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Mediastinal Lymph Node Metastasis from Head and Neck Cancer: Predictive Factors and Imaging Features

Purpose To assess the predictive factors and describe the imaging features of mediastinal lymph node (MLN) metastases in patients with head and neck cancer. Materials and Methods We compared the clinical features and disease characteristics (sex, age, site of primary tumor, histologic type, history of prior treatments, TNM stages, and metastasis in cervical LNs) of patients with head and neck cancers between the MLN metastasis and no MLN metastasis groups. We also evaluated the chest CT (distribution and maximum dimension of the largest LN) and PET/CT (maximum standardized uptake value) features of MLN metastases based on the MLN classification. Results Of the 470 patients with head and neck cancer, 55 (11.7%) had MLN metastasis, involv-ing 150 mediastinal stations. Hypopharynx cancer, recurrent tumor, T4 stage, N2/N3 stages, and M1 stage were found to be significant predicting factors for MLN metastasis. The most common location of MLN metastasis was ipsilateral station 2 (upper paratracheal LNs, 36.4%), followed


INTRODUCTION
Tumor metastasis to lymph nodes (LNs) is one of the most important prognostic factors for patients with head and neck cancers (1). Head and neck cancers usually spread to regional LNs in the neck. However, although uncommon, they may metastasize to extra-cervical LNs, such as mediastinal LNs (MLNs) (2)(3)(4)(5). Metastasis to MLNs may significantly affect treatment planning and have profound impact on the prognosis of the head and neck cancer (6)(7)(8). The drainage pathway of neck and mediastinal lymphatic system is divided into superficial or deep and it has ipsilateral or contralateral pathways. Therefore, the distribution of MLN metastasis is also important in the treatment of metastatic disease (9).
There have been only a limited number of studies on the incidence of MLN metastases from head and neck (2)(3)(4)(5). To our knowledge, however, no previous studies reported the predictive factors and imaging features of MLN metastasis from head and neck cancer.
Therefore, this study was aimed to assess the predicting factors, and to describe the imaging features of MLN metastases in patients with head and neck cancer.

PATIENTS
This study was approved by the Institutional Review Board. The requirement to obtain written informed consent from each patient was waived because of the retrospective nature of the study.
We retrospectively reviewed the medical records and imaging results of 829 patients with head and neck cancer, who underwent curative surgical resection in a tertiary head and neck cancer center, between January 2015 and December 2018. Of these, adequate pathological Tor N-staging was not available for 25 patients, and PET/CT was not performed for evaluation of distant metastasis for 334 patients. These patients were excluded from the study. Therefore, a total of 470 patients were finally selected for the study, including 329 men, and 141 women; their ages ranged from 21 to 91 years, with a mean of 58.9 ± 13.0 years.
MLN metastasis was diagnosed with mediastinal dissection/LN biopsy (n = 11) or CT imaging features (n = 44). MLNs were considered to be metastatic based on imaging findings, if they met at least two of the following criteria: 1) the short-axis diameter ≥ 10 mm or central necrosis, irrespective of its nodal size in contrast-enhanced chest CT (10); 2) maximum standardized uptake (SUVmax) ≥ 6.0 in PET/CT (11); 3) ≥ 30% increased in the maximal diameter in following-up chest CT; and 4) ≥ 30% reduction in the maximal diameter after radiotherapy/chemotherapy in following-up chest CT.

IMAGING STUDIES
In accordance with our institutional guidelines, all 470 patients underwent head and neck CT, and torso PET/CT. Additional chest CT scans were performed in 218 patients with suspected MLN metastasis, based on PET/CT findings.
All head and neck CT scans were carried out with a 256-row multidetector CT scanner (Brilliance iCT, Philips Medical Systems, Best, the Netherlands). The technical parameters were J Korean Soc Radiol as follows: pitch, 0.61; gantry rotation time, 50 ms; collimation, 6.4 × 0.625 mm; 120 kVp; 200 mAs; and matrix, 512 × 512. The scanning range was from the level of the maxillary sinus to the tracheal bifurcation (mean coverage, 250 mm). Image acquisition was started 90 seconds after administration of intravenous injection of 100 mL of lomeprol 350 mg/mL (lomeron 350, Bracco, Milan, Italy). Axial, coronal, and sagittal images were reconstructed with contiguous slices of 3-mm thickness.
All PET/CT scans were acquired on a combined whole-body PET/CT system (Discovery STE; GE Medical Systems, Milwaukee, WI, USA). The protocol of PET was as follows: mini-

ANALYSIS
For each patient, we retrieved the following data: sex, age at the time of diagnosis, site of primary tumor, histologic type of tumor, history of prior treatments for malignancy (primary tumor or recurrent tumor after treatment), pT, pN, and pM (or cM) status based on the 8th edition of American Joint Committee on Cancer staging system, location of metastatic cervical LNs, and location of MLNs with metastatic involvement (12).
Cervical LNs were classified based on imaging-based nodal classification (13). MLNs were classified based on the International Association for the Study of Lung Cancer Lymph Node Map (14). However, when using these two LN classifications, the levels IV, V, VI, and VII of In our study, all cervical LN and MLN metastases were interpreted on level-by-level and station-by-station bases, respectively. For example, if at least 1 node was confirmed as metastatic node in a given nodal level or station, this level or station was considered to be positive, regardless of the number and size of metastatic nodes. All LN groups were recorded as ipsilateral or contralateral to the primary head and neck cancer because laterality of LN metastasis may affect the prognosis in patient (9).
We also evaluated the chest CT for distribution of MLN metastasis, and for the maximum dimension of the largest LN in each involved station and PET/CT for the highest value of SUVmax of LN in each involved station.
We analyzed the association between clinicopathologic features of head and neck cancer, and MLN metastasis. Statistical analysis was performed using the paired Student t test for continuous variables and chi-square or Fisher's exact test for categorical variables. A p-value of < 0.05 was considered to indicate statistical significance. All statistical analyses were performed using SPSS version 21.0 (IBM Corp., Armonk, NY, USA).

RESULTS
Among 470 patients with head and neck cancer, 55 (11.7%) had MLN metastasis at the time of diagnosis. Table 1 (Table 3).    Measurements were performed on station-by-station basis. LN = lymph node, SUVmax = maximum standardized uptake value  (17)(18)(19). The deep lymphatic pathways merge into the right or left jugular lymphatic trunk and are drained into each subclavian vein via the thoracic duct and the right lymphatic duct (16). The efferent upper jugular communicating pathway crosses the midline,  A variety of screening techniques are employed in routine practice for evaluation of MLN or lung metastasis, in patients with head and neck cancer. Plain chest radiography is relatively cost-effective and is the most commonly performed test for patients with malignancies. If there is a high likelihood of thoracic metastasis, a CT scan of the chest may be more informative than plain chest radiography alone. Nowadays, FDG-PET/CT has generally been considered a useful diagnostic tool for detecting regional and distant metastases (25). In addition, a PET/CT scan would be more useful in head and neck cancers for identifying distant metastasis, especially extrathoracic, as compared to CT of the chest (26,27). In contrast, PET/CT has also been reported to have low sensitivity for the detection of LN metastasis (28). FDG-PET may fail to detect metastases with low metabolic activity. The usefulness of PET/CT is also limited in non-tumorous hypermetabolic conditions, such as inflammation, which can lead to false positive uptake (29). It is assumed that routine PET/CT scanning for distant metastasis evaluation for head and neck cancer is not justified, and PET/CT is most effective in cases with a higher risk of distant metastasis, for evaluation of distant metastasis, for example, hypopharynx cancer, recurrent tumor, and advanced TNM stages.