Radiologic Extranodal Extension Research Articles

Efficacy of salvage surgery versus re-irradiation for isolated regional lymph node recurrence in patients with nasopharyngeal carcinoma

BackgroundTo compare the clinical characteristics and prognoses of patients with isolated regional lymph node recurrent nasopharyngeal carcinoma (irrNPC) who underwent surgery or re-irradiation treatment.MethodsWe retrospectively reviewed 124 irrNPC patients who underwent initial radiotherapy between January 2010 and December 2020. The staging of regional lymph node recurrence was as follows: 75.8% for rN1, 14.5% for rN2, and 9.7% for rN3. Fifty-five patients underwent regional lymph node surgery (Surgery group), and sixty-nine patients received salvage radiotherapy with or without chemotherapy (Re-irradiation group). The survival rate was compared using Kaplan‒Meier analysis and evaluated by the log-rank test. Cox proportional hazard models were used to analyze prognostic factors.ResultsThe median follow-up time was 70 months, the 5-year overall survival (OS) was 74%, and the median survival time was 60.8 months. There were no significant differences in 5-year OS (75.6% vs. 72.4%, P = 0.973), regional recurrence-free survival (RRFS, 62.7% vs. 71.1%, P = 0.330) or distant metastasis-free survival (DMFS, 4.2% vs.78.7%, P = 0.677) between the Surgery group and Re-irradiation group. Multivariate analysis revealed age at recurrence, radiologic extra-nodal extension (rENE) status, and recurrent lymph node (rN) classification as independent prognostic factors for OS. The rENE status was an independent prognostic factor for DMFS. Subgroup analysis of the Surgery group revealed that the rN3 classification was an adverse prognostic factor for OS. Age at recurrence ≥ 50 years, GTV-N dose, and induction chemotherapy were found to be independent prognostic factors for OS, RRFS, and DMFS, respectively, in the Re-irradiation group.ConclusionsFor NPC patients with isolated regional lymph node recurrence after initial radiotherapy, those who underwent surgery had survival prognosis similar to those who underwent re-radiotherapy with or without chemotherapy. A prospective study is needed to validate these findings.

The feasibility of level Ib-sparing intensity-modulated radiation therapy in patients with nasopharyngeal carcinoma and high-risk factors classified based on the International Guideline

Background and PurposeTo examine the feasibility of level Ib-sparing intensity-modulated radiation therapy (IMRT) in patients with nasopharyngeal carcinoma (NPC) who had high-risk factors classified based on the International Guideline (IG). Materials and MethodsWe evaluated 961 non-metastatic NPC cases based on IG recommendations for prophylactic Ib irradiation. Four high-risk factors were used to categorise patients into three cohorts: A, B, and C. Propensity score matching was used to balance baseline characteristics in Cohort C, resulting in a matched Cohort C. Recurrence rates at level Ib and regional relapse-free survival (RRFS) rates were evaluated. ResultsAmong patients with negative Ib lymph nodes (LNs), 18, 54, 420, and 444 exhibited involvement of structures that drain to level Ib as the first echelon (FES), involvement of the submandibular gland (SMG), level II LNs with radiologic extranodal extension (rENE), and level II nodes with a maximal axial diameter (MAD) ≥ 2 cm, respectively. The recurrence rate was highest in Cohort A (11.1 %). Cohort B had no level Ib recurrence. In matched Cohort C, recurrence rates were low in both groups (Ib-sparing group: 0.6 % vs. Ib-covering group: 0.6 %, P > 0.999). No significant differences were observed in 5-year RRFS rates between the two groups in cohort A (p = 0.208), cohort B (p = 0.905), and matched cohort C (p = 0.423). ConclusionsLevel Ib-sparing IMRT could be performed safely for NPC patients with level II LNs who had rENE and/or MAD ≥ 2 cm. Further research should determine the necessity of level Ib prophylactic irradiation for patients with FES or SMG involvement.

Significance of radiologic extranodal extension in locoregionally advanced nasopharyngeal carcinoma with lymph node metastasis: a comprehensive nomogram

