PURPOSE: Extranodal extension (ENE) increases the risk of recurrence and death in head and neck squamous cell carcinoma (HNSCC) patients and is an indication for treatment escalation. Histopathology forms the mainstay of diagnosing ENE. There is substantial variation in the diagnosis of ENE and related terminology. Harmonising the diagnostic criteria for ENE was identified as a priority by the Head and Neck Consensus Language for Ease of Reproducibility (HN CLEAR) Steering Committee and its global stakeholders. METHODS: An international working group including 16 head and neck pathologists from eight countries across five continents evaluated whole slide images of haematoxylin and eosin-stained sections depicting potential diagnostic problems through nine virtual meetings to develop consensus guidelines. RESULTS: ENE should be diagnosed only when viable carcinoma extends through the primary lymph node (LN) capsule and directly interacts with the extranodal host environment with or without desmoplastic stromal response. Identifying the original LN capsule and reconstruction of its contour can assist in the detection and assessment of ENE. The term matting is recommended for confluence of two or more nodes due to histologically identifiable tumour extending from one LN to another. Matting constitutes major form of ENE. On the other hand, the terms fusion/adhesion/confluence/conglomeration and other synonyms of adhesion should be limited to confluence due to fibrosis or inflammation without histologically identifiable tumour between involved lymph nodes. Tumour extension along narrow needle tracks or spillage of cyst contents following an FNA do not constitute ENE. CONCLUSIONS: The consensus recommendations encompassing the definition of ENE, macroscopic and histologic examination of lymph nodes (LN) and practical guidelines for handling challenging cases are provided.

ACT Pathology Canberra Health Services Canberra Australia

Department of Anatomic and Molecular Pathology Massachusetts General Hospital Harvard Medical School Boston MA USA

Department of Mathematics and Statistics University of Sydney Sydney Australia

Department of Pathology All India Institute of Medical Sciences New Delhi Delhi India

Department of Pathology and Immunology Washington University School of Medicine Saint Louis MO USA

Department of Pathology Faculty of Medicine Dalhousie University Halifax Nova Scotia Canada

Department of Pathology NSW Health Pathology Westmead Hospital Sydney NSW Australia

Department of Pathology Rajiv Gandhi Cancer Institute and Research Centre New Delhi India

Department of Pathology Rigshospitalet Copenhagen University Hospital Copenhagen Denmark

Department of Pathology Tata Memorial Center Homi Bhabha National Institute Mumbai Maharashtra India

Department of Pathology University of Pittsburgh Pittsburgh Pennsylvania USA

Department of Pathology Yonsei University College of Medicine Severance Hospital Seoul Korea

Department of Radiation Oncology Princess Margaret Cancer Centre University of Toronto Toronto ON Canada

Department of Tissue Pathology and Diagnostic Oncology Royal Prince Alfred Hospital NSW Health Pathology Sydney NSW Australia

Faculty of Medicine and Health University of Sydney Sydney NSW Australia

Institute of Pathology Faculty of Medicine University of Ljubljana Ljubljana Slovenia

NHMRC Center of Research Excellence for Applied Innovations in Oral Cancer Sydney NSW Australia

School of Medicine and Psychology ANU College of Science and Medicine Canberra Australia

The Fingerland Department of Pathology Charles University Faculty of Medicine in Hradec Kralove Hradec Kralove Czech Republic

The Fingerland Department of Pathology University Hospital Hradec Kralove Hradec Kralove Czech Republic

Tissue Pathology and Diagnostic Oncology Royal Prince Alfred Hospital| NSW Health Pathology Building 12 Missenden Road Camperdown NSW 2050 Australia

University of Sydney Central Clinical School Royal Prince Alfred Hospital Building 12 Missenden Road Camperdown NSW 2050 Australia

Head Neck Pathol. 2025 Mar 19;19(1):36. doi: 10.1007/s12105-025-01772-4. PubMed

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Bernier J, Cooper JS, Pajak TF et al (2005) Defining risk levels in locally advanced head and neck cancers: a comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (# 9501). 10.1002/hed.20279. Head Neck PubMed

Johnson JT, Barnes EL, Myers EN et al (1981) The extracapsular spread of tumors in cervical node metastasis. Arch Otolaryngol. 10.1001/archotol.1981.00790480001001 PubMed

Olsen KD, Caruso M, Foote RL et al (1994) Primary head and neck cancer. Histopathologic predictors of recurrence after neck dissection in patients with lymph node involvement. Arch Otolaryngol Head Neck Surg. 10.1001/archotol.1994.01880360066012 PubMed

