• Users Online: 688
  • Print this page
  • Email this page

 Table of Contents  
Year : 2022  |  Volume : 3  |  Issue : 1  |  Page : 24-27

Stage migration in head-and-neck cancers due to extranodal extension: Clinical experience from a tertiary care centre

1 Department of Radiation Oncology, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India
2 Department of Radiation Oncology, Maharshi Markandeshwar Institute of Medical Sciences and Research, Ambala, Haryana, India

Date of Submission20-Feb-2021
Date of Decision16-Jun-2021
Date of Acceptance06-Nov-2021
Date of Web Publication28-Apr-2022

Correspondence Address:
Dr. Rajesh Pasricha
Department of Radiation Oncology, Vth Floor, Collage Building, All India Institute of Medical Sciences, Rishikesh, Uttarakhand
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/JME.JME_76_20

Rights and Permissions

Background: Extranodal extension (ENE) has been included as a factor for the staging of head-and-neck cancer (HNC) considering its prognostic value. Aim: The present study aimed to find out the percentage of patients with HNC getting upstaged because of ENE and their treatment outcome. Patients and Methods: A retrospective analysis of all patients with HNC registered in the Department of Radiation Oncology, All India Institute of Medical Sciences, Rishikesh, India, between January 2018 and January 2019. American Joint Committee on Cancer (AJCC) criteria were used for defining clinical and radiological ENE. The site, subsite, stage and presence of ENE were documented. The clinical outcome of all these patients was collected and analysed. Results: A total of 562 patients were registered with HNC. Among them 45 patients were identified to have ENE (8%). The majority of the cases were oral cavity (44.4%) and oropharyngeal tumours (26.8%). Thirty-three patients had clinically documented ENE and 11 were radiological and one patient had pathological ENE. Among those who got upstaged to N3b disease due to ENE, 29 patients (64.4%) had N2 disease as per the 7th edition AJCC. When stage grouping was considered, 28 patients (62.2%) who got upstaged had stage Isovaleric acidaemia (IVA) disease as per the AJCC 7th Edition. Twelve patients were treated with radical intent and 16 received palliative treatment and rest did not complete the treatment or defaulted. Overall, the outcomes of these patients remained poor. Conclusion: A significant proportion of HNC patients got upstaged when ENE was included in the staging. Patients with ENE had a poor prognosis irrespective of the treatment modality.

Keywords: Extranodal extension, head-and-neck cancer, nodal metastasis, staging, treatment

How to cite this article:
Joseph D, Pandey L, Pasricha R, Raut S, Yanpothung Y, Ibrahim A, Gupta M. Stage migration in head-and-neck cancers due to extranodal extension: Clinical experience from a tertiary care centre. J Med Evid 2022;3:24-7

How to cite this URL:
Joseph D, Pandey L, Pasricha R, Raut S, Yanpothung Y, Ibrahim A, Gupta M. Stage migration in head-and-neck cancers due to extranodal extension: Clinical experience from a tertiary care centre. J Med Evid [serial online] 2022 [cited 2023 Jun 3];3:24-7. Available from: http://www.journaljme.org/text.asp?2022/3/1/24/344297

  Introduction Top

Head-and-neck cancer (HNC) is one of the common malignancies in the Indian population. As per the GLOBOCAN data, lip and oral cavity constitutes the second most common malignancy in men and third most common cancer overall in India.[1] The staging of an accurate tumour nodal metastasis is important for optimal treatment. The presence of lymph nodal metastasis is one of the most significant prognostic factors in defining the outcome of HNC. Extracapsular extension (ECE) was well-known to be a prognostic factor in HNC squamous cell carcinomas for many years. This has recently been renamed as extranodal extension (ENE). Many reports were recommending its formal inclusion in the staging of HNC considering the prognostic value.[2]