ObjectiveWe aimed to assess the significance of rENE and creat a predictive tool (nomogram) for estimating Overall Survival (OS) in locoregionally advanced Nasopharyngeal Carcinoma (NPC) patients with Lymph Node Metastasis (LNM) based on their clinical characteristics and Radiologic Extranodal Extension (rENE). MethodsFive hundred and sixty-nine NPC patients with LNM were randomly divided into training and validation groups. Significant factors were identified using univariate and multivariate analyses in the training cohort. Then, the nomogram based on the screening results was established to predict the Overall Survival (OS). Calibration curves and the Concordance index (C-index) gauged predictive accuracy and discrimination. Receiver Operating Characteristic (ROC) analysis assessed risk stratification, and clinical utility was measured using Decision Curve Analysis (DCA). The nomogram's performance was validated for discrimination and calibration in an independent validation cohort. ResultsA total of 360 (63.2%) patients were present with radiologic extranodal extension at initial diagnosis. Patients with rENE had significantly lower OS than other patients. Multivariate analysis identified the five factors, including rENE, for the nomogram model. The C-index was 0.75 (0.71–0.78) in the training cohort and 0.76 (0.69–0.83) in the validation cohort. Notably, the nomogram outperformed the 8th TNM staging system, as evident from the higher AUC values (0.77 vs. 0.60 for 2year and 0.75 vs. 0.65 for 3year) and well-calibrated calibration curves. Decision curve analysis indicated improved Net Benefit (NB) with the nomogram for predicting OS. The log-rank test confirmed significant survival distinctions between risk groups in both training and validation cohorts. ConclusionsWe demonstrated the prognostic value of rENE in nasopharyngeal carcinoma and developed a nomogram based on rENE and other factors to provide individual prediction of OS for locoregionally advanced nasopharyngeal carcinoma with lymph node metastasis. Level of evidenceIII.

The Feasibility of Level Ib Sparing Intensity Modulated Radiation Therapy in Nasopharyngeal Carcinoma Patients with High-Risk Factors: Based on International Guideline

In spite of the rarity of level Ib recurrence after intensity-modulated radiation therapy, the International Guideline (IG) provides the risk factors for prophylactic coverage. In practice, however, there are significant differences between institutions. The purpose of this study is to examine the feasibility of sparing level Ib IMRT in NPC patients with high-risk factors based on IG. From January 2014 to October 2017, newly-diagnostic, non-metastatic NPC patients in our center were retrospectively reviewed. According to the risk factors of prophylactic level Ib coverage in patients with negative level Ib recommended by IG, the characteristics of pre-treatment MRI were analyzed. Four high-risk factors were identified: a. involvement of the structures that drain to level Ib as first echelon (FES), including anterior half of nasal cavity, oral cavity, b. involvement of submandibular gland (SMG), c. with radiologic extranodal extension (rENE) in level II LNs, or d. maximal axial diameter (MAD)≧2 cm in level II LNs. Patients with risk factors were divided into Cohort A (with risk factors a), Cohort B (with risk factor b, but without a), and Cohort C (only with risk factors c and/or d). Recurrence rates of level Ib and regional relapse-free survival (RRFS) rates were evaluated in different cohorts. A total of 961 patients were finally included. Thirty-six cases (3.7%) presented with radiologically positive level Ib metastasis. For the other patients with negative Ib LNs, there were 18, 65, 421, and 444 cases classified as FES involvement, SMG involvement, level II LNs with rENE, and level II nodal with MAD ≧2 cm. Excluding overlap, a total of 571 patients with risk factors were divided into three groups: Cohort A (n = 18), Cohort B (n = 49) and Cohort C (n = 504). Nine patients (9/961, 0.94%) developed level Ib recurrence. Except for 1 patient with positive Ib LNs at diagnosis, 2 did not meet any of the risk factors, while the other six (6/9, 66.7%) met at least one risk factor. The rate of recurrence at neck level Ib was highest in Cohort A (11.1%, 2/18; Ib-sparing group: 0/10, 0.0% vs Ib-covering group: 2/8, 25.0%; P = 0.183). In Cohort B, no cases were found with level Ib recurrence (0.0%, 0/49). In Cohort C, the rates were rare (0.8%, 4/504) in both groups (0.7%, 2/276 vs 0.9%, 2/228; P > 0.999). Among the three Cohorts, there were no significant differences in 5-year RRFS between two groups, which were 90.0% vs 62.5% (p = 0.248), 90.9% vs 92.0% (p = 0.905), and 92.6% vs 90.1% (p = 0.445), respectively. Among patients with high-risk factors, the incidence of grade 3-4 late dry mouth symptom was higher in the level Ib-covering group (3.1% vs 7.5%, P = 0.033). Level Ib sparing appears safe and feasible for NPC patients with negative level Ib LNs, even if combined with risk factors: SMG involvement, and/or level II with rENE, and/or level II MAD ≧2 cm. Level Ib-sparing irradiation reduces dry mouth symptoms compared with level Ib-irradiation.

Radiologic Extranodal Extension of Metastatic Lymph Nodes in Patients With Non-Small Cell Lung Cancer: Prognostic Utility and Diagnostic Performance.

