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Histopathological Definitions of Extranodal Extension: A Systematic Review

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Abstract

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.

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References

  1. Carter RL, et al. Transcapsular spread of metastatic squamous cell carcinoma from cervical lymph nodes. Am J Surg. 1985;150(4):495–9.

    Article  CAS  PubMed  Google Scholar 

  2. Jose J, et al. Cervical node metastases in squamous cell carcinoma of the upper aerodigestive tract: the significance of extracapsular spread and soft tissue deposits. Head Neck. 2003;25(6):451–6.

    Article  PubMed  Google Scholar 

  3. Willis RA. Epidermoid carcinoma of the head and neck, with special reference to metastasis. J Pathol Bacteriol. 1930;33(3):501–26.

    Article  Google Scholar 

  4. Bennett SH, et al. Prognostic significance of histologic host response in cancer of the larynx or hypopharynx. Cancer. 1971;28(5):1255–65.

    Article  CAS  PubMed  Google Scholar 

  5. Schuller DE, et al. The prognostic significance of metastatic cervical lymph nodes. Laryngoscope. 1980;90(4):557–70.

    Article  CAS  PubMed  Google Scholar 

  6. Grandi C, et al. Prognostic significance of lymphatic spread in head and neck carcinomas: therapeutic implications. Head Neck Surg. 1985;8(2):67–73.

    Article  CAS  PubMed  Google Scholar 

  7. Ferlito A, et al. Prognostic significance of microscopic and macroscopic extracapsular spread from metastatic tumor in the cervical lymph nodes. Oral Oncol. 2002;38(8):747–51.

    Article  PubMed  Google Scholar 

  8. Dunne AA, et al. Meta-analysis of the prognostic significance of perinodal spread in head and neck squamous cell carcinomas (HNSCC) patients. Eur J Cancer. 2006;42(12):1863–8.

    Article  CAS  PubMed  Google Scholar 

  9. Bernier J, et al. 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). Head Neck. 2005;27(10):843–50.

    Article  PubMed  Google Scholar 

  10. Snow GB, et al. Prognostic factors of neck node metastasis. Clin Otolaryngol Allied Sci. 1982;7(3):185–92.

    Article  CAS  PubMed  Google Scholar 

  11. Shaw RJ, et al. Extracapsular spread in oral squamous cell carcinoma. Head Neck. 2010;32(6):714–22.

    PubMed  Google Scholar 

  12. Brannan AG, Johnstone PA, Cooper J. Extracapsular tumor extension in cervical lymph nodes: reconciling the literature and seer data. Head Neck. 2011;33(4):525–8.

    Article  PubMed  Google Scholar 

  13. van den Brekel MW, et al. Observer variation in the histopathologic assessment of extranodal tumor spread in lymph node metastases in the neck. Head Neck. 2012;34(6):840–5.

    Article  PubMed  Google Scholar 

  14. Lewis JS Jr, et al. Inter- and intra-observer variability in the classification of extracapsular extension in p16 positive oropharyngeal squamous cell carcinoma nodal metastases. Oral Oncol. 2015;51(11):985–90.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Fleiss JL. Statistical methods for rates and proportions. In: Shewart WA, Wilks SS, editors. Wiley series in probability and statistics. Hoboken: Wiley; 2003. p. 761–768.

    Google Scholar 

  16. Aiken AH, et al. Accuracy of preoperative imaging in detecting nodal extracapsular spread in oral cavity squamous cell carcinoma. AJNR Am J Neuroradiol. 2015;36(9):1776–811.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Almulla A, et al. Radiologic-pathologic correlation of extranodal extension in patients with squamous cell carcinoma of the oral cavity: implications for future editions of the TNM classification. Int J Radiat Oncol Biol Phys. 2018;102(4):698–708.

    Article  PubMed  Google Scholar 

  18. Boeve K, et al. Addition of tumour infiltration depth and extranodal extension improves the prognostic value of the pathological TNM classification for early-stage oral squamous cell carcinoma. Histopathology. 2019;75(3):329–37.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Bullock MJ. Current challenges in the staging of oral cancer. Head Neck Pathol. 2019;13(3):440–8.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Bullock MJ, et al. 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. 2019;143(4):452–62.

