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Page 2 of 8 Dankbaar et al. J Cancer Metastasis Treat 2021;7:56 https://dx.doi.org/10.20517/2394-4722.2021.112

[2,3]
factor in these patients . Prognosis further decreases with the presence of extranodal extension (ENE) in
[8]
lymph node metastases . The incidence of ENE varies between 21% and 85% . In a meta-analysis with
[4-8]
1620 patients, the five-year overall survival rate in patients with encapsulated lymph node metastases was
[8]
58.1%. In patients with ENE, the survival rate was only 30.7% . A comparative analysis of the EORTC
(#22931) and RTOG (#9501) trials showed that addition of concomitant chemotherapy to postoperative
radiotherapy seems to improve the outcome of patients with ENE [9,10] . Therefore, ENE was introduced in the
8th Edition TNM Classification (TNM8) for Head and Neck Cancer as an important staging variable in all
HPV-negative HNSCC. In TNM8, ENE is clinically defined as follows: skin involvement or soft tissue
invasion with deep fixation/tethering to underlying muscle or adjacent structures or clinical signs of nerve
involvement supported by radiological evidence. Radiologic evidence alone is not enough for nodal
upstaging. ENE is histologically defined as any metastatic tumor cell microscopically extending outside the
lymph node capsule. In the above-mentioned trials that identified ENE as a significant prognostic factor for
poor outcome, ENE was determined histologically. The extent of ENE was not determined, and it was not
mentioned whether patients met the criteria for the clinical definition in TNM8 before lymph node
dissection was performed. Intuitively, one would say that the clinical definition of ENE identifies cases with
much more advanced disease extension than the histological definition. It has been shown that not only the
presence but also the extent of ENE is associated with the presence of distant metastases and adverse
prognosis [4-7,11] . In one study evaluating the association between outcome and extent of ENE on
[7]
histopathology in patients with HNSCC, ENE was graded according to the scale proposed by Lewis et al. .
In this scale, an extension of 1 mm is used to differentiate minor from more extensive ENE. The results of
the study show that dichotomization between “no ENE” and “any ENE” has limited additional prognostic
value in the setting of adjuvant chemotherapy and radiotherapy (CRT). Patients with a high grade of ENE
with complete replacement of the lymph node by metastatic tumor with no residual lymph node
architecture retained a poorer prognosis with regard to overall survival despite CRT. CRT effectively
mitigated the difference in prognosis between patients with lower grades of ENE (e.g., ≤ 1 mm vs. > 1
[12]
mm) . In TNM8, all lymph nodes larger than 3 cm with histologically determined ENE result in
classification N3b. If ENE is clinically evident or if there are multiple metastatic lymph nodes with at least
one node with ENE, the node diameter is not taken into account. An extent of more or less than 2 mm was
chosen as a cut-off between microscopic and macroscopic ENE . This differentiation does not influence
[13]
the TNM classification, but it was introduced to collect data to refine the use of ENE in future TNM
classifications [Figure 1]. In a study investigating the difference in survival between patients with ENE of ≤ 2
mm or > 2 mm, no difference was found . Patients with both ENE and multiple positive lymph nodes had
[14]
decreased overall survival compared to patients with a single positive lymph node with ENE. Patients with
multiple lymph nodes with ENE had the worst prognosis . In a study subdividing patients into
[14]
microscopic and macroscopic ENE, there was a consistent trend for worsening survival with increasing
[15]
degree of ENE . Regarding these findings, it would be of great interest to determine what degree of ENE
contributes most to poor prognosis. Patients with poor prognosis due to a high grade of ENE may be
candidates for trials investigating novel methods of adjuvant therapy intensification.

In daily practice, not all patients with advanced disease will undergo a neck dissection. Histologic proof of
ENE will therefore not always be available. In these cases, it would be of great help to be able to accurately
determine ENE with radiological imaging. Determining clinically relevant ENE first could greatly improve
the contribution of radiological imaging to tumor staging with regards to ENE and thereby primary
treatment selection. Although not yet proven, it can be anticipated that the addition of concurrent
chemotherapy to primary radiotherapy will also improve locoregional control and survival in patients with
ENE.