ENE was officially included as a part of staging in the American Joint Committee on Cancer (AJCC) in its Eighth Edition.[3] Histopathological examination is the gold standard in determining ENE in HNC. The ability of radiological evaluation and clinical examination to determine the presence of ENE unequivocally remains inferior to microscopic examination to date. The follow-up imaging is necessary to evaluate the treatment response and recurrence of nodal metastasis in the patients with HNC. Residual tumour needs to be differentiated from degenerated tissue, particularly after chemo-radiotherapy.[4]

Even though prognostic significance of ENE has been well described, being a recent inclusion in AJCC, literature on stage migration is lacking, especially from India. Hence, this study was designed with a rationale to identify the percentage of such an upstaging and its relative treatment outcome.

  Subjects and Methods Top

Study design and setting

This was a retrospective study conducted at the Department of Radiation Oncology, All India Institute of Medical Sciences, Rishikesh, India. The department maintains comprehensive treatment records of all patients who are registered with us.

Study population included all HNC patients treated in our department during January 2018 to January 2019. The treatment records of all HNC patients treated between this time period were collected. Among them, the patients with ENE were identified. Epidemiological data of those with ENE were obtained from the hospital records. AJCC criteria used for the classification into ENE were divided into either clinical, radiological or pathological and the exact criteria were noted from records. Data on the site and size of primary tumour were obtained and described. For those with N3B disease, nodal staging was done also as per the 7th edition of AJCC. Treatment details of each patient with ENE and their follow-up data were checked. Data were collected in Microsoft Excel. A written consent was obtained from all patients for the use of their data for research purpose.

  Results Top

Out of 562 patients registered with HNC during the study period, 45 (8%) patients were identified to have ENE. The median age of the patients was 60 years. There were 38 males and 7 females. Patient characteristics are described in [Table 1]. The majority of the cases were oral cavity (44.4%) and oropharyngeal tumours (26.8%). Tumour size varied from 1.5 to 8 cm with an average of 4.8 cm. Lymph nodal size varied from 1.5 to 11 cm, with an average of 5.56 cm. The majority of the patient (44.4%) had T4a disease. Out of 45 patients, 33 patients had clinical, 11 had radiological [Figure 1] and one patient had pathological documented ENE. Ten had skin involvement and the rest (35) had either infiltration of musculature or tight tethering to adjacent structures.
Table 1: Patient characteristics

Click here to view
Figure 1: Axial contrast-enhanced computed tomography image showing infiltration of sternocleidomastoid muscle

Click here to view

Among those who got upstaged to N3b disease due to ENE, all the patients had either N2 or N3 disease as per previous staging and none of the patient had N1 disease. A total of 29 patients (64.4%) had N2 disease as per the 7th edition AJCC. When stage grouping was considered, 28 patients (62.2%) who got upstaged had stage isovaleric acidaemia (IVA) disease as per the AJCC 7th edition. When nodal size was examined, around 87% of the patients had a nodal size more than 3 cm. Nodal staging and stage grouping according to AJCC 7th edition are mentioned in [Table 2].
Table 2: Clinical nodal staging and stage group according to American Joint Committee on Cancer 7th Edition

Click here to view

Twelve patients were treated with radical intent and sixteen received palliative treatment and the others received either incomplete treatment or defaulted treatment. Patients who were treated radically received either upfront chemoradiation Cardiotoxicity of Radiation Therapy (CTRT), neoadjuvant chemotherapy (NACT) followed by CTRT, or NACT followed by surgery and later CTRT. Palliative treatment was either palliative radiotherapy or palliative chemotherapy. In general, the outcome of these patients remained poor.

