Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Prognostic impact of extranodal extension (ENE) in surgically managed treatment-naive HPV-positive oropharyngeal squamous cell carcinoma with nodal metastasis


Extranodal extension (ENE) is a significant prognostic factor for human papilloma virus (HPV)-negative head and neck squamous cell carcinoma and is incorporated into AJCC 8th edition pN stage. It remains controversial whether ENE or the degree of ENE is prognostically relevant in HPV-positive oropharyngeal squamous cell carcinoma (OPSCC). A detailed clinicopathologic review was conducted in a large retrospective cohort of 232 surgically treated patients with HPV-positive OPSCC and nodal metastasis. Fifty-six patients (24%) had nodal metastasis with ENE. The median vertical extent of ENE was 2.9 mm (range 0.2–20.3 mm), and the median horizontal span of ENE was 2.5 mm (range: 0.3–14.0 mm). Comparing with patients without ENE, those with ENE were associated with a higher number of positive lymph nodes, lymphovascular invasion, perineural invasion, adjuvant chemotherapy, larger primary tumor size, and shorter follow up period. Patients with ENE had shortened overall survival (OS), disease specific survival (DSS), disease free survival (DFS), distant metastasis free survival (DMFS), and regional recurrence free survival (RRFS) on univariate survival analysis. The 5-year OS, DSS, and DFS were 95%, 97%, and 90% respectively for the group without ENE, and 64%, 71%, and 65% respectively for the group with ENE. On Multivariate survival analysis, the presence of ENE was an independent adverse prognostic factor for OS, DSS, and DFS. Additionally, major ENE defined as a vertical extent of ≥4 mm or irregular soft tissue deposit independently predicted shortened OS, DSS, and RFS. In conclusion, the presence of ENE, in particular major ENE, is an independent prognostic factor in HPV-positive OPSCC. Therefore, we propose to document the presence and extent of ENE for these tumors. Consideration may be given for AJCC 9th edition to include ENE into pN stage of HPV-positive OPSCC.

Your institute does not have access to this article

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: Extranodal extension (ENE) in HPV-positive oropharyngeal squamous cell carcinoma.
Fig. 2: The impacts of extranodal extension (ENE, top row) and the extent of ENE (bottom row) on survival.

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.


  1. Pfister, D. G., Spencer, S., Adelstein, D., Adkins, D., Brizel, D. M., Bruce, J. Y. et al. NCCN clinical practice guidelines in oncology: head and neck cancers. Version 3.2021, Accessed 12/21/2021, (2021).

  2. Puri, S. K., Fan, C. Y. & Hanna, E. Significance of extracapsular lymph node metastases in patients with head and neck squamous cell carcinoma. Curr Opin Otolaryngol Head Neck Surg 11, 119–123 (2003).

  3. Maxwell, J. H., Ferris, R. L., Gooding, W., Cunningham, D., Mehta, V., Kim, S. et al. Extracapsular spread in head and neck carcinoma: impact of site and human papillomavirus status. Cancer 119, 3302–3308 (2013).

  4. Mermod, M., Tolstonog, G., Simon, C. & Monnier, Y. Extracapsular spread in head and neck squamous cell carcinoma: A systematic review and meta-analysis. Oral Oncol 62, 60–71 (2016).

  5. Wreesmann, V. B., Katabi, N., Palmer, F. L., Montero, P. H., Migliacci, J. C., Gonen, M. et al. Influence of extracapsular nodal spread extent on prognosis of oral squamous cell carcinoma. Head & neck 38 Suppl 1, E1192–1199 (2016).

  6. Huang, S. H., Chernock, R., O’Sullivan, B. & Fakhry, C. Assessment Criteria and Clinical Implications of Extranodal Extension in Head and Neck Cancer. Am Soc Clin Oncol Educ Book 41, 265–278 (2021).

  7. Saliba, M., Ghossein, R. & Xu, B. HPV-related head and neck cancers: Pathology and biology. Journal of surgical oncology 124, 923–930 (2021).

  8. Kumar, B., Cipolla, M. J., Old, M. O., Brown, N. V., Kang, S. Y., Dziegielewski, P. T. et al. Surgical management of oropharyngeal squamous cell carcinoma: Survival and functional outcomes. Head & neck 38 Suppl 1, E1794–1802 (2016).