BACKGROUND. Pathologic extranodal extension (ENE) in metastatic lymph nodes (LNs) has been associated with unfavorable prognosis in patients with non-small cell lung cancer (NSCLC). OBJECTIVE. The purpose of this article was to evaluate the prognostic utility of radiologic ENE and its diagnostic performance in predicting pathologic ENE in patients with NSCLC. METHODS. This retrospective study included 382 patients (mean age, 67 ± 10 [SD] years; 297 men, 85 women) diagnosed with NSCLC and clinical N1 or N2 disease between January 2010 and December 2016. Two thoracic radiologists reviewed staging chest CT examinations to record subjective overall impression for radiologic ENE (no ENE, possible/probable ENE, or unambiguous ENE), reviewing 30 examinations in consensus and the remaining examinations independently. Kaplan-Meier survival analysis and multivariable Cox proportional hazards model were used to evaluate the utility of radiologic ENE in predicting overall survival (OS). Prognostic utility of radiologic ENE was also assessed in patients with clinical N2a disease. In patients who underwent surgery, sensitivity and specificity were determined of radiologic unambiguous ENE in predicting pathologic ENE. RESULTS. The 5-year OS rates for no ENE, possible/probable ENE, and unambiguous ENE were 44.4%, 39.1%, and 20.9% for reader 1 and 45.7%, 36.6%, and 25.6% for reader 2, respectively. Unambiguous ENE was an independent prognostic factor for worse OS (reader 1: adjusted HR, 1.72, p = .008; reader 2: adjusted HR, 1.56, p = .03), whereas possible/probable ENE was not (reader 1: adjusted HR, 1.18, p = .33; reader 2: adjusted HR, 1.21, p = .25). In patients with clinical N2a disease, 5-year OS rate in patients with versus without unambiguous ENE for reader 1 was 22.2% versus 40.6% (p = .59) and for reader 2 was 27.6% versus 41.0% (p = .49). In 203 patients who underwent surgery (66 with pathologic ENE), sensitivity and specificity of radiologic unambiguous ENE for predicting pathologic ENE were 11% and 93% for reader 1 and 23% and 87% for reader 2. CONCLUSION. Radiologic unambiguous ENE was an independent predictor of worse OS in patients with NSCLC. The finding had low sensitivity but high specificity for pathologic ENE. CLINICAL IMPACT. Radiologic ENE may have a role in NSCLC staging workup and treatment selection.

Unambiguous radiologic extranodal extension determined by MRI could be a biomarker in predicting metastatic prostate cancer

To explore the relationship between unambiguous radiologic extranodal extension (rENE) and M1 staging in patients with metastatic PCa. A respective analysis of 1073 patients of PCa N1 staging from January 2004 to May 2022 was retrospectively enrolled. They were divided into rENE + and rENE - groups and retrospectively analyzed the M staging with nuclear medicine data. The correlation index between unambiguous rENE and M1b staging was calculated. Logistic regression was used to evaluate the predictive performance of unambiguous rENE in M1b staging. ROC curves were used to investigate the relationship between unambiguous rENE and M staging in patients who underwent 68Ga-PSMA PET/CT. A total of 1073 patients were included. Seven hundred and eighty patients were classified into the rENE + group (mean age, 69.6years ± 8.7 [standard deviation]), and 293 were classified into rENE - group (mean age, 66.7years ± 9.4 [standard deviation]). Relationship between unambiguous rENE and M1b existed (r = 0.58, 95%CI: 0.52-0.64, P < 0.05). Unambiguous rENE could be an independent predictor for M1b (OR = 13.64, 95%CI: 9.23-20.14, P < 0.05). The AUC of unambiguous rENE in predicting M1b and M staging was 0.835 and 0.915, respectively, in patients who underwent 68Ga-PSMA PET/CT. Unambiguous rENE could be a strong biomarker to predict M1b and M staging in patients with PCa. When rENE came up, patients should perform nuclear medicine immediately, and a systematic treatment should be considered.

Prognostic significance of cervical radiologic carotid artery invasion by lymph node on magnetic resonance imaging in nasopharyngeal carcinoma

