Extranodal Extension – Exploring an Enigma in Oral Cavity Cancers

1. Introduction

ENE (Extranodal extension) is defined as extension of the tumor cells through the lymph node capsule into the surrounding connective tissue. ENE in head and neck cancer was first described by Willis¹ in autopsy material from a head and neck epidermoid carcinoma in 1930. Its prognostic importance was confirmed in subsequently². It presents a challenge to disease clearance regionally but more importantly, also augments risk of distant metastasis^3,4.

ENE is found in up to 20% of patients at the time of their initial surgery⁵. The eighth edition of the American Joint Committee on Cancer (AJCC) staging manual has incorporated ENE as a poor prognostic indicator, reflecting the significance of ENE for cancer management, but not by quantification of the size of ENE⁶. Although ENE classified as major (>2 mm) has been associated with worse overall survival compared to minor (≤2 mm) ENE^7,8.

Pooled analysis and long-term follow up of two prospective randomized controlled trials (RTOG 9501 and EORTC 22931) show that patients with locally advanced head and neck cancer with ENE benefit from adjuvant cisplatin-based chemoradiation over radiation therapy alone ^(9-12).

Despite aggressive treatment approach, oral cavity cancers with major ENE (>2 mm) remain challenging to treat, with poor overall survival and high recurrence rates.

2. Methods and Materials

1. Patients

We prospectively collected the clinical and radiological data of 62 consecutive patients with pathologically detected major ENE (>2mm) in primary squamous cell carcinoma of the oral cavity from January 2015 to December 2021. Patients were included with up-front surgery of the primary tumor and neck dissection with high-risk pathological feature of major ENE necessitating chemoradiotherapy, an Eastern Cooperative Oncology Group (ECOG) performance status of <2, no distant metastasis at presentation.

The exclusion criteria for the study were as follows: patients with an ECOG performance status of ≥2, those who received neoadjuvant chemotherapy before primary surgical resection, patients with positive high risk features other than ENE, cases where the surgical resection was done with palliative or debulking intent, patients with recurrent head and neck malignancies, and individuals with a prior history of radiation therapy (RT) to the head and neck region.

As part of the pretreatment evaluation, a complete medical history was taken, followed by a physical examination including fiberoptic nasopharyngoscopy. Imaging studies such as computed tomography (CT) and/or magnetic resonance imaging (MRI) of the head and neck were performed.

In addition, other imaging techniques like a plain radiograph, CT of the chest, or positron emission tomography (PET) were also included to assess the extent of the disease. Although the American Joint Committee on Cancer (AJCC) 7th edition was utilized for staging and management at the time of treatment, the AJCC 8th edition was applied to incorporate extranodal extension (ENE).

2. Treatment

All patients underwent appropriate surgical management of the primary tumor and adjuvant chemo-radiotherapy (RT) was initiated within 4 to 6 weeks post-surgery. Concurrent chemotherapy, consisting of weekly cisplatin (40 mg/m²) or carboplatin (AUC 2), was indicated in patients with positive resection margins or extranodal extension (ENE). For adjuvant chemoradiotherapy (CRT) planning, patients were generally considered for weekly cisplatin. However, elderly patients or those deemed unfit for cisplatin received carboplatin or cetuximab instead.

The clinical target volume (CTV) for radiation included the post-operative tumor bed with a 1 cm margin, along with the ipsilateral nodal volumes, based on the risk factors identified in the post-operative histopathological report and the potential sites of clinical and nodal spread. The planning target volume (PTV) was created by adding a 0.5 cm uniform margin to the CTV to accommodate setup and motion errors. Radiotherapy was delivered using 6 MV photons to a dose of 64–66 Gy with a 2-Gy dose fractionation, one fraction per day, 5 days a week, using volumetric modulated arc therapy (VMAT) via a linear accelerator (Infinity and Synergy; Elekta) or TomoTherapy® (Accuray).

Patient follow-up was conducted weekly during treatment, every 2 to 3 months for the first 2 years, and then every 4 to 6 months thereafter. Post-treatment imaging, including PET and CT or MRI of the neck, was performed 3 months after treatment. Subsequent imaging studies were done as clinically indicated. Recurrences, whether locoregional or distant, were confirmed by biopsy unless clear radiographic evidence of metastatic disease was present.

3. Statistics

Primary endpoint was to assess the pattern of locoregional, and distant failures and secondary end point was to evaluate the survival outcomes: disease-free survival (DFS) and overall survival (OS).

Local treatment failure was defined as recurrence at the site of the initial primary tumor, regional treatment failure as the development of recurrence in cervical lymph nodes. It could further be classified as marginal failure defined as recurrence at the radiation field margins, out of field loco-regional failure defined as recurrence at any other head and neck site not included in the radiation field.

Distant failure was defined as the appearance of widespread metastasis at other sites like lung, bone, distant lymph nodes, liver etc., outside the radiation fields. All time intervals were calculated from the date of diagnosis to the date of the event of interest. DFS was defined as the time from the day of diagnosis to the date of failure (either locoregional or distant or both) or death. Statistical analysis was performed with SPSS statistical software package for Mac (version 29.0.2.0; IBM, NY, USA). All survival analyses were performed using the Kaplan-Meier method.

3. Results

1. Clinicopathological factors (Table 1)

Table 1: Patient and tumour characteristics

The median age was 56 years (range, 27 to 86 years) with a male: female incidence ratio of 7.85:1. All patients had stage IV disease.

2. Failure patterns

Out of the 62 patients studied, 36 (58%) experienced treatment failures, predominantly distant. Specifically, 13/36 patients (36.1%) had in-field recurrences (within the radiation field), while 2/36 patients (8.3%) developed second primary tumors outside the radiation field within the head and neck region. Importantly, there were no cases of marginal failure.