    Article  CAS  PubMed  Google Scholar 

  21. Coatesworth AP, MacLennan K. Squamous cell carcinoma of the upper aerodigestive tract: the prevalence of microscopic extracapsular spread and soft tissue deposits in the clinically N0 neck. Head Neck. 2002;24(3):258–61.

    Article  PubMed  Google Scholar 

  22. Cole I, Hughes L. The relationship of cervical lymph node metastases to primary sites of carcinoma of the upper aerodigestive tract: a pathological study. Aust N Z J Surg. 1997;67(12):860–5.

    Article  CAS  PubMed  Google Scholar 

  23. Crescenzi D, et al. TNM classification of the oral cavity carcinomas: some suggested modifications. Otolaryngol Pol. 2015;69(4):18–27.

    PubMed  Google Scholar 

  24. de Juan J, et al. Inclusion of extracapsular spread in the pTNM classification system: a proposal for patients with head and neck carcinoma. JAMA Otolaryngol Head Neck Surg. 2013;139(5):483–8.

    Article  PubMed  Google Scholar 

  25. Fletcher KT, et al. Prognostic indicators and survival in salvage surgery for laryngeal cancer. Head Neck. 2017;39(10):2021–6.

    Article  PubMed  Google Scholar 

  26. Garcia J, et al. Validation of the pathological classification of lymph node metastasis for head and neck tumors according to the 8th edition of the TNM Classification of Malignant Tumors. Oral Oncol. 2017;70:29–33.

    Article  PubMed  Google Scholar 

  27. Hirabayashi H, et al. Extracapsular spread of squamous cell carcinoma in neck lymph nodes: prognostic factor of laryngeal cancer. Laryngoscope. 1991;101(5):502–6.

    Article  CAS  PubMed  Google Scholar 

  28. Huang DT, et al. Postoperative radiotherapy in head and neck carcinoma with extracapsular lymph node extension and/or positive resection margins: a comparative study. Int J Radiat Oncol Biol Phys. 1992;23(4):737–42.

    Article  CAS  PubMed  Google Scholar 

  29. Huang SH, et al. Patterns of failure and histopathologic outcome predictors following definitive radiotherapy and planned neck dissection with residual disease. Head Neck. 2012;34(7):913–22.

    Article  PubMed  Google Scholar 

  30. Ishii J, et al. Ultrasonography and computed tomography of extracapsular invasion in cervical lymph nodes of squamous cell carcinoma in the oral cavity. J Med Ultrason. 2004;31(2):75–9.

    Article  Google Scholar 

  31. Kehrl W, Wenzel S, Niendorf A. Effect of various forms of metastatic lymph node involvement on prognosis of squamous epithelial carcinomas of the upper aerodigestive tract. Laryngorhinootologie. 1998;77(10):569–75.

    Article  CAS  PubMed  Google Scholar 

  32. Krstevska V. Evolution of treatment and high-risk features in resectable locally advanced head and neck squamous cell carcinoma with special reference to extracapsular extension of nodal disease. J BUON. 2015;20(4):943–53.

    PubMed  Google Scholar 

  33. Lewis JS Jr, et al. Extracapsular extension is a poor predictor of disease recurrence in surgically treated oropharyngeal squamous cell carcinoma. Mod Pathol. 2011;24(11):1413–20.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Lodder WL, et al. Can extranodal spread in head and neck cancer be detected on MR imaging. Oral Oncol. 2013;49(6):626–33.

    Article  PubMed  Google Scholar 

  35. Lop J, et al. Prognostic significance of extranodal extension in head and neck squamous cell carcinoma cN0 patients with occult metastatic neck nodes. Acta Otorrinolaringol Esp. 2018;69(3):156–64.

    Article  Google Scholar 

  36. Lydiatt WM, et al. Head and Neck cancers-major changes in the American Joint Committee on cancer eighth edition cancer staging manual. CA Cancer J Clin. 2017;67(2):122–37.