PurposeCarotid artery invasion (CAI) has been demonstrated to be an important prognosticator in some head and neck cancers. This study aimed to examine the prognostic value of radiologic CAI (rCAI) by cervical lymphadenopathy in nasopharyngeal carcinoma (NPC).MethodsNPC patients treated between January 2013 and December 2016 were included. Pre-treatment MRIs were reviewed for cervical rCAI according to the radiologic criteria. Univariate and multivariate models were constructed to assess the association between cervical rCAI and clinical outcomes. A new N classification system was proposed and compared to the 8th AJCC system.ResultsThe percentage of patients with MRI-positive lymph nodes was 84.7% (494/583), of whom cervical rCAI cases accounted for 42.3% (209/494). Cervical rCAI was associated with significantly poorer OS, DFS, DFFS and RFFS compared to non-rCAI (P < 0.05). Multivariate analyses confirmed that cervical rCAI was an independent prognosticator for DFS and DFFS, surpassing other nodal features, such as laterality, size, cervical node necrosis (CNN) and radiologic extranodal extension (rENE), while location of positive LNs remained independently associated with OS, DFS and DFFS. We propose a refined N classification: New_N1: upper neck LNs only without cervical rCAI; New_N2: upper neck LNs only with cervical rCAI; New_N3: upper and lower LNs. The proposed classification broadened the differences in OS, DFS and DFFS between N1 and N2 disease, and achieved a higher c-index for DFS and DFFS.ConclusionsCervical rCAI was an independent unfavorable indicator of NPC. Compared to the AJCC system, the proposed N category showed satisfactory stratification between N1 and N2 disease, and better prediction of distant metastasis and disease failure.

The role of radiologic extranodal extension in predicting prognosis and chemotherapy benefit for T1-2 N1 nasopharyngeal carcinoma: A multicenter retrospective study

Background and PurposeThis multicenter retrospective study aimed to investigated the prognostic value of unequivocal radiologic extranodal extension (rENE) and the efficacy of chemotherapy for stage T1-2 N1 nasopharyngeal carcinoma (NPC) in the IMRT era. Materials and MethodsWe included 1,082 patients treated in 2005–2017 from three centers. rENE was recorded as G1 (coalescent nodal mass comprising ≥ 2 inseparable nodes) or G2 (invading beyond perinodal fat to frankly infiltrate adjacent structures). Multivariable analysis (MVA) evaluated the prognostic value of rENE. The value of chemotherapy was assessed in rENE-positive (rENE + ) and rENE-negative (rENE − ) subset separately. ResultsCenters 1, 2, and 3 had 139/515 (27.0 %), 100/365 (27.4 %), and 43/202 (21.3 %) cN + patients with rENE, respectively. Compared to rENE−, rENE + patients had a worse distant metastasis-free survival (DMFS) and overall survival (OS) (all p < 0.001). MVA confirmed the prognostic of both G1-rENE and G2-rENE for distant metastasis [G1: hazard ratio (HR): 2.933, G2: HR: 6.942, all p < 0.001] and death (G1: HR: 1.587, p = 0.040; G2: HR: 6.162, p < 0.001). There was no significant difference for DMFS and OS between chemo-radiotherapy and radiotherapy alone in rENE + and rENE − groups (all p > 0.1). However, rENE + patients with a cumulative cisplatin/nedaplatin dose (CCND) of > 160 mg/m2 had an improved DMFS (p = 0.033) but no OS (p = 0.197). ConclusionUnequivocal rENE is prognostic in patients with T1-2 N1 NPC. Addition of chemotherapy to radiotherapy did not affect DMFS and OS in rENE − patients. Chemotherapy with a CCND of > 160 mg/m2 improved DMFS in rENE + patients.

Neck level Ib-sparing versus level Ib-irradiation in intensity-modulated radiotherapy for the treatment of nasopharyngeal carcinoma with high-risk factors: A propensity score-matched cohort study

AimLevel Ib lymph nodes metastasis is rare in nasopharyngeal carcinoma (NPC). We aimed to evaluate the feasibility of sparing level Ib-irradiation in NPC patients with high-risk factors. Materials and methodsFour hundred forty-three NPC patients with radiologic extranodal extension (rENE) or level II lymph node maximal axial diameter (MAD) ≥ 20 mm treated by intensity-modulated radiotherapy (IMRT) between 2009 and 2012 were included in this study. Propensity score matching (PSM) was applied to balance potential prognostic factors (including age, sex, T and N stage, pretreatment EBV DNA level, and level II rENE and MAD) between patients who received and omitted level Ib irradiation. Kaplan–Meier analysis and the log-rank test were used to compare regional survival outcomes. ResultsPSM resulted in 169 matched pairs of eligible patients. The median follow-up period was 119 months in the matched cohort. The number of level Ib failure in the level Ib-sparing and level-Ib irradiation groups were 3/169 (1.8 %) vs 2/169 (1.2 %), P > 0.999. And the 5-year regional relapse-free survival (RRFS) rates of the two groups were 88.4 % vs 92.6 %, respectively. After PSM, RRFS (hazard ratio [HR]: 1.508, 95 % confidence interval [CI]: 0.762–2.986, P = 0.239), OS (HR: 1.219, 95 % CI: 0.754–1.972, P = 0.418), distant metastasis-free survival (DMFS) (HR: 1.605, 95 % CI: 0.900–2.863, P = 0.109), and local relapse-free (LRFS) (HR: 0.956, 95 % CI: 0.436–2.095, P = 0.910) were similar in the two arms. The incidence of grade ≥ 1 dry mouth after 5 years was higher in the level Ib-irradiation group (27.5 % vs 16.5 %, P = 0.029). However, the incidences of grade 3–4 late toxicities were similar between the two groups. ConclusionNeck level Ib-sparing appears to be safe and feasible in NPC patients with rENE or level II MAD ≥ 20 mm and negative level Ib lymph nodes. Compared with cervical level Ib-irradiation, omission of irradiation to level Ib provides less dry mouth symptom.