Additionally, 5/36 patients (13.8%) experienced both in-field recurrences and distant metastasis, and widespread distant metastatic recurrence was observed in 16/36 patients (44.4%), out of which 14 patients had lung metastasis, 12 patients had bone metastasis, 4 patient had liver metastasis, 3 patient had muscle metastasis and 1 patient had brain metastasis. Most patients had a combination of these organs as metastatic sites.

3. Survival analysis and prognostic factors

Figure 1 (A, B, C, D)

The median follow-up duration was 98 months (ranging from 5.17 to 121 months). The median overall survival (OS) duration was 44.27 months. The 2-year and 5-year rates overall survival (OS) were 66% and 47%, respectively (Fig 1 A). The median disease-free survival (DFS) duration was 24.17 months. The 2-year and 5-year disease-free survival (DFS) rates were 49% and 38.68%, respectively (Fig 1 B).

All the high-risk factors like age margin close/positive, PNI +, LVSI +, comorbidities, smoking, alcohol intake and tobacco intake were further evaluated by Cox regression multivariate analysis where tobacco intake was found to have significant association with poor DFS (p=0.018) and OS (p=0.011). The 5-year DFS for patients with history of tobacco intake was 14.4%- and 5-year OS was 35.6%. (Fig 1 C,D).

Figure Legend:

Fig 1: A: Overall survival (OS) curve, B: Disease free survival (DFS) curve, C: Overall survival for habit like chewing pan, gutka, or tobacco intake (no history vs. history present: 57.6% vs. 35.6%; p = 0.011), D: Disease free survival for habit like chewing pan, gutka, or tobacco intake (no history vs. history present: 55.41% vs. 14.4%; p = 0.018).

4. Discussion and Conclusion

In our cohort of 62 patients with oral cavity squamous cell carcinoma (OCSCC) with major ENE (>2mm), we performed an in-depth analysis of treatment failure patterns, other prognostic factors, and survival outcomes.

All patients in our cohort received adjuvant chemoradiation post-surgery, reflecting the established benefit of CCT in cases with ENE, as supported by landmark trials EORTC-22931 and RTOG-9501 ^(9-12). Despite this, ENE continued to have a significant impact on DFS and overall survival emphasizing its poor prognostic impact. This finding aligns with previous retrospective studies, which have identified ENE as a key predictor of overall survival in OCSCC ^(13-15).

In their prospective randomized study, Laskar et al¹⁶ demonstrated a survival benefit for a subset of patients with a combination of high-risk features (advanced N-stage, T-stage, and extranodal extension positive) when treated with chemoradiation, the 5-year actuarial DFS estimates being 44% and OS around 38%.

The extent of ENE (major i.e. >2mm) is further identified as poor prognostic marker. According to a recent study by Joshi et al¹⁷, the 2-year survival rate when compared for microscopic ENE (≤2 mm) vs macroscopic ENE (>2 mm) was 72.6% and 0% respectively. They also reported the distal failure rate for major ENE group as 44.83%. Another study by Kolarski et al¹⁸ found that patients with major ENE who received chemoradiation had overall survival of 44% and John et al¹⁹ also reported that patients with major ENE had marginally lower 5-year local control of 59%, lower distant control of around 58% and DFS of 13%.

In their paper Best et al²⁰ reported 5-year OS for major ENE as 20.7% and 5-year DFS as 18.1%. The authors secondarily found that patients with multiple ENE-positive nodes had worse OS (P = .001) and DFS (P = .001) than subjects with only 1 ENE-positive node. This was also consolidated in the paper by Agarwal et al²¹ who found that ENE grade 3 through 4 (i.e. major ENE) and ENE in more than two lymph nodes conferred poor prognosis (3-year OS: 18%; P = 0.000).

We also found the 5-year DFS and OS rate for the entire study population as 38.68% and 47%, respectively, similar to these studies and notably around 63% patients in our cohort also had ENE positive in 2 or more nodes. Out of the 62 patients studied, 36 (58%) experienced treatment failures, which comprised predominantly of distant failures. We found that 5/36 patients (13.8%) experienced both in-field recurrences and distant metastasis while widespread distant only metastatic recurrence was observed in 16/36 patients (44.4%).

Alcohol, smoking and tobacco are well-documented prognostic factors for head and neck oral cavity cancer²². In our Indian population, the adverse impact of pan/gutka/tobacco intake on DFS was particularly notable and showed a significant negative impact on DFS (p=0.018) and OS (p=0.011) in multivariate analysis.

In conclusion, distant failure remains the predominant cause of treatment failure in major ENE positive OCSCC and combined with the history of tobacco intake, it further led to poor survival outcomes. Despite the modest survival outcomes, there is potential to improve prognosis further. This single-institution study, with uniform treatment protocol, helps minimize confounding effects from variations in the quality of locoregional treatment and highlights the biological aggressiveness of the disease. This also provides an addition to the published real-world data on ENE, which is needed to strengthen the research work.

Abbreviations

AJCC – American Joint Committee on Cancer
CRT – Chemoradiotherapy
CT – Computed Tomography
CTV – Clinical Target Volume
DFS – Disease-Free Survival
ENE – Extranodal Extension
ECOG – Eastern Cooperative Oncology Group
Gy – Gray
MRI – Magnetic Resonance Imaging
OCSCC – Oral Cavity Squamous Cell Carcinoma
OS – Overall Survival
PET – Positron Emission Tomography
PNI – Perineural Invasion
PTV – Planning Target Volume
RT – Radiotherapy
VMAT – Volumetric Modulated Arc Therapy
LVSI – Lymphovascular Space Invasion

Statements

Conflict of Interest: None

Funding: None

Acknowledgement: None

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