  Discussion Top

ENE is defined as the presence of a tumour outside the nodal capsule.[2] Clinical examination showing invasion of skin, infiltration of musculature or dense tethering to adjacent structures, or cranial nerve, brachial plexus, sympathetic trunk or phrenic nerve invasion with dysfunction supported by strong radiographic evidence is required to include it in staging.[3] Radiologic criteria proposed for the detection of ENE, include presence of a thick-walled, enhancing nodal margin; loss of outer nodal margin definitions and infiltration of the adjacent fat lanes around portions of the node.[3]

In 1971, Bennett et al. first demonstrated an association between ENE and a poor outcome in patients with HNC. Since then, there has been a lot of literature on the impact of ECE in this malignancy.[5] Landmark European Organisation for Research and Treatment of Cancer 22931 trial and Radiation Therapy Oncology Group 9501 clearly showed ENE as a clear prognostic factor in HNC and established improvement in locoregional control and disease-free survival with the addition of post-operative chemoradiation.[6],[7],[8]

In the present study, the key findings were: 8% of patients of total HNC treated in 1 year was identified to have ENE and this classification was based on AJCC clinical criteria in 73.3% and radiological in 24.5%. Twelve patients were treated with radical intent and 16 received palliative treatment with poor outcomes. Prognostic value of ENE has been widely described in oral cavity cancers and oropharyngeal cancers.[9] It has been proposed that the lymph nodal microenvironment plays an important role in ENE, especially in oral cavity cancers.[10],[11] In general, better outcomes have been reported in oropharyngeal cancers associated with human papilloma virus (HPV) and treatment de-escalation strategies are being explored in this subgroup of patients. The presence of ENE in HPV-positive tumours appears to have a negative impact on survival. Prognostic value of ENE in oropharyngeal cancers associated with HPV has been explored in various studies. There are conflicting reports available in the literature regarding this,[12],[13] even though in general, it appears to be a negative prognostic marker.

Radiological ENE in HPV-positive patients did not show any significant difference in progression-free survival in a study by Lee et al.[14] Contrary to this report, a strong negative correlation in overall survival has been described in various other studies.[15],[16] The prognostic significance of surgical ENE in laryngeal and hypopharyngeal cancers probably differs from that of oral cavity cancers.[17] Much retrospective analysis of ENE has been reported following its inclusion in AJCC.[18],[19],[20]

Grading of ENE and lymph node density has also been evaluated further in prognostication of HNC.[21] AJCC suggests documentation of pathological grade of ENE as major and minor ENE. Lymph node density has been defined as the ratio of the number of positive nodes and the total number of resected nodes.[22] There are ongoing trials in this regard.[23]

The best method to recognise ENE is by the identification of tumor spread beyond nodal capsule by the histopathological examination.[24] The expertise of the pathologist reviewing the specimen has been reported to be of a significant role in nodal staging of HNC.[21] Both computed tomography (CT) and magnetic resonance imaging (MRI) have been used to evaluate ENE in clinical settings and both show almost similar results.[25] Recent studies have reported a good correlation between radiological and pathological ENE, even though the sensitivity of imaging was relatively less.[26] The majority of our patients had clinically evident ENE and additional radiological ENE was detected in around 25% of patients using contrast-enhanced CT scan. No histopathological correlation was possible as the majority of these patients were treated with non-surgical approach.

There was a major stage migration with 64.4% of these patients being staged as having N2 disease as per AJCC 7th Edition and a similar value was observed when stage grouping was also considered. Twenty-eight patients (62.2%) who were staged as Stage IVA as per 7th edition AJCC got upstaged to Stage IVB. This was a major change as the prognosis differs between the groups. It was also noted that none of these patients had N1 disease and almost all patients had multiple lymph nodal involvement. Only one patient who had N2a disease got upstaged to N3, but it is noteworthy that this patient had a very advanced primary (T4B). Other published literature shows that risk of ENE increase with increasing nodal size.

It was also noticed during this analysis that there was a long gap between the initial biopsy, proof of malignancy and presentation to our hospital for definitive treatment. The average time gap between tissue proof of malignancy and presentation in the present outpatient department was 54 days. Poor socioeconomic status, illiteracy, prolonged treatment resulting in family stress and certain misconceptions regarding cancer and its treatment are major challenges in management of HNC in developing countries.[27] Frequent treatment default and poor follow-up of these patients have been reported in previous studies from India.[28],[29] The issue of delay in presentation for treatment and poor compliance to treatment and follow-up need to be further explored and addressed by national health policy-makers.