Augmenting inter-rater concordance of radiologic extranodal extension in HPV-positive oropharyngeal carcinoma: A multicenter study.

To assess intra- and inter-institutional concordance and identify methods to increase precision in radiologic extranodal extension (rENE) ascertainment in HPV+ oropharyngeal carcinoma. Six radiologists, blinded to clinical outcomes, from three centers assessed rENE in two phases: Phase-I (20 cases) utilized each individual's a priori appreciation of the literature. Phase-II (30 additional cases) was performed after deliberating experience and consolidating operating definitions. Intra- and inter-institutional Kappa were calculated at >50% and >75% certainty levels, respectively. The Phase-I intra-institutional kappa was 0.76, 0.32, and 0.44 at >50% certainty and improved to 0.89, 0.61, and 0.66 at >75% certainty.Inter-institutional Fleiss' kappa also improved with higher certainty (from 0.40 to 0.57, p = 0.039). The Phase-II inter-rater kappa was significantly higher than Phase-I at the same certainty level (both p < 0.001). A learning curve exists for rENE assessment. Strategies to augment reliability include high certainty for declaration, consolidated operating definitions, and sharing experience among radiologists.

Radiologic-pathologic correlation of major versus minor extranodal extension in oral cavity cancer.

To evaluate the diagnostic performance of radiologic extranodal extension (rENE) in predicting major (>2 mm) and minor (≤2 mm) pathologic ENE (pENE). All oral cavity squamous cell carcinoma patients who underwent neck dissection with pathological nodal disease (pN+) between 2010 and 2015 were reviewed. Preoperative computed tomography and/or magnetic resonance imaging were reviewed by two head and neck neuroradiologists. Three hundred and thirty-four patients were included. The sensitivity and specificity of rENE were 37% [95% CI 29-44] and 98% [95% CI 96-100], respectively. Sensitivity for pENE improved in the subset of patients with major ENE (48% [95% CI 38-57]). The presence of rENE was associated with inferior 3-year overall survival: 26% [95% CI 17-41] versus 60% [95% CI 54-67]. This large cohort study demonstrates high specificity, but low sensitivity for preoperative imaging in the detection of pENE in OCSCC. Patients with rENE demonstrated poor OS. pENE in the absence of rENE is still an adverse risk factor.

Unfinished Business in Classifying HPV-Positive Oropharyngeal Carcinoma: Identifying the Bad Apples in a Good Staging Barrel.

This commentary highlights three important findings in the study by Vijayvargiya et al, published in this journal, involving 9554 oropharyngeal cancer patients from the SEER database. Firstly, there is improved performance in outcome prediction with TNM-8 in HPV+ OPC. However, heterogeneity exists, especially in TNM-8 stage I disease, and there is need for ongoing improvement in risk stratification. Several anatomical and non-anatomical prognostic factors have been proposed. Among them, radiologic extranodal extension has emerged as one of the promising parameters to be considered for future staging. These baseline prognostic factors should address sensitivity, specificity, and diagnostic accuracy to serve different clinical needs. Secondly, cure is possible for some patients presenting with M1 disease. Optimal management of such patients remains to be explored, and clinical trials targeting de novo M1 disease should be encouraged to optimize outcomes for this subset. Finally, methodologies to address missing tumor HPV status in historical cohorts have been discussed, including using baseline demographics and clinical characteristics, as well as statistical procedures such as multiple imputation.