  9. Iyer, N. G., Dogan, S., Palmer, F., Rahmati, R., Nixon, I. J., Lee, N. et al. Detailed Analysis of Clinicopathologic Factors Demonstrate Distinct Difference in Outcome and Prognostic Factors Between Surgically Treated HPV-Positive and Negative Oropharyngeal Cancer. Ann Surg Oncol 22, 4411–4421 (2015).

  10. Klozar, J., Koslabova, E., Kratochvil, V., Salakova, M. & Tachezy, R. Nodal status is not a prognostic factor in patients with HPV-positive oral/oropharyngeal tumors. J Surg Oncol. 107, 625–633 (2013).

  11. Sinha, P., Lewis, J. S., Jr., Piccirillo, J. F., Kallogjeri, D. & Haughey, B. H. Extracapsular spread and adjuvant therapy in human papillomavirus-related, p16-positive oropharyngeal carcinoma. Cancer 118, 3519–3530 (2012).

  12. Lewis, J. S., Jr., Carpenter, D. H., Thorstad, W. L., Zhang, Q. & Haughey, B. H. Extracapsular extension is a poor predictor of disease recurrence in surgically treated oropharyngeal squamous cell carcinoma. Mod Pathol, 24, 1413–1420 (2011).

  13. Ho, A. S., Luu, M., Kim, S., Tighiouart, M., Mita, A. C., Scher, K. S. et al. Nodal staging convergence for HPV- and HPV+ oropharyngeal carcinoma. Cancer 127, 1590–1597 (2021).

  14. Gal, T. J., O’Brien, K. J., Chen, Q. & Huang, B. Clinical vs Microscopic Extranodal Extension and Survival in Oropharyngeal Carcinoma in the Human Papillomavirus Era. Otolaryngol Head Neck Surg. 162, 693–701 (2020).

  15. Day, A. T., Yang, A. M., Tanamal, P., Blackwell, J. M., Wang, E., Sumer, B. D. et al. Extracapsular extension, pathologic node status, and adjuvant treatment in primary surgery patients with human papillomavirus-mediated oropharyngeal cancer: National hospital-based retrospective cohort analysis. Head & neck 43, 3345–3363 (2021).

  16. Bauer, E., Mazul, A., Chernock, R., Rich, J., Jackson, R. S., Paniello, R. et al. Extranodal extension is a strong prognosticator in HPV-positive oropharyngeal squamous cell carcinoma. Laryngoscope 130, 939–945 (2020).

  17. Miccio, J. A., Verma, V., Kelly, J., Kann, B. H., An, Y., Park, H. S. et al. Impact of contralateral lymph nodal involvement and extranodal extension on survival of surgically managed HPV-positive oropharyngeal cancer staged with the AJCC eighth edition. Oral Oncol 99, 104447 (2019).

  18. Zhan, K. Y., Eskander, A., Kang, S. Y., Old, M. O., Ozer, E., Agrawal, A. A. et al. Appraisal of the AJCC 8th edition pathologic staging modifications for HPV-positive oropharyngeal cancer, a study of the National Cancer Data Base. Oral Oncol 73, 152–159 (2017).

  19. Benchetrit, L., Torabi, S. J., Givi, B., Haughey, B. & Judson, B. L. Prognostic Significance of Extranodal Extension in HPV-Mediated Oropharyngeal Carcinoma: A Systematic Review and Meta-analysis. Otolaryngol Head Neck Surg. 164, 720–732 (2021).

  20. Amin, M. B., Greene, F. L., Edge, S. B.,Compton, C.C., Greshenwald, J. E., Brookland, R. K. et al. AJCC Cancer Staging Manual. Eighth edition., (Springer Nature: New York, 2017).

  21. Seethala, R. R., Weinreb, I., Bullock, M. J., Calson, D. L., Ferris, R. L., Harrison, L. B. et al. Protocol for the Examination of Specimens From Patients With Cancers of the Pharynx Accessed 12/21/2021, (2021).

  22. Mamic, M., Lucijanic, M., Manojlovic, L., Muller, D., Suton, P. & Luksic, I. Prognostic significance of extranodal extension in oral cavity squamous cell carcinoma with occult neck metastases. Int J Oral Maxillofac Surg 50, 309–315 (2021).