Our study is limited by poor treatment compliance in a large number of patients and lack of good follow-up data.

  Conclusion Top

Few key messages can be obtained from our analysis. ENE is an important prognostic factor in head-and-neck carcinoma. In our patient population, 8% got upstaged when ENE was included as per the 8th edition AJCC which is a well-established poor prognostic factor in head-and-neck carcinomas. Late presentation after initial diagnosis of malignancy was identified in the majority of our patients who had ENE. Reasons for delay in seeking treatment should be further explored and some national health policy intervention is required to address this issue.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68:394-424.  Back to cited text no. 1
de Juan J, García J, López M, Orús C, Esteller E, Quer M, 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;139:483-8.  Back to cited text no. 2
Amin MB, Greene FL, Edge SB, Compton CC, Gershenwald JE, Brookland RK, et al. The eighth edition AJCC cancer staging manual: Continuing to build a bridge from a population-based to a more “personalized” approach to cancer staging. CA Cancer J Clin 2017;67:93-9.  Back to cited text no. 3
King AD, Yu KH, Mo FK, Law BK, Yuen TW, Bhatia KS, et al. Cervical nodal metastases from head and neck squamous cell carcinoma: MRI criteria for treatment assessment. Head Neck 2016;38 Suppl 1:E1598-604.  Back to cited text no. 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 2016;62:60-71.  Back to cited text no. 5
Bernier J, Domenge C, Ozsahin M, Matuszewska K, Lefèbvre JL, Greiner RH, et al. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med 2004;350:1945-52.  Back to cited text no. 6
Bernier J. Chemoradiation in locally advanced head and neck cancer: New evidence, new challenges. Expert Rev Anticancer Ther 2004;4:335-9.  Back to cited text no. 7
Cooper JS, Pajak TF, Forastiere AA, Jacobs J, Campbell BH, Saxman SB, et al. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med 2004;350:1937-44.  Back to cited text no. 8
Greenberg JS, Fowler R, Gomez J, Mo V, Roberts D, El Naggar AK, et al. Extent of extracapsular spread: A critical prognosticator in oral tongue cancer. Cancer 2003;97:1464-70.  Back to cited text no. 9
Pilborough AE, Lambert DW, Khurram SA. Extranodal extension in oral cancer: A role for the nodal microenvironment? J Oral Pathol Med 2019;48:863-70.  Back to cited text no. 10
Chang JE, Turley SJ. Stromal infrastructure of the lymph node and coordination of immunity. Trends Immunol 2015;36:30-9.  Back to cited text no. 11
Rath TJ, Narayanan S, Hughes MA, Ferris RL, Chiosea SI, Branstetter BF 4th. Solid lymph nodes as an imaging biomarker for risk stratification in human papillomavirus-related oropharyngeal squamous cell carcinoma. AJNR Am J Neuroradiol 2017;38:1405-10.  Back to cited text no. 12
Liu JT, Kann BH, De B, Buckstein M, Bakst RL, Genden EM, et al. Prognostic value of radiographic extracapsular extension in locally advanced head and neck squamous cell cancers. Oral Oncol 2016;52:52-7.  Back to cited text no. 13
Lee B, Choi YJ, Kim SO, Lee YS, Hong JY, Baek JH, et al. Prognostic value of radiologic extranodal extension in human papillomavirus-related oropharyngeal squamous cell carcinoma. Korean J Radiol 2019;20:1266-74.  Back to cited text no. 14
An Y, Park HS, Kelly JR, Stahl JM, Yarbrough WG, Burtness BA, et al. The prognostic value of extranodal extension in human papillomavirus-associated oropharyngeal squamous cell carcinoma. Cancer 2017;123:2762-72.  Back to cited text no. 15