Prognostic importance of radiologic extranodal extension in nasopharyngeal carcinoma treated in a Canadian cohort

PurposeTo confirm the prognostic value of radiologic extranodal extension (rENE) and its role in clinical-N classification in nasopharyngeal carcinoma (NPC) treated in a western institution. Methods and materialsNPC treated between 2010 and 2017 were included. Pre-treatment MRI were reviewed for unequivocal rENE and its grade: grade-1: tumour invading through any nodal capsule but confined to perinodal fat; grade-2: ≥2 adjacent nodes forming a coalescent nodal mass; grade-3: tumour extending beyond perinodal fat to invade/encase adjacent structures. Overall survival (OS) and disease-free survival (DFS) were compared between rENE-positive (rENE+) and rENE-negative (rENE−) patients. Multivariable analysis (MVA) confirmed the prognostic importance of rENE and its grade. Staging schemas including rENE in N-classification were proposed and their performance evaluated. ResultsA total of 274 patients were eligible (43 cN0; 231 cN-positive). rENE was identified in 83/231 (36%) cN-positive, including grade 1/2/3 rENE in 14/58/11 cases. Compared to rENE−, rENE+ patients had a lower OS (68% vs 89%, p < 0.001) and DFS (58% vs 80%, p < 0.001). MVA confirmed the prognostic importance of grade-2 [HR: OS: 2.85 (p = 0.005); DFS: 2.89 (p < 0.001)] and grade-3 rENE [HR: OS 5.28 (p = 0.004); DFS 3.86 (p = 0.005)], with a trend for grade-1 vs rENE− [HR: OS 2.63 (p = 0.13); DFS 1.49 (p = 0.520)]. We evaluated classifying any rENE as cN3 (Proposal-I) or any grade-2/grade-3 rENE as cN3 (Proposal-II). The stage schema with Proposal-I cN-classification ranked the highest in the performance evaluation. ConclusionsrENE is an important prognostic factor in this western NPC cohort. We propose classifying any unequivocal rENE as cN3.

Radiotherapy vs. Surgery in Early Stage HPV-Positive Oropharyngeal Cancer

To compare the outcomes of upfront (chemo)radiotherapy ((CC)RT) versus surgery in early stage human papilloma virus-positive oropharyngeal squamous cell carcinoma (hpv+OPC), and investigate for preoperative clinical factors that can predict eventual requirement for postoperative (CC)RT.A multicenter retrospective study including 166 patients with histologically proven AJCC 8th ed. stage I-II hpv+OPC was conducted. We excluded patients who received induction chemotherapy (CT) and adjuvant cetuximab CT. Patients who didn't receive concurrent cisplatin-based CT with a single lymph node (LN) > 3cm or multiple LNs were also excluded from the analysis. As a result, sixty (36.1%) and one-hundred six (63.9%) patients received upfront (CC)RT and surgery, respectively. Seventy-eight (73.6%) patients in the upfront surgery group received postoperative (CC)RT.With a median follow-up of 45.1 months, the 2-year overall survival (OS), progression free survival (PFS) and locoregional control (LC) for (CC)RT/surgery were 97.8%/96.4% (P = 0.755), 91.1%/92.0% (P = 0.810) and 92.9%/93.3% (P = 0.721), respectively. In multivariate analyses, patients showing synchronous radiologic extranodal extension and conglomeration (ENEcong) of metastatic LNs showed significantly poor OS (P = 0.047), PFS (P = 0.001) and LC (P = 0.003). In patients undergoing upfront surgery, the number of clinically positive LN ≥2 (OR, 5.15; P = 0.004) and LN with ENEcong (OR, 3.75; P = 0.009) were predictors of postoperative CCRT. No patient in the (CC)RT group demonstrated late severe toxicity whereas 3 (2.8%), 1 (0.9%), and 1 (0.9%) patient in the surgery group showed grade 3 dysphagia, grade 3 xerostomia, and fatal oral cavity bleeding.We found no differences in OS, PFS, and LC between (CC)RT vs. surgery as initial treatment in stage I-II hpv+OPC which warrants comparison via a prospective trial in the treatment de-escalation era. However, most patients undergoing upfront surgery needed adjuvant (CC)RT. Pretreatment findings of LN metastases are prognostic as well as predictive for the need of adjuvant treatment.

The prognostic value of radiologic extranodal extension in nasopharyngeal carcinoma: Systematic review and meta-analysis

ObjectivesThe prognostic value of radiologic extranodal extension (rENE) in nasopharyngeal carcinoma remains controversial. In this study, a meta-analysis was performed to assess the prognostic value of ungraded rENE and unambiguous advanced rENE. MethodsA literature search through PubMed, Cochrane Library, EMBASE and manual searches was conducted until May 2021. The adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) of overall survival and distant metastasis-free survival were extracted and pooled. ResultsNine eligible studies were published between 2012 and 2021. The pooled patient number was 7532 (range 61–1887). Seven studies were eligible for the analysis of ungraded rENE, while 3 studies were eligible for unambiguous advanced rENE. The results showed that ungraded rENE was associated with worse overall survival (HR 1.85, 95% CI 1.04–3.27) and significantly associated with worse distant metastasis-free survival (HR 2.07, 95% CI 1.36–3.13). On the other hand, unambiguous advanced rENE was significantly associated with worse overall survival (HR 2.62, 95% CI 2.12–3.25) and worse distant metastasis-free survival (HR 3.14, 95% CI 1.85–5.33). ConclusionsIn nasopharyngeal carcinoma, both ungraded and unambiguous advanced rENE are significant prognosticators of overall survival and distant metastasis-free survival. More prospective studies are required to determine its role in risk stratification or clinical staging.

