Microscopic Extranodal Extension in HPV‐Negative Head and Neck Cancer and the Role of Adjuvant Chemoradiation

Abstract

Objective Pathologic extranodal extension (ENE) is an important adverse feature for human papillomavirus (HPV)–negative head and neck squamous cell carcinoma (HNSCC), but the prognostic significance of microscopic ENE (ENEmi) and role of adjuvant concurrent chemoradiation (CRT) for ENEmi remain unclear. This study evaluates (1) the prognostic significance of ENEmi in HPV-negative HNSCC and (2) whether adjuvant CRT is associated with improved overall survival (OS) for these patients. Study Design Retrospective cohort study. Setting Commission on Cancer (CoC)–accredited facilities. Methods This retrospective cohort study included patients in the National Cancer Database from 2009 to 2015 with pathologic node-positive (pN+) HPV-negative HNSCC with either pathologic ENEmi or no ENE who had undergone margin-negative surgery. The association of ENEmi with OS was evaluated using Cox proportional hazard analyses. Analyses were repeated in patients with ENEmi receiving adjuvant therapy to evaluate the association of adjuvant CRT with OS. Results We included 5483 patients with pN+ HPV-negative HNSCC, of whom 24% had ENEmi. On multivariable analysis, ENEmi was associated with decreased OS relative to no ENE (adjusted hazard ratio [aHR], 1.43; 95% CI, 1.28-1.59). Among patients with ENEmi who received ≥60 Gy of adjuvant radiation therapy (RT) (n = 617), adjuvant CRT was not associated with improved OS relative to RT (aHR, 0.91; 95% CI, 0.66-1.27). Conclusion For patients with HPV-negative HNSCC, pN+ with ENEmi is associated with worse OS than pN+ without ENE. However, for patients with ENEmi, concurrent CRT is not associated with improved OS relative to RT. The optimal adjuvant paradigm for ENEmi requires additional investigation.

Development and validation of a novel TNM staging N‐classification of oral cavity squamous cell carcinoma

“…Capturing the extent of ENE in N classification is important for two reasons. Several studies have demonstrated the unique prognosis of minor and major ENE subgroups 9–11,22,23 . The stratification of ENE into minor or major may also have therapeutic implications.…”

“…The stratification of ENE into minor or major may also have therapeutic implications. Two studies demonstrated that patients with minor ENE may not benefit from adjuvant chemoradiotherapy, unlike those with major ENE 10,11 . The recommendation by the ICCR to capture minor or major ENE as a core element in pathologic reporting of neck dissection specimens will result in additional real‐world data to validate the importance of this pathologic feature.…”

“…7 Recent studies have shown that major ENE is associated with a significantly worse outcome than minor ENE, suggesting that these two subgroups should be considered as separate entities. [8][9][10][11] Here, we re-evaluate several established nodal prognostic features of LNs while addressing limitations of TNM-8 for OSCC.…”

“…The International Collaboration of Cancer Reporting (ICCR) have emphasized the importance of classifying ENE as either minor (≤2 mm) or major (>2 mm) extension in the pathological reporting of neck dissection specimens 7 . Recent studies have shown that major ENE is associated with a significantly worse outcome than minor ENE, suggesting that these two subgroups should be considered as separate entities 8–11 . Here, we re‐evaluate several established nodal prognostic features of LNs while addressing limitations of TNM‐8 for OSCC.…”