Bauer E, Mazul A, Chernock R, Rich J, Jackson RS, Paniello R, et al. Extranodal extension is a strong prognosticator in HPV-positive oropharyngeal squamous cell carcinoma. Laryngoscope 2020;130:939-45.  Back to cited text no. 16
Matsumoto F, Mori T, Matsumura S, Matsumoto Y, Fukasawa M, Teshima M, et al. Prognostic significance of surgical extranodal extension in head and neck squamous cell carcinoma patients. Jpn J Clin Oncol 2017;47:699-704.  Back to cited text no. 17
Fan KH, Hung SP, Lin CY, Chang JT, Ng SH, Yeh CH. Prognostic value of extranodal extension on imaging studies in oropharyngeal, laryngeal, and hypopharyngeal cancers treated by primary chemoradiation. Int J Radiat Oncol Biol Physics 2019;105:E364-5.  Back to cited text no. 18
Joseph DM, Raut S, Pasricha R, Gupta S. Upstaging of head and neck cancers due to extranodal extension: An Indian study. J Clin Oncol 2019;37:e17553.  Back to cited text no. 19
Bulgurcu S, Idil M, Kucuk U, Cukurova I. The effect of extranodal extension on survival in laryngeal carcinoma. Ear Nose Throat J 2020;99:305-8.  Back to cited text no. 20
Agarwal JP, Kane S, Ghosh-Laskar S, Pilar A, Manik V, Oza N, et al. Extranodal extension in resected oral cavity squamous cell carcinoma: More to it than meets the eye. Laryngoscope 2019;129:1130-6.  Back to cited text no. 21
Chang WC, Lin CS, Yang CY, Lin CK, Chen YW. Lymph node density as a prognostic predictor in patients with betel nut-related oral squamous cell carcinoma. Clin Oral Investig 2018;22:1513-21.  Back to cited text no. 22
Iocca O, Farcomeni A, De Virgilio A, Di Maio P, Golusinski P, Malvezzi L, et al. Prognostic significance of lymph node yield and lymph node ratio in patients affected by squamous cell carcinoma of the oral cavity and oropharynx: Study protocol for a prospective, multicenter, observational study. Contemp Clin Trials Commun 2019;14:100324.  Back to cited text no. 23
Greenberg JS, El Naggar AK, Mo V, Roberts D, Myers JN. Disparity in pathologic and clinical lymph node staging in oral tongue carcinoma. Implication for therapeutic decision making. Cancer 2003;98:508-15.  Back to cited text no. 24
King AD, Tse GM, Yuen EH, To EW, Vlantis AC, Zee B, et al. Comparison of CT and MR imaging for the detection of extranodal neoplastic spread in metastatic neck nodes. Eur J Radiol 2004;52:264-70.  Back to cited text no. 25
Almulla A, Noel CW, Lu L, Xu W, O'Sullivan B, Goldstein DP, 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;102:698-708.  Back to cited text no. 26
Joshi P, Dutta S, Chaturvedi P, Nair S. Head and neck cancers in developing countries. Rambam Maimonides Med J 2014;5:e0009.  Back to cited text no. 27
Mohanti BK, Umapathy H, Bahadur S, Thakar A, Pathy S. Short course palliative radiotherapy of 20 Gy in 5 fractions for advanced and incurable head and neck cancer: AIIMS study. Radiother Oncol 2004;71:275-80.  Back to cited text no. 28
Kumar S, Lal P. Comment on: “Short course palliative radiotherapy of 20 Gy in 5 fractions for advanced and incurable head and neck cancer: AIIMS study” [Radiother Oncol 2004; 71:275-80]. Radiother Oncol 2005;74:75.  Back to cited text no. 29


  [Figure 1]

  [Table 1], [Table 2]


Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

  In this article
Subjects and Methods
Article Figures
Article Tables

 Article Access Statistics
    PDF Downloaded133    
    Comments [Add]    

Recommend this journal