    Article  PubMed  Google Scholar 

  37. Majercakova K, et al. Postoperative staging of the neck dissection using extracapsular spread and lymph node ratio as prognostic factors in HPV-negative head and neck squamous cell carcinoma patients. Oral Oncol. 2018;77:37–42.

    Article  PubMed  Google Scholar 

  38. Maxwell JH, et al. Accuracy of computed tomography to predict extracapsular spread in p16-positive squamous cell carcinoma. Laryngoscope. 2015;125(7):1613–8.

    Article  PubMed  Google Scholar 

  39. Mermod M, et al. Correlation between podoplanin expression and extracapsular spread in squamous cell carcinoma of the oral cavity using subjective immunoreactivity scores and semiquantitative image analysis. Head Neck. 2017;39(1):98–108.

    Article  PubMed  Google Scholar 

  40. Mermod M, et al. Extracapsular spread in head and neck squamous cell carcinoma: a systematic review and meta-analysis. Oral Oncol. 2016;62:60–71.

    Article  PubMed  Google Scholar 

  41. Michikawa C, et al. Epidermal growth factor receptor gene copy number aberration at the primary tumour is significantly associated with extracapsular spread in oral cancer. Br J Cancer. 2011;104(5):850–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Noor A, et al. Predictive value of computed tomography in identifying extracapsular spread of cervical lymph node metastases in p16 positive oropharyngeal squamous cell carcinoma. J Med Imaging Radiat Oncol. 2019;63(4):500–9.

    Article  PubMed  Google Scholar 

  43. Park YM, et al. Does p16+ predict a favorable prognosis for oropharyngeal cancer? risk factors for treatment failure for patients who underwent surgery-based therapy. Ann Surg Oncol. 2019;26(2):547–54.

    Article  PubMed  Google Scholar 

  44. Pilborough AE, Lambert DW, Khurram SA. Extranodal extension in oral cancer: a role for the nodal microenvironment? J Oral Pathol Med. 2019;48(10):863–70.

    Article  PubMed  Google Scholar 

  45. Prim MP, et al. Extracapsular spread and desmoplastic pattern in neck lymph nodes: two prognostic factors of laryngeal cancer. Ann Otol Rhinol Laryngol. 1999;108(7 Pt 1):672–6.

    Article  CAS  PubMed  Google Scholar 

  46. Rajappa SK, et al. Extracapsular extension in oral cavity cancers-predictive factors and impact on recurrence pattern and survival. Int J Oral Maxillofac Surg. 2019;48(8):989–94.

    Article  CAS  PubMed  Google Scholar 

  47. Saito Y, et al. Prognostic value of lymphovascular invasion of the primary tumor in hypopharyngeal carcinoma after total laryngopharyngectomy. Head Neck. 2017;39(8):1535–43.

    Article  PubMed  Google Scholar 

  48. Sandulache VC, et al. High-risk TP53 mutations are associated with extranodal extension in oral cavity squamous cell carcinoma. Clin Cancer Res. 2018;24(7):1727–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Shevach J, et al. Extracapsular extension is associated with worse distant control and progression-free survival in patients with lymph node-positive human papillomavirus-related oropharyngeal carcinoma. Oral Oncol. 2017;74:56–61.

    Article  PubMed  Google Scholar 

  50. Shingaki S, et al. The impact of extranodal spread of lymph node metastases in patients with oral cancer. Int J Oral Maxillofac Surg. 1999;28(4):279–84.

    Article  CAS  PubMed  Google Scholar 

  51. Steinkamp HJ, et al. Extracapsular neoplastic spread of cervical lymph node metastasis: Diagnostic value of computed tomography. Rofo. 1999;170(5):457–62.

    Article  CAS  PubMed  Google Scholar 

  52. Taghavi N, Yazdi I. Prognostic factors of survival rate in oral squamous cell carcinoma: clinical, histologic, genetic and molecular concepts. Arch Iran Med. 2015;18(5):314–9.

    PubMed  Google Scholar 

  53. Violaris NS, et al. Soft tissue cervical metastases of squamous carcinoma of the head and neck. Clin Otolaryngol Allied Sci. 1994;19(5):394–9.