Radiotherapy versus Surgery in Early-Stage HPV-Positive Oropharyngeal Cancer.

PurposeThis study aimed to compare the outcomes of primary radiotherapy (RT) versus surgery in early-stage human papilloma virus–positive oropharyngeal squamous cell carcinoma (hpv+OPC), and investigate the preoperative clinical factors that can predict the requirement for postoperative adjuvant treatment.Materials and MethodsThis multicenter study included 166 patients with American Joint Committee on Cancer 8th edition-Stages I–II hpv+OPC. Sixty (36.1%) and 106 (63.9%) patients underwent primary (concurrent chemo)radiotherapy [(CC)RT] and surgery, respectively. Seventy-eight patients (73.6%) in the surgery group received postoperative (CC)RT.ResultsWith a median follow-up of 45.6 months for survivors, the 2-year overall survival (OS), progression-free survival (PFS), and locoregional control (LC) for RT/surgery were 97.8%/96.4%, 91.1%/92.0%, and 92.9%/93.3%, respectively. In multivariate analyses, patients with synchronous radiologic extranodal extension and conglomeration (ENEcong) of metastatic lymph nodes (LNs) showed significantly poorer OS (p=0.047), PFS (p=0.001), and LC (p=0.003). In patients undergoing primary surgery, two or more clinically positive LN metastases (odds ratio [OR], 5.15; p=0.004) and LN metastases with ENEcong (OR, 3.75; p=0.009) were predictors of postoperative chemoradiotherapy. No patient in the primary RT group demonstrated late severe toxicity whereas three (2.8%), one (0.9%), and one (0.9%) patient in the surgery group showed grade 3 dysphagia, grade 3 xerostomia, and fatal oral cavity bleeding.ConclusionWe found no differences in OS, PFS, and LC between upfront RT and surgery in stage I–II hpv+OPC which warrants comparison through a prospective trial in the treatment de-escalation era. However, most early-stage hpv+OPC patients undergoing surgery received adjuvant (CC)RT. Pretreatment LN findings were prognostic and predictive for adjuvant treatment.

Assessment Criteria and Clinical Implications of Extranodal Extension in Head and Neck Cancer.

Tumor breaching the capsule of a lymph node is termed extranodal extension (ENE). It reflects aggressiveness of a tumor, creates anatomic challenges for disease clearance, and increases the risk of distant metastasis. Extranodal extension can be assessed on a pathology specimen, by radiology studies, and by clinical examination. Presence of ENE in a pathology specimen has long been considered a high-risk feature of disease progression and would ordinarily benefit from the addition of chemotherapy to adjuvant radiotherapy. Although the eighth edition of the Union for International Cancer Control/American Joint Committee on Cancer stage classification dichotomizes pathologic ENE according to its presence or absence, emerging evidence suggests that the extent of a pathologic ENE may provide additional value for risk stratification to guide adjuvant therapy. Recent data suggest that the prognostic importance of pathologic ENE is also applicable for HPV-associated head and neck squamous cell carcinoma. In addition, compelling data demonstrate that indisputable radiologic ENE is a powerful risk stratification tool to identify patients at high risk for treatment failure, especially distant metastasis, applicable for both HPV-positive and HPV-negative head and neck squamous cell carcinoma. However, the definition and taxonomy of radiologic ENE requires standardization. The goal of this review is to clarify the contemporary understanding of the prognostic implications of ENE in head and neck squamous cell carcinoma, present the nuances of what is presently known and unknown, and elucidate how to classify ENE pathologically and radiologically with an understanding of the strengths and weaknesses of each approach. Finally, with the development of several risk stratification methods, the relative role of ENE and other prognostic schema will be explored.

