centers (median follow-up: 27 mo). InterventionAll subjects underwent RC and bilateral pelvic lymphadenectomy. Outcome measurements and statistical analysisEach LNM was microscopically evaluated for the presence of ENE. The number of LNs removed, number of positive LNs, and LN density were recorded and calculated. Univariable and multivariable analyses addressed time to disease recurrence and cancer-specific mortality after RC. Results and limitationsA total of 375 patients (50.1%) had ENE. The median number of LNs removed, number of positive LNs, and LN density were 15, 2, and 15, respectively. The rate of ENE increased with advancing pT stage (p<0.001). In multivariable Cox regression analyses that adjusted for the effects of established clinicopathologic features and LN parameters, ENE was associated with disease recurrence (hazard ratio [HR]: 1.89; 95% confidence interval [CI], 1.55–2.31; p<0.001) and cancer-specific mortality (HR: 1.90; 95% CI, 1.52–2.37; p<0.001). The addition of ENE to a multivariable model that included pT stage, tumor grade, age, gender, lymphovascular invasion, surgical margin status, LN density, number of LNs removed, number of positive LNs, and adjuvant chemotherapy improved predictive accuracy for disease recurrence and cancer-specific mortality from 70.3% to 77.8% (p<0.001) and from 71.8% to 77.8% (p=0.007), respectively. The main limitation of the study is its retrospective nature. ConclusionsENE is an independent predictor of both cancer recurrence and cancer-specific mortality in RC patients with LNM. Knowledge of ENE status could help with patient counseling, clinical decision making regarding inclusion in clinical trials of adjuvant therapy, and tailored follow-up scheduling after RC.

1904 EXTRANODAL EXTENSION IS A POWERFUL PROGNOSTIC FACTOR IN BLADDER CANCER PATIENTS WITH LYMPH NODE METASTASIS

1904 EXTRANODAL EXTENSION IS A POWERFUL PROGNOSTIC FACTOR IN BLADDER CANCER PATIENTS WITH LYMPH NODE METASTASIS

Extranodal extension in node‐positive bladder cancer: the continuing controversy

• To examine whether extranodal extension (ENE) has an impact on the outcome of node-positive patients who underwent radical cystectomy for bladder cancer. • Of 543 consecutive patients who underwent radical cystectomy for urothelial carcinoma of the bladder between 1990 and 2007, 112 patients with lymph node metastasis detected on histological examination were evaluated with regard to recurrence-free survival (RFS) and disease-specific survival (DSS) based on ENE status. • The overall 5-year RFS and DSS rates were 22.3% and 33.8%, respectively. ENE was observed in 41 (36.6%) of the 112 patients. • The presence of ENE was associated with advanced pathological nodal status (P= 0.004), more positive lymph nodes (P= 0.006), and higher lymph node density (P < 0.001). • The incidence of positive ENE increased with large positive lymph node diameter (P < 0.001). • Multivariate analysis showed that lymph node density (hazard ratio (HR) = 2.39, 95% CI 1.09-5.24, P= 0.029; and HR = 3.13, 1.43-6.84, P= 0.004) and use of adjuvant chemotherapy (HR = 1.80, 1.02-3.20, P= 0.041; and HR = 2.07, 1.13-3.79, P= 0.018) were significant predictors of RFS and DSS, respectively. • After adjustment for other prognostic factors, ENE was not significantly related to RFS (P= 0.825) and DSS (P= 0.961) by multivariate analysis. • The presence of ENE was not an independent prognostic factor in node-positive patients after radical cystectomy for bladder cancer. • Additional prospective studies are needed to determine the independent prognostic role of ENE.