Oral cavity squamous cell carcinoma (OCSCC) is a major cause of morbidity and mortality globally. Lymph node metastasis is arguably the single most important prognostic determinant, resulting in a reduction of survival by up to 50% [1]. Regional nodal metastasis with extranodal extension (ENE) has been associated with a significant decrease in survival and increased rate of regional recurrence and distant metastasis [2]. The recent 8th edition of the AJCC introduced a modification in the nodal staging by incorporating ENE [3]. This incorporation was intended for better prognostication of patients.
Till now there is enough data on ENE of lymph nodes in OSCC. It is one of the two key adverse features (other is margin positivity) for which the adjunction of concomitant chemotherapy to adjuvant radiation therapy is recommended in postoperative settings [4–7]. There is paucity of level I data for decision making, and optimal treatment for N3b nodal disease is rather ill-defined. In spite of following standard guidelines for management of N3b, which comprises post-operative RT and concomitant cisplatin based weekly chemotherapy, outcomes are still dismal with short recurrence free survival (RFS) and overall survival (OS). Randomized control trials stating standard of care for locally advanced OCSCC have not frequently used this cohort of patients.
Therefore, the goal of this article is to provide an institutional experience on relevant aspects of N3b nodal disease in OCSCC, including its impact on loco-regional recurrence and the development of distant metastasis and satellite dermal nodules. This article provides a systematic review of current knowledge in the field, discusses controversies and lists key issues that need to be addressed in order to improve prognosis of N3b OCSCC patients and whether there is any need to change our treatment paradigm.
Clinico-pathological Data
Indexed clinical data included age, sex, primary tumor, number of positive lymph nodes, ENE status, adjuvant radiation and/or chemotherapy, status at last follow-up, and tumor-node-metastasis classification for staging as defined by the 8th edition of the American Joint Committee on Cancer (AJCC) [3], and primary tumor site for OCSCC patients (buccal mucosa, lower alveolus, tongue, upper alveolus and hard palate)
N3b disease and Review of Literature
AJCC staging (8th edition) classified N3b nodal disease as either extra-nodal extension in a single node with size more than 3 cm, or metastatic deposit in single or multiple lymph nodes either ipsilateral, contralateral or bilateral necks with size more than 6 cm. The incidence of clinical N3b nodal disease was usually higher in patients with multiple lymph node involvement or bulky nodes.
The presence of ENE in metastatic lymph nodes derived from patients with HNSCC was first documented by Willis. [8] However, it was not until 1971 that Bennett [19] et al reported its unfavorable prognostic features in patients with squamous cell carcinoma (SCC) of the hypopharynx. Pathologic ENE is defined as extension of metastatic carcinoma through the fibrous capsule of a lymph node into the surrounding connective tissue, regardless of the presence of stromal reaction (Figure.1). Tumor that stretches the capsule, without breaching it, does not constitute ENE [11].
The presence of ENE, reflects the aggressiveness of N3b nodal disease [12]. This creates anatomic challenges for disease clearance, and increases the possibility of tumor cells entering the bloodstream, increasing the risk of distant metastasis, reduced recurrence free survival (RFS) and low overall survival (OS) [13].
The results of the preliminary report of the prospective randomized trial by Bachaud et al evaluating the efficacy of postoperative concurrent cisplatin-based chemoradiotherapy in patients with advanced head and neck squamous cell carcinoma (HNSCC) cancer and histological evidence of extra-nodal spread of the tumor in lymph node metastases, revealed that in one-variable analysis, extracapsular spread was one of the three factors being significantly predictive of survival and locoregional failure [20].
In 2004, two landmark randomized multi-institutional studies, RTOG 9501 and EORTC 22931, demonstrated the advantages of the addition of platinum-based chemotherapy to postoperative radiation in patients with high-risk, resectable HNSCC [9, 11]. Combined review of the two studies clearly defined patients with extranodal spread of disease and positive surgical margins as a subgroup that derived significant benefit from escalated treatment [10], and these are now definitive indications for the addition of concurrent cisplatin to post-operative RT.
In 2007, Fan and colleagues published their analysis of 201 patients treated with post-operative RT for advanced OCSCC, confirming the correlation between multiple positive nodes, ENE and higher-grade tumors with worse DFS [21]. That group later updated this study and found that only stage IV B and absence of chemotherapy were predictors of poor outcome.
The role of extracapsular extension was further elucidated in a 2015 study at the Memorial Sloan Kettering Cancer Center that identified tumor extension > 1.7 mm beyond the nodal capsule as a poor prognostic factor in disease-free survival .
College of American Pathologists (CAP) also proposed stratification of ENE as ≤ 2mm (ENEmi) and > 2 mm (ENEma), however, this is not yet a mandatory part of reporting and staging.
Though the primary modality of treatment for patients with oral cavity squamous cell carcinoma (OSCC) remains surgical resection, many patients present with advanced disease and are thus treated using a multi-disciplinary approach. Over the past two decades there is significant improvement in survival rates due to advanced imaging and treatment modalities. 5-year survival for patients with advanced-stage IV OCSCC remains low at 33–42% with locoregional recurrence rates ranging from 16–35% following adjuvant radiation therapy [11–17].
Retrospective analysis of N3 HNSCC done by Huaising C. Ko et al in 2017, demonstrated 5-year rates of locoregional and distant control of approximately 75% and 60% at 5 years, respectively [18].