Prognostic Significance of Radiologic Extranodal Extension in Nasopharyngeal Cancer

ObjectiveThe aim of the present study was to evaluate the prognostic value of radiologic extranodal extension (rENE) in patients with nasopharyngeal cancer.Study DesignRetrospective review.SettingTertiary university hospital.MethodsWe identified patients with nasopharyngeal cancer and lymph node metastasis who underwent pretreatment neck computed tomography or magnetic resonance imaging and evaluated rENE from the involved lymph node. Univariate Kaplan‐Meier and multivariate Cox regression analyses were used to compare rENE+ and rENE– groups for local regional relapse–free survival, distant metastasis–free survival, and overall survival.ResultsOf 61 cases, 24 (39.3%) were rENE+ and 37 (60.7%) were rENE–. The median follow‐up was 65.5 months. The 5‐year distant metastasis–free survival and overall survival rates were lower in the rENE+ group than the rENE– group (70.8% vs 89.2%, P =. 016; 66.7% vs 89.2%, P =. 01, respectively). Differences in locoregional control between the groups were not significant (P =. 18). The 5‐year rates for local regional relapse–free survival were 87.5% for rENE+ and 91.9% for rENE–. In multivariate analysis, the presence of rENE was a significant independent adverse prognostic factor for distant metastasis–free survival and overall survival.ConclusionsWe showed that rENE is an independent prognostic factor for poor distant control and survival in patients with nasopharyngeal cancer.

Unambiguous advanced radiologic extranodal extension determined by MRI predicts worse outcomes in nasopharyngeal carcinoma: Potential improvement for future editions of N category systems

Background and purposeTo explore the prognostic value of different radiologic extranodal extension (rENE) grades and their potential improvement for the 8th edition N category in nasopharyngeal carcinoma (NPC). Materials and methodsFrom 2009 to 2013, a cohort of 1887 patients with NPC was retrospectively enrolled and randomized to the training (n = 955) and validation (n = 932) groups. rENE was categorized as follows: grade 0, nodes without rENE; grade 1, nodes with rENE infiltrating the surrounding fat only; grade 2, matted nodes; grade 3, nodes with rENE infiltrating adjacent structures. ResultsThe percentage of patients with MRI-positive cervical nodes was 66.5% (1254/1887), of whom grade 0, 1, 2 and 3 rENE cases accounted for 33.2% (416/1254), 14.9% (187/1254), 36.5% (458/1254) and 15.4% (193/1254), respectively. The kappa coefficients for the inter-rater and intra-rater assessments were 0.63, 0.51, 0.65 and 0.93, and 0.76, 0.69, 0.72 and 1.0 in grade 0, 1, 2 and 3 rENE, respectively. Grade 3 rENE rather than grades 0–2 rENE was an independent unfavorable predictor of overall survival and disease-free survival (P < 0.001). Recursive partitioning analysis was applied to refine the N category: eN0 (N0), eN1 (N1 without grade 3), eN2 (N2 without grade 3), and eN3 (N1/N2 with grade 3, N3). Compared to the current system, the proposed N category performed better in hazard consistency, hazard discrimination, sample size balance and outcome prediction. ConclusionGrade 3 rENE was an independent unfavorable indicator of NPC. Upstaging patients in N1-2 with grade 3 rENE to N3 led to a superior prognostic performance.

Prognostic value of clinical and radiologic extranodal extension and their role in the 8th edition TNM cN classification for HPV-negative oropharyngeal carcinoma.

We evaluate the performance between the TNM-8 versus TNM-7 cN-classification and explore the relative prognostic contribution of radiologic extranodal extension (rENE) for HPV-negative oropharyngeal cancer (HPV-OPC). All HPV- OPC treated with IMRT between 2005 and 2016 were included. cENE was defined as unambiguous "fixation" of a neck mass or "skin involvement" on clinical examination. rENE was recorded by re-reviewing pre-treatment CT/MR. Disease-free survival (DFS) stratified by cENE or rENE were compared. Multivariable analyses (MVA) calculated the adjusted hazard ratio (aHR) for the separate cENE and rENE attributes and their combination. A refined cN-category incorporating both cENE and rENE parameters was proposed. The performance of the revision was compared to TNM-8 and TNM-7. Of 361 HPV- OPC, 97 were cN0 and 264 were cN+ with 48 cENE+ and 72 rENE+ respectively. Median follow-up was 5.4years. The 3-year DFS was lower in cENE+ vs cENE-negative (cENE-) (23% vs 45%; aHR=1.68, p=0.008) and rENE+ vs rENE-negative (rENE-) patients (29% vs 45%; aHR=1.44, p=0.037). The cENE+/rENE+ subset had the worse DFS vs cENE-/rENE+ or cENE-/rENE- (24%/37%/46%, p=0.005). We propose a refined cN-category wherein any cENE-/rENE+ case is reclassified one N-stratum higher while any cENE+ case remains cN3b. The stage schema with the refined N-categorization outperformed TNM-8, and both outperformed TNM-7. cENE and rENE are both prognostic but the cENE+/rENE+ subset has the worst outcome. The TNM-8 cN-categories improves outcome prediction compared to the TNM-7. Incorporation of rENE into TNM-8 cN-categories may further augment performance.