    Article  CAS  PubMed  Google Scholar 

  54. Woolgar JA. Detailed topography of cervical lymph-note metastases from oral squamous cell carcinoma. Int J Oral Maxillofac Surg. 1997;26(1):3–9.

    Article  CAS  PubMed  Google Scholar 

  55. Woolgar JA, et al. Pathological findings in clinically false-negative and false-positive neck dissections for oral carcinoma. Ann R Coll Surg Engl. 1994;76(4):237–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Wreesmann VB, et al. Influence of extracapsular nodal spread extent on prognosis of oral squamous cell carcinoma. Head Neck. 2016;38(Suppl 1):E1192–E1199199.

    Article  PubMed  Google Scholar 

  57. Yamada S, et al. Evaluation of the level of progression of extracapsular spread for cervical lymph node metastasis in oral squamous cell carcinoma. Int J Oral Maxillofac Surg. 2016;45(2):141–6.

    Article  CAS  PubMed  Google Scholar 

  58. Agarwal JP, et al. Extranodal extension in resected oral cavity squamous cell carcinoma: more to it than meets the eye. Laryngoscope. 2019;129(5):1130–6.

    Article  PubMed  Google Scholar 

  59. Apisarnthanarax S, et al. Determining optimal clinical target volume margins in head-and-neck cancer based on microscopic extracapsular extension of metastatic neck nodes. Int J Radiat Oncol Biol Phys. 2006;64(3):678–83.

    Article  PubMed  Google Scholar 

  60. Corby MR, et al. A novel radiographic grading system to evaluate extranodal extension in regional nodal metastases from head and neck squamous cell carcinoma. Int J Radiat Oncol Biol Phys. 2018;100(5):1359–1359.

    Article  Google Scholar 

  61. extraCarpenter DH, et al. Extracapsular extension in oropharyngeal squamous cell carcinoma: only soft tissue metastasis predicts disease recurrence but does so independent of HPV status. Mod Pathol. 2010;23:273a–.

    Google Scholar 

  62. Ghadjar P, et al. Quantitative analysis of extracapsular extension of metastatic lymph nodes and its significance in radiotherapy planning in head and neck squamous cell carcinoma. Int J Radiat Oncol Biol Phys. 2010;76(4):1127–32.

    Article  PubMed  Google Scholar 

  63. Jose J, Coatesworth AP, MacLennan K. Cervical metastases in upper aerodigestive tract squamous cell carcinoma: histopathologic analysis and reporting. Head Neck. 2003;25(3):194–7.

    Article  PubMed  Google Scholar 

  64. Jose J, et al. Soft tissue deposits in neck dissections of patients with head and neck squamous cell carcinoma: prospective analysis of prevalence, survival, and its implications. Arch Otolaryngol Head Neck Surg. 2004;130(2):157–60.

    Article  PubMed  Google Scholar 

  65. Kwon M, et al. Extranodal extension and thickness of metastatic lymph node as a significant prognostic marker of recurrence and survival in head and neck squamous cell carcinoma. J Craniomaxillofac Surg. 2015;43(6):769–78.

    Article  PubMed  Google Scholar 

  66. Lodder WL, et al. Detection of extranodal spread in head and neck cancer with [18F] FDG PET and MRI: improved accuracy? Q J Nucl Med Mol Imaging. 2015;59(3):327–35.

    CAS  PubMed  Google Scholar 

  67. Matos LL, et al. External validation of the AJCC Cancer Staging Manual, 8th edition, in an independent cohort of oral cancer patients. Oral Oncol. 2017;71:47–53.

    Article  PubMed  Google Scholar 

  68. Michikawa C, et al. Small size of metastatic lymph nodes with extracapsular spread greatly impacts treatment outcomes in oral squamous cell carcinoma patients. Int J Oral Maxillofac Surg. 2018;47(7):830–5.

    Article  CAS  PubMed  Google Scholar 

  69. Moor JW, et al. Upper aerodigestive tract squamous cell carcinoma: distribution of extracapsular spread and soft tissue deposits in the neck. Acta Otolaryngol. 2004;124(1):97–101.