  23. Ferris, R. L., Flamand, Y., Weinstein, G. S., Li, S., Quon, H., Mehra, R. et al. Transoral robotic surgical resection followed by randomization to low- or standard-dose IMRT in resectable p16+ locally advanced oropharynx cancer: A trial of the ECOG-ACRIN Cancer Research Group (E3311). Journal of Clinical Oncology 38, 6500–6500 (2020).

  24. Sinha, P., Kallogjeri, D., Gay, H., Thorstad, W. L., Lewis, J. S., Jr., Chernock, R. et al. High metastatic node number, not extracapsular spread or N-classification is a node-related prognosticator in transorally-resected, neck-dissected p16-positive oropharynx cancer. Oral Oncol 51, 514–520 (2015).

  25. Kompelli, A. R., Morgan, P., Li, H., Harris, W., Day, T. A. & Neskey, D. M. Prognostic Impact of High-Risk Pathologic Features in HPV-Related Oropharyngeal Squamous Cell Carcinoma and Tobacco Use. Otolaryngol Head Neck Surg. 160, 855–861 (2019).

  26. Kowalchuk, R. O., Van Abel, K. M., Yin, L. X., Garcia, J., Harmsen, W. S., Moore, E. J. et al. Correlation between radiographic and pathologic lymph node involvement and extranodal extension via CT and PET in HPV-associated oropharyngeal cancer. Oral Oncol 123, 105625 (2021).

  27. Zebolsky, A. L., George, E., Gulati, A., Wai, K. C., Carpenter, P., Van Zante, A. et al. Risk of Pathologic Extranodal Extension and Other Adverse Features After Transoral Robotic Surgery in Patients With HPV-Positive Oropharynx Cancer. JAMA Otolaryngol Head Neck Surg. 147, 1080–1088 (2021).

  28. Hararah, M. K., Stokes, W. A., Jones, B. L., Oweida, A., Ding, D., McDermott, J. et al. Nomogram for preoperative prediction of nodal extracapsular extension or positive surgical margins in oropharyngeal squamous cell carcinoma. Oral Oncol 83, 73–80 (2018).

  29. An, Y., Park, H. S., Kelly, J. R., Stahl, J. M., Yarbrough, W. G., Burtness, B. A. et al. The prognostic value of extranodal extension in human papillomavirus-associated oropharyngeal squamous cell carcinoma. Cancer 123, 2762–2772 (2017).

  30. Abdel-Halim, C. N., Rosenberg, T., Larsen, S. R., Høilund-Carlsen, P. F., Sørensen, J. A., Rohde, M. et al. Histopathological Definitions of Extranodal Extension: A Systematic Review. Head Neck Pathol 15, 599–607 (2021).

  31. van den Brekel, M. W., Lodder, W. L., Stel, H. V., Bloemena, E., Leemans, C. R. & van der Waal, I. Observer variation in the histopathologic assessment of extranodal tumor spread in lymph node metastases in the neck. Head & neck 34, 840–845 (2012).

  32. Waltonen, J. D., Thomas, S. G., Russell, G. B. & Sullivan, C. A. Oropharyngeal Carcinoma Treated with Surgery Alone: Outcomes and Predictors of Failure. Ann Otol Rhino Laryngol., 34894211021287 (2021).

  33. Freitag, J., Wald, T., Kuhnt, T., Gradistanac, T., Kolb, M., Dietz, A. et al. Extracapsular extension of neck nodes and absence of human papillomavirus 16-DNA are predictors of impaired survival in p16-positive oropharyngeal squamous cell carcinoma. Cancer 126, 1856–1872 (2020).

Download references


Research reported in this publication was supported in part by the Cancer Center Support Grant of the National Institutes of Health/National Cancer Institute under award number P30CA008748.

Author information

Authors and Affiliations



Study design and conception; BX, NK. Pathology and clinical review: BX, MS, BA, SD, RAG, NK. Database management and statistics: BX. Manuscript drafting: BX. Manuscript editing: MS, BA, MA, NL, NR, SGP, IG, SD, RAG, NK.

Corresponding author

Correspondence to Nora Katabi.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval

The study was approved by the institutional review board of MSKCC. All of the research meets the ethics guidelines, including adherence to the legal requirements of the country where the study was performed.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Xu, B., Saliba, M., Alzumaili, B. et al. Prognostic impact of extranodal extension (ENE) in surgically managed treatment-naive HPV-positive oropharyngeal squamous cell carcinoma with nodal metastasis. Mod Pathol (2022).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI:


Quick links