Extranodal extension and thickness of metastatic lymph node as a significant prognostic marker of recurrence and survival in head and neck squamous cell carcinoma
Introduction
Cervical lymph node (LN) metastasis is a significant prognostic factor for patients with head and neck squamous cell carcinoma (HNSCC) (Layland et al., 2005). In addition, extranodal extension (ENE) is associated with an increased risk of recurrence and death (Wenzel et al., 2004). Current universal guidelines for HNSCC treatment strongly recommend that HNSCC patients with ENE receive adjuvant chemoradiotherapy (CRT) to reduce the risk of treatment failure (National Comprehensive Cancer Network).
The tumor-node-metastasis (TNM) staging system devised by the American Joint Committee on Cancer defines nodal-stage HNSCC according to largest diameter, number, or laterality of metastasized LNs (Edge et al., 2010). Treatment of HNSCC patients is usually based on TNM staging; however, this system does not provide reliable predictions of prognosis or treatment results (Takes et al., 2010). Therefore, other staging parameters, particularly regarding LN features, have been introduced to overcome these limitations. For example, Prabhu et al. reported that the LN ratio (calculated by dividing the number of positive LN by the total number removed during neck dissection [ND]) was an independent prognostic factor for locoregional recurrence and survival in HNSCC patients (Prabhu et al., 2014a). Another study proposed a modified pathological TNM staging system that accounts for ENE status when making treatment decisions and predicting prognosis (de Juan et al., 2013).
Recent reports suggest that the mere presence of ENE is a poor predictor of disease recurrence and has little prognostic value because there is little evidence to support the beneficial effects of chemotherapy in addition to adjuvant radiotherapy (RT) in such patients (Lewis et al., 2011, Sinha et al., 2012, Prabhu et al., 2014b). Therefore, a new grading or risk stratification system for ENE is needed to avoid unnecessary treatment and to improve the survival of HNSCC patients. Because greater thickness/invasion depth of tumors in the oral cavity is a risk factor for LN metastasis, we assumed that ENE thickness (ENET) in metastatic LNs would have significant prognostic value. Therefore, the aim of the present study was to examine the association between ENET and other pathologic findings in HNSCC patients, and to analyze whether ENET is a predictor of tumor recurrence and patient survival. Furthermore, we sought to define a cut-off value for ENET, which could then be used to identify patients who would benefit from postoperative adjuvant treatment.
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Study patients
The medical records (including pathology reports) of patients diagnosed with HNSCC and treated surgically (primary tumor resection plus ND with curative intent) at our tertiary referral hospital from January 2000 to December 2011 were retrospectively reviewed. The inclusion criteria were as follows: age >18 years; pathologically proven squamous cell carcinoma arising in the oral cavity, oropharynx, larynx, and/or hypopharynx; no distant metastasis at initial presentation; and follow up for more
Patient characteristics
The characteristics of the 438 eligible patients (350 men and 88 women; mean age, 58 years [range, 20–82 years]) are summarized in Table 1. Primary tumors were most frequently found in the oral cavity (n = 179), followed by the larynx (n = 149), oropharynx (n = 85), and hypopharynx (n = 25). Of the 438 patients examined, 182 (41.6%) were pathologic stage T3–4 and 219 (50%) were node positive. Adverse characteristics of the primary tumors were also identified: close-to-positive margin in 57
Discussion
Extranodal extension is the term used to describe the spread of cancer cells beyond the LN capsule, which usually acts as a barrier, and is suggestive of metastatic activity. Here, we suggest that the extent of ENE (measured in terms of ENET) may be correlated with a higher risk of progression and metastasis of index HNSCC. Lewis et al. graded ENE according to the extent of LN capsular invasion, and confirmed that prognosis and treatment responses were worse in patients with grade 4 ENE
Conclusion
The results of the present study show that ENE and ENET were associated with a greater number of positive LNs, larger size, bilateral cervical involvement, and a higher LN ratio. The presence of ENE in HNSCC patients with metastatic LN was significantly associated with a greater risk of recurrence and reduced OS, but not with CSS. However, ENET ≥2 mm was also strongly associated with a poor CSS; thus, ENET ≥2 mm may be a complementary prognostic factor for CSS prediction. Adjuvant CRT did not
Source of funding
This study was supported by a grant (HI14C23050000) of the Korean Health Technology R&D Project, Ministry of Health and Welfare, Seoul, Republic of Korea (J.-L. Roh).
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