Histopathological Definitions of Extranodal Extension: A Systematic Review

Head Neck Pathol. 2021 Jun;15(2):599-607. doi: 10.1007/s12105-020-01221-4. Epub 2020 Sep 12.


Extranodal extension (ENE) is a very strong prognostic factor in head and neck squamous cell carcinoma. However, significant variance in reported incidence of ENE suggests discordance in perception of ENE among pathologists. This study aims to map the different definitions of histopathological ENE used in the literature. A systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement. Guided by the research question: "How is histopathological ENE defined?" the databases Medline, Embase, and Cochrane were systematically searched. All retrieved studies were reviewed and qualitatively analyzed. Three categories of existing definitions were formed. The systematic literature search yielded 1786 studies after removal of duplicates. Nine hundred and thirty-four full text articles were assessed for inclusion and 44 unique ENE definitions were identified and categorized 1-3; (1) simple definitions only describing a breach in the capsule (48%), (2) definitions also including a description of the perinodal tissue (43%), and (3) definitions adding a description of a specific reaction in the perinodal structure (9%). No consensus definition of ENE exists, but based on the level of details in the identified definitions, three overall categories of ENE definitions were established.

Keywords: Definition; Extracapsular; Extranodal extension; HPV; Head and neck cancer; Head and neck squamous cell carcinoma; Hypopharynx; Larynx; Lymph node; Metastasis; Oral cavity; Oropharynx; Perinodal; p16.

Publication types

  • Systematic Review

MeSH terms

  • Extranodal Extension / pathology*
  • Humans
  • Pathology, Clinical / standards*
  • Squamous Cell Carcinoma of Head and Neck / pathology*