    Article  PubMed  Google Scholar 

  70. Prabhu RS, et al. Extent of pathologic extracapsular extension and outcomes in patients with nonoropharyngeal head and neck cancer treated with initial surgical resection. Cancer. 2014;120(10):1499–506.

    Article  PubMed  Google Scholar 

  71. Prabhu RS, et al. Accuracy of computed tomography for predicting pathologic nodal extracapsular extension in patients with head-and-neck cancer undergoing initial surgical resection. Int J Radiat Oncol Biol Phys. 2014;88(1):122–9.

    Article  PubMed  Google Scholar 

  72. Sinha P, et al. Soft tissue metastasis in p16-positive oropharynx carcinoma: prevalence and association with distant metastasis. Oral Oncol. 2015;51(8):778–86.

    Article  PubMed  Google Scholar 

  73. Sinha P, et al. Extracapsular spread and adjuvant therapy in human papillomavirus-related, p16-positive oropharyngeal carcinoma. Cancer. 2012;118(14):3519–30.

    Article  CAS  PubMed  Google Scholar 

  74. Steinkamp HJ, et al. Extracapsular spread of cervical lymph node metastases: diagnostic value of magnetic resonance imaging. Rofo. 2002;174(1):50–5.

    Article  CAS  PubMed  Google Scholar 

  75. Wenzel S, et al. A new histological scheme for the evaluation of cervical lymph node metastases in squamous cell carcinoma of the head and neck. Laryngo-Rhino-Otologie. 1998;77(11): 657–62.

    Article  Google Scholar 

  76. Wenzel S, Koch U. Squamous cell carcinomas of the upper aerodigestive tract. Prognostic significance of the capsular rupture and extracapsular spread of lymph node metastases. HNO. 2004;52(9):783–9.

    Article  CAS  PubMed  Google Scholar 

  77. Wenzel S, et al. Capsular rupture of lymph node metastases as most significant prognostic factor in head and neck squamous cell Carcinomas–Hamburg experiences. Laryngorhinootologie. 2003;82(10):707–12.

    Article  CAS  PubMed  Google Scholar 

  78. Yamada SI, et al. Progression level of extracapsular spread and tumor budding for cervical lymph node metastasis of OSCC. Clin Oral Investig. 2018;22(3):1311–8.

    Article  PubMed  Google Scholar 

  79. Woolgar JA, Triantafyllou A. Pitfalls and procedures in the histopathological diagnosis of oral and oropharyngeal squamous cell carcinoma and a review of the role of pathology in prognosis. Oral Oncol. 2009;45(4–5):361–85.

    Article  PubMed  Google Scholar 

  80. Brierley J, Wittekind C, Gospodarowicz MK. TNM classification of malignant tumours. 8th ed. New Jersey: Wiley Blackwell; 2017.

    Google Scholar 

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Funding

The study was funded by the University of Southern Denmark, the Region of Southern Denmark, Odense University Hospital, and the Harboe fund.

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Authors and Affiliations

  1. Department of ORL – Head and Neck Surgery and Audiology, Odense University Hospital, J. B. Winsløws Vej 4, 5000, Odense, Denmark

    Chadi Nimeh Abdel-Halim, Tine Rosenberg, Max Rohde & Christian Godballe

  2. Department of Pathology, Odense University Hospital, J. B. Winsløws Vej 4, 5000, Odense, Denmark

    Stine Rosenkilde Larsen

  3. Department of Nuclear Medicine, Odense University Hospital, Kløvervænget 47, 5000, Odense, Denmark

    Poul Flemming Høilund-Carlsen

  4. Department of Plastic Surgery, Odense University Hospital, J. B. Winsløws Vej 4, 5000, Odense, Denmark

    Jens Ahm Sørensen

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  1. Chadi Nimeh Abdel-Halim
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Correspondence to Chadi Nimeh Abdel-Halim.

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Abdel-Halim, C.N., Rosenberg, T., Larsen, S.R. et al. Histopathological Definitions of Extranodal Extension: A Systematic Review. Head and Neck Pathol 15, 599–607 (2021). https://doi.org/10.1007/s12105-020-01221-4

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