Maxwell JH, Ferris RL, Gooding W et al (2013) Extracapsular spread in head and neck carcinoma: impact of site and human papillomavirus status. Cancer Https. 10.1002/cncr.28169 PubMed

Amin MB, Edge SB, Greene FL et al (2017) AJCC Cancer Staging Manual. Springer, Chicago

Ho AS, Luu M, Kim S et al (2021) Nodal staging convergence for HPV– and HPV + oropharyngeal carcinoma. Cancer Https. 10.1002/cncr.33414 PubMed

Huang SH, O’Sullivan B, Su J et al (2020) Prognostic importance of radiologic extranodal extension in HPV-positive oropharyngeal carcinoma and its potential role in refining TNM-8 cN-classification. Radiother Oncol. 10.1016/j.radonc.2019.10.011 PubMed

Cooper JS, Zhang Q, Pajak TF et al (2012) Long-term follow-up of the RTOG 9501/intergroup phase III trial: postoperative concurrent radiation therapy and chemotherapy in high-risk squamous cell carcinoma of the head and neck. Int J Radiat Oncol Biol Phys Https. 10.1016/j.ijrobp.2012.05.008 PubMed PMC

Rosenthal DI, Mohamed ASR, Garden AS et al (2017) Final report of a prospective Randomized Trial to evaluate the dose-response relationship for postoperative Radiation Therapy and pathologic risk groups in patients with Head and Neck Cancer. Int J Radiat Oncol Biol Phys Https. 10.1016/j.ijrobp.2017.02.218 PubMed PMC

Abdel-Halim CN, Rosenberg T, Dyrvig A et al (2021) Diagnostic accuracy of imaging modalities in detection of histopathological extranodal extension: a systematic review and meta-analysis. Oral Oncol. 10.1016/j.oraloncology.2020.105169 PubMed

Lewis JS Jr, Tarabishy Y, Luo J et al (2015) Inter- and intra-observer variability in the classification of extracapsular extension in p16 positive oropharyngeal squamous cell carcinoma nodal metastases. Oral Oncol. 10.1016/j.oraloncology.2015.08.003 PubMed PMC

Yamada S, Yanamoto S, Otani S et al (2016) Evaluation of the level of progression of extracapsular spread for cervical lymph node metastasis in oral squamous cell carcinoma. Int J Oral Maxillofac Surg. 10.1016/j.ijom.2015.09.005 PubMed

Abdel-Halim CN, Rohde M, Larsen SR et al (2022) Inter- and intrarater reliability and agreement among Danish Head and Neck pathologists assessing Extranodal Extension in Lymph Node metastases from Oropharyngeal Squamous Cell Carcinomas. 10.1007/s12105-022-01468-z. Head Neck Pathol PubMed PMC

Gupta R, Bal M, Bishop JA et al (2023) HN-CLEAR: Head and Neck Consensus Language for Ease and Reproducibility, a Multidisciplinary Consensus mechanism for Head and Neck Pathology. 10.1007/s12105-023-01570-w. Head Neck Pathol PubMed PMC

Arakawa N, Bader LR (2022) Consensus development methods: considerations for national and global frameworks and policy development. Res Social Adm Pharm Https. 10.1016/j.sapharm.2021.06.024 PubMed

Bullock MJ, Beitler JJ, Carlson DL et al (2019) Data set for the reporting of nodal excisions and Neck dissection specimens for Head and Neck tumors: explanations and recommendations of the guidelines from the International collaboration on Cancer Reporting. Arch Pathol Lab Med. 10.5858/arpa.2018-0421-SA PubMed

Abou-Foul AK, Henson C, Chernock RD et al (2024) Standardised definitions and diagnostic criteria for extranodal extension detected on histopathological examination in head and neck cancer: Head and Neck Cancer International Group consensus recommendations. Lancet Oncol. 10.1016/S1470-2045(24)00143-8 PubMed

Abdel-Halim CN, Rosenberg T, Larsen SR et al (2021) Histopathological definitions of Extranodal Extension: a systematic review. Head Neck Pathol Https. 10.1007/s12105-020-01221-4 PubMed PMC

Bullock M, Carlson DL, Fonseca I et al (2024) Nodal Excisions and Neck Dissection Specimens for Head and Neck Tumours Histopathology Reporting Guide. 2nd edition. International Collaboration on Cancer Reporting, Sydney PubMed

Ferris RL, Flamand Y, Weinstein GS et al (2021) Phase II randomized trial of Transoral surgery and low-dose intensity modulated Radiation Therapy in Resectable p16 + locally Advanced Oropharynx Cancer: an ECOG-ACRIN Cancer Research Group Trial (E3311). J Clin Oncol. 10.1200/JCO.21.01752